DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.

STUDY OBJECTIVE: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects. DESIGN: Retrospective case-control study. SETTING: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication. PATIENTS AND PARTICIPANTS: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included. MEASUREMENTS AND RESULTS: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified. CONCLUSION: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

Threshold Effects of Dismissal Protection Regulation and the Emergence of Temporary Work Agencies

Labour market regulations aimed at enhancing job-security are dominant in several OECD countries. These regulations seek to reduce dismissals of workers and fluctuations in employment. The main theoretical contribution is to gauge the effects of such regulations on labour demand across establishment sizes. In order to achieve this, we investigate an optimising model of labour demand under uncertainty through the application of real option theory. We also consider other forms of employment which increase the flexibility of the labour market. In particular, we are modelling the contribution of temporary employment agencies (Zeitarbeit) allowing for quick personnel adjustments in client firms. The calibration results indicate that labour market rigidities may be crucial for understanding sluggishness in firms´ labour demand and the emergence and growth of temporary work.

Employment Protection, Flexibility and Firms’ Strategic Location Decisions under Uncertainty

We construct a model in which oligopolistic firms decide between locating in a country where employment protection implies costly output adjustments and in one without employment protection. Using a two-period three-stage game with uncertainty, we demonstrate that location is influenced by both flexibility and strategic concerns. The strategic effects under Cournot work towards domestic anchorage in the country with employment protection while those under Bertrand do not. Strategic agglomeration can occur in the inflexible country under Cournot and even under Bertrand, provided uncertainty and foreign direct investment costs are low.

La participation des consommateurs à la construction de l'autorité des normes internationales : vers une économie politique internationale de la traduction

Cette thèse explore les implications politiques de la montée en puissance des normes internationales sur nos sociétés contemporaines et pose la problématique des dynamiques participatives des représentants des consommateurs au sein des formes de pouvoir non étatique à l'aide du cas de l'Organisation internationale de normalisation (ISO). Le renforcement du pouvoir des normes internationales et autres spécifications techniques soulève d'importants enjeux démocratiques qui portent aussi bien sur la représentativité des acteurs qui les élaborent, sur l'articulation des prérogatives publiques et privées dans la gouvernance de la mondialisation, que sur le rôle de l'expertise dans la reconnaissance de ces nouvelles formes de pouvoir. La participation du monde associatif intervient sur ces différents enjeux de manière complexe. Cette recherche s'inscrit à la suite des études en relations internationales/économie politique internationale sur les formes d'autorité non étatique et s'inspire du concept de traduction issu de la sociologie des sciences et techniques pour mettre en lumière le rôle des spécifications techniques dans la construction d'une société de consommation centrée sur la liberté de choix et la façon dont les associations de consommateurs se saisissent des arènes de normalisation pour y faire valoir des préoccupations collectives, leur expertise et leur identité. Cette thèse défend l'idée que les consommateurs participent à la construction de l'autorité des normes internationales par leur rôle dans la traduction qui permet de relier les spécifications techniques au fonctionnement des marchés, au cadre réglementaire de la loi et aux préoccupations sociétales. L'analyse repose sur une observation ethnographique des délibérations d'un comité technique de l'ISO, une recherche-­‐action, la réalisation d'entretiens et la consultation de documents d'archives de l'ISO. -- This thesis explores the political significance of the rise of international standards on contemporary societies and questions the participatory dynamics of consumers' representatives within nonstate forms of power, using the case of the International organization for standardization (ISO). The power granted to international standards and other technical specifications raises important democratic issues regarding the representativity of standard-­‐ writers, the public-­‐private relationships involved in this form of governance or the expertise sustaining the recognition of such new forms of power. The participation of civil society associations affect such issues in complex ways. This research relies on international relations/international political economy approaches of nonstate authority and takes inspiration from the concept of translation developed by science and technology studies to highlight the crucial role played by technical specifications in building a consumer society based on the freedom of choice as well as how consumers' associations take stock of standardization arenas to promote collective issues and claim their expertise and identity. This thesis argues that consumers contribute to the construction of the authority of international standards through their role in the translation that links international standards to the market society, the regulatory state as well as to societal preoccupation. The analysis is based on an ethnographic observation of deliberations within an ISO technical committee, a research-­‐action, interviews as well as on the consultation of ISO archives.

Child sun protection in New Zealand: parental view and societal responsibilities

Issue addressed: Cutaneous melanoma is a significant health problem in New Zealand. Excessive sun exposure in early life increases subsequent risk. This study investigated parental opinions, understanding and practices concerning the sun protection of young children. The study aimed to identify areas where improvements in sun protection may be most needed. Methods: Parents were recruited through licensed childcare centres and kindergartens in Dunedin to take part in semi-structured focus groups. Feedback was obtained from participants in response to summary reports based on audiotapes. Results: Parents noted increased social acceptability of sun protective behaviours and child sunburn was now unacceptable. Past media campaigns were well recalled. The 'time to burn' used in media weather reports was easier to understand than the Ultra Violet Index (UVI), about which more information was wanted. Protective messages were expected to be straightforward, consistent and readily and regularly available. Local radio may provide the most timely, relevant information. There was a perceived lack of authoritative information about sunscreens and sunglasses and a shortage of acceptable protective clothing. Fuller information on sunscreen containers and greater use of UV Protection Factor (UPF) ratings for clothing and Eye Protection Factor (EPF) for sunglasses would assist. The use of shade and rescheduling of activities were scarcely mentioned. Conclusions: Parents were aware of the need for child sun protection but lacked confidence about how best to achieve this. Future health promotion programs should emphasise how optimal protection can be achieved more than why sun protection is needed. Programs should include a repertoire of strategies targeted towards individuals through the education of children and caregivers. They should also aim at achieving modifications in physical and social environments, including appropriate product design and promotion. So what?: The development of a balanced, comprehensive program with environmental components that reinforce protective behaviours has the potential to sustain sun protection among the largest number of children in the longer term.

NALP3 is not necessary for early protection against experimental tuberculosis.

In vitro, Toll-like receptors (TLR)2, 4 and 9 as well as NOD-like receptor 2 critically determine macrophage responses to Mycobacterium tuberculosis (Mtb) infection. However, in low-dose experimental murine tuberculosis, single or multiple deficiencies in TLRs 2, 4, 9 or NOD2 have little, if any, impact on early mycobacterial growth containment, granuloma formation and survival. Here, we analyzed the relevance of NALP3, one component of the danger-signaling inflammasome, for (i) Mtb-induced cytokine secretion in vitro and in vivo, (ii) restriction of Mtb replication in infected organs and (iii) granuloma formation. In the absence of functional NALP3, there was no IL-1beta and IL-18 production in Mtb-infected dendritic cells and macrophages in vitro, whereas secretion of IL-1alpha, IL-12p40 and TNF remained unaffected. After three weeks of infection, NALP3-deficient as well as IL-18-deficient mice were as capable as wildtype mice of restricting Mtb loads at a plateau level within well-differentiated granulomas. In conclusion, despite its involvement in cytokine processing, NALP3 is not essential for induction of protective immunity to Mtb.

Protection of aouts monkeys after immunization with recombinant antigens of Plasmodium falciparum

The genus Aotus spp. (owl monkey) is one of the WHO recommended experimental models for Plasmodium falciparum blood stage infection, especially relevant for vaccination studies with asexual blood stage antigens of this parasite. For several immunization trials with purified recombinant merozoite/schizont antigens, the susceptible Aouts kenotypes II, III, IV and VI were immunized with Escherichia coli derived fusion proteins containg partial sequences of the proteins MSAI (merozoite surface antigen I), SERP (serine-strech protein) and HRPII (histidine alanine rich protein II) as well as with a group of recombinant antigens obtained by an antiserum raised against a protective 41 kD protein band. The subcutaneous application (3x) of the antigen preparations was carried out in intact animals followed by splenectomy prior to challange, in order to increase the susceptibility of the experimental hosts to the parasite. A partial sequence of HRPII, the combination of three different fusion proteins of the 41 kD group and mixture of two sequences of SERP in the presence of the modified Al(OH)3 adjuvant conferred significant protection against a challange infection with P. falciparum blood stages (2-5 x 10 (elevado a sexta potência) i. RBC). Monkey immunized with the MS2-fusion protein carrying the N-terminal part of the 195 kD precursor of the major merozoite surface antigens induced only marginal protection showing some correlation between antibody titer and degree of parasitaemia. Based on the protective capacity of these recombinant antigens we have expressed two hybrid proteins (MS2/SERP/HRPII and SERP/MSAI/HRPII) in E. coli containing selected partial sequences of SERP, HRPII and MSAI. Antibodies raised against both hybrid proteins in rabbits and Aotus monkeys recognize the corresponding schizont polypeptides. In two independent immunization trials using 13 animals (age 7 months to 3 years) we could show that immunization of Aotus monkeys with either of the two hybrid proteins administered in an oil-based well tolerated formulation protected the animals frm a severe experimental P. falciparum (strain Palo Alto) infection.