The Monetary policy rules and the inflation process in open emerging

This paper has three objectives. First, it aims at revealing the logic of interest rate setting pursued by monetary authorities of 12 new EU members. Using estimation of an augmented Taylor rule, we find that this setting was not always consistent with the official monetary policy. Second, we seek to shed light on the inflation process of these countries. To this end, we carry out an estimation of an open economy Philips curve (PC). Our main finding is that inflation rates were not only driven by backward persistency but also held a forward-looking component. Finally, we assess the viability of existing monetary arrangements for price stability. The analysis of the conditional inflation variance obtained from GARCH estimation of PC is used for this purpose. We conclude that inflation targeting is preferable to an exchange rate peg because it allowed decreasing the inflation rate and anchored its volatility.

Optimisation of antiretroviral therapy : pharmacokinetic and pharmacogenetic approaches

Les progrès de la thérapie antirétrovirale ont transformé l'infection par le VIH d'une condition inévitablement fatale à une maladie chronique. En dépit de ce succès, l'échec thérapeutique et la toxicité médicamenteuse restent fréquents. Une réponse inadéquate au traitement est clairement multifactorielle et une individualisation de la posologie des médicaments qui se baserait sur les facteurs démographiques et génétiques des patients et sur les taux sanguins totaux, libres et/ou cellulaires des médicaments pourrait améliorer à la fois l'efficacité et la tolérance de la thérapie, cette dernière étant certainement un enjeu majeur pour un traitement qui se prend à vie.L'objectif global de cette thèse était de mieux comprendre les facteurs pharmacocinétiques (PK) et pharmacogénétiques (PG) influençant l'exposition aux médicaments antirétroviraux (ARVs) nous offrant ainsi une base rationnelle pour l'optimisation du traitement antiviral et pour l'ajustement posologique des médicaments chez les patients VIH-positifs. Une thérapie antirétrovirale adaptée au patient est susceptible d'augmenter la probabilité d'efficacité et de tolérance à ce traitement, permettant ainsi une meilleure compliance à long terme, et réduisant le risque d'émergence de résistance et d'échec thérapeutique.A cet effet, des méthodes de quantification des concentrations plasmatiques totales, libres et cellulaires des ARVs ainsi que de certains de leurs métabolites ont été développées et validées en utilisant la chromatographie liquide coupée à la spectrométrie de masse en tandem. Ces méthodes ont été appliquées pour la surveillance des taux d'ARVs dans diverses populations de patients HIV-positifs. Une étude clinique a été initiée dans le cadre de l'étude VIH Suisse de cohorte mère-enfant afin de déterminer si la grossesse influence la cinétique des ARVs. Les concentrations totales et libres du lopînavir, de l'atazanavir et de la névirapine ont été déterminées chez les femmes enceintes suivies pendant leur grossesse, et celles-ci ont été trouvées non influencées de manière cliniquement significative par la grossesse. Un ajustement posologique de ces ARVs n'est donc pas nécessaire chez les femmes enceintes. Lors d'une petite étude chez des patients HIV- positifs expérimentés, la corrélation entre l'exposition cellulaire et plasmatique des nouveaux ARVs, notamment le raltégravir, a été déterminée. Une bonne corrélation a été obtenue entre taux plasmatiques et cellulaires de raltégravir, suggérant que la surveillance des taux totaux est un substitut satisfaisant. Cependant, une importante variabilité inter¬patient a été observée dans les ratios d'accumulation cellulaire du raltégravir, ce qui devrait encourager des investigations supplémentaires chez les patients en échec sous ce traitement. L'efficacité du suivi thérapeutique des médicaments (TDM) pour l'adaptation des taux d'efavirenz chez des patients avec des concentrations au-dessus de la cible thérapeutique recommandée a été évaluée lors d'une étude prospective. L'adaptation des doses d'efavirenz basée sur le TDM s'est montrée efficace et sûre, soutenant l'utilisation du TDM chez les patients avec concentrations hors cible thérapeutique. L'impact des polymorphismes génétiques des cytochromes P450 (CYP) 2B6, 2A6 et 3A4/5 sur la pharmacocinétique de l'efavirenz et de ces métabolites a été étudié : un modèle de PK de population intégrant les covariats génétiques et démographiques a été construit. Les variations génétiques fonctionnelles dans les voies de métabolisation principales (CYP2B6) et accessoires {CYP2A6et 3A4/S) de l'efavirenz ont un impact sur sa disposition, et peuvent mener à des expositions extrêmes au médicament. Un? ajustement des doses guidé par le TDM est donc recommandé chez ces patients, en accord avec les polymorphismes génétiques.Ainsi, nous avons démonté qu'en utilisant une approche globale tenant compte à la fois des facteurs PK et PG influençant l'exposition aux ARVs chez les patients infectés, il est possible, si nécessaire, d'individualiser la thérapie antirétrovirale dans des situations diverses. L'optimisation du traitement antirétroviral contribue vraisemblablement à une meilleure efficacité thérapeutique à iong terme tout en réduisant la survenue d'effets indésirables.Résumé grand publicOptimisation de la thérapie antirétrovirale: approches pharmacocinétiques et pharmacogénétiquesLes progrès effectués dans le traitement de l'infection par le virus de llmmunodéficienoe humaine acquise (VIH) ont permis de transformer une affection mortelle en une maladie chronique traitable avec des médicaments de plus en plus efficaces. Malgré ce succès, un certain nombre de patients ne répondent pas de façon optimale à leur traitement etyou souffrent d'effets indésirables médicamenteux entraînant de fréquentes modifications dans leur thérapie. Il a été possible de mettre en évidence que l'efficacité d'un traitement antirétroviral est dans la plupart des cas corrélée aux concentrations de médicaments mesurées dans le sang des patients. Cependant, le virus se réplique dans la cellule, et seule la fraction des médicaments non liée aux protéines du plasma sanguin peut entrer dans la cellule et exercer l'activité antirétrovirale au niveau cellulaire. Il existe par ailleurs une importante variabilité des concentrations sanguines de médicament chez des patients prenant pourtant la même dose de médicament. Cette variabilité peut être due à des facteurs démographiques et/ou génétiques susceptibles d'influencer la réponse au traitement antirétroviral.Cette thèse a eu pour objectif de mieux comprendre les facteurs pharmacologiques et génétiques influençant l'efficacité et ta toxicité des médicaments antirétroviraux, dans le but d'individualiser la thérapie antivirale et d'améliorer le suivi des patients HIV-positifs.A cet effet, des méthodes de dosage très sensibles ont été développées pour permettre la quantification des médicaments antirétroviraux dans le sang et les cellules. Ces méthodes analytiques ont été appliquées dans le cadre de diverses études cliniques réalisées avec des patients. Une des études cliniques a recherché s'il y avait un impact des changements physiologiques liés à la grossesse sur les concentrations des médicaments antirétroviraux. Nous avons ainsi pu démontrer que la grossesse n'influençait pas de façon cliniquement significative le devenir des médicaments antirétroviraux chez les femmes enceintes HIV- positives. La posologie de médicaments ne devrait donc pas être modifiée dans cette population de patientes. Par ailleurs, d'autres études ont portés sur les variations génétiques des patients influençant l'activité enzymatique des protéines impliquées dans le métabolisme des médicaments antirétroviraux. Nous avons également étudié l'utilité d'une surveillance des concentrations de médicament (suivi thérapeutique) dans le sang des patients pour l'individualisation des traitements antiviraux. Il a été possible de mettre en évidence des relations significatives entre l'exposition aux médicaments antirétroviraux et l'existence chez les patients de certaines variations génétiques. Nos analyses ont également permis d'étudier les relations entre les concentrations dans le sang des patients et les taux mesurés dans les cellules où le virus HIV se réplique. De plus, la mesure des taux sanguins de médicaments antirétroviraux et leur interprétation a permis d'ajuster la posologie de médicaments chez les patients de façon efficace et sûre.Ainsi, la complémentarité des connaissances pharmacologiques, génétiques et virales s'inscrit dans l'optique d'une stratégie globale de prise en charge du patient et vise à l'individualisation de la thérapie antirétrovirale en fonction des caractéristiques propres de chaque individu. Cette approche contribue ainsi à l'optimisation du traitement antirétroviral dans la perspective d'un succès du traitement à long terme tout en réduisant la probabilité des effets indésirables rencontrés. - The improvement in antirétroviral therapy has transformed HIV infection from an inevitably fatal condition to a chronic, manageable disease. However, treatment failure and drug toxicity are frequent. Inadequate response to treatment is clearly multifactorial and, therefore, dosage individualisation based on demographic factors, genetic markers and measurement of total, free and/or cellular drug level may increase both drug efficacy and tolerability. Drug tolerability is certainly a major issue for a treatment that must be taken indefinitely.The global objective of this thesis aimed at increasing our current understanding of pharmacokinetic (PK) and pharmacogenetic (PG) factors influencing the exposition to antirétroviral drugs (ARVs) in HIV-positive patients. In turn, this should provide us with a rational basis for antiviral treatment optimisation and drug dosage adjustment in HIV- positive patients. Patient's tailored antirétroviral regimen is likely to enhance treatment effectiveness and tolerability, enabling a better compliance over time, and hence reducing the probability of emergence of viral resistance and treatment failure.To that endeavour, analytical methods for the measurement of total plasma, free and cellular concentrations of ARVs and some of their metabolites have been developed and validated using liquid chromatography coupled with tandem mass spectrometry. These assays have been applied for the monitoring of ARVs levels in various populations of HIV- positive patients. A clinical study has been initiated within the frame of the Mother and Child Swiss HIV Cohort Study to determine whether pregnancy influences the exposition to ARVs. Free and total plasma concentrations of lopinavir, atazanavir and nevirapine have been determined in pregnant women followed during the course of pregnancy, and were found not influenced to a clinically significant extent by pregnancy. Dosage adjustment for these drugs is therefore not required in pregnant women. In a study in treatment- experienced HIV-positive patients, the correlation between cellular and total plasma exposure to new antirétroviral drugs, notably the HIV integrase inhibitor raltegravir, has been determined. A good correlation was obtained between total and cellular levels of raltegravir, suggesting that monitoring of total levels are a satisfactory. However, significant inter-patient variability was observed in raltegravir cell accumulation which should prompt further investigations in patients failing under an integrase inhibitor-based regimen. The effectiveness of therapeutic drug monitoring (TDM) to guide efavirenz dose reduction in patients having concentrations above the recommended therapeutic range was evaluated in a prospective study. TDM-guided dosage adjustment of efavirenz was found feasible and safe, supporting the use of TDM in patients with efavirenz concentrations above therapeutic target. The impact of genetic polymorphisms of cytochromes P450 (CYP) 2B6, 2A6 and 3A4/5 on the PK of efavirenz and its metabolites was studied: a population PK model was built integrating both genetic and demographic covariates. Functional genetic variations in main (CYP2B6) and accessory (2A6, 3A4/5) metabolic pathways of efavirenz have an impact on efavirenz disposition, and may lead to extreme drug exposures. Dosage adjustment guided by TDM is thus required in those patients, according to the pharmacogenetic polymorphism.Thus, we have demonstrated, using a comprehensive approach taking into account both PK and PG factors influencing ARVs exposure in HIV-infected patients, the feasibility of individualising antirétroviral therapy in various situations. Antiviral treatment optimisation is likely to increase long-term treatment success while reducing the occurrence of adverse drug reactions.

'Modern' Phillips Curves and the Implications For The Statistical Process of Inflation

'Modern' theories of the Phillips curve imply that inflation is an integrated, or near integrated process. This paper explains this implication and why these 'modern' theories are logically inconsistent with what is commonly known about the statistical process of inflation.

Reforms of the pre-graduate curriculum for medical students: the Bologna process and beyond.

For several years, all five medical faculties of Switzerland have embarked on a reform of their training curricula for two reasons: first, according to a new federal act issued in 2006 by the administration of the confederation, faculties needed to meet international standards in terms of content and pedagogic approaches; second, all Swiss universities and thus all medical faculties had to adapt the structure of their curriculum to the frame and principles which govern the Bologna process. This process is the result of the Bologna Declaration of June 1999 which proposes and requires a series of reforms to make European Higher Education more compatible and comparable, more competitive and more attractive for Europeans students. The present paper reviews some of the results achieved in the field, focusing on several issues such as the shortage of physicians and primary care practitioners, the importance of public health, community medicine and medical humanities, and the implementation of new training approaches including e-learning and simulation. In the future, faculties should work on several specific challenges such as: students' mobility, the improvement of students' autonomy and critical thinking as well as their generic and specific skills and finally a reflection on how to improve the attractiveness of the academic career, for physicians of both sexes.

Macrophages induce neutrophil apoptosis through membrane TNF, a process amplified by Leishmania major.

Neutrophils are recruited to the site of parasite inoculation within a few hours of infection with the protozoan parasite Leishmania major. In C57BL/6 mice, which are resistant to infection, neutrophils are cleared from the site of s.c. infection within 3 days, whereas they persist for at least 10 days in susceptible BALB/c mice. In the present study, we investigated the role of macrophages (MPhi) in regulating neutrophil number. Inflammatory cells were recruited by i.p. injection of either 2% starch or L. major promastigotes. Neutrophils were isolated and cultured in the presence of increasing numbers of MPhi. Extent of neutrophil apoptosis positively correlated with the number of MPhi added. This process was strictly dependent on TNF because MPhi from TNF-deficient mice failed to induce neutrophil apoptosis. Assays using MPhi derived from membrane TNF knock-in mice or cultures in Transwell chambers revealed that contact with MPhi was necessary to induce neutrophil apoptosis, a process requiring expression of membrane TNF. L. major was shown to exacerbate MPhi-induced apoptosis of neutrophils, but BALB/c MPhi were not as potent as C57BL/6 MPhi in this induction. Our results emphasize the importance of MPhi-induced neutrophil apoptosis, and membrane TNF in the early control of inflammation.

Analysing the innovation process in the EU Integrated Programme, ISAFRUIT

ISAFRUIT is an integrated European Union Project focussed on increasing fruit consumption as a means to improve human health, through evaluating the fruit chain and addressing bottlenecks therein.The innovations which are being developed throughout the ISAFRUIT Project have been analysed to determine both the success factors and the obstacles in reaching the commercialisation stage. Only 9.58% of the deliverables planned within the Project were focussed on developing technological innovations.There is evidence, however, of successes in the development of new innovations arising from the ISAFRUIT Project, with several other potential innovations in the pipeline. Of the technologies identified, 67% are still at the “invention stage”; that is, the stage prior to bridging the so-called “valley of death”, the stage between an invention and an innovation. Those which are considered to have moved over the “valley of death” either had industry partners included in the Project, or had consulted with industry to ensure that the technology was relevant, or met a recognised industry need. Many of the technologies which made less progress did not have the same interactions with industry. A number of other issues were identified which prevented further progress towards innovation. The need for scientists to publish scientific papers, both for their career pathways and to increase their chances of future funding, was identified as one issue, although the filing of patents is now becoming more accepted and recognised. The patenting system is considered complex by many scientists and is not well-understood. Finally, agreements between partners on the sharing of intellectual property rights can cause a delay in the innovation process.

Immigrants'assimilation process in a segmented labor market

While much of the literature on immigrants' assimilation has focused on countries with a large tradition of receiving immigrants and with flexible labor markets, very little is known on how immigrants adjust to other types of host economies. With its severe dual labor market, and an unprecedented immigration boom, Spain presents a quite unique experience to analyze immigrations' assimilation process. Using data from the 2000 to 2008 Labor Force Survey, we find that immigrants are more occupationally mobile than natives, and that much of this greater flexibility is explained by immigrants' assimilation process soon after arrival. However, we find little evidence of convergence, especially among women and high skilled immigrants. This suggests that instead of integrating, immigrants occupationally segregate, providing evidence consistent with both imperfect substitutability and immigrants' human capital being under-valued. Additional evidence on the assimilation of earnings and the incidence of permanent employment by different skill levels also supports the hypothesis of segmented labor markets.

Bacillus thuringiensis: fermentation process and risk assessment: a short review

Several factors make the local production of Bacillus thuringiensis (Bt) highly appropriate for pest control in developing nations. Bt can be cheaply produced on a wide variety of low cost, organic substrates. Local production results in considerable savings in hard currency which otherwise would be spent on importation of chemical and biological insecticides. The use of Bt in Brazil has been limited in comparison with chemical insecticides. Although Bt is imported, some Brazilian researchers have been working on its development and production. Fermentation processes (submerged and semi-solid) were applied, using by-products from agro-industries. As the semi-solid fermentation process demonstrated to be interesting for Bt endotoxins production, it could be adopted for small scale local production. Although promising results had been achieved, national products have not been registered due to the absence of a specific legislation for biological products. Effective actions are being developed in order to solve this gap. Regardless of the biocontrol agents being considered atoxic and harmless to the environment, information related to direct and indirect effects of microbials are still insufficient in many cases. The risk analysis of the use of microbial control agents is of upmost importance nowadays, and is also discussed.