The role of clade competition in the diversification of North American canids.

The history of biodiversity is characterized by a continual replacement of branches in the tree of life. The rise and demise of these branches (clades) are ultimately determined by changes in speciation and extinction rates, often interpreted as a response to varying abiotic and biotic factors. However, understanding the relative importance of these factors remains a major challenge in evolutionary biology. Here we analyze the rich North American fossil record of the dog family Canidae and of other carnivores to tease apart the roles of competition, body size evolution, and climate change on the sequential replacement of three canid subfamilies (two of which have gone extinct). We develop a novel Bayesian analytic framework to show that competition from multiple carnivore clades successively drove the demise and replacement of the two extinct canid subfamilies by increasing their extinction rates and suppressing their speciation. Competitive effects have likely come from ecologically similar species from both canid and felid clades. These results imply that competition among entire clades, generally considered a rare process, can play a more substantial role than climate change and body size evolution in determining the sequential rise and decline of clades.

A Reappraisal of the Allocation Puzzle through the Portfolio Approach

Paradoxically, high-growth, high-investment developing countries tend to experience capital outflows. This paper shows that this allocation puzzle can be explained simply by introducing uninsurable idiosyncratic investment risk in the neoclassical growth model with international trade in bonds, and by taking into account not only TFP catch-up, but also the capital wedge, that is, the distortions on the return to capital. The model fits the two following facts, documented on a sample of 67 countries between 1980 and 2003: (i) TFP growth is positively correlated with capital outflows in a sample including creditor countries; (ii) the long-run level of capital per efficient unit of labor is positively correlated with capital outflows. Consistently, we show that the capital flows predicted by the model are positively correlated with the actual ones in this sample once the capital wedge is accounted for. The fact that Asia dominates global imbalances can be explained by its relatively low capital wedge.

Detecting patterns of species diversification in the presence of both rate shifts and mass extinctions.

BACKGROUND: Recent methodological advances allow better examination of speciation and extinction processes and patterns. A major open question is the origin of large discrepancies in species number between groups of the same age. Existing frameworks to model this diversity either focus on changes between lineages, neglecting global effects such as mass extinctions, or focus on changes over time which would affect all lineages. Yet it seems probable that both lineages differences and mass extinctions affect the same groups. RESULTS: Here we used simulations to test the performance of two widely used methods under complex scenarios of diversification. We report good performances, although with a tendency to over-predict events with increasing complexity of the scenario. CONCLUSION: Overall, we find that lineage shifts are better detected than mass extinctions. This work has significance to assess the methods currently used to estimate changes in diversification using phylogenetic trees. Our results also point toward the need to develop new models of diversification to expand our capabilities to analyse realistic and complex evolutionary scenarios.

Fifty years after Ehrlich and Raven, is there support for plant-insect coevolution as a major driver of species diversification?

Since Ehrlich & Raven's seminal paper 50 years ago, coevolution has been seen as a major driver of species diversification. Here, we review classical and more recent case studies on the coevolution of plants and associated insects, to examine whether the coevolutionary component holds as an explanation of their current diversity. We discuss the main dogmas in coevolution and argue that coevolutionary processes should not be considered as major drivers of diversification in plants and insects. Instead, we suggest that coevolution essentially occurs through relatively short 'interludes', making the pattern difficult to detect. We also criticize the use of comparative phylogenetics to investigate coevolutionary processes, as coevolution may not necessarily produce congruent phylogenies among interacting lineages and, in turn, other processes may produce patterns of codivergence. Finally, we propose new lines of investigation for future research.

Ownership Effects on Unrelated Diversification: An Institutions' Perspective

Purpose To show that differences in the extent to which firms engage in unrelated diversification can be attributed to differences in ownership structure. Methodology/approach We draw on longitudinal data and use a panel analysis specification to test our hypotheses. Findings We find that unrelated diversification destroys value; pressure-sensitive Anglo-American owners in a firm’s equity reduce unrelated diversification, whereas pressure-resistant domestic owners increase unrelated diversification; the greater the firm’s free cash flow, the greater the negative effect of pressure-sensitive Anglo-American owners on unrelated diversification. Research limitations/implications We contribute to corporate governance and strategy research by bringing in owners’ institutional origin as a shaper of owner preferences in particular with regards to unrelated diversification. Future research may expand our investigation to more than one home institutional context, and theorize on institutional origin effects beyond the dichotomy between Anglo-American and non-Anglo-American (not oriented toward shareholder value maximization) owners. Practical implications Policy makers, financial analysts, owners, and managers may want to reflect about the implications of ownership structure, as well as promoting or joining corporations with particular ownership configurations. Social implications A shareholder value-destroying strategy, such as unrelated diversification has adverse consequences for society at large, in terms of opportunity costs, that is, resources could be allocated to value-creating activities instead. Promoting an ownership configuration that creates value should contribute to social welfare. Originality/value Owners may not be exclusively driven by shareholder value maximization, but can be influenced by normative beliefs (biases) stemming from the institutional context they originate from.

Three essays on the psychology of investment and financial markets

Préface My thesis consists of three essays where I consider equilibrium asset prices and investment strategies when the market is likely to experience crashes and possibly sharp windfalls. Although each part is written as an independent and self contained article, the papers share a common behavioral approach in representing investors preferences regarding to extremal returns. Investors utility is defined over their relative performance rather than over their final wealth position, a method first proposed by Markowitz (1952b) and by Kahneman and Tversky (1979), that I extend to incorporate preferences over extremal outcomes. With the failure of the traditional expected utility models in reproducing the observed stylized features of financial markets, the Prospect theory of Kahneman and Tversky (1979) offered the first significant alternative to the expected utility paradigm by considering that people focus on gains and losses rather than on final positions. Under this setting, Barberis, Huang, and Santos (2000) and McQueen and Vorkink (2004) were able to build a representative agent optimization model which solution reproduced some of the observed risk premium and excess volatility. The research in behavioral finance is relatively new and its potential still to explore. The three essays composing my thesis propose to use and extend this setting to study investors behavior and investment strategies in a market where crashes and sharp windfalls are likely to occur. In the first paper, the preferences of a representative agent, relative to time varying positive and negative extremal thresholds are modelled and estimated. A new utility function that conciliates between expected utility maximization and tail-related performance measures is proposed. The model estimation shows that the representative agent preferences reveals a significant level of crash aversion and lottery-pursuit. Assuming a single risky asset economy the proposed specification is able to reproduce some of the distributional features exhibited by financial return series. The second part proposes and illustrates a preference-based asset allocation model taking into account investors crash aversion. Using the skewed t distribution, optimal allocations are characterized as a resulting tradeoff between the distribution four moments. The specification highlights the preference for odd moments and the aversion for even moments. Qualitatively, optimal portfolios are analyzed in terms of firm characteristics and in a setting that reflects real-time asset allocation, a systematic over-performance is obtained compared to the aggregate stock market. Finally, in my third article, dynamic option-based investment strategies are derived and illustrated for investors presenting downside loss aversion. The problem is solved in closed form when the stock market exhibits stochastic volatility and jumps. The specification of downside loss averse utility functions allows corresponding terminal wealth profiles to be expressed as options on the stochastic discount factor contingent on the loss aversion level. Therefore dynamic strategies reduce to the replicating portfolio using exchange traded and well selected options, and the risky stock.

Discordances between phylogenetic and morphological patterns in alpine leaf beetles attest to an intricate biogeographic history of lineages in postglacial Europe.

Pleistocene glacial and interglacial periods have moulded the evolutionary history of European cold-adapted organisms. The role of the different mountain massifs has, however, not been accurately investigated in the case of high-altitude insect species. Here, we focus on three closely related species of non-flying leaf beetles of the genus Oreina (Coleoptera, Chrysomelidae), which are often found in sympatry within the mountain ranges of Europe. After showing that the species concept as currently applied does not match barcoding results, we show, based on more than 700 sequences from one nuclear and three mitochondrial genes, the role of biogeography in shaping the phylogenetic hypothesis. Dating the phylogeny using an insect molecular clock, we show that the earliest lineages diverged more than 1 Mya and that the main shift in diversification rate occurred between 0.36 and 0.18 Mya. By using a probabilistic approach on the parsimony-based dispersal/vicariance framework (MP-DIVA) as well as a direct likelihood method of state change optimization, we show that the Alps acted as a cross-roads with multiple events of dispersal to and reinvasion from neighbouring mountains. However, the relative importance of vicariance vs. dispersal events on the process of rapid diversification remains difficult to evaluate because of a bias towards overestimation of vicariance in the DIVA algorithm. Parallels are drawn with recent studies of cold-adapted species, although our study reveals novel patterns in diversity and genetic links between European mountains, and highlights the importance of neglected regions, such as the Jura and the Balkanic range.

New insights into the phylogenetics and biogeography of Arum (Araceae): unravelling its evolutionary history

The heat- and odour-producing genus Arum (Araceae) has interested scientists for centuries. This long-term interest has allowed a deep knowledge of some complex processes, such as the physiology and dynamics of its characteristic lure-and-trap pollination system, to be built up. However, mainly because of its large distributional range and high degree of morphological variation, species' limits and relationships are still under discussion. Today, the genus comprises 28 species subdivided into two subgenera, two sections and six subsections. In this study, the phylogeny of the genus is inferred on the basis of four plastid regions, and the evolution of several morphological characters is investigated. Our phylogenetic hypothesis is not in agreement with the current infrageneric classification of the genus and challenges the monophyly of several species. This demonstrates the need for a new infrageneric classification based on characters reflecting the evolution of this enigmatic genus. To investigate the biogeography of Arum deeply, further spatiotemporal analyses were performed, addressing the importance of the Mediterranean basin in the diversification of Arum. Our results suggest that its centre of origin was the European-Aegean region, and that major diversification happened during the last 10 Myr.

Genetic survey of "spinturnix sp" (Acari, Mesostigmata) and their bat hosts in Western Palearctic

SUMMARY : The coevolution between two intimately associated organisms, like host and parasite, is a widely investigated theme in evolutionary biology. Recently, the use of genetic data in the study of host-parasite systems evidences that the genetic information from some parasites can complement genetic data from their hosts and thus may help to better understand their host's evolutionary history. Phylogenetic and population genetic aspects of bat parasites have been poorly investigated. Spinturnicid mites are highly specialized ectoparasites, exclusively associated with bats and therefore represent an ideal model to extant our knowledge on bat and parasite biology and on their coevolutionary history. In this thesis, I developed several molecular markers (mitochondrial DNA) to compare the genetic patterns of Spinturnix mites with their bat hosts at different levels. The molecular co-phylogeny between Spinturnix sp. and their bat hosts suggests a partial cospeciation and the occurrence of failure to speciate events and multiple host switches. Thus, Spinturnix mites do not exactly mirror the phylogenetic pattern of their hosts, despite their intimate association. Similar roosting habits of the hosts seem to promote host switches between different species, as far as ecological conditions are favourable. The phylogeographic study of the Maghrebian bat M. punicus in the Mediterranean area confirms the presence of M. punicus in North Africa, Corsica and Sardinia and highlights that islands and mainland are genetically highly divergent. The comparison between the parasitic mite S. myoti and the Maghrebian bat suggests that the phylogeographic pattern of the mite is moulded by its host, with open water as main barrier for host and parasite dispersal. Moreover, the unique presence of a European S. myoti lineage on M. punicus from Corsica strongly suggests the former presence of mouse-eared bats (M. myotis and/or M. blythii) in Corsica. By highlighting the probable presence of a nowadays locally extinct host species, S. myoti may represent a good proxy for inferring complex evolutionary history of bat hosts. Finally, population genetic surveys of S. myoti and S. bechsteinii suggest that these mites benefit from close contacts between individuals during the mating season and/or hibernation to disperse among remote colonies. The contrasted genetic patterns of these two distinct bat-mite systems evidence that bat social structure is a determinant factor of the genetic structure of mite populations. Altogether, this PhD thesis demonstrates the usefulness of parasites to gather information about their bat hosts. In addition, my results illustrate how different ecological and biological characteristics of bat species allow the emergence of a surprising diversity in the genetic patterns of the parasites, which may contribute to the diversification and speciation of parasites. RESUME : La co-évolution entre deux organismes intimement liés, comme un parasite et son hôte, fait partie des questions largement étudiées en biologie évolutive. Récemment, l'utilisation de données génétique dans l'étude des interactions hôte-parasite a montré que l'information génétique de certains parasites peut compléter les données génétiques de l'hôte et ainsi peut éclairer l'histoire évolutive de leur hôte. Très peu études ont étudié les interactions entre les chauves-souris et leurs parasites d'un point de vue moléculaire. Les acariens du genre Spinturnix sont des ectoparasites très spécialisés exclusivement associés aux chauves-souris. Ils représentent donc un model idéal pour élargir nos connaissances tant sur l'écologie des parasites de chauves-souris que sur leur coévolution. Durant cette thèse, plusieurs marqueurs moléculaires (ADN mitochondrial) ont été développés pour ainsi comparer la distribution de la variation génétique des parasites du genre Spinturnix avec celle de leurs hôtes, et ceci à différents niveaux. Tout d'abord, la co-phylogénie moléculaire entre les espèces de Spinturnix et les leurs hôtes révèle une co-spéciation partielle ainsi que la présence d'événement de non spéciation et de transferts horizontaux. Ces parasites ne reflètent donc pas entièrement l'histoire évolutive de leurs hôtes, malgré leurs intimes associations. La cohabitation de plusieurs espèces de chauves-souris dans un même gîte permet aux parasites un transfert entre différentes espèces, atténuant ainsi leur degré de co-spéciation. Deuxièmement, l'étude phylogéographique du marin du Maghreb dans le bassin Méditerranéen confirme sa présence en Afrique du Nord, en Corse et en Sardaigne. La comparaison avec un de ses parasites S. myoti suggère que la répartition génétique de S. myoti est façonnée par celle de leurs hôtes, avec les étendues d'eau comme barrière principale tant à la dispersion de l'hôte que de son parasite. De plus, la présence unique d'une lignée européenne de ces parasites sur des marins du Maghreb de Corse suggère fortement la présence du grand ou petit marin en Corse dans le passé. En reflétant la présence potentielle à un endroit donné d'une espèce de chauve-souris actuellement disparue, S. myoti peut représenter une bonne alternative pour comprendre l'histoire évolutive complexe des chauves-souris. Finalement, l'étude des structures génétiques des populations des parasites S. myoti et S. bechsteinii suggère que les contacts corporels entre chauves-souris durant la saison de reproduction ou l'hibernation peuvent permettre la dispersion des parasites entre des colonies éloignées géographiquement. La différence de structure génétique entre ces deux associations particulières montre que la structure génétique des populations de parasites dépend fortement des traits d'histoire de vie de son hôte. Dans l'ensemble, cette thèse démontre l'importance des parasites pour amener des informations sur leurs hôtes, les chauves-souris. Elle illustre aussi comment les différences écologique et biologique des différentes espèces de chauves-souris peuvent amener une étonnante diversité de structure génétique au sein de populations de parasites, ce qui peut peut-être contribuer à la diversification et à la spéciation des parasites.

Behavior of endogenous tumor-associated macrophages assessed in vivo using a functionalized nanoparticle.

Tumor-associated macrophages (TAMs) invade the tumor stroma in many cancers, yet their role is incompletely understood. To visualize and better understand these critical cells in tumor progression, we screened a portfolio of rationally selected, injectable agents to image endogenous TAMs ubiquitously in three different cancer models (colon carcinoma, lung adenocarcinoma, and soft tissue sarcoma). AMTA680, a functionally derivatized magneto-fluorescent nanoparticle, labeled a subset of myeloid cells with an "M2" macrophage phenotype, whereas other neighboring cells, including tumor cells and a variety of other leukocytes, remained unlabeled. We further show that AMTA680-labeled endogenous TAMs are not altered and can be tracked noninvasively at different resolutions and using various imaging modalities, e.g., fluorescence molecular tomography, magnetic resonance imaging, and multiphoton and confocal intravital microscopy. Quantitative assessment of TAM distribution and activity in vivo identified that these cells cluster in delimited foci within tumors, show relatively low motility, and extend cytoplasmic protrusions for prolonged physical interactions with neighboring tumor cells. Noninvasive imaging can also be used to monitor TAM-depleting regimen quantitatively. Thus, AMTA680 or related cell-targeting agents represent appropriate injectable vehicles for in vivo analysis of the tumor microenvironment.

Cdc42 explores the cell periphery for mate selection in fission yeast.

How cells polarize in response to external cues is a fundamental biological problem. For mating, yeast cells orient growth toward the source of a pheromone gradient produced by cells of the opposite mating type. Polarized growth depends on the small GTPase Cdc42, a central eukaryotic polarity regulator that controls signaling, cytoskeleton polarization, and vesicle trafficking. However, the mechanisms of polarity establishment and mate selection in complex cellular environments are poorly understood. Here we show that, in fission yeast, low-level pheromone signaling promotes a novel polarization state, where active Cdc42, its GEF Scd1, and scaffold Scd2 form colocalizing dynamic zones that sample the periphery of the cell. Two direct Cdc42 effectors--actin cables marked by myosin V Myo52 and the exocyst complex labeled by Sec6 and Sec8--also dynamically colocalize with active Cdc42. However, these cells do not grow due to a block in the exocytosis of cell wall synthases Bgs1 and Bgs4. High-level pheromone stabilizes active Cdc42 zones and promotes cell wall synthase exocytosis and polarized growth. However, in the absence of prior low-level pheromone signaling, exploration fails, and cells polarize growth at cell poles by default. Consequently, these cells show altered partner choice, mating preferentially with sister rather than nonsister cells. Thus, Cdc42 exploration serves to orient growth for partner selection. This process may also promote genetic diversification.

Reconstructing the origins of high-alpine niches and cushion life form in the genus Androsace S.L. (Primulaceae).

Relatively, few species have been able to colonize extremely cold alpine environments. We investigate the role played by the cushion life form in the evolution of climatic niches in the plant genus Androsace s.l., which spreads across the mountain ranges of the Northern Hemisphere. Using robust methods that account for phylogenetic uncertainty, intraspecific variability of climatic requirements and different life-history evolution scenarios, we show that climatic niches of Androsace s.l. exhibit low phylogenetic signal and that they evolved relatively recently and punctually. Models of niche evolution fitted onto phylogenies show that the cushion life form has been a key innovation providing the opportunity to occupy extremely cold environments, thus contributing to rapid climatic niche diversification in the genus Androsace s.l. We then propose a plausible scenario for the adaptation of plants to alpine habitats.

Analyse de facteurs déterminants de la substitution par des médicaments génériques en Suisse

Cadre de l'étude La part des dépenses de santé dans les budgets des pays occidentaux est importante et tend à croître depuis plusieurs décennies. Une des conséquences, notamment pour la Suisse, est une augmentation régulière des primes d'assurance maladie, dont l'impopularité incite les responsables politiques à trouver des stratégies de frein à la croissance des coûts de la santé. Les médicaments, qui contribuent notablement à l'augmentation de ces coûts, constituent l'une des cibles classiques d'interventions visant à une réduction des dépenses de santé. Le niveau de coûts des médicaments représente plus de 20% des dépenses de soins du domaine ambulatoire à la charge de l'assurance obligatoire des soins (AOS), soit une dépense annuelle de plus de 4 milliards de francs. Différentes mesures peuvent être utilisées par le gouvernement pour contenir cette facture à charge de la collectivité : baisse du prix des médicaments, limitation du nombre de produits remboursés par l'assurance de base et incitations à la concurrence sur les prix en autorisant les importations parallèles. Depuis que de plus en plus de brevets pour des médicaments sont arrivés à échéance, un autre angle d'attaque s'est concrétisé avec l'incitation à la prescription de médicaments génériques. Les génériques sont définis comme des produits thérapeutiques chimiquement identiques à des composés déjà utilisés, appelés médicaments originaux. En principe, une économie substantielle devrait pouvoir être réalisée sur les coûts totaux des médicaments si tous les génériques disponibles sur le marché étaient systématiquement prescrits par les professionnels et acceptés par les patients. Les résultats publiés par les caisses maladie et les offices fédéraux sont des estimations globales et les montants publiés par l'industrie pharmaceutique concernent l'ensemble du marché, incluant les médicaments utilisés dans les séjours hospitaliers, sont par ailleurs exprimés en prix de fabrique. De plus, aucune étude n'a tenu compte de la substituabilité des produits d'un point de vue pharmaceutique. L'objectif général de la thèse est d'évaluer aussi précisément que possible l'économie pouvant être encore réalisée dans le secteur ambulatoire en substituant aux médicaments originaux les produits génériques présents sur le marché et de caractériser plusieurs facteurs qui influencent la substitution générique. Pour cette étude, nous avons pu disposer de l'ensemble des factures pharmaceutiques de la caisse maladie CSS, pour tous ses assurés des cantons d'Argovie, du Tessin et de Vaud, soit plus de 169'000 assurés représentant les trois régions linguistiques de la Suisse. Les 1'341'197 prescriptions médicales qui ont été analysées concernent l'année 2003. C'est un moment critique dans l'histoire des génériques en Suisse, approprié pour établir un premier bilan après l'entrée en vigueur de la première mesure relative au droit de substituer octroyé en 2001 aux pharmaciens et, pour identifier idéalement les principaux déterminants de la substitution par les praticiens avant l'introduction de la quote-part différenciée en 2006. La présence d'un même principe actif n'est pas une condition suffisante pour permettre une substitution et pour ce travail des critères tenant compte des caractéristiques pharmaceutiques des produits ont été établis et appliqués pour valider la substituabilité des originaux par les génériques disponibles sur le marché. Ces critères concernent notamment le mode d'administration, le dosage et le nombre de doses dans l'emballage. L'étude a été réalisée selon deux approches, d'abord par une analyse descriptive sur l'ensemble de la population source pour estimer le marché des génériques et ensuite par une analyse statistique (régression logit multivariée) sur 173'212 prescriptions agrégées, qui concernent spécifiquement soit un générique soit un original substituable, pour caractériser les facteurs déterminants de la substitution générique. Résultats Dans l'ensemble de la population source, les génériques et les originaux substituables représentent 17,4% du marché en termes de coûts facturés, avec 3,4% de génériques et 14,0% d'originaux substituables ce qui correspond à un taux de substitution de 19,5%. En termes de dépenses, les substitutions génériques réalisées représentent une économie de 1,3% du total du marché étudié alors qu'il reste un potentiel notable d'économie par la substitution de 4,6%. Les taux de substitution sont très variables selon les cantons : 10,1% au Tessin, 29,0% pour le canton de Vaud et 35,8% pour Argovie. L'analyse univariée des 173'212 prescriptions de génériques ou d'originaux substituables, montre des taux de substitution plus élevés chez les patients jeunes et lorsqu'il y a d'importantes différences de prix entre les originaux et les génériques. Des taux de substitution peu élevés sont observés chez les patients les plus âgés et pour ceux qui ont des traitements médicamenteux complexes. Les patients ayant plus de 10 médicaments différents durant la même année, présentent une probabilité relative de substituer inférieure (-24%) par rapport aux patients ayant 6 à 10 médicaments différents dans l'année. Cependant, l'analyse multivariée montre que l'effet négatif sur le taux de substitution de l'âge combiné à la complexité des traitements n'excède pas 3%. Bien que le niveau de franchises et la participation financière à la quote-part soient liées à une augmentation de la prescription de génériques, leurs effets sont modérés pour les patients avec des franchises supérieures à 300 francs (effet marginal de 1%) et pour les patients qui n'ont pas atteint le plafond de participation (effet marginal de 2%). La différence de taux substitution entre les médecins hospitaliers et les spécialistes est diminuée de façon notable (effet marginal de -13%) et elle est cependant moins marquée avec les médecins généralistes (effet marginal de -3%). Les facteurs associés au marché ont une influence notable sur la substitution générique et des effets positifs sont observés avec l'augmentation de la taille du marché, du nombre de génériques pour un même original substituable et de l'économie relative entre l'original et le générique. Par contre, la diversification des formes galéniques et des tailles d'emballages au niveau de l'offre des médicaments originaux a des effets fortement négatifs sur la substitution générique (-7%). Le canton de domicile a aussi un impact notable sur la substitution et le canton du Tessin présente un taux plus bas (-26%) que le canton d'Argovie. Conclusion et perspectives Ce travail a montré qu'il y a encore un important potentiel d'économies à réaliser par la substitution générique, calculé à plus de 4% des dépenses pharmaceutiques prises en charge par l'AOS en ambulatoires. Une extrapolation à l'ensemble du marché suisse, qui doit être faite avec prudence, fait apparaître un potentiel d'économies de 127 millions pour les médicaments délivrés par les pharmacies en 2003. L'étude a mis en évidence un certain nombre de déterminants qui freinent la substitution générique, notamment la prescription par un médecin hospitalier. Sur ce point la prescription en DCI (dénomination commune internationale) pourrait favoriser la dispensation de génériques moins chers. Un taux de substitution plus faible est observé chez les patients âgés avec des traitements complexes. Ce constat peut être mis en relation avec la crainte d'avoir un traitement moins efficace ou moins bien supporté et les risques de confusion lors du passage d'un original substituable à un générique ou d'un générique à un autre générique. Sur ces éléments, l'indication claire et précise du nom de la substance, aussi bien sur les emballages des originaux substituables que sur ceux des génériques, pourrait rassurer les patients et diminuer les risques d'erreurs dans la prise des médicaments. Certaines précautions à prendre lors de la prescription de génériques sont reconnues, notamment pour les médicaments à faible marge thérapeutique, et des informations sur la bioéquivalence, régulièrement mises à jour et à disposition des professionnels, pourraient augmenter la confiance dans l'utilisation des génériques. Les industries pharmaceutiques préservent par différentes tactiques leurs parts de marché et notamment avec succès en introduisant de nouvelles formes galéniques juste avant l'expiration des brevets. Des directives complémentaires sur la fixation des prix pour le remboursement, en particulier l'introduction d'un prix de référence quelle que soit la forme galénique, pourraient diminuer l'effet de barrage des médicaments originaux. Les incitations économiques, telles que la franchise et les participations sont efficaces si l'on considère l'impact sur les taux de substitution. Leur effet global reste toutefois modeste et il serait nécessaire de mesurer concrètement l'impact de l'introduction en 2006 de la quote-part différenciée. Les différences de prix entre les originaux et les génériques exigées à 50% pour les gros marchés, c'est-à-dire de plus de 16 millions, devraient aussi avoir un impact qu'il serait opportun de mesurer.

Phylogeny of subtribe Gentianinae (Gentianaceae): biogeographic inferences despite limitations in temporal calibration points

The subtribe Gentianinae comprises ca. 425 species, most of them within the well-studied genus Gentiana and mainly distributed over the Eurasian continent. Phylogenetic relationships between Gentiana and its closest relatives, the climbing gentians (Crawfurdia, Tripterospermum) and the new genus Metagentiana, remain unclear. All three genera were recently found to be polyphyletic, possibly because of poor sampling of Tripterospermum and Crawfurdia. Highest diversity of Gentianinae occurs in the western Himalaya, but the absence of uncontroversial fossil evidence limits our understanding of its biogeography. In the present study, we generated ITS and atpB-rbcL sequences for 19 species of Tripterospermum, 9 of Crawfurdia and 11 of Metagentiana, together representing about 60 percent of the species diversity of these genera. Our results show that only Metagentiana is polyphyletic and divided into three monophyletic entities. No unambiguous synapomorphies were associated with the three Metagentiana entities. Different combinations of three approximate calibration points were used to generate three divergence time estimation scenarios. Although dating hypotheses were mostly inconsistent, they concurred in associating radiation of Gentiana to an orogenic phase of the Himalaya between 15 and 10 million years ago. Our study illustrates the conceptual difficulties in addressing the time frame of diversification in a group lacking sufficient fossil number and quality.

Routes of administration of cannabis used for nonmedical purposes and associations with patterns of drug use.

PURPOSE: Little is known regarding cannabis administration routes for nonmedical use-that is, its delivery methods (e.g., joints, water pipe, food). Therefore, we examined the prevalence rates of different cannabis delivery methods and assessed the relationship of the distinct administration routes with problematic drug use. Subgroups of cannabis users were also investigated (i.e., "pure" cannabis users, previously described as employing a harmless route of administration, and water pipe users, previously described as using a harmful route of administration). METHODS: As part of the Cohort Study on Substance Use Risk Factors, 1,763 cannabis users answered questions concerning their drug use (i.e., routes of administration, problematic cannabis use, other illicit drug use). Descriptive statistics, latent class analysis, correlations and t-tests were assessed. RESULTS: The main administration route was "joints with tobacco"; other routes of administration had prevalence rates from 23.99% to 38.23%. In addition, increasing the number of administration routes was associated with more problematic cannabis use, as well as heavier illicit drug use. Water pipes without tobacco were especially linked to heavy drug use patterns, whereas "pure" cannabis use seemed less harmful. CONCLUSIONS: Our findings highlighted that diversification in routes of administration can be associated with heavier illicit drug use. This was especially true for water pipe users, whereas "pure" cannabis users, who did not mix cannabis with tobacco, were an exception. Indeed, these results may be useful for future preventive programs, which may need to focus on those who have diversified routes of administration for cannabis.