Descriptive epidemiology of Cornelia de Lange syndrome in Europe.

Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly/mental retardation syndrome consisting of characteristic dysmorphic features, microcephaly, hypertrichosis, upper limb defects, growth retardation, developmental delay, and a variety of associated malformations. We present a population-based epidemiological study of the classical form of CdLS. The data were extracted from the database of European Surveillance of Congenital Anomalies (EUROCAT) database, a European network of birth defect registries which follow a standard methodology. Based on 23 years of epidemiologic monitoring (8,558,346 births in the 1980-2002 period), we found the prevalence of the classical form of CdLS to be 1.24/100,000 births or 1:81,000 births and estimated the overall CdLS prevalence at 1.6-2.2/100,000. Live born children accounted for 91.5% (97/106) of cases, fetal deaths 2.8% (3/106), and terminations of pregnancy following prenatal diagnosis 5.7% (6/106). The most frequent associated congenital malformations were limb defects (73.1%), congenital heart defects (45.6%), central nervous system malformations (40.2%), and cleft palate (21.7%). In the last 11 years, as much as 68% of cases with major malformations were not detected by routine prenatal US. Live born infants with CdLS have a high first week survival (91.4%). All patients were sporadic. Maternal and paternal age did not seem to be risk factors for CdLS. Almost 70% of patients, born after the 37th week of gestation, weighed <or=2,500 g. Low birth weight correlated with a more severe phenotype. Severe limb anomalies were significantly more often present in males.

Effect of added dead space on sleep disordered breathing at high altitude.

OBJECTIVE: Sleep disordered breathing with central apnea or hypopnea frequently occurs at high altitude and is thought to be caused by a decrease in blood CO(2) level. The aim of this study was to assess the effects of added respiratory dead space on sleep disordered breathing.¦METHODS: Full polysomnographies were performed on 12 unacclimatized swiss mountaineers (11 males, 1 female, mean age 39±12 y.o.) in Leh, Ladakh (3500m). In random order, half of the night was spent with a 500ml increase in dead space through a custom designed full face mask and the other half without it.¦RESULTS: Baseline data revealed two clearly distinct groups: one with severe sleep disordered breathing (n=5, AHI>30) and the other with moderate to no disordered breathing (n=7, AHI<30). DS markedly improved breathing in the first group (baseline vs DS): apnea hypopnea index (AHI) 70.3±25.8 vs 29.4±6.9 (p=0.013), oxygen desaturation index (ODI): 72.9±24.1/h vs 42.5±14.4 (p=0.031), whereas it had no significant effect in the second group or in the total population. Respiratory events were almost exclusively central apnea or hypopnea. Microarousal index, sleep efficiency, and sleep architecture remained unchanged with DS. A minor increase in mean PtcCO(2) (n=3) was observed with DS.¦CONCLUSION: A 500ml increase in dead space through a fitted mask may improve nocturnal breathing in mountaineers with severe altitude-induced sleep disordered breathing.

The immune space: a concept and template for rationalizing vaccine development.

Abstract Empirical testing of candidate vaccines has led to the successful development of a number of lifesaving vaccines. The advent of new tools to manipulate antigens and new methods and vectors for vaccine delivery has led to a veritable explosion of potential vaccine designs. As a result, selection of candidate vaccines suitable for large-scale efficacy testing has become more challenging. This is especially true for diseases such as dengue, HIV, and tuberculosis where there is no validated animal model or correlate of immune protection. Establishing guidelines for the selection of vaccine candidates for advanced testing has become a necessity. A number of factors could be considered in making these decisions, including, for example, safety in animal and human studies, immune profile, protection in animal studies, production processes with product quality and stability, availability of resources, and estimated cost of goods. The "immune space template" proposed here provides a standardized approach by which the quality, level, and durability of immune responses elicited in early human trials by a candidate vaccine can be described. The immune response profile will demonstrate if and how the candidate is unique relative to other candidates, especially those that have preceded it into efficacy testing and, thus, what new information concerning potential immune correlates could be learned from an efficacy trial. A thorough characterization of immune responses should also provide insight into a developer's rationale for the vaccine's proposed mechanism of action. HIV vaccine researchers plan to include this general approach in up-selecting candidates for the next large efficacy trial. This "immune space" approach may also be applicable to other vaccine development endeavors where correlates of vaccine-induced immune protection remain unknown.

Les méthodes d'ajustement dans les modèles d'évaluation de la mortalité hospitalière. Partie 1, Etude descriptive : document de travail

Suite à la demande du Président de la République de disposer d'indicateurs de mortalité en établissements de santé » (discours du 18 septembre 2008 sur le thème de la politique de la santé et de la réforme du système de soins), la Direction de la recherche, des études, de l'évaluation et des statistiques (DREES) a piloté en 2009, en lien avec la Direction générale de l'offre de soins (DGOS) et la Haute autorité de santé (HAS), l'instruction des aspects méthodologiques relatifs à la construction de ces indicateurs de mortalité. Cette revue de littérature portant sur les différentes méthodes d'ajustement a été réalisée dans ce cadre, à la demande conjointe de la DREES et de la HAS.Ce rapport décrit les méthodes et modèles d'estimation et d'ajustement de la mortalité hospitalière identifiées dans la littérature.Il ressort de cette revue, que d'une manière générale, trois questions méthodologiques majeures préoccupent les épidémiologistes, les chercheurs et les décideurs s'intéressant à l'indicateur de la mortalité hospitalière : i) premièrement, sur l'opportunité d'établir l'indicateur de mortalité hospitalière à partir de groupes de population de patients homogènes définis par des pathologies et/ou des procédures médicales/chirurgicales cibles ; ii) deuxièmement, sur le type d'approche analytique et de l'intérêt de prendre en compte plusieurs niveaux dans l'analyse statistique ; iii) enfin troisièmement, sur le choix des variables d'ajustement permettant de contrôler les différences de case-mix entre plusieurs établissements ou groupes de patients pour réaliser des comparaisons. [Ed.]

Partition coefficient and molecular flexibility: the concept of lipophilicity space.

The rationale of this study was to investigate molecular flexibility and its influence on physicochemical properties with a view to uncovering additional information on the fuzzy concept of dynamic molecular structure. Indeed, it is now known that computed molecular interaction fields (MIFs) such as molecular electrostatic potentials (MEPs) and lipophilicity potentials (MLPs) are conformation-dependent, as are dipole moments. A database of 125 compounds was used whose conformational space was explored, while conformation-dependent parameters were computed for each non-redundant conformer found in the conformational space of the compounds. These parameters were the virtual log P (log P(MLP), calculated by a MLP approach), the apolar surface area (ASA), polar surface area (PSA), and solvent-accessible surface (SAS). For each compound, the range taken by each parameter (its property space) was divided by the number of rotors taken as an index of flexibility, yielding a parameter termed 'molecular sensitivity'. This parameter was poorly correlated with others (i.e., it contains novel information) and showed the compounds to fall into two broad classes. 'Sensitive' molecules are those whose computed property ranges are markedly sensitive to conformational effects, whereas 'insensitive' (in fact, less sensitive) molecules have property ranges which are comparatively less affected by conformational fluctuations. A pharmacokinetic application is presented.

Shift in cytotype frequency and niche space in the invasive plant Centaurea maculosa.

Polyploidy is often assumed to increase the spread and thus the success of alien plant species, but few empirical studies exist. We tested this hypothesis with Centaurea maculosa Lam., a species native to Europe and introduced into North America approximately 120 years ago where it became highly invasive. We analyzed the ploidy level of more than 2000 plants from 93 native and 48 invasive C. maculosa populations and found a pronounced shift in the relative frequency of diploid and tetraploid cytotypes. In Europe diploid populations occur in higher frequencies than tetraploids and only four populations had both cytotypes, while in North America diploid plants were found in only one mixed population and thus tetraploids clearly dominated. Our results showed a pronounced shift in the climatic niche between tetraploid populations in the native and introduced range toward drier climate in North America and a similar albeit smaller shift between diploids and tetraploids in the native range. The field data indicate that diploids have a predominately monocarpic life cycle, while tetraploids are often polycarpic. Additionally, the polycarpic life-form seems to be more prevalent among tetraploids in the introduced range than among tetraploids in the native range. Our study suggests that both ploidy types of C. maculosa were introduced into North America, but tetraploids became the dominant cytotype with invasion. We suggest that the invasive success of C. maculosa is partly due to preadaptation of the tetraploid cytotype in Europe to drier climate and possibly further adaptation to these conditions in the introduced range. The potential for earlier and longer seed production associated with the polycarpic life cycle constitutes an additional factor that may have led to the dominance of tetraploids over diploids in the introduced range.

Faire la ville juste : une analyse "in itinere" de la maîtrise publique d'ouvrage du projet urbain Carré de Soie (métropole lyonnaise)

Dans certaines portions des agglomérations (poches de pauvreté de centre-ville, couronnes suburbaines dégradées, espaces périurbains sans aménité), un cumul entre des inégalités sociales (pauvreté, chômage, etc.) et environnementales (exposition au bruit, aux risques industriels, etc.) peut être observé. La persistance de ces inégalités croisées dans le temps indique une tendance de fond : la capacité d'accéder à un cadre de vie de qualité n'est pas équitablement partagée parmi les individus. Ce constat interroge : comment se créent ces inégalités ? Comment infléchir cette tendance et faire la ville plus juste ?¦Apporter des réponses à cette problématique nécessite d'identifier les facteurs de causalités qui entrent en jeu dans le système de (re)production des inégalités urbaines. Le fonctionnement des marchés foncier et immobilier, la « tyrannie des petites décisions » et les politiques publiques à incidence spatiale sont principalement impliqués. Ces dernières, agissant sur tous les éléments du système, sont placées au coeur de ce travail. On va ainsi s'intéresser précisément à la manière dont les collectivités publiques pilotent la production de la ville contemporaine, en portant l'attention sur la maîtrise publique d'ouvrage (MPO) des grands projets urbains.¦Poser la question de la justice dans la fabrique de la ville implique également de questionner les référentiels normatifs de l'action publique : à quelle conception de la justice celle-ci doit- elle obéir? Quatre perspectives (radicale, substantialiste, procédurale et intégrative) sont caractérisées, chacune se traduisant par des principes d'action différenciés. Une méthodologie hybride - empruntant à la sociologie des organisations et à l'analyse des politiques publiques - vient clore le volet théorique, proposant par un détour métaphorique d'appréhender le projet urbain comme une pièce de théâtre dont le déroulement dépend du jeu d'acteurs.¦Cette méthodologie est utilisée dans le volet empirique de la recherche, qui consiste en une analyse de la MPO d'un projet urbain en cours dans la première couronne de l'agglomération lyonnaise : le Carré de Soie. Trois grands objectifs sont poursuivis : descriptif (reconstruire le scénario), analytique (évaluer la nature de la pièce : conte de fée, tragédie ou match d'improvisation ?) et prescriptif (tirer la morale de l'histoire). La description de la MPO montre le déploiement successif de quatre stratégies de pilotage, dont les implications sur les temporalités, le contenu du projet (programmes, morphologies) et les financements publics vont être déterminantes. Sur la base de l'analyse, plusieurs recommandations peuvent être formulées - importance de l'anticipation et de l'articulation entre planification et stratégie foncière notamment - pour permettre à la sphère publique de dominer le jeu et d'assurer la production de justice par le projet urbain (réalisation puis entretien des équipements et espaces publics, financement de logements de qualité à destination d'un large éventail de populations, etc.). Plus généralement, un décalage problématique peut être souligné entre les territoires stratégiques pour le développement de l'agglomération et les capacités de portage limitées des communes concernées. Ce déficit plaide pour le renforcement des capacités d'investissement de la structure intercommunale.¦La seule logique du marché (foncier, immobilier) mène à la polarisation sociale et à la production d'inégalités urbaines. Faire la ville juste nécessite une forte volonté des collectivités publiques, laquelle doit se traduire aussi bien dans l'ambition affichée - une juste hiérarchisation des priorités dans le développement urbain - que dans son opérationnalisation - une juste maîtrise publique d'ouvrage des projets urbains.¦Inner-city neighborhoods, poor outskirts, and peri-urban spaces with no amenities usually suffer from social and environmental inequalities, such as poverty, unemployment, and exposure to noise and industrial hazards. The observed persistence of these inequalities over time points to an underlying trend - namely, that access to proper living conditions is fundamentally unequal, thus eliciting the question of how such inequalities are effected and how this trend can be reversed so as to build a more equitable city.¦Providing answers to such questions requires that the causal factors at play within the system of (re)production of urban inequalities be identified. Real estate markets, "micromotives and macrobehavior", and public policies that bear on space are mostly involved. The latter are central in that they act on all the elements of the system. This thesis therefore focuses on the way public authorities shape the production of contemporary cities, by studying the public project ownership of major urban projects.¦The study of justice within the urban fabric also implies that the normative frames of reference of public action be questioned: what conception of justice should public action refer to? This thesis examines four perspectives (radical, substantialist, procedural, and integrative) each of which results in different principles of action. This theoretical part is concluded by a hybrid methodology that draws from sociology of organizations and public policy analysis and that suggests that the urban project may be understood as a play, whose outcome hinges on the actors' acting.¦This methodology is applied to the empirical analysis of the public project ownership of an ongoing urban project in the Lyon first-ring suburbs: the Carré de Soie. Three main objectives are pursued: descriptive (reconstructing the scenario), analytical (assessing the nature of the play - fairy tale, tragedy or improvisation match), and prescriptive (drawing the moral of the story). The description of the public project ownership shows the successive deployment of four control strategies, whose implications on deadlines, project content (programs, morphologies), and public funding are significant. Building on the analysis, several recommendations can be made to allow the public sphere to control the process and ensure the urban project produces equity (most notably, anticipation and articulation of planning and real- estate strategy, as well as provision and maintenance of equipment and public spaces, funding of quality housing for a wide range of populations, etc.). More generally, a gap can be highlighted between those territories that are strategic to the development of the agglomeration and the limited resources of the municipalities involved. This deficit calls for strengthening the investment abilities of the intermunicipal structure.¦By itself, the real-estate market logic brings about social polarization and urban inequalities. Building an equitable city requires a strong will on the part of public authorities, a will that must be reflected both in the stated ambition - setting priorities of urban development equitably - and in its implementation managing urban public projects fairly.

The hourglass and the early conservation models--co-existing patterns of developmental constraints in vertebrates.

Developmental constraints have been postulated to limit the space of feasible phenotypes and thus shape animal evolution. These constraints have been suggested to be the strongest during either early or mid-embryogenesis, which corresponds to the early conservation model or the hourglass model, respectively. Conflicting results have been reported, but in recent studies of animal transcriptomes the hourglass model has been favored. Studies usually report descriptive statistics calculated for all genes over all developmental time points. This introduces dependencies between the sets of compared genes and may lead to biased results. Here we overcome this problem using an alternative modular analysis. We used the Iterative Signature Algorithm to identify distinct modules of genes co-expressed specifically in consecutive stages of zebrafish development. We then performed a detailed comparison of several gene properties between modules, allowing for a less biased and more powerful analysis. Notably, our analysis corroborated the hourglass pattern at the regulatory level, with sequences of regulatory regions being most conserved for genes expressed in mid-development but not at the level of gene sequence, age, or expression, in contrast to some previous studies. The early conservation model was supported with gene duplication and birth that were the most rare for genes expressed in early development. Finally, for all gene properties, we observed the least conservation for genes expressed in late development or adult, consistent with both models. Overall, with the modular approach, we showed that different levels of molecular evolution follow different patterns of developmental constraints. Thus both models are valid, but with respect to different genomic features.

Comprehensive assessment of patients in palliative care: a descriptive study utilizing the INTERMED.

Documentation in palliative care is often restricted to medical and sociodemographic information, and the assessment of physical and psychological symptoms or the quality of life. In order to overcome the lack of comprehensive information, we have evaluated the utility of the INTERMED-a biopsychosocial assessment method to document integrated information of patients' needs-in 82 consecutive patients for whom a palliative care consultation was requested. Results confirm the biopsychosocial heterogeneity of the sample, and the importance of integrated information to clinical, scientific, educational, and health care policy agendas. The INTERMED could become a useful method to tailor interdisciplinary interventions based on comprehensive patient needs assessment.