Concept of fat balance in human obesity revisited with particular reference to de novo lipogenesis.

The measurement of fat balance (fat input minus fat output) involves the accurate estimation of both metabolizable fat intake and total fat oxidation. This is possible mostly under laboratory conditions and not yet in free-living conditions. In the latter situation, net fat retention/mobilization can be estimated based on precise and accurate sequential body composition measurements. In case of positive balance, lipids stored in adipose tissue can originate from dietary (exogenous) lipids or from nonlipid precursors, mainly from carbohydrates (CHOs) but also from ethanol, through a process known as de novo lipogenesis (DNL). Basic equations are provided in this review to facilitate the interpretation of the different subcomponents of fat balance (endogenous vs exogenous) under different nutritional circumstances. One difficulty is methodological: total DNL is difficult to measure quantitatively in man; for example, indirect calorimetry only tracks net DNL, not total DNL. Although the numerous factors (mostly exogenous) influencing DNL have been studied, in particular the effect of CHO overfeeding, there is little information on the rate of DNL in habitual conditions of life, that is, large day-to-day fluctuations of CHO intakes, different types of CHO ingested with different glycemic indexes, alcohol combined with excess CHO intakes, etc. Three issues, which are still controversial today, will be addressed: (1) Is the increase of fat mass induced by CHO overfeeding explained by DNL only, or by decreased endogenous fat oxidation, or both? (2) Is DNL different in overweight and obese individuals as compared to their lean counterparts? (3) Does DNL occur both in the liver and in adipose tissue? Recent studies have demonstrated that acute CHO overfeeding influences adipose tissue lipogenic gene expression and that CHO may stimulate DNL in skeletal muscles, at least in vitro. The role of DNL and its importance in health and disease remain to be further clarified, in particular the putative effect of DNL on the control of energy intake and energy expenditure, as well as the occurrence of DNL in other tissues (such as in myocytes) in addition to hepatocytes and adipocytes.

La douleur prolongée chez le nouveau-né: étude de cas [Prolonged pain in neonates: retrospective analysis].

INTRODUCTION: infants hospitalised in neonatology are inevitably exposed to pain repeatedly. Premature infants are particularly vulnerable, because they are hypersensitive to pain and demonstrate diminished behavioural responses to pain. They are therefore at risk of developing short and long-term complications if pain remains untreated. CONTEXT: compared to acute pain, there is limited evidence in the literature on prolonged pain in infants. However, the prevalence is reported between 20 and 40 %. OBJECTIVE : this single case study aimed to identify the bio-contextual characteristics of neonates who experienced prolonged pain. METHODS : this study was carried out in the neonatal unit of a tertiary referral centre in Western Switzerland. A retrospective data analysis of seven infants' profile, who experienced prolonged pain ,was performed using five different data sources. RESULTS : the mean gestational age of the seven infants was 32weeks. The main diagnosis included prematurity and respiratory distress syndrome. The total observations (N=55) showed that the participants had in average 21.8 (SD 6.9) painful procedures that were estimated to be of moderate to severe intensity each day. Out of the 164 recorded pain scores (2.9 pain assessment/day/infant), 14.6 % confirmed acute pain. Out of those experiencing acute pain, analgesia was given in 16.6 % of them and 79.1 % received no analgesia. CONCLUSION: this study highlighted the difficulty in managing pain in neonates who are exposed to numerous painful procedures. Pain in this population remains underevaluated and as a result undertreated.Results of this study showed that nursing documentation related to pain assessment is not systematic.Regular assessment and documentation of acute and prolonged pain are recommended. This could be achieved with clear guidelines on the Assessment Intervention Reassessment (AIR) cyclewith validated measures adapted to neonates. The adequacy of pain assessment is a pre-requisite for appropriate pain relief in neonates.

Are Simple Signatures So Easy to Simulate?

Is it possible to perfectly simulate a signature, in the particular and challenging case where the signature is simple? A set of signatures of six writers, considered to be simple on the basis of highlighted criteria, was sampled. These signatures were transferred to forgers requested to produce freehand simulations. Among these simulations, those capable of reproducing the features of the reference signatures were submitted for evaluation to forensic document experts through proficiency testing. The results suggest that there is no perfect simulation. With the supplementary aim of assessing the influence of forger's skills on the results, forgers were selected from three distinct populations, which differ according to professional criteria. The results indicate some differences in graphical capabilities between individuals. However, no trend could be established regarding age, degrees, years of practice and time dedicated to the exercise. The findings show that simulation is made easier if a graphical compatibility exists between the forger's own writing and the signature to be reproduced. Moreover, a global difficulty to preserve proportions and slant as well as the shape of capital letters and initials has been noticed.

The diagnosis of chronic inflammatory demyelinating polyneuropathy: a Delphi-method approach.

The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) is based on a set of clinical and neurophysiological parameters. However, in clinical practice, CIDP remains difficult to diagnose in atypical cases. In the present study, 32 experts from 22 centers (the French CIDP study group) were asked individually to score four typical, and seven atypical, CIDP observations (TOs and AOs, respectively) reported by other physicians, according to the Delphi method. The diagnoses of CIDP were confirmed by the group in 96.9 % of the TO and 60.1 % of the AO (p < 0.0001). There was a positive correlation between the consensus of CIDP diagnosis and the demyelinating features (r = 0.82, p < 0.004). The European CIDP classification was used in 28.3 % of the TOs and 18.2 % of the AOs (p < 0.002). The French CIDP study group diagnostic strategy was used in 90 % of the TOs and 61 % of the AOs (p < 0.0001). In 3 % of the TOs and 21.6 % of the AOs, the experts had difficulty determining a final diagnosis due to a lack of information. This study shows that a set of criteria and a diagnostic strategy are not sufficient to reach a consensus for the diagnosis of atypical CIDP in clinical practice.

Energy gap in the aetiology of body weight gain and obesity: a challenging concept with a complex evaluation and pitfalls.

The concept of energy gap(s) is useful for understanding the consequence of a small daily, weekly, or monthly positive energy balance and the inconspicuous shift in weight gain ultimately leading to overweight and obesity. Energy gap is a dynamic concept: an initial positive energy gap incurred via an increase in energy intake (or a decrease in physical activity) is not constant, may fade out with time if the initial conditions are maintained, and depends on the 'efficiency' with which the readjustment of the energy imbalance gap occurs with time. The metabolic response to an energy imbalance gap and the magnitude of the energy gap(s) can be estimated by at least two methods, i.e. i) assessment by longitudinal overfeeding studies, imposing (by design) an initial positive energy imbalance gap; ii) retrospective assessment based on epidemiological surveys, whereby the accumulated endogenous energy storage per unit of time is calculated from the change in body weight and body composition. In order to illustrate the difficulty of accurately assessing an energy gap we have used, as an illustrative example, a recent epidemiological study which tracked changes in total energy intake (estimated by gross food availability) and body weight over 3 decades in the US, combined with total energy expenditure prediction from body weight using doubly labelled water data. At the population level, the study attempted to assess the cause of the energy gap purported to be entirely due to increased food intake. Based on an estimate of change in energy intake judged to be more reliable (i.e. in the same study population) and together with calculations of simple energetic indices, our analysis suggests that conclusions about the fundamental causes of obesity development in a population (excess intake vs. low physical activity or both) is clouded by a high level of uncertainty.

Sexualité des adolescents: epidémiologie, approche clinique et stratégies préventives [Adolescent sexuality: epidemiology, clinical approach and preventive measures].

The interest in sexuality of adolescents in medical practice is often mainly focussed on the onset of sexual intercourse and on the emergence of contraceptive needs, though the beginning of adolescence takes place much earlier with the first signs of puberty followed by the menarche. At the issue of this profound metamorphosis the adolescent needs to adapt herself to a modified, sexual body. Adolescence is also a time of identity development and of changes in relationships, which are influenced by gender role in family and perception related to gender during childhood. This article shows epidemiological data to consider and the main issues of gynaecologic consultation with the adolescent. The different stages of development depend on biological and environmental factors which either favour resilience or weaken the individual due to a lack of affection or to abusive relationships. Medical consultation for a gynaecological problem, questions on puberty and development or on contraception give medical professionals and especially gynaecologists a chance to address sexual issues naturally, to anticipate questions as well as contraceptive needs. The consultation with the adolescent includes also the screening for behaviour related to a lack of information or a personal or relational difficulty.

Gériatrie [Review in geriatric medicine].

In 2010, a study emphasizes the difficulty to predict disability trajectories in the last year of life. A meta analysis shows the effectiveness of post-acute geriatric rehabilitation in reducing functional decline after hospitalisation. Several studies evaluated pneumococcal and herpes zoster vaccines' efficacy. A short and simple intervention is effective in reducing benzodiazepine use. The effect of vitamine D on falls and fractures has been further evaluated in several studies. Diagnostic criteria for dementias, including Alzheimer's disease, are moving to better acknowledge their preclinical stages.

Mesozoic oceanic terranes of southern Central America : geology, geochemistry and gedynamics

Abstract The Northwestern edge of the modern Caribbean Plate, located in central Middle America (S-Guatemala to N-Costa Rica), is characterized by a puzzle of oceanic and continental terranes that belonged originally to the Pacific façade of North America. South of the Motagua Fault Zone, the actual northern strike slip boundary of the Caribbean Plate, three continental slivers (Copán, Chortis s. str. and Patuca) are sandwiched between two complex suture zones that contain HP/LT mafic and ultramafic oceanic rocks: The Motagua Mélanges to the North, extensively studied in the last ten years and the' newly defined Mesquito Composite Oceanic Terrane (MCOT) to the South. No modem geological data were available for the oceanic terrane located in the southern part of the so called continental "Chortis Block". Classically, the southern limit of this block with the Caribbean Large Igneous Province (CLIP) was placed at a hypothetical fault line connecting the main E-W fault in the Santa Elena Peninsula (N-Costa Rica) with the Hess Escarpment. However, our study in eastern Nicaragua and northwestern Costa Rica evidences an extensive assemblage of oceanic upper mantle and crustal rocks outcropping between the Chortis/Patuca continental blocks and the CLIP. They comprise collided and accreted exotic terranes of Pacific origin recording a polyphased tectonic history. We distinguish: 1- The MCOT that comprises a Late Triassic to Early Cretaceous puzzle of oceanic crust and arc-derived rocks set in a serpentinite matrix, and 2- The Manzanillo and Nicoya Terranes that are made of Cretaceous plateau-like rocks associated with oceanic sediments older than the CLIP. This study has been focused on the rocks of the MCOT. The MCOT comprises the southern half of the former "Chortis Block" and is defined by 4 comer localities characterized by ultramafic and mafic oceanic rocks of Late Triassic, Jurassic and Early Cretaceous age: 1- The Siuna Serpentinite Mélange (NE-Nicaragua), 2- The El Castillo Mélange (Nicaragua/Costa Rica border), 3- DSDP Legs 67 and 84 (Guatemala fore-arc basin), and 4- The Santa Elena Peridiotite (NW-Costa Rica). The Siuna Serpentinite Mélange (SSM) is a HP/LT subduction zone mélange set in a serpentinite matrix that contains oceanic crust and arc-related greenschist to blueschist/eclogite facies metamafic and metasedimentary blocks. Middle Jurassic (Bajocian-Bathonian) radiolarites are found in original sedimentary contact with arc-derived greenstones. Late Jurassic black detrital chert possibly formed in a marginal (fore-arc?) basin shortly before subduction. A phengite 40Ar/39Ar -cooling age dates the exhumation of the high pressure rocks as 139 Ma. The El Castillo Mélange (ECM) is composed of serpentinite matrix with OIB metabasalts and Late Triassic (Rhaetian) red and green radiolarite blocks. Recent studies of the DSDP Legs 67/84 show that the Guatemala/Nicaragua fore-arc basin is composed of a pile of ultramafic, mafic (OIB-like) and arc related rocks with ages ranging from Late Triassic to Campanian. Finally, the Santa Elena peridiotites that mark the limit of the MCOT with the Manzanillo/Nicoya Terranes and correspond to an association of ultramafic rocks that comprise peridiotites, dunites and chromites of abyssal and fore-arc origin. The SSM is the result of a collision between a Middle Jurassic island arc and the Patuca Terrane, a fragment of the Western N-American active continental margin. The Siuna Mélange (SSM) and the South Montagna Mélange share common characteristics with the Pacific N-American suture zone (E-Franciscan and Vizcaino mélanges), in particular, the Mesozoic ages of HP/LT metamorphic and the arc-derived blocks. For us, these mélanges imply an originally continuous, but slightly diachronous suture that affected the entire W-American active margin. It may imply the arrival and collision of an exotic intraoceanic arc (Guerrero-Phoenix) related to the origin of the Pacific Plate that initiated as a back arc basin of this arc. The present disposition of the fragments of this suture zone is the result of a northward shift of the active left-lateral strike slip motion between the N-American and the Caribbean Plates. Résumé Le coin nord-ouest de la Plaque Caraïbe moderne se trouve en Amérique Centrale, entre le sud du Guatemala et le nord du Costa Rica. Cette région est composée d'un puzzle de terrains océaniques et continentaux dont les origines se situent sur la façade pacifique de l'Amérique du Nord. Au sud de la faille de Motagua, la limite septentrionale actuelle, décrochante, de la Plaque Caraïbe, se trouvent 3 copeaux continentaux (Copàn, Chortis s. str. et Patuca) coincés entre deux zones de suture complexes à roches mafiques et ultramafiques qui ont subi un métamorphisme de haute pression/basse température (HP/LT). Il s'agit des Mélanges de Motagua au nord, largement étudiés ces dernières années, et du Mesquito Composite Oceanic Terrane (MCOT), récemment défini par nous, au sud. En vue de l'absence de données géologiques modernes concernant les terrains océaniques qui se trouvent dans la partie sud du "Chortis Block" considérée comme continentale, nous avons dédié cette étude à cette région. Classiquement, la limite méridionale entre le "Chortis Block" et la "Caribbean Large Igneous Province" (CLIP) a été associée à une faille hypothétique reliant la faille E-W de Santa Elena (nord du Costa Rica) à l'Escarpement de Hess. Notre étude au Nicaragua oriental et au Costa Rica nord-occidental a révélé l'existence de larges terrains composés d'assemblages de roches mantéliques et océaniques qui se placent entre les blocs continentaux Chortis/Patuca et le CLIP. Ces assemblages révèlent des terrains collisionnés et accrétés d'origine pacifique enregistrant une histoire tectonique polyphasée. Nous distinguons: 1- Le MCOT, un puzzle de roches océaniques d'arc d'âge Triassique supérieur au Crétacée inférieur, 2- Les terrains de Manzanillo et de Nicoya, des morceaux de plateaux océaniques associés à des sédiments océaniques plus âgés que le CLIP. Cette étude se focalisera sur les roches du MCOT. Le MCOT occupe la moitié sud de l'ancien "Chortis Block" et peut se définir par 4 localités de référence qui montrent des roches mafiques et ultramafiques océaniques d'âges compris entre le Trias supérieur et le Crétacée inférieur. 1- Le Siuna Serpentinite Mélange (NE-Nicaragua), 2- Le El Castillo Mélange (Nicaragua/Costa Rica border), 3- Le DSDP Legs 67/84 (Guatemala fore-arc basin) et 4- La Santa Elena Peridiotite (nord-ouest du Costa Rica). Le Siuna Serpentinite Mélange (SSM) est un mélange de subduction HP/BT dans une matrice de serpentinite. On y trouve des éléments de croûte océanique et d'arc insulaire en faciès de schistes verts et schistes bleus. Des radiolarites du Jurassique moyen se trouvent en contact sédimentaire sur des roches vertes d'arc. En revanche, des cherts noirs détritiques datent du Jurassique supérieur et sont probablement issus d'un bassin marginal (fore-arc ?) peu avant leur subduction, car un âge 40Ar/39Ar de refroidissement des phengites date l'exhumation des roches de haute pression à 139 Ma. Le Mélange d'El Castillo (ECM) est constitué d'une matrice serpentinitique et contient des blocs de metabasaltes OIB et des blocs de radiolarites du Trias terminal. Des études récentes ont repris les roches forées lors des DSDP Legs 67 et 84 et montrent que le soubassement du bassin d'avant-arc du Guatemala-Nicaragua est composé de roches ultramafiques et mafiques (OIB et arc), dont les âges isotopiques vont du Trias au Crétacé supérieur. Finalement, les péridiotites de Santa Elena forment la limite sud du MCOT par rapport aux terrains de Manzanillo et Nicoya. Elles contiennent des serpentinites et localement des dunites et chromites à affinité abyssale et de fore-arc. Le SSM témoigne d'une collision entre un arc insulaire d'âge Jurassique moyen et le Patuca Terrane, un fragment de la marge active nord-américaine. Le SSM et le South Motagua Mélange ont des caractéristiques en commun avec les zones de suture de la façade pacifique de l'Amérique du nord (E-Franciscan et Vizcaino mélanges), notamment les âges Mésozoïques du métamorphisme HP/BT et les blocs de roches d'arc. Ce fait nous conduit à penser qu'il s'agit d'une grande zone de suture qui était à l'origine continue sur toute la marge ouest-américaine, mais légèrement diachrone. Cette suture implique l'arrivée et la collision d'un arc intraocéanique exotique (Guerrero-Phoenix) qui est à l'origine de la Plaque Pacifique qui s'ouvrait en back arc par rapport à celui-ci. La disposition actuelle des fragments de cette suture est due à la migration vers le nord du décrochement actif senestre entre la Plaque nord-américaine et la Plaque Caraïbe. K. Flores, 2009 Mesozoic oceanic terranes of southern central America Résumé Grand Public La présente thèse est le résultat de travaux de terrain effectués de 2005 à 2008 au nord-est et au sud du Nicaragua et au nord du Costa Rica, en Amérique Centrale, des analyses pétrologiques et géochimiques en laboratoire ainsi que de la modélisation de l'évolution géodynamique. La région étudiée se situe en bordure nord - ouest de la Plaque Caraïbe moderne. Dans la majorité des publications récentes cette région est représentée comme un vaste bloc continental (le "Bloc Chortis") qui serait limité, (i) au nord, par la faille décrochante de Motagua, la limite actuelle entre la Plaque Nord-Américaine et la Plaque Caraïbe, et (ii) au sud, par une suture hypothétique qui se trouverait aux confins entre le Nicaragua et le Costa Rica. La région du Costa Rica a été considérée presque entièrement comme une partie du Plateau Caraïbe ("Caribbean Large Igneous Province" (CLIP)). L'étude détaillée des affleurements nous a permis de mettre en évidence : - Au nord-est du Nicaragua (Siuna) : Des roches océaniques datées du Jurassique moyen, grâce aux faunes à radiolaires qui ont été extraites des radiolarites rouges. Ces roches ont subi un métamorphisme de haute pression typique des zones de collision. L'étude radio-isotopique Ar/Ar a permis de dater la collision du Crétacé basal (139 Ma). - Au sud du Nicaragua : Des roches océaniques d'âge Trias terminal (200 millions d'années), également datées à l'aide de faunes à radiolaires. Il s'agit actuellement des roches océaniques les plus anciennes connues de l'Amérique Centrale. - L'étude géochimique et les âges des fossiles démontrent que le tiers septentrional du Costa Rica possède un soubassement construit d'au moins deux terrains (Nicoya et Manzanillo), qui ont des caractéristiques de Plateau océanique (Nicoya) et d'arc volcanique du Crétacé moyen (Manzanillo). Ces deux terrains sont plus anciens que le CLIP. En conclusion, nous constatons que la région étudiée est constituée d'un puzzle de 3 blocs continentaux et d'un vaste terrain océanique composite que nous appelons Mesquito Composite Oceanic Terrane (MCOT). En plus, nous définissons les terrains de Nicoya et de Manzanillo comme plus âgés et distincts du CLIP. Le MCOT est caractérisé par la présence de roches du manteau supérieur (les serpentinites) et de la croûte océanique, ainsi que des morceaux d'arcs, d'âge allant du Trias supérieur au Crétacé. Ce terrain est comparable à d'autres zones de suture de la façade pacifique de l'Amérique du nord, notamment en ce qui concerne les âges Mésozoïques, le métamorphisme de haute pression et l'association de roches mantéliques et crustales océaniques. Ce fait nous conduit à penser qu'il s'agit d'une grande zone de suture qui était à l'origine continue sur toute la marge ouest-américaine. Cette suture implique l'arrivée et la collision d'un arc infra-océanique exotique qui serait à l'origine de la Plaque Pacifique qui se serait ouverte en bassin d'arrière arc par rapport à celui-ci. La disposition actuelle des fragments de cette suture est due à la migration vers le nord du décrochement actif senestre entre la Plaque nord-américaine et la Plaque Caraïbe.

Ophthalmic features of PLA2G6-related paediatric neurodegeneration with brain iron accumulation.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) refers to genetically heterogenous paediatric neurodegenerative disorders characterised by basal ganglia iron deposition. One major cause is recessive mutations in the PLA2G6 gene. While strabismus and optic nerve pallor have been reported for PLA2G6-related disease, the ophthalmic phenotype is not carefully defined. In this study we characterise the ophthalmic phenotype of PLA2G6-related NBIA. METHODS: Prospective cohort study. RESULTS: The eight patients were 4-26 years old when examined. All had progressive cognitive and motor regression first noted between 9 months and 6 years of age that typically first manifested as difficulty walking (ataxia). Ophthalmic examination was sometimes limited by cognitive ability. Four of eight had exotropia, 7/7 bilateral supraduction defect, 5/7 poor convergence, 6/8 saccadic pursuit, 4/8 saccadic intrusions that resembled square-wave jerks, and 8/8 bilateral optic nerve head pallor. All patients lacked Bell phenomenon. CONCLUSIONS: Upgaze palsy, although not a previously reported finding, was confirmed in all patients (except in one for whom assessment could not be performed) and thus can be considered part of the phenotype in children and young adults. Other frequent findings not previously highlighted were abnormal convergence, saccadic pursuit, and saccadic intrusions. Optic nerve head pallor and strabismus, previously reported findings in the disease, were found in 100% and 50% of our cohort, respectively, and the strabismus in our series was always exotropia. Taken together, these clinical findings may be helpful in distinguishing PLA2G6-related neurodegeneration from the other major cause of NBIA, recessive PANK2 mutations.

European Integration Without EU Membership : Models, Experiences, Perspectives

At the beginning of the 1990s, the concept of "European integration" could still be said to be fairly unambiguous. Nowadays, it has become plural and complex almost to the point of unintelligibility. This is due, of course, to the internal differentiation of EU membership, with several Member States pulling out of key integrative projects such as establishing an area without frontiers, the "Schengen" area, and a common currency. But this is also due to the differentiated extension of key integrative projects to European non-EU countries - Schengen is again a case in point. Such processes of "integration without membership", the focus of the present publication, are acquiring an ever-growing topicality both in the political arena and in academia. International relations between the EU and its neighbouring countries are crucial for both, and their development through new agreements features prominently on the continent's political agenda. Over and above this aspect, the dissemination of EU values and standards beyond the Union's borders raises a whole host of theoretical and methodological questions, unsettling in some cases traditional conceptions of the autonomy and separation of national legal orders. This publication brings together the papers presented at the Integration without EU Membership workshop held in May 2008 at the EUI (Max Weber Programme and Department of Law). It aims to compare different models and experiences of integration between the EU, on the one hand, and those European countries that do not currently have an accession perspective on the other hand. In delimiting the geographical scope of the inquiry, so as to scale it down to manageable proportions, the guiding principles have been to include both the "Eastern" and "Western" neighbours of the EU, and to examine both structured frameworks of cooperation, such as the European Neighbourhood Policy and the European Economic Area, and bilateral relations developing on a more ad hoc basis. These principles are reflected in the arrangement of the papers, which consider in turn the positions of Ukraine, Russia, Norway, and Switzerland in European integration - current standing, perspectives for evolution, consequences in terms of the EU-ization of their respective legal orders1. These subjects are examined from several perspectives. We had the privilege of receiving contributions from leading practitioners and scholars from the countries concerned, from EU highranking officials, from prominent specialists in EU external relations law, and from young and talented researchers. We wish to thank them all here for their invaluable insights. We are moreover deeply indebted to Marise Cremona (EUI, Law Department, EUI) for her inspiring advice and encouragement, as well as to Ramon Marimon, Karin Tilmans, Lotte Holm, Alyson Price and Susan Garvin (Max Weber Programme, EUI) for their unflinching support throughout this project. A word is perhaps needed on the propriety and usefulness of the research concept embodied in this publication. Does it make sense to compare the integration models and experiences of countries as different as Norway, Russia, Switzerland, and Ukraine? Needless to say, this list of four evokes a staggering diversity of political, social, cultural, and economic conditions, and at least as great a diversity of approaches to European integration. Still, we would argue that such diversity only makes comparisons more meaningful. Indeed, while the particularities and idiosyncratic elements of each "model" of integration are fully displayed in the present volume, common themes and preoccupations run through the pages of every contribution: the difficulty in conceptualizing the finalité and essence of integration, which is evident in the EU today but which is greatly amplified for non-EU countries; the asymmetries and tradeoffs between integration and autonomy that are inherent in any attempt to participate in European integration from outside; the alteration of deeply seated legal concepts, and concepts about the law, that are already observable in the most integrated of the non-EU countries concerned. These issues are not transient or coincidental: they are inextricably bound up with the integration of non-EU countries in the EU project. By publishing this collection, we make no claim to have dealt with them in an exhaustive, still less in a definitive manner. Our ambition is more modest: to highlight the relevance of these themes, to place them more firmly on the scientific agenda, and to provide a stimulating basis for future research and reflection.

Prematurity, maternal stress and mother-child interactions.

OBJECTIVE: Previous studies have shown that premature birth and the immaturity of the child can affect the quality of the parent-child relationship. The present study examines the relationship between maternal and infant interactional behavior over time and infant perinatal risk factors as well as maternal perinatal recollected traumatic experience. Few studies have explored the relationship between maternal stress and the quality of parent-infant interaction. DESIGN: Mother-child interaction was recorded at 6 and 18 months of infant's age, in a population of 47 preterm infants (GA<34 weeks) and 25 full-term infants, born in 1998, during a play interaction. According to the Care Index, sensitivity, control and unresponsiveness have been used to code maternal interactional characteristics, and cooperation, compliance-compulsiveness, difficulty and passivity have been used to code the infant's interactional characteristics. The level of maternal stress was evaluated with the Perinatal Posttraumatic Stress Disorder Questionnaire (PPQ), and the infant's perinatal risk factors were assessed with the Perinatal Risk Inventory (PERI). RESULTS: Mothers of high-risk infants, as well as mothers that had experienced traumatic stress in the perinatal period, were less sensitive and more controlling at 6 months. The interactional behavior of the preterm infant was different from that of the full-term infant at 18 months of age, and was correlated with maternal traumatic stress but not with perinatal risk factors. CONCLUSION: These results underline the importance of maternal traumatic experience related to premature birth and its potential long lasting influence on mother-child interactional behavior.

A PiggyBac-mediated approach for muscle gene transfer or cell therapy.

An emerging therapeutic approach for Duchenne muscular dystrophy is the transplantation of autologous myogenic progenitor cells genetically modified to express dystrophin. The use of this approach is challenged by the difficulty in maintaining these cells ex vivo while keeping their myogenic potential, and ensuring sufficient transgene expression following their transplantation and myogenic differentiation in vivo. We investigated the use of the piggyBac transposon system to achieve stable gene expression when transferred to cultured mesoangioblasts and into murine muscles. Without selection, up to 8% of the mesoangioblasts expressed the transgene from 1 to 2 genomic copies of the piggyBac vector. Integration occurred mostly in intergenic genomic DNA and transgene expression was stable in vitro. Intramuscular transplantation of mouse Tibialis anterior muscles with mesoangioblasts containing the transposon led to sustained myofiber GFP expression in vivo. In contrast, the direct electroporation of the transposon-donor plasmids in the mouse Tibialis muscles in vivo did not lead to sustained transgene expression despite molecular evidence of piggyBac transposition in vivo. Together these findings provide a proof-of-principle that piggyBac transposon may be considered for mesoangioblast cell-based therapies of muscular dystrophies.

Tapping the innovation potential of corporate engagement with stakeholders

Summary This dissertation explores how stakeholder dialogue influences corporate processes, and speculates about the potential of this phenomenon - particularly with actors, like non-governmental organizations (NGOs) and other representatives of civil society, which have received growing attention against a backdrop of increasing globalisation and which have often been cast in an adversarial light by firms - as a source of teaming and a spark for innovation in the firm. The study is set within the context of the introduction of genetically-modified organisms (GMOs) in Europe. Its significance lies in the fact that scientific developments and new technologies are being generated at an unprecedented rate in an era where civil society is becoming more informed, more reflexive, and more active in facilitating or blocking such new developments, which could have the potential to trigger widespread changes in economies, attitudes, and lifestyles, and address global problems like poverty, hunger, climate change, and environmental degradation. In the 1990s, companies using biotechnology to develop and offer novel products began to experience increasing pressure from civil society to disclose information about the risks associated with the use of biotechnology and GMOs, in particular. Although no harmful effects for humans or the environment have been factually demonstrated even to date (2008), this technology remains highly-contested and its introduction in Europe catalysed major companies to invest significant financial and human resources in stakeholder dialogue. A relatively new phenomenon at the time, with little theoretical backing, dialogue was seen to reflect a move towards greater engagement with stakeholders, commonly defined as those "individuals or groups with which. business interacts who have a 'stake', or vested interest in the firm" (Carroll, 1993:22) with whom firms are seen to be inextricably embedded (Andriof & Waddock, 2002). Regarding the organisation of this dissertation, Chapter 1 (Introduction) describes the context of the study, elaborates its significance for academics and business practitioners as an empirical work embedded in a sector at the heart of the debate on corporate social responsibility (CSR). Chapter 2 (Literature Review) traces the roots and evolution of CSR, drawing on Stakeholder Theory, Institutional Theory, Resource Dependence Theory, and Organisational Learning to establish what has already been developed in the literature regarding the stakeholder concept, motivations for engagement with stakeholders, the corporate response to external constituencies, and outcomes for the firm in terms of organisational learning and change. I used this review of the literature to guide my inquiry and to develop the key constructs through which I viewed the empirical data that was gathered. In this respect, concepts related to how the firm views itself (as a victim, follower, leader), how stakeholders are viewed (as a source of pressure and/or threat; as an asset: current and future), corporate responses (in the form of buffering, bridging, boundary redefinition), and types of organisational teaming (single-loop, double-loop, triple-loop) and change (first order, second order, third order) were particularly important in building the key constructs of the conceptual model that emerged from the analysis of the data. Chapter 3 (Methodology) describes the methodology that was used to conduct the study, affirms the appropriateness of the case study method in addressing the research question, and describes the procedures for collecting and analysing the data. Data collection took place in two phases -extending from August 1999 to October 2000, and from May to December 2001, which functioned as `snapshots' in time of the three companies under study. The data was systematically analysed and coded using ATLAS/ti, a qualitative data analysis tool, which enabled me to sort, organise, and reduce the data into a manageable form. Chapter 4 (Data Analysis) contains the three cases that were developed (anonymised as Pioneer, Helvetica, and Viking). Each case is presented in its entirety (constituting a `within case' analysis), followed by a 'cross-case' analysis, backed up by extensive verbatim evidence. Chapter 5 presents the research findings, outlines the study's limitations, describes managerial implications, and offers suggestions for where more research could elaborate the conceptual model developed through this study, as well as suggestions for additional research in areas where managerial implications were outlined. References and Appendices are included at the end. This dissertation results in the construction and description of a conceptual model, grounded in the empirical data and tied to existing literature, which portrays a set of elements and relationships deemed important for understanding the impact of stakeholder engagement for firms in terms of organisational learning and change. This model suggests that corporate perceptions about the nature of stakeholder influence the perceived value of stakeholder contributions. When stakeholders are primarily viewed as a source of pressure or threat, firms tend to adopt a reactive/defensive posture in an effort to manage stakeholders and protect the firm from sources of outside pressure -behaviour consistent with Resource Dependence Theory, which suggests that firms try to get control over extemal threats by focussing on the relevant stakeholders on whom they depend for critical resources, and try to reverse the control potentially exerted by extemal constituencies by trying to influence and manipulate these valuable stakeholders. In situations where stakeholders are viewed as a current strategic asset, firms tend to adopt a proactive/offensive posture in an effort to tap stakeholder contributions and connect the organisation to its environment - behaviour consistent with Institutional Theory, which suggests that firms try to ensure the continuing license to operate by internalising external expectations. In instances where stakeholders are viewed as a source of future value, firms tend to adopt an interactive/innovative posture in an effort to reduce or widen the embedded system and bring stakeholders into systems of innovation and feedback -behaviour consistent with the literature on Organisational Learning, which suggests that firms can learn how to optimize their performance as they develop systems and structures that are more adaptable and responsive to change The conceptual model moreover suggests that the perceived value of stakeholder contribution drives corporate aims for engagement, which can be usefully categorised as dialogue intentions spanning a continuum running from low-level to high-level to very-high level. This study suggests that activities aimed at disarming critical stakeholders (`manipulation') providing guidance and correcting misinformation (`education'), being transparent about corporate activities and policies (`information'), alleviating stakeholder concerns (`placation'), and accessing stakeholder opinion ('consultation') represent low-level dialogue intentions and are experienced by stakeholders as asymmetrical, persuasive, compliance-gaining activities that are not in line with `true' dialogue. This study also finds evidence that activities aimed at redistributing power ('partnership'), involving stakeholders in internal corporate processes (`participation'), and demonstrating corporate responsibility (`stewardship') reflect high-level dialogue intentions. This study additionally finds evidence that building and sustaining high-quality, trusted relationships which can meaningfully influence organisational policies incline a firm towards the type of interactive, proactive processes that underpin the development of sustainable corporate strategies. Dialogue intentions are related to type of corporate response: low-level intentions can lead to buffering strategies; high-level intentions can underpin bridging strategies; very high-level intentions can incline a firm towards boundary redefinition. The nature of corporate response (which encapsulates a firm's posture towards stakeholders, demonstrated by the level of dialogue intention and the firm's strategy for dealing with stakeholders) favours the type of learning and change experienced by the organisation. This study indicates that buffering strategies, where the firm attempts to protect itself against external influences and cant' out its existing strategy, typically lead to single-loop learning, whereby the firm teams how to perform better within its existing paradigm and at most, improves the performance of the established system - an outcome associated with first-order change. Bridging responses, where the firm adapts organisational activities to meet external expectations, typically leads a firm to acquire new behavioural capacities characteristic of double-loop learning, whereby insights and understanding are uncovered that are fundamentally different from existing knowledge and where stakeholders are brought into problem-solving conversations that enable them to influence corporate decision-making to address shortcomings in the system - an outcome associated with second-order change. Boundary redefinition suggests that the firm engages in triple-loop learning, where the firm changes relations with stakeholders in profound ways, considers problems from a whole-system perspective, examining the deep structures that sustain the system, producing innovation to address chronic problems and develop new opportunities - an outcome associated with third-order change. This study supports earlier theoretical and empirical studies {e.g. Weick's (1979, 1985) work on self-enactment; Maitlis & Lawrence's (2007) and Maitlis' (2005) work and Weick et al's (2005) work on sensegiving and sensemaking in organisations; Brickson's (2005, 2007) and Scott & Lane's (2000) work on organisational identity orientation}, which indicate that corporate self-perception is a key underlying factor driving the dynamics of organisational teaming and change. Such theorizing has important implications for managerial practice; namely, that a company which perceives itself as a 'victim' may be highly inclined to view stakeholders as a source of negative influence, and would therefore be potentially unable to benefit from the positive influence of engagement. Such a selfperception can blind the firm from seeing stakeholders in a more positive, contributing light, which suggests that such firms may not be inclined to embrace external sources of innovation and teaming, as they are focussed on protecting the firm against disturbing environmental influences (through buffering), and remain more likely to perform better within an existing paradigm (single-loop teaming). By contrast, a company that perceives itself as a 'leader' may be highly inclined to view stakeholders as a source of positive influence. On the downside, such a firm might have difficulty distinguishing when stakeholder contributions are less pertinent as it is deliberately more open to elements in operating environment (including stakeholders) as potential sources of learning and change, as the firm is oriented towards creating space for fundamental change (through boundary redefinition), opening issues to entirely new ways of thinking and addressing issues from whole-system perspective. A significant implication of this study is that potentially only those companies who see themselves as a leader are ultimately able to tap the innovation potential of stakeholder dialogue.

Exploring the implementation of a medication adherence programme by community pharmacists: a qualitative study

BACKGROUND: Medication adherence has been identified as an important factor for clinical success. Twenty-four Swiss community pharmacists participated in the implementation of an adherence support programme for patients with hypertension, diabetes mellitus and/or dyslipidemia. The programme combined tailored consultations with patients about medication taking (expected at an average of one intervention per month) and the delivery of each drug in an electronic monitoring system (MEMS6?). OBJECTIVE: To explore pharmacists' perceptions and experiences with implementation of the medication adherence programme and to clarify why only seven patients were enrolled in total. SETTING: Community pharmacies in French-speaking Switzerland. METHOD: Individual in-depth interviews were audio-recorded, with 20 of the pharmacists who participated in the adherence programme. These were transcribed verbatim, coded and thematically analysed. Process quality was ensured by using an audit trail detailing the development of codes and themes; furthermore, each step in the coding and analysis was verified by a second, experienced qualitative researcher. MAIN OUTCOME MEASURE: Community pharmacists' experiences and perceptions of the determining factors influencing the implementation of the adherence programme. RESULTS: Four major barriers were identified: (1) poor communication with patients resulting in insufficient promotion of the programme; (2) insufficient collaboration with physicians; (3) difficulty in integrating the programme into pharmacy organisation; and (4) insufficient pharmacist motivation. This was related to the remuneration perceived as insufficient and to the absence of clear strategic thinking about the pharmacist position in the health care system. One major facilitator of the programme's implementation was pre-existing collaboration with physicians. CONCLUSION: A wide range of barriers was identified. The implementation of medication adherence programmes in Swiss community pharmacies would benefit from an extended training aimed at developing communication and change management skills. Individualised onsite support addressing relevant barriers would also be necessary throughout the implementation process.

The Same, but Different: Central Banks, Regulatory Agencies, and the Politics of Delegation to Independent Authorities

Independent regulatory agencies are the institutional foundations of the regulatory state that, during the past 15 years, has gained prominence throughout Europe. This article studies the rise of independent authorities in European countries by comparing regulatory agencies and central banks. Delegation to independent central banks and to independent regulatory agencies is similar in many respects. In both cases, agents are deliberately made independent from political principals through a specific institutional design. Moreover, it has been argued that delegation to both central banks and regulatory agencies is linked to the need for policy-makers to improve the credibility of policy commitments, to the wish of incumbent politicians to tie the hands of future majorities, and to the extent to which the institutional contexts safeguard policy stability. Through an analysis of the formal independence of central banks and regulatory agencies in Western Europe, this article identifies an empirical puzzle that casts doubts on the accuracy of current explanations. Veto players and the uncertainty of incumbent policy-makers in respect to their re-election prospects matter for delegation to both central banks and regulatory agencies, but in opposite ways. Making sense of these anomalies is necessary to achieve a better understanding of delegation to independent authorities.