BrainCheck - a very brief tool to detect incipient cognitive decline: optimized case-finding combining patient- and informant-based data.

INTRODUCTION: Optimal identification of subtle cognitive impairment in the primary care setting requires a very brief tool combining (a) patients' subjective impairments, (b) cognitive testing, and (c) information from informants. The present study developed a new, very quick and easily administered case-finding tool combining these assessments ('BrainCheck') and tested the feasibility and validity of this instrument in two independent studies. METHODS: We developed a case-finding tool comprised of patient-directed (a) questions about memory and depression and (b) clock drawing, and (c) the informant-directed 7-item version of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Feasibility study: 52 general practitioners rated the feasibility and acceptance of the patient-directed tool. Validation study: An independent group of 288 Memory Clinic patients (mean ± SD age = 76.6 ± 7.9, education = 12.0 ± 2.6; 53.8% female) with diagnoses of mild cognitive impairment (n = 80), probable Alzheimer's disease (n = 185), or major depression (n = 23) and 126 demographically matched, cognitively healthy volunteer participants (age = 75.2 ± 8.8, education = 12.5 ± 2.7; 40% female) partook. All patient and healthy control participants were administered the patient-directed tool, and informants of 113 patient and 70 healthy control participants completed the very short IQCODE. RESULTS: Feasibility study: General practitioners rated the patient-directed tool as highly feasible and acceptable. Validation study: A Classification and Regression Tree analysis generated an algorithm to categorize patient-directed data which resulted in a correct classification rate (CCR) of 81.2% (sensitivity = 83.0%, specificity = 79.4%). Critically, the CCR of the combined patient- and informant-directed instruments (BrainCheck) reached nearly 90% (that is 89.4%; sensitivity = 97.4%, specificity = 81.6%). CONCLUSION: A new and very brief instrument for general practitioners, 'BrainCheck', combined three sources of information deemed critical for effective case-finding (that is, patients' subject impairments, cognitive testing, informant information) and resulted in a nearly 90% CCR. Thus, it provides a very efficient and valid tool to aid general practitioners in deciding whether patients with suspected cognitive impairments should be further evaluated or not ('watchful waiting').

Liver, Gastrointestinal, and Cardiac Toxicity in Intermediate Hepatocellular Carcinoma Treated With PRECISION TACE With Drug-Eluting Beads: Results From the PRECISION V Randomized Trial.

OBJECTIVE. The purpose of our study was to evaluate hepatic, gastrointestinal, and cardiac toxicity after PRECISION transarterial chemoembolization (TACE) with drug-eluting beads (DEB) versus conventional TACE with doxorubicin in the treatment of intermediate-stage hepatocellular carcinoma (HCC).SUBJECTS AND METHODS. Two hundred twelve patients (185 men and 27 women; mean age, 67 years) were randomized to TACE with DEB or conventional TACE. The majority of patients (67% in both groups) presented in a more advanced stage. Safety was measured by rate of adverse events (Southwest Oncology Group criteria) and changes in laboratory parameters. Cardiotoxicity was assessed with left ventricular ejection fraction (LVEF) mainly on MRI or echocardiography.RESULTS. The mean maximum postchemoembolization alanine transaminase increase in the DEB group was 50% less than in the conventional TACE group (p < 0.001) and 41% less in respect to aspartate transaminase (p < 0.001). End-of-study values returned to approximately baseline levels but with greater variability in conventional TACE patients. Treatment-emergent adverse events in the hepatobiliary system organ class occurred in 16.1% of DEB group patients compared with 25% of conventional TACE patients. There were fewer liver toxicity events in the DEB group. There was a small but statistically significant difference in mean change from baseline in LVEF between the two groups of 4 percentage points for the conventional TACE group (95% CI, 0.71-7.3; p = 0.018).CONCLUSION. PRECISION TACE with DEB loaded with doxorubicin offers a safe therapy option for intermediate-stage HCC, even in patients with more advanced liver disease.

Phylogeny of shrews (Soricidae) : taxonomic and biogeographic implications

Résumé Les Soricidae sont l'une des plus grandes familles de mammifères avec plus de 300 espèces décrites. Elle a été récemment divisée en trois sous-familles, les Soricidae, qui sont distribuées dans la région Holarctique, les Crocidurinae en Afrique et en Eurasie, et les Myosoricinae en Afrique. La diversité spécifique de cette famille a conduit à des interprétations taxonomiques multiples, qui sont à l'origine de polémiques entre spécialistes, et même les premiers résultats moléculaires ont été fortement contradictoires. Le but de cette thèse est donc d'appliquer des meilleures techniques sur des échantillons mieux ciblés, afin de résoudre les contradictions taxonomiques et comprendre l'histoire de cette famille. Par le biais de marqueurs génétiques mitochondriaux et nucléaires, j'ai étudié: (i) Les relations taxonomiques à différent niveaux hiérarchiques au sein des Soricidae, c'est-à dire, entre les sous-familles, tribus, et genres, ainsi qu'au sein de deux complexes d'espèces largement distribués, et d'une espèce européenne, le but étant d'établir la congruence entre les données génétiques et les interprétations morphologiques classiques. (ii) Les relations biogéographiques, soit l'origine potentielle des différentes sous-familles, tribus, et genres, le nombre d'échanges intercontinentaux, ainsi que la structure phylogéographique à un niveau (péri)-spécifique, afin d'établir l'histoire de la diversification de cette famille. Les analyses combinées d'ADN mitochondrial et nucléaire ont montré un rapport clair entre les taxa à un niveau taxonomique élevé, mettant en évidence les rapports entre les sous-familles, les tribus, et les genres. Bien que Myosorex constitue un groupe monophylétique distinct, sa définition en tant que sous-famille séparée ne peut pas être reconnue. Ainsi, nous proposons d'attribuer un niveau de tribu pour ce clade (inclus dans les Crocidurinae). Nous avons également montré l'inclusion du genre Anourosorex dans les Soricinae et non en position basale dans les Soricidae. Au sein des Crocidurinae, Suncus s'est révélé être paraphylétique, et le genre Diplomesodon devrait être considéré d'un point de vue génétique comme invalide, puisque il se trouve au sein du clade du genre Crocidura. À un niveau taxonomique plus bas, nous avons montré la monophylie de deux complexes d'espèces largement distribués, le groupe de C. suaveolens et de C. olivieri. Néanmoins à l'intérieur de ceux-ci, des différences majeures avec la classification morphologique se sont révélées. Par exemples, C. sibirica n'est pas une espèce valide, les analyses de phylogénie moléculaire ne montrant pas de variations génétiques entre celle-ci et un échantillon de la localité type de C. suaveolens. D'un point de vue biogéographique, les fluctuations climatiques et les activités tectoniques des 20 derniers millions d'années ont fortement influencé la diversité actuelle des Soricidae. À un niveau taxonomique élevé, l'apparition de connexions de terre temporaires entre le Vieux et le Nouveau Monde au Miocène moyen ont mené à plusieurs colonisations indépendantes de l'Amérique par les Soricinae. Celles-ci ónt conduit à une diversification d'une tribu (Notiosoricini), ainsi que de genres (par ex: Cryptotis, Blarina) et d'un sous-genre (Otisorex) endémique au Néarctique. Dans le Vieux Monde, les barrières entre l'Afrique et Eurasie étaient plus perméables, menant à plusieurs échanges bidirectionnels de Crocidurinae. La diversification des clades principaux s'est produite au Miocène, certains clades étant endémiques d'Afrique ou d'Eurasie, tandis que d'autres se sont diversifiés à travers le Vieux Monde. À un niveau spécifique ou péri-spécifique, la fluctuation climatique du Pliocène et les glaciations du Pléistocène ont fortement divisé les populations dans tout le Paléarctique, menant à des entités génétiques distinctes. En Europe, les populations du groupe de C. suaveolens ont été divisées en une lignée Sud-Ouest et une Sud-Est, alors qu'au Proche-Orient et au Moyen-Orient, la diversité de clades est plus importante. En conclusion, mes études ont révélé que du Miocène à nos jours, la diversification des Soricidae a été provoquée par la colonisation de nouveaux habitats (dispersion), ainsi que par l'isolement des populations par diverses barrières (vicariance). Abstract The Soricidae is one of the largest mammalian families with more than 300 species described. It has been recently divided into three subfamilies, the Soricinae, which are distributed in the Holartic region, the Crocidurinae in Africa and Eurasia, and the Myosoricinae in Africa. The specific diversity of this family have led to multiple systematic interpretations and controversies between authors. Fortunately, today, cytotaxonomic, allozymic and molecular studies have permitted to clarify some uncertainties. Nevertheless, the Soricidae remains still poorly known. In this thesis, we aim at understanding with the use of mitochondrial and nuclear markers: (i) the taxonomic relationships at different hierarchical levels within Soricidae, i.e., between the subfamilies, tribes, and genera, as well as within two largely distributed species complexes, and within a European species, the goal being to establish congruence between the genetic data and traditional morphological interpretations; (ii) the biogeographic relationships, especially the potential origin of the different subfamilies, tribes, and genera, the number of transcontinental exchanges, as well as the phylogeographic structure at a (peri)-specific level, in order to establish the history of the genetic diversification of this family. The combined analyses of mitochondrial and nuclear DNA highlight for the first time a clear relationship between taxa at a high taxonomical level, permitting to distinguish the relationships between subfamilies, tribes, and genera. Although Myosorex formed a distinct monophyletic group, its definition as a distinct sub-family cannot be advocated. Thus, we propose to attribute a tribe level for this Glade (included within the Crocidurinae). Additionally, this combination of genes pleads in favour of the inclusion of the genus Anourosorex within the Soricinae and not in a basal position within the Soricidae. Within the Crocidurinae, Suncus appeared to be paraphyletic, and Diplomesodon should be considered from a genetic point of view as invalid, and is presently considered as Crocidura. At a lower taxonomic level, we showed the monophyly of two widely distributed species complexes, the C. suaveolens group and the C. olivieri group. Nevertheless within those, we showed major differences compared to morphological classification. For examples, C. sibirica revealed to not be a valid species, the molecular phylogenetic analyses failed to evidence genetical variations between it and samples of the type locality of C. suaveolens. In a biogeographic point of view, the climatic fluctuations and the tectonic plate activities of the last 20 Myr have strongly influenced the actual diversity of the family. At a high taxonomic level, the successive land bridge connections between the Old and the New World, which occurred during the Middle Miocene, have led to several independent colonisations of America by Soricinae, and a subsequent diversification of endemic Nearctic's tribe (Notiosoricini), genera (e.g. Cryptotis, Blaring) and sub-genus (Otisorex) within the Soricinae. Within the Old World, the barriers between Africa and Eurasia were more permeable, leading to several bidirectional exchanges within the Crocidurinae. The diversification of major clades occurred through the Miocene, some clades being endemic to Africa or Eurasia, whereas others diversified through the Old World. At a species level or a peri-specific level, the Pliocene climatic fluctuation and the Pleistocene glaciations have strongly divided the populations throughout the Palaearctic, leading to well defined genetic entities. In Europe, populations of the C. suaveolens group were split in a classical south-western and south-eastern lineage. In contrast, the Near East and the Middle East reveal many differentiated clades. In conclusion, our studies revealed that, from the Miocene to present, the diversification and speciation events within the Soricidae were caused by natural colonisation of new habitats (dispersion) and isolation of populations by various barriers (vicariance).

Role of ATH5 in the specification of retinal ganglion cells and expression and cell compartmentalization of EFEMP1, a protein associated with Malattia Leventinese

ABSTRACT : The development of the retina is a very complex process, occurring through the progressive restriction of cell fates, from pluripotent cell populations to complex tissues and organs. In all vertebrate species analyzed so far, retinal differentiation starts with the generation of retinal ganglion cells (RGC)s. One of the documented key essential events in the specification of RGCs is the expression of ATHS, an atonal homolog encoding a bHLH transcription factor. Despite the putative role of master regulator of RGC differentiation, the mechanism of integrating its functions into a coherent program underlying the production of this subclass of retinal neurons has not yet been elucidated. By using chromatin immunoprecipitation combined with microarray (ChIP-on-chip) we have screened for ATH5 direct targets in the developing chick retina at two consecutive periods: E3.5 (stage HH22) and E6 (stage HH30), covering the stages of progenitor proliferation, neuroepithelium patterning, RGC specification, cell cycle exit and early neuronal differentiation. In parallel, complementary analysis with Affymetrix expression microarrays was conducted. We compared RGCs versus retina to see if the targets correspond to genes preferentially expressed in RGCs. We also precociously overexpressed ATH5 in the retina of individual embryo, and contralateral retina vas used as a control. Our integrated approach allowed us to establish a compendium of ATH5-targets and enabled us to position ATH5 in the transcription network underlying neurogenesis in the retina. Malattia Leventinese (ML) is an autosomal, dominant retinal dystrophy characterized by extracellular, amorphous deposits known as drusen, between the retinal pigment epithelium (RPE) and Bruch's membrane. On the genetic level, it has been associated with a single missense mutation (R345W) in a widely expressed gene with unknown function called EFEMP1. We determined expression patterns of the EFEMP1 gene in normal and ML human retinas. Our data shown that the upregulation of EFEMP1 is not specific to ML eye, except for the region of the ciliary body. We also analyzed the cell compartmentalization of different versions of the protein (both wild type and mutant). Our studies indicate that both abnormal expression of the EFEMP1 gene and mutation and accumulation of EFEMP 1 protein (inside or outside the cells) might contribute to the ML pathology. Résumé : 1er partie : L'ontogenèse de la rétine est un processus complexe au cours duquel des cellules progénitrices sont engagée, par vagues successives, dans des lignées où elles vont d'abord être déterminées puis vont se différencier pour finalement construire un tissu rétinien composé de cinq classes de neurones (les photorécepteurs, les cellules horizontales, bipolaires, amacrines et ganglionnaires) et d'une seule de cellules gliales (les cellules de Muller). Chez tous les vertébrés, la neurogenèse rétinienne est d'abord marquée par la production des cellules ganglionnaires (RGCs). La production de cette classe de neurone est liée à l'expression du gène ATH5 qui est un homologue du gène atonal chez la Drosophile et qui code pour un facteur de transcription de la famille des protéines basic Helix-Loop-Helix (bHLH). Malgré le rôle central que joue ATH5 dans la production des RGCs, le mécanisme qui intègre la fonction de cette protéine dans le programme de détermination neuronale et ceci en relation avec le développement de la rétine n'est pas encore élucidé. Grâce à une technologie qui permet de combiner la sélection de fragments de chromatine liant ATH5 et la recherche de séquences grâce à des puces d'ADN non-codants (ChIP-on-chip), nous avons recherché des cibles potentielles de la protéine ATH5 dans la rétine en développement. Nous avons conduit cette recherche à deux stades de développement de manière à englober la phase de prolifération cellulaire, la détermination des RGCs, la sortie du cycle cellulaire ainsi que les premières étapes de la différentiation de ces neurones. Des expériences complémentaires nous ont permis de définir les patrons d'expression des gènes sélectionnés ainsi que l'activité promotrice des éléments de régulation identifiés lors de notre criblage. Ces approches expérimentales diverses et complémentaires nous ont permis de répertorier des gènes cibles de la protéine ATH5 et d'établir ainsi des liens fonctionnels entre des voies métaboliques dont nous ne soupçonnions pas jusqu'alors qu'elles puissent être associées à la production d'une classe de neurones centraux. 2ème partie : Malattia Leventinese (ML) est une maladie génétique qui engendre une dystrophie de la rétine. Elle se caractérise par l'accumulation de dépôt amorphe entre l'épithélium pigmentaire et la membrane de Bruch et connu sous le nom de drusen. Cette maladie est liée à une simple mutation non-sens (R345W) dans un gène dénommé EFEMP1 qui est exprimé dans de nombreux tissus mais dont la fonction reste mal définie. Une étude détaillée de l'expression de ce gène dans des rétines humaines a révélé une expression à un niveau élevé du gène EFEMP1 dans divers tissus de l'oeil ML mais également dans des yeux contrôles. Alors que l'accumulation d'ARN messager EFEMP1 dans les cellules de l'épithélium pigmentaire n'est pas spécifique à ML, l'expression de ce gène dans le corps cilié n'a été observée que dans l'oeil ML. Nous avons également comparé la sécrétion de la protéine sauvage avec celle porteuse de la mutation. En résumé, notre étude révèle que le niveau élevé d'expression du gène EFEMP1 ainsi que l'accumulation de la protéine dans certains compartiments cellulaires pourraient contribuer au développement de pathologies rétiniennes liées à ML.

Cancer mortality in Europe, 2000-2004, and an overview of trends since 1975.

BACKGROUND: To update the pattern of cancer mortality in Europe. Materials and methods: We analysed cancer mortality in 34 European countries during 2000-2004, with an overview of trends in 1975-2004 using data from the World Health Organization. RESULTS: From 1990-1994 to 2000-2004, overall cancer mortality in the European Union declined from 185.2 to 168.0/100 000 (world standard, -9%) in men and from 104.8 to 96.9 (-8%) in women, with larger falls in middle age. Total cancer mortality trends were favourable, though to a variable degree, in all major European countries, including Russia, but not in Romania. The major determinants of these favourable trends were the decline of lung (-16%) and other tobacco-related cancers in men, together with the persistent falls in gastric cancer, and the recent appreciable falls in colorectal cancer. In women, relevant contributions came from the persistent decline in cervical cancer and the recent falls in breast cancer mortality, particularly in northern and western Europe. Favourable trends were also observed for testicular cancer, Hodgkin lymphomas, leukaemias, and other neoplasms amenable to treatment, though the reductions were still appreciably smaller in eastern Europe. CONCLUSION: This updated analysis of cancer mortality in Europe showed a persistent favourable trend over the last years.

Common variants associated with plasma triglycerides and risk for coronary artery disease.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Late migration of percutaneous bio-absorbable devices--a word of caution.

BACKGROUND: Closures of atrial septal defects or a patent foramen ovale (PFO) are increasingly performed percutaneously. The experience of late migration of a new bio-absorbable device is presented here, followed by conceptual discussion. METHODS: Six months post PFO closure with a BioSTAR® device a patient presented with chest pain. Echocardiography showed a hyperechogenic structure perforating the aortic wall. RESULTS: Surgical exploration showed a perforation of the ascending aorta by one metallic, non absorbable arm. This is the second case of late (>6 months) dislocation of the residual framework of the occluder. CONCLUSIONS: The overall incidence of perforation of cardiac structures due to secondary dislocation is low. However this complication exists and should kept in mind in symptomatic patients with new onset of chest pain, after percutaneous procedures. The concept of biodegradation, with residual, non absorbable metal braiding, should be reviewed, analyzing in particular long term results and incidence of secondary dislocation.

Testing the predictive adaptive response in a host-parasite system

1. Harsh environmental conditions experienced during development can reduce the performance of the same individuals in adulthood. However, the 'predictive adaptive response' hypothesis postulates that if individuals adapt their phenotype during development to the environments where they are likely to live in the future, individuals exposed to harsh conditions in early life perform better when encountering the same harsh conditions in adulthood compared to those never exposed to these conditions before. 2. Using the common vole (Microtus arvalis) as study organism, we tested how exposure to flea parasitism during the juvenile stage affects the physiology (haematocrit, resistance to oxidative stress, resting metabolism, spleen mass, and testosterone), morphology (body mass, testis mass) and motor performance (open field activity and swimming speed) of the same individuals when infested with fleas in adulthood. According to the 'predictive adaptive response' hypothesis, we predicted that voles parasitized at the adult stage would perform better if they had already been parasitized with fleas at the juvenile stage. 3. We found that voles exposed to fleas in adulthood had a higher metabolic rate if already exposed to fleas when juvenile, compared to voles free of fleas when juvenile and voles free of fleas in adulthood. Independently of juvenile parasitism, adult parasitism impaired adult haematocrit and motor performances. Independently of adult parasitism, juvenile parasitism slowed down crawling speed in adult female voles. 4. Our results suggest that juvenile parasitism has long-term effects that do not protect from the detrimental effects of adult parasitism. On the contrary, experiencing parasitism in early-life incurs additional costs upon adult parasitism measured in terms of higher energy expenditure, rather than inducing an adaptive shift in the developmental trajectory. 5. Hence, our study provides experimental evidence for long term costs of parasitism. We found no support for a predictive adaptive response in this host-parasite system.

Marseille. Collection de copies et de documents originaux concernant l'histoire de Marseille. Collection Mortreuil sur Marseille vol. 12 : Corps religieux (Préfecture des Bouches du Rhône. Archives de l’église d’Arcoules, du monastère de Saint Sauveur et des Grands Trinitaires de Marseille. Actes antérieurs au XIV e siècle. A.M. 1855.)

Copie manuscrite de documents d’archives : F. 1-91. Archives de l’Eglise d’Arcoules de Marseille. F. 92-104. Augustins. F. 105-149. Archives des Dominicains (precheurs) de Marseille. F. 150-153. Abbaye de l’Huveaune, prémontrés. F. 154-178. Frères Mineurs. F. 179-180. La Major. F. 181 -184. St Carmat. F. 185-186. St Etienne des îles Ratoneau. F. 187-191. St Jacques de Corrégie. F. 192-193. St Laurent. F. 194-195. Prieuré de St Lazare. F. 196-199. St Martin F. 200-206. St Michel et St Etienne du Plan. F. 207 -379. Archives du monastère de Saint Sauveur de Marseille. F. 381-387. Sainte Claire. F. 388-391. N.D. de Syon. F. 392 459. Archives des Grands Trinitaires de Marseille.

Missale ad usum Sancti Cornelii Compendiensis.

Ex-libris "S. Cornelii Compend. Congr. S. Mauri", XVIIe s., f. 1. Compiègne.

[Recueil].

Capitulare ecclesiasticum (1-7v). - Capitula legibus addenda (7v-14v). - Capitula per se scibenda (14v-16v). - Capitulare missorum (16v-20). "Domine Deus omnipotens propitius est omni peccatori..." [Ajout du Xe s.] (20v). - Collectio capitularium Ansegisi (21-40v). - Lex salica (41-83v). Les cahiers des ff. 1-20 et 41-83 faisaient partie du même ms. Ils ont été copiés durant le second quart ou vers le milieu du IXe s., et sont signés de QI à QVI, tandis que les ff. 21-40v ont été copiés plus tardivement, durant la seconde moitié du IXe s. ou la première moitié du Xe s. Les ff. 44-45 ont été rajoutés pour compléter une lacune du texte, mentionnée au f. 43v par une main du XIVe s.: "hic deficiunt II° folia". La portion manquante du texte a été recopiée par deux mains différentes, du XVIIe s. Les mss. lat. 18237 et 18238 ont été consultés par Etienne Baluze (1630-1718), bibliothécaire de Colbert et canoniste, pour son édition des Capitularia regum francorum."