External Validation of the Prestroke Independence, Sex, Age, National Institutes of Health Stroke Scale (ISAN) Score for Predicting Stroke-Associated Pneumonia in the Athens Stroke Registry.

BACKGROUND AND PURPOSE: The Prestroke Independence, Sex, Age, National Institutes of Health Stroke Scale (ISAN) score was developed recently for predicting stroke-associated pneumonia (SAP), one of the most common complications after stroke. The aim of the present study was to externally validate the ISAN score. METHODS: Data included in the Athens Stroke Registry between June 1992 and December 2011 were used for this analysis. Inclusion criteria were the availability of all ISAN score variables (prestroke independence, sex, age, National Institutes of Health Stroke Scale score). Receiver operating characteristic curves and linear regression analyses were used to determine the discriminatory power of the score and to assess the correlation between actual and predicted pneumonia in the study population. Separate analyses were performed for patients with acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH). RESULTS: The analysis included 3204 patients (AIS: 2732, ICH: 472). The ISAN score demonstrated excellent discrimination in patients with AIS (area under the curve [AUC]: .83 [95% confidence interval {CI}: .81-.85]). In the ICH group, the score was less effective (AUC: .69 [95% CI: .63-.74]). Higher-risk groups of ISAN score were associated with an increased relative risk of SAP; risk increase was more prominent in the AIS population. Predicted pneumonia correlated very well with actual pneumonia (AIS group: R(2) = .885; β-coefficient = .941, P < .001; ICH group: R(2) = .880, β-coefficient = .938, P < .001). CONCLUSIONS: In our external validation in the Athens Stroke Registry cohort, the ISAN score predicted SAP very accurately in AIS patients and demonstrated good discriminatory power in the ICH group. Further validation and assessment of clinical usefulness would strengthen the score's utility further.

Imaging the time-integrated cerebral metabolic activity with subcellular resolution through nanometer-scale detection of biosynthetic products deriving from (13)C-glucose.

Glucose is the primary source of energy for the brain but also an important source of building blocks for proteins, lipids, and nucleic acids. Little is known about the use of glucose for biosynthesis in tissues at the cellular level. We demonstrate that local cerebral metabolic activity can be mapped in mouse brain tissue by quantitatively imaging the biosynthetic products deriving from [U-(13)C]glucose metabolism using a combination of in situ electron microscopy and secondary ion mass-spectroscopy (NanoSIMS). Images of the (13)C-label incorporated into cerebral ultrastructure with ca. 100nm resolution allowed us to determine the timescale on which the metabolic products of glucose are incorporated into different cells, their sub-compartments and organelles. These were mapped in astrocytes and neurons in the different layers of the motor cortex. We see evidence for high metabolic activity in neurons via the nucleus (13)C enrichment. We observe that in all the major cell compartments, such as e.g. nucleus and Golgi apparatus, neurons incorporate substantially higher concentrations of (13)C-label than astrocytes.

Divergence with gene flow and fine-scale phylogeographical structure in the wedge-billed woodcreeper, Glyphorynchus spirurus, a Neotropical rainforest bird.

Determining the relative roles of vicariance and selection in restricting gene flow between populations is of central importance to the evolutionary process of population divergence and speciation. Here we use molecular and morphological data to contrast the effect of isolation (by mountains and geographical distance) with that of ecological factors (altitudinal gradients) in promoting differentiation in the wedge-billed woodcreeper, Glyphorynchus spirurus, a tropical forest bird, in Ecuador. Tarsus length and beak size increased relative to body size with altitude on both sides of the Andes, and were correlated with the amount of moss on tree trunks, suggesting the role of selection in driving adaptive divergence. In contrast, molecular data revealed a considerable degree of admixture along these altitudinal gradients, suggesting that adaptive divergence in morphological traits has occurred in the presence of gene flow. As suggested by mitochondrial DNA sequence data, the Andes act as a barrier to gene flow between ancient subspecific lineages. Genome-wide amplified fragment length polymorphism markers reflected more recent patterns of gene flow and revealed fine-scale patterns of population differentiation that were not detectable with mitochondrial DNA, including the differentiation of isolated coastal populations west of the Andes. Our results support the predominant role of geographical isolation in driving genetic differentiation in G. spirurus, yet suggest the role of selection in driving parallel morphological divergence along ecological gradients.

CSF biomarkers for the differential diagnosis of Alzheimer's disease: A large-scale international multicenter study.

INTRODUCTION: The aim of this study was to test the diagnostic value of cerebrospinal fluid (CSF) beta-amyloid (Aβ1-42), phosphorylated tau, and total tau (tau) to discriminate Alzheimer's disease (AD) dementia from other forms of dementia. METHODS: A total of 675 CSF samples collected at eight memory clinics were obtained from healthy controls, AD dementia, subjective memory impairment, mild cognitive impairment, vascular dementia, Lewy body dementia (LBD), fronto-temporal dementia (FTD), depression, or other neurological diseases. RESULTS: CSF Aβ1-42 showed the best diagnostic accuracy among the CSF biomarkers. At a sensitivity of 85%, the specificity to differentiate AD dementia against other diagnoses ranged from 42% (for LBD, 95% confidence interval or CI = 32-62) to 77% (for FTD, 95% CI = 62-90). DISCUSSION: CSF Aβ1-42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, possibly reflecting the underlying mixed pathologies.

MetaNetX/MNXref - reconciliation of metabolites and biochemical reactions to bring together genome-scale metabolic networks.

MetaNetX is a repository of genome-scale metabolic networks (GSMNs) and biochemical pathways from a number of major resources imported into a common namespace of chemical compounds, reactions, cellular compartments-namely MNXref-and proteins. The MetaNetX.org website (http://www.metanetx.org/) provides access to these integrated data as well as a variety of tools that allow users to import their own GSMNs, map them to the MNXref reconciliation, and manipulate, compare, analyze, simulate (using flux balance analysis) and export the resulting GSMNs. MNXref and MetaNetX are regularly updated and freely available.

The composition of airborne and grain-dust fungal communities is shaped at regional scale by plant genotypes and farming practices

Chronic exposure to airborne fungi has been associated with different respiratory symptoms and pathologies in occupational populations, such as grain workers. However, the homogeneity in the fungal species composition of these bioaerosols on a large geographical scale and the different drivers that shape these fungal communities remain unclear. In this study, the diversity of fungi in grain dust and in the aerosols released during harvesting was determined across 96 sites at a geographical scale of 560 km(2) along an elevation gradient of 500 m by tag-encoded 454-pyrosequencing of the internal transcribed spacer (ITS) sequences. Associations between the structure of fungal communities in the grain dust and different abiotic (farming system, soil characteristics, geographic and climatic parameters) and biotic (wheat cultivar, previous crop culture) factors were explored. These analyses revealed a strong relationship between the airborne and grain dust fungal communities and showed the presence of allergenic and mycotoxigenic species in most samples, which highlights the potential contribution of these fungal species to work-related respiratory symptoms of grain workers. The farming system was the major driver of the alpha and beta phylogenetic diversity of fungal communities. In addition, elevation and soil CaCO3 concentrations shaped the alpha diversity whereas wheat cultivar, cropping history and the number of freezing days per year shaped the taxonomic beta diversity of these communities.

GENETIC ARCHITECTURE, EVOLUTION AND MAINTENANCE OF A COLOR CLINE AT A CONTINENTAL SCALE

On a geological time scale the conditions on earth are very variable and biological patterns (for example the distributions of species) are very dynamic. Understanding large scale patterns of variation observed today thus requires a deep understanding of the historical factors that drove their evolution. In this thesis, we reevaluated the evolution and maintenance of a continental color cline observed in the European barn owl (Tyto alba) using population genetic tools. The colour cline spans from south-est Europe where most individual have pure white underparts to north and east Europe where most individuals have rufous-brown underparts. Our results globally showed that the old scenario, stipulating that the color cline evolved by secondary contact of two color morphs (white and rufous) that evolved in allopatry during the last ice age has to be revised. We collected samples of about 700 barn owls from the Western Palearctic to establish the first population genetic data set for this species. Individuals were genotyped at 22 microsatellites markers, at one mitochondrial gene, and at a candidate color gene. The color of each individuals was assessed and their sex determined by molecular methods. We first showed that the genetic variation in Western Europe is very limited compared to the heritable color variation. We found no evidences of different glacial lineages, and showed that selection must be involved in the maintenance of the color cline (chapter 1). Using computer simulations, we demonstrated that the post-glacial colonization of Europe occurred from the Iberian Peninsula and that the color cline could not have evolved by neutral demographic processes during this colonization (chapter 2). Finally we reevaluated the whole history of the establishment of the Western Palearctic variation of the barn owl (chapter 3): This study showed that all Western European barn owls descend from white barn owls phenotypes from the Middle East that colonized the Iberian Peninsula via North-Africa. Following the end of the last ice age (20'000 years ago), these white barn owls colonized Western Europe and under selection a novel rufous phenotype evolved (during or after the colonization). An important part of the color variation could be explained by a single mutation in the melanocortin-1-receptor (MC1R) gene that appeared during or after the colonization. The colonization of Europe reached until Greece, where the rufous birds encountered white ones (which reached Greece from the Middle East over the Bosporus) in a secondary contact zone. Our analyses show that white and rufous barn owls in Greece interbreed only to a limited extent. This suggests that barn owls are at the verge of becoming two species in Greece and demonstrates that European barn owls represent an incipient ring species around the Mediterranean. The revisited history of the establishment of the European barn owl color cline makes this model system remarkable for several aspects. It is a very clear example of strong local adaptation that can be achieved despite high gene flow (strong color and MC1R differentiation despite almost no neutral genetic differentiation). It also offers a wonderful model system to study the interactions between colonization processes and selection processes which have, for now, been remarkably understudied despite their potentially ubiquitous importance. Finally it represents a very interesting case in the speciation continuum and appeals for further studying the amount of gene flow that occurs between the color morphs in Greece. -- Sur l'échelle des temps géologiques, les conditions sur terre sont très variables et les patrons biologiques (telle que la distribution des espèces) sont très dynamiques. Si l'on veut comprendre des patrons que l'on peut observer à large échelle aujourd'hui, il est nécessaire de d'abord comprendre les facteurs historiques qui ont gouverné leur établissement. Dans cette thèse, nous allons réévaluer, grâce à des outils modernes de génétique des populations, l'évolution et la maintenance d'un cline de couleur continental observé chez l'effraie des clochers européenne (Tyto alba). Globalement, nos résultats montrent que le scenario accepté jusqu'à maintenant, qui stipule que le cline de couleur a évolué à partir du contact secondaire de deux morphes de couleur (blanches et rousses) ayant évolué en allopatrie durant les dernières glaciations, est à revoir. Afin de constituer le premier jeu de données de génétique des populations pour cette espèce, nous avons récolté des échantillons d'environ 700 effraies de l'ouest Paléarctique. Nous avons génotypé tous les individus à 22 loci microsatellites, sur un gène mitochondrial et sur un autre gène participant au déterminisme de la couleur. Nous avons aussi mesuré la couleur de tous les individus et déterminé leur sexe génétiquement. Nous avons tout d'abord pu montrer que la variation génétique neutre est négligeable en comparaison avec la variation héritable de couleur, qu'il n'existe qu'une seule lignée européenne et que de la sélection doit être impliquée dans le maintien du cline de couleur (chapitre 1). Grâce à des simulations informatiques, nous avons démontré que l'ensemble de l'Europe de l'ouest a été recolonisé depuis la Péninsule Ibérique après les dernières glaciations et que le cline de couleur ne peut pas avoir évolué par des processus neutre durant cette colonisation (chapitre 2). Finalement, nous avons réévalué l'ensemble de l'histoire postglaciaire de l'espèce dans l'ouest Paléarctique (chapitre 3): l'ensemble des effraies du Paléarctique descendent d'effraie claire du Moyen-Orient qui ont colonisé la péninsule ibérique en passant par l'Afrique du nord. Après la fin de la dernière glaciation (il y a 20'000 ans), ces effraies claires ont colonisé l'Europe de l'ouest et ont évolués par sélection le phénotype roux (durant ou après la colonisation). Une part importante de la variation de couleur peut être expliquée par une mutation sur le gène MC1R qui est apparue durant ou juste après la colonisation. Cette vague de colonisation s'est poursuivie jusqu'en Grèce où ces effraies rousses ont rencontré dans une zone de contact secondaire des effraies claires (qui sont remontées en Grèce depuis le Moyen-Orient via le Bosphore). Nos analyses montrent que le flux de gènes entre effraies blanches et rousses est limité en Grèce, ce qui suggère qu'elles sont en passe de former deux espèces et ce qui montre que les effraies constituent un exemple naissant de spéciation en anneaux autour de la Méditerranée. L'histoire revisitée des effraies des clochers de l'ouest Paléarctique en fait un système modèle remarquable pour plusieurs aspects. C'est un exemple très claire de forte adaptation locale maintenue malgré un fort flux de gènes (différenciation forte de couleur et sur le gène MC1R malgré presque aucune structure neutre). Il offre également un très bon système pour étudier l'interaction entre colonisation et sélection, un thème ayant été remarquablement peu étudié malgré son importance. Et il offre finalement un cas très intéressant dans le « continuum de spéciation » et il serait très intéressant d'étudier plus en détail l'importance du flux de gènes entre les morphes de couleur en Grèce.

Development and validation of a visual grading scale for assessing image quality of AP pelvis radiographic images.

OBJECTIVE: The aim of this article was to apply psychometric theory to develop and validate a visual grading scale for assessing the visual perception of digital image quality anteroposterior (AP) pelvis. METHODS: Psychometric theory was used to guide scale development. Seven phantom and seven cadaver images of visually and objectively predetermined quality were used to help assess scale reliability and validity. 151 volunteers scored phantom images, and 184 volunteers scored cadaver images. Factor analysis and Cronbach's alpha were used to assess scale validity and reliability. RESULTS: A 24-item scale was produced. Aggregated mean volunteer scores for each image correlated with the rank order of the visually and objectively predetermined image qualities. Scale items had good interitem correlation (≥0.2) and high factor loadings (≥0.3). Cronbach's alpha (reliability) revealed that the scale has acceptable levels of internal reliability for both phantom and cadaver images (α = 0.8 and 0.9, respectively). Factor analysis suggested that the scale is multidimensional (assessing multiple quality themes). CONCLUSION: This study represents the first full development and validation of a visual image quality scale using psychometric theory. It is likely that this scale will have clinical, training and research applications. ADVANCES IN KNOWLEDGE: This article presents data to create and validate visual grading scales for radiographic examinations. The visual grading scale, for AP pelvis examinations, can act as a validated tool for future research, teaching and clinical evaluations of image quality.

Complex patterns of global spread in invasive insects: eco-evolutionary and management consequences

The advent of simple and affordable tools for molecular identification of novel insect invaders and assessment of population diversity has changed the face of invasion biology in recent years. The widespread application of these tools has brought with it an emerging understanding that patterns in biogeography, introduction history and subsequent movement and spread of many invasive alien insects are far more complex than previously thought. We reviewed the literature and found that for a number of invasive insects, there is strong and growing evidence that multiple introductions, complex global movement, and population admixture in the invaded range are commonplace. Additionally, historical paradigms related to species and strain identities and origins of common invaders are in many cases being challenged. This has major consequences for our understanding of basic biology and ecology of invasive insects and impacts quarantine, management and biocontrol programs. In addition, we found that founder effects rarely limit fitness in invasive insects and may benefit populations (by purging harmful alleles or increasing additive genetic variance). Also, while phenotypic plasticity appears important post-establishment, genetic diversity in invasive insects is often higher than expected and increases over time via multiple introductions. Further, connectivity among disjunct regions of global invasive ranges is generally far higher than expected and is often asymmetric, with some populations contributing disproportionately to global spread. We argue that the role of connectivity in driving the ecology and evolution of introduced species with multiple invasive ranges has been historically underestimated and that such species are often best understood in a global context.

A matter of scale: apparent niche differentiation of diploid and tetraploid plants may depend on extent and grain of analysis

Aim: Emerging polyploids may depend on environmental niche shifts for successful establishment. Using the alpine plant Ranunculus kuepferi as a model system, we explore the niche shift hypothesis at different spatial resolutions and in contrasting parts of the species range. Location: European Alps. Methods: We sampled 12 individuals from each of 102 populations of R. kuepferi across the Alps, determined their ploidy levels, derived coarse-grain (100x100m) environmental descriptors for all sampling sites by downscaling WorldClim maps, and calculated fine-scale environmental descriptors (2x2m) from indicator values of the vegetation accompanying the sampled individuals. Both coarse and fine-scale variables were further computed for 8239 vegetation plots from across the Alps. Subsequently, we compared niche optima and breadths of diploid and tetraploid cytotypes by combining principal components analysis and kernel smoothing procedures. Comparisons were done separately for coarse and fine-grain data sets and for sympatric, allopatric and the total set of populations. Results: All comparisons indicate that the niches of the two cytotypes differ in optima and/or breadths, but results vary in important details. The whole-range analysis suggests differentiation along the temperature gradient to be most important. However, sympatric comparisons indicate that this climatic shift was not a direct response to competition with diploid ancestors. Moreover, fine-grained analyses demonstrate niche contraction of tetraploids, especially in the sympatric range, that goes undetected with coarse-grained data. Main conclusions: Although the niche optima of the two cytotypes differ, separation along ecological gradients was probably less decisive for polyploid establishment than a shift towards facultative apomixis, a particularly effective strategy to avoid minority cytotype exclusion. In addition, our results suggest that coarse-grained analyses overestimate niche breadths of widely distributed taxa. Niche comparison analyses should hence be conducted at environmental data resolutions appropriate for the organism and question under study.