Reliability of panel-based guidelines for colonoscopy: an international comparison.

BACKGROUND: This study examined the reliability of explicit guidelines developed using the RAND-UCLA appropriateness method. METHODS: The appropriateness of over 400 indications for colonoscopy was rated by two multispecialty expert panels (United States and Switzerland). A nine-point scale was used, which was consolidated into three categories of appropriateness: appropriate, uncertain, inappropriate. The distribution of appropriateness ratings between the two panels and the intrapanel and interpanel agreement for categories of appropriateness were calculated for all possible indications. Similar statistics were calculated for a series of 577 primary care patients referred for colonoscopy in Switzerland. RESULTS: Over 80% of all indications (348) could be directly compared. The proportions of indications classified as appropriate, uncertain, or inappropriate were 28.4%, 24.7%, 46.6% and 33.0%, 23.0%, 44.0% for the U.S. and the Swiss panels, respectively. Interpanel agreement was excellent for all the possible indications (kappa value: 0.75) and lower for actual cases (kappa value: 0.51) because of lower agreement for the most frequently encountered indications. CONCLUSIONS: Good agreement between the two sets of criteria was found, pointing to the reliability of the method. Partial disagreement occurred essentially for a few, albeit frequently encountered, indications for use of colonoscopy in cases of uncomplicated lower abdominal pain or constipation.

Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study.

BACKGROUND: The quality of colon cleansing is a major determinant of quality of colonoscopy. To our knowledge, the impact of bowel preparation on the quality of colonoscopy has not been assessed prospectively in a large multicenter study. Therefore, this study assessed the factors that determine colon-cleansing quality and the impact of cleansing quality on the technical performance and diagnostic yield of colonoscopy. METHODS: Twenty-one centers from 11 countries participated in this prospective observational study. Colon-cleansing quality was assessed on a 5-point scale and was categorized on 3 levels. The clinical indication for colonoscopy, diagnoses, and technical parameters related to colonoscopy were recorded. RESULTS: A total of 5832 patients were included in the study (48.7% men, mean age 57.6 [15.9] years). Cleansing quality was lower in elderly patients and in patients in the hospital. Procedures in poorly prepared patients were longer, more difficult, and more often incomplete. The detection of polyps of any size depended on cleansing quality: odds ratio (OR) 1.73: 95% confidence interval (CI)[1.28, 2.36] for intermediate-quality compared with low-quality preparation; and OR 1.46: 95% CI[1.11, 1.93] for high-quality compared with low-quality preparation. For polyps >10 mm in size, corresponding ORs were 1.0 for low-quality cleansing, OR 1.83: 95% CI[1.11, 3.05] for intermediate-quality cleansing, and OR 1.72: 95% CI[1.11, 2.67] for high-quality cleansing. Cancers were not detected less frequently in the case of poor preparation. CONCLUSIONS: Cleansing quality critically determines quality, difficulty, speed, and completeness of colonoscopy, and is lower in hospitalized patients and patients with higher levels of comorbid conditions. The proportion of patients who undergo polypectomy increases with higher cleansing quality, whereas colon cancer detection does not seem to critically depend on the quality of bowel preparation.

Quantitative estimation of foot-flat and stance phase of gait using foot-worn inertial sensors.

Time periods composing stance phase of gait can be clinically meaningful parameters to reveal differences between normal and pathological gait. This study aimed, first, to describe a novel method for detecting stance and inner-stance temporal events based on foot-worn inertial sensors; second, to extract and validate relevant metrics from those events; and third, to investigate their suitability as clinical outcome for gait evaluations. 42 subjects including healthy subjects and patients before and after surgical treatments for ankle osteoarthritis performed 50-m walking trials while wearing foot-worn inertial sensors and pressure insoles as a reference system. Several hypotheses were evaluated to detect heel-strike, toe-strike, heel-off, and toe-off based on kinematic features. Detected events were compared with the reference system on 3193 gait cycles and showed good accuracy and precision. Absolute and relative stance periods, namely loading response, foot-flat, and push-off were then estimated, validated, and compared statistically between populations. Besides significant differences observed in stance duration, the analysis revealed differing tendencies with notably a shorter foot-flat in healthy subjects. The result indicated which features in inertial sensors' signals should be preferred for detecting precisely and accurately temporal events against a reference standard. The system is suitable for clinical evaluations and provides temporal analysis of gait beyond the common swing/stance decomposition, through a quantitative estimation of inner-stance phases such as foot-flat.

Petrography and geochemistry of accreted oceanic fragments below the Western Cordillera of Ecuador

The Western Cordillera of Ecuador consists of Cretaceous crustal fragments of oceanic plateaux and superimposed insular arcs, which were accreted to the northwestern South American margin during the Late Cretaceous and Paleocene. Slices of high-grade metabasites, ultramafic rocks, gabbros and basalts, unmetamorphosed radiolarian cherts and scarce garnet-bearing metasediments were randomly exhumed along Miocene to Recent transcurrent faults crosscutting the Western Cordillera. The basalts show geochemical characteristics of oceanic plateau basalts (flat REE patterns, La/Nb = 0.85). The gabbros differ from the basalts in having lower REE levels, positive Eu anomalies, and negative Nb and Ta anomalies; they are interpreted as resulting from arc magmatism. The amphibolites and banded amphibolites have major and trace element chemistry similar to that of oceanic plateau basalts (flat REE patterns, La/Nb = 0.86) or to cumulate gabbros. The granulite shares with oceanic plateaus similar trace element chemistry (flat REE patterns, La/Nb < 1) and epsilon(Ndi) values (+7.6). Continent-derived metasediments are depleted in heavy REE (La/Y = 4.8) and have a negative Eu anomaly. Foliated Iherzolites, melagabbronorites and pyroxenites consist of serpentinized olivine + cpx + opx +/- Ca-plagioclase. Lherzolites, melagabbronorites and pyroxenites are LREE depleted with positive Eu anomalies, while the harzburgite displays a U-shaped REE pattern. The trace element abundances of the ultramafic rocks are very low (0.1 to 1 times the chonctritic and primitive mantle values). The ultramafic rocks represent fragments of depleted mantle, deformed cpx-rich cumulate, and continental lithospheric mantle or mantle contaminated by subduction-fluid. Except the scarce quartz-rich metasediments, all these rocks likely represent remnants of accreted oceanic crustal fragments and associated depleted mantle. Since these samples were randomly sampled at depth by the fault, we propose that the Western Cordillera and its crustal root are mainly of oceanic nature.

Molecular evolution of the Drosophila olfactory system

The olfactory system is an attractive model to study the genetic mechanisms underlying evolution of the nervous system. This sensory system mediates the detection and behavioural responses to an enormous diversity of volatile chemicals in the environment and displays rapid evolution, as species acquire, modify and discard olfactory receptors and circuits to adapt to new olfactory stimuli. Drosophilids provide an attractive model to study these processes. The availability of 12 sequenced genomes of Drosophila species occupying diverse ecological niches provides a rich resource for genomic analyses. Moreover, one of these species, Drosophila melanogaster, is amenable to a powerful combination of genetic and electrophysiological analyses. D. melanogaster has two distinct families of olfactory receptors to detect odours, the well-characterised Odorant Receptors (ORs) and the recently identified lonotropic Receptors (IRs). In my thesis, I have provided new insights into the genetic mechanisms underlying olfactory system evolution through three distinct, but interrelated projects. First, I performed a comparative genomic analysis of the IR repertoire in 12 sequenced Drosophila species, which has revealed that the olfactory IRs are highly conserved across species. By contrast, a large fraction of IRs that are not expressed in the olfactory system - and which may be gustatory receptors - are much more variable in sequence and gene copy number. Second, to identify ligands for IR expressing olfactory sensory neurons, I have performed an electrophysiological screen in D. melanogaster using a panel of over 160 odours. I found that the IRs respond to a number of amines, aldehydes and acids, contrasting with the chemical specificity of the OR repertoire, which is mainly tuned to esters, alcohols and ketones. Finally, the identification of ligands for IRs in this species allowed me to investigate in detail the molecular and functional evolution of a tandem array of IRs, IR75a/IR75b/IR75c, in D. sechellia. This species is endemic to the Seychelles archipelago and highly specialised to breed on the fruits of Morinda citrifolia, which is repulsive and toxic for other Drosophila species. These studies led me to discover that receptor loss, changes in receptor specificity and changes in receptor expression have likely played an important role during the evolution of these IRs in D. sechellia. These changes may explain, in part, the unique chemical ecology of this species. - Le système olfactif est un excellent modèle pour étudier les mécanismes génétiques impliqués dans l'étude de l'évolution du système nerveux. Ce système sensoriel permet la détection de nombreux composés volatils présents dans l'environnement et est à la base des réponses comportementales. Il est propre à chaque espèce et évolue rapidement en modifiant ou en éliminant des récepteurs et leurs circuits olfactifs correspondants pour s'adapter à de nouvelles odeurs. Pour étudier le système olfactif et son évolution, nous avons décidé d'utiliser la drosophile comme modèle. Le séquençage complet de 12 souches de drosophiles habitant différentes niches écologiques permet une analyse génomique conséquente. De plus, l'une de ces espèces Drosophila melanogaster permet la combinaison d'analyses génétiques et électrophysiologiques. En effet, D. melanogaster possède 2 familles distinctes de récepteurs olfactifs qui permettent la détection d'odeurs: les récepteurs olfactifs (ORs) étant les mieux caractérisés et les récepteurs ionotropiques (IRs), plus récemment identifiés. Au cours de ma thèse, j'ai apporté des nouvelles connaissances qui m'ont permis de mieux comprendre les mécanismes génétiques à la base de l'évolution du système olfactif au travers de trois projets différents, mais interdépendants. Premièrement, j'ai réalisé une analyse génomique comparative de l'ensemble des IRs dans les 12 souches de drosophiles séquencées jusqu'à présent. Ceci a montré que les récepteurs olfactifs IRs sont hautement conservés parmi l'ensemble de ces espèces. Au contraire, une grande partie des IRs qui ne sont pas exprimés dans le système olfactif, et qui semblent être des récepteurs gustatifs, sont beaucoup plus variables dans leur séquence et dans le nombre de copie de gènes. Deuxièmement, pour identifier les ligands des récepteurs IRs exprimés par les neurones sensoriels olfactifs, j'ai réalisé une étude électrophysiologique chez D. melanogaster e η testant l'effet de plus de 160 composés chimiques sur les IRs. J'ai trouvé que les IRs répondent à un nombre d'amines, d'aldéhydes et d'acides, contrairement aux récepteurs olfactifs ORs qui eux répondent principalement aux esthers, alcools et cétones. Finalement, l'identification de ligands pour les IRs dans ces espèces m'a permis d'étudier en détail l'évolution fonctionnelle et moléculaire des IR75a/IR75b/IR75c dans D. sechellia. Cette espèce est endémique de l'archipel des Seychelles et se nourrit spécifiquement du fruit Morinda citrifolia qui est répulsif et toxique pour d'autres souches de drosophiles. Ces études m'ont poussé à découvrir que, la perte de IR75a, le changement dans la spécificité de IR75b ainsi que le changement dans l'expression de IR75c ont probablement joué un rôle important dans l'évolution des IRs chez D. sechellia. Ces changements peuvent expliquer, en partie, l'écologie chimique propre à cette espèce. Résumé français large public Le système olfactif permet aux animaux de détecter des milliers de molécules odorantes, les aidant ainsi à trouver de la nourriture, à distinguer si elle est fraîche ou avariée, à trouver des partenaires sexuels, ainsi qu'à éviter les prédateurs. Selon l'environnement et le mode de vie des espèces, le système olfactif doit détecter des odeurs très diverses ; en effet, un moustique qui recherche du sang humain pour se nourrir doit détecter des odeurs bien différentes d'une abeille qui recherche des fleurs. Dans ma thèse, j'ai essayé de comprendre comment les systèmes olfactifs d'une espèce évoluent pour s'adapter aux exigences induites par son environnement. Un très bon modèle pour étudier cela est la drosophile dont les différentes espèces se nichent dans des habitats très divers. Pour ce faire, j'ai étudié les récepteurs olfactifs de différentes espèces de la drosophile. Ces récepteurs sont des protéines qui se lient à des odeurs spécifiques. Lorsqu'ils se lient, ils activent un neurone qui envoie un signal électrique au cerveau. Ce signal est ensuite traité par ce dernier qui indique à la mouche si l'odeur est attractive ou répulsive. J'ai identifié les récepteurs olfactifs de plusieurs espèces de drosophile et étudié s'il y avait des différences entre elles. La plupart des récepteurs sont similaires entre les espèces, cependant dans l'une d'entre elles, certains récepteurs sont différents. Ce fait est particulièrement intéressant car cette espèce de drosophile se nourrit de fruits que les autres espèces n'apprécient pas. Comme nous ne savons pas quels récepteurs se lient à quelles odeurs, j'ai testé un grand nombre de composants odorants. Ceci m'a permis de constater que, effectivement, certains changements produits dans ces récepteurs expliquent pourquoi cette espèce aime particulièrement ces fruits. En outre, mes résultats contribuent à mieux comprendre les changements génétiques qui sont impliqués dans l'évolution du système olfactif.

A receptor-like kinase mutant with absent endodermal diffusion barrier displays selective nutrient homeostasis defects.

The endodermis represents the main barrier to extracellular diffusion in plant roots, and it is central to current models of plant nutrient uptake. Despite this, little is known about the genes setting up this endodermal barrier. In this study, we report the identification and characterization of a strong barrier mutant, schengen3 (sgn3). We observe a surprising ability of the mutant to maintain nutrient homeostasis, but demonstrate a major defect in maintaining sufficient levels of the macronutrient potassium. We show that SGN3/GASSHO1 is a receptor-like kinase that is necessary for localizing CASPARIAN STRIP DOMAIN PROTEINS (CASPs)--major players of endodermal differentiation--into an uninterrupted, ring-like domain. SGN3 appears to localize into a broader band, embedding growing CASP microdomains. The discovery of SGN3 strongly advances our ability to interrogate mechanisms of plant nutrient homeostasis and provides a novel actor for localized microdomain formation at the endodermal plasma membrane.

Biases of the ordinary least squares and instrumental variables estimators of the intergenerational earnings elasticity : revisited in the light of panel data

The OLS estimator of the intergenerational earnings correlation is biased towards zero, while the instrumental variables estimator is biased upwards. The first of these results arises because of measurement error, while the latter rests on the presumption that the education of the parent family is an invalid instrument. We propose a panel data framework for quantifying the asymptotic biases of these estimators, as well as a mis-specification test for the IV estimator. [Author]

Performance of panel-based criteria to evaluate the appropriateness of colonoscopy: a prospective study.

BACKGROUND: Prospective data describing the appropriateness of use of colonoscopy based on detailed panel-based clinical criteria are not available. METHODS: In a cohort of 553 consecutive patients referred for colonoscopy to two university-based Swiss outpatient clinics, the percentage of patients who underwent colonoscopy for appropriate, equivocal, and inappropriate indications and the relationship between appropriateness of use and the presence of relevant endoscopic lesions was prospectively assessed. This assessment was based on criteria of the American Society for Gastrointestinal Endoscopy and explicit American and Swiss criteria developed in 1994 by a formal panel process using the RAND/UCLA appropriateness method. RESULTS: The procedures were rated appropriate or equivocal in 72.2% by criteria of the American Society for Gastrointestinal Endoscopy, in 68.5% by explicit American criteria, and in 74.4% by explicit Swiss criteria (not statistically significant, NS). Inappropriate use (overuse) of colonoscopy was found in 27.8%, 31.5%, and 25.6%, respectively (NS). The proportion of appropriate procedures was higher with increasing age. Almost all reasons for using colonoscopy could be assessed by the two explicit criteria sets, whereas 28.4% of reasons for using colonoscopy could not be evaluated by the criteria of the American Society for Gastrointestinal Endoscopy (p < 0.0001). The probability of finding a relevant endoscopic lesion was distinctly higher in the procedures rated appropriate or equivocal than in procedures judged inappropriate. CONCLUSIONS: The rate of inappropriate use of colonoscopy is substantial in Switzerland. Explicit criteria allow assessment of almost all indications encountered in clinical practice. In this study, all sets of appropriateness criteria significantly enhanced the probability of finding a relevant endoscopic lesion during colonoscopy.

A natural structural variant of the mouse TCR beta-chain displays intrinsic receptor function and antigen specificity.

The Cbeta0 alternate cassette exon is located between the Jbeta1 and Cbeta1 genes in the mouse TCR beta-locus. In T cells with a VDJbeta1 rearrangement, the Cbeta0 exon may be included in TCRbeta transcripts (herein called TCRbeta-Cbeta0 transcripts), potentially inserting an additional 24 aa between the V and C domains of the TCR beta-chain. These TCRbeta splice isoforms may be differentially regulated after Ag activation, because we detected TCRbeta-Cbeta0 transcripts in a high proportion (>60%) of immature and mature T cells having VDJbeta1 rearrangements but found a substantially reduced frequency (<35%) of TCRbeta-Cbeta0 expression among CD8 T cells selected by Ag in vivo. To study the potential activity of the TCRbeta-Cbeta0 splice variant, we cloned full-length TCR cDNAs by single-cell RT-PCR into retroviral expression vectors. We found that the TCRbeta-Cbeta0 splice isoform can function during an early stage of T cell development normally dependent on TCR beta-chain expression. We also demonstrate that T hybridoma-derived cells expressing a TCRbeta-Cbeta0 isoform together with the clonally associated TCR alpha-chain recognize the same cognate peptide-MHC ligand as the corresponding normal alphabetaTCR. This maintenance of receptor function and specificity upon insertion of the Cbeta0 peptide cassette signifies a remarkable adaptability for the TCR beta-chain, and our findings open the possibility that this splice isoform may function in vivo.

Reactivity spectrum of 30 monoclonal antimelanoma antibodies to a panel of 28 melanoma and control cell lines.

Thirty monoclonal antibodies from eight laboratories exchanged after the First Workshop on Monoclonal Antibodies to Human Melanoma held in March 1981 at NIH were tested in an antibody-binding radioimmunoassay using a panel of 28 different cell lines. This panel included 12 melanomas, three neuroblastomas, four gliomas, one retinoblastoma, four colon carcinomas, one lung carcinoma, one cervical carcinoma, one endometrial carcinoma, and one breast carcinoma. The reactivity pattern of the 30 monoclonal antibodies tested showed that none of them were directed against antigens strictly restricted to melanoma, but that several of them recognize antigenic structures preferentially expressed on melanoma cells. A large number of antibodies were found to crossreact with gliomas and neuroblastomas. Thus, they seem to recognize neuroectoderm associated differentiation antigens. Four monoclonal antibodies produced in our laboratory were further studied for the immunohistological localization of melanoma associated antigens on fresh tumor material. In a three-layer biotin-avidin-peroxidase system each antibody showed a different staining pattern with the tumor cells, suggesting that they were directed against different antigens.

Toxoplasma gondii: flat-mounting of retina as a new tool for the observation of ocular infection in mice.

Ocular toxoplasmosis is the principal cause of posterior uveitis and a leading cause of blindness. Animal models are required to improve our understanding of the pathogenesis of this disease. The method currently used for the detection of retinal cysts in animals involves the observation, under a microscope, of all the sections from infected eyes. However, this method is time-consuming and lacks sensitivity. We have developed a rapid, sensitive method for observing retinal cysts in mice infected with Toxoplasma gondii. This method involves combining the flat-mounting of retina - a compromise between macroscopic observation and global analysis of this tissue - and the use of an avirulent recombinant strain of T. gondii expressing the Escherichia coli beta-galactosidase gene, visually detectable at the submacroscopic level. Single cyst unilateral infection was found in six out of 17 mice killed within 28 days of infection, whereas a bilateral infection was found in only one mouse. There was no correlation between brain cysts number and ocular infection.