Variability of the relative afferent pupillary defect.

PURPOSE: Afferent asymmetry of visual function is detectable in both normal and pathologic conditions. With a computerized test, we assessed the variability in measuring afferent asymmetry of the pupillary light reflex, that is, the relative afferent pupillary defect. METHODS: In ten normal subjects, pupillary responses to an alternating light stimulus were recorded with computerized infrared pupillography. The relative afferent pupillary defect for each test was determined by using a new computer analysis. The 95% confidence interval of each determination of relative afferent pupillary defect was used to represent the short-term fluctuation in its measurement. To optimize the test for clinical use, we studied the influence of stimulus intensity, duration, and number on the variability of the relative afferent pupillary defect. RESULTS: When the relative afferent pupillary defect was based on only a few light alternations (stimulus pairs), there was excessive variability in its measurement (95% confidence interval > 0.5 log units). With approximately 200 stimulus pairs, the 95% confidence interval was reduced to less than 0.1 log unit (relative afferent pupillary defect +/- 0.05 log unit). Also, there was less variability when the dark interval between alternating light stimulation was less than one second. CONCLUSIONS: Computerized infrared pupillography can standardize the alternating light test and minimize the error in quantifying a relative afferent pupillary defect. A reproducible relative afferent pupillary defect measurement is desirable for defining afferent injury and following the course of disease.

Etave sur Indian [1000 cmc, concurrent de la course motocycliste Paris-Nice] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57969

Harold Petty [n°116], [V. E.] Horsman [n°117], Stanley Parker [n°122] sur Norton [750 cmc, concurrents de la course motocycliste Paris-Nice] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57962

11-2-20, pesage de Paris-Nice, Colombel sur Douglas [350 cmc, concurrent de la course motocycliste Paris-Nice] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57957

11-2-20, pesage de Paris-Nice, Gisquet [n°15], [L.] Horton [n°10], Rigal [n°16] sur New Imperial [350 cmc, concurrents de la course motocycliste Paris-Nice] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57956

[W. J.] Brunnel [250 cmc], Fred Dove [750 cmc], [Geoffrey] Hill [550 cmc], sur Triumph [concurrents de la course motocycliste Paris-Nice] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57951

P. W. White sur Sunbeam [500 cmc, concurrent de la course motocycliste Paris-Nice] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 57961

Cross-species and cross-platform gene expression studies with the Bioconductor-compliant R package 'annotationTools'.

Background: The variety of DNA microarray formats and datasets presently available offers an unprecedented opportunity to perform insightful comparisons of heterogeneous data. Cross-species studies, in particular, have the power of identifying conserved, functionally important molecular processes. Validation of discoveries can now often be performed in readily available public data which frequently requires cross-platform studies.Cross-platform and cross-species analyses require matching probes on different microarray formats. This can be achieved using the information in microarray annotations and additional molecular biology databases, such as orthology databases. Although annotations and other biological information are stored using modern database models ( e. g. relational), they are very often distributed and shared as tables in text files, i.e. flat file databases. This common flat database format thus provides a simple and robust solution to flexibly integrate various sources of information and a basis for the combined analysis of heterogeneous gene expression profiles.Results: We provide annotationTools, a Bioconductor-compliant R package to annotate microarray experiments and integrate heterogeneous gene expression profiles using annotation and other molecular biology information available as flat file databases. First, annotationTools contains a specialized set of functions for mining this widely used database format in a systematic manner. It thus offers a straightforward solution for annotating microarray experiments. Second, building on these basic functions and relying on the combination of information from several databases, it provides tools to easily perform cross-species analyses of gene expression data.Here, we present two example applications of annotationTools that are of direct relevance for the analysis of heterogeneous gene expression profiles, namely a cross-platform mapping of probes and a cross-species mapping of orthologous probes using different orthology databases. We also show how to perform an explorative comparison of disease-related transcriptional changes in human patients and in a genetic mouse model.Conclusion: The R package annotationTools provides a simple solution to handle microarray annotation and orthology tables, as well as other flat molecular biology databases. Thereby, it allows easy integration and analysis of heterogeneous microarray experiments across different technological platforms or species.

Tools in pharmacovigilance in psychiatry: therapeutic drug monitoring, pharmacogenetic tests and drug-drug interactions databases

SUMMARYIn order to increase drug safety we must better understand how medication interacts with the body of our patients and this knowledge should be made easily available for the clinicians prescribing the medication. This thesis contributes to how the knowledge of some drug properties can increase and how to make information readily accessible for the medical professionals. Furthermore it investigates the use of Therapeutic drug monitoring, drug interaction databases and pharmacogenetic tests in pharmacovigilance.Two pharmacogenetic studies in the naturalistic setting of psychiatric in-patients clinics have been performed; one with the antidepressant mirtazapine, the other with the antipsychotic clozapine. Forty-five depressed patients have been treated with mirtazapine and were followed for 8 weeks. The therapeutic effect was as seen in other previous studies. Enantioselective analyses could confirm an influence of age, gender and smoking in the pharmacokinetics of mirtazapine; it showed a significant influence of the CYP2D6 genotype on the antidepressant effective S-enantiomer, and for the first time an influence of the CYP2B6 genotype on the plasma concentrations of the 8-OH metabolite was found. The CYP2B6*/*6 genotype was associated to better treatment response. A detailed hypothesis of the metabolic pathways of mirtazapine is proposed. In the second pharmacogenetic study, analyses of 75 schizophrenic patients treated with clozapine showed the influence of CYP450 and ABCB1 genotypes on its pharmacokinetics. For the first time we could demonstrate an in vivo effect of the CYP2C19 genotype and an influence of P-glycoprotein on the plasma concentrations of clozapine. Further we confirmed in vivo the prominent role of CYP1A2 in the metabolism of clozapine.Identifying risk factors for the occurrence of serious adverse drug reactions (SADR) would allow a more individualized and safer drug therapy. SADR are rare events and therefore difficult to study. We tested the feasibility of a nested matched case-control study to examine the influence of high drug plasma levels and CYP2D6 genotypes on the risk to experience an SADR. In our sample we compared 62 SADR cases with 82 controls; both groups were psychiatric patients from the in-patient clinic Königsfelden. Drug plasma levels of >120% of the upper recommended references could be identified as a risk factor with a statistically significant odds ratio of 3.5, a similar trend could be seen for CYP2D6 poor metaboliser. Although a matched case-control design seems a valid method, 100% matching is not easy to perform in a relative small cohort of one in-patient clinic. However, a nested case-control study is feasible.On the base of the experience gained in the AMSP+ study and the fact that we have today only sparse data indicating that routine drug plasma concentration monitoring and/or pharmacogenetic testing in psychiatry are justified to minimize the risk for ADR, we developed a test algorithm named "TDM plus" (TDM plus interaction checks plus pharmacogenetic testing).Pharmacovigilance programs such as the AMSP project (AMSP = Arzneimittelsicherheit in der Psychiatrie) survey psychiatric in-patients in order to collect SADR and to detect new safety signals. Case reports of such SADR are, although anecdotal, valuable to illustrate rare clinical events and sometimes confirm theoretical assumptions of e.g. drug interactions. Seven pharmacovigilance case reports are summarized in this thesis.To provide clinicians with meaningful information on the risk of drug combinations, during the course of this thesis the internet based drug interaction program mediQ.ch (in German) has been developed. Risk estimation is based on published clinical and pharmacological information of single drugs and alimentary products, including adverse drug reaction profiles. Information on risk factors such as renal and hepatic insufficiency and specific genotypes are given. More than 20'000 drug pairs have been described in detail. Over 2000 substances with their metabolic and transport pathways are included and all information is referenced with links to the published scientific literature or other information sources. Medical professionals of more than 100 hospitals and 300 individual practitioners do consult mediQ.ch regularly. Validations with comparisons to other drug interaction programs show good results.Finally, therapeutic drug monitoring, drug interaction programs and pharmacogenetic tests are helpful tools in pharmacovigilance and should, in absence of sufficient routine tests supporting data, be used as proposed in our TDM plus algorithm.RESUMEPour améliorer la sécurité d'emploi des médicaments il est important de mieux comprendre leurs interactions dans le corps des patients. Ensuite le clinicien qui prescrit une pharmacothérapie doit avoir un accès simple à ces informations. Entre autres, cette thèse contribue à mieux connaître les caractéristiques pharmacocinétiques de deux médicaments. Elle examine aussi l'utilisation de trois outils en pharmacovigilance : le monitorage thérapeutique des taux plasmatiques des médicaments (« therapeutic drug monitoring »), un programme informatisé d'estimation du risque de combinaisons médicamenteuses, et enfin des tests pharmacogénétiques.Deux études cliniques pharmacogénétiques ont été conduites dans le cadre habituel de clinique psychiatrique : l'une avec la mirtazapine (antidépresseur), l'autre avec la clozapine (antipsychotique). On a traité 45 patients dépressifs avec de la mirtazapine pendant 8 semaines. L'effet thérapeutique était semblable à celui des études précédentes. Nous avons confirmé l'influence de l'âge et du sexe sur la pharmacocinétique de la mirtazapine et la différence dans les concentrations plasmatiques entre fumeurs et non-fumeurs. Au moyen d'analyses énantiomères sélectives, nous avons pu montrer une influence significative du génotype CYP2D6 sur l'énantiomère S+, principalement responsable de l'effet antidépresseur. Pour la première fois, nous avons trouvé une influence du génotype CYP2B6 sur les taux plasmatiques de la 8-OH-mirtazapine. Par ailleurs, le génotype CYP2B6*6/*6 était associé à une meilleure réponse thérapeutique. Une hypothèse sur les voies métaboliques détaillées de la mirtazapine est proposée. Dans la deuxième étude, 75 patients schizophrènes traités avec de la clozapine ont été examinés pour étudier l'influence des génotypes des iso-enzymes CYP450 et de la protéine de transport ABCB1 sur la pharmacocinétique de cet antipsychotique. Pour la première fois, on a montré in vivo un effet des génotypes CYP2C19 et ABCB1 sur les taux plasmatiques de la clozapine. L'importance du CYP1A2 dans le métabolisme de la clozapine a été confirmée.L'identification de facteurs de risques dans la survenue d'effets secondaire graves permettrait une thérapie plus individualisée et plus sûre. Les effets secondaires graves sont rares. Dans une étude de faisabilité (« nested matched case-control design » = étude avec appariement) nous avons comparé des patients avec effets secondaires graves à des patients-contrôles prenant le même type de médicaments mais sans effets secondaires graves. Des taux plasmatiques supérieurs à 120% de la valeur de référence haute sont associés à un risque avec « odds ratio » significatif de 3.5. Une tendance similaire est apparue pour le génotype du CYP2D6. Le « nested matched case-control design » semble une méthode valide qui présente cependant une difficulté : trouver des patients-contrôles dans le cadre d'une seule clinique psychiatrique. Par contre la conduite d'une « nested case-control study » sans appariement est recommandable.Sur la base de notre expérience de l'étude AMSP+ et le fait que nous disposons que de peux de données justifiant des monitorings de taux plasmatiques et/ou de tests pharmacogénétiques de routine, nous avons développé un test algorithme nommé « TDMplus » (TDM + vérification d'interactions médicamenteuses + tests pharmacogénétique).Des programmes de pharmacovigilances comme celui de l'AMSP (Arzneimittelsicherheit in der Psychiatrie = pharmacovigilance en psychiatrie) collectent les effets secondaires graves chez les patients psychiatriques hospitalisés pour identifier des signaux d'alertes. La publication de certains de ces cas même anecdotiques est précieuse. Elle décrit des événements rares et quelques fois une hypothèse sur le potentiel d'une interaction médicamenteuse peut ainsi être confirmée. Sept publications de cas sont résumées ici.Dans le cadre de cette thèse, on a développé un programme informatisé sur internet (en allemand) - mediQ.ch - pour estimer le potentiel de risques d'une interaction médicamenteuse afin d'offrir en ligne ces informations utiles aux cliniciens. Les estimations de risques sont fondées sur des informations cliniques (y compris les profils d'effets secondaires) et pharmacologiques pour chaque médicament ou substance combinés. Le programme donne aussi des informations sur les facteurs de risques comme l'insuffisance rénale et hépatique et certains génotypes. Actuellement il décrit en détail les interactions potentielles de plus de 20'000 paires de médicaments, et celles de 2000 substances actives avec leurs voies de métabolisation et de transport. Chaque information mentionne sa source d'origine; un lien hypertexte permet d'y accéder. Le programme mediQ.ch est régulièrement consulté par les cliniciens de 100 hôpitaux et par 300 praticiens indépendants. Les premières validations et comparaisons avec d'autres programmes sur les interactions médicamenteuses montrent de bons résultats.En conclusion : le monitorage thérapeutique des médicaments, les programmes informatisés contenant l'information sur le potentiel d'interaction médicamenteuse et les tests pharmacogénétiques sont de précieux outils en pharmacovigilance. Nous proposons de les utiliser en respectant l'algorithme « TDM plus » que nous avons développé.

Cultural self-identification(s) and personal social networks among first and second-generation immigrants

L’estudi examina les relacions entre (1) les xarxes socials personals de la població immigrant resident a Barcelona i (2) les seves identitats culturals múltiples. L’objectiu principal de l’estudi és entendre com el contingut i l’estructura de les relacions socials dels immigrants facilita o dificulta (1) tenir un sentiment de pertinença a les noves cultures d’acollida, la catalana i la espanyola, i (2) la integració d’aquestes noves identitats socioculturals amb la seva identitat d’origen en una nova identitat bicultural cohesiva. El nostre plantejament inicial era que els immigrants amb xarxes socials més diverses des del punt de vista de la seva composició cultural tindrien més recursos socials i experiències cognitives més diverses , factors que afavoreixen les identificacions múltiples i la participació cívica. Els resultats de l’estudi mostren que el grau d’identificació dels participants amb la seva cultura ètnica o d’origen és força alt i, en certa mesura, més alt en comparació amb les cultures d’acollida ( catalana, cívica i espanyola). Tanmateix, el vincle dels participants amb les cultures d’acollida (p. ex., la cultura catalana) és prou rellevant per a indicar una orientació bicultural (catalana i ètnica). Les anàlisis de correlacions revelen que sentir-se català no impedeix sentir-se part de la comunitat etnocultural d’origen. A més, existeix una interrelació entre l'orientació cultural catalana i la identificació amb les comunitats cíviques locals. De la mateixa manera, tenir competències en llengua catalana no va en detriment de les competències en llengua castellana. Les anàlisis també mostren que factors com l’orientació cultural catalana, l’ús del català i la identificació amb la cultura catalana tenen una correlació positiva amb el grau de chohesio de la indentitat bicultural, afavoreixen el benestar psicològic i disminueixen l’estrès aculturatiu. L’anàlisi de les xarxes socials mostra que la identificació amb la cultura catalana, l’orientació cultural catalana i la integració de la identitat són factors clau per tenir xarxes socials més diverses des del punt de vista ètnic i lingüístic, amb menys membres del col•lectiu d’origen, i amb subgrups o “cliques” culturalment més heterogenis. La identificació espanyola també prediu, en mesura més reduïda, la diversitat de les xarxes. Els nostres resultats contribueixen a la recerca actual i les teories sobre interculturalitat i identitat cultural.

Anharmonicity contributions to the vibrational second hyperpolarizability of conjugated oligomers

Restricted Hartree-Fock 6-31G calculations of electrical and mechanical anharmonicity contributions to the longitudinal vibrational second hyperpolarizability have been carried out for eight homologous series of conjugated oligomers - polyacetylene, polyyne, polydiacetylene, polybutatriene, polycumulene, polysilane, polymethineimine, and polypyrrole. To draw conclusions about the limiting infinite polymer behavior, chains containing up to 12 heavy atoms along the conjugated backbone were considered. In general, the vibrational hyperpolarizabilities are substantial in comparison with their static electronic counterparts for the dc-Kerr and degenerate four-wave mixing processes (as well as for static fields) but not for electric field-induced second harmonic generation or third harmonic generation. Anharmonicity terms due to nuclear relaxation are important for the dc-Kerr effect (and for the static hyperpolarizability) in the σ-conjugated polymer, polysilane, as well as the nonplanar π systems polymethineimine and polypyrrole. Restricting polypyrrole to be planar, as it is in the crystal phase, causes these anharmonic terms to become negligible. When the same restriction is applied to polymethineimine the effect is reduced but remains quantitatively significant due to the first-order contribution. We conclude that anharmonicity associated with nuclear relaxation can be ignored, for semiquantitative purposes, in planar π-conjugated polymers. The role of zero-point vibrational averaging remains to be evaluated

The curvature of the conical intersection seam: an approximate second-order analysis

We present a method for analyzing the curvature (second derivatives) of the conical intersection hyperline at an optimized critical point. Our method uses the projected Hessians of the degenerate states after elimination of the two branching space coordinates, and is equivalent to a frequency calculation on a single Born-Oppenheimer potential-energy surface. Based on the projected Hessians, we develop an equation for the energy as a function of a set of curvilinear coordinates where the degeneracy is preserved to second order (i.e., the conical intersection hyperline). The curvature of the potential-energy surface in these coordinates is the curvature of the conical intersection hyperline itself, and thus determines whether one has a minimum or saddle point on the hyperline. The equation used to classify optimized conical intersection points depends in a simple way on the first- and second-order degeneracy splittings calculated at these points. As an example, for fulvene, we show that the two optimized conical intersection points of C2v symmetry are saddle points on the intersection hyperline. Accordingly, there are further intersection points of lower energy, and one of C2 symmetry - presented here for the first time - is found to be the global minimum in the intersection space

Second-order Møller-Plesset perturbation theory without basis set superposition error : II : open-shell systems

The basis set superposition error-free second-order MØller-Plesset perturbation theory of intermolecular interactions was studied. The difficulties of the counterpoise (CP) correction in open-shell systems were also discussed. The calculations were performed by a program which was used for testing the new variants of the theory. It was shown that the CP correction for the diabatic surfaces should be preferred to the adiabatic ones

Quadrennial Need Study Report on Highways, Roads, and Streets for Study Years 2002-2021, Second Annual Update, January 2004

Study report on highways, roads and streets for future years by Iowa Department of Transportation

Drugs, schizotypy and cognition: Cognitive attenuations seem more consistently associated with substance use than schizotypal symptoms

Psychosis is a debilitating disease, causing harm to the individual and society. Since early detection of the disease is associated with a more benign course, factors are warranted that enable the early detection of psychosis. In the present thesis we will be focusing on two potential risk factors, namely schizotypy and drug use. The schizotypy concept, originally developed by Meehl (1962), states that schizophrenia symptoms exist on a spectrum, with symptoms ranging from the most severe in patients with schizophrenia to the least affected individual in the general population. Along the schizophrenia spectrum cognitive impairments are commonly found, for instance reduced hemispheric asymmetry or frontal lobe functions. The second risk factor (drug use), affects similar cognitive functions as those attenuated along the schizophrenia spectrum, and drug use is elevated in schizophrenia and people scoring high on schizotypy. Therefore, we set out to investigate whether cognitive attenuations formerly allocated to schizotypal symptoms could have been influenced by elevated substance use in this population. To test this idea, we assessed various drugs (nicotine, cannabis, mephedrone, general substance dependence) and schizotypy symptoms (O-LIFE), and measured either hemispheric asymmetry of function (left hemisphere dominance for language, and right hemisphere dominance for facial processing) or functions largely relying on the frontal lobes (such as cognitive flexibility, working memory, verbal short-term memory, verbal learning and verbal fluency). Results of all studies suggest that it is mostly drugs, and not schizotypy in general that predict cognitive functioning. Therefore, cognitive attenuations subscribed to schizotypy dimensions are likely to have been affected by enhanced drug use. Future studies should extend the list of potential risk factors (e.g. depression and IQ) to acquire a comprehensive overview of the most reliable predictors of disadvantageous cognitive profiles.