Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients

RESUME : Objectif: Le glioblastome multiforme (GBM) est la tumeur cérébrale maligne la plus agressive qui conduit au décès de la majorité des patients moins d'une année après le diagnostic. La plupart des agents chimiothérapeutiques actuellement disponibles ne traversent pas la barrière hémato¬encéphalique et ne peuvent par conséquent pas être utilisés pour ce type de tumeur. Le Temozolomide (TMZ) est un nouvel agent alkylant récemment développé pour le traitement des gliomes malins. A ce jour, très peu d'informations sont disponibles sur la pénétration intra-cérébrale de cet agent. Au cours d'une étude pilote de phase II menée auprès de 64 patients atteints de GBM, l'administration précoce de TMZ combinée à une radiothérapie standard (RT) afin d'intervenir au plus tôt dans l'évolution de la maladie, a permis de prolonger la survie de ces patients, résultat qui pu être confirmé par la suite lors de l'étude randomisée de phase III. L'objectif de cette étude a été de déterminer les paramètres pharmacocinétique du TMZ dans le plasma et le liquide céphalo-rachidien (LCR), d'évaluer l'influence de certains facteurs individuels (âge, sexe, surface corporelle, fonction rénale/hépatique, co-médications, RT concomitante) sur ces différents paramètres, et enfin d'explorer la relation existant entre l'exposition au TMZ et certains marqueurs cliniques d'efficacité et de toxicité. Matériel et Méthode: Les concentrations de TMZ ont été mesurées par chromatographie liquide à haute performance (HPLC) dans le plasma et le LCR de 35 patients atteints de GBM nouvellement diagnostiqués (étude pilote) ou de gliomes malins en récidive (étude récidive). L'analyse pharmacocinétique de population a été réalisée à l'aide du programme NONMEM. L'exposition systémique et cérébrale, définie par les AUC (Area Under the time-concentration Curve) dans le plasma et le LCR, a été estimée pour chaque patient et corrélée à la toxicité, la survie ainsi que la survie sans progression tumorale. Résultats: Un modèle à 1 compartiment avec une cinétique d'absorption et de transfert Kplasma -> LCR de ordre a été retenu afin de décrire le profil pharmacocinétique du TMZ. Les valeurs moyennes de population ont été de 10 L/h pour la clairance, de 30.3 L pour le volume de distribution, de 2.1 h pour la 1/2 vie d'élimination, de 5.78 hE-1 pour la constante d'absorption, de 7.2 10E4 hE-1 pour Kplasma->LCR et de 0.76 hE-1 pour KLCR plasma. La surface corporelle a montré une influence significative sur la clairance et le volume de distribution, alors que le sexe influence la clairance uniquement. L'AUC mesurée dans le LCR représente ~20% de celle du plasma et une augmentation de 15% de Kplasma->LCR a été observée lors du traitement concomitant de radiochimiothérapie. Conclusions: Cette étude est la première analyse pharmacocinétique effectuée chez l'homme permettant de quantifier la pénétration intra-cérébrale du TMZ. Le rapport AUC LCR/AUC Plasma a été de 20%. Le degré d'exposition systémique et cérébral au TMZ ne semble pas être un meilleur facteur prédictif de la survie ou de la tolérance au produit que ne l'est la dose cumulée seule. ABSTRACT Purpose: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of ma¬lignant brain tumors. The purpose was to assess TNIZ phar¬macokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covari¬ates and to explore relationships between systemic or cere¬bral drug exposure and clinical outcomes. Experimental Design: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacoki¬netic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area un¬der the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival. Results: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (VD), 30.3 liters; absorption constant rate, 5.8 hE-1; elimination half-time, 2.1 h; transfer rate from plasma to CSF (Kplasma->CSF), 7.2 x 10E-4hE-1 and the backwards rate, 0.76hE-1. Body surface area signifi¬cantly influenced both clearance and VD, and clearance was sex dependent. The AU CSF corresponded to 20% of the AUCplasma. A trend toward an increased K plasma->CSF of 15% was observed in case of concomitant radiochemo-therapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect. Conclusions: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUC CSF/ AUC plasma ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.

Personality changes in patients with beginning Alzheimer disease

Objective: To investigate personality traits in patients with Alzheimer disease, compared with mentally healthy control subjects. We compared both current personality characteristics using structured interviews as well as current and previous personality traits as assessed by proxies.Method: Fifty-four patients with mild Alzheimer disease and 64 control subjects described their personality traits using the Structured Interview for the Five-Factor Model. Family members filled in the Revised NEO Personality Inventory, Form R, to evaluate their proxies' current personality traits, compared with 5 years before the estimated beginning of Alzheimer disease or 5 years before the control subjects.Results: After controlling for age, the Alzheimer disease group presented significantly higher scores than normal control subjects on current neuroticism, and significantly lower scores on current extraversion, openness, and conscientiousness, while no significant difference was observed on agreeableness. A similar profile, though less accentuated, was observed when considering personality traits as the patients' proxies remembered them. Diachronic personality assessment showed again significant differences between the 2 groups for the same 4 domains, with important personality changes only for the Alzheimer disease group.Conclusions: Group comparison and retrospective personality evaluation are convergent. Significant personality changes follow a specific trend in patients with Alzheimer disease and contrast with the stability generally observed in mentally healthy people in their personality profile throughout their lives. Whether or not the personality assessment 5 years before the current status corresponds to an early sign of Alzheimer disease or real premorbid personality differences in people who later develop Alzheimer disease requires longitudinal studies.

Validation of the antenatal perceived stress inventory

This article presents the Antenatal Perceived Stress Inventory. The originality of this scale is to assess the impact of events experienced during pregnancy on the stress perceived by mothers. Scale validation was performed using data from 150 French-speaking nulliparous mothers and collected between 36 and 39 weeks of gestation (T1), and between 2 days (T2) and 6 weeks postpartum (T3). Factor analysis revealed a hierarchical three-factor structure that closely fit the data, including medical and obstetric risks/fetal health (F1), psychosocial changes (F2), and the prospect of childbirth (F3). The Antenatal Perceived Stress Inventory is a valid French prenatal stress scale with good psychometric properties.

Beta(1)-selective agonist (-)-1-(3,4-dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(-)-RO363] differentially interacts with key amino acids responsible for beta(1)-selective binding in resting and active states.

(-)-1-(3,4-Dimethoxyphenetylamino)-3-(3,4-dihydroxy)-2-propanol [(-)-RO363] is a highly selective beta(1)-adrenergic receptor (beta(1)AR) agonist. To study the binding site of beta(1)-selective agonist, chimeric beta(1)/beta(2)ARs and Ala-substituted beta(1)ARs were constructed. Several key residues of beta(1)AR [Leu(110) and Thr(117) in transmembrane domain (TMD) 2], and Phe(359) in TMD 7] were found to be responsible for beta(1)-selective binding of (-)-RO363, as determined by competitive binding. Based on these results, we built a three-dimensional model of the binding domain for (-)-RO363. The model indicated that TMD 2 and TMD 7 of beta(1)AR form a binding pocket; the methoxyphenyl group of N-substituent of (-)-RO363 seems to locate within the cavity surrounded by Leu(110), Thr(117), and Phe(359). The amino acids Leu(110) and Phe(359) interact with the phenyl ring of (-)-RO363, whereas Thr(117) forms hydrogen bond with the methoxy group of (-)-RO363. To examine the interaction of these residues with beta(1)AR in an active state, each of the amino acids was changed to Ala in a constitutively active (CA)-beta(1)AR mutant. The degree of decrease in the affinity of CA-beta(1)AR for (-)-RO363 was essentially the same as that of wild-type beta(1)AR when mutated at Leu(110) and Thr(117). However, the affinity was decreased in Ala-substituted mutant of Phe(359) compared with that of wild-type beta(1)AR. These results indicated that Leu(110) and Thr(117) are necessary for the initial binding of (-)-RO363 with beta(1)-selectivity, and interaction of Phe(359) with the N-substituent of (-)-RO363 in an active state is stronger than in the resting state.

GateKeeper - Käyttäjienhallintaohjelma

Tämän insinöörityön tavoitteena oli suunnitella ja toteuttaa selainpohjainen käyttäjienhallintaohjelma GateKeeper Karttakeppi.com-työryhmälle. GateKeeper-ohjelma kuuluu osana laajempaan ohjelmistoprojektiin, jonka tarkoituksena on tuottaa opetusmateriaalia etäopiskelijoille Internetissä. Etäopetusmateriaalin tuottamisessa käytetään useita ohjelmia, joille on määriteltävä eritasoisia käyttäjätunnuksia ja käyttöoikeuksia. Ohjelmien käyttäjienhallintamekanismit ovat erilaisia, mikä osaltaan lisää järjestelmän ylläpitäjien työtä ja vastuuta. GateKeeper-ohjelman tavoitteena on nopeuttaa, helpottaa ja yksinkertaistaa käyttäjienhallintaan liittyviä toimintoja tietoturvallisesti. GateKeeper-ohjelma on suunniteltu siten, että uusien käyttäjien ja ohjelmien lisäämiselle ei ole asetettu rajoja. Jokaisen lisättävän ohjelman yhteydessä on kuitenkin selvitettävä kyseisen ohjelman käyttäjienhallintamekanismi. Tässä insinöörityössä tutkittiin, miten versionhallintaohjelma Subversionin, julkaisujärjestelmä Mambon, sekä oppimisalusta Moodlen käyttäjiä voidaan keskitetysti hallinnoida GateKeeper-ohjelman avulla. GateKeeper-ohjelma noudattaa arkkitehtuuriltaan kolmikerrosmallia, jossa käyttöliittymä, sovelluslogiikka ja tietovarasto on erotettu toisistaan. Ohjelma koostuu joukosta PHP-kielellä toteutettuja dynaamisia web-sivuja. Tietovarastona käytetään tietokantapalvelimella sijaitsevaa MySQL-tietokantaa.

On the term structure of Interbank interest rates: Jump-diffusion processes and option pricing

In this paper we study the dynamic behavior of the term structureof Interbank interest rates and the pricing of options on interest ratesensitive securities. We posit a generalized single factor model withjumps to take into account external influences in the market. Daily datais used to test for jump effects. Qualitative examination of the linkagebetween Monetary Authorities' interventions and jumps are studied. Pricingresults suggests a systematic underpricing in bonds and call options ifthe jumps component is not included. However, the pricing of put optionson bonds presents indeterminacies.

Personality traits, cognition and volumetric MRI changes in elderly patients with early-onset depression: A 2-year follow-up study.

Previous studies revealed personality changes in elderly patients with early-onset depression (EOD) that persist in euthymic stages. However, depression in older patients is a complex disorder that may affect not only personality, but also cognition and brain structure. To address this issue, a cross-sectional comparison and 2-year follow-up of 28 EOD elderly patients and 48 healthy controls included detailed neurocognitive assessment, estimates of brain volumes in limbic areas and white matter hyperintensities, as well as evaluation of the Five Factor Model of personality, in a remitted mood state. Results revealed that cognitive performances as well as brain volumes were preserved in EOD patients both at baseline and at follow-up. The increased Neuroticism factor and Anxiety facet scores as well as the decreased Warmth and Positive Emotions facet scores found at baseline reached the level of healthy controls after 2years. Only the Depression facet scores remained significantly higher in EOD patients compared to controls upon follow-up. Results were independent of depressive relapse since baseline (25% of patients). These findings suggest that both cognitive performances and brain volumes show long-term preservation in older EOD patients. In contrast, the depression-related personality facet might be a trait like marker that persists in the long-term evolution of this disorder.

Gestió d'un portal web d'intercanvi de coneixement

En aquest món on ens ha tocat viure i patir canvis tan durs amb la crisi econòmica que patim, que ens ha fet passar de lligar els gossos amb llonganisses a vigilar en les despeses del dia a dia per poder arribar just a final de mes, és el moment de reinventar-se. És per aquest motiu que presento aquesta idea, on el seu objectiu és desenvolupar una pàgina web que esdevingui un punt de trobada entre usuaris que volen transmetre o ampliar el seu coneixement i oferir-los la possibilitat que entre ells puguin compartir les seves habilitats i destreses. El web consistirà en un panell d’activitats on els usuaris un cop s’hagin registrat puguin crear les activitats que vulguin aprendre o bé ensenyar, tot demanant, si ho desitgen, quelcom a canvi. Aleshores la resta d’usuaris si els interessa l’activitat, poden acceptar la demanda o bé fer una proposta pròpia. A partir d’aquí els usuaris s’han de posar d’acord a l’hora de dur a terme l’activitat. El web disposarà d’una part pels usuaris amb permisos d’administrador perquè puguin gestionar el portal. Aquest projecte s’ha desenvolupat amb el framework de PHP Codeigniter, el qual utilitza la programació per capes MVC, la qual separa la programació en tres parts: el Model, la Vista i el Controlador. També s’han utilitzat els llenguatges HTML5 i CSS3, i jQuery, que és una llibreria de JavaScript. Com a sistema gestor de base de dades s’ha utilitzat el MySQL.

French version of the Family Attitude Scale: Psychometric properties and relation of attitudes to the respondent's psychiatric status.

The Family Attitude Scale (FAS) is a self-report measure of critical or hostile attitudes and behaviors towards another family member, and demonstrates an ability to predict relapse in psychoses. Data are not currently available on a French version of the scale. The present study developed a French version of the FAS, using a large general population sample to test its internal structure, criterion validity and relationships with the respondents' symptoms and psychiatric diagnoses, and examined the reciprocity of FAS ratings by respondents and their partners. A total of 2072 adults from an urban population undertook a diagnostic interview and completed self-report measures, including an FAS about their partner. A subset of participants had partners who also completed the FAS. Confirmatory factor analyses revealed an excellent fit by a single-factor model, and the FAS demonstrated a strong association with dyadic adjustment. FAS scores of respondents were affected by their anxiety levels and mood, alcohol and anxiety diagnoses, and moderate reciprocity of attitudes and behaviors between the partners was seen. The French version of the FAS has similarly strong psychometric properties to the original English version. Future research should assess the ability of the French FAS to predict relapse of psychiatric disorders.

Soil infiltration based on bp neural network and grey relational analysis

Soil infiltration is a key link of the natural water cycle process. Studies on soil permeability are conducive for water resources assessment and estimation, runoff regulation and management, soil erosion modeling, nonpoint and point source pollution of farmland, among other aspects. The unequal influence of rainfall duration, rainfall intensity, antecedent soil moisture, vegetation cover, vegetation type, and slope gradient on soil cumulative infiltration was studied under simulated rainfall and different underlying surfaces. We established a six factor-model of soil cumulative infiltration by the improved back propagation (BP)-based artificial neural network algorithm with a momentum term and self-adjusting learning rate. Compared to the multiple nonlinear regression method, the stability and accuracy of the improved BP algorithm was better. Based on the improved BP model, the sensitive index of these six factors on soil cumulative infiltration was investigated. Secondly, the grey relational analysis method was used to individually study grey correlations among these six factors and soil cumulative infiltration. The results of the two methods were very similar. Rainfall duration was the most influential factor, followed by vegetation cover, vegetation type, rainfall intensity and antecedent soil moisture. The effect of slope gradient on soil cumulative infiltration was not significant.

The Inaccuracy of National Character Stereotypes

Consensual stereotypes of some groups are relatively accurate, whereas others are not. Previous work suggesting that national character stereotypes are inaccurate has been criticized on several grounds. In this article we (a) provide arguments for the validity of assessed national mean trait levels as criteria for evaluating stereotype accuracy and (b) report new data on national character in 26 cultures from descriptions (N = 3323) of the typical male or female adolescent, adult, or old person in each. The average ratings were internally consistent and converged with independent stereotypes of the typical culture member, but were weakly related to objective assessments of personality. We argue that this conclusion is consistent with the broader literature on the inaccuracy of national character stereotypes.

Psychometric evaluation of the IWQOL-Lite (Spanish version) when applied to a sample of obese patients awaiting bariatric surgery

Background Obesity may have an impact on key aspects of health-related quality of life (HRQOL). In this context, the Impact of Weight Quality of Life (IWQOL) questionnaire was the first scale designed to assess HRQOL. The aim of the present study was twofold: to assess HRQOL in a sample of Spanish patients awaiting bariatric surgery and to determine the psychometric properties of the IWQOL-Lite and its sensitivity to detect differences in HRQOL across groups. Methods Participants were 109 obese adult patients (BMI¿ 35 kg/m2) from Barcelona, to whom the following measurement instruments were applied: IWQOL-Lite, Depression Anxiety Stress Scales, Brief Symptom Inventory, and self-perception items. Results Descriptive data regarding the IWQOL-Lite scores obtained by these patients are reported. Principal components analysis revealed a five-factor model accounting for 72.05% of the total variance, with factor loadings being adequate for all items. Corrected itemtotal correlations were acceptable for all items. Cronbach"s alpha coefficients were excellent both for the subscales (0.880.93) and the total scale (0.95). The relationship between the IWQOLLite and other variables supports the construct validity of the scale. Finally, sensitivity analysis revealed large effect sizes when comparing scores obtained by extreme BMI groups. Conclusions This is the first study to report the application of the IWQOL-Lite to a sample of Spanish patients awaiting bariatric surgery and to confirm that the Spanish version of the instrument has adequate psychometric properties.

Modelling hydrodynamics in the Rio Parana, Argentina : an evaluation and inter-comparison of reduced-complexity and physics based models applied to a large sand-bed river

Depth-averaged velocities and unit discharges within a 30 km reach of one of the world's largest rivers, the Rio Parana, Argentina, were simulated using three hydrodynamic models with different process representations: a reduced complexity (RC) model that neglects most of the physics governing fluid flow, a two-dimensional model based on the shallow water equations, and a three-dimensional model based on the Reynolds-averaged Navier-Stokes equations. Row characteristics simulated using all three models were compared with data obtained by acoustic Doppler current profiler surveys at four cross sections within the study reach. This analysis demonstrates that, surprisingly, the performance of the RC model is generally equal to, and in some instances better than, that of the physics based models in terms of the statistical agreement between simulated and measured flow properties. In addition, in contrast to previous applications of RC models, the present study demonstrates that the RC model can successfully predict measured flow velocities. The strong performance of the RC model reflects, in part, the simplicity of the depth-averaged mean flow patterns within the study reach and the dominant role of channel-scale topographic features in controlling the flow dynamics. Moreover, the very low water surface slopes that typify large sand-bed rivers enable flow depths to be estimated reliably in the RC model using a simple fixed-lid planar water surface approximation. This approach overcomes a major problem encountered in the application of RC models in environments characterised by shallow flows and steep bed gradients. The RC model is four orders of magnitude faster than the physics based models when performing steady-state hydrodynamic calculations. However, the iterative nature of the RC model calculations implies a reduction in computational efficiency relative to some other RC models. A further implication of this is that, if used to simulate channel morphodynamics, the present RC model may offer only a marginal advantage in terms of computational efficiency over approaches based on the shallow water equations. These observations illustrate the trade off between model realism and efficiency that is a key consideration in RC modelling. Moreover, this outcome highlights a need to rethink the use of RC morphodynamic models in fluvial geomorphology and to move away from existing grid-based approaches, such as the popular cellular automata (CA) models, that remain essentially reductionist in nature. In the case of the world's largest sand-bed rivers, this might be achieved by implementing the RC model outlined here as one element within a hierarchical modelling framework that would enable computationally efficient simulation of the morphodynamics of large rivers over millennial time scales. (C) 2012 Elsevier B.V. All rights reserved.

Violent adolescents and their educational environment: a multilevel analysis.

OBJECTIVE: This study examined the respective roles of personal and environmental factors in youth violence in a nationally representative sample of 7548 postmandatory school students and apprentices ages 16-20 years in Switzerland. METHODS: Youth violence was defined as having committed at least one of the following in the previous 12 months: attacking an adult, snatching something, carrying a weapon, or using a weapon in a fight. Different ecological levels were tested, resulting in a three-level model only in males (individual, classroom, and school) as the low prevalence of female violence did not allow for a multilevel analysis. Dependent variables were attributed to each level. For males, the classroom level (10%) and the school level (24%) accounted for more than one third in interindividual variance. RESULTS: Factors associated with violence perpetration in females were being a victim of physical violence and sensation seeking at the individual level. In males, practicing unsafe sex, sensation seeking, being a victim of physical violence, having a poor relationship with parents, being depressed, and living in a single-parent household at the individual level; violence and antisocial acts at the classroom level; and being in a vocational school at the school level showed a correlation with violence perpetration. CONCLUSION: Interventions at the classroom level as well as an explicit school policy on violence and other risk behaviors should be considered a priority when dealing with the problem of youth violence. Furthermore, prevention should take into account gender differences.

A Spanish version of the short Mathematics Anxiety Rating Scale (sMARS)

The aim of this studywas to adapt and assess the psychometric properties of the Spanish version of the sMARS in terms of evidence of validity and reliability of scores. The sMARS was administered to 342 students and, in order to assess convergent and discriminant validity, several subsamples completed a series of related tests. The factorial structure of the sMARSwas analyzed by means of a confirmatory factor analysis and results showed that the three-factor structure reported in the original test fits well with the data. Thus, three dimensions were established in the test: math test, numerical task and math course anxiety. The results of this study provide sound evidence that demonstrates the good psychometric properties of the scores of the Spanish version of the sMARS: strong internal consistency, high 7-week testretest reliability and good convergent/discriminant validity were evident. Overall, this study provides an instrument that allows us to obtain valid and reliable math anxiety measurements. This instrument may be a useful tool for educators and psychologists interested in identifying individuals that may have a low level of math mastery because of their anxiety.