Effect of physical exercise on glycogen turnover and net substrate utilization according to the nutritional state.

To determine the metabolic effects of a single bout of exercise performed after a meal or in the fasting state, nine healthy subjects were studied over two 8-h periods during which net substrate oxidation was monitored by indirect calorimetry. On one occasion, exercise was performed 90 min after ingestion of a meal labeled with [U-13C]glucose [protocol meal-exercise (M-E)]. On the second occasion, exercise was performed after an overnight fast and was followed 30 min later by ingestion of an identical meal [protocol exercise-meal (E-M)]. Energy balances were similar in both protocols, but carbohydrate balance was positive (42.2 +/- 5.1 g), and lipid balance was negative (-11.1 +/- 2.0) during E-M, whereas they were nearly even during M-E. Total glycogen synthesis was calculated as carbohydrate intake minus oxidation of exogenous 13C-labeled carbohydrate (calculated from 13CO2 production). Total glycogen synthesis was increased by 90% (from 47.6 +/- 3.8 to 90.7 +/- 5.4 g, P < 0.0001) during E-M vs. M-E. Endogenous glycogen breakdown was calculated as net carbohydrate oxidation minus oxidation of exogenous carbohydrate and was increased by 44% (from 35.8 +/- 5.6 to 51.7 +/- 6.6 g, P < 0.004) during E-M. It is concluded that exercise performed in the fasting state stimulates glycogen turnover and fat oxidation.

Numerical Modelling of Combustion and Emission Formation in a Diesel Engine with Different Fuel Injection Characteristics

Päästöjen vähentäminen on ollut viime vuosina tärkeässä osassa polttomoottoreita kehitettäessä.Monet viralliset tahot asettavat uusia tiukempia päästörajoituksia. Päästörajatovat tyypillisesti olleet tiukimmat autoteollisuuden valmistamille pienille nopeakäyntisille diesel-moottoreille, mutta viime aikoina paineita on kohdistunut myös suurempiin keskinopeisiin ja hidaskäyntisiin diesel-moottoreihin. Päästörajat ovat erilaisia riippuen moottorin tyypistä, käytetystä polttoaineesta ja paikasta missä moottoria käytetään johtuen erilaisista paikallisista laeista ja asetuksista. Eniten huomiota diesel-moottorin päästöissä täytyy kohdistaa typen oksideihin, savun muodostukseen sekä partikkeleihin. Laskennallisen virtausmekaniikan (CFD) avulla on hyvät mahdollisuudet tutkia diesel-moottorin sylinterissä tapahtuvia ilmiöitä palamisen aikana. CFD on hyödyllinen työkalu arvioitaessa moottorin suorituskykyä ja päästöjen muodostumista. CFD:llä on mahdollista testata erilaisten parametrien ja geometrioiden vaikutusta ilman kalliita moottorinkoeajoja. CFD:tä voidaan käyttää myös opetustarkoituksessa lisäämään paloprosessin tuntemusta. Tulevaisuudessa palamissimuloinnit CFD:llä tulevat epäilemättä olemaan tärkeä osa moottorin kehityksessä. Tässä diplomityössä on tehty palamissimuloinnit kahteen erilaisilla poittoaineenruiskutuslaitteistoilla varustettuun Wärtsilän keskinopeaan diesel-moottoriin. W46 moottorin ruiskutuslaitteisto on perinteinen mekaanisesti ohjattu pumppusuutin ja W46-CR moottorissa on elektronisesti ohjattu 'common rail' ruiskutuslaitteisto. Näiden moottorien ja käytössä olevien ruiskutusprofiilien lisäksi on simuloinneilla testattu erilaisia uusia ruiskutusprofiileja, jotta erityyppisten profiilien hyvät ja huonot ominaisuudet tulisivat selville. Matalalla kuormalla kiinnostuksen kohteena on nokipäästöjen muodostus ja täydellä kuormalla NOx-päästöjen muodostus ja polttoaineen kulutus. Simulointien tulokset osoittivat, että noen muodostusta matalalla kuormalla voidaan selvästi vähentää monivaiheisella ruiskutuksella, jossa yksi ruiskutusjakso jaetaan kahteen tai useampaan jaksoon. Erityisen tehokas noen vähentämisessä vaikuttaa olevan ns. jälkiruiskutus (post injection). Matalat NOx-päästöt ja hyvä polttoaineen kulutus täydellä kuormalla on mahdollista saavuttaaasteittain nostettavalla ruiskutusnopeudella.

Using digital RNA counting and flow cytometry to compare mRNA with protein expression in acute leukemias.

BACKGROUND: The diagnosis of malignant hematologic diseases has become increasingly complex during the last decade. It is based on the interpretation of results from different laboratory analyses, which range from microscopy to gene expression profiling. Recently, a method for the analysis of RNA phenotypes has been developed, the nCounter technology (Nanostring® Technologies), which allows for simultaneous quantification of hundreds of RNA molecules in biological samples. We evaluated this technique in a Swiss multi-center study on eighty-six samples from acute leukemia patients. METHODS: mRNA and protein profiles were established for normal peripheral blood and bone marrow samples. Signal intensities of the various tested antigens with surface expression were similar to those found in previously performed Affymetrix microarray analyses. Acute leukemia samples were analyzed for a set of twenty-two validated antigens and the Pearson Correlation Coefficient for nCounter and flow cytometry results was calculated. RESULTS: Highly significant values between 0.40 and 0.97 were found for the twenty-two antigens tested. A second correlation analysis performed on a per sample basis resulted in concordant results between flow cytometry and nCounter in 44-100% of the antigens tested (mean = 76%), depending on the number of blasts present in a sample, the homogeneity of the blast population, and the type of leukemia (AML or ALL). CONCLUSIONS: The nCounter technology allows for fast and easy depiction of a mRNA profile from hematologic samples. This technology has the potential to become a valuable tool for the diagnosis of acute leukemias, in addition to multi-color flow cytometry.

Converter-flux-based current control of voltage source PWM rectifiers - analysis and implementation

Pulsewidth-modulated (PWM) rectifier technology is increasingly used in industrial applications like variable-speed motor drives, since it offers several desired features such as sinusoidal input currents, controllable power factor, bidirectional power flow and high quality DC output voltage. To achieve these features,however, an effective control system with fast and accurate current and DC voltage responses is required. From various control strategies proposed to meet these control objectives, in most cases the commonly known principle of the synchronous-frame current vector control along with some space-vector PWM scheme have been applied. Recently, however, new control approaches analogous to the well-established direct torque control (DTC) method for electrical machines have also emerged to implement a high-performance PWM rectifier. In this thesis the concepts of classical synchronous-frame current control and DTC-based PWM rectifier control are combined and a new converter-flux-based current control (CFCC) scheme is introduced. To achieve sufficient dynamic performance and to ensure a stable operation, the proposed control system is thoroughly analysed and simple rules for the controller design are suggested. Special attention is paid to the estimationof the converter flux, which is the key element of converter-flux-based control. Discrete-time implementation is also discussed. Line-voltage-sensorless reactive reactive power control methods for the L- and LCL-type line filters are presented. For the L-filter an open-loop control law for the d-axis current referenceis proposed. In the case of the LCL-filter the combined open-loop control and feedback control is proposed. The influence of the erroneous filter parameter estimates on the accuracy of the developed control schemes is also discussed. A newzero vector selection rule for suppressing the zero-sequence current in parallel-connected PWM rectifiers is proposed. With this method a truly standalone and independent control of the converter units is allowed and traditional transformer isolation and synchronised-control-based solutions are avoided. The implementation requires only one additional current sensor. The proposed schemes are evaluated by the simulations and laboratory experiments. A satisfactory performance and good agreement between the theory and practice are demonstrated.

Selective catalytic reduction of nitrogen oxides with ammonia in forced unsteady state reactors - Case based reasoning and mathematical model simulation reasoning

The application of forced unsteady-state reactors in case of selective catalytic reduction of nitrogen oxides (NOx) with ammonia (NH3) is sustained by the fact that favorable temperature and composition distributions which cannot be achieved in any steady-state regime can be obtained by means of unsteady-state operations. In a normal way of operation the low exothermicity of the selective catalytic reduction (SCR) reaction (usually carried out in the range of 280-350°C) is not enough to maintain by itself the chemical reaction. A normal mode of operation usually requires supply of supplementary heat increasing in this way the overall process operation cost. Through forced unsteady-state operation, the main advantage that can be obtained when exothermic reactions take place is the possibility of trapping, beside the ammonia, the moving heat wave inside the catalytic bed. The unsteady state-operation enables the exploitation of the thermal storage capacity of the catalyticbed. The catalytic bed acts as a regenerative heat exchanger allowing auto-thermal behaviour when the adiabatic temperature rise is low. Finding the optimum reactor configuration, employing the most suitable operation model and identifying the reactor behavior are highly important steps in order to configure a proper device for industrial applications. The Reverse Flow Reactor (RFR) - a forced unsteady state reactor - corresponds to the above mentioned characteristics and may be employed as an efficient device for the treatment of dilute pollutant mixtures. As a main disadvantage, beside its advantages, the RFR presents the 'wash out' phenomena. This phenomenon represents emissions of unconverted reactants at every switch of the flow direction. As a consequence our attention was focused on finding an alternative reactor configuration for RFR which is not affected by the incontrollable emissions of unconverted reactants. In this respect the Reactor Network (RN) was investigated. Its configuration consists of several reactors connected in a closed sequence, simulating a moving bed by changing the reactants feeding position. In the RN the flow direction is maintained in the same way ensuring uniformcatalyst exploitation and in the same time the 'wash out' phenomena is annulated. The simulated moving bed (SMB) can operate in transient mode giving practically constant exit concentration and high conversion levels. The main advantage of the reactor network operation is emphasizedby the possibility to obtain auto-thermal behavior with nearly uniformcatalyst utilization. However, the reactor network presents only a small range of switching times which allow to reach and to maintain an ignited state. Even so a proper study of the complex behavior of the RN may give the necessary information to overcome all the difficulties that can appear in the RN operation. The unsteady-state reactors complexity arises from the fact that these reactor types are characterized by short contact times and complex interaction between heat and mass transportphenomena. Such complex interactions can give rise to a remarkable complex dynamic behavior characterized by a set of spatial-temporal patterns, chaotic changes in concentration and traveling waves of heat or chemical reactivity. The main efforts of the current research studies concern the improvement of contact modalities between reactants, the possibility of thermal wave storage inside the reactor and the improvement of the kinetic activity of the catalyst used. Paying attention to the above mentioned aspects is important when higher activity even at low feeding temperatures and low emissions of unconverted reactants are the main operation concerns. Also, the prediction of the reactor pseudo or steady-state performance (regarding the conversion, selectivity and thermal behavior) and the dynamicreactor response during exploitation are important aspects in finding the optimal control strategy for the forced unsteady state catalytic tubular reactors. The design of an adapted reactor requires knowledge about the influence of its operating conditions on the overall process performance and a precise evaluation of the operating parameters rage for which a sustained dynamic behavior is obtained. An apriori estimation of the system parameters result in diminution of the computational efforts. Usually the convergence of unsteady state reactor systems requires integration over hundreds of cycles depending on the initial guess of the parameter values. The investigation of various operation models and thermal transfer strategies give reliable means to obtain recuperative and regenerative devices which are capable to maintain an auto-thermal behavior in case of low exothermic reactions. In the present research work a gradual analysis of the SCR of NOx with ammonia process in forced unsteady-state reactors was realized. The investigation covers the presentationof the general problematic related to the effect of noxious emissions in the environment, the analysis of the suitable catalysts types for the process, the mathematical analysis approach for modeling and finding the system solutions and the experimental investigation of the device found to be more suitable for the present process. In order to gain information about the forced unsteady state reactor design, operation, important system parameters and their values, mathematical description, mathematicalmethod for solving systems of partial differential equations and other specific aspects, in a fast and easy way, and a case based reasoning (CBR) approach has been used. This approach, using the experience of past similarproblems and their adapted solutions, may provide a method for gaining informations and solutions for new problems related to the forced unsteady state reactors technology. As a consequence a CBR system was implemented and a corresponding tool was developed. Further on, grooving up the hypothesis of isothermal operation, the investigation by means of numerical simulation of the feasibility of the SCR of NOx with ammonia in the RFRand in the RN with variable feeding position was realized. The hypothesis of non-isothermal operation was taken into account because in our opinion ifa commercial catalyst is considered, is not possible to modify the chemical activity and its adsorptive capacity to improve the operation butis possible to change the operation regime. In order to identify the most suitable device for the unsteady state reduction of NOx with ammonia, considering the perspective of recuperative and regenerative devices, a comparative analysis of the above mentioned two devices performance was realized. The assumption of isothermal conditions in the beginningof the forced unsteadystate investigation allowed the simplification of the analysis enabling to focus on the impact of the conditions and mode of operation on the dynamic features caused by the trapping of one reactant in the reactor, without considering the impact of thermal effect on overall reactor performance. The non-isothermal system approach has been investigated in order to point out the important influence of the thermal effect on overall reactor performance, studying the possibility of RFR and RN utilization as recuperative and regenerative devices and the possibility of achieving a sustained auto-thermal behavior in case of lowexothermic reaction of SCR of NOx with ammonia and low temperature gasfeeding. Beside the influence of the thermal effect, the influence of the principal operating parameters, as switching time, inlet flow rate and initial catalyst temperature have been stressed. This analysis is important not only because it allows a comparison between the two devices and optimisation of the operation, but also the switching time is the main operating parameter. An appropriate choice of this parameter enables the fulfilment of the process constraints. The level of the conversions achieved, the more uniform temperature profiles, the uniformity ofcatalyst exploitation and the much simpler mode of operation imposed the RN as a much more suitable device for SCR of NOx with ammonia, in usual operation and also in the perspective of control strategy implementation. Theoretical simplified models have also been proposed in order to describe the forced unsteady state reactors performance and to estimate their internal temperature and concentration profiles. The general idea was to extend the study of catalytic reactor dynamics taking into account the perspectives that haven't been analyzed yet. The experimental investigation ofRN revealed a good agreement between the data obtained by model simulation and the ones obtained experimentally.

Prospective motion correction of 3D echo-planar imaging data for functional MRI using optical tracking.

We evaluated the performance of an optical camera based prospective motion correction (PMC) system in improving the quality of 3D echo-planar imaging functional MRI data. An optical camera and external marker were used to dynamically track the head movement of subjects during fMRI scanning. PMC was performed by using the motion information to dynamically update the sequence's RF excitation and gradient waveforms such that the field-of-view was realigned to match the subject's head movement. Task-free fMRI experiments on five healthy volunteers followed a 2×2×3 factorial design with the following factors: PMC on or off; 3.0mm or 1.5mm isotropic resolution; and no, slow, or fast head movements. Visual and motor fMRI experiments were additionally performed on one of the volunteers at 1.5mm resolution comparing PMC on vs PMC off for no and slow head movements. Metrics were developed to quantify the amount of motion as it occurred relative to k-space data acquisition. The motion quantification metric collapsed the very rich camera tracking data into one scalar value for each image volume that was strongly predictive of motion-induced artifacts. The PMC system did not introduce extraneous artifacts for the no motion conditions and improved the time series temporal signal-to-noise by 30% to 40% for all combinations of low/high resolution and slow/fast head movement relative to the standard acquisition with no prospective correction. The numbers of activated voxels (p<0.001, uncorrected) in both task-based experiments were comparable for the no motion cases and increased by 78% and 330%, respectively, for PMC on versus PMC off in the slow motion cases. The PMC system is a robust solution to decrease the motion sensitivity of multi-shot 3D EPI sequences and thereby overcome one of the main roadblocks to their widespread use in fMRI studies.

Plantar flexor neuromuscular adjustments following match-play football in hot and cool conditions.

We assessed neuromuscular fatigue and recovery of the plantar flexors after playing football with or without severe heat stress. Neuromuscular characteristics of the plantar flexors were assessed in 17 male players at baseline and ∼30 min, 24, and 48 h after two 90-min football matches in temperate (∼20 °C and 55% rH) and hot (∼43 °C and 20% rH) environments. Measurements included maximal voluntary strength, muscle activation, twitch contractile properties, and rate of torque development and soleus EMG (i.e., root mean square activity) rise from 0 to 30, -50, -100, and -200 ms during maximal isometric contractions for plantar flexors. Voluntary activation and peak twitch torque were equally reduced (-1.5% and -16.5%, respectively; P < 0.05) post-matches relative to baseline in both conditions, the latter persisting for at least 48 h, whereas strength losses (∼5%) were not significant. Absolute explosive force production declined (P < 0.05) 30 ms after contraction onset independently of condition, with no change at any other epochs. Globally, normalized rate of force development and soleus EMG activity rise values remained unchanged. In football, match-induced alterations in maximal and rapid torque production capacities of the plantar flexors are moderate and do not differ after competing in temperate and hot environments.

REGSTATTOOLS: freeware statistical tools for the analysis of disease population databases used in health and social studies

Background: The repertoire of statistical methods dealing with the descriptive analysis of the burden of a disease has been expanded and implemented in statistical software packages during the last years. The purpose of this paper is to present a web-based tool, REGSTATTOOLS http://regstattools.net intended to provide analysis for the burden of cancer, or other group of disease registry data. Three software applications are included in REGSTATTOOLS: SART (analysis of disease"s rates and its time trends), RiskDiff (analysis of percent changes in the rates due to demographic factors and risk of developing or dying from a disease) and WAERS (relative survival analysis). Results: We show a real-data application through the assessment of the burden of tobacco-related cancer incidence in two Spanish regions in the period 1995-2004. Making use of SART we show that lung cancer is the most common cancer among those cancers, with rising trends in incidence among women. We compared 2000-2004 data with that of 1995-1999 to assess percent changes in the number of cases as well as relative survival using RiskDiff and WAERS, respectively. We show that the net change increase in lung cancer cases among women was mainly attributable to an increased risk of developing lung cancer, whereas in men it is attributable to the increase in population size. Among men, lung cancer relative survival was higher in 2000-2004 than in 1995-1999, whereas it was similar among women when these time periods were compared. Conclusions: Unlike other similar applications, REGSTATTOOLS does not require local software installation and it is simple to use, fast and easy to interpret. It is a set of web-based statistical tools intended for automated calculation of population indicators that any professional in health or social sciences may require.

BioSuper: A web tool for the superimposition of biomolecules and assemblies with rotational symmetry

Background Most of the proteins in the Protein Data Bank (PDB) are oligomeric complexes consisting of two or more subunits that associate by rotational or helical symmetries. Despite the myriad of superimposition tools in the literature, we could not find any able to account for rotational symmetry and display the graphical results in the web browser. Results BioSuper is a free web server that superimposes and calculates the root mean square deviation (RMSD) of protein complexes displaying rotational symmetry. To the best of our knowledge, BioSuper is the first tool of its kind that provides immediate interactive visualization of the graphical results in the browser, biomolecule generator capabilities, different levels of atom selection, sequence-dependent and structure-based superimposition types, and is the only web tool that takes into account the equivalence of atoms in side chains displaying symmetry ambiguity. BioSuper uses ICM program functionality as a core for the superimpositions and displays the results as text, HTML tables and 3D interactive molecular objects that can be visualized in the browser or in Android and iOS platforms with a free plugin. Conclusions BioSuper is a fast and functional tool that allows for pairwise superimposition of proteins and assemblies displaying rotational symmetry. The web server was created after our own frustration when attempting to superimpose flexible oligomers. We strongly believe that its user-friendly and functional design will be of great interest for structural and computational biologists who need to superimpose oligomeric proteins (or any protein). BioSuper web server is freely available to all users at http://ablab.ucsd.edu/BioSuper webcite.

Rapid analysis of multiclass antibiotic residues and some of their metabolites in hospital, urban wastewater and river water by ultra-highperformance liquid chromatography coupled to quadrupole-linear ion trap tandem mass spectrometry

The present work describes the development of a fast and robust analytical method for the determination of 53 antibiotic residues, covering various chemical groups and some of their metabolites, in environmental matrices that are considered important sources of antibiotic pollution, namely hospital and urban wastewaters, as well as in river waters. The method is based on automated off-line solid phase extraction (SPE) followed by ultra-high-performance liquid chromatography coupled to quadrupole linear ion trap tandem mass spectrometry (UHPLC–QqLIT). For unequivocal identification and confirmation, and in order to fulfill EU guidelines, two selected reaction monitoring (SRM) transitions per compound are monitored (the most intense one is used for quantification and the second one for confirmation). Quantification of target antibiotics is performed by the internal standard approach, using one isotopically labeled compound for each chemical group, in order to correct matrix effects. The main advantages of the method are automation and speed-up of sample preparation, by the reduction of extraction volumes for all matrices, the fast separation of a wide spectrum of antibiotics by using ultra-high-performance liquid chromatography, its sensitivity (limits of detection in the low ng/L range) and selectivity (due to the use of tandem mass spectrometry) The inclusion of β-lactam antibiotics (penicillins and cephalosporins), which are compounds difficult to analyze in multi-residue methods due to their instability in water matrices, and some antibiotics metabolites are other important benefits of the method developed. As part of the validation procedure, the method developed was applied to the analysis of antibiotics residues in hospital, urban influent and effluent wastewaters as well as in river water samples

Identification of new transformation products during enzymatic treatment of tetracycline and erythromycin antibiotics at laboratory scale by an on-line turbulent flow liquid-chromatography coupled to a high resolution mass spectrometer LTQ-Orbitrap

This work describes the formation of transformation products (TPs) by the enzymatic degradation at laboratory scale of two highly consumed antibiotics: tetracycline (Tc) and erythromycin (ERY). The analysis of the samples was carried out by a fast and simple method based on the novel configuration of the on-line turbulent flow system coupled to a hybrid linear ion trap – high resolution mass spectrometer. The method was optimized and validated for the complete analysis of ERY, Tc and their transformation products within 10 min without any other sample manipulation. Furthermore, the applicability of the on-line procedure was evaluated for 25 additional antibiotics, covering a wide range of chemical classes in different environmental waters with satisfactory quality parameters. Degradation rates obtained for Tc by laccase enzyme and ERY by EreB esterase enzyme without the presence of mediators were ∼78% and ∼50%, respectively. Concerning the identification of TPs, three suspected compounds for Tc and five of ERY have been proposed. In the case of Tc, the tentative molecular formulas with errors mass within 2 ppm have been based on the hypothesis of dehydroxylation, (bi)demethylation and oxidation of the rings A and C as major reactions. In contrast, the major TP detected for ERY has been identified as the “dehydration ERY-A”, with the same molecular formula of its parent compound. In addition, the evaluation of the antibiotic activity of the samples along the enzymatic treatments showed a decrease around 100% in both cases

Pharmacogenetic and clinical study on adverse effects induced by psychotropic drugs

Second-generation antipsychotics (SGAs) have become the first-line antipsychotic treatment for psychotic disorders due to their better overall tolerance compared to classical antipsychotics. However, metabolic side effects such as weight gain are frequently described during treatment with SGAs and/or other psychotropic drugs including some antidepressants and mood stabilizers, which may also result in poor adherence to treatment. The aim of this work was to investigate different methods to predict common side effects, in particular weight gain during treatment with weight gain inducing psychotropic drugs. Firstly, clinical data were used to determine the potential predictive power of a one month weight gain on weight increase after three and 12 months of treatment (n=351 patients). A fast and strong weight gain of >5% after a period of one month (>5%WG) was found to be the best predictor for an important weight gain at three (>15%) and 12 months (>20%). Similar analyses in an independent cohort of psychiatric adolescents (n=42), showed that a comparable >4% weight gain at one month is the best predictor for an important weight gain at three months (>15%). Secondly, we aimed to determine whether an extensive analysis of genes could be used, in addition to clinical factors, to predict patients at risk for >5%WG or for type 2 diabetes (T2D). Adding genetic markers to clinical variables to predict >5%WG increased significantly the area under the curve (AUC) of the analysis (AUCfinai:0.92, AUCdmicai:0.75, pcO.OOOl, n=248). Conversely, genetic risk scores were found to be associated with T2D (OR: 2.5, p=0.03, n=285) but without a significant increase of AUC'when compared to the prediction based to clinical factors alone. Finally, therapeutic drug monitoring was used to predict extrapyramidal symptoms during risperidone treatment (n=150). Active moiety (sum of risperidone and of its active metabolite 9- hydroxyrisperidone plasma concentrations) of >40 ng/ml should be targeted only in case of insufficient response. These results highlight different approaches for personalizing psychotropic treatments in order to reduce related side effects. Further research is needed, in particular on the identification of genetic markers, to improve the implementation of these results into clinical practice. Résumé Les antipsychotiques atypiques (APA) sont devenus le traitement antipsychotique de première intention pour le traitement des psychoses, grâce à un profil d'effets secondaires plus favorables comparé aux antipsychotiques typiques. Néanmoins, d'autres effets indésirables d'ordre métabolique (ex. prise pondérale) sont observés sous APA, stabilisateurs de l'humeur et/ou certains antidépresseurs, pouvant aussi limiter l'adhérence au traitement. L'objectif de ce travail est d'explorer différentes méthodes permettant de prédire des effets secondaires courants, en particulier la prise de poids durant un traitement avec des psychotropes pouvant induire un tel effet. Dans une première partie, des données cliniques ont été évaluées pour leurs potentiels prédictifs d'une prise de poids à un mois sur une prise de poids à trois et 12 mois de traitement (n=351 patients). Une prise de poids rapide et forte >5% à un mois (PP>5%) s'est avérée être le meilleur prédicteur pour une prise pondérale importante à trois (>15%) et 12 (>20%) mois de traitement. Des analyses similaires dans une cohorte pédiatrique (n=42) ont indiqué une prise de poids >4% à un mois comme le meilleur prédicteur pour une prise pondérale importante (>15%) à trois mois de traitement. Dans une deuxième partie, des marqueurs génétiques, en complément aux données cliniques, ont été analysés pour leur contribution potentielle à la prédiction d'une PP>5% et au dépistage du diabète de type 2 (DT2). L'ajout de variants génétiques aux données cliniques afin de prédire une PP>5% a augmenté significativement l'aire sous la courbe (ASC) de l'analyse (ASCflnai:0.92, ASCC|inique:0.75, p<0.0001, n=248). Concernant le DT2, un score génétique est associé au DT2 (OR: 2.5, p=0.03, n=285), néanmoins aucune augmentation significative de l'ASC n'a été observée par rapport à l'analyse avec les données cliniques seules. Finalement, des mesures de concentrations plasmatiques de médicaments ont été utilisées pour prédire la survenue de symptômes extrapyramidaux sous rispéridone (n=150). Cette analyse nous a permis d'établir qu'une concentration plasmatique de rispéridone associée à son métabolite actif >40 ng/ml ne devrait être recherchée qu'en cas de réponse clinique insuffisante. Ces différents résultats soulignent différentes approches pour personnaliser la prescription de psychotropes afin de réduire la survenue d'effets secondaires. Des études supplémentaires sont néanmoins nécessaires, en particulier sur l'identification de marqueurs génétiques, afin d'améliorer l'implémentation de ces résultats en pratique clinique. Résumé large publique Les antipsychotiques atypiques et autres traitements psychotropes sont couramment utilisés pour traiter les symptômes liés à la schizophrénie et aux troubles de l'humeur. Comme pour tout médicament, des effets secondaires sont observés. L'objectif de ce travail est d'explorer différentes méthodes qui permettraient de prédire la survenue de certains effets indésirables, en particulier une prise de poids et la survenue d'un diabète. Dans une première partie, nous avons évalué l'effet d'une prise de poids précoce sur une prise de poids au long terme sous traitement psychotrope. Les analyses ont mis en évidence dans une population psychiatrique qu'une prise de poids à un mois >5% par rapport au poids initial permettait de prédire une prise pondérale importante après trois (>15%) et 12 (>20%) mois de traitement. Un résultat semblable a. été observé dans un autre groupe de patients exclusivement pédiatriques. Dans une deuxième partie, nous avons évalué la contribution potentielle de marqueurs génétiques à la prédiction d'une prise pondérale de >5% après un mois de traitement ainsi que dans la survenue d'un diabète de type 2. Pour la prise de poids, la combinaison des données génétiques aux données cliniques a permis d'augmenter de 17% la précision de la prédiction, en passant de 70% à 87%. Concernant la survenue d'un diabète, les données génétiques n'ont pas amélioré la prédiction. Finalement, nous avons analysé la relation possible entre les concentrations sanguines d'un antipsychotique atypique couramment utilisé, la rispéridone, et la survenue d'effets secondaires (ici les tremblements). Il est ressorti de cette étude qu'une concentration plasmatique du médicament supérieure à 40 ng/ml ne devrait être dépassée qu'en cas de réponse thérapeutique insuffisante, au risque de voir augmenter la survenue d'effets secondaires du type tremblements. Ces résultats démontrent la possibilité de prédire avec une bonne précision la survenue de certains effets secondaires. Cependant, en particulier dans le domaine de la génétique, d'autres études sont nécessaires afin de confirmer les résultats obtenus dans nos analyses. Une fois cette étape franchie, il serait possible d'utiliser ces outils dans la pratique clinique. A terme, cela pourrait permettre au prescripteur de sélectionner les traitements les mieux adaptés aux profils spécifiques de chaque patient.

Accelerated Microstructure Imaging via Convex Optimisation for regions with multiple fibres (AMICOx)

This paper reviews and extends our previous work to enable fast axonal diameter mapping from diffusion MRI data in the presence of multiple fibre populations within a voxel. Most of the existing mi-crostructure imaging techniques use non-linear algorithms to fit their data models and consequently, they are computationally expensive and usually slow. Moreover, most of them assume a single axon orientation while numerous regions of the brain actually present more complex configurations, e.g. fiber crossing. We present a flexible framework, based on convex optimisation, that enables fast and accurate reconstructions of the microstructure organisation, not limited to areas where the white matter is coherently oriented. We show through numerical simulations the ability of our method to correctly estimate the microstructure features (mean axon diameter and intra-cellular volume fraction) in crossing regions.

Sleep and Menopause. Hormone Therapy and Sleep Deprivation

This study evaluated the effect of menopause, hormone therapy (HT) and aging on sleep. Further, the mechanisms behind these effects were examined by studying the associations between sleep and the nocturnal profiles of sleep-related hormones. Crosssectional study protocols were used to evaluate sleep in normal conditions and during recovery from sleep deprivation. The effect of initiation of HT on sleep and sleeprelated hormones was studied in a prospective controlled trial. Young, premenopausal and postmenopausal women were studied, and the methods included polysomnography, 24-h blood sampling, questionnaires and cognitive tests of attention. Postmenopausal women were less satisfied with their sleep quality than premenopausal women, but this was not reflected in sleepiness or attention. The objective sleep quality was mainly similar in pre- and postmenopausal women, but differed from young women. The recovery mechanisms from sleep deprivation were relatively well-preserved after menopause. HT offered no advantage to sleep after sleep deprivation or under normal conditions. The decreased growth hormone (GH) and prolactin (PRL) levels after menopause were reversible with HT. Neither menopause nor HT had any effect on cortisol levels. In premenopausal women, HT had only minor effects on PRL and cortisol levels. The temporal link between GH and slow wave sleep (SWS) was weaker after menopause. PRL levels were temporally associated with sleep stages, and higher levels were seen during SWS and lower during rapid-eye-movement (REM) sleep. Sleep quality after menopause is better determined by age than by menopausal state. Although HT restores the decreased levels of GH and PRL after menopause, it offers no advantage to sleep quality under normal conditions or after sleep deprivation.

Reconstruction and analysis of surface variation using photometric stereo

In many industrial applications, accurate and fast surface reconstruction is essential for quality control. Variation in surface finishing parameters, such as surface roughness, can reflect defects in a manufacturing process, non-optimal product operational efficiency, and reduced life expectancy of the product. This thesis considers reconstruction and analysis of high-frequency variation, that is roughness, on planar surfaces. Standard roughness measures in industry are calculated from surface topography. A fast and non-contact method to obtain surface topography is to apply photometric stereo in the estimation of surface gradients and to reconstruct the surface by integrating the gradient fields. Alternatively, visual methods, such as statistical measures, fractal dimension and distance transforms, can be used to characterize surface roughness directly from gray-scale images. In this thesis, the accuracy of distance transforms, statistical measures, and fractal dimension are evaluated in the estimation of surface roughness from gray-scale images and topographies. The results are contrasted to standard industry roughness measures. In distance transforms, the key idea is that distance values calculated along a highly varying surface are greater than distances calculated along a smoother surface. Statistical measures and fractal dimension are common surface roughness measures. In the experiments, skewness and variance of brightness distribution, fractal dimension, and distance transforms exhibited strong linear correlations to standard industry roughness measures. One of the key strengths of photometric stereo method is the acquisition of higher frequency variation of surfaces. In this thesis, the reconstruction of planar high-frequency varying surfaces is studied in the presence of imaging noise and blur. Two Wiener filterbased methods are proposed of which one is optimal in the sense of surface power spectral density given the spectral properties of the imaging noise and blur. Experiments show that the proposed methods preserve the inherent high-frequency variation in the reconstructed surfaces, whereas traditional reconstruction methods typically handle incorrect measurements by smoothing, which dampens the high-frequency variation.