Population pharmacokinetics of imatinib in CML and GIST patients under long-term treatment

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukaemia (CML) and gastro-intestinal stromal tumour (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occur in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualisation. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after latest dose, were measured in 59 patients receiving Glivec® at diverse regimens, using a validated chromatographic method (HPLC-UV) developed for this study. The results were analysed by non-linear mixed effect modelling (NONMEM). A one- compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. The MDR1 polymorphism 3435C>T appears to affect the disposition of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40%) and distribution volume (71%). Together with intra-patient variability (34%), this translates into an 8-fold width of the 90%-prediction interval of plasma concentrations expected under a fixed dosing regimen ! This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring programme for imatinib. It may help to individualise the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Development of Abutment Design Standards for Local Bridge Designs, Volume 1 of 3, Development of Design Methodology, August 2004

Several superstructure design methodologies have been developed for low volume road bridges by the Iowa State University Bridge Engineering Center. However, to date no standard abutment designs have been developed. Thus, there was a need to establish an easy to use design methodology in addition to generating generic abutment standards and other design aids for the more common substructure systems used in Iowa. The final report for this project consists of three volumes. The first volume (this volume) summarizes the research completed in this project. A survey of the Iowa County Engineers was conducted from which it was determined that while most counties use similar types of abutments, only 17 percent use some type of standard abutment designs or plans. A literature review revealed several possible alternative abutment systems for future use on low volume road bridges in addition to two separate substructure lateral load analysis methods. These consisted of a linear and a non-linear method. The linear analysis method was used for this project due to its relative simplicity and the relative accuracy of the maximum pile moment when compared to values obtained from the more complex non-linear analysis method. The resulting design methodology was developed for single span stub abutments supported on steel or timber piles with a bridge span length ranging from 20 to 90 ft and roadway widths of 24 and 30 ft. However, other roadway widths can be designed using the foundation design template provided. The backwall height is limited to a range of 6 to 12 ft, and the soil type is classified as cohesive or cohesionless. The design methodology was developed using the guidelines specified by the American Association of State Highway Transportation Officials Standard Specifications, the Iowa Department of Transportation Bridge Design Manual, and the National Design Specifications for Wood Construction. The second volume introduces and outlines the use of the various design aids developed for this project. Charts for determining dead and live gravity loads based on the roadway width, span length, and superstructure type are provided. A foundation design template was developed in which the engineer can check a substructure design by inputting basic bridge site information. Tables published by the Iowa Department of Transportation that provide values for estimating pile friction and end bearing for different combinations of soils and pile types are also included. Generic standard abutment plans were developed for which the engineer can provide necessary bridge site information in the spaces provided. These tools enable engineers to design and detail county bridge substructures more efficiently. The third volume provides two sets of calculations that demonstrate the application of the substructure design methodology developed in this project. These calculations also verify the accuracy of the foundation design template. The printouts from the foundation design template are provided at the end of each example. Also several tables provide various foundation details for a pre-cast double tee superstructure with different combinations of soil type, backwall height, and pile type.

Development of Abutment Design Standards for Local Bridge Designs, Volume 3 of 3, Verification of Design Methodology, August 2004

Several superstructure design methodologies have been developed for low volume road bridges by the Iowa State University Bridge Engineering Center. However, to date no standard abutment designs have been developed. Thus, there was a need to establish an easy to use design methodology in addition to generating generic abutment standards and other design aids for the more common substructure systems used in Iowa. The final report for this project consists of three volumes. The first volume summarizes the research completed in this project. A survey of the Iowa County Engineers was conducted from which it was determined that while most counties use similar types of abutments, only 17 percent use some type of standard abutment designs or plans. A literature review revealed several possible alternative abutment systems for future use on low volume road bridges in addition to two separate substructure lateral load analysis methods. These consisted of a linear and a non-linear method. The linear analysis method was used for this project due to its relative simplicity and the relative accuracy of the maximum pile moment when compared to values obtained from the more complex non-linear analysis method. The resulting design methodology was developed for single span stub abutments supported on steel or timber piles with a bridge span length ranging from 20 to 90 ft and roadway widths of 24 and 30 ft. However, other roadway widths can be designed using the foundation design template provided. The backwall height is limited to a range of 6 to 12 ft, and the soil type is classified as cohesive or cohesionless. The design methodology was developed using the guidelines specified by the American Association of State Highway Transportation Officials Standard Specifications, the Iowa Department of Transportation Bridge Design Manual, and the National Design Specifications for Wood Construction. The second volume introduces and outlines the use of the various design aids developed for this project. Charts for determining dead and live gravity loads based on the roadway width, span length, and superstructure type are provided. A foundation design template was developed in which the engineer can check a substructure design by inputting basic bridge site information. Tables published by the Iowa Department of Transportation that provide values for estimating pile friction and end bearing for different combinations of soils and pile types are also included. Generic standard abutment plans were developed for which the engineer can provide necessary bridge site information in the spaces provided. These tools enable engineers to design and detail county bridge substructures more efficiently. The third volume (this volume) provides two sets of calculations that demonstrate the application of the substructure design methodology developed in this project. These calculations also verify the accuracy of the foundation design template. The printouts from the foundation design template are provided at the end of each example. Also several tables provide various foundation details for a pre-cast double tee superstructure with different combinations of soil type, backwall height, and pile type.

Development of Abutment Design Standards for Local Bridge Designs, Volume 2 of 3, Design Manual, August 2004

Several superstructure design methodologies have been developed for low volume road bridges by the Iowa State University Bridge Engineering Center. However, to date no standard abutment designs have been developed. Thus, there was a need to establish an easy to use design methodology in addition to generating generic abutment standards and other design aids for the more common substructure systems used in Iowa. The final report for this project consists of three volumes. The first volume summarizes the research completed in this project. A survey of the Iowa County Engineers was conducted from which it was determined that while most counties use similar types of abutments, only 17 percent use some type of standard abutment designs or plans. A literature review revealed several possible alternative abutment systems for future use on low volume road bridges in addition to two separate substructure lateral load analysis methods. These consisted of a linear and a non-linear method. The linear analysis method was used for this project due to its relative simplicity and the relative accuracy of the maximum pile moment when compared to values obtained from the more complex non-linear analysis method. The resulting design methodology was developed for single span stub abutments supported on steel or timber piles with a bridge span length ranging from 20 to 90 ft and roadway widths of 24 and 30 ft. However, other roadway widths can be designed using the foundation design template provided. The backwall height is limited to a range of 6 to 12 ft, and the soil type is classified as cohesive or cohesionless. The design methodology was developed using the guidelines specified by the American Association of State Highway Transportation Officials Standard Specifications, the Iowa Department of Transportation Bridge Design Manual, and the National Design Specifications for Wood Construction. The second volume (this volume) introduces and outlines the use of the various design aids developed for this project. Charts for determining dead and live gravity loads based on the roadway width, span length, and superstructure type are provided. A foundation design template was developed in which the engineer can check a substructure design by inputting basic bridge site information. Tables published by the Iowa Department of Transportation that provide values for estimating pile friction and end bearing for different combinations of soils and pile types are also included. Generic standard abutment plans were developed for which the engineer can provide necessary bridge site information in the spaces provided. These tools enable engineers to design and detail county bridge substructures more efficiently. The third volume provides two sets of calculations that demonstrate the application of the substructure design methodology developed in this project. These calculations also verify the accuracy of the foundation design template. The printouts from the foundation design template are provided at the end of each example. Also several tables provide various foundation details for a pre-cast double tee superstructure with different combinations of soil type, backwall height, and pile type.

Asymmetries in the opportunity structure. Intergenerational mobility trends in Europe

It remains unclear whether social mobility is increasing in the advancednations. The answer may depend on mobility patterns within very recentbirth cohorts. We use the inter-generational module in the 2005 EUSILCwhich allows us to include more recent cohorts. Comparingacross two Nordic and three Continental European countries, weestimate inter-generational mobility trends for sons both indirectly, viasocial origin effects on educational attainment, and directly in terms ofadult income attainment. In line with other studies we find substantiallymore mobility in Scandinavia, but also that traditionally less mobilesocieties, like Spain, are moving towards greater equality. We focusparticularly on non-linear relations. Most interestingly, we revealevident asymmetries in the process of equalizing life chances, inDenmark. The disadvantages associated with low social class originshave largely disappeared, but the advantages related to privilegedorigins persist.

Wavelet analysis residual kriging vs. neural network residual kriging

This paper deals with the problem of spatial data mapping. A new method based on wavelet interpolation and geostatistical prediction (kriging) is proposed. The method - wavelet analysis residual kriging (WARK) - is developed in order to assess the problems rising for highly variable data in presence of spatial trends. In these cases stationary prediction models have very limited application. Wavelet analysis is used to model large-scale structures and kriging of the remaining residuals focuses on small-scale peculiarities. WARK is able to model spatial pattern which features multiscale structure. In the present work WARK is applied to the rainfall data and the results of validation are compared with the ones obtained from neural network residual kriging (NNRK). NNRK is also a residual-based method, which uses artificial neural network to model large-scale non-linear trends. The comparison of the results demonstrates the high quality performance of WARK in predicting hot spots, reproducing global statistical characteristics of the distribution and spatial correlation structure.

Detection of Optimal Models in Parameter Space with Support Vector Machines

The paper proposes an approach aimed at detecting optimal model parameter combinations to achieve the most representative description of uncertainty in the model performance. A classification problem is posed to find the regions of good fitting models according to the values of a cost function. Support Vector Machine (SVM) classification in the parameter space is applied to decide if a forward model simulation is to be computed for a particular generated model. SVM is particularly designed to tackle classification problems in high-dimensional space in a non-parametric and non-linear way. SVM decision boundaries determine the regions that are subject to the largest uncertainty in the cost function classification, and, therefore, provide guidelines for further iterative exploration of the model space. The proposed approach is illustrated by a synthetic example of fluid flow through porous media, which features highly variable response due to the parameter values' combination.

BME-based uncertainty assessment of the Chernobyl fallout

The vast territories that have been radioactively contaminated during the 1986 Chernobyl accident provide a substantial data set of radioactive monitoring data, which can be used for the verification and testing of the different spatial estimation (prediction) methods involved in risk assessment studies. Using the Chernobyl data set for such a purpose is motivated by its heterogeneous spatial structure (the data are characterized by large-scale correlations, short-scale variability, spotty features, etc.). The present work is concerned with the application of the Bayesian Maximum Entropy (BME) method to estimate the extent and the magnitude of the radioactive soil contamination by 137Cs due to the Chernobyl fallout. The powerful BME method allows rigorous incorporation of a wide variety of knowledge bases into the spatial estimation procedure leading to informative contamination maps. Exact measurements (?hard? data) are combined with secondary information on local uncertainties (treated as ?soft? data) to generate science-based uncertainty assessment of soil contamination estimates at unsampled locations. BME describes uncertainty in terms of the posterior probability distributions generated across space, whereas no assumption about the underlying distribution is made and non-linear estimators are automatically incorporated. Traditional estimation variances based on the assumption of an underlying Gaussian distribution (analogous, e.g., to the kriging variance) can be derived as a special case of the BME uncertainty analysis. The BME estimates obtained using hard and soft data are compared with the BME estimates obtained using only hard data. The comparison involves both the accuracy of the estimation maps using the exact data and the assessment of the associated uncertainty using repeated measurements. Furthermore, a comparison of the spatial estimation accuracy obtained by the two methods was carried out using a validation data set of hard data. Finally, a separate uncertainty analysis was conducted that evaluated the ability of the posterior probabilities to reproduce the distribution of the raw repeated measurements available in certain populated sites. The analysis provides an illustration of the improvement in mapping accuracy obtained by adding soft data to the existing hard data and, in general, demonstrates that the BME method performs well both in terms of estimation accuracy as well as in terms estimation error assessment, which are both useful features for the Chernobyl fallout study.

Cytogenetic response to imatinib in chronic myeloid leukaemia patients: concentration dependency and associated influences under field-conditions

Introduction: Imatinib, a first-line drug for chronic myeloid leukaemia (CML), has been increasingly proposed for therapeutic drug monitoring (TDM), as trough concentrations >=1000 ng/ml (Cmin) have been associated with improved molecular and complete cytogenetic response (CCyR). The pharmacological monitoring project of EUTOS (European Treatment and Outcome Study) was launched to validate retrospectively the correlation between Cmin and response in a large population of patients followed by central TDM in Bordeaux.¦Methods: 1898 CML patients with first TDM 0-9 years after imatinib initiation, providing cytogenetic data along with demographic and comedication (37%) information, were included. Individual Cmin, estimated by non-linear regression (NONMEM), was adjusted to initial standard dose (400 mg/day) and stratified at 1000 ng/ml. Kaplan-Meier estimates of overall cumulative CCyR rates (stratified by sex, age, comedication and Cmin) were compared using asymptotic logrank k-sample test for interval-censored data. Differences in Cmin were assessed by Wilcoxon test.¦Results: There were no significant differences in overall cumulative CCyR rates between Cmin strata, sex and comedication with P-glycoprotein inhibitors/inducers or CYP3A4 inhibitors (p >0.05). Lower rates were observed in 113 young patients <30 years (p = 0.037; 1-year rates: 43% vs 60% in older patients), as well as in 29 patients with CYP3A4 inducers (p = 0.001, 1-year rates: 40% vs 66% without). Higher rates were observed in 108 patients on organic-cation-transporter-1 (hOCT-1) inhibitors (p = 0.034, 1-year rates: 83% vs 56% without). Considering 1-year CCyR rates, a trend towards better response for Cmin above 1000 ng/ml was observed: 64% (95%CI: 60-69%) vs 59% (95%CI: 56-61%). Median Cmin (400 mg/day) was significantly reduced in male patients (732 vs 899ng/ml, p <0.001), young patients <30 years (734 vs 802 ng/ml, p = 0.037) and under CYP3A4 inducers (758 vs 859 ng/ml, p = 0.022). Under hOCT-1 inhibitors, Cmin was increased (939 vs 827 ng/ml, p = 0.038).¦Conclusion: Based on observational TDM data, the impact of imatinib Cmin >1000 ng/ml on CCyR was not salient. Young CML patients (<30 years) and patients taking CYP3A4 inducers probably need close monitoring and possibly higher imatinib doses, due to lower Cmin along with lower CCyR rates. Patients taking hOCT-1 inhibitors seem in contrast to have improved CCyR response rates. The precise role for imatinib TDM remains to be established prospectively.

DISTINCT TEMPORALITIES IN THE BREAST CANCER DISEASE PROCESS

Comprehensive approach study aimed understanding the reflections and contrasts between personal time and medical therapy protocol time in the life of a young woman with breast cancer. Addressed as a situational study and grounded in Beth’s life story about getting sick and dying of cancer at age 34, the study’s data collection process employed interviews, observation and medical record analysis. The construction of the analytic-synthetic box based on the chronology of Beth’s clinical progression, treatment phases and temporal perception of occurrences enabled us to point out a linear medical therapy protocol time identified by the diagnosis and treatment sequencing process. On the other hand, Beth’s experienced time was marked by simultaneous and non-linear events that generated suffering resulting from the disease. Such comprehension highlights the need for healthcare professionals to take into account the time experienced by the patient, thus providing an indispensable cancer therapeutic protocol with a personal character.

Parameterized expectations approach; Some practical issues

We discuss some practical issues related to the use of the Parameterized Expectations Approach (PEA) for solving non-linear stochastic dynamic models with rational expectations. This approach has been applied in models of macroeconomics, financial economics, economic growth, contracttheory, etc. It turns out to be a convenient algorithm, especially when there is a large number of state variables and stochastic shocks in the conditional expectations. We discuss some practical issues having to do with the application of the algorithm, and we discuss a Fortran program for implementing the algorithm that is available through the internet.We discuss these issues in a battery of six examples.

Mobile termination and mobile penetration

In this paper, we study how access pricing affects network competition when subscription demand is elastic and each network uses non-linear prices and can applytermination-based price discrimination. In the case of a fixed per minute terminationcharge, we find that a reduction of the termination charge below cost has two opposing effects: it softens competition but helps to internalize network externalities. Theformer reduces mobile penetration while the latter boosts it. We find that firms always prefer termination charge below cost for either motive while the regulator preferstermination below cost only when this boosts penetration.Next, we consider the retail benchmarking approach (Jeon and Hurkens, 2008)that determines termination charges as a function of retail prices and show that thisapproach allows the regulator to increase penetration without distorting call volumes.

Estimating overidentified, nonrecursive, time-varying coefficients structural VARs

This paper provides a method to estimate time varying coefficients structuralVARs which are non-recursive and potentially overidentified. The procedureallows for linear and non-linear restrictions on the parameters, maintainsthe multi-move structure of standard algorithms and can be used toestimate structural models with different identification restrictions. We studythe transmission of monetary policy shocks and compare the results with thoseobtained with traditional methods.

Abcès du sein: privilégier la ponction-aspiration échoguidée [Ultrasonography-guided drainage should be considered as the first-line approach for breast abscesses treatment].

The abscesses of the breast are puerperal or non puerperal. The Staphylococcus aureus is the most common germ. The diagnosis is based on clinical criterias and confirmed by the ultrasonography. The percutaneous ultrasonography-guided drainage must be proposed in first intent to treat. Surgical treatment is still valid with a relapsing or chronic abscess, or after the non operative processes have failed.

Nucleation and growth of metamorphic minerals in contact aureoles

THESIS ABSTRACT Nucleation and growth of metamorphic minerals are the consequence of changing P-T-X-conditions. The thesis presented here focuses on processes governing nucleation and growth of minerals in contact metamorphic environments using a combination of geochemical analytics (chemical-, isotope-, and trace element composition), statistical treatments of spatial data, and numerical models. It is shown, that a combination of textural modeling and stable isotope analysis allows a distinction between several possible reaction paths for olivine growth in a siliceous dolomite contact aureole. It is suggested that olivine forms directly from dolomite and quartz. The formation of olivine from this metastable reaction implies metamorphic crystallization far from equilibrium. As a major consequence, the spatial distribution of metamorphic mineral assemblages in a contact aureole cannot be interpreted as a proxy for the temporal evolution of a single rock specimen, because each rock undergoes a different reaction path, depending on temperature, heating rate, and fluid-infiltration rate. A detailed calcite-dolomite thermometry study was initiated on multiple scales ranging from aureole scale to the size of individual crystals. Quantitative forward models were developed to evaluate the effect of growth zoning, volume diffusion and the formation of submicroscopic exsolution lamellae (<1 µm) on the measured Mg-distribution in individual calcite crystals and compare the modeling results to field data. This study concludes that Mg-distributions in calcite grains of the Ubehebe Peak contact aureole are the consequence of rapid crystal growth in combination with diffusion and exsolution. The crystallization history of a rock is recorded in the chemical composition, the size and the distribution of its minerals. Near the Cima Uzza summit, located in the southern Adamello massif (Italy), contact metamorphic brucite bearing dolomite marbles are exposed as xenoliths surrounded by mafic intrusive rocks. Brucite is formed retrograde pseudomorphing spherical periclase crystals. Crystal size distributions (CSD's) of brucite pseudomorphs are presented for two profiles and combined with geochemistry data and petrological information. Textural analyses are combined with geochemistry data in a qualitative model that describes the formation periclase. As a major outcome, this expands the potential use of CSD's to systems of mineral formation driven by fluid-infiltration. RESUME DE LA THESE La nucléation et la croissance des minéraux métamorphiques sont la conséquence de changements des conditions de pression, température et composition chimique du système (PT-X). Cette thèse s'intéresse aux processus gouvernant la nucléation et la croissance des minéraux au cours d'un épisode de métamorphisme de contact, en utilisant la géochimie analytique (composition chimique, isotopique et en éléments traces), le traitement statistique des données spatiales et la modélisation numérique. Il est montré que la combinaison d'un modèle textural avec des analyses en isotopes stables permet de distinguer plusieurs chemins de réactions possibles conduisant à la croissance de l'olivine dans une auréole de contact riche en Silice et dolomite. Il est suggéré que l'olivine se forme directement à partir de la dolomie et du quartz. Cette réaction métastable de formation de l'olivine implique une cristallisation métamorphique loin de l'équilibre. La principale conséquence est que la distribution spatiale des assemblages de minéraux métamorphiques dans une auréole de contact ne peut pas être considérée comme un témoin de l'évolution temporelle d'un type de roche donné, puisque chaque type de roche suit différents chemins de réactions, en fonction de la température, la vitesse de réchauffement et le taux d'infiltration du fluide. Une étude thermométrique calcite-dolomite détaillée a été réalisée à diverses échelles, depuis l'échelle de l'auréole de contact jusqu'à l'échelle du cristal. Des modèles numériques quantitatifs ont été développés pour évaluer l'effet des zonations de croissance, de la diffusion volumique et de la formation de lamelles d'exsolution submicroscopiques (<1µm) sur la distribution du magnésium mesuré dans des cristaux de calcite individuels. Les résultats de ce modèle ont été comparés ä des échantillons naturels. Cette étude montre que la distribution du Mg dans les grains de calcite de l'auréole de contact de l'Ubehebe Peak (USA) résulte d'une croissance cristalline rapide, associée aux processus de diffusion et d'exsolution. L'histoire de cristallisation d'une roche est enregistrée dans la composition chimique, la taille et la distribution de ses minéraux. Près du sommet Cima Uzza situé au sud du massif d'Adamello (Italie), des marbres dolomitiques à brucite du métamorphisme de contact forment des xénolithes dans une intrusion mafique. La brucite constitue des pseudomorphes rétrogrades du périclase. Les distributions de taille des cristaux (CSD) des pseudomorphes de brucite sont présentées pour deux profiles et sont combinées aux données géochimiques et pétrologiques. Les analyses textorales sont combinées aux données géochimiques dans un modèle qualitatif qui décrit la formation du périclase. Ceci élargit l'utilisation potentielle de la C5D aux systèmes de formation de minéraux controlés par les infiltrations fluides. THESIS ABSTRACT (GENERAL PUBLIC) Rock textures are essentially the result of a complex interaction of nucleation, growth and deformation as a function of changing physical conditions such as pressure and temperature. Igneous and metamorphic textures are especially attractive to study the different mechanisms of texture formation since most of the parameters like pressure-temperature-paths are quite well known for a variety of geological settings. The fact that textures are supposed to record the crystallization history of a rock traditionally allowed them to be used for geothermobarometry or dating. During the last decades the focus of metamorphic petrology changed from a static point of view, i.e. the representation of a texture as one single point in the petrogenetic grid towards a more dynamic view, where multiple metamorphic processes govern the texture formation, including non-equilibrium processes. This thesis tries to advance our understanding on the processes governing nucleation and growth of minerals in contact metamorphic environments and their dynamic interplay by using a combination of geochemical analyses (chemical-, isotope-, and trace element composition), statistical treatments of spatial data and numerical models. In a first part the thesis describes the formation of metamorphic olivine porphyroblast in the Ubehebe Peak contact aureole (USA). It is shown that not the commonly assumed succession of equilibrium reactions along a T-t-path formed the textures present in the rocks today, but rather the presence of a meta-stable reaction is responsible for forming the olivine porphyroblast. Consequently, the spatial distribution of metamorphic minerals within a contact aureole can no longer be regarded as a proxy for the temporal evolution of a single rock sample. Metamorphic peak temperatures for samples of the Ubehebe Peak contact aureole were determined using calcite-dolomite. This geothermometer is based on the temperature-dependent exchange of Mg between calcite and dolomite. The purpose of the second part of this thesis was to explain the interfering systematic scatter of measured Mg-content on different scales and thus to clarify the interpretation of metamorphic temperatures recorded in carbonates. Numerical quantitative forward models are used to evaluate the effect of several processes on the distribution of magnesium in individual calcite crystals and the modeling results were then compared to measured field. Information about the crystallization history is not only recorded in the chemical composition of grains, like isotope composition or mineral zoning. Crystal size distributions (CSD's) provide essential information about the complex interaction of nucleation and growth of minerals. CSD's of brucite pseudomorphs formed retrograde after periclase of the southern Adamello massif (Italy) are presented. A combination of the textural 3D-information with geochemistry data is then used to evaluate reaction kinetics and to constrain the actual reaction mechanism for the formation of periclase. The reaction is shown to be the consequence of the infiltration of a limited amount of a fluid phase at high temperatures. The composition of this fluid phase is in large disequilibrium with the rest of the rock resulting in very fast reaction rates. RESUME DE LA THESE POUR LE GRAND PUBLIC: La texture d'une roche résulte de l'interaction complexe entre les processus de nucléation, croissance et déformation, en fonction des variations de conditions physiques telles que la pression et la température. Les textures ignées et métamorphiques présentent un intérêt particulier pour l'étude des différents mécanismes à l'origine de ces textures, puisque la plupart des paramètres comme les chemin pression-température sont relativement bien contraints dans la plupart des environnements géologiques. Le fait que les textures soient supposées enregistrer l'histoire de cristallisation des roches permet leur utilisation pour la datation et la géothermobarométrie. Durant les dernières décennies, la recherche en pétrologie métamorphique a évolué depuis une visualisation statique, c'est-à-dire qu'une texture donnée correspondait à un point unique de la grille pétrogénétique, jusqu'à une visualisation plus dynamique, où les multiples processus métamorphiques qui gouvernent 1a formation d'une texture incluent des processus hors équilibre. Cette thèse a pour but d'améliorer les connaissances actuelles sur les processus gouvernant la nucléation et la croissance des minéraux lors d'épisodes de métamorphisme de contact et l'interaction dynamique existant entre nucléation et croissance. Pour cela, les analyses géochimiques (compositions chimiques en éléments majeurs et traces et composition isotopique), le traitement statistique des données spatiales et la modélisation numérique ont été combinés. Dans la première partie, cette thèse décrit la formation de porphyroblastes d'olivine métamorphique dans l'auréole de contact de l'Ubehebe Peak (USA). Il est montré que la succession généralement admise des réactions d'équilibre le long d'un chemin T-t ne peut pas expliquer les textures présentes dans les roches aujourd'hui. Cette thèse montre qu'il s'agirait plutôt d'une réaction métastable qui soit responsable de la formation des porphyroblastes d'olivine. En conséquence, la distribution spatiale des minéraux métamorphiques dans l'auréole de contact ne peut plus être interprétée comme le témoin de l'évolution temporelle d'un échantillon unique de roche. Les pics de température des échantillons de l'auréole de contact de l'Ubehebe Peak ont été déterminés grâce au géothermomètre calcite-dolomite. Celui-ci est basé sur l'échange du magnésium entre la calcite et la dolomite, qui est fonction de la température. Le but de la deuxième partie de cette thèse est d'expliquer la dispersion systématique de la composition en magnésium à différentes échelles, et ainsi d'améliorer l'interprétation des températures du métamorphisme enregistrées dans les carbonates. Des modèles numériques quantitatifs ont permis d'évaluer le rôle de différents processus sur la distribution du magnésium dans des cristaux de calcite individuels. Les résultats des modèles ont été comparés aux échantillons naturels. La composition chimique des grains, comme la composition isotopique ou la zonation minérale, n'est pas le seul témoin de l'histoire de la cristallisation. La distribution de la taille des cristaux (CSD) fournit des informations essentielles sur les interactions entre nucléation et croissance des minéraux. La CSD des pseudomorphes de brucite retrograde formés après le périclase dans le sud du massif Adamello (Italie) est présentée dans la troisième partie. La combinaison entre les données textorales en trois dimensions et les données géochimiques a permis d'évaluer les cinétiques de réaction et de contraindre les mécanismes conduisant à la formation du périclase. Cette réaction est présentée comme étant la conséquence de l'infiltration d'une quantité limitée d'une phase fluide à haute température. La composition de cette phase fluide est en grand déséquilibre avec le reste de la roche, ce qui permet des cinétiques de réactions très rapides.