Thermogenic effect of amrinone in healthy men.

OBJECTIVES: The thermogenic effect of amrinone is unknown and its utilization in patients with severe cardiac failure could potentially increase oxygen requirements and therefore aggravate oxygen debt. Consequently, the present study was undertaken to assess the thermogenic response to amrinone at three different plasma concentrations under controlled conditions and to analyze amrinone's effects on various biochemical variables. DESIGN: A prospective, unblinded, controlled study. The initial control period was followed by three sequential, experimental treatments. SUBJECTS: Ten young, healthy, male volunteers with normal body weight. INTERVENTIONS: Three experimental periods. Amrinone was administered intravenously in progressive doses: a) 0.5 mg/kg followed by 5 micrograms/kg/min; b) 0.5 mg/kg followed by 10 micrograms/kg/min; and c) 1.0 mg/kg followed by 10 micrograms/kg/min. MEASUREMENTS AND MAIN RESULTS: Oxygen consumption (VO2) and CO2 production were continuously measured by means of a computerized indirect calorimeter. At the highest dose, amrinone produced a slight and significant (p < .01) increase in VO2 and in resting metabolic rate (+4.5% and +3.7%, respectively), while no change in CO2 production or in respiratory quotient occurred throughout the study. At the medium and high doses, amrinone increased plasma free fatty acid concentrations by 38% and 53%, respectively (p < .05). No variation in plasma glucose, lactate, insulin, norepinephrine, or epinephrine concentrations was observed during the study. CONCLUSIONS: Amrinone administered intravenously at therapeutic doses has minimal thermogenic and metabolic effects in humans without cardiac failure.

Voriconazole-Induced Inhibition of the Fungicidal Activity of Amphotericin B in Candida Strains with Reduced Susceptibility to Voriconazole: an Effect Not Predicted by the MIC Value Alone.

An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicans strains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candida strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains, C. albicans strains with characterized mechanisms of resistance against voriconazole, as well as Candida glabrata and Candida krusei strains with differences in their degrees of susceptibility to voriconazole were exposed to voriconazole or amphotericin B alone, to both drugs simultaneously, or to voriconazole followed by amphotericin B in an in vitro kinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced (median reduction, 61%; range, 9 to 94%). Levels of voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but were not correlated with the MIC values (correlation coefficient, -0.19; P = 0.65). Inhibition was found in C. albicans strains with increases in CDR1 and CDR2 expression but not in the strain with an increase in MDR1 expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant Candida strains. The degree of interaction could not be predicted by the MIC value alone.

Characteristic bimodal profiles of RNA polymerase II at thousands of active mammalian promoters.

BACKGROUND: In mammals, ChIP-seq studies of RNA polymerase II (PolII) occupancy have been performed to reveal how recruitment, initiation and pausing of PolII may control transcription rates, but the focus is rarely on obtaining finely resolved profiles that can portray the progression of PolII through sequential promoter states. RESULTS: Here, we analyze PolII binding profiles from high-coverage ChIP-seq on promoters of actively transcribed genes in mouse and humans. We show that the enrichment of PolII near transcription start sites exhibits a stereotypical bimodal structure, with one peak near active transcription start sites and a second peak 110 base pairs downstream from the first. Using an empirical model that reliably quantifies the spatial PolII signal, gene by gene, we show that the first PolII peak allows for refined positioning of transcription start sites, which is corroborated by mRNA sequencing. This bimodal signature is found both in mouse and humans. Analysis of the pausing-related factors NELF and DSIF suggests that the downstream peak reflects widespread pausing at the +1 nucleosome barrier. Several features of the bimodal pattern are correlated with sequence features such as CpG content and TATA boxes, as well as the histone mark H3K4me3. CONCLUSIONS: We thus show how high coverage DNA sequencing experiments can reveal as-yet unnoticed bimodal spatial features of PolII accumulation that are frequent at individual mammalian genes and reminiscent of transcription initiation and pausing. The initiation-pausing hypothesis is corroborated by evidence from run-on sequencing and immunoprecipitation in other cell types and species.

Probability of achieving optimal molecular response to imatinib in chronic myeloid leukemia (CML) patients: Pharmacokinetic/Pharmacodynamic (PK/PD) relationships observed under field-conditions

Objectives: Imatinib has been increasingly proposed for therapeutic drug monitoring (TDM), as trough concentrations (Cmin) correlate with response rates in CML patients. This analysis aimed to evaluate the impact of imatinib exposure on optimal molecular response rates in a large European cohort of patients followed by centralized TDM.¦Methods: Sequential PK/PD analysis was performed in NONMEM 7 on 2230 plasma (PK) samples obtained along with molecular response (PD) data from 1299 CML patients. Model-based individual Bayesian estimates of exposure, parameterized as to initial dose adjusted and log-normalized Cmin (log-Cmin) or clearance (CL), were investigated as potential predictors of optimal molecular response, while accounting for time under treatment (stratified at 3 years), gender, CML phase, age, potentially interacting comedication, and TDM frequency. PK/PD analysis used mixed-effect logistic regression (iterative two-stage method) to account for intra-patient correlation.¦Results: In univariate analyses, CL, log-Cmin, time under treatment, TDM frequency, gender (all p<0.01) and CML phase (p=0.02) were significant predictors of the outcome. In multivariate analyses, all but log-Cmin remained significant (p<0.05). Our model estimates a 54.1% probability of optimal molecular response in a female patient with a median CL of 14.4 L/h, increasing by 4.7% with a 35% decrease in CL (percentile 10 of CL distribution), and decreasing by 6% with a 45% increased CL (percentile 90), respectively. Male patients were less likely than female to be in optimal response (odds ratio: 0.62, p<0.001), with an estimated probability of 42.3%.¦Conclusions: Beyond CML phase and time on treatment, expectedly correlated to the outcome, an effect of initial imatinib exposure on the probability of achieving optimal molecular response was confirmed in field-conditions by this multivariate analysis. Interestingly, male patients had a higher risk of suboptimal response, which might not exclusively derive from their 18.5% higher CL, but also from reported lower adherence to the treatment. A prospective longitudinal study would be desirable to confirm the clinical importance of identified covariates and to exclude biases possibly affecting this observational survey.

Noninvasive imaging of 5-HT3 receptor trafficking in live cells: from biosynthesis to endocytosis.

Sequential stages in the life cycle of the ionotropic 5-HT(3) receptor (5-HT(3)R) were resolved temporally and spatially in live cells by multicolor fluorescence confocal microscopy. The insertion of the enhanced cyan fluorescent protein into the large intracellular loop delivered a fluorescent 5-HT(3)R fully functional in terms of ligand binding specificity and channel activity, which allowed for the first time a complete real-time visualization and documentation of intracellular biogenesis, membrane targeting, and ligand-mediated internalization of a receptor belonging to the ligand-gated ion channel superfamily. Fluorescence signals of newly expressed receptors were detectable in the endoplasmic reticulum about 3 h after transfection onset. At this stage receptor subunits assembled to form active ligand binding sites as demonstrated in situ by binding of a fluorescent 5-HT(3)R-specific antagonist. After novel protein synthesis was chemically blocked, the 5-HT(3) R populations in the endoplasmic reticulum and Golgi cisternae moved virtually quantitatively to the cell surface, indicating efficient receptor folding and assembly. Intracellular 5-HT(3) receptors were trafficking in vesicle-like structures along microtubules to the cell surface at a velocity generally below 1 mum/s and were inserted into the plasma membrane in a characteristic cluster distribution overlapping with actin-rich domains. Internalization of cell surface 5-HT(3) receptors was observed within minutes after exposure to an extracellular agonist. Our orchestrated use of spectrally distinguishable fluorescent labels for the receptor, its cognate ligand, and specific organelle markers can be regarded as a general approach allowing subcellular insights into dynamic processes of membrane receptor trafficking.

Recurrent idiopathic neuroretinitis: natural history and effect of treatment.

BACKGROUND: Previous reports have emphasized the self-limited nature of idiopathic neuroretinitis. There is less information about a subgroup of patients who suffer recurrent episodes with worse visual outcome. We sought to better characterize the clinical features of recurrent idiopathic neuroretinitis including the effects of immunosuppressive treatment. METHODS: Retrospective chart review of neuroretinitis patients from a single institution from 1983 to 2008. Inclusion criteria included two or more episodes of acute visual loss with disc oedema and macular exudates in a star pattern. Cases due to a specific infectious or inflammatory aetiology were excluded. RESULTS: Forty-one patients were included with an average follow up of 67 months. Median age at the time of the first episode was 28 years (range 10-54 years). Attacks were bilateral sequential in 34 patients (83%). We documented a total of 147 episodes in 75 eyes with an average of 3.6 attacks per patient. The average interval between attacks was 3 years. Visual field loss had a nerve fibre bundle pattern in most cases. Only 36% of eyes retained 6/12 or better visual acuity and greater than two-thirds of their visual field. Long-term immunosuppressive treatment in 13 patients decreased the attack rate by 72%. CONCLUSIONS: Recurrent idiopathic neuroretinitis typically affects young adults, with no gender preference. Recovery is limited and visual loss is cumulative with repeated attacks, often resulting in severe permanent visual loss. Immunosuppressive treatment appears to lessen the attack frequency.

Urinary sphincter based on electronics and artificial muscles

Objectives: The AMS 800TM is the current artificial urinary sphincter (AUS) for incontinence due to intrinsic sphincter deficiency. Despite good clinical results, technical failures inherent to the hydraulic mechanism or urethral ischemic injury contribute to revisions up to 60%. We are developing an electronic AUS, called ARTUS to overcome the rigors of AMS. The objective of this study was to evaluate the technical efficacy and tissue tolerance of the ARTUS system in an animal model.Methods: The ARTUS is composed by three parts: the contractile unit, a series of rings and an integrated microprocessor. The contractile unit is made of Nitinol fibers. The rings are placed around the urethra to control the flow of urine by squeezing the urethra. They work in a sequential alternative mode and are controlled by a microprocessor. In the first phase a three-rings device was used while in the second phase a two-rings ARTUS was used. The device was implanted in 14 sheep divided in two groups of six and eight animals for study purpose. The first group aimed at bladder leak point pressure (BLPP) measurement and validation of the animal model; the second group aimed at verifying mid-term tissue tolerance by explants at twelve weeks. General animal tolerance was also evaluated.Results: The ARTUS system implantation was uneventful. When the system was activated, the BLPP was measured at 1.038±0.044 bar (mean±SD). Urethral tissue analysis did not show significant morphological changes. No infection and no sign of discomfort were noted in animals at 12 weeks.Conclusions: The ARTUS proved to be effective in continence achievement in this study. Histological results support our idea that a sequential alternative mode can avoid urethral atrophy and ischemia. Further technical developments are needed to verify long-term outcome and permit human use.

Effect of antiretroviral therapy on apoptosis markers and morphology in peripheral lymph nodes of HIV-infected individuals.

BACKGROUND: CD4+ T cell depletion and destruction and the involution of the lymphoid tissue are hallmarks of HIV infection. Although the underlying mechanisms are still unclear, apoptosis appears to play a central role. The objective of this study was to investigate the effect of antiretroviral therapy on the lymph node tissue, particularly with respect to morphology and apoptosis. PATIENTS AND METHODS: Between 1997 and 1999, two inguinal lymph nodes were excised from 31 previously untreated individuals who were in an early stage of HIV infection, the first one prior to treatment and the second after 16 to 20 months of treatment. Paraffin sections were investigated for lymph node architecture, distribution of cellular and viral markers, apoptosis, and expression of apoptotic key molecules which indirectly reflect apoptotic processes. RESULTS: After 16-20 months of antiretroviral therapy, a significant decrease in highly activated HIV-driven immune response was observed in the lymph node tissue as a marked reduction in follicular hyperplasia, a normalization of the follicular dendritic cell network, a significant increase in the number of CD4+ T cells, and a significant decrease in the number of CD8+ T cells. The expression of several proapoptotic (Fas, TRAIL, and active caspase 3) and antiapoptotic (Bcl-2 and IL-7Ralpha) molecules that were reconstituted in the tissues during therapy resembled their expression in lymph nodes of HIV-negative individuals. Limitations of the study are (a) the lack of untreated patients in the late stages, (b) for ethical reasons, the lack of a control group with untreated patients, and (c) for methodological reasons, the restriction of sequential measurements of apotpotic markers to one-third of the patients. CONCLUSION: Antiretroviral therapy initiated in the early stages in HIV infection may halt the irreversible destruction of the lymph node tissue and may partially normalize apoptotic processes.

Comparability of clinical wear measurements by optical 3D laser scanning in two different centers.

OBJECTIVE: The purpose of this study was to compare the use of different variables to measure the clinical wear of two denture tooth materials in two analysis centers. METHODS: Twelve edentulous patients were provided with full dentures. Two different denture tooth materials (experimental material and control) were placed randomly in accordance with the split-mouth design. For wear measurements, impressions were made after an adjustment phase of 1-2 weeks and after 6, 12, 18, and 24 months. The occlusal wear of the posterior denture teeth of 11 subjects was assessed in two study centers by use of plaster replicas and 3D laser-scanning methods. In both centers sequential scans of the occlusal surfaces were digitized and superimposed. Wear was described by use of four different variables. Statistical analysis was performed after log-transformation of the wear data by use of the Pearson and Lin correlation and by use of a mixed linear model. RESULTS: Mean occlusal vertical wear of the denture teeth after 24 months was between 120μm and 212μm, depending on wear variable and material. For three of the four variables, wear of the experimental material was statistically significantly less than that of the control. Comparison of the two study centers, however, revealed correlation of the wear variables was only moderate whereas strong correlation was observed among the different wear variables evaluated by each center. SIGNIFICANCE: Moderate correlation was observed for clinical wear measurements by optical 3D laser scanning in two different study centers. For the two denture tooth materials, wear measurements limited to the attrition zones led to the same qualitative assessment.

Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics.

PURPOSE: It is generally assumed that the biodistribution and pharmacokinetics of radiolabelled antibodies remain similar between dosimetric and therapeutic injections in radioimmunotherapy. However, circulation half-lives of unlabelled rituximab have been reported to increase progressively after the weekly injections of standard therapy doses. The aim of this study was to evaluate the evolution of the pharmacokinetics of repeated 131I-rituximab injections during treatment with unlabelled rituximab in patients with non-Hodgkin's lymphoma (NHL). METHODS: Patients received standard weekly therapy with rituximab (375 mg/m2) for 4 weeks and a fifth injection at 7 or 8 weeks. Each patient had three additional injections of 185 MBq 131I-rituximab in either treatment weeks 1, 3 and 7 (two patients) or weeks 2, 4 and 8 (two patients). The 12 radiolabelled antibody injections were followed by three whole-body (WB) scintigraphic studies during 1 week and blood sampling on the same occasions. Additional WB scans were performed after 2 and 4 weeks post 131I-rituximab injection prior to the second and third injections, respectively. RESULTS: A single exponential radioactivity decrease for WB, liver, spleen, kidneys and heart was observed. Biodistribution and half-lives were patient specific, and without significant change after the second or third injection compared with the first one. Blood T(1/2)beta, calculated from the sequential blood samples and fitted to a bi-exponential curve, was similar to the T(1/2) of heart and liver but shorter than that of WB and kidneys. Effective radiation dose calculated from attenuation-corrected WB scans and blood using Mirdose3.1 was 0.53+0.05 mSv/MBq (range 0.48-0.59 mSv/MBq). Radiation dose was highest for spleen and kidneys, followed by heart and liver. CONCLUSION: These results show that the biodistribution and tissue kinetics of 131I-rituximab, while specific to each patient, remained constant during unlabelled antibody therapy. RIT radiation doses can therefore be reliably extrapolated from a preceding dosimetry study.

Blunting the response to endotoxin in healthy subjects: effects of various doses of intravenous fish oil.

To test the dose response effect of infused fish oil (FO) rich in n-3 PUFAs on the inflammatory response to endotoxin (LPS) and on membrane incorporation of fatty acids in healthy subjects. Prospective, sequential investigation comparing three different FO doses. Three groups of male subjects aged 26.8 +/- 3.2 years (BMI 22.5 +/- 2.1). One of three FO doses (Omegaven10%) as a slow infusion before LPS: 0.5 g/kg 1 day before LPS, 0.2 g/kg 1 day before, or 0.2 g/kg 2 h before. Temperature, hemodynamic variables, indirect calorimetry and blood samples (TNF-alpha, stress hormones) were collected. After LPS temperature, ACTH and TNF-alpha concentrations increased in the three groups: the responses were significantly blunted (p < 0.0001) compared with the control group of the Pluess et al. trial. Cortisol was unchanged. Lowest plasma ACTH, TNF-alpha and temperature AUC values were observed after a single 0.2 g/kg dose of FO. EPA incorporation into platelet membranes was dose-dependent. Having previously shown that the response to LPS was reproducible, this study shows that three FO doses blunted it to various degrees. The 0.2 g/kg perfusion immediately before LPS was the most efficient in blunting the responses, suggesting LPS capture in addition to the systemic and membrane effects.

Experimental evaluation of an electromechanical artificial urinary sphincter in an animal model.

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The AMS 800 urinary control system is the gold standard for the treatment of urinary incontinence due to sphincter insufficiency. Despite excellent functional outcome and latest technological improvements, the revision rate remains significant. To overcome the shortcomings of the current device, we developed a modern electromechanical artificial urinary sphincter. The results demonstrated that this new sphincter is effective and well tolerated up to 3 months. This preliminary study represents a first step in the clinical application of novel technologies and an alternative compression mechanism to the urethra. OBJECTIVES: To evaluate the effectiveness in continence achievement of a new electromechanical artificial urinary sphincter (emAUS) in an animal model. To assess urethral response and animal general response to short-term and mid-term activation of the emAUS. MATERIALS AND METHODS: The principle of the emAUS is electromechanical induction of alternating compression of successive segments of the urethra by a series of cuffs activated by artificial muscles. Between February 2009 and May 2010 the emAUS was implanted in 17 sheep divided into three groups. The first phase aimed to measure bladder leak point pressure during the activation of the device. The second and third phases aimed to assess tissue response to the presence of the device after 2-9 weeks and after 3 months respectively. Histopathological and immunohistochemistry evaluation of the urethra was performed. RESULTS: Bladder leak point pressure was measured at levels between 1091 ± 30.6 cmH2 O and 1244.1 ± 99 cmH2 O (mean ± standard deviation) depending on the number of cuffs used. At gross examination, the explanted urethra showed no sign of infection, atrophy or stricture. On microscopic examination no significant difference in structure was found between urethral structure surrounded by a cuff and control urethra. In the peripheral tissues, the implanted material elicited a chronic foreign body reaction. Apart from one case, specimens did not show significant presence of lymphocytes, polymorphonuclear leucocytes, necrosis or cell degeneration. Immunohistochemistry confirmed the absence of macrophages in the samples. CONCLUSIONS: This animal study shows that the emAUS can provide continence. This new electronic controlled sequential alternating compression mechanism can avoid damage to urethral vascularity, at least up to 3 months after implantation. After this positive proof of concept, long-term studies are needed before clinical application could be considered.

Quantitative integration of geophysical and hydraulic data : from the local towards the regional scale range

Des progrès significatifs ont été réalisés dans le domaine de l'intégration quantitative des données géophysique et hydrologique l'échelle locale. Cependant, l'extension à de plus grandes échelles des approches correspondantes constitue encore un défi majeur. Il est néanmoins extrêmement important de relever ce défi pour développer des modèles fiables de flux des eaux souterraines et de transport de contaminant. Pour résoudre ce problème, j'ai développé une technique d'intégration des données hydrogéophysiques basée sur une procédure bayésienne de simulation séquentielle en deux étapes. Cette procédure vise des problèmes à plus grande échelle. L'objectif est de simuler la distribution d'un paramètre hydraulique cible à partir, d'une part, de mesures d'un paramètre géophysique pertinent qui couvrent l'espace de manière exhaustive, mais avec une faible résolution (spatiale) et, d'autre part, de mesures locales de très haute résolution des mêmes paramètres géophysique et hydraulique. Pour cela, mon algorithme lie dans un premier temps les données géophysiques de faible et de haute résolution à travers une procédure de réduction déchelle. Les données géophysiques régionales réduites sont ensuite reliées au champ du paramètre hydraulique à haute résolution. J'illustre d'abord l'application de cette nouvelle approche dintégration des données à une base de données synthétiques réaliste. Celle-ci est constituée de mesures de conductivité hydraulique et électrique de haute résolution réalisées dans les mêmes forages ainsi que destimations des conductivités électriques obtenues à partir de mesures de tomographic de résistivité électrique (ERT) sur l'ensemble de l'espace. Ces dernières mesures ont une faible résolution spatiale. La viabilité globale de cette méthode est testée en effectuant les simulations de flux et de transport au travers du modèle original du champ de conductivité hydraulique ainsi que du modèle simulé. Les simulations sont alors comparées. Les résultats obtenus indiquent que la procédure dintégration des données proposée permet d'obtenir des estimations de la conductivité en adéquation avec la structure à grande échelle ainsi que des predictions fiables des caractéristiques de transports sur des distances de moyenne à grande échelle. Les résultats correspondant au scénario de terrain indiquent que l'approche d'intégration des données nouvellement mise au point est capable d'appréhender correctement les hétérogénéitées à petite échelle aussi bien que les tendances à gande échelle du champ hydraulique prévalent. Les résultats montrent également une flexibilté remarquable et une robustesse de cette nouvelle approche dintégration des données. De ce fait, elle est susceptible d'être appliquée à un large éventail de données géophysiques et hydrologiques, à toutes les gammes déchelles. Dans la deuxième partie de ma thèse, j'évalue en détail la viabilité du réechantillonnage geostatique séquentiel comme mécanisme de proposition pour les méthodes Markov Chain Monte Carlo (MCMC) appliquées à des probmes inverses géophysiques et hydrologiques de grande dimension . L'objectif est de permettre une quantification plus précise et plus réaliste des incertitudes associées aux modèles obtenus. En considérant une série dexemples de tomographic radar puits à puits, j'étudie deux classes de stratégies de rééchantillonnage spatial en considérant leur habilité à générer efficacement et précisément des réalisations de la distribution postérieure bayésienne. Les résultats obtenus montrent que, malgré sa popularité, le réechantillonnage séquentiel est plutôt inefficace à générer des échantillons postérieurs indépendants pour des études de cas synthétiques réalistes, notamment pour le cas assez communs et importants où il existe de fortes corrélations spatiales entre le modèle et les paramètres. Pour résoudre ce problème, j'ai développé un nouvelle approche de perturbation basée sur une déformation progressive. Cette approche est flexible en ce qui concerne le nombre de paramètres du modèle et lintensité de la perturbation. Par rapport au rééchantillonage séquentiel, cette nouvelle approche s'avère être très efficace pour diminuer le nombre requis d'itérations pour générer des échantillons indépendants à partir de la distribution postérieure bayésienne. - Significant progress has been made with regard to the quantitative integration of geophysical and hydrological data at the local scale. However, extending corresponding approaches beyond the local scale still represents a major challenge, yet is critically important for the development of reliable groundwater flow and contaminant transport models. To address this issue, I have developed a hydrogeophysical data integration technique based on a two-step Bayesian sequential simulation procedure that is specifically targeted towards larger-scale problems. The objective is to simulate the distribution of a target hydraulic parameter based on spatially exhaustive, but poorly resolved, measurements of a pertinent geophysical parameter and locally highly resolved, but spatially sparse, measurements of the considered geophysical and hydraulic parameters. To this end, my algorithm links the low- and high-resolution geophysical data via a downscaling procedure before relating the downscaled regional-scale geophysical data to the high-resolution hydraulic parameter field. I first illustrate the application of this novel data integration approach to a realistic synthetic database consisting of collocated high-resolution borehole measurements of the hydraulic and electrical conductivities and spatially exhaustive, low-resolution electrical conductivity estimates obtained from electrical resistivity tomography (ERT). The overall viability of this method is tested and verified by performing and comparing flow and transport simulations through the original and simulated hydraulic conductivity fields. The corresponding results indicate that the proposed data integration procedure does indeed allow for obtaining faithful estimates of the larger-scale hydraulic conductivity structure and reliable predictions of the transport characteristics over medium- to regional-scale distances. The approach is then applied to a corresponding field scenario consisting of collocated high- resolution measurements of the electrical conductivity, as measured using a cone penetrometer testing (CPT) system, and the hydraulic conductivity, as estimated from electromagnetic flowmeter and slug test measurements, in combination with spatially exhaustive low-resolution electrical conductivity estimates obtained from surface-based electrical resistivity tomography (ERT). The corresponding results indicate that the newly developed data integration approach is indeed capable of adequately capturing both the small-scale heterogeneity as well as the larger-scale trend of the prevailing hydraulic conductivity field. The results also indicate that this novel data integration approach is remarkably flexible and robust and hence can be expected to be applicable to a wide range of geophysical and hydrological data at all scale ranges. In the second part of my thesis, I evaluate in detail the viability of sequential geostatistical resampling as a proposal mechanism for Markov Chain Monte Carlo (MCMC) methods applied to high-dimensional geophysical and hydrological inverse problems in order to allow for a more accurate and realistic quantification of the uncertainty associated with the thus inferred models. Focusing on a series of pertinent crosshole georadar tomographic examples, I investigated two classes of geostatistical resampling strategies with regard to their ability to efficiently and accurately generate independent realizations from the Bayesian posterior distribution. The corresponding results indicate that, despite its popularity, sequential resampling is rather inefficient at drawing independent posterior samples for realistic synthetic case studies, notably for the practically common and important scenario of pronounced spatial correlation between model parameters. To address this issue, I have developed a new gradual-deformation-based perturbation approach, which is flexible with regard to the number of model parameters as well as the perturbation strength. Compared to sequential resampling, this newly proposed approach was proven to be highly effective in decreasing the number of iterations required for drawing independent samples from the Bayesian posterior distribution.

Error estimate and control in the MSFV method for multiphase flow in porous media

n this paper the iterative MSFV method is extended to include the sequential implicit simulation of time dependent problems involving the solution of a system of pressure-saturation equations. To control numerical errors in simulation results, an error estimate, based on the residual of the MSFV approximate pressure field, is introduced. In the initial time steps in simulation iterations are employed until a specified accuracy in pressure is achieved. This initial solution is then used to improve the localization assumption at later time steps. Additional iterations in pressure solution are employed only when the pressure residual becomes larger than a specified threshold value. Efficiency of the strategy and the error control criteria are numerically investigated. This paper also shows that it is possible to derive an a-priori estimate and control based on the allowed pressure-equation residual to guarantee the desired accuracy in saturation calculation.

Cadmium distribution in soils covering Jurassic oolitic limestone with high Cd contents in the Swiss Jura

Oolitic carbonates belonging to the Hauptrogenstein Formation of Bajocian (Middle Jurassic) age have been shown to be anomalously enriched in cadmium (Cd) throughout the Jura Mountains. Soils associated with this type of rock substratum may be naturally polluted with regards to Cd. At Schleifenberg (Canton Basel Land, Switzerland) the Hauptrogenstein Formation is almost entirely exposed along a trail on its SW flank. Cadmium concentrations were systematically measured throughout this formation and Cd enrichments in rocks are shown to occur to a maximum content of 4.9 mg kg(-1). We investigated associated soils, which cover the entire outcrop, and show that they have been formed through the weathering of the underlying bedrock and through the uptake of colluvial limestone fragments from the same and older formations. Cadmium contents in the soils reach a maximum value of 2.0 mg kg(-1), thereby exceeding the official Swiss indicative guideline value for soils fixed at 0.8 mg.kg(-1). Mineralogical analyses on the soils and associated bedrock suggest that no allochthonous component related to aeolian transport is present. Sequential extractions applied to selected soil samples show that about half of the Cd resides in the carbonate fraction coming from the fractured parent-rock, while the Cd released from the weathered carbonates is associated either with organic matter (over 10%) or with Fe and Mn-oxihydroxides (approximately 30%). No exchangeable Cd phase was found and this, together with the buffer capacity of this calcareous soil, suggests that the amount of mobile Cd is quite negligible in this soil, which also greatly reduces the amount of bioavailable