Regensburg, Univ., Diss., 2009.

Jusqu’à présent, les seuls traitements efficaces dans la schizophrénie agissent en bloquant les récepteurs dopaminergiques. L’hypothèse selon laquelle les symptômes dits « positifs » de schizophrénie (hallucinations et délires), sont l’expression d’une hyperdopaminergie au niveau du Striatum Ventral, est depuis quarante la principale explication neurobiologique avancée pour rendre compte de ces symptômes. Cette hypothèse est toutefois discutée aujourd’hui car d’autres modèles pharmacologiques ont été proposés pour expliquer la survenue des symptômes positifs, en particulier des hallucinations visuelles. De plus, le rôle central du Striatum Ventral a été remis en question par des données récentes de neuroimagerie. Aujourd’hui la schizophrénie est envisagée comme un processus dynamique, découlant d’anomalies successives à la fois neurodéveloppementales et neurodégénératives, et certaines de ces anomalies seraient liées au stress oxydant. La dérégulation de la transmission dopaminergique et les symptômes qui en résultent peuvent dès lors être considérés comme le mode d’expression final d’une cascade de mécanismes pathologiques dont le début est bien antérieur à l’apparition des symptômes. Une intervention pharmacologique précoce, permettant de réduire l’impact de tels mécanismes, pourrait avoir des conséquences directes ou retardées sur la transmission dopaminergique et sur les symptômes qui en découlent. Nous faisons l’hypothèse que l’activation précoce des Peroxisome-Proliferator Activated Receptors (PPARs), molécules qui réduisent le stress oxydant et ont également une action directe sur la transmission dopaminergique, constitue un mécanisme pharmacothérapeutique potentiel dans la schizophrénie. Notre premier objectif est d’évaluer l’effet du fénofibrate sur des anomalies comportementales liées à la dopamine et induites par une lésion oxydative néonatale. En parallèle, en prévision d’une étude clinique, nous voulions montrer que le Striatum Ventral et la dopamine sont impliqués dans différents types de symptômes positifs. L’effet du fénofibrate est évalué sur un modèle expérimental de lésion neurodéveloppementale par stress oxydant induisant à l’âge adulte un trouble de l’axe dopaminergique avec altération du Prepulse Inhibition (PPI), réflexe comportemental dépendant de la dopamine. Parallèlement, nous avons réalisé une étude d’Imagerie par Résonnance Magnétique fonctionnelle (IRMf) comparant la connectivité fonctionnelle du Nucleus Accumbens, zone appartenant au Striatum Ventral, en cas d’hallucinations acousticoverbales simples ou acoustico-visuelles. Nous montrons que l’introduction précoce de fénofibrate après une lésion oxydative néonatale permet de restaurer partiellement mais significativement l’intégrité du PPI à l’âge adulte. Nous montrons par ailleurs cher le patient, dans notre étude en IRMf, que des zones impliquées à la fois dans la transmission dopaminergique et dans la symptomatologie hallucinatoire sont fonctionnellement connectées au NAcc quelle que soit la modalité hallucinatoire concernée. Un effet disease-modifier du fénofibrate est observé sur des anomalies dopaminergiques neurodéveloppementalement induites. Cet effet devra toutefois être précisé par le recours à d’autres modèles animaux permettant de compléter nos résultats par des données comportementales, histologiques, et électro-physiologiques additionnelles. Par ailleurs, nous observons que le Striatum Ventral semble impliqué dans différents types d’hallucinations, ce qui permet de faire l’hypothèse que cette structure est mise en jeu dans les différents types de symptômes positifs. Ce travail permet à terme d’envisager une évaluation directe de l’effet du fénofibrate sur la symptomatologie positive et le fonctionnement du Striatum Ventral chez des patients en début de schizophrénie. / Until now, the sole effective treatments in schizophrenia act by blocking the dopaminergic receptors. The hypothesis according to which the so-called “positive” symptoms of schizophrenia (i.e. hallucinations and delusions) are the expression of a hyperdopaminergic transmission within the Ventral Striatum, has be for forty years the main neurobiological explication that has been proposed for these symptoms. However, this hypothesis is questioned as other pharmacological models have been considered about the occurrence of the positive symptoms, notably of the visual hallucinations. In addition, the key role of the Ventral Striatum has been called into question by recent neuroimaging data. Today, schizophrenia is seen as a dynamic process, which consists of both neurodevelopmental and neurodegenerative anomalies, in which oxidative stress might be involved. Therefore, the deregulation of the dopaminergic transmission and the subsequent symptoms may be considered as the final expression of a pathological mechanisms cascade whose beginning is much prior to the symptoms onset. An early pharmacological intervention that may reduce the impact of such mechanisms could have some direct or delayed consequences on the dopaminergic transmission and the related symptoms. We hypothesize that the early activation of Peroxisome-Proliferator Activated Receptors (PPARs), molecules that reduce the oxidative stress processes and may have a direct action on the dopamine transmission, have a potential pharmacological interest in schizophrenia. We want to show that the use of the PPARα agonist fenofibrate during the onset of schizophrenia, can reduce the dopaminergic dysfunction state and the positive symptoms intensity, and thus have a disease-modifier effect. Objectives : Our first goal is to study the effect of fenofibrate on behavioral dopamine-related anomalies that are triggered by a neonatal oxidative lesion. Meanwhile, anticipating a clinical study, we want to prove that the ventral Striatum and the dopamine are involved in the different types of positive symptoms.Methods: The effect of fenofibrate is studied on an experimental model of oxidative neurodevelopmental lesion which induces only at adult age a dopaminergic dysfunction with an alteration of the Prepulse Inhibition (PPI), a behavioral dopamine-related reflex. In addition, we have performed a functional Magnetic Resonance Imaging (fMRI) study that compares the functional connectivity of the Nucleus Accumbens, which belongs to the Ventral Striatum, in case of sole auditory hallucinations or of both visual and auditory hallucinations. Results: we observe that the early introduction of fenofibrate after a neonatal oxidative lesion allows to partially but significantly restore the PPI’s integrity at adult age. Moreover, we show in our fMRI study on patients with schizophrenia that the dopaminergic transmission appears to be involved in the different hallucinatory modalities. Discussion: A disease modifier effect of fenofibrate is reported on neurodevelopmentally-induced dopaminergic dysfunctions. We will complete our results using other models which allow getting additional behavioural, histological and electrophysiological data. Meanwhile, we report that the Ventral Striatum is involved in different types of positive symptoms. Our work makes considering a future evaluation of the fenofibrate’s effect on the positive symptoms and the Ventral Striatum functioning in patient at the onset of schizophrenia.

No description available.

The advantages of supercritical fluid chromatography (SFC) and supercritical fluid extraction (SFE) which utilize supercritical fluids (SF) as the mobile phase are being realized by the scientific community. SF are more advantageous than traditionally used organic solvents because SF exhibits the solvating strength of liquids while maintaining the higher mass transport properties of gases. Currently, the most common SF which is CO₂ is available in two preparations of pure CO₂ and helium headspace CO₂. SFC of polyaromatic hydrocarbons (PAH) was performed with pure carbon dioxide and helium headspace carbon dioxide at various cylinder fill levels. The capacity factors of the PAH's increased when helium headspace carbon dioxide was used as a carrier fluid relative to pure carbon dioxide. As more liquid carbon dioxide was removed from the cylinder, the effect of helium on the solvating power of CO₂ was reduced because the relative amount of helium dissolved in the liquid phase decreased. Furthermore, the effect of helium headspace carbon dioxide was investigated with methanol-modified carbon dioxide mobile phases for the analysis of steroids. The capacity factors of the steroids increased when helium headspace CO₂ was used relative to pure CO₂. Although two types of carbon dioxide can be utilized, both have found widespread use in packed-column SFC. Unfortunately, the activity of the stationary phase of packed-columns may prevent the elution of moderately polar analytes when using 100% carbon dioxide. The stationary phase activity can usually be overcome by adding a modifier or modifier with an additive. Unfortunately, the introduction of modifier/additive can interfere with the use of most commonly used detectors like the flame ionization detector (FID) and ultraviolet detector (UV). Therefore, a detector is needed in which the modifier/additive does not interfere and detection is possible. Two such detectors are the electron capture detector (ECD) and evaporative light scattering detector (ELSD). Response surfaces were obtained for packed-column SFC-ECD under various detector conditions to optimize the ECD for use with modified CO₂. Limits of detection, correlation coefficient, and linear dynamic range were found to vary with increasing amounts of modifier for several nitrogen containing and halogenated compounds. Low detection (pg) was achieved in the presence of 5% methanol-modified CO₂. Applications of packed column SFC-ECD to the separation of nitrogen containing compounds extracted from propellants, phenylurea herbicides, and felodipine extracted from a sustained release tablet by SFE are presented. A high performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD) has been modified and interfaced with SFC. The detector performance was evaluated by monitoring the response of several steroids. Specifically, the effect of N, make-up gas flow rate, CO₂ modifier type, modifier concentration, ELSD orifice size, and detector temperature was determined. As the N₂ gas flow rate was increased the response of the analyte decreased, but the increased flow improved the peak shape to mimic that seen by ultraviolet detection. Furthermore, increasing detector temperature caused the response of the analytes to decrease. A detection limit of 10 ng or less was determined for progesterone and testosterone using 2% and 20% (v/v) methanol-modified CO₂ on a Deltabond® cyano column (4.6 mm X 15 cm, 5 um) at 150 mL/min and 1000 mL/min decompressed CO₂. Using the detector's optimized conditions, the separations of polyethylene glycols and ginkgo biloba leak extract are reported. / Ph. D.

Contact antimicrobials for use in the medical device industry are being studied extensively to minimize the risk of hospital acquired infections, which are among the top ten leading causes of death in the US. Surfaces modified with quaternary ammonium containing side chains have been known to demonstrate excellent antimicrobial properties. Prior work has indicated that polyurethane surfaces with copolyoxetane soft blocks consisting of fluorinated and quaternary ammonium side chains can act as good antimicrobials. However, stabilizing the positive charge on the surface has been a challenge. The dissertation is aimed at creating a surface modifier that would confer a stable contact kill antimicrobial surface at very low modifier content, that is, less than 2 wt%. To achieve this objective, the study explored the introduction of a different fluorous group in the soft block to enhance stability. In particular, prior studies by other groups and early work by Kurt have shown that replacement of one of the terminal “chaperone” C-F bonds by C-H decreased surface tension. This led to the hypothesis that a –CF2H terminated “chaperone” group would be “amphiphilic” resulting in surface stability under both dry and wet conditions. Keeping this hypothesis in mind, a –CF2-CF2H (4F) terminal “chaperone” group was created in a modifier having two different 4F to quaternerary C12 ratios. It was found that polyurethanes prepared with a 66:34 ratio of 4F:C12 as the diol, performed as a very good surface modifier with high zeta potentials over a long period of time compared to the –CF3 based modifier. Antimicrobial tests performed within one week and four weeks after coating preparation have provided promising results that demonstrate improved biocidal stability. Guided by improved antimicrobial properties obtained with surface modifier polyurethanes made from P[(4F)(C12)-66:34-Mn], a new concept was explored by end-capping the same diol with isocyanatopropyltriethoxysilane and blending the end-capped diol with base polyurethane along with a 10 wt % cross linker. These modifiers show excellent antimicrobial properties (100% kill of bacteria) over one month with no observable changes in the zeta potential or surface morphologies. XPS analysis confirms the presence of quaternary ammonium on the surface. Preliminary kinetic studies show excellent antimicrobial properties for a 2 wt% modifier and 100% kill within 1 hr.

Bioplastics are emerging as most promising materials to replace oil based thermoplastics particularly in packaging. Bioplastics can mitigate and address concerns about the negative role of plastics in the environment creating pollution and depleting resources hence bioplastics can enable an innovative approach toward addressing these issues. However, manufacturing of bioplastic is still costly and their mechanical and thermal properties require extensive development. Therefore there has been substantial interest to improve processing and properties of bioplastics to diminish the environmental impacts caused by continuous use of synthetic polymers of petroleum origin. In this research, Poly (3-hydroxybutyrate-co-3-hydroxyvalerate) or PHBV and Polybutylene succinate (PBS) composites and blends were developed to improve the properties of PHBV as the matrix polymer and hence produce a novel formulation for product development. Three approaches were studied in this work:  The effect of talcum powder as a nucleating agent and reinforcing filler.  The effect of oligomer chain extenders on miscibility, crystallinity, thermal and thermomechanical, mechanical and morphological properties of PHBV/PBS blends.  The effect of acrylic core-shell impact modifier on crystallinity, thermal and thermomechanical, mechanical and morphological properties of PHBV were also evaluated. All the above scientific approaches have been studied. It was noticed that talc can change the sluggish crystallinity of PHBV. Talc enhances nucleation of PHBV in the composites which leads to a faster crystallization rate. The heat distortion temperature, crystallinity and the modulus of PHBV/talc composite were also increased. In the presence of the chain extender (CE) the miscibility conditions of PHBV/PBS blends were changed. The results were supported by calculation of the activation energies. The elongation at break and tensile strength of PHBV/PBS/Chain extender blends increased indicating miscibility change. The possible reaction mechanism between PHBV, PBS and CE are proposed and the results supported by using FTIR. Immiscibility results of the PHBV/PBS blends are supported by SEM images. Addition of the impact modifier to PHBV reduced the crystallization rate and prolonged crystallization time. It has been found that the shell of impact modifier (PMMA) is partially miscible with PHBV. The absorbed impact energy is improved by the impact modifier but the improvement was not as satisfactory as results noted for PLA. The SEM images showed the average fine dispersion of different sized particles inside the matrix.

Cystic Fibrosis is one of the most common genetic recessive diseases among Caucasians and is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene on chromosome 7. There are different classes of CFTR mutation, leading to differences in disease severity among patients. In addition to the CFTR genotype, secondary genetic factors, modifier genes, also influence CF phenotypes. Due to the dysfunction of CFTR protein and production of thickened mucus, bacterial infection in the lungs is favored and can lead to further clinical complications in CF patients. Pseudomonas aeruginosa is one of the most common bacteria detected among patients. The aim of this project was to investigate four candidate modifier genes, Factor B, Complement Factor 3, Toll-like Receptor 4 and Heme oxygenase-1, which might affect the status of Pseudomonas aeruginosa infection. A total of 22 single nucleotide polymorphisms (SNPs) were selected in these four genes and they were tested against five phenotypic traits, including age of diagnosis, FEV1% predicted andstandard deviation value, age of first Pseudomonas aeruginosa infection and Pseudomonas aeruginosa infection status. Among the selected SNPs, both case-control studies and family-based analysis were performed in order to establish any correlation between the genotypes and the phenotypes. In addition, haplotype analysis was performed to determine whether there was interaction between SNPs or whether there were unidentified SNPs in the vicinity of the selected ones that might contribute to the observed phenotypic traits. Among the 22 chosen SNPs, 13 of them were found to be significantly linked to one or more of the tested phenotypes. The three most significant associations were BF_2557 with lung function, HMOX1_9531 with lung function and BF_7202 with age of diagnosis. Several haplotypes were significantly associated with one of the five phenotypes. There was no evidence for the presence of unidentified SNPs or interaction between SNPs. Most of haplotype associations were likely due to the presence of a single SNP which was found to be significantly linked to the phenotype. Conclusively, both SNPs and haplotype analyses suggest that the four candidate genes are modifiers of disease severity in CF.

Cystic Fibrosis is one of the most common genetic recessive diseases among Caucasians and is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene on chromosome 7. There are different classes of CFTR mutation, leading to differences in disease severity among patients. In addition to the CFTR genotype, secondary genetic factors, modifier genes, also influence CF phenotypes. Due to the dysfunction of CFTR protein and production of thickened mucus, bacterial infection in the lungs is favored and can lead to further clinical complications in CF patients. Pseudomonas aeruginosa is one of the most common bacteria detected among patients. The aim of this project was to investigate four candidate modifier genes, Factor B, Complement Factor 3, Toll-like Receptor 4 and Heme oxygenase-1, which might affect the status of Pseudomonas aeruginosa infection. A total of 22 single nucleotide polymorphisms (SNPs) were selected in these four genes and they were tested against five phenotypic traits, including age of diagnosis, FEV1% predicted andstandard deviation value, age of first Pseudomonas aeruginosa infection and Pseudomonas aeruginosa infection status. Among the selected SNPs, both case-control studies and family-based analysis were performed in order to establish any correlation between the genotypes and the phenotypes. In addition, haplotype analysis was performed to determine whether there was interaction between SNPs or whether there were unidentified SNPs in the vicinity of the selected ones that might contribute to the observed phenotypic traits. Among the 22 chosen SNPs, 13 of them were found to be significantly linked to one or more of the tested phenotypes. The three most significant associations were BF_2557 with lung function, HMOX1_9531 with lung function and BF_7202 with age of diagnosis. Several haplotypes were significantly associated with one of the five phenotypes. There was no evidence for the presence of unidentified SNPs or interaction between SNPs. Most of haplotype associations were likely due to the presence of a single SNP which was found to be significantly linked to the phenotype. Conclusively, both SNPs and haplotype analyses suggest that the four candidate genes are modifiers of disease severity in CF.

Complex diseases such as cancer or obesity are thought to be caused by abnormalities in multiple  genes and cannot be derived to one specific location in the genome. It has been shown that  identification of disease associated genes can be made through looking at interaction patterns in a  protein‐protein interaction network, where the disease associated genes are represented in clusters,  or disease modules. There are several algorithms developed to infer these disease modules, but  studies have shown that the reliability of the results increase if multiple algorithms are used and a  consensus module is derived from them. MODifieR is an R package developed to combine the results  of multiple  disease module inferring algorithms and has proven to provide a stable result. To  increase usability of the R package and make it available not only for users with programmatic skills,  MODifieR Web was developed as a web based tool with a graphical user interface. The tool was built  using Angular and .NET core, invoking the MODifieR R package in the backend. The interface requires  input in the form of an expression matrix and a probe map from the user, easily uploadable in a  drag‐and‐drop  interface.  It  gives  the  user  the  possibility  to  analyze  data  using  seven  different  algorithms and provide results as gene lists and visualizes the consensus module in a network image.  MODifieR Web is a first version of an application that is a novel contribution to the existing tools for  identification of disease modules, although in need of further improvements to be able to serve a  greater  pool  of  users  in  a  more  effective  way.  The  tool  is  available  to  try  out  at   http://transbioinfo.liu.se/modifier#/home and the source code is released as an open‐source project  in Github (https://github.com/emmape/MODifieRProject).

Cystic Fibrosis is one of the most common genetic recessive diseases among Caucasians and is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene on chromosome 7. There are different classes of CFTR mutation, leading to differences in disease severity among patients. In addition to the CFTR genotype, secondary genetic factors, modifier genes, also influence CF phenotypes. Due to the dysfunction of CFTR protein and production of thickened mucus, bacterial infection in the lungs is favored and can lead to further clinical complications in CF patients. Pseudomonas aeruginosa is one of the most common bacteria detected among patients. The aim of this project was to investigate four candidate modifier genes, Factor B, Complement Factor 3, Toll-like Receptor 4 and Heme oxygenase-1, which might affect the status of Pseudomonas aeruginosa infection. A total of 22 single nucleotide polymorphisms (SNPs) were selected in these four genes and they were tested against five phenotypic traits, including age of diagnosis, FEV1% predicted andstandard deviation value, age of first Pseudomonas aeruginosa infection and Pseudomonas aeruginosa infection status. Among the selected SNPs, both case-control studies and family-based analysis were performed in order to establish any correlation between the genotypes and the phenotypes. In addition, haplotype analysis was performed to determine whether there was interaction between SNPs or whether there were unidentified SNPs in the vicinity of the selected ones that might contribute to the observed phenotypic traits. Among the 22 chosen SNPs, 13 of them were found to be significantly linked to one or more of the tested phenotypes. The three most significant associations were BF_2557 with lung function, HMOX1_9531 with lung function and BF_7202 with age of diagnosis. Several haplotypes were significantly associated with one of the five phenotypes. There was no evidence for the presence of unidentified SNPs or interaction between SNPs. Most of haplotype associations were likely due to the presence of a single SNP which was found to be significantly linked to the phenotype. Conclusively, both SNPs and haplotype analyses suggest that the four candidate genes are modifiers of disease severity in CF. / Medicine, Faculty of / Medicine, Department of / Experimental Medicine, Division of / Graduate