Dysregulation of dopaminergic homeostasis has been established as the primary source of numerous neurological disorders including Parkinson’s and drug addiction. A tonic increase of dopamine (DA) in the nucleus accumbens is required for associating everyday events and behaviors with rewards. Yet many addictive exogenous compounds such as amphetamine (AMPH) and cocaine (COC) produce a much greater augmentation of synaptic DA levels that are linked to euphoria and a shift in behavior towards drug seeking. The protein responsible for maintaining extracellular levels of DA is the dopamine transporter (DAT). It is primarily located in the perisynaptic area at terminals of pre-synaptic neurons where its main function is to sequester DA from the extracellular space and to transport it back into the cell, a process that is electrogenic. AMPH and COC directly interact with DAT and alter its ionic currents. Not much is known about the effect of psychostimulant-induced DAT currents on neuronal excitability and neurotransmitter release. We use synthetic chemistry, molecular biology, and biophysics in heterologous expression systems to decipher the actions of drugs of abuse on DAT. Furthermore we demonstrate drug-induced DAT currents can activate Ca2+ channels associated with dopaminergic excitability. Lastly, we focused on investigating drug effects on excitability in a human midbrain dopaminergic cell line. Understanding how psychostimulants interact with DAT to produce the dysfunctional states of the transporter may facilitate the development of unique therapeutic strategies to treat psychostimulant dependence.

ABSTRACT All members registered on the managed care database for the chronic condition Rheumatoid Arthritis (RA), for the period 01 January 2003 to 30 June 2003, were evaluated to determine the prescribing pattern of the cyclo-oxygenase (COX) II inhibitors and non-selective non-steroidal anti-inflammatory (NSAIDs). A total of 2818 members were registered on the managed care database of the chronic condition RA and 1372 members were identified as using COX II inhibitors and 827 members were using nonsteroidal anti-inflammatory (NSAIDs). The prescribing frequency determined for the COX II inhibitors were 48.60% and 29.35% for the NSAIDs. The members identified as either using a COX II inhibitor or a NSAIDs were divided into two groups. The prescribing patterns of each group such as age, gender, co-morbid conditions, concomitant medication use and frequency were analysed and compared to the national institute of clinical excellence (NICE) and the South African Rheumatism and Arthritis Association (SARAA) guidelines for the appropriate prescribing of the COX II inhibitors. Celecoxib was the most frequently prescribed COX II inhibitor accounting for 46% of all the COX II inhibitors identified and diclofenac was the most frequently prescribed NSAID accounting for 34% of all the NSAIDs prescriptions. COX II inhibitors were prescribed more frequently to females with a mean age of 55 years than males. A similar prescribing trend was found with the NSAIDs. The COX II inhibitors were frequently prescribed to patients over the age of 56 with co morbid gastro-oesophageal disease and concomitant warfarin and steroid use. The prescribing patterns found in the managed care environment were similar to those recommended by the NICE and SARAA guidelines. The managed care data showed that the COX II inhibitors, which are supposed to have less gastric adverse side effects, were frequently used in combination with gastroprotective agents (GPA’s). This study indicates that even though COX II inhibitors were prescribed more frequently than NSAIDs in the managed care environment the recommended clinical guidelines and protocols employed by the managed care environment were adhered to. However, there v is a need to closely monitor patients on concomitant GPA’s treatment and COX II inhibitors. This study helped to evaluate the current prescribing patterns of COX II inhibitors in the managed health care environment. This study confirmed that guidelines and protocols were adhered to. These are excellent tools to be used in the managed health care environment to ensure effective and appropriate prescribing.

Chain of custody in the forest sector is very dependent on effectively tracking products though the supply chain and manufacturing processes, including sawmilling, drying, planing, and pulp processes. The effectiveness of a tracking system is largely influenced by the characteristics of the process it works within, the nature of the tracking system being used, and increasingly by the penetration of technologically advanced material tracking methods into on-the-ground CoC practices. A variety of CoC systems that exist in the global marketplace accommodate the use of advanced materials tracking systems as a tool for their their implementation. These advances not only offer the potential to reinforce the traceability of products in inventory, but also promote maintenance of their certified status between the various organizations that exist along the wood product supply chain, and ultimately to the end consumer. In the past, a number of different product tracking methods have been used, all of which suffer certain shortcomings in the challenging environment of the forest industry, and the extremely complex nature of Chain of Custody tracking. This work explores the development of a novel material tracking method using the innate IR signatures of polymeric compounds, varied by compound and concentration to develop millions of potential combinations, and consequently millions of unique identities. The combined variation of multiple IR peak frequencies and magnitudes provide the conceptual basis of a chemical barcode system, named "Chemi-Code", to be explored. To prove the validity of this concept, a series of polymers were assayed for suitability in such a system by tracking their IR response stability in the presence of solar UV radiation and over time. As well, the feasibility of varying polymer concentration, and subsequently identification of concentrations by DRIFT spectroscopy was explored by constructing response curves between polymer concentration and peak absorbance, and assessing associated error. Seven polymers were identified and assessed. Only two of these polymers were found to be sufficiently stable for use in the context of the forest industry, and of those two, only one behaved in a manner that would allow peak absorbance to be used as an identifiable chemical variable. Although only one of the seven polymers was suitable for use in the "Chemi-Code" system, the study did demonstrate the validity of the concept by showing that polymers can be exploited for use in such a system.

Chain of custody in the forest sector is very dependent on effectively tracking products though the supply chain and manufacturing processes, including sawmilling, drying, planing, and pulp processes. The effectiveness of a tracking system is largely influenced by the characteristics of the process it works within, the nature of the tracking system being used, and increasingly by the penetration of technologically advanced material tracking methods into on-the-ground CoC practices. A variety of CoC systems that exist in the global marketplace accommodate the use of advanced materials tracking systems as a tool for their their implementation. These advances not only offer the potential to reinforce the traceability of products in inventory, but also promote maintenance of their certified status between the various organizations that exist along the wood product supply chain, and ultimately to the end consumer. In the past, a number of different product tracking methods have been used, all of which suffer certain shortcomings in the challenging environment of the forest industry, and the extremely complex nature of Chain of Custody tracking. This work explores the development of a novel material tracking method using the innate IR signatures of polymeric compounds, varied by compound and concentration to develop millions of potential combinations, and consequently millions of unique identities. The combined variation of multiple IR peak frequencies and magnitudes provide the conceptual basis of a chemical barcode system, named "Chemi-Code", to be explored. To prove the validity of this concept, a series of polymers were assayed for suitability in such a system by tracking their IR response stability in the presence of solar UV radiation and over time. As well, the feasibility of varying polymer concentration, and subsequently identification of concentrations by DRIFT spectroscopy was explored by constructing response curves between polymer concentration and peak absorbance, and assessing associated error. Seven polymers were identified and assessed. Only two of these polymers were found to be sufficiently stable for use in the context of the forest industry, and of those two, only one behaved in a manner that would allow peak absorbance to be used as an identifiable chemical variable. Although only one of the seven polymers was suitable for use in the "Chemi-Code" system, the study did demonstrate the validity of the concept by showing that polymers can be exploited for use in such a system.

Chain of custody in the forest sector is very dependent on effectively tracking products though the supply chain and manufacturing processes, including sawmilling, drying, planing, and pulp processes. The effectiveness of a tracking system is largely influenced by the characteristics of the process it works within, the nature of the tracking system being used, and increasingly by the penetration of technologically advanced material tracking methods into on-the-ground CoC practices. A variety of CoC systems that exist in the global marketplace accommodate the use of advanced materials tracking systems as a tool for their their implementation. These advances not only offer the potential to reinforce the traceability of products in inventory, but also promote maintenance of their certified status between the various organizations that exist along the wood product supply chain, and ultimately to the end consumer. In the past, a number of different product tracking methods have been used, all of which suffer certain shortcomings in the challenging environment of the forest industry, and the extremely complex nature of Chain of Custody tracking. This work explores the development of a novel material tracking method using the innate IR signatures of polymeric compounds, varied by compound and concentration to develop millions of potential combinations, and consequently millions of unique identities. The combined variation of multiple IR peak frequencies and magnitudes provide the conceptual basis of a chemical barcode system, named "Chemi-Code", to be explored. To prove the validity of this concept, a series of polymers were assayed for suitability in such a system by tracking their IR response stability in the presence of solar UV radiation and over time. As well, the feasibility of varying polymer concentration, and subsequently identification of concentrations by DRIFT spectroscopy was explored by constructing response curves between polymer concentration and peak absorbance, and assessing associated error. Seven polymers were identified and assessed. Only two of these polymers were found to be sufficiently stable for use in the context of the forest industry, and of those two, only one behaved in a manner that would allow peak absorbance to be used as an identifiable chemical variable. Although only one of the seven polymers was suitable for use in the "Chemi-Code" system, the study did demonstrate the validity of the concept by showing that polymers can be exploited for use in such a system. / Forestry, Faculty of / Graduate

L’objet de ce travail est l’étude de la biocompatibilité in vitro des matériaux à base de COC, afin d’évaluer leur potentiel de biomatériaux implantables.Cette évaluation est réalisée par le suivi de plusieurs paramètres : viabilité cellulaire/cytotoxicité, évaluation des phénomènes de stress oxydant, inflammatoires et hémocompatibilité. Une relation entre ces réponses biologiques et les propriétés physico chimiques des matériaux étudiés a été appréhendée.Les résultats montrent une bonne biocompatibilité des films testés avec un impact significatif de la présence des additifs (anti-oxydant et lubrifiant) sur les paramètres biologiques et physico-chimiques évalués.L’effet simulé du vieillissement biologique de ces matériaux sur leur biocompatibilité et leurs caractères physico-chimiques a également été étudié. Des conditions de pH et d’oxydation extrêmes, ainsi que le contact avec des macrophages pendant 1 mois, ont un effet sur la surface et sur l’interaction des films de COC avec l’environnement biologique sans compromettre leur biocompatbilité. La présence d’additifs a également eu un impact sur ces modifications.En suivant une logique de management du risque, la systématisation de l’ensemble des méthodes développées a permis d’obtenir une approche simplifiée et validée au sein du laboratoire, applicable à l’ensemble des matériaux naturels ou synthétiques susceptibles d’être utilisés dans la fabrication des DM implantables / Abstract : The purpose of this work is the study of the in vitro biocompatibility of COC-based materials in order to evaluate their potential as implantable biomaterials.This evaluation is carried out by monitoring several parameters: cell viability / cytotoxicity, evaluation of oxidative stress, inflammatory reactions and hemocompatibility. A relationship between these biological responses and physicochemical properties of the studied materials has been apprehended.Results show a good biocompatibility of the tested films with a significant impact of the presence of additives (anti-oxidant and lubricant) on the evaluated biological and physicochemical parameters.The simulated effect of biological aging of these materials on their biocompatibility and physico-chemical characteristics has also been studied. Extreme pH and oxidation conditions, as well as contact with macrophages during 1 month, affect the surface and interaction of COC films with the biological environment without compromising their biocompatibility. The presence of additives also had an impact on these changes.Following a risk management logic, the systematization of the developed methods within the laboratory made it possible to obtain a simplified and validated approach, applicable to all natural or synthetic materials that could be used for manufacturing implantable medical devices.

Pseudomonas Aeruginosa est un pathogène opportuniste qui adapte son comportement aux molécules présentes dans son milieu. Il augmente en virulence lorsqu’il détecte des peptides natriurétiques dans son environnement. L’isatine est une molécule qui bloque cet effet. Pour mieux comprendre sur quel récepteur l’isatine agit, la conception d’un biocapteur a été menée. Un biocapteur est un outil alliant un bioélément, réagissant spécifiquement avec une cible biologique, et un support physique permettant la transduction du signal pour le rendre mesurable. Les travaux de thèse suivants décrivent la préparation d’un transducteur polymérique, le copolymère d’oléfines cycliques (COC), par greffage de sels de diazonium en surface. La modification de l’isatine par couplage pallado-catalysé compose la partie principale des travaux de synthèse organique effectués. Les méthodes de couplages peptidiques en surface et techniques d’accroche des isatines modifiées sur les surfaces des transducteurs (or ou COC) sont également décrites dans ce manuscrit. Pour finir, l’évaluation des effets biologiques des isatines modifiées et des biocapteurs conçus a été effectuée sur Pseudomonas Aeruginosa et sur d’autres bactéries. / Pseudomonas Aeruginosa is an opportunistic pathogen which can adapt its behavior to the present molecules in its surrounding. It increases in virulence when it detects natriuretics peptides in its environment. Isatin is a molecule which can block this effect. To determine on which receptor isatin acts on, the conception of a biosensor have been conducted. A biosensor is a tool combining a bioelement, reacting specifically with a biological target, and a physical support allowing the transduction of the signal to make it measurable. The following thesis describes the preparation of a polymeric transducer, the cyclic olefin copolymer (COC), by diazonium salts surface grafting. Isatin modification by palladium-catalysed coupling reaction represents the major part of the organic synthesis carried out. Surface peptide coupling methods and techniques to link the modified isatins to the surfaces of transducers (gold or COC) are also described in this dissertation. To finish, biological effects of the modified isatins and designed biosensors have been evaluated on Pseudomonas Aeruginosa and others bacteria.

Ce travail de thèse avait pour objectif d’étudier différents vieillissements des copolymères d’éthylène et de norbornène (ENC), utilisés comme conditionnement de produits pharmaceutiques. Grâce à la stratégie analytique adoptée qui a fait appel à différentes techniques de caractérisation, telles que les techniques séparatives comme la chromatographie d’exclusion stérique, la chromatographie liquide haute performance à polarité de phases inversée, les techniques spectrales dont la spectroscopie infra rouge à transformée de Fourier et la spectroscopie UV, les techniques d’analyse thermique à travers l’analyse thermogravimétrie et la calorimétrie différentielle à balayage, puis d’une étude de toxicité des produits de dégradations, nous avons pu mettre en évidence différents types de modifications dans le volume du matériau après vieillissement. La modification principale dans la masse du matériau, observée à la dose réglementaire de stérilisation (25 kGy), est la scission des chaînes du polymère qui s’accompagne de la création de composés de basses masses molaires, donc de migrants potentiels risquant d’influencer la sécurité d’emploi des ENC. Puis pour des doses élevées de rayonnement (150 kGy) et pendant 500h d’exposition UV, on a la réticulation des chaînes.La présence de l’additif (l’antioxydant phénolique l’Irganox 1010®) empêche la création des CBMM après vieillissements. Cependant, en absence d’additif, les vieillissements génèrent de nouveaux CBMM.Toutefois, l’étude de toxicité montre une certaine toxicité à 150 kGy du grade ENC / The aim of this thesis work was to study different ages of copolymers of ethylene and norbornene (ENC), used as packaging of pharmaceutical products. Thanks to the analytical strategy adopted using different characterization techniques, such as separation techniques such as size exclusion chromatography, reverse phase high performance liquid chromatography, spectral techniques including infrared spectroscopy transforming of Fourier and UV spectroscopy, thermal analysis techniques through thermogravimetric analysis and differential scanning calorimetry, and then a toxicity study of degradation products, we were able to highlight different types of modifications in the volume of the material after aging. The main modification in the bulk of the material, observed at the prescribed sterilization dose (25 kGy), is the cleavage of the polymer chains, which is accompanied by the creation of compounds with low molar masses, and therefore potential migrants, which are likely to influence ENC job security. Then for high doses of radiation (150 kGy) and for 500h UV exposure, there is the crosslinking of the chains. The presence of the additive (the phenolic antioxidant Irganox 1010®) prevents the creation of MBMM after aging. However, in the absence of an additive, aging generates new CBMMs. However, the toxicity study shows some toxicity at 150 kGy of the ENC.

Background: Exposure of non-sustainable practices put MNCs in bad light, hurting their brand image. Therefore, it is of great importance to ensure supplier sustainability upwards the chain. Vast focus has been put on the first-tier suppliers. However, there are few studies that have investigated the issue of second-tier supplier sustainability, and there are many real life examples of firms’ who failed to ensure second-tier supplier sustainability. Hence, the need for further investigation within the subject.   Purpose: The purpose of this study was to investigate how two Scandinavian-based MNCs ensure second-tier supplier sustainability within their supply chain.   Methodology: This thesis is conducted with an inductive approach, collecting qualitative data through semi-structured interviews and archival research, at two independent companies. Thus, a multiple case study. Empirical findings were analyzed through a template analysis. Based on the theoretical framework and formulated research questions, categories have been derived, constructing the outline for our empirical findings and analysis.   Conclusions: (I) Social and cultural distance are major determinants settling which second-tier suppliers being regarded as critical. Conclusively, these two factors are the major determinants identifying whom to prioritize. Furthermore, IT is recognized as a vital and beneficial tool to utilize when mapping the network of second-tier suppliers. (II) In order to achieve second-tier supplier compliance of CoC, “the grey area approach” is identified as the used approach by investigated companies. Further, long-term relationships with first-tier suppliers are a major key in order to ensure second-tier sustainability in long-term perspective. (III) Last but not least, first-tier supplier network investigation is regarded prior to choosing a first-tier supplier. However, it is nothing decisive since other factors are more important in the process.

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