No description available.

This study examined the effects of chronic ethanol intake on the density, affinity, and allosteric modulation of rat brain GABAA receptor subtypes. In the presence of GABA, the apparent affinity for the benzodiazepine agonist flunitrazepam was increased and for the inverse agonist R015-4513 was decreased. No alteration in the capacity of GABA to modulate flunitrazepam and R015-4513 binding was observed in membranes prepared from cortex, hippocampus or cerebellum following chronic ethanol intake or withdrawal. The results also demonstrate two different binding sites for [3H]RO 15-4513 in rat cerebellum that differ in their affinities for diazepam. Chronic ethanol treatment and withdrawal did not significantly change the apparent affinity or density of these two receptor subtypes.

Yes / Non-invasive imaging methods are required to monitor the inflammatory content of atherosclerotic plaques. FEDAA1106 (N-(5-fluoro-2-phenoxyphenyl)-N-(2-(2-fluoroethoxy)-5- methoxybenzyl) acetamide) is a selective ligand for TSPO-18kDa (also known as peripheral benzodiazepine receptor), which is expressed by activated macrophages. We compared 18F- FEDAA1106 and 18F-FDG (a marker of glucose metabolism) for PET imaging of vascular inflammation. This was tested using a murine model where focal inflammation was induced in the carotid artery via placement of a constrictive cuff. Immunostaining revealed CD68-positive cells (macrophages) at a disturbed flow site located downstream from the cuff. Dynamic PET imaging using 18F-FEDAA1106 or 18F-FDG was registered to anatomical data generated by CT/CT angiography. Standardized uptake values (SUV) were significantly increased at cuffed compared to contralateral arteries using either 18F-FEDAA1106 (p<0.01) or FDG (p<0.05). However, the 18F-FEDAA1106 signal was significantly higher at the inflamed disturbed flow region compared to the non-inflamed uniform flow regions, whereas differences in FDG uptake were less distinct. We conclude that 18F-FEDAA1106 can be used in vivo for detection of vascular inflammation. Moreover, the signal pattern of 18F-FEDAA1106 correlated with vascular inflammation more specifically than FDG uptake. / : This study was funded by the British Heart Foundation and through a grant from the Swiss National Science Foundation (310030_143343/1 to B.R.K.)

No description available.

No description available.

No description available.

Os calmantes benzodiazepínicos são intensamente consumidos no mundo e no Brasil, principalmente por mulheres com idade igual ou superior a 60 anos. O consumo de calmantes envolve fatores sociais, econômicos e culturais, fazendo com que a maneira de utilização seja adaptada à realidade de determinados grupos sociais. Objetivando analisar essas questões, fizemos uso, através de abordagem qualitativa, de entrevistas semi-estruturadas com dezoito mulheres idosas, pertencentes a classes populares e consumidoras desses medicamentos há mais de um ano. Assim, observamos que o modo de consumo dos calmantes é construído socialmente e essa construção é formada através do tempo de uso, da aproximação com os serviços de saúde, da classe social à qual pertencem seus consumidores, da definição social do papel da mulher na sociedade (no sentido de gênero) e do envelhecimento de seus usuários, acompanhado de experiências e conhecimentos sobre os medicamentos. As mulheres entrevistadas mostraram ter autonomia e conhecimento sobre o uso dos calmantes, sentindo-se capazes de utilizar, indicar, emprestar, ou não, esses medicamentos, de acordo com suas concepções. Pudemos, portanto, observar e analisar as interações entre os diversos fatores – socioeconômicos e culturais, gênero e envelhecimento – envolvidos nesse processo de utilização de calmantes. / Benzodiazepine tranquillizers are widely consumed throughout Brazil and the world in general, mainly by women sixty or older. This consumption involves social, economic and cultural factors, with use influenced by reality of determined social groups. Aiming to analyze these questions, through qualitative approach, semi-structured interviews were administered to eighteen elderly women belonging to popular classes, who had been using these medicines for one year or more. We observed that consumption patterns of tranquilizer use are constructed socially and this construction is dependant upon the length of time of use, access to health services, their social class, social definition about the gender in society and the aging process. The construction is also influenced by experiences and knowledge about medicines. The interviewees showed that they possessed autonomy and knowledge about tranquillizer use, feeling able to use, to recommend, to lend, or not, these medicines, in accordance with their conceptions. Therefore we are able to observe and analyze the interactions between several factors – socio-economic and cultural, gender, and aging – involved in the process of tranquillizer use.

Os calmantes benzodiazepínicos são intensamente consumidos no mundo e no Brasil, principalmente por mulheres com idade igual ou superior a 60 anos. O consumo de calmantes envolve fatores sociais, econômicos e culturais, fazendo com que a maneira de utilização seja adaptada à realidade de determinados grupos sociais. Objetivando analisar essas questões, fizemos uso, através de abordagem qualitativa, de entrevistas semi-estruturadas com dezoito mulheres idosas, pertencentes a classes populares e consumidoras desses medicamentos há mais de um ano. Assim, observamos que o modo de consumo dos calmantes é construído socialmente e essa construção é formada através do tempo de uso, da aproximação com os serviços de saúde, da classe social à qual pertencem seus consumidores, da definição social do papel da mulher na sociedade (no sentido de gênero) e do envelhecimento de seus usuários, acompanhado de experiências e conhecimentos sobre os medicamentos. As mulheres entrevistadas mostraram ter autonomia e conhecimento sobre o uso dos calmantes, sentindo-se capazes de utilizar, indicar, emprestar, ou não, esses medicamentos, de acordo com suas concepções. Pudemos, portanto, observar e analisar as interações entre os diversos fatores – socioeconômicos e culturais, gênero e envelhecimento – envolvidos nesse processo de utilização de calmantes. / Benzodiazepine tranquillizers are widely consumed throughout Brazil and the world in general, mainly by women sixty or older. This consumption involves social, economic and cultural factors, with use influenced by reality of determined social groups. Aiming to analyze these questions, through qualitative approach, semi-structured interviews were administered to eighteen elderly women belonging to popular classes, who had been using these medicines for one year or more. We observed that consumption patterns of tranquilizer use are constructed socially and this construction is dependant upon the length of time of use, access to health services, their social class, social definition about the gender in society and the aging process. The construction is also influenced by experiences and knowledge about medicines. The interviewees showed that they possessed autonomy and knowledge about tranquillizer use, feeling able to use, to recommend, to lend, or not, these medicines, in accordance with their conceptions. Therefore we are able to observe and analyze the interactions between several factors – socio-economic and cultural, gender, and aging – involved in the process of tranquillizer use.

La TSPO préalablement connue sous le nom de récepteur périphérique aux benzodiazépines (PBR), est une protéine membranaire principalement impliquée dans le transport du cholestérol du cytosol vers la matrice des mitochondries, étape limitante dans la synthèse des stéroïdes et des sels biliaires.La production de la forme murine de la TSPO recombinante a été réalisée par un plasmide exprimé dans la bactérie Escherichia coli. La purification a été obtenue par colonne d'affinité grâce à l'étiquette polyhistidine codée dans le gène recombinant. Différents environnements mimétiques membranaires, détergents, lysodérivés, lipides ont été testés d'un point de vue structural et fonctionnel. Parmi les détergents étudiés, la dodécyl phosphocholine (DPC) a permis le meilleur repliement de la protéine. L'ajout de lysodérivés (LMPE) ou de phospholipides (DMPC/DMPE) a permis d'accroître la stabilité. La liaison des ligands spécifiques de la TSPO (PK 11195, cholestérol, protoporphyrine IX) a été observée dans plusieurs conditions étudiées par différentes approches biophysiques et biochimiques. Les trois approches structurales (ME, RX et RMN) ont pu être réalisées après optimisation des conditions de production et de stabilisation. Les résultats obtenus sont discutés en lien avec la structure de la TSPO publiée ces derniers mois. En parallèle à l'étude structurale, des mesures fonctionnelles par mutagenèse dirigée ont été réalisées afin d'obtenir des informations sur la liaison du ligand PK 11195. Ces données ont été confrontées à la structure récemment déterminée permettant de proposer un rôle pour les résidus mutés. Le mécanisme de transport du cholestérol par la TSPO est discuté. / TSPO previously named peripheral-type benzodiazepine receptor (PBR) is a membrane protein mostly involved in cholesterol transport from the cytosol to the matrix of mitochondria, a limiting step in steroids and bile salts biosynthesis.Production of recombinant mouse TSPO has been performed by plasmid expression in Escherichia coli bacteria. Purification has been obtained by immobilized affinity chromatography (IMAC) using polyhistidine tag encoded by recombinant gene. Various membranous mimetic environments such as detergents, lysoderivates, lipids have been tested from structural and functional point of view. Among tested detergents, dodecyl phosphocholine (DPC) has permitted the best protein refolding. The presence of lysoderivate (LMPE) or phospholipids (DMPC/DMPE) increased protein stability. Binding of TSPO high affinity ligands (PK 11195, cholesterol, protoporphyrin IX) has been measured in different conditions studied by biochemical and biophysical techniques. Three structural approaches (EM, XR and NMR) have been performed after optimization of production conditions and protein stabilization. Results gained have been discussed in line with TSPO atomic structure published within these last months. In parallel with structural studies, functional measurements have been carried out by site directed mutagenesis in order to gain data on binding site of PK 11195. These data have been faced with recently published TSPO atomic structure stabilized with this ligand and enabled to propose functional implication of mutated amino acids. Transport mechanism of cholesterol by TSPO is discussed.

Prescription opioid use is highly prevalent and may be replacing heroin as the predominant illicit opioid that is used. Little is known about specific prescription opioid use characteristics, or issues faced by these individuals in treatment. The major aims of the two studies comprising this thesis were: 1) to systematically and quantitatively assess different occasions of use for the prescription opioid hydromorphone; and 2) to evaluate how current substance use and psychiatric symptoms may be related in a population of prescription opioid users enrolled in a low-threshold Methadone Maintenance Treatment (MMT) program. Eighty-two participants from a low-threshold MMT program in Halifax, Nova Scotia were interviewed regarding their lifetime and current substance use, specific past occasions of hydromorphone use, and current psychiatric symptoms. A subsample of 26 participants was interviewed a second time, one day later, to assess reliability of participants’ self-report on the above-mentioned study measures. It was found that many variables were reliably reported between the two interviews by the subsample. With regards to the first major thesis aim, hydromorphone was found to be a prevalent, highly-favoured prescription opioid in the sample. Characteristics of initial, but not later, hydromorphone use varied by prescription status at initiation. Later use of hydromorphone shared many characteristics previously documented with heroin. With regards to the second major thesis aim, participants reported high rates of current substance use and psychiatric symptoms. Current substance use and psychiatric symptoms appeared to be related; notably, non-prescribed benzodiazepine use predicted depression and anxiety symptoms, and general anxiety predicted non-prescribed benzodiazepine use. In summary, while the results may not be representative of all prescription opioid users, or MMT clients, the thesis presented novel findings with a unique and vulnerable population. The findings supplement the existing literature in terms of describing how prescription opioids may be used during specific occasions, and in describing psychiatric and substance use issues faced by prescription opioid users enrolled in low-threshold MMT in Nova Scotia.