Dans de nombreuses espèces doiseaux chanteurs (ou Passériformes), dont fait partie le canari domestique (Serinus canaria), le comportement de chant est produit à la fois pour défendre un territoire ou attirer un partenaire. Le Système de Conntrôle du Chant est un réseau nerveux central spécialisé, principalement localisé au niveau du télencéphale et associé au contrôle de lapprentissage, la perception et la production du chant. Ce comportement a été décrit subir la modulation de facteurs externes, tels que la testostérone, la photopériode et les interactions sociales. En parallèle avec le comportement de chant, certains des noyaux appartenant au Système de Contrôle du Chant (HVC, RA et Area X) présentent un phénomène de plasticité saisonnière nerveuse fascinante. Le volume de ces noyaux augmente notamment par espacement des cellules, agrandissement de la taille du neuropile et de larborisation dendritique et, dans le cas particulier dHVC, par incorporation de neurones nouveaux-nés. Nous proposons ici une synthèse de la littérature concernant ce phénomène tout à fait particulier ; en effet, la régénération des neurones du système nerveux central est considérée comme inexistante -ou uniquement limitée à la production de quelques interneurones- chez les mammifères. Létude de la neuroplasticité chez loiseau chanteur constitue dès lors un modèle tout à fait remarquable et offrant des perspectives nouvelles dans létude du cerveau des vertébrés.

Actuellement le criblage en vue de la recherche de nouveaux agents antitumoraux se base principalement sur la qualité cytotoxique d’une molécule. Le principal défaut de cette approche est qu’aucune sélection n’est faite sur le mode d’action du médicament. L’objectif de ce travail est la mise au point d’une méthode permettant un classement rapide et objectif du mode d’action de molécules à visée thérapeutique par spectroscopie infrarouge. La spectroscopie infrarouge est une technique d’absorption de la lumière fournit la signature chimique d’un échantillon. L’excellente qualité du signal rend possible son utilisation comme outil discriminant. En outre, cette technique d’analyse se démarque des autres par son caractère non destructif et la rapidité d’acquisition des données. Elle se révèlerait donc une méthode de choix pour effectuer du criblage de molécules en vue de la recherche de nouveaux agents thérapeutiques. Dans un premier temps nous avons voulu évaluer la possibilité d’utiliser la spectroscopie infrarouge pour isoler la signature spectrale du mode d’action induit par des concentrations sub-létales de ouabaïne, un composé de la famille des cardénolides, sur une lignée tumorale de prostate. Nous avons montré que cette signature évolue au cours du temps et peut-être corrélée aux données biologiques décrites dans la littérature. Nous avons également mis en évidence pour la première fois une modification de la composition lipidique de la cellule. Cette altération a été caractérisée au cours du temps par spectrométrie de masse. Nous avons ensuite voulu définir les limites de la méthode. La littérature souligne la diversité des modes d’action que peut induire un agent thérapeutique selon sa concentration. Nous avons montré que cette diversité se reflète sur le spectre infrarouge de cellules tumorales traitées à la ouabaïne en distinguant au moins deux modes d’action distincts, dépendant de la concentration en ouabaïne. Par ailleurs, nous avons montré que la confluence pouvait modifier significativement le spectre infrarouge d’une cellule. Neanmoins cette signature est unique et orthogonale à celle induite par la ouabaïne. Finalement, nous avons évalué le potentiel de la spectroscopie infrarouge à distinguer des modes d’action induits par des molécules à la structure chimique proche. Nous avons montré qu’il était possible de caractériser spécifiquement chacun des modes d’action. D’autre part nous avons mis en évidence que les modes d’action de molécules issues d’une même classe d’agent thérapeutique conduisaient à des signatures spectrales similaires. Cette partie du travail souligne la possibilité d’utilisation de la spectroscopie infrarouge pour un classement objectif, uniquement basé sur leur mode d’action d’agents thérapeutiques potentiels.

Anabolic Androgenic Steroids (AAS) have been associated with adverse psychiatric effects, aggression and violent behaviour. The use of them has spread to a larger subpopulation, and the use has been connected to different risk behaviours, such as use of other illicit substances and carrying a gun. Case reports tell about a connection between AAS use and violent crimes, including homicide. The aim of this thesis is to investigate the proposed connection between AAS and crime, focusing on violent crimes, and to inquire into whether this proposed connection between AAS and criminality is affected by other risk factors for criminal behaviour. The first two studies of this thesis investigated the registered criminality of individuals testing positively for AAS, with individuals testing negatively serving as control groups. In the two last studies individuals at a clinic for substance abuse treatment (Paper III) and in a prison (Paper IV) were asked about their use of AAS, and their history was assessed using the Addiction Severity Index. The main finding of Paper I was the development of criminal patterns over time, with a clear increase of the proportion of violent crimes and weapons offences seen only among the pure AAS users. In Paper II an increased risk for weapons offences among AAS users was reported. In Paper III an increased risk of having been prosecuted for violent crimes and of having been physically abused was seen among the AAS users. In Paper IV, the main finding was the close resemblance of users and non users. In summary, this thesis have concluded that the violence previously reported as connected to use of AAS can, to a large extent, be accounted for by other risk factors. There seems, however, to be a connection between use of AAS and a heavy, more planned form of criminality.

The use of anabolic androgenic steroids (AAS) has been associated with use of illegal or unprescribed prescription drugs, as well as different adverse psychiatric effects, such as ma-nia, psychosis and hostility. Further, there is an association between use of AAS and other different risk behaviours, including carrying guns and reckless driving. Taken together, these data suggest that there is a group of AAS users that are not elite athletes, but rather young men at risk for psychiatric illness and criminality, and who use AAS primarily for their aes-thetic effects and possibly for their psychoactive effects. The aim of this thesis is to investi-gate further the connection between use of AAS and use of other drugs, and to investigate whether the proposed side effects of AAS cause an increase in morbidity and mortality. The first study (Paper I) investigates morbidity and mortality in persons testing positive for AAS compared to persons testing negative for AAS at a doping laboratory. Paper II of this thesis studies the presence of psychoactive drugs in diseased men who tested positive for AAS upon autopsy and whether there is any difference between deceased users of AAS and deceased users of heroin or amphetamine (control group). The third article (Paper III) dis-cusses a surprising finding in paper I of increased seizures NOS in users of AAS. Paper IV and V are interview studies from an out-patient substance abuse clinic. The main findings in Paper I was that the majority of deceased users of AAS were also positive for other drugs and/or alcohol on autopsy, and that users of AAS more often than the control group had died from intentional death (suicide or homicide). The main finding of Paper II was that users of AAS were severely at risk for premature death compared to both the control group and the general population. Paper III concluded that the high prevalence of Convulsion NOS in users of AAS most likely was the result of concomitant substance abuse and withdrawal from such use. Paper IV concluded that twelve percent of the patients at the substance abuse clinic had used AAS for at least one cycle. Users of AAS had a higher risk of having been convicted of a violent offence, and users of AAS more often reported having been physically abused. In Paper V, long-terme users of AAS were found to have an increased risk for developing depression in connection with cessation of AAS use. AAS was also re-ported to be used in preparation for crime. In summary, this thesis concludes that there is a solid association between use of AAS and use of other psychotropic drugs in certain subpopulations, and that users of AAS are at risk for premature death due to unnatural causes that may be secondary to use of AAS.

Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction.

The purpose of this study was to compare the myocardial structure and function among endurance athletes (n.12), powerlifters/steroid users (n=5), powerlifters/non-steroid users (n=6), and sedentary controls (n=4). All subjects had a M-mode echocardiographic examination of their left ventricles under resting conditions. The echocardiographic measurements recorded and analyzed were of the left ventricular posterior wall at diastole and systole, left ventricular internal diameter at diastole and systole, and inter-ventricular septal thickness at diastole and systole. Myocardial function measurements consisting of left ventricle ejection time, left ventricular mass, mean ventricular contractile force, and percent fractional shortening were also recorded and analyzed. A One Way Analysis of Variance was used to analyze the data for statistical significance. A Tukey's HSD post-hoc test was used to determine statistical significance between the groups. A significant difference (p =0.02) was found for inter-ventricular septal thickness during diastole. All three athletic groups had significantly thicker inter-ventricular septa' thickness during diastole as compared to the controls. Power lifters/steroid users had the thickest inter-ventricular septal thickness (18.7 mm), followed by endurance athletes (18.6 mm), and powerlifters/nonsteroid users (16.5 mm). Overall, powerlifters/steroid users had the thickest walls at systole and diastole, while endurance athletes had the greatest internal diameters relative to the size of the left ventricle. Statistically significant differences among the groups were found for all four myocardial functional parameters: left ventricular ejection time (p = 0.03), left ventricular mass (p = 0.002), mean ventricular contractile force of (p 0.0013), and percent fractional shortening (p = 0.05). Power lifters/steroid users had the fastest left ventricular ejection times, largest left ventricular mass, greatest mean ventricular contractile force, and greatest percent fractional shortening. Endurance athletes had the slowest left ventricular ejection times, second largest left ventricular mass, lowest mean ventricular contractile force, and third lowest percent fractional shortening. The results indicated that not all individuals participating in high level endurance or powerlifting training and competition demonstrated complete adaptations in myocardial structure and function. Power lifters/steroid users however, demonstrated myocardial functional adaptations that were significantly different from powerlifters/non-steroid users, endurance athletes, and controls. The results of this study cannot attribute these changes either to the use of large amounts of anabolic steroids, or long-term, high-intensity training and competition in powerlifting. However, the study identified alterations in myocardial functions in powerlifters/steroid users, and contributes to the existing body of knowledge regarding the use of anabolic steroids by athletes. / Graduation date: 1990

Interpersonal violence and suicide are major health concerns, leading to premature death, extensive human suffering and staggering monetary costs. Although violent behaviour has multiple causes, it is well known that acute substance intake and abuse increase the risks of both interpersonal and self-directed violence. This association is quite well established for alcohol, while a more ambiguous literature exists for other common drugs of abuse. For example, anabolic androgenic steroids (AAS), synthetic analogues to the “male” sex hormone testosterone are suggested to elicit violent and aggressive behaviour. Two studies (I and III) in the present thesis addressed the association between AAS use and being suspected or convicted of a violent crime among remand prisoners and in a general population sample, respectively. Further, using the case-crossover design to control for confounders stable within individuals, I also investigated the triggering (short-term risk) effect of alcohol and drugs such as benzodiazepines and AAS, on violent crime (Study II). Finally, a fourth study (IV) based on a large national forensic sample of suicide completers (n=18,894) examined the risk of using a violent, more lethal, suicide method, when under acute influence of alcohol, central stimulants or cannabis. The results of this thesis suggested that AAS use in itself is not a proximal risk factor for violent crime; the observed risk is probably due to the co-occurrence of abuse of other substances. Alcohol is a strong triggering risk factor for violent crime, constant across males and females as well as individuals with or without behavioral and psychiatric vulnerability. Intake of high doses of benzodiazepines is associated with an increased risk for violent crime. Cannabis use is associated with an increased risk of using the lethal suicide method of jumping from a height. I conclude that mapping substance abuse patterns may inform violence risk assessment and treatment planning.

Previous studies on the secondary metabolites of Formosan octocoral Isis hippuris were collected only at Green Island. In the course of our studies on secondary metabolites from marine organisms, the acetone-solubles of the Formosan octocoral Isis hippuris collected at Orchid Island has led to the isolation of eleven polyoxygenated steroids (1¡V11), along with two known compounds (12 and 13). The structures of these compounds were determined on the basis of their spectroscopic and physical data, including NMR, IR, MS, etc. The cytotoxicity against of A-549 (human lung epithelial carcinoma), HT-29 (human colon adenocarcinoma), and P-388 (mouse lymphocytic leukemia) cells, and anti-HCMV (human cytomegalovirus) activity of metabolites 1¡V13 were evaluated. Compounds 12 and 13 displayed cytotoxicity against P-388 cell line with ED50 values of 3.2 and 3.6 £gg/mL, respectively. Compound 12 exhibited cytotoxicity against A-549 cell line with an ED50 value of 3.8 £gg/mL. Compound 8 exhibit inhibitory activity against HCMV, with EC50 values of 2.0 £gg/mL.

Soft corals belonging to the genus Nephthea have been found to be a rich source of terpenoids and steroids. Chromatographic separation of acetone and CH2Cl2/MeOH extracts of Formosan soft coral Nephthea chabrolii resulted in the isolation of thirteen new steroids, including nine 4£\-methylated steroids (1−6, 8−10), three 19-oxygenated steroids (11−13), and a novel skeleton 19-norsteroid (7). The structures of these metabolites were elucidated by extensive spectral analyses and anti-inflammatory activities were measured in vitro. Compounds 1−2, 4−5, 7−11 and 13 at a concentration of 10 £gM significantly reduce the levels of iNOS (inducible nitric oxide synthase ). Compounds 2, 4, 6−7 and 10−11 at a concentration of 10 £gM also significantly reduce the levels of COX-2 (cyclooxygenase-2). Compounds 2, 4, 7, 10 and 11 can reduce the levels of both iNOS and COX-2. All compounds at a concentration of 10 £gM did not affect the housekeeping £]-actin protein expression.

The present study described the daily moods of male bodybuilders who self-administered large doses of anabolic-androgenic steroids (AS) through a full cycle of steroid use. Male bodybuilders (N = 13) who had been self-administering AS for 2.5 to 12 years served as subjects and participated in a 14 to 16 week experience sampling procedure wherein brief mood questionnaires were filled out twice daily. / Findings revealed that 11 of the 13 subjects experienced self-reported mood changes in association with AS use. In particular, 2 subjects (subjects 4 & 11) experienced quite dramatic changes in mood. It is concluded that there is much variability with regards to the psychological effects that humans may display in association with AS use. / Data are discussed in terms of the effects that AS use may have on mental health.