The enzyme 11β-Hydroxysteroid Dehydrogenase 1 (11β-HSD1) catalyses the intracellular biosynthesis of the active glucocorticoid cortisol. Tissue specific dysregulation of the enzyme has been implicated in the development of metabolic syndrome and other associated diseases. Experiments with transgenic mice and prototype inhibitors show that inhibition of 11β-HSD1 in visceral adipose tissue and liver leads to a resistance of diet-induced hyperglycemia and a favourable lipid and lipoprotein profile as compared to controls. 11β-HSD1 inhibition has thus been proposed as an effective strategy to decrease intracellular glucocorticoid levels without affecting circulating glucocorticoid levels that are essential for stress responses. The clinical development of selective and potent drugs has therefore become a priority. In this research, a process of virtual screening employing the novel algorithm UFSRAT (Ultra Fast Shape Recognition with Atom Types) was used to discover compounds which had specific physicochemical and spatial atomic parameters deemed essential for inhibition of 11β-HSD1. The top scoring compounds were assayed for inhibitory activity against recombinant human and mouse enzyme, using a fluorescence spectroscopy approach. In addition, HEK-293 cell based assays with either human, mouse or rat enzymes were carried out using a scintillation proximity assay (SPA). The most potent compound competitively inhibited human 11β-HSD1 with a Kiapp value of 51 nM. Recombinant mouse and human enzyme were expressed, purified and characterised and used in a series of ligand binding assays. Further to this, an X-ray crystal structure of mouse 11β-HSD1 in complex with a tight binding inhibitor – carbenoxolone was solved.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Le souffle équin est une maladie inflammatoire chronique des petites voies respiratoires, très fréquente chez les chevaux gardés à l’intérieur avec de la paille et du foin moisi et poussiéreux. Les signes cliniques peuvent être prévenus par le contrôle de l’environnement et soulagés par l’administration de corticostéroïdes systémiques et inhalés. L’objectif de cette étude était de déceler les effets secondaires présents sur des chevaux atteints de souffle traités à la fluticasone (Flovent 250 μg HFA®, 2000 μg BID, pendant six mois, et puis 2000 μg SID, pendant six autres mois) par le cortisol sérique et la présence d’ulcères gastriques. Cinq chevaux exempts de maladie respiratoire et onze chevaux atteints du souffle ont été gardés à l’intérieur d’une écurie avec du foin moisi et de la paille dans le but de provoquer la maladie chez le groupe atteints du souffle. Une fois les chevaux atteints de souffle devenus symptomatique, ils ont été divisés en deux groupes : un premier groupe traité avec de la fluticasone, nourri avec du foin et gardé sur une litière de paille, et un deuxième groupe non traité nourrie avec de la moulée et gardé sur une litière de ripe, pendant six mois. Par la suite, les deux groupes ont été mis au pâturage. Le cortisol a été mesuré par Immunoessai enzymatique par chimiluminescence (CEIA, Immunolite 1000, Siemmens®) les 12e et 10e jours avant et les 7e, 28e, 80e, 160e, 200e, 250e, 290e et 320e jours après le début du traitement afin de déterminer le degré de suppression du cortisol sérique. On a également fait une suivi de la présence d`ulcères gastriques à l`aide de vidéo endoscopique. La fluticasone inhalée deux fois par jour cause une diminution du cortisol sérique les 28e, 80e et 160e jours, mais elle n’entraîne pas d’effets sur le score des ulcères gastriques. Les pellets de luzerne causent quant à elles, une augmentation du score des ulcères gastrique chez les animaux exempts de maladie respiratoire. / Recurrent Airways Obstruction (RAO) is a small airways inflammatory disease, very common in horses stabled in mouldy-dusty hay and straw environments. The clinical signs are prevented by environmental control, relieved by systemic and inhaled corticosteroids. Our objectives were to determine whether inhaled corticosteroids cause a suppression of cortisol levels and gastric ulceration in RAO horses treated with fluticasone 2000μg (Flovant HFA®) BID for 6 months and 2000μg SID for another 6 months. Five (5) healthy horses were used as controls and eleven (11) RAO affected horses were stabled in a moldy-dusty environment to induce disease exacerbation. Once they were symptomatic, they were divided into two groups, the treated group was kept on hay/straw and the untreated group was fed with pellets food and bedded on wood shavings six months. Afterwards, all horses were pasture for the next 6 months. Serum cortisol was mesured by Immuno-essai enzymatique par chimiluminescence (CEIA, Immunolite 1000®, Siemmens) 12, 10 days before and 7, 28, 80, 160, 200, 250, 290, 320 days after treatment initiation, in order to determine cortisol suppression. Fluticasone administered twice a day reduces blood cortisol levels after 28, 80 and 160 days, but did not cause any change in gastric ulcers. However, pellets slightly increased gastric ulcer scores in healthy horses.

The study of stress is limited in professional nursing, but it is nearly non-existent in professional military nursing. The purpose of this study was to explore the relationships among psychological, environmental, biological and demographic factors of stress in new Army nurses during the Army Medical Department’s 8-week Officer Basic Leadership Course (OBLC). Using a descriptive prospective, correlational repeated measures design, 33 study participants completed two psychological stress measures (Perceived Stress Scale [PSS] and the Impact of Event Scale – Revised[IES-R]), an environmental measure (Life Experiences Survey [LES]), a biologic measure (salivary cortisol) and a demographic questionnaire at three different time points during OBLC: at the beginning of OBLC, during the field training exercise and at the end of OBLC. The majority of participants were single, Caucasian females under 30 years of age with no RN experience and no deployment experience. No significant gender differences were detected among study variables. A simple (single-group) repeated measures analysis of the PSS scores, IES-R scores, and salivary cortisol was conducted using the LES score as a covariate. While the PSS scores and salivary cortisol levels did not change significantly over time, the IES-R score did change significantly over time (p = 0.001). The environmental factor (LES score) was not significant as a covariate in any of the three models. The unique baseline findings in this study may provide a springboard for further studies in stress particularly with military nurses who will eventually be deployed and experience a variety of stressful events. Longitudinal research could yield important predictive information related to how the stress response evolves over the course of one’s military career which may include frequent deployments to the combat zone.

The primary study aim was to evaluate the latent biological effect of childhood sexual abuse (CSA) on adults by quantifying acquired cytogenetic changes and cortisol levels in identical twins who were discordant (N=22) or concordant (N=2) for a history of CSA. Although the difference scores for cortisol values between discordant identical co-twins were not significantly different from zero, a trend was observed for the twins exposed to intercourse, the most severe form of CSA, to have a blunted cortisol awakening response. Acquired cytogenetic changes were assessed by scoring telomere lengths and somatic cell abnormality frequencies via a cytokinesis-block micronucleus (MN) assay. No significant difference in overall telomere intensity values was observed between co-twins, but chromosome-specific telomere differences were observed in the individuals exposed to intercourse compared to their unabused co-twins ([χ2(45)= 62.88; p= 0.040 and χ2(45)= 73.72; p= 0.004). Specifically, shortened telomeres were observed on the short arms of chromosomes 3, 5, & 6, and long arms of chromosomes 11 & 13. A significant increase in MN frequencies was observed in the abused twins compared to unabused twins (t=2.65; df=16; p=0.009). A significant interaction between micronuclei frequencies and age was also observed, suggesting that the biological effects of stress are cumulative (coefficient [SE] = 0.030 [0.009]; p=0.0006). However, the pattern of chromatin present in MN, which was assessed using spectral karyotyping methodologies, was not limited to the subset of chromosomes with telomeric attrition. In summary, this is the first assessment of acquired chromosomal abnormalities, chromosome-specific telomere lengths and cortisol levels in identical adult twins discordant for exposure to CSA. Given that a portion of biological changes were most pronounced in the intercourse discordant twins, these findings support a possible dose-response relationship with CSA severity. Our data also suggest that the MN assay is a superior tool in assessing the latent effects of stress compared to either cortisol profiling or the measurement of telomere lengths. Collectively, application of the information gained from these studies may allow for novel screening techniques to identify individuals who are most at risk for developing stress-associated disease states.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Male mammals compete for reproductive access to females. Gaining and maintaining this access can be stressful and anxiety-provoking. In humans, anxiety and associated protective behaviors can manifest as jealousy. Physiological stress is likely to increase in relation to jealousy as it does with anxiety. Hypothetically, higher levels of anxiety and cortisol may indicate, and may even promote, strong territorial or jealous behavior. Chronically elevated cortisol has been shown to be deleterious to prefrontal and hippocampal neurons and result in emotional and stress-response dysregulation. In very anxious and jealous individuals, chronic stress activation could further promote these tendencies via emotional disinhibition. Cortisol production also related to vasopressin (AVP) levels and AVP has been shown to increase mate preference and territoriality. Furthermore, physiological measures may be more valid than self-report of less socially desirable behaviors such as jealousy and anxiety. As a preliminary study, we measured salivary cortisol, heart-rate, and blood pressure in relation to self-reported anxiety and jealousy in healthy men and women in response to threatening male faces paired with smiling female faces. Elevated anxiety positively predicted jealousy in men but not women. Anxiety and jealousy also predicted elevated heart rate and blood pressure. Cortisol levels in response to the threat task and in relation to jealousy approached statistical significance (ps < 0.07) and suggest the need for a larger sample size.

No description available.

This thesis has examined what long-term psychological and neurological effects that are apparent in children and adults who have experienced parental divorce. It was predicted that significantly more children and adult children from divorced families would have increased symptoms of mental disorders than children and adult children from married homes e.g., anxiety, depression, panic disorder, and generalized anxiety disorder. It was further predicted that parental divorce would negatively affect the neurological system in the offspring. The correlation between children of divorce and negative neurological effects was not found to be true. However, adult children of divorce have significantly lower baseline cortisol levels compared to adult children of marriage. Dysregulated cortisol levels are highly associated with the development of e.g., anxiety, depression, and brain damage. Parental divorce did not only influence how secretion of the hormone cortisol is regulated within adult children of divorce, but how both children and adult children of divorce psychologically adapt post-divorce. Children of divorce have for instance lower general well-being, more symptoms of anxiety and depression, lower self-esteem, and feel more stress than children of marriage. Adult children of divorce are more likely to experience marital discord, getting divorced themselves, anxiety and depression, lower academic performance, and substance abuse, etc. The result of the thesis suggests that children and adult children from divorced families are negatively affected, both psychologically and neurologically, regardless of age. Parental divorce and supplementary effects make it more likely for children and adult children to experience more symptoms of mental disorders.

This thesis has examined what long-term psychological and neurological effects that are apparent in children and adults who have experienced parental divorce. It was predicted that significantly more children and adult children from divorced families would have increased symptoms of mental disorders than children and adult children from married homes e.g., anxiety, depression, panic disorder, and generalized anxiety disorder. It was further predicted that parental divorce would negatively affect the neurological system in the offspring. The correlation between children of divorce and negative neurological effects was not found to be true. However, adult children of divorce have significantly lower baseline cortisol levels compared to adult children of marriage. Dysregulated cortisol levels are highly associated with the development of e.g., anxiety, depression, and brain damage. Parental divorce did not only influence how secretion of the hormone cortisol is regulated within adult children of divorce, but how both children and adult children of divorce psychologically adapt postdivorce. Children of divorce have for instance lower general well-being, more symptoms of anxiety and depression, lower self-esteem, and feel more stress than children of marriage. Adult children of divorce are more likely to experience marital discord, getting divorced themselves, anxiety and depression, lower academic performance, and substance abuse, etc. The result of the thesis suggests that children and adult children from divorced families are negatively affected, both psychologically and neurologically, regardless of age. Parental divorce and supplementary effects make it more likely for children and adult children to experience more symptoms of mental disorders.