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Full Text, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Pharmacy & Med Sci, Griffith Health, The demands of modern life are often challenging and require psychological efforts in order to be effectively met. Conserved through evolution, acute psychological stress (in response to an acute threat) activates physiological systems that are advantageous, exerting appropriately timed responses to promote survival. However, the advantageous outcomes of the acute stress response are reversed under prolonged conditions (chronic stress), detrimentally influencing biological processes and/or behaviours and increasing disease risks. This disease risk is imposed on virtually all organ systems, and ranges from mood disorders (e.g., major depressive disorder; MDD) to cardiovascular (e.g., ischaemic heart disease; IHD) and metabolic (e.g., type 2 diabetes; T2D) diseases. Although the impact of chronic psychological stress on mood disorders has been well documented, its effects on other body systems (including cardiovascular, circulatory, and hepatic systems) are less detailed. Furthermore, chronic psychological stress outcomes vary between females and males, both in disease risk and presentation, yet we lack definitive understanding of the specific mechanistic differences. Our understanding of psychological stress has increased considerably since it’s early conception in 1915 by Walter Bradford Cannon, a view that would later be defined by Hans Selye in 1956. However, our knowledge regarding the systems biology of chronic stress, the neurobiological adaptations and underpinnings of aberrant behaviour, and the mechanistic basis of sex-dependent outcomes, remain relatively limited. The doctoral work presented in this thesis describes the establishment of models of chronic stress in mice and their application in addressing these issues. The first (and fundamental) step in this doctoral project consisted of the development and characterization of murine chronic stress models for further potential study. Three distinct categories of stress were initially trialled: homotypic phy

The demands of modern life are often challenging and require psychological efforts in order to be effectively met. Conserved through evolution, acute psychological stress (in response to an acute threat) activates physiological systems that are advantageous, exerting appropriately timed responses to promote survival. However, the advantageous outcomes of the acute stress response are reversed under prolonged conditions (chronic stress), detrimentally influencing biological processes and/or behaviours and increasing disease risks. This disease risk is imposed on virtually all organ systems, and ranges from mood disorders (e.g., major depressive disorder; MDD) to cardiovascular (e.g., ischaemic heart disease; IHD) and metabolic (e.g., type 2 diabetes; T2D) diseases. Although the impact of chronic psychological stress on mood disorders has been well documented, its effects on other body systems (including cardiovascular, circulatory, and hepatic systems) are less detailed. Furthermore, chronic psychological stress outcomes vary between females and males, both in disease risk and presentation, yet we lack definitive understanding of the specific mechanistic differences. Our understanding of psychological stress has increased considerably since it’s early conception in 1915 by Walter Bradford Cannon, a view that would later be defined by Hans Selye in 1956. However, our knowledge regarding the systems biology of chronic stress, the neurobiological adaptations and underpinnings of aberrant behaviour, and the mechanistic basis of sex-dependent outcomes, remain relatively limited. The doctoral work presented in this thesis describes the establishment of models of chronic stress in mice and their application in addressing these issues. The first (and fundamental) step in this doctoral project consisted of the development and characterization of murine chronic stress models for further potential study. Three distinct categories of stress were initially trialled: homotypic phy, Thesis (PhD Doctorate), Doctor of Philosophy (PhD), School of Pharmacy & Med Sci, Griffith Health, Full Text

AIMS: To explore the national prevalence, mutation spectrum, cardiac phenotype, and outcome of the uncommon Jervell and Lange-Nielsen syndrome (JLNS), associated with a high risk of sudden cardiac death. METHODS AND RESULTS: A national inventory of clinical JLNS cases was performed. Genotype and area of origin were ascertained in index families. Retrospective clinical data were collected from medical records and interviews. We identified 19 cases in 13 Swedish families. A JLNS prevalence >1:200 000 was revealed (five living cases <10 years of age). The mutation spectrum consisted of eight KCNQ1 mutations, whereof p.R518X in 12/24 alleles. Geographic clustering of four mutations (20/24 alleles) and similarities to Norway's mutation spectrum were seen. A high prevalence of heterozygotes was suggested. Three paediatric cases on β-blockers since birth were as yet asymptomatic. Seven symptomatic cases had suffered an aborted cardiac arrest and four had died suddenly. QTc prolongation was significantly longer in symptomatic cases (mean 605 ± 62 vs. 518 ± 50 ms, P = 0.016). β-Blockers reduced, but did not abolish, cardiac events in any previously symptomatic case. β-Blocker type, dosage, and compliance probably affect outcome significantly. Implantable cardioverter-defibrillator therapy (ICD, n = 6) was associated with certain complications; however, no case of sudden death. CONCLUSION: Founder effects could explain 83% of the Swedish JLNS mutation spectrum and probably contribute to the high JLNS prevalence found in preadolescent Swedish children. Due to the severe cardiac phenotype in JLNS, the importance of stringent β-blocker therapy and compliance, and consideration of ICD implantation in the case of therapy failure is stressed.