Browsing by Author "Benecke, Rohan Meerholz"

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    Comparative assessment of neurological vs metabolic allostasis as reflected in human skin fibroblasts
    (Stellenbosch : Stellenbosch University, 2022-12) Benecke, Rohan Meerholz; Smith, Carine; Van de Vyver, Mari; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Incidence of mental health disorders are rising in modernity. Many mental health disorders share molecular and genetic overlap as well as having high incidence of comorbidities. Stress and the compounded effect of multiple low-grade stressors may be contributing to a relative increase in the pro-inflammatory and oxidative state seen in mental health disorders and other complex diseases. This leads to allostatic changes that potentially contribute to disease aetiology and progression. Allostasis is the process of homeostatic equilibrium under stress. Inflammation, which is often used to measure allostatic load, is potentially the incorrect measure as inflammation is transient and the damage ascribed to chronic inflammation is due to increases in reactive oxygen species (ROS) and decreases in antioxidant capacity. Post-traumatic stress disorder (PTSD) is a mental health disorder that is characterised by severe stressors and a maladaptive response to these stressors. Although the role of inflammation and oxidative stress have been implicated in the disease aetiology it is still a relatively neglected aspect of PTSD research. Furthermore, despite the high rate of comorbidities associated with PTSD there is still a lack of understanding in terms of the peripheral effects of PTSD. PTSD and potentially comorbid obesity, present ideal health paradigms to assess this relative neglect of allostatic changes, in particular those in the periphery, that may be contributing to disease outcome in PTSD. A novel therapeutic target, namely the trace amine system, is investigated as a potential anxiolytic in zebrafish larvae that could address allostatic changes of chronic diseases such as PTSD and obesity. Patient derived fibroblasts are used as model cell type to investigate potential functional changes in the periphery of PTSD patients as result of allostatic load. Finally, the potential for peripheral signalling to influence central function is explored in astrocytes, that represent the ideal candidate cell to investigate allostatic load in the context of mental health. Changes in peripheral calcium function and central redox function indicate the allostatic load of PTSD can modulate the chemiosmotic potential of cells through longitudinal shifts in the homeostatic set point. As a result, low grade cumulative stressors may be damaging to cellular function without activating endogenous defence mechanisms.
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    Genetic aetiology of anxiety disorders
    (Stellenbosch : Stellenbosch University, 2016-12) Benecke, Rohan Meerholz; Hemmings, Sian; Seedat, Soraya; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Molecular Biology and Human Genetics.
    ENGLISH SUMMARY: Anxiety disorders are among the most prevalent psychiatric disorders among both adults and adolescents. Comorbidity with other psychiatric disorders, including other anxiety disorders, is common and it is clear that a high degree of burden of distress and impairment is associated with the condition. Substantial evidence has been presented to suggest a strong genetic component in the aetiology of anxiety disorders. Twin and family studies suggest that panic disorder, general anxiety disorder, phobias and obsessive-compulsive disorder (OCD) aggregate in families. Twin studies in particular shown greater intrapair resemblance between monozygotic twins compared to dizygotic twins, suggesting a strong genetic component. Several genes have been implicated in the genetic aetiology of anxiety disorders, the most prominent of which are BDNF and SCL6A4. Furthermore, the role of the HPA axis in the regulation of the normal response to fear and stress may be influenced by genes contributing to cortisol functions such as FKBP5 and CRHR1. The severity of childhood trauma can contribute to the development of anxiety disorders by modulating gene expression. In this study anxiety sensitivity (AS) is investigated as a possible predictive marker for development of anxiety disorders. Adolescents (13-18 years of age) were recruited from senior secondary schools in the Cape Town area of the Western Cape. Participants were subjected to psychological screening, which included the childhood anxiety sensitivity index (CASI) as well as the childhood trauma questionnaire (CTQ), and saliva samples were collected and genotyping conducted. Gene-environment (G × E) interactions, focussing on the severity of childhood trauma and selected genetic variants, were investigated to determine how levels of AS in a South African adolescent population were modulated. Our cohort consisted of predominantly Xhosa and Coloured individuals and analysis was done on both ethnic groups separately. Significant findings in FKBP5 and CRHR1 in males of both ethnic groups suggests sex linked effect in genes regulating cortisol function. The severity of childhood trauma was found to modulate selected variants which is in line with previous literature. AS may be seen as a precursor to the development of anxiety- and anxiety-related disorders, and a potential clinical marker for early diagnoses of anxiety disorders.