ETD Collection
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Item Gender differences in the response to short term beta-adrenergic induced cardiomyocyte apoptosis and necrosis in rats(2011-01-26) Mielke, CarmellaBackground: Males have a higher prevalence of cardiovascular diseases compared to premenopausal women. However, postmenopausal women are at equal risk to men. It has therefore been suggested that estrogen is cardioprotective. Although the exact mechanisms of the purported cardioprotective effects of estrogen are unknown, estrogen administration has been reported to suppress beta-adrenergic receptor up-regulation in ovariectomized female rats. As beta-adrenergic activation induces cardiomyocyte apoptosis and necrosis, and hence adverse cardiac remodelling and heart failure, I aimed to determine whether the extent of beta-adrenergic induced apoptosis and necrosis differs between males and females. Methods: 27 male Wistar rats were assigned to one of two groups: ISO M (n=14) receiving a beta-adrenergic receptor agonist, isoproterenol (0.02mg/kg) and CON M (n=13) receiving vehicle (saline, 0.2ml). 29 female Wistar rats were assigned to one of two groups: ISO F (n=15) receiving a beta-adrenergic receptor agonist, isoproterenol (0.02mg/kg) and CON F (n=14) receiving vehicle. Isoproterenol and saline were administered by means of daily subcutaneous injections for 5 days. On the 5th day, cardiac geometry and function were assessed before and after ISO or saline administration using echocardiography. Rats were then terminated under anaesthesia within 30 minutes of ISO (or vehicle) administration and blood samples collected for the determination of serum estrogen concentration (ELISA). Female rats were terminated in proestrus which corresponds to peak estrogen concentrations. Cardiac myocyte apoptosis was assessed histologically using the DeadEndTM Colorimetric TUNEL system (Promega, Madison, WI, USA). The number of apoptotic cardiomyocyte nuclei was expressed as a percentage of the total number of cardiomyocyte nuclei per slide (heamotoxylin and eosin stain). Necrosis and fibrosis (pathological score) were assessed by assigning a pathological score to sections stained for fibrosis (van Gieson). Groups were iii compared using two-way (gender and regimen; and including repeated measures for echocardiography data) ANOVA followed by the Tukey-Kramer post hoc test. Results: As expected estrogen concentrations were higher in female compared to male rats (mean±SEM, pg.ml-1; ISO M: 7.04±1.41; CON M: 7.14±0.53; ISO F: 23.00±3.47; CON F: 19.31±3.66; p<0.01). Five days of ISO or saline administration had no effect on cardiac function or geometry in either the male or the female rats. Inotropic effects (increased heart rate and cardiac function) were observed in response to acute ISO administration in both male and female rats. The female rats had slower heart rates (p<0.05) and showed a greater heart rate response to acute ISO administration than the male rats (p<0.05). But the acute ISO induced increments in cardiac function were similar between genders. Five days of ISO administration induced cardiomyocyte apoptosis in male rats but not in female rats (mean±SEM, % ; ISO M: 0.086±0.013; CON M: 0.030±0.004; ISO F: 0.053±0.004; CON F: 0.041±0.007; p<0.05). Furthermore, 5 days of ISO administration induced cardiomyocyte necrosis in male rats but not in female rats (mean±SEM, pathological score; ISO M: 1.21±0.21, CON M: 0.46±0.14, ISO F: 0.50±0.11, CON F: 0.68±0.12, p<0.01). Conclusion: Male rats are more susceptible than female rats to beta-adrenergic induced cardiomyocyte apoptosis and necrosis. The protective effects of estrogen against the adverse effects of beta-adrenergic activation on the heart, may explain the lower risk of cardiovascular disease in premenopausal women compare to men; however, the possible role of progesterone cannot be ignored.Item Gender differences in clinical and immunological outcomes in South African HIV-infected patients on HAART(2008-09-01T13:17:15Z) Maskew, MhairiABSTRACT Introduction South Africa is estimated to have the largest number of HIV infected adults in Southern Africa with a higher HIV prevalence in females compared to males. While significant reductions in morbidity and mortality due to HIV and AIDS have been realized for over a decade internationally, HIV treatment involving highly active antiretroviral therapy (HAART) is still a relatively new phenomenon in this country and gender differences in HIV outcomes between males and females in South Africa have not been previously well described. This study aimed to determine and describe gender differences in clinical and immunological outcomes in a population of HIV infected South African adults initiated on HAART. Materials and Methods This retrospective data analysis reviewed 6,617 HIV-infected adultsABSTRACT Introduction South Africa is estimated to have the largest number of HIV infected adults in Southern Africa with a higher HIV prevalence in females compared to males. While significant reductions in morbidity and mortality due to HIV and AIDS have been realized for over a decade internationally, HIV treatment involving highly active antiretroviral therapy (HAART) is still a relatively new phenomenon in this country and gender differences in HIV outcomes between males and females in South Africa have not been previously well described. This study aimed to determine and describe gender differences in clinical and immunological outcomes in a population of HIV infected South African adults initiated on HAART. Materials and Methods This retrospective data analysis reviewed 6,617 HIV-infected adults initiated on HAART at the Themba Lethu Clinic, an urban public-sector antiretroviral rollout facility in Johannesburg, South Africa between 1st April 2004 and 31st March 2007. Clinical data from these antiretroviral naïve patients was analysed for gender differences in mortality, rates of loss to follow up, CD4 cell count response, virologic suppression and weight gain. Cox regression models and logistic regression models were used to estimate hazard ratios (HR) and odds ratios (OR), respectively, for associations between gender and outcomes. Models were adjusted for age and baseline CD4 count. Results At baseline, 4,388 (66.3%) women were significantly younger (p<0.0001) and less likely to be employed than the 2,229 (33.7%) men (p<0.001). Furthermore, women had significantly higher baseline CD4 counts (p<0.0001) and higher body mass index (BMI) (p<0.0001). Males experienced significantly reduced survival compared to females (p=0.0053) by Kaplan-Meier analysis. In adjusted multivariate analysis, men were 22% more likely to die or become lost to follow up than women [HR = 1.22 (95% CI 1.06 - 1.39]. The period with the highest risk of mortality or loss to follow up was within six months of starting HAART. Female gender was associated with better CD4 count response. In multivariate analysis adjusted for age and baseline CD4 count, women were 35% more likely to achieve a 100 cell increase in CD4 count at four months after initiation of HAART [OR =1.35 (95% CI = 1.19 -1.54)] and 45% more likely to increase their CD4 counts by 100 cells/mm3 after ten months on HAART [OR =1.42 (95% CI = 1.20 -1.68)] when compared to men. Women were also more likely to achieve virologic suppression at ten months post HAART initiation [OR =1.54 (95% CI =1.21-1.97)] and were more likely to have gained weight after four months on treatment than males [OR = 1.26 (95% CI = 1.07–1.49)] after adjusting for age, baseline CD4 count and baseline BMI. Conclusions Women had significant advantages over men in terms of short-term clinical and immunological outcomes. Earlier access treatment for men should be facilitated and adherence should be promoted once on treatment. Further research is required to determine if these gender differences persist during long-term HAART.Item Qualities of Restless Legs Syndrome and Periodic Limb Movements(2008-03-25T08:38:23Z) Bentley, Alison JABSTRACT The two disorders of Restless Legs Syndrome (RLS) and Periodic Limb Movements (PLM) are well recognised as fairly common neurological disorders. The presentation is of a sensory and motor component suggestive of a state of hyperexcitability of the nervous system. The underlying abnormality is believed to involve a dopamine deficiency but many of characteristics of the disorders have not been adequately described or quantified. I investigated, firstly, the possible reasons for the gender bias in the prevalence studies and found that women were more likely to have some associated conditions which may be related to RLS as well as a higher symptom load when compared to men subjects with RLS. I then looked at the problems of analysing the sensations occurring in RLS. Due to the lack of an adequate measuring tool and the possibility of a relationship between the sensations of RLS and those of pain, I used a validated descriptive pain questionnaire (the McGill pain questionnaire) to measure the sensations of RLS. Subjects with RLS were able to describe the sensations with the pain questionnaire and severity indices calculated from the McGill correlated well with measures of RLS severity but not with other intensity measures for pain. In the area of motor events I investigated the possibility of creating a classification system for the muscle activations documented as PLM. I recorded multiple muscle groups in the legs during sleep and devised a classification using sequence of activation and timing of activations from the different muscles. I also used the classification to show subtle changes in the leg activation patterns associated with change in sleep stage.