Browsing by Author "Owen, E P"

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    Open Access
    Distal sensory polyneuropathy in South Africans infected with human immunodeficiency virus : a cross-sectional analysis of a community cohort
    (2009) Maritz, Jean; Heckmann, Jeannine; Owen, E P
    Introduction: Distal sensory polyneuropathy (DSP), the most common neurological complication of HIV infection, is related to either HIV or antiretroviral therapy (ART). Dideoxynucleoside reverse transcriptase inhibitors such as stavudine are widely used in resource-poor countries and often associated with neuropathy. The prevalence of DSP in developed countries range from 21% to 63%; little data is available from Africa. We aimed to estimate the prevalence of DSP in a South African community clinic-based population and to investigate associated risk factors. Methods: In a cross-sectional study, DSP status was determined in 598 HIV-infected adults using validated tools (Brief Peripheral Neuropathy Screen and a modified version of the Total Neuropathy Score) to categorize subjects. Symptomatic DSP required the presence of at least two neuropathic signs together with at least one symptom. Asymptomatic DSP required the presence of two neuropathic signs. Clinical, anthropometric, quality of life and laboratory evaluations were prospectively performed. Information about CD4 counts, antiretroviral therapy (ART) and questionnaires regarding previous tuberculosis (TB) and alcohol exposure was retrospectively collected Results: Approximately half (49%) of the study population were diagnosed with DSP (30% symptomatic DSP). In the ART-naĂŻve group 37% had evidence of neuropathy (23% symptomatic) compared to 63% of the ART-exposed subjects (39% symptomatic). Overall, subjects with DSP were older (p<0.001) and had lower CD4 counts (p<0.001) compared to those without neuropathy. Previously treated TB infection (p<0.001) and ART use (p<0.001) showed strong associations with DSP. In multivariate analyses the odds (95% confidence interval) of developing DSP was independently associated with ART use (OR 1.7, 1.0-2.9), age (per 10 year increments) (OR 1.7, 1.4-2.2) and previously treated TB infection (OR 2.0, 1.3-3.0). Although stavudine significantly associated with DSP, the duration of exposure was similar irrespective of neuropathy status. Pain or paresthesia was reported by 69% of those with symptomatic DSP and rated as at least moderate to severe. ART-exposed subjects had a tendency towards lower pain scores compared to ART-naĂŻves (p=0.032). Conclusions: DSP is a clinically significant problem in urban HIV-infected Africans. The findings of this study raise the possibility that with avoidance of stavudine-containing regimens in older subjects, especially those with a history of previously treated TB infection, the prevalence of DSP may be reduced.
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    The R563Q mutation of the beta subunit of the epithelial sodium channel : prevalence and effect
    (2009) Jones, Erika Sherad Wilshire; Rayner, B L; Owen, E P; Meissner, P N
    Hypertension is a major worldwide predictor of morbidity and mortality. The search for genes that contribute to blood pressure is ongoing. The epithelial sodium channel genes were implicated when the beta subunit (SCNN1B, gene ID 6338) was found to have a mutation that caused Liddle’s syndrome. The R563Q mutation in the beta subunit has been associated with hypertension and pre-eclampsia in the Xhosa and Coloured people in Cape Town. The thesis consists of a cross-sectional analysis of the prevalence of the R563Q mutation in multiple ethnic groups in South Africa and a longitudinal functional assessment in response to saline infusion. The objectives were to determine the prevalence of the R563Q mutation and association with hypertension, and if it persists within families; to speculate as to the origins of the mutation; to determine if there were any relevant clinical differences between comparable patients with essential hypertension; to determine if the mutation predicted a difference in response to acute sodium loading and if a physiological difference is observed in sodium channel activity when expressed in oocytes. A high frequency of hypertensives in Johannesburg and Cape Town were found to be heterozygous and the mutation associated with hypertension, including within families. In the Khoisan the R563Q mutation was found at a high frequency (19%) in a random sample, suggesting the mutation originated from this population. The saline challenge illustrated the in vivo effects of the mutation. The results suggest that the sodium channel is innately overactive in heterozygous subjects and that counter-regulatory mechanisms are in place to compensate for changes in renal sodium handling. However, preliminary in vitro testing in oocytes did not show a difference in sodium channel activity.
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    The R563Q Mutation of the Beta Subunit of the Epithelial Sodium Channel: Prevalence and Effect
    (2009) Jones, Dr Erika Sherad Wilshire; Rayner, B L; Owen, E P; Meissner, P N
    Hypertension is a major worldwide predictor of morbidity and mortality. The search for genes that contribute to blood pressure is ongoing. The epithelial sodium channel genes were implicated when the beta subunit (SCNN1B, gene ID 6338) was found to have a mutation that caused Liddle's syndrome. The R563Q mutation in the beta subunit has been associated with hypertension and pre-eclampsia in the Xhosa and Coloured people in Cape Town. The thesis consists of a cross-sectional analysis of the prevalence of the R563Q mutation in multiple ethnic groups in South Africa and a longitudinal functional assessment in response to saline infusion. The objectives were to determine the prevalence of the R563Q mutation and association with hypertension, and if it persists within families; to speculate as to the origins of the mutation; to determine if there were any relevant clinical differences between comparable patients with essential hypertension; to determine if the mutation predicted a difference in response to acute sodium loading and if a physiological difference is observed in sodium channel activity when expressed in oocytes. 8 A high frequency of hypertensives in Johannesburg and Cape Town were found to be heterozygous and the mutation associated with hypertension, including within families. In the Khoisan the R563Q mutation was found at a high frequency (19%) in a random sample, suggesting the mutation originated from this population. The saline challenge illustrated the in vivo effects of the mutation. The results suggest that the sodium channel is innately overactive in heterozygous subjects and that counter-regulatory mechanisms are in place to compensate for changes in renal sodium handling. However, preliminary in vitro testing in oocytes did not show a difference in sodium channel activity. Conclusion: This thesis has shown that the R563Q mutation is found in multiple ethnic groups in South Africa, in which it associates with hypertension; and possibly originated from the Khoisan. In vivo effects are described. The results are important because hypertension resulting from the R563Q mutation is a common and treatable cause of hypertension. It is recommended that hypertension units in South Africa screen for the mutation and alter treatment appropriately. A further recommendation is that a sodium channel inhibitor, such as amiloride, in an appropriate form, is registered in South Africa for the treatment of hypertension.
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    Screening for thiopurine s-methyltransferase (TPMT) gene mutations in South Africa
    (2002) Olufadi, Rasaq; Harley, Eric; Owen, E P
    Several studies have shown that patients with low TPMT activity are at risk for severe and potentially fatal haematopoietic toxicity when treated with conventional doses of thiopurine drugs. Genetic polymorphism in the TPMT gene is an important determinant of mercaptopurine toxicity. Patients with mutations in the TPMT gene have a less efficient methylation process, and are therefore, predisposed to severe myelosuppression.