A cross-sectional epidemiologic survey of the respiratory health status was conducted in the adult (15 years and older) Indian South African population resident in Lenasia, Johannesburg to study the distribution and determinants of respiratory symptoms, disease and lung function level. A slightly modified self-administered version of a standardised respiratory health questionnaire and a wedge spirometer was used. There were a high proportion of current smokers among men. Although women smoked less than men in other communities they nevertheless smoked on average more heavily than other Indian South African women. Indian men and women who smoked had a high prevalence of respiratory symptoms. The women also demonstrated an increased susceptibility to the effects of cigarette smoking when compared with women in other communities. Indians in this study had spirometric lung function levels that were lower than that recorded in recent studies in Blacks and Whites in South Africa. Respiratory symptoms, disease and lung function level were examined in a multiple logistic regression model which contained all the potential determinants recorded in the present study. Voluntary tobacco smoking, recent chest illnesses and any kind of heart trouble was associated with a significant risk for having most of the respiratory symptoms and diseases in men and women. In addition exposure to dust in the work environment, little or no exercise,>Std. 8 education a history of any kind of chest trouble and respiratory trouble before the age of 16 years was associated with an increased risk for having respiratory symptoms in men in this model. An increased risk for respiratory symptoms was demonstrated in women only with age. Age and standing height were the most important determinants of lung function level in men and women in the regression model. Dust exposure in the work environment was associated with a significantly lower lung function level in men. Alcohol consumption and a history of whooping cough was also independently associated with a lower lung function level in men but were of borderline significance. In women involuntary /passive tobacco smoke exposure and respiratory trouble before the age of 16 years were associated with a lower lung function level. Women who spent most of their lives in a rural area and those who had a university education had a higher lung function level. The deleterious effects of smoking on lung function were minimal in this study possibly because lung function was performed only in subjects in the 18-45 year age category. A "healthy smoker" effect was demonstrated in men. Men who ever smoked and were without cardiorespiratory symptoms had significantly higher lung function levels compared to men who never smoked and were without symptoms. / Thesis (M.D.)-University of Natal, Durban, 1992.

Background: Although glucocorticoids are the most effective treatment for asthma, some patients show a poor response. In such patients with steroid resistant asthma, this has been ascribed to altered glucocorticoid receptor (GR) ligand-binding affinity induced by IL-2 combined with IL-4 or IL-13 alone- all of which can also modulate glucocorticoid function in vitro. Objective: We sought to assess the ligand-binding affinity in a distinct group of oral steroid-dependent asthmatic subjects and examine the mechanisms by which IL-2 and IL-4 (or IL-13) modify the ligand-binding affinity of the GR. Methods: Using dexamethasone-binding assays, we examined PBMCs ex vivo from healthy subjects, subjects with controlled asthma, and oral steroiddependent subjects with severe asthma. In addition, IL-2 and IL-4 were used to alter GR affinity in vitro. We used mediators or inhibitors of signal transduction to investigate the mechanisms of resistance. We also determined cytokine production of PBMC's by means of ELISA. Results: GR ligand-binding affinity was significantly reduced in the nucleus but not in the cytoplasm of oral steroid-dependent asthmatic subjects compared with that seen in steroid-sensitive and healthy subjects (dissociation constant, 41.37 ± 17.83 vs. 25.36 ± 2.63 nmol/L vs. 9.40 ± 4.01 nmol/L, respectively [p<.05 for both in comparison to normals] ). This difference in ligand-binding affinity could be mimicked by IL-2 and IL-4 co-treatment and was blocked by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. PBMC's rendered resistant in vitro demonstrated lower IL-10 and increased GM-CSF production following LPS or PMA & PHA stimulation compared to cells with normal GR affinity. Resistant cells also showed reduced dexamethasone repression of LPSstimulated IL-10 release. These effects were also reversed by SB203580. Inhibition of the ERK MAPK pathway by PD098059 (10 mol/L), phosphoinositol 3 kinase by wortmannin (5 nmol/L) or treatment with IL-10 (10 ng/mL) failed to modulate the effect of IL-2 and IL-4 on receptor affinity. Ro318220 (10 nmol/L), a specific protein kinase C inhibitor and theophylline, similarly, had no effect on affinity. Conclusion: GR ligand binding affinity is tiered; compared to normal subjects; steroid responsive asthmatics have a mild reduction in ligand binding whereas oral steroid dependent asthmatics have greater reductions. When mononuclear cells are rendered resistant in vitro, cytokine production (low IL-10 and high GM-CSF) favours a pro-inflammatory state. Our data do not support the ERK MAPK, phosphoinositol 3 kinase, protein kinase C pathways in steroid resistance. Treatment with IL-10 and theophylline also failed to modulate the effect of IL-2 and IL-4 on receptor affinity. However, P38 MAPK inhibitors may have potential in reversing glucocorticoid insensitivity and re-establishing the beneficial effects of glucocorticoids in patients with severe asthma. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2007.