Effect of gender on health related quality of life in sarcoidosis.

BACKGROUND: Sarcoidosis has different phenotypic manifestations which may have a diverse effect on functional status and quality of life. There are few studies in sarcoidosis addressing gender disparity and its effect on Health-Related Quality of Life (HRQL) and functional status. OBJECTIVE: The purpose of this study was to investigate the effects of gender on HRQL and to identify associations between poor HRQL and the results of common clinical tests. DESIGN: We assessed HRQL for 221 patients with sarcoidosis in a prospective, cross-sectional study using the Short Form-36 Health Survey and Sarcoidosis Health Questionnaire. We evaluated the association between the scores of these measures with patient characteristics, pulmonary function test (PFT) and 6-minute walk test (6MWT) data. RESULTS: Women had lower scores than men on every measure of HRQL and weaker associations to findings from PFT and 6MWT. Multivariate linear regression analyses demonstrated that reduced 6MWT distance and DLCO were significantly associated with poor HRQL in both genders but the sensation of dyspnea played a significant role in women only. CONCLUSIONS: Our results indicate that women with sarcoidosis have a lower HRQL score and a greater degree of functional impairment than men. The factors that are associated with poor HRQL differ by gender. Predictors of poor HRQL include reduction in DLCO and 6MWT distance and an increased sensation of dyspnea.

Clinical predictors of pulmonary hypertension in sarcoidosis.

Pulmonary hypertension (PH) adversely affects outcome in sarcoidosis and is an important predictor of mortality in these patients. Early and accurate diagnosis of this complication may improve outcome. The current authors hypothesised that integration of 6-min walk test (6MWT) as part of the evaluation leads to an earlier diagnosis of this complication. A total of 162 patients with sarcoidosis underwent 6MWT. Demographic and pulmonary function results were analysed. Patients were further assessed by echocardiography and right heart catheterisation when clinically indicated. Patients with sarcoidosis-associated PH had significantly decreased results on pulmonary function testing. They also walked shorter distances and desaturated to lower levels on 6MWT. On logistic regression analyses, significant predictors of PH were oxygen saturation <90% on 6MWT (odds ratio (OR) 12.1, 95% confidence interval (CI) 3.66-19.73) and diffusing capacity of the lung for carbon monoxide <60% predicted (OR 7.3, 95% CI 1.98-24.82). Moreover, by combining the results of oxygen saturation at 6 min with those of echocardiography, the ability to correctly predict the presence of PH by right heart catheterisation was improved. Patients with diffusing capacity of the lung for carbon monoxide <60% predicted and oxygen desaturation <90% on 6-min walk test have a high likelihood of pulmonary hypertension and should undergo further evaluation for the presence of this disorder.

Lipopolysaccharide induces Rac1-dependent reactive oxygen species formation and coordinates tumor necrosis factor-alpha secretion through IKK regulation of NF-kappa B.

Reactive oxygen species (ROS) are important second messengers generated in response to many types of environmental stress. In this setting, changes in intracellular ROS can activate signal transduction pathways that influence how cells react to their environment. In sepsis, a dynamic proinflammatory cellular response to bacterial toxins (e.g. lipopolysaccharide or LPS) leads to widespread organ damage and death. The present study demonstrates for the first time that the activation of Rac1 (a GTP-binding protein), and the subsequent production of ROS, constitutes a major pathway involved in NFkappaB-mediated tumor necrosis factor-alpha (TNFalpha) secretion following LPS challenge in macrophages. Expression of a dominant negative mutant of Rac1 (N17Rac1) reduced Rac1 activation, ROS formation, NFkappaB activation, and TNFalpha secretion following LPS stimulation. In contrast, expression of a dominant active form of Rac1 (V12Rac1) mimicked these effects in the absence of LPS stimulation. IKKalpha and IKKbeta were both required downstream modulators of LPS-activated Rac1, since the expression of either of the IKK dominant mutants (IKKalphaKM or IKKbetaKA) drastically reduced NFkappaB-dependent TNFalpha secretion. Moreover, studies using CD14 blocking antibodies suggest that Rac1 induces TNFalpha secretion through a pathway independent of CD14. However, a maximum therapeutic inhibition of LPS-induced TNFalpha secretion occurred when both CD14 and Rac1 pathways were inhibited. Our results suggest that targeting both Rac1- and CD14-dependent pathways could be a useful therapeutic strategy for attenuating the proinflammatory cytokine response during the course of sepsis.