Publications

Key parasite polymorphisms were assessed in subjects treated for malaria with artesunate-amodiaquine in Tororo, Uganda. For pfcrt, all of the isolates tested had the CVIET haplotype. For pfmdr1, 86Y and 1246Y were common at baseline and their prevalences were significantly higher in new isolates after therapy, indicating that treatment selected for mutations associated with a decreased response to amodiaquine.

BACKGROUND

Current practice guidelines emphasize the importance of attaining asthma control. We sought to quantify the degree of quality-of-life impairment associated with different levels of asthma control.

METHODS

We analyzed prospective data for 987 adults in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. Asthma control was assessed by using the Asthma Therapy Assessment Questionnaire, a validated index of control problems ranging from 0 to 4. Disease-specific quality of life and preference-based health utilities were assessed after 12 months of follow-up by using the Mini-Asthma Quality of Life Questionnaire (AQLQ) and EuroQoL 5-D (EQ-5D). We used multiple linear regression to model the relationship between asthma control and the AQLQ and EQ-5D while controlling for severity classification and lung function.

RESULTS

Asthma control varied widely, even within a population with predominantly moderate-to-severe disease. An inverse relationship was observed between the number of asthma control problems and quality of life. Specifically, poorer control at baseline predicted worse AQLQ and EQ-5D scores at follow-up. Asthma control remained an independent predictor of disease-specific quality of life and general health in multivariate models and was a better longitudinal predictor of health status than asthma severity at baseline.

CONCLUSION

Poor asthma control is associated with a substantial degree of impairment and predicts quality of life at 12 months, even after taking baseline asthma severity into account.

CLINICAL IMPLICATIONS

Self-assessed measures of asthma control might help to identify and manage those patients at greatest risk for future health impairment.

OBJECTIVE

Sphingosine kinase (SphK) is a key enzyme in the synthesis of sphingosine 1-phosphate (S1P), a bioactive sphingolipid. SphK is involved in ischemic preconditioning (IPC). To date no studies in genetically altered animals have examined the role of SphK1 in myocardial ischemia/reperfusion (IR) injury and IPC.

METHODS AND RESULTS

Wild-type and SphK1 null mouse hearts were subjected to IR (50 min global ischemia and 40 min reperfusion) in a Langendorff apparatus. IPC consisted of 2 min of global ischemia and 2 min of reperfusion for two cycles. At baseline, there were no differences in left ventricular developed pressure (LVDP), +/-dP/dtmax, and LV end-diastolic pressure (EDP) between SphK1 mutant and wild-type (WT) mouse hearts. In the mutants, total SphK enzyme activity was reduced by 44% and S1P levels were decreased by 41%. SphK1 null hearts subjected to IR exhibited more cardiac damage compared with WT: LVDP and +/-dP/dtmax decreased, LVEDP increased, and infarct size increased (n=6, P<0.05). Apoptosis was markedly enhanced in SphK1 mutant IR mouse hearts. IPC was cardioprotective in WT hearts, but this protection appeared to be ineffective in SphK1 null hearts. There was no change in infarct size in the IPC+IR group compared to the IR group in the null hearts (50.1+/-5.0% vs 45.0+/-3.8%, n=6, P=NS). IPC remained ineffective in the null hearts even when the index ischemia time was shortened by 10 min.

CONCLUSIONS

Deletion of the SphK1 gene sensitizes the myocardium to IR injury and appears to impair the protective effect of IPC. These data provide the first genetic evidence that the SphK1-S1P pathway is a critical mediator of IPC and cell survival.