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Background: Salicylate (SAL) toxicity, in vitro, produces mitochondrial membrane permeability transition (MPT), an inner membrane pore formed, at least in part, from the adenine nucleotide transporter (ANT) and cyclophilin-D (CyP-D). MPT increases permeability of the inner membrane to molecules < 1500 Da, including [H.sup.+], thereby uncoupling oxidative phosphorylation. Cyclosporine A (CSA) inhibits SAL-induced MPT formation in vitro by binding to CyP-D. This study's purpose was to determine if pretreatment with CSA prolongs survival time in rats poisoned with SAL. Methods: 29 rats were randomized to receive pretreatment with either 30 mg/kg CSA or an equal volume of control diluent IP. 4 h later, when circulating [CSA] exceeded concentrations that had been shown to prevent MPT in vitro, all rats received 1700 mg/kg sodium SAL IP. Time until death was recorded. Heart blood for measurement of serum [CSA] and [SAL] were obtained immediately after death. With 11 animals in each group, we calculated a power of > 0.95 to detect a doubling of survival time. Results: Median survival time in controls was 18 minutes (95% C. I. of 14-22 minutes) and for CSA animals was 14 minutes (95% C.I. of 13-15 minutes). The log rank test for the survival distributions between the 2 groups was significant, indicating shortened survival time for the CSA group (p < 0.001). Using Cox proportional hazards, salicylate level did not significantly influence survival time (p = 0.60). Conclusion: Pre-treatment with CSA shortened survival time in rats with SAL toxicity., Katz K, Curry S, Brooks D, Gerkin R, Ruha AM, Beuhler M, Watts D. Good Samaritan Regional Medical Center, Phoenix, Arizona, [...]

Objective: Lung inflammation may lead to accelerated rate of decline in lung function. Interleukin-10 (IL-10) suppresses inflammation through modulation of inflammatory mediators. The IL-10 single nucleotide polymorphism (SNP) at -1082 is associated with differential expression of IL-10, and the effects of other IL-10 SNPs have not been as well characterized. To purpose of the study was to evaluate the role of IL-10 SNPs in susceptibility to accelerated loss of lung function. Methods: Blood or mouthwash samples were collected from City of Phoenix Fire Department firefighters after obtaining informed consent. Information on age, present smoking, and annual forced expiratory volume in one second (FE[V.sub.1]) were collected from medical surveillance records. DNA was extracted from blood using alcohol precipitation and from buccal cells using Qiagen QiaAmp DNA mini Kit. IL-10 SNPs at -1082 and -819 were screened using the TaqMan[R] assay. Results: 314 subjects with at least three annual FE[V.sub.1] tests were included in the study. Average age was 41.6 [+ or -] 7 years, 18% were ever smokers, and annual mean decline in FE[V.sub.1] was -40 [+ or -] 40 ml. Genotype frequencies at -1082 were AA 31%, AG 50% and GG 17%, and at -952 were CC 55%, CT 37% and TT 8%. After adjusting for baseline FE[V.sub.1], age, and smoking using linear regression analysis, there were no significant differences in annual decline for SNPs at -1082 (p = 0.974) and -819 (p = 0.126). Conclusion: There were no associations between IL-10 SNPs at -1082 and -819 and longitudinal decline in lung function in our study population. Inclusion of environmental and occupational exposure data and analysis of additional cytokine polymorphisms may help to better define the genetic basis of variation in decline in lung function., Fierro MA, Burgess JL, Hysong TA, Fleming JE, Conley SM, Gerkin R, Klimecki W. University of Arizona, Tucson, AZ; Good Samaritan Medical Center, Phoenix, [...]