Differential gene expression in coronary arteries from patients presenting with ischemic heart disease: further evidence for the inflammatory basis of atherosclerosis.

BACKGROUND AND OBJECTIVE: The pathogenesis of human coronary artery disease (CAD) is likely to require the transcription of many different genes. We report here the differential gene expression profiling of human CAD using copy DNA (cDNA)/nylon array hybridization techniques. METHODS AND RESULTS: Human coronary arteries were obtained at the time of cardiac transplantation. Ten patients were transplanted for ischemic heart disease (IHD) and 5 for dilated cardiomyopathy (DCM). We generated a customized cDNA array containing 9206 clones and after hybridization of patient samples, data reduction, and refinement, identified 515 sequence-verified, differentially expressed clones. These clones represented 361 genes that were differentially expressed at significant levels between IHD and DCM arteries (t test, P < .05). Of these clones, 70% were defined genes of known function and 30% were genes of unknown function. Of the differentially expressed genes, 53.6% were up-regulated and 46.4% were down-regulated. Hierarchical clustering was performed and several distinct functional clusters were identified, including a cluster of genes related to inflammatory mechanisms. Validation by real-time polymerase chain reaction was undertaken with 2 genes known to be up-regulated in atherosclerosis (interleukin 1beta [IL-1beta] and IL-8) and 2 novel genes identified by the array analysis (signal transducer and activator of transcription 6 [STAT6] and IL-1 receptor-associated kinase [IRAK]). Differential expression of IL-1beta, IL-8, and STAT6 were confirmed by this method. Immunohistochemistry of STAT6 demonstrated increased expression in vascular smooth muscle cells of IHD coronary arteries. CONCLUSION: These data support the inflammatory basis of human atherosclerotic CAD and identify novel genes in atherosclerosis.

Zanamivir: a significant reduction in viral load during treatment in military conscripts with influenza.

A randomized, double-blind, placebo-controlled, parallel-group trial performed at 5 residential units of the Finnish Defence Forces was conducted to assess the antiviral activity, efficacy and safety of inhaled zanamivir for the treatment of naturally acquired influenza. Conscripts were recruited within 2 d of onset of typical influenza symptoms and received inhaled zanamivir 10 mg via a Diskhaler twice daily for 5 d or matching placebo. Time to alleviation of clinically significant symptoms of influenza was the primary endpoint. Viral load measurements were made using quantitative real-time polymerase chain reaction assays. 435/588 patients (74%) had laboratory-confirmed influenza infection. The mean area under the curve for viral load during the first 48 h of treatment was 8.48 [95% confidence interval (95% CI) 2.85 to 14.11] log10 vRNA copies/ml x h lower in the zanamivir group compared with placebo (p = 0.003). Zanamivir reduced the time to alleviation of symptoms versus placebo in the influenza-positive group (medians 2.0 vs 2.33 d; 95% CI-0.17 to 1.0 d, p = 0.08). Zanamivir rapidly reduced viral load following the start of therapy compared with placebo and was well tolerated.