Redox regulation of lipopolysaccharide-mediated sulfiredoxin induction, which depends on both AP-1 and Nrf2.

Sulfiredoxin (Srx) is an enzyme that catalyzes the reduction of cysteine sulfinic acid of hyperoxidized peroxiredoxins and exerts a protective antioxidant role. Here we investigated the regulatory mechanism of Srx induction by lipopolysaccharide (LPS) in mouse macrophages. LPS up-regulated Srx expression on the transcriptional level. The promoter region of the Srx gene contained putative NF-κB and AP-1 (activator protein-1) sites, and the proximal site of three AP-1 sites was embedded within the antioxidant response element (ARE), a cis-acting element for Nrf2 (nuclear factor erythroid 2-related factor). Mutational analysis of the Srx promoter revealed that Srx induction is dependent on AP-1 sites and ARE but not on NF-κB sites. Consistently, both transcription factors, AP-1 and Nrf2, were required for LPS-mediated Srx induction, as revealed by chromatin immunoprecipitation using antibodies specific for c-Jun and c-Fos and little Srx induction in Nrf2-null bone marrow-derived macrophages. Among mitogen-activated protein kinases that mediate the signal transduction by LPS, JNK played a major role in Srx induction. Moreover, chemical antioxidants, such as N-acetylcysteine and butylated hydroxyanisole, and the NADPH oxidase inhibitor diphenyleneiodonium inhibited Srx induction as well as generation of reactive oxygen species, both of which were also suppressed in Nox2 (NADPH oxidase 2)-deficient bone marrow-derived macrophages. These results suggest that LPS-mediated Srx induction is dependent on both AP-1 and Nrf2, which is regulated by Nox2-derived reactive oxygen species.

Paying for quality: providers' incentives for quality improvement.

Paying health care providers to meet quality goals is an idea with widespread appeal, given the common perception that quality of care in the United States remains unacceptably low despite a decade of benchmarking and public reporting. There has been little critical analysis of the design of the current generation of quality incentive programs. In this paper we examine public reports of paying for quality over the past five years and assess each of the identified programs in terms of key design features, including the market share of payers, the structure of the reward system, the amount of revenue at stake, and the targeted domains of health care quality.

Climbing up the pay-for-performance learning curve: where are the early adopters now?

The diffusion of performance-based payment incentives is arguably the most striking change in the U.S. health care system since the managed care era. Because there is little knowledge about best practices, sponsors of payment-incentive programs must learn by doing. We examine the experiences of twenty-seven early adopters and profile the evolution of their pay-for-performance (P4P) strategies as well as perceptions of key lessons learned. Our findings suggest that leading-edge sponsors of P4P have expanded the reach of their efforts, particularly with regard to specialists, and increasingly are focused on outcome and cost-efficiency measures, rather than clinical process measures alone.