Thrombin-activable fibrinolysis inhibitor (TAFI) has recently been identified as a positive acute phase protein in mice, an observation that may have important implications for the interaction of the coagulation, fibrinolytic, and inflammatory systems. Activated TAFI (TAFIa) inhibits fibrinolysis by removing the carboxylterminal lysines from partially degraded fibrin that are important for maximally efficient plasminogen activation. In addition, TAFIa has been shown to be capable of removing the carboxyl-terminal arginine residues from the anaphylatoxins and bradykinin, thus implying a role for the TAFI pathway in the vascular responses to inflammation. In the current study, we investigated the ability of acute phase mediators to modulate human TAFI gene expression in cultured human hepatoma (HepG2) cells. Surprisingly, we found that treatment of HepG2 cells with a combination of interleukin (IL)-1␤ and IL-6 suppressed endogenous TAFI mRNA abundance in HepG2 cells (ϳ60% decrease), while treatment with IL-1␤ or IL-6 alone had no effect. Treatment with IL-1␤ and/or IL-6 had no effect on TAFI promoter activity as measured using a luciferase reporter plasmid containing the human TAFI 5 -flanking region, whereas treatment with IL-1␤ and IL-6 in combination, but not alone, decreased the stability of the endogenous TAFI mRNA. Treatment with the synthetic glucocorticoid dexamethasone resulted in a 2-fold increase of both TAFI mRNA levels and promoter activity. We identified a functional glucocorticoid response element (GRE) in the human TAFI promoter between nucleotides ؊92 and ؊78. The GRE was capable of binding the glucocorticoid receptor, as assessed by gel mobility shift assays, and mutation of this element markedly decreased the ability of the TAFI promoter to be activated by dexamethasone.Thrombin activable fibrinolysis inhibitor (TAFI) 1 was first identified in 1989 by two independent groups as a basic carboxypeptidase present in fresh serum that was distinct from the constitutive basic carboxypeptidase N (1, 2). By virtue of the intrinsic instability of this enzyme, whose activity disappeared within 2 h upon incubation at 37°C, Hendriks et al.(1) designated the novel activity "unstable" carboxypeptidase or carboxypeptidase U (1). Campbell and Okada (2) determined that the enzyme removed arginine residues from substrates more efficiently than lysines and therefore designated it carboxypeptidase R (2). In 1991, Eaton et al. (3) isolated a cDNA encoding the zymogen form of the enzyme and found that it was highly homologous to pancreatic procarboxypeptidase B. Bajzar et al. (4) independently isolated a protein on the basis of its ability to inhibit fibrinolysis in the setting of sustained activation of the coagulation cascade; on the basis of this property, they named the protein TAFI. Amino acid sequence analysis of TAFI revealed it to be identical to plasma procarboxypeptidase B and procarboxypeptidases U and R. TAFI can be activated by thrombin (4), plasmin (5), and thrombin in complex with thrombomodulin (6), wi...

This Article explores the prospects for integrating criminal law into the widespread trend elsewhere in the executive branch of using costbenefit analysis (CBA) to improve criminal justice policy making and enforcement practice. The Article describes an array of unnoticed and undervalued costs created by America's unique and fairly recent commitment to severe incarceration policies. It then maps the challenges for employing CBA in criminal enforcement practice. Those challenges include CBA 's own methodological and conceptual limitations, public choice problems created by the populist structure of criminal justice administration, constraints on CBA in criminal justice in light of theoretical commitments to retributivism, and practical limits to employing such a policy in the executive branch when legislatures are unwilling to reduce statutory punishment mandates. Despite these obstacles, the Article argues that a properly devised, CBA-based decision procedure-one that takes account of distributive and other non-quantifiable, qualitative concerns-is a promising avenue for rationalization and reform of state and federal criminal justice.

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