The evolution of a Department of Internal Medicine under an integrated clinical enterprise model: the University of Kentucky experience.

The impact on the Department of Internal Medicine of the emergence of the University of Kentucky Healthcare Enterprise as an integrated clinical model has been enormous. In fiscal year 2004, the department was financially insolvent and on the verge of implementing plans to decrease faculty from 127 to 65. Since that time, the department has changed dramatically with a corresponding improvement in its clinical, academic, and financial activity. The department has grown to 175 faculty, with a healthy financial outlook and a shared vision with the clinical enterprise. Departmental clinical growth has been accompanied by growth in extramural research funding. The clinical growth of the department, in turn, supported the growth of the integrated clinical enterprise overall.The purpose of this article is to present a case history of the impact of transition to an integrated clinical enterprise financial model on the clinical, research, and educational functions of a department of internal medicine, and the opportunities and lessons learned from this transition. The implementation of an enterprise model allowed revival and expansion of the clinical programs of the department. This expansion did not occur at the expense of the research and educational missions of the department but, rather, was associated with improved performance in these areas. The processes which were established during the conversion to the enterprise model, which involve strategic planning, monitoring of plan implementation, recalibration of objectives, financial transparency, and accountability of leadership and faculty, may better prepare the institution to face the challenges of the rapidly changing economic environment.

Serum amyloid A and lipoprotein retention in murine models of atherosclerosis.

OBJECTIVE: Elevated serum amyloid A (SAA) levels are associated with increased cardiovascular risk in humans. Because SAA associates primarily with lipoproteins in plasma and has proteoglycan binding domains, we postulated that SAA might mediate lipoprotein retention on atherosclerotic extracellular matrix. METHODS AND RESULTS: Immunohistochemistry was performed for SAA, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), and perlecan on proximal aortic lesions from chow-fed low-density lipoprotein receptor (LDLR)-/- and apoE-/- mice euthanized at 10, 50, and 70 weeks. SAA was detected on atherosclerotic lesion extracellular matrix at all time points in both strains. SAA area correlated highly with lesion areas (apoE-/-, r=0.76; LDLR-/-, r=0.86), apoA-I areas (apoE-/-, r=0.88; LDLR-/-, r=0.80), apoB areas (apoE-/-, r=0.74; LDLR-/-, r=0.89), and perlecan areas (apoE-/-, r=0.83; LDLR-/-, r=0.79) (all P<0.0001). In vitro, SAA enrichment increased high-density lipoprotein (HDL) binding to heparan sulfate proteoglycans, and immunoprecipitation experiments using plasma from apoE-/- and LDLR-/- mice demonstrated that SAA was present on both apoA-I-containing and apoB-containing lipoproteins. CONCLUSIONS: In chow-fed apoE-/- and LDLR-/- mice, SAA is deposited in murine atherosclerosis at all stages of lesion development, and SAA immunoreactive area correlates highly with lesion area, apoA-I area, apoB area, and perlecan area. These findings are consistent with a possible role for SAA-mediated lipoprotein retention in atherosclerosis.

Human secretory phospholipase A2 mediates decreased plasma levels of HDL cholesterol and apoA-I in response to inflammation in human apoA-I transgenic mice.

OBJECTIVE: Plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein (apo)A-I are decreased in inflammatory states. Secretory phospholipase A2 (sPLA2), an acute-phase protein, may play a key role in the pathophysiology of this phenomenon. METHODS AND RESULTS: To investigate the effects of sPLA2 on human-like HDL particles in vivo, we generated transgenic mice overexpressing human apoA-I and human sPLA2 (apoA-I/sPLA2 mice). Compared with apoA-I mice, apoA-I/sPLA2 mice had significantly lower plasma levels of phospholipids, HDL cholesterol, and apoA-I (each P<0.01). HDL from apoA-I/sPLA2 mice was significantly depleted in phospholipids and cholesteryl esters (each P<0.001) but was enriched in protein and triglycerides (each P<0.001). As assessed by gel filtration and nondenaturing gel electrophoresis, sPLA2 overexpression in apoA-I mice resulted in a dramatic shift of the HDL particle size toward smaller particles. Furthermore, virtually all plasma sPLA2 in apoA-I/sPLA2 mice was found in association with the HDL fraction. The acute-phase response was induced in apoA-I/sPLA2 double-transgenic and apoA-I single-transgenic mice by intraperitoneal lipopolysaccharide (LPS) injection. Plasma sPLA2 was significantly increased after LPS injection in apoA-I/sPLA2 mice. Twelve hours after LPS administration, plasma total cholesterol, HDL cholesterol, apoA-I, and phospholipids were unchanged in apoA-I transgenic control mice but had decreased significantly in the apoA-I/sPLA2 mice (-57%, -62%, and -54%, -61%, respectively; each P<0.001). Both groups of mice had increased plasma levels of serum amyloid A (SAA) in response to LPS. To test the hypothesis that SAA may be an in vivo activator of sPLA2, we specifically overexpressed SAA in apoA-I/sPLA2 mice by means of liver-directed gene transfer. Despite high plasma levels of SAA, plasma lipid and lipoprotein profiles were not different than those in control mice. CONCLUSIONS: These results in a mouse model of human-like HDL indicate that sPLA2 expression significantly influences HDL particle size and composition and demonstrate that an induction of sPLA2 is required for the decrease in plasma HDL cholesterol in response to inflammatory stimuli in mice and that this effect is independent of SAA.