Impact of weekly feedback on test ordering patterns.

OBJECTIVES: We examined the impact of weekly feedback reports on the test-ordering behavior of internal medicine residents. STUDY DESIGN: Retrospective analysis of a performance improvement effort. METHODS: In a large, urban, academic medical center, we extracted raw data on every inpatient laboratory test ordered by all internal medicine residents during two 26-week time periods. The pre-intervention phase established baseline ordering volume as each resident rotated through the various clinical services. The intervention consisted of a 1-hour educational seminar detailing the potential harm and costs of laboratory overutilization followed by the post intervention phase, which consisted of weekly feedback reports graphically illustrating individual versus group ordering patterns, where the identity of individual residents was protected. The total numbers of tests ordered during the 2 phases were compared using an independent t test. RESULTS: During the post intervention phase, we observed a net reduction of 21% in tests ordered-an average of 941 tests per week-with the greatest reduction in the chemistry section of the laboratory, followed by hematology, coagulation, and all others combined. This reduction in test volume corresponded to a $1.3 million reduction in charges. CONCLUSIONS: Providing physicians-in-training with a weekly feedback report detailing their test ordering volume in comparison with those of their peers is an effective method for reducing laboratory overutilization. Benefits to our approach include maintaining physician autonomy without alteration of existing infrastructure or disclosure of test fees.

Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline.

A classic physiologic response to hypoxia in humans is the up-regulation of the ERYTHROPOIETIN (EPO) gene, which is the central regulator of red blood cell mass. The EPO gene, in turn, is activated by hypoxia inducible factor (HIF). HIF is a transcription factor consisting of an alpha subunit (HIF-alpha) and a beta subunit (HIF-beta). Under normoxic conditions, prolyl hydroxylase domain protein (PHD, also known as HIF prolyl hydroxylase and egg laying-defective nine protein) site specifically hydroxylates HIF-alpha in a conserved LXXLAP motif (where underlining indicates the hydroxylacceptor proline). This provides a recognition motif for the von Hippel Lindau protein, a component of an E3 ubiquitin ligase complex that targets hydroxylated HIF-alpha for degradation. Under hypoxic conditions, this inherently oxygen-dependent modification is arrested, thereby stabilizing HIF-alpha and allowing it to activate the EPO gene. We previously identified and characterized an erythrocytosis-associated HIF2A mutation, G537W. More recently, we reported two additional erythrocytosis-associated HIF2A mutations, G537R and M535V. Here, we describe the functional characterization of these two mutants as well as a third novel erythrocytosis-associated mutation, P534L. These mutations affect residues C-terminal to the LXXLAP motif. We find that all result in impaired degradation and thus aberrant stabilization of HIF-2alpha. However, each exhibits a distinct profile with respect to their effects on PHD2 binding and von Hippel Lindau interaction. These findings reinforce the importance of HIF-2alpha in human EPO regulation, demonstrate heterogeneity of functional defects arising from these mutations, and point to a critical role for residues C-terminal to the LXXLAP motif in HIF-alpha.

Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine beta-synthase-deficient mice.

Previous in vitro experiments have shown that hyperhomocysteinemia leads to oxidative inactivation of nitric oxide, in part by inhibiting the expression of cellular glutathione peroxidase (GPx-1). To elucidate the role of intracellular redox status on homocysteine-induced endothelial dysfunction and oxidant stress, heterozygous cystathionine beta-synthase-deficient (CBS(-/+)) and wild-type (CBS(+/+)) mice were treated with the cysteine donor L-2-oxothiazolidine-4-carboxylic acid (OTC). CBS(-/+) mice had significantly lower GPx-1 activity compared with their CBS(+/+) littermates, and OTC treatment led to a modest increase in tissue GPx-1 activity and significant increases in total thiols and in reduced glutathione levels in both CBS(+/+) and CBS(-/+) mice. Superfusion of the mesentery with beta-methacholine or bradykinin produced dose-dependent vasodilation of mesenteric arterioles in CBS(+/+) mice and in CBS(+/+) mice treated with OTC. In contrast, mesenteric arterioles from CBS(-/+) mice manifested dose-dependent vasoconstriction in response to both agonists. OTC treatment of CBS(-/+) mice restored normal microvascular vasodilator reactivity to beta-methacholine and bradykinin. These findings demonstrate that mild hyperhomocysteinemia leads to endothelial dysfunction in association with decreased bioavailable nitric oxide. Increasing the cellular thiol and reduced glutathione pools and increasing GPx-1 activity restores endothelial function. These findings emphasize the importance of intracellular redox balance for nitric oxide bioactivity and endothelial function.