The cardiac Na ؉ -Ca 2؉ exchanger (NCX1) is the principal Ca 2؉ efflux mechanism in cardiocytes. The exchanger is up-regulated in both cardiac hypertrophy and failure. In this report, we identify the cis-acting elements that control cardiac expression and ␣-adrenergic up-regulation of the exchanger gene. Deletion analysis revealed that a minimal cardiac promoter fragment from ؊184 to ؉172 is sufficient for cardiac expression and ␣-adrenergic stimulation. Mutational analysis revealed that both the CArG element at ؊80 and the GATA element at ؊50 were required for cardiac expression. Gel mobility shift assay supershift analysis demonstrated that the serum response factor binds to the CArG element and GATA-4 binds to the GATA element. Point mutations in the ؊172 E-box demonstrated that it was required for ␣-adrenergic induction. In addition, deletion analysis revealed one or more enhancer elements in the first intron (؉103 to ؉134) that are essential for phenylephrine up-regulation but bear no homology to any known transcription element. Therefore, this work demonstrates that SRF and GATA-4 are critical for NCX1 expression in neonatal cardiomyocytes and that the ؊172 E-box in addition to a novel enhancer element(s) are required for phenylephrine up-regulation of NCX1 and may mediate its hypertrophic up-regulation.The Na ϩ -Ca 2ϩ exchanger (NCX1) 1 catalyzes the electrogenic exchange of one intracellular calcium ion for three extracellular sodium ions across the plasma membrane in many mammalian cells. Transport is reversible and can facilitate calcium entry, which in the heart is capable of triggering calcium release from the sarcoplasmic reticulum (1). The exchanger is most abundant in the heart, where it regulates Ca 2ϩ fluxes across the sarcolemma and serves a critical role in the maintenance of the cellular calcium balance for excitation-contraction coupling. Na ϩ -Ca 2ϩ exchanger activity in cardiomyocytes is regulated by several factors. It is activated by cytosolic Ca 2ϩ and MgATP (2) and inhibited by cytosolic sodium (3) and ATP depletion (4). A high affinity Ca 2ϩ -binding domain has been identified in the large cytoplasmic loop (residues 371-508) that is believed to be responsible for calcium regulation (5). It is also inhibited by the exchanger inhibitory peptide, which corresponds to a 20-amino acid segment at the N terminus of the large cytoplasmic loop (6). A recent study has demonstrated that the exchanger is phosphorylated via a protein kinase C-dependent pathway and that NCX1 phosphorylation appears to coincide with up-regulation of exchanger activity (7).In addition, the exchanger is regulated at the transcriptional level in cardiac hypertrophy, ischemia, and failure. In the feline model of acute right ventricular hypertrophy, NCX1 message levels are rapidly up-regulated following pressure overload (8,9). An increase in NCX1 mRNA expression is also observed in cultured cardiac myocytes following ␣-adrenergic stimulation by phenylephrine or exposure to veratridine. Importantly, the exchanger is also...

Objective To explore the relation between hospital orthopaedic specialisation and postoperative outcomes after total hip or knee replacement surgery. Design Retrospective analysis of US Medicare data, 2001-5.

The utilization of arthroplasty is increasing at similar rates in markets with and without new arthroplasty programs.

Published studies of physician-owned specialty hospitals have typically examined the impact of these hospitals on disparities, quality, and utilization at a national level. Our objective was to examine the impact of newly opened physician-owned specialty orthopaedic hospitals on individual competing general hospitals. We used Medicare Part A administrative data to identify all physician-owned specialty orthopaedic hospitals performing total hip arthroplasty (THA) and total knee arthroplasty (TKA) between 1991 and 2005. We identified newly opened specialty hospitals in three representative markets (Durham, NC, Kansas City, and Oklahoma City) and assessed their impact on surgical volume and patient case complexity for the five competing general hospitals located closest to each specialty hospital. The average general hospital maintained THA and TKA volume following the opening of the specialty hospitals. The average general hospital also did not experience an increase in patient case complexity. Thus, based on these three markets, we found no clear evidence that entry of physician-owned specialty orthopaedic hospitals resulted in declines in THA or TKA volume or increases in patient case complexity for the average competing general hospital.