Some b-blockers are efficiently removed from the circulation by hemodialysis ("high dialyzability") whereas others are not ("low dialyzability"). This characteristic may influence the effectiveness of the b-blockers among patients receiving long-term hemodialysis. To determine whether new use of a highdialyzability b-blocker compared with a low-dialyzability b-blocker associates with a higher rate of mortality in patients older than age 66 years receiving long-term hemodialysis, we conducted a propensity-matched population-based retrospective cohort study using the linked healthcare databases of Ontario, Canada. The high-dialyzability group (n=3294) included patients initiating atenolol, acebutolol, or metoprolol. The low-dialyzability group (n=3294) included patients initiating bisoprolol or propranolol. Initiation of a highversus low-dialyzability b-blocker was associated with a higher risk of death in the following 180 days (relative risk, 1.4; 95% confidence interval, 1.1 to 1.8; P,0.01). Supporting this finding, we repeated the primary analysis in a cohort of patients not receiving hemodialysis and found no significant association between dialyzability and the risk of death (relative risk, 1.0; 95% confidence interval, 0.9 to 1.3; P=0.71). b-Blocker exposure was not randomly allocated in this study, so a causal relationship between dialyzability and mortality cannot be determined. However, our findings should raise awareness of this potentially important drug characteristic and prompt further study.

Liver X receptor (LXR) activation represents a mechanism to prevent macrophage foam cell formation. Previously, we demonstrated that partial inhibition of oxidosqualene:lanosterol cyclase (OSC) stimulated synthesis of the LXR agonist 24(S),25-epoxycholesterol (24(S),25-epoxy) and enhanced ABCA1-mediated cholesterol efflux. In contrast to a synthetic, nonsteroidal LXR activator, TO-901317, triglyceride accumulation was not observed. In the present study, we determined whether endogenous 24(S),25-epoxy synthesis selectively enhanced expression of macrophage LXR-regulated cholesterol efflux genes but not genes that regulate fatty acid metabolism. THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15 nM) significantly reduced cholesterol synthesis and maximized synthesis of 24(S),25-epoxy. Endogenous 24(S),25-epoxy increased ABCA1, ABCG1, and APOE mRNA abundance and consequently increased cholesterol efflux to apoAI. In contrast, OSCi had no effect on LXR-regulated genes LPL (lipoprotein lipase) and FAS (fatty acid synthase). TO-901317 (>10 nM) significantly enhanced expression of all genes examined. OSCi and TO-901317 increased the mRNA and precursor form of SREBP1c, a major regulator of fatty acid and triglyceride synthesis. However, conversion of the precursor to the active form (nSREBP-1c) was blocked by OSCi-induced 24(S),25-epoxy but not by TO-901317 (>10 nM), which instead markedly increased nSREBP-1c. Disruption of nSREBP-1c formation by 24(S),25-epoxy accounted for diminished FAS and LPL expression. In summary, endogenous synthesis of 24(S),25-epoxy selectively up-regulates expression of macrophage LXR-regulated cholesterol efflux genes without stimulating genes linked to fatty acid and triglyceride synthesis.Macrophage-derived cholesteryl ester-rich foam cells develop within the arterial wall as a result of excessive internalization of lipoproteins, which subsequently promote early atherosclerotic plaque formation. In addition, foam cells enhance susceptibility to plaque rupture within advanced stage lesions, leading to further atherosclerosis complications (1, 2). The ligand-activated nuclear receptors known as liver X receptors (LXRs), 5 whose natural ligands are oxysterols, regulate the expression of genes involved in lipid homeostasis through binding to LXR response elements (LXREs) within the promoter of several responsive genes. These include ABCA1 (ATP-binding cassette A1), ABCG1, and APOE (apolipoprotein E), which mediate cellular cholesterol efflux from human and mouse macrophages to extracellular acceptors (3). Additionally, activated LXR increases expression of SREBP-1c (sterol regulatory element-binding protein 1c), FAS (fatty acid synthase), and LPL (lipoprotein lipase), which together act to stimulate cellular free fatty acid synthesis and free fatty acid uptake, respectively, leading to enhanced triglyceride synthesis (4 -6). SREBP-1c is itself a master regulator of genes involved in lipogenesis, such as LPL (7) and FAS (8), and is also self-regulating, since it posit...

This study examined diploid and triploid shortnose sturgeon hematology and stress physiology through the investigation of various characteristics and components of whole blood and blood plasma. Erythrocytic cellular and nuclear length and width were significantly larger in triploids than in diploids. Hematocrit was depressed in triploid sturgeon in comparison to diploids, but total blood hemoglobin content and mean erythrocytic hemoglobin concentration (MEHC) did not differ between ploidies. The mean erythrocytic hemoglobin (MEH) was elevated in proportion to the increase in erythrocyte size. Taken together, these data suggest that triploids and diploids likely have similar oxygen carrying and aerobic capacities. In response to an acute stressor of 15 min chasing, plasma cortisol and glucose levels did not differ between ploidies. Cortisol levels were significantly depressed at 2 h post-stress with an increase back to 0 h poststress levels at 6 h into recovery, whereas glucose levels did not change during the recovery period. There was a significant interaction between ploidy and time post-stress for blood hemoglobin concentrations, with diploids demonstrating elevated hemoglobin content at 6 h post-stress. Plasma osmolality, chloride ion concentrations and lactate levels were elevated in triploids. Overall, it does not appear that sturgeon have developed an elaborate stress response and the triploid stress response appears to be slightly reduced in comparison to diploids.Abbreviations: ELISA À enzyme linked immunosorbent assay; GLM À general linear model; Hb À total hemoglobin concentration; Hct À hematocrit; MEH À mean erythrocytic hemoglobin; MEHC À mean erythrocytic hemoglobin concentration; MEV À mean erythrocytic volume; PIT À passively integrated transponder; RBC À red blood cell

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