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...

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.

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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Objective: To provide family physicians with a practical, evidence-based approach to managing patients with cerumen impaction. Methods: MEDLINE, The Cochrane Library, and the Turning Research Into Practice (TRIP) database were searched for English-language cerumen impaction guidelines and reviews. All such articles published between 1992 and 2018 were reviewed, with most providing level II and III evidence. Results: Cerumen impaction is a common presentation seen in primary care and cerumen removal is one of the most common otolaryngologic procedures performed in general practice. Cerumen impaction is often harmless but can be accompanied by more serious symptoms. Cerumenolytics and irrigation of the ear canal are reasonable first-line therapies and can be used in conjunction or isolation. If irrigation and cerumenolytics are contraindicated, manual removal is appropriate, but the tools necessary are not commonplace in primary care clinics and specialized training may be required to prevent adverse outcomes. Conclusion: Family physicians play a key role in the assessment and management of cerumen impaction and are well equipped to do so. Knowledge of the available techniques for cerumen removal as well as their contraindications ensures that cerumen is removed safely and effectively. When cerumen removal cannot be removed safely in a primary care setting, referral to Otolaryngology-Head and Neck Surgery is appropriate.

BackgroundFoam cell formation by intimal smooth muscle cells (SMCs) inhibits the elaboration of extracellular matrix, which is detrimental to plaque stabilization. In the present study, we examined the lipoproteins and receptors involved in human SMC foam cell formation and investigated the ability of 24(S),25-epoxycholesterol [24(S),25-EC], an oxysterol agonist of the liver X receptor, to attenuate SMC foam cell formation.Methods and ResultsIncubation of human internal thoracic SMCs with atherogenic lipoproteins demonstrated that low-density lipoprotein (LDL), but not oxidized or acetylated LDL, was the primary lipoprotein taken up, resulting in marked cholesteryl ester deposition (6-fold vs 1.8-fold; P<0.05; n=4). Exposure of SMCs to exogenous or endogenously synthesized 24(S),25-EC attenuated LDL uptake (−90% and −47% respectively; P<0.05; n=3) through decreased sterol regulatory element–binding protein-2 expression (−30% and −17%, respectively; P<0.001; n=3), decreased LDL receptor expression (−75% and −40%, respectively; P<0.05; n=3) and increased liver X receptor–mediated myosin regulatory light chain interacting protein expression (7- and 3-fold, respectively; P<0.05; n=4). Furthermore, exogenous 24(S),25-EC increased adenosine triphosphate–binding cassettes A1– and G1–mediated cholesterol efflux to apolipoprotein AI (1.9-fold; P<0.001; n=5) and high-density lipoprotein3 (1.3-fold; P<0.05; n=5). 24(S),25-EC, unlike a nonsteroidal liver X receptor agonist, T0901317, did not stimulate sterol regulatory element–binding protein-1c–mediated fatty acid synthesis or triglyceride accumulation. 24(S),25-EC preserved the assembly of fibronectin and type I collagen by SMCs.ConclusionsThe oxysterol 24(S),25-EC prevented foam cell formation in human SMCs by attenuation of LDL receptor–mediated LDL uptake and stimulation of cholesterol efflux, restoring the elaboration of extracellular matrix. In contrast to T0901317, 24(S),25-EC prevented the development of a triglyceride-rich foam cell phenotype. (J Am Heart Assoc. 2012;1:e000810 doi: 10.1161/JAHA.112.000810.)

ObjectiveTo define geographical regions (forward sortation areas; FSAs) in Southwestern Ontario, Canada from which patients would reliably present to a hospital with linked laboratory data if they developed adverse events related to medications dispensed in outpatient pharmacies.DesignDescriptive research.SettingForty-five hospitals in Southwestern Ontario, Canada, from 2003 to 2009.ParticipantsPatients aged 66 years and older who received an outpatient prescription for any drug and presented to the emergency department in the subsequent 120 days.Main outcome measureThe proportion of patients in a given FSA presenting to an emergency department at a hospital with linked laboratory data versus a hospital without linked laboratory data. To be included in the catchment area at least 90% of emergency department visits in an FSA must have occurred at laboratory-linked hospitals in a given year.ResultsOver the study period, there were 649 713 emergency department visits by patients with recent prescription claims from pharmacies in 1 of 118 FSAs. In total, 141 302 of these patients presented to an emergency department at a laboratory-linked hospital. For the year 2003, 12 FSAs met our criteria to be in the catchment area and this number grew to 25 FSAs by the year 2009.ConclusionsThe relevant geographical regions for hospitals with linked laboratory data have been successfully identified. Studies can now be conducted using these well-defined areas to obtain reliable information on the incidence and absolute risk of presenting to hospital with laboratory abnormalities in older adults dispensed commonly prescribed medications in outpatient pharmacies.