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Background:Cholesterol efflux capacity (CEC) is inversely related to incident cardiovascular events. CSL112 (apoA-I (human)) infusion rapidly and robustly increases CEC in AMI patients, but it is unknown whether this translates to increased hepatocyte cholesterol uptake, the subsequent step in reverse cholesterol transport.Purpose:To determine whether CSL112 increases cholesterol uptake by hepatocytes when administered post AMI.Methods:Patients from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study received either placebo, 2g or 6g CSL112 post AMI. Serum samples from a subset of subjects (n=15 per group) were studied ex vivo. Firstly, CEC was assessed using J774 macrophages loaded with labelled [3H]cholesterol tracer. Cholesterol uptake media (200μL) was then collected and applied to Fu5AH hepatocytes for assessment of labelled cholesterol uptake.Results:CSL112 infusion dose-dependently increased hepatocyte cholesterol uptake, with the 6g dose inducing a < 2-fold increase at the end of infusion (2 h), and sustained elevation above baseline at 24 - 48 h (Fig 1A). Hepatocyte cholesterol uptake across all dose groups and timepoints was strongly correlated with total CEC (r=0.949; p<0.001; Fig 1B) and plasma apoA-I (r=0.746; p<0.001).Conclusion:Infusion of CSL112 increased uptake of cholesterol into hepatocytes in direct proportion to increased CEC and apoA-I levels. This study demonstrates that the rapid, robust increase in CEC induced by CSL112 is also associated with substantial elevation in hepatocyte cholesterol uptake using an assay which models the final step in reverse cholesterol transport prior to cholesterol excretion in bile.Figure 1: (A)Effect of CSL112 on hepatocyte cholesterol uptake (mean±SEM). (B)Intra-subject correlation using individual data points across all timepoints.

LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. To gain insight into LCAT and the role of free cholesterol (FC) in atherosclerosis, we examined the effect of LCAT over- and underexpression in diet-induced atherosclerosis in scavenger receptor class B member I-deficient [Scarab(−/−)] mice, which have a secondary defect in cholesterol esterification. Scarab(−/−)×LCAT-null [Lcat(−/−)] mice had a decrease in HDL-cholesterol and a high plasma ratio of FC/total cholesterol (TC) (0.88 ± 0.033) and a marked increase in VLDL-cholesterol (VLDL-C) on a high-fat diet. Scarab(−/−)×LCAT-transgenic (Tg) mice had lower levels of VLDL-C and a normal plasma FC/TC ratio (0.28 ± 0.005). Plasma from Scarab(−/−)×LCAT-Tg mice also showed an increase in cholesterol esterification during in vitro cholesterol efflux, but increased esterification did not appear to affect the overall rate of cholesterol efflux or hepatic uptake of cholesterol. Scarab(−/−)×LCAT-Tg mice also displayed a 51% decrease in aortic sinus atherosclerosis compared with Scarab(−/−) mice (P< 0.05). In summary, we demonstrate that increased cholesterol esterification by LCAT is atheroprotective, most likely through its ability to increase HDL levels and decrease pro-atherogenic apoB-containing lipoprotein particles.

MDCO-216, a complex of dimeric recombinant apoA-IMilano (apoA-IM) and palmitoyl-oleoyl-phosphatidylcholine (POPC), was administered to cynomolgus monkeys at 30, 100, and 300 mg/kg every other day for a total of 21 infusions, and effects on lipids, (apo)lipoproteins, and ex-vivo cholesterol efflux capacity were monitored. After 7 or 20 infusions, free cholesterol (FC) and phospholipids (PL) were strongly increased, and HDL-cholesterol (HDL-C), apoA-I, and apoA-II were strongly decreased. We then measured short-term effects on apoA-IM, lipids, and (apo)lipoproteins after the first or the last infusion. After the first infusion, PL and FC went up in the HDL region and also in the LDL and VLDL regions. ApoE shifted from HDL to LDL and VLDL regions, while ApoA-IM remained located in the HDL region. On day 41, ApoE levels were 8-fold higher than on day 1, and FC, PL, and apoE resided mostly in LDL and VLDL regions. Drug infusion quickly decreased the endogenous cholesterol esterification rate. ABCA1-mediated cholesterol efflux on day 41 was markedly increased, whereas scavenger receptor type B1 (SRB1) and ABCG1-mediated effluxes were only weakly increased. Strong increase of FC is due to sustained stimulation of ABCA1-mediated efflux, and drop in HDL and formation of large apoE-rich particles are due to lack of LCAT activation.

The article discusses the Event safety Guide provided by the organization Event Safety Alliance (ESA) for public safety. It mentions that the primary goal of ESA is to provide the information in simpler form that can be easily used by the busy professionals for planning the events of first line safety. It further mentions that the guide is available online which included 37 chapters that are available at the website www.eventsafetyalliance.org for free downloading. INSETS: Crowd Sourcing for Crowd Safety;'Reasonably Foreseeable'.

Endothelial lipase is a phospholipase with activity against high-density lipoprotein. Although a small number of mutations in LIPGhave been described, the role of LIPGin protection against atherosclerosis is unclear.

The article discusses the changes that took place at Fenway Park in Massachusetts that has celebrated 100 years in establishment including the remarkable rebirth of the oldest ballpark in Major League Baseball (MLB). It notes the significant impact of fire and life safety improvements on the transformation of Fenway. The author also details the improvements of the 10-year renovation of stadium from 2002-2012. INSETS: TEN YEARS OF FENWAY TLC 2002/2003;TEN YEARS OF FEN WAY TLC 2004/2005/2006.

The article addresses the incidents at Fenway Park in Massachusetts of fans falling from stadium seats particularly on a 39-year-old man who died from head injuries after losing his balance while leaning over the stadium's rail. It cites the compliance of the park with the National Fire Protection Association (NFPA) 101 Life Safety Code as safety measures in response to such incidences. It also notes that such incidents had brought out issues on the standard heights of rails.

Sirolimus (rapamycin), a macrolide antibiotic approved for use as an immunosuppressive agent in the prevention of organ rejection, is a cell proliferation inhibitor and regulator of the immune response which acts through inhibition of TOR (target of rapamycin), a kinase essential to cell cycle progression. Recent studies suggest that the TOR pathway is critical to overall cell function, and at a basic mechanistic level, may be a regulator and potential therapeutic target involved in many of the major (and minor) disorders seen in man today. Cardiovascular diseases including restenosis following percutaneous coronary intervention as well as the more widespread condition of atherosclerosis, share this common involvement of TOR. The present report addresses the current state of intervention in cardiovascular disorders with Sirolimus and similar inhibitors of TOR, including the rationale for this approach and the successes observed to date. Success of the first drug-eluting stent to locally treat restenosis in the clinic is discussed, as are preclinical studies addressing a role in overall atherosclerosis in animal models. In addition, due to the known toxicities when given systemically, an approach for targeted delivery to local areas of vascular disease is discussed.

The discovery of novel intervention points in the inflammatory pathway has been a focus of drug development in recent years. We have identified pathway selective ligands for the estrogen receptor (ER) that inhibit NF-kB mediated inflammatory gene expression causing a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes. SAR development of a series of 4-(Indazol-3-yl)-phenols has led to the identification of WAY-169916 an orally active non-steroidal ligand with the potential use in the treatment of inflammatory diseases without the classical proliferative effects associated with non-selective estrogens.

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ERα and ERβ. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17β-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ERα-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ERβ-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139–151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ERβ agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ERα-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

Atherosclerosis is a chronic inflammatory disease that develops in response to injury to the vessel wall, and is augmented by hypercholesterolemia. To further delineate the role of the immune system and local factors in this process, we assessed the effects of the immunosuppressant sirolimus (Rapamycin, RAPAMUNE^®, Wyeth, Collegeville, PA) on atherosclerosis in the apoE-deficient (apoE KO) mouse, a well-accepted model of cardiovascular disease. ApoE KO mice were fed a high fat diet and sirolimus was administered. After 12 weeks, atherosclerotic lesions and plasma lipoproteins were measured. The expression of cytokines associated with atherosclerosis was also examined. All groups demonstrated plasma total cholesterol (TC) >1100 mg/dL. Sirolimus treatment was associated with a 30% increase in LDL-cholesterol (LDLc) and a dose-dependent elevation in HDL-cholesterol (HDLc). Despite increased LDLc, aortic atherosclerosis was markedly reduced in all sirolimus-treated groups. Sirolimus treatment resulted in decreased expression of IL-12p40, IFN-γ and IL-10 mRNA. In contrast, TGF-β1 was elevated. Sirolimus significantly reduced atherosclerosis in apo E-KO mice; this effect is independent of, and obviates, elevated plasma TC and LDLc. Sirolimus might therefore be of benefit on atherosclerosis in patients undergoing therapy, independent of any impact on circulating lipids.

Atherosclerosis is a chronic inflammatory disease that develops in response to injury to the vessel wall, and is augmented by hypercholesterolemia. To further delineate the role of the immune system and local factors in this process, we assessed the effects of the immunosuppressant sirolimus (Rapamycin, RAPAMUNE®, Wyeth, Collegeville, PA) on atherosclerosis in the apoE-deficient (apoE KO) mouse, a well-accepted model of cardiovascular disease. ApoE KO mice were fed a high fat diet and sirolimus was administered. After 12 weeks, atherosclerotic lesions and plasma lipoproteins were measured. The expression of cytokines associated with atherosclerosis was also examined. All groups demonstrated plasma total cholesterol (TC) >1100 mg/dL. Sirolimus treatment was associated with a 30% increase in LDL-cholesterol (LDLc) and a dose-dependent elevation in HDL-cholesterol (HDLc). Despite increased LDLc, aortic atherosclerosis was markedly reduced in all sirolimus-treated groups. Sirolimus treatment resulted in decreased expression of IL-12p40, IFN-γ and IL-10 mRNA. In contrast, TGF-β1 was elevated. Sirolimus significantly reduced atherosclerosis in apo E-KO mice; this effect is independent of, and obviates, elevated plasma TC and LDLc. Sirolimus might therefore be of benefit on atherosclerosis in patients undergoing therapy, independent of any impact on circulating lipids.

The scientific conference on the correlation of clinical syndromes of atherosclerosis with lesion morphologies as seen by pathology and imaging techniques was an excellent summation of current knowledge of the role and impact of atherosclerosis and vascular dysfunction in a variety of disease states. A number of the most respected researchers in the field of atherosclerosis were present and discussed topics such as coronary artery atherosclerosis, carotid atherosclerosis, aortic atherosclerosis and femoral/iliac atherosclerosis. These discussions included the correlation of diseases of the different vascular beds, the clinical syndromes associated with the different sites, and the current status and utility of imaging techniques. In summary, atherosclerosis appears to play the major role in coronary artery disease (including unstable angina), stroke (both embolic and haemorrhagic), aortic aneurysm and peripheral vascular disease. Additionally, atherosclerosis appears to play a significant role in instances of renal failure even under circumstances of pharmacologic control of hypertension due to the extension of aortic atherosclerosis into the renal arteries.

The incidence of thrombosis as a complication of invasive surgery, in cancer patients, as a cause or complication of stroke, acute myocardial infarction (AMI), thrombolysis, unstable angina (UA) or angioplasty is substantial. To better serve this patient population in the prevention and prophylaxis of thrombosis, new types of anticoagulant drugs are under development by the pharmaceutical industry. The goal of these efforts are orally-active anticoagulants with specificity and pharmacokinetic properties that could translate into better control of anticoagulation and thrombosis and less bleading liability compared to the currently used anticoagulants: heparin, the low molecular weight heparins and warfarin. Various approaches for which there is a great deal of activity include: tissue factor/Factor VIIa inhibitors, Factor Xa inhibitors, thrombin inhibitors, glycoprotein IIb/IIIa antagonists. There is also interest in Factor IXa inhibitors, thrombin receptor antagonists and inhibitors of plasminogen activator inhibitor-1.

Current alcohol treatment programs are comprised of a combination of diverse therapeutic modalities. The use of carefully prescribed psychotropic medications is an important treatment component for selected alcoholic patients. The prescription of medication to alcoholics sometimes raises psychodynamic issues which influence the treatment. Identifying these issues may enhance the treatment process for both patlent and doctor. Two case examples which illustrate these points are presented and discussed.

Some concepts in condensed phase chemical kinetics which have emerged from a recent rigorous statistical mechanical treatment of condensed phase chemical reaction dynamics [S, A. Adelman,Adv. Chem. Phys.53:61 (1983)] are discussed in simple physical terms.

A review of several of the available theories of vibrational energy transfer (VET) in the gas and liquid phases is presented. First the classical theory of gas phase VET mainly due to Landau and Teller, to Jackson and Mott and to Zener is developed in some detail. Next the Schwartz-Slawsky-Herzfeld theory, a framework for analysing VET data based on the classical theory, is outlined. Experimental tests of the classical theory and theoretical critiques of its assumptions are then described. Next a brief review of the modern ab-initio quantum approach to gas phase VET rates, taking as an example the work of Banks, Clary and Werner, is given. Theories of VET at elevated densities are then discussed. The isolated binary collision model is reviewed and a new molecular approach to the density, temperature and isotope dependences of vibrational energy relaxation rates, due to Adelman and co-workers, is outlined.

Summary: A number of cell lines derived from the stromal-vascular fraction of rat adipose tissue have been established that represent a variety of morphologic types. Despite their differing morphology, all of these cell lines secrete lipoprotein lipase in response to heparin. Because lipoprotein lipase secretion has been attributed to the presence of preadipocytes in the stromal-vascular fraction, we examined these cell lines for adipocyte conversion. None of the cell lines converted to adipocyte morphology when held at confluency or when exposed to media supplemented with high concentrations of fatty acid or very low density lipoproteins. These cell lines therefore do not seem to be preadiocytes, despite the presence of lipoprotein lipase. Among these cell lines are several that disply the “cobblestone” morphology of endothelial cells, although the lack angiotensin-converting enzyme activity, reactivity with Factor VIII antibodies, and Weibel-Palade bodies. A number of authentic endothelial cells were found to be negative for lipoprotein lipase secretion. These data suggest that the “endothelial-like” cell lines established from adipose tissue are not endothelial cells.

• Sleep apnea in association with neurologic disease is uncommon, and its documentation with nocturnal polysomnography (PSG) is rare. Two patients with posterior fossa neurologic disease had obstructive and central sleep apnea on PSG. The first was a 40-year-old woman who experienced a respiratory arrest ten days after neurosurgical decompression of a cervical syrinx associated with syringobulbia. Nocturnal PSG demonstrated obstructive sleep apnea. Tracheostomy was performed and a second nocturnal PSG showed no sleep apnea. The second patient was a 76-year-old woman with daytime hypersomnolence, nocturnal choking spells, progressive spastic para-paresis, and left-sided cerebellar tremor. Neurologic evaluation led to the diagnosis of olivopontocerebellar degeneration. Nocturnal PSG showed multiple episodes of central and obstructive apnea. These cases support the hypothesis that central and obstructive sleep apnea can originate from a central mechanism.