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Showing 1441–1460 of 2058 publications.
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Zhang, Bo; Miura, Shinichiro; Fan, Ping; Kumagai, Kouichirou; Takeuchi, Kazuma; Uehara, Yoshinari; McMahon, Monica R.; Rye, Kerry Anne; Saku, KeijiroObjective: Capillary isotachophoresis (cITP) is a technique for characterizing plasma lipoprotein subfractions according to their electrophoretic charges. We used this technique to examine the mechanism by which apoA-I/phosphatidylcholine (POPC) discs increase pre-? HDL. Methods and results: The cITP analysis was performed using plasma prestained with a lipophilic dye on a Beckman P/ACE MDQ system. Plasma from a patient with lecithin:cholesterol acyltransferase (LCAT) deficiency who had increased apoE-containing HDL was used to characterize the charge distribution of apoA-I/POPC discs. cITP analysis of apoB- and E-depleted plasma of the patient in the presence of apoA-I/POPC discs indicated two major subfractions of apoA-I/POPC discs with mobilities of triglyceride-rich lipoproteins (fast and slow apoA-I). Incubation of whole plasma from a normolipidemic subject in the presence of apoA-I/POPC discs caused a reduction in cITP fast (f)- and intermediate (i)-migrating HDL, and fast and slow apoA-I, and an increase in slow (s)-migrating HDL. The changes in cITP lipoprotein subfractions were not affected by the inhibition of LCAT activity. ApoA-I/POPC discs increased the fractional esterification rate of cholesterol in apoB-depleted plasma. Conclusion: ApoA-I/POPC discs remodeled cITP fHDL and iHDL to sHDL independent of LCAT activity. 2005 Elsevier Ireland Ltd. All rights reserved.
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Reinders, Laurien; Mos, Christianne; Thornton, Charlene Eliza; Ogle, Robert F.; Makris, Angela; Child, Andrew G.; Hennessy, AnnemarieBackground: In pregnancy, absolute blood pressure (BP) limits define preeclampsia. Therefore, BP in pregnancy should be measured accurately and in accordance with accepted guidelines. Accuracy of BP readings determined by rate of cuff deflation was analyzed. This study also investigated the compliance of clinical staff at Royal Prince Alfred Hospital, Australia, to guidelines for BP measurement. Methods: The study was an observational trial of 98 normotensive antenatal or recently postnatal patients. Two BP readings were taken, each with fast (>5 mm Hg/sec) and slow (?2 mm Hg/sec) descent of mercury and compared by Bland-Altman analysis. Also, BP techniques used by junior doctors, specialist obstetricians, and midwives were compared using a 9-point scale. Findings: Australian national guidelines recommend slow descent of mercury. Fast descent underestimated the systolic BP by 9 mm Hg (95% confidence interval [CI], -23 to +5 mm Hg) (p < 0.001). Fast descent measured the diastolic BP within 2 mm Hg (95% CI, -10 to +14 mm Hg) (not different, p = 0.151). Accuracy of fast cuff deflation was 28% for systolic BP and 50% for diastolic BP for <5 mm Hg, and respectively, 64% and 68% for <10 mm Hg, 84% and 80% for <15 mm Hg and 91% and 87% for <20 mm Hg. Compliance with guidelines was greatest for specialists and midwives (p = 0.001) and their most commonly missed feature (76% to100%) was slow cuff deflation. Interpretation: Rapid cuff deflation underestimates the systolic BP compared to accepted guidelines (?2 mm Hg/sec). Medical and midwifery staff may not follow accepted guidelines for BP measurement, particularly with regard to rate of cuff deflation. Potential misdiagnosis and under-treatment of patients with hypertension may compromise pregnancy outcomes. Copyright Taylor & Francis Group, LLC.
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Pattison, David I.; Davies, Michael J.Hypochlorous acid (HOCl) is a powerful oxidant generated from H <inf>2</inf>O<inf>2</inf> and Cl- by the heme enzyme myeloperoxidase, which is released from activated leukocytes. HOCl possesses potent antibacterial properties, but excessive production can lead to host tissue damage that is implicated in a wide range of human diseases (e.g., atherosclerosis). Histamine and carnosine have been proposed as protective agents against such damage. However, as recent studies have shown that histidine-containing compounds readily form imidazole chloramines that can rapidly chlorinate other targets, it was hypothesized that similar reactions may occur with histamine and carnosine, leading to propagation, rather than prevention, of HOCl-mediated damage. In this study, the reactions of HOCl with histamine, histidine, carnosine, and other compounds containing imidazole and free amine sites were examined. In all cases, rapid formation (k, 1.6 105 M-1 s-1) of imidazole chloramines was observed, followed by chlorine transfer to yield more stable, primary chloramines (R-NHCl). The rates of most of these secondary reactions are dependent upon substrate concentrations, consistent with intermolecular mechanisms (k, 103-104 M-1 s-1). However, for carnosine, the imidazole chloramine transfer rates are independent of the concentration, indicative of intramolecular processes (k, 0.6 s -1). High-performance liquid chromatography studies show that in all cases the resultant R-NHCl species can slowly chlorinate N-?-acetyl-Tyr. Thus, the current data indicate that the chloramines formed on the imidazole and free amine groups of these compounds can oxidize other target molecules but with limited efficiency, suggesting that histamine and particularly carnosine may be able to limit HOCl-mediated oxidation in vivo. 2006 American Chemical Society.
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McCaskie, Pamela A.; Cadby, Gemma; Hung, Joseph C.; McQuillan, Brendan M.; Chapman, Caroline L.; Carter, Kim Warwick; Thompson, Peter Lindsay; Palmer, Lyle J.; Beilby, John P.High-density lipoprotein cholesterol (HDL-C) is a known predictor of coronary heart disease (CHD). Studies have shown that the C-480T polymorphism of the hepatic lipase (HL) gene is predictive of HDL-C; however, its observed relationship with the risk of CHD has been inconsistent. We analysed four biallelic polymorphisms in the HL gene inparticipants from three independent Western Australian populations. Samples were collected from two cross-sectional studies of 1111 and 4822 community-based subjects assessed for cardiovascular risk factors, and a third sample of 556 subjects with physician-diagnosed CHD. Genotypes were tested for association with plasma lipids and the risk of CHD. All polymorphisms were highly correlated (D? > 0.97, r2 > 0.90); therefore, only C-480T was analysed. The -480T allele was significantly associated with an increase in HDL-C of between 0.08 and 0.16 mmol/l in all three populations (p < 0.001). No associations with other lipids were observed, nor was an association with CHD in a case control study of males. The TT genotype was however associated with decreased risk of myocardial infarction among cases (odds ratio = 0.39, 95% confidence interval = 0.19-0.78, p = 0.008). These findings replicate those of previous studies in three independent populations and suggest that the genetic determinants of CHD are complex and cannot be entirely explained through intermediate phenotypes. 2006 Blackwell Munksgaard.
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Barter, Philip J.; Rye, Kerry AnnePURPOSE OF REVIEW: The relationship between the concentration of high-density lipoprotein cholesterol and their protective function is addressed. RECENT FINDINGS: Strong epidemiologic evidence indicates that the concentration of high-density lipoproteins is a powerful inverse predictor of cardiovascular risk. This is consistent with the fact that high levels of high-density lipoprotein are generally associated with an increased concentration of large high-density lipoprotein particles that are now known to be the preferred acceptors of cholesterol released from macrophages via the adenosine triphosphate-binding cassette A1 pathway. Some of the protective activity, however, of high-density lipoproteins may reflect functions of specific subpopulations or variations in the 'quality' of high-density lipoprotein particles and may be unrelated to the concentration of the total high-density lipoprotein fraction. This review summarizes the cardiovascular protective role of high-density lipoproteins and addresses how the concentration and antiatherogenic activity of high-density lipoproteins are related. SUMMARY: Some of the protective functions of high-density lipoprotein are closely related to the simple concentration of high-density lipoproteins; others may not be related. Given the current high level of interest in therapies that raise the concentration of high-density lipoprotein, it is essential to conduct further research to identify precisely how high-density lipoproteins protect. 2006 Lippincott Williams & Wilkins.
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Barter, Philip J.Treatment with statins reduces coronary risk In all people but do not remove the risk associated with a low HDL-C or with other features of the metabolic syndrome such as an elevated level of plasma triglyceride or with a high BMI. Treatment with a fibrate such as gemfibrozil (a PPAR alpha agonist) has been shown to be especially effective in people with low HDL-C and other features of the metabolic syndrome. Potential beneficial effects of the combination of a statin and an agent with PPAR alpha activity in patients with type2 diabetes is currently being addressed in the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. 2006 Elsevier Ireland Ltd. All rights reserved.
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Rodgers, Kenneth John; Hume, Peter M.; Morris, John G.L.; Dean, Roger T.Levodopa (L-dopa) is the most widely used agent for the symptomatic relief of Parkinson's disease. There is concern that chronic L-dopa treatment may be detrimental, with some studies suggesting that L-dopa may be neurotoxic. A potentially important mechanism whereby L-dopa may exert neurotoxic effects has been overlooked: that of the incorporation of L-dopa into proteins by protein synthesis. L-Dopa competes with tyrosine as a substrate in protein synthesis in vitro. We provide evidence that L-dopa can also be incorporated into proteins in vivo. Blood from L-dopa-treated and -non-treated patients was separated into protein, erythrocyte and lymphocyte fractions and levels of protein-incorporated dopa quantified by HPLC. Levels of protein-incorporated dopa were significantly increased in lymphocyte cell proteins from L-dopa-treated patients. This has not arisen from oxidative pathways as there was no evidence of oxidative damage to proteins. In addition, there was no increase in protein-incorporated dopa in erythrocytes, which are not actively synthesizing proteins. We suggest that protein-incorporated dopa could also be generated in the CNS. The accumulation of protein-incorporated dopa in cells is associated with oxidative stress and impaired function and could contribute to some of the problems associated with long-term L-dopa treatment. 2006 The Authors.
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Shepherd, James; Barter, Philip J.; Carmena, Rafael; Deedwania, Prakash ?.; Fruchart, Jean Charles; Haffner, Steven M.; Hsia, Judith A.; Breazna, Andrei; LaRosa, John C.; Grundy, Scott M.; Waters, David D.OBJECTIVE - The Treating to New Targets study showed that intensive lipid-lowering therapy with atorvastatin 80 mg/day provides significant clinical benefit beyond that afforded by atorvastatin 10 mg/day in patients with stable coronary heart disease (CHD). The objective of our study was to investigate whether similar benefits of high-dose intensive atorvastatin therapy can be achieved in patients with CHD and diabetes. RESEARCH DESIGN AND METHODS - A total of 1,501 patients with diabetes and CHD, with LDL cholesterol levels of <130 mg/dl, were randomized to double-blind therapy with either atorvastatin 10 (n = 753) or 80 (n = 748) mg/day. Patients were followed for a median of 4.9 years. The primary end point was the time to first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or nonfatal stroke. RESULTS - End-of-treatment mean LDL cholesterol levels were 98.6 mg/dl with atorvastatin 10 mg and 77.0 mg/dl with atorvastatin 80 mg. A primary event occurred in 135 patients (17.9%) receiving atorvastatin 10 mg, compared with 103 patients (13.8%) receiving atorvastatin 80 mg (hazard ratio 0.75 [95% CI 0.58-0.97], P = 0.026). Significant differences between the groups in favor of atorvastatin 80 mg were also observed for time to cerebrovascular event (0.69 [0.48-0.98], P = 0.037) and any cardiovascular event (0.85 [0.73-1.00], P = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events and persistent elevations in liver enzymes. 2006 by the American Diabetes Association.
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Nicholls, Stephen J.; Lundman, Pia; Harmer, Jason A.; Di Bartolo, Belinda Ann; Griffiths, Kaye A.; Rye, Kerry Anne; Barter, Philip J.; Celermajer, David S.Objectives: The purpose of this study was to investigate the influence of dietary fatty acids on the anti-inflammatory properties of high-density lipoproteins (HDL) and vascular function. Background: The effect of dietary fatty acids on atherogenesis remains uncertain. Methods: Fourteen adults consumed an isocaloric meal containing either a polyunsaturated or a saturated fat on 2 occasions. The effects of post-prandial HDL on endothelial cell expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were determined. Flow-mediated dilation (FMD) and microvascular reactivity were assessed before and 3 and 6 h after the meal. Results: Plasma triglycerides, insulin, and nonesterified fatty acids rose after the meals. The HDL collected 6 h after the saturated meal were less effective than HDL isolated from fasting plasma in terms of their ability to inhibit expression of ICAM-1 and VCAM-1, whereas HDL collected 6 h after the polyunsaturated meal had an inhibitory activity that was greater than that of HDL collected from fasting plasma (p < 0.004 and p = 0.01 for comparison of effect of meals on ICAM-1 and VCAM-1, respectively). Post-hyperemic microvascular flow significantly increased at 3 h after the polyunsaturated meal by 45 14% and by 21 11% after the saturated meal. The FMD decreased 3 h after the saturated meal by 2.2 0.9% (p < 0.05 compared with baseline) and by 0.9 1% after the polyunsaturated meal. Conclusions: Consumption of a saturated fat reduces the anti-inflammatory potential of HDL and impairs arterial endothelial function. In contrast, the anti-inflammatory activity of HDL improves after consumption of polyunsaturated fat. These findings highlight novel mechanisms by which different dietary fatty acids may influence key atherogenic processes. 2006 American College of Cardiology Foundation.
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Wood, Geoffrey P.F.; Easton, Christopher J.; Rauk, Arvi; Davies, Michael J.; Radom, LeoHigh-level quantum chemistry calculations have been carried out to investigate ?-scission reactions of alkoxyl radicals located at the ?-carbon of a peptide backbone. This type of alkoxyl radical may undergo three possible ?-scission reactions, namely C-C ?-scission of the backbone, C-N ?-scission of the backbone, and C-R ?-scission of the side chain. We find that the rates for the C-C ?-scission reactions are all very fast, with rate constants of the order 10 12 s -1 that are essentially independent of the side chain. The C-N ?-scission reactions are all slow, with rate constants that range from 10 -0.7 to 10 -4.5 s -1. The rates of the C-R ?-scission reactions depend on the side chain and range from moderately fast (10 7 s -1) to very fast (10 12 s -1) The rates of the C-R ?-scission reactions correlate well with the relative stabilities of the resultant side-chain product radicals (R), as reflected in calculated radical stabilization energies (RSEs). The order of stabilities for the side-chain fragment radicals for the natural amino acids is found to be Ala < Glu < Gin ? Leu ? Met ? Lys ? Arg < Asp ? Ile ? Asn ? Val < Ser ? Thr ? Cys < Phe ? Tyr ? His ? Trp. We predict that for side-chain C-R ?-scission reactions to effectively compete with the backbone C-C ?-scission reactions, the side-chain fragment radicals would generally need an RSE greater than ?30 kJ mol -1. Thus, the residues that may lead to competitive side-chain ?-scission reactions are Ser, Thr, Cys, Phe, Tyr, His, and Trp. 2006 American Chemical Society.
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Pattison, David I.; Davies, Michael J.The heme enzyme myeloperoxidase (MPO) is released at sites of inflammation by activated leukocytes. A key function of MPO is the production of hypohalous acids (HOX, X = Cl, Br) which are strong oxidants with potent antibacterial properties. However, HOX can also damage host tissue when produced at the wrong place, time or concentration; this has been implicated in several human diseases. Thus, elevated blood and leukocyte levels of MPO are significant independent risk factors for atherosclerosis, and specific markers of HOX-mediated protein oxidation are often present at elevated levels in patients with inflammatory diseases (e.g. asthma). HOX react readily with amino acids, proteins, carbohydrates, lipids, nucleobases and antioxidants. Sulfur-containing amino acids (Cys, Met, cystine) and amines on amino acids, nucleobases, sugars and lipids are the major targets for HOX. Reaction with amines generates chloramines (RNHCl) and bromamines (RNHBr), which are more selective oxidants than HOX and are key intermediates in HOX biochemistry. As these and other products of MPO-derived oxidants are unstable, understanding the role of HOX-induced damage, in disease cannot be obtained solely by stable product analysis, and knowledge of the reaction kinetics is essential. This review collates kinetic and product data for HOX, chloramine and bromamine reactions with biological substrates. It highlights how kinetic data may be used to predict the effect of HOX-mediated oxidation on complex biological targets, such as lipoproteins and extracellular matrix in atherosclerosis, or protein-DNA complexes in cancer, thereby providing a basis for unraveling the mechanisms by which these oxidants generate biological damage. 2006 Bentham Science Publishers Ltd.
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Zeng, Jingmin; Dunlop, Rachael Anne; Rodgers, Kenneth John; Davies, Michael J.Hyperglycaemia, triose phosphate decomposition and oxidation reactions generate reactive aldehydes in vivo. These compounds react non-enzymatically with protein side chains and N-terminal amino groups to give adducts and cross-links, and hence modified proteins. Previous studies have shown that free or protein-bound carbonyls inactivate glyceraldehyde-3-phosphate dehydrogenase with concomitant loss of thiol groups [Morgan, Dean and Davies (2002) Arch. Biochem. Biophys. 403, 259-269]. It was therefore hypothesized that modification of lysosomal cysteine proteases (and the structurally related enzyme papain) by free and protein-bound carbonyls may modulate the activity of these components of the cellular proteolytic machinery responsible for the removal of modified proteins and thereby contribute to a decreased removal of modified proteins from cells. It is shown that MGX (methylglyoxal), GO (glyoxal) and glycolaldehyde, but not hydroxyacetone and glucose, inhibit catB (cathepsin B), catL (cathepsin L) and catS (cathepsin S) activity in macrophage cell lysates, in a concentration-dependent manner. Protein-bound carbonyls produced similar inhibition with both cell lysates and intact macrophage cells. Inhibition was also observed with papain, with this paralleled by loss of the active site cysteine residue and formation of the adduct species S-carboxymethylcysteine, from GO, in a concentration-dependent manner. Inhibition of autolysis of papain by MGX, along with cross-link formation, was detected by SDS/PAGE. Treatment of papain and catS with the dialdehyde o-phthalaldehyde resulted in enzyme inactivation and an intramolecular active site cysteine-lysine cross-link. These results demonstrate that reactive aldehydes inhibit cysteine proteases by modification of the active site cysteine residue. This process may contribute to the accumulation of modified proteins in tissues of people with diabetes and age-related pathologies, including atherosclerosis, cataract and Alzheimer's disease. 2006 Biochemical Society.
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Watts, Gerald F.; Ji, Juying; Chan, Dick C.F.; Ooi, Esther M.; Johnson, Anthony G.; Rye, Kerry Anne; Barrett, Hugh Hugh R.The aim of the present study was to investigate the association between changes in apoB (apolipoprotein B-100) kinetics and plasma PLTP (phospholipid transfer protein) and CETP (cholesteryl ester transfer protein) activities in men with MetS (the metabolic syndrome) treated with fenofibrate. Eleven men with MetS underwent a double-blind cross-over treatment with fenofibrate (200 mg/day) or placebo for 5 weeks. Compared with placebo, fenofibrate significantly increased the FCRs (fractional catabolic rates) of apoB in VLDL (very-low-density lipoprotein), IDL (intermediate-density lipoprotein) and LDL (low-density lipoprotein) (all P < 0.01), with no significant reduction (- 8%; P = 0.131) in VLDL-apoB PR (production rate), but an almost significant increase (+ 15 %, P = 0.061) in LDL-apoB PR. Fenofibrate significantly lowered plasma TG [triacylglycerol (triglyceride); P < 0.001], the VLDL-TG/apoB ratio (P = 0.003) and CETP activity (P = 0.004), but increased plasma HDL (high-density lipoprotein)-cholesterol concentration (P<0.001) and PLTP activity (P = 0.03). The increase in PLTP activity was positively associated with the increase in both LDL-apoB FCR (r = 0.641, P = 0.034) and PR (r = 0.625, P = 0.040), and this was independent of the fall in plasma CETP activity and lathosterol level. The decrease in CETP activity was positively associated with the decrease in VLDL-apoB PR (r = 0.615, P = 0.044), but this association was not robust and not independent of changes in PLTP activity and lathosterol levels. Hence, in MetS, the effects of fenofibrate on plasma lipid transfer protein activities, especially PLTP activity, may partially explain the associated changes in apoB kinetics. 2006 The Biochemical Society.
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Barter, Philip J.; Rye, Kerry Anne; Gotto, Antonio M.[No abstract available]
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Barter, Philip J.; Rye, Kerry Anne[No abstract available]
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Deedwania, Prakash ?.; Barter, Philip J.; Carmena, Rafael; Fruchart, Jean Charles; Grundy, Scott M.; Haffner, Steven M.; Kastelein, Johannes Jacob Pieter; LaRosa, John C.; Schachner, Holly C.; Shepherd, James; Waters, David D.Background: Despite the prognostic value of metabolic syndrome for predicting cardiovascular events, few trials have investigated the effects of statin therapy on cardiovascular morbidity and mortality in patients with the metabolic syndrome. Our post hoc analysis of the Treating to New Targets (TNT) study assessed whether intensive lowering of low-density lipoprotein cholesterol with high-dose atorvastatin therapy results in cardiovascular benefits for patients with both coronary heart disease and the metabolic syndrome. Methods: The TNT study was a prospective, double blind, parallel-group trial done at 256 sites in 14 countries between April, 1998, and August, 2004, with a median follow-up of 49 years. 10 001 patients were enrolled aged 35-75 years with clinically evident coronary heart disease. Our analysis includes 5584 patients with metabolic syndrome based on the 2005 NCEP ATP III criteria. Patients were randomly assigned to receive either atorvastatin 10 mg per day (n=2820) or 80 mg per day (n=2764). The primary outcome measure was time to first major cardiovascular event, defined as death from coronary heart disease, non-fatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or non-fatal stroke. Findings: In patients with coronary heart disease and metabolic syndrome, mean on-treatment low-density lipoprotein cholesterol concentrations at 3 months were 26 mmol/L (993 mg/dL) with atorvastatin 10 mg, and 19 mmol/L (726 mg/dL) with atorvastatin 80 mg. At a median follow-up of 49 years, major cardiovascular events occurred in 367 (13%) patients receiving atorvastatin 10 mg, compared with 262 (95%) receiving atorvastatin 80 mg (hazard ratio 071; 95% CI 061-084; p<00001). Irrespective of treatment assignment, significantly more patients with metabolic syndrome (113%) had a major cardiovascular event at a median of 49 years than those without metabolic syndrome (80%; hazard ratio 144; 95% CI 126-164; p<00001). This increased risk was significantly reduced by intensive therapy with atorvastatin 80 mg beyond that achieved with atorvastatin 10 mg. Interpretation: These data indicate that patients with coronary heart disease and metabolic syndrome derive incremental benefit from high-dose atorvastatin therapy, irrespective of the presence of diabetes. 2006 Elsevier Ltd. All rights reserved.
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Barter, Philip J.'Atherogenic dyslipidaemia' and the 'lipid triad' are collective terms for the low HDL-cholesterol, elevated triglycerides, and small, dense LDL that is often found in insulin-resistant patients with abdominal obesity, the metabolic syndrome, or type 2 diabetes. This dyslipidaemia phenotype is believed to underlie a substantial burden of excess cardiovascular risk. Although statins provide effective control of LDL-cholesterol, their effects on the lipid triad are relatively modest and combination therapies will be required to normalize the lipid profiles of these patients. Increasing HDL-cholesterol, in particular, exerts a range of anti-atherogenic effects within the evolving atherosclerotic plaque. Fibrates and nicotinic acid (niacin) each increase HDL-cholesterol, with nicotinic acid being the more effective of the two. Studies with Niaspan, a prolonged-release formulation of nicotinic acid with equivalent efficacy but superior tolerability compared with immediate-release nicotinic acid, shows that this agent preferentially increases levels of larger, more atheroprotective, ApoAI-containing HDLs. Combinations of nicotinic acid with a statin appears to provide effective control of LDL-cholesterol while maximizing the anti-atherogenic potential of HDL-cholesterol. The European Society of Cardiology 2006. All rights reserved.
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Harman, David G.; Ramachandran, Aravind; Gracanin, Michelle; Blanksby, Stephen J.The unimolecular reactivities of a range of perbenzoate anions (X-C 6H<inf>5</inf>CO<inf>3</inf>-), including the perbenzoate anion itself (X = H), nitroperbenzoates (X = para-, meta-, orrtho-NO <inf>2</inf>), and methoxyperbenzoates (X = para-, meta-OCH<inf>3</inf>) were investigated in the gas phase by electrospray ionization tandem mass spectrometry. The collision-induced dissociation mass spectra of these compounds reveal product ions consistent with a major loss of carbon dioxide requiring unimolecular rearrangement of the perbenzoate anion prior to fragmentation. Isotopic labeling of the perbenzoate anion supports rearrangement via an initial nucleophilic aromatic substitution at the ortho carbon of the benzene ring, while data from substituted perbenzoates indicate that nucleophilic attack at the ipso carbon can be induced in the presence of electron-withdrawing moieties at the ortho and para positions. Electronic structure calculations carried out at the B3LYP/6-311++G(d,p) level of theory reveal two competing reaction pathways for decarboxylation of perbenzoate anions via initial nucleophilic substitution at the ortho and ipso positions, respectively. Somewhat surprisingly, however, the computational data indicate that the reaction proceeds in both instances via epoxidation of the benzene ring with decarboxylation resulting-at least initially-in the formation of oxepin or benzene oxide anions rather than the energetically favored phenoxide anion. As such, this novel rearrangement of perbenzoate anions provides an intriguing new pathway for epoxidation of the usually inert benzene ring. 2006 American Chemical Society.
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Di Bartolo, Belinda Ann; Hime, Neil J.; Nicholls, Stephen J.High-density lipoproteins (HDLs) have been well established to protect against the development of atherosclerotic cardiovascular disease. It has become apparent that in addition to the promotion of reverse cholesterol transport, HDLs possess a number of additional functional properties that may contribute to their beneficial influence on the arterial wall. A number of exciting therapeutic strategies have been developed that target HDL and its ability to protect against the development of atherosclerotic plaque. This paper will review how the promotion of the functional properties of HDL inhibits the formation of atherosclerotic plaque and stabilises lesions in patients with established disease. 2006 IBCB, SIBS, CAS. All rights reserved.
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Zhang, Bo; Katafuchi, Ritsuko; Arishima, Hiroaki; Matsunaga, Akira; Rye, Kerry Anne; Saku, KeijiroBackground: The present study examined the effects of atorvastatin and the in vitro effect of apolipoprotein (apo) A-I/phosphatidylcholine (POPC) discs on charge-based triglyceride-rich lipoprotein (TRL) subfractions in a patient with type III hyperlipoproteinemia (HLP) and the apoE2/2 phenotype. Methods: Charge-based lipoprotein subfractions were characterized by capillary isotachophoresis (cITP). cITP analysis was performed using plasma that had been prestained with a lipophilic dye on a Beckman P/ACE MDQ system. Results: Treatment with atorvastatin for 4weeks markedly decreased the slow (s)-migrating TRL subfraction and both fast- and slow-migrating low-density lipoprotein (LDL) subfractions, but did not affect the fast (f)-migrating TRL subfraction in this patient. ApoA-I/POPC discs consisted of two major charge-based subfractions that had the mobility of cITP fTRL and sTRL. Incubation of plasma from this patient in the presence of apoA-I/POPC discs caused not only a reduction in cITP fast- and intermediate-migrating HDL and an increase in cITP sHDL but also a reduction in fTRL and sTRL and an increase in sLDL. Conclusion: Atorvastatin and apoA-I/POPC discs decreased cITP TRL subfractions in a complementary manner, suggesting that the combination of apoA-I/POPC discs and atorvastatin could be a promising therapeutic approach for hypertriglyceridemia. 2006 Elsevier B.V. All rights reserved.
