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Showing 1361–1380 of 2058 publications.
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Whitelock, John; Ma, J. Leo; Davies, Neil P.; Nielsen, Natasja; Chuang, Christine Y.; Rees, Martin D.; Iozzo, Renato V.; Knox, Sarah M.; Lord, Megan S.Background: Heparan sulfate (HS) is an important component of many extracellular matrices that interacts with mitogens and morphogens to guide and control tissue and organ development. These interactions are controlled by its structure, which varies when produced by different cell types and different species. The major aim of the studies reported here was to isolate and characterize the HS expressed on the N-terminal domain of human perlecan when it is expressed in human cells. Results: The recombinant proteoglycan was expressed in greatest quantities when the cells were grown as monolayers in the presence of Medium 199. It was purified as a proteoglycan with a molecular weight between 75 and 150 kDa, which was decorated with HS, chondroitin sulfate (CS) and keratan sulfate (KS) in a similar way to the full-length perlecan from the same cells. Compositional analysis of the glycosaminoglycan (GAG) chains suggested that it contained the same amount of CS and HS, suggesting that one of the attachment sites may not be glycosylated. The HS chains were responsible for the binding of fibroblast growth factor 2 (FGF2), while the specific roles of the CS and KS remain unclear. Conclusion: Expressing the N-terminal domain of the proteoglycan perlecan results in a hybrid truncated molecule that binds to growth factors via it's HS and may prove useful to add to scaffolds to encourage cells to respond to growth signals, such as those produced by the FGFs. 2008 Society of Chemical Industry.
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Glaros, Elias N.; Kim, Woojin Scott; Quinn, Carmel M.; Jessup, Wendy K.; Rye, Kerry Anne; Garner, BrettThe serine palmitoyl transferase inhibitor myriocin potently suppresses the development of atherosclerosis in apolipoprotein E (apoE) gene knockout (apoE-/-) mice fed a high-fat diet. This is associated with reduced plasma sphingomyelin (SM) and glycosphingolipid levels. Furthermore, oral administration of myriocin decreases plasma cholesterol and triglyceride (TG) levels. Here, we aimed to determine whether myriocin could inhibit the progression (or stimulate the regression) of established atherosclerotic lesions and to examine potential changes in hepatic and plasma lipid concentrations. Adult apoE-/- mice were fed a high-fat diet for 30 days, and lesion formation was histologically confirmed. Replicate groups of mice were then transferred to either regular chow or chow containing myriocin (0.3 mg/kg/day) and maintained for a further 60 days. Myriocin significantly inhibited the progression of established atherosclerosis when combined lesion areas (aortic sinus, arch, and celiac branch point) were measured. Although the inhibition of lesion progression was observed mainly in the distal regions of the aorta, regression of lesion size was not detected. The inhibition of lesion progression was associated with reductions in hepatic and plasma SM, cholesterol, and TG levels and increased hepatic and plasma apoA-I levels, indicating that the modulation of pathways associated with several classes of atherogenic lipids may be involved. Copyright 2008 by the American Society for Biochemistry and Molecular Biology, Inc.
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Woolcock, Jane G.; Hennessy, Annemarie; Xu, Bei; Thornton, Charlene Eliza; Tooher, Jane M.; Makris, Angela; Ogle, Robert F.Backgound: Serum levels of soluble fms-like tyrosine kinase (sFlt-1) increase in pre-eclampsia (PE). Aims: To determine whether concentrations of serum sFlt-1 can differentiate PE or superimposed PE (SPE) from gestational hypertension (GH) or chronic hypertension (CH). Methods: Blood was collected from pregnant women being investigated for hypertension (blood pressure of > 140 and/or 90 mmHg). Normotensive (NP) and pre-eclamptic (PE-C) control ranges were measured. Results: Patients with evolving hypertension in pregnancy eventually fell into four groups: GH (n = 14), PE (n = 7), CH (n = 9) and SPE (n = 9). Patients who later developed pre-eclampsia had a higher sFlt-1 (PE: 2.61 ng/mL and SPE: 2.77 ng/mL, respectively) than GH (P < 0.001) or CH (1.05 ng/mL, P = 0.11). Women with established PE at recruitment (PE-C; (n = 18) (3.13 ng/mL; interquartile range (IQR): 2.14-4.17 ng/mL) had a median sFlt-1 higher than NP (n = 18) (0.47 ng/mL; IQR: 0.11-0.89) (P < 0.0008). Patients with GH compared to NP had a slight increase (1.33 ng/mL, P < 0.003). Using a sFlt-1 cut-off of ? 1.9 ng/mL yielded a sensitivity of 94% (95% confidence interval (CI) 73-100%) and specificity of 78% (95% CI 64-82%). Conclusions: sFlt-1 was elevated in women with PE compared to NP. The sFlt-1 also differentiated women destined to develop PE among those who presented with a diagnostic rise in maternal blood pressure. The sFlt-1 test is a useful diagnostic test for PE. 2008 The Authors.
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Rodgers, Kenneth John; Shiozawa, NaeDespite astounding diversity in their structure and function, proteins are constructed from 22 protein or 'canonical' amino acids. Hundreds of amino acid analogues exist; many occur naturally in plants, some are synthetically produced or can be produced in vivo by oxidation of amino acid side-chains. Certain structural analogues of the protein amino acids can escape detection by the cellular machinery for protein synthesis and become misincorporated into the growing polypeptide chain of proteins to generate non-native proteins. In this review we seek to provide a comprehensive overview of the current knowledge on the biosynthetic incorporation of amino acid analogues into proteins by mammalian cells. We highlight factors influencing their incorporation and how the non-native proteins generated can alter cell function. We examine the ability of amino acid analogues, representing those commonly found in damaged proteins in pathological tissues, to be misincorporated into proteins by cells in vitro, providing us with a useful tool in the laboratory to generate modified proteins representing those present in a wide-range of pathologies. We also discuss the evidence for amino acid analogue incorporation in vivo and its association with autoimmune symptoms. We confine the review to studies in which the synthetic machinery of cell has not been modified to accept non-protein amino acids. 2008 Elsevier Ltd. All rights reserved.
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Sieveking, Daniel P.; Buckle, Andrew M.; Celermajer, David S.; Ng, Martin K.C.Objectives: An endothelial cell (EC)-specific angiogenesis assay was developed to functionally characterize angiogenic properties of 2 distinct putative endothelial progenitor cells (EPCs): early EPCs and late outgrowth endothelial cells (OECs). Background: Endothelial progenitor cells promote revascularization of ischemic tissue. However, the nature of different EPCs and their role in angiogenesis remains debated. Methods: Tubulogenesis was assessed by immunohistochemistry in co-cultures of differentiated ECs (including human umbilical vein, coronary artery, and microvascular ECs) or non-ECs with monolayers of human fibroblasts (MRC5). Using adaptations of the co-culture assay, early EPCs and OECs, isolated from peripheral blood mononuclear cells, were assessed by 3-dimensional immunofluorescence microscopy for their capacity for: 1) independent tubulogenesis; 2) incorporation into pre-existing vascular networks; and 3) paracrine angiogenic effects using transwell cultures. Results: Branched interconnecting EC-specific tubules formed with all differentiated ECs after 72 h. Proangiogenic and antiangiogenic agents modulated tubulogenesis appropriately (vascular endothelial growth factor 10 ng: +142 13%, 1 ?M anti-vascular endothelial growth factor: -44 7% vs. control, p < 0.001). In contrast, early EPCs, along with nonendothelial cell types, failed to independently form tubules or incorporate into differentiated EC tubules. Nevertheless, early EPCs indirectly augmented tubulogenesis by differentiated ECs even when physically separated by transwells (+115 4% vs. control; p < 0.001). By contrast, OECs independently formed tubules and incorporated into differentiated EC tubules but exerted no significant paracrine angiogenic effects. Conclusions: A novel EC-specific tubulogenesis assay highlights strikingly different angiogenic properties of different EPCs: late OECs directly participate in tubulogenesis, whereas early EPCs augment angiogenesis in a paracrine fashion, with implications for optimizing cell therapies for neovascularization. 2008 American College of Cardiology Foundation.
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Dunlop, Rachael Anne; Dean, Roger T.; Rodgers, Kenneth JohnOxidized protein deposition and accumulation have been implicated in the aetiology of a wide variety of age-related pathologies. Protein oxidation in vivo commonly results in the in situ modification of amino acid side chains, generating new oxidized amino acid residues in proteins. We have demonstrated previously that certain oxidized amino acids can be (mis)incorporated into cell proteins in vitro via protein synthesis. In the present study, we show that incorporation of o- and m-tyrosine resulted in increased protein catabolism, whereas dopa incorporation generated proteins that were inefficiently degraded by cells. Incorporation of higher levels of L-dopa into proteins resulted in an increase in the activity of lysosomal cathepsins, increased autofluorescence and the generation of high-molecular-mass SDS-stable complexes, indicative of protein aggregation. These effects were due to proteins containing incorporated L-dopa, since they were not seen with the stereoisomer D-dopa, which enters the cell and generates the same reactive species as L-dopa, but cannot be incorporated into proteins. The present study highlights how the nature of the oxidative modification to the protein can determine the efficiency of its removal from the cell by proteolysis. Protection against the generation of dopa and other species that promote resistance to proteolysis might prove to be critical in preventing toxicity from oxidative stress in pathologies associated with protein deposition, such as atherosclerosis, Alzheimer's disease and Parkinson's disease. The Authors.
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Millar, John S.; Brousseau, Margaret E.; Diffenderfer, Margaret R.; Barrett, Hugh Hugh R.; Welty, Francine K.; Cohn, Jeffrey S.; Wilson, Aisha; Wolfe, Megan L.; Nartsupha, Chorthip; Schaefer, Peter M.; DiGenio, Andres G.; Mancuso, James P.; Dolnikowski, Gregory G.; Schaefer, Ernst J.; Rader, Daniel J.Cholesteryl ester transfer protein (CETP) inhibition leads to changes in lipoprotein metabolism. We studied the effect of the CETP inhibitor torcetrapib on VLDL apolipoprotein E (apoE) metabolism. Subjects, pretreated with atorvastatin (n = 9) or untreated (n = 10), received placebo followed by torcetrapib (4 weeks each). After each treatment, subjects underwent a primed-constant infusion of D3-leucine to determine the VLDL apoE production rate (PR) and fractional catabolic rate (FCR). Torcetrapib alone reduced the VLDL apoE pool size (PS) (-28%) by increasing the VLDL apoE FCR (77%) and leaving the VLDL apoE PR unchanged. In subjects pretreated with atorvastatin, torcetrapib increased the VLDL apoE FCR (25%) and PR (21%). This left the VLDL apoE PS unchanged but increased the VLDL apoE content, likely enhancing VLDL clearance and reducing LDL production in this group. Used alone, torcetrapib reduces the VLDL apoE PS by increasing the apoE FCR while leaving the VLDL apoE content unchanged. In contrast, torcetrapib added to atorvastatin treatment increases both the VLDL apoE FCR and PR, leaving the VLDL apoE PS unchanged. Adding torcetrapib to atorvastatin treatment increases the VLDL apoE content, likely leading to decreased conversion of VLDL to LDL, reduced LDL production, and lower levels of circulating VLDL and LDL. Copyright 2008 by the American Society for Biochemistry and Molecular Biology, Inc.
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Mizdrak, Jasminka; Hains, Peter G.; Truscott, Roger John Willis; Jamie, Joanne F.; Davies, Michael J.The human eye is chronically exposed to light of wavelengths > 300nm. In the young human lens, light of wavelength 300-400nm is predominantly absorbed by the free Trp derivatives kynurenine (Kyn), 3-hydroxykynurenine (3OHKyn), and 3-hydroxykynurenine-O-?-D-glucoside (3OHKynG). These ultraviolet (UV) filter compounds are poor photosensitizers. With age, the levels of the free UV filters in the lens decreases and those of protein-bound UV filters increases. The photochemical behavior of these protein-bound UV filters and their role in UV damage are poorly elucidated and are examined here. UVA illumination of protein-bound UV filters generated peroxides (principally H<inf>2</inf>O<inf>2</inf>) in a metabolite-, photolysis-time-, and wavelength-dependent manner. Unmodified proteins, free Trp metabolites, and Trp metabolites that do not bind to lens proteins gave low peroxide yields. Protein-bound 3OHKyn (principally at Cys residues) yielded more peroxide than comparable Kyn and 3OHKynG adducts. Studies using D<inf>2</inf>O and sodium azide implicated 1O<inf>2</inf> as a key intermediate. Illumination of the protein-bound adducts also yielded protein-bound Tyr oxidation products (DOPA, di-tyrosine) and protein cross-links via alternative mechanisms. These data indicate that the covalent modification of lens proteins by Kyn derivatives yields photosensitizers that may enhance oxidation in older lenses and contribute to age-related nuclear cataract. 2008 Elsevier Inc. All rights reserved.
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Lund, Marianne Nissen; Luxford, Catherine; Skibsted And, Leif H.; Davies, Michael J.Previous studies have reported that myosin can be modified by oxidative stress and particularly by activated haem proteins. These reactions have been implicated in changes in the properties of this protein in food samples (changes in meat tenderness and palatability), in human physiology (alteration of myocyte function and force generation) and in disease (e.g. cardiomyopathy, chronic heart failure). The oxidant species, mechanisms of reaction and consequences of these reactions are incompletely characterized. In the present study, the nature of the transient species generated on myosin as a result of the reaction with activated haem proteins (horseradish peroxidase/H <inf>2</inf>O<inf>2</inf> and met-myoglobin/H<inf>2</inf>O<inf>2</inf>) has been investigated by EPR spectroscopy and amino-acid consumption, product formation has been characterized by HPLC, and changes in protein integrity have been determined by SDS/PAGE. Multiple radical species have been detected by EPR in both the presence and the absence of spin traps. Evidence has been obtained for the presence of thiyl, tyrosyl and other unidentified radical species on myosin as a result of damage-transfer from oxidized myoglobin or horseradish peroxidase. The generation of thiyl and tyrosyl radicals is consistent with the observed consumption of cysteine and tyrosine residues, the detection of di-tyrosine by HPLC and the detection of both reducible (disulfide bond) and non-reducible cross-links between myosin molecules by SDS/PAGE. The time course of radical formation on myosin, product generation and cross-link induction are consistent with these processes being interlinked. These changes are consistent with the altered function and properties of myosin in muscle tissue exposed to oxidative stress arising from disease or from food processing. The Authors.
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Stirnadel-Farrant, Heide A.; Lin, Xiwu; Ling, Hua; Song, Kjioung S.; Barter, Philip J.; Kesaniemi, YrjAntero; Mahley, Robert W.; McPherson, Ruth M.; Waeber, Gard; Bersot, Thomas P.; Cohen, Jonathan C.; Grundy, Scott M.; Mitchell, Braxton D.; Mooser, Vincent E.; Waterworth, Dawn M.Atherogenic dyslipidemia, manifest by low HDL-cholesterol and high TG levels, is an important component of ATP-III defined metabolic syndrome. Here, we dissected the phenotypic and genetic architecture of these traits by assessing their relationships with other metabolically relevant measures, including plasma adipo-cytokines, highly sensitive C-reactive protein (hsCRP) and LDL particle size, in a large family data set (n = 2800) and in an independent set of dyslipidemic cases (n = 716) and normolipidemic controls (n = 1073). We explored the relationships among these phenotypes using variable clustering and then estimated their genetic heritabilities and cross-trait correlations. In families, four clusters explained 61% of the total variance, with one adiposity-related cluster (including hsCRP), one BP-related cluster, and two lipid-related clusters (HDL-C, TG, adiponectin and LDL particle size; apoB and non-HDL-C). A similar structure was observed in dyslipidemic cases and normolipidemic controls. The genetic correlations in the families largely paralleled the phenotype clustering results, suggesting that common genes having pleiotropic effects contributed to the correlations observed. In summary, our analyses support a model of metabolic syndrome with two major components, body fat and lipids, each with two subcomponents, and quantifies their degree of overlap with each other and with metabolic-syndrome related measures (adipokines, LDL particle size and hsCRP). 2007 Elsevier Ireland Ltd. All rights reserved.
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Cohn, Jeffrey S.; Wat, Elaine C.L.; Kamili, Alvin; Tandy, SallyPURPOSE OF REVIEW: An increasing number of studies in experimental animals suggest that dietary phospholipids might be of benefit in the treatment of fatty liver disease. This raises the possibility that synthetic or naturally occurring phospholipid isolates could be used as hepatoprotective nutraceuticals or functional foods. The aim of the present article is to review published data describing the beneficial effects of dietary phospholipids on hepatic lipid metabolism and their potential to affect atherosclerosis and cardiovascular disease. RECENT FINDINGS: Consistent results have been obtained supporting the concept that phospholipid from various sources (i.e., soybean, safflower, egg and fish roe) can reduce liver lipid levels. The primary site of action for this effect appears to be in the intestinal lumen, where dietary phospholipids are able to interfere with neutral sterol absorption. Results have also been obtained suggesting that dietary phospholipids can stimulate bile acid and cholesterol secretion. Additional work suggests that dietary phospholipids can have a beneficial effect on plasma lipid and lipoprotein levels. SUMMARY: The concept of using naturally occurring compounds such as phospholipid to treat or prevent hepatic steatosis is very attractive. Controlled human trials are, however, required to verify the efficacy of this approach. It is also important that additional research be conducted to determine the extent to which certain phospholipids have the ability to increase plasma HDL levels and potentially affect the onset or development of cardiovascular disease. 2008 Lippincott Williams & Wilkins, Inc.
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McGrath, Kristine C.Y.; McRobb, Lucinda S.; Heather, Alison KayCardiovascular disease (CVD) remains the leading cause of death in Western society today. There is a striking gender difference in CVD with men predisposed to earlier onset and more severe disease. Following the recent reevaluation and ongoing debate regarding the estrogen protection hypothesis, and given that androgen use and abuse is increasing in our society, the alternate view that androgens may promote CVD in men is assuming increasing importance. Whether androgens adversely affect CVD in either men or women remains a contentious issue within both the cardiovascular and endocrinological fraternities. This review draws from basic science, animal and clinical studies to outline our current understanding regarding androgen effects on atherosclerosis, the major CVD, and asks where future directions of atherosclerosis-related androgen research may lie. 2008 Dove Medical Press Limited. All rights reserved.
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Imaizumi, Satoshi; Miura, Shinichiro; Nakamura, Kazuto T.; Kiya, Yoshihiro; Uehara, Yoshinari; Zhang, Bo; Matsuo, Yoshino; Urata, Hidenori; Ideishi, Munehito; Rye, Kerry Anne; Sata, Masataka; Saku, KeijiroObjectives: This study analyzed the antiarrhythmogenic effect of reconstituted high-density lipoprotein (rHDL) against ischemia/reperfusion in vivo. Background: Recent studies have suggested that a reduction in the plasma HDL level may contribute to cardiac sudden death. Although there are currently only a few therapeutic strategies for increasing HDL, an exciting new therapeutic option, rHDL, has recently been developed to prevent coronary artery disease. Methods: To analyze the suppression of reperfusion arrhythmia by rHDL (apolipoproteinA-I with 1-palmitoyl-2-oleoyl-phosphatidyl-choline), 92 male Wistar rats were divided into 10 groups: rats that had been pre-treated with or without rHDL, apolipoproteinA-I, or 1-palmitoyl-2-oleoyl-phosphatidyl-choline in the presence or absence of inhibitors of Akt protein kinase, nitric oxide (NO), or extracellular-signal-regulated kinase (ERK) administered intravenously before left coronary artery occlusion. We also used human coronary artery endothelial cells and adenosine triphosphate-binding cassette transporter (ABC) A1-, ABCG1-, or scavenger receptor class B, type I-transfected ldlA7 cells systems. Results: The duration of ventricular tachycardia or ventricular fibrillation after reperfusion in rHDL-pre-treated rats was much shorter than that in untreated rats. ApolipoproteinA-I or 1-palmitoyl-2-oleoyl-phosphatidyl-choline alone had no effect. The effect of rHDL was blocked by inhibitors of Akt, NO, and ERK. Plasma NO concentration in the rHDL group was significantly higher. In addition, rHDL activated phospho(p)-Akt, p-ERK, and p-endothelial NO synthesis in endothelial cells. The rHDL activated p-ERK in ABCA1- or ABCG1-transfected but not scavenger receptor class B, type I-transfected ldlA7 cells. Conclusions: The rHDL-induced NO production, probably mediated by ABCA1 or ABCG1 through an Akt/ERK/NO pathway in endothelial cells, may suppress reperfusion-induced arrhythmias. The HDL-based therapy may hold the promise of reducing the incidence of such arrhythmias after ischemia/reperfusion. 2008 American College of Cardiology Foundation.
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Barter, Philip J.; Shear, Charles L.; Revkin, James H.[No abstract available]
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Stadler, Nadina; Stanley, Naomi R.; Heeneman, Sylvia; Vata, Vladim; Daemen, Mat Jap; Bannon, Paul Gerard; Waltenberger, Johannes L.; Davies, Michael J.OBJECTIVE - Oxidized lipids and proteins, as well as decreased antioxidant levels, have been detected in human atherosclerotic lesions, with oxidation catalyzed by iron and copper postulated to contribute to lesion development. Zinc has been postulated to displace iron from critical sites and thereby protect against damage. In this study, metal ion and protein oxidation levels were quantified in human carotid and abdominal artery specimens containing early-to-advanced lesions, to determine whether zinc concentrations correlate inversely with iron levels and protein oxidation. METHODS AND RESULTS - Metal ions were quantified by EPR and inductively coupled plasma mass spectroscopy. Native and oxidized protein side-chains were quantified by high-performance liquid chromatography. Elevated levels of zinc (?6-fold) were detected in advanced lesions compared to healthy tissue or early lesions. Zinc did not correlate negatively with iron or copper levels suggesting that zinc does not displace these metal ions. Highly significant positive correlations (P<0.005) were detected between zinc and calcium levels. CONCLUSIONS - Zinc did not correlate with low iron levels and reduced protein oxidation. These data indicate that zinc does not prevent protein oxidation in advanced lesions. The reported protective effect of zinc accumulation is proposed to be associated with lesion calcification. 2008 American Heart Association, Inc.
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Handelsman, David J.; Heather, Alison KayAndrogens remain the most effective and widely abused ergogenic drugs in sport. Although androgen doping has been prohibited for over 3 decades with a ban enforced by mass spectrometric (MS)-based urine testing for synthetic and exogenous natural androgens, attempts continue to develop increasingly complex schemes to circumvent the ban. A prominent recent approach has been the development of designer androgens. Such never-marketed androgens evade detection because mass spectrometry relies on identifying characteristic chemical signatures requiring prior knowledge of chemical structure. Although once known, designer androgens are readily detected and added to the Prohibited List. However, until their structures are elucidated, designer androgens can circumvent the ban on androgen doping. To combat this, in vitro androgen bioassays offer powerful new possibilities for the generic detection of unidentified bioactive androgens, regardless of their chemical structure. Another approach to circumvent the ban on androgen doping has been the development of indirect androgen doping, the use of exogenous drugs to produce a sustained increase in endogenous testosterone (T) production. Apart from estrogen blockers, however, such neuroendocrine active drugs mostly provide only transient increases in blood T. Finally the ban on androgen doping must allow provision for rare athletes with incidental, proven androgen deficiency who require T replacement therapy. The Therapeutic Use Exemption mechanism makes provision for such necessary medical treatment, subject to rigorous criteria for demonstrating a genuine ongoing need for T and monitoring of T dosage. Effective deterrence of sports doping requires novel, increasingly sophisticated detection options calibrated to defeat these challenges, without which fairness in sport is tarnished and the social and health idealization of sporting champions devalued. 2008 Asian Journal of Andrology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
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Hung, Joseph C.; McQuillan, Brendan M.; Thompson, Peter Lindsay; Beilby, John P.Background: Adiponectin is an abundantly expressed adipocyte-specific protein, whose level is decreased in obesity, and which appears to be a key participant in developing inflammation, insulin resistance and metabolic syndrome (MetS). We examined whether the relationship between adiponectin and inflammatory markers, insulin resistance and MetS was independent of obesity. Methods and results: The study was performed in 1094 men and women, aged 27-77 years, from a representative community population. We measured serum inflammatory markers, homoeostasis model assessment of insulin resistance (HOMA-IR) and prevalent MetS using National Cholesterol Education Program ATPIII criteria. Sex- and age-adjusted plasma adiponectin concentration was inversely correlated with body mass index (BMI), waist-hip ratio, diastolic blood pressure, triglycerides, glucose and fasting insulin, and positively correlated with HDL cholesterol (all P<0.005). Log plasma adiponectin was a significant negative correlate of the levels of C-reactive protein, interleukin-6, interleukin-18, fibrinogen and white cell count independent of level of obesity. Log plasma adiponectin was also an inverse associate of log HOMA-IR (P<0.001) independent of obesity. Subjects in the top compared to bottom sex-specific plasma adiponectin quartile had a multivariate-adjusted odds ratio (OR) of 0.21 (95% CI, 0.11-0.42; P<0.001) for prevalent MetS, and the association was independent of age, sex, BMI, log insulin and log intereukin-18 levels. Conclusion: Our findings suggest that higher circulating adiponectin levels may mitigate against adipose-related inflammation, insulin resistance and MetS as much in lean as obese persons. At any rate circulating adiponectin level is a strong risk marker for MetS, which is independent of measures of adiposity, insulin resistance and inflammatory markers. 2008 Nature Publishing Group All rights reserved.
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Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassayMcRobb, Lucinda S.; Handelsman, David J.; Kazlauskas, Rymantas; Wilkinson, Shane M.; McLeod, Malcolm D.; Heather, Alison KayThe recent identification of tetrahydrogestrinone (THG), a non-marketed designer androgen used for sports doping but previously undetectable by established mass spectrometry-based urine drug screens, and its production by a facile chemical modification of gestrinone has raised concerns about the risks of developing designer androgens from numerous marketed progestins. We therefore have used yeast-based in vitro androgen and progesterone bioassays to conduct a structure-activity study assessing the intrinsic androgenic potential of commercially available progestins and their derivatives, to identify those compounds or structures with the highest risk of forming a basis for such misapplication. Progestins had a wide range of androgenic bioactivity that was not reliably predicted for individual steroids by their progestin bioactivity. 17?-Hydroxyprogesterone and 19-norprogesterone derivatives with their bulky 17?-substituents were strong progestins but generally weak androgens. 17?-Ethynylated derivatives of testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone such as gestrinone, ethisterone, norethisterone and norgestrel had the most significant intrinsic androgenicity of all the commercially marketed progestins. Facile chemical modification of the 17?-ethynyl group of each of these progestins produces 17?-methyl, ethyl and allyl derivatives, including THG and norbolethone, which further enhanced androgenic bioactivity. Thus by using the rapid and sensitive yeast bioassay we have screened a comprehensive set of progestins and associated structures and identified the ethynylated testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone derivatives as possessing the highest risk for abuse and potential for conversion to still more potent androgens. By contrast, modern progestins such as progesterone, 17?-hydroxyprogesterone and 19-norprogesterone derivatives had minimal androgenic bioactivity and pose low risk. 2008 Elsevier Ltd. All rights reserved.
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Shah, Sanjiv Jayendra; Waters, David D.; Barter, Philip J.; Kastelein, Johannes Jacob Pieter; Shepherd, James; Wenger, Nanette Kass; DeMicco, David A.; Breazna, Andrei; LaRosa, John C.Objectives: The aim of this post hoc analysis from the TNT (Treating to New Targets) trial is to determine whether patients with previous coronary artery bypass grafting (CABG) surgery achieved clinical benefit from intensive low-density lipoprotein (LDL)-cholesterol lowering. Background: The development and progression of atherosclerosis is accelerated in coronary venous bypass grafts. Methods: A total of 10,001 patients with documented coronary disease, including 4,654 with previous CABG, were randomized to atorvastatin 80 or 10 mg/day and were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event (cardiac death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke). Results: A first major cardiovascular event occurred in 11.4% of the patients with prior CABG and 8.5% of those without prior CABG (p < 0.001). In CABG patients, mean LDL-cholesterol levels at study end were 79 mg/dl in the 80-mg arm and 101 mg/dl in the 10-mg arm, and the primary event rate was 9.7% in the 80-mg arm and 13.0% in the 10-mg arm (hazard ratio 0.73, 95% confidence interval 0.62 to 0.87, p = 0.0004). Repeat revascularization during follow-up, either CABG or percutaneous coronary intervention, was performed in 11.3% of the CABG patients in the 80-mg arm and 15.9% in the 10-mg arm (hazard ratio 0.70, 95% confidence interval 0.60 to 0.82, p < 0.0001). Conclusions: Intensive LDL-cholesterol lowering to a mean of 79 mg/dl with atorvastatin 80 mg/day in patients with previous CABG reduces major cardiovascular events by 27% and the need for repeat coronary revascularization by 30%, compared with less intensive cholesterol-lowering to a mean of 101 mg/dl with atorvastatin 10 mg/day. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691). 2008 American College of Cardiology Foundation.
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Nobourt, Estelle; Zeng, Jingmin; Davies, Michael J.; Brown, Bronwyn E.; Yadav, S.; Barter, Philip J.; Rye, Kerry AnneAims/hypothesis: Hyperglycaemia, a key feature of diabetes, is associated with non-enzymatic glycation of plasma proteins. We have shown previously that the reactive ?-oxoaldehyde, methylglyoxal, non-enzymatically glycates apolipoprotein (Apo)A-I, the main apolipoprotein of HDL, and prevents it from activating lecithin:cholesterol acyltransferase (LCAT), the enzyme that generates almost all of the cholesteryl esters in plasma. This study investigates whether the glycation inhibitors aminoguanidine and pyridoxamine, the insulin sensitiser metformin and the cross-link breaker alagebrium can inhibit and/or reverse the methylglyoxal-mediated glycation of ApoA-I and whether these changes can preserve or restore the ability of ApoA-I to activate LCAT. Methods: Inhibition of ApoA-I glycation was assessed by incubating aminoguanidine, pyridoxamine, metformin and alagebrium with mixtures of methylglyoxal and discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and ApoA-I, ([A-I]rHDL). Glycation was assessed as the modification of ApoA-I arginine, lysine and tryptophan residues, and by the extent of ApoA-I cross-linking. The reversal of ApoA-I glycation was investigated by pre-incubating discoidal (A-I)rHDL with methylglyoxal, then incubating the modified rHDL with aminoguanidine, pyridoxamine or alagebrium. Results: Aminoguanidine, pyridoxamine, metformin and alagebrium all decreased the methylglyoxal-mediated glycation of the ApoA-I in discoidal rHDL and conserved the ability of the particles to act as substrates for LCAT. However, neither aminoguanidine, pyridoxamine nor alagebrium could reverse the glycation of ApoA-I or restore its ability to activate LCAT. Conclusions/interpretation: Glycation inhibitors, insulin sensitisers and cross-link breakers are important for preserving normal HDL function in diabetes. 2008 Springer-Verlag.
