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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  128. Kongress der Deutschen Gesellschaft für Chirurgie; 20110503-20110506; München; DOC11dgch574 /20110520/
    Publication Date: 2011-05-20
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Deutscher Kongress für Orthopädie und Unfallchirurgie; 72. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 94. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 49. Tagung des Berufsverbandes der Fachärzte für Orthopädie; 20081022-20081025; Berlin; DOCWI29-1086 /20081016/
    Publication Date: 2008-10-17
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
    Abstract: BACKGROUND: Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD). METHODS AND RESULTS: A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5)). CONCLUSION: Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.
    Type of Publication: Journal article published
    PubMed ID: 20529992
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  • 4
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; proliferation ; MODEL ; VITRO ; GENE ; GENE-EXPRESSION ; METABOLISM ; ACTIVATION ; kidney ; MACROPHAGES ; TRANSPLANTATION ; INDUCTION ; RAT ; prevention ; PROGRESSION ; ATHEROSCLEROSIS ; REJECTION ; NEPHROPATHY ; TOLL-LIKE RECEPTORS ; inflammation ; NUCLEAR RECEPTORS ; in vitro ; GAIN ; RENAL-ALLOGRAFTS
    Abstract: Liver X receptors (LXR)-alpha,beta regulate intracellular cholesterol homeostasis and inhibit inflammatory gene expression. We studied the effects of the LXR alpha,beta-agonist GW3965 on acute and chronic organ damage in the F344-LEW rat kidney transplantation model. In addition, to gain LXR isoform and cell-specific insights BALB/c kidneys were transplanted into mice with macrophage overexpression of LXR alpha (mLXR alpha-tg) and evaluated 7 and 42 days after transplantation. After 56 days GW3965 improved significantly function and morphology of rat kidney allografts by substantial reduction of mononuclear cell infiltrate and fibrosis; in vitro GW3965 reduced inflammatory activity of bone marrow derived macrophages (BMDMs) and alloreactivity of T cells. Kidneys transplanted into mLXR alpha-tg mice were also protected from development of chronic allograft dysfunction. Similarly to GW3965-activated BMDMs, mLXR alpha-tg macrophages secreted significantly less monocyte chemoattractant protein 1 and macrophage inflammatory protein 1 beta. Interestingly, 7 days after transplantation, when the total number of intragraft macrophages did not differ, evidently more arginase 1 and mannose receptor C type 1 positive cells were found in LXR rat and mice kidney allografts; in vitro both LXR activation by GW3965 and mLXR alpha overexpression accentuated the induction of alternative activation of BMDMs by IL-4/IL-13, suggesting an additional mechanism by LXRs to prevent graft damage. The results highlight the relevance of macrophage LXRa in allograft rejection and prevention of fibrosis.
    Type of Publication: Journal article published
    PubMed ID: 21703396
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  • 5
    Keywords: INHIBITOR ; RISK ; TRIAL ; EVENTS ; SERUM-LEVELS ; ARTERY-DISEASE ; MENDELIAN RANDOMIZATION ; HEALTHY-MEN ; EPIC-NORFOLK ; ACUTE CORONARY SYNDROMES
    Abstract: OBJECTIVES: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. BACKGROUND: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. METHODS: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. RESULTS: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. CONCLUSIONS: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
    Type of Publication: Journal article published
    PubMed ID: 23916927
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  • 6
    Keywords: MACROPHAGES ; ATHEROSCLEROSIS ; DEFICIENT MICE ; NUCLEAR RECEPTORS ; xanthine oxidoreductase ; DIABETIC-NEPHROPATHY ; LXR-ALPHA ; FOAM CELL-FORMATION ; MODIFIED LIPOPROTEINS ; INHIBITS DEVELOPMENT
    Abstract: Dyslipidemia is a frequent component of the metabolic disorder of diabetic patients contributing to organ damage. Herein, in low-density lipoprotein receptor-deficient hyperlipidemic and streptozotozin-induced diabetic mice, hyperglycemia and hyperlipidemia acted reciprocally, accentuating renal injury and altering renal function. In hyperglycemic-hyperlipidemic kidneys, the accumulation of Tip47-positive lipid droplets in glomeruli, tubular epithelia, and macrophages was accompanied by the concomitant presence of the oxidative stress markers xanthine oxidoreductase and nitrotyrosine, findings that could also be evidenced in renal biopsy samples of diabetic patients. As liver X receptors (LXR alpha,beta) regulate genes linked to lipid and carbohydrate homeostasis and inhibit inflammatory gene expression in macrophages, the effects of systemic and macrophage-specific LXR activation were analyzed on renal damage in hyperlipidemic-hyperglycemic mice. LXR stimulation by GW3965 up-regulated genes involved in cholesterol efflux and down-regulated proinflammatory/profibrotic cytokines, inhibiting the pathomorphology of diabetic nephropathy, renal lipid accumulation, and improving renal function. Xanthine oxidoreductase and nitrotyrosine levels were reduced. In macrophages, GW3965 or LXR alpha overexpression significantly suppressed glycated or acetylated low-density lipoprotein-induced cytokines and reactive oxygen species. Specifically, in mice, transgenic expression of LXR alpha in macrophages significantly ameliorated hypertipidemic-hyperglycemic nephropathy. The results demonstrate the presence of lipid droplet-induced oxidative mechanisms and the pathophysiologic role of macrophages in diabetic kidneys and indicate the potent regulatory role of LXRs in preventing renal damage in diabetes.
    Type of Publication: Journal article published
    PubMed ID: 23318573
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Zeitschrift für Kardiologie 87 (1998), S. 777-787 
    ISSN: 1435-1285
    Keywords: Schlüsselwörter Atherosklerose – koronare Herzerkrankung – Myokardinfarkt – Genetik – Polymorphismus – Tiermodelle ; Key words Atherosclerosis – coronary heart disease – myocardial infarction – genetics – polymorphisms – animal models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Atherosclerosis is a complex multifactorial disease of the arterial wall, dependent on genetic disposition and multiple other risk factors. There are probably several candidate genes, that determine the individual susceptibility of the vessel wall to develop atherosclerosis. In recent years, a growing number of gene polymorphisms, associated with an elevated risk of myocardial infarction, has been identified. These genes and gene clusters play a crucial role in lipid metabolism, regulation of blood pressure and clotting. In contrast to rare monogenetic diseases with severe clinical signs and symptoms (e.g. familial hypercholesterolemia), genetic polymorphisms are relatively frequent. Due to their frequency, there is a high probability that one individual carries several alleles predisposing to coronary heart disease. Genetic polymorphisms become clinically important by interacting with lifestyle, environmental factors or endogenous metabolic disorders. We have recently established an animal model of rabbits, which may prove useful in the search for new genes predisposing to or protecting from atherosclerosis. Rabbits with high atherosclerotic response (HAR) show more than 70% atherosclerotic involvement of the aorta when fed a high cholesterol diet. In contrast, rabbits with low atherosclerotic response (LAR) show less than 20% atherosclerosis in spite of comparably high plasma cholesterol levels. Preliminary studies indicate that macrophages of LAR rabbits have a high scavenger receptor activity and high apolipoprotein E expression and thus appear to be very efficient in uptake and elimination of modified lipoproteins. This may result in a more efficient removal of cholesterol from the arterial wall and thus protect the animals from developing atherosclerosis. Today we are only at the beginning of understanding the complexity of gene interaction in atherosclerosis. Further identification of genetic factors of atherosclerosis will no doubt lead to a more efficient and economic prevention of coronary heart disease in the future.
    Notes: Zusammenfassung Die Atherosklerose ist eine komplizierte, multifaktorielle Erkrankung, die von einer besonderen genetischen Disposition und einer Vielzahl verschiedener Risikofaktoren abhängig ist. Als zweifellos wichtigster Kausalfaktor ist eine Erhöhung des Plasma-LDL-Cholesterins anzusehen, dessen atherogene Wirkung durch andere Faktoren erheblich verstärkt werden kann. Vermutlich determinieren mehrere Kandidatengene die individuell sehr unterschiedliche Atheroskleroseempflindlichkeit der Gefäßwand. In den letzten Jahren wurde eine wachsende Zahl von Genpolymorphismen identifiziert, die mit einem erhöhten Myokardinfarktrisiko assoziiert sind. Dies betrifft insbesondere Gene und Gencluster, die im Fettstoffwechsel, der Blutdruckregulation und der Blutgerinnung eine zentrale Rolle spielen. Im Gegensatz zu den seltenen monogenetischen Erkrankungen, die mit einem schweren Krankheitsbild einhergehen (z.B. familiäre Hypercholesterinämie), sind Genpolymorphismen relativ häufig. Aufgrund ihrer hohen Frequenz ist das Zusammentreffen mehrerer für die Atherosklerose prädisponierender Allele in einem Individuum durchaus wahrscheinlich, dies könnte die koronare Risikodisposition eines Patienten entscheidend bestimmen. Genetische Polymorphismen wirken sich klinisch meist erst durch die Interaktion mit Lebensstil- und Umweltfaktoren oder bei endogenen Stoffwechselstörungen aus. Die Rolle genetischer Faktoren in der Atherogenese kann heute tierexperimentell durch gentechnische Überexpression oder Knockout von bekannten Kandidatengenen gezielt untersucht werden. Zur Suche nach Genen der Atherosklerosedisposition wurde von uns ein Tiermodell atheroskleroseempfindlicher und resistenter Kaninchen etabliert. Atheroskleroseempfindliche Kaninchen (HAR) entwickeln unter einer Cholesterindiät eine Aortenatherosklerose über 70%, dagegen zeigen resistente Kaninchen (LAR) trotz einer massiven Hypercholesterinämie nur etwa 20% Oberflächenläsionen der Aorta. Nach neuen Untersuchungen verfügen Makrophagen der atheroskleroseresistenten Kaninchen aufgrund einer auffällig hohen Scavenger-Rezeptoraktivität und ApoE-Expression über sehr effiziente Mechanismen zur Aufnahme und Elimination modifizierter Lipoproteine. Diese besondere Makrophagenfunktion könnte bei diesen Tieren der zellulären Cholesterinspeicherung und der Entstehung der Atherosklerose entgegenwirken. Die molekularbiologische Aufklärung genetischer Faktoren der Atherosklerosedisposition steht erst an ihrem Beginn und ist zweifellos klinisch und gesundheitspolitisch ein wichtiges Ziel. Es ist zu erwarten, daß die weitere Charakterisierung genetischer Faktoren der Atherosklerose in der Zukunft eine wesentlich gezieltere, effektivere und ökonomisch vertretbarere primäre Prävention der koronaren Herzerkrankung ermöglichen wird, als dies heute der Fall ist.
    Type of Medium: Electronic Resource
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