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Showing 1201–1220 of 2058 publications.
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Barter, Philip J.Type 2 diabetes is commonly accompanied by a low level of high density lipoprotein cholesterol (HDL-C) that contributes to the increased cardiovascular risk associated with this condition. Given that HDLs have the ability to improve increase the uptake of glucose by skeletal muscle and to stimulate the secretion of insulin from pancreatic beta cells the possibility arises that a low HDL concentration in type 2 diabetes may also contribute to a worsening of diabetic control. Thus, there is a double case for raising the level of HDL-C in patients with type 2 diabetes: to reduce cardiovascular risk and to improve glycemic control. Approaches to raising HDL-C include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. Of currently available drugs, the most effective is niacin. Newer formulations of niacin are reasonably well tolerated and have the ability to increase HDL-C by up to 30%. The effect of niacin on cardiovascular events in type 2 diabetes is currently being tested in a largescale clinical outcome trial. 2011 Korean Diabetes Association.
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Dunlop, Rachael Anne[No abstract available]
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Xu, Bei; Nakhla, Shirley; Makris, Angela; Hennessy, AnnemariePreeclampsia has been linked to shallow trophoblast invasion and failure of uterine spiral artery transformation. Interaction between trophoblast cells and maternal uterine endothelium is critically important for this remodelling. The aim of our study was to investigate the effect of TNF-? on the interactions of trophoblast-derived JEG-3 cells into capillary-like cellular networks. We have employed an in vitro trophoblast-endothelial cell co-culture model to quantify trophoblast integration into endothelial cellular networks and to investigate the effects of TNF-?. Controlled co-cultures were also treated with anti-TNF-? antibody (5 ?g/ml) to specifically block the effect of TNF-?. The invasion was evaluated by performing quantitative PCR (Q-PCR) to analyse gene expression of matrix metalloproteinases-2 (MMP-2), MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, integrins (?<inf>1</inf>?<inf>1</inf> and ?<inf>6</inf>? <inf>4</inf>), plasminogen activator inhibitor (PAI)-1, E-cadherin and VE-cadherin. JEG-3 cell integration into endothelial networks was significantly inhibited by exogenous TNF-?. The inhibition was observed in the range of 0.2-5 ng/ml, to a maximum 56% inhibition at the highest concentration. This inhibition was reversed by anti-TNF-? antibody. Q-PCR analysis showed that mRNA expression of integrins ?<inf>1</inf>?<inf>1</inf> and MMP-2 was significantly decreased. VE-cadherin mRNA expression was significantly up-regulated (32-80%, p < 0.01) but its protein concentration in the cell lysates was significantly reduced (20-45%, p < 0.01). PAI-1, MMP-9, TIMP-1 and E-cadherin were not affected. In conclusion, TNF-? can inhibit trophoblast-like cells (JEG-3) integration into maternal endothelial cellular networks, and this process involves the inhibition of MMP-2 and a failure of integrins switch from ?<inf>6</inf>?<inf>4</inf> to ?<inf>1</inf>?<inf>1.</inf> These molecular correlations reflect the changes identified in human preeclampsia. 2011 Elsevier Ltd. All rights reserved.
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Tang, J.; Dunlop, Rachael Anne; Rowe, Anthony; Rodgers, Kenneth John; Ramzan, Iqbal M.While cases of severe kava hepatotoxicity have been reported, studies examining the toxicity of individual kavalactones are limited. The present study examined the in vitro hepatotoxicity of kavain, methysticin and yangonin on human hepatocytes (HepG2) and the possible mechanism(s) involved. Cytotoxicity was assessed using lactate dehydrogenase (LDH) and ethidium bromide (EB) assays. The mode of cell death was analysed with acridine orange/ethidium bromide dual staining with fluorescence microscopy. Glutathione oxidation was measured using the ortho-phthalaldehyde (OPT) fluorescence assay. Kavain had minimal cytotoxicity, methysticin showed moderate concentration-dependent toxicity and yangonin displayed marked toxicity with ?40% reduction in viability in the EB assay. Acridine orange/ethidium bromide staining showed the predominant mode of cell death was apoptosis rather than necrosis. No significant changes were observed in glutathione levels, excluding this as the primary mechanism of cell death in this model. Further studies may elucidate the precise apoptotic pathways responsible and whether toxic kavalactone metabolites are involved. Copyright 2010 John Wiley & Sons, Ltd.
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Watts, Gerald F.; Cohn, Jeffrey S.[No abstract available]
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Akram, Omar N.; Bursill, C. A.; Desai, Reena; Heather, Alison Kay; Kazlauskas, Rymantas; Handelsman, David J.; Lambert, GillesAndrogenic steroids marketed online as nutraceuticals are a growing concern in sport doping. The inability of conventional mass spectrometry (MS)-based techniques to detect structurally novel androgens has led to the development of in vitro androgen bioassays to identify such designer androgens by their bioactivity. The objective of this study was to determine the androgenic bioactivity of novel steroidal compounds isolated from nutraceuticals using both yeast and mammalian cell-based androgen bioassays. We developed two new in vitro androgen bioassays by stably transfecting HEK293 and HuH7 cells with the human androgen receptor (hAR) expression plasmid together with a novel reporter gene vector (enhancer/ARE/SEAP). The yeast ?-galactosidase androgen bioassay was used for comparison. Our new bioassay featuring the enhancer/ARE/SEAP construct (-S) displayed simpler assay format and higher specificity with lower sensitivity compared with the commonly used mouse mammary tumour virus (MMTV)-luciferase. The relative potencies (RP), defined as [EC<inf>50</inf>] of testosterone/[EC<inf>50</inf>] of steroid, of nutraceutical extracts in the yeast, HEK293-S, and HuH7-S, were 34, 333, and 80 000 for Hemapolin; 208, 250, and 80 for Furazadrol; 0.38, 10, and 106 for Oxyguno; 2.7, 0.28, and 15 for Trena; and 4.5, 0.1, and 0.4 for Formadrol, respectively. The wide discrepancies in rank RP of these compounds was reconciled into a consistent potency ranking when the cells were treated with meclofenamic acid, a nonselective inhibitor of steroid metabolizing enzymes. These findings indicate that steroids extracted from nutraceuticals can be converted in vitro into more or less potent androgens in mammalian but not in yeast cells. We conclude that the putative androgenic bioactivity of a new compound may depend on the bioassay cellular format and that mammalian cell bioassays may have an added benefit in screening for proandrogens but sacrifice specificity for sensitivity in quantitation. 2011 American Chemical Society.
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Pattison, David I.; O'Reilly, Robert J.; Skaff, Ojia; Radom, Leo; Anderson, Robert F.; Davies, Michael J.Hypochlorous (HOCl) and hypobromous (HOBr) acids are strong bactericidal oxidants that are generated by the human immune system but are implicated in the development of many human inflammatory diseases (e.g., atherosclerosis, asthma). These oxidants react readily with sulfur- and nitrogen-containing nucleophiles, with the latter generating N-halogenated species (e.g., chloramines/bromamines (RR?NX; X = Cl, Br)) as initial products. Redox-active metal ions and superoxide radicals (O<inf>2</inf> -) can reduce N-halogenated species to nitrogen- and carbon-centered radicals. N-Halogenated species and O<inf>2</inf> - are generated simultaneously at sites of inflammation, but the significance of their interactions remains unclear. In the present study, rate constants for the reduction of N-halogenated amines, amides, and imides to model potential biological substrates have been determined. Hydrated electrons reduce these species with k<inf>2</inf> > 109 M-1 s-1, whereas O<inf>2</inf>- reduced only N-halogenated imides with complex kinetics indicative of chain reactions. For N-bromoimides, heterolytic cleavage of the N-Br bond yielded bromine atoms (Br), whereas for other substrates, N-centered radicals and Cl-/Br- were produced. High-level quantum chemical procedures have been used to calculate gas-phase electron affinities and aqueous solution reduction potentials. The effects of substituents on the electron affinities of aminyl, amidyl, and imidyl radicals are rationalized on the basis of differential effects on the stabilities of the radicals and anions. The calculated reduction potentials are consistent with the experimental observations, with Br production predicted for N-bromosuccinimide, while halide ion formation is predicted in all other cases. These data suggest that interaction of N-halogenated species with O <inf>2</inf>- may produce deleterious N-centered radicals and Br. 2011 American Chemical Society.
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Bradshaw, Pamela J.; Alfonso, Helman S.; Finn, Judith C.; Owen, Julie; Thompson, Peter LindsayBackground: Age-specific death from cardiovascular disease among Australian Aboriginals is estimated to be four to seven times that of general population, and the major cause of premature death. There is little reliable information on the incidence of coronary heart disease (CHD). This study compares CHD event rates in urbandwelling Aboriginal people and the general population. Methods The Perth Aboriginal Atherosclerosis Risk Study (PAARS) cohort was assessed at baseline (1998/1999) and 913 participants followed-up to 2006. A comparison group of age-matched, sex-matched and postcode-matched non-Aboriginals (n=3582) were selected from the Perth, Western Australia, Electoral Roll. Electronic record linkage captured prior CHD and first CHD events in both groups. The rates of first CHD events (hospital admission or CHD death) per 1000 person years (PY) and incidence rate ratios (IRR) were calculated. Results: The event rate for the PAARS population was 14.9 per 1000 PY (95% CI 12.3 to 18.2) versus 2.4 (1.9 to 3.1) for the general population. The IRR was 6.1 (4.5 to 8.4). For Aboriginal men the rate was 15.0 (11.2 to 20.0) versus 3.8 (2.5 to 5.0) per 1000 PY, with age-specific rates being two to five times that of non-Aboriginals. Incidence for Aboriginal women was 15.0 (11.5 to 19.5) versus 1.4 (0.9 to 2.1) with age-specific rates being 8-25 times that of non-Aboriginals. Conclusions Age and sex-specific CHD event rates in urban Aboriginals far exceeded that of a matched general population. Events occurred at a much younger age among the Aboriginal participants and were equally excessive among men and women.
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Dunlop, Rachael Anne; Brunk, Ulf T.; Rodgers, Kenneth JohnCellular deposits of oxidized and aggregated proteins are hallmarks of a variety of age-related disorders, but whether such proteins contribute to pathology is not well understood. We previously reported that oxidized proteins form lipofuscin/ceroid-like bodies with a lysosomal-type distribution and up-regulate the transcription and translation of proteolytic lysosomal enzymes in cultured J774 mouse macrophages. Given the recently identified role of lysosomes in the induction of apoptosis, we have extended our studies to explore a role for oxidized proteins in apoptosis. Oxidized proteins were biosynthetically generated in situ by substituting oxidized analogues for parent amino acids. Apoptosis was measured with Annexin-V/PI (propidium iodide), TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling), MMP (mitochondrial membrane permeabilization), caspase activation and cytochrome c release, and related to lysosomal membrane permeabilization. Synthesized proteins containing the tyrosine oxidation product L-DOPA (L-3,4- dihydroxyphenylalanine) were more potent inducers of apoptosis than proteins containing the phenylalanine oxidation product o-tyrosine. Apoptosis was dependent upon incorporation of oxidized residues, as indicated by complete abrogation in cultures incubated with the non-incorporation control D-DOPA (D-3,4-dihydroxyphenylalanine) or when incorporation was competed out by parent amino acids. The findings of the present study suggest that certain oxidized proteins could play an active role in the progression of age-related disorders by contributing to LMP (lysosomal membrane permeabilization)-initiated apoptosis and may have important implications for the long-term use of L-DOPA as a therapeutic agent in Parkinson's disease. The Authors Journal compilation 2011 Biochemical Society.
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Waterhouse, Anna; Wise, Steven G.; Ng, Martin K.C.; Weiss, Anthony StevenSurface-induced thrombosis is a significant issue for artificial blood-contacting materials used in the treatment of cardiovascular diseases. The development of biomaterials and tissue-engineered constructs that mimic the vasculature represents a way to overcome this problem. Elastin is an extracellular matrix macromolecule that imparts arterial elasticity where it comprises up to 50% of the nonhydrated mass of the vessel. In addition to its critical role in maintaining vessel integrity and elastic properties under pulsatile flow, elastin plays an important role in signaling and regulating luminal endothelial cells and smooth muscle cells in the arterial wall. Despite its well-established significance in the vasculature and its growing use as a biomaterial in tissue engineering, the hemocompatibility of elastin is often overlooked. Past studies pointing to the potential of arterial elastin and decellularized elastin as nonthrombogenic materials have begun to be realized, with elastin scaffolds and coatings displaying increased hemocomptibility. This review explores the mechanisms of elastin's nonthrombogenicity and highlights the current problems limiting its wider application as a biomaterial. We discuss the benefits of constructing biomaterials encompassing the relevant mechanical and biological features of elastin to provide enhanced hemocompatibility to biomaterials. 2011 Mary Ann Liebert, Inc.
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Sacks, Frank M.; Zheng, Chunyu; Cohn, Jeffrey S.[No abstract available]
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Waters, David D.; Ho, Jennifer E.; DeMicco, David A.; Breazna, Andrei; Arsenault, Beno J.; Wun, Chuanchuan; Kastelein, Johannes Jacob Pieter; Colhoun, Helen M.; Barter, Philip J.Objectives: We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin. Background: Statin therapy might modestly increase the risk of new-onset T2DM. Methods: We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM. Results: In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69). Conclusions: High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials. 2011 American College of Cardiology Foundation.
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Wu, Zhiping; Gogonea, Valentin; Lee, Xavier; May, Roland Peter; Pipich, Vitaliy; Wagner, Matthew A.; Undurti, Arundhati; Tallant, Thomas C.; Beanu-Gogonea, Camia; Charlton, Francesca; Ioffe, Alexander I.; Didonato, Joseph A.; Rye, Kerry Anne; Hazen, Stanley L.Spherical high density lipoprotein (sHDL), a key player in reverse cholesterol transport and the most abundant form of HDL, is associated with cardiovascular diseases. Small angle neutron scattering with contrast variation was used to determine the solution structure of protein and lipid components of reconstituted sHDL. Apolipoprotein A1, the major protein of sHDL, forms a hollow structure that cradles a central compact lipid core. Three apoA1 chains are arranged within the low resolution structure of the protein component as one of three possible global architectures: (i) a helical dimer with a hairpin (HdHp), (ii) three hairpins (3Hp), or (iii) an integrated trimer (iT) in which the three apoA1 monomers mutually associate over a portion of the sHDL surface. Cross-linking and mass spectrometry analyses help to discriminate among the three molecular models and are most consistent with the HdHp overall architecture of apoA1 within sHDL. 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
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Dunlop, Rachael Anne[No abstract available]
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Thornton, Charlene Eliza; von Dadelszen, Peter; Makris, Angela; Tooher, Jane M.; Ogle, Robert F.; Hennessy, AnnemarieObjective. To determine rates of and potential causative factors for acute pulmonary oedema (APO) in hypertensive women. Methods. Statistical analysis, including logistic regression, was applied to the individual patient data (IPD) of all hypertensive women who delivered in 2005 at two comparable units. Results. Of 880 cases analysed, there were no women with APO in unit one and 19 women in unit two. The women with APO received larger quantities of intravenous fluids, delivered at earlier gestations, via Caesarean section, following failed induction of labour and had a longer hospital stay. Conclusion. The development of APO in women with hypertension during pregnancy is associated with high levels of intravenous fluid administration. 2011 Informa Healthcare USA, Inc.
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Brnes, Ana Mar; Tabet, Fatiha; Callera, Glcia Elena; Montezano, Augusto Cesar I.; Yogi, varo; He, Ying; Quinn, Mark T.; Salaes, Mercedes; Touyz, Rhian M.The functional significance and regulation of NAD(P)H oxidase (Nox) isoforms by angiotensin II (Ang II) and endothelin-1 (ET-1) in vascular smooth muscle cells (VSMCs) from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) was studied. Expression of Nox1, Nox2, and Nox4 (gene and protein) and NAD(P)H oxidase activity were increased in SHR. Basal NAD(P)H oxidase activity was blocked by GKT136901 (Nox1/4 inhibitor) and by Nox1 siRNA in WKY cells and by siNOX1 and siNOX2 in SHR. Whereas Ang II increased expression of all Noxes in WKY, only Nox1 was influenced in SHR. Ang II-induced NAD(P)H activity was inhibited by siNOX1 in WKY and by siNOX1 and siNOX2 in SHR. ET-1 upregulated Nox expression only in WKY and increased NAD(P)H oxidase activity, an effect inhibited by siNOX1 and siNOX2. Nox1 co-localized with Nox2 but not with Nox4, implicating association between Nox1 and Nox2 but not between Nox1 and Nox4. These data highlight the complexity of Nox biology in VSMCs, emphasising that more than one Nox member, alone or in association, may be involved in NAD(P)H oxidase-mediated O<inf>2</inf>- production. Nox1 regulation by Ang II, but not by ET-1, may be important in O <inf>2</inf>- formation in VSMCs from SHR. 2011 American Society of Hypertension. All rights reserved.
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Tabet, Fatiha; Lambert, Gilles; Cuesta Torres, Luisa F.; Hou, Liming; Sotirchos, Irene M.; Touyz, Rhian M.; Jenkins, Alicia J.; Barter, Philip J.; Rye, Kerry AnneObjective- The goal of this study was to investigate the mechanisms by which apolipoprotein (apo) A-I, in the lipid-free form or as a constituent of discoidal reconstituted high-density lipoproteins ([A-I]rHDL), inhibits high-glucose-induced redox signaling in human monocyte-derived macrophages (HMDM). Methods and Results- HMDM were incubated under normal (5.8 mmol/L) or high-glucose (25 mmol/L) conditions with native high-density lipoproteins (HDL) lipid-free apoA-I from normal subjects and from subjects with type 2 diabetes (T2D) or (A-I)rHDL. Superoxide (O2) production was measured using dihydroethidium fluorescence. NADPH oxidase activity was assessed using lucigenin-derived chemiluminescence and a cyotochrome c assay. p47phox translocation to the plasma membrane, Nox2, superoxide dismutase 1 (SOD1), and SOD2 mRNA and protein levels were determined by real-time polymerase chain reaction and Western blotting. Native HDL induced a time-dependent inhibition of O2 generation in HMDM incubated with 25 mmol/L glucose. Lipid-free apoA-I and (A-I)rHDL increased SOD1 and SOD2 levels and attenuated 25 mmol/L glucose-mediated increases in cellular O2, NADPH oxidase activity, p47 translocation, and Nox2 expression. Lipid-free apoA-I mediated its effects on Nox2, SOD1, and SOD2 via ABCA1. (A-I)rHDL-mediated effects were via ABCG1 and scavenger receptor BI. Lipid-free apoA-I from subjects with T2D inhibited reactive oxygen species generation less efficiently than normal apoA-I. Conclusion- Native HDL, lipid-free apoA-I and (A-I)rHDL inhibit high-glucose-induced redox signaling in HMDM. The antioxidant properties of apoA-I are attenuated in T2D. Copyright 2011 American Heart Association. All rights reserved.
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Chan, Kim Hoe; Ng, Martin K.C.; Stocker, RolandCardiovascular disease remains the leading cause of death worldwide. Despite progress in management, there remain a significant number of patients who are not eligible for current treatment options. Traditionally, HO-I (haem oxygenase-I), one of two isoenzymes that initiate haem catabolism, was thought to only play a metabolic role. However, HO-I is now recognized to have additional protective activities in states of heightened noxious stimuli or stress such as acute coronary syndromes. The present review article provides an overview of the mode of action of HO-I in vascular protection, with particular emphasis on its atheroprotective, anti-inflammatory and antioxidative properties, as well as its role in vascular repair. Furthermore, we present evidence for the protective effects of HO-I in CVD (cardiovascular disease) in both animal and human studies. Given its potential in vascular protection and repair, strategies aimed at inducing HO-I emerge as a novel and alternative therapeutic target in the management of CVD. The Authors Journal compilation 2011 Biochemical Society.
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Sunderland, Neroli; Hennessy, Annemarie; Makris, AngelaThe cardinal features of human pre-eclampsia, hypertension and proteinuria, are mimicked in animal models. Increasingly, the accuracy of inducing 'pure' systemic endothelial dysfunction is regarded as critical in differentiating mechanisms of pre-eclampsia from other conditions which induce hypertension (e.g. glomerulonephritis, renal denervation or manipulation of the renin-angiotensin system). A recent study in baboons has identified the timing of induction of maternal endothelial damage after acute uteroplacental ischaemia (UPI). The endothelial changes in the glomerulus are indicative of a direct endothelial toxin and mimic the lesions seen in human pre-eclampsia; the extent of hypertension and proteinuria are also similar. This animal model identifies systemic and placental sFLT-1 (soluble fms-like tyrosine kinase-1) as a potential mediator of endothelial damage. This research involving primates with haemomonochorial placentas makes translation of these results to humans very compelling for understanding the mechanisms of human disease. Similar endothelial dysfunction has been identified in baboons treated with anti-inflammatory inhibitors. Similar studies in rodents have identified a relationship between angiotensin II agonistic antibodies, UPI/reduced uteroplacental perfusion pressure, angiogenic markers, and cytokines. We can now identify vasoconstrictive mediators of the hypertensive and endothelial response such as endothelin 1, the renin-angiotensin system, or other hormones such as oestrogens in primate models. 2010 John Wiley & Sons A/S.
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Dunlop, Rachael Anne[No abstract available]
