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Showing 761–780 of 2058 publications.
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Pilowsky, Paul M.[No abstract available]
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Lawley, Claire Margaret; Broadhouse, Kathryn M.; Callaghan, Fraser Maurice; Winlaw, David S.; Figtree, Gemma A.; Grieve, Stuart M.Imaging-based evaluation of cardiac structure and function remains paramount in the diagnosis and monitoring of congenital heart disease in childhood. Accurate measurements of intra- and extracardiac hemodynamics are required to inform decision making, allowing planned timing of interventions prior to deterioration of cardiac function. Four-dimensional flow magnetic resonance imaging is a nonionizing noninvasive technology that allows accurate and reproducible delineation of blood flow at any anatomical location within the imaging volume of interest, and also permits derivation of physiological parameters such as kinetic energy and wall shear stress. Four-dimensional flow is the focus of a great deal of attention in adult medicine, however, the translation of this imaging technique into the pediatric population has been limited to date. A more broad-scaled application of 4-dimensional flow in pediatric congenital heart disease stands to increase our fundamental understanding of the cause and significance of abnormal blood flow patterns, may improve risk stratification, and inform the design and use of surgical and percutaneous correction techniques. This paper seeks to outline the application of 4-dimensional flow in the assessment and management of the pediatric population affected by congenital heart disease. 2017, The Author(s) 2017.
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Ren, Wei; Wen, Shihui; Tawfik, Sherif Abdulkader; Su, Qian Peter; Lin, Gungun; Ju, Lining Arnold; Ford, Michael J.; Ghodke, Harshad B.; Van Oijen, Antoine M.; Jin, DayongDespite significant advances toward accurate tuning of the size and shape of colloidal nanoparticles, the precise control of the surface chemistry thereof remains a grand challenge. It is desirable to conjugate functional bio-molecules onto the selected facets of nanoparticles owing to the versatile capabilities rendered by the molecules. We report here facet-selective conjugation of DNA molecules onto upconversion nanoparticles via ligand competition reaction. Different binding strengths of phosphodiester bonds and phosphate groups on DNA and the surfactant molecules allow one to create heterogeneous bio-chemistry surface for upconversion nanoparticles. The tailored surface properties lead to the formation of distinct self-assembly structures. Our findings provide insight into the interactions between biomolecules and nanoparticles, unveiling the potential of using nanoparticles as fundamental building blocks for creating self-assembled nano-architectures. 2018 The Royal Society of Chemistry.
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Hammett, Christopher J.K.; Amerena, John V.; Brieger, David B.; Sindone, Andrew Paul; Thompson, Peter Lindsay; Worthley, Matthew Ian; Aylward, Philip E.G.Objective: There remain substantial gaps in implementation of evidence-based care in patients with acute coronary syndromes (ACS) in Australia, which contribute to high recurrent event rates. Improved translation of evidence into effective action is a key health-care priority. We engaged cardiovascular experts from across Australia to develop straightforward, easily actionable recommendations on key medications to use following ACS. Methods: An eight-person steering committee (SC) reviewed the published evidence and developed an initial set of statements to be developed into consensus recommendations using a modified Delphi technique. A panel of 21 expert cardiologists in the ACS field (including the SC) voted on their level of agreement with the statements using a 6 point Likert scale. Statements that did not reach consensus (?80% agreement) were reviewed by the SC, modified as appropriate based on input from the panel and circulated for re-voting. Results: Twenty-eight statements were developed by the SC across six classes of medication: low-density lipoprotein (LDL) cholesterol lowering agents, aspirin, dual antiplatelet therapy, renin-angiotensin- aldosterone system inhibitors, beta blockers and other. Twenty-six recommendations were endorsed by the voting panel; two statements did not reach consensus. Conclusions: Despite the extensive evidence base and detailed guidelines outlining best practice post ACS, there remain considerable gaps in translating these into everyday care. We used an internationally recognized technique to develop practical consensus recommendations on medical treatment following ACS. These simple, up-to-date recommendations aim to improve evidence-based medication use and thereby reduce the risk of future cardiovascular events for Australian patients with ACS. 2017 Informa UK Limited, trading as Taylor and Francis Group.
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Akhavan, Behnam; Bakhshandeh, Sadra; Najafi-Ashtiani, Hamed; Fluit, Adriaan Camille; Boel, Edwin C.H.; Vogely, Charles H.; van der Wal, Bart C.H.; Zadpoor, Amir A.; Weinans, Harrie H.; Hennink, Wim E.; Bilek, Marcela M.M.; Yavari, Saber AminPrevention and treatment of biomaterial-associated infections (BAI) are imperative requirements for the effective and long-lasting function of orthopedic implants. Surface-functionalization of these materials with antibacterial agents, such as antibiotics, nanoparticles and peptides, is a promising approach to combat BAI. The well-known silver nanoparticles (AgNPs) in particular, although benefiting from strong and broad-range antibacterial efficiency, have been frequently associated with mammalian cell toxicity when physically adsorbed on biomaterials. The majority of irreversible immobilization techniques employed to fabricate AgNP-functionalized surfaces are based on wet-chemistry methods. However, these methods are typically substrate-dependent, complex, and time-consuming. Here we present a simple and dry strategy for the development of polymeric coatings used as platforms for the direct, linker-free covalent attachment of AgNPs onto solid surfaces using ion-assisted plasma polymerization. The resulting coating not only exhibits long-term antibiofilm efficiency against adherent Staphylococcus aureus (S. aureus), but also enhances osteoblast adhesion and proliferation. High resolution X-ray photoelectron spectroscopy (XPS), before and after sodium dodecyl sulfate (SDS) washing, confirms covalent bonding. The development of such silver-functionalized surfaces through a simple, plasma-based process holds great promise for the fabrication of implantable devices with improved tissue-implant integration and reduced biomaterial associated infections. The Royal Society of Chemistry.
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Witsch, Jens; Merkler, Alexander Eliot; Chen, Monica Lin; Navi, Babak B.; Sheth, Kevin N.; Freedman, Ben Ben; Schwamm, Lee H.; Kamel, HoomanBackground and Purpose-It is unclear whether atrial fibrillation/flutter (AF) newly diagnosed after ischemic stroke represents a preexisting risk factor that led to stroke, an arrhythmia triggered by poststroke autonomic dysfunction, or an incidental finding. Methods-We compared AF incidence after hospitalizations for ischemic stroke, hemorrhagic stroke, and nonstroke conditions using inpatient and outpatient claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. We used validated International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify AF-free patients hospitalized with ischemic or hemorrhagic stroke and matched them in a 1:1 ratio by age, sex, race, calendar year, vascular risk factors, and Charlson comorbidities. We then matched the combined stroke cohort in a 1:1 ratio to patients hospitalized for nonstroke diagnoses. We used survival statistics and Cox regression to compare postdischarge AF incidence among groups. Results-We matched 2580 patients with ischemic stroke, 2580 with hemorrhagic stroke, and 5160 patients with other conditions. The annual postdischarge AF incidence was 3.4% (95% CI, 3.1%-3.7%) after ischemic stroke, 2.2% (95% CI, 1.9%-2.4%) after hemorrhagic stroke, and 2.9% (95% CI, 2.6%-3.1%) after nonstroke hospitalization. Ischemic stroke was associated with a somewhat higher risk of AF than hemorrhagic stroke (hazard ratio, 1.5; 95% CI, 1.3-1.8) or nonstroke conditions (hazard ratio, 1.2; 95% CI, 1.1-1.3). The latter association attenuated in sensitivity analyses limiting the outcome to AF diagnoses made by cardiologists (hazard ratio, 1.1; 95% CI, 0.8-1.5) or limiting the outcome to a minimum of 2 AF claims on separate dates (hazard ratio, 1.2; 95% CI, 1.0-1.5; P=0.09). Conclusions-New diagnoses of AF were more common after hospitalization for ischemic stroke than after hospitalization for hemorrhagic stroke or nonstroke conditions, but all hospitalized patients had a substantial incidence of new AF diagnoses after discharge and differences were attenuated when using more stringent definitions. 2018 American Heart Association, Inc.
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Vanags, Laura Z.; Wong, Nathan K.P.; Nicholls, Stephen J.; Bursill, C. A.Revascularization because of coronary artery disease is commonly achieved by percutaneous coronary intervention with stent deployment. Refinement in interventional techniques, major improvements in stent design (particularly drug-eluting stents), and adjunctive pharmacotherapy with dual antiplatelet regimens have led to marked reductions in the overall rates of stent failure. However, even with the advancements made in the latest generation of drug-eluting stents, unresolved biological problems persist including delayed re-endothelialization and neoatherosclerosis, which can promote late expansion of the neointima and late stent thrombosis. Novel strategies are still needed beyond what is currently available to specifically address the pathobiological processes that underpin the residual risk for adverse clinical events. This review focuses on the emerging evidence that HDL (high-density lipoproteins) and its main apo (apolipoprotein), apoA-I, exhibit multiple vascular biological functions that are associated with an improvement in stent biocompatibility. HDL/apoA-I have recently been shown to inhibit in-stent restenosis in animal models of stenting and suppress smooth muscle cell proliferation in in vitro studies. Reconstituted HDL also promotes endothelial cell migration, endothelial progenitor cell mobilization, and re-endothelialization. Furthermore, reconstituted HDL decreases platelet activation and HDL cholesterol is inversely associated with the risk of thrombosis. Finally, reconstituted HDL/apoA-I suppresses key inflammatory mechanisms that initiate in-stent neoatherosclerosis and can efflux cholesterol from plaque macrophages, an important function of HDLs that prevents plaque progression. These unique multifunctional effects of HDL/apoA-I suggest that, if translated appropriately, have the potential to improve stent biocompatibility. This may provide an alternate and more efficacious therapeutic pathway for the translation of HDL. 2018 American Heart Association, Inc.
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Orchard, Jessica Joan; Neubeck, Lis; Freedman, Ben Ben; Webster, Ruth J.; Patel, Anushka A.; Gallagher, Robyn D.; Li, Jialin; Hespe, Charlotte Mary; Ferguson, Caleb; Zwar, Nicholas Arnold; Lowres, NicoleIntroduction Screening for atrial fibrillation (AF) in people ?65 years is now recommended by guidelines and expert consensus. While AF is often asymptomatic, it is the most common heart arrhythmia and is associated with increased risk of stroke. Early identification and treatment with oral anticoagulants can substantially reduce stroke risk. The general practice setting is ideal for opportunistic screening and provides a natural pathway for treatment for those identified. This study aims to investigate the feasibility of implementing screening for AF in rural general practice using novel electronic tools. It will assess whether screening will fit within an existing workflow to quickly and accurately identify AF, and will potentially inform a generalisable, scalable approach. Methods and analysis Screening with a smartphone ECG will be conducted by general practitioners and practice nurses in rural general practices in New South Wales, Australia for 3-4 months during 2018-2019. Up to 10 practices will be recruited, and we aim to screen 2000 patients aged ?65 years. Practices will be given an electronic screening prompt and electronic decision support to guide evidence-based treatment for those with AF. De-identified data will be collected using a clinical audit tool and qualitative interviews will be conducted with selected practice staff. A process evaluation and cost-effectiveness analysis will also be undertaken. Outcomes include implementation success (proportion of eligible patients screened, fidelity to protocol), proportion of people screened identified with new AF and rates of treatment with anticoagulants and antiplatelets at baseline and completion. Results will be compared against an earlier metropolitan study and a 'control' dataset of practices. Ethics and dissemination Ethics approval was received from the University of Sydney Human Research Ethics Committee on 27 February 2018 (Project no.: 2017/1017). Results will be disseminated through various forums, including peer-reviewed publication and conference presentations. 2018 Author(s) (or their employer(s)).
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Lam, Yuen Ting; Lecce, Laura; Yuen, Gloria S.C.; Wise, Steven G.; Handelsman, David J.; Ng, Martin K.C.Bone marrow-derived progenitor cell-mediated vasculogenesis is a key process for vascular repair and regeneration. However, the role of androgens in the mechanism of ischemia-induced vasculogenesis remains unclear. In this study, a gender-mismatch murine bone marrow transplant model was used to allow tissue tracking of transplanted cells. Bone marrow from 2-month-old male mice was transplanted into irradiated age-matched female recipients. Following the transplantation, ovariectomized female recipients were subjected to unilateral hindlimb ischemia and immediately implanted with either dihydrotestosterone (DHT) or placebo pellets. Laser Doppler perfusion imaging revealed that DHT significantly augmented blood flow recovery, with increased capillary density compared to placebo-treated female recipient controls. Flow cytometry analysis showed that DHT modulated vasculogenesis by increasing Sca1+/CXC4+ progenitor cell production in bone marrow and spleen and enhancing cell mobilization in circulating blood following hindlimb ischemia. Bone marrow cell homing was examined by detecting expression levels of male-specific SRY gene in the ischemic female tissues. DHT treatment promoted bone marrow cell homing to ischemic tissue shown by significantly higher SRY expression compared to placebo-treated females as well as reduced apoptotic features in DHT-treated females, including increased Bcl-2 expression, reduced Bax levels and decreased TUNEL staining. In conclusion, the gender-mismatched bone marrow transplant study shows that androgens directly enhance bone marrow cell-mediated vasculogenesis that contributes to ischemia-induced neovascularization. Ivyspring International Publisher.
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Pilowsky, Paul M.Serotonin: The Mediator That Spans Evolution provides a comprehensive review of the widespread roles for serotonin in respiratory, cardiovascular and thermoregulatory control, and for growth and development in early life. This important resource highlights serotonins role in normal (unstressed) conditions, and in response to a variety of physiological stressors. It focuses on new animal models, comparing and contrasting data from mice and rats. In addition, the book compares and contrasts the physiological effects of brain and blood serotonin systems and includes new data suggesting that the influence of serotonin is in part through the regulation of gene expression. Finally, it discusses the role of serotonin system dysfunction in a variety of pathophysiological conditions, including sleep apnea, obesity and hypertension, and presents compelling evidence that this dysfunction is involved in Sudden Infant Death Syndrome (SIDS). 2019 Elsevier Inc. All rights reserved.
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Maclean, Jessica A.A.; Schoenwaelder, Simone M.The discovery of serotonin in platelets in the 1950s heralded a new era of research in the study of blood clot formation. Platelets, which represent the cellular components in the blood responsible for initiating blood clot formation, are responsible for maintaining a low concentration of plasma serotonin by sequestering and storing a remarkable concentration of serotonin. While platelets are vital for regulating circulating serotonin levels in the plasma, serotonin itself is suggested to play a fundamental role in both platelet function and blood clot formation. However, despite many studies, the role for serotonin in thrombus formation is still not completely elucidated. This chapter will explore a brief history of both platelets and serotonin and present a current understanding of the interactions between the two. Here we discuss the vital role of platelets in the regulation of circulating serotonin concentrations, the significant role of serotonin in platelets for the hemostatic and thrombotic responses, and the clinical implications of modulating this process in health and disease. 2019 Elsevier Inc. All rights reserved.
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Pilowsky, Paul M.Receptor distribution: Serotonin (5-HT; 5HT; 5-hydroxytryptamine) is a ligand that achieves an astonishing diversity of actions through its effects on at least 15 different receptors. All but one of the serotonin receptors are G-protein coupled as discussed extensively elsewhere in this book. Activation of some serotonin receptors leads to cell excitation, whereas others cause inhibition. Here, I will assess the role played by serotonergic systems in the rostral ventrolateral medulla, rostroventromedial medulla, and spinal sympathetic cell groups that affect blood pressure. Possible roles in psycho-affective disorders and autonomic functions that are clearly important, but do not affect blood pressure, will only be mentioned parenthetically. For an initial summary of the pharmacology of the 5-HT receptor family, I strongly recommend the Guide to Receptors and Channels, which is published and updated by the British Journal of Pharmacology and in Pharmacological reviews. The section on 5-HT currently lists seven main receptors, but in addition, several of these have subtypes. Some subtypes are present in some species but not others. For example, there are five types of 5HT1x receptor, although some have confusing duplicate names; 5HT1F receptor, 5HT1E? receptor, and 5HT6 receptor are all the same. All five 5HT1 receptors operate Gi/o as their principal transduction system, preventing the formation of cAMP, and are therefore inhibitory. The rest of this chapter will focus on the role of serotonin in the nervous system of the cardiovascular system. 2019 Elsevier Inc. All rights reserved.
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Ju, Lining Arnold; Chen, Yunfeng; Li, Zhenhai; Zhu, ChengOne example demonstrating the significance of studying cell mechanosensing is the platelet-mediated blood clot formation (thrombosis) under shear that causes heart attack and stroke-the No. 1 killer worldwide. As an emerging concept, shear forces generated by the hemodynamic flow disturbances have been shown to promote rapid platelet aggregation, which is usually seen in a narrowing vessel due to a growing thrombus, an atherosclerotic plaque, or an interventional device. Notably, this biomechanical mechanism not only challenges the classic agonist-dependent (biochemical) thrombosis model but also demonstrates resistance to the existing antithrombotic agents. Furthermore, recent studies indicate that this biomechanical platelet aggregation requires the interaction of platelet receptor glycoprotein Ib? (GPIb?) with von Willebrand factor (VWF) in plasma. This chapter will summarize the latest understandings on the platelet mechanosensing principles that center the VWF-GPIb? axis. Clinically, this platelet mechanosensing pathway represents a novel therapeutic target for an anti-thrombotic purpose. 2018 Elsevier Inc. All rights reserved.
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Waterhouse, Anna; Santos, Miguel; Lee, Bob S.L.; Chan, Alex H.P.; Tan, Richard P.; Michael, Praveesuda Lorwattanapongsa; Filipe, Elysse C.; Hung, Juichien; Wise, Steven G.; Bilek, Marcela M.M.This chapter describes a simple measure to address issues in the use of stents, that is, the inherent thrombogenicity of metallic implants, destruction of the protective endothelial cell layer lining arterial walls, chronic inflammation, and the renarrowing of the treated artery (restenosis). Unfortunately, the drugs (taxus and limus family) eluted from drug-eluting stents (DES) to halt restenosis cause endothelial dysfunction and hypersensitivity, contributing to thrombogenic potential. The deposition of biofunctional thin-film coatings, suitable for coronary stents, has been previously demonstrated using plasma-activated coatings (PAC) on various substrates. PAC was designed to overcome many of the thrombogenic properties of metal and DES drugs. Modified tropoelastin, fibronectin, plasmin, and streptokinase, all bound to the stent surface by PAC, have showed promise, as tropoelastin is the major regulator of smooth muscle cell proliferation in vivo, fibronectin encourages endothelial cell regeneration, and plasmin and streptokinase have thrombolytic properties. 2018 Elsevier Ltd. All rights reserved.
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Ju, Lining Arnold; Zhu, Cheng[No abstract available]
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Samson, Andre L.; Alwis, Imala D.; Maclean, Jessica A.A.; Priyananda, Pramith; Hawkett, Brian S.; Schoenwaelder, Simone M.; Jackson, Shaun P.Clot retraction refers to the process whereby activated platelets transduce contractile forces onto the fibrin network of a thrombus, which over time increases clot density and decreases clot size. This process is considered important for promoting clot stability and maintaining blood vessel patency. Insights into the mechanisms regulating clot retraction at sites of vascular injury have been hampered by a paucity of in vivo experimental models. By pairing localized vascular injury with thrombin microinjection in the mesenteric circulation of mice, we have demonstrated that the fibrin network of thrombi progressively compacts over a 2-hour period. This was a genuine retraction process, as treating thrombi with blebbistatin to inhibit myosin IIamediated platelet contractility prevented shrinkage of the fibrin network. Real-time confocal analysis of fibrinolysis after recombinant tissue-type plasminogen activator (tPA) administration revealed that incomplete proteolysis of fibrin polymers markedly facilitated clot retraction. Similarly, inhibiting endogenous fibrinolysis with tranexamic acid reduced retraction of fibrin polymers in vivo. In vitro clot retraction experiments indicated that subthreshold doses of tPA facilitated clot retraction through a plasmin-dependent mechanism. These effects correlated with changes in the elastic modulus of fibrin clots. These findings define the endogenous fibrinolytic system as an important regulator of clot retraction, and show that promoting clot retraction is a novel and complementary means by which fibrinolytic enzymes can reduce thrombus size. 2017 by The American Society of Hematology.
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Chung, Rosanna W.S.; Wang, Zeneng; Bursill, C. A.; Wu, Ben Jing; Barter, Philip J.; Rye, Kerry AnneSphingomyelin (SM) levels in the circulation correlate positively with atherosclerosis burden. SM is a ubiquitous component of human diets, but it is unclear if dietary SM increases circulating SM levels. Dietary choline increases atherosclerosis by raising circulating trimethylamine N-oxide (TMAO) levels in mice and humans. As SM has a choline head group, we ask in this study if dietary SM accelerates atherosclerotic lesion development by increasing circulating SM and TMAO levels. Three studies were performed: (Study 1) C57BL/6 mice were maintained on a high fat diet with or without SM supplementation for 4 weeks prior to quantification of serum TMAO and SM levels; (Study 2) atherosclerosis was studied in apoE-/-mice after 16 weeks of a high fat diet without or with SM supplementation and (Study 3) apoE-/- mice were maintained on a chow diet for 19 weeks without or with SM supplementation and antibiotic treatment prior to quantification of atherosclerotic lesions and serum TMAO and SM levels. SM consumption did not increase circulating SM levels or atherosclerosis in high fat-fed apoE-/- mice. Serum TMAO levels in C57BL/6 mice were low and had no effect atherosclerosis lesion development. Dietary SM supplementation significantly reduced atherosclerotic lesion area in the aortic arch of chow-fed apoE-/- mice. This study establishes that dietary SM does not affect circulating SM levels or increase atherosclerosis in high fat-fed apoE-/- mice, but it is anti-atherogenic in chow-fed apoE-/- mice. 2017 Chung et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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OSullivan, John F.; Morningstar, Jordan E.; Yang, Qiong; Zheng, Baohui; Gao, Yan; Jeanfavre, Sarah T.; Scott, Justin M.; Fernandez, Cine; Zheng, Hui; OConnor, Sean; Cohen, Paul; Ramachandran, Vasan S.; Long, Michelle T.; Wilson, James G.; Melander, Olle; Wang, Thomas J.; Fox, Caroline S.; Peterson, Randall T.; Clish, Clary B.; Corey, Kathleen E.; Gerszten, Robert E.Unbiased, nontargeted metabolite profiling techniques hold considerable promise for biomarker and pathway discovery, in spite of the lack of successful applications to human disease. By integrating nontargeted metabolomics, genetics, and detailed human phenotyping, we identified dimethylguanidino valeric acid (DMGV) as an independent biomarker of CT-defined nonalcoholic fatty liver disease (NAFLD) in the offspring cohort of the Framingham Heart Study (FHS) participants. We verified the relationship between DMGV and early hepatic pathology. Specifically, plasma DMGV levels were correlated with biopsy-proven nonalcoholic steatohepatitis (NASH) in a hospital cohort of individuals undergoing gastric bypass surgery, and DMGV levels fell in parallel with improvements in post-procedure cardiometabolic parameters. Further, baseline DMGV levels independently predicted future diabetes up to 12 years before disease onset in 3 distinct human cohorts. Finally, we provide all metabolite peak data consisting of known and unidentified peaks, genetics, and key metabolic parameters as a publicly available resource for investigations in cardiometabolic diseases.
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Anzovino, Amy; Chiang, Shannon; Brown, Bronwyn E.; Hawkins, Clare L.; Richardson, Des Raymond; Huang, Michael L.H.Nuclear factorerythroid 2related factor-2 (Nrf2) is a master regulator of the antioxidant response. However, studies in models of Friedreich ataxia, a neurodegenerative and cardiodegenerative disease associated with oxidative stress, reported decreased Nrf2 expression attributable to unknown mechanisms. Using a mouse conditional frataxin knockout (KO) model in the heart and skeletal muscle, we examined the Nrf2 pathway in these tissues. Frataxin KO results in fatal cardiomyopathy, whereas skeletal muscle was asymptomatic. In the KO heart, protein oxidation and a decreased glutathione/oxidized glutathione ratio were observed, but the opposite was found in skeletal muscle. Decreased total and nuclear Nrf2 and increased levels of its inhibitor, Kelch-like ECH-associated protein 1, were evident in the KO heart, but not in skeletal muscle. Moreover, a mechanism involving activation of the nuclear Nrf2 export/degradation machinery via glycogen synthase kinase-3? (Gsk3?) signaling was demonstrated in the KO heart. This process involved the following: i) increased Gsk3? activation, ii) ?-transducin repeat containing E3 ubiquitin protein ligase nuclear accumulation, and iii) Fyn phosphorylation. A corresponding decrease in Nrf2-DNAbinding activity and a general decrease in Nrf2-target mRNA were observed in KO hearts. Paradoxically, protein levels of some Nrf2 antioxidant targets were significantly increased in KO mice. Collectively, cardiac frataxin deficiency reduces Nrf2 levels via two potential mechanisms: increased levels of cytosolic Kelch-like ECH-associated protein 1 and activation of Gsk3? signaling, which decreases nuclear Nrf2. These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not decreased. 2017 American Society for Investigative Pathology
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Freedman, Ben Ben; Boriani, Giuseppe; Glotzer, Taya V.; Healey, Jeff S.; Kirchhof, Paulus F.; Potpara, Tatjana S.Cardiac implanted electronic devices (CIEDs), including pacemakers and implantable defibrillators that perform atrial sensing typically using an atrial electrode, frequently detect subclinical atrial high-rate episodes (AHREs). When the intracardiac electrograms are carefully examined, the majority of AHREs are atrial fibrillation (AF) or other atrial tachyarrhythmias, which have been shown to be associated with both an increased risk of stroke, and subsequent development of clinical AF. However, the absolute risk of stroke among patients with AHREs is less than might be expected for clinically diagnosed paroxysmal AF. In addition, a close temporal relationship between AHREs and stroke is seen in only 15% of strokes in patients with a CIED: The majority have either no AHREs before the stroke, or AHREs very distant from incident stroke, suggesting that AHREs might be more of a risk marker than a risk factor for stroke. Management of AHREs should not be the same as for clinical AF, and a degree of uncertainty underpins the rationale for much-needed, ongoing, randomized trials of oral anticoagulation in patients with CIED-detected AHREs. We propose a management algorithm that takes into account both the stroke risk and the AHRE burden, but highlights the current uncertainty and evidence gaps for this condition. 2017 Macmillan Publisher Limited, part of Springer Natur.
