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Showing 801–820 of 2058 publications.
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Indja, Ben Elias; Seco, Michael; Seamark, Richard W.; Kaplan, Jason M.; Bannon, Paul Gerard; Grieve, Stuart M.; Vallely, Michael P.Neurocognitive and psychiatric complications are common following cardiac surgery and impact on patient quality of life, recovery from surgery, participation in rehabilitation and long-term mortality. Postoperative cognitive decline, depressive disorders, post-traumatic stress disorder and neurocognitive impairment related to silent brain infarcts have all been linked to the perioperative period of cardiac surgery, and potentially have serious consequences. The accurate assessment of these conditions, particularly in determining the aetiology, and impact on patients is difficult due to the poorly recognised nature of these complications as well as similarities in presentation with postoperative delirium. This review aims to summarise current understanding surrounding psychiatric disturbances following cardiac surgery including the impact on patient quality of life and long-term outcomes. 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)
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Freedman, Ben BenApproximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country- and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.
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Bhandare, Amol M.; Kapoor, Komal; Powell, Kim L.; Braine, Emma L.; Casilla-Espinosa, Pablo Miguel; OBrien, Terence J.; Farnham, M. M. J.; Pilowsky, Paul M.The incidence of sudden unexpected death in epilepsy (SUDEP) is highest in people with chronic and drug-resistant epilepsy. Chronic spontaneous recurrent seizures cause cardiorespiratory autonomic dysfunctions. Pituitary adenylate cyclase-activating polypeptide (PACAP) is neuroprotective, whereas microglia produce both pro- and anti-inflammatory effects in the CNS. During acute seizures in rats, PACAP and microglia produce sympathoprotective effect at the intermediolateral cell column (IML), whereas their action on the presympathetic rostral ventrolateral medulla (RVLM) neurons mediates proarrhythmogenic changes. We evaluated the effect of PACAP and microglia at the IML on sympathetic nerve activity (SNA), cardiovascular reflex responses, and electrocardiographic changes in the post-status epilepticus (SE) model of acquired epilepsy, and control rats. Chronic spontaneous seizures in rats produced tachycardia with profound proarrhythmogenic effects (prolongation of QT interval). Antagonism of microglia, but not PACAP, significantly reduced the SNA and the corrected QT interval in post-SE rats. PACAP and microglia antagonists did not change baroreflex and peripheral or central chemoreflex responses with varied effect on somatosympathetic responses in post-SE and control rats. We did not notice changes in microglial morphology or changes in a number of M2 phenotype in epileptic nor control rats in the vicinity of RVLM neurons. Our findings establish that microglial activation, and not PACAP, at the IML accounts for higher SNA and proarrhythmogenic changes during chronic epilepsy in rats. This is the first experimental evidence to support a neurotoxic effect of microglia during chronic epilepsy, in contrast to their neuroprotective action during acute seizures. 2017 IBRO
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Bagdade, John D.; Barter, Philip J.; Quiroga, Carmen; Alaupovic, PierreIn the ILLUMINATE Trial, treatment with the cholesteryl ester transfer protein inhibitor torcetrapib resulted in a significant increase in both atherosclerotic cardiovascular disease events and total mortality which was not explained by changes in the routinely measured plasma lipids. To determine whether alterations in lipoproteins defined by their apoprotein content that are not estimated with conventional laboratory methods contributed to these unexpected events, we measured the apoB- and apoA-containing subclasses in a subgroup of ILLUMINATE participants. We find that torcetrapib treatment significantly increasedthe high-density lipoprotein subclasses LpA-I and LpA-I:A-II equally (p <0.0001) and the apoC-III content of high-density lipoprotein (p <0.001) without altering theapoB-containing subclasses. In conclusion, these findings provide further evidence thatthe untoward effects of torcetrapib were attributable to off-target effects and not related to disturbances in lipoprotein transport. 2017 Elsevier Inc.
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Gray, Belinda R.; Kirby, Adrienne C.; Kabunga, Peter; Freedman, Ben Ben; Yeates, Laura; Kanthan, Ajita; Medi, Caroline; Keech, Anthony C.; Semsarian, Christopher; Sy, Raymond W.Background Patients with Brugada syndrome (BrS) are diagnosed and risk stratified on the basis of a spontaneous or drug-induced type 1 electrocardiographic (ECG) pattern, often at single time points not accounting for variation throughout the day. Objectives The purpose of this study was to prospectively assess the overall burden of type 1 Brugada ECG changes using 12-lead 24-hour Holter monitoring and evaluate association with cardiac events. Methods From July 1, 2013 to December 31, 2015, patients with BrS were recruited from 3 Australian centers and the Australian Genetic Heart Disease Registry. All patients underwent clinical review, baseline ECG, and 12-lead 24-hour Holter assessment with precordial leads placed in the left and right second, third, and fourth intercostal spaces. The frequency, temporal, and spatial burden of type 1 BrS ECG pattern were analyzed and assessed for association with cardiac events. Results A total of 54 patients with BrS were recruited (n=44, 81% men; mean age 44 13 years); the mean follow-up was 2.3 2.5 years. Eleven of 32 patients (34%) initially classified as drug-induced BrS demonstrated a spontaneous type 1 pattern at least once over 24 hours. Patients with cardiac events had a significantly higher temporal burden of type 1 ST-segment elevation in the 24-hour monitoring period (total area under the curve 21% vs 15%; P =.008), being most pronounced between the hours of 1600 and 2400 (P =.027). Conclusion Patients with BrS traditionally classified as drug-induced can exhibit spontaneous ECG changes with longer-term monitoring, particularly in the evening. Temporal burden on 12-lead Holter monitor was associated with cardiac events. Ambulatory 12-lead ECG monitoring may have potential utility in the diagnosis and risk stratification of patients with BrS. 2017 Heart Rhythm Society
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McRobb, Lucinda S.; McGrath, Kristine C.Y.; Tsatralis, Tania; Liong, Eleanore C.; Tan, Joanne Tsui Ming; Hughes, Gillian; Handelsman, David J.; Heather, Alison KayObjective-Vascular calcification is associated with increased risk of myocardial infarction and stroke. The objective of this work was to examine the ability of 17?-estradiol (E2) to stimulate calcification of vascular smooth muscle cells (VSMC) in vivo, using aged apolipoprotein E-null mice with advanced atherosclerotic lesions, and subsequently to explore underlying mechanisms in vitro. Approach and Results-Silastic E2 capsules were implanted into male and female apolipoprotein E-null mice aged 34 weeks. Plaque and calcified area were measured in the aortic sinus and innominate artery after 8 weeks. Immunohistochemical analysis examined expression of the estrogen receptors (estrogen receptor alpha and estrogen receptor beta [ER?]). VSMC expression of osteogenic markers was examined using digital polymerase chain reaction. Advanced atherosclerotic lesions were present in all mice at the end of 8 weeks. In both male and female mice, E2 increased calcified area in a site-specific manner in the aortic sinus independently of plaque growth or lipid levels and occurred in association with a site-specific decrease in the proportion of ER?-positive intimal cells. Calcified lesions expressed collagen I and bone sialoprotein, with decreased matrix Gla protein. In vitro, E2 suppressed ER? expression and increased VSMC mineralization, demonstrating increased collagen I and II, osteocalcin and bone sialoprotein, and reduced matrix Gla protein and osteopontin. Antagonism or RNA silencing of estrogen receptor alpha, ER?, or both further increased VSMC mineralization. Conclusions-We have demonstrated that E2 can drive calcification in advanced atherosclerotic lesions by promoting the differentiation of VSMC to osteoblast-like cells, a process which is augmented by inhibition of estrogen receptor alpha or ER? activity. 2017 American Heart Association, Inc.
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Sherrah, Andrew G.; Callaghan, Fraser Maurice; Puranik, Rajesh; Jeremy, Richmond William; Bannon, Paul Gerard; Vallely, Michael P.; Grieve, Stuart M.Background: Chronic descending thoracic aortic dissection (CDTAD) following surgical repair of ascending aortic dissection requires long-term imaging surveillance. We investigated four-dimensional (4D)-flow magnetic resonance imaging (MRI) with a novel multi-velocity encoding (multi-VENC) technique as an emerging clinical method enabling the dynamic quantification of blood volume and velocity throughout the cardiac cycle. Methods: Patients with CDTAD (n = 10; mean age, 55.1 years; standard deviation (SD) 10.8) and healthy volunteers (n = 9; mean age, 37.1 years; SD 11.4; p < 0.01) underwent 3T MRI, and standard views and 4D-flow data were obtained. Flow measurements were made in selected regions of interest within the ascending and descending thoracic aorta. Results: The overall flow profile at peak systole was reduced in the false lumen (FL) compared with the true lumen (TL) and normal aortas (p < 0.05 for velocity < 0.4 m/s). Peak systolic flow rate per aortic lumen area (mL/s/cm 2) was lower in the FL than in the TL (p < 0.05), and both rates were lower than that of control aortas (p < 0.05). Blood flow reversal was higher in the FL than in the TL throughout the descending aorta in CDTAD patients (p < 0.05). A derived pulsatility index was elevated in the TL compared with that in the FL in CDTAD patients. Generated pathline images demonstrated flow patterns in detail, including sites of communication between the true and FL. Conclusions: 4D-flow MRI revealed FL blood flow and reduced blood flow velocity and flow rate in the TL of CDTAD patients compared with normal aortas of healthy participants. Thus, multi-VENC 4D-flow MRI could serve as an adjunct in the long-term assessment of CDTAD following surgical repair of ascending aortic dissection. 2017 GeorgThieme. All rights reserved.
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Simons, Leon A.; Ortiz, M.; Freedman, Ben Ben; Waterhouse, Benjamin J.; Colquhoun, David M.Objective: Long-term anticoagulant therapy with non-valvular atrial fibrillation (AF) is essential to prevent thromboembolic complications, especially ischemic stroke. This study examines medium-term persistence in AF patients using a non-vitamin-K antagonist oral anticoagulant drug (NOAC). Research design and methods: We assessed national Pharmaceutical Benefit Scheme records December 2013 through September 2016 for initial prescription of a NOAC in a 10% random sample of concessional patients. Key outcome measures were: (a) proportions filling first repeat prescription, (b) proportions persisting with NOAC over 12 and 30 months and (c) proportions switching to another NOAC or warfarin. Results: A total of 8656 patients with AF initiated a NOAC (3352 apixaban, 1340 dabigatran, 3964 rivaroxaban). Mean age was 77 years, 53% male; 91% collected the first repeat prescription for any NOAC, 70% and 57% collected any NOAC or subsequent warfarin prescription over 12 months and 30 months respectively; 8.9% had switched to warfarin. The proportions switching from apixaban, dabigatran and rivaroxaban to a different NOAC were 14%, 31% and 17% respectively. In a regression model adjusting for age, gender and comorbidity, apixaban-initiated patients over 30 months were 28% more likely to persist with any anticoagulant therapy compared with dabigatran-initiated patients (hazard ratio [95% CI] 1.28 [1.161.42]) and 15% more likely to persist compared with rivaroxaban-initiated (1.15 [1.061.24]). Rivaroxaban-initiated patients were 12% more likely to persist compared with dabigatran-initiated patients (1.12 [1.021.24]). Conclusions: Long-term persistence with anticoagulation in patients with AF remains a concern, even with NOACs. Patients initiated to apixaban appear to experience better medium-term persistence compared with rivaroxaban or dabigatran. 2017 Informa UK Limited, trading as Taylor & Francis Group.
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Kondyurina, Irina V.; Wise, Steven G.; Ngo, Alan K.Y.; Filipe, Elysse C.; Kondyurin, Alexey V.; Weiss, Anthony Steven; Bao, Shishan San; Bilek, Marcela M.M.Polyurethanes are a diverse class of polymers, with independently tunable mechanical and biodegradation properties making them a versatile platform material for biomedical implants. Previous iterations have failed to adequately embody appropriate mechanical and biological properties, particularly for vascular medicine where strength, compliance and multifaceted biocompatibility are required. We have synthesized a new polyurethane formulation with finely tuned mechanical properties, combining high strength and extensibility with a low Young's modulus. Additional cross-linking during synthesis enhanced stability and limits leaching. Under cyclic testing, hysteresis was minimal following completion of the initial cycles, indicating the robustness of the material. Building on this platform, we used plasma immersion ion implantation to activate the polymer surface and functionalized it with recombinant human tropoelastin. With tropoelastin covalently bound to the surface, human coronary endothelial cells showed improved attachment and proliferation. In the presence of heparinized whole blood, tropoelastin-coated polyurethane showed very low thrombogenicity in both static and flow conditions. Using this formulation, we synthesized robust, elastic prototype conduits which easily retained multiple sutures and were successfully implanted in a pilot rat aortic interposition model. We have thus created an elastic, strong biomaterial platform, functionalized with an important regulator of vascular biology, with the potential for further evaluation as a new synthetic graft material. 2017 IOP Publishing Ltd.
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Grieve, Stuart M.; Maller, Jerome Joseph[No abstract available]
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Leslie, Daniel C.; Waterhouse, Anna; Ingber, Donald E.[No abstract available]
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Carroll, Luke; Pattison, David I.; Fu, Shanlin; Schiesser, Cart H.; Davies, Michael J.; Hawkins, Clare L.Myeloperoxidase produces strong oxidants during the immune response to destroy invading pathogens. However, these oxidants can also cause tissue damage, which contributes to the development of numerous inflammatory diseases. Selenium containing compounds, including selenomethionine (SeMet) and 1,4-anhydro-5-seleno-D-talitol (SeTal), react rapidly with different MPO-derived oxidants to form the respective selenoxides (SeMetO and SeTalO). This study investigates the susceptibility of these selenoxides to undergo reduction back to the parent compounds by intracellular reducing systems, including glutathione (GSH) and the glutathione reductase and thioredoxin reductase systems. GSH is shown to reduce SeMetO and SeTalO, with consequent formation of GSSG with apparent second order rate constants, k<inf>2</inf>, in the range 103104M?1s?1. Glutathione reductase reduces both SeMetO and SeTalO at the expense of NADPH via formation of GSSG, whereas thioredoxin reductase acts only on SeMetO. The presence of SeMet and SeTal also increased the rate at which NADPH was consumed by the glutathione reductase system in the presence of N-chloramines. In contrast, the presence of SeMet and SeTal reduced the rate of NADPH consumption by the thioredoxin reductase system after addition of N-chloramines, consistent with the rapid formation of selenoxides, but only slow reduction by thioredoxin reductase. These results support a potential role of seleno compounds to act as catalytic scavengers of MPO-derived oxidants, particularly in the presence of glutathione reductase and NADPH, assuming that sufficient plasma levels of the parent selenoether can be achieved in vivo following supplementation. 2017
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Brazilek, Rose J.; Tovar-Lez, Francisco Javier; Wong, Angus K.T.; Tran, Huyen Anh M.; Davis, Amanda S.; McFadyen, James D.; Kaplan, Zane S.; Chunilal, Sanjeev Daya; Jackson, Shaun P.; Nandurkar, Harshal H.; Mitchell, Arnan A.; Nesbitt, Warwick S.Von Willebrand's disease (VWD) is the most common inherited bleeding disorder caused by either quantitative or qualitative defects of von Willebrand factor (VWF). Current tests for VWD require relatively large blood volumes, have low throughput, are time-consuming, and do not incorporate the physiologically relevant effects of haemodynamic forces. We developed a microfluidic device incorporating micro-contractions that harnesses well-defined haemodynamic strain gradients to initiate platelet aggregation in citrated whole blood. The microchannel architecture has been specifically designed to allow for continuous real-time imaging of platelet aggregation dynamics. Subjects aged ?18 years with previously diagnosed VWD or who presented for evaluation of a bleeding disorder, where the possible diagnosis included VWD, were tested. Samples were obtained for device characterization as well as for pathology-based testing. Platelet aggregation in the microfluidic device is independent of platelet amplification loops but dependent on low-level platelet activation, GPIb/IX/V and integrin ?<inf>IIb</inf>?<inf>3</inf> engagement. Microfluidic output directly correlates with VWF antigen levels and is able to sensitively detect aggregation defects associated with VWD subtypes. Testing demonstrated a strong correlation with standard clinical laboratory-based tests. Head-to-head comparison with PFA100 demonstrated equivalent, if not improved, sensitivity for screening aggregation defects associated with VWD. This strain rate gradient microfluidic prototype has the potential to be a clinically useful, rapid and high throughput-screening tool for VWD as well as other strain-dependent platelet disorders. In addition, the microfluidic device represents a novel approach to examine the effects of high magnitude/short duration (ms) strain rate gradients on platelet function. 2017 The Royal Society of Chemistry.
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O'Neill, Edward S.; Kaur, Amandeep; Bishop, David P.; Shishmarev, Dmitry; Khel, Philip W.; Grieve, Stuart M.; Figtree, Gemma A.; Renfrew, Anna K.; Bonnitcha, Paul D.; New, Elizabeth J.Dense tumors are resistant to conventional chemotherapies due to the unique tumor microenvironment characterized by hypoxic regions that promote cellular dormancy. Bioreductive drugs that are activated in response to this hypoxic environment are an attractive strategy for therapy with anticipated lower harmful side effects in normoxic healthy tissue. Cobalt bioreductive pro-drugs that selectively release toxic payloads upon reduction in hypoxic cells have shown great promise as anticancer agents. However, the bioreductive response in the tumor microenvironment must be better understood, as current techniques for monitoring bioreduction to Co(II) such as X-ray absorption near-edge structure and extended X-ray absorption fine structure provide limited information on speciation and require synchrotron radiation sources. Here, we present magnetic resonance imaging (MRI) as an accessible and powerful technique to monitor bioreduction by treating the cobalt complex as an MRI contrast agent and monitoring the change in water signal induced by reduction from diamagnetic Co(III) to paramagnetic Co(II). Cobalt pro-drugs built upon the tris(2-pyridylmethyl)amine ligand scaffold with varying charge were investigated for distribution and activity in a 3D tumor spheroid model by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and MRI. In addition, paramagnetic 1H NMR spectroscopy of spheroids enabled determination of the speciation of activated Co(II)TPAx complexes. This study demonstrates the utility of MRI and associated spectroscopy techniques for understanding bioreductive cobalt pro-drugs in the tumor microenvironment and has broader implications for monitoring paramagnetic metal-based therapies. 2017 American Chemical Society.
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Neubeck, Lis; Orchard, Jessica Joan; Lowres, Nicole; Freedman, Ben BenAtrial fibrillation (AF) is the most common cardiac arrhythmia, with a lifetime risk of one in four of developing AF over the age of 40 years. Around 40% of patients are asymptomatic, which is of concern as AF is a major risk factor for stroke. Early detection and appropriate management reduces stroke risk by two-thirds. Atrial fibrillation screening is now recommended in international guidelines, but there are some common arguments against screening. Overall, to be of value any screening program must fulfil the World Health Organization (WHO) Wilson and Jungner criteria for screening programs. In this paper we address the common arguments, and determine if AF screening fulfils the WHO criteria. 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)
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Chami, Belal; Jeong, Gloria; Varda, Adrina; Maw, Aung Min; Kim, Hyunbo; Fong, Genevieve M.; Simone, Martin; Rayner, Benjamin Saul; Wang, Xiaosuo; Dennis, Joanne Marie; Witting, Paul KennethAfter acute myocardial infarction (AMI), neutrophils are recruited to the affected myocardium. Hypochlorous acid (HOCl) produced by neutrophil myeloperoxidase (MPO) damages cardiomyocytes and potentially expands the primary infarct. Rat cardiomyocyte-like cells were incubated with isolated human neutrophils treated with chemical activators in the absence or presence of nitroxide 4-methoxy-Tempo (MetT; 25 ?M) for 4, 6 or 24 h; studies with reagent HOCl served as positive control. Treating cardiomyocytes with activated neutrophils or reagent HOCl resulted in a marked increase in protein tyrosine chlorination and a decline in protein tyrosine phosphatase (PTP) activity. On balance our data also supported an increase in phosphorylation of MAPK p38 and ERK1/2 suggestive of an intracellular hyperphosphorylation status and this was accompanied by decreases in cell viability, as judged by assessing caspases-3/7 activity. For cells exposed to activated neutrophils receptor-mediated uptake of transferrin decreased although total matrix metalloproteinase (MMP) activity was unaffected. Addition of MetT ameliorated protein tyrosine chlorination, decreased MAPK activity and restored receptor-mediated transferrin uptake and PTP activity in cardiomyocytes. Overall, adverse effects of neutrophil-derived HOCl on cultured cardiomyocytes were ameliorated by MetT suggesting that nitroxides may be beneficial to inflammatory pathologies, where neutrophil recruitment/activation is a prominent and early feature. 2017
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Cholan, Pradeep Manuneedhi; Cartland, Si; Kavurma, Mary M.Peripheral artery disease (PAD) is caused by narrowing of arteries in the limbs, normally occurring in the lower extremities, with severe cases resulting in amputation of the foot or leg. A potential approach for treatment is to stimulate the formation of new blood vessels to restore blood flow to limb tissues. This is a process called angiogenesis and involves the proliferation, migration, and differentiation of endothelial cells. Angiogenesis can be stimulated by reactive oxygen species (ROS), with NADPH oxidases (NOX) being a major source of ROS in endothelial cells. This review summarizes the recent evidence implicating NOX isoforms in their ability to regulate angiogenesis in vascular endothelial cells in vitro, and in PAD in vivo. Increasing our understanding of the involvement of the NOX isoforms in promoting therapeutic angiogenesis may lead to new treatment options to slow or reverse PAD. 2017 by the authors. Licensee MDPI, Basel, Switzerland.
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Yao, Yimin; Hildreth, Cara M.; Li, Sheran; Boyd, Rochelle A.; Kouchaki, Zahra; Butlin, Mark; Avolio, Alberto P.; Pilowsky, Paul M.; Phillips, Jacqueline K.Renal denervation is a novel device based therapy promoted to reduce high blood pressure. We examined the impact of renal denervation on systolic blood pressure, renal function, and arterial stiffness in the Lewis Polycystic Kidney disease (LPK) rodent model of kidney disease. Animals were subjected to bilateral renal denervation or sham surgeries at age 6 and 12 weeks. Systolic blood pressure was monitored by tail-cuff plethysmography and renal function by urinalysis and creatinine clearance. At age 16 weeks, beat-to-beat aortic pulse wave velocity as a functional indicator of arterial stiffness was determined. Renal denervation produced an overall reduction in blood pressure in the LPK [(denervated 1644 vs. sham-operated 1806 mmHg, n = 6 per group, P=0.003)] and delayed, but did not prevent, the decline in renal function. Aortic pulse wave velocity was markedly elevated in the LPK compared with Lewis and was not altered by renal denervation in the LPK however a reduction was seen in the control Lewis animals. These results support the hypothesis that renal nerves contribute to secondary hypertension in conditions such as kidney disease. 2017 IEEE.
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Murphy, Nicholas J.; Eyles, Jillian Peta; Bennell, Kim L.; Bohensky, Megan A.; Burns, Alexander W.R.; Callaghan, Fraser Maurice; Dickenson, Edward J.; Fary, Camdon J.; Grieve, Stuart M.; Griffin, Damian R.; Hall, Michelle; Hobson, Rachel; Kim, Young-jo; Linklater, James M.; Lloyd, David G.; Molnar, Robert B.; O'Connell, Rachel L.; O'Donnell, John M.; O'Sullivan, Michael D.; Randhawa, Sunny; Reichenbach, Stephan; Saxby, David John; Singh, Parminder J.; Spiers, Libby N.; Tran, Phong; Wrigley, Tim V.; Hunter, David JohnBackground: Femoroacetabular impingement syndrome (FAI), a hip disorder affecting active young adults, is believed to be a leading cause of hip osteoarthritis (OA). Current management approaches for FAI include arthroscopic hip surgery and physiotherapy-led non-surgical care; however, there is a paucity of clinical trial evidence comparing these approaches. In particular, it is unknown whether these management approaches modify the future risk of developing hip OA. The primary objective of this randomised controlled trial is to determine if participants with FAI who undergo hip arthroscopy have greater improvements in hip cartilage health, as demonstrated by changes in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to those who undergo physiotherapy-led non-surgical management. Methods: This is a pragmatic, multi-centre, two-arm superiority randomised controlled trial comparing hip arthroscopy to physiotherapy-led management for FAI. A total of 140 participants with FAI will be recruited from the clinics of participating orthopaedic surgeons, and randomly allocated to receive either surgery or physiotherapy-led non-surgical care. The surgical intervention involves arthroscopic FAI surgery from one of eight orthopaedic surgeons specialising in this field, located in three different Australian cities. The physiotherapy-led non-surgical management is an individualised physiotherapy program, named Personalised Hip Therapy (PHT), developed by a panel to represent the best non-operative care for FAI. It entails at least six individual physiotherapy sessions over 12 weeks, and up to ten sessions over six months, provided by experienced musculoskeletal physiotherapists trained to deliver the PHT program. The primary outcome measure is the change in dGEMRIC score of a ROI containing both acetabular and femoral head cartilages at the chondrolabral transitional zone of the mid-sagittal plane between baseline and 12 months. Secondary outcomes include patient-reported outcomes and several structural and biomechanical measures relevant to the pathogenesis of FAI and development of hip OA. Interventions will be compared by intention-to-treat analysis. Discussion: The findings will help determine whether hip arthroscopy or an individualised physiotherapy program is superior for the management of FAI, including for the prevention of hip OA. Trial registration: Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549. Trial registered 2/11/2015 (retrospectively registered). 2017 The Author(s).
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Yuan, Yuping; Alwis, Imala D.; Wu, Mike C.L.; Kaplan, Zane S.; Ashworth, Katrina J.; Bark, David L.; Pham, Alan; McFadyen, James D.; Schoenwaelder, Simone M.; Josefsson, Emma C.; Kile, Benjamin T.; Jackson, Shaun P.Gut ischemia is common in critically ill patients, promoting thrombosis and inflammation in distant organs. The mechanisms linking hemodynamic changes in the gut to remote organ thrombosis remain ill defined. We demonstrate that gut ischemia in the mouse induces a distinct pulmonary thrombotic disorder triggered by neutrophil macroaggregates. These neutrophil aggregates lead to widespread occlusion of pulmonary arteries, veins, and the microvasculature. A similar pulmonary neutrophil-rich thrombotic response occurred in humans with the acute respiratory distress syndrome. Intravital microscopy during gut ischemia-reperfusion injury revealed that rolling neutrophils extract large membrane fragments from remnant dying platelets in multiple organs. These platelet fragments bridge adjacent neutrophils to facilitate macroaggregation. Platelet-specific deletion of cyclophilin D, mitochondrial regulator of cell necrosis, prevented neutrophil macroaggregation and pulmonary thrombosis. Our studies demonstrate the existence of a distinct pulmonary thrombotic disorder triggered by dying platelets and neutrophil macroaggregates. Therapeutic targeting of platelet death pathways may reduce pulmonary thrombosis in critically ill patients 2017 The Authors, some rights reserve.
