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Showing 601–620 of 2058 publications.
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Seimon, Radhika V.; Wild-Taylor, Anthony L.; Keating, Shelley E.; McClintock, Sally; Harper, Claudia; Gibson, A. A.; Johnson, Nathan A.; Fernando, Hamish Alexander; Markovic, Tania P.; Center, J. R.; Franklin, Janet L.; Liu, Peter Y.; Grieve, Stuart M.; Lagopoulos, Jim; Caterson, Ian Douglas; Byrne, Nuala M.; Sainsbury, Amanda J.Importance: Severely energy-restricted diets are the most effective dietary obesity treatment. However, there are concerns regarding potential adverse effects on body composition. Objective: To compare the long-Term effects of weight loss via severe vs moderate energy restriction on lean mass and other aspects of body composition. Design, Setting, and Participants: The Type of Energy Manipulation for Promoting Optimum Metabolic Health and Body Composition in Obesity (TEMPO) Diet Trial was a 12-month, single-center, randomized clinical trial. A total of 101 postmenopausal women, aged 45 to 65 years with body mass index (calculated as weight in kilograms divided by height in meters squared) from 30 to 40, who were at least 5 years after menopause, had fewer than 3 hours of structured physical activity per week, and lived in the Sydney metropolitan area of New South Wales, Australia, were recruited between March 2013 and July 2016. Data analysis was conducted between October 2018 and August 2019. Intervention: Participants were randomized to either 12 months of moderate (25%-35%) energy restriction with a food-based diet (moderate intervention) or 4 months of severe (65%-75%) energy restriction with a total meal replacement diet followed by moderate energy restriction for an additional 8 months (severe intervention). Both interventions had a prescribed protein intake of 1.0 g/kg of actual body weight per day, and physical activity was encouraged but not supervised. Main Outcomes and Measures: The primary outcome was whole-body lean mass at 12 months after commencement of intervention. Secondary outcomes were body weight, thigh muscle area and muscle function (strength), bone mineral density, and fat mass and distribution, measured at 0, 4, 6, and 12 months. Results: A total of 101 postmenopausal women were recruited (mean [SD] age, 58.0 [4.2] years; mean [SD] weight, 90.8 [9.1] kg; mean [SD] body mass index, 34.4 [2.5]). Compared with the moderate group at 12 months, the severe group lost more weight (effect size,-6.6 kg; 95% CI,-8.2 to-5.1 kg), lost more whole-body lean mass (effect size,-1.2 kg; 95% CI,-2.0 to-0.4 kg), and lost more thigh muscle area (effect size,-4.2 cm2; 95% CI,-6.5 to-1.9 cm2). However, decreases in whole-body lean mass and thigh muscle area were proportional to total weight loss, and there was no difference in muscle (handgrip) strength between groups. Total hip bone mineral density (effect size,-0.017 g/cm2; 95% CI,-0.029 to-0.005 g/cm2), whole-body fat mass (effect size,-5.5 kg; 95% CI,-7.1 to-3.9 kg), abdominal subcutaneous adipose tissue (effect size,-1890 cm3; 95% CI,-2560 to-1219 cm3), and visceral adipose tissue (effect size,-1389 cm3; 95% CI,-1748 to-1030 cm3) loss were also greater for the severe group than for the moderate group at 12 months. Conclusions and Relevance: Severe energy restriction had no greater adverse effect on relative whole-body lean mass or handgrip strength compared with moderate energy restriction and was associated with 2-fold greater weight and fat loss over 12 months. However, there was significantly greater loss of total hip bone mineral density with severe vs moderate energy restriction. Therefore, caution is necessary when implementing severe energy restriction in postmenopausal women, particularly those with osteopenia or osteoporosis. Trial Registration: Anzctr.org.au Identifier: 12612000651886. 2019 Georg Thieme Verlag. All rights reserved.
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Farnham, M. M. J.; Tallapragada, Vikram J.; OConnor, Edward T.; Nedoboy, Polina E.; Dempsey, Bowen; Mohammed, Suja; Fong, Angelina Y.; Lung, Mandy Siu Yu; Derakhshan, Fatemeh N.; Wilson, Richard J.A.; Pilowsky, Paul M.Repetitive hypoxia is a key feature of obstructive sleep apnoea (OSA), a condition characterized by intermittent airways obstruction. Patients with OSA present with persistent increases in sympathetic activity and commonly develop hypertension. The objectives of this study were to determine if the persistent increases in sympathetic nerve activity, known to be induced by acute intermittent hypoxia (AIH), are mediated through activation of the pituitary adenylate cyclase activating polypeptide (PACAP) signaling system. Here, we show that the excitatory neuropeptide PACAP, acting in the spinal cord, is important for generating the sympathetic response seen following AIH. Using PACAP receptor knockout mice, and pharmacological agents in Sprague Dawley rats, we measured blood pressure, heart rate, pH, PaCO<inf>2</inf>, and splanchnic sympathetic nerve activity, under anaesthesia, to demonstrate that the sympathetic response to AIH is mediated via the PAC1 receptor, in a cAMP-dependent manner. We also report that both intermittent microinjection of glutamate into the rostroventrolateral medulla (RVLM) and intermittent infusion of a sub-threshold dose of PACAP into the subarachnoid space can mimic the sympathetic response to AIH. All the sympathetic responses are independent of blood pressure, pH or PaCO<inf>2</inf> changes. Our results show that in AIH, PACAP signaling in the spinal cord helps drive persistent increases in sympathetic nerve activity. This mechanism may be a precursor to the development of hypertension in conditions of chronic intermittent hypoxia, such as OSA. Copyright 2019 Farnham, Tallapragada, OConnor, Nedoboy, Dempsey, Mohammed, Fong, Lung, Derakhshan, Wilson and Pilowsky.
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Shanmugalingam, Renuka; Wang, Xiaosuo; Muench, Gerald W.; Fulcher, Ian; Lee, Gaksoo; Chau, Katrina; Xu, Bei; Kumar, Roshika; Hennessy, Annemarie; Makris, AngelaBackground: The benefit of aspirin in preventing preeclampsia is well established; however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing, and preparation of aspirin. Objective: We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid, in pregnant women and nonpregnant women, and to examine the effect of dose (100 mg vs 150 mg), preparation (enteric coated vs non?enteric-coated), and chronotherapy of aspirin (morning vs evening) between the 2 groups. Materials and Methods: Twelve high-risk pregnant women and 3 nonpregnant women were enrolled in this study. Pregnant women were in 1 of 4 groups (100 mg enteric coated, 100 mg non?enteric-coated, 150 mg non?enteric-coated morning dosing, and 150 mg non?enteric-coated evening dosing), whereas nonpregnant women undertook each of the 4 dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (before ingestion) and at 1, 2, 4, 6, 12, and 24 hours after ingestion of aspirin. Plasma obtained was analyzed for salicylic acid levels by means of liquid chromatography?mass spectrometry. Pharmacokinetic values of area under the curve from time point 0 to 24 hours point of maximum concentration, time of maximum concentration, volume of distribution, clearance, and elimination half-life were analyzed for statistical significance with SPSS v25 software. Results: Pregnant women had a 40% 4% reduction in area under the curve from time point 0 to 24 hours (P <.01) and 29% 3% reduction in point of maximum concentration (P <.01) with a 44% 8% increase in clearance (P <.01) in comparison to that in nonpregnant women when 100 mg aspirin was administered. The reduction in the area under the curve from time point 0 to 24 hours, however, was minimized with the use of 150 mg aspirin in pregnant women, with which the area under the curve from time point 0 to 24 hours was closer to that achieved with the use of 100 mg aspirin in nonpregnant women. There was a 4-hour delay (P <.01) in the time of maximum concentration, a 47% 3% reduction in point of maximum concentration (P <.01) and a 48% 1% increase in volume of distribution (P <.01) with the use of 100 mg enteric-coated aspirin compared to non?enteric-coated aspirin, with no difference in the overall area under the curve. There was no difference in the pharmacokinetics of aspirin between morning and evening dosing. Conclusion: There is a reduction in the total drug metabolite concentration of aspirin in pregnancy, and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy, with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric-coated and non?enteric-coated aspirin and between morning and evening dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings. 2019
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Tang, Vickie; Fu, Shanlin; Rayner, Benjamin Saul; Hawkins, Clare L.Infiltration of leukocytes within the vessel at sites of inflammation and the subsequent generation of myeloperoxidase-derived oxidants, including hypochlorous acid, are key characteristics of atherosclerosis. Hypochlorous acid is a potent oxidant that reacts readily with most biological molecules, including DNA and RNA. This results in nucleic acid modification and the formation of different chlorinated products. These products have been used as biomarkers of inflammation, owing to their presence in elevated amounts in different inflammatory fluids and diseased tissue, including atherosclerotic lesions. However, it is not clear whether these materials are simply biomarkers, or could also play a role in the development of chronic inflammatory pathologies. In this study, we examined the reactivity of different chlorinated nucleosides with human coronary artery endothelial cells (HCAEC). Evidence was obtained for the incorporation of each chlorinated nucleoside into the cellular RNA or DNA. However, only 8-chloro-adenosine (8ClA) had a significant effect on the cell viability and metabolic activity. Exposure of HCAEC to 8ClA decreased glycolysis, and resulted in a reduction in ATP, with a corresponding increase in the chlorinated analogue, 8Cl-ATP in the nucleotide pool. 8ClA also induced sustained endoplasmic reticulum stress within the HCAEC, which resulted in activation of the unfolded protein response, the altered expression of antioxidant genes and culminated in the release of calcium into the cytosol and cell death by apoptosis. Taken together, these data provide new insight into pathways by which myeloperoxidase activity and resultant hypochlorous acid generation could promote endothelial cell damage during chronic inflammation, which could be relevant to the progression of atherosclerosis. 2019 The Authors
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Akhavan, Behnam; Croes, Michiel; Wise, Steven G.; Zhai, Chongpu; Hung, Juichien; Stewart, Callum A.C.; Ionescu, Mihail H.; Weinans, Harrie H.; Gan, Yixiang; Yavari, Saber Amin; Bilek, Marcela M.M.Application of bio-functionalized coatings on bone implantable devices is a promising approach to direct rapid bone-implant integration. Plasma polymer (PP) films have become increasingly popular as platforms for surface bio-functionalization of implantable devices. However, the production of a reactive, yet stable PP film represents a technological challenge; as achieving a balance between the film's stability and functional group density is not trivial. Here we report the development of highly reactive and stable radical-functionalized PP films, using a combination of plasma polymerization and plasma immersion ion implantation. We provide new insights into the role of energetic ion bombardment on the growth mechanisms of plasma polymers by measuring the hydrogen content of PP structures using elastic recoil detection analysis. Nano-indentation and nano-scratch tests, as well as stability studies in simulated body fluid show a strong correlation between the degree of energetic ion bombardment and physico-chemical stability of the coatings. The potential of such ion-treated PP films to fabricate biofunctionalized implants that promote the functionality of primary osteoprogenitor cells is confirmed by studying cellular interactions after covalent attachment of fibronectin or bone morphogenetic protein (BMP)-2. We found that covalent attachment of fibronectin improved adhesion, spreading and proliferation of primary osteoblasts; whereas covalent attachment of BMP-2 enhanced the osteocalcin expression in bone-marrow isolated mesenchymal stem cells (MSC). These results present great promise for the fabrication of a new class of robust, biologically-functionalized interfaces for the surface engineering of biomaterials, particularly implants that need to be overgrown with bone-producing cells and thereby become firmly attached to host tissue. 2019 Elsevier Ltd
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Wild, Johannes; Scher, Rebecca L.; Knopp, Tanja; Molitor, Michael; Kossmann, Sabine; Mzel, Tomas F.; Daiber, Andreas; Waisman, Ari; Wenzel, Philip; Karbach, Susanne HelenaBackground: Psoriasis is hallmarked by vascular dysfunction, arterial hypertension, and an increased risk for cardiovascular diseases. We have shown recently that skin-driven interleukin (IL)-17A expression promotes psoriasis-like disease in mice, and this is associated with vascular inflammation, vascular dysfunction, and hypertension. As an intensive risk-factor reduction is recommended for psoriasis patients, we aimed to elucidate the impact of the angiotensin II receptor type 1 (AT1) antagonist telmisartan in a mouse model of severe psoriasis-like skin disease. Methods and Results: Elevated blood pressure measured by tail-cuff plethysmography in mice with keratinocyte-specific IL-17A overexpression (K14-IL-17Aind/+ mice) was significantly reduced in response to telmisartan. Importantly, vascular dysfunction, as assessed by isometric tension studies of isolated aortic rings, vascular inflammation measured by flow cytometry analysis of CD45+CD11b+ immune cells, as well as the increased peripheral oxidative stress levels assessed by L-012-enhanced chemiluminescence were not attenuated by telmisartan treatment of K14-IL-17Aind/+ mice, nor was the persisting skin inflammation. Conclusion: We provide first evidence for an effective antihypertensive treatment in experimental psoriasis by AT1 blockade, but without any impact on vascular inflammation and dysfunction in our mouse model of severe psoriasis-like skin disease. This suggests that vascular function and inflammation in psoriasis might not be attenuated as long as skin inflammation persists. 2019 by the authors. Licensee MDPI, Basel, Switzerland.
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Kott, Katharine A.; Vernon, Stephen Thomas; Hansen, Thomas S.; Yu, Christine; Bubb, Kristen J.; Coffey, Sean; Sullivan, David R.; Yang, Jean Yee Hwa; OSullivan, John F.; Chow, Clara Kayei; Patel, Sanjay; Chong, James J.H.; Celermajer, David S.; Kritharides, Leonard; Grieve, Stuart M.; Figtree, Gemma A.Introduction Coronary artery disease (CAD) persists as a major cause of morbidity and mortality worldwide despite intensive identification and treatment of traditional risk factors. Data emerging over the past decade show a quarter of patients have disease in the absence of any known risk factor, and half have only one risk factor. Improvements in quantification and characterisation of coronary atherosclerosis by CT coronary angiography (CTCA) can provide quantitative measures of subclinical atherosclerosis - enhancing the power of unbiased omics' studies to unravel the missing biology of personal susceptibility, identify new biomarkers for early diagnosis and to suggest new targeted therapeutics. Methods and analysis BioHEART-CT is a longitudinal, prospective cohort study, aiming to recruit 5000 adult patients undergoing clinically indicated CTCA. After informed consent, patient data, blood samples and CTCA imaging data are recorded. Follow-up for all patients is conducted 1 month after recruitment, and then annually for the life of the study. CTCA data provide volumetric quantification of total calcified and non-calcified plaque, which will be assessed using established and novel scoring systems. Comprehensive molecular phenotyping will be performed using state-of-the-art genomics, metabolomics, proteomics and immunophenotyping. Complex network and machine learning approaches will be applied to biological and clinical datasets to identify novel pathophysiological pathways and to prioritise new biomarkers. Discovery analysis will be performed in the first 1000 patients of BioHEART-CT, with validation analysis in the following 4000 patients. Outcome data will be used to build improved risk models for CAD. Ethics and dissemination The study protocol has been approved by the human research ethics committee of North Shore Local Health District in Sydney, Australia. All findings will be published in peer-reviewed journals or at scientific conferences. Trial registration number ACTRN12618001322224. 2019 Author(s).
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Tucker, Bradley; Kurup, Rahul; Barraclough, Jennifer Y.; Henriquez, Rodney; Cartland, Si; Arnott, Clare; Misra, Ashish K.; Martez, Gonzalo J.; Kavurma, Mary M.; Patel, SanjayPurpose: Existing literature reports that colchicine inhibits inflammasome activation and downstream inflammatory cytokine production and stabilizes coronary plaque. However, colchicine's effect on chemokines, which orchestrate multiple atheroinflammatory pathways, is unknown. Methods: Patients with acute coronary syndrome (ACS) were randomly assigned to colchicine (1.5 mg PO) (n = 12; mean age, 65.2 years) or no treatment (n = 13; mean age, 62.2 years). Blood samples were collected during cardiac catheterization within 24 hours of colchicine administration from the coronary sinus, aortic root, and right atrium. Patients with colchicine-naive stable angina (SAP) (n = 13; mean age, 66.8 years) were additionally sampled. Serum chemokine levels were analyzed with ELISA. In parallel, monocytes from healthy donors were isolated and subjected to colchicine treatment. Findings: Transcoronary (TC) levels of chemokine ligand 2 (CCL2) and C-X3-C motif chemokine ligand 1 (CX3CL1) were significantly elevated in patients with ACS versus patients with SAP (P < 0.01). TC chemokine ligand 5 (CCL5) levels were not significantly (P = 0.084) elevated in patients with ACS versus patients with SAP. Colchicine treatment markedly reduced TC levels of CCL2, CCL5, and CX3CL1 in patients with ACS (P < 0.05). In vitro colchicine suppressed CCL2 gene expression in stimulated monocytes (P < 0.05). Colchicine treatment reduced the intracellular concentration of all 3 chemokines (P < 0.01) and impaired monocyte chemotaxis (P < 0.05). Implications: Here, we report for the first time that short-term colchicine therapy significantly reduces the local production of coronary chemokines, in part by attenuating production of these mediators by monocytes. These data provide further evidence of colchicine's beneficial role in patients with ACS. 2019
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Orchard, Jessica Joan; Neubeck, Lis; Orchard, John William; Puranik, Rajesh; Raju, Hariharan; Freedman, Ben Ben; La Gerche, AndrCrossed D.Sign; Semsarian, ChristopherScreening asymptomatic people with a resting electrocardiogram (ECG) has been theorized to detect latent cardiovascular disease. However, resting ECG screening is not recommended for numerous populations, such as asymptomatic middle-aged (sedentary) people, as it is not sufficiently sensitive to detect coronary artery disease. While the issues raised in this article are largely common to all screening programs, this review focuses on 2 distinct programs: (1) screening elite athletes for conditions associated with sudden cardiac death (SCD); and (2) screening people aged ?65 years for atrial fibrillation (AF). These 2 settings have recently gained attention for their promise and concerns regarding prevention of SCD and stroke, respectively. If screening is to be done, it must be done well. Organizations conducting screening must consider a range of legal, ethical, and logistical responsibilities that arise from the beginning to the end of the process. This includes consideration of who to screen, timing of screening, whether screening is mandatory, consent issues, and auditing systems to ensure quality control. Good infrastructure for interpretation of ECG results according to expert guidelines and follow-up testing for abnormal screening results, including a pathway to treatment, are essential. Finally, there may be significant implications for those diagnosed with cardiac disease, including insurance, employment, the ability to play sport, and mental health issues. There are several legal risks, and the best protective measures are good communication systems, thorough clinical record-keeping, careful handling of eligibility questions for those diagnosed, and reference to expert guidelines as the standard of care. 2019 Heart Rhythm Society
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Liu, Guozhen; Bursill, C. A.; Cartland, Si; Anwer, Ayad G.; Parker, Lindsay M.; Zhang, Kaixin; Feng, Shilun; He, Meng; Inglis, David W.; Kavurma, Mary M.; Hutchinson, Mark R.; Goldys, Ewa M.Sensor; Biotechnology; Cell; Nanomaterials; We developed a universal method termed OnCELISA to detect cytokine secretion from individual cells by applying a capture technology on the cell membrane. OnCELISA uses fluorescent magnetic nanoparticles as assay reporters that enable detection on a single-cell level in microscopy and flow cytometry and fluorimetry in cell ensembles. This system is flexible and can be modified to detect different cytokines from a broad range of cytokine-secreting cells. Using OnCELISA we have been able to select and sort highly cytokine-secreting cells and identify cytokine-secreting expression profiles of different cell populations in vitro and ex vivo. We show that this system can be used for ultrasensitive monitoring of cytokines in the complex biological environment of atherosclerosis that contains multiple cell types. The ability to identify and select cell populations based on their cytokine expression characteristics is valuable in a host of applications that require the monitoring of disease progression. 2019 The Author(s); 2019 The Author(s)
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Stewart, Callum A.C.; Akhavan, Behnam; Wise, Steven G.; Bilek, Marcela M.M.Orthopedic implants are increasing in global prevalence, with hundreds of thousands of operations performed annually. However, a significant proportion of these operations experiences failure due to poor bone integration. Many avenues of investigation have been explored to address this issue and improve the biocompatibility of orthopedic devices by modifying the biological response to the implant surface. Biomimetic functionalization of orthopedic surfaces enables control over the biological response by signaling through immobilized proteins and other biomolecules. This approach seeks to promote osteoblast differentiation and bone formation at the implant surface, leading to integration between the orthopedic surface and the local bone tissue. This review commences by highlighting the need for biomimetic functionalization from a materials and biological perspective. The surface properties that govern protein-surface interactions are subsequently explained. Progress in biomolecule functionalization of orthopedic surfaces performed via adsorption, chemical covalent immobilization, and physical covalent immobilization are discussed and reviewed. The immobilization mechanisms for each approach are examined and the strategies are evaluated according to their complexity, efficacy, reproducibility, and scalability. Emerging and prospective avenues for the transition from 2D to 3D substrates and the multi-functionalization of biomimetic surfaces are then explored. 2019 Elsevier Ltd
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DAmbrosio, Paolo; Tran, Derek L.; Verrall, Charlotte E.; Attard, Chantal; Fiatarone Singh, Maria A.; Ayer, Julian Ganesh J.; d'Udekem, Yves A.; Twigg, Stephen Morris; Celermajer, David S.; Cordina, Rachael LouiseObjective and Patients: This study aimed to characterize bone mineral density abnormalities and pathophysiological associations in young adults living with a Fontan circulation. Design: Participants underwent bone mineral density measurement using dual-energy X-ray absorptiometry and serum biochemical analysis, cardiopulmonary exercise and strength testing and transthoracic echocardiography. Results: In our cohort (n=28), 29% had osteopenic-range bone mineral density and one patient was osteoporotic (average hip t score: ?0.61.1; spine t score: ?0.60.9). Four patients (14%) had z scores<?2.0. Parathyroid hormone levels were increased compared with laboratory median (6.13.5 vs 4pmol/L, P=.01) and 27% had 25-hydroxy-vitamin D<50nmol/L. 25-hydroxy-vitamin D negatively correlated with parathyroid hormone (?=?0.53, P=.01) suggesting secondary hyperparathyroidism. Atrioventricular valve systolic to diastolic duration ratio, an echocardiographic measure of diastolic dysfunction, inversely correlated with hip t and z scores (P<.01). Hip t scores were positively associated with oxygen saturations (?=0.45, P=.05) and tended to be inversely associated with parathyroid hormone levels (?=?0.44, P=.07) and N-Terminal pro b-type natriuretic peptide (?=?0.42, P=.08). Conclusions: Many young adults with a Fontan circulation have abnormal bone mineral density. The underlying pathophysiology is likely multifactorial. Possible contributors include secondary hyperparathyroidism, hypoxemia, diastolic cardiac dysfunction and neurohormonal activation. As low bone mineral density is clinically relevant and potentially treatable, assessment of bone mineral density should be part of routine care in this cohort. 2019 Wiley Periodicals, Inc.
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Finger, Stefanie; Knorr, Maike; Molitor, Michael; Scher, Rebecca L.; Garlapati, Venkata S.; Waisman, Ari; Brandt, Moritz; Mzel, Tomas F.; Bopp, Tobias; Kossmann, Sabine; Karbach, Susanne Helena; Wenzel, PhilipAims: Myelomonocytic cells are critical in injury and healing post-myocardial infarction (MI). Mechanisms of regulation, however, are incompletely understood. The aim of the study was to elucidate the role of interferon gamma (IFN-?) in the orchestrated inflammatory response in a murine model of MI. Methods and results: MI was induced in 8-to 12-week-old male mice (C57BL/6 background) by permanent ligation of the left anterior descending (LAD) coronary artery. Lysozyme M (LysM)+ cell-depleted LysMiDTR transgenic mice displayed a reduced influx of CD45.2+/CD3-/CD11b+/Gr-1high neutrophils into infarcted myocardium 1 day post-MI compared with infarcted controls, paralleled by decreased cardiac mRNA levels of IFN-?and tumour necrosis factor alpha (TNF-?). Mortality after MI was significantly increased in LysM+ cell-depleted mice within 28 days post-MI. To more specifically address the role of neutrophils, we depleted C57BL/6 mice with a monoclonal anti-Gr-1 antibody and found increased mortality, deteriorated cardiac function as well as decreased cardiac IFN-?mRNA expression early after MI. Ccl2, Cxcl1, Cx3cl1, and Il12b mRNA were reduced 3 days after MI, as was the amount of CD11b+/Ly-6G-/Ly-6Chigh inflammatory monocytes. LAD-ligated Cramp-/- mice lacking cathelicidin important in neutrophil-dependent monocyte chemotaxis as well as IFN?-/- and TNF?-/- mice phenocopied Gr-1+ cell-depleted mice, supporting a regulatory role of IFN-?impacting on both the sequence of inflammatory cell invasion and cardiac outcome early after MI. The use of conditional IFN-?receptor deficient mice indicated a direct effect of IFN-?on LysM+ cells in cardiac injury post-MI. Using IFN-?reporter mice and flow cytometry, we identified cardiac lymphoid cells (CD4+ and CD8+ T cells and natural killer cells) as primary source of this cytokine in the cardiac inflammatory response post-MI. Conclusion: IFN-?directs a sequential chemotactic cellular immune response and determines survival and cardiac function post-MI. 2019 The Author(s).
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Zhang, Yunjia; Rayner, Benjamin Saul; Jensen, Mathias; Hawkins, Clare L.The release of extracellular traps (ETs) by neutrophils has been identified as a contributing factor to the development of diseases related to chronic inflammation. Neutrophil ETs (NETs) consist of a mesh of DNA, histone proteins, and various granule proteins (i.e., myeloperoxidase, elastase, and cathepsin G). Other immune cells, including macrophages, can also produce ETs; however, to what extent this occurs in vivo and whether macrophage extracellular traps (METs) play a role in pathological mechanisms has not been examined in detail. To better understand the role of METs in inflammatory pathologies, a protocol was developed for visualizing MET release from primary human macrophages in vitro, which can also be exploited in immunofluorescence experiments. This allows further characterization of these structures and their comparison to ETs released from neutrophils. Human monocyte-derived macrophages (HMDM) produce METs upon exposure to different inflammatory stimuli following differentiation to the M1 pro-inflammatory phenotype. The release of METs can be visualized by microscopy using a green fluorescent nucleic acid stain that is impermeant to live cells (e.g., SYTOX green). Use of freshly isolated primary macrophages, such as HMDM, is advantageous in modeling in vivo inflammatory events that are relevant to potential clinical applications. This protocol can also be used to study MET release from human monocyte cell lines (e.g., THP-1) following differentiation into macrophages with phorbol myristate acetate or other macrophage cell lines (e.g., the murine macrophage-like J774A.1 cells). 2019 Journal of Visualized Experiments.
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Reyes, Leila; Bishop, David P.; Hawkins, Clare L.; Rayner, Benjamin SaulOxidative stress is a major hallmark of cardiac ischemia/reperfusion (I/R) injury. This partly arises from the presence of activated phagocytes releasing myeloperoxidase (MPO) and its production of hypochlorous acid (HOCl). The dietary supplement selenomethionine (SeMet) has been shown to bolster endogenous antioxidant processes as well as readily react with MPO-derived oxidants. The aim of this study was to assess whether supplementation with SeMet could modulate the extent of cellular damage observed in an in vitro cardiac myocyte model exposed to (patho)-physiological levels of HOCl and an in vivo rat model of cardiac I/R injury. Exposure of the H9c2 cardiac myoblast cell line to HOCl resulted in a dose-dependent increase in necrotic cell death, which could be prevented by SeMet supplementation and was attributed to SeMet preventing the HOCl-induced loss of mitochondrial inner trans-membrane potential, and the associated cytosolic calcium accumulation. This protection was credited primarily to the direct oxidant scavenging ability of SeMet, with a minor contribution arising from the ability of SeMet to bolster cardiac myoblast glutathione peroxidase (GPx) activity. In vivo, a significant increase in selenium levels in the plasma and heart tissue were seen in male Wistar rats fed a diet supplemented with 2 mg kg?1 SeMet compared to controls. However, SeMet-supplementation demonstrated only limited improvement in heart function and did not result in better heart remodelling following I/R injury. These data indicate that SeMet supplementation is of potential benefit within pathological settings where excessive HOCl is known to be generated but has limited efficacy as a therapeutic agent for the treatment of heart attack. 2019 by the authors. Licensee MDPI, Basel, Switzerland. article distributed under the terms and conditions of the Cr.
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Kirollos, Shady; Skilton, Michael R.; Patel, Sanjay; Arnott, ClareHypertensive disorders of pregnancy, such as pre-eclampsia, are known to be independently associated with the development of premature cardiovascular disease (CVD) in women. In pre-eclampsia, the placenta secretes excess anti-angiogenic factors into the maternal circulation, leading to widespread endothelial damage, and inflammation. This endothelial damage is evidenced to persist beyond the acute illness. However, whether it is permanent and responsible for the elevated rates of premature CVD seen in this at-risk group remains unclear. A systematic review of the available literature with respect to vascular structure and function prior to, during and after a pregnancy complicated by pre-eclampsia was performed. Studies non-invasively assessing vascular structure using carotid intima-media thickness (CIMT), retinal microvasculature caliber, CT coronary angiogram, or coronary calcium scores were included. Vascular function was assessed using brachial flow-mediated dilation (FMD), pulse wave analysis (PWA), and peripheral arterial tonometry (PAT). In total 59 articles were included (13 CIMT, 5 CTCA/Ca score, five retinal microvasculature, 27 FMD, 7 PAT, and 14 PWV/PWA), consisting of prospective and retrospective cohort, and case-control studies. Change in vascular structure was evidenced with significant increases in CIMT by 73180 ?m greater than that of non-affected women. This is tempered by other studies reporting resolution of structural changes postpartum, highlighting the need for further research. Accelerated coronary calcification and plaque deposition was identified, with greater rates of increased calcium scores and subclinical coronary artery disease shown by CTCA in women with a history of pre-eclampsia at 30 years postpartum. Impaired endothelial function was consistently reported prior to, during and immediately after pregnancy as evidenced by differences in FMD of 1.712.2% less than non-affected women, an increase in PWV by 13.226%, and reduced retinal microvascular caliber and arterial elasticity indices. The evidence was less conclusive for the persistence of long-term endothelial dysfunction. Understanding the underlying mechanistic links between pre-eclampsia and CVD is a key step to identifying targeted therapies aimed at repairing the endothelium and attenuating risk. This review has highlighted the need for a greater understanding of vascular structure and function following pre-eclampsia through high quality studies with large sample sizes, particularly in the longer postpartum period when clinical CVD disease starts to manifest. Copyright 2019 Kirollos, Skilton, Patel and Arnott.
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Schnabel, Renate B.; Haeusler, Karl Georg; Healey, Jeff S.; Freedman, Ben Ben; Boriani, Giuseppe; Brachmann, Johannes; Brandes, Axel; Bustamante, Alejandro C.; Casadei, Barbara; Crijns, Harry JGM; Doehner, Wolfram; Engstr, Gunnar; Fauchier, Laurent; Friberg, Leif; Gladstone, David J.; Glotzer, Taya V.; Goto, Shinya; Hankey, Graeme J.; Harbison, Joseph A.; Hobbs, FD Richard; Johnson, Linda S.B.; Kamel, Hooman; Kirchhof, Paulus F.; Korompoki, Eleni; Krieger, Derk Wolfgang; Lip, Gregory Y.H.; Lhen, Maja Lisa; Mairesse, Georges H.; Montaner, J. M.; Neubeck, Lis; Ntaios, George C.; Piccini, Jonathan Paul; Potpara, Tatjana S.; Quinn, Terry J.; Reiffel, James A.; Ribeiro, Antonio L.; Rienstra, Michiel; Rosenqvist, Mten; Sakis, Themistoclakis; Sinner, Moritz F.; Svendsen, Jesper Hastrup; van Gelder, Isabelle C.; Wachter, Rolf; Wijeratne, Tissa; Yan, BernardCardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non-vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non-vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated. 2019 American Heart Association, Inc.
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Maller, Jerome Joseph; Welton, Thomas; Middione, Matthew J.; Callaghan, Fraser Maurice; Rosenfeld, Jeffrey V.; Grieve, Stuart M.The hippocampus is a key component of emotional and memory circuits and is broadly connected throughout the brain. We tracked the whole-brain connections of white matter fibres from the hippocampus using ultra-high angular resolution diffusion MRI in both a single 1150-direction dataset and a large normal cohort (n = 94; 391-directions). Using a connectomic approach, we identified six dominant pathways in terms of strength, length and anatomy, and characterised them by their age and gender variation. The strongest individual connection was to the ipsilateral thalamus. There was a strong age dependence of hippocampal connectivity to medial occipital regions. Overall, our results concur with preclinical and ex-vivo data, confirming that meaningful in vivo characterisation of hippocampal connections is possible in an individual. Our findings extend the collective knowledge of hippocampal anatomy, highlighting the importance of the spinal-limbic pathway and the striking lack of hippocampal connectivity with motor and sensory cortices. 2019, The Author(s).
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Boriani, Giuseppe; Healey, Jeff S.; Schnabel, Renate B.; Les, Renato Delcio; Calkins, Hugh G.; Camm, John A.; Freedman, Ben BenAims: At present, there is little evidence on how to treat subclinical atrial fibrillation (SCAF) or atrial high rate episodes (AHREs) detected by cardiac implantable electronic devices (CIEDs). Our aim was to assess current practice around oral anticoagulation (OAC) in such patients. Methods: A web-based survey undertaken by 310 physicians: 59 AF-SCREEN International Collaboration members and 251 non-members. Results: In patients with SCAF/AHRE and a CHA<inf>2</inf>DS<inf>2</inf>VASc ? 2 in males or ? 3 in female the amount of SCAF/AHRE triggering use of OAC was variable but <2% of respondents considered that no AHRE would require OAC. Around one third (34%) considered SCAF/AHRE duration of >56 min as the basis for OAC prescription, while 16% and 18% required a burden of at least 5.5 h or 24 h, respectively. The propensity to prescribe OAC for a low burden of AHREs differed according to certain respondent characteristics (greater propensity to prescribe OAC for neurologists). When the clinical scenario included a prior stroke or a prior cardioembolic stroke, stated prescription of OAC was very high. More than 96% felt that any SCAF/AHRE should be treated with OAC. Conclusions: There is substantial heterogeneity in the perception of the risk of stroke/systemic embolism associated with SCAF/AHRE of variable duration. The threshold of AHRE burden that would trigger initiation of OAC is highly variable, and differs according to the clinical scenario (lower threshold in case of previous stroke). Ongoing trials will clarify the real benefit and risk/benefit ratio of OAC in this specific clinical setting. 2019 Elsevier B.V.
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Hellewell, Sarah Claire; Welton, Thomas; Maller, Jerome Joseph; Lyon, Matthew; Korgaonkar, Mayuresh S.; Koslow, Stephen H.; Williams, Leanne M.; Rush, Augustus John; Gordon, Evian; Grieve, Stuart M.Reduced gray matter (GM) volume may represent a hallmark of major depressive disorder (MDD) neuropathology, typified by wide-ranging distribution of structural alteration. In the study, we aimed to replicate and extend our previous finding of profound and widespread GM loss in MDD, and evaluate the diagnostic accuracy of a structural biomarker derived from GM volume in an interconnected pattern across the brain. In a sub-study of the International Study to Predict Optimized Treatment in Depression (iSPOT-D), two cohorts of clinically defined MDD participants Test (n = 98) and Replication (n = 131) were assessed alongside healthy controls (n = 66). Using 3T MRI T1-weighted volumes, GM volume differences were evaluated using voxel-based morphometry. Sensitivity, specificity, and area under the receiver operating characteristic curve were used to evaluate an MDD diagnostic biomarker based on a precise spatial pattern of GM loss constructed using principal component analysis. We demonstrated a highly conserved symmetric widespread pattern of reduced GM volume in MDD, replicating our previous findings. Three bilateral dominant clusters were observed: Cluster 1: midline/cingulate (GM reduction: Test: 6.4%, Replication: 5.3%), Cluster 2: medial temporal lobe (GM reduction: Test: 8.2%, Replication: 11.9%), Cluster 3: prefrontal cortex (GM reduction: Test: 12.1%, Replication: 23.2%). We developed a biomarker reflecting the global pattern of GM reduction, achieving good diagnostic classification performance (AUC: Test = 0.75, Replication = 0.84). This study establishes that a highly specific pattern of reduced GM volume is a feature of MDD, suggestive of a structural basis for this disease. We introduce and validate a novel diagnostic biomarker based on this pattern. 2019, The Author(s).
