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Showing 661–680 of 2058 publications.
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Welton, Thomas; Maller, Jerome Joseph; Lebel, R. Marc; Tan, Ek T.; Rowe, Dominic B.; Grieve, Stuart M.Objective: To construct a clinical diagnostic biomarker using state-of-the-art microstructural MRI in the motor cortex of people with amyotrophic lateral sclerosis (ALS). Methods: Clinical and MRI data were obtained from 21 ALS patients (aged 54 14 years, 33% female) and 63 age- and gender-matched controls (aged 48 18 years, 43% female). MRI was acquired at 3T and included T1-weighted scan (for volumetrics), arterial spin labelling (for cerebral blood flow), susceptibility-weighted angiography (for iron deposition) and multiband diffusion kurtosis imaging (for tissue microstructure). Group differences in imaging measures in the motor cortex were tested by general linear model and relationships to clinical variables by linear regression. Results: The ALS group had mild-to-moderate impairment (disease duration: 1.8 0.8 years; ALS functional rating scale 40.2 6.0; forced vital capacity 83% 22%). No age or gender differences were present between groups. We found significant group differences in diffusion kurtosis metrics (apparent, mean, radial and axial kurtosis: p < .01) and iron deposition in the motor cortex (p = .03). Within the ALS group, we found significant relationships between motor cortex volume, apparent diffusion and disease duration (adjusted R2 = 0.27, p = .011); and between the apparent and radial kurtosis metrics and ALS functional rating scale (adjusted R2 = 0.25, p = .033). A composite imaging biomarker comprising kurtosis and iron deposition measures yielded a maximal diagnostic accuracy of 83% (81% sensitivity, 85% specificity) and an area-under-the-curve of 0.86. Conclusion: Diffusion kurtosis is sensitive to early changes present in the motor region in ALS. We propose a composite imaging biomarker reflecting tissue microstructural changes in early ALS that may provide clinically valuable diagnostic information. 2019 The Authors
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Orchard, Jessica Joan; Neubeck, Lis; Freedman, Ben Ben; Li, Jialin; Webster, Ruth J.; Zwar, Nicholas Arnold; Gallagher, Robyn D.; Ferguson, Caleb; Lowres, NicoleBackgroundThis eHealth implementation study aimed to evaluate strategies to promote opportunistic atrial fibrillation (AF) screening using electronic screening prompts and improve treatment using electronic decision support (EDS) software. Methods and ResultsAn electronic screening prompt appeared whenever an eligible patients (aged ?65 years, no AF diagnosis) medical record was opened in participating general practices. General practitioners and practice nurses offered screening using a smartphone ECG, with validated AF algorithm. Guideline-based EDS was provided to assist treatment decisions. Deidentified data were collected from practices using a data extraction tool. General practices (n=8) across Sydney, Australia, screened for a median of 6 months. A total of 1805 of 11 476 (16%) eligible patients who attended were screened (44% men, mean age 75.7 years). Screening identified 19 (1.1%) new cases of AF (mean age, 79 years; mean CHA <inf>2</inf> DS <inf>2</inf> -VASc, 3.7; 53% men). General practitioners (n=30) performed 70% of all screenings (range 1448 patients per general practitioner). The proportion of patients with AF who had CHA <inf>2</inf> DS <inf>2</inf> -VASc ?2 for men or ?3 for women prescribed oral anticoagulants was higher for those diagnosed during the study: 15 of 18 (83%) for screen-detected and 39 of 46 (85%) for clinically detected, compared with 933 of 1306 (71%) patients diagnosed before the study (P<0.001). The EDS was accessed 111 times for patients with AF and for 4 of 19 screen-detected patients. ConclusionsThe eHealth tools showed promise. Adherence to guideline-based oral anticoagulant prescription was significantly higher in patients diagnosed during the study period, although the EDS was only used in a minority. While the proportion of eligible patients screened and EDS use was relatively low, further refinements may improve uptake in clinical practice. Clinical Trial RegistrationURL: www.anzctr.org.au. Unique identifier: ACTRN12616000850471. 2018 The Authors.
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Vallejo, Abigail; Chami, Belal; Dennis, Joanne Marie; Simone, Martin; Ahmad, Gulfam A.U.; Abdo, Adrian I.; Sharma, Arpeeta; Shihata, Waled A.; Martin, Nathan J.J.; Chin-Dusting, Jaye P.F.; de Haan, Judy B.; Witting, Paul KennethThe acute phase protein serum amyloid A (SAA) is associated with endothelial dysfunction and early-stage atherogenesis. Stimulation of vascular cells with SAA increases gene expression of pro-inflammation cytokines and tissue factor (TF). Activation of the transcription factor, nuclear factor kappa-B (NF?B), may be central to SAA-mediated endothelial cell inflammation, dysfunction and pro-thrombotic responses, while targeting NF?B with a pharmacologic inhibitor, BAY11-7082, may mitigate SAA activity. Human carotid artery endothelial cells (HCtAEC) were pre-incubated (1.5 h) with 10 M BAY11-7082 or vehicle (control) followed by SAA (10 g/mL; 4.5 h). Under these conditions gene expression for TF and Tumor Necrosis Factor (TNF) increased in SAA-treated HCtAEC and pre-treatment with BAY11-7082 significantly (TNF) and marginally (TF) reduced mRNA expression. Intracellular TNF and interleukin 6 (IL-6) protein also increased in HCtAEC supplemented with SAA and this expression was inhibited by BAY11-7082. Supplemented BAY11-7082 also significantly decreased SAA-mediated leukocyte adhesion to apolipoprotein E-deficient mouse aorta in ex vivo vascular flow studies. In vascular function studies, isolated aortic rings pre-treated with BAY11-7082 prior to incubation with SAA showed improved endothelium-dependent vasorelaxation and increased vascular cyclic guanosine monophosphate (cGMP) content. Together these data suggest that inhibition of NF?B activation may protect endothelial function by inhibiting the pro-inflammatory and pro-thrombotic activities of SAA. 2018 by the authors. Licensee MDPI, Basel, Switzerland.
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Lyon, Matthew; Welton, Thomas; Varda, Adrina; Maller, Jerome Joseph; Broadhouse, Kathryn M.; Korgaonkar, Mayuresh S.; Koslow, Stephen H.; Williams, Leanne M.; Gordon, Evian; Rush, Augustus John; Grieve, Stuart M.Background: Major depressive disorder (MDD) is a chronic disease with a large global impact. There are currently no clinically useful predictors of treatment outcome, and the development of biomarkers to inform clinical treatment decisions is highly desirable. Methods: In this exploratory study we performed fixel-based analysis of diffusion MRI data from the International Study to Predict Optimized Treatment in Depression with the aim of identifying novel biomarkers at baseline that may relate to diagnosis and outcome to treatment with antidepressant medications. Analyses used MR data from individuals with MDD (n = 221) and healthy controls (n = 67). Results: We show focal, gender-specific differences in the anterior limb of the internal capsule (males) and bilaterally in the genu of the corpus callosum (females) associated with diagnosis. Lower fibre cross-section in the tapetum, the conduit between the right and left hippocampi, were also associated with a decreased probability of remission. Analysis of conventional fractional anisotropy showed scattered abnormalities in the corona radiata, cerebral peduncles and mid-brain which were much lower in total volume compared to fixel-based analysis. Conclusions: Fixel-based analysis appeared to identify different underlying abnormalities than conventional tensor-based metrics, with almost no overlap between significant regions. We show that MDD is associated with gender specific abnormalities in the genu of the corpus callosum (females) and in the anterior limb of the internal capsule (males), as well as gender-independent differences in the tapetum that predict remission. Diffusion MRI may play a key role in future guidance of clinical decision-making for MDD. 2019
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Jackson, Shaun P.; Darbousset, Roxane; Schoenwaelder, Simone M.Thrombosis with associated inflammation (thromboinflammation) occurs commonly in a broad range of human disorders. It is well recognized clinically in the context of superficial thrombophlebitis (thrombosis and inflammation of superficial veins); however, it is more dangerous when it develops in the microvasculature of injured tissues and organs. Microvascular thrombosis with associated inflammation is well recognized in the context of sepsis and ischemia-reperfusion injury; however, it also occurs in organ transplant rejection, major trauma, severe burns, the antiphospholipid syndrome, preeclampsia, sickle cell disease, and biomaterial-induced thromboinflammation. Central to thromboinflammation is the loss of the normal antithrombotic and antiinflammatory functions of endothelial cells, leading to dysregulation of coagulation, complement, platelet activation, and leukocyte recruitment in the microvasculature. a-Thrombin plays a critical role in coordinating thrombotic and inflammatory responses and has long been considered an attractive therapeutic target to reduce thromboinflammatory complications. This review focuses on the role of basic aspects of coagulation and a-thrombin in promoting thromboinflammatory responses and discusses insights gained from clinical trials on the effects of various inhibitors of coagulation on thromboinflammatory disorders. Studies in sepsis patients have been particularly informative because, despite using anticoagulant approaches with different pharmacological profiles, which act at distinct points in the coagulation cascade, bleeding complications continue to undermine clinical benefit. Future advances may require the development of therapeutics with primary antiinflammatory and cytoprotective properties, which have less impact on hemostasis. This may be possible with the growing recognition that components of blood coagulation and platelets have prothrombotic and proinflammatory functions independent of their hemostatic effects. 2019 by The American Society of Hematology.
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Carelli, Matheus Guimaraes; Seco, Michael; Bannon, Paul Gerard; Grieve, Stuart M.[No abstract available]
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Ju, Lining ArnoldAn emerging concept in chemical biology is that protein function that can be regulated by the redox state of disulphide bonds. This chapter describes the dynamic force spectroscopy method for analyzing redox regulation of receptorligand interactions at the surface of living cells. The main method described in this chapter is the biomembrane force probe (BFP), in which an ultrasoft human red blood cell is used as an ultrasensitive mechanical force probe. The BFP uses a high-speed camera and real-time imaging tracking techniques to characterize a single molecular bond with ~1 pN (10?12 N), ~3 nm (10?9 m), and ~0.5 ms (10?3 s) in force, spatial, and temporal resolution. As a test bed model, we use the BFP to examine the autoregulation of von Willebrand factor function by a disulphide bond switch in its A2 domain. With the survival frequency analysis on measured bond lifetimes, we can identify distinct states of VWF binding kinetics and correlate with redox states of its A2 disulphide bond validated by mass spectrometry. The methodologies and analytical frameworks can be used to study other membrane receptorligand interactions under redox regulation. Springer Science+Business Media, LLC, part of Springer Nature 2019.
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Dupuy, Alexander; Passam, Freda H.Endoplasmic reticulum protein 5 (ERp5) is a member of the thiol isomerase family of enzymes, whose prototype member is protein disulphide isomerase (PDI). Thiol isomerases catalyze reduction/oxidation (redox) reactions which lead to the cleavage, formation, or isomerization of disulphide bonds in protein substrates. Thiol isomerase reactions on protein disulphides are important for the correct folding of proteins in the endoplasmic reticulum and for the regulation of various protein functions in the extracellular space. Apart from the disulphide reactions, thiol isomerases assist protein folding by chaperone activity. The disulphide redox activity of ERp5 can be measured with functional assays involving artificial or natural substrates containing disulphide bonds. Herein we describe step-by-step assays of ERp5 reductase, isomerization, and de-nitrosylation activity. Disulphide reductase assays include insulin or di-eosin-GSSG as substrates whereas the isomerization assay includes RNase as substrate. The reduction of natural substrates, i.e., integrin ?IIb?3, can be detected using maleimide labels of free thiols and Western blotting. The biotin switch assay is used to measure the de-nitrosylation of S-nitrosylated substrates. These assays can measure the activity of purified ERp5 protein but can also be applied for the measurement of thiol isomerase activity in cellular samples. Springer Science+Business Media, LLC, part of Springer Nature 2019.
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Watson, Emma E.; Ripoll-Rozada, Jorge; Lee, Ashley C.; Wu, Mike C.L.; Franck, Charlotte; Pasch, Tim; Premdjee, Bhavesh; Sayers, Jessica; Pinto, Maria Filipa; Martins, Pedro M.; Jackson, Shaun P.; Pereira, Pedro JosBarbosa; Payne, Richard J.Hematophagous organisms produce a suite of salivary proteins which interact with the hosts coagulation machinery to facilitate the acquisition and digestion of a bloodmeal. Many of these bio-molecules inhibit the central blood-clotting serine proteinase thrombin that is also the target of several clinically approved anticoagulants. Here a bioinformatics approach is used to identify seven tick proteins with putative thrombin inhibitory activity that we predict to be posttranslationally sulfated at two conserved tyrosine residues. To corroborate the biological role of these molecules and investigate the effects of amino acid sequence and sulfation modifications on thrombin inhibition and anticoagulant activity, a library of 34 homogeneously sulfated protein variants were rapidly assembled using one-pot diselenide-selenoester ligation (DSL)-deselenization chemistry. Downstream functional characterization validated the thrombin-directed activity of all target molecules and revealed that posttranslational sulfation of specific tyrosine residues crucially modulates potency. Importantly, access to this homogeneously modified protein library not only enabled the determination of key structureactivity relationships and the identification of potent anticoagulant leads, but also revealed subtleties in the mechanism of thrombin inhibition, between and within the families, that would be impossible to predict from the amino acid sequence alone. The synthetic platform described here therefore serves as a highly valuable tool for the generation and thorough characterization of libraries of related peptide and/or protein molecules (with or without modifications) for the identification of lead candidates for medicinal chemistry programs. 2019 National Academy of Sciences. All rights reserved.
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Lam, Yuen Ting; Lecce, Laura; Yuen, Sui Ching G.; Wise, Steven G.; Handelsman, David J.; Karas, Richard H.; Ng, Martin K.C.There is abundant evidence that low circulating testosterone levels in older men are associated with adverse cardiovascular outcomes; however, the direction of causality is unclear. Although there is burgeoning interest in the potential of androgen therapy in older men, the effect of androgens on cardiovascular regeneration in aging males remains poorly defined. We investigated the role of androgens in age-related impairment in ischemia-induced neovascularization. Castrated young (2 months) and old (24 months) male mice were subjected to unilateral hindlimb ischemia and treated with subdermal DHT or placebo Silastic implants. Blood flow recovery was enhanced by DHT treatment in young and old mice compared with age-matched placebo controls. DHT augmented angiogenesis in young mice and ameliorated age-related impairment in neovascularization in old mice. Administration of DHT was associated with increased hypoxia inducible factor-1? (HIF-1?) and stromal cell-derived factor-1 expression in young mice, but not in old mice. In vitro, DHT-induced HIF-1? transcriptional activation was attenuated in fibroblasts from old mice. Interaction between androgen receptor (AR) and importins, key proteins that facilitate nuclear translocation of AR, was impaired with age. In contrast, DHT treatment stimulated the production and mobilization of Sca1+/CXCR4+ circulating progenitor cells in both young and old mice. DHT stimulated the migration and proangiogenic paracrine effect of ex vivo cultured bone marrow-derived angiogenic cells from young and old mice. In conclusion, androgens ameliorated age-related impairment in ischemia-induced neovascularization. Although age-dependent dysfunction in androgen signaling attenuated some androgen effects on angiogenesis, provasculogenic effects of androgens were partially preserved with age. 2019 Endocrine Society.
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Tan, Richard P.; Chan, Alex H.P.; Wei, Simon; Santos, Miguel; Lee, Bob S.L.; Filipe, Elysse C.; Akhavan, Behnam; Bilek, Marcela M.M.; Ng, Martin K.C.; Xiao, Yin; Wise, Steven G.Cardiovascular disease is an inflammatory disorder that may benefit from appropriate modulation of inflammation. Systemic treatments lower cardiac events but have serious adverse effects. Localized modulation of inflammation in current standard treatments such as bypass grafting may more effectively treat CAD. The present study investigated a bioactive vascular graft coated with the macrophage polarizing cytokine interleukin-4. These grafts repolarize macrophages to anti-inflammatory phenotypes, leading to modulation of the pro-inflammatory microenvironment and ultimately to a reduction of foreign body encapsulation and inhibition of neointimal hyperplasia development. These resulting functional improvements have significant implications for the next generation of synthetic vascular grafts. 2019 The Authors
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Zhong, Liang; Schrauben, Eric Mathew; Garc, Julio; Uribe, Sergio A.; Grieve, Stuart M.; Elbaz, Mohammed S.M.; Barker, Alex J.; Geiger, Julia; Nordmeyer, Sarah; Marsden, Alison Lesley; Carlsson, Marcus; Tan, Ru San; Garg, Pankaj; Westenberg, Jos M.; Markl, Michael; Ebbers, Tino[No abstract available]
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Chen, Yunfeng; Liao, Jiexi; Yuan, Zhou; Li, Kaitao; Liu, Baoyu; Ju, Lining Arnold; Zhu, ChengForce plays critical roles in cell adhesion and mechano-signaling, partially by regulating the dissociation rate, i.e., off-rate, of receptor-ligand bonds. However, the mechanism of such regulation still remains elusive. As a controversial topic of the field, when measuring the off-rate vs. force relation of the same molecular system, different dynamic force spectroscopy (DFS) assays (namely, force-clamp and force-ramp assays) often yield contradictive results. Such discrepancies hurdled our further understanding of molecular binding, and casted doubt on the existing theoretical models. In this work, we used a live-cell DFS technique, biomembrane force probe, to measure the single-bond dissociation in three receptor-ligand systems which respectively have important functions in vascular and immune systems: human platelet GPIb?-VWF, mouse T cell receptor-OVA peptide:MHC, and mouse platelet integrin ?IIb?3-fibrinogen. Using force-clamp and force-ramp assays in parallel, we identified that the force loading disrupted the stability of molecular bonds in a rate-dependent manner. This disruptive effect was achieved by the transitioning of bonds between two dissociation states: faster force loading induces more bonds to adopt the fast-dissociating state (and less to adopt the slow-dissociating state). Based on this mechanism, a new biophysical model of bond dissociation was established which took into account the effects of both force magnitude and loading rate. Remarkably, this model reconciled the results from the two assays in all three molecular systems under study. Our discoveries provided a new paradigm for understanding how force regulates receptor-ligand interactions and a guideline for the proper use of DFS technologies. Furthermore, our work highlighted the opportunity of using different DFS assays to answer specific biological questions in the field of cell adhesion and mechano-signaling. 2019 Tech Science Press. All rights reserved.
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Lowres, Nicole; Olivier, Jake; Chao, Tzefan; Chen, Shihann; Chen, Yi; Diederichsen, Axel Cp; Fitzmaurice, David Andrew; Gez-Doblas, Juan Jos Harbison, Joseph A.; Healey, Jeff S.; Hobbs, FD Richard; Kaasenbrood, Femke; Keen, William D.; Lee, Vivian Wing Yan; Lindholt, J. Sanddal; Lip, Gregory Y.H.; Mairesse, Georges H.; Mant, Jonathan W.F.; Martin, Julie W.; Mart-Riobo Enrique; McManus, David D.; Muz, Javier A.; Mzel, Tomas F.; Nakamya, Juliet; Neubeck, Lis; Orchard, Jessica Joan; Pula-De-Torres, Lu gel; Proietti, Marco; Quinn, F. Russell; Roalfe, Andrea K.; Sandhu, Roopinder Kaur; Schnabel, Renate B.; Smyth, Breda; Soni, Apurv V.; Tieleman, Robert G.; Wang, Jiguang; Wild, Philipp Sebastian; Yan, Bryan Ping Yen; Freedman, Ben BenBackground: The precise age distribution and calculated stroke risk of screen-detected atrial fibrillation (AF) is not known. Therefore, it is not possible to determine the number needed to screen (NNS) to identify one treatable new AF case (NNS-Rx) (i.e., Class-1 oral anticoagulation [OAC] treatment recommendation) in each age stratum. If the NNS-Rx is known for each age stratum, precise cost-effectiveness and sensitivity simulations can be performed based on the age distribution of the population/region to be screened. Such calculations are required by national authorities and organisations responsible for health system budgets to determine the best age cutoffs for screening programs and decide whether programs of screening should be funded. Therefore, we aimed to determine the exact yield and calculated stroke-risk profile of screen-detected AF and NNS-Rx in 5-year age strata. Methods and findings: A systematic review of Medline, Pubmed, and Embase was performed (January 2007 to February 2018), and AF-SCREEN international collaboration members were contacted to identify additional studies. Twenty-four eligible studies were identified that performed a single time point screen for AF in a general ambulant population, including people ?65 years. Authors from eligible studies were invited to collaborate and share patient-level data. Statistical analysis was performed using random effects logistic regression for AF detection rate, and Poisson regression modelling for CHA<inf>2</inf>DS<inf>2</inf>-VASc scores. Nineteen studies (14 countries from a mix of low- to middle- and high-income countries) collaborated, with 141,220 participants screened and 1,539 new AF cases. Pooled yield of screening was greater in males across all age strata. The age/sex-adjusted detection rate for screen-detected AF in ?65-year-olds was 1.44% (95% CI, 1.13%-1.82%) and 0.41% (95% CI, 0.31%-0.53%) for <65-year-olds. New AF detection rate increased progressively with age from 0.34% (<60 years) to 2.73% (?85 years). Neither the choice of screening methodology or device, the geographical region, nor the screening setting influenced the detection rate of AF. Mean CHA<inf>2</inf>DS<inf>2</inf>-VASc scores (n = 1,369) increased with age from 1.1 (<60 years) to 3.9 (?85 years); 72% of ?65 years had ?1 additional stroke risk factor other than age/sex. All new AF ?75 years and 66% between 65 and 74 years had a Class-1 OAC recommendation. The NNS-Rx is 83 for ?65 years, 926 for 60-64 years; and 1,089 for <60 years. The main limitation of this study is there are insufficient data on sociodemographic variables of the populations and possible ascertainment biases to explain the variance in the samples. Conclusions: People with screen-detected AF are at elevated calculated stroke risk: above age 65, the majority have a Class-1 OAC recommendation for stroke prevention, and >70% have ?1 additional stroke risk factor other than age/sex. Our data, based on the largest number of screen-detected AF collected to date, show the precise relationship between yield and estimated stroke risk profile with age, and strong dependence for NNS-RX on the age distribution of the population to be screened: essential information for precise cost-effectiveness calculations. 2019 Lowres et al.
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Lowres, Nicole; Giskes, Katrina; Hespe, Charlotte Mary; Freedman, Ben BenAtrial fibrillation (AF) is a significant risk factor for avoidable stroke. Among high-risk patients with AF, stroke risk can be mitigated using oral anticoagulants (OACs), however reduction is largely contingent on physician prescription and patient persistence with OAC therapy. Over the past decade significant advances have occurred, with revisions to clinical practice guidelines relating to management of stroke risk in AF in several countries, and the introduction of non-vitamin K antagonist OACs (NOACs). This paper summarises the evolving body of research examining guideline-based clinician prescription over the past decade, and patient-level factors associated with OAC persistence. The review shows clinicians' management over the past decade has increasingly reflected guideline recommendations, with an increasing proportion of high-risk patients receiving OACs, driven by an upswing in NOACs. However, a treatment gap remains, as 2535% of high-risk patients still do not receive OAC treatment, with great variation between countries. Reduction in stroke risk directly relates to level of OAC prescription and therapy persistence. Persistence and adherence to OAC thromboprophylaxis remains an ongoing issue, with 2-year persistence as low as 50%, again with wide variation between countries and practice settings. Multiple patient-level factors contribute to poor persistence, in addition to concerns about bleeding. Considered review of individual patient's factors and circumstances will assist clinicians to implement appropriate strategies to address poor persistence. This review highlights the interplay of both clinician's awareness of guideline recommendations and understanding of individual patient-level factors which impact adherence and persistence, which are required to reduce the incidence of preventable stroke attributable to AF. 2019. The Korean Society of Cardiology
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Dupuy, Alexander; Ju, Lining Arnold; Passam, Freda H.Microfluidic devices have become an integral method of cardiovascular research as they enable the study of shear force in biological processes, such as platelet function and thrombus formation. Furthermore, microfluidic chips offer the benefits of ex vivo testing of platelet adhesion using small amounts of blood or purified platelets. Microfluidic chips comprise flow channels of varying dimensions and geometries which are connected to a syringe pump. The pump draws blood or platelet suspensions through the channel(s) allowing for imaging of platelet adhesion and thrombus formation by fluorescence microscopy. The chips can be fabricated from various blood-compatible materials. The current protocol uses commercial plastic or in-house polydimethylsiloxane (PDMS) chips. Commercial biochips offer the advantage of standardization whereas in-house chips offer the advantage of decreased cost and flexibility in design. Microfluidic devices are a powerful tool to study the biorheology of platelets and other cell types with the potential of a diagnostic and monitoring tool for cardiovascular diseases. Bio-protocol. All rights reserved.
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Vernon, Stephen Thomas; OSullivan, John F.; Figtree, Gemma A.Dysregulated redox signalling plays a central role in the development and progression of cardiovascular disease (CVD). To date only a small number of biomarkers that reflect cellular redox status have been identified and these markers have not been utilised in the clinical setting. There are currently no good circulating biomarkers that closely represent sub-cellular dysregulated redox signalling in the tissue, arterial wall or myocardium. Improved prognostic ability, and potentially early disease detection and risk stratification may be achieved through a more reflective biomarker of the dysregulated signalling microdomain. Whilst there is no currently identified circulating redox biomarker reflecting the intricacies of sub-cellular redox dysregulation in cardiovascular disease, there are some markers that are either directly or indirectly related to redox state that have been associated with cardiovascular diseases. Metabolomics platforms allow for the measurement of metabolites that are related to or result from lipid and protein oxidation. Metabolomics is an unbiased approach that allows the identification and quantification of small molecules within a biological fluid. Advances in metabolomic platform technologies as well as bioinformatic approaches may allow for the rapid identification and utilisation of novel biomarkers that accurately reflect intracellular redox status relevant to the development of CVD. Omics studies allow incorporation and analysis of large amounts of data that represent the entirety of a particular biological parameter within a biological fluid or tissue. Metabolic signatures identified through metabolomic analysis may be relatively simple, involving a small number of metabolites, or may be complex and may include permutations of hundreds or even thousands of metabolites. These diverse metabolic signatures have a vast array of potential utility including: early disease detection and diagnosis; disease activity and treatment monitoring; and in identifying new biological pathways and potential treatment targets. Systems biology provides a platform to try to unpack the underlying relationships, interconnected networks and mechanisms contained within the complex signatures. Advances in metabolomics technologies, and bioinformatics capabilities will assist in identification and precise measurement of both candidate and unsuspected metabolites in the circulation that reflect dysregulated redox signalling and may be of relevance to clinical practice and our efforts to improve cardiovascular health. Springer Nature Singapore Pte Ltd. 2019.
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Biglari, Sahar; Le, Thi Yen Loan; Tan, Richard P.; Wise, Steven G.; Zambon, Alessandro; Codolo, Gaia; de Bernard, Marina; Ebrahimi Warkiani, Majid; Schindeler, Aaron; Naficy, Sina; Valtchev, Peter; Khademhosseini, Ali U.; Dehghani, FaribaConsiderable progress has been made in the field of microfluidics to develop complex systems for modeling human skin and dermal wound healing processes. While microfluidic models have attempted to integrate multiple cell types and/or 3D culture systems, to date they have lacked some elements needed to fully represent dermal wound healing. This paper describes a cost-effective, multicellular microfluidic system that mimics the paracrine component of early inflammation close to normal wound healing. Collagen and Matrigel are tested as materials for coating and adhesion of dermal fibroblasts and human umbilical vein endothelial cells (HUVECs). The wound-on-chip model consists of three interconnecting channels and is able to simulate wound inflammation by adding tumor necrosis factor alpha (TNF-?) or by triculturing with macrophages. Both the approaches significantly increase IL-1?, IL-6, IL-8 in the supernatant (p < 0.05), and increases in cytokine levels are attenuated by cotreatment with an anti-inflammatory agent, Dexamethasone. Incorporation of M1 and M2 macrophages cocultured with fibroblasts and HUVECs leads to a stimulation of cytokine production as well as vascular structure formation, particularly with M2 macrophages. In summary, this wound-on-chip system can be used to model the paracrine component of the early inflammatory phase of wound healing and has the potential for the screening of anti-inflammatory compounds. 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Vernon, Stephen Thomas; Hansen, Thomas S.; Kott, Katharine A.; Yang, Jean Yee Hwa; OSullivan, John F.; Figtree, Gemma A.Identification of the four standard modifiable cardiovascular risk factors (SMuRFs)diabetes mellitus, hyperlipidaemia, hypertension, and cigarette smokinghas allowed the development of risk scores. These have been used in conjunction with primary and secondary prevention strategies targeting SMuRFs to reduce the burden of CAD. Recent studies show that up to 25% of ACS patients do not have any SMuRFs. Thus, SMuRFs do not explain the entire burden of CAD. There appears to be variation at the individual level rendering some individuals relatively susceptible or resilient to developing atherosclerosis. Important disease pathways remain to be discovered, and there is renewed enthusiasm to discover novel biomarkers, biological mechanisms, and therapeutic targets for atherosclerosis. Two broad approaches are being taken: traditional approaches investigating known candidate pathways and unbiased omics approaches. We review recent progress in the field and discuss opportunities made possible by technological and data science advances. Developments in network analytics and machine learning algorithms used in conjunction with large-scale multi-omic platforms have the potential to uncover biological networks that may not have been identifiable using traditional approaches. These approaches are useful for both biomedical research and precision medicine strategies. 2018 John Wiley & Sons Ltd
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Freedman, Ben Ben; Schnabel, Renate B.; Calkins, Hugh G.[No abstract available]
