Search
Showing 821–840 of 2058 publications.
-
Yu, Teresa; Korgaonkar, Mayuresh S.; Grieve, Stuart M.This study examined patterns of cerebellar volumetric gray matter (GM) loss across the adult lifespan in a large cross-sectional sample. Four hundred and seventy-nine healthy participants (age range: 786years) were drawn from the Brain Resource International Database who provided T1-weighted MRI scans. The spatially unbiased infratentorial template (SUIT) toolbox in SPM8 was used for normalisation of the cerebellum structures. Global volumetric and voxel-based morphometry analyses were performed to evaluate age-associated trends and gender-specific age-patterns. Global cerebellar GM shows a cross-sectional reduction with advancing age of 2.5% per decadeapproximately half the rate seen in the whole brain. The male cerebellum is larger with a lower percentage of GM, however, after controlling for total brain volume, no gender difference was detected. Analysis of age-related changes in GM volume revealed large bilateral clusters involving the vermis and cerebellar crus where regional loss occurred at nearly twice the average cerebellar rate. No gender-specific patterns were detected. These data confirm that regionally specific GM loss occurs in the cerebellum with age, and form a solid base for further investigation to find functional correlates for this global and focal loss. 2016, Springer Science+Business Media New York.
-
Ridiandries, Anisyah; Bursill, C. A.; Tan, Joanne Tsui MingAngiogenesis is involved in the inflammation and proliferation stages of wound healing, to bring inflammatory cells to the wound and provide a microvascular network to maintain new tissue formation. An excess of inflammation, however, leads to prolonged wound healing and scar formation, often resulting in unfavourable outcomes such as amputation. CC-chemokines play key roles in the promotion of inflammation and inflammatory-driven angiogenesis. Therefore, inhibition of the CC-chemokine class may improve wound healing. We aimed to determine if the broad-spectrum CC-chemokine inhibitor 35K could accelerate wound healing in vivo in mice. In a murine wound healing model, 35K protein or phosphate buffered saline (PBS, control) were added topically daily to wounds. Cohorts of mice were assessed in the early stages (four days post-wounding) and in the later stages of wound repair (10 and 21 days post-wounding). Topical application of the 35K protein inhibited CC-chemokine expression (CCL5, CCL2) in wounds and caused enhanced blood flow recovery and wound closure in early-mid stage wounds. In addition, 35K promoted neovascularisation in the early stages of wound repair. Furthermore, 35K treated wounds had significantly lower expression of the p65 subunit of NF-?B, a key inflammatory transcription factor, and augmented wound expression of the pro-angiogenic and pro-repair cytokine TGF-?. These findings show that broad-spectrum CC-chemokine inhibition may be beneficial for the promotion of wound healing. 2017 by the authors.
-
Breukelaar, Isabella A.; Antees, Cassandra; Grieve, Stuart M.; Foster, Sheryl L.; Gomes, Lavier J.; Williams, Leanne M.; Korgaonkar, Mayuresh S.Cognitive control is the process of employing executive functions, such as attention, planning or working memory, to guide appropriate behaviors in order to achieve a specific goal. Functional magnetic resonance imaging studies suggest a superordinate cognitive control network, comprising the dorsal regions of the lateral prefrontal cortex (DLPFC), anterior cingulate cortex (dACC) and parietal cortex (DPC). How gray matter structure changes across this network throughout neurodevelopment and how these changes impact cognitive control are not yet fully understood. Here we investigate changes in gray matter volume of the key nodes of the cognitive control network using structural MRI scans from 176 participants aged 838 years. One hundred and eleven of these also completed a longitudinal follow-up at two years. We compare these with performance on a cognitive battery also measured at these two time points. We found that volume decreases in the cognitive control network were associated with improved performance in executive function (in left DLPFC and bilateral DPC), information processing (in bilateral dACC and right DPC) and emotion identification tasks (left DLPFC). These results were significant after controlling for age. Furthermore, gray matter changes were coordinated across the network. These findings imply age-independent synaptic pruning in the cognitive control network may have a role in improving performance in cognitive domains. This study provides insight into the direct impact of structural changes on behavior within this network during neurodevelopment and provides a normative evidence base to better understand development of cognitive dysfunction in brain disorders. Hum Brain Mapp 38:631643, 2017. 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
-
Zhang, Ling; Gallagher, Robyn D.; Lowres, Nicole; Orchard, Jessica Joan; Freedman, Ben Ben; Neubeck, LisAims and Objectives To investigate whether using the think aloud technique during standard quality of life surveys provides useful additional information about patients experiences of living with atrial fibrillation (AF) and health related quality of life (HRQoL). Background Atrial fibrillation is the most common cardiac arrhythmia and has serious health consequences, particularly ischaemic stroke, high rates of morbidity and mortality and poor HRQoL. Standard quality-of-life questionnaires are often used but may not provide sufficient detail of patients experiences living with AF. Design A qualitative interpretative study based on semi-structured interviews. Methods Patients with AF (n=12) were recruited from the Choice of Health Options in Prevention of Cardiovascular Events-in Atrial Fibrillation (CHOICE-AF), a risk factor management program. Participants were interviewed using a think aloud technique with questions guided by the AF Effects on Quality Of Life Questionnaire (AFEQT) and the Short Form-12 (SF-12). Interviews were audio-recorded, transcribed and analysed thematically. Results Participants had a median age of 71 years (interquartile range 52 to 77 years), and included four women and eight men. Four themes were identified related to experiences of living with AF and HRQoL including: (1) the adverse impact of atrial fibrillation symptoms, treatments, and related knowledge; (2) loss of function or independence; (3) the influence of age; and (4) approach to life. Conclusions Atrial fibrillation, especially in older adults, creates an additional layer of requirements for self-management onto existing self-care needs. Even for patients with relatively high HRQoL, the think aloud technique together with standard HRQoL questionnaires can help identify additional issues that can be addressed by health professionals to improve the HRQoL of these patients. 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)
-
Aggarwal, Shikha; Sunderland, Neroli; Thornton, Charlene Eliza; Xu, Bei; Hennessy, Annemarie; Makris, AngelaBackground Preeclampsia can be caused by shallow trophoblast invasion and results in endothelial dysfunction. Angiotensin II type 1 receptor antibodies may have a role in both processes. Other angiogenic markers (placental growth factor, soluble fms-like tyrosine kinase-1, and soluble endoglin) have been shown to alter before clinically evident preeclampsia. Objective The aim of this study is to assess the longitudinal changes and utility of biomarker angiotensin II type 1 receptor antibodies and angiogenic markers in hypertensive disorders of pregnancy, gestational hypertension, and preeclampsia. Study Design A longitudinal prospective cohort observational study of angiogenic markers and a secondary retrospective case-control study of angiotensin II type 1 receptor antibody changes were conducted. The studies were conducted in a large tertiary metropolitan teaching hospital (Sydney, Australia). Sequential recruitment of women with a singleton pregnancy (N= 351) was undertaken. Plasma concentrations of angiotensin II type 1 receptor antibodies, placental growth factor, soluble fms-like tyrosine kinase-1, and soluble endoglin were measured using validated enzyme-linked immunosorbent assays at 12, 18, 28, 36, and 40 weeks gestation and 6 weeks postpartum. Clinical, demographic, and pregnancy data were prospectively collected. Pregnancy outcomes were classified as normotensive, gestational hypertension, or preeclampsia. Analyses were carried out using software and significance set at P <.05. Results In all, 351 women were recruited, 17 developed gestational hypertension, and 18 developed preeclampsia. Women with preeclampsia at baseline were heavier (P=.015), were taller (P=.046), and had higher systolic (P=.029) and diastolic (P=.006) blood pressure. The preeclampsia group had higher soluble fms-like tyrosine kinase-1 from ?28 weeks (P=.003) and lower placental growth factor from 18 weeks (P=.004). Soluble endoglin and angiotensin II type 1 receptor antibodies did not vary over timeorbetween groups. Angiotensin II type 1 receptor antibody (12weeks)was positively correlated with serum pregnancy associated plasma protein A (P=.008) and human chorionic gonadotrophin (P=.04). Conclusion Angiogenic markers vary longitudinally during pregnancy and placental growth factor and soluble fms-like tyrosine kinase-1 have a role for predicting and diagnosing preeclampsia later in disease. Our data show that angiotensin II type 1 receptor antibodies are not sensitive for disease and hence not useful as a biomarker. Larger studies are required to describe the role and functionality of angiotensin II type 1 receptor antibodies in preeclampsia. 2016
-
Martez, Gonzalo J.; Barraclough, Jennifer Y.; Nakhla, Shirley; Kienzle, Vivian J.; Robertson, Stacy; Mallat, Ziad; Celermajer, David S.; Patel, SanjayTo evaluate (i) local coronary and systemic levels of microparticles (MP) in acute coronary syndrome (ACS) and stable angina pectoris (SAP) patients and (ii) their release after plaque disruption with percutaneous coronary intervention (PCI). MP are small vesicles originating from plasma membranes of cells after activation or apoptosis and are implicated in the pathogenesis of atherosclerosis. Neutrophils play a role in plaque destabilization and shed neutrophil-derived MP that have the potential to drive significant proinflammatory and thrombotic downstream effects. Eight ACS and eight SAP patients were included. Coronary sinus (CS) samples pre-intervention (CS1), 45 s following balloon angioplasty (CS2) and at 45 s intervals following stent deployment (CS3, CS4 and CS5), together with peripheral vein samples, pre- and post-PCI were analysed for neutrophil-derived (CD66b+), endothelial-derived (CD144+), platelet-derived (CD41a+), monocyte-derived (CD14+) and apoptotic (Annexin V+) MP. ELISA for interleukin (IL)-6, myeloperoxidase (MPO) and P-selectin was also performed. CD66b+ MP levels were similar in both groups pre-intervention. Post-PCI, CS levels rose significantly in ACS but not SAP patients (ACS area under the curve (AUC): 549 83, SAP AUC: 24 29, P<0.01). CS CD41a+, CD144+, CD14+ and Annexin V+ MP levels did not differ between groups. Acute neutrophil-derived MP release post-PCI occurs in ACS compared with stable patients, likely to be reflective of plaque MP content in vulnerable lesions. 2017 The Author(s).
-
Xu, Bei; Bobek, Gabriele; Makris, Angela; Hennessy, AnnemarieMedications used to control hypertension in pregnancy also improve trophoblast and endothelial cellular interaction in vitro. Tumour necrosis factor-? (TNF-?) inhibits trophoblast and endothelial cellular interactions and simultaneously decreases endothelial nitric oxide synthase (eNOS) expression. This study investigated whether antihypertensive medications improved these cellular interactions by modulating eNOS and inducible nitric oxide synthase (iNOS) expression. Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre-incubated with (or without) low dose TNF-? (0.5ng/mL) or TNF-? plus soluble fms-like tyrosine kinase-1 (sFlt-1) (100ng/mL). The endothelial cells were cultured on Matrigel. After endothelial cellular networks appeared, trophoblast derived HTR-8/SVneo cells were co-cultured in the presence of clinically relevant doses of methyldopa, labetalol, hydralazine or clonidine for 24hours. Cells were retrieved from the Matrigel to extract mRNA and eNOS and iNOS expression were examined by quantitative PCR. Methyldopa, labetalol, hydralazine and clonidine reversed the inhibitory effect of TNF-? on eNOS mRNA expression. After pre-incubating endothelial cells with TNF-? and sFlt-1, all the medications except methyldopa lost their effect on eNOS mRNA expression. In the absence of TNF-?, antihypertensive medications did not change eNOS expression. The mRNA expression of iNOS was not affected by TNF-? or any medications. This study shows that selected antihypertensive medications used in the treatment of hypertension in pregnancy increase eNOS expression in vitro when induced by the inflammatory TNF-?. The anti-angiogenic molecule sFlt-1 may antagonise the potential benefit of these medications by interfering with the NOS pathway. 2016 John Wiley & Sons Australia, Ltd
-
Ridiandries, Anisyah; Tan, Joanne Tsui Ming; Ravindran, Dhanya; Williams, Helen; Medbury, Heather Jean; Lindsay, Laura A.; Hawkins, Clare L.; Prosser, Hamish C.G.; Bursill, C. A.Increasing evidence shows that CC-chemokines promote inflammatory-driven angiogenesis,with little to no effect on hypoxia-mediated angiogenesis. Inhibition of the CC-chemokine class may therefore affect angiogenesis differently depending on the pathophysiological context.We compared the effect of CCchemokine inhibition in inflammatory and physiological conditions. In vitro, the broad-spectrum CCchemokine inhibitor "35K" inhibited inflammatory-induced endothelial cell proliferation, migration, and tubulogenesis, with more modest effects in hypoxia. In vivo, adenoviruses were used to overexpress 35K (Ad35K) and GFP (AdGFP, control virus). Plasma chemokine activity was suppressed by Ad35K in both models. In the periarterial femoral cuff model of inflammatory-driven angiogenesis, overexpression of 35K inhibited adventitial neovessel formation compared with control AdGFP-infused mice. In contrast, 35K preserved neovascularization in the hindlimb ischemia model and had no effect on physiological neovascularization in the chick chorioallantoic membrane assay. Mechanistically, 2 key angiogenic proteins (VEGF and hypoxia-inducible factor-1a) were conditionally regulated by 35K, such that expression was inhibited in inflammation but was unchanged in hypoxia. In conclusion, CC-chemokine inhibition by 35K suppresses inflammatory-driven angiogenesis while preserving physiological ischemia-mediated angiogenesis via conditional regulation of VEGF and hypoxia-inducible factor-1a. CC-chemokine inhibition may be an alternative therapeutic strategy for suppressing diseases associated with inflammatory angiogenesis without inducing the side effects caused by global inhibition. FASEB.
-
Ravindran, Dhanya; Ridiandries, Anisyah; Vanags, Laura Z.; Henriquez, Rodney; Cartland, Si; Tan, Joanne Tsui Ming; Bursill, C. A.Chemokines are important in macrophage recruitment and the progression of atherosclerosis. The 'M3' chemokine binding protein inactivates key chemokines involved in atherosclerosis (e.g. CCL2, CCL5 and CX<inf>3</inf>CL1). We aimed to determine the effect of M3 on plaque development and composition. In vitro chemotaxis studies confirmed that M3 protein inhibited the activity of chemokines CCL2, CCL5 and CX<inf>3</inf>CL1 as primary human monocyte migration as well as CCR2-, CCR5- and CX3CR1-directed migration was attenuated by M3. In vivo, adenoviruses encoding M3 (AdM3) or green fluorescence protein (AdGFP; control) were infused systemically into apolipoprotein (apo)-E-/- mice. Two models of atherosclerosis development were used in which the rate of plaque progression was varied by diet including: (1) a 'rapid promotion' model (6-week high-fat-fed) and (2) a 'slow progression' model (12-week chow-fed). Plasma chemokine activity was suppressed in AdM3-infused mice as indicated by significantly less monocyte migration towards AdM3 mouse plasma ex vivo (29.56%, p = 0.014). In the 'slow progression' model AdM3 mice had reduced lesion area (45.3%, p = 0.035) and increased aortic smooth muscle cell ?-actin expression (60.3%, p = 0.014). The reduction in lesion size could not be explained by changes in circulating inflammatory monocytes as they were higher in the AdM3 group. In the 'rapid promotion' model AdM3 mice had no changes in plaque size but reduced plaque macrophage content (46.8%, p = 0.006) and suppressed lipid deposition in thoracic aortas (66.9%, p<0.05). There was also a reduction in phosphorylated p65, the active subunit of NF-?b, in the aortas of AdM3 mice (37.3%, p<0.0001). M3 inhibited liver CCL2 concentrations in both models with no change in CCL5 or systemic chemokine levels. These findings show M3 causes varying effects on atherosclerosis progression and plaque composition depending on the rate of lesion progression. Overall, our studies support a promising role for chemokine inhibition with M3 for the treatment of atherosclerosis. 2017 Ravindran et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
-
Chan, Alex H.P.; Tan, Richard P.; Michael, Praveesuda Lorwattanapongsa; Lee, Bob S.L.; Vanags, Laura Z.; Ng, Martin K.C.; Bursill, C. A.; Wise, Steven G.Current animal models for the evaluation of synthetic grafts are lacking many of the molecular tools and transgenic studies available to other branches of biology. A mouse model of vascular grafting would allow for the study of molecular mechanisms of graft failure, including in the context of clinically relevant disease states. In this study, we comprehensively characterise a sutureless grafting model which facilitates the evaluation of synthetic grafts in the mouse carotid artery. Using conduits electrospun from polycaprolactone (PCL) we show the gradual development of a significant neointima within 28 days, found to be greatest at the anastomoses. Histological analysis showed temporal increases in smooth muscle cell and collagen content within the neointima, demonstrating its maturation. Endotheliali-sation of the PCL grafts, assessed by scanning electron microscopy (SEM) analysis and CD31 staining, was near complete within 28 days, together replicating two critical aspects of graft performance. To further demonstrate the potential of this mouse model, we used longitudinal non-invasive tracking of bone-marrow mononuclear cells from a transgenic mouse strain with a dual reporter construct encoding both luciferase and green fluorescent protein (GFP). This enabled characterisation of mononuclear cell homing and engraftment to PCL using bioluminescence imaging and histological staining over time (7, 14 and 28 days). We observed peak luminescence at 7 days post-graft implantation that persisted until sacrifice at 28 days. Collectively, we have established and characterised a high-throughput model of grafting that allows for the evaluation of key clinical drivers of graft performance. 2017 Chan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
-
Indja, Ben Elias; Fanning, Jonathon Paul; Maller, Jerome Joseph; Fraser, John F.; Bannon, Paul Gerard; Vallely, Michael P.; Grieve, Stuart M.Cognitive dysfunction is a poorly understood but potentially devastating complication of cardiac surgery. Clinically meaningful assessment of cognitive changes after surgery is problematic because of the absence of a means to obtain reproducible, objective, and quantitative measures of the neural disturbances that cause altered brain function. By using both structural and functional connectivity magnetic resonance imaging data to construct a map of the inter-regional connections within the brain, connectomics has the potential to increase the specificity and sensitivity of perioperative neurological assessment, permitting rational individualized assessment and improvement of surgical techniques. 2017 The Author(s)
-
Zukor, Katherine A.; Wang, Hong; Hurst, Brett L.; Siddharthan, Venkatraman; Van Wettere, Arnaud J.N.J.; Pilowsky, Paul M.; Morrey, John D.Neurological respiratory deficits are serious outcomes of West Nile virus (WNV) disease. WNV patients requiring intubation have a poor prognosis. We previously reported that WNV-infected rodents also appear to have respiratory deficits when assessed by whole-body plethysmography and diaphragmatic electromyography. The purpose of this study was to determine if the nature of the respiratory deficits in WNV-infected rodents is neurological and if deficits are due to a disorder of brainstem respiratory centers, cervical spinal cord (CSC) phrenic motor neuron (PMN) circuitry, or both. We recorded phrenic nerve (PN) activity and found that in WNV-infected mice, PN amplitude is reduced, corroborating a neurological basis for respiratory deficits. These results were associated with a reduction in CSC motor neuron number. We found no dramatic deficits, however, in brainstem-mediated breathing rhythm generation or responses to hypercapnia. PN frequency and pattern parameters were normal, and all PN parameters changed appropriately upon a CO<inf>2</inf> challenge. Histological analysis revealed generalized microglia activation, astrocyte reactivity, T cell and neutrophil infiltration, and mild histopathologic lesions in both the brainstem and CSC, but none of these were tightly correlated with PN function. Similar results in PN activity, brainstem function, motor neuron number, and histopathology were seen in WNV-infected hamsters, except that histopathologic lesions were more severe. Taken together, the results suggest that respiratory deficits in acute WNV infection are primarily due to a lower motor neuron disorder affecting PMNs and the PN rather than a brainstem disorder. Future efforts should focus on markers of neuronal dysfunction, axonal degeneration, and myelination. 2016, The Author(s).
-
Kavurma, Mary M.; Rayner, Katey J.; Karunakaran, DenujaPurpose of review To highlight recent studies that describe novel inflammatory and signaling mechanisms that regulate macrophage death in atherosclerosis. Recent findings Macrophages contribute to all stages of atherosclerosis. The traditional dogma states that in homeostatic conditions, macrophages undergo apoptosis and are efficiently phagocytosed to be cleared by a process called efferocytosis. In advanced atherosclerosis, however, defective efferocytosis results in secondary necrosis of these uncleared apoptotic cells, which ultimately contributes to the formation of the characteristic necrotic core and the vulnerable plaque. Here, we outline the different types of lesional macrophage death: Apoptosis, autophagic and the newly defined necroptosis (i.e. a type of programmed necrosis). Recent discoveries demonstrate that macrophage necroptosis directly contributes to necrotic core formation and plaque instability. Further, promoting the resolution of inflammation using preresolving mediators has been shown to enhance efferocytosis and decrease plaque vulnerability. Finally, the canonical 'don't eat me' signal CD47 has recently been described as playing an important role in atherosclerotic lesion progression by impairing efficient efferocytosis. Although we have made significant strides in improving our understanding of cell death and clearance mechanisms in atherosclerosis, there still remains unanswered questions as to how these pathways can be harnessed using therapeutics to promote lesion regression and disease stability. Summary Improving our understanding of the mechanisms that regulate macrophage death in atherosclerosis, in particular apoptosis, necroptosis and efferocytosis, will provide novel therapeutic opportunities to resolve atherosclerosis and promote plaque stability. Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved.
-
Iseger, Tabitha A.; Korgaonkar, Mayuresh S.; Kenemans, Johannes Leon; Grieve, Stuart M.; Baeken, Chris; Fitzgerald, Paul B.; Arns, Martijn W.Antidepressant medication is the most common treatment for major depressive disorder (MDD), however, the precise working mechanism underlying these treatments remains unclear. Recent neuromodulation treatments demonstrate that direct stimulation of the dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and subgenual anterior cingulate (sgACC) relate to clinical improvement, suggesting connectivity alterations of the DLPFC-DMPFC-sgACC network to mediate antidepressant response. The international Study to Predict Optimized Treatment in Depression (iSPOT-D) is an international multicentre study that collected EEG data for 1008 MDD patients, randomized to 3 different antidepressant medications (N=447 MDD with complete pre- and post-treatment data and N=336 non-MDD). Treatment response was defined by a decline of >50% on the Hamilton Rating Score for Depression (HRSD<inf>17</inf>). We investigated whether connectivity in alpha and theta frequencies of the DLPFC-DMPFC-sgACC network changed from pre- to post-treatment between: (i) patients and controls, and (ii) responders (R) and non-responders (NR). Women exhibited higher alpha and theta connectivity compared to males, both pre- and post-treatment. Furthermore, theta, but not alpha, hypo-connectivity was found for MDD patients. A decreased alpha connectivity after treatment was found only for male responders, while non-responders and females exhibited no changes in alpha connectivity. Decreasing alpha connectivity could potentially serve as a treatment emergent biomarker, in males only. Furthermore, it could be useful to a priori stratify by gender for future MDD studies. 2017 Elsevier B.V. and ECNP
-
Callaghan, Fraser Maurice; Arnott, Clare; Figtree, Gemma A.; Kutty, Shelby; Celermajer, David S.; Grieve, Stuart M.Purpose: To quantitatively characterize the central role of vortex formation on the flow patterns and energy transfer within the right atrium (RA). Materials and Methods: 4D-flow magnetic resonance imaging (MRI) data with multiple encoding velocities was acquired in 12 healthy subjects at 3T. Particles entering the RA were classified according to the origin of entry. Vortex membership was numerically derived by assessing the location of pathline center of curvature relative to the vortex core, defined by Q-criteria. Flow dynamics and energetics were assessed using paired t-tests. Results: The majority of flow (74%) passes through the RA in a single beat, with a very small volume fraction retained longer than two beats (<1%). RA flow was dominated by a governing vortex, comprising 79% of total flow, and acting to preserve kinetic energy. Flow comprising the vortex enters the RA significantly earlier than nonvortex flow (P < 0.01). The majority of nonvortex flow enters the RA during systole, traversing the RA via a direct path with a significantly shorter residence time and distance traveled (both P < 0.01). Conclusion: Blood flow momentum is preserved during systole within a dominant vortex, which we are able to characterize numerically using a semiautomated approach. Our analytical approach has potential for application to understanding right heart function in health and disease. Level of Evidence: 1. J. Magn. Reson. Imaging 2017;45:11. 2017 International Society for Magnetic Resonance in Medicine
-
Stevens, Michael Charles; Callaghan, Fraser Maurice; Forrest, Paul; Bannon, Paul Gerard; Grieve, Stuart M.Peripheral veno-arterial extra-corporeal membrane oxygenation (ECMO) is an artificial circulation that supports patients with severe cardiac and respiratory failure. Differential hypoxia during ECMO support has been reported, and it has been suggested that it is due to the mixing of well-perfused retrograde ECMO flow and poorly-perfused antegrade left ventricle (LV) flow in the aorta. This study aims to quantify the relationship between ECMO support level and location of the mixing zone (MZ) of the ECMO and LV flows. Steady-state and transient computational fluid dynamics (CFD) simulations were performed using a patient-specific geometrical model of the aorta. A range of ECMO support levels (from 5% to 95% of total cardiac output) were evaluated. For ECMO support levels above 70%, the MZ was located in the aortic arch, resulting in perfusion of the arch branches with poorly perfused LV flow. The MZ location was stable over the cardiac cycle for high ECMO flows (>70%), but moved 5cm between systole and diastole for ECMO support level of 60%. This CFD approach has potential to improve individual patient care and ECMO design. 2017 Elsevier Ltd
-
Non-invasive tracking of injected bone marrow mononuclear cells to injury and implanted biomaterialsTan, Richard P.; Lee, Bob S.L.; Chan, Alex H.P.; Yuen, Sui Ching G.; Hung, Juichien; Wise, Steven G.; Ng, Martin K.C.Biomaterial scaffolds enhancing the engraftment of transplanted bone-marrow mononuclear cells (BM-MNC) have enormous potential for tissue regeneration applications. However, development of appropriate materials is challenging given the precise microenvironments required to support BM-MNC engraftment and function. In this study, we have developed a non-invasive, real-time tracking model of injected BM-MNC engraftment to wounds and implanted biomaterial scaffolds. BM-MNCs, encoded with firefly luciferase and enhanced GFP reporter genes, were tail vein injected into subcutaneously wounded mice. Luciferase-dependent cell bioluminescence curves revealed our injected BM-MNCs homed to and engrafted within subcutaneous wound sites over the course of 21days. Further immunohistochemical characterization showed that these engrafted cells drove functional changes by increasing the number of immune cells present at early time points and remodelling cell phenotypes at later time points. Using this model, we subcutaneously implanted electrospun polycaprolactone (PCL) and PCL/Collagen scaffolds, to determine differences in exogenous BM-MNC response to these materials. Following BM-MNC injection, immunohistochemical analysis revealed a high exogenous BM-MNC density around the periphery of PCL scaffolds consistent with a classical foreign body response. In contrast, transplanted BM-MNCs engrafted throughout PCL/Collagen scaffolds indicating an improved biological response. Importantly, these differences were closely correlated with the real-time bioluminescence curves, with PCL/Collagen scaffolds exhibiting a?2-fold increase in maximum bioluminescence compared with PCL scaffolds. Collectively, these results demonstrate a new longitudinal cell tracking model that can non-invasively determine transplanted BM-MNC homing and engraftment to biomaterials, providing a valuable tool to inform the design scaffolds that help augment current BM-MNC tissue engineering strategies. Statement of Significance Tracking the dynamic behaviour of transplanted bone-marrow mononuclear cells (BM-MNCs) is a long-standing research goal. Conventional methods involving contrast and tracer agents interfere with cellular function while also yielding false signals. The use of bioluminescence addresses these shortcomings while allowing for real-time non-invasive tracking in vivo. Given the failures of transplanted BM-MNCs to engraft into injured tissue, biomaterial scaffolds capable of attracting and enhancing BM-MNC engraftment at sites of injury are highly sought in numerous tissue engineering applications. To this end, the results from this study demonstrate a new longitudinal tracking model that can non-invasively determine exogenous BM-MNC homing and engraftment to biomaterials, providing a valuable tool to inform the design of scaffolds with implications for countless tissue engineering applications. 2017 Acta Materialia Inc.
-
Thompson, Peter Lindsay; Davis, Timothy M.E.Purpose The purpose of this study was to review the results of clinical trials assessing the cardiovascular effects of drugs for type 2 diabetes and the cardiovascular effects of newer available drugs. Methods We performed a detailed search of PubMed-listed publications, reports from international meetings, and ongoing studies from clinical trials.gov. Findings Currently available drugs have neutral or, in some cases, negative effects on cardiovascular outcomes. Modern sulfonylureas appear to be safe, although the biguanide metformin has a slightly better cardiovascular safety profile than the sulfonylureas and is the first choice for monotherapy. The cardiovascular tolerability of thiazolidinediones (glitazones) remains controversial, with particularly adverse effects in patients with cardiac failure. The cardiovascular effects of insulin in type 2 diabetes appear neutral. Newer incretin-based therapies have been closely examined in a large number of clinical trials, some of which are still ongoing. The dipeptidyl peptidase-4 inhibitor (gliptins) trials to date have all found a neutral effect. Of the glucagon-like peptide-1 (GLP-1) agonists, lixisenatide had a neutral effect, whereas liraglutide and semaglutide had a benefit on outcomes. The results of the sodium-glucose transporter-2 (SGLT-2) inhibitor empaglifozin attracted interest when it was the first to report a strong benefit on cardiovascular mortality. Liraglutide and semaglutide had a neutral effect on cardiac failure admissions, whereas empaglifozin had a benefit. In each of the trials, there was not a clear effect on myocardial infarction and stroke. The mechanism of the cardiovascular benefit is debated, and further studies with other GLP-1 agonists and SGLT-2 inhibitors are awaited. Implications After 2 decades of disappointment in attempting to control cardiovascular progression in type 2 diabetes with careful glycemic control, there is distinct hope that newer drugs, particularly the GLP-1 agonists and the SGLT-2 inhibitors, will have cardiovascular benefits independent of glycemic control. 2017 Elsevier HS Journals, Inc.
-
Clayton, Zoe E.; Yuen, Gloria S.C.; Sadeghipour, Sara; Hywood, Jack D.; Wong, Jack W.T.; Huang, Ngan Fong Tina; Ng, Martin K.C.; Cooke, John P.; Patel, SanjayBackground Endothelial cells derived from human induced pluripotent stem cells (iPSC-ECs) promote angiogenesis, and more recently induced endothelial cells (iECs) have been generated via fibroblast trans-differentiation. These cell types have potential as treatments for peripheral arterial disease (PAD). However, it is unknown whether different reprogramming methods produce cells that are equivalent in terms of their pro-angiogenic capabilities. Objectives We aimed to directly compare iPSC-ECs and iECs in an animal model of PAD, in order to identify which cell type, if any, displays superior therapeutic potential. Methods IPSC-ECs and iECs were generated from human fibroblasts, and transduced with a reporter construct encoding GFP and firefly luciferase for bioluminescence imaging (BLI). Endothelial phenotype was confirmed using in vitro assays. NOD-SCID mice underwent hindlimb ischaemia surgery and received an intramuscular injection of either 1נ106 iPSC-ECs, 1נ106 iECs or control vehicle only. Perfusion recovery was measured by laser Doppler. Hindlimb muscle samples were taken for histological analyses. Results Perfusion recovery was enhanced in iPSC-EC treated mice on day 14 (Control vs. iPSC-EC; 0.350.04 vs. 0.540.08, p<0.05) and in iEC treated mice on days 7 (Control vs. iEC; 0.230.02 vs. 0.440.06, p<0.05), 10 (0.310.04 vs. 0.640.07, p<0.001) and 14 (0.350.04 vs. 0.680.07, p<0.001) post-treatment. IEC-treated mice also had greater capillary density in the ischaemic gastrocnemius muscle (Control vs. iEC; 12510 vs. 17911 capillaries/image; p<0.05). BLI detected iPSC-EC and iEC presence in vivo for two weeks post-treatment. Conclusions IPSC-ECs and iECs exhibit similar, but not identical, endothelial functionality and both cell types enhance perfusion recovery after hindlimb ischaemia. 2017 Elsevier B.V.
-
Chong, Albert Y.; Doyle, Barry J.; Jansen, Shirley Jane; Ponosh, Stefan; Cisonni, Julien; Sun, ZhonghuaCovered Endovascular Reconstruction of Aortic Bifurcation (CERAB) is a new technique to treat extensive aortoiliac occlusive disease with covered expandable stent grafts to rebuild the aortoiliac bifurcation. Post stenting Doppler ultrasound (DUS) measurement of maximum peak systolic velocity (PSV<inf>max</inf>) in the stented segment is widely used to determine patency and for follow up surveillance due to the portability, affordability and ease of use. Anecdotally, changes in hemodynamics created by CERAB can lead to falsely high PSV<inf>max</inf> requiring CT angiography (CTA) for further assessment. Therefore, the importance of DUS would be enhanced with a proposed PSV<inf>max</inf> prediction tool to ascertain whether PSV<inf>max</inf> falls within the acceptable range of prediction. We have developed a prediction tool based on idealized models of aortoiliac bifurcations with various infra-renal PSV (PSV<inf>in</inf>), iliac to aortic area ratios (R) and aortoiliac bifurcation angles (?). Taguchi method with orthogonal arrays (OA) was utilized to minimize the number of Computational Fluid Dynamics (CFD) simulations performed under physiologically realistic conditions. Analysis of Variance (ANOVA) and Multiple Linear Regression (MLR) analyses were performed to assess Goodness of fit and to predict PSV<inf>max.</inf> PSV<inf>in</inf> and R were found to contribute 94.06% and 3.36% respectively to PSV<inf>max</inf>. The Goodness of fit based on adjusted R2 improved from 99.1% to 99.9% based on linear and exponential functions. The PSV<inf>max</inf> predictor based on the exponential model was evaluated with sixteen patient specific cases with a mean prediction error of 9.9% and standard deviation of 6.4%. Eleven out of sixteen cases (69%) in our current retrospective studies would have avoided CTA if the proposed predictor was used to screen out DUS measured PSV<inf>max</inf> with prediction error greater than 15%. The predictor therefore has the potential to be used as a clinical tool to detect PSV<inf>max</inf> more accurately post aortoiliac stenting and might reduce diagnostic errors and avoid unnecessary expense and risk from CTA follow-up imaging. 2017 Elsevier Ltd
