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Sample records for enhances cardiac commitment

  1. Hepatocyte growth factor (HGF) enhances cardiac commitment of differentiating embryonic stem cells by activating PI3 kinase

    SciTech Connect

    Roggia, Cristiana; Ukena, Christian; Boehm, Michael; Kilter, Heiko . E-mail: kilter@med-in.uni-saarland.de

    2007-03-10

    Hepatocyte growth factor (HGF) is a pleiotropic cytokine promoting proliferation, migration and survival in several cell types. HGF and its cognate receptor c-Met are expressed in cardiac cells during early cardiogenesis, but data concerning its role in cardiac differentiation of embryonic stem cells (ESCs) and the underlying molecular mechanisms involved are limited. In the present study we show that HGF significantly increases the number of beating embryoid bodies of differentiating ESCs without affecting beating frequency. Furthermore, HGF up-regulates the expression of the cardiac-specific transcription factors Nkx 2.5 and GATA-4 and of markers of differentiated cardiomyocytes, i.e. {alpha}-MHC, {beta}-MHC, ANF, MLC2v and Troponin T. The HGF-induced increase in Nkx 2.5 expression was inhibited by co-treatment with the PI3 kinase inhibitors Wortmannin and LY294002, but not by its inactive homolog LY303511, suggesting an involvement of the PI3 kinase/Akt pathway in this effect. We conclude that HGF is an important growth factor involved in cardiac differentiation and/or proliferation of ESCs and may therefore be critical for the in vitro generation of pre- or fully differentiated cardiomyocytes as required for clinical use of embryonic stem cells in cardiac diseases.

  2. Cardiac Progenitor Cell Commitment is Inhibited by Nuclear Akt Expression

    PubMed Central

    Fischer, Kimberlee M.; Din, Shabana; Gude, Natalie; Konstandin, Mathias H.; Wu, Weitao; Quijada, Pearl; Sussman, Mark A.

    2011-01-01

    Rationale Stem cell therapies to regenerate damaged cardiac tissue represent a novel approach to treat heart disease. However, the majority of adoptively transferred stem cells delivered to damaged myocardium do not survive long enough to impart protective benefits, resulting in modest functional improvements. Strategies to improve survival and proliferation of stem cells show promise for significantly enhancing cardiac function and regeneration. Objective Determine if injected cardiac progenitor cells (CPCs) genetically modified to overexpress nuclear Akt (CPCeA) increase structural and functional benefits to infarcted myocardium relative to control CPCs. Methods and Results CPCeA exhibit significantly increased proliferation and secretion of paracrine factors compared to CPCs. However, CPCeA exhibit impaired capacity for lineage commitment in vitro. Infarcted hearts receiving intramyocardial injection of CPCeA have increased recruitment of endogenous c-kit cells compared to CPCs, but neither population provides long-term functional and structural improvements compared to saline injected controls. Pharmacologic inhibition of Akt alleviated blockade of lineage commitment in CPCeA. Conclusions Although overexpression of nuclear Akt promotes rapid proliferation and secretion of protective paracrine factors, the inability of CPCeA to undergo lineage commitment hinders their capacity to provide functional or structural benefits to infarcted hearts. Despite enhanced recruitment of endogenous CPCs, lack of functional improvement in CPCeA treated hearts demonstrates CPC lineage commitment is essential to the regenerative response. Effective stem cell therapies must promote cellular survival and proliferation without inhibiting lineage commitment. Since CPCeA exhibit remarkable proliferative potential, an inducible system mediating nuclear Akt expression could be useful to augment cell therapy approaches. PMID:21350213

  3. Haptoglobin Enhances Cardiac Transplant Rejection

    PubMed Central

    Shen, Hua; Heuzey, Elizabeth; Mori, Daniel; Wong, Christine; Colangelo, Christopher; Chung, Lisa M.; Bruce, Can; Slizovskiy, Ilya B.; Booth, Carmen J.; Kreisel, Daniel; Goldstein, Daniel R.

    2015-01-01

    Rationale Early graft inflammation enhances both acute and chronic rejection of heart transplants, but it is unclear how this inflammation is initiated. Objective To identify specific inflammatory modulators and determine their underlying molecular mechanisms after cardiac transplantation. Methods and Results We used a murine heterotopic cardiac transplant model to identify inflammatory modulators of early graft inflammation. Unbiased mass spectrometric analysis of cardiac tissue before and up to 72 hours after transplantation revealed that 22 proteins including haptoglobin, a known anti-oxidant, are significantly upregulated in our grafts. Through the use of haptoglobin deficient mice, we show that 80% of haptoglobin deficient recipients treated with peri-operative administration of the costimulatory blocking agent CTLA4 immunoglobulin exhibited > 100 days survival of full major histocompatibility complex mismatched allografts, whereas all similarly treated wild type recipients rejected their transplants by 21 days post transplantation. We found that haptoglobin modifies the intra-allograft inflammatory milieu by enhancing levels of the inflammatory cytokine IL-6 and the chemokine MIP-2 but impair levels of the immunosuppressive cytokine IL-10. Haptoglobin also enhances dendritic cell graft recruitment and augments anti-donor T cell responses. Moreover, we confirmed that the protein is present in human cardiac allograft specimens undergoing acute graft rejection. Conclusions Our findings provide new insights into the mechanisms of inflammation after cardiac transplantation and suggest that, in contrast to its prior reported anti-oxidant function in vascular inflammation, haptoglobin is an enhancer of inflammation after cardiac transplantation. Haptoglobin may also be a key component in other sterile inflammatory conditions. PMID:25801896

  4. Enhanced autophagy ameliorates cardiac proteinopathy

    PubMed Central

    Bhuiyan, Md. Shenuarin; Pattison, J. Scott; Osinska, Hanna; James, Jeanne; Gulick, James; McLendon, Patrick M.; Hill, Joseph A.; Sadoshima, Junichi; Robbins, Jeffrey

    2013-01-01

    Basal autophagy is a crucial mechanism in cellular homeostasis, underlying both normal cellular recycling and the clearance of damaged or misfolded proteins, organelles and aggregates. We showed here that enhanced levels of autophagy induced by either autophagic gene overexpression or voluntary exercise ameliorated desmin-related cardiomyopathy (DRC). To increase levels of basal autophagy, we generated an inducible Tg mouse expressing autophagy-related 7 (Atg7), a critical and rate-limiting autophagy protein. Hearts from these mice had enhanced autophagy, but normal morphology and function. We crossed these mice with CryABR120G mice, a model of DRC in which autophagy is significantly attenuated in the heart, to test the functional significance of autophagy activation in a proteotoxic model of heart failure. Sustained Atg7-induced autophagy in the CryABR120G hearts decreased interstitial fibrosis, ameliorated ventricular dysfunction, decreased cardiac hypertrophy, reduced intracellular aggregates and prolonged survival. To determine whether different methods of autophagy upregulation have additive or even synergistic benefits, we subjected the autophagy-deficient CryABR120G mice and the Atg7-crossed CryABR120G mice to voluntary exercise, which also upregulates autophagy. The entire exercised Atg7-crossed CryABR120G cohort survived to 7 months. These findings suggest that activating autophagy may be a viable therapeutic strategy for improving cardiac performance under proteotoxic conditions. PMID:24177425

  5. Brg1 modulates enhancer activation in mesoderm lineage commitment

    DOE PAGESBeta

    Alexander, Jeffrey M.; Hota, Swetansu K.; He, Daniel; Thomas, Sean; Ho, Lena; Pennacchio, Len A.; Bruneau, B. G.

    2015-03-26

    The interplay between different levels of gene regulation in modulating developmental transcriptional programs, such as histone modifications and chromatin remodeling, is not well understood. Here, we show that the chromatin remodeling factor Brg1 is required for enhancer activation in mesoderm induction. In an embryonic stem cell-based directed differentiation assay, the absence of Brg1 results in a failure of cardiomyocyte differentiation and broad deregulation of lineage-specific gene expression during mesoderm induction. We find that Brg1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at distal enhancers that are activated during mesoderm induction. Brg1 is also requiredmore » to maintain Polycomb-mediated repression of non-mesodermal developmental regulators, suggesting cooperativity between Brg1 and Polycomb complexes. Thus, Brg1 is essential for modulating active and repressive chromatin states during mesoderm lineage commitment, in particular the activation of developmentally important enhancers. In conclusion, these findings demonstrate interplay between chromatin remodeling complexes and histone modifications that, together, ensure robust and broad gene regulation during crucial lineage commitment decisions.« less

  6. Brg1 modulates enhancer activation in mesoderm lineage commitment

    SciTech Connect

    Alexander, Jeffrey M.; Hota, Swetansu K.; He, Daniel; Thomas, Sean; Ho, Lena; Pennacchio, Len A.; Bruneau, B. G.

    2015-03-26

    The interplay between different levels of gene regulation in modulating developmental transcriptional programs, such as histone modifications and chromatin remodeling, is not well understood. Here, we show that the chromatin remodeling factor Brg1 is required for enhancer activation in mesoderm induction. In an embryonic stem cell-based directed differentiation assay, the absence of Brg1 results in a failure of cardiomyocyte differentiation and broad deregulation of lineage-specific gene expression during mesoderm induction. We find that Brg1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at distal enhancers that are activated during mesoderm induction. Brg1 is also required to maintain Polycomb-mediated repression of non-mesodermal developmental regulators, suggesting cooperativity between Brg1 and Polycomb complexes. Thus, Brg1 is essential for modulating active and repressive chromatin states during mesoderm lineage commitment, in particular the activation of developmentally important enhancers. In conclusion, these findings demonstrate interplay between chromatin remodeling complexes and histone modifications that, together, ensure robust and broad gene regulation during crucial lineage commitment decisions.

  7. Enhancing Commitment Improves Adherence to a Medical Regimen.

    ERIC Educational Resources Information Center

    Putnam, Dana E.; And Others

    1994-01-01

    Evaluated commitment-based intervention for improvement of adherence to 10-day antibiotic regimen. Subjects were 60 college students. Experimental subjects made verbal and written commitments for adherence and completed tasks designed to increase their investment in medication regimen. Controls performed similarly structured tasks unrelated to…

  8. Commitment to Change Instrument Enhances Program Planning, Implementation, and Evaluation

    ERIC Educational Resources Information Center

    White, Marc I.; Grzybowski, Stefan; Broudo, Marc

    2004-01-01

    Introduction: This study investigates the use of a commitment to change (CTC) instrument as an integral approach to continuing medical education (CME) planning, implementation, and evaluation and as a means of facilitating physician behavior change. Methods: Descriptive statistics and grounded theory methods were employed. Data were collected from…

  9. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress

    PubMed Central

    Liu, Li; Goldberg, Ira J.

    2015-01-01

    Elevated cardiac triacylglycerol (TAG) content is traditionally equated with cardiolipotoxicity and suggested to be a culprit in cardiac dysfunction. However, previous work demonstrated that myosin heavy-chain–mediated cardiac-specific overexpression of diacylglycerol transferase 1 (MHC-DGAT1), the primary enzyme for TAG synthesis, preserved cardiac function in two lipotoxic mouse models despite maintaining high TAG content. Therefore, we examined whether increased cardiomyocyte TAG levels due to DGAT1 overexpression led to changes in cardiac TAG turnover rates under normoxia and ischemia-reperfusion conditions. MHC-DGAT1 mice had elevated TAG content and synthesis rates, which did not alter cardiac function, substrate oxidation, or myocardial energetics. MHC-DGAT1 hearts had ischemia-induced lipolysis; however, when a physiologic mixture of long-chain fatty acids was provided, enhanced TAG turnover rates were associated with improved functional recovery from low-flow ischemia. Conversely, exogenous supply of palmitate during reperfusion suppressed elevated TAG turnover rates and impaired recovery from ischemia in MHC-DGAT1 hearts. Collectively, this study shows that elevated TAG content, accompanied by enhanced turnover, does not adversely affect cardiac function and, in fact, provides cardioprotection from ischemic stress. In addition, the results highlight the importance of exogenous supply of fatty acids when assessing cardiac lipid metabolism and its relationship with cardiac function. PMID:25858561

  10. Enhancing Cardiac Triacylglycerol Metabolism Improves Recovery From Ischemic Stress.

    PubMed

    Kolwicz, Stephen C; Liu, Li; Goldberg, Ira J; Tian, Rong

    2015-08-01

    Elevated cardiac triacylglycerol (TAG) content is traditionally equated with cardiolipotoxicity and suggested to be a culprit in cardiac dysfunction. However, previous work demonstrated that myosin heavy-chain-mediated cardiac-specific overexpression of diacylglycerol transferase 1 (MHC-DGAT1), the primary enzyme for TAG synthesis, preserved cardiac function in two lipotoxic mouse models despite maintaining high TAG content. Therefore, we examined whether increased cardiomyocyte TAG levels due to DGAT1 overexpression led to changes in cardiac TAG turnover rates under normoxia and ischemia-reperfusion conditions. MHC-DGAT1 mice had elevated TAG content and synthesis rates, which did not alter cardiac function, substrate oxidation, or myocardial energetics. MHC-DGAT1 hearts had ischemia-induced lipolysis; however, when a physiologic mixture of long-chain fatty acids was provided, enhanced TAG turnover rates were associated with improved functional recovery from low-flow ischemia. Conversely, exogenous supply of palmitate during reperfusion suppressed elevated TAG turnover rates and impaired recovery from ischemia in MHC-DGAT1 hearts. Collectively, this study shows that elevated TAG content, accompanied by enhanced turnover, does not adversely affect cardiac function and, in fact, provides cardioprotection from ischemic stress. In addition, the results highlight the importance of exogenous supply of fatty acids when assessing cardiac lipid metabolism and its relationship with cardiac function. PMID:25858561

  11. Cardiac Rehabilitation

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Cardiac Rehabilitation? Cardiac rehabilitation (rehab) is a medically supervised program ... be designed to meet your needs. The Cardiac Rehabilitation Team Cardiac rehab involves a long-term commitment ...

  12. Secondary Sphere Formation Enhances the Functionality of Cardiac Progenitor Cells

    PubMed Central

    Cho, Hyun-Jai; Lee, Ho-Jae; Youn, Seock-Won; Koh, Seok-Jin; Won, Joo-Yun; Chung, Yeon-Ju; Cho, Hyun-Ju; Yoon, Chang-Hwan; Lee, Sae-Won; Lee, Eun Ju; Kwon, Yoo-Wook; Lee, Hae-Young; Lee, Sang Hun; Ho, Won-Kyung; Park, Young-Bae; Kim, Hyo-Soo

    2012-01-01

    Loss of cardiomyocytes impairs cardiac function after myocardial infarction (MI). Recent studies suggest that cardiac stem/progenitor cells could repair the damaged heart. However, cardiac progenitor cells are difficult to maintain in terms of purity and multipotency when propagated in two-dimensional culture systems. Here, we investigated a new strategy that enhances potency and enriches progenitor cells. We applied the repeated sphere formation strategy (cardiac explant → primary cardiosphere (CS) formation → sphere-derived cells (SDCs) in adherent culture condition → secondary CS formation by three-dimensional culture). Cells in secondary CS showed higher differentiation potentials than SDCs. When transplanted into the infarcted myocardium, secondary CSs engrafted robustly, improved left ventricular (LV) dysfunction, and reduced infarct sizes more than SDCs did. In addition to the cardiovascular differentiation of transplanted secondary CSs, robust vascular endothelial growth factor (VEGF) synthesis and secretion enhanced neovascularization in the infarcted myocardium. Microarray pathway analysis and blocking experiments using E-selectin knock-out hearts, specific chemicals, and small interfering RNAs (siRNAs) for each pathway revealed that E-selectin was indispensable to sphere initiation and ERK/Sp1/VEGF autoparacrine loop was responsible for sphere maturation. These results provide a simple strategy for enhancing cellular potency for cardiac repair. Furthermore, this strategy may be implemented to other types of stem/progenitor cell-based therapy. PMID:22713697

  13. Stop Managing, Start Coaching! How Performance Coaching Can Enhance Commitment and Improve Productivity.

    ERIC Educational Resources Information Center

    Gilley, Jerry W.; Boughton, Nathaniel W.

    This book, which is intended for managers responsible for training and managing employees, outlines an approach to employee management and training that is based on the premise that, if managers are to enhance employees' commitment to the organization and improve productivity, they must first stop managing their employees and start coaching them.…

  14. Using a Cohort Model for School Counselor Preparation to Enhance Commitment to Social Justice

    ERIC Educational Resources Information Center

    Paisley, Pamela O.; Bailey, Deryl F.; Hayes, Richard L.; McMahon, H. George; Grimmett, Marc A.

    2010-01-01

    This article describes a cohort model of school counselor preparation designed to enhance graduate student commitment to social justice. Foundational principles of group work are used as the vehicle for understanding self in context and for integrating the tenets associated with social justice advocacy. Key components related to program mission,…

  15. Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase

    PubMed Central

    Fischer, Kimberlee M.; Cottage, Chistopher T.; Wu, Weitao; Din, Shabana; Gude, Natalie A.; Avitable, Daniele; Quijada, Pearl; Collins, Brett L.; Fransioli, Jenna; Sussman, Mark A.

    2009-01-01

    Background Despite numerous studies demonstrating efficacy of cellular adoptive transfer for therapeutic myocardial regeneration, problems remain for donated cells with regard to survival, persistence, engraftment, and long-term benefits. This study redresses these concerns by enhancing the regenerative potential of adoptively transferred cardiac progenitor cells (CPCs) via genetic engineering to overexpress Pim-1, a cardioprotective kinase that enhances cell survival and proliferation. Methods and Results Intramyocardial injections of CPCs overexpressing Pim-1 were given to infarcted female mice. Animals were monitored over 4, 12, and 32-weeks to assess cardiac function and engraftment of Pim-1 CPCs using echocardiography, in vivo hemodynamics, and confocal imagery. CPCs overexpressing Pim-1 show increased proliferation and expression of markers consistent with cardiogenic lineage commitment following dexamethasone exposure in vitro. Animals that received CPCs overexpressing Pim-1 also produce greater levels of cellular engraftment, persistence, and functional improvement relative to control CPCs up to 32-weeks post-delivery. Salutary effects include reduction of infarct size, greater number of c-kit+ cells, and increased vasculature in the damaged region. Conclusions Myocardial repair is significantly enhanced by genetic engineering of CPCs using Pim-1 kinase. Ex vivo gene delivery to enhance cellular survival, proliferation, and regeneration may overcome current limitations of stem cell-based therapeutic approaches. PMID:19901187

  16. Cardiac LXRα protects against pathological cardiac hypertrophy and dysfunction by enhancing glucose uptake and utilization

    PubMed Central

    Cannon, Megan V; Silljé, Herman HW; Sijbesma, Jürgen WA; Vreeswijk-Baudoin, Inge; Ciapaite, Jolita; van der Sluis, Bart; van Deursen, Jan; Silva, Gustavo JJ; de Windt, Leon J; Gustafsson, Jan-Åke; van der Harst, Pim; van Gilst, Wiek H; de Boer, Rudolf A

    2015-01-01

    Pathological cardiac hypertrophy is characterized by a shift in metabolic substrate utilization from fatty acids to glucose, but the molecular events underlying the metabolic remodeling remain poorly understood. Here, we investigated the role of liver X receptors (LXRs), which are key regulators of glucose and lipid metabolism, in cardiac hypertrophic pathogenesis. Using a transgenic approach in mice, we show that overexpression of LXRα acts to protect the heart against hypertrophy, fibrosis, and dysfunction. Gene expression profiling studies revealed that genes regulating metabolic pathways were differentially expressed in hearts with elevated LXRα. Functionally, LXRα overexpression in isolated cardiomyocytes and murine hearts markedly enhanced the capacity for myocardial glucose uptake following hypertrophic stress. Conversely, this adaptive response was diminished in LXRα-deficient mice. Transcriptional changes induced by LXRα overexpression promoted energy-independent utilization of glucose via the hexosamine biosynthesis pathway, resulting in O-GlcNAc modification of GATA4 and Mef2c and the induction of cytoprotective natriuretic peptide expression. Our results identify LXRα as a key cardiac transcriptional regulator that helps orchestrate an adaptive metabolic response to chronic cardiac stress, and suggest that modulating LXRα may provide a unique opportunity for intervening in myocyte metabolism. PMID:26160456

  17. Cardiac Output Monitoring Managing Intravenous Therapy (COMMIT) to Treat Emergency Department Patients with Sepsis

    PubMed Central

    Hou, Peter C.; Filbin, Michael R.; Napoli, Anthony; Feldman, Joseph; Pang, Peter S.; Sankoff, Jeffrey; Lo, Bruce M.; Dickey-White, Howard; Birkhahn, Robert H.; Shapiro, Nathan I.

    2016-01-01

    ABSTRACT Objective: Fluid responsiveness is proposed as a physiology-based method to titrate fluid therapy based on preload dependence. The objectives of this study were to determine if a fluid responsiveness protocol would decrease progression of organ dysfunction, and a fluid responsiveness protocol would facilitate a more aggressive resuscitation. Methods: Prospective, 10-center, randomized interventional trial. Inclusion criteria: suspected sepsis and lactate 2.0 to 4.0 mmol/L. Exclusion criteria (abbreviated): systolic blood pressure more than 90 mmHg, and contraindication to aggressive fluid resuscitation. Intervention: fluid responsiveness protocol using Non-Invasive Cardiac Output Monitor (NICOM) to assess for fluid responsiveness (>10% increase in stroke volume in response to 5 mL/kg fluid bolus) with balance of a liter given in responsive patients. Control: standard clinical care. Outcomes: primary—change in Sepsis-related Organ Failure Assessment (SOFA) score at least 1 over 72 h; secondary—fluids administered. Trial was initially powered at 600 patients, but stopped early due to a change in sponsor's funding priorities. Results: Sixty-four patients were enrolled with 32 in the treatment arm. There were no significant differences between arms in age, comorbidities, baseline vital signs, or SOFA scores (P > 0.05 for all). Comparing treatment versus Standard of Care—there was no difference in proportion of increase in SOFA score of at least 1 point (30% vs. 33%) (note bene underpowered, P = 1.0) or mean preprotocol fluids 1,050 mL (95% confidence interval [CI]: 786–1,314) vs. 1,031 mL (95% CI: 741–1,325) (P = 0.93); however, treatment patients received more fluids during the protocol (2,633 mL [95% CI: 2,264–3,001] vs. 1,002 mL [95% CI: 707–1,298]) (P < 0.001). Conclusions: In this study of a “preshock” population, there was no change in progression of organ dysfunction with a fluid responsiveness protocol

  18. Utility of late gadolinium enhancement in pediatric cardiac MRI.

    PubMed

    Etesami, Maryam; Gilkeson, Robert C; Rajiah, Prabhakar

    2016-07-01

    Late gadolinium enhancement (LGE) cardiac magnetic resonance (MR) imaging sequence is increasingly used in the evaluation of pediatric cardiovascular disorders, and although LGE might be a normal feature at the sites of previous surgeries, it is pathologically seen as a result of extracellular space expansion, either from acute cell damage or chronic scarring or fibrosis. LGE is broadly divided into ischemic and non-ischemic patterns. LGE caused by myocardial infarction occurs in a vascular distribution and always involves the subendocardial portion, progressively involving the outer regions in a waveform pattern. Non-ischemic cardiomyopathies can have a mid-myocardial (either linear or patchy), subepicardial or diffuse subendocardial distribution. Idiopathic dilated cardiomyopathy can have a linear mid-myocardial pattern, while hypertrophic cardiomyopathy can have fine, patchy enhancement in hypertrophied and non-hypertrophied segments as well as right ventricular insertion points. Myocarditis and sarcoidosis have a mid-myocardial or subepicardial pattern of LGE. Fabry disease typically affects the basal inferolateral segment while Danon disease typically spares the septum. Pericarditis is characterized by diffuse or focal pericardial thickening and enhancement. Thrombus, the most common non-neoplastic cardiac mass, is characterized by absence of enhancement in all sequences, while neoplastic masses show at least some contrast enhancement, depending on the pathology. Regardless of the etiology, presence of LGE is associated with a poor prognosis. In this review, we describe the technical modifications required for performing LGE cardiac MR sequence in children, review and illustrate the patterns of LGE in children, and discuss their clinical significance. PMID:26718199

  19. Human Cardiac Progenitor Spheroids Exhibit Enhanced Engraftment Potential

    PubMed Central

    Colangelo, Donato; Gregoletto, Luca; Reano, Simone; Pietronave, Stefano; Merlin, Simone; Talmon, Maria; Novelli, Eugenio; Diena, Marco; Nicoletti, Carmine; Musarò, Antonio; Filigheddu, Nicoletta; Follenzi, Antonia; Prat, Maria

    2015-01-01

    A major obstacle to an effective myocardium stem cell therapy has always been the delivery and survival of implanted stem cells in the heart. Better engraftment can be achieved if cells are administered as cell aggregates, which maintain their extra-cellular matrix (ECM). We have generated spheroid aggregates in less than 24 h by seeding human cardiac progenitor cells (hCPCs) onto methylcellulose hydrogel-coated microwells. Cells within spheroids maintained the expression of stemness/mesenchymal and ECM markers, growth factors and their cognate receptors, cardiac commitment factors, and metalloproteases, as detected by immunofluorescence, q-RT-PCR and immunoarray, and expressed a higher, but regulated, telomerase activity. Compared to cells in monolayers, 3D spheroids secreted also bFGF and showed MMP2 activity. When spheroids were seeded on culture plates, the cells quickly migrated, displaying an increased wound healing ability with or without pharmacological modulation, and reached confluence at a higher rate than cells from conventional monolayers. When spheroids were injected in the heart wall of healthy mice, some cells migrated from the spheroids, engrafted, and remained detectable for at least 1 week after transplantation, while, when the same amount of cells was injected as suspension, no cells were detectable three days after injection. Cells from spheroids displayed the same engraftment capability when they were injected in cardiotoxin-injured myocardium. Our study shows that spherical in vivo ready-to-implant scaffold-less aggregates of hCPCs able to engraft also in the hostile environment of an injured myocardium can be produced with an economic, easy and fast protocol. PMID:26375957

  20. Cardiac Optogenetics: Enhancement by All-trans-Retinal

    PubMed Central

    Yu, Jinzhu; Chen, Kay; Lucero, Rachel V.; Ambrosi, Christina M.; Entcheva, Emilia

    2015-01-01

    All-trans-Retinal (ATR) is a photosensitizer, serving as the chromophore for depolarizing and hyperpolarizing light-sensitive ion channels and pumps (opsins), recently employed as fast optical actuators. In mammalian optogenetic applications (in brain and heart), endogenous ATR availability is not considered a limiting factor, yet it is unclear how ATR modulation may affect the response to optical stimulation. We hypothesized that exogenous ATR may improve light responsiveness of cardiac cells modified by Channelrhodopsin2 (ChR2), hence lowering the optical pacing energy. In virally-transduced (Ad-ChR2(H134R)-eYFP) light-sensitive cardiac syncytium in vitro, ATR supplements ≤2 μM improved cardiomyocyte viability and augmented ChR2 membrane expression several-fold, while >4 μM was toxic. Employing integrated optical actuation (470 nm) and optical mapping, we found that 1–2 μM ATR dramatically reduced optical pacing energy (over 30 times) to several μW/mm2, lowest values reported to date, but also caused action potential prolongation, minor changes in calcium transients and no change in conduction. Theoretical analysis helped explain ATR-caused reduction of optical excitation threshold in cardiomyocytes. We conclude that cardiomyocytes operate at non-saturating retinal levels, and carefully-dosed exogenous ATR can enhance the performance of ChR2 in cardiac cells and yield energy benefits over orders of magnitude for optogenetic stimulation. PMID:26568132

  1. Implementation of efficacy enhancement nursing interventions with cardiac elders.

    PubMed

    Hiltunen, Elizabeth F; Winder, Patricia A; Rait, Michelle A; Buselli, Elizabeth F; Carroll, Diane L; Rankin, Sally H

    2005-01-01

    Intervention strategies based on social cognitive theory and encompassing the bio-psycho-behavioral domains are proposed to enhance self-efficacy in men and women 65 years and older recovering from myocardial infarction and coronary artery bypass grafting. This paper describes a study in which the theory-based development of efficacy enhancement (EE) nursing interventions and their implementation and utilization with interventions from the Nursing Interventions Classification (NIC) were used with cardiac elders in the treatment group of the community-based randomized clinical, trial, "Improving Health Outcomes in Unpartnered Cardiac Elders." Advanced practice nurses (APNs) provided the nursing intervention to 110 participants (mean age = 76.2, SD = 6.0) for the first 12 weeks after discharge to home. After an initial introductory meeting in the acute-care setting, participant contacts by the APNs were made at a home visit and telephone calls at 2, 6, and 10 weeks. Results describe the number of participants receiving interventions at all contacts over 12 weeks, at specified contact points, and the intensity (nurse time) of the interventions. Verbal encouragement and mastery were EE interventions used with the greatest number of participants. Exercise promotion, energy management and active listening were NIC interventions used with the most participants. Variations in the use of interventions over 12 weeks and their intensities, suggest patterns of recovery in the elders. During rehabilitation EE interventions can be successfully implemented with men and women 65 years and older and individualized to the recovery trajectory. Nurses can integrate specific EE interventions with more general interventions from the bio-psycho-behavioral domains to enhance the recovery process for cardiac elders. PMID:16294801

  2. Classification enhancible grey relational analysis for cardiac arrhythmias discrimination.

    PubMed

    Lin, Chia-Hung

    2006-04-01

    This paper proposes a method for electrocardiogram (ECG) heartbeat recognition using classification enhancible grey relational analysis (GRA). The ECG beat recognition can be divided into a sequence of stages, starting with feature extraction and then according to characteristics to identify the cardiac arrhythmias including the supraventricular ectopic beat, bundle branch ectopic beat, and ventricular ectopic beat. Gaussian wavelets are used to enhance the features from each heartbeat, and GRA performs the recognition tasks. With the MIT-BIH arrhythmia database, the experimental results demonstrate the efficiency of the proposed non-invasive method. Compared with artificial neural network, the test results also show high accuracy, good adaptability, and faster processing time for the detection of heartbeat signals. PMID:16937172

  3. CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis.

    PubMed

    Ounzain, Samir; Micheletti, Rudi; Arnan, Carme; Plaisance, Isabelle; Cecchi, Dario; Schroen, Blanche; Reverter, Ferran; Alexanian, Michael; Gonzales, Christine; Ng, Shi Yan; Bussotti, Giovanni; Pezzuto, Iole; Notredame, Cedric; Heymans, Stephane; Guigó, Roderic; Johnson, Rory; Pedrazzini, Thierry

    2015-12-01

    Long noncoding RNAs (lncRNAs) are emerging as important regulators of developmental pathways. However, their roles in human cardiac precursor cell (CPC) remain unexplored. To characterize the long noncoding transcriptome during human CPC cardiac differentiation, we profiled the lncRNA transcriptome in CPCs isolated from the human fetal heart and identified 570 lncRNAs that were modulated during cardiac differentiation. Many of these were associated with active cardiac enhancer and super enhancers (SE) with their expression being correlated with proximal cardiac genes. One of the most upregulated lncRNAs was a SE-associated lncRNA that was named CARMEN, (CAR)diac (M)esoderm (E)nhancer-associated (N)oncoding RNA. CARMEN exhibits RNA-dependent enhancing activity and is upstream of the cardiac mesoderm-specifying gene regulatory network. Interestingly, CARMEN interacts with SUZ12 and EZH2, two components of the polycomb repressive complex 2 (PRC2). We demonstrate that CARMEN knockdown inhibits cardiac specification and differentiation in cardiac precursor cells independently of MIR-143 and -145 expression, two microRNAs located proximal to the enhancer sequences. Importantly, CARMEN expression was activated during pathological remodeling in the mouse and human hearts, and was necessary for maintaining cardiac identity in differentiated cardiomyocytes. This study demonstrates therefore that CARMEN is a crucial regulator of cardiac cell differentiation and homeostasis. PMID:26423156

  4. Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease

    SciTech Connect

    Ounzain, Samir; Pezzuto, Iole; Micheletti, Rudi; Burdet, Frédéric; Sheta, Razan; Nemir, Mohamed; Gonzales, Christine; Sarre, Alexandre; Alexanian, Michael; Blow, Matthew J.; May, Dalit; Johnson, Rory; Dauvillier, Jérôme; Pennacchio, Len A.; Pedrazzini, Thierry

    2014-08-19

    We report here that the key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Through a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived lncRNAs.

  5. Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease

    DOE PAGESBeta

    Ounzain, Samir; Pezzuto, Iole; Micheletti, Rudi; Burdet, Frédéric; Sheta, Razan; Nemir, Mohamed; Gonzales, Christine; Sarre, Alexandre; Alexanian, Michael; Blow, Matthew J.; et al

    2014-08-19

    We report here that the key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Throughmore » a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived lncRNAs.« less

  6. Conditional Cripto overexpression in satellite cells promotes myogenic commitment and enhances early regeneration

    PubMed Central

    Prezioso, Carolina; Iaconis, Salvatore; Andolfi, Gennaro; Zentilin, Lorena; Iavarone, Francescopaolo; Guardiola, Ombretta; Minchiotti, Gabriella

    2015-01-01

    Skeletal muscle regeneration mainly depends on satellite cells, a population of resident muscle stem cells. Despite extensive studies, knowledge of the molecular mechanisms underlying the early events associated with satellite cell activation and myogenic commitment in muscle regeneration remains still incomplete. Cripto is a novel regulator of postnatal skeletal muscle regeneration and a promising target for future therapy. Indeed, Cripto is expressed both in myogenic and inflammatory cells in skeletal muscle after acute injury and it is required in the satellite cell compartment to achieve effective muscle regeneration. A critical requirement to further explore the in vivo cellular contribution of Cripto in regulating skeletal muscle regeneration is the possibility to overexpress Cripto in its endogenous configuration and in a cell and time-specific manner. Here we report the generation and the functional characterization of a novel mouse model for conditional expression of Cripto, i.e., the Tg:DsRedloxP/loxPCripto-eGFP mice. Moreover, by using a satellite cell specific Cre-driver line we investigated the biological effect of Cripto overexpression in vivo, and provided evidence that overexpression of Cripto in the adult satellite cell compartment promotes myogenic commitment and differentiation, and enhances early regeneration in a mouse model of acute injury. PMID:26052513

  7. Proinflammatory Mediators Enhance the Osteogenesis of Human Mesenchymal Stem Cells after Lineage Commitment

    PubMed Central

    Croes, Michiel; Oner, F. Cumhur; Kruyt, Moyo C.; Blokhuis, Taco J.; Bastian, Okan; Dhert, Wouter J. A.; Alblas, Jacqueline

    2015-01-01

    Several inflammatory processes underlie excessive bone formation, including chronic inflammation of the spine, acute infections, or periarticular ossifications after trauma. This suggests that local factors in these conditions have osteogenic properties. Mesenchymal stem cells (MSCs) and their differentiated progeny contribute to bone healing by synthesizing extracellular matrix and inducing mineralization. Due to the variation in experimental designs used in vitro, there is controversy about the osteogenic potential of proinflammatory factors on MSCs. Our goal was to determine the specific conditions allowing the pro-osteogenic effects of distinct inflammatory stimuli. Human bone marrow MSCs were exposed to tumor necrosis factor alpha (TNF-α) and lipopolysaccharide (LPS). Cells were cultured in growth medium or osteogenic differentiation medium. Alternatively, bone morphogenetic protein 2 (BMP-2) was used as osteogenic supplement to simulate the conditions in vivo. Alkaline phosphatase activity and calcium deposition were indicators of osteogenicity. To elucidate lineage commitment-dependent effects, MSCs were pre-differentiated prior treatment. Our results show that TNF-α and LPS do not affect the expression of osteogenic markers by MSCs in the absence of an osteogenic supplement. In osteogenic differentiation medium or together with BMP-2 however, these mediators highly stimulated their alkaline phosphatase activity and subsequent matrix mineralization. In pre-osteoblasts, matrix mineralization was significantly increased by these mediators, but irrespective of the culture conditions. Our study shows that inflammatory factors potently enhance the osteogenic capacity of MSCs. These properties may be harnessed in bone regenerative strategies. Importantly, the commitment of MSCs to the osteogenic lineage greatly enhances their responsiveness to inflammatory signals. PMID:26176237

  8. Late Gadolinium Enhancement Among Survivors of Sudden Cardiac Arrest

    PubMed Central

    Neilan, Tomas G.; Farhad, Hoshang; Mayrhofer, Thomas; Shah, Ravi V.; Dodson, John A.; Abbasi, Siddique A.; Danik, Stephan B.; Verdini, Daniel J.; Tokuda, Michifumi; Tedrow, Usha B.; Jerosch-Herold, Michael; Hoffmann, Udo; Ghoshhajra, Brian B.; Stevenson, William G.; Kwong, Raymond Y.

    2016-01-01

    OBJECTIVES The aim of this study was to describe the role of contrast-enhanced cardiac magnetic resonance (CMR) in the workup of patients with aborted sudden cardiac arrest (SCA) and in the prediction of long-term outcomes. BACKGROUND Myocardial fibrosis is a key substrate for SCA, and late gadolinium enhancement (LGE) on a CMR study is a robust technique for imaging of myocardial fibrosis. METHODS We performed a retrospective review of all survivors of SCA who were referred for CMR studies and performed follow-up for the subsequent occurrence of an adverse event (death and appropriate defibrillator therapy). RESULTS After a workup that included a clinical history, electrocardiogram, echocardiography, and coronary angiogram, 137 patients underwent CMR for workup of aborted SCA (66% male; mean age 56 ± 11 years; left ventricular ejection fraction 43 ± 12%). The presenting arrhythmias were ventricular fibrillation (n = 105 [77%]) and ventricular tachycardia (n = 32 [23%]). Overall, LGE was found in 98 patients (71%), with an average extent of 9.9 ± 5% of the left ventricular myocardium. CMR imaging provided a diagnosis or an arrhythmic substrate in 104 patients (76%), including the presence of an infarct-pattern LGE in 60 patients (44%), noninfarct LGE in 21 (15%), active myocarditis in 14 (10%), hypertrophic cardiomyopathy in 3 (2%), sarcoidosis in 3, and arrhythmogenic cardiomyopathy in 3. In a median follow-up of 29 months (range 18 to 43 months), there were 63 events. In a multivariable analysis, the strongest predictors of recurrent events were the presence of LGE (adjusted hazard ratio: 6.7; 95% CI: 2.38 to 18.85; p < 0.001) and the extent of LGE (hazard ratio: 1.15; 95% CI: 1.11 to 1.19; p < 0.001). CONCLUSIONS Among patients with SCA, CMR with contrast identified LGE in 71% and provided a potential arrhythmic substrate in 76%. In follow-up, both the presence and extent of LGE identified a group at markedly increased risk of future adverse events. PMID

  9. Enhancement of committed hematopoietic stem cell colony formation by nandrolone decanoate after sublethal whole body irradiation

    SciTech Connect

    Gallicchio, V.S.; Chen, M.G.; Watts, T.D.

    1984-11-01

    The ability of an anabolic steroid, nandrolone decanoate, to increase committed topoietic stem cell (CFU-gm, CFU-e, and BFU-e) colony formation after sublethal irradiation was evaluated. Immediately after receiving whole body irradiation and on the next two days, each mouse was injected intraperitoneally with nandrolone decanoate (1.25 mg) in propylene glycol. Irradiated control mice received only propylene glycol. Compared to controls, drug-treated mice showed marked peripheral blood leukocytosis and more stable packed red cell volume. Drug-treated mice also demonstrated increased erythropoiesis, as CFU-e/BFU-e concentrations from both marrow (9% to 581%) and spleen (15% to 797%) were elevated. Granulopoiesis was increased similarly, as CFU-gm concentrations from marrow (38% to 685%) and spleen (9% to 373%) were elevated. These results demonstrate that nandrolone decanoate enhances hematopoietic stem cell recovery after sublethal whole body irradiation. This suggests that following hematopoietic suppression, nandrolone decanoate may stimulate the recovery of hematopoiesis at the stem cell level and in peripheral blood.

  10. Enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with heart failure induced by adriamycin.

    PubMed

    Zhang, Shujuan; Zhang, Feng; Sun, Haijian; Zhou, Yebo; Han, Ying

    2012-11-01

    Our previous studies have shown that the cardiac sympathetic afferent reflex is enhanced in rats with chronic heart failure (CHF) induced by coronary artery ligation and contributes to the over-excitation of sympathetic activity. We sought to determine whether sympathetic activity and cardiac sympathetic afferent reflex were enhanced in adriamycin-induced CHF and whether angiotensin II (Ang II) in the paraventricular nucleus (PVN) was involved in enhancing sympathetic activity and cardiac sympathetic afferent reflex. Heart failure was induced by intraperitoneal injection of adriamycin for six times during 2 weeks (15 mg/kg). Six weeks after the first injection, the rats underwent anesthesia with urethane and α-chloralose. After vagotomy and baroreceptor denervation, cardiac sympathetic afferent reflex was evaluated by renal sympathetic nerve activity and mean arterial pressure (MAP) response to epicardial application of capsaicin (1.0 nmol). The response of MAP to ganglionic blockade with hexamethonium in conscious rats was performed to evaluate sympathetic activity. The renal sympathetic nerve activity and cardiac sympathetic afferent reflex were enhanced in adriamycin rats and the maximum depressor response of MAP induced by hexamethonium was significantly greater in adriamycin rats than that in control rats. Bilateral PVN microinjection of angiotensin II (Ang II) caused larger responses of the cardiac sympathetic afferent reflex, baseline renal sympathetic nerve activity and MAP in adriamycin rats than control rats. These results indicated that both sympathetic activity and cardiac sympathetic afferent reflex were enhanced and Ang II in the PVN was involved in the enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with adriamycin-induced heart failure. PMID:23554781

  11. Enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with heart failure induced by adriamycin

    PubMed Central

    Zhang, Shujuan; Zhang, Feng; Sun, Haijian; Zhou, Yebo; Han, Ying

    2012-01-01

    Our previous studies have shown that the cardiac sympathetic afferent reflex is enhanced in rats with chronic heart failure (CHF) induced by coronary artery ligation and contributes to the over-excitation of sympathetic activity. We sought to determine whether sympathetic activity and cardiac sympathetic afferent reflex were enhanced in adriamycin-induced CHF and whether angiotensin II (Ang II) in the paraventricular nucleus (PVN) was involved in enhancing sympathetic activity and cardiac sympathetic afferent reflex. Heart failure was induced by intraperitoneal injection of adriamycin for six times during 2 weeks (15 mg/kg). Six weeks after the first injection, the rats underwent anesthesia with urethane and α-chloralose. After vagotomy and baroreceptor denervation, cardiac sympathetic afferent reflex was evaluated by renal sympathetic nerve activity and mean arterial pressure (MAP) response to epicardial application of capsaicin (1.0 nmol). The response of MAP to ganglionic blockade with hexamethonium in conscious rats was performed to evaluate sympathetic activity. The renal sympathetic nerve activity and cardiac sympathetic afferent reflex were enhanced in adriamycin rats and the maximum depressor response of MAP induced by hexamethonium was significantly greater in adriamycin rats than that in control rats. Bilateral PVN microinjection of angiotensin II (Ang II) caused larger responses of the cardiac sympathetic afferent reflex, baseline renal sympathetic nerve activity and MAP in adriamycin rats than control rats. These results indicated that both sympathetic activity and cardiac sympathetic afferent reflex were enhanced and Ang II in the PVN was involved in the enhanced sympathetic activity and cardiac sympathetic afferent reflex in rats with adriamycin-induced heart failure. PMID:23554781

  12. Cardiac sarcoidosis evaluated with gadolinium-enhanced magnetic resonance and contrast-enhanced 64-slice computed tomography.

    PubMed

    Smedema, Jan-Peter; Truter, Rene; de Klerk, Petra A; Zaaiman, Leonie; White, Leonie; Doubell, Anton F

    2006-09-20

    Sarcoidosis is a multi-system granulomatous disorder of unknown etiology with symptomatic cardiac involvement in up to 7% of patients. The clinical features of sarcoid heart disease include congestive heart failure, arrhythmias, conduction disturbances, and sudden death. We evaluated the value of contrast-enhanced multi-detector computed tomography in delineating myocardial scar and granulomatous inflammation by comparing our findings with gadolinium magnetic resonance in a patient diagnosed with cardiac sarcoidosis. PMID:16257460

  13. Scl binds to primed enhancers in mesoderm to regulate hematopoietic and cardiac fate divergence.

    PubMed

    Org, Tõnis; Duan, Dan; Ferrari, Roberto; Montel-Hagen, Amelie; Van Handel, Ben; Kerényi, Marc A; Sasidharan, Rajkumar; Rubbi, Liudmilla; Fujiwara, Yuko; Pellegrini, Matteo; Orkin, Stuart H; Kurdistani, Siavash K; Mikkola, Hanna Ka

    2015-03-12

    Scl/Tal1 confers hemogenic competence and prevents ectopic cardiomyogenesis in embryonic endothelium by unknown mechanisms. We discovered that Scl binds to hematopoietic and cardiac enhancers that become epigenetically primed in multipotent cardiovascular mesoderm, to regulate the divergence of hematopoietic and cardiac lineages. Scl does not act as a pioneer factor but rather exploits a pre-established epigenetic landscape. As the blood lineage emerges, Scl binding and active epigenetic modifications are sustained in hematopoietic enhancers, whereas cardiac enhancers are decommissioned by removal of active epigenetic marks. Our data suggest that, rather than recruiting corepressors to enhancers, Scl prevents ectopic cardiogenesis by occupying enhancers that cardiac factors, such as Gata4 and Hand1, use for gene activation. Although hematopoietic Gata factors bind with Scl to both activated and repressed genes, they are dispensable for cardiac repression, but necessary for activating genes that enable hematopoietic stem/progenitor cell development. These results suggest that a unique subset of enhancers in lineage-specific genes that are accessible for regulators of opposing fates during the time of the fate decision provide a platform where the divergence of mutually exclusive fates is orchestrated. PMID:25564442

  14. Ultrafine ambient particulate matter enhances cardiac ischemia and reperfusion injury

    EPA Science Inventory

    Epidemiological studies have demonstrated a consistent link between exposure to ambient particulate air pollutant (PM) and the incidence of cardiovascular morbidity and mortality. The present study was designed to evaluate the cardiac effects of ambient PM. Mice were exposed to 1...

  15. Increasing the Institutional Commitment of College Students: Enhanced Measurement and Test of a Nomological Model

    ERIC Educational Resources Information Center

    Davidson, William B.; Beck, Hall P.; Grisaffe, Douglas B.

    2015-01-01

    Measurement shortcomings have hampered the understanding of institutional commitment (IC) in college students. Therefore, this study sought to (a) develop validated indices of IC and associated psychosocial attributes and (b) use these indices to test a nomological network of variables and their direct and indirect relationships to IC. Exploratory…

  16. AAV6-mediated Cardiac-specific Overexpression of Ribonucleotide Reductase Enhances Myocardial Contractility.

    PubMed

    Kolwicz, Stephen C; Odom, Guy L; Nowakowski, Sarah G; Moussavi-Harami, Farid; Chen, Xiaolan; Reinecke, Hans; Hauschka, Stephen D; Murry, Charles E; Mahairas, Gregory G; Regnier, Michael

    2016-02-01

    Impaired systolic function, resulting from acute injury or congenital defects, leads to cardiac complications and heart failure. Current therapies slow disease progression but do not rescue cardiac function. We previously reported that elevating the cellular 2 deoxy-ATP (dATP) pool in transgenic mice via increased expression of ribonucleotide reductase (RNR), the enzyme that catalyzes deoxy-nucleotide production, increases myosin-actin interaction and enhances cardiac muscle contractility. For the current studies, we initially injected wild-type mice retro-orbitally with a mixture of adeno-associated virus serotype-6 (rAAV6) containing a miniaturized cardiac-specific regulatory cassette (cTnT(455)) composed of enhancer and promotor portions of the human cardiac troponin T gene (TNNT2) ligated to rat cDNAs encoding either the Rrm1 or Rrm2 subunit. Subsequent studies optimized the system by creating a tandem human RRM1-RRM2 cDNA with a P2A self-cleaving peptide site between the subunits. Both rat and human Rrm1/Rrm2 cDNAs resulted in RNR enzyme overexpression exclusively in the heart and led to a significant elevation of left ventricular (LV) function in normal mice and infarcted rats, measured by echocardiography or isolated heart perfusions, without adverse cardiac remodeling. Our study suggests that increasing RNR levels via rAAV-mediated cardiac-specific expression provide a novel gene therapy approach to potentially enhance cardiac systolic function in animal models and patients with heart failure. PMID:26388461

  17. Evaluation of apical subtype of hypertrophic cardiomyopathy using cardiac magnetic resonance imaging with gadolinium enhancement.

    PubMed

    Kebed, Kalie Y; Al Adham, Raed I; Bishu, Kalkidan; Askew, J Wells; Klarich, Kyle W; Araoz, Philip A; Foley, Thomas A; Glockner, James F; Nishimura, Rick A; Anavekar, Nandan S

    2014-09-01

    Apical hypertrophic cardiomyopathy (HC) is an uncommon variant of HC. We sought to characterize cardiac magnetic resonance imaging (MRI) findings among apical HC patients. This was a retrospective review of consecutive patients with a diagnosis of apical HC who underwent cardiac MRI examinations at the Mayo Clinic (Rochester, MN) from August 1999 to October 2011. Clinical and demographic data at the time of cardiac MRI study were abstracted. Cardiac MRI study and 2-dimensional echocardiograms performed within 6 months of the cardiac MRI were reviewed; 96 patients with apical HC underwent cardiac MRI examinations. LV end-diastolic and end-systolic volumes were 130.7 ± 39.1 ml and 44.2 ± 20.9 ml, respectively. Maximum LV thickness was 19 ± 5 mm. Hypertrophy extended beyond the apex into other segments in 57 (59.4%) patients. Obstructive physiology was seen in 12 (12.5%) and was more common in the mixed apical phenotype than the pure apical (19.3 vs 2.6%, p = 0.02). Apical pouches were noted in 39 (40.6%) patients. Late gadolinium enhancement (LGE) was present in 70 (74.5%) patients. LGE was associated with severe symptoms and increased maximal LV wall thickness. In conclusion, cardiac MRI is well suited for studying the apical form of HC because of difficulty imaging the cardiac apex with standard echocardiography. Cardiac MRI is uniquely suited to delineate the presence or absence of an apical pouch and abnormal myocardial LGE that may have implications in the natural history of apical HM. In particular, the presence of abnormal LGE is associated with clinical symptoms and increased wall thickness. PMID:25037678

  18. Delayed Myocardial Enhancement in Cardiac Magnetic Resonance Imaging

    PubMed Central

    Franco, Arie; Javidi, Saeed; Ruehm, Stefan G

    2015-01-01

    Delayed myocardial enhancement MRI is a highly valuable but non-specific imaging technique that is ancillary in the diagnosis of a variety of diseases including myocardial viability, cardiomyopathy, myocarditis and other infiltrative myocardial processes. The lack of specificity stems from the wide variety of differential diagnoses that may present with overlapping patterns of delayed enhancement. Many of these differential diagnoses have been presented and discussed in this article. PMID:26622933

  19. The GATA-4 transcription factor transactivates the cardiac muscle-specific troponin C promoter-enhancer in nonmuscle cells.

    PubMed Central

    Ip, H S; Wilson, D B; Heikinheimo, M; Tang, Z; Ting, C N; Simon, M C; Leiden, J M; Parmacek, M S

    1994-01-01

    The unique contractile phenotype of cardiac myocytes is determined by the expression of a set of cardiac muscle-specific genes. By analogy to other mammalian developmental systems, it is likely that the coordinate expression of cardiac genes is controlled by lineage-specific transcription factors that interact with promoter and enhancer elements in the transcriptional regulatory regions of these genes. Although previous reports have identified several cardiac muscle-specific transcriptional elements, relatively little is known about the lineage-specific transcription factors that regulate these elements. In this report, we demonstrate that the slow/cardiac muscle-specific troponin C (cTnC) enhancer contains a specific binding site for the lineage-restricted zinc finger transcription factor GATA-4. This GATA-4-binding site is required for enhancer activity in primary cardiac myocytes. Moreover, the cTnC enhancer can be transactivated by overexpression of GATA-4 in non-cardiac muscle cells such as NIH 3T3 cells. In situ hybridization studies demonstrate that GATA-4 and cTnC have overlapping patterns of expression in the hearts of postimplantation mouse embryos and that GATA-4 gene expression precedes cTnC expression. Indirect immunofluorescence reveals GATA-4 expression in cultured cardiac myocytes from neonatal rats. Taken together, these results are consistent with a model in which GATA-4 functions to direct tissue-specific gene expression during mammalian cardiac development. Images PMID:7935467

  20. Pharmacologic And Genetic Strategies To Enhance Cell Therapy For Cardiac Regeneration

    PubMed Central

    Kanashiro-Takeuchi, Rosemeire M.; Schulman, Ivonne Hernandez; Hare, Joshua M.

    2012-01-01

    Cell-based therapy is emerging as an exciting potential therapeutic approach for cardiac regeneration following myocardial infarction (MI). As heart failure (HF) prevalence increases over time, development of new interventions designed to aid cardiac recovery from injury are crucial and should be considered more broadly. In this regard, substantial efforts to enhance the efficacy and safety of cell therapy are continuously growing along several fronts, including modifications to improve the reprogramming efficiency of inducible pluripotent stem cells (iPS), genetic engineering of adult stem cells, and administration of growth factors or small molecules to activate regenerative pathways in the injured heart. These interventions are emerging as potential therapeutic alternatives and/or adjuncts based on their potential to promote stem cell homing, proliferation, differentiation, and/or survival. Given the promise of therapeutic interventions to enhance the regenerative capacity of multipotent stem cells as well as specifically guide endogenous or exogenous stem cells into a cardiac lineage, their application in cardiac regenerative medicine should be the focus of future clinical research. This article is part of a Special Issue entitled ‘Key Signaling Molecules Special Issue’. PMID:21645519

  1. Cardiac Amyloidosis: Typical Imaging Findings and Diffuse Myocardial Damage Demonstrated by Delayed Contrast-Enhanced MRI

    SciTech Connect

    Sueyoshi, Eijun Sakamoto, Ichiro; Okimoto, Tomoaki; Hayashi, Kuniaki; Tanaka, Kyouei; Toda, Genji

    2006-08-15

    Amyloidosis is a rare systemic disease. However, involvement of the heart is a common finding and is the most frequent cause of death in amyloidosis. We report the sonographic, scintigraphic, and MRI features of a pathologically proven case of cardiac amyloidosis. Delayed contrast-enhanced MR images, using an inversion recovery prepped gradient-echo sequence, revealed diffuse enhancement in the wall of both left and right ventricles. This enhancement suggested expansion of the extracellular space of the myocardium caused by diffuse myocardial necrosis secondary to deposition of amyloid.

  2. Modified multipurpose catheter enhances clinical utility for cardiac catheterizations.

    PubMed

    Mannino, S C; Scavina, M; Palmer, S

    1994-10-01

    The Multipurpose technique for coronary arteriography employs a single catheter. The benefits are a reduction in the cost of the procedure and a shorter procedural time by experienced operators. To enhance the performance of these catheters, a modification was made in the materials and tip design, and these modifications were clinically evaluated in a small study. Compared to the control group of patients (n = 41), patients catheterized with the Multipurpose-SM (n = 43) were shown to have a shorter procedural time as measured by a reduced fluoroscopy time (7.08 min vs. 9.52 min, P = .007). This difference is statistically significant at a 95% confidence level and resulted in less radiation exposure to the operator and cath lab staff. The procedural time was significantly reduced by fewer catheter exchanges (19% study vs. 46% control; P = .006), which were needed to successfully complete the procedure. The new Multipurpose-SM catheter also demonstrated enhanced flexibility for cannulating coronary arteries with superior or anterior takeoffs. This study concludes that the utilization of a modified Multipurpose-SM catheter is safe and effective in cannulating both the left and right coronary arteries, bypass grafts, and performing left ventriculography. The primary benefits of using this modified catheter are reduced fluoroscopy time and the need for fewer catheter exchanges. PMID:7834732

  3. Synchronized Drumming Enhances Activity in the Caudate and Facilitates Prosocial Commitment - If the Rhythm Comes Easily

    PubMed Central

    Kokal, Idil; Engel, Annerose; Kirschner, Sebastian; Keysers, Christian

    2011-01-01

    Why does chanting, drumming or dancing together make people feel united? Here we investigate the neural mechanisms underlying interpersonal synchrony and its subsequent effects on prosocial behavior among synchronized individuals. We hypothesized that areas of the brain associated with the processing of reward would be active when individuals experience synchrony during drumming, and that these reward signals would increase prosocial behavior toward this synchronous drum partner. 18 female non-musicians were scanned with functional magnetic resonance imaging while they drummed a rhythm, in alternating blocks, with two different experimenters: one drumming in-synchrony and the other out-of-synchrony relative to the participant. In the last scanning part, which served as the experimental manipulation for the following prosocial behavioral test, one of the experimenters drummed with one half of the participants in-synchrony and with the other out-of-synchrony. After scanning, this experimenter “accidentally” dropped eight pencils, and the number of pencils collected by the participants was used as a measure of prosocial commitment. Results revealed that participants who mastered the novel rhythm easily before scanning showed increased activity in the caudate during synchronous drumming. The same area also responded to monetary reward in a localizer task with the same participants. The activity in the caudate during experiencing synchronous drumming also predicted the number of pencils the participants later collected to help the synchronous experimenter of the manipulation run. In addition, participants collected more pencils to help the experimenter when she had drummed in-synchrony than out-of-synchrony during the manipulation run. By showing an overlap in activated areas during synchronized drumming and monetary reward, our findings suggest that interpersonal synchrony is related to the brain's reward system. PMID:22110623

  4. A Mindfulness-Acceptance-Commitment-Based Approach to Athletic Performance Enhancement: Theoretical Considerations

    ERIC Educational Resources Information Center

    Gardner, Frank L.; Moore, Zella E.

    2004-01-01

    While traditional cognitive-behavioral skills-training-based approaches to athletic performance enhancement posit that negative thoughts and emotions must be controlled, eliminated, or replaced for athlete-clients to perform optimally, recent evidence suggests that efforts to control, eliminate, or suppress these internal states may actually have…

  5. Increased Intracellular [dATP] Enhances Cardiac Contraction in Embryonic Chick Cardiomyocytes

    PubMed Central

    Schoffstall, Brenda; Chase, P. Bryant

    2016-01-01

    Although ATP is the physiological substrate for cardiac contraction, cardiac contractility is significantly enhanced in vitro when only 10% of ATP substrate is replaced with 2’-deoxy-ATP (dATP). To determine the functional effects of increased intracellular [dATP] ([dATP]i) within living cardiac cells, we used hypertonic loading with varying exogenous dATP/ATP ratios, but constant total nucleotide concentration, to elevate [dATP]i in contractile monolayers of embryonic chick cardiomyocytes. The increase in [dATP]i was estimated from dilution of dye added in parallel with dATP. Cell viability, average contractile amplitude, rates of contraction/relaxation, spontaneous beat frequency, and Ca2+ transient amplitude and kinetics were examined. At total [dATP]i above ~70 μM, spontaneous contractions ceased, and above ~100 μM [dATP]i, membrane blebbing was also observed, consistent with apoptosis. Interestingly, [dATP]i of ~60 μM (~40% increase over basal [dATP]i levels) enhanced both amplitude of contraction and the rates of contraction and relaxation without affecting beat frequency. With total [dATP]i of ~60 μM or less, we found no significant change in Ca2+ transients. These data indicate that there is an “optimal” concentration of exogenously loaded [dATP]i that under controlled conditions can enhance contractility in living cardiomyocytes without affecting beat frequency or Ca2+ transients. PMID:18452163

  6. Heart-specific Rpd3 downregulation enhances cardiac function and longevity.

    PubMed

    Kopp, Zachary A; Hsieh, Jo-Lin; Li, Andrew; Wang, William; Bhatt, Dhelni T; Lee, Angela; Kim, Sae Yeon; Fan, David; Shah, Veevek; Siddiqui, Emaad; Ragam, Radhika; Park, Kristen; Ardeshna, Dev; Park, Kunwoo; Wu, Rachel; Parikh, Hardik; Parikh, Ayush; Lin, Yuh-Ru; Park, Yongkyu

    2015-09-01

    Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan in Drosophila melanogaster. Once revealed that long-lived fruit flies exhibit limited cardiac decline, we investigated whether Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three different stressors (oxidation, starvation and heat), heart-specific Rpd3 downregulation significantly enhanced stress resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted in other tissues or when other long-lived flies were tested in the heart-specific manner. Interestingly, the expressions of anti-aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart-specific Rpd3 downregulation. Showing higher resistance to oxidative stress, the heart-specific Rpd3 downregulation concurrently exhibited improved cardiac functions, demonstrating an increased heart rate, decreased heart failure and accelerated heart recovery. Conversely, Rpd3 upregulation in cardiac tissue reduced systemic resistance against heat stress with decreased heart function, also specifying phosphorylated Rpd3 levels as a significant modulator. Continual downregulation of Rpd3 throughout aging increased lifespan, implicating that Rpd3 deacetylase in the heart plays a significant role in cardiac function and longevity to systemically modulate the fly's response to the environment. PMID:26399365

  7. Enhanced cardiac perception predicts impaired performance in the Iowa Gambling Task in patients with panic disorder

    PubMed Central

    Wölk, Julian; Sütterlin, Stefan; Koch, Stefan; Vögele, Claus; Schulz, Stefan M

    2014-01-01

    Objective Somatic marker theory predicts that somatic cues serve intuitive decision making; however, cardiovascular symptoms are threat cues for patients with panic disorder (PD). Therefore, enhanced cardiac perception may aid intuitive decision making only in healthy individuals, but impair intuitive decision making in PD patients. Methods PD patients and age-and sex-matched volunteers without a psychiatric diagnosis (n = 17, respectively) completed the Iowa Gambling Task (IGT) as a measure of intuitive decision making. Interindividual differences in cardiac perception were assessed with a common mental-tracking task. Results In line with our hypothesis, we found a pattern of opposing associations (Fisher's Z = 1.78, P = 0.04) of high cardiac perception with improved IGT-performance in matched control-participants (r = 0.36, n = 14) but impaired IGT-performance in PD patients (r = −0.38, n = 13). Conclusion Interoceptive skills, typically assumed to aid intuitive decision making, can have the opposite effect in PD patients who experience interoceptive cues as threatening, and tend to avoid them. This may explain why PD patients frequently have problems with decision making in everyday life. Screening of cardiac perception may help identifying patients who benefit from specifically tailored interventions. PMID:24683516

  8. HCV Infection Enhances Th17 Commitment, Which Could Affect the Pathogenesis of Autoimmune Diseases

    PubMed Central

    Kondo, Yasuteru; Ninomiya, Masashi; Kimura, Osamu; Machida, Keigo; Funayama, Ryo; Nagashima, Takeshi; Kobayashi, Koju; Kakazu, Eiji; Kato, Takanobu; Nakayama, Keiko; Lai, Michael M. C.; Shimosegawa, Tooru

    2014-01-01

    Background Various kinds of autoimmune diseases have been reported to have a significant relationship with persistent hepatitis c virus (HCV) infection and Th17 cells. Previously, our group reported that the existence of HCV in T lymphocytes could affect the development of CD4+ helper T cells and their proliferation, in addition to the induction of immunoglobulin hyper-mutation. Methods Therefore, we analyzed the relationship between persistent infection of HCV and the mechanism of Th17 cell induction ex vivo and in vitro. Results The prevalence of autoimmune-related diseases in chronic hepatitis c patients (CH-C) was significantly higher than in other types of chronic hepatitis (hepatitis B and NASH). A significantly higher frequency of IL6 and TGF-β double-high patients was detected in CH-C than in other liver diseases. Moreover, these double-high patients had significantly higher positivity of anti-nuclear antibody, cryoglobulinemia, and lymphotropic HCV and higher amounts of IL1-β, IL21, IL23. In addition to the previously reported lymphotropic SB-HCV strain, we found a novel, genotype 1b lymphotropic HCV (Ly-HCV), by deep sequencing analysis. Lymphotropic-HCV replication could be detected in the lymphoid cells with various kinds of cytokine-conditions including IL1β, IL23, IL6 and TGF-β in vitro. Infection by HCV could significantly enhance the development of Th17 cells. The HCV protein responsible for inducing the Th17 cells was HCV-Core protein, which could enhance the STAT-3 signaling and up-regulate the expression of RORγt as a Th17 master gene. Conclusion Infection by lymphotropic HCV might enhance the Th17 development and contribute to understanding the pathogenesis of autoimmune-related diseases. PMID:24905921

  9. HUMAN CARDIAC PROGENITOR CELLS ENGINEERED WITH PIM-1 KINASE ENHANCE MYOCARDIAL REPAIR

    PubMed Central

    Mohsin, Sadia; Khan, Mohsin; Toko, Haruhiro; Bailey, Brandi; Cottage, Christopher T.; Wallach, Kathleen; Nag, Divya; Lee, Andrew; Siddiqi, Sailay; Lan, Feng; Fischer, Kimberlee M.; Gude, Natalie; Quijada, Pearl; Avitabile, Daniele; Truffa, Silvia; Collins, Brett; Dembitsky, Walter; Wu, Joseph C; Sussman, Mark A

    2012-01-01

    Objective Enhancement of human cardiac progenitor cell (hCPC) reparative and regenerative potential by genetic modification for treatment of myocardial infarction. Background Regenerative potential of stem cells to repair acute infarction is limited. Improved hCPC survival, proliferation and differentiation into functional myocardium will increase efficacy and advance translational implementation of cardiac regeneration. Methods hCPCs isolated from myocardium of heart failure patients undergoing left ventricular assist device (LVAD) implantation are engineered to express green fluorescent protein (GFP; hCPCe) or Pim-1-GFP (hCPCeP). Functional tests of hCPC regenerative potential are performed with immunocompromised mice by intramyocardial adoptive transfer injection after infarction. Myocardial structure and function is monitored by echocardiographic and hemodynamic assessment for 20 weeks following delivery. hCPCe and hCPCeP expressing luciferase are followed by bioluminesence imaging (BLI) to non-invasively track persistence. Results hCPCeP exhibit augmentation of reparative potential relative to hCPCe control cells as demonstrated by significantly increased proliferation coupled with amelioration of infarction injury and increased hemodynamic performance at 20 weeks post-transplantation. Concurrent with enhanced cardiac structure and function, hCPCeP demonstrate increased cellular engraftment and differentiation with improved vasculature and reduced infarct size. Enhanced persistence of hCPCeP versus hCPCe is revealed by BLI at up to 8 weeks post delivery. Conclusion Genetic engineering of hCPCs with Pim-1 enhances repair of damaged myocardium. Ex vivo gene delivery to modify stem cells has emerged as a viable option addressing current limitations in the field. This study demonstrates that efficacy of human CPCs from the failing myocardium can be safely and significantly enhanced through expression of Pim-1 kinase, setting the stage for use of engineered cells

  10. Semi-automated scar detection in delayed enhanced cardiac magnetic resonance images

    NASA Astrophysics Data System (ADS)

    Morisi, Rita; Donini, Bruno; Lanconelli, Nico; Rosengarden, James; Morgan, John; Harden, Stephen; Curzen, Nick

    2015-06-01

    Late enhancement cardiac magnetic resonance images (MRI) has the ability to precisely delineate myocardial scars. We present a semi-automated method for detecting scars in cardiac MRI. This model has the potential to improve routine clinical practice since quantification is not currently offered due to time constraints. A first segmentation step was developed for extracting the target regions for potential scar and determining pre-candidate objects. Pattern recognition methods are then applied to the segmented images in order to detect the position of the myocardial scar. The database of late gadolinium enhancement (LE) cardiac MR images consists of 111 blocks of images acquired from 63 patients at the University Hospital Southampton NHS Foundation Trust (UK). At least one scar was present for each patient, and all the scars were manually annotated by an expert. A group of images (around one third of the entire set) was used for training the system which was subsequently tested on all the remaining images. Four different classifiers were trained (Support Vector Machine (SVM), k-nearest neighbor (KNN), Bayesian and feed-forward neural network) and their performance was evaluated by using Free response Receiver Operating Characteristic (FROC) analysis. Feature selection was implemented for analyzing the importance of the various features. The segmentation method proposed allowed the region affected by the scar to be extracted correctly in 96% of the blocks of images. The SVM was shown to be the best classifier for our task, and our system reached an overall sensitivity of 80% with less than 7 false positives per patient. The method we present provides an effective tool for detection of scars on cardiac MRI. This may be of value in clinical practice by permitting routine reporting of scar quantification.

  11. A Review and Discussion of Epistemological Commitments, Metacognition, and Critical Thinking with Suggestions on Their Enhancement in Internet-Assisted Chemistry Classrooms

    NASA Astrophysics Data System (ADS)

    Tsai, Chin-Chung

    2001-07-01

    Recently, educators have focused on students' internal control of learning. Epistemological commitments, metacognition, and critical thinking are relevant considerations when addressing this topic. This paper explores the relationships among these domains as a theoretical framework for enhancing chemistry education. The framework shows that these domains share many commonalities. For example, they all focus on learners' self-reflection and they all are rooted in the constructivist theory. This paper further proposes a role for Internet technology in helping students develop appropriate epistemological commitments, metacognitive skills, and critical thinking.

  12. Bone marrow transplantation modulates tissue macrophage phenotype and enhances cardiac recovery after subsequent acute myocardial infarction

    PubMed Central

    Protti, Andrea; Mongue-Din, Heloise; Mylonas, Katie J.; Sirker, Alexander; Sag, Can Martin; Swim, Megan M.; Maier, Lars; Sawyer, Greta; Dong, Xuebin; Botnar, Rene; Salisbury, Jon; Gray, Gillian A.; Shah, Ajay M.

    2016-01-01

    Background Bone marrow transplantation (BMT) is commonly used in experimental studies to investigate the contribution of BM-derived circulating cells to different disease processes. During studies investigating the cardiac response to acute myocardial infarction (MI) induced by permanent coronary ligation in mice that had previously undergone BMT, we found that BMT itself affects the remodelling response. Methods and results Compared to matched naive mice, animals that had previously undergone BMT developed significantly less post-MI adverse remodelling, infarct thinning and contractile dysfunction as assessed by serial magnetic resonance imaging. Cardiac rupture in male mice was prevented. Histological analysis showed that the infarcts of mice that had undergone BMT had a significantly higher number of inflammatory cells, surviving cardiomyocytes and neovessels than control mice, as well as evidence of significant haemosiderin deposition. Flow cytometric and histological analyses demonstrated a higher number of alternatively activated (M2) macrophages in myocardium of the BMT group compared to control animals even before MI, and this increased further in the infarcts of the BMT mice after MI. Conclusions The process of BMT itself substantially alters tissue macrophage phenotype and the subsequent response to acute MI. An increase in alternatively activated macrophages in this setting appears to enhance cardiac recovery after MI. PMID:26688473

  13. Severe Left Ventricular Hypertrophy, Small Pericardial Effusion, and Diffuse Late Gadolinium Enhancement by Cardiac Magnetic Resonance Suspecting Cardiac Amyloidosis: Endomyocardial Biopsy Reveals an Unexpected Diagnosis

    PubMed Central

    Hofmann, Nina P.; Giusca, Sorin; Klingel, Karin; Nunninger, Peter; Korosoglou, Grigorios

    2016-01-01

    Left ventricular (LV) hypertrophy can be related to a multitude of cardiac disorders, such as hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and hypertensive heart disease. Although the presence of LV hypertrophy is generally associated with poorer cardiac outcomes, the early differentiation between these pathologies is crucial due to the presence of specific treatment options. The diagnostic process with LV hypertrophy requires the integration of clinical evaluation, electrocardiography (ECG), echocardiography, biochemical markers, and if required CMR and endomyocardial biopsy in order to reach the correct diagnosis. Here, we present a case of a patient with severe LV hypertrophy (septal wall thickness of 23 mm, LV mass of 264 g, and LV mass index of 147 g/m2), severely impaired longitudinal function, and preserved radial contractility (ejection fraction = 55%), accompanied by small pericardial effusion and diffuse late gadolinium enhancement (LGE) by cardiac magnetic resonance (CMR). Due to the imaging findings, an infiltrative cardiomyopathy, such as cardiac amyloidosis, was suspected. However, amyloid accumulation was excluded by endomyocardial biopsy, which revealed the presence of diffuse myocardial fibrosis in an advanced hypertensive heart disease. PMID:27247807

  14. Fuzzy Commitment

    NASA Astrophysics Data System (ADS)

    Juels, Ari

    The purpose of this chapter is to introduce fuzzy commitment, one of the earliest and simplest constructions geared toward cryptography over noisy data. The chapter also explores applications of fuzzy commitment to two problems in data security: (1) secure management of biometrics, with a focus on iriscodes, and (2) use of knowledge-based authentication (i.e., personal questions) for password recovery.

  15. An efficient method for accurate segmentation of LV in contrast-enhanced cardiac MR images

    NASA Astrophysics Data System (ADS)

    Suryanarayana K., Venkata; Mitra, Abhishek; Srikrishnan, V.; Jo, Hyun Hee; Bidesi, Anup

    2016-03-01

    Segmentation of left ventricle (LV) in contrast-enhanced cardiac MR images is a challenging task because of high variability in the image intensity. This is due to a) wash-in and wash-out of the contrast agent over time and b) poor contrast around the epicardium (outer wall) region. Current approaches for segmentation of the endocardium (inner wall) usually involve application of a threshold within the region of interest, followed by refinement techniques like active contours. A limitation of this method is under-segmentation of the inner wall because of gradual loss of contrast at the wall boundary. On the other hand, the challenge in outer wall segmentation is the lack of reliable boundaries because of poor contrast. There are four main contributions in this paper to address the aforementioned issues. First, a seed image is selected using variance based approach on 4D time-frame images over which initial endocardium and epicardium is segmented. Secondly, we propose a patch based feature which overcomes the problem of gradual contrast loss for LV endocardium segmentation. Third, we propose a novel Iterative-Edge-Refinement (IER) technique for epicardium segmentation. Fourth, we propose a greedy search algorithm for propagating the initial contour segmented on seed-image across other time frame images. We have experimented our technique on five contrast-enhanced cardiac MR Datasets (4D) having a total of 1097 images. The segmentation results for all 1097 images have been visually inspected by a clinical expert and have shown good accuracy.

  16. Enhanced QSAR models for drug-triggered inhibition of the main cardiac ion currents.

    PubMed

    Wiśniowska, Barbara; Mendyk, Aleksander; Szlęk, Jakub; Kołaczkowski, Michał; Polak, Sebastian

    2015-09-01

    The currently changing cardiac safety testing paradigm suggests, among other things, a shift towards using in silico models of cellular electrophysiology and assessment of a concomitant block of multiple ion channels. In this study, a set of four enhanced QSAR models have been developed: for the rapid delayed rectifying potassium current (IKr), slow delayed rectifying potassium current (IKs), peak sodium current (INa) and late calcium current (ICaL), predicting ion currents changes for the specific in vitro experiment from the 2D structure of the compounds. The models are a combination of both in vitro study parameters and physico-chemical descriptors, which is a novel approach in drug-ion channels interactions modeling. Their predictive power assessed in the enhanced, more demanding than standard procedure, 10-fold cross validation was reasonably high. Rough comparison with published pure in silico hERG interaction models shows that the quality of the model predictions does not differ from other models available in the public domain, however, it takes its advantage in accounting for inter-experimental settings variability. Developed models are implemented in the Cardiac Safety Simulator, a commercially available platform enabling the in vitro-in vivo extrapolation of the drugs proarrhythmic effect and ECG simulation. A more comprehensive assessment of the effects of the compounds on ion channels allows for making more informed decisions regarding the risk - and thus avoidance - of exclusion of potentially safe and effective drugs. PMID:25559930

  17. Prognostic Value of Late Gadolinium Enhancement Cardiovascular Magnetic Resonance in Cardiac Amyloidosis

    PubMed Central

    Fontana, Marianna; Pica, Silvia; Reant, Patricia; Abdel-Gadir, Amna; Treibel, Thomas A.; Banypersad, Sanjay M.; Maestrini, Viviana; Barcella, William; Rosmini, Stefania; Bulluck, Heerajnarain; Sayed, Rabya H.; Patel, Ketna; Mamhood, Shameem; Bucciarelli-Ducci, Chiara; Whelan, Carol J.; Herrey, Anna S.; Lachmann, Helen J.; Wechalekar, Ashutosh D.; Manisty, Charlotte H.; Schelbert, Eric B.; Kellman, Peter; Gillmore, Julian D.; Hawkins, Philip N.

    2015-01-01

    Background— The prognosis and treatment of the 2 main types of cardiac amyloidosis, immunoglobulin light chain (AL) and transthyretin (ATTR) amyloidosis, are substantially influenced by cardiac involvement. Cardiovascular magnetic resonance with late gadolinium enhancement (LGE) is a reference standard for the diagnosis of cardiac amyloidosis, but its potential for stratifying risk is unknown. Methods and Results— Two hundred fifty prospectively recruited subjects, 122 patients with ATTR amyloid, 9 asymptomatic mutation carriers, and 119 patients with AL amyloidosis, underwent LGE cardiovascular magnetic resonance. Subjects were followed up for a mean of 24±13 months. LGE was performed with phase-sensitive inversion recovery (PSIR) and without (magnitude only). These were compared with extracellular volume measured with T1 mapping. PSIR was superior to magnitude-only inversion recovery LGE because PSIR always nulled the tissue (blood or myocardium) with the longest T1 (least gadolinium). LGE was classified into 3 patterns: none, subendocardial, and transmural, which were associated with increasing amyloid burden as defined by extracellular volume (P<0.0001), with transitions from none to subendocardial LGE at an extracellular volume of 0.40 to 0.43 (AL) and 0.39 to 0.40 (ATTR) and to transmural at 0.48 to 0.55 (AL) and 0.47 to 0.59 (ATTR). Sixty-seven patients (27%) died. Transmural LGE predicted death (hazard ratio, 5.4; 95% confidence interval, 2.1–13.7; P<0.0001) and remained independent after adjustment for N-terminal pro-brain natriuretic peptide, ejection fraction, stroke volume index, E/E′, and left ventricular mass index (hazard ratio, 4.1; 95% confidence interval, 1.3–13.1; P<0.05). Conclusions— There is a continuum of cardiac involvement in systemic AL and ATTR amyloidosis. Transmural LGE is determined reliably by PSIR and represents advanced cardiac amyloidosis. The PSIR technique provides incremental information on outcome even after

  18. Application of novel anodized titanium for enhanced recruitment of H9C2 cardiac myoblast

    PubMed Central

    Behjati, Mohaddeseh; Moradi, Iman; Kazemi, Mohammad

    2015-01-01

    Objective(s): Anodized treated titanium surfaces, have been proposed as potential surfaces with better cell attachment capacities. We have investigated the adhesion and proliferation properties of H9C2 cardiac myoblasts on anodized treated titanium surface. Materials and Methods: Surface topography and anodized tubules were examined by high-resolution scanning electron microscopy (SEM). Control and test substrates were inserted to the bottom of 24-well tissue culture plates. Culture media including H9C2 cells were loaded on the surface of substrate and control wells at the second passage. Evaluation of cell growth, proliferation, viability and surface cytotoxicity was performed using MTT test. After 48 hr, some samples were inspected by SEM. DAPI-staining was used to count attached cells. Results: MTT results for cells cultured on anodized titanium and unanodized titanium surfaces was equal to 1.56 and 0.55 fold change compared to tissue culture polystyrene (TCPS). The surface had no cytotoxic effects on cells. The average cell attachment to TCPS, unanodized and anodized titanium surface was 2497±40.16, 1250±20.11 and 4859.5±54.173, respectively. Cell adhesion to anodized titanium was showed 1.95 and 3.89 fold increase compared to TCPS and unanodized titanium, respectively (P<0.05). Conclusion: Anodized titanium surfaces can be potentially applied for enhanced recruitment of H9C2 cells. This unique property makes these inexpensive anodized surfaces as a candidate surface for attachment of cardiac cells and consequently for cardiac regeneration purposes. PMID:26526098

  19. Akap1 Deficiency Promotes Mitochondrial Aberrations and Exacerbates Cardiac Injury Following Permanent Coronary Ligation via Enhanced Mitophagy and Apoptosis

    PubMed Central

    Schiattarella, Gabriele Giacomo; Cattaneo, Fabio; Pironti, Gianluigi; Magliulo, Fabio; Carotenuto, Giuseppe; Pirozzi, Marinella; Polishchuk, Roman; Borzacchiello, Domenica; Paolillo, Roberta; Oliveti, Marco; Boccella, Nicola; Avvedimento, Marisa; Sepe, Maria; Lombardi, Assunta; Busiello, Rosa Anna; Trimarco, Bruno; Esposito, Giovanni; Feliciello, Antonio; Perrino, Cinzia

    2016-01-01

    A-kinase anchoring proteins (AKAPs) transmit signals cues from seven-transmembrane receptors to specific sub-cellular locations. Mitochondrial AKAPs encoded by the Akap1 gene have been shown to modulate mitochondrial function and reactive oxygen species (ROS) production in the heart. Under conditions of hypoxia, mitochondrial AKAP121 undergoes proteolytic degradation mediated, at least in part, by the E3 ubiquitin ligase Seven In-Absentia Homolog 2 (Siah2). In the present study we hypothesized that Akap1 might be crucial to preserve mitochondrial function and structure, and cardiac responses to myocardial ischemia. To test this, eight-week-old Akap1 knockout mice (Akap1-/-), Siah2 knockout mice (Siah2-/-) or their wild-type (wt) littermates underwent myocardial infarction (MI) by permanent left coronary artery ligation. Age and gender matched mice of either genotype underwent a left thoracotomy without coronary ligation and were used as controls (sham). Twenty-four hours after coronary ligation, Akap1-/- mice displayed larger infarct size compared to Siah2-/- or wt mice. One week after MI, cardiac function and survival were also significantly reduced in Akap1-/- mice, while cardiac fibrosis was significantly increased. Akap1 deletion was associated with remarkable mitochondrial structural abnormalities at electron microscopy, increased ROS production and reduced mitochondrial function after MI. These alterations were associated with enhanced cardiac mitophagy and apoptosis. Autophagy inhibition by 3-methyladenine significantly reduced apoptosis and ameliorated cardiac dysfunction following MI in Akap1-/- mice. These results demonstrate that Akap1 deficiency promotes cardiac mitochondrial aberrations and mitophagy, enhancing infarct size, pathological cardiac remodeling and mortality under ischemic conditions. Thus, mitochondrial AKAPs might represent important players in the development of post-ischemic cardiac remodeling and novel therapeutic targets. PMID

  20. Cardiac Non-myocyte Cells Show Enhanced Pharmacological Function Suggestive of Contractile Maturity in Stem Cell Derived Cardiomyocyte Microtissues

    PubMed Central

    Ravenscroft, Stephanie M.; Pointon, Amy; Williams, Awel W.; Cross, Michael J.; Sidaway, James E.

    2016-01-01

    The immature phenotype of stem cell derived cardiomyocytes is a significant barrier to their use in translational medicine and pre-clinical in vitro drug toxicity and pharmacological analysis. Here we have assessed the contribution of non-myocyte cells on the contractile function of co-cultured human embryonic stem cell derived cardiomyocytes (hESC-CMs) in spheroid microtissue format. Microtissues were formed using a scaffold free 96-well cell suspension method from hESC-CM cultured alone (CM microtissues) or in combination with human primary cardiac microvascular endothelial cells and cardiac fibroblasts (CMEF microtissues). Contractility was characterized with fluorescence and video-based edge detection. CMEF microtissues displayed greater Ca2+ transient amplitudes, enhanced spontaneous contraction rate and remarkably enhanced contractile function in response to both positive and negative inotropic drugs, suggesting a more mature contractile phenotype than CM microtissues. In addition, for several drugs the enhanced contractile response was not apparent when endothelial cell or fibroblasts from a non-cardiac tissue were used as the ancillary cells. Further evidence of maturity for CMEF microtissues was shown with increased expression of genes that encode proteins critical in cardiac Ca2+ handling (S100A1), sarcomere assembly (telethonin/TCAP) and β-adrenergic receptor signalling. Our data shows that compared with single cell-type cardiomyocyte in vitro models, CMEF microtissues are superior at predicting the inotropic effects of drugs, demonstrating the critical contribution of cardiac non-myocyte cells in mediating functional cardiotoxicity. PMID:27125969

  1. Cardiac Non-myocyte Cells Show Enhanced Pharmacological Function Suggestive of Contractile Maturity in Stem Cell Derived Cardiomyocyte Microtissues.

    PubMed

    Ravenscroft, Stephanie M; Pointon, Amy; Williams, Awel W; Cross, Michael J; Sidaway, James E

    2016-07-01

    The immature phenotype of stem cell derived cardiomyocytes is a significant barrier to their use in translational medicine and pre-clinical in vitro drug toxicity and pharmacological analysis. Here we have assessed the contribution of non-myocyte cells on the contractile function of co-cultured human embryonic stem cell derived cardiomyocytes (hESC-CMs) in spheroid microtissue format. Microtissues were formed using a scaffold free 96-well cell suspension method from hESC-CM cultured alone (CM microtissues) or in combination with human primary cardiac microvascular endothelial cells and cardiac fibroblasts (CMEF microtissues). Contractility was characterized with fluorescence and video-based edge detection. CMEF microtissues displayed greater Ca(2+ )transient amplitudes, enhanced spontaneous contraction rate and remarkably enhanced contractile function in response to both positive and negative inotropic drugs, suggesting a more mature contractile phenotype than CM microtissues. In addition, for several drugs the enhanced contractile response was not apparent when endothelial cell or fibroblasts from a non-cardiac tissue were used as the ancillary cells. Further evidence of maturity for CMEF microtissues was shown with increased expression of genes that encode proteins critical in cardiac Ca(2+ )handling (S100A1), sarcomere assembly (telethonin/TCAP) and β-adrenergic receptor signalling. Our data shows that compared with single cell-type cardiomyocyte in vitro models, CMEF microtissues are superior at predicting the inotropic effects of drugs, demonstrating the critical contribution of cardiac non-myocyte cells in mediating functional cardiotoxicity. PMID:27125969

  2. Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function

    PubMed Central

    Bibee, Kristin P.; Cheng, Ya-Jian; Ching, James K.; Marsh, Jon N.; Li, Allison J.; Keeling, Richard M.; Connolly, Anne M.; Golumbek, Paul T.; Myerson, Jacob W.; Hu, Grace; Chen, Junjie; Shannon, William D.; Lanza, Gregory M.; Weihl, Conrad C.; Wickline, Samuel A.

    2014-01-01

    Duchenne muscular dystrophy in boys progresses rapidly to severe impairment of muscle function and death in the second or third decade of life. Current supportive therapy with corticosteroids results in a modest increase in strength as a consequence of a general reduction in inflammation, albeit with potential untoward long-term side effects and ultimate failure of the agent to maintain strength. Here, we demonstrate that alternative approaches that rescue defective autophagy in mdx mice, a model of Duchenne muscular dystrophy, with the use of rapamycin-loaded nanoparticles induce a reproducible increase in both skeletal muscle strength and cardiac contractile performance that is not achievable with conventional oral rapamycin, even in pharmacological doses. This increase in physical performance occurs in both young and adult mice, and, surprisingly, even in aged wild-type mice, which sets the stage for consideration of systemic therapies to facilitate improved cell function by autophagic disposal of toxic byproducts of cell death and regeneration.—Bibee, K. P., Cheng, Y.-J., Ching, J. K., Marsh, J. N., Li, A. J., Keeling, R. M., Connolly, A. M., Golumbek, P. T., Myerson, J. W., Hu, G., Chen, J., Shannon, W. D., Lanza, G. M., Weihl, C. C., Wickline, S. A. Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function. PMID:24500923

  3. Enhanced fluorescence anisotropy assay for human cardiac troponin I and T detection.

    PubMed

    Qiao, Yanling; Tang, Hongmin; Munske, Gerhard R; Dutta, Prashanta; Ivory, Cornelius F; Dong, Wen-Ji

    2011-11-01

    Human cardiac troponin I (hcTnI) and troponin T (hcTnT) are the biomarkers of choice for the diagnosis of cardiac diseases. In an effort to improve assay sensitivity, in this study we developed a novel approach to simultaneously detect hcTnI and hcTnT in homogenous solutions by monitoring enhanced-fluorescence-anisotropy changes. Specifically, our design was based on a competition assay by measuring anisotropy change of fluorophore-labeled peptides bound to primary monoclonal antibodies in the presence of nano-gold-modified secondary antibody in response to the presence of target proteins. Enhanced-fluorescence-anisotropy resulted from interaction between the primary antibody and the nano-gold-labeled secondary antibody, which significantly increased the size and decreased tumbling motion of the complex of peptide-antibodies. The measurements were performed to detect hcTnI and hcTnT either individually or simultaneously in a homogenous buffer solution and in the solutions containing human plasma. Our results showed that when fluorescence emission was monitored at a single wavelength selected by a monochromator the assay at all experimental conditions had excellent linear response to the target proteins within the concentration range of 0.5-40 nM. The detection limit is 0.5 nM for both hcTnI and hcTnT in the presence of human plasma. However, when fluorescence emission was monitored using a cutoff filter, the linear response of the assay to the target proteins is within 15-500 pM. The detection limit is 15 pM which is close to the recommended 99th percentile cutoff point for concentrations of hcTnI and hcTnT tests to discriminate healthy and diseased conditions. Homogenous nature, rapid response time, and easy implementation of our assay design make it a useful tool for disease biomarker and protein sensing. PMID:21647606

  4. Enhanced Fluorescence Anisotropy Assay for Human Cardiac Troponin I and T Detection

    PubMed Central

    Qiao, Yanling; Tang, Hongmin; Munske, Gerhard R.; Dutta, Prashanta; Ivory, Cornelius F.

    2012-01-01

    Human cardiac troponin I (hcTnI) and troponin T (hcTnT) are the biomarkers of choice for the diagnosis of cardiac diseases. In an effort to improve assay sensitivity, in this study we developed a novel approach to simultaneously detect hcTnI and hcTnT in homogenous solutions by monitoring enhanced-fluorescence-anisotropy changes. Specifically, our design was based on a competition assay by measuring anisotropy change of fluorophore-labeled peptides bound to primary monoclonal antibodies in the presence of nano-gold-modified secondary antibody in response to the presence of target proteins. Enhanced-fluorescence-anisotropy resulted from interaction between the primary antibody and the nano-gold-labeled secondary antibody, which significantly increased the size and decreased tumbling motion of the complex of peptide-antibodies. The measurements were performed to detect hcTnI and hcTnT either individually or simultaneously in a homogenous buffer solution and in the solutions containing human plasma. Our results showed that when fluorescence emission was monitored at a single wavelength selected by a monochromator the assay at all experimental conditions had excellent linear response to the target proteins within the concentration range of 0.5–40 nM. The detection limit is 0.5 nM for both hcTnI and hcTnT in the presence of human plasma. However, when fluorescence emission was monitored using a cutoff filter, the linear response of the assay to the target proteins is within 15–500 pM. The detection limit is 15 pM which is close to the recommended 99th percentile cutoff point for concentrations of hcTnI and hcTnT tests to discriminate healthy and diseased conditions. Homogenous nature, rapid response time, and easy implementation of our assay design make it a useful tool for disease biomarker and protein sensing. PMID:21647606

  5. Heparin-enhanced plasma phospholipase A2 activity and prostacyclin synthesis in patients undergoing cardiac surgery.

    PubMed Central

    Nakamura, H; Kim, D K; Philbin, D M; Peterson, M B; Debros, F; Koski, G; Bonventre, J V

    1995-01-01

    Although eicosanoid production contributes to physiological and pathophysiological consequences of cardiopulmonary bypass (CPB), the mechanisms accounting for the enhanced eicosanoid production have not been defined. Plasma phospholipase A2 (PLA2) activity, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) levels were measured at various times during cardiac surgery. Plasma PLA2 activity increased after systemic heparinization, before CPB. This was highly correlated with concurrent increases in plasma 6-keto-PGF1 alpha, TXB2 concentrations did not increase with heparin administration but did increase significantly after initiation of CPB. High plasma PLA2 activity, 6-keto-PGF1 alpha, and TXB2 concentrations were measured throughout the CPB period. Protamine, administered to neutralize the heparin, caused an acute reduction of both plasma PLA2 activity and plasma 6-keto-PGF1 alpha, but no change in plasma TXB2 concentrations. Thus the ratio of TXB2 to 6-keto-PGF1 alpha increased significantly after protamine administration. Enhanced plasma PLA2 activity was also measured in patients with lower doses of heparin used clinically for nonsurgical applications. Human plasma PLA2 was identified as group II PLA2 by its sensitivity to deoxycholate and dithiothreitol, its substrate specificity, and its elution characteristics on heparin affinity chromatography. Heparin addition to PMNs in vitro resulted in dose-dependent increases in cellular PLA2 activity and release of PLA2. The PLA2 released from the PMN had characteristics similar to those of post-heparin plasma PLA2. In conclusion, plasma PLA2 activity and 6-keto-PGF1 alpha concentrations are markedly enhanced with systemic heparinization. Part of the anticoagulant and vasodilating effects of heparin may be due to increased plasma prostacyclin (PGI2) levels. In addition the pulmonary vasoconstriction sometimes associated with protamine infusion during cardiac surgery might be due to decreased

  6. Epicardial delivery of VEGF and cardiac stem cells guided by 3-dimensional PLLA mat enhancing cardiac regeneration and angiogenesis in acute myocardial infarction.

    PubMed

    Chung, Hye-Jin; Kim, Jong-Tae; Kim, Hee-Jung; Kyung, Hei-Won; Katila, Pramila; Lee, Jeong-Han; Yang, Tae-Hyun; Yang, Young-Il; Lee, Seung-Jin

    2015-05-10

    Congestive heart failure is mostly resulted in a consequence of the limited myocardial regeneration capacity after acute myocardial infarction. Targeted delivery of proangiogenic factors and/or stem cells to the ischemic myocardium is a promising strategy for enhancing their local and sustained therapeutic effects. Herein, we designed an epicardial delivery system of vascular endothelial growth factor (VEGF) and cardiac stem cells (CSCs) using poly(l-lactic acid) (PLLA) mat applied to the acutely infarcted myocardium. The fibrous VEGF-loaded PLLA mat was fabricated by an electrospinning method using PLLA solution emulsified VEGF. This mat not only allowed for sustained release of VEGF for 4weeks but boosted migration and proliferation of both endothelial cells and CSCs in vitro. Furthermore, sustained release of VEGF showed a positive effect on in vitro capillary-like network formation of endothelial cells compared with bolus treatment of VEGF. PLLA mat provided a permissive 3-dimensional (3D) substratum that led to spontaneous cardiomyogenic differentiation of CSCs in vitro. Notably, sustained stimulation by VEGF-loaded PLLA mat resulted in a substantial increase in the expression of proangiogenic mRNAs of CSCs in vitro. The epicardially implanted VEGF-loaded PLLA mat showed modest effects on angiogenesis and cardiomyogenesis in the acutely infarcted hearts. However, co-implantation of VEGF and CSCs using the PLLA mat showed meaningful therapeutic effects on angiogenesis and cardiomyogenesis compared with controls, leading to reduced cardiac remodeling and enhanced global cardiac function. Collectively, the PLLA mat allowed a smart cargo that enabled the sustained release of VEGF and the delivery of CSCs, thereby synergistically inducing angiogenesis and cardiomyogenesis in acute myocardial infarction. PMID:25681051

  7. Engineered Biomaterials to Enhance Stem Cell-Based Cardiac Tissue Engineering and Therapy.

    PubMed

    Hasan, Anwarul; Waters, Renae; Roula, Boustany; Dana, Rahbani; Yara, Seif; Alexandre, Toubia; Paul, Arghya

    2016-07-01

    Cardiovascular disease is a leading cause of death worldwide. Since adult cardiac cells are limited in their proliferation, cardiac tissue with dead or damaged cardiac cells downstream of the occluded vessel does not regenerate after myocardial infarction. The cardiac tissue is then replaced with nonfunctional fibrotic scar tissue rather than new cardiac cells, which leaves the heart weak. The limited proliferation ability of host cardiac cells has motivated investigators to research the potential cardiac regenerative ability of stem cells. Considerable progress has been made in this endeavor. However, the optimum type of stem cells along with the most suitable matrix-material and cellular microenvironmental cues are yet to be identified or agreed upon. This review presents an overview of various types of biofunctional materials and biomaterial matrices, which in combination with stem cells, have shown promises for cardiac tissue replacement and reinforcement. Engineered biomaterials also have applications in cardiac tissue engineering, in which tissue constructs are developed in vitro by combining stem cells and biomaterial scaffolds for drug screening or eventual implantation. This review highlights the benefits of using biomaterials in conjunction with stem cells to repair damaged myocardium and give a brief description of the properties of these biomaterials that make them such valuable tools to the field. PMID:26953627

  8. Enhanced Effect of Human Cardiac Stem Cells and Bone Marrow Mesenchymal Stem Cells to Reduce Infarct Size and Restore Cardiac Function after Myocardial Infarction

    PubMed Central

    Williams, Adam R.; Hatzistergos, Konstantinos E.; Addicott, Benjamin; McCall, Fred; Carvalho, Decio; Suncion, Viky; Morales, Azorides R.; Silva, Jose Da; Sussman, Mark A.; Heldman, Alan W.; Hare, Joshua M.

    2013-01-01

    Background As mesenchymal stem cells (MSCs) induce proliferation and differentiation of c-kit+ cardiac stem cells (CSCs) in vivo and in vitro, we hypothesized that combining human (h)MSCs with c-kit+ hCSCs produces greater infarct size reduction compared to either cell administered alone after MI. Methods and Results Yorkshire swine underwent balloon occlusion of the LAD coronary artery followed by reperfusion, and were immunosuppressed after MI with cyclosporine and methylprednisolone. Intramyocardial injection of either: combination hCSCs/hMSCs (1M/200M, n=5), hCSCs alone (1M, n=5), hMSCs alone (200M, n=5), or placebo (PBS, n=5) was administered to the infarct border zones at 14 days post-MI. Phenotypic response to cell therapy was assessed by cardiac MRI and micromanometer conductance catheterization hemodynamics. While each cell therapy group had reduced MI size relative to placebo (p<0.05), the MI size reduction was 2-fold greater in combination vs. either cell therapy alone (p<0.05). Accompanying enhanced MI size reduction was substantial improvement in LV chamber compliance (end-diastolic pressure volume relationship, p<0.01) and contractility (preload recruitable stroke work and dP/dtmax, p<0.05) in combination treated swine. EF was restored to baseline in cell treated pigs, while placebo pigs had persistently depressed LV function (p<0.05). Immunohistochemistry showed 7-fold enhanced engraftment of stem cells in the combination therapy group vs. either cell type alone (P<0.001). Conclusions Combining hMSCs and hCSCs as a cell therapeutic enhances scar size reduction, and restores diastolic and systolic function toward normal after MI. Taken together these findings illustrate important biological interactions between c-kit+ CSCs and MSCs that enhance cell-based therapeutic responses. PMID:23224061

  9. Modified Wideband Three-Dimensional Late Gadolinium Enhancement MRI for Patients with Implantable Cardiac Devices

    PubMed Central

    Rashid, Shams; Rapacchi, Stanislas; Shivkumar, Kalyanam; Plotnik, Adam; Finn, J. Paul; Hu, Peng

    2015-01-01

    Purpose To study the effects of cardiac devices on three-dimensional (3D) late gadolinium enhancement (LGE) MRI and to develop a 3D LGE protocol for implantable cardioverter defibrillator (ICD) patients with reduced image artifacts. Theory and Methods The 3D LGE sequence was modified by implementing a wideband inversion pulse, which reduces hyperintensity artifacts, and by increasing bandwidth of the excitation pulse. The modified wideband 3D LGE sequence was tested in phantoms and evaluated in six volunteers and five patients with ICDs. Results Phantom and in vivo studies results demonstrated extended signal void and ripple artifacts in 3D LGE that were associated with ICDs. The reason for these artifacts was slab profile distortion and the subsequent aliasing in the slice-encoding direction. The modified wideband 3D LGE provided significantly reduced ripple artifacts than 3D LGE with wideband inversion only. Comparison of 3D and 2D LGE images demonstrated improved spatial resolution of the heart using 3D LGE. Conclusion Increased bandwidth of the inversion and excitation pulses can significantly reduce image artifacts associated with ICDs. Our modified wideband 3D LGE protocol can be readily used for imaging patients with ICDs given appropriate safety guidelines are followed. PMID:25772155

  10. Subject-specific patch-based denoising for contrast-enhanced cardiac MR images

    NASA Astrophysics Data System (ADS)

    Ma, Lorraine; Ebrahimi, Mehran; Pop, Mihaela

    2016-03-01

    Many patch-based techniques in imaging, e.g., Non-local means denoising, require tuning parameters to yield optimal results. In real-world applications, e.g., denoising of MR images, ground truth is not generally available and the process of choosing an appropriate set of parameters is a challenge. Recently, Zhu et al. proposed a method to define an image quality measure, called Q, that does not require ground truth. In this manuscript, we evaluate the effect of various parameters of the NL-means denoising on this quality metric Q. Our experiments are based on the late-gadolinium enhancement (LGE) cardiac MR images that are inherently noisy. Our described exhaustive evaluation approach can be used in tuning parameters of patch-based schemes. Even in the case that an estimation of optimal parameters is provided using another existing approach, our described method can be used as a secondary validation step. Our preliminary results suggest that denoising parameters should be case-specific rather than generic.

  11. Effect of heart rate on CT angiography using the enhanced cardiac model of the 4D NCAT

    NASA Astrophysics Data System (ADS)

    Segars, W. P.; Taguchi, K.; Fung, G. S. K.; Fishman, E. K.; Tsui, B. M. W.

    2006-03-01

    We investigate the effect of heart rate on the quality and artifact generation in coronary artery images obtained using multi-slice computed tomography (MSCT) with the purpose of finding the optimal time resolution for data acquisition. To perform the study, we used the 4D NCAT phantom, a computer model of the normal human anatomy and cardiac and respiratory motions developed in our laboratory. Although capable of being far more realistic, the 4D NCAT cardiac model was originally designed for low-resolution imaging research, and lacked the anatomical detail to be applicable to high-resolution CT. In this work, we updated the cardiac model to include a more detailed anatomy and physiology based on high-resolution clinical gated MSCT data. To demonstrate its utility in high-resolution dynamic CT imaging research, the enhanced 4D NCAT was then used in a pilot simulation study to investigate the effect of heart rate on CT angiography. The 4D NCAT was used to simulate patients with different heart rates (60-120 beats/minute) and with various cardiac plaques of known size and location within the coronary arteries. For each simulated patient, MSCT projection data was generated with data acquisition windows ranging from 100 to 250 ms centered within the quiet phase (mid-diastole) of the heart using an analytical CT projection algorithm. CT images were reconstructed from the projection data, and the contrast of the plaques was then measured to assess the effect of heart rate and to determine the optimal time resolution required for each case. The 4D NCAT phantom with its realistic model for the cardiac motion was found to provide a valuable tool from which to optimize CT cardiac applications. Our results indicate the importance of optimizing the time resolution with regard to heart rate and plaque location for improved CT images at a reduced patient dose.

  12. Cardiac expression of the Drosophila Sulphonylurea receptor gene is regulated by an intronic enhancer dependent upon the NK homeodomain factor Tinman

    PubMed Central

    Hendren, Jill D.; Shah, Ankita P.; Arguelles, Alicia M.; Cripps, Richard M.

    2007-01-01

    Cardiac development proceeds via the activation of a complex network of regulatory factors which both directly and indirectly impact downstream cardiac structural genes. In Drosophila, the NK homeodomain transcription factor Tinman is critical to cardiac specification and development via the activation of a number of key regulatory genes which mediate heart development. In this manuscript we demonstrate that Tinman also functions in Drosophila to directly activate transcription of the ATP binding cassette gene Sulphonylurea receptor (Sur). Cardiac expression of Sur is regulated by Tinman via an intronic enhancer which first becomes active at stage 12 of embryogenesis and whose function is restricted to the Tin cardial cells by the end of embryogenesis. Cardiac Sur enhancer activity subsequently persists through larval and adult development, but interestingly becomes modulated in several unique subsets of Tin-expressing cardial cells. The cardiac enhancer contains four binding sites for Tinman protein; mutation of two of these sites significantly reduces enhancer activity at all stages of development, and activation of the wild-type enhancer by ectopic Tinman protein confirms Sur is a direct target of Tinman transcriptional activation. These findings delineate at the molecular level specific sub-types of Tin cardial cells, and define an important regulatory pathway between two Drosophila genes for which mutations in human homologs have been shown to result in cardiac disease. PMID:17433632

  13. Myocardial Extracellular Volume Fraction with Dual-Energy Equilibrium Contrast-enhanced Cardiac CT in Nonischemic Cardiomyopathy: A Prospective Comparison with Cardiac MR Imaging.

    PubMed

    Lee, Hye-Jeong; Im, Dong Jin; Youn, Jong-Chan; Chang, Suyon; Suh, Young Joo; Hong, Yoo Jin; Kim, Young Jin; Hur, Jin; Choi, Byoung Wook

    2016-07-01

    Purpose To evaluate the feasibility of equilibrium contrast material-enhanced dual-energy cardiac computed tomography (CT) to determine extracellular volume fraction (ECV) in nonischemic cardiomyopathy (CMP) compared with magnetic resonance (MR) imaging. Materials and Methods This study was approved by the institutional review board; informed consent was obtained. Seven healthy subjects and 23 patients (six with hypertrophic CMP, nine with dilated CMP, four with amyloidosis, and four with sarcoidosis) (mean age ± standard deviation, 57.33 years ± 14.82; 19 male participants [63.3%]) were prospectively enrolled. Twelve minutes after contrast material injection (1.8 mL/kg at 3 mL/sec), dual-energy cardiac CT was performed. ECV was measured by two observers independently. Hematocrit levels were compared between healthy subjects and patients with the Mann-Whitney U test. In per-subject analysis, interobserver agreement for CT was assessed with the intraclass correlation coefficient (ICC), and intertest agreement between MR imaging and CT was assessed with Bland-Altman analysis. In per-segment analysis, Student t tests in the linear mixed model were used to compare ECV on CT images between healthy subjects and patients. Results Hematocrit level was 43.44% ± 1.80 for healthy subjects and 41.23% ± 5.61 for patients with MR imaging (P = .16) and 43.50% ± 1.92 for healthy subjects and 41.35% ± 5.92 for patients with CT (P = .15). For observer 1 in per-subject analysis, ECV was 34.18% ± 8.98 for MR imaging and 34.48% ± 8.97 for CT. For observer 2, myocardial ECV was 34.42% ± 9.03 for MR imaging and 33.98% ± 9.05 for CT. Interobserver agreement for ECV at CT was excellent (ICC = 0.987). Bland-Altman analysis between MR imaging and CT showed a small bias (-0.06%), with 95% limits of agreement of -1.19 and 1.79. Compared with healthy subjects, patients with hypertrophic CMP, dilated CMP, amyloidosis, and sarcoidosis had significantly higher myocardial ECV at dual

  14. Omega-3 fatty acid supplementation enhances stroke volume and cardiac output during dynamic exercise.

    PubMed

    Walser, Buddy; Stebbins, Charles L

    2008-10-01

    Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have beneficial effects on cardiovascular function. We tested the hypotheses that dietary supplementation with DHA (2 g/day) + EPA (3 g/day) enhances increases in stroke volume (SV) and cardiac output (CO) and decreases in systemic vascular resistance (SVR) during dynamic exercise. Healthy subjects received DHA + EPA (eight men, four women) or safflower oil (six men, three women) for 6 weeks. Both groups performed 20 min of bicycle exercise (10 min each at a low and moderate work intensity) before and after DHA + EPA or safflower oil treatment. Mean arterial pressure (MAP), heart rate (HR), SV, CO, and SVR were assessed before exercise and during both workloads. HR was unaffected by DHA + EPA and MAP was reduced, but only at rest (88 +/- 5 vs. 83 +/- 4 mm Hg). DHA + EPA augmented increases in SV (14.1 +/- 6.3 vs. 32.3 +/- 8.7 ml) and CO (8.5 +/- 1.0 vs. 10.3 +/- 1.2 L/min) and tended to attenuate decreases in SVR (-7.0 +/- 0.6 vs. -10.1 +/- 1.6 mm Hg L(-1) min(-1)) during the moderate workload. Safflower oil treatment had no effects on MAP, HR, SV, CO or SVR at rest or during exercise. DHA + EPA-induced increases in SV and CO imply that dietary supplementation with these fatty acids can increase oxygen delivery during exercise, which may have beneficial clinical implications for individuals with cardiovascular disease and reduced exercise tolerance. PMID:18563435

  15. Cardiac-specific miRNA in cardiogenesis, heart function, and cardiac pathology (with focus on myocardial infarction).

    PubMed

    Chistiakov, Dimitry A; Orekhov, Alexander N; Bobryshev, Yuri V

    2016-05-01

    Cardiac miRNAs (miR-1, miR133a, miR-208a/b, and miR-499) are abundantly expressed in the myocardium. They play a central role in cardiogenesis, heart function and pathology. While miR-1 and miR-133a predominantly control early stages of cardiogenesis supporting commitment of cardiac-specific muscle lineage from embryonic stem cells and mesodermal precursors, miR-208 and miR-499 are involved in the late cardiogenic stages mediating differentiation of cardioblasts to cardiomyocytes and fast/slow muscle fiber specification. In the heart, miR-1/133a control cardiac conductance and automaticity by regulating all phases of the cardiac action potential. miR-208/499 located in introns of the heavy chain myosin genes regulate expression of sarcomeric contractile proteins. In cardiac pathology including myocardial infarction (MI), expression of cardiac miRNAs is markedly altered that leads to deleterious effects associated with heart wounding, arrhythmia, increased apoptosis, fibrosis, hypertrophy, and tissue remodeling. In acute MI, circulating levels of cardiac miRNAs are significantly elevated making them to be a promising diagnostic marker for early diagnosis of acute MI. Great cardiospecific capacity of these miRNAs is very helpful for enhancing regenerative properties and survival of stem cell and cardiac progenitor transplants and for reprogramming of mature non-cardiac cells to cardiomyocytes. PMID:27056419

  16. Characteristics and clinical relevance of late gadolinium enhancement in cardiac magnetic resonance in patients with systemic sclerosis.

    PubMed

    Sano, Makoto; Satoh, Hiroshi; Suwa, Kenichiro; Nobuhara, Mamoru; Saitoh, Takeji; Saotome, Masao; Urushida, Tsuyoshi; Katoh, Hideki; Shimoyama, Kumiko; Suzuki, Daisuke; Ogawa, Noriyoshi; Takehara, Yasuo; Sakahara, Harumi; Hayashi, Hideharu

    2015-11-01

    Cardiac involvement in systemic sclerosis (SSc) is considerably frequent in autopsy, but the early identification is clinically difficult. Recent advantages in cardiac magnetic resonance (CMR) enabled to detect myocardial fibrotic scar as late gadolinium enhancement (LGE). We aimed to examine the prevalence and distribution of LGE in patients with SSc, and associate them with clinical features, electrocardiographic abnormalities and cardiac function. Forty patients with SSc (58 ± 14 years-old, 35 females, limited/diffuse 25/15, disease duration 106 ± 113 months) underwent serological tests, 12-lead electrocardiogram (ECG) and CMR. Seven patients (17.5 %) showed LGE in 26 segments of left ventricle (LV). LGE distributed mainly in the basal to mid inter-ventricular septum and the right ventricular (RV) insertion points, but involved all the myocardial regions. More patients with LGE showed NYHA functional class II and more (71 vs. 21 %, p < 0.05), bundle branch blocks (57 vs. 6 %, p < 0.05), LV ejection fraction (LVEF) < 50 % (72 vs. 6 %, p < 0.01), LV asynergy (43 vs. 0 %, p < 0.01) and RVEF < 40 % (100 vs. 39 %, p < 0.01). There was no difference in disease duration, disease types, or prevalence of positive autoimmune antibodies or high serum NT-proBNP level (>125 pg/ml). When cardiac involvement of SSc was defined as low LVEF, ECG abnormalities or high NT-proBNP, the sensitivity, specificity positive and negative predictive values of LGE were 36, 92, 71 and 72 %, respectively. We could clarify the prevalence and distribution of LGE in Japanese patients with SSc. The presence of LGE was associated with cardiac symptom, conduction disturbance and impaired LV/RV contraction. PMID:24996373

  17. Enhanced care assistant training to address the workforce crisis in home care: changes related to job satisfaction and career commitment.

    PubMed

    Coogle, Constance L; Parham, Iris A; Jablonski, Rita; Rachel, Jason A

    2007-01-01

    Changes in job satisfaction and career commitment were observed as a consequence of a geriatric case management training program focusing on skills development among personal care attendants in home care. A comparison of pretraining and posttraining scores uncovered a statistically significant increase in Intrinsic Job Satisfaction scores for participants 18-39 years of age, whereas levels declined among the group of middle aged participants and no change was observed among participants age 52 and older. On the other hand, a statistically significant decline in Extrinsic Job Satisfaction was documented over all participants, but this was found to be primarily due to declines among participants 40-51 years of age. When contacted 6-12 months after the training series had concluded participants indicated that the training substantially increased the likelihood that they would stay in their current jobs and improved their job satisfaction to some extent. A comparison of pretraining and posttraining scores among participants providing follow-up data revealed a statistically significant improvement in levels of Career Resilience. These results are discussed as they relate to similar training models and national data sets, and recommendations are offered for targeting future educational programs designed to address the long-term care workforce shortage. PMID:17595925

  18. The effectiveness of acceptance and commitment therapy bibliotherapy for enhancing the psychological health of Japanese college students living abroad.

    PubMed

    Muto, Takashi; Hayes, Steven C; Jeffcoat, Tami

    2011-06-01

    International students often experience significant psychological distress but empirically tested programs are few. Broadly distributed bibliotherapy may provide a cost-effective approach. About half of the Japanese international students in a western university in the United States (N=70) were randomly assigned to a wait-list or to receive a Japanese translation of a broadly focused acceptance and commitment therapy (ACT) self-help book. Although recruited without regard to health status, the sample was highly distressed with nearly 80% exceeding clinical cutoffs on one or more measures. After a 2-months period for the first treatment group to read the book and a 2-month follow up, wait-list participants also received the book. Students receiving the book showed significantly better general mental health at post and follow up. Moderately depressed or stressed, and severely anxious students showed improvement compared to those not receiving the book. These patterns were repeated when the wait-list participants finally received the book. Improvements in primary outcomes were related to how much was learned about an ACT model from the book. Follow-up outcomes were statistically mediated by changes in psychological flexibility, but not vice versa and were moderated by level of initial flexibility. Overall, the data suggest that ACT bibliotherapy improved the mental health and psychological flexibility of Japanese international students. PMID:21496516

  19. Carbon nanotubes enhance intercalated disc assembly in cardiac myocytes via the β1-integrin-mediated signaling pathway.

    PubMed

    Sun, Hongyu; Lü, Shuanghong; Jiang, Xiao-Xia; Li, Xia; Li, Hong; Lin, Qiuxia; Mou, Yongchao; Zhao, Yuwei; Han, Yao; Zhou, Jin; Wang, Changyong

    2015-07-01

    Carbon nanotubes (CNTs) offer a new paradigm for constructing functional cardiac patches and repairing myocardial infarction (MI). However, little is known about how CNTs enhance the mechanical integrity and electrophysiological function of cardiac myocytes. To address this issue, we investigated the regularity and precise mechanism of the influence of CNTs on the assembly of intercalated disc (IDs). Here, single walled CNTs incorporated into collagen substrates were utilized as growth supports for neonatal cardiomyocytes, which enhanced cardiomyocyte adhesion and maturation. Furthermore, through the use of immunohistochemical staining, western blotting, transmission electron microscopy, and intracellular calcium transient measurement, we discovered that the addition of CNTs remarkably increased ID-related protein expression and enhanced ID assembly and functionality. On that basis, we further explored the underlying mechanism for how CNTs enhanced ID assembly through the use of immunohistochemical staining and western blotting. We found that the β1-integrin-mediated signaling pathway mediated CNT-induced upregulation of electrical and mechanical junction proteins. Notably, CNTs remarkably accelerated gap junction formation via activation of the β1-integrin-mediated FAK/ERK/GATA4 pathway. These findings provide valuable insight into the mechanistic effects that CNTs have on neonatal cardiomyocyte performance and will have a significant impact on the future of nanomedical research. PMID:25934454

  20. The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides.

    PubMed

    Zhi, Duo; Feng, Pan-Feng; Sun, Jia-Liang; Guo, Fengfeng; Zhang, Rui; Zhao, Xin; Li, Bao-Xin

    2015-08-30

    As is well-known, hERG plays an essential role in phase III repolarization of cardiac action potentials. Blocking of hERG channels can lead to LQTS. Inhibition of the metabolism of CYPs activities may elevate plasma levels, to further increase accumulation of drug on cardiac. The elevated serum levels may however elicit unexpected toxicities. Therefore, the inhibition tests of hERG and CYP are central to the preclinical studies because they may lead to severe cardiac toxicity. Berberine is widely used as an antibacterial agent and often combined with macrolides to treat gastropathy. Our objective was to assess cardiac toxicity during the combined use of Berberine with macrolides. (1) Azithromycin reduced hERG currents by accelerated channel inactivation. (2) The combination of Berberine with Azithromycin reduced hERG currents, producing an inhibitive effect stronger than use of a single drug alone, due to the high binding affinity for the onset of inactivation. (3) When cells were perfused concomitantly with Berberine and Clarithromycin, they showed a stronger inhibitive effect on hERG currents by decreasing the time constant for the onset of inactivation. (4) The combined administration of Berberine with Clarithromycin had a powerful inhibitive effect on CYP3A activities than use of a single drug alone. Collectively, these results demonstrated that concomitant use of Berberine with macrolides may require close monitoring because of potential drug toxicities, especially cardiac toxicity. PMID:25976224

  1. Guanfacine enhances cardiac acetylcholine release with little effect on norepinephrine release in anesthetized rabbits.

    PubMed

    Shimizu, Shuji; Kawada, Toru; Akiyama, Tsuyoshi; Turner, Michael James; Shishido, Toshiaki; Kamiya, Atsunori; Shirai, Mikiyasu; Sugimachi, Masaru

    2015-01-01

    An α2A-adrenergic agonist guanfacine improves autonomic imbalance in attention-deficit hyperactivity disorder, suggesting that it may be useful to correct autonomic imbalance in chronic heart failure (CHF) patients. To investigate the effects of guanfacine on cardiac autonomic nerve activities, a microdialysis technique was applied to anesthetized rabbit heart. Acetylcholine (ACh) and norepinephrine (NE) concentrations in atrial dialysates were measured as indices of cardiac autonomic nerve activities. Guanfacine at a dose of 100 μg/kg significantly decreased heart rate and increased dialysate ACh concentration without decreasing sympathetic NE release. Guanfacine may be useful for vagal activation therapy in CHF patients. PMID:25498385

  2. Peptide conjugation of 2'-O-methyl phosphorothioate antisense oligonucleotides enhances cardiac uptake and exon skipping in mdx mice.

    PubMed

    Jirka, Silvana M G; Heemskerk, Hans; Tanganyika-de Winter, Christa L; Muilwijk, Daan; Pang, Kar Him; de Visser, Peter C; Janson, Anneke; Karnaoukh, Tatyana G; Vermue, Rick; 't Hoen, Peter A C; van Deutekom, Judith C T; Aguilera, Begoña; Aartsma-Rus, Annemieke

    2014-02-01

    Antisense oligonucleotide (AON)-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy that is currently being tested in various clinical trials. This approach is based on restoring the open reading frame of dystrophin transcripts resulting in shorter but partially functional dystrophin proteins as found in patients with Becker muscular dystrophy. After systemic administration, a large proportion of AONs ends up in the liver and kidneys. Therefore, enhancing AON uptake by skeletal and cardiac muscle would improve the AONs' therapeutic effect. For phosphorodiamidate morpholino oligomer, AONs use nonspecific positively charged cell penetrating peptides to enhance efficacy. However, this is challenging for negatively charged 2'-O-methyl phosphorothioate oligomer. Therefore, we screened a 7-mer phage display peptide library to identify muscle and heart homing peptides in vivo in the mdx mouse model and found a promising candidate peptide capable of binding muscle cells in vitro and in vivo. Upon systemic administration in dystrophic mdx mice, conjugation of a 2'-O-methyl phosphorothioate AON to this peptide indeed improved uptake in skeletal and cardiac muscle, and resulted in higher exon skipping levels with a significant difference in heart and diaphragm. Based on these results, peptide conjugation represents an interesting strategy to enhance the therapeutic effect of exon skipping with 2'-O-methyl phosphorothioate AONs for Duchenne muscular dystrophy. PMID:24320790

  3. Delay and block of cardiac impulse caused by enhanced phase-4 depolarization in the His-Purkinje system.

    PubMed Central

    Kretz, A; Da Rous, H O; Palumbo, J R

    1975-01-01

    The underlying mechanism of bradycardia-dependent bundle-branch and paroxysmal atrioventricular block appears to be enhancement of phase-4 depolarization in a branch or in a natural or acquired monofascicular pathway. Clinical records of these forms of impaired conduction occurring in the bundle-branches, with either longer or shorter cardiac cycle lengths, are presented and analysed. These also include the combination of Mobitz typw I atrioventricular block with variable degrees of bundle-branch block, as a representative example of narrow ventricular escape beats firing in the zone where prominent diastolic depolarization is present. PMID:123463

  4. Amino acid substitutions in the FXYD motif enhance phospholemman-induced modulation of cardiac L-type calcium channels.

    PubMed

    Guo, Kai; Wang, Xianming; Gao, Guofeng; Huang, Congxin; Elmslie, Keith S; Peterson, Blaise Z

    2010-11-01

    We have found that phospholemman (PLM) associates with and modulates the gating of cardiac L-type calcium channels (Wang et al., Biophys J 98: 1149-1159, 2010). The short 17 amino acid extracellular NH(2)-terminal domain of PLM contains a highly conserved PFTYD sequence that defines it as a member of the FXYD family of ion transport regulators. Although we have learned a great deal about PLM-dependent changes in calcium channel gating, little is known regarding the molecular mechanisms underlying the observed changes. Therefore, we investigated the role of the PFTYD segment in the modulation of cardiac calcium channels by individually replacing Pro-8, Phe-9, Thr-10, Tyr-11, and Asp-12 with alanine (P8A, F9A, T10A, Y11A, D12A). In addition, Asp-12 was changed to lysine (D12K) and cysteine (D12C). As expected, wild-type PLM significantly slows channel activation and deactivation and enhances voltage-dependent inactivation (VDI). We were surprised to find that amino acid substitutions at Thr-10 and Asp-12 significantly enhanced the ability of PLM to modulate Ca(V)1.2 gating. T10A exhibited a twofold enhancement of PLM-induced slowing of activation, whereas D12K and D12C dramatically enhanced PLM-induced increase of VDI. The PLM-induced slowing of channel closing was abrogated by D12A and D12C, whereas D12K and T10A failed to impact this effect. These studies demonstrate that the PFXYD motif is not necessary for the association of PLM with Ca(V)1.2. Instead, since altering the chemical and/or physical properties of the PFXYD segment alters the relative magnitudes of opposing PLM-induced effects on Ca(V)1.2 channel gating, PLM appears to play an important role in fine tuning the gating kinetics of cardiac calcium channels and likely plays an important role in shaping the cardiac action potential and regulating Ca(2+) dynamics in the heart. PMID:20720179

  5. Unique pattern of late gadolinium enhancement on cardiac magnetic resonance imaging in Duchenne muscular dystrophy

    PubMed Central

    Ganigara, Madhusudan; Sharma, Bharti; Komalla, Ravi Babu; Vyas, Suman Y.; Mannam, Gopichand; Rao, Nitin Krishna

    2016-01-01

    Cardiomyopathy is an important cause of morbidity and mortality in patients with Duchenne muscular dystrophy (DMD). Early recognition of myocardial involvement and initiation of therapy are important for improved outcomes. Cardiac magnetic resonance imaging (CMR) is a sensitive tool in early detection of myocardial fibrosis in these children. PMID:27212861

  6. TBX1 Represses Vegfr2 Gene Expression and Enhances the Cardiac Fate of VEGFR2+ Cells

    PubMed Central

    Lania, Gabriella; Ferrentino, Rosa; Baldini, Antonio

    2015-01-01

    The T-box transcription factor TBX1 has critical roles in maintaining proliferation and inhibiting differentiation of cardiac progenitor cells of the second heart field (SHF). Haploinsufficiency of the gene that encodes it is a cause of congenital heart disease. Here, we developed an embryonic stem (ES) cell-based model in which Tbx1 expression can be modulated by tetracycline. Using this model, we found that TBX1 down regulates the expression of VEGFR2, and we confirmed this finding in vivo during embryonic development. In addition, we found a Vegfr2 domain of expression, not previously described, in the posterior SHF and this expression is extended by loss of Tbx1. VEGFR2 has been previously described as a marker of a subpopulation of cardiac progenitors. Clonal analysis of ES-derived VEGFR2+ cells indicated that 12.5% of clones expressed three markers of cardiac lineage (cardiomyocyte, smooth muscle and endothelium). However, a pulse of Tbx1 expression was sufficient to increase the percentage to 20.8%. In addition, the percentage of clones expressing markers of multiple cardiac lineages increased from 41.6% to 79.1% after Tbx1 pulse. These results suggest that TBX1 plays a role in maintaining a progenitor state in VEGFR2+ cells. PMID:26382615

  7. Enhanced Cardiac Perception Is Associated with Increased Susceptibility to Framing Effects

    ERIC Educational Resources Information Center

    Sutterlin, Stefan; Schulz, Stefan M.; Stumpf, Theresa; Pauli, Paul; Vogele, Claus

    2013-01-01

    Previous studies suggest in line with dual process models that interoceptive skills affect controlled decisions via automatic or implicit processing. The "framing effect" is considered to capture implicit effects of task-irrelevant emotional stimuli on decision-making. We hypothesized that cardiac awareness, as a measure of interoceptive…

  8. Older Adults in Cardiac Rehabilitation: A New Strategy for Enhancing Physical Function.

    ERIC Educational Resources Information Center

    Rejeski, W. Jack; Foy, Capri Gabrielle; Brawley, Lawrence R.; Brubaker, Peter H.; Focht, Brian C.; Norris, James L., III; Smith, Marci L.

    2002-01-01

    Contrasted the effect of a group-mediated cognitive- behavioral intervention (GMCB) versus traditional cardiac rehabilitation (CRP) upon changes in objective and self-reported physical function of older adults after 3 months of exercise therapy. Both groups improved significantly. Adults with lower function at the outset of the intervention…

  9. Taurine depresses cardiac contractility and enhances systemic heart glucose utilization in the cuttlefish, Sepia officinalis.

    PubMed

    MacCormack, Tyson J; Callaghan, N I; Sykes, A V; Driedzic, W R

    2016-02-01

    Taurine is the most abundant amino acid in the blood of the cuttlefish, Sepia officinalis, where levels can exceed 200 mmol L(-1). In mammals, intracellular taurine modulates cardiac Ca(2+) handling and carbohydrate metabolism at much lower concentrations but it is not clear if it exerts similar actions in cephalopods. Blood Ca(2+) levels are high in cephalopods and we hypothesized that taurine would depress cardiac Ca(2+) flux and modulate contractility in systemic and branchial hearts of cuttlefish. Heart performance was assessed with an in situ perfused systemic heart preparation and contractility was evaluated using isometrically contracting systemic and branchial heart muscle rings. Stroke volume, cardiac output, and Ca(2+) sensitivity were significantly lower in systemic hearts perfused with supplemental taurine (100 mmol L(-1)) than in controls. In muscle ring preparations, taurine impaired relaxation at high contraction frequencies, an effect abolished by supra-physiological Ca(2+) levels. Taurine did not affect oxygen consumption in non-contracting systemic heart muscle, but extracellular glucose utilization was twice that of control preparations. Collectively, our results suggest that extracellular taurine depresses cardiac Ca(2+) flux and potentiates glucose utilization in cuttlefish. Variations in taurine levels may represent an important mechanism for regulating cardiovascular function and metabolism in cephalopods. PMID:26644087

  10. Unique pattern of late gadolinium enhancement on cardiac magnetic resonance imaging in Duchenne muscular dystrophy.

    PubMed

    Ganigara, Madhusudan; Sharma, Bharti; Komalla, Ravi Babu; Vyas, Suman Y; Mannam, Gopichand; Rao, Nitin Krishna

    2016-01-01

    Cardiomyopathy is an important cause of morbidity and mortality in patients with Duchenne muscular dystrophy (DMD). Early recognition of myocardial involvement and initiation of therapy are important for improved outcomes. Cardiac magnetic resonance imaging (CMR) is a sensitive tool in early detection of myocardial fibrosis in these children. PMID:27212861

  11. Shared medical appointments after cardiac surgery-the process of implementing a novel pilot paradigm to enhance comprehensive postdischarge care.

    PubMed

    Harris, Marianne D

    2010-01-01

    To facilitate the physical and emotional needs of patients undergoing cardiac surgery and their families, our Cardiac Surgery Outpatient Clinic at Cleveland Clinic, a nonprofit multispecialty academic medical center in Cleveland, Ohio, decided to implement a trial of a novel care delivery paradigm called Shared Medical Appointments (SMAs). The purpose of this venture was to facilitate timely access to care 3 to 5 days after hospital discharge, include family members in the education process and the care of the patient, and provide a forum for support and shared learning among patients who have been through like surgical experiences. The clinic system, which performed 3,597 open heart surgeries and 213 robotically assisted cardiac surgeries in 2008, already used family education classes to provide instruction to the patients and family prior to surgery. Because this medium was an effective way to disseminate knowledge, we theorized that using an SMA would be an effective strategy to provide timely medical care after discharge and garner support, education, and increased access to timely medical care after discharge. Although there were many physicians in subspecialties performing these types of clinic visits at our institution since 2002, by the spring of 2007, a group of cardiothoracic nurses decided to perform a trial on this model in this cohort of patients and be a fully nurse-led SMA to provide comprehensive care after discharge. Preliminary patient satisfaction surveys have revealed that 92% of post-cardiac surgery patients rated the experience as good or excellent, and 82% would prefer an SMA for their next clinic visit rather than an individual visit. These data are consistent with physician-led SMA satisfaction surveys in our organization to date. Although still in its relative infancy, an SMA for this cohort appears to have merit in enhancing the support and education as well as providing for the complex medical needs of these patients. PMID:20168192

  12. High-quality anatomical structure enhancement for cardiac image dynamic volume rendering

    NASA Astrophysics Data System (ADS)

    Zhang, Qi; Eagleson, Roy; Guiraudon, Gerard M.; Peters, Terry M.

    2008-03-01

    Dynamic volume rendering of the beating heart is an important element in cardiac disease diagnosis and therapy planning, providing the clinician with insight into the internal cardiac structure and functional behavior. Most clinical applications tend to focus upon a particular set of organ structures, and in the case of cardiac imaging, it would be helpful to embed anatomical features into the dynamic volume that are of particular importance to an intervention. A uniform transfer function (TF), such as is generally employed in volume rendering, cannot effectively isolate such structures because of the lack of spatial information and the small intensity differences between adjacent tissues. Explicit segmentation is a powerful way to approach this problem, which usually yields a single binary mask volume (MV), where a unit value in a voxel within the MV acts as a tag label representing the anatomical structure of interest (ASOI). These labels are used to determine the TF employed to adjust the ASOI display. Traditional approaches for rendering such segmented volumetric datasets usually deliver unsatisfactory results, such as noninteractive rendering speed, low image quality, intermixing artifacts along the rendered subvolume boundaries, and speckle noise. In this paper, we introduce a new "color coding" approach, based on the graphics processing unit (GPU) accelerated raycasting algorithm and a pre-integrated voxel classification method, to address this problem. The mask tag labels derived from segmentation are first smoothed with a Gaussian filter, and multiple TFs are designed for each of the MVs and the source cardiac volume respectively, mapping the voxel's intensity to color and opacity at each sampling point along the casting ray. The resultant values are composited together using a boundary color adjustment technique, which acts as "coding" the segmented anatomical structure information into the rendered source volume of the beating heart. Our algorithm

  13. An automatic machine learning system for coronary calcium scoring in clinical non-contrast enhanced, ECG-triggered cardiac CT

    NASA Astrophysics Data System (ADS)

    Wolterink, Jelmer M.; Leiner, Tim; Takx, Richard A. P.; Viergever, Max A.; Išgum, Ivana

    2014-03-01

    Presence of coronary artery calcium (CAC) is a strong and independent predictor of cardiovascular events. We present a system using a forest of extremely randomized trees to automatically identify and quantify CAC in routinely acquired cardiac non-contrast enhanced CT. Candidate lesions the system could not label with high certainty were automatically identified and presented to an expert who could relabel them to achieve high scoring accuracy with minimal effort. The study included 200 consecutive non-contrast enhanced ECG-triggered cardiac CTs (120 kV, 55 mAs, 3 mm section thickness). Expert CAC annotations made as part of the clinical routine served as the reference standard. CAC candidates were extracted by thresholding (130 HU) and 3-D connected component analysis. They were described by shape, intensity and spatial features calculated using multi-atlas segmentation of coronary artery centerlines from ten CTA scans. CAC was identified using a randomized decision tree ensemble classifier in a ten-fold stratified cross-validation experiment and quantified in Agatston and volume scores for each patient. After classification, candidates with posterior probability indicating uncertain labeling were selected for further assessment by an expert. Images with metal implants were excluded. In the remaining 164 images, Spearman's p between automatic and reference scores was 0.94 for both Agatston and volume scores. On average 1.8 candidate lesions per scan were subsequently presented to an expert. After correction, Spearman's p was 0.98. We have described a system for automatic CAC scoring in cardiac CT images which is able to effectively select difficult examinations for further refinement by an expert.

  14. Enhanced cardiac perception is associated with increased susceptibility to framing effects.

    PubMed

    Sütterlin, Stefan; Schulz, Stefan M; Stumpf, Theresa; Pauli, Paul; Vögele, Claus

    2013-07-01

    Previous studies suggest in line with dual process models that interoceptive skills affect controlled decisions via automatic or implicit processing. The "framing effect" is considered to capture implicit effects of task-irrelevant emotional stimuli on decision-making. We hypothesized that cardiac awareness, as a measure of interoceptive skills, is positively associated with susceptibility to the framing effect. Forty volunteers performed a risky-choice framing task in which the effect of loss versus gain frames on decisions based on identical information was assessed. The results show a positive association between cardiac awareness and the framing effect, accounting for 24% of the variance in the framing effect. These findings demonstrate that good interoceptive skills are linked to poorer performance in risky choices based on ambivalent information when implicit bias is induced by task-irrelevant emotional information. These findings support a dual process perspective on decision-making and suggest that interoceptive skills mediate effects of implicit bias on decisions. PMID:23607678

  15. Ischemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts.

    PubMed

    Dashkevich, A; Raissadati, A; Syrjälä, S O; Zarkada, G; Keränen, M A I; Tuuminen, R; Krebs, R; Anisimov, A; Jeltsch, M; Leppänen, V-M; Alitalo, K; Nykänen, A I; Lemström, K B

    2016-04-01

    Organ damage and innate immunity during heart transplantation may evoke adaptive immunity with serious consequences. Because lymphatic vessels bridge innate and adaptive immunity, they are critical in immune surveillance; however, their role in ischemia-reperfusion injury (IRI) in allotransplantation remains unknown. We investigated whether the lymphangiogenic VEGF-C/VEGFR3 pathway during cardiac allograft IRI regulates organ damage and subsequent interplay between innate and adaptive immunity. We found that cardiac allograft IRI, within hours, increased graft VEGF-C expression and lymphatic vessel activation in the form of increased lymphatic VEGFR3 and adhesion protein expression. Pharmacological VEGF-C/VEGFR3 stimulation resulted in early lymphatic activation and later increase in allograft inflammation. In contrast, pharmacological VEGF-C/VEGFR3 inhibition during cardiac allograft IRI decreased early lymphatic vessel activation with subsequent dampening of acute and chronic rejection. Genetic deletion of VEGFR3 specifically in the lymphatics of the transplanted heart recapitulated the survival effect achieved by pharmacological VEGF-C/VEGFR3 inhibition. Our results suggest that tissue damage rapidly changes lymphatic vessel phenotype, which, in turn, may shape the interplay of innate and adaptive immunity. Importantly, VEGF-C/VEGFR3 inhibition during solid organ transplant IRI could be used as lymphatic-targeted immunomodulatory therapy to prevent acute and chronic rejection. PMID:26689983

  16. A Statistically Enhanced Spectral Counting Approach to TCDD Cardiac Toxicity in the Adult Zebrafish Heart

    PubMed Central

    Zhang, Jiang; Lanham, Kevin A; Heideman, Warren; Peterson, Richard E.; Li, Lingjun

    2013-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant and teratogen that produces cardiac toxicity in the developing zebrafish. Here we adopted a label free quantitative proteomic approach based on normalized spectral abundance factor (NSAF) to investigate the disturbance of the cardiac proteome induced by TCDD in the adult zebrafish heart. The protein expression level changes between heart samples from TCDD treated and control zebrafish were systematically evaluated by a large scale MudPIT analysis which incorporated triplicate analyses for both control and TCDD exposed heart proteomic samples to overcome the data dependant variation in shotgun proteomic experiments and obtain a statistically significant protein dataset with improved quantification confidence. A total of 519 and 443 proteins were identified in hearts collected from control and TCDD treated zebrafish, respectively, among which 106 proteins showed statistically significant expression changes. After correcting for the experimental variation between replicate analyses by statistical evaluation, 55 proteins exhibited NSAF ratio above 2 and 43 proteins displayed NSAF ratio smaller than 0.5, with statistical significance by t-test (p < 0.05). The proteins identified as altered by TCDD encompass a wide range of biological functions including calcium handling, myocardium cell architecture, energy production and metabolism, mitochondrial homeostasis, and stress response. Collectively, our results indicate that TCDD exposure alters the adult zebrafish heart in a way that could result in cardiac hypertrophy and heart failure, and suggests a potential mechanism for the diastolic dysfunction observed in TCDD exposed embryos. PMID:23682714

  17. Vibration Induced Osteogenic Commitment of Mesenchymal Stem Cells is Enhanced by Cytoskeletal Remodeling but not Fluid Shear

    PubMed Central

    Uzer, Gunes; Pongkitwitoon, Suphannee; Chan, M Ete; Judex, Stefan

    2013-01-01

    Consistent across studies in humans, animals and cells, the application of vibrations can be anabolic and/or anti-catabolic to bone. The physical mechanisms modulating the vibration-induced response have not been identified. Recently, we developed an in vitro model in which candidate parameters including acceleration magnitude and fluid shear can be controlled independently during vibrations. Here, we hypothesized that vibration induced fluid shear does not modulate mesenchymal stem cell (MSC) proliferation and mineralization and that cell’s sensitivity to vibrations can be promoted via actin stress fiber formation. Adipose derived human MSCs were subjected to vibration frequencies and acceleration magnitudes that induced fluid shear stress ranging from 0.04Pa to 5Pa. Vibrations were applied at magnitudes of 0.15g, 1g, and 2g using frequencies of both 100Hz and 30Hz. After 14d and under low fluid shear conditions associated with 100Hz oscillations, mineralization was greater in all vibrated groups than in controls. Greater levels of fluid shear produced by 30Hz vibrations enhanced mineralization only in the 2g group. Over 3d, vibrations led to the greatest increase in total cell number with the frequency/acceleration combination that induced the smallest level of fluid shear. Acute experiments showed that actin remodeling was necessary for early mechanical up-regulation of RUNX-2 mRNA levels. During osteogenic differentiation, mechanically induced up-regulation of actin remodeling genes including Wiskott-Aldrich syndrome (WAS) protein, a critical regulator of Arp2/3 complex, was related to the magnitude of the applied acceleration but not to fluid shear. These data demonstrate that fluid shear does not regulate vibration induced proliferation and mineralization and that cytoskeletal remodeling activity may play a role in MSC mechanosensitivity. PMID:23870506

  18. The Apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development

    PubMed Central

    Deshwar, Ashish R; Chng, Serene C; Ho, Lena; Reversade, Bruno; Scott, Ian C

    2016-01-01

    The Apelin receptor (Aplnr) is essential for heart development, controlling the early migration of cardiac progenitors. Here we demonstrate that in zebrafish Aplnr modulates Nodal/TGFβ signaling, a key pathway essential for mesendoderm induction and migration. Loss of Aplnr function leads to a reduction in Nodal target gene expression whereas activation of Aplnr by a non-peptide agonist increases the expression of these same targets. Furthermore, loss of Aplnr results in a delay in the expression of the cardiogenic transcription factors mespaa/ab. Elevating Nodal levels in aplnra/b morphant and double mutant embryos is sufficient to rescue cardiac differentiation defects. We demonstrate that loss of Aplnr attenuates the activity of a point source of Nodal ligands Squint and Cyclops in a non-cell autonomous manner. Our results favour a model in which Aplnr is required to fine-tune Nodal output, acting as a specific rheostat for the Nodal/TGFβ pathway during the earliest stages of cardiogenesis. DOI: http://dx.doi.org/10.7554/eLife.13758.001 PMID:27077952

  19. Transforming growth factor-{beta}2 enhances differentiation of cardiac myocytes from embryonic stem cells

    SciTech Connect

    Kumar, Dinender . E-mail: Dinender.Kumar@uvm.edu; Sun, Baiming

    2005-06-24

    Stem cell therapy holds great promise for the treatment of injured myocardium, but is challenged by a limited supply of appropriate cells. Three different isoforms of transforming growth factor-{beta} (TGF-{beta}) -{beta}1, -{beta}2, and -{beta}3 exhibit distinct regulatory effects on cell growth, differentiation, and migration during embryonic development. We compared the effects of these three different isoforms on cardiomyocyte differentiation from embryonic stem (ES) cells. In contrast to TGF-{beta}1, or -{beta}3, treatment of mouse ES cells with TGF-{beta}2 isoform significantly increased embryoid body (EB) proliferation as well as the extent of the EB outgrowth that beat rhythmically. At 17 days, 49% of the EBs treated with TGF-{beta}2 exhibited spontaneous beating compared with 15% in controls. Cardiac myocyte specific protein markers sarcomeric myosin and {alpha}-actin were demonstrated in beating EBs and cells isolated from EBs. In conclusion, TGF-{beta}2 but not TGF-{beta}1, or -{beta}3 promotes cardiac myocyte differentiation from ES cells.

  20. Dietary nitrate improves cardiac contractility via enhanced cellular Ca²⁺ signaling.

    PubMed

    Pironti, Gianluigi; Ivarsson, Niklas; Yang, Jiangning; Farinotti, Alex Bersellini; Jonsson, William; Zhang, Shi-Jin; Bas, Duygu; Svensson, Camilla I; Westerblad, Håkan; Weitzberg, Eddie; Lundberg, Jon O; Pernow, John; Lanner, Johanna; Andersson, Daniel C

    2016-05-01

    The inorganic anion nitrate (NO3 (-)), which is naturally enriched in certain vegetables (e.g., spinach and beetroot), has emerged as a dietary component that can regulate diverse bodily functions, including blood pressure, mitochondrial efficiency, and skeletal muscle force. It is not known if dietary nitrate improves cardiac contractility. To test this, mice were supplemented for 1-2 weeks with sodium nitrate in the drinking water at a dose similar to a green diet. The hearts from nitrate-treated mice showed increased left ventricular pressure and peak rate of pressure development as measured with the Langendorff heart technique. Cardiomyocytes from hearts of nitrate-treated and control animals were incubated with the fluorescent indicator Fluo-3 to measure cytoplasmic free [Ca(2+)] and fractional shortening. Cardiomyocytes from nitrate-treated mice displayed increased fractional shortening, which was linked to larger Ca(2+) transients. Moreover, nitrate hearts displayed increased protein expression of the L-type Ca(2+) channel/dihydropyridine receptor and peak L-type Ca(2+) channel currents. The nitrate-treated hearts displayed increased concentration of cAMP but unchanged levels of cGMP compared with controls. These findings provide the first evidence that dietary nitrate can affect the expression of important Ca(2+) handling proteins in the heart, resulting in increased cardiomyocyte Ca(2+) signaling and improved left ventricular contractile function. Our observation shows that dietary nitrate impacts cardiac function and adds understanding to inorganic nitrate as a physiological modulator. PMID:27071401

  1. Estimation of Cardiac Respiratory-Motion by Semi-Automatic Segmentation and Registration of Non-Contrast-Enhanced 4D-CT Cardiac Datasets

    PubMed Central

    Dey, Joyoni; Pan, Tinsu; Choi, David J.; Robotis, Dennis; Smyczynski, Mark S.; Pretorius, P. Hendrik; King, Michael A.

    2010-01-01

    The goal of this work is to investigate, for a large set of patients, the motion of the heart with respiration during free-breathing supine medical imaging. For this purpose we analyzed the motion of the heart in 32 non-contrast enhanced respiratory-gated 4D-CT datasets acquired during quiet unconstrained breathing. The respiratory-gated CT images covered the cardiac region and were acquired at each of 10 stages of the respiratory cycle, with the first stage being end-inspiration. We devised a 3-D semi-automated segmentation algorithm that segments the heart in the 4D-CT datasets acquired without contrast enhancement for use in estimating respiratory motion of the heart. Our semi-automated segmentation results were compared against interactive hand segmentations of the coronal slices by a cardiologist and a radiologist. The pairwise difference in segmentation among the algorithm and the physicians was on the average 11% and 10% of the total average segmented volume across the patient, with a couple of patients as outliers above the 95% agreement limit. The mean difference among the two physicians was 8% with an outlier above the 95% agreement limit. The 3-D segmentation was an order of magnitude faster than the Physicians’ manual segmentation and represents significant reduction of Physicians’ time. The segmented first stages of respiration were used in 12 degree-of-freedom (DOF) affine registration to estimate the motion at each subsequent stage of respiration. The registration results from the 32 patients indicate that the translation in the superior-inferior direction was the largest component motion, with a maximum of 10.7 mm, mean of 6.4 mm, and standard deviation of 2.2 mm. Translation in the anterior-posterior direction was the next largest component of motion, with a maximum of 4.0 mm, mean of 1.7 mm, and standard deviation of 1.0 mm. Rotation about the right-left axis was on average the largest component of rotation observed, with a maximum of 4

  2. Late gadolinium enhancement in cardiac amyloidosis: attributable both to interstitial amyloid deposition and subendocardial fibrosis caused by ischemia.

    PubMed

    Hashimura, Hiromi; Ishibashi-Ueda, Hatsue; Yonemoto, Yumiko; Ohta-Ogo, Keiko; Matsuyama, Taka-Aki; Ikeda, Yoshihiko; Morita, Yoshiaki; Yamada, Naoaki; Yasui, Hiroki; Naito, Hiroaki

    2016-06-01

    Gadolinium contrast agents used for late gadolinium enhancement (LGE) distribute in the extracellular space. Global diffuse myocardial LGE pronounced in the subendocardial layers is common in cardiac amyloidosis. However, the pathophysiological basis of these findings has not been sufficiently explained. A 64-year-old man was admitted to our hospital with leg edema and nocturnal dyspnea. Bence Jones protein was positive in the urine, and an endomyocardial and skin biopsy showed light-chain (AL) amyloidosis. He died of ventricular fibrillation 3 months later. 9 days before death, the patient was examined by cardiac magnetic resonance (CMR) imaging on a 3-T system. We acquired LGE data at 2, 5, 10, and 20 min after the injection of gadolinium contrast agents, with a fixed inversion time of 350 ms. Myocardial LGE developed sequentially. The myocardium was diffusely enhanced at 2 min, except for the subendocardium, but LGE had extended to almost the entire left ventricle at 5 min and predominantly localized to the subendocardial region at 10 and 20 min. An autopsy revealed massive and diffused amyloid deposits in perimyocytes throughout the myocardium. Old and recent ischemic findings, such as replacement fibrosis and coagulative myocyte necrosis, were evident in the subendocardium. In the intramural coronary arteries, mild amyloid deposits were present within the subepicardial to the mid layer of the left ventricle, but no stenotic lesions were evident. However, capillaries were obstructed by amyloid deposits in the subendocardium. In conclusion, the late phase of dynamic LGE (at 10 and 20 min) visualized in the subendocardium corresponded to the interstitial amyloid deposition and subendocardial fibrosis caused by ischemia in our patient. PMID:25794983

  3. Myosin regulatory light chain phosphorylation enhances cardiac β-myosin in vitro motility under load.

    PubMed

    Karabina, Anastasia; Kazmierczak, Katarzyna; Szczesna-Cordary, Danuta; Moore, Jeffrey R

    2015-08-15

    Familial hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and myofibrillar disarray, and often results in sudden cardiac death. Two HCM mutations, N47K and R58Q, are located in the myosin regulatory light chain (RLC). The RLC mechanically stabilizes the myosin lever arm, which is crucial to myosin's ability to transmit contractile force. The N47K and R58Q mutations have previously been shown to reduce actin filament velocity under load, stemming from a more compliant lever arm (Greenberg, 2010). In contrast, RLC phosphorylation was shown to impart stiffness to the myosin lever arm (Greenberg, 2009). We hypothesized that phosphorylation of the mutant HCM-RLC may mitigate distinct mutation-induced structural and functional abnormalities. In vitro motility assays were utilized to investigate the effects of RLC phosphorylation on the HCM-RLC mutant phenotype in the presence of an α-actinin frictional load. Porcine cardiac β-myosin was depleted of its native RLC and reconstituted with mutant or wild-type human RLC in phosphorylated or non-phosphorylated form. Consistent with previous findings, in the presence of load, myosin bearing the HCM mutations reduced actin sliding velocity compared to WT resulting in 31-41% reductions in force production. Myosin containing phosphorylated RLC (WT or mutant) increased sliding velocity and also restored mutant myosin force production to near WT unphosphorylated values. These results point to RLC phosphorylation as a general mechanism to increase force production of the individual myosin motor and as a potential target to ameliorate the HCM-induced phenotype at the molecular level. PMID:26116789

  4. Myosin regulatory light chain phosphorylation enhances cardiac β-myosin in vitro motility under load

    PubMed Central

    Karabina, Anastasia; Kazmierczak, Katarzyna; Szczesna-Cordary, Danuta; Moore, Jeffrey R.

    2016-01-01

    Familial hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and myofibrillar disarray, and often results in sudden cardiac death. Two HCM mutations, N47K and R58Q, are located in the myosin regulatory light chain (RLC). The RLC mechanically stabilizes the myosin lever arm, which is crucial to myosin’s ability to transmit contractile force. The N47K and R58Q mutations have previously been shown to reduce actin filament velocity under load, stemming from a more compliant lever arm (Greenberg, 2010). In contrast, RLC phosphorylation was shown to impart stiffness to the myosin lever arm (Greenberg, 2009). We hypothesized that phosphorylation of the mutant HCM-RLC may mitigate distinct mutation-induced structural and functional abnormalities. In vitro motility assays were utilized to investigate the effects of RLC phosphorylation on the HCM-RLC mutant phenotype in the presence of an α-actinin frictional load. Porcine cardiac β-myosin was depleted of its native RLC and reconstituted with mutant or wild-type human RLC in phosphorylated or non-phosphorylated form. Consistent with previous findings, in the presence of load, myosin bearing the HCM mutations reduced actin sliding velocity compared to WT resulting in 31–41% reductions in force production. Myosin containing phosphorylated RLC (WT or mutant) increased sliding velocity and also restored mutant myosin force production to near WT unphosphorylated values. These results point to RLC phosphorylation as a general mechanism to increase force production of the individual myosin motor and as a potential target to ameliorate the HCM-induced phenotype at the molecular level. PMID:26116789

  5. A novel site in the muscle creatine kinase enhancer is required for expression in skeletal but not cardiac muscle.

    PubMed

    Fabre-Suver, C; Hauschka, S D

    1996-03-01

    Expression of the muscle creatine kinase (MCK) gene in skeletal and heart muscle is controlled in part by a 5' tissue-specific enhancer. In order to identify new regulatory elements, we designed mutations in a previously untested conserved portion of this enhancer. Transfection analysis of these mutations delineated a new control element, named Trex (Transcriptional regulatory element x), which is required for full transcriptional activity of the MCK enhancer in skeletal but not cardiac muscle cells. Gel mobility shift assays demonstrate that myocyte, myoblast, and fibroblast nuclear extracts but not primary cardiomyocyte nuclear extracts contain a trans-acting factor that binds specifically to Trex. The Trex sequence is similar (7/8 bases) to the TEF-1 consensus DNA-binding site involved in regulating other muscle genes. To determine if TEF-1 interacts with Trex, selected TEF-1 binding sites such as GTIIc and M-CAT and two anti-TEF-1 antisera were used in gel shift assays. These experiments strongly suggest that a factor distinct from TEF-1 binds specifically to Trex. Thus it appears that MCK transcription is regulated in skeletal muscles through a Trex-dependent pathway while Trex is not required for MCK expression in heart. This distinction could account partially for the difference in levels of muscle creatine kinase in these tissues. PMID:8617727

  6. Early recurrence of atrial fibrillation after catheter ablation with left atrial fibrosis identified at cardiac magnetic resonance by late gadolinium enhancement.

    PubMed

    Totaro, Antonio; Casavecchia, Graziapia; Gravina, Matteo; Ieva, Riccardo; Santoro, Francesco; Grimaldi, Massimo; Pellegrino, Pier Luigi; Macarini, Luca; Di Biase, Matteo; Brunetti, Natale Daniele

    2016-08-01

    In patients with atrial fibrillation (AF), extensive atrial tissue fibrosis identified by delayed enhancement magnetic resonance imaging has been associated with early recurrence of AF after catheter ablation. We present a case of a patient with extensive atrial fibrosis and AF recurrence.The study of late gadolinium enhancement with cardiac magnetic resonance imaging in patients with AF could be a valuable noninvasive tool for the selection of patients suitable for successful catheter ablation. PMID:26826170

  7. Cardiac telocytes in normal and diseased hearts.

    PubMed

    Kostin, Sawa

    2016-07-01

    Our previous studies suggested that an important variable of the progression of contractile dysfunction to terminal heart failure is the imbalance between myocyte cell death and myocyte renewal. For this reason, preventing myocyte cell death and an increasing generation of new myocytes may represent attractive targets in the treatment of human heart failure. Prospective clues to enhance myocardial regeneration are the newly discovered cells termed telocytes, formerly called interstitial Cajal-like cells, which are believed to nurse or guide the endogenous and exogenous stem cells for activation and commitment, but they also act as supporting cells for progenitor cells migration toward injured myocardium. We have recently found that telocytes are reduced in the diseased and failing myocardium. Importantly, the imbalance between telocyte proliferation and telocyte death is responsible for the telocytes depletion in cardiac diseases leading to heart failure. We have also demonstrated that telocytes are influenced by the extracellular matrix protein composition such that the telocytes are almost absent in areas of severe fibrosis. It is plausible that the reduction in telocytes in diseased human hearts could participate in the abnormal three-dimensional spatial organization and disturbed intercellular signalling of the myocardium. Decreased telocytes in diseased hearts would also be predicted to alter the property of telocytes to maintain cardiac stem cell niche by decreasing the pool of cardiac stem cells and thereby impairing cardiac regeneration. PMID:26912117

  8. Cardiac gated ventilation

    SciTech Connect

    Hanson, C.W. III; Hoffman, E.A.

    1995-12-31

    There are several theoretic advantages to synchronizing positive pressure breaths with the cardiac cycle, including the potential for improving distribution of pulmonary and myocardial blood flow and enhancing cardiac output. The authors evaluated the effects of synchronizing respiration to the cardiac cycle using a programmable ventilator and electron beam CT (EBCT) scanning. The hearts of anesthetized dogs were imaged during cardiac gated respiration with a 50 msec scan aperture. Multi slice, short axis, dynamic image data sets spanning the apex to base of the left ventricle were evaluated to determine the volume of the left ventricular chamber at end-diastole and end-systole during apnea, systolic and diastolic cardiac gating. The authors observed an increase in cardiac output of up to 30% with inspiration gated to the systolic phase of the cardiac cycle in a non-failing model of the heart.

  9. Cardiac gated ventilation

    NASA Astrophysics Data System (ADS)

    Hanson, C. William, III; Hoffman, Eric A.

    1995-05-01

    There are several theoretic advantages to synchronizing positive pressure breaths with the cardiac cycle, including the potential for improving distribution of pulmonary and myocardial blood flow and enhancing cardiac output. We evaluated the effects of synchronizing respiration to the cardiac cycle using a programmable ventilator and electron beam CT (EBCT) scanning. The hearts of anesthetized dogs were imaged during cardiac gated respiration with a 50msec scan aperture. Multislice, short axis, dynamic image data sets spanning the apex to base of the left ventricle were evaluated to determine the volume of the left ventricular chamber at end-diastole and end-systole during apnea, systolic and diastolic cardiac gating. We observed an increase in cardiac output of up to 30% with inspiration gated to the systolic phase of the cardiac cycle in a nonfailing model of the heart.

  10. Calcifications of the Thoracic Aorta on Extended Non-Contrast-Enhanced Cardiac CT

    PubMed Central

    Craiem, Damian; Chironi, Gilles; Casciaro, Mariano E.; Graf, Sebastian; Simon, Alain

    2014-01-01

    Background The presence of calcified atherosclerosis in different vascular beds has been associated with a higher risk of mortality. Thoracic aorta calcium (TAC) can be assessed from computed tomography (CT) scans, originally aimed at coronary artery calcium (CAC) assessment. CAC screening improves cardiovascular risk prediction, beyond standard risk assessment, whereas TAC performance remains controversial. However, the curvilinear portion of the thoracic aorta (TA), that includes the aortic arch, is systematically excluded from TAC analysis. We investigated the prevalence and spatial distribution of TAC all along the TA, to see how those segments that remain invisible in standard TA evaluation were affected. Methods and Results A total of 970 patients (77% men) underwent extended non-contrast cardiac CT scans including the aortic arch. An automated algorithm was designed to extract the vessel centerline and to estimate the vessel diameter in perpendicular planes. Then, calcifications were quantified using the Agatston score and associated with the corresponding thoracic aorta segment. The aortic arch and the proximal descending aorta, “invisible” in routine CAC screening, appeared as two vulnerable sites concentrating 60% of almost 11000 calcifications. The aortic arch was the most affected segment per cm length. Using the extended measurement method, TAC prevalence doubled from 31% to 64%, meaning that 52% of patients would escape detection with a standard scan. In a stratified analysis for CAC and/or TAC assessment, 111 subjects (46% women) were exclusively identified with the enlarged scan. Conclusions Calcium screening in the TA revealed that the aortic arch and the proximal descending aorta, hidden in standard TA evaluations, concentrated most of the calcifications. Middle-aged women were more prone to have calcifications in those hidden portions and became candidates for reclassification. PMID:25302677

  11. Inhibition of myocyte-specific enhancer factor 2A improved diabetic cardiac fibrosis partially by regulating endothelial-to-mesenchymal transition.

    PubMed

    Chen, Xue-Ying; Lv, Rui-Juan; Zhang, Wei; Yan, Yu-Gang; Li, Peng; Dong, Wen-Qian; Liu, Xue; Liang, Er-Shun; Tian, Hong-Liang; Lu, Qing-Hua; Zhang, Ming-Xiang

    2016-05-24

    Cardiac fibrosis is an important pathological process of diabetic cardiomyopathy, the underlying mechanism remains elusive. This study sought to identify whether inhibition of Myocyte enhancer factor 2A (MEF2A) alleviates cardiac fibrosis by partially regulating Endothelial-to-mesenchymal transition (EndMT). We induced type 1 diabetes mellitus using the toxin streptozotocin (STZ) in mice and injected with lentivirus-mediated short-hairpin RNA (shRNA) in myocardium to inhibit MEF2A expression. Protein expression, histological and functional parameters were examined twenty-one weeks post-STZ injection. We found that Diabetes mellitus increased cardiac MEF2A expression, aggravated cardiac dysfunction and myocardial fibrosis through the accumulation of fibroblasts via EndMT. All of these features were abolished by MEF2A inhibition. MEF2A gene silencing by shRNA in cultured human umbilical vein endothelial cells (HUVECs) ameliorated high glucose-induced phenotypic transition and acquisition of mesenchymal markers through interaction with p38MAPK and Smad2. We conclude that inhibition of endothelial cell-derived MEF2A might be beneficial in the prevention of diabetes mellitus-induced cardiac fibrosis by partially inhibiting EndMT through interaction with p38MAPK and Smad2. PMID:27105518

  12. Enhanced neuronal nitric oxide synthase expression is central to cardiac vagal phenotype in exercise-trained mice

    PubMed Central

    Danson, E J F; Paterson, D J

    2003-01-01

    We investigated whether enhanced cardiac vagal responsiveness elicited by exercise training is dependent on neuronal nitric oxide synthase (NOS-1), since the NO-cGMP pathway facilitates acetylcholine release. Isolated atria with intact right vagal innervation were taken from male mice (18-22 weeks old) after a period of 10 weeks voluntary wheel-running (+EX, n = 27; peaked 9.8 ± 0.6 km day−1 at 5 weeks), and from mice housed in cages without wheels (-EX, n = 27). Immunostaining of whole atria for NOS-1 identified intrinsic neurones, all of which co-localized with choline acetyltransferase-positive ganglia. Western blot analysis confirmed that NOS-1 protein level was significantly greater in +EX compared to -EX atria (P < 0.05, unpaired t test). Basal heart rates (HR) were slower in +EX than in -EX atria (322 ± 6 versus 360 ± 7 beats min−1; P < 0.05, unpaired t test) However, in +EX atria, HR responses to vagal stimulation (VNS, 3 and 5 Hz) were significantly enhanced compared to -EX atria (3 Hz, +EX: −76 ± 8 beats min−1versus -EX: −62 ± 7 beats min−1; 5 Hz, +EX: −106 ± 4 beats min−1versus -EX: −93 ± 3 beats min−1; P < 0.01, unpaired t test). Inhibition of NOS-1 with vinyl-l-N-5-(1-imino-3-butenyl)-l-ornithine (l-VNIO, 100 μm) or soluble guanylyl cyclase with 1H-[1, 2, 4]oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ, 10 μm) abolished the difference in HR responses to VNS between +EX and -EX atria, and effects of l-VNIO were reversed by excess l-arginine (1 mm; P < 0.01, ANOVA). There were no differences between the HR responses to the bath-applied acetylcholine analogue carbamylcholine chloride in +EX and -EX atria (IC50 concentrations were 5.9 ± 0.4 μm (-EX) and 5.7 ± 0.4 μm (+EX)), suggesting that the changes in vagal responsiveness resulted from presynaptic facilitation of neurotransmission. In conclusion, NOS-1 appears to be a key protein in generating the cardiac vagal gain of function elicited by exercise training. PMID:12509490

  13. Autoantibodies enhance agonist action and binding to cardiac muscarinic receptors in chronic Chagas' disease.

    PubMed

    Hernandez, Ciria C; Nascimento, Jose H; Chaves, Elen A; Costa, Patricia C; Masuda, Masako O; Kurtenbach, Eleonora; Campos DE Carvalho, Antonio C; Gimenez, Luis E

    2008-01-01

    Chronic Chagasic patient immunoglobulins (CChP-IgGs) recognize an acidic amino acid cluster at the second extracellular loop (el2) of cardiac M(2)-muscarinic acetylcholine receptors (M(2)AChRs). These residues correspond to a common binding site for various allosteric agents. We characterized the nature of the M(2)AChR/CChP-IgG interaction in functional and radioligand binding experiments applying the same mainstream strategies previously used for the characterization of other allosteric agents. Dose-response curves of acetylcholine effect on heart rate were constructed with data from isolated heart experiments in the presence of CChP or normal blood donor (NBD) sera. In these experiments, CChP sera but not NBD sera increased the efficacy of agonist action by augmenting the onset of bradyarrhythmias and inducing a Hill slope of 2.5. This effect was blocked by gallamine, an M(2)AChR allosteric antagonist. Correspondingly, CChP-IgGs increased acetylcholine affinity twofold and showed negative cooperativity for [(3)H]-N-methyl scopolamine ([(3)H]-NMS) in allosterism binding assays. A peptide corresponding to the M(2)AChR-el2 blocked this effect. Furthermore, dissociation assays showed that the effect of gallamine on the [(3)H]-NMS off-rate was reverted by CChP-IgGs. Finally, concentration-effect curves for the allosteric delay of W84 on [(3)H]-NMS dissociation right shifted from an IC(50) of 33 nmol/L to 78 nmol/L, 992 nmol/L, and 1670 nmol/L in the presence of 6.7 x 10(- 8), 1.33 x 10(- 7), and 2.0 x 10(- 7) mol/L of anti-el2 affinity-purified CChP-IgGs. Taken together, these findings confirmed a competitive interplay of these ligands at the common allosteric site and revealed the novel allosteric nature of the interaction of CChP-IgGs at the M(2)AChRs as a positive cooperativity effect on acetylcholine action. PMID:18702010

  14. Autoantibodies Enhance Agonist Action and Binding to Cardiac Muscarinic Receptors in Chronic Chagas’ Disease

    PubMed Central

    Hernández, Ciria C.; Nascimento, José H.; Chaves, Elen A.; Costa, Patrícia C.; Masuda, Masako O.; Kurtenbach, Eleonora; Campos de Carvalho, Antônio C.; Giménez, Luis E.

    2009-01-01

    Chronic Chagasic patient immunoglobulins (CChP-IgGs) recognize an acidic amino acid cluster at the second extracellular loop (el2) of cardiac M2-muscarinic acetylcholine receptors (M2AChRs). These residues correspond to a common binding site for various allosteric agents. We characterized the nature of the M2AChR/CChP-IgG interaction in functional and radioligand binding experiments applying the same mainstream strategies previously used for the characterization of other allosteric agents. Dose-response curves of acetylcholine effect on heart rate were constructed with data from isolated heart experiments in the presence of CChP or normal blood donor (NBD) sera. In these experiments, CChP sera but not NBD sera increased the efficacy of agonist action by augmenting the onset of bradyarrhythmias and inducing a Hill slope of 2.5. This effect was blocked by gallamine, an M2AChR allosteric antagonist. Correspondingly, CChP-IgGs increased acetylcholine affinity twofold and showed negative cooperativity for [3H]-N-methyl scopolamine ([3H]-NMS) in allosterism binding assays. A peptide corresponding to the M2AChR-el2 blocked this effect. Furthermore, dissociation assays showed that the effect of gallamine on the [3H]-NMS off-rate was reverted by CChP-IgGs. Finally, concentration-effect curves for the allosteric delay of W84 on [3H]-NMS dissociation right shifted from an IC50 of 33 nmol/L to 78 nmol/L, 992 nmol/L, and 1670 nmol/L in the presence of 6.7 × 10−8, 1.33 × 10−7, and 2.0 × 10−7 mol/L of anti-el2 affinity-purified CChP-IgGs. Taken together, these findings confirmed a competitive interplay of these ligands at the common allosteric site and revealed the novel allosteric nature of the interaction of CChP-IgGs at the M2AChRs as a positive cooperativity effect on acetylcholine action. PMID:18702010

  15. Making it stick: chasing the optimal stem cells for cardiac regeneration

    PubMed Central

    Quijada, Pearl; Sussman, Mark A

    2014-01-01

    Despite the increasing use of stem cells for regenerative-based cardiac therapy, the optimal stem cell population(s) remains in a cloud of uncertainty. In the past decade, the field has witnessed a surge of researchers discovering stem cell populations reported to directly and/or indirectly contribute to cardiac regeneration through processes of cardiomyogenic commitment and/or release of cardioprotective paracrine factors. This review centers upon defining basic biological characteristics of stem cells used for sustaining cardiac integrity during disease and maintenance of communication between the cardiac environment and stem cells. Given the limited successes achieved so far in regenerative therapy, the future requires development of unprecedented concepts involving combinatorial approaches to create and deliver the optimal stem cell(s) that will enhance myocardial healing. PMID:25340282

  16. Development of Bipotent Cardiac/Skeletal Myogenic Progenitors from MESP1+ Mesoderm

    PubMed Central

    Chan, Sunny Sun-Kin; Hagen, Hannah R.; Swanson, Scott A.; Stewart, Ron; Boll, Karly A.; Aho, Joy; Thomson, James A.; Kyba, Michael

    2016-01-01

    Summary The branchiomeric skeletal muscles co-evolved with new chambers of the heart to enable predatory feeding in chordates. These co-evolved tissues develop from a common population in anterior splanchnic mesoderm, referred to as cardiopharyngeal mesoderm (CPM). The regulation and development of CPM are poorly understood. We describe an embryonic stem cell-based system in which MESP1 drives a PDGFRA+ population with dual cardiac and skeletal muscle differentiation potential, and gene expression resembling CPM. Using this system, we investigate the regulation of these bipotent progenitors, and find that cardiac specification is governed by an antagonistic TGFβ-BMP axis, while skeletal muscle specification is enhanced by Rho kinase inhibition. We define transcriptional signatures of the first committed CPM-derived cardiac and skeletal myogenic progenitors, and discover surface markers to distinguish cardiac (PODXL+) from the skeletal muscle (CDH4+) CPM derivatives. These tools open an accessible window on this developmentally and evolutionarily important population. PMID:26771351

  17. Insulin-like growth factor-I and slow, bi-directional perfusion enhance the formation of tissue-engineered cardiac grafts.

    PubMed

    Cheng, Mingyu; Moretti, Matteo; Engelmayr, George C; Freed, Lisa E

    2009-03-01

    Biochemical and mechanical signals enabling cardiac regeneration can be elucidated using in vitro tissue-engineering models. We hypothesized that insulin-like growth factor-I (IGF) and slow, bi-directional perfusion could act independently and interactively to enhance the survival, differentiation, and contractile performance of tissue-engineered cardiac grafts. Heart cells were cultured on three-dimensional porous scaffolds in medium with or without supplemental IGF and in the presence or absence of slow, bi-directional perfusion that enhanced transport and provided shear stress. Structural, molecular, and electrophysiologic properties of the resulting grafts were quantified on culture day 8. IGF had independent, beneficial effects on apoptosis (p < 0.01), cellular viability (p < 0.01), contractile amplitude (p < 0.01), and excitation threshold (p < 0.01). Perfusion independently affected the four aforementioned parameters and also increased amounts of cardiac troponin-I (p < 0.01), connexin-43 (p < 0.05), and total protein (p < 0.01) in the grafts. Interactive effects of IGF and perfusion on apoptosis were also present (p < 0.01). Myofibrillogenesis and spontaneous contractility were present only in grafts cultured with perfusion, although contractility was inducible by electrical field stimulation of grafts from all groups. Our findings demonstrate that multi-factorial stimulation of tissue-engineered cardiac grafts using IGF and perfusion resulted in independent and interactive effects on heart cell survival, differentiation, and contractility. PMID:18759675

  18. Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway.

    PubMed Central

    Pinsky, D J; Oz, M C; Koga, S; Taha, Z; Broekman, M J; Marcus, A J; Liao, H; Naka, Y; Brett, J; Cannon, P J

    1994-01-01

    Nitric oxide (NO) is a novel biologic messenger with diverse effects but its role in organ transplantation remains poorly understood. Using a porphyrinic microsensor, the first direct measurements of coronary vascular and endocardial NO production were made. NO was measured directly in the effluent of preserved, heterotopically transplanted rat hearts stimulated with L-arginine and bradykinin; NO concentrations fell from 2.1 +/- 0.4 microM for freshly explanted hearts to 0.7 +/- 0.2 and 0.2 +/- 0.08 microM for hearts preserved for 19 and 38 h, respectively. NO levels were increased by SOD, suggesting a role for superoxide-mediated destruction of NO. Consistent with these data, addition of the NO donor nitroglycerin (NTG) to a balanced salt preservation solution enhanced graft survival in a time- and dose-dependent manner, with 92% of hearts supplemented with NTG surviving 12 h of preservation versus only 17% in its absence. NTG similarly enhanced preservation of hearts stored in University of Wisconsin solution, the clinical standard for preservation. Other stimulators of the NO pathway, including nitroprusside, L-arginine, or 8-bromoguanosine 3',5' monophosphate, also enhanced graft survival, whereas the competitive NO synthase antagonist NG-monomethyl-L-arginine was associated with poor preservation. Likely mechanisms whereby supplementation of the NO pathway enhanced preservation included increased blood flow to the reperfused graft and decreased graft leukostasis. NO was also measured in endothelial cells subjected to hypoxia/reoxygenation and detected based on its ability to inhibit thrombin-mediated platelet aggregation and serotonin release. NO became undetectable in endothelial cells exposed to hypoxia followed by reoxygenation and was restored to normoxic levels on addition of SOD. These studies suggest that the NO pathway fails during preservation/transplantation because of formation of oxygen free radicals during reperfusion, which quench available NO

  19. Randomized controlled trial of a self-efficacy enhancement program for the cardiac rehabilitation of Thai patients with myocardial infarction.

    PubMed

    Vibulchai, Nisakorn; Thanasilp, Sureeporn; Preechawong, Sunida

    2016-06-01

    This study examined the effects of a self-efficacy enhancement program for the cardiac rehabilitation of Thai patients who had a myocardial infarction. Sixty-six hospitalized patients of various ages and both genders were randomly assigned to either an experimental or a control group. Participants in the experimental group took part in three individualized in-hospital education sessions and three weekly sessions of telephone counseling. The control group primarily engaged in a supervised exercise and activities of a daily living performance regimen, and received education in this regard. Self-efficacy and functional status were measured via questionnaire. Four weeks after discharge, the experimental group was found to have significantly higher total self-efficacy and functional status scores than the control group. In addition, the experimental group exhibited significantly higher subscale scores on social activity, household tasks, occupation, and exercise self-efficacy than the control group. These results indicate that the program is effective in improving the self-efficacy and functional status of Thai patients who have had a myocardial infarction. PMID:26415520

  20. T2∗ Measurement During First-Pass Contrast-Enhanced Cardiac Perfusion Imaging

    PubMed Central

    Kellman, Peter; Aletras, Anthony H.; Hsu, Li-yueh; McVeigh, Elliot R.; Arai, Andrew E.

    2007-01-01

    First-pass contrast-enhanced (CE) myocardial perfusion imaging will experience T2∗ effects at peak concentrations of contrast agent. A reduction in the signal intensity of left ventricular (LV) blood due to T2∗ losses may effect estimates of the arterial input function (AIF) used for quantitative perfusion measurement. Imaging artifacts may also result from T2∗ losses as well as off-resonance due to the bolus susceptibility. We hypothesized that T2∗ losses would not be significant for measurement of the AIF in full-dose studies using a short echo time (TE = 0.6 ms). The purpose of this study was to directly measure T2∗ in the LV cavity during first-pass perfusion. For single-dose Gd-DTPA (0.1 mmol/kg at 5 ml/s), the LV blood pool T2∗ had a mean value of 9 ms (N = 10) at peak enhancement. Distortion of the AIF due to T2∗ signal intensity loss will be less than 10% using TE = 0.6 ms. PMID:17029226

  1. Object identification accuracy under ultrasound enhanced virtual reality for minimally invasive cardiac surgery

    NASA Astrophysics Data System (ADS)

    Wiles, Andrew D.; Moore, John; Linte, Cristian A.; Wedlake, Christopher; Ahmad, Anis; Peters, Terry M.

    2008-03-01

    A 2D ultrasound enhanced virtual reality surgical guidance system has been under development for some time in our lab. The new surgical guidance platform has been shown to be effective in both the laboratory and clinical settings, however, the accuracy of the tracked 2D ultrasound has not been investigated in detail in terms of the applications for which we intend to use it (i.e., mitral valve replacement and atrial septal defect closure). This work focuses on the development of an accuracy assessment protocol specific to the assessment of the calibration methods used to determine the rigid transformation between the ultrasound image and the tracked sensor. Specifically, we test a Z-bar phantom calibration method and a phantomless calibration method and compared the accuracy of tracking ultrasound images from neuro, transesophageal, intracardiac and laparoscopic ultrasound transducers. This work provides a fundamental quantitative description of the image-guided accuracy that can be obtained with this new surgical guidance system.

  2. Milrinone enhances cytosolic calcium transient and contraction in rat cardiac myocytes during beta-adrenergic stimulation.

    PubMed

    Raffaeli, S; Ferroni, C; Spurgeon, H A; Capogrossi, M C

    1989-01-01

    We have investigated the mechanism that underlies the absence of a positive inotropic effect of milrinone on rat myocardium. The twitch characteristics of enzymatically dissociated left ventricular myocytes from the adult rat and guinea pig were assessed by edge tracking during field stimulation. In some rat myocytes loaded with the ester derivative of the Ca2+ probe Indo-1 we simultaneously measured changes in cell length and in the associated cytosolic Ca2+ (Cai) transient. Our results show that in guinea pig myocytes bathed in 0.5 mM [Ca2+] and field stimulated at 1 Hz, milrinone (10 microM) had a positive inotropic effect. In contrast milrinone had no effect on the contractile properties of rat myocytes studied under similar conditions and field stimulated at 0.2 Hz. In rat myocytes bathed in 0.5 mM [Ca2+] and stimulated at 0.2 Hz isoproterenol (1 nM) increased the amplitude and shortened the duration of the contraction and of the associated Cai transient; these effects of beta-adrenergic stimulation were further enhanced by the addition of milrinone (10 microM) in the presence of isoproterenol. Under conditions of higher cell Ca2+ loading achieved by raising bathing [Ca2+] to 1 mM and isoproterenol to 3 nM the positive inotropic effect of milrinone (10 microM) in rat myocytes saturated when spontaneous oscillatory Ca2+ release appeared in the diastolic intervals between electrically stimulated twitches. Our results suggest that an enhancement in the baseline beta-adrenergic stimulation is required for milrinone to exercise a positive inotropic action on rat myocardial tissue. PMID:2576017

  3. Peptide-enhanced mRNA transfection in cultured mouse cardiac fibroblasts and direct reprogramming towards cardiomyocyte-like cells

    PubMed Central

    Lee, Kunwoo; Yu, Pengzhi; Lingampalli, Nithya; Kim, Hyun Jin; Tang, Richard; Murthy, Niren

    2015-01-01

    The treatment of myocardial infarction is a major challenge in medicine due to the inability of heart tissue to regenerate. Direct reprogramming of endogenous cardiac fibroblasts into functional cardiomyocytes via the delivery of transcription factor mRNAs has the potential to regenerate cardiac tissue and to treat heart failure. Even though mRNA delivery to cardiac fibroblasts has the therapeutic potential, mRNA transfection in cardiac fibroblasts has been challenging. Herein, we develop an efficient mRNA transfection in cultured mouse cardiac fibroblasts via a polyarginine-fused heart-targeting peptide and lipofectamine complex, termed C-Lipo and demonstrate the partial direct reprogramming of cardiac fibroblasts towards cardiomyocyte cells. C-Lipo enabled the mRNA-induced direct cardiac reprogramming due to its efficient transfection with low toxicity, which allowed for multiple transfections of Gata4, Mef2c, and Tbx5 (GMT) mRNAs for a period of 2 weeks. The induced cardiomyocyte-like cells had α-MHC promoter-driven GFP expression and striated cardiac muscle structure from α-actinin immunohistochemistry. GMT mRNA transfection of cultured mouse cardiac fibroblasts via C-Lipo significantly increased expression of the cardiomyocyte marker genes, Actc1, Actn2, Gja1, Hand2, and Tnnt2, after 2 weeks of transfection. Moreover, this study provides the first direct evidence that the stoichiometry of the GMT reprogramming factors influence the expression of cardiomyocyte marker genes. Our results demonstrate that mRNA delivery is a potential approach for cardiomyocyte generation. PMID:25834424

  4. Cardiac Catheterization

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Cardiac Catheterization? Cardiac catheterization (KATH-eh-ter-ih-ZA-shun) is a ... disease. Doctors also can use ultrasound during cardiac catheterization to see blockages in the coronary arteries. Ultrasound ...

  5. Salmeterol enhances the cardiac response to gene therapy in Pompe disease.

    PubMed

    Han, Sang-Oh; Li, Songtao; Koeberl, Dwight D

    2016-05-01

    Enzyme replacement therapy (ERT) with recombinant human (rh) acid α-glucosidase (GAA) has prolonged the survival of patients. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up rhGAA, correlated with a poor response to ERT by muscle in Pompe disease. Clenbuterol, a selective β2 receptor agonist, enhanced the CI-MPR expression in striated muscle through Igf-1 mediated muscle hypertrophy, which correlated with increased CI-MPR (also the Igf-2 receptor) expression. In this study we have evaluated 4 new drugs in GAA knockout (KO) mice in combination with an adeno-associated virus (AAV) vector encoding human GAA, 3 alternative β2 agonists and dehydroepiandrosterone (DHEA). Mice were injected with AAV2/9-CBhGAA (1E+11 vector particles) at a dose that was not effective at clearing glycogen storage from the heart. Heart GAA activity was significantly increased by either salmeterol (p<0.01) or DHEA (p<0.05), in comparison with untreated mice. Furthermore, glycogen content was reduced in the heart by treatment with DHEA (p<0.001), salmeterol (p<0.05), formoterol (p<0.01), or clenbuterol (p<0.01) in combination with the AAV vector, in comparison with untreated GAA-KO mice. Wirehang testing revealed that salmeterol and the AAV vector significantly increased performance, in comparison with the AAV vector alone (p<0.001). Similarly, salmeterol with the vector increased performance significantly more than any of the other drugs. The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice. Thus, salmeterol should be further developed as adjunctive therapy in combination with either ERT or gene therapy for Pompe disease. PMID:27017193

  6. Commitment Tracking System (CTS)

    Energy Science and Technology Software Center (ESTSC)

    2009-08-07

    The CTS enables the identification and management of compliance actions and issues originating from multiple sources. CTS also possesses search capabilities enabling quick identification of upcoming commitments while providing a method of documenting and maintaining completion dates and compliance information when a commitment is met.

  7. Managing by commitments.

    PubMed

    Sull, Donald N

    2003-06-01

    What makes a great manager great? Despite differences in their personal attributes, successful managers all excel in the making, honoring, and remaking of commitments. Managerial commitments take many forms, from capital investments to personnel decisions to public statements, but each exerts both immediate and enduring influence on a company. A leader's commitments shape a business's identity, define its strengths and weaknesses, establish its opportunities and limitations, and set its direction. Executives can all too easily forget that commitments are extraordinarily powerful. Caught up in the present, managers often take actions that, while beneficial in the near term, impose lasting constraints on their operations and organizations. When market or competitive conditions change, they can find themselves unable to respond effectively. Managers who understand the nature and power of their commitments can wield them more effectively throughout a company's life cycle. Entrepreneurs can avoid taking actions that imprint a new venture with a dysfunctional character. Managers in established enterprises can buttress past commitments that retain their currency and learn to recognize when commitments have become roadblocks to needed changes. The manager can then replace those roadblocks with new, rejuvenating commitments. That doesn't mean you should try to anticipate all the long-run consequences of every commitment--and it certainly doesn't mean you should shy away from making commitments. But it does mean that before making important decisions about, say, operating processes or partnerships, you should always ask yourself: Is this a process or relationship that we can live with in the future? Am I locking us into a course that we'll come to regret? PMID:12800719

  8. The H29D Mutation Does Not Enhance Cytosolic Ca2+ Activation of the Cardiac Ryanodine Receptor

    PubMed Central

    Xiao, Zhichao; Guo, Wenting; Yuen, Siobhan M. Wong King; Wang, Ruiwu; Zhang, Lin; Van Petegem, Filip; Chen, S. R. Wayne

    2015-01-01

    The N-terminal domain of the cardiac ryanodine receptor (RyR2) harbors a large number of naturally occurring mutations that are associated with stress-induced ventricular tachyarrhythmia and sudden death. Nearly all these disease-associated N-terminal mutations are located at domain interfaces or buried within domains. Mutations at these locations would alter domain-domain interactions or the stability/folding of domains. Recently, a novel RyR2 mutation H29D associated with ventricular arrhythmia at rest was found to enhance the activation of single RyR2 channels by diastolic levels of cytosolic Ca2+. Unlike other N-terminal disease-associated mutations, the H29D mutation is located on the surface of the N-terminal domain. It is unclear how this surface-exposed H29D mutation that does not appear to interact with other parts of the RyR2 structure could alter the intrinsic properties of the channel. Here we carried out detailed functional characterization of the RyR2-H29D mutant at the molecular and cellular levels. We found that the H29D mutation has no effect on the basal level or the Ca2+ dependent activation of [3H]ryanodine binding to RyR2, the cytosolic Ca2+ activation of single RyR2 channels, or the cytosolic Ca2+- or caffeine-induced Ca2+ release in HEK293 cells. In addition, the H29D mutation does not alter the propensity for spontaneous Ca2+ release or the thresholds for Ca2+ release activation or termination. Furthermore, the H29D mutation does not have significant impact on the thermal stability of the N-terminal region (residues 1–547) of RyR2. Collectively, our data show that the H29D mutation exerts little or no effect on the function of RyR2 or on the folding stability of the N-terminal region. Thus, our results provide no evidence that the H29D mutation enhances the cytosolic Ca2+ activation of RyR2. PMID:26405799

  9. The H29D Mutation Does Not Enhance Cytosolic Ca2+ Activation of the Cardiac Ryanodine Receptor.

    PubMed

    Xiao, Zhichao; Guo, Wenting; Yuen, Siobhan M Wong King; Wang, Ruiwu; Zhang, Lin; Van Petegem, Filip; Chen, S R Wayne

    2015-01-01

    The N-terminal domain of the cardiac ryanodine receptor (RyR2) harbors a large number of naturally occurring mutations that are associated with stress-induced ventricular tachyarrhythmia and sudden death. Nearly all these disease-associated N-terminal mutations are located at domain interfaces or buried within domains. Mutations at these locations would alter domain-domain interactions or the stability/folding of domains. Recently, a novel RyR2 mutation H29D associated with ventricular arrhythmia at rest was found to enhance the activation of single RyR2 channels by diastolic levels of cytosolic Ca2+. Unlike other N-terminal disease-associated mutations, the H29D mutation is located on the surface of the N-terminal domain. It is unclear how this surface-exposed H29D mutation that does not appear to interact with other parts of the RyR2 structure could alter the intrinsic properties of the channel. Here we carried out detailed functional characterization of the RyR2-H29D mutant at the molecular and cellular levels. We found that the H29D mutation has no effect on the basal level or the Ca2+ dependent activation of [3H]ryanodine binding to RyR2, the cytosolic Ca2+ activation of single RyR2 channels, or the cytosolic Ca2+- or caffeine-induced Ca2+ release in HEK293 cells. In addition, the H29D mutation does not alter the propensity for spontaneous Ca2+ release or the thresholds for Ca2+ release activation or termination. Furthermore, the H29D mutation does not have significant impact on the thermal stability of the N-terminal region (residues 1-547) of RyR2. Collectively, our data show that the H29D mutation exerts little or no effect on the function of RyR2 or on the folding stability of the N-terminal region. Thus, our results provide no evidence that the H29D mutation enhances the cytosolic Ca2+ activation of RyR2. PMID:26405799

  10. Thin filament incorporation of an engineered cardiac troponin C variant (L48Q) enhances contractility in intact cardiomyocytes from healthy and infarcted hearts

    PubMed Central

    Feest, Erik R.; Korte, F. Steven; Tu, An-yue; Dai, Jin; Razumova, Maria V.; Murry, Charles E.; Regnier, Michael

    2014-01-01

    Many current pharmaceutical therapies for systolic heart failure target intracellular [Ca2+] ([Ca2+]i) metabolism, or cardiac troponin C (cTnC) on thin filaments, and can have significant side-effects, including arrhythmias or adverse effects on diastolic function. In this study, we tested the feasibility of directly increasing the Ca2+ binding properties of cTnC to enhance contraction independent of [Ca2+]i in intact cardiomyocytes from healthy and myocardial infarcted (MI) hearts. Specifically, cardiac thin filament activation was enhanced through adenovirus-mediated over-expression of a cardiac troponin C (cTnC) variant designed to have increased Ca2+ binding affinity conferred by single amino acid substitution (L48Q). In skinned cardiac trabeculae and myofibrils we and others have shown that substitution of L48Q cTnC for native cTnC increases Ca2+ sensitivity of force and the maximal rate of force development. Here we introduced L48Q cTnC into myofilaments of intact cardiomyocytes via adeno-viral transduction to deliver cDNA for the mutant or wild type (WT) cTnC protein. Using video-microscopy to monitor cell contraction, relaxation, and intracellular Ca2+ transients (Fura-2), we report that incorporation of L48Q cTnC significantly increased contractility of cardiomyocytes from healthy and MI hearts without adversely affecting Ca2+ transient properties or relaxation. The improvements in contractility from L48Q cTnC expression are likely the result of enhanced contractile efficiency, as intracellular Ca2+ transient amplitudes were not affected. Expression and incorporation of L48Q cTnC into myofilaments was confirmed by Western blot analysis of myofibrils from transduced cardiomyocytes, which indicated replacement of 18±2% of native cTnC with L48Q cTnC. These experiments demonstrate the feasibility of directly targeting cardiac thin filament proteins to enhance cardiomyocyte contractility that is impaired following MI. PMID:24690333

  11. Insulin-like Growth Factor-I and Slow, Bi-directional Perfusion Enhance the Formation of Tissue-Engineered Cardiac Grafts

    PubMed Central

    Cheng, Mingyu; Moretti, Matteo; Engelmayr, George C.

    2009-01-01

    Biochemical and mechanical signals enabling cardiac regeneration can be elucidated using in vitro tissue-engineering models. We hypothesized that insulin-like growth factor-I (IGF) and slow, bi-directional perfusion could act independently and interactively to enhance the survival, differentiation, and contractile performance of tissue-engineered cardiac grafts. Heart cells were cultured on three-dimensional porous scaffolds in medium with or without supplemental IGF and in the presence or absence of slow, bi-directional perfusion that enhanced transport and provided shear stress. Structural, molecular, and electrophysiologic properties of the resulting grafts were quantified on culture day 8. IGF had independent, beneficial effects on apoptosis (p < 0.01), cellular viability (p < 0.01), contractile amplitude (p < 0.01), and excitation threshold (p < 0.01). Perfusion independently affected the four aforementioned parameters and also increased amounts of cardiac troponin-I (p < 0.01), connexin-43 (p < 0.05), and total protein (p < 0.01) in the grafts. Interactive effects of IGF and perfusion on apoptosis were also present (p < 0.01). Myofibrillogenesis and spontaneous contractility were present only in grafts cultured with perfusion, although contractility was inducible by electrical field stimulation of grafts from all groups. Our findings demonstrate that multi-factorial stimulation of tissue-engineered cardiac grafts using IGF and perfusion resulted in independent and interactive effects on heart cell survival, differentiation, and contractility. PMID:18759675

  12. Intramyocardial implantation of differentiated rat bone marrow mesenchymal stem cells enhanced by TGF-β1 improves cardiac function in heart failure rats

    PubMed Central

    Lv, Y.; Liu, B.; Wang, H.P.; Zhang, L.

    2016-01-01

    The present study tested the hypotheses that i) transforming growth factor beta 1 (TGF-β1) enhances differentiation of rat bone marrow mesenchymal stem cells (MSCs) towards the cardiomyogenic phenotype and ii) intramyocardial implantation of the TGF-β1-treated MSCs improves cardiac function in heart failure rats. MSCs were treated with different concentrations of TGF-β1 for 72 h, and then morphological characteristics, surface antigens and mRNA expression of several transcription factors were assessed. Intramyocardial implantation of these TGF-β1-treated MSCs to infarcted heart was also investigated. MSCs were initially spindle-shaped with irregular processes. On day 28 after TGF-β1 treatment, MSCs showed fusiform shape, orientating parallel with one another, and were connected with adjoining cells forming myotube-like structures. Immunofluorescence revealed the expression of cardiomyocyte-specific proteins, α-sarcomeric actin and troponin T, in these cells. The mRNA expression of GATA4 and Nkx2.5 genes was slightly increased on day 7, enhanced on day 14 and decreased on day 28 while α-MHC gene was not expressed on day 7, but expressed slightly on day 14 and enhanced on day 28. Transmission electron microscopy showed that the induced cells had myofilaments, z line-like substances, desmosomes, and gap junctions, in contrast with control cells. Furthermore, intramyocardial implantation of TGF-β1-treated MSCs to infarcted heart reduced scar area and increased the number of muscle cells. This structure regeneration was concomitant with the improvement of cardiac function, evidenced by decreased left ventricular end-diastolic pressure, increased left ventricular systolic pressure and increased maximal positive pressure development rate. Taken together, these results indicate that intramyocardial implantation of differentiated MSCs enhanced by TGF-β1 improved cardiac function in heart failure rats. PMID:27254663

  13. Intramyocardial implantation of differentiated rat bone marrow mesenchymal stem cells enhanced by TGF-β1 improves cardiac function in heart failure rats.

    PubMed

    Lv, Y; Liu, B; Wang, H P; Zhang, L

    2016-01-01

    The present study tested the hypotheses that i) transforming growth factor beta 1 (TGF-β1) enhances differentiation of rat bone marrow mesenchymal stem cells (MSCs) towards the cardiomyogenic phenotype and ii) intramyocardial implantation of the TGF-β1-treated MSCs improves cardiac function in heart failure rats. MSCs were treated with different concentrations of TGF-β1 for 72 h, and then morphological characteristics, surface antigens and mRNA expression of several transcription factors were assessed. Intramyocardial implantation of these TGF-β1-treated MSCs to infarcted heart was also investigated. MSCs were initially spindle-shaped with irregular processes. On day 28 after TGF-β1 treatment, MSCs showed fusiform shape, orientating parallel with one another, and were connected with adjoining cells forming myotube-like structures. Immunofluorescence revealed the expression of cardiomyocyte-specific proteins, α-sarcomeric actin and troponin T, in these cells. The mRNA expression of GATA4 and Nkx2.5 genes was slightly increased on day 7, enhanced on day 14 and decreased on day 28 while α-MHC gene was not expressed on day 7, but expressed slightly on day 14 and enhanced on day 28. Transmission electron microscopy showed that the induced cells had myofilaments, z line-like substances, desmosomes, and gap junctions, in contrast with control cells. Furthermore, intramyocardial implantation of TGF-β1-treated MSCs to infarcted heart reduced scar area and increased the number of muscle cells. This structure regeneration was concomitant with the improvement of cardiac function, evidenced by decreased left ventricular end-diastolic pressure, increased left ventricular systolic pressure and increased maximal positive pressure development rate. Taken together, these results indicate that intramyocardial implantation of differentiated MSCs enhanced by TGF-β1 improved cardiac function in heart failure rats. PMID:27254663

  14. Three-dimensional scaffolds of fetal decellularized hearts exhibit enhanced potential to support cardiac cells in comparison to the adult.

    PubMed

    Silva, A C; Rodrigues, S C; Caldeira, J; Nunes, A M; Sampaio-Pinto, V; Resende, T P; Oliveira, M J; Barbosa, M A; Thorsteinsdóttir, S; Nascimento, D S; Pinto-do-Ó, P

    2016-10-01

    A main challenge in cardiac tissue engineering is the limited data on microenvironmental cues that sustain survival, proliferation and functional proficiency of cardiac cells. The aim of our study was to evaluate the potential of fetal (E18) and adult myocardial extracellular matrix (ECM) to support cardiac cells. Acellular three-dimensional (3D) bioscaffolds were obtained by parallel decellularization of fetal- and adult-heart explants thereby ensuring reliable comparison. Acellular scaffolds retained main constituents of the cardiac ECM including distinctive biochemical and structural meshwork features of the native equivalents. In vitro, fetal and adult ECM-matrices supported 3D culture of heart-derived Sca-1(+) progenitors and of neonatal cardiomyocytes, which migrated toward the center of the scaffold and displayed elongated morphology and excellent viability. At the culture end-point, more Sca-1(+) cells and cardiomyocytes were found adhered and inside fetal bioscaffolds, compared to the adult. Higher repopulation yields of Sca-1(+) cells on fetal ECM relied on β1-integrin independent mitogenic signals. Sca-1(+) cells on fetal bioscaffolds showed a gene expression profile that anticipates the synthesis of a permissive microenvironment for cardiomyogenesis. Our findings demonstrate the superior potential of the 3D fetal microenvironment to support and instruct cardiac cells. This knowledge should be integrated in the design of next-generation biomimetic materials for heart repair. PMID:27424216

  15. Enhanced Cardiac Akt/Protein Kinase B Signaling Contributes to Pathological Cardiac Hypertrophy in Part by Impairing Mitochondrial Function via Transcriptional Repression of Mitochondrion-Targeted Nuclear Genes

    PubMed Central

    Wende, Adam R.; O'Neill, Brian T.; Bugger, Heiko; Riehle, Christian; Tuinei, Joseph; Buchanan, Jonathan; Tsushima, Kensuke; Wang, Li; Caro, Pilar; Guo, Aili; Sloan, Crystal; Kim, Bum Jun; Wang, Xiaohui; Pereira, Renata O.; McCrory, Mark A.; Nye, Brenna G.; Benavides, Gloria A.; Darley-Usmar, Victor M.; Shioi, Tetsuo; Weimer, Bart C.

    2014-01-01

    Sustained Akt activation induces cardiac hypertrophy (LVH), which may lead to heart failure. This study tested the hypothesis that Akt activation contributes to mitochondrial dysfunction in pathological LVH. Akt activation induced LVH and progressive repression of mitochondrial fatty acid oxidation (FAO) pathways. Preventing LVH by inhibiting mTOR failed to prevent the decline in mitochondrial function, but glucose utilization was maintained. Akt activation represses expression of mitochondrial regulatory, FAO, and oxidative phosphorylation genes in vivo that correlate with the duration of Akt activation in part by reducing FOXO-mediated transcriptional activation of mitochondrion-targeted nuclear genes in concert with reduced signaling via peroxisome proliferator-activated receptor α (PPARα)/PGC-1α and other transcriptional regulators. In cultured myocytes, Akt activation disrupted mitochondrial bioenergetics, which could be partially reversed by maintaining nuclear FOXO but not by increasing PGC-1α. Thus, although short-term Akt activation may be cardioprotective during ischemia by reducing mitochondrial metabolism and increasing glycolysis, long-term Akt activation in the adult heart contributes to pathological LVH in part by reducing mitochondrial oxidative capacity. PMID:25535334

  16. Unit commitment literature synopsis

    SciTech Connect

    Sheble, G.B. . Dept. of Electrical Engineering); Fahd, G.N. )

    1994-02-01

    Several optimization techniques have been applied to the solution of the thermal unit commitment problem. They range from heuristics such as complete enumeration to the more sophisticated ones such as Augmented LaGrangian. The heuristics have even reappeared as expert systems. The problem to solve is the optimal scheduling of generating units over a short-term horizon, typically 168 hours. This paper is an overview of the literature in the unit commitment field over the past twenty five years.

  17. The Δ14 Mutation of Human Cardiac Troponin T Enhances ATPase Activity and Alters the Cooperative Binding of S1-ADP to Regulated Actin†

    PubMed Central

    Gafurov, Boris; Fredricksen, Scott; Cai, Anmei; Brenner, Bernhard; Chase, P. Bryant; Chalovich, Joseph M.

    2005-01-01

    The complex of tropomyosin and troponin binds to actin and inhibits activation of myosin ATPase activity and force production of striated muscles at low free Ca2+ concentrations. Ca2+ stimulates ATP activity, and at subsaturating actin concentrations, the binding of NEM-modified S1 to actin–tropomyosin–troponin increases the rate of ATP hydrolysis even further. We show here that the Δ14 mutation of troponin T, associated with familial hypertrophic cardiomyopathy, results in an increase in ATPase rate like that seen with wild-type troponin in the presence of NEM-S1. The enhanced ATPase activity was not due to a decreased incorporation of mutant troponin T with troponin I and troponin C to form an active troponin complex. The activating effect was more prominent with a hybrid troponin (skeletal TnI, TnC, and cardiac TnT) than with all cardiac troponin. Thus it appears that changes in the troponin–troponin contacts that result from mutations or from forming hybrids stabilize a more active state of regulated actin. An analysis of the effect of the Δ14 mutation on the equilibrium binding of S1-ADP to actin was consistent with stabilization of an active state of actin. This change in activation may be important in the development of cardiac disease. PMID:15568820

  18. Coxsackievirus group B type 3 infection upregulates expression of monocyte chemoattractant protein 1 in cardiac myocytes, which leads to enhanced migration of mononuclear cells in viral myocarditis.

    PubMed

    Shen, Yan; Xu, Wei; Chu, Yi-Wei; Wang, Ying; Liu, Quan-Sheng; Xiong, Si-Dong

    2004-11-01

    Coxsackievirus group B type 3 (CVB3) is an important cause of viral myocarditis. The infiltration of mononuclear cells into the myocardial tissue is one of the key events in viral myocarditis. Immediately after CVB3 infects the heart, the expression of chemokine(s) by infected myocardial cells may be the first trigger for inflammatory infiltration and immune response. However, it is unknown whether CVB3 can induce the chemokine expression in cardiac myocytes. Monocyte chemoattractant protein 1 (MCP-1) is a potent chemokine that stimulates the migration of mononuclear cells. The objective of the present study was to investigate the effect of CVB3 infection on MCP-1 expression in murine cardiac myocytes and the role of MCP-1 in migration of mononuclear cells in viral myocarditis. Our results showed that the expression of MCP-1 was significantly increased in cardiac myocytes after wild-type CVB3 infection in a time- and dose-dependent manner, which resulted in enhanced migration of mononuclear cells in mice with viral myocarditis. The migration of mononuclear cells was partially abolished by antibodies specific for MCP-1 in vivo and in vitro. Administration of anti-MCP-1 antibody prevented infiltration of mononuclear cells bearing the MCP-1 receptor CCR2 in mice with viral myocarditis. Infection by UV-irradiated CVB3 induced rapid and transient expression of MCP-1 in cardiac myocytes. In conclusion, our results indicate that CVB3 infection stimulates the expression of MCP-1 in myocardial cells, which subsequently leads to migration of mononuclear cells in viral myocarditis. PMID:15507642

  19. More Than Tiny Sacks: Stem Cell Exosomes as Cell-Free Modality for Cardiac Repair.

    PubMed

    Kishore, Raj; Khan, Mohsin

    2016-01-22

    Stem cell therapy provides immense hope for regenerating the pathological heart, yet has been marred by issues surrounding the effectiveness, unclear mechanisms, and survival of the donated cell population in the ischemic myocardial milieu. Poor survival and engraftment coupled to inadequate cardiac commitment of the adoptively transferred stem cells compromises the improvement in cardiac function. Various alternative approaches to enhance the efficacy of stem cell therapies and to overcome issues with cell therapy have been used with varied success. Cell-free components, such as exosomes enriched in proteins, messenger RNAs, and miRs characteristic of parental stem cells, represent a potential approach for treating cardiovascular diseases. Recently, exosomes from different kinds of stem cells have been effectively used to promote cardiac function in the pathological heart. The aim of this review is to summarize current research efforts on stem cell exosomes, including their potential benefits and limitations to develop a potentially viable therapy for cardiovascular problems. PMID:26838317

  20. Simulated Microgravity and 3D Culture Enhance Induction, Viability, Proliferation and Differentiation of Cardiac Progenitors from Human Pluripotent Stem Cells.

    PubMed

    Jha, Rajneesh; Wu, Qingling; Singh, Monalisa; Preininger, Marcela K; Han, Pengcheng; Ding, Gouliang; Cho, Hee Cheol; Jo, Hanjoong; Maher, Kevin O; Wagner, Mary B; Xu, Chunhui

    2016-01-01

    Efficient generation of cardiomyocytes from human pluripotent stem cells is critical for their regenerative applications. Microgravity and 3D culture can profoundly modulate cell proliferation and survival. Here, we engineered microscale progenitor cardiac spheres from human pluripotent stem cells and exposed the spheres to simulated microgravity using a random positioning machine for 3 days during their differentiation to cardiomyocytes. This process resulted in the production of highly enriched cardiomyocytes (99% purity) with high viability (90%) and expected functional properties, with a 1.5 to 4-fold higher yield of cardiomyocytes from each undifferentiated stem cell as compared with 3D-standard gravity culture. Increased induction, proliferation and viability of cardiac progenitors as well as up-regulation of genes associated with proliferation and survival at the early stage of differentiation were observed in the 3D culture under simulated microgravity. Therefore, a combination of 3D culture and simulated microgravity can be used to efficiently generate highly enriched cardiomyocytes. PMID:27492371

  1. Simulated Microgravity and 3D Culture Enhance Induction, Viability, Proliferation and Differentiation of Cardiac Progenitors from Human Pluripotent Stem Cells

    PubMed Central

    Jha, Rajneesh; Wu, Qingling; Singh, Monalisa; Preininger, Marcela K.; Han, Pengcheng; Ding, Gouliang; Cho, Hee Cheol; Jo, Hanjoong; Maher, Kevin O.; Wagner, Mary B.; Xu, Chunhui

    2016-01-01

    Efficient generation of cardiomyocytes from human pluripotent stem cells is critical for their regenerative applications. Microgravity and 3D culture can profoundly modulate cell proliferation and survival. Here, we engineered microscale progenitor cardiac spheres from human pluripotent stem cells and exposed the spheres to simulated microgravity using a random positioning machine for 3 days during their differentiation to cardiomyocytes. This process resulted in the production of highly enriched cardiomyocytes (99% purity) with high viability (90%) and expected functional properties, with a 1.5 to 4-fold higher yield of cardiomyocytes from each undifferentiated stem cell as compared with 3D-standard gravity culture. Increased induction, proliferation and viability of cardiac progenitors as well as up-regulation of genes associated with proliferation and survival at the early stage of differentiation were observed in the 3D culture under simulated microgravity. Therefore, a combination of 3D culture and simulated microgravity can be used to efficiently generate highly enriched cardiomyocytes. PMID:27492371

  2. Human umbilical cord perivascular cells exhibit enhanced cardiomyocyte reprogramming and cardiac function after experimental acute myocardial infarction.

    PubMed

    Yannarelli, Gustavo; Dayan, Victor; Pacienza, Natalia; Lee, Chyan-Jang; Medin, Jeffrey; Keating, Armand

    2013-01-01

    We were interested in evaluating the ability of the mesenchymal stromal cell (MSC) population, human umbilical cord perivascular cells (HUCPVCs), to undergo cardiomyocyte reprogramming in an established coculture system with rat embryonic cardiomyocytes. Results were compared with human bone marrow-derived (BM) MSCs. The transcription factors GATA4 and Mef 2c were expressed in HUCPVCs but not BM-MSCs at baseline and, at 7 days, increased 7.6- and 3.5-fold, respectively, compared with BM-MSCs. Although cardiac-specific gene expression increased in both cell types in coculture, upregulation was more significant in HUCPVCs, consistent with Mef 2c-GATA4 synergism. Using a lentivector with eGFP transcribed from the α-myosin heavy chain (α-MHC) promoter, we found that cardiac gene expression was greater in HUCPVCs than BM-MSCs after 14 days coculture (52±17% vs. 29±6%, respectively). A higher frequency of HUCPVCs expressed α-MHC protein compared with BM-MSCs (11.6±0.9% vs. 5.3±0.3%); however, both cell types retained MSC-associated determinants. We also assessed the ability of the MSC types to mediate cardiac regeneration in a NOD/SCID γ mouse model of acute myocardial infarction (AMI). Fourteen days after AMI, cardiac function was significantly better in cell-treated mice compared with control animals and HUCPVCs exhibited greater improvement. Although human cells persisted in the infarct area, the frequency of α-MHC expression was low. Our results indicate that HUCPVCs exhibit a greater degree of cardiomyocyte reprogramming but that differentiation for both cell types is partial. We conclude that HUCPVCs may be preferable to BM-MSCs in the cell therapy of AMI. PMID:23043977

  3. Influences on Researchers' Commitment.

    ERIC Educational Resources Information Center

    Bailey, Jeffrey G.

    1994-01-01

    A study in a new university investigated the relative importance of six factors (job security/promotion, availability of research resources, contribution to university mission, personal stimulation/challenge, colleague relationship, and professional recognition/development) on research commitment and productivity. Discipline, rank, and gender were…

  4. Committed Sport Event Volunteers

    ERIC Educational Resources Information Center

    Han, Keunsu; Quarterman, Jerome; Strigas, Ethan; Ha, Jaehyun; Lee, Seungbum

    2013-01-01

    The purpose of this study was to investigate the relationships among selected demographic characteristics (income, education and age), motivation and commitment of volunteers at a sporting event. Three-hundred and five questionnaires were collected from volunteers in a marathon event and analyzed using structural equation modeling (SEM). Based on…

  5. Induced apnea enhances image quality and visualization of cardiopulmonary anatomic during contrastenhanced cardiac computerized tomographic angiography in children

    PubMed Central

    Chakravarthy, Murali; Sunilkumar, Gubbihalli; Pargaonkar, Sumant; Hosur, Rajathadri; Harivelam, Chidananda; Kavaraganahalli, Deepak; Srinivasan, Pradeep

    2015-01-01

    Objective: The purpose of our study was to determine the effect of induced apnea on quality of cardiopulmonary structures during computerized tomographic (CT) angiography images in children with congenital heart diseases. Methods: Pediatric patients with congenital heart defects undergoing cardiac CT angiography at our facility in the past 3 years participated in this study. The earlier patients underwent cardiac CT angiography without induced apnea and while, later, apnea was induced in patients, which was followed by electrocardiogram gated cardiac CT angiography. General anesthesia was induced using sleep dose of intravenous propofol. After the initial check CT, on request by the radiologist, apnea was induced by the anesthesiologist by administering 1 mg/kg of intravenous suxamethonium. Soon after apnea ensued, the contrast was injected, and CT angiogram carried out. CT images in the “apnea group” were compared with those in “nonapnea group.” After the completion of the procedure, the patients were mask ventilated with 100% oxygen till the spontaneous ventilation was restored. Results: We studied 46 patients, of whom 36 with apnea and yet another 10 without. The quality of the image, visualization of structures such as cardiac wall, outflow tracts, lung field, aortopulmonary shunts, and coronary arteries were analyzed and subjected to statistical analysis (Mann–Whitney U, Fischer's exact test and Pearson's Chi-square test). In the induced apnea group, overall image quality was considered excellent in 89% (n = 33) of the studies, while in the “no apnea group,” only 30% of studies were excellent. Absent or minimal motion artifacts were seen in a majority of the studies in apnea group (94%). In the nonapnea group, the respiratory and body motion artifacts were severe in 50%, moderate in 30%, and minimal in 20%, but they were significantly lesser in the apnea group. All the studied parameters were statistically significant in the apnea group in

  6. From controlled to committed.

    PubMed

    Hess, J C

    1996-02-01

    Most of us agree that people are our most important resource. Yet we spend a minimal amount of time learning more about human behavior, communication, and how our attitudes and behavior impact employee performance. Instead we rely on traditional methods of negative reinforcement in an attempt to control our areas of responsibility. While these methods can render some short-term success, managers and organizations that succeed during these times of change and fierce competition will be those that take the time to understand and capture the power of a committed workforce. The committed workforce is energized, not simply compliant, as a result of having basic human needs for achievement satisfied, belonging to a group, and receiving recognition for its contributions. Committed workers typically describe the manager as one who has the ability to give them a great degree of control over their area of influence. We all know that we don't change our leadership style like we change clothes. Old habits die hard. it takes a personal commitment and lots of practice to rid outselves of habits and behavior that no longer serve our departments and facilities. This commitment, however, is crucial to survival. As managers, we must cope with increasing ambiguity and uncertainty in the workplace. To survive these challenges, we must improve our interpersonal skills and ability to successfully bring out the best in others. I believe that success will continue for managers who not only increase their knowledge and technical ability, but who also inspire their workers to move forward with a collective sense of enthusiasm and purpose. PMID:10154218

  7. NPY1-36 and PYY1-36 activate cardiac fibroblasts: an effect enhanced by genetic hypertension and inhibition of dipeptidyl peptidase 4.

    PubMed

    Zhu, Xiao; Gillespie, Delbert G; Jackson, Edwin K

    2015-11-01

    Cardiac sympathetic nerves release neuropeptide Y (NPY)1-36, and peptide YY (PYY)1-36 is a circulating peptide; therefore, these PP-fold peptides could affect cardiac fibroblasts (CFs). We examined the effects of NPY1-36 and PYY1-36 on the proliferation of and collagen production ([(3)H]proline incorporation) by CFs isolated from Wistar-Kyoto (WKY) normotensive rats and spontaneously hypertensive rats (SHRs). Experiments were performed with and without sitagliptin, an inhibitor of dipeptidyl peptidase 4 [DPP4; an ectoenzyme that metabolizes NPY1-36 and PYY1-36 (Y1 receptor agonists) to NPY3-36 and PYY3-36 (inactive at Y1 receptors), respectively]. NPY1-36 and PYY1-36, but not NPY3-36 or PYY3-36, stimulated proliferation of CFs, and these effects were more potent than ANG II, enhanced by sitagliptin, blocked by BIBP3226 (Y1 receptor antagonist), and greater in SHR CFs. SHR CF membranes expressed more receptor for activated C kinase (RACK)1 [which scaffolds the Gi/phospholipase C (PLC)/PKC pathway] compared with WKY CF membranes. RACK1 knockdown (short hairpin RNA) and inhibition of Gi (pertussis toxin), PLC (U73122), and PKC (GF109203X) blocked the proliferative effects of NPY1-36. NPY1-36 and PYY1-36 stimulated collagen production more potently than did ANG II, and this was enhanced by sitagliptin and greater in SHR CFs. In conclusion, 1) NPY1-36 and PYY1-36, via the Y1 receptor/Gi/PLC/PKC pathway, activate CFs, and this pathway is enhanced in SHR CFs due to increased localization of RACK1 in membranes; and 2) DPP4 inhibition enhances the effects of NPY1-36 and PYY1-36 on CFs, likely by inhibiting the metabolism of NPY1-36 and PYY1-36. The implications are that endogenous NPY1-36 and PYY1-36 could adversely affect cardiac structure/function by activating CFs, and this may be exacerbated in genetic hypertension and by DPP4 inhibitors. PMID:26371160

  8. NADPH Oxidase/ROS-Dependent VCAM-1 Induction on TNF-α-Challenged Human Cardiac Fibroblasts Enhances Monocyte Adhesion

    PubMed Central

    Lin, Chih-Chung; Yang, Chien-Chung; Wang, Chen-Yu; Tseng, Hui-Ching; Pan, Chih-Shuo; Hsiao, Li-Der; Yang, Chuen-Mao

    2016-01-01

    The inflammation-dependent adhesion molecule expressions are characterized in cardiovascular diseases and myocardial tissue infiltrations. Several pro-inflammatory cytokines are elevated in the acute myocardial injury and infarction. Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, is raised in the injury tissues and inflammatory regions and involved in the pathogenesis of cardiac injury, inflammation, and apoptosis. In fibroblasts, TNF-α-triggered expression of vascular cell adhesion molecule (VCAM)-1 aggravated the heart inflammation. However, the mechanisms underlying TNF-α-mediated VCAM-1 expression in cardiac fibroblasts remain unclear. Here, the primary cultured human cardiac fibroblasts (HCFs) were used to investigate the effects of TNF-α on VCAM-1 expression. The molecular evidence, including protein, mRNA, and promoter analyses, indicated that TNF-α-induced VCAM-1 gene expression is mediated through the TNFR-dependent manner. Activation of TNF-α/TNFR system triggered PKCα-dependent NADPH oxidase (Nox)/reactive oxygen species (ROS) signal linking to MAPK cascades, and then led to activation of the transcription factor, AP-1. Moreover, the results of mRNA and promoter assay demonstrated that c-Jun/AP-1 phosphorylated by TNF-α turns on VCAM-1 gene expression. Subsequently, up-regulated VCAM-1 on the cell surface of TNF-α-challenged HCFs increased the number of monocytes adhering to these cells. These results indicated that in HCFs, activation of AP-1 by PKCα-dependent Nox/ROS/MAPKs cascades is required for TNF-α-induced VCAM-1 expression. To clarify the mechanisms of TNF-α-induced VCAM-1 expression in HCFs may provide therapeutic strategies for heart injury and inflammatory diseases. PMID:26858641

  9. Protein kinase C enhances myosin light-chain kinase effects on force development and ATPase activity in rat single skinned cardiac cells.

    PubMed Central

    Clement, O; Puceat, M; Walsh, M P; Vassort, G

    1992-01-01

    Many neurohormones alter the force of cardiac contraction by variations in the intracellular Ca2+ concentration. alpha 1-Adrenergic and muscarinic stimulations, rather, modify the sensitivity of contractile proteins to Ca(2+)-calmodulin-myosin light-chain kinase (MLCK) complex induces a large increase in Ca2+ sensitivity (0.14 pCa unit) of these easily accessible myofilaments. This increase is further enhanced by up to 0.19 pCa unit when protein kinase C (PKC) is added together with MLCK. Similarly, the Ca2+ ATPase activity of skinned cells in suspension is increased in the presence of MLCK and further in the presence of both kinases. 32P-labelling and SDS/PAGE show that these changes are associated with light-chain 2 (LC2) phosphorylation together with phosphorylation of troponin I and troponin T when PKC is added. Although to a smaller extent than in smooth muscle, phosphorylation of cardiac myosin LC2 may be involved in the modulation of heart contractility. Images Fig. 4. Fig. 5. Fig. 6. PMID:1386218

  10. Gene Therapy Delivery Systems for Enhancing Viral and Nonviral Vectors for Cardiac Diseases: Current Concepts and Future Applications

    PubMed Central

    Katz, Michael G.; Fargnoli, Anthony S.; Williams, Richard D.

    2013-01-01

    Abstract Gene therapy is one of the most promising fields for developing new treatments for the advanced stages of ischemic and monogenetic, particularly autosomal or X-linked recessive, cardiomyopathies. The remarkable ongoing efforts in advancing various targets have largely been inspired by the results that have been achieved in several notable gene therapy trials, such as the hemophilia B and Leber's congenital amaurosis. Rate-limiting problems preventing successful clinical application in the cardiac disease area, however, are primarily attributable to inefficient gene transfer, host responses, and the lack of sustainable therapeutic transgene expression. It is arguable that these problems are directly correlated with the choice of vector, dose level, and associated cardiac delivery approach as a whole treatment system. Essentially, a delicate balance exists in maximizing gene transfer required for efficacy while remaining within safety limits. Therefore, the development of safe, effective, and clinically applicable gene delivery techniques for selected nonviral and viral vectors will certainly be invaluable in obtaining future regulatory approvals. The choice of gene transfer vector, dose level, and the delivery system are likely to be critical determinants of therapeutic efficacy. It is here that the interactions between vector uptake and trafficking, delivery route means, and the host's physical limits must be considered synergistically for a successful treatment course. PMID:24164239

  11. Enhanced carotid-cardiac baroreflex response and elimination of orthostatic hypotension 24 hours after acute exercise in paraplegics

    NASA Technical Reports Server (NTRS)

    Engelke, K. A.; Shea, J. D.; Doerr, D. F.; Convertino, V. A.

    1992-01-01

    To test the hypothesis that an acute bout of maximal exercise can ameliorate orthostatic hypotension consequent to prolonged wheelchair confinement, we evaluated heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure responses during 15 minutes of 70 degrees head-up tilt (HUT) in 10 paraplegic subjects 24 hours after arm crank exercise designed to elicit maximal effort, and during a control (no exercise) conditions. Additionally, the carotid baroreceptor stimulus-cardiac response relationship was determined by measurement of R-R interval during external application of graded pressures to the carotid sinuses. One week separated the treatment conditions. The maximum slope of the carotid-cardiac baroreflex response was increased (p = 0.049) by exercise (6.2 +/- 1.7 msec/mmHg) compared to control (3.3 +/- 0.6). During control HUT, HR increased from 61 +/- 1 to 90 +/- 7 bpm (p = 0.001) while SBP decreased from 118 +/- 5 to 106 +/- 9 mmHg (p = 0.025). During HUT 24 hours after exercise, HR increased from 60 +/- 2 to 90 +/- 4 bpm (p = 0.001), but the reduction in SBP was essentially eliminated (116 +/- 5 to 113 +/- 5 mmHg).

  12. Acute Preconditioning of Cardiac Progenitor Cells with Hydrogen Peroxide Enhances Angiogenic Pathways Following Ischemia-Reperfusion Injury

    PubMed Central

    Pendergrass, Karl D.; Boopathy, Archana V.; Seshadri, Gokulakrishnan; Maiellaro-Rafferty, Kathryn; Che, Pao Lin; Brown, Milton E.

    2013-01-01

    There are a limited number of therapies available to prevent heart failure following myocardial infarction. One novel therapy that is currently being pursued is the implantation of cardiac progenitor cells (CPCs); however, their responses to oxidative stress during differentiation have yet to be elucidated. The objective of this study was to determine the effect of hydrogen peroxide (H2O2) treatment on CPC differentiation in vitro, as well as the effect of H2O2 preconditioning before implantation following ischemia-reperfusion (I/R) injury. CPCs were isolated and cloned from adult rat hearts, and then cultured in the absence or presence of H2O2 for 2 or 5 days. CPC survival was assessed with Annexin V, and cellular differentiation was evaluated through mRNA expression for cardiogenic genes. We found that 100 μM H2O2 decreased serum withdrawal-induced apoptosis by at least 45% following both 2 and 5 days of treatment. Moreover, 100 μM H2O2 treatment for 2 days significantly increased endothelial and smooth muscle markers compared to time-matched untreated CPCs. However, continued H2O2 treatment significantly decreased these markers. Left ventricular cardiac function was assessed 28 days after I/R and I/R with the implantation of Luciferase/GFP+ CPCs, which were preconditioned with 100 μM H2O2 for 2 days. Hearts implanted with Luciferase/GFP+ CPCs had significant improvement in both positive and negative dP/dT over I/R. Furthermore, cardiac fibrosis was significantly decreased in the preconditioned cells versus both I/R alone and I/R with control cells. We also observed a significant increase in endothelial cell density in the preconditioned CPC hearts compared to untreated CPC hearts, which also coincided with a higher density of Luciferase+ vessels. These findings suggest that preconditioning of CPCs with H2O2 for 2 days stimulates neoangiogenesis in the peri-infarct area following I/R injury and could be a viable therapeutic option to prevent heart

  13. Fibroblast Growth Factor-9 Enhances M2 Macrophage Differentiation and Attenuates Adverse Cardiac Remodeling in the Infarcted Diabetic Heart

    PubMed Central

    Singla, Dinender K.; Singla, Reetu D.; Abdelli, Latifa S.; Glass, Carley

    2015-01-01

    Inflammation has been implicated as a perpetrator of diabetes and its associated complications. Monocytes, key mediators of inflammation, differentiate into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages upon infiltration of damaged tissue. However, the inflammatory cell types, which propagate diabetes progression and consequential adverse disorders, remain unclear. The current study was undertaken to assess monocyte infiltration and the role of fibroblast growth factor-9 (FGF-9) on monocyte to macrophage differentiation and cardioprotection in the diabetic infarcted heart. Db/db diabetic mice were assigned to sham, myocardial infarction (MI), and MI+FGF-9 groups. MI was induced by permanent coronary artery ligation and animals were subjected to 2D transthoracic echocardiography two weeks post-surgery. Immunohistochemical and immunoassay results from heart samples collected suggest significantly increased infiltration of monocytes (Mean ± SEM; MI: 2.02% ± 0.23% vs. Sham 0.75% ± 0.07%; p<0.05) and associated pro-inflammatory cytokines (TNF-α, MCP-1, and IL-6), adverse cardiac remodeling (Mean ± SEM; MI: 33% ± 3.04% vs. Sham 2.2% ± 0.33%; p<0.05), and left ventricular dysfunction (Mean ± SEM; MI: 35.4% ± 1.25% vs. Sham 49.19% ± 1.07%; p<0.05) in the MI group. Importantly, treatment of diabetic infarcted myocardium with FGF-9 resulted in significantly decreased monocyte infiltration (Mean ± SEM; MI+FGF-9: 1.39% ± 0.1% vs. MI: 2.02% ± 0.23%; p<0.05), increased M2 macrophage differentiation (Mean ± SEM; MI+FGF-9: 4.82% ± 0.86% vs. MI: 0.85% ± 0.3%; p<0.05) and associated anti-inflammatory cytokines (IL-10 and IL-1RA), reduced adverse remodeling (Mean ± SEM; MI+FGF-9: 11.59% ± 1.2% vs. MI: 33% ± 3.04%; p<0.05), and improved cardiac function (Fractional shortening, Mean ± SEM; MI+FGF-9: 41.51% ± 1.68% vs. MI: 35.4% ± 1.25%; p<0.05). In conclusion, our data suggest FGF-9 possesses novel therapeutic potential in its ability to

  14. Exendin-4 Pretreated Adipose Derived Stem Cells Are Resistant to Oxidative Stress and Improve Cardiac Performance via Enhanced Adhesion in the Infarcted Heart

    PubMed Central

    Yin, Yujing; Wang, Liman; Liu, Zhiqiang; Yang, Junjie; Chen, Yundai; Wang, Changyong

    2014-01-01

    Reactive oxygen species (ROS), which were largely generated after myocardial ischemia, severely impaired the adhesion and survival of transplanted stem cells. In this study, we aimed to determine whether Exendin-4 pretreatment could improve the adhesion and therapeutic efficacy of transplanted adipose derived stem cells (ADSCs) in ischemic myocardium. In vitro, H2O2 was used to provide ROS environments, in which ADSCs pretreated with Exendin-4 were incubated. ADSCs without pretreatment were used as control. Then, cell adhesion and viability were analyzed with time. Compared with control ADSCs, Exendin-4 treatment significantly increased the adhesion of ADSCs in ROS environment, while reduced intracellular ROS and cell injury as determined by dihydroethidium (DHE) staining live/Dead staining, lactate dehydrogenase-release assay and MTT assay. Western Blotting demonstrated that ROS significantly decreased the expression of adhesion-related integrins and integrin-related focal adhesion proteins, which were significantly reversed by Exendin-4 pretreatment and followed by decreases in caspase-3, indicating that Exendin-4 may facilitate cell survival through enhanced adhesion. In vivo, myocardial infarction (MI) was induced by the left anterior descending artery ligation in SD rats. Autologous ADSCs with or without Exendin-4 pretreatment were injected into the border area of infarcted hearts, respectively. Multi-techniques were used to assess the beneficial effects after transplantation. Longitudinal bioluminescence imaging and histological staining revealed that Exendin-4 pretreatment enhanced the survival and differentiation of engrafted ADSCs in ischemic myocardium, accompanied with significant benefits in cardiac function, matrix remodeling, and angiogenesis compared with non-pretreated ADSCs 4 weeks post-transplantation. In conclusion, transplantation of Exendin-4 pretreated ADSCs significantly improved cardiac performance and can be an innovative approach in the

  15. Exendin-4 pretreated adipose derived stem cells are resistant to oxidative stress and improve cardiac performance via enhanced adhesion in the infarcted heart.

    PubMed

    Liu, Jianfeng; Wang, Haibin; Wang, Yan; Yin, Yujing; Wang, Liman; Liu, Zhiqiang; Yang, Junjie; Chen, Yundai; Wang, Changyong

    2014-01-01

    Reactive oxygen species (ROS), which were largely generated after myocardial ischemia, severely impaired the adhesion and survival of transplanted stem cells. In this study, we aimed to determine whether Exendin-4 pretreatment could improve the adhesion and therapeutic efficacy of transplanted adipose derived stem cells (ADSCs) in ischemic myocardium. In vitro, H2O2 was used to provide ROS environments, in which ADSCs pretreated with Exendin-4 were incubated. ADSCs without pretreatment were used as control. Then, cell adhesion and viability were analyzed with time. Compared with control ADSCs, Exendin-4 treatment significantly increased the adhesion of ADSCs in ROS environment, while reduced intracellular ROS and cell injury as determined by dihydroethidium (DHE) staining live/Dead staining, lactate dehydrogenase-release assay and MTT assay. Western Blotting demonstrated that ROS significantly decreased the expression of adhesion-related integrins and integrin-related focal adhesion proteins, which were significantly reversed by Exendin-4 pretreatment and followed by decreases in caspase-3, indicating that Exendin-4 may facilitate cell survival through enhanced adhesion. In vivo, myocardial infarction (MI) was induced by the left anterior descending artery ligation in SD rats. Autologous ADSCs with or without Exendin-4 pretreatment were injected into the border area of infarcted hearts, respectively. Multi-techniques were used to assess the beneficial effects after transplantation. Longitudinal bioluminescence imaging and histological staining revealed that Exendin-4 pretreatment enhanced the survival and differentiation of engrafted ADSCs in ischemic myocardium, accompanied with significant benefits in cardiac function, matrix remodeling, and angiogenesis compared with non-pretreated ADSCs 4 weeks post-transplantation. In conclusion, transplantation of Exendin-4 pretreated ADSCs significantly improved cardiac performance and can be an innovative approach in the

  16. Geometric feature-based multimodal image registration of contrast-enhanced cardiac CT with gated myocardial perfusion SPECT

    PubMed Central

    Woo, Jonghye; Slomka, Piotr J.; Dey, Damini; Cheng, Victor Y.; Hong, Byung-Woo; Ramesh, Amit; Berman, Daniel S.; Karlsberg, Ronald P.; Kuo, C.-C. Jay; Germano, Guido

    2009-01-01

    Purpose: Cardiac computed tomography (CT) and single photon emission computed tomography (SPECT) provide clinically complementary information in the diagnosis of coronary artery disease (CAD). Fused anatomical and physiological data acquired sequentially on separate scanners can be coregistered to accurately diagnose CAD in specific coronary vessels. Methods: A fully automated registration method is presented utilizing geometric features from a reliable segmentation of gated myocardial perfusion SPECT (MPS) volumes, where regions of myocardium and blood pools are extracted and used as an anatomical mask to de-emphasize the inhomogeneities of intensity distribution caused by perfusion defects and physiological variations. A multiresolution approach is employed to represent coarse-to-fine details of both volumes. The extracted voxels from each level are aligned using a similarity measure with a piecewise constant image model and minimized using a gradient descent method. The authors then perform limited nonlinear registration of gated MPS to adjust for phase differences by automatic cardiac phase matching between CT and MPS. For phase matching, they incorporate nonlinear registration using thin-plate-spline-based warping. Rigid registration has been compared with manual alignment (n=45) on 20 stress/rest MPS and coronary CTA data sets acquired from two different sites and five stress CT perfusion data sets. Phase matching was also compared to expert visual assessment. Results: As compared with manual alignment obtained from two expert observers, the mean and standard deviation of absolute registration errors of the proposed method for MPS were4.3±3.5, 3.6±2.6, and 3.6±2.1mm for translation and 2.1±3.2°, 0.3±0.8°, and 0.7±1.2° for rotation at site A and 3.8±2.7, 4.0±2.9, and 2.2±1.8mm for translation and 1.1±2.0°, 1.6±3.1°, and 1.9±3.8° for rotation at site B. The results for CT perfusion were 3.0±2.9, 3.5±2.4, and 2.8±1.0mm for translation and 3

  17. Commitment and energy conservation

    SciTech Connect

    Pallak, M.S.; Cook, D.A.; Sullivan, J.J.

    1980-01-01

    The authors discuss the process of becoming committed to energy conservation research, then describe practical issues of field research and several data sets on household energy conservation. Their results show that taking a stand affected behavior in reducing the levels of natural gas and electricity usage, with the effect continuing even after the study ended. Although based on the assumption that homeowners were initially favorable toward energy conservation, the studies suggest that energy-related behavior is malleable and amenable to approaches familiar to psychologists. The study indicates that feedback on energy use during peak seasons could help to avoid power shortages. 16 references, 6 tables.

  18. Synergy between intention recognition and commitments in cooperation dilemmas

    NASA Astrophysics Data System (ADS)

    Han, The Anh; Santos, Francisco C.; Lenaerts, Tom; Pereira, Luís Moniz

    2015-03-01

    Commitments have been shown to promote cooperation if, on the one hand, they can be sufficiently enforced, and on the other hand, the cost of arranging them is justified with respect to the benefits of cooperation. When either of these constraints is not met it leads to the prevalence of commitment free-riders, such as those who commit only when someone else pays to arrange the commitments. Here, we show how intention recognition may circumvent such weakness of costly commitments. We describe an evolutionary model, in the context of the one-shot Prisoner's Dilemma, showing that if players first predict the intentions of their co-player and propose a commitment only when they are not confident enough about their prediction, the chances of reaching mutual cooperation are largely enhanced. We find that an advantageous synergy between intention recognition and costly commitments depends strongly on the confidence and accuracy of intention recognition. In general, we observe an intermediate level of confidence threshold leading to the highest evolutionary advantage, showing that neither unconditional use of commitment nor intention recognition can perform optimally. Rather, our results show that arranging commitments is not always desirable, but that they may be also unavoidable depending on the strength of the dilemma.

  19. Synergy between intention recognition and commitments in cooperation dilemmas

    PubMed Central

    Han, The Anh; Santos, Francisco C.; Lenaerts, Tom; Pereira, Luís Moniz

    2015-01-01

    Commitments have been shown to promote cooperation if, on the one hand, they can be sufficiently enforced, and on the other hand, the cost of arranging them is justified with respect to the benefits of cooperation. When either of these constraints is not met it leads to the prevalence of commitment free-riders, such as those who commit only when someone else pays to arrange the commitments. Here, we show how intention recognition may circumvent such weakness of costly commitments. We describe an evolutionary model, in the context of the one-shot Prisoner's Dilemma, showing that if players first predict the intentions of their co-player and propose a commitment only when they are not confident enough about their prediction, the chances of reaching mutual cooperation are largely enhanced. We find that an advantageous synergy between intention recognition and costly commitments depends strongly on the confidence and accuracy of intention recognition. In general, we observe an intermediate level of confidence threshold leading to the highest evolutionary advantage, showing that neither unconditional use of commitment nor intention recognition can perform optimally. Rather, our results show that arranging commitments is not always desirable, but that they may be also unavoidable depending on the strength of the dilemma. PMID:25791431

  20. Synergy between intention recognition and commitments in cooperation dilemmas.

    PubMed

    Han, The Anh; Santos, Francisco C; Lenaerts, Tom; Pereira, Luís Moniz

    2015-01-01

    Commitments have been shown to promote cooperation if, on the one hand, they can be sufficiently enforced, and on the other hand, the cost of arranging them is justified with respect to the benefits of cooperation. When either of these constraints is not met it leads to the prevalence of commitment free-riders, such as those who commit only when someone else pays to arrange the commitments. Here, we show how intention recognition may circumvent such weakness of costly commitments. We describe an evolutionary model, in the context of the one-shot Prisoner's Dilemma, showing that if players first predict the intentions of their co-player and propose a commitment only when they are not confident enough about their prediction, the chances of reaching mutual cooperation are largely enhanced. We find that an advantageous synergy between intention recognition and costly commitments depends strongly on the confidence and accuracy of intention recognition. In general, we observe an intermediate level of confidence threshold leading to the highest evolutionary advantage, showing that neither unconditional use of commitment nor intention recognition can perform optimally. Rather, our results show that arranging commitments is not always desirable, but that they may be also unavoidable depending on the strength of the dilemma. PMID:25791431

  1. Cardiac metastases

    PubMed Central

    Bussani, R; De‐Giorgio, F; Abbate, A; Silvestri, F

    2007-01-01

    Tumours metastatic to the heart (cardiac metastases) are among the least known and highly debated issues in oncology, and few systematic studies are devoted to this topic. Although primary cardiac tumours are extremely uncommon (various postmortem studies report rates between 0.001% and 0.28%), secondary tumours are not, and at least in theory, the heart can be metastasised by any malignant neoplasm able to spread to distant sites. In general, cardiac metastases are considered to be rare; however, when sought for, the incidence seems to be not as low as expected, ranging from 2.3% and 18.3%. Although no malignant tumours are known that diffuse preferentially to the heart, some do involve the heart more often than others—for example, melanoma and mediastinal primary tumours. This paper attempts to review the pathophysiology of cardiac metastatic disease, epidemiology and clinical presentation of cardiac metastases, and pathological characterisation of the lesions. PMID:17098886

  2. Indirubin-3'-oxime, an activator of Wnt/β-catenin signaling, enhances osteogenic commitment of ST2 cells and restores bone loss in high-fat diet-induced obese male mice.

    PubMed

    Zahoor, Muhammad; Cha, Pu-Hyeon; Choi, Kang-Yell

    2014-08-01

    Obesity is a growing issue of the modern world, and its negative impact on bones in obese male patients has been recently reported. The Wnt/β-catenin pathway has an established role in the regulation of body fat content and bone density. We investigated the effects of indirubin-3'-oxime (I3O), the GSK3β inhibitor that activates Wnt/β-catenin signaling, on trabecular bone in high-fat diet (HFD)-induced obese male mice. I3O reverses the downregulating effect of fatty acid (FA) on Wnt/β-catenin signaling and enhances the osteogenic commitment of the bone marrow-derived stromal cell line ST2. FA induces the adipogenic differentiation of bone marrow stromal cells in vitro. In a male mouse model of HFD-induced obesity, trabecular bone loss was observed in the femora, with a gross increase in abdominal fat; however, the HFD effects were rescued with the activation of Wnt/β-catenin signaling by I3O treatment. I3O administration also reversed the increase in the number of HFD-induced adipocytes in the femur bone marrow in trabecular bone. Overall, our results indicate that I3O could be a potential therapeutic agent for obese male patients through downregulation of abdominal fat and net increment in trabecular bone density. PMID:24815917

  3. Use of cardiac output to improve measurement of input function in quantitative dynamic contrast-enhanced MRI

    PubMed Central

    Zhang, Jeff L.; Rusinek, Henry; Bokacheva, Louisa; Chen, Qun; Storey, Pippa; Lee, Vivian S.

    2009-01-01

    Purpose: To validate a new method for converting MR arterial signal intensity versus time curves to arterial input functions (AIF). Materials and Methods: The method constrains AIF with patient's cardiac output (Q). Monte Carlo simulations of MR renography and tumor perfusion protocols were carried out for comparison with two alternative methods: direct measurement and population-averaged input function. MR renography was performed to assess the method's inter- and intra-day reproducibility for renal parameters. Results: In simulations of tumor perfusion, the precision of the parameters (Ktrans and ve) computed using the proposed method was improved by at least a factor of three compared to direct measurement. Similar improvements were obtained in simulations of MR renography. Volunteer study for testing inter-day reproducibility confirmed the improvement of precision in renal parameters when using the proposed method, compared to conventional methods. In another patient study (two injections within one session), the proposed method significantly increased the correlation coefficient (R) between GFR of the two exams (0.92 vs. 0.83), compared to direct measurement. Conclusion: A new method significantly improves the precision of DCE parameters. The method may be especially useful for analyzing repeated DCE examinations, such as monitoring tumor therapy or ACE-inhibitor renography. PMID:19711414

  4. Desmin enters the nucleus of cardiac stem cells and modulates Nkx2.5 expression by participating in transcription factor complexes that interact with the nkx2.5 gene

    PubMed Central

    Fuchs, Christiane; Gawlas, Sonja; Heher, Philipp; Nikouli, Sofia; Paar, Hannah; Ivankovic, Mario; Schultheis, Martina; Klammer, Julia; Gottschamel, Teresa; Capetanaki, Yassemi; Weitzer, Georg

    2016-01-01

    ABSTRACT The transcription factor Nkx2.5 and the intermediate filament protein desmin are simultaneously expressed in cardiac progenitor cells during commitment of primitive mesoderm to the cardiomyogenic lineage. Up-regulation of Nkx2.5 expression by desmin suggests that desmin may contribute to cardiogenic commitment and myocardial differentiation by directly influencing the transcription of the nkx2.5 gene in cardiac progenitor cells. Here, we demonstrate that desmin activates transcription of nkx2.5 reporter genes, rescues nkx2.5 haploinsufficiency in cardiac progenitor cells, and is responsible for the proper expression of Nkx2.5 in adult cardiac side population stem cells. These effects are consistent with the temporary presence of desmin in the nuclei of differentiating cardiac progenitor cells and its physical interaction with transcription factor complexes bound to the enhancer and promoter elements of the nkx2.5 gene. These findings introduce desmin as a newly discovered and unexpected player in the regulatory network guiding cardiomyogenesis in cardiac stem cells. PMID:26787680

  5. Experimental unconditionally secure bit commitment

    NASA Astrophysics Data System (ADS)

    Liu, Yang; Cao, Yuan; Curty, Marcos; Liao, Sheng-Kai; Wang, Jian; Cui, Ke; Li, Yu-Huai; Lin, Ze-Hong; Sun, Qi-Chao; Li, Dong-Dong; Zhang, Hong-Fei; Zhao, Yong; Chen, Teng-Yun; Peng, Cheng-Zhi; Zhang, Qiang; Cabello, Adan; Pan, Jian-Wei

    2014-03-01

    Quantum physics allows unconditionally secure communication between parties that trust each other. However, when they do not trust each other such as in the bit commitment, quantum physics is not enough to guarantee security. Only when relativistic causality constraints combined, the unconditional secure bit commitment becomes feasible. Here we experimentally implement a quantum bit commitment with relativistic constraints that offers unconditional security. The commitment is made through quantum measurements in two quantum key distribution systems in which the results are transmitted via free-space optical communication to two agents separated with more than 20 km. Bits are successfully committed with less than 5 . 68 ×10-2 cheating probability. This provides an experimental proof of unconditional secure bit commitment and demonstrates the feasibility of relativistic quantum communication.

  6. Imaging patients with cardiac trauma.

    PubMed

    Restrepo, Carlos S; Gutierrez, Fernando R; Marmol-Velez, Juan A; Ocazionez, Daniel; Martinez-Jimenez, Santiago

    2012-01-01

    In the United States, trauma is the leading cause of death among those who are 1-44 years old, with cardiovascular injuries representing the second most common cause of traumatic death after central nervous system injuries. Evaluation of trauma patients with suspected cardiac injury may be complex and include electrocardiography, measurement of cardiac biomarkers, and imaging examinations. Contrast material-enhanced computed tomography (CT) has become one of the most valuable imaging tools available for evaluating hemodynamically stable patients with suspected cardiac injury. The presence of hemopericardium, with or without cardiac tamponade, is one of the most significant findings of cardiac injury. Other complications that result from blunt cardiac injury, such as pericardial rupture and cardiac herniation, may be readily depicted at multidetector CT. Assessment of patients with cardiac injuries, particularly those with penetrating injuries, is a challenging and time-critical matter, with clinical and imaging findings having complementary roles in the formation of an accurate diagnosis. Patients who are hemodynamically stable, particularly those with penetrating cardiac injuries, also may benefit from a timely imaging examination. In addition to chest radiography, other available modalities such as transthoracic and transesophageal echocardiography, nuclear medicine, and magnetic resonance imaging may play a role in selected cases. PMID:22582351

  7. Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts

    PubMed Central

    Jain, Rajan; Li, Deqiang; Gupta, Mudit; Manderfield, Lauren J.; Ifkovits, Jamie L.; Wang, Qiaohong; Liu, Feiyan; Liu, Ying; Poleshko, Andrey; Padmanabhan, Arun; Raum, Jeffrey C.; Li, Li; Morrisey, Edward E.; Lu, Min Min; Won, Kyoung-Jae; Epstein, Jonathan A.

    2016-01-01

    Cardiac progenitor cells are multipotent and give rise to cardiac endothelium, smooth muscle, and cardiomyocytes. Here, we define and characterize the cardiomyoblast intermediate that is committed to the cardiomyocyte fate, and we characterize the niche signals that regulate commitment. Cardiomyoblasts express Hopx, which functions to coordinate local Bmp signals to inhibit the Wnt pathway, thus promoting cardiomyogenesis. Hopx integrates Bmp and Wnt signaling by physically interacting with activated Smads and repressing Wnt genes. The identification of the committed cardiomyoblast that retains proliferative potential will inform cardiac regenerative therapeutics. In addition, Bmp signals characterize adult stem cell niches in other tissues where Hopx-mediated inhibition of Wnt is likely to contribute to stem cell quiescence and to explain the role of Hopx as a tumor suppressor. PMID:26113728

  8. HEART DEVELOPMENT. Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts.

    PubMed

    Jain, Rajan; Li, Deqiang; Gupta, Mudit; Manderfield, Lauren J; Ifkovits, Jamie L; Wang, Qiaohong; Liu, Feiyan; Liu, Ying; Poleshko, Andrey; Padmanabhan, Arun; Raum, Jeffrey C; Li, Li; Morrisey, Edward E; Lu, Min Min; Won, Kyoung-Jae; Epstein, Jonathan A

    2015-06-26

    Cardiac progenitor cells are multipotent and give rise to cardiac endothelium, smooth muscle, and cardiomyocytes. Here, we define and characterize the cardiomyoblast intermediate that is committed to the cardiomyocyte fate, and we characterize the niche signals that regulate commitment. Cardiomyoblasts express Hopx, which functions to coordinate local Bmp signals to inhibit the Wnt pathway, thus promoting cardiomyogenesis. Hopx integrates Bmp and Wnt signaling by physically interacting with activated Smads and repressing Wnt genes. The identification of the committed cardiomyoblast that retains proliferative potential will inform cardiac regenerative therapeutics. In addition, Bmp signals characterize adult stem cell niches in other tissues where Hopx-mediated inhibition of Wnt is likely to contribute to stem cell quiescence and to explain the role of Hopx as a tumor suppressor. PMID:26113728

  9. Cardiac Lymphoma.

    PubMed

    Jeudy, Jean; Burke, Allen P; Frazier, Aletta Ann

    2016-07-01

    Lymphoma of the heart and pericardium may develop in up to 25% of patients with disseminated nodal disease, but primary cardiac lymphoma is rare. The majority are diffuse large B-cell lymphomas, which arise in immunocompetent older individuals, men twice as often as women. Subsets are found in immunocompromised patients, including those with HIV-AIDS or allograft recipients. Cardiac lymphomas tend to arise in the wall of the right heart, especially right atrium, with contiguous infiltration of epicardium and pericardium. Pericardial implants and effusions are common. The disease is often multifocal in the heart, but cardiac valves are usually spared. PMID:27265603

  10. 24 CFR 232.510 - Commitment and commitment fee.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 2 2011-04-01 2011-04-01 false Commitment and commitment fee. 232.510 Section 232.510 Housing and Urban Development Regulations Relating to Housing and Urban... HOUSING AND URBAN DEVELOPMENT MORTGAGE AND LOAN INSURANCE PROGRAMS UNDER NATIONAL HOUSING ACT AND...

  11. Cardiac rehabilitation

    MedlinePlus

    ... 123-210. Thomas PD. Exercise-Based, Comprehensive Cardiac Rehabilitation. In: Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 9th ed. Philadelphia, PA: Saunders Elsevier; 2011: ...

  12. Cardiac rehabilitation

    MedlinePlus

    ... goal of cardiac rehab is to: Improve your cardiovascular function Improve your overall health and quality of ... E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine . 10th ed. Philadelphia, PA: Elsevier Saunders; 2015: ...

  13. Cardiac arrest

    MedlinePlus

    ... treatment for cardiac arrest. It is a medical device that gives an electrical shock to the heart. The shock can get the heart beating normally again. Small, portable defibrillators are often available in public areas for ...

  14. Cardiac amyloidosis

    MedlinePlus

    ... the way electrical signals move through the heart (conduction system). This can lead to abnormal heart beats ( ... due to medication) Sick sinus syndrome Symptomatic cardiac conduction system disease (arrhythmias related to abnormal conduction of ...

  15. Cardiac Sarcoidosis

    MedlinePlus

    ... is Cardiac Sarcoidosis? Sarcoidosis is a poorly understood disease that commonly affects the lungs. It can also involve the lymph nodes, liver, spleen, eyes, skin, bones, salivary glands and heart. ...

  16. Organizational Commitment as Symbolic Process.

    ERIC Educational Resources Information Center

    Larkey, Linda; Morrill, Calvin

    1995-01-01

    Offers a processual (sic) approach suited to the complex nature of organizational commitment during times of radical change. Emphasizes commitment as communication processes that are integrally tied to the creation of organizational cultures, involve identification via symbolic processes, and encompass various degrees of linkages between…

  17. Work empowerment and organizational commitment.

    PubMed

    McDermott, K; Laschinger, H K; Shamian, J

    1996-05-01

    As organizations struggle to deliver the same level and quality of services with fewer resources, administrators are challenged with redesigning workplaces to maximize nurses' commitment. This study used Kanter's Structural Theory of Organizational Behavior to examine the relationship between job-related empowerment perceptions of staff nurses and their commitment to the organization. Strategies for creating more empowered work environments are discussed. PMID:8710344

  18. Organizational Climate and Teacher Commitment

    ERIC Educational Resources Information Center

    Douglas, Stephen Michael

    2010-01-01

    This study examined the relationship of school climate and teacher commitment in elementary schools in Alabama. A total of 67 elementary schools were surveyed and 1353 teachers voluntarily participated in the study. The instruments used in this study were the Organizational Climate Index (OCI) and the Organizational Commitment Questionnaire (OCQ).…

  19. The Measurement of Organizational Commitment.

    ERIC Educational Resources Information Center

    Mowday, Richard T.; And Others

    1979-01-01

    This paper summarizes a stream of research aimed at developing and validating a measure of employee commitment to work organizations. The instrument, developed by Porter and his colleagues, is called the Organizational Commitment Questionnaire. Satisfactory test-retest reliabilities and internal consistency reliabilities were found. (Author)

  20. Experimental Unconditionally Secure Bit Commitment

    NASA Astrophysics Data System (ADS)

    Liu, Yang; Cao, Yuan; Curty, Marcos; Liao, Sheng-Kai; Wang, Jian; Cui, Ke; Li, Yu-Huai; Lin, Ze-Hong; Sun, Qi-Chao; Li, Dong-Dong; Zhang, Hong-Fei; Zhao, Yong; Chen, Teng-Yun; Peng, Cheng-Zhi; Zhang, Qiang; Cabello, Adán; Pan, Jian-Wei

    2014-01-01

    Quantum physics allows for unconditionally secure communication between parties that trust each other. However, when the parties do not trust each other such as in the bit commitment scenario, quantum physics is not enough to guarantee security unless extra assumptions are made. Unconditionally secure bit commitment only becomes feasible when quantum physics is combined with relativistic causality constraints. Here we experimentally implement a quantum bit commitment protocol with relativistic constraints that offers unconditional security. The commitment is made through quantum measurements in two quantum key distribution systems in which the results are transmitted via free-space optical communication to two agents separated with more than 20 km. The security of the protocol relies on the properties of quantum information and relativity theory. In each run of the experiment, a bit is successfully committed with less than 5.68×10-2 cheating probability. This demonstrates the experimental feasibility of quantum communication with relativistic constraints.

  1. Experimental unconditionally secure bit commitment.

    PubMed

    Liu, Yang; Cao, Yuan; Curty, Marcos; Liao, Sheng-Kai; Wang, Jian; Cui, Ke; Li, Yu-Huai; Lin, Ze-Hong; Sun, Qi-Chao; Li, Dong-Dong; Zhang, Hong-Fei; Zhao, Yong; Chen, Teng-Yun; Peng, Cheng-Zhi; Zhang, Qiang; Cabello, Adán; Pan, Jian-Wei

    2014-01-10

    Quantum physics allows for unconditionally secure communication between parties that trust each other. However, when the parties do not trust each other such as in the bit commitment scenario, quantum physics is not enough to guarantee security unless extra assumptions are made. Unconditionally secure bit commitment only becomes feasible when quantum physics is combined with relativistic causality constraints. Here we experimentally implement a quantum bit commitment protocol with relativistic constraints that offers unconditional security. The commitment is made through quantum measurements in two quantum key distribution systems in which the results are transmitted via free-space optical communication to two agents separated with more than 20 km. The security of the protocol relies on the properties of quantum information and relativity theory. In each run of the experiment, a bit is successfully committed with less than 5.68×10(-2) cheating probability. This demonstrates the experimental feasibility of quantum communication with relativistic constraints. PMID:24483878

  2. Contexts as Shared Commitments

    PubMed Central

    García-Carpintero, Manuel

    2015-01-01

    Contemporary semantics assumes two influential notions of context: one coming from Kaplan (1989), on which contexts are sets of predetermined parameters, and another originating in Stalnaker (1978), on which contexts are sets of propositions that are “common ground.” The latter is deservedly more popular, given its flexibility in accounting for context-dependent aspects of language beyond manifest indexicals, such as epistemic modals, predicates of taste, and so on and so forth; in fact, properly dealing with demonstratives (perhaps ultimately all indexicals) requires that further flexibility. Even if we acknowledge Lewis (1980)'s point that, in a sense, Kaplanian contexts already include common ground contexts, it is better to be clear and explicit about what contexts constitutively are. Now, Stalnaker (1978, 2002, 2014) defines context-as-common-ground as a set of propositions, but recent work shows that this is not an accurate conception. The paper explains why, and provides an alternative. The main reason is that several phenomena (presuppositional treatments of pejoratives and predicates of taste, forces other than assertion) require that the common ground includes non-doxastic attitudes such as appraisals, emotions, etc. Hence the common ground should not be taken to include merely contents (propositions), but those together with attitudes concerning them: shared commitments, as I will defend. PMID:26733087

  3. Contexts as Shared Commitments.

    PubMed

    García-Carpintero, Manuel

    2015-01-01

    Contemporary semantics assumes two influential notions of context: one coming from Kaplan (1989), on which contexts are sets of predetermined parameters, and another originating in Stalnaker (1978), on which contexts are sets of propositions that are "common ground." The latter is deservedly more popular, given its flexibility in accounting for context-dependent aspects of language beyond manifest indexicals, such as epistemic modals, predicates of taste, and so on and so forth; in fact, properly dealing with demonstratives (perhaps ultimately all indexicals) requires that further flexibility. Even if we acknowledge Lewis (1980)'s point that, in a sense, Kaplanian contexts already include common ground contexts, it is better to be clear and explicit about what contexts constitutively are. Now, Stalnaker (1978, 2002, 2014) defines context-as-common-ground as a set of propositions, but recent work shows that this is not an accurate conception. The paper explains why, and provides an alternative. The main reason is that several phenomena (presuppositional treatments of pejoratives and predicates of taste, forces other than assertion) require that the common ground includes non-doxastic attitudes such as appraisals, emotions, etc. Hence the common ground should not be taken to include merely contents (propositions), but those together with attitudes concerning them: shared commitments, as I will defend. PMID:26733087

  4. Who commits matricide?

    PubMed

    Singhal, S; Dutta, A

    1992-07-01

    The authors studied sixteen men who committed matricide. Fifteen out of sixteen cases had a diagnosis of schizophrenia and the remaining patient had a diagnosis of schizophrenia with personality disorder. All were single at the time of the matricide. Data indicate an intense conflict-laden and ambivalent relationship between the majority of patients with their mothers. Thirteen out of sixteen cases described their mothers as quite domineering and demanding but the EMBU inventory revealed that the Matricidal group differed from the Control group in how tolerant they saw their parents. The sample as a whole saw mothers were more over-involved, overprotective, tolerant, affectionate, stimulating, performance-orientated and shaming. The matricidal group differed from the control group in the way they viewed the difference between mother and father on various scales, like over-involved, tolerant, affectionate and performance-orientated. The matricidal groups' mothers were found to be more over-involved, tolerant, affectionate, and fathers more abusive. Mothers in the control group were more performance-orientated. PMID:1513219

  5. Detection of cardiac biomarkers exploiting surface enhanced Raman scattering (SERS) using a nanofluidic channel based biosensor towards coronary point-of-care diagnostics

    NASA Astrophysics Data System (ADS)

    Benford, Melodie E.; Wang, Miao; Kameoka, Jun; Coté, Gerard L.

    2009-02-01

    According to the World Health Organization, cardiovascular disease is the most common cause of death in the world. In the US, over 115 million people visit the emergency department (ED), 5 million of which may have acute coronary syndrome (ACS). Cardiac biomarkers can provide early identification and diagnosis of ACS, and can provide information on the prognosis of the patient by assessing the risk of death. In addition, the biomarkers can serve as criteria for admission, indicate possibility of re-infarction, or eliminate ACS as a diagnosis altogether. We propose a SERSbased multi-marker approach towards a point-of-care diagnostic system for ACS. Using a nanofluidic device consisting of a microchannel leading into a nanochannel, we formed SERS active sites by mechanically aggregating gold particles (60 nm) at the entrance to the nanochannel (40nm×1μm). The induced capillary flow produces a high density of aggregated nanoparticles at this precise region, creating areas with enhanced electromagnetic fields within the aggregates, shifting the plasmon resonance to the near infrared region, in resonance with incident laser wavelength. With this robust sensing platform, we were able to obtain qualitative information of brain natriuretic peptide (biomarker of ventricular dysfunction or pulmonary stress), troponin I (biomarker of myocardial necrosis), and C-reactive protein (biomarker of inflammation potentially caused by atherosclerosis).

  6. Muscle-Specific Splicing of a Heterologous Exon Mediated by a Single Muscle-Specific Splicing Enhancer from the Cardiac Troponin T Gene

    PubMed Central

    Cooper, Thomas A.

    1998-01-01

    The chicken cardiac troponin T (cTNT) gene contains a single 30-nucleotide alternative exon that is included in embryonic striated muscle and skipped in the adult. Transient-transfection analysis of cTNT minigenes in muscle and fibroblast cell cultures previously identified four muscle-specific splicing enhancers (MSEs) that promote exon inclusion specifically in embryonic striated muscle cultures. Three MSEs located in the intron downstream from the alternative exon were sufficient for muscle-specific exon inclusion. In the present study, the boundaries of these MSEs were defined by scanning mutagenesis, allowing analysis of individual elements in gain-of-function experiments. Concatamers of MSE2 were necessary and sufficient to promote muscle-specific inclusion of a heterologous exon, indicating that it is a target for muscle-specific regulation. Sequences present in MSE2 are also found in MSE4, suggesting that these two MSEs act in a similar manner. MSE3 appears to be different from MSE2 and MSE4 yet is able to functionally replace both of these elements, demonstrating functional redundancy of elements that are likely to bind different factors. MSE2 and MSE4 each contain a novel sequence motif that is found adjacent to a number of alternative exons that undergo regulated splicing in striated muscle, suggesting a common role for this element in muscle-specific regulation. PMID:9671461

  7. Hydroxychloroquine Protects against Cardiac Ischaemia/Reperfusion Injury In Vivo via Enhancement of ERK1/2 Phosphorylation

    PubMed Central

    Bourke, Lauren; McCormick, James; Taylor, Valerie; Pericleous, Charis; Blanchet, Benoit; Costedoat-Chalumeau, Nathalie; Stuckey, Daniel; Lythgoe, Mark F.; Stephanou, Anastasis; Ioannou, Yiannis

    2015-01-01

    An increasing number of investigations including human studies demonstrate that pharmacological ischaemic preconditioning is a viable way to protect the heart from myocardial ischaemia/reperfusion (I/R) injury. This study investigated the role of hydroxychloroquine (HCQ) in the heart during I/R injury. In vitro and in vivo models of myocardial I/R injury were used to assess the effects of HCQ. It was found that HCQ was protective in neonatal rat cardiomyocytes through inhibition of apoptosis, measured by TUNEL and cleaved caspase-3. This protection in vitro was mediated through enhancement of ERK1/2 phosphorylation mediated by HCQ in a dose-dependent fashion. A decrease in infarct size was observed in an in vivo model of myocardial I/R injury in HCQ treated animals and furthermore this protection was blocked in the presence of the ERK1/2 inhibitor U0126. For the first time, we have shown that HCQ promotes a preconditioning like protection in an in vivo simulated rat myocardial I/R injury model. Moreover, it was shown that HCQ is protective via enhanced phosphorylation of the pro-survival kinase ERK1/2. PMID:26636577

  8. Acceptance and Commitment: Implications for Prevention Science

    PubMed Central

    Biglan, Anthony; Hayes, Steven C.; Pistorello, Jacqueline

    2009-01-01

    Recent research in behavior analysis and clinical psychology points to the importance of language processes having to do with the control of negative cognition and emotion and the commitment to valued action. Efforts to control unwanted thoughts and feelings, also referred to as experiential avoidance, appear to be associated with a diverse array of psychological and behavioral difficulties. Recent research shows that interventions that reduce experiential avoidance (EA) and help people to identify and commit to the pursuit of valued directions is beneficial for ameliorating diverse problems in living. These developments have the potential to improve the efficacy of many preventive interventions. This paper reviews the basic findings in these areas and points to some ways in which these developments could enhance the impact of preventive interventions. PMID:18690535

  9. Diagnostic accuracy of late iodine enhancement on cardiac computed tomography with a denoise filter for the evaluation of myocardial infarction.

    PubMed

    Matsuda, Takuya; Kido, Teruhito; Itoh, Toshihide; Saeki, Hideyuki; Shigemi, Susumu; Watanabe, Kouki; Kido, Tomoyuki; Aono, Shoji; Yamamoto, Masaya; Matsuda, Takeshi; Mochizuki, Teruhito

    2015-12-01

    We evaluated the image quality and diagnostic performance of late iodine enhancement (LIE) in dual-source computed tomography (DSCT) with low kilo-voltage peak (kVp) images and a denoise filter for the detection of acute myocardial infarction (AMI) in comparison with late gadolinium enhancement (LGE) magnetic resonance imaging (MRI). The Hospital Ethics Committee approved the study protocol. Before discharge, 19 patients who received percutaneous coronary intervention after AMI underwent DSCT and 1.5 T MRI. Immediately after coronary computed tomography (CT) angiography, contrast medium was administered at a slow injection rate. LIE-CT scans were acquired via dual-energy CT and reconstructed as 100-, 140-kVp, and mixed images. An iterative three-dimensional edge-preserved smoothing filter was applied to the 100-kVp images to obtain denoised 100-kVp images. The mixed, 140-kVp, 100-kVp, and denoised 100-kVp images were assessed using contrast-to-noise ratio (CNR), and their diagnostic performance in comparison with MRI and infarcted volumes were evaluated. Three hundred four segments of 19 patients were evaluated. Fifty-three segments showed LGE in MRI. The median CNR of the mixed, 140-, 100-kVp and denoised 100-kVp images was 3.49, 1.21, 3.57, and 6.08, respectively. The median CNR was significantly higher in the denoised 100-kVp images than in the other three images (P < 0.05). The denoised 100-kVp images showed the highest diagnostic accuracy and sensitivity. The percentage of myocardium in the four CT image types was significantly correlated with the respective MRI findings. The use of a denoise filter with a low-kVp image can improve CNR, sensitivity, and accuracy in LIE-CT. PMID:26202159

  10. Cross-talk between glycogen synthase kinase 3β (GSK3β) and p38MAPK regulates myocyte enhancer factor 2 (MEF2) activity in skeletal and cardiac muscle.

    PubMed

    Dionyssiou, M G; Nowacki, N B; Hashemi, S; Zhao, J; Kerr, A; Tsushima, R G; McDermott, J C

    2013-01-01

    Characterizing the signaling network that controls MEF2 transcription factors is crucial for understanding skeletal and cardiac muscle gene expression. Glycogen synthase kinase 3β (GSK3β) regulates MEF2 activity indirectly through reciprocal regulation of p38MAPK. Cross-talk between GSK3β and p38MAPK regulates MEF2 activity in skeletal and cardiac muscle. Understanding cross-talk in the signaling network converging at MEF2 control has therapeutic implications in cardiac and skeletal muscle pathology. Glycogen synthase kinase 3β (GSK3β) is a known regulator of striated muscle gene expression suppressing both myogenesis and cardiomyocyte hypertrophy. Since myocyte enhancer factor 2 (MEF2) proteins are key transcriptional regulators in both systems, we assessed whether MEF2 is a target for GSK3β. Pharmacological inhibition of GSK3β resulted in enhanced MEF2A/D expression and transcriptional activity in skeletal myoblasts and cardiac myocytes. Even though in silico analysis revealed GSK3β consensus (S/T)XXX(S/T) sites on MEF2A, a subsequent in vitro kinase assay revealed that MEF2A is only a weak substrate. However, we did observe a posttranslational modification in MEF2A in skeletal myoblasts treated with a GSK3β inhibitor which coincided with increased p38MAPK phosphorylation, a potent MEF2A activator, indicating that GSK3β inhibition may de-repress p38MAPK. Heart specific excision of GSK3β in mice also resulted in up-regulation of p38MAPK activity. Interestingly, upon pharmacological p38MAPK inhibition (SB203580), GSK3β inhibition loses its effect on MEF2 transcriptional activity suggesting potent cross-talk between the two pathways. Thus we have documented that cross-talk between p38MAPK and GSK3β signaling converges on MEF2 activity having potential consequences for therapeutic modulation of cardiac and skeletal muscle gene expression. PMID:23137781

  11. Cardiac Sarcoidosis.

    PubMed

    Birnie, David H; Nery, Pablo B; Ha, Andrew C; Beanlands, Rob S B

    2016-07-26

    Clinically manifest cardiac involvement occurs in perhaps 5% of patients with sarcoidosis. The 3 principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. An estimated 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic cardiac involvement (clinically silent disease). In 2014, the first international guideline for the diagnosis and management of CS was published. In patients with clinically manifest CS, the extent of left ventricular dysfunction seems to be the most important predictor of prognosis. There is controversy in published reports as to the outcome of patients with clinically silent CS. Despite a paucity of data, immunosuppression therapy (primarily with corticosteroids) has been advocated for the treatment of clinically manifest CS. Device therapy, primarily with implantable cardioverter-defibrillators, is often recommended for patients with clinically manifest disease. PMID:27443438

  12. Arbitrarily Long Relativistic Bit Commitment

    NASA Astrophysics Data System (ADS)

    Chakraborty, Kaushik; Chailloux, André; Leverrier, Anthony

    2015-12-01

    We consider the recent relativistic bit commitment protocol introduced by Lunghi et al. [Phys. Rev. Lett. 115, 030502 (2015)] and present a new security analysis against classical attacks. In particular, while the initial complexity of the protocol scales double exponentially with the commitment time, our analysis shows that the correct dependence is only linear. This has dramatic implications in terms of implementation: in particular, the commitment time can easily be made arbitrarily long, by only requiring both parties to communicate classically and perform efficient classical computation.

  13. Cardiac sarcoidosis

    PubMed Central

    Smedema, J.P.; Zondervan, P.E.; van Hagen, P.; ten Cate, F.J.; Bresser, P.; Doubell, A.F.; Pattynama, P.; Hoogsteden, H.C.; Balk, A.H.M.M.

    2002-01-01

    Sarcoidosis is a multi-system granulomatous disorder of unknown aetiology. Symptomatic cardiac involvement occurs in approximately 5% of patients. The prevalence of sarcoidosis in the Netherlands is unknown, but estimated to be approximately 20 per 100,000 population (3200 patients). We report on five patients who presented with different manifestations of cardiac sarcoidosis, and give a brief review on the current management of this condition. Magnetic Resonance Imaging (MRI) can be of great help in diagnosing this condition as well as in the follow-up of the response to therapy. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6 PMID:25696121

  14. Activation of GATA4 gene expression at the early stage of cardiac specification

    NASA Astrophysics Data System (ADS)

    Yilbas, Ayse; Hamilton, Alison; Wang, Yingjian; Mach, Hymn; Lacroix, Natascha; Davis, Darryl; Chen, Jihong; LI, Qiao

    2014-03-01

    Currently, there are no effective treatments to directly repair damaged heart tissue after cardiac injury since existing therapies focus on rescuing or preserving reversibly damaged tissue. Cell-based therapies using cardiomyocytes generated from stem cells present a promising therapeutic approach to directly replace damaged myocardium with new healthy tissue. However, the molecular mechanisms underlying the commitment of stem cells into cardiomyocytes are not fully understood and will be critical to guide this new technology into the clinic. Since GATA4 is a critical regulator of cardiac differentiation, we examined the molecular basis underlying the early activation of GATA4 gene expression during cardiac differentiation of pluripotent stem cells. Our studies demonstrate the direct involvement of histone acetylation and transcriptional coactivator p300 in the regulation of GATA4 gene expression. More importantly, we show that histone acetyltransferase (HAT) activity is important for GATA4 gene expression with the use of curcumin, a HAT inhibitor. In addition, the widely used histone deacetylase inhibitor valproic acid enhances both histone acetylation and cardiac specification.

  15. Mesodermal iPSC–derived progenitor cells functionally regenerate cardiac and skeletal muscle

    PubMed Central

    Quattrocelli, Mattia; Swinnen, Melissa; Giacomazzi, Giorgia; Camps, Jordi; Barthélemy, Ines; Ceccarelli, Gabriele; Caluwé, Ellen; Grosemans, Hanne; Thorrez, Lieven; Pelizzo, Gloria; Muijtjens, Manja; Verfaillie, Catherine M.; Blot, Stephane; Janssens, Stefan; Sampaolesi, Maurilio

    2015-01-01

    Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles. PMID:26571398

  16. Enhanced extravasation, stability and in vivo cardiac gene silencing via in situ siRNA-albumin conjugation.

    PubMed

    Lau, Shannen; Graham, Bim; Cao, Nga; Boyd, Ben J; Pouton, Colin W; White, Paul J

    2012-01-01

    A potential barrier to progression of siRNA therapeutics to the clinic is the ability of these agents to cross the vascular endothelium to reach target cells. This study aimed to bypass the endothelial barrier by harnessing the extravasation capability of the serum protein albumin to allow siRNA to reach cardiomyocytes. A strategy for conjugating siRNA to albumin in vivo was developed that involved activating 3'-amine, 2'-O-methyl, phosphorothioate modified siRNA with succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (SMCC) to yield maleimide-functionalized siRNA ("activated siRNA"); this thiol-reactive species can then irreversibly link to the single surface-exposed cysteine residue of endogenous albumin following intravenous administration. An IGF-I-receptor (IGF-IR) siRNA sequence which was effective in vitro was used to test the ability of the siRNA-albumin conjugate to bypass the endothelial barrier in Balb/C mice and produce silencing. In situ conjugation of maleimide-functionalized siRNA to albumin in mouse serum occurred within minutes of addition, and the resulting conjugate was found to be nuclease stable by SDS-PAGE analysis. In Sprague-Dawley rats, activated siRNA showed a significantly enhanced elimination half-life (75.9 ± 18.2 min) compared to unactivated siRNA (5.1 ± 0.2 min). Intravenous injection of this activated siRNA (1 mg/kg daily for four days) significantly reduced left ventricle IGF-IR mRNA to 64.1 ± 4.1% of that in vehicle-treated animals (mean ± SEM), while the control siRNA (unconjugated) had no effect (n = 4, P > 0.05). Imaging of microvessels from mice treated with fluorescein-labeled activated siRNA showed clear evidence of extravasation and cellular uptake in capillary endothelial cells, cardiomyocytes and vascular smooth muscle cells for mice treated with the activated siRNA but not mice treated with the unactivated siRNA. siRNA-albumin constructs are therefore capable of extravasation to the myocardium resulting in

  17. Antimicrobial innovation: combining commitment, creativity and coherence.

    PubMed

    van der Meer, Jos W M; Fears, Robin; Davies, Sally C; ter Meulen, Volker

    2014-10-01

    Enhanced antibiotic innovation depends on many things--defining and validating new and better targets, resourcing and facilitating high-quality preclinical and clinical research, streamlining regulation and solving market problems so as to provide incentives to the private sector. Further detail is provided in our recent report (see further information). Acting on these critical steps in concert to provide long-term solutions requires that urgent attention be paid to tackling policy disconnects. Sustaining the political commitment depends on raising the visibility of the problems and their solutions worldwide. The academies of science in the EU recognize their continuing responsibility to help do this. PMID:25270944

  18. O-GlcNAcylation Negatively Regulates Cardiomyogenic Fate in Adult Mouse Cardiac Mesenchymal Stromal Cells.

    PubMed

    Zafir, Ayesha; Bradley, James A; Long, Bethany W; Muthusamy, Senthilkumar; Li, Qianhong; Hill, Bradford G; Wysoczynski, Marcin; Prabhu, Sumanth D; Bhatnagar, Aruni; Bolli, Roberto; Jones, Steven P

    2015-01-01

    In both preclinical and clinical studies, cell transplantation of several cell types is used to promote repair of damaged organs and tissues. Nevertheless, despite the widespread use of such strategies, there remains little understanding of how the efficacy of cell therapy is regulated. We showed previously that augmentation of a unique, metabolically derived stress signal (i.e., O-GlcNAc) improves survival of cardiac mesenchymal stromal cells; however, it is not known whether enhancing O-GlcNAcylation affects lineage commitment or other aspects of cell competency. In this study, we assessed the role of O-GlcNAc in differentiation of cardiac mesenchymal stromal cells. Exposure of these cells to routine differentiation protocols in culture increased markers of the cardiomyogenic lineage such as Nkx2.5 and connexin 40, and augmented the abundance of transcripts associated with endothelial and fibroblast cell fates. Differentiation significantly decreased the abundance of O-GlcNAcylated proteins. To determine if O-GlcNAc is involved in stromal cell differentiation, O-GlcNAcylation was increased pharmacologically during the differentiation protocol. Although elevated O-GlcNAc levels did not significantly affect fibroblast and endothelial marker expression, acquisition of cardiomyocyte markers was limited. In addition, increasing O-GlcNAcylation further elevated smooth muscle actin expression. In addition to lineage commitment, we also evaluated proliferation and migration, and found that increasing O-GlcNAcylation did not significantly affect either; however, we found that O-GlcNAc transferase--the protein responsible for adding O-GlcNAc to proteins--is at least partially required for maintaining cellular proliferative and migratory capacities. We conclude that O-GlcNAcylation contributes significantly to cardiac mesenchymal stromal cell lineage and function. O-GlcNAcylation and pathological conditions that may affect O-GlcNAc levels (such as diabetes) should be

  19. Endogenous Mechanisms of Cardiac Regeneration.

    PubMed

    Xiang, M S W; Kikuchi, K

    2016-01-01

    Zebrafish possess a remarkable capacity for cardiac regeneration throughout their lifetime, providing a model for investigating endogenous cellular and molecular mechanisms regulating myocardial regeneration. By contrast, adult mammals have an extremely limited capacity for cardiac regeneration, contributing to mortality and morbidity from cardiac diseases such as myocardial infarction and heart failure. However, the viewpoint of the mammalian heart as a postmitotic organ was recently revised based on findings that the mammalian heart contains multiple undifferentiated cell types with cardiogenic potential as well as a robust regenerative capacity during a short period early in life. Although it occurs at an extremely low level, continuous cardiomyocyte turnover has been detected in adult mouse and human hearts, which could potentially be enhanced to restore lost myocardium in damaged human hearts. This review summarizes and discusses recent advances in the understanding of endogenous mechanisms of cardiac regeneration. PMID:27572127

  20. Risk stratification for major adverse cardiac events and ventricular tachyarrhythmias by cardiac MRI in patients with cardiac sarcoidosis

    PubMed Central

    Yasuda, Masakazu; Iwanaga, Yoshitaka; Kato, Takao; Izumi, Toshiaki; Inuzuka, Yasutaka; Nakamura, Takashi; Miyaji, Yuki; Kawamura, Takayuki; Ikeguchi, Shigeru; Inoko, Moriaki; Kurita, Takashi; Miyazaki, Shunichi

    2016-01-01

    Background The presence of myocardial fibrosis by cardiac MRI has prognostic value in cardiac sarcoidosis, and localisation may be equally relevant to clinical outcomes. Objective We aimed to analyse cardiac damage and function in detail and explore the relationship with clinical outcomes in patients with cardiac sarcoidosis using cardiac MRI. Methods We included 81 consecutive patients with cardiac sarcoidosis undergoing cardiac MR. Left ventricular mass and fibrosis mass were calculated, and localisation was analysed using a 17-segment model. Participants underwent follow-up through 2015, and the development of major adverse cardiac events including ventricular tachyarrhythmias was recorded. Results Increased left ventricular fibrosis mass was associated with increased prevalence of ventricular tachyarrhythmias (p<0.001). When localisation was defined as the sum of late gadolinium enhancement in the left ventricular basal anterior and basal anteroseptal areas, or the right ventricular area, it was associated with ventricular tachyarrhythmias (p<0.001). Kaplan-Meier analysis during a median follow-up of 22.1 months showed that both the mass and localisation groupings for fibrosis were significantly associated with major adverse cardiac events or ventricular tachyarrhythmias and that when combined, the risk stratification was better than for each variable alone (p<0.001, respectively). By Cox-proportional hazard risk analysis, the localisation grouping was an independent predictor for the both. Conclusions In patients with cardiac sarcoidosis, both fibrosis mass and its localisation to the basal anterior/anteroseptal left ventricle, or right ventricle was associated with the development of major adverse cardiac events or ventricular tachyarrhythmias. Cardiac MR with late gadolinium enhancement may be useful for improving risk stratification in patients with cardiac sarcoidosis. PMID:27547432

  1. Epigenetic mechanisms in cardiac development and disease.

    PubMed

    Vallaster, Marcus; Vallaster, Caroline Dacwag; Wu, Sean M

    2012-01-01

    During mammalian development, cardiac specification and ultimately lineage commitment to a specific cardiac cell type is accomplished by the action of specific transcription factors (TFs) and their meticulous control on an epigenetic level. In this review, we detail how cardiac-specific TFs function in concert with nucleosome remodeling and histone-modifying enzymes to regulate a diverse network of genes required for processes such as cell growth and proliferation, or epithelial to mesenchymal transition (EMT), for instance. We provide examples of how several cardiac TFs, such as Nkx2.5, WHSC1, Tbx5, and Tbx1, which are associated with developmental and congenital heart defects, are required for the recruitment of histone modifiers, such as Jarid2, p300, and Ash2l, and components of ATP-dependent remodeling enzymes like Brg1, Baf60c, and Baf180. Binding of these TFs to their respective sites at cardiac genes coincides with a distinct pattern of histone marks, indicating that the precise regulation of cardiac gene networks is orchestrated by interactions between TFs and epigenetic modifiers. Furthermore, we speculate that an epigenetic signature, comprised of TF occupancy, histone modifications, and overall chromatin organization, is an underlying mechanism that governs cardiac morphogenesis and disease. PMID:22194017

  2. Human Embryonic Stem Cells and Cardiac Repair

    PubMed Central

    Zhu, Wei-Zhong; Hauch, Kip; Xu, Chunhui; Laflamme, Michael A.

    2008-01-01

    The muscle lost after a myocardial infarction is replaced with non-contractile scar tissue, often initiating heart failure. Whole-organ cardiac transplantation is the only currently available clinical means of replacing the lost muscle, but this option is limited by the inadequate supply of donor hearts. Thus, cell-based cardiac repair has attracted considerable interest as an alternative means of ameliorating cardiac injury. Because of their tremendous capacity for expansion and unquestioned cardiac potential, pluripotent human embryonic stem cells (hESCs) represent an attractive candidate cell source for obtaining cardiomyocytes and other useful mesenchymal cell types for such therapies. hESC-derived cardiomyocytes (hESC-CMs) exhibit a committed cardiac phenotype and robust proliferative capacity, and recent testing in rodent infarct models indicates that they can partially remuscularize injured hearts and improve contractile function. Although the latter successes give good reason for optimism, considerable challenges remain to the successful application of hESCs to cardiac repair, including the need for preparations of high cardiac purity, improved methods of delivery, and approaches to overcome immune rejection and other causes of graft cell death. This review will describe the phenotype of hESC-CMs and preclinical experience with these cells and will consider strategies to overcoming the aforementioned challenges. PMID:18657407

  3. Our commitment to quality

    SciTech Connect

    1995-05-01

    The Office of Science Education and Technical Information (OSETI) provides leadership in leveraging the Department of Energy`s (DOE) unique scientific and technical resources to enhance the United States (U.S.) global competitiveness and the development of a diverse, well-educated, scientifically literate workforce. The Office provides scientific and technical information management policy, guidance, and services, as well as education program assistance, to a wide range of customers to help the Department contribute to the Nation`s welfare. OSETI was established in July 1993 within the Science and Technology cluster. The Office has two subcomponents, the Office of Scientific and Technical Information (OSTI), located in Oak Ridge, Tennessee, and the Office of Science Education Programs (OSEP), located in Washington, D.C. (see organization chart on page 5). OSTI, the larger of the two offices, has 164 full-time equivalent (FTE) federal staff and 100 contractor employees, while OSEP has 21 federal and 5 contractor employees.

  4. Antecedents and Outcomes of Career Commitment.

    ERIC Educational Resources Information Center

    Aryee, Samuel; Tan, Kevin

    1992-01-01

    A model of antecedents and outcomes of career commitment was tested with data from 510 of 650 Singaporean teachers and nurses surveyed. The model did not fit the data: career satisfaction did not affect career commitment directly or indirectly through organizational commitment. Career commitment was not significantly related to work quality. (SK)

  5. Cardiac optogenetics

    PubMed Central

    2013-01-01

    Optogenetics is an emerging technology for optical interrogation and control of biological function with high specificity and high spatiotemporal resolution. Mammalian cells and tissues can be sensitized to respond to light by a relatively simple and well-tolerated genetic modification using microbial opsins (light-gated ion channels and pumps). These can achieve fast and specific excitatory or inhibitory response, offering distinct advantages over traditional pharmacological or electrical means of perturbation. Since the first demonstrations of utility in mammalian cells (neurons) in 2005, optogenetics has spurred immense research activity and has inspired numerous applications for dissection of neural circuitry and understanding of brain function in health and disease, applications ranging from in vitro to work in behaving animals. Only recently (since 2010), the field has extended to cardiac applications with less than a dozen publications to date. In consideration of the early phase of work on cardiac optogenetics and the impact of the technique in understanding another excitable tissue, the brain, this review is largely a perspective of possibilities in the heart. It covers the basic principles of operation of light-sensitive ion channels and pumps, the available tools and ongoing efforts in optimizing them, overview of neuroscience use, as well as cardiac-specific questions of implementation and ideas for best use of this emerging technology in the heart. PMID:23457014

  6. Cardiac Surgery

    PubMed Central

    Weisse, Allen B.

    2011-01-01

    Well into the first decades of the 20th century, medical opinion held that any surgical attempts to treat heart disease were not only misguided, but unethical. Despite such reservations, innovative surgeons showed that heart wounds could be successfully repaired. Then, extracardiac procedures were performed to correct patent ductus arteriosus, coarctation of the aorta, and tetralogy of Fallot. Direct surgery on the heart was accomplished with closed commissurotomy for mitral stenosis. The introduction of the heart-lung machine and cardiopulmonary bypass enabled the surgical treatment of other congenital and acquired heart diseases. Advances in aortic surgery paralleled these successes. The development of coronary artery bypass grafting greatly aided the treatment of coronary heart disease. Cardiac transplantation, attempts to use the total artificial heart, and the application of ventricular assist devices have brought us to the present day. Although progress in the field of cardiovascular surgery appears to have slowed when compared with the halcyon times of the past, substantial challenges still face cardiac surgeons. It can only be hoped that sufficient resources and incentive can carry the triumphs of the 20th century into the 21st. This review covers past developments and future opportunities in cardiac surgery. PMID:22163121

  7. Launch Commit Criteria Monitoring Agent

    NASA Technical Reports Server (NTRS)

    Semmel, Glenn S.; Davis, Steven R.; Leucht, Kurt W.; Rowe, Dan A.; Kelly, Andrew O.; Boeloeni, Ladislau

    2005-01-01

    The Spaceport Processing Systems Branch at NASA Kennedy Space Center has developed and deployed a software agent to monitor the Space Shuttle's ground processing telemetry stream. The application, the Launch Commit Criteria Monitoring Agent, increases situational awareness for system and hardware engineers during Shuttle launch countdown. The agent provides autonomous monitoring of the telemetry stream, automatically alerts system engineers when predefined criteria have been met, identifies limit warnings and violations of launch commit criteria, aids Shuttle engineers through troubleshooting procedures, and provides additional insight to verify appropriate troubleshooting of problems by contractors. The agent has successfully detected launch commit criteria warnings and violations on a simulated playback data stream. Efficiency and safety are improved through increased automation.

  8. Mesenchymal stem cells and cardiac repair

    PubMed Central

    Nesselmann, Catharina; Ma, Nan; Bieback, Karen; Wagner, Wolfgang; Ho, Anthony; Konttinen, Yrjö T; Zhang, Hao; Hinescu, Mihail E; Steinhoff, Gustav

    2008-01-01

    Accumulating clinical and experimental evidence indicates that mesenchymal stem cells (MSCs) are promising cell types in the treatment of cardiac dysfunction. They may trigger production of reparative growth factors, replace damaged cells and create an environment that favours endogenous cardiac repair. However, identifying mechanisms which regulate the role of MSCs in cardiac repair is still at work. To achieve the maximal clinical benefits, ex vivo manipulation can further enhance MSC therapeutic potential. This review focuses on the mechanism of MSCs in cardiac repair, with emphasis on ex vivo manipulation. PMID:18684237

  9. Commitment Profiles: Combinations of Organizational Commitment Forms and Job Outcomes

    ERIC Educational Resources Information Center

    Wasti, S. Arzu

    2005-01-01

    Although the three-component model of organizational commitment by Meyer and Allen (1991) posits that an employee can experience the three components concurrently, previous research has been largely variable-centered, looking at the antecedents and outcomes of each component separately. Two studies explored how the three components combine to…

  10. The impact of work rewards on radiographers' organizational commitment.

    PubMed

    Akroyd, D; Mulkey, W; Utley-Smith, Q

    1995-01-01

    Organizational commitment is an affective work outcome that has been used to predict work-related behaviors such as turnover, absenteeism and intent-to-leave. There has been little research in organizational commitment for the allied health professions and no empirical studies in the radiologic sciences. The purpose of this study was to examine the predictive value of selected intrinsic and extrinsic work reward variables--involvement, significance, autonomy, general working conditions, supervision and salary--on staff radiographers' organizational commitment. In this study of 600 full-time staff radiographers in North and South Carolina, supervision (for ages 20-37 years) and involvement (for ages 38-66 years) were significant predictors of organizational commitment. The results of the study indicate that healthcare organizations should provide potential supervisors with managerial training, especially for radiographers who move to supervisory positions based on clinical skills and years of experience. In the long run, such programs are much less expensive than costs associated with replacing employees who leave the organization because of low organizational commitment. Also, management strategies and programs to redesign and enhance job tasks may help maintain or increase organizational commitment. PMID:10143137

  11. Beyond the three-component model of organizational commitment.

    PubMed

    Solinger, Omar N; van Olffen, Woody; Roe, Robert A

    2008-01-01

    This article offers a conceptual critique of the three-component model (TCM) of organizational commitment (Allen & Meyer, 1990) and proposes a reconceptualization based on standard attitude theory. The authors use the attitude-behavior model by Eagly and Chaiken (1993) to demonstrate that the TCM combines fundamentally different attitudinal phenomena. They argue that general organizational commitment can best be understood as an attitude regarding the organization, while normative and continuance commitment are attitudes regarding specific forms of behavior (i.e., staying or leaving). The conceptual analysis shows that the TCM fails to qualify as general model of organizational commitment but instead represents a specific model for predicting turnover. The authors suggest that the use of the TCM be restricted to this purpose and that Eagly and Chaiken's model be adopted as a generic commitment model template from which a range of models for predicting specific organizational behaviors can be extracted. Finally, they discuss the definition and measurement of the organizational commitment attitude. Covering the affective, cognitive, and behavioral facets of this attitude helps to enhance construct validity and to differentiate the construct from other constructs. PMID:18211136

  12. Enhancement of Anti-Hypoxic Activity and Differentiation of Cardiac Stem Cells by Supernatant Fluids from Cultured Macrophages that Phagocytized Dead Mesenchymal Stem Cells

    PubMed Central

    Liu, Liang; Jin, Xian; Zhou, Zhong’e; Shen, Chengxing

    2016-01-01

    Background: Most mesenchymal stem cells (MSCs) die shortly after transplantation into a myocardial infarcted area. Dead MSCs (dMSCs) are phagocytized by macrophages (pMΦ) in vivo and in vitro; however, the effects of pMΦ on cardiac stem cells (CSCs) remain unknown. Methods: MSCs, CSCs, and macrophages were obtained from bone marrow, hearts, and peritoneal cavity of mice, respectively. dMSCs were harvested after hypoxia for 24 h, and incubated with macrophages (2:1) for another 2 days with or without lipopolysaccharide (LPS, 50 ng/mL) and sorted by flow cytometry to obtain pMΦ. Viability and apoptosis of CSCs were respectively evaluated with the cell counting kit-8 (CCk-8) assay and Annexin V-PE/7-AAD staining at 0, 6, 12, and 24 h of culture with supernatant fluids from macrophages (MΦ), LPS-stimulated macrophages (LPS-pMΦ), pMΦ, and MSCs. GATA-4 and c-TnI expression was measured by flow cytometry on the seventh day. Expression of inflammation and growth factors was assessed by real-time polymerase chain reaction (RT-PCR) in MΦ, LPS-pMΦ, and pMΦ cells. Results: pMΦ expressed higher levels of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β)and lower levels of tumor necrosis factor-α(TNF-α)and IL-6 than LPS-pMΦ, higher levels of growth factors and of GATA-4 and c-TnI at the 7th day, which were similar to those in MSCs. CSCs cultured with supernatant fluids of pMΦ exhibited higher proliferative, anti-hypoxic, and differentiation activities. Conclusion: The supernatant fluids of macrophages that had phagocytized dead MSCs encouraged changes in phenotype and growth factor expression, enhanced proliferation, differentiation, and anti-hypoxic activity of CSCs, which is relevant to understanding the persistent therapeutic effect of MSCs after their massive demise upon transplantation in myocardial infarction. Furthermore, some miRNAs or proteins which were extracted from the supernatant fluids may give us a new insight into the treatment of

  13. Prevalence, Patterns, and Clinical Predictors of Left Ventricular Late Gadolinium Enhancement in Patients Undergoing Cardiac Magnetic Resonance Prior to Pulmonary Vein Antral Isolation for Atrial Fibrillation

    PubMed Central

    Nance, John W.; Khurram, Irfan M.; Nazarian, Saman; DeWire, Jane; Calkins, Hugh; Zimmerman, Stefan L.

    2015-01-01

    Abstract Cardiac magnetic resonance (CMR) imaging is increasingly used to evaluate patients with atrial fibrillation (AF) before pulmonary vein antral isolation (PVAI). The purpose of this study was to assess the incidence and pattern of left ventricular (LV) late gadolinium enhancement (LGE) in patients undergoing CMR before PVAI and compare the clinical and demographic differences of patients with and without LV LGE. Clinical and demographic data on 62 patients (mean age 61 ± 7.9, 69% male) undergoing CMR before PVAI for AF were collected. Two observers, masked to clinical histories, independently recorded the prevalence, extent (number of myocardial segments), and pattern (subendocardial, midmyocardial, or subepicardial) of LV LGE in each patient. Clinical and demographic predictors of LV LGE were determined using logistic regression. Twenty-three patients (37%) demonstrated LV LGE affecting a mean of 3.0 ± 2.1 myocardial segments. There was no difference in LV ejection fraction between patients with and without LGE, and most (65%) patients with LGE had normal wall motion. Only age (P = 0.04) and a history of congestive heart failure (P = .03) were statistically significant independent predictors of LGE. The most common LGE pattern was midmyocardial, seen in 17 of 23 (74%) patients. Only 4 of 23 (17%) patients had LGE in an “expected” pattern based on clinical history. Of the remaining 19 patients, 4 had known congestive heart failure, 5 nonischemic cardiomyopathy, 4 known coronary artery disease, and 2 prior aortic valve replacement. Six of 23 (26%) patients had no known coronary artery, valvular, or myocardial disease. There is a high prevalence of unexpected LV scar in patients undergoing CMR before PVAI for AF, with most patients demonstrating a nonischemic pattern of LV LGE and no wall motion abnormalities (ie, subclinical disease). The high prevalence of unexpected LGE in these patients may argue for CMR as the modality of choice for

  14. Evaluation of Known or Suspected Cardiac Sarcoidosis.

    PubMed

    Blankstein, Ron; Waller, Alfonso H

    2016-03-01

    Sarcoidosis is a multisystem disorder of unknown cause, and cardiac sarcoidosis affects at least 25% of patients and accounts for substantial mortality and morbidity from this disease. Cardiac sarcoidosis may present with heart failure, left ventricular systolic dysfunction, AV block, atrial or ventricular arrhythmias, and sudden cardiac death. Cardiac involvement can be challenging to detect and diagnose because of the focal nature of the disease, as well as the fact that clinical criteria have limited diagnostic accuracy. Nevertheless, the diagnosis of cardiac sarcoidosis can be enhanced by integrating both clinical and imaging findings. This article reviews the various roles that different imaging modalities provide in the evaluation and management of patients with known or suspected cardiac sarcoidosis. PMID:26926267

  15. Regulatory Foci and Organizational Commitment

    ERIC Educational Resources Information Center

    Markovits, Yannis; Ullrich, Johannes; van Dick, Rolf; Davis, Ann J.

    2008-01-01

    We use regulatory focus theory to derive specific predictions regarding the differential relationships between regulatory focus and commitment. We estimated a structural equation model using a sample of 520 private and public sector employees and found in line with our hypotheses that (a) promotion focus related more strongly to affective…

  16. Faculty Organizational Commitment and Citizenship

    ERIC Educational Resources Information Center

    Lawrence, Janet; Ott, Molly; Bell, Alli

    2012-01-01

    Building on a theoretical framework that links characteristics of individuals and their work settings to organizational commitment (OC) and citizenship behavior, this study considers why faculty may be disengaging from institutional service. Analyses of survey data collected from a state system of higher education suggest that job characteristics,…

  17. School Climate and Teacher Commitment

    ERIC Educational Resources Information Center

    Smith, Larry Don

    2009-01-01

    This study examined the relationship between school climate and teacher commitment. The study focused on elementary schools in Northeast Alabama. Thirty-four elementary schools consisting of 522 teachers took part in the study. The teachers completed two survey instruments: the Organizational Climate Index (OCI) and the Organizational Commitment…

  18. Parenting--Challenge and Commitment

    ERIC Educational Resources Information Center

    Luckey, Eleanore Braun

    1973-01-01

    This is a revised version of the National Council on Family Relations Presidential address delivered November 3, 1972, Portland Oregon. This address concerned the new constitution and reorganization of N.C.F.R. and a plea for reexamination of the membership's commitment to family issues. (JC)

  19. Commitment Profiles and Employee Turnover

    ERIC Educational Resources Information Center

    Stanley, Laura; Vandenberghe, Christian; Vandenberg, Robert; Bentein, Kathleen

    2013-01-01

    We examined how affective (AC), normative (NC), perceived sacrifice (PS), and few alternatives (FA) commitments combine to form profiles and determine turnover intention and turnover. We theorized that three mechanisms account for how profiles operate, i.e., the degree to which membership is internally regulated, the perceived desirability and…

  20. Hampshire Country School Staff Commitments.

    ERIC Educational Resources Information Center

    Hampshire Country School, Rindge, NH.

    Intended for professional personnel of the Hampshire Country School, which treats gifted children with immobilizing emotional dysfunctions, the handbook specifies staff commitments. The Code of Ethics, adapted from the National Education Association Code as supplemented by The Council for Exceptional Children, sets forth four principles:…

  1. Higher Education and Social Commitment.

    ERIC Educational Resources Information Center

    Nasution, S.; Virasai, Banphot, Eds.

    The proceedings of the Regional Institute of Higher Education and Development's seminar and the meaning and implications of social commitment in higher education are reported. The welcoming address (S. Nasution) and the opening address (Y. B. Dato' Murad bin Mohd. Noor) welcome the participants and set the tone for the discussions to follow. The…

  2. Commitment of Licensed Social Workers to Aging Practice

    ERIC Educational Resources Information Center

    Simons, Kelsey; Bonifas, Robin; Gammonley, Denise

    2011-01-01

    This study sought to identify client, professional, and employment characteristics that enhance licensed social workers' commitment to aging practice. A series of binary logistic regressions were performed using data from 181 licensed, full-time social workers who reported aging as their primary specialty area as part of the 2004 NASW's national…

  3. Matters relating to commitments criteria for joint implementation

    SciTech Connect

    1995-11-01

    This paper discusses issues pertaining to commitments criteria for joint implementation activities. In cases where emissions limitations are mentioned, this should be taken to refer to policies and measures to protect and enhance greenhouse gas sinks and reservoirs, with equivalent results.

  4. Biomechanics of Cardiac Function.

    PubMed

    Voorhees, Andrew P; Han, Hai-Chao

    2015-10-01

    The heart pumps blood to maintain circulation and ensure the delivery of oxygenated blood to all the organs of the body. Mechanics play a critical role in governing and regulating heart function under both normal and pathological conditions. Biological processes and mechanical stress are coupled together in regulating myocyte function and extracellular matrix structure thus controlling heart function. Here, we offer a brief introduction to the biomechanics of left ventricular function and then summarize recent progress in the study of the effects of mechanical stress on ventricular wall remodeling and cardiac function as well as the effects of wall mechanical properties on cardiac function in normal and dysfunctional hearts. Various mechanical models to determine wall stress and cardiac function in normal and diseased hearts with both systolic and diastolic dysfunction are discussed. The results of these studies have enhanced our understanding of the biomechanical mechanism in the development and remodeling of normal and dysfunctional hearts. Biomechanics provide a tool to understand the mechanism of left ventricular remodeling in diastolic and systolic dysfunction and guidance in designing and developing new treatments. PMID:26426462

  5. The Relationships between Collegiate DECA Commitment, Mentoring and College Students' Perceived Career Commitment

    ERIC Educational Resources Information Center

    Duke, Linda

    2013-01-01

    This study investigated relationships between student's Collegiate DECA commitment, psychological capital, mentoring, and perceived career commitment. Proposed relationships were supported with several psychological theories and frameworks including Organizational Commitment, Psychological Capital, and Social Identity Theory. Data was…

  6. Overexpression of ryanodine receptor type 1 enhances mitochondrial fragmentation and Ca2+-induced ATP production in cardiac H9c2 myoblasts

    PubMed Central

    O-Uchi, Jin; Jhun, Bong Sook; Hurst, Stephen; Bisetto, Sara; Gross, Polina; Chen, Ming; Kettlewell, Sarah; Park, Jongsun; Oyamada, Hideto; Smith, Godfrey L.; Murayama, Takashi

    2013-01-01

    Ca+ influx to mitochondria is an important trigger for both mitochondrial dynamics and ATP generation in various cell types, including cardiac cells. Mitochondrial Ca2+ influx is mainly mediated by the mitochondrial Ca2+ uniporter (MCU). Growing evidence also indicates that mitochondrial Ca2+ influx mechanisms are regulated not solely by MCU but also by multiple channels/transporters. We have previously reported that skeletal muscle-type ryanodine receptor (RyR) type 1 (RyR1), which expressed at the mitochondrial inner membrane, serves as an additional Ca2+ uptake pathway in cardiomyocytes. However, it is still unclear which mitochondrial Ca2+ influx mechanism is the dominant regulator of mitochondrial morphology/dynamics and energetics in cardiomyocytes. To investigate the role of mitochondrial RyR1 in the regulation of mitochondrial morphology/function in cardiac cells, RyR1 was transiently or stably overexpressed in cardiac H9c2 myoblasts. We found that overexpressed RyR1 was partially localized in mitochondria as observed using both immunoblots of mitochondrial fractionation and confocal microscopy, whereas RyR2, the main RyR isoform in the cardiac sarcoplasmic reticulum, did not show any expression at mitochondria. Interestingly, overexpression of RyR1 but not MCU or RyR2 resulted in mitochondrial fragmentation. These fragmented mitochondria showed bigger and sustained mitochondrial Ca2+ transients compared with basal tubular mitochondria. In addition, RyR1-overexpressing cells had a higher mitochondrial ATP concentration under basal conditions and showed more ATP production in response to cytosolic Ca2+ elevation compared with nontransfected cells as observed by a matrix-targeted ATP biosensor. These results indicate that RyR1 possesses a mitochondrial targeting/retention signal and modulates mitochondrial morphology and Ca2+-induced ATP production in cardiac H9c2 myoblasts. PMID:24124188

  7. Cardiac rehabilitation.

    PubMed

    Ehsani, A A

    1984-02-01

    Exercise training is a major, and the most important, component of cardiac rehabilitation. Besides providing psychological benefits and promoting a "sense of well being," it elicits a number of adaptations in patients with ischemic heart disease. Among the clinically important adaptations are changes in the trained skeletal muscles and autonomic nervous system, resulting not only in increased maximum exercise capacity but also a slower heart rate and, at times, a lower systolic blood pressure during submaximal exercise. The reduction in the rate pressure product decreases myocardial O2 demand at any given submaximal exercise intensity and may thus alleviate myocardial ischemia and angina in patients with coronary artery disease. These adaptive responses occur even with a relatively modest exercise intensity. Although short-term exercise training of moderate intensity has not been reported to result in improvement in left ventricular performance, recent data suggest that exercise training of higher intensity and longer duration (12 months or longer) than has conventionally been used in cardiac rehabilitation programs may favorably affect the heart. This is characterized by improvements in left ventricular function, diminished electrocardiographic criteria of myocardial ischemia and increased stroke volume during exercise. Modest weight reduction accompanies regularly performed prolonged exercise training. It is important, however, to recognize that high-intensity exercise programs are suitable for only some patients with coronary artery disease who are stable and should be used only under strict medical supervision. PMID:6400004

  8. Transcriptional, epigenetic and retroviral signatures identify regulatory regions involved in hematopoietic lineage commitment.

    PubMed

    Romano, Oriana; Peano, Clelia; Tagliazucchi, Guidantonio Malagoli; Petiti, Luca; Poletti, Valentina; Cocchiarella, Fabienne; Rizzi, Ermanno; Severgnini, Marco; Cavazza, Alessia; Rossi, Claudia; Pagliaro, Pasqualepaolo; Ambrosi, Alessandro; Ferrari, Giuliana; Bicciato, Silvio; De Bellis, Gianluca; Mavilio, Fulvio; Miccio, Annarita

    2016-01-01

    Genome-wide approaches allow investigating the molecular circuitry wiring the genetic and epigenetic programs of human somatic stem cells. Hematopoietic stem/progenitor cells (HSPC) give rise to the different blood cell types; however, the molecular basis of human hematopoietic lineage commitment is poorly characterized. Here, we define the transcriptional and epigenetic profile of human HSPC and early myeloid and erythroid progenitors by a combination of Cap Analysis of Gene Expression (CAGE), ChIP-seq and Moloney leukemia virus (MLV) integration site mapping. Most promoters and transcripts were shared by HSPC and committed progenitors, while enhancers and super-enhancers consistently changed upon differentiation, indicating that lineage commitment is essentially regulated by enhancer elements. A significant fraction of CAGE promoters differentially expressed upon commitment were novel, harbored a chromatin enhancer signature, and may identify promoters and transcribed enhancers driving cell commitment. MLV-targeted genomic regions co-mapped with cell-specific active enhancers and super-enhancers. Expression analyses, together with an enhancer functional assay, indicate that MLV integration can be used to identify bona fide developmentally regulated enhancers. Overall, this study provides an overview of transcriptional and epigenetic changes associated to HSPC lineage commitment, and a novel signature for regulatory elements involved in cell identity. PMID:27095295

  9. Transcriptional, epigenetic and retroviral signatures identify regulatory regions involved in hematopoietic lineage commitment

    PubMed Central

    Romano, Oriana; Peano, Clelia; Tagliazucchi, Guidantonio Malagoli; Petiti, Luca; Poletti, Valentina; Cocchiarella, Fabienne; Rizzi, Ermanno; Severgnini, Marco; Cavazza, Alessia; Rossi, Claudia; Pagliaro, Pasqualepaolo; Ambrosi, Alessandro; Ferrari, Giuliana; Bicciato, Silvio; De Bellis, Gianluca; Mavilio, Fulvio; Miccio, Annarita

    2016-01-01

    Genome-wide approaches allow investigating the molecular circuitry wiring the genetic and epigenetic programs of human somatic stem cells. Hematopoietic stem/progenitor cells (HSPC) give rise to the different blood cell types; however, the molecular basis of human hematopoietic lineage commitment is poorly characterized. Here, we define the transcriptional and epigenetic profile of human HSPC and early myeloid and erythroid progenitors by a combination of Cap Analysis of Gene Expression (CAGE), ChIP-seq and Moloney leukemia virus (MLV) integration site mapping. Most promoters and transcripts were shared by HSPC and committed progenitors, while enhancers and super-enhancers consistently changed upon differentiation, indicating that lineage commitment is essentially regulated by enhancer elements. A significant fraction of CAGE promoters differentially expressed upon commitment were novel, harbored a chromatin enhancer signature, and may identify promoters and transcribed enhancers driving cell commitment. MLV-targeted genomic regions co-mapped with cell-specific active enhancers and super-enhancers. Expression analyses, together with an enhancer functional assay, indicate that MLV integration can be used to identify bona fide developmentally regulated enhancers. Overall, this study provides an overview of transcriptional and epigenetic changes associated to HSPC lineage commitment, and a novel signature for regulatory elements involved in cell identity. PMID:27095295

  10. Cardiac stem cell genetic engineering using the αMHC promoter

    PubMed Central

    Bailey, Brandi; Izarra, Alberto; Alvarez, Roberto; Fischer, Kimberlee M; Cottage, Christopher T; Quijada, Pearl; Díez-Juan, Antonio; Sussman, Mark A

    2010-01-01

    Aims Cardiac stem cells (CSCs) show potential as a cellular therapeutic approach to blunt tissue damage and facilitate reparative and regenerative processes after myocardial infarction. Despite multiple published reports of improvement, functional benefits remain modest using normal stem cells delivered by adoptive transfer into damaged myocardium. The goal of this study is to enhance survival and proliferation of CSCs that have undergone lineage commitment in early phases as evidenced by expression of proteins driven by the α-myosin heavy chain (αMHC) promoter. The early increased expression of survival kinases augments expansion of the cardiogenic CSC pool and subsequent daughter progeny. Materials & methods Normal CSCs engineered with fluorescent reporter protein constructs under control of the αMHC promoter show transgene protein expression, confirming activity of the promoter in CSCs. Cultured CSCs from both nontransgenic and cardiac-specific transgenic mice expressing survival kinases driven by the αMHC promoter were analyzed to characterize transgene expression following treatments to promote differentiation in culture. Results & conclusion Therapeutic genes controlled by the αMHC promoter can be engineered into and expressed in CSCs and cardiomyocyte progeny with the goal of improving the efficacy of cardiac stem cell therapy. PMID:19903002

  11. Social commitment robots and dementia.

    PubMed

    Roger, Kerstin; Guse, Lorna; Mordoch, Elaine; Osterreicher, Angela

    2012-03-01

    In 2010, approximately 500,000 Canadians suffered from a dementia-related illness. The number of sufferers is estimated to double in about 25 years. Due to this growing demographic, dementia (most frequently caused by Alzheimer's disease) will increasingly have a significant impact on our aging community and their caregivers. Dementia is associated with challenging behaviours such as agitation, wandering, and aggression. Care providers must find innovative strategies that facilitate the quality of life for this population; moreover, such strategies must value the individual person. Social commitment robots - designed specifically with communication and therapeutic purposes - provide one means towards attaining this goal. This paper describes a study in which Paro (a robotic baby harp seal) was used as part of a summer training program for students. Preliminary conclusions suggest that the integration of social commitment robots may be clinically valuable for older, agitated persons living with dementia in long-term care settings. PMID:22336517

  12. Deterministic relativistic quantum bit commitment

    NASA Astrophysics Data System (ADS)

    Adlam, Emily; Kent, Adrian

    2015-06-01

    We describe new unconditionally secure bit commitment schemes whose security is based on Minkowski causality and the monogamy of quantum entanglement. We first describe an ideal scheme that is purely deterministic, in the sense that neither party needs to generate any secret randomness at any stage. We also describe a variant that allows the committer to proceed deterministically, requires only local randomness generation from the receiver, and allows the commitment to be verified in the neighborhood of the unveiling point. We show that these schemes still offer near-perfect security in the presence of losses and errors, which can be made perfect if the committer uses an extra single random secret bit. We discuss scenarios where these advantages are significant.

  13. Donor commitment and patient needs.

    PubMed

    Bakken, R; van Walraven, A-M; Egeland, T

    2004-01-01

    The article discusses views and recommendations of the World Marrow Donor Association concerning ethical issues related to the donation of hematopoietic stem cell products with respect to recruitment, evaluation, workup, and follow-up of unrelated donors. Particular emphasis is placed upon commitment of individual donors, in particular, with respect to the needs of patients to find HLA-matched donors, who may be asked to donate stem cell and other cell products more than once for given patients. PMID:14628078

  14. Spermatogenesis: The Commitment to Meiosis.

    PubMed

    Griswold, Michael D

    2016-01-01

    Mammalian spermatogenesis requires a stem cell pool, a period of amplification of cell numbers, the completion of reduction division to haploid cells (meiosis), and the morphological transformation of the haploid cells into spermatozoa (spermiogenesis). The net result of these processes is the production of massive numbers of spermatozoa over the reproductive lifetime of the animal. One study that utilized homogenization-resistant spermatids as the standard determined that human daily sperm production (dsp) was at 45 million per day per testis (60). For each human that means ∼1,000 sperm are produced per second. A key to this level of gamete production is the organization and architecture of the mammalian testes that results in continuous sperm production. The seemingly complex repetitious relationship of cells termed the "cycle of the seminiferous epithelium" is driven by the continuous commitment of undifferentiated spermatogonia to meiosis and the period of time required to form spermatozoa. This commitment termed the A to A1 transition requires the action of retinoic acid (RA) on the undifferentiated spermatogonia or prospermatogonia. In stages VII to IX of the cycle of the seminiferous epithelium, Sertoli cells and germ cells are influenced by pulses of RA. These pulses of RA move along the seminiferous tubules coincident with the spermatogenic wave, presumably undergoing constant synthesis and degradation. The RA pulse then serves as a trigger to commit undifferentiated progenitor cells to the rigidly timed pathway into meiosis and spermatid differentiation. PMID:26537427

  15. 24 CFR 203.7 - Commitment process.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Commitment process. 203.7 Section 203.7 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued... Insurance, and Commitments § 203.7 Commitment process. For single family mortgage programs that are...

  16. Anchors of Religious Commitment in Adolescents

    ERIC Educational Resources Information Center

    Layton, Emily; Dollahite, David C.; Hardy, Sam A.

    2011-01-01

    This study explores adolescent religious commitment using qualitative data from a religiously diverse (Jewish, Christian, Muslim) sample of 80 adolescents. A new construct, "anchors of religious commitment," grounded in interview data, is proposed to describe what adolescents commit to as a part of their religious identity. Seven anchors of…

  17. Antecedents and Outcomes of Organizational Commitment

    ERIC Educational Resources Information Center

    Steers, Richard M.

    1977-01-01

    Personal characteristics, job characteristics, and work experiences influenced commitment. Moreover, commitment was found to be strongly related to intent and desire to remain for both samples and moderately related to attendance and turnover for one sample. Performance was generally unrelated to commitment. (Author)

  18. 24 CFR 203.7 - Commitment process.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 24 Housing and Urban Development 2 2011-04-01 2011-04-01 false Commitment process. 203.7 Section 203.7 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued... Insurance, and Commitments § 203.7 Commitment process. For single family mortgage programs that are...

  19. 24 CFR 203.7 - Commitment process.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 24 Housing and Urban Development 2 2012-04-01 2012-04-01 false Commitment process. 203.7 Section 203.7 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued... Insurance, and Commitments § 203.7 Commitment process. For single family mortgage programs that are...

  20. 24 CFR 203.7 - Commitment process.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 2 2014-04-01 2014-04-01 false Commitment process. 203.7 Section 203.7 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued... Insurance, and Commitments § 203.7 Commitment process. For single family mortgage programs that are...

  1. Organizational and Client Commitment among Contracted Employees

    ERIC Educational Resources Information Center

    Coyle-Shapiro, Jacqueline A-M.; Morrow, Paula C.

    2006-01-01

    This study examines affective commitment to employing and client organizations among long-term contracted employees, a new and growing employment classification. Drawing on organizational commitment and social exchange literatures, we propose two categories of antecedents of employee commitment to client organizations. We tested our hypotheses…

  2. An Internet- and Mobile-Based Tailored Intervention to Enhance Maintenance of Physical Activity After Cardiac Rehabilitation: Short-Term Results of a Randomized Controlled Trial

    PubMed Central

    Wangberg, Silje C

    2014-01-01

    Background An increase in physical activity for secondary prevention of cardiovascular disease and cardiac rehabilitation has multiple therapeutic benefits, including decreased mortality. Internet- and mobile-based interventions for physical activity have shown promising results in helping users increase or maintain their level of physical activity in general and specifically in secondary prevention of cardiovascular diseases and cardiac rehabilitation. One component related to the efficacy of these interventions is tailoring of the content to the individual. Objective Our trial assessed the effect of a longitudinally tailored Internet- and mobile-based intervention for physical activity as an extension of a face-to-face cardiac rehabilitation stay. We hypothesized that users of the tailored intervention would maintain their physical activity level better than users of the nontailored version. Methods The study population included adult participants of a cardiac rehabilitation program in Norway with home Internet access and a mobile phone. The participants were randomized in monthly clusters to a tailored or nontailored (control) intervention group. All participants had access to a website with information regarding cardiac rehabilitation, an online discussion forum, and an online activity calendar. Those using the tailored intervention received tailored content based on models of health behavior via the website and mobile fully automated text messages. The main outcome was self-reported level of physical activity, which was obtained using an online international physical activity questionnaire at baseline, at discharge, and at 1 month and 3 months after discharge from the cardiac rehabilitation program. Results Included in the study were 69 participants. One month after discharge, the tailored intervention group (n=10) had a higher median level of overall physical activity (median 2737.5, IQR 4200.2) than the control group (n=14, median 1650.0, IQR 2443.5), but

  3. Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment

    PubMed Central

    Cai, Wenqing; Albini, Sonia; Wei, Ke; Willems, Erik; Guzzo, Rosa M.; Tsuda, Masanao; Giordani, Lorenzo; Spiering, Sean; Kurian, Leo; Yeo, Gene W.; Puri, Pier Lorenzo; Mercola, Mark

    2013-01-01

    A critical but molecularly uncharacterized step in heart formation and regeneration is the process that commits progenitor cells to differentiate into cardiomyocytes. Here, we show that the endoderm-derived dual Nodal/bone morphogenetic protein (BMP) antagonist Cerberus-1 (Cer1) in embryonic stem cell cultures orchestrates two signaling pathways that direct the SWI/SNF chromatin remodeling complex to cardiomyogenic loci in multipotent (KDR/Flk1+) progenitors, activating lineage-specific transcription. Transient inhibition of Nodal by Cer1 induces Brahma-associated factor 60c (Baf60c), one of three Baf60 variants (a, b, and c) that are mutually exclusively assembled into SWI/SNF. Blocking Nodal and BMP also induces lineage-specific transcription factors Gata4 and Tbx5, which interact with Baf60c. siRNA to Cer1, Baf60c, or the catalytic SWI/SNF subunit Brg1 prevented the developmental opening of chromatin surrounding the Nkx2.5 early cardiac enhancer and cardiomyocyte differentiation. Overexpression of Baf60c fully rescued these deficits, positioning Baf60c and SWI/SNF function downstream from Cer1. Thus, antagonism of Nodal and BMP coordinates induction of the myogenic Baf60c variant and interacting transcription factors to program the developmental opening of cardiomyocyte-specific loci in chromatin. This is the first demonstration that cues from the progenitor cell environment direct the subunit variant composition of SWI/SNF to remodel the transcriptional landscape for lineage-specific differentiation. PMID:24186978

  4. Imaging of cardiac sarcoidosis.

    PubMed

    Erthal, Fernanda; Juneau, Daniel; Lim, Siok P; Dwivedi, Girish; Nery, Pablo B; Birnie, David; Beanlands, Rob S

    2016-09-01

    Sarcoidosis is a multisystem inflammatory disease. Cardiac involvement is described in up to 50% of the cases. The disease spectrum is wide and cardiac manifestations ranges from being asymptomatic to heart failure, arrhythmias and sudden cardiac death. The diagnosis of cardiac sarcoidosis can be challenging due to its non-specific nature and the focal involvement of the heart. In this review, we discuss the utility of a stepwise approach with multimodality cardiac imaging in the diagnosis and management of CS. PMID:27225318

  5. Resolution of abnormal cardiac MRI T2 signal following immune suppression for cardiac sarcoidosis.

    PubMed

    Crouser, Elliott D; Ruden, Emily; Julian, Mark W; Raman, Subha V

    2016-08-01

    Cardiac MR (CMR) with late gadolinium enhancement is commonly used to detect cardiac damage in the setting of cardiac sarcoidosis. The addition of T2 mapping to CMR was recently shown to enhance cardiac sarcoidosis detection and correlates with increased cardiac arrhythmia risk. This study was conducted to determine if CMR T2 abnormalities and related arrhythmias are reversible following immune suppression therapy. A retrospective study of subjects with cardiac sarcoidosis with abnormal T2 signal on baseline CMR and a follow-up CMR study at least 4 months later was conducted at The Ohio State University from 2011 to 2015. Immune suppression treated participants had a significant reduction in peak myocardial T2 value (70.0±5.5 vs 59.2±6.1 ms, pretreatment vs post-treatment; p=0.017), and 83% of immune suppression treated subjects had objective improvement in cardiac arrhythmias. Two subjects who had received inadequate immune suppression treatment experienced progression of cardiac sarcoidosis. This report indicates that abnormal CMR T2 signal represents an acute inflammatory manifestation of cardiac sarcoidosis that is potentially reversible with adequate immune suppression therapy. PMID:27354042

  6. The Sense of Commitment: A Minimal Approach

    PubMed Central

    Michael, John; Sebanz, Natalie; Knoblich, Günther

    2016-01-01

    This paper provides a starting point for psychological research on the sense of commitment within the context of joint action. We begin by formulating three desiderata: to illuminate the motivational factors that lead agents to feel and act committed, to pick out the cognitive processes and situational factors that lead agents to sense that implicit commitments are in place, and to illuminate the development of an understanding of commitment in ontogeny. In order to satisfy these three desiderata, we propose a minimal framework, the core of which is an analysis of the minimal structure of situations which can elicit a sense of commitment. We then propose a way of conceptualizing and operationalizing the sense of commitment, and discuss cognitive and motivational processes which may underpin the sense of commitment. PMID:26779080

  7. Measuring government commitment to vaccination.

    PubMed

    Glassman, Amanda; Zoloa, Juan Ignacio; Duran, Denizhan

    2013-04-18

    Vaccination is among the most cost-effective health interventions and has attracted ever greater levels of funding from public and private donors. However, some countries, mainly populous lower-middle income countries, are lagging behind on vaccination financing and performance. In this paper, we discuss the rationale for investing in vaccination and construct a metric to measure government commitment to vaccination that could promote accountability and better tracking of performance. While noting the limitations of available data, we find that populous middle-income countries, which stand to gain tremendously from increased vaccination uptake, perform poorly in terms of their vaccination outcomes. PMID:23598491

  8. Our Commitment to Bioenergy Sustainability

    SciTech Connect

    2015-06-18

    The U.S. Department of Energy’s Bioenergy Technologies Office (BETO) is committed to developing the resources, technologies, and systems needed to support a thriving bioenergy industry that protects natural resources and ad- vances environmental, economic, and social benefits. BETO’s Sustainability Technology Area proactively identifies and addresses issues that affect the scale-up potential, public acceptance, and long-term viability of advanced bioenergy systems; as a result, the area is critical to achieving BETO’s overall goals.

  9. Commit to Sit in Radiology.

    PubMed

    Pittsenbargar, Jared; Amos, Gwendolyn; Gaudet, Jo-Anne

    2015-01-01

    At Houston Methodist Hospital, Commit to Sit is a program that encourages radiology professionals to communicate with patients in a way that demonstrates compassion, respect, empathy, and competence in order to foster a trusting relationship. Using active and empathic listening, dialogue is received and understood in the way it was intended, creating a patient centric environment resulting in high quality, safe patient care with improved outcomes. The implicit understanding derived from results and outcomes confirms the fact that patients prefer the radiology staff to sit while communicating with them. This understanding allows the voice of the patient to be heard and should be a consistent practice among all staff. PMID:26485897

  10. X-Linked Inhibitor of Apoptosis Protein-Mediated Attenuation of Apoptosis, Using a Novel Cardiac-Enhanced Adeno-Associated Viral Vector

    PubMed Central

    Piacentino III, Valentino; Milano, Carmelo A.; Bolanos, Michael; Schroder, Jacob; Messina, Emily; Cockrell, Adam S.; Jones, Edward; Krol, Ava; Bursac, Nenad; Mao, Lan; Devi, Gayathri R.; Samulski, R. Jude

    2012-01-01

    Abstract Successful amelioration of cardiac dysfunction and heart failure through gene therapy approaches will require a transgene effective at attenuating myocardial injury, and subsequent remodeling, using an efficient and safe delivery vehicle. Our laboratory has established a well-curated, high-quality repository of human myocardial tissues that we use as a discovery engine to identify putative therapeutic transgene targets, as well as to better understand the molecular basis of human heart failure. By using this rare resource we were able to examine age- and sex-matched left ventricular samples from (1) end-stage failing human hearts and (2) nonfailing human hearts and were able to identify the X-linked inhibitor of apoptosis protein (XIAP) as a novel target for treating cardiac dysfunction. We demonstrate that XIAP is diminished in failing human hearts, indicating that this potent inhibitor of apoptosis may be central in protecting the human heart from cellular injury culminating in heart failure. Efforts to ameliorate heart failure through delivery of XIAP compelled the design of a novel adeno-associated viral (AAV) vector, termed SASTG, that achieves highly efficient transduction in mouse heart and in cultured neonatal rat cardiomyocytes. Increased XIAP expression achieved with the SASTG vector inhibits caspase-3/7 activity in neonatal cardiomyocytes after induction of apoptosis through three common cardiac stresses: protein kinase C-γ inhibition, hypoxia, or β-adrenergic receptor agonist. These studies demonstrate the potential benefit of XIAP to correct heart failure after highly efficient delivery to the heart with the rationally designed SASTG AAV vector. PMID:22339372