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Sample records for mybp-c knockout cardiac

  1. Cardiac-Specific Knockout of ETA Receptor Mitigates Paraquat-Induced Cardiac Contractile Dysfunction.

    PubMed

    Wang, Jiaxing; Lu, Songhe; Zheng, Qijun; Hu, Nan; Yu, Wenjun; Li, Na; Liu, Min; Gao, Beilei; Zhang, Guoyong; Zhang, Yingmei; Wang, Haichang

    2016-07-01

    Paraquat (1,1'-dim ethyl-4-4'-bipyridinium dichloride), a highly toxic quaternary ammonium herbicide widely used in agriculture, exerts potent toxic prooxidant effects resulting in multi-organ failure including the lung and heart although the underlying mechanism remains elusive. Recent evidence suggests possible involvement of endothelin system in paraquat-induced acute lung injury. This study was designed to examine the role of endothelin receptor A (ETA) in paraquat-induced cardiac contractile and mitochondrial injury. Wild-type (WT) and cardiac-specific ETA receptor knockout mice were challenged to paraquat (45 mg/kg, i.p.) for 48 h prior to the assessment of echocardiographic, cardiomyocyte contractile and intracellular Ca(2+) properties, as well as apoptosis and mitochondrial damage. Levels of the mitochondrial proteins for biogenesis and oxidative phosphorylation including UCP2, HSP90 and PGC1α were evaluated. Our results revealed that paraquat elicited cardiac enlargement, mechanical anomalies including compromised echocardiographic parameters (elevated left ventricular end-systolic and end-diastolic diameters as well as reduced factional shortening), suppressed cardiomyocyte contractile function, intracellular Ca(2+) handling, overt apoptosis and mitochondrial damage. ETA receptor knockout itself failed to affect myocardial function, apoptosis, mitochondrial integrity and mitochondrial protein expression. However, ETA receptor knockout ablated or significantly attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) defect, apoptosis and mitochondrial damage. Taken together, these findings revealed that endothelin system in particular the ETA receptor may be involved in paraquat-induced toxic myocardial contractile anomalies possibly related to apoptosis and mitochondrial damage.

  2. Cardiac and skeletal muscle abnormality in taurine transporter-knockout mice.

    PubMed

    Ito, Takashi; Oishi, Shohei; Takai, Mika; Kimura, Yasushi; Uozumi, Yoriko; Fujio, Yasushi; Schaffer, Stephen W; Azuma, Junichi

    2010-08-24

    Taurine, a sulfur-containing beta-amino acid, is highly contained in heart and skeletal muscle. Taurine has a variety of biological actions, such as ion movement, calcium handling and cytoprotection in the cardiac and skeletal muscles. Meanwhile, taurine deficiency leads various pathologies, including dilated cardiomyopathy, in cat and fox. However, the essential role of taurine depletion on pathogenesis has not been fully clarified. To address the physiological role of taurine in mammalian tissues, taurine transporter-(TauT-) knockout models were recently generated. TauTKO mice exhibited loss of body weight, abnormal cardiac function and the reduced exercise capacity with tissue taurine depletion. In this chapter, we summarize pathological profile and histological feature of heart and skeletal muscle in TauTKO mice.

  3. Conditional Knockout of Prolyl Hydroxylase Domain Protein 2 Attenuates High Fat-Diet-Induced Cardiac Dysfunction in Mice

    PubMed Central

    Zeng, Heng; Chen, Jian-Xiong

    2014-01-01

    Oxygen sensor prolyl hydroxylases (PHDs) play important roles in the regulation of HIF-α and cell metabolisms. This study was designed to investigate the direct role of PHD2 in high fat-diet (HFD)-induced cardiac dysfunction. In HFD fed mice, PHD2 expression was increased without significant changes in PHD1 and PHD3 levels in the heart. This was accompanied by a significant upregulation of myeloid differentiation factor 88 (MYD88) and NF-κB. To explore the role of PHD2 in HFD-induced cardiac dysfunction, PHD2 conditional knockout mice were fed a HFD for 16 weeks. Intriguingly, knockout of PHD2 significantly reduced MYD88 and NF-κb expression in HFD mouse hearts. Moreover, knockout of PHD2 inhibited TNFα and ICAM-1 expression, and reduced cell apoptosis and macrophage infiltration in HFD mice. This was accompanied by a significant improvement of cardiac function. Most importantly, conditional knockout of PHD2 at late stage in HFD mice significantly improved glucose tolerance and reversed cardiac dysfunction. Our studies demonstrate that PHD2 activity is a critical contributor to the HFD-induced cardiac dysfunction. Inhibition of PHD2 attenuates HFD-induced cardiac dysfunction by a mechanism involving suppression of MYD88/NF-κb pathway and inflammation. PMID:25546437

  4. Global Gene Expression Profiling in PAI-1 Knockout Murine Heart and Kidney: Molecular Basis of Cardiac-Selective Fibrosis

    PubMed Central

    Ghosh, Asish K.; Murphy, Sheila B.; Kishore, Raj; Vaughan, Douglas E.

    2013-01-01

    Fibrosis is defined as an abnormal matrix remodeling due to excessive synthesis and accumulation of extracellular matrix proteins in tissues during wound healing or in response to chemical, mechanical and immunological stresses. At present, there is no effective therapy for organ fibrosis. Previous studies demonstrated that aged plasminogen activator inhibitor-1(PAI-1) knockout mice develop spontaneously cardiac-selective fibrosis without affecting any other organs. We hypothesized that differential expressions of profibrotic and antifibrotic genes in PAI-1 knockout hearts and unaffected organs lead to cardiac selective fibrosis. In order to address this prediction, we have used a genome-wide gene expression profiling of transcripts derived from aged PAI-1 knockout hearts and kidneys. The variations of global gene expression profiling were compared within four groups: wildtype heart vs. knockout heart; wildtype kidney vs. knockout kidney; knockout heart vs. knockout kidney and wildtype heart vs. wildtype kidney. Analysis of illumina-based microarray data revealed that several genes involved in different biological processes such as immune system processing, response to stress, cytokine signaling, cell proliferation, adhesion, migration, matrix organization and transcriptional regulation were affected in hearts and kidneys by the absence of PAI-1, a potent inhibitor of urokinase and tissue-type plasminogen activator. Importantly, the expressions of a number of genes, involved in profibrotic pathways including Ankrd1, Pi16, Egr1, Scx, Timp1, Timp2, Klf6, Loxl1 and Klotho, were deregulated in PAI-1 knockout hearts compared to wildtype hearts and PAI-1 knockout kidneys. While the levels of Ankrd1, Pi16 and Timp1 proteins were elevated during EndMT, the level of Timp4 protein was decreased. To our knowledge, this is the first comprehensive report on the influence of PAI-1 on global gene expression profiling in the heart and kidney and its implication in fibrogenesis and

  5. Microarray analysis of active cardiac remodeling genes in a familial hypertrophic cardiomyopathy mouse model rescued by a phospholamban knockout

    PubMed Central

    Rajan, Sudarsan; Pena, James R.; Jegga, Anil G.; Aronow, Bruce J.; Wolska, Beata M.

    2013-01-01

    Familial hypertrophic cardiomyopathy (FHC) is a disease characterized by ventricular hypertrophy, fibrosis, and aberrant systolic and/or diastolic function. Our laboratories have previously developed two mouse models that affect cardiac performance. One mouse model encodes an FHC-associated mutation in α-tropomyosin: Glu → Gly at amino acid 180, designated as Tm180. These mice display a phenotype that is characteristic of FHC, including severe cardiac hypertrophy with fibrosis and impaired physiological performance. The other model was a gene knockout of phospholamban (PLN KO), a regulator of calcium uptake in the sarcoplasmic reticulum of cardiomyocytes; these hearts exhibit hypercontractility with no pathological abnormalities. Previous work in our laboratories shows that when mice were genetically crossed between the PLN KO and Tm180, the progeny (PLN KO/Tm180) display a rescued hypertrophic phenotype with improved morphology and cardiac function. To understand the changes in gene expression that occur in these models undergoing cardiac remodeling (Tm180, PLN KO, PLN KO/Tm180, and nontransgenic control mice), we conducted microarray analyses of left ventricular tissue at 4 and 12 mo of age. Expression profiling reveals that 1,187 genes changed expression in direct response to the three genetic models. With these 1,187 genes, 11 clusters emerged showing normalization of transcript expression in the PLN KO/Tm180 hearts. In addition, 62 transcripts are highly involved in suppression of the hypertrophic phenotype. Confirmation of the microarray analysis was conducted by quantitative RT-PCR. These results provide insight into genes that alter expression during cardiac remodeling and are active during modulation of the cardiomyopathic phenotype. PMID:23800848

  6. In vivo assessment of coronary flow and cardiac function after bolus adenosine injection in adenosine receptor knockout mice.

    PubMed

    Teng, Bunyen; Tilley, Stephen L; Ledent, Catherine; Mustafa, S Jamal

    2016-06-01

    Bolus injections of adenosine and the A2A adenosine receptor (AR) selective agonist (regadenoson) are used clinically as a substitute for a stress test in people who cannot exercise. Using isolated tissue preparations, our lab has shown that coronary flow and cardiac effects of adenosine are mostly regulated by the AR subtypes A1, A2A, and A2B In this study, we used ultrasound imaging to measure the in vivo effects of adenosine on coronary blood flow (left coronary artery) and cardiac function in anesthetized wild-type, A1 knockout (KO), A2AKO, A2BKO, A3KO, A1, and A3 double KO (A1/3 DKO) and A2A and A2B double KO (A2A/2B DKO) mice in real time. Echocardiographic and Doppler studies were performed using a Visualsonic Vevo 2100 ultrasound system. Coronary blood flow (CBF) baseline data were obtained when animals were anesthetized with 1% isoflourane. Diameter (D) and velocity time integral (VTI) were measured on the left coronary arteries (CBF = ((π/4) × D(2) × VTI × HR)/1000). CBF changes were the highest within 2 min of injection (about 10 mg/kg). Heart rate, cardiac output, and stroke volume were measured by tracing the left ventricle long axis. Our data support a role for the A2 AR in CBF and further support our conclusions of previous studies from isolated tissues. Adenosine-mediated decreases in cardiac output and stroke volume may be A2B and/or A3 AR-mediated; however, the A1 and A2 ARs also play roles in overall cardiac function. These data further provide a powerful translational tool in studying the cardiovascular effects of adenosine in disease states.

  7. Knockout of Toll-Like Receptors 2 and 4 Prevents Renal Ischemia-Reperfusion-Induced Cardiac Hypertrophy in Mice.

    PubMed

    Trentin-Sonoda, Mayra; da Silva, Rogério Cirino; Kmit, Fernanda Vieira; Abrahão, Mariana Vieira; Monnerat Cahli, Gustavo; Brasil, Guilherme Visconde; Muzi-Filho, Humberto; Silva, Paulo André; Tovar-Moll, Fernanda Freire; Vieyra, Adalberto; Medei, Emiliano; Carneiro-Ramos, Marcela Sorelli

    2015-01-01

    We investigated whether the pathways linked to Toll-like receptors 2 and 4 (TLRs) are involved in renal ischemia-reperfusion (I/R)-induced cardiac hypertrophy. Wild type (WT) C57BL/6J, TLR2-/- and TLR4-/- mice were subjected to left kidney ischemia for 60 min followed by reperfusion for 5, 8, 12 and 15 days. Proton density magnetic resonance showed alterations in the injured kidney from WT mice, together with signs of parenchymal edema and higher levels of vimentin mRNA, accompanied by: (i) small, but significant, increase in serum urea after 24 h, (ii) 100% increase in serum creatinine at 24 h. A serum peak of inflammatory cytokines occurred after 5 days of reperfusion. Heart weight/body weight and heart weight/tibia length ratios increased after 12 and 15 days of reperfusion, respectively. Cardiac hypertrophy markers, B-type natriuretic peptide (BNP) and α-actin, left ventricle mass, cardiac wall thickness and myocyte width increased after 15 days of reperfusion, together with longer QTc and action potential duration. Cardiac TLRs, MyD88, HSP60 and HSP70 mRNA levels also increased. After 15 days of reperfusion, absence of TLRs prevented cardiac hypertrophy, as reflected by similar values of left ventricular cardiac mass and heart weight/body weight ratio compared to the transgenic Sham. Renal tissular injury also ameliorated in both knockout mice, as revealed by the comparison of their vimentin mRNA levels with those found in the WT on the same day after I/R. The I/R TLR2-/- group had TNF-α, IFN-γ and IL-1β levels similar to the non-I/R group, whereas the TLR4-/- group conserved the p-NF-κB/NF- κB ratio contrasting with that found in TLR2-/-. We conclude: (i) TLRs are involved in renal I/R-induced cardiac hypertrophy; (ii) absence of TLRs prevents I/R-induced cardiac hypertrophy, despite renal lesions seeming to evolve towards those of chronic disease; (iii) TLR2 and TLR4 selectively regulate the systemic inflammatory profile and NF- κB activation.

  8. Cardiac Morphology and Function, and Blood Gas Transport in Aquaporin-1 Knockout Mice

    PubMed Central

    Al-Samir, Samer; Wang, Yong; Meissner, Joachim D.; Gros, Gerolf; Endeward, Volker

    2016-01-01

    We have studied cardiac and respiratory functions of aquaporin-1-deficient mice by the Pressure-Volume-loop technique and by blood gas analysis. In addition, the morphological properties of the animals' hearts were analyzed. In anesthesia under maximal dobutamine stimulation, the mice exhibit a moderately elevated heart rate of < 600 min−1 and an O2 consumption of ~0.6 ml/min/g, which is about twice the basal rate. In this state, which is similar to the resting state of the conscious animal, all cardiac functions including stroke volume and cardiac output exhibited resting values and were identical between deficient and wildtype animals. Likewise, pulmonary and peripheral exchange of O2 and CO2 were normal. In contrast, several morphological parameters of the heart tissue of deficient mice were altered: (1) left ventricular wall thickness was reduced by 12%, (2) left ventricular mass, normalized to tibia length, was reduced by 10–20%, (3) cardiac muscle fiber cross sectional area was decreased by 17%, and (4) capillary density was diminished by 10%. As the P-V-loop technique yielded normal end-diastolic and end-systolic left ventricular volumes, the deficient hearts are characterized by thin ventricular walls in combination with normal intraventricular volumes. The aquaporin-1-deficient heart thus seems to be at a disadvantage compared to the wild-type heart by a reduced left-ventricular wall thickness and an increased diffusion distance between blood capillaries and muscle mitochondria. While under the present quasi-resting conditions these morphological alterations have no consequences for cardiac function, we expect that the deficient hearts will show a reduced maximal cardiac output. PMID:27252655

  9. Macrophage Migration Inhibitory Factor (MIF) Knockout Preserves Cardiac Homeostasis through Alleviating Akt-Mediated Myocardial Autophagy Suppression in High Fat Diet-Induced Obesity

    PubMed Central

    Xu, Xihui; Ren, Jun

    2014-01-01

    Background Macrophage migration inhibitory factor (MIF) plays a role in the development of obesity and diabetes. However, whether MIF plays a role in fat diet-induced obesity and associated cardiac anomalies still remains unknown. The aim of this study was to examine the impact of MIF knockout on high fat diet-induced obesity, obesity-associated cardiac anomalies and the underlying mechanisms involved with a focus on Akt-mediated autophagy. Methods Adult male wild-type (WT) and MIF knockout (MIF−/−) mice were placed on 45% high fat diet for 5 months. Oxygen consumption, CO2 production, respiratory exchange ratio (RER), locomotor activity, and heat generation were measured using energy calorimeter. Echocardiographic, cardiomyocyte mechanical and intracellular Ca2+ properties were assessed. Apoptosis was examined using TUNEL staining and western blot analysis. Akt signaling pathway and autophagy markers were evaluated. Cardiomyocytes isolated from WT and MIF−/− mice were treated with recombinant mouse MIF (rmMIF). Results High fat diet feeding elicited increased body weight gain, insulin resistance, and caloric disturbance in WT and MIF−/− mice. High fat diet induced unfavorable geometric, contractile and histological changes in the heart, the effects of which were alleviated by MIF knockout. In addition, fat diet-induced cardiac anomalies were associated with Akt activation and autophagy suppression, which were nullified by MIF deficiency. In cardiomyocytes from WT mice, autophagy was inhibited by exogenous rmMIF through Akt activation. In addition, MIF knockout rescued palmitic acid-induced suppression of cardiomyocyte autophagy, the effect of which was nullified by rmMIF. Conclusions These results indicate that MIF knockout preserved obesity-associated cardiac anomalies without affecting fat diet-induced obesity, probably through restoring myocardial autophagy in an Akt-dependent manner. Our findings provide new insights for the role of MIF in obesity

  10. Taurine transporter knockout depletes muscle taurine levels and results in severe skeletal muscle impairment but leaves cardiac function uncompromised.

    PubMed

    Warskulat, Ulrich; Flögel, Ulrich; Jacoby, Christoph; Hartwig, Hans-Georg; Thewissen, Michael; Merx, Marc W; Molojavyi, Andrej; Heller-Stilb, Birgit; Schrader, Jürgen; Häussinger, Dieter

    2004-03-01

    Taurine is the most abundant free amino acid in heart and skeletal muscle. In the present study, the effects of hereditary taurine deficiency on muscle function were examined in taurine transporter knockout (taut-/-) mice. These mice show an almost complete depletion of heart and skeletal muscle taurine levels. Treadmill experiments demonstrated that total exercise capacity of taut-/- mice was reduced by >80% compared with wild-type controls. The decreased performance of taut-/- mice correlated with increased lactate levels in serum during exercise. Surprisingly, cardiac function of taut-/- mice as assessed by magnetic resonance imaging, echocardiography, and isolated heart studies showed a largely normal phenotype under both control and stimulated conditions. However, analysis of taut-/- skeletal muscle revealed electromyographic abnormalities. (1)H nuclear magnetic resonance spectroscopy of tissue extracts showed that in the heart of taut-/- mice the lack of taurine was compensated by the up-regulation of various organic solutes. In contrast, a deficit of >10 mM in total organic osmolyte concentration was found in skeletal muscle. The present study identifies taurine transport as a crucial factor for the maintenance of skeletal muscle function and total exercise capacity, while cardiac muscle apparently can compensate for the loss of taurine.

  11. TLR4 knockout attenuated high fat diet-induced cardiac dysfunction via NF-κB/JNK-dependent activation of autophagy.

    PubMed

    Hu, Nan; Zhang, Yingmei

    2017-01-17

    Obesity is commonly associated with a low grade systemic inflammation, which may contribute to the onset and development of myocardial remodeling and contractile dysfunction. Toll-like receptor 4 (TLR4) plays an important role in innate immunity and inflammation although its role in high fat diet-induced obesity cardiac dysfunction remains elusive. This study was designed to examine the effect of TLR4 ablation on high fat diet intake-induced cardiac anomalies, if any, and underlying mechanism(s) involved. Wild-type (WT) and TLR4 knockout mice were fed normal or high fat (60% calorie from fat) diet for 12weeks prior to assessment of mechanical and intracellular Ca(2+) properties. The inflammatory signaling proteins (TLR4, NF-κB, and JNK) and autophagic markers (Atg5, Atg12, LC3B and p62) were evaluated. Our results revealed that high fat diet intake promoted obesity, marked decrease in fractional shortening, and cardiomyocyte contractile capacity with dampened intracellular Ca(2+) release and clearance, elevated ROS generation and oxidative stress as measured by aconitase activity, the effects of which were significantly attenuated by TLR4 knockout. In addition, high fat intake downregulated levels of Atg5, Atg12 and LC3B, while increasing p62 accumulation. TLR4 knockout itself did not affect Atg5, Atg12, LC3B and p62 levels while it reconciled high fat diet intake-induced changes in autophagy. In addition, TLR4 knockout alleviated high fat diet-induced phosphorylation of IKKβ, JNK and mTOR. In vitro study revealed that palmitic acid suppressed cardiomyocyte contractile function, the effect of which was inhibited the TLR4 inhibitor CLI-095, the JNK inhibitor AS601245 or the NF-κB inhibitor Celastrol. Taken together, these data showed that TLR4 knockout ameliorated high fat diet-induced cardiac contractile and intracellular Ca(2+) anomalies through inhibition of inflammation and ROS, possibly through a NF-κB/JNK-dependent activation of autophagy. This article is

  12. Cell volume control in phospholemman (PLM) knockout mice: do cardiac myocytes demonstrate a regulatory volume decrease and is this influenced by deletion of PLM?

    PubMed

    Bell, James R; Lloyd, David; Curl, Claire L; Delbridge, Lea M D; Shattock, Michael J

    2009-03-01

    In addition to modulatory actions on Na+-K+-ATPase, phospholemman (PLM) has been proposed to play a role in cell volume regulation. Overexpression of PLM induces ionic conductances, with 'PLM channels' exhibiting selectivity for taurine. Osmotic challenge of host cells overexpressing PLM increases taurine efflux and augments the cellular regulatory volume decrease (RVD) response, though a link between PLM and cell volume regulation has not been studied in the heart. We recently reported a depressed cardiac contractile function in PLM knockout mice in vivo, which was exacerbated in crystalloid-perfused isolated hearts, indicating that these hearts were osmotically challenged. To address this, the present study investigated the role of PLM in osmoregulation in the heart. Isolated PLM wild-type and knockout hearts were perfused with a crystalloid buffer supplemented with mannitol in a bid to prevent perfusate-induced cell swelling and maintain function. Accordingly, and in contrast to wild-type control hearts, contractile function was improved in PLM knockout hearts with 30 mM mannitol. To investigate further, isolated PLM wild-type and knockout cardiomyocytes were subjected to increasing hyposmotic challenges. Initial validation studies showed the IonOptix video edge-detection system to be a simple and accurate 'real-time' method for tracking cell width as a marker of cell size. Myocytes swelled equally in both genotypes, indicating that PLM, when expressed at physiological levels in cardiomyocytes, is not essential to limit water accumulation in response to a hyposmotic challenge. Interestingly, freshly isolated adult cardiomyocytes consistently failed to mount RVDs in response to cell swelling, adding to conflicting reports in the literature. A proposed perturbation of the RVD response as a result of the cell isolation process was not restored, however, with short-term culture in either adult or neonatal cardiomyocytes.

  13. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development

    PubMed Central

    Baardman, Maria E.; Zwier, Mathijs V.; Wisse, Lambertus J.; Gittenberger-de Groot, Adriana C.; Kerstjens-Frederikse, Wilhelmina S.; Hofstra, Robert M. W.; Jurdzinski, Angelika; Hierck, Beerend P.; Jongbloed, Monique R. M.; Berger, Rolf M. F.; Plösch, Torsten; DeRuiter, Marco C.

    2016-01-01

    ABSTRACT Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the cardiovascular development of Lrp2 KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. The Lrp2 KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in the Lrp2 KO. This explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans with LRP2 mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis. PMID:26822476

  14. Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development.

    PubMed

    Baardman, Maria E; Zwier, Mathijs V; Wisse, Lambertus J; Gittenberger-de Groot, Adriana C; Kerstjens-Frederikse, Wilhelmina S; Hofstra, Robert M W; Jurdzinski, Angelika; Hierck, Beerend P; Jongbloed, Monique R M; Berger, Rolf M F; Plösch, Torsten; DeRuiter, Marco C

    2016-04-01

    Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts ofLrp2knockout (KO) mice have not yet been investigated. We studied the cardiovascular development ofLrp2KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. TheLrp2KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in theLrp2KO. This explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans withLRP2mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis.

  15. Cardiac catheterization

    MedlinePlus

    Catheterization - cardiac; Heart catheterization; Angina - cardiac catheterization; CAD - cardiac catheterization; Coronary artery disease - cardiac catheterization; Heart valve - cardiac catheterization; Heart failure - ...

  16. Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

    PubMed Central

    Lakhal-Littleton, Samira; Wolna, Magda; Carr, Carolyn A.; Miller, Jack J. J.; Christian, Helen C.; Ball, Vicky; Santos, Ana; Diaz, Rebeca; Biggs, Daniel; Stillion, Richard; Holdship, Philip; Clarke, Kieran; Davies, Benjamin; Robbins, Peter A.

    2015-01-01

    Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion of Fpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes of Fpn knockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation. PMID:25713362

  17. Knockout, Transfer and Spectroscopic Factors

    NASA Astrophysics Data System (ADS)

    Kemper, Kirby; Keeley, Nicholas; Rusek, Krzysztof

    2011-10-01

    As derived quantities rather than observables, spectroscopic factors extracted from fits to data are model dependent. The main source of uncertainty is the choice of binding potential, but other factors such as adequate modeling of the reaction mechanism, the Perey effect, choice of distorting nuclear potentials etc. can also play a significant role. Recently, there has been some discussion of apparent discrepancies in spectroscopic factors derived from knockout reactions compared to those obtained from low-energy direct reactions. It should be possible to reconcile these discrepancies and we explore this prospect by attempting to describe the 10Be(d,t)9Be data of Nucl. Phys. A157, 305 (1970) using the 10Be/9Be form factors from a recent knockout study, Phys. Rev. Lett. 106, 162502 (2011). The influence of such factors as choice of distorting potentials and multi-step reactions paths will be explored.

  18. Cardiac catheterization - discharge

    MedlinePlus

    Catheterization - cardiac - discharge; Heart catheterization - discharge: Catheterization - cardiac; Heart catheterization; Angina - cardiac catheterization discharge; CAD - cardiac catheterization discharge; Coronary artery disease - cardiac catheterization ...

  19. CAP2 in cardiac conduction, sudden cardiac death and eye development.

    PubMed

    Field, Jeffrey; Ye, Diana Z; Shinde, Manasi; Liu, Fang; Schillinger, Kurt J; Lu, MinMin; Wang, Tao; Skettini, Michelle; Xiong, Yao; Brice, Angela K; Chung, Daniel C; Patel, Vickas V

    2015-11-30

    Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease.

  20. CAP2 in cardiac conduction, sudden cardiac death and eye development

    PubMed Central

    Field, Jeffrey; Ye, Diana Z.; Shinde, Manasi; Liu, Fang; Schillinger, Kurt J.; Lu, MinMin; Wang, Tao; Skettini, Michelle; Xiong, Yao; Brice, Angela K.; Chung, Daniel C.; Patel, Vickas V.

    2015-01-01

    Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2−/cap2− males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2−/cap2− females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease. PMID:26616005

  1. Neuron-specific (pro)renin receptor knockout prevents the development of salt-sensitive hypertension.

    PubMed

    Li, Wencheng; Peng, Hua; Mehaffey, Eamonn P; Kimball, Christie D; Grobe, Justin L; van Gool, Jeanette M G; Sullivan, Michelle N; Earley, Scott; Danser, A H Jan; Ichihara, Atsuhiro; Feng, Yumei

    2014-02-01

    The (pro)renin receptor (PRR), which binds both renin and prorenin, is a newly discovered component of the renin-angiotensin system that is highly expressed in the central nervous system. The significance of brain PRRs in mediating local angiotensin II formation and regulating blood pressure remains unclear. The current study was performed to test the hypothesis that PRR-mediated, nonproteolytic activation of prorenin is the main source of angiotensin II in the brain. Thus, PRR knockout in the brain is expected to prevent angiotensin II formation and development of deoxycorticosterone acetate-salt-induced hypertension. A neuron-specific PRR (ATP6AP2) knockout mouse model was generated using the Cre-LoxP system. Physiological parameters were recorded by telemetry. PRR expression, detected by immunostaining and reverse transcription-polymerase chain reaction, was significantly decreased in the brains of knockout mice compared with wild-type mice. Intracerebroventricular infusion of mouse prorenin increased blood pressure and angiotensin II formation in wild-type mice. This hypertensive response was abolished in PRR-knockout mice in association with a reduction in angiotensin II levels. Deoxycorticosterone acetate-salt increased PRR expression and angiotensin II formation in the brains of wild-type mice, an effect that was attenuated in PRR-knockout mice. PRR knockout in neurons prevented the development of deoxycorticosterone acetate-salt-induced hypertension as well as activation of cardiac and vasomotor sympathetic tone. In conclusion, nonproteolytic activation of prorenin through binding to the PRR mediates angiotensin II formation in the brain. Neuron-specific PRR knockout prevents the development of deoxycorticosterone acetate-salt-induced hypertension, possibly through diminished angiotensin II formation.

  2. Kanamycin ototoxicity in glutamate transporter knockout mice.

    PubMed

    Shimizu, Yoshitaka; Hakuba, Nobuhiro; Hyodo, Jun; Taniguchi, Masafumi; Gyo, Kiyofumi

    2005-06-03

    Glutamate-aspartate transporter (GLAST), a powerful glutamate uptake system, removes released glutamate from the synaptic cleft and facilitates the re-use of glutamate as a neurotransmitter recycling system. Aminoglycoside-induced hearing loss is mediated via a glutamate excitotoxic process. We investigated the effect of aminoglycoside ototoxicity in GLAST knockout mice using the recorded auditory brainstem response (ABR) and number of hair cells in the cochlea. Kanamycin (100 mg/mL) was injected directly into the posterior semicircular canal of mice. Before the kanamycin treatment, there was no difference in the ABR threshold average between the wild-type and knockout mice. Kanamycin injection aggravated the ABR threshold in the GLAST knockout mice compared with the wild-type mice, and the IHC degeneration was more severe in the GLAST knockout mice. These findings suggest that GLAST plays an important role in preventing the degeneration of inner hair cells in aminoglycoside ototoxicity.

  3. Cardiac Sarcoidosis.

    PubMed

    Birnie, David; Ha, Andrew C T; Gula, Lorne J; Chakrabarti, Santabhanu; Beanlands, Rob S B; Nery, Pablo

    2015-12-01

    Studies suggest clinically manifest cardiac involvement occurs in 5% of patients with pulmonary/systemic sarcoidosis. The principal manifestations of cardiac sarcoidosis (CS) are conduction abnormalities, ventricular arrhythmias, and heart failure. Data indicate that an 20% to 25% of patients with pulmonary/systemic sarcoidosis have asymptomatic (clinically silent) cardiac involvement. An international guideline for the diagnosis and management of CS recommends that patients be screened for cardiac involvement. Most studies suggest a benign prognosis for patients with clinically silent CS. Immunosuppression therapy is advocated for clinically manifest CS. Device therapy, with implantable cardioverter defibrillators, is recommended for some patients.

  4. CARD9 knockout ameliorates myocardial dysfunction associated with high fat diet-induced obesity.

    PubMed

    Cao, Li; Qin, Xing; Peterson, Matthew R; Haller, Samantha E; Wilson, Kayla A; Hu, Nan; Lin, Xin; Nair, Sreejayan; Ren, Jun; He, Guanglong

    2016-03-01

    Obesity is associated with chronic inflammation which plays a critical role in the development of cardiovascular dysfunction. Because the adaptor protein caspase recruitment domain-containing protein 9 (CARD9) in macrophages regulates innate immune responses via activation of pro-inflammatory cytokines, we hypothesize that CARD9 mediates the pro-inflammatory signaling associated with obesity en route to myocardial dysfunction. C57BL/6 wild-type (WT) and CARD9(-/-) mice were fed normal diet (ND, 12% fat) or a high fat diet (HFD, 45% fat) for 5months. At the end of 5-month HFD feeding, cardiac function was evaluated using echocardiography. Cardiomyocytes were isolated and contractile properties were measured. Immunofluorescence was performed to detect macrophage infiltration in the heart. Heart tissue homogenates, plasma, and supernatants from isolated macrophages were collected to measure the concentrations of pro-inflammatory cytokines using ELISA kits. Western immunoblotting analyses were performed on heart tissue homogenates and isolated macrophages to explore the underlying signaling mechanism(s). CARD9 knockout alleviated HFD-induced insulin resistance and glucose intolerance, prevented myocardial dysfunction with preserved cardiac fractional shortening and cardiomyocyte contractile properties. CARD9 knockout also significantly decreased the number of infiltrated macrophages in the heart with reduced myocardium-, plasma-, and macrophage-derived cytokines including IL-6, IL-1β and TNFα. Finally, CARD9 knockout abrogated the increase of p38 MAPK phosphorylation, the decrease of LC3BII/LC3BI ratio and the up-regulation of p62 expression in the heart induced by HFD feeding and restored cardiac autophagy signaling. In conclusion, CARD9 knockout ameliorates myocardial dysfunction associated with HFD-induced obesity, potentially through reduction of macrophage infiltration, suppression of p38 MAPK phosphorylation, and preservation of autophagy in the heart.

  5. Cardiac Cephalgia

    PubMed Central

    Wassef, Nancy; Ali, Ali Turab; Katsanevaki, Alexia-Zacharoula; Nishtar, Salman

    2014-01-01

    Although most of the patients presenting with ischemic heart disease have chest pains, there are other rare presenting symptoms like cardiac cephalgia. In this report, we present a case of acute coronary syndrome with an only presentation of exertional headache. It was postulated as acute presentation of coronary artery disease, due to previous history of similar presentation associated with some chest pains with previous left coronary artery stenting. We present an unusual case with cardiac cephalgia in a young patient under the age of 50 which was not reported at that age before. There are four suggested mechanisms for this cardiac presentation. PMID:28352454

  6. Human knockout research: new horizons and opportunities.

    PubMed

    Alkuraya, Fowzan S

    2015-02-01

    Although numerous approaches have been pursued to understand the function of human genes, Mendelian genetics has by far provided the most compelling and medically actionable dataset. Biallelic loss-of-function (LOF) mutations are observed in the majority of autosomal recessive Mendelian disorders, representing natural human knockouts and offering a unique opportunity to study the physiological and developmental context of these genes. The restriction of such context to 'disease' states is artificial, however, and the recent ability to survey entire human genomes for biallelic LOF mutations has revealed a surprising landscape of knockout events in 'healthy' individuals, sparking interest in their role in phenotypic diversity beyond disease causation. As I discuss in this review, the potentially wide implications of human knockout research warrant increased investment and multidisciplinary collaborations to overcome existing challenges and reap its benefits.

  7. Proton Knock-Out in Hall A

    SciTech Connect

    Kees de Jager

    2002-06-01

    Proton knock-out is studied in a broad program in Hall A at Jefferson Lab. The first experiment performed in Hall A studied the {sup 16}O(e,e'p) reaction. Since then proton knock-out experiments have studied a variety of aspects of that reaction, from single-nucleon properties to its mechanism, such as final-state interactions and two-body currents, in nuclei from {sup 2}H to {sup 16}O. In this review the results of this program will be summarized and an outlook given of future accomplishments.

  8. Nuclear cardiac

    SciTech Connect

    Slutsky, R.; Ashburn, W.L.

    1982-01-01

    The relationship between nuclear medicine and cardiology has continued to produce a surfeit of interesting, illuminating, and important reports involving the analysis of cardiac function, perfusion, and metabolism. To simplify the presentation, this review is broken down into three major subheadings: analysis of myocardial perfusion; imaging of the recent myocardial infarction; and the evaluation of myocardial function. There appears to be an increasingly important relationship between cardiology, particularly cardiac physiology, and nuclear imaging techniques. (KRM)

  9. Cardiac cameras.

    PubMed

    Travin, Mark I

    2011-05-01

    Cardiac imaging with radiotracers plays an important role in patient evaluation, and the development of suitable imaging instruments has been crucial. While initially performed with the rectilinear scanner that slowly transmitted, in a row-by-row fashion, cardiac count distributions onto various printing media, the Anger scintillation camera allowed electronic determination of tracer energies and of the distribution of radioactive counts in 2D space. Increased sophistication of cardiac cameras and development of powerful computers to analyze, display, and quantify data has been essential to making radionuclide cardiac imaging a key component of the cardiac work-up. Newer processing algorithms and solid state cameras, fundamentally different from the Anger camera, show promise to provide higher counting efficiency and resolution, leading to better image quality, more patient comfort and potentially lower radiation exposure. While the focus has been on myocardial perfusion imaging with single-photon emission computed tomography, increased use of positron emission tomography is broadening the field to include molecular imaging of the myocardium and of the coronary vasculature. Further advances may require integrating cardiac nuclear cameras with other imaging devices, ie, hybrid imaging cameras. The goal is to image the heart and its physiological processes as accurately as possible, to prevent and cure disease processes.

  10. CD38 promotes angiotensin II-induced cardiac hypertrophy.

    PubMed

    Guan, Xiao-Hui; Hong, Xuan; Zhao, Ning; Liu, Xiao-Hong; Xiao, Yun-Fei; Chen, Ting-Tao; Deng, Li-Bin; Wang, Xiao-Lei; Wang, Jian-Bin; Ji, Guang-Ju; Fu, Mingui; Deng, Ke-Yu; Xin, Hong-Bo

    2017-03-12

    Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and regulated by various signalling pathways. Recently, we observed that mouse embryonic fibroblasts from CD38 knockout mice were significantly resistant to oxidative stress such as H2 O2 -induced injury and hypoxia/reoxygenation-induced injury. In addition, we also found that CD38 knockout mice protected heart from ischaemia reperfusion injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway. However, the role of CD38 in cardiac hypertrophy is not explored. Here, we investigated the roles and mechanisms of CD38 in angiotensin II (Ang-II)-induced cardiac hypertrophy. Following 14 days of Ang-II infusion with osmotic mini-pumps, a comparable hypertension was generated in both of CD38 knockout and wild-type mice. However, the cardiac hypertrophy and fibrosis were much more severe in wild-type mice compared with CD38 knockout mice. Consistently, RNAi-induced knockdown of CD38 decreased the gene expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and reactive oxygen species generation in Ang-II-stimulated H9c2 cells. In addition, the expression of SIRT3 was elevated in CD38 knockdown H9c2 cells, in which SIRT3 may further activate the FOXO3 antioxidant pathway. The intracellular Ca(2+) release induced by Ang-II markedly decreased in CD38 knockdown H9c2 cells, which might be associated with the decrease of nuclear translocation of NFATc4 and inhibition of ERK/AKT phosphorylation. We concluded that CD38 plays an essential role in cardiac hypertrophy probably via inhibition of SIRT3 expression and activation of Ca(2+) -NFAT signalling pathway. Thus, CD38 may be a novel target for treating cardiac hypertrophy.

  11. BK Knockout by TALEN-Mediated Gene Targeting in Osteoblasts: KCNMA1 Determines the Proliferation and Differentiation of Osteoblasts

    PubMed Central

    Hei, Hongya; Gao, Jianjun; Dong, Jibin; Tao, Jie; Tian, Lulu; Pan, Wanma; Wang, Hongyu; Zhang, Xuemei

    2016-01-01

    Large conductance calcium-activated potassium (BK) channels participate in many important physiological functions in excitable tissues such as neurons, cardiac and smooth muscles, whereas the knowledge of BK channels in bone tissues and osteoblasts remains elusive. To investigate the role of BK channels in osteoblasts, we used transcription activator-like effector nuclease (TALEN) to establish a BK knockout cell line on rat ROS17/2.8 osteoblast, and detected the proliferation and mineralization of the BK-knockout cells. Our study found that the BK-knockout cells significantly decreased the ability of proliferation and mineralization as osteoblasts, compared to the wild type cells. The overall expression of osteoblast differentiation marker genes in the BK-knockout cells was significantly lower than that in wild type osteoblast cells. The BK-knockout osteoblast cell line in our study displays a phenotype decrease in osteoblast function which can mimic the pathological state of osteoblast and thus provide a working cell line as a tool for study of osteoblast function and bone related diseases. PMID:27329042

  12. PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

    PubMed Central

    Knight, Walter E.; Chen, Si; Zhang, Yishuai; Oikawa, Masayoshi; Wu, Meiping; Zhou, Qian; Miller, Clint L.; Cai, Yujun; Mickelsen, Deanne M.; Moravec, Christine; Small, Eric M.; Abe, Junichi; Yan, Chen

    2016-01-01

    Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance. PMID:27791092

  13. Nitric oxide synthase in cardiac sarcoplasmic reticulum.

    PubMed

    Xu, K Y; Huso, D L; Dawson, T M; Bredt, D S; Becker, L C

    1999-01-19

    NO. is a free radical that modulates heart function and metabolism. We report that a neuronal-type NO synthase (NOS) is located on cardiac sarcoplasmic reticulum (SR) membrane vesicles and that endogenous NO. produced by SR-associated NOS inhibits SR Ca2+ uptake. Ca2+-dependent biochemical conversion of L-arginine to L-citrulline was observed from isolated rabbit cardiac SR vesicles in the presence of NOS substrates and cofactors. Endogenous NO. was generated from the vesicles and detected by electron paramagnetic resonance spin-trapping measurements. Immunoelectron microscopy demonstrated labeling of cardiac SR vesicles by using anti-neuronal NOS (nNOS), but not anti-endothelial NOS (eNOS) or anti-inducible NOS (iNOS) antibodies, whereas skeletal muscle SR vesicles had no nNOS immunoreactivity. The nNOS immunoreactivity also displayed a pattern consistent with SR localization in confocal micrographs of sections of human myocardium. Western blotting demonstrated that cardiac SR NOS is larger than brain NOS (160 vs. 155 kDa). No immunodetection was observed in cardiac SR vesicles from nNOS knockout mice or with an anti-nNOS mu antibody, suggesting the possibility of a new nNOS-type isoform. 45Ca uptake by cardiac SR vesicles, catalyzed by Ca2+-ATPase, was inhibited by NO. produced endogenously from cardiac SR NOS, and 7-nitroindazole, a selective nNOS inhibitor, completely prevented this inhibition. These results suggest that a cardiac muscle nNOS isoform is located on SR of cardiac myocytes, where it may respond to intracellular Ca2+ concentration and modulate SR Ca2+ ion active transport in the heart.

  14. Nitric oxide synthase in cardiac sarcoplasmic reticulum

    PubMed Central

    Xu, Kai Y.; Huso, David L.; Dawson, Ted M.; Bredt, David S.; Becker, Lewis C.

    1999-01-01

    NO⋅ is a free radical that modulates heart function and metabolism. We report that a neuronal-type NO synthase (NOS) is located on cardiac sarcoplasmic reticulum (SR) membrane vesicles and that endogenous NO⋅ produced by SR-associated NOS inhibits SR Ca2+ uptake. Ca2+-dependent biochemical conversion of l-arginine to l-citrulline was observed from isolated rabbit cardiac SR vesicles in the presence of NOS substrates and cofactors. Endogenous NO⋅ was generated from the vesicles and detected by electron paramagnetic resonance spin-trapping measurements. Immunoelectron microscopy demonstrated labeling of cardiac SR vesicles by using anti-neuronal NOS (nNOS), but not anti-endothelial NOS (eNOS) or anti-inducible NOS (iNOS) antibodies, whereas skeletal muscle SR vesicles had no nNOS immunoreactivity. The nNOS immunoreactivity also displayed a pattern consistent with SR localization in confocal micrographs of sections of human myocardium. Western blotting demonstrated that cardiac SR NOS is larger than brain NOS (160 vs. 155 kDa). No immunodetection was observed in cardiac SR vesicles from nNOS knockout mice or with an anti-nNOSμ antibody, suggesting the possibility of a new nNOS-type isoform. 45Ca uptake by cardiac SR vesicles, catalyzed by Ca2+-ATPase, was inhibited by NO⋅ produced endogenously from cardiac SR NOS, and 7-nitroindazole, a selective nNOS inhibitor, completely prevented this inhibition. These results suggest that a cardiac muscle nNOS isoform is located on SR of cardiac myocytes, where it may respond to intracellular Ca2+ concentration and modulate SR Ca2+ ion active transport in the heart. PMID:9892689

  15. Toll-like receptor 4 knockout alleviates paraquat-induced cardiomyocyte contractile dysfunction through an autophagy-dependent mechanism.

    PubMed

    Wang, Shuyi; Zhu, Xiaoling; Xiong, Lize; Zhang, Yingmei; Ren, Jun

    2016-08-22

    Paraquat, a quarternary nitrogen herbicide, is a toxic prooxidant leading to multi-organ failure including the heart although the underlying mechanism remains poorly understood. This study was designed to examine the role of the innate proinflammatory mediator toll-like receptor 4 (TLR4) in paraquat-induced cardiac contractile anomalies and the underlying mechanisms involved with a focus on autophagy, a conservative machinery governing protein and organelle degradation and recycling for cardiac homeostasis. Wild-type (WT) and TLR4 knockout (TLR4(-/-)) mice were challenged with paraquat (45mg/kg, i.p.) for 48h. Paraquat challenge did not affect mRNA levels of TLR2, TLR4 and TLR9 in WT mice nor did paraquat treatment alter TREM-1 levels. Paraquat challenge elicited cardiac mechanical defects including compromised cardiomyocyte contractile function, intracellular Ca(2+) handling, and overt autophagy as manifested by increased LC3BII-to-LC3BI ratio, Atg5, Atg7 and p62 levels. Interestingly, TLR4 knockout significantly attenuated paraquat-induced cardiac contractile and intracellular Ca(2+) derangement as well as alterations of autophagy markers. Paraquat-elicited changes in cardiac autophagy markers (LC3BII, LC3BII-to-LC3BI ratio and p62) were augmented by lysosomal inhibition using bafilomycin A1 in WT mice. TLR4 knockout significantly attenuated or negated paraquat-elicited increase in LC3BII, LC3BII-to-LC3BI ratio and p62 levels in the presence of lysosomal inhibition. In addition, paraquat challenge promoted phosphorylation of AMPK while suppressing the phosphorylation of mTOR and ULK1 (the autophagy inhibitory Ser(757)), the effects of which were significantly attenuated by TLR4 ablation. In vitro study revealed that AMPK activation using AICAR or mTOR inhibition using rapamycin effectively negated the beneficial cardiomyocyte mechanical effects of TLR4 inhibition (CLI-095) against paraquat toxicity, supporting a permissive role for AMPK-mTOR in TLR4 inhibition

  16. Novel Protective Role of Endogenous Cardiac Myocyte P2X4 Receptors in Heart Failure

    PubMed Central

    Yang, Tiehong; Shen, Jian-bing; Yang, Ronghua; Redden, John; Dodge-Kafka, Kimberly; Grady, James; Jacobson, Kenneth A.; Liang, Bruce T.

    2014-01-01

    Background Heart failure (HF), despite continuing progress, remains a leading cause of mortality and morbidity. P2X4 receptors (P2X4R) have emerged as potentially important molecules in regulating cardiac function and as potential targets for HF therapy. Transgenic P2X4R overexpression can protect against HF, but this does not explain the role of native cardiac P2X4R. Our goal is to define the physiological role of endogenous cardiac myocyte P2X4R under basal conditions and during HF induced by myocardial infarction or pressure overload. Methods and Results Mice established with conditional cardiac-specific P2X4R knockout were subjected to left anterior descending coronary artery ligation–induced postinfarct or transverse aorta constriction–induced pressure overload HF. Knockout cardiac myocytes did not show P2X4R by immunoblotting or by any response to the P2X4R-specific allosteric enhancer ivermectin. Knockout hearts showed normal basal cardiac function but depressed contractile performance in postinfarct and pressure overload models of HF by in vivo echocardiography and ex vivo isolated working heart parameters. P2X4R coimmunoprecipitated and colocalized with nitric oxide synthase 3 (eNOS) in wild-type cardiac myocytes. Mice with cardiac-specific P2X4R overexpression had increased S-nitrosylation, cyclic GMP, NO formation, and were protected from postinfarct and pressure overload HF. Inhibitor of eNOS, L-N5-(1-iminoethyl)ornithine hydrochloride, blocked the salutary effect of cardiac P2X4R overexpression in postinfarct and pressure overload HF as did eNOS knockout. Conclusions This study establishes a new protective role for endogenous cardiac myocyte P2X4R in HF and is the first to demonstrate a physical interaction between the myocyte receptor and eNOS, a mediator of HF protection. PMID:24622244

  17. Cardiac Rehabilitation

    MedlinePlus

    ... your risk of future heart problems, and to improve your health and quality of life. Cardiac rehabilitation programs increase ... exercise routine at home or at a local gym. You may also continue to ... health concerns. Education about nutrition, lifestyle and weight loss ...

  18. Knockout mouse production assisted by Blm knockdown

    PubMed Central

    FUKUDA, Mikiko; INOUE, Mayuko; MURAMATSU, Daisuke; MIYACHI, Hitoshi; SHINKAI, Yoichi

    2015-01-01

    Production of knockout mice using targeted embryonic stem cells (ESCs) is a powerful approach for investigating the function of specific genes in vivo. Although the protocol for gene targeting via homologous recombination (HR) in ESCs is already well established, the targeting efficiency varies at different target loci and is sometimes too low. It is known that knockdown of the Bloom syndrome gene, BLM, enhances HR-mediated gene targeting efficiencies in various cell lines. However, it has not yet been investigated whether this approach in ESCs is applicable for successful knockout mouse production. Therefore, we attempted to answer this question. Consistent with previous reports, Blm knockdown enhanced gene targeting efficiencies for three gene loci that we examined by 2.3–4.1-fold. Furthermore, the targeted ESC clones generated good chimeras and were successful in germline transmission. These data suggest that Blm knockdown provides a general benefit for efficient ESC-based and HR-mediated knockout mouse production. PMID:26598326

  19. Heat shock response: lessons from mouse knockouts.

    PubMed

    Christians, E S; Benjamin, I J

    2006-01-01

    Organisms are endowed with integrated regulatory networks that transduce and amplify incoming signals into effective responses, ultimately imparting cell death and/or survival pathways. As a conserved cytoprotective mechanism from bacteria to humans, the heat shock response has been established as a paradigm for inducible gene expression, stimulating the interests of biologists and clinicians alike to tackle fundamental questions related to the molecular switches, lineage-specific requirements, unique and/or redundant roles, and even efforts to harness the response therapeutically. Gene targeting studies in mice confirm HSF1 as a master regulator required for cell growth, embryonic development, and reproduction. For example, sterility of Hsf1-null female but not null male mice established strict requirements for maternal HSF1 expression in the oocyte. Yet Hsf2 knockouts by three independent laboratories have not fully clarified the role of mammalian HSF2 for normal development, fertility, and postnatal neuronal function. In contrast, Hsf4 knockouts have provided a consistent demonstration for HSF4's critical role during lens formation. In the future, molecular analysis of HSF knockout mice will bring new insights to HSF interactions, foster better understanding of gene regulation at the genome level, lead to a better integration of the HSF pathway in life beyond heat shock, the classical laboratory challenge.

  20. Macrophage Migration Inhibitory Factor (MIF) Deficiency Exacerbates Aging-Induced Cardiac Remodeling and Dysfunction Despite Improved Inflammation: Role of Autophagy Regulation

    PubMed Central

    Xu, Xihui; Pang, Jiaojiao; Chen, Yuguo; Bucala, Richard; Zhang, Yingmei; Ren, Jun

    2016-01-01

    Aging leads to unfavorable geometric and functional sequelae in the heart. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) plays a role in the maintenance of cardiac homeostasis under stress conditions although its impact in cardiac aging remains elusive. This study was designed to evaluate the role of MIF in aging-induced cardiac anomalies and the underlying mechanism involved. Cardiac geometry, contractile and intracellular Ca2+ properties were examined in young (3–4 mo) or old (24 mo) wild type and MIF knockout (MIF−/−) mice. Our data revealed that MIF knockout exacerbated aging-induced unfavorable structural and functional changes in the heart. The detrimental effect of MIF knockout was associated with accentuated loss in cardiac autophagy with aging. Aging promoted cardiac inflammation, the effect was attenuated by MIF knockout. Intriguingly, aging-induced unfavorable responses were reversed by treatment with the autophagy inducer rapamycin, with improved myocardial ATP availability in aged WT and MIF−/− mice. Using an in vitro model of senescence, MIF knockdown exacerbated doxorubicin-induced premature senescence in H9C2 myoblasts, the effect was ablated by MIF replenishment. Our data indicated that MIF knockout exacerbates aging-induced cardiac remodeling and functional anomalies despite improved inflammation, probably through attenuating loss of autophagy and ATP availability in the heart. PMID:26940544

  1. Macrophage Migration Inhibitory Factor (MIF) Deficiency Exacerbates Aging-Induced Cardiac Remodeling and Dysfunction Despite Improved Inflammation: Role of Autophagy Regulation.

    PubMed

    Xu, Xihui; Pang, Jiaojiao; Chen, Yuguo; Bucala, Richard; Zhang, Yingmei; Ren, Jun

    2016-03-04

    Aging leads to unfavorable geometric and functional sequelae in the heart. The proinflammatory cytokine macrophage migration inhibitory factor (MIF) plays a role in the maintenance of cardiac homeostasis under stress conditions although its impact in cardiac aging remains elusive. This study was designed to evaluate the role of MIF in aging-induced cardiac anomalies and the underlying mechanism involved. Cardiac geometry, contractile and intracellular Ca(2+) properties were examined in young (3-4 mo) or old (24 mo) wild type and MIF knockout (MIF(-/-)) mice. Our data revealed that MIF knockout exacerbated aging-induced unfavorable structural and functional changes in the heart. The detrimental effect of MIF knockout was associated with accentuated loss in cardiac autophagy with aging. Aging promoted cardiac inflammation, the effect was attenuated by MIF knockout. Intriguingly, aging-induced unfavorable responses were reversed by treatment with the autophagy inducer rapamycin, with improved myocardial ATP availability in aged WT and MIF(-/-) mice. Using an in vitro model of senescence, MIF knockdown exacerbated doxorubicin-induced premature senescence in H9C2 myoblasts, the effect was ablated by MIF replenishment. Our data indicated that MIF knockout exacerbates aging-induced cardiac remodeling and functional anomalies despite improved inflammation, probably through attenuating loss of autophagy and ATP availability in the heart.

  2. Generating double knockout mice to model genetic intervention for diabetic cardiomyopathy in humans.

    PubMed

    Chavali, Vishalakshi; Nandi, Shyam Sundar; Singh, Shree Ram; Mishra, Paras Kumar

    2014-01-01

    Diabetes is a rapidly increasing disease that enhances the chances of heart failure twofold to fourfold (as compared to age and sex matched nondiabetics) and becomes a leading cause of morbidity and mortality. There are two broad classifications of diabetes: type1 diabetes (T1D) and type2 diabetes (T2D). Several mice models mimic both T1D and T2D in humans. However, the genetic intervention to ameliorate diabetic cardiomyopathy in these mice often requires creating double knockout (DKO). In order to assess the therapeutic potential of a gene, that specific gene is either overexpressed (transgenic expression) or abrogated (knockout) in the diabetic mice. If the genetic mice model for diabetes is used, it is necessary to create DKO with transgenic/knockout of the target gene to investigate the specific role of that gene in pathological cardiac remodeling in diabetics. One of the important genes involved in extracellular matrix (ECM) remodeling in diabetes is matrix metalloproteinase-9 (Mmp9). Mmp9 is a collagenase that remains latent in healthy hearts but induced in diabetic hearts. Activated Mmp9 degrades extracellular matrix (ECM) and increases matrix turnover causing cardiac fibrosis that leads to heart failure. Insulin2 mutant (Ins2+/-) Akita is a genetic model for T1D that becomes diabetic spontaneously at the age of 3-4 weeks and show robust hyperglycemia at the age of 10-12 weeks. It is a chronic model of T1D. In Ins2+/- Akita, Mmp9 is induced. To investigate the specific role of Mmp9 in diabetic hearts, it is necessary to create diabetic mice where Mmp9 gene is deleted. Here, we describe the method to generate Ins2+/-/Mmp9-/- (DKO) mice to determine whether the abrogation of Mmp9 ameliorates diabetic cardiomyopathy.

  3. 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

  4. 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

  5. Universal statistics of the knockout tournament

    NASA Astrophysics Data System (ADS)

    Baek, Seung Ki; Yi, Il Gu; Park, Hye Jin; Kim, Beom Jun

    2013-11-01

    We study statistics of the knockout tournament, where only the winner of a fixture progresses to the next. We assign a real number called competitiveness to each contestant and find that the resulting distribution of prize money follows a power law with an exponent close to unity if the competitiveness is a stable quantity and a decisive factor to win a match. Otherwise, the distribution is found narrow. The existing observation of power law distributions in various kinds of real sports tournaments therefore suggests that the rules of those games are constructed in such a way that it is possible to understand the games in terms of the contestants' inherent characteristics of competitiveness.

  6. Universal statistics of the knockout tournament.

    PubMed

    Baek, Seung Ki; Yi, Il Gu; Park, Hye Jin; Kim, Beom Jun

    2013-11-12

    We study statistics of the knockout tournament, where only the winner of a fixture progresses to the next. We assign a real number called competitiveness to each contestant and find that the resulting distribution of prize money follows a power law with an exponent close to unity if the competitiveness is a stable quantity and a decisive factor to win a match. Otherwise, the distribution is found narrow. The existing observation of power law distributions in various kinds of real sports tournaments therefore suggests that the rules of those games are constructed in such a way that it is possible to understand the games in terms of the contestants' inherent characteristics of competitiveness.

  7. Action of SNAIL1 in Cardiac Myofibroblasts Is Important for Cardiac Fibrosis following Hypoxic Injury

    PubMed Central

    Biswas, Hirak; Longmore, Gregory D.

    2016-01-01

    Hypoxic injury to the heart results in cardiac fibrosis that leads to cardiac dysfunction and heart failure. SNAIL1 is a zinc finger transcription factor implicated in fibrosis following organ injury and cancer. To determine if the action of SNAIL1 contributed to cardiac fibrosis following hypoxic injury, we used an endogenous SNAIL1 bioluminescence reporter mice, and SNAIL1 knockout mouse models. Here we report that SNAIL1 expression is upregulated in the infarcted heart, especially in the myofibroblasts. Utilizing primary cardiac fibroblasts in ex vivo cultures we find that pro-fibrotic factors and collagen I increase SNAIL1 protein level. SNAIL1 is required in cardiac fibroblasts for the adoption of myofibroblast fate, collagen I expression and expression of fibrosis-related genes. Taken together this data suggests that SNAIL1 expression is induced in the cardiac fibroblasts after hypoxic injury and contributes to myofibroblast phenotype and a fibrotic scar formation. Resultant collagen deposition in the scar can maintain elevated SNAIL1 expression in the myofibroblasts and help propagate fibrosis. PMID:27706205

  8. Cardiac-specific overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic preconditioning

    PubMed Central

    Tsutsumi, Yasuo M.; Horikawa, Yousuke T.; Jennings, Michelle M.; Kidd, Michael W.; Niesman, Ingrid R.; Yokoyama, Utako; Head, Brian P.; Hagiwara, Yasuko; Ishikawa, Yoshihiro; Miyanohara, Atsushi; Patel, Piyush M.; Insel, Paul A.; Patel, Hemal H.; Roth, David M.

    2009-01-01

    Background Caveolae, lipid-rich microdomains of the sarcolemma, localize and enrich cardiac protective signaling molecules. Caveolin-3 (Cav-3), the dominant isoform in cardiac myocytes, is a determinant of caveolae formation. We hypothesized that cardiac myocyte-specific overexpression of Cav-3 would enhance the formation of caveolae and augment cardiac protection in vivo. Methods and Results Ischemic preconditioning (IPC) in vivo increased formation of caveolae. Adenovirus for Cav-3 increased caveolar formation and phosphorylation of survival kinases in cardiac myocytes. A transgenic (TG) mouse with cardiac myocyte-specific overexpression of Cav-3 (Cav-3 OE) showed enhanced formation of caveolae on the sarcolemma. Cav-3 OE mice subjected to ischemia/reperfusion injury had a significantly reduced infarct size relative to TGneg mice. Endogenous cardiac protection in Cav-3 OE mice was similar to wild-type mice undergoing IPC; no increased protection was observed in preconditioned Cav-3 OE mice. Cav-3 knockout mice did not show endogenous protection and showed no protection in response to IPC. Cav-3 OE mouse hearts had increased basal Akt and GSK3β phosphorylation comparable to wild-type mice exposed to IPC. Wortmannin, a PI3K inhibitor, attenuated basal phosphorylation of Akt and GSK3β and blocked cardiac protection in Cav-3 OE mice. Cav-3 OE mice had improved functional recovery and reduced apoptosis at 24 h of reperfusion. Conclusion Expression of caveolin-3 is both necessary and sufficient for cardiac protection, a conclusion that unites long-standing ultrastructural and molecular observations in the ischemic heart. The current results indicate that increased expression of caveolins, apparently via actions that depend on PI3K, has the potential to protect hearts exposed to ischemia-reperfusion injury. PMID:18936328

  9. Altered Reward Circuitry in the Norepinephrine Transporter Knockout Mouse

    PubMed Central

    Hall, F. Scott; Uhl, George R.; Bearer, Elaine L.; Jacobs, Russell E.

    2013-01-01

    Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET), using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of

  10. [Preliminary exploration on knockout drops (Meng Han Agents)].

    PubMed

    Zhang, Z

    1996-05-01

    This author points out, based on relevant materials, that knockout drops were vertigo powder. Due to homophonic reasons in Chinese language, the term "mingxuan" was transliterated into the former Chinese term (menghan). Knockout drops for medicinal use were merely made up of compound recipes containing stramonium flowers. The knockout drops in old fictions and opera books were powder of stramonium flower. The ingredients and application of such recipes are discussed here, the anti-remedies for such recipes are also mentioned.

  11. About Cardiac Arrest

    MedlinePlus

    ... Thromboembolism Aortic Aneurysm More About Cardiac Arrest Updated:Mar 10,2017 What is cardiac arrest? Cardiac arrest is the abrupt loss of heart function in a person who may or may not have diagnosed heart ...

  12. Maximal Oxygen Consumption Is Reduced in Aquaporin-1 Knockout Mice

    PubMed Central

    Al-Samir, Samer; Goossens, Dominique; Cartron, Jean-Pierre; Nielsen, Søren; Scherbarth, Frank; Steinlechner, Stephan; Gros, Gerolf; Endeward, Volker

    2016-01-01

    We have measured maximal oxygen consumption (V˙O2,max) of mice lacking one or two of the established mouse red-cell CO2 channels AQP1, AQP9, and Rhag. We intended to study whether these proteins, by acting as channels for O2, determine O2 exchange in the lung and in the periphery. We found that V˙O2,max as determined by the Helox technique is reduced by ~16%, when AQP1 is knocked out, but not when AQP9 or Rhag are lacking. This figure holds for animals respiring normoxic as well as hypoxic gas mixtures. To see whether the reduction of V˙O2,max is due to impaired O2 uptake in the lung, we measured carotid arterial O2 saturation (SO2) by pulse oximetry. Neither under normoxic (inspiratory O2 21%) nor under hypoxic conditions (11% O2) is there a difference in SO2 between AQP1null and WT mice, suggesting that AQP1 is not critical for O2 uptake in the lung. The fact that the % reduction of V˙O2,max is identical in normoxia and hypoxia indicates moreover that the limitation of V˙O2,max is not due to an O2 diffusion problem, neither in the lung nor in the periphery. Instead, it appears likely that AQP1null animals exhibit a reduced V˙O2,max due to the reduced wall thickness and muscle mass of the left ventricles of their hearts, as reported previously. We conclude that very likely the properties of the hearts of AQP1 knockout mice cause a reduced maximal cardiac output and thus cause a reduced V˙O2,max, which constitutes a new phenotype of these mice. PMID:27559317

  13. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension.

    PubMed

    Martínez-Martínez, Ernesto; Calvier, Laurent; Fernández-Celis, Amaya; Rousseau, Elodie; Jurado-López, Raquel; Rossoni, Luciana V; Jaisser, Frederic; Zannad, Faiez; Rossignol, Patrick; Cachofeiro, Victoria; López-Andrés, Natalia

    2015-10-01

    Hypertensive cardiac remodeling is accompanied by molecular inflammation and fibrosis, 2 mechanisms that finally affect cardiac function. At cardiac level, aldosterone promotes inflammation and fibrosis, although the precise mechanisms are still unclear. Galectin-3 (Gal-3), a β-galactoside-binding lectin, is associated with inflammation and fibrosis in the cardiovascular system. We herein investigated whether Gal-3 inhibition could block aldosterone-induced cardiac inflammation and fibrosis and its potential role in cardiac damage associated with hypertension. Aldosterone-salt-treated rats presented hypertension, cardiac inflammation, and fibrosis that were prevented by the pharmacological inhibition of Gal-3 with modified citrus pectin. Cardiac inflammation and fibrosis presented in spontaneously hypertensive rats were prevented by modified citrus pectin treatment, whereas Gal-3 blockade did not modify blood pressure levels. In the absence of blood pressure modifications, Gal-3 knockout mice were resistant to aldosterone-induced cardiac inflammation. In human cardiac fibroblasts, aldosterone increased Gal-3 expression via its mineralocorticoid receptor. Gal-3 and aldosterone enhanced proinflammatory and profibrotic markers, as well as metalloproteinase activities in human cardiac fibroblasts, effects that were not observed in Gal-3-silenced cells treated with aldosterone. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac inflammation and fibrosis, alterations that were prevented by Gal-3 blockade independently of blood pressure levels. These data suggest that Gal-3 could be a new molecular mechanism linking cardiac inflammation and fibrosis in situations with high-aldosterone levels, such as hypertension.

  14. Oxytocin and behavior: Lessons from knockout mice.

    PubMed

    Caldwell, Heather K; Aulino, Elizabeth A; Freeman, Angela R; Miller, Travis V; Witchey, Shannah K

    2017-02-01

    It is well established that the nonapeptide oxytocin (Oxt) is important for the neural modulation of behaviors in many mammalian species. Since its discovery in 1906 and synthesis in the early 1950s, elegant pharmacological work has helped identify specific neural substrates on which Oxt exerts its effects. More recently, mice with targeted genetic disruptions of the Oxt system-i.e., both the peptide and its receptor (the Oxtr)-have further defined Oxt's actions and laid some important scientific groundwork for studies in other species. In this article, we highlight the scientific contributions that various mouse knockouts of the Oxt system have made to our understanding of Oxt's modulation of behavior. We specifically focus on how the use of these mice has shed light on our understanding of social recognition memory, maternal behavior, aggression, and several nonsocial behaviors. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 190-201, 2017.

  15. p53 regulates the cardiac transcriptome

    PubMed Central

    Mak, Tak W.; Hauck, Ludger; Grothe, Daniela; Billia, Filio

    2017-01-01

    The tumor suppressor Trp53 (p53) inhibits cell growth after acute stress by regulating gene transcription. The mammalian genome contains hundreds of p53-binding sites. However, whether p53 participates in the regulation of cardiac tissue homeostasis under normal conditions is not known. To examine the physiologic role of p53 in adult cardiomyocytes in vivo, Cre-loxP–mediated conditional gene targeting in adult mice was used. Genome-wide transcriptome analyses of conditional heart-specific p53 knockout mice were performed. Genome-wide annotation and pathway analyses of >5,000 differentially expressed transcripts identified many p53-regulated gene clusters. Correlative analyses identified >20 gene sets containing more than 1,000 genes relevant to cardiac architecture and function. These transcriptomic changes orchestrate cardiac architecture, excitation-contraction coupling, mitochondrial biogenesis, and oxidative phosphorylation capacity. Interestingly, the gene expression signature in p53-deficient hearts confers resistance to acute biomechanical stress. The data presented here demonstrate a role for p53, a previously unrecognized master regulator of the cardiac transcriptome. The complex contributions of p53 define a biological paradigm for the p53 regulator network in the heart under physiological conditions. PMID:28193895

  16. ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism

    PubMed Central

    Tian, Zhe; Miyata, Keishi; Kadomatsu, Tsuyoshi; Horiguchi, Haruki; Fukushima, Hiroyuki; Tohyama, Shugo; Ujihara, Yoshihiro; Okumura, Takahiro; Yamaguchi, Satoshi; Zhao, Jiabin; Endo, Motoyoshi; Morinaga, Jun; Sato, Michio; Sugizaki, Taichi; Zhu, Shunshun; Terada, Kazutoyo; Sakaguchi, Hisashi; Komohara, Yoshihiro; Takeya, Motohiro; Takeda, Naoki; Araki, Kimi; Manabe, Ichiro; Fukuda, Keiichi; Otsu, Kinya; Wada, Jun; Murohara, Toyoaki; Mohri, Satoshi; Yamashita, Jun K.; Sano, Motoaki; Oike, Yuichi

    2016-01-01

    A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure. PMID:27677409

  17. Cardiac xenotransplantation.

    PubMed

    DiSesa, V J

    1997-12-01

    Heart failure is an important medical and public health problem. Although medical therapy is effective for many people, the only definitive therapy is heart transplantation, which is limited severely by the number of donors. Mechanical devices presently are used as "bridges" to transplantation. Their widespread use may solve the donor shortage problem, but at present, mechanical devices are limited by problems related to blood clotting, power supply, and foreign body infection. Cardiac xenotransplantation using animal donors is a potential biologic solution to the donor organ shortage. The immune response, consisting of hyperacute rejection, acute vascular rejection, and cellular rejection, currently prevents clinical xenotransplantation. Advances in the solution of these problems have been made using conventional immunosuppressive drugs and newer agents whose use is based on an understanding of important steps in xenoimmunity. The most exciting approaches use tools of molecular biology to create genetically engineered donors and to induce states of donor and recipient bone marrow chimerism and tolerance in xenogeneic organ recipients. The successful future strategy may use a combination of a genetically engineered donor and a chimeric recipient with or without nonspecific immunosuppressive drugs.

  18. Deletion of Pr130 Interrupts Cardiac Development in Zebrafish

    PubMed Central

    Yang, Jie; Li, Zuhua; Gan, Xuedong; Zhai, Gang; Gao, Jiajia; Xiong, Chenling; Qiu, Xueping; Wang, Xuebin; Yin, Zhan; Zheng, Fang

    2016-01-01

    Protein phosphatase 2 regulatory subunit B, alpha (PPP2R3A), a regulatory subunit of protein phosphatase 2A (PP2A), is a major serine/threonine phosphatase that regulates crucial function in development and growth. Previous research has implied that PPP2R3A was involved in heart failure, and PR130, the largest transcription of PPP2R3A, functioning in the calcium release of sarcoplasmic reticulum (SR), plays an important role in the excitation-contraction (EC) coupling. To obtain a better understanding of PR130 functions in myocardium and cardiac development, two pr130-deletion zebrafish lines were generated using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas) system. Pr130-knockout zebrafish exhibited cardiac looping defects and decreased cardiac function (decreased fractional area and fractional shortening). Hematoxylin and eosin (H&E) staining demonstrated reduced cardiomyocytes. Subsequent transmission electron microscopy revealed that the bright and dark bands were narrowed and blurred, the Z- and M-lines were fogged, and the gaps between longitudinal myocardial fibers were increased. Additionally, increased apoptosis was observed in cardiomyocyte in pr130-knockout zebrafish compared to wild-type (WT). Taken together, our results suggest that pr130 is required for normal myocardium formation and efficient cardiac contractile function. PMID:27845735

  19. AMPK: Lessons from transgenic and knockout animals

    PubMed Central

    Viollet, Benoit; Athea, Yoni; Mounier, Remi; Guigas, Bruno; Zarrinpashneh, Elham; Horman, Sandrine; Lantier, Louise; Hebrard, Sophie; Devin-Leclerc, Jocelyne; Beauloye, Christophe; Foretz, Marc; Andreelli, Fabrizio; Ventura-Clapier, Renee; Bertrand, Luc

    2009-01-01

    AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been proposed to function as a ‘fuel gauge’ to monitor cellular energy status in response to nutritional environmental variations. AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. Numerous observations obtained with pharmacological activators and agents that deplete intracellular ATP have been supportive of AMPK playing a role in the control of energy metabolism but none of these studies have provided conclusive evidence. Relatively recent developments in our understanding of precisely how AMPK complexes might operate to control energy metabolism is due in part to the development of transgenic and knockout mouse models. Although there are inevitable caveats with genetic models, some important findings have emerged. In the present review, we discuss recent findings obtained from animal models with inhibition or activation of AMPK signaling pathway. PMID:19273052

  20. Lipid transport in cholecystokinin knockout mice.

    PubMed

    King, Alexandra; Yang, Qing; Huesman, Sarah; Rider, Therese; Lo, Chunmin C

    2015-11-01

    Cholecystokinin (CCK) is released in response to lipid feeding and regulates pancreatic digestive enzymes vital to the absorption of nutrients. Our previous reports demonstrated that cholecystokinin knockout (CCK-KO) mice fed for 10 weeks of HFD had reduced body fat mass, but comparable glucose uptake by white adipose tissues and skeletal muscles. We hypothesized that CCK is involved in energy homeostasis and lipid transport from the small intestine to tissues in response to acute treatment with dietary lipids. CCK-KO mice with comparable fat absorption had increased energy expenditure and were resistant to HFD-induced obesity. Using intraduodenal infusion of butter fat and intravenous infusion using Liposyn III, we determined the mechanism of lipid transport from the small intestine to deposition in lymph and adipocytes in CCK-KO mice. CCK-KO mice had delayed secretion of Apo B48-chylomicrons, lipid transport to the lymphatic system, and triglyceride (TG)-derived fatty acid uptake by epididymal fat in response to acute treatment of intraduodenal lipids. In contrast, CCK-KO mice had comparable TG clearance and lipid uptake by white adipocytes in response to TGs in chylomicron-like emulsion. Thus, we concluded that CCK is important for lipid transport and energy expenditure to control body weight in response to dietary lipid feeding.

  1. Manipulation of Mouse Embryonic Stem Cells for Knockout Mouse Production

    PubMed Central

    Limaye, Advait; Hall, Bradford; Kulkarni, Ashok B

    2009-01-01

    The establishment of mouse embryonic stem (ES) cell liness has allowed for the generation of the knockout mouse. ES cells that are genetically altered in culture can then be manipulated to derive a whole mouse containing the desired mutation. To successfully generate a knockout mouse, however, the ES cells must be carefully cultivated in a pluripotent state throughout the gene targeting experiment. This unit describes detailed step-by-step protocols, reagents, equipment, and strategies needed for the successful generation of gene knockout embryonic stem cells using homologous recombination technologies. PMID:19731225

  2. Human Knockout Carriers: Dead, Diseased, Healthy, or Improved?

    PubMed Central

    Narasimhan, Vagheesh M.; Xue, Yali; Tyler-Smith, Chris

    2016-01-01

    Whole-genome and whole-exome sequence data from large numbers of individuals reveal that we all carry many variants predicted to inactivate genes (knockouts). This discovery raises questions about the phenotypic consequences of these knockouts and potentially allows us to study human gene function through the investigation of homozygous loss-of-function carriers. Here, we discuss strategies, recent results, and future prospects for large-scale human knockout studies. We examine their relevance to studying gene function, population genetics, and importantly, the implications for accurate clinical interpretations. PMID:26988438

  3. Phenotype of the taurine transporter knockout mouse.

    PubMed

    Warskulat, Ulrich; Heller-Stilb, Birgit; Oermann, Evelyn; Zilles, Karl; Haas, Helmut; Lang, Florian; Häussinger, Dieter

    2007-01-01

    This chapter reports present knowledge on the properties of mice with disrupted gene coding for the taurine transporter (taut-/- mice). Study of those mice unraveled some of the roles of taurine and its membrane transport for the development and maintenance of normal organ functions and morphology. When compared with wild-type controls, taut-/- mice have decreased taurine levels in skeletal and heart muscle by about 98%, in brain, kidney, plasma, and retina by 80 to 90%, and in liver by about 70%. taut-/- mice exhibit a lower body mass as well as a strongly reduced exercise capacity compared with taut+/- and wild-type mice. Furthermore, taut-/- mice show a variety of pathological features, for example, subtle derangement of renal osmoregulation, changes in neuroreceptor expression, and loss of long-term potentiation in the striatum, and they develop clinically relevant age-dependent disorders, for example, visual, auditory, and olfactory dysfunctions, unspecific hepatitis, and liver fibrosis. Taurine-deficient animal models such as acutely dietary-manipulated foxes and cats, pharmacologically induced taurine-deficient rats, and taurine transporter knockout mouse are powerful tools allowing identification of the mechanisms and complexities of diseases mediated by impaired taurine transport and taurine depletion (Chapman et al., 1993; Heller-Stilb et al., 2002; Huxtable, 1992; Lake, 1993; Moise et al., 1991; Novotny et al., 1991; Pion et al., 1987; Timbrell et al., 1995; Warskulat et al., 2004, 2006b). Taurine, which is the most abundant amino acid in many tissues, is normally found in intracellular concentrations of 10 to 70 mmol/kg in mammalian heart, brain, skeletal muscle, liver, and retina (Chapman et al., 1993; Green et al., 1991; Huxable, 1992; Timbrell et al., 1995). These high taurine levels are maintained by an ubiquitous expression of Na(+)-dependent taurine transporter (TAUT) in the plasma membrane (Burg, 1995; Kwon and Handler, 1995; Lang et al., 1998

  4. Pleiotropic effects in Eya3 knockout mice

    PubMed Central

    Söker, Torben; Dalke, Claudia; Puk, Oliver; Floss, Thomas; Becker, Lore; Bolle, Ines; Favor, Jack; Hans, Wolfgang; Hölter, Sabine M; Horsch, Marion; Kallnik, Magdalena; Kling, Eva; Moerth, Corinna; Schrewe, Anja; Stigloher, Christian; Topp, Stefanie; Gailus-Durner, Valerie; Naton, Beatrix; Beckers, Johannes; Fuchs, Helmut; Ivandic, Boris; Klopstock, Thomas; Schulz, Holger; Wolf, Eckhard; Wurst, Wolfgang; Bally-Cuif, Laure; de Angelis, Martin Hrabé; Graw, Jochen

    2008-01-01

    Background In Drosophila, mutations in the gene eyes absent (eya) lead to severe defects in eye development. The functions of its mammalian orthologs Eya1-4 are only partially understood and no mouse model exists for Eya3. Therefore, we characterized the phenotype of a new Eya3 knockout mouse mutant. Results Expression analysis of Eya3 by in-situ hybridizations and β-Gal-staining of Eya3 mutant mice revealed abundant expression of the gene throughout development, e.g. in brain, eyes, heart, somites and limbs suggesting pleiotropic effects of the mutated gene. A similar complex expression pattern was observed also in zebrafish embryos. The phenotype of young adult Eya3 mouse mutants was systematically analyzed within the German Mouse Clinic. There was no obvious defect in the eyes, ears and kidneys of Eya3 mutant mice. Homozygous mutants displayed decreased bone mineral content and shorter body length. In the lung, the tidal volume at rest was decreased, and electrocardiography showed increased JT- and PQ intervals as well as decreased QRS amplitude. Behavioral analysis of the mutants demonstrated a mild increase in exploratory behavior, but decreased locomotor activity and reduced muscle strength. Analysis of differential gene expression revealed 110 regulated genes in heart and brain. Using real-time PCR, we confirmed Nup155 being down regulated in both organs. Conclusion The loss of Eya3 in the mouse has no apparent effect on eye development. The wide-spread expression of Eya3 in mouse and zebrafish embryos is in contrast to the restricted expression pattern in Xenopus embryos. The loss of Eya3 in mice leads to a broad spectrum of minor physiological changes. Among them, the mutant mice move less than the wild-type mice and, together with the effects on respiratory, muscle and heart function, the mutation might lead to more severe effects when the mice become older. Therefore, future investigations of Eya3 function should focus on aging mice. PMID:19102749

  5. Sleep in Kcna2 knockout mice

    PubMed Central

    Douglas, Christopher L; Vyazovskiy, Vladyslav; Southard, Teresa; Chiu, Shing-Yan; Messing, Albee; Tononi, Giulio; Cirelli, Chiara

    2007-01-01

    Background Shaker codes for a Drosophila voltage-dependent potassium channel. Flies carrying Shaker null or hypomorphic mutations sleep 3–4 h/day instead of 8–14 h/day as their wild-type siblings do. Shaker-like channels are conserved across species but it is unknown whether they affect sleep in mammals. To address this issue, we studied sleep in Kcna2 knockout (KO) mice. Kcna2 codes for Kv1.2, the alpha subunit of a Shaker-like voltage-dependent potassium channel with high expression in the mammalian thalamocortical system. Results Continuous (24 h) electroencephalograph (EEG), electromyogram (EMG), and video recordings were used to measure sleep and waking in Kcna2 KO, heterozygous (HZ) and wild-type (WT) pups (P17) and HZ and WT adult mice (P67). Sleep stages were scored visually based on 4-s epochs. EEG power spectra (0–20 Hz) were calculated on consecutive 4-s epochs. KO pups die by P28 due to generalized seizures. At P17 seizures are either absent or very rare in KO pups (< 1% of the 24-h recording time), and abnormal EEG activity is only present during the seizure. KO pups have significantly less non-rapid eye movement (NREM) sleep (-23%) and significantly more waking (+21%) than HZ and WT siblings with no change in rapid eye movement (REM) sleep time. The decrease in NREM sleep is due to an increase in the number of waking episodes, with no change in number or duration of sleep episodes. Sleep patterns, daily amounts of sleep and waking, and the response to 6 h sleep deprivation are similar in HZ and WT adult mice. Conclusion Kv1.2, a mammalian homologue of Shaker, regulates neuronal excitability and affects NREM sleep. PMID:17925011

  6. Exploring the opioid system by gene knockout.

    PubMed

    Kieffer, Brigitte L; Gavériaux-Ruff, Claire

    2002-04-01

    The endogenous opioid system consists of three opioid peptide precursor genes encoding enkephalins (preproenkephalin, Penk), dynorphins (preprodynorphin, Pdyn) and beta-endorphin (betaend), proopiomelanocortin (POMC) and three receptor genes encoding mu-opiod receptor (MOR), delta-opiod receptor (DOR) and kappa-opiod receptor (KOR). In the past years, all six genes have been inactivated in mice by homologous recombination. The analysis of spontaneous behavior in mutant mice has demonstrated significant and distinct roles of each gene in modulating locomotion, pain perception and emotional behaviors. The observation of opposing phenotypes of MOR- and DOR-deficient mice in several behaviors highlights unexpected roles for DOR to be further explored genetically and using more specific delta compounds. The analysis of responses of mutant mice to exogenous opiates has definitely clarified the essential role of MOR in both morphine analgesia and addiction, and demonstrated that DOR and KOR remain promising targets for pain treatment. These studies also show that prototypic DOR agonists partially require MOR for their biological activity and provide some support for the postulated mu-delta interactions in vivo. Finally, data confirm and define a role for several genes of the opioid system in responses to other drugs of abuse, and the triple opioid receptor knockout mutant allows exploring non-classical opioid pharmacology. In summary, the study of null mutant mice has extended our previous knowledge of the opioid system by identifying the molecular players in opioid pharmacology and physiology. Future studies should involve parallel behavioral analysis of mice lacking receptors and peptides and will benefit from more sophisticated gene targeting approaches, including site-directed and anatomically-restricted mutations.

  7. Methylphenidate restores novel object recognition in DARPP-32 knockout mice.

    PubMed

    Heyser, Charles J; McNaughton, Caitlyn H; Vishnevetsky, Donna; Fienberg, Allen A

    2013-09-15

    Previously, we have shown that Dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32) knockout mice required significantly more trials to reach criterion than wild-type mice in an operant reversal-learning task. The present study was conducted to examine adult male and female DARPP-32 knockout mice and wild-type controls in a novel object recognition test. Wild-type and knockout mice exhibited comparable behavior during the initial exploration trials. As expected, wild-type mice exhibited preferential exploration of the novel object during the substitution test, demonstrating recognition memory. In contrast, knockout mice did not show preferential exploration of the novel object, instead exhibiting an increase in exploration of all objects during the test trial. Given that the removal of DARPP-32 is an intracellular manipulation, it seemed possible to pharmacologically restore some cellular activity and behavior by stimulating dopamine receptors. Therefore, a second experiment was conducted examining the effect of methylphenidate. The results show that methylphenidate increased horizontal activity in both wild-type and knockout mice, though this increase was blunted in knockout mice. Pretreatment with methylphenidate significantly impaired novel object recognition in wild-type mice. In contrast, pretreatment with methylphenidate restored the behavior of DARPP-32 knockout mice to that observed in wild-type mice given saline. These results provide additional evidence for a functional role of DARPP-32 in the mediation of processes underlying learning and memory. These results also indicate that the behavioral deficits in DARPP-32 knockout mice may be restored by the administration of methylphenidate.

  8. Cardiac tamponade (image)

    MedlinePlus

    Cardiac tamponade is a condition involving compression of the heart caused by blood or fluid accumulation in the space ... they cannot adequately fill or pump blood. Cardiac tamponade is an emergency condition that requires hospitalization.

  9. Cardiac conduction system

    MedlinePlus Videos and Cool Tools

    ... cardiac muscle cells in the walls of the heart that send signals to the heart muscle causing it to contract. The main components ... the cardiac conduction system's electrical activity in the heart.

  10. Sudden Cardiac Arrest

    MedlinePlus

    ... from American Heart Association Aneurysms and Dissections Angina Arrhythmia Bundle Branch Block Cardiomyopathy Carotid Artery Disease Chronic ... terms: SCA, sudden cardiac death (SCD), sudden death, arrhythmias, ... ventricular fibrillation, defibrillator, automatic cardiac defibrillator ( ...

  11. What Is Cardiac Rehabilitation?

    MedlinePlus

    ANSWERS by heart Treatments + Tests What Is Cardiac Rehabilitation? A cardiac rehabilitation (rehab) program takes place in a hospital or ... special help in making lifestyle changes. During your rehabilitation program you’ll… • Have a medical evaluation to ...

  12. Exercise, Nrf2 and Antioxidant Signaling in Cardiac Aging

    PubMed Central

    Narasimhan, Madhusudhanan; Rajasekaran, Namakkal S.

    2016-01-01

    Aging is represented by a progressive decline in cellular functions. The age-related deformities in cardiac behaviors are the loss of cardiac myocytes through apoptosis or programmed cell death. Oxidative stress (OS) and its deleterious consequence contribute to age-related mechanical remodeling, reduced regenerative capacity, and apoptosis in cardiac tissue. The pathogenesis of OS in the elderly can predispose the heart to other cardiac complications such as atherosclerosis, hypertension, ischemic heart disease, cardiac myopathy, and so on. At the molecular level, oxidant-induced activation of Nrf2 (Nuclear erythroid-2-p45-related factor-2), a transcription factor, regulates several genes containing AREs (Antioxidant Response Element) and bring the respective translates to counteract the reactive radicals and establish homeostasis. Myriad of Nrf2 gene knockout studies in various organs such as lung, liver, kidney, brain, etc. have shown that dysregulation of Nrf2 severely affects the oxidant/ROS sensitivity and predispose the system to several pathological changes with aberrant cellular lesions. On the other hand, its gain of function chemical interventions exhibited oxidant stress resistance and cytoprotection. However, thus far, only a few investigations have shown the potential role of Nrf2 and its non-pharmacological induction in cardiac aging. Therefore, here we review the involvement of Nrf2 signaling along with its responses and ramifications on the cascade of OS under acute exercise stress (AES), moderate exercise training (MET), and endurance exercise stress (EES) conditions in the aging heart. PMID:27378947

  13. p21{sup WAF1/Cip1/Sdi1} knockout mice respond to doxorubicin with reduced cardiotoxicity

    SciTech Connect

    Terrand, Jerome; Xu, Beibei; Morrissy, Steve; Dinh, Thai Nho; Williams, Stuart; Chen, Qin M.

    2011-11-15

    Doxorubicin (Dox) is an antineoplastic agent that can cause cardiomyopathy in humans and experimental animals. As an inducer of reactive oxygen species and a DNA damaging agent, Dox causes elevated expression of p21{sup WAF1/Cip1/Sdi1} (p21) gene. Elevated levels of p21 mRNA and p21 protein have been detected in the myocardium of mice following Dox treatment. With chronic treatment of Dox, wild type (WT) animals develop cardiomyopathy evidenced by elongated nuclei, mitochondrial swelling, myofilamental disarray, reduced cardiac output, reduced ejection fraction, reduced left ventricular contractility, and elevated expression of ANF gene. In contrast, p21 knockout (p21KO) mice did not show significant changes in the same parameters in response to Dox treatment. In an effort to understand the mechanism of the resistance against Dox induced cardiomyopathy, we measured levels of antioxidant enzymes and found that p21KO mice did not contain elevated basal or inducible levels of glutathione peroxidase and catalase. Measurements of 6 circulating cytokines indicated elevation of IL-6, IL-12, IFN{gamma} and TNF{alpha} in Dox treated WT mice but not p21KO mice. Dox induced elevation of IL-6 mRNA was detected in the myocardium of WT mice but not p21KO mice. While the mechanism of the resistance against Dox induced cardiomyopathy remains unclear, lack of inflammatory response may contribute to the observed cardiac protection in p21KO mice. -- Highlights: Black-Right-Pointing-Pointer Doxorubicin induces p21 elevation in the myocardium. Black-Right-Pointing-Pointer Doxorubicin causes dilated cardiomyopathy in wild type mice. Black-Right-Pointing-Pointer p21 Knockout mice are resistant against doxorubicin induced cardiomyopathy. Black-Right-Pointing-Pointer Lack of inflammatory response correlates with the resistance in p21 knockout mice.

  14. Cardiac ion channels

    PubMed Central

    Priest, Birgit T; McDermott, Jeff S

    2015-01-01

    Ion channels are critical for all aspects of cardiac function, including rhythmicity and contractility. Consequently, ion channels are key targets for therapeutics aimed at cardiac pathophysiologies such as atrial fibrillation or angina. At the same time, off-target interactions of drugs with cardiac ion channels can be the cause of unwanted side effects. This manuscript aims to review the physiology and pharmacology of key cardiac ion channels. The intent is to highlight recent developments for therapeutic development, as well as elucidate potential mechanisms for drug-induced cardiac side effects, rather than present an in-depth review of each channel subtype. PMID:26556552

  15. Controlled Cardiac Computed Tomography

    PubMed Central

    Wang, Chenglin; Liu, Ying; Wang, Ge

    2006-01-01

    Cardiac computed tomography (CT) has been a hot topic for years because of the clinical importance of cardiac diseases and the rapid evolution of CT systems. In this paper, we propose a novel strategy for controlled cardiac CT that may effectively reduce image artifacts due to cardiac and respiratory motions. Our approach is radically different from existing ones and is based on controlling the X-ray source rotation velocity and powering status in reference to the cardiac motion. We theoretically show that by such a control-based intervention the data acquisition process can be optimized for cardiac CT in the cases of periodic and quasiperiodic cardiac motions. Specifically, we formulate the corresponding coordination/control schemes for either exact or approximate matches between the ideal and actual source positions, and report representative simulation results that support our analytic findings. PMID:23165017

  16. Endothelial Jarid2/Jumonji is required for normal cardiac development and proper Notch1 expression.

    PubMed

    Mysliwiec, Matthew R; Bresnick, Emery H; Lee, Youngsook

    2011-05-13

    Jarid2/Jumonji critically regulates developmental processes including cardiovascular development. Jarid2 knock-out mice exhibit cardiac defects including hypertrabeculation with noncompaction of the ventricular wall. However, molecular mechanisms underlying Jarid2-mediated cardiac development remain unknown. To determine the cardiac lineage-specific roles of Jarid2, we generated myocardial, epicardial, cardiac neural crest, or endothelial conditional Jarid2 knock-out mice using Cre-loxP technology. Only mice with an endothelial deletion of Jarid2 recapitulate phenotypic defects observed in whole body mutants including hypertrabeculation and noncompaction of the ventricle. To identify potential targets of Jarid2, combinatorial approaches using microarray and candidate gene analyses were employed on Jarid2 knock-out embryonic hearts. Whole body or endothelial deletion of Jarid2 leads to increased endocardial Notch1 expression in the developing ventricle, resulting in increased Notch1-dependent signaling to the adjacent myocardium. Using quantitative chromatin immunoprecipitation analysis, Jarid2 was found to occupy a specific region on the endogenous Notch1 locus. We propose that failure to properly regulate Notch signaling in Jarid2 mutants likely leads to the defects in the developing ventricular chamber. The identification of Jarid2 as a potential regulator of Notch1 signaling has broad implications for many cellular processes including development, stem cell maintenance, and tumor formation.

  17. Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression, Signaling Mechanisms, Physiologic Function, and Clinical Importance

    PubMed Central

    O’Connell, Timothy D.; Jensen, Brian C.; Baker, Anthony J.

    2014-01-01

    Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate “inside-out” signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure. PMID:24368739

  18. Stimulating endogenous cardiac repair

    PubMed Central

    Finan, Amanda; Richard, Sylvain

    2015-01-01

    The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair. However, the potential of these cells to completely regenerate the heart is limited. Efforts are now being focused on ways to augment these natural pathways to improve cardiac healing, primarily after ischemic injury but in other cardiac pathologies as well. Cell and gene therapy or pharmacological interventions are proposed mechanisms. Cell therapy has demonstrated modest results and has passed into clinical trials. However, the beneficial effects of cell therapy have primarily been their ability to produce paracrine effects on the cardiac tissue and recruit endogenous stem cell populations as opposed to direct cardiac regeneration. Gene therapy efforts have focused on prolonging or reactivating natural signaling pathways. Positive results have been demonstrated to activate the endogenous stem cell populations and are currently being tested in clinical trials. A potential new avenue may be to refine pharmacological treatments that are currently in place in the clinic. Evidence is mounting that drugs such as statins or beta blockers may alter endogenous stem cell activity. Understanding the effects of these drugs on stem cell repair while keeping in mind their primary function may strike a balance in myocardial healing. To maximize endogenous cardiac regeneration, a combination of these approaches could ameliorate the overall repair process to incorporate the participation of multiple cellular players. PMID:26484341

  19. Generation of conditional knockout alleles for PRL-3.

    PubMed

    Yan, Hong; Kong, Dong; Ge, Xiaomei; Gao, Xiang; Han, Xiao

    2011-11-01

    Phosphatase of regenerating liver-3 (PRL-3) is a member of the protein tyrosine phosphatase (PTP) superfamily and is highly expressed in cancer metastases. For better understanding of the role of PRL-3 in tumor metastasis, we applied a rapid and efficient method for generating PRL-3 floxed mice and investigated its phenotypes. A BAC retrieval strategy was applied to construct the PRL-3 conditional gene-targeting vector. Exon 4 was selected for deletion to generate a nonfunctional prematurely terminated short peptide as it will cause a frame-shift mutation. Conditional knockout PRL-3 mice were generated by using the Cre-loxP system and were validated by Southern blot and RT-PCR analysis. Further analysis revealed the phenotype characteristics of PRL-3 knockout mice and wildtype mice. In this study, we successfully constructed the PRL-3 conditional knockout mice, which will be helpful to clarify the roles of PRL-3 and the mechanisms in tumor metastasis.

  20. Using engineered endonucleases to create knockout and knockin zebrafish models.

    PubMed

    Bedell, Victoria M; Ekker, Stephen C

    2015-01-01

    Over the last few years, the technology to create targeted knockout and knockin zebrafish animals has exploded. We have gained the ability to create targeted knockouts through the use of zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR associated system (CRISPR/Cas). Furthermore, using the high-efficiency TALEN system, we were able to create knockin zebrafish using a single-stranded DNA (ssDNA) protocol described here. Through the use of these technologies, the zebrafish has become a valuable vertebrate model and an excellent bridge between the invertebrate and mammalian model systems for the study of human disease.

  1. Mammalian enabled (Mena) is a critical regulator of cardiac function.

    PubMed

    Aguilar, Frédérick; Belmonte, Stephen L; Ram, Rashmi; Noujaim, Sami F; Dunaevsky, Olga; Protack, Tricia L; Jalife, Jose; Todd Massey, H; Gertler, Frank B; Blaxall, Burns C

    2011-05-01

    Mammalian enabled (Mena) of the Drosophila enabled/vasodilator-stimulated phosphoprotein gene family is a cytoskeletal protein implicated in actin regulation and cell motility. Cardiac Mena expression is enriched in intercalated discs (ICD), the critical intercellular communication nexus between adjacent muscle cells. We previously identified Mena gene expression to be a key predictor of human and murine heart failure (HF). To determine the in vivo function of Mena in the heart, we assessed Mena protein expression in multiple HF models and characterized the effects of genetic Mena deletion on cardiac structure and function. Immunoblot analysis revealed significant upregulation of Mena protein expression in left ventricle tissue from patients with end-stage HF, calsequestrin-overexpressing mice, and isoproterenol-infused mice. Characterization of the baseline cardiac function of adult Mena knockout mice (Mena(-/-)) via echocardiography demonstrated persistent cardiac dysfunction, including a significant reduction in percent fractional shortening compared with wild-type littermates. Electrocardiogram PR and QRS intervals were significantly prolonged in Mena(-/-) mice, manifested by slowed conduction on optical mapping studies. Ultrastructural analysis of Mena(-/-) hearts revealed disrupted organization and widening of ICD structures, mislocalization of the gap junction protein connexin 43 (Cx43) to the lateral borders of cardiomyoycytes, and increased Cx43 expression. Furthermore, the expression of vinculin (an adherens junction protein) was significantly reduced in Mena(-/-) mice. We report for the first time that genetic ablation of Mena results in cardiac dysfunction, highlighted by diminished contractile performance, disrupted ICD structure, and slowed electrical conduction.

  2. Adipocyte-specific loss of PPARγ attenuates cardiac hypertrophy

    PubMed Central

    Fang, Xi; Stroud, Matthew J.; Ouyang, Kunfu; Fang, Li; Zhang, Jianlin; Dalton, Nancy D.; Gu, Yusu; Wu, Tongbin; Peterson, Kirk L.; Huang, Hsien-Da; Wang, Nanping

    2016-01-01

    Adipose tissue is a key endocrine organ that governs systemic homeostasis. PPARγ is a master regulator of adipose tissue signaling that plays an essential role in insulin sensitivity, making it an important therapeutic target. The selective PPARγ agonist rosiglitazone (RSG) has been used to treat diabetes. However, adverse cardiovascular effects have seriously hindered its clinical application. Experimental models have revealed that PPARγ activation increases cardiac hypertrophy. RSG stimulates cardiac hypertrophy and oxidative stress in cardiomyocyte-specific PPARγ knockout mice, implying that RSG might stimulate cardiac hypertrophy independently of cardiomyocyte PPARγ. However, candidate cell types responsible for RSG-induced cardiomyocyte hypertrophy remain unexplored. Utilizing cocultures of adipocytes and cardiomyocytes, we found that stimulation of PPARγ signaling in adipocytes increased miR-200a expression and secretion. Delivery of miR-200a in adipocyte-derived exosomes to cardiomyocytes resulted in decreased TSC1 and subsequent mTOR activation, leading to cardiomyocyte hypertrophy. Treatment with an antagomir to miR-200a blunted this hypertrophic response in cardiomyocytes. In vivo, specific ablation of PPARγ in adipocytes was sufficient to blunt hypertrophy induced by RSG treatment. By delineating mechanisms by which RSG elicits cardiac hypertrophy, we have identified pathways that mediate the crosstalk between adipocytes and cardiomyocytes to regulate cardiac remodeling. PMID:27734035

  3. Loss of TRADD attenuates pressure overload-induced cardiac hypertrophy through regulating TAK1/P38 MAPK signalling in mice.

    PubMed

    Wu, Lianpin; Cao, Zhiyong; Ji, Ling; Mei, Liqin; Jin, Qike; Zeng, Jingjing; Lin, Jiafeng; Chu, Maoping; Li, Lei; Yang, Xiangjun

    2017-02-05

    We investigated the role of tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) on pressure overload-induced cardiac hypertrophy and the underlying molecular mechanisms by using a TRADD deficiency mice model. 6-8 weeks wild-type and TRADD knockout mice were performed to transverse aorta constriction (TAC) or sham operation (6-8 mice for each group). 14 days after TAC, cardiac function was measured by echocardiography, as well as by pathological and molecular analyses of heart samples. The expressions of cardiac hypertrophic and fibrotic markers were detected by qPCR. Phosphorylated and total TAK1, Akt, and p38 MAPK levels were examined by Western blotting. The ratios of lung or heart/body weight, wall thickness/chamber diameter of left ventricular and cross area of cardiomyocyte were significantly reduced in TRADD knockout (KO) mice than those of wild-type mice after TAC. Moreover, cardiac hypertrophic and fibrotic markers were downregulated in TRADD knockout mice than those of wild-type mice following TAC. Protein expression analysis showed phosphorylated TAK1, p38 MAPK and AKT were upregulated after TAC in both wild-type and TRADD KO mice, phosphorylation of TAK1 and p38 MAPK was reduced more remarkably after TRADD deficiency, while phosphorylated AKT expression was similar between TRADD KO and wild-type mice following TAC. Our data suggest that TRADD KO blunts pressure overload-induced cardiac hypertrophy through mediating TAK1/p38 MAPK but not AKT phosphorylation in mice.

  4. Disruption of ROCK1 gene attenuates cardiac dilation and improves contractile function in pathological cardiac hypertrophy.

    PubMed

    Shi, Jianjian; Zhang, Yi-Wei; Summers, Lelia J; Dorn, Gerald W; Wei, Lei

    2008-03-01

    The development of left ventricular cardiomyocyte hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response. However, persistent stress eventually leads to dilated heart failure, which is a common cause of heart failure in human hypertensive and valvular heart disease. We have recently reported that Rho-associated coiled-coil containing protein kinase 1 (ROCK1) homozygous knockout mice exhibited reduced cardiac fibrosis and cardiomyocyte apoptosis, while displaying a preserved compensatory hypertrophic response to pressure overload. In this study, we have tested the effects of ROCK1 deficiency on cardiac hypertrophy, dilation, and dysfunction. We have shown that ROCK1 deletion attenuated left ventricular dilation and contractile dysfunction, but not hypertrophy, in a transgenic model of Galphaq overexpression-induced hypertrophy which represents a well-characterized and highly relevant genetic mouse model of pathological hypertrophy. Although the development of cardiomyocyte hypertrophy was not affected, ROCK1 deletion in Galphaq mice resulted in a concentric hypertrophic phenotype associated with reduced induction of hypertrophic markers indicating that ROCK1 deletion could favorably modify hypertrophy without inhibiting it. Furthermore, ROCK1 deletion also improved contractile response to beta-adrenergic stimulation in Galphaq transgenic mice. Consistent with this observation, ROCK1 deletion prevented down-regulation of type V/VI adenylyl cyclase expression, which is associated with the impaired beta-adrenergic signaling in Galphaq mice. The present study establishes for the first time a role for ROCK1 in cardiac dilation and contractile dysfunction.

  5. In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: effects on fetal and adult cardiac gene expression and adult cardiac and renal morphology.

    PubMed

    Aragon, Andrea C; Kopf, Phillip G; Campen, Matthew J; Huwe, Janice K; Walker, Mary K

    2008-02-01

    The mouse heart is a target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during fetal development, and microarray analysis demonstrates significant changes in expression of cardiac genes involved in extracellular matrix (ECM) remodeling. We tested the hypothesis that developmental TCDD exposure would disrupt cardiac ECM expression and be associated with changes in cardiac morphology in adulthood. In one study, time-pregnant C57BL/6 mice were dosed with corn oil or 1.5, 3.0, or 6.0 microg TCDD/kg on gestation day (GD) 14.5 and sacrificed on GD 17.5, when changes in fetal cardiac mRNA expression were analyzed using quantitative PCR. TCDD induced mRNA expression of genes associated with ECM remodeling (matrix metalloproteinase 9 and 13, preproendothelin-1 [preproET-1]), cardiac hypertrophy (atrial natriuretic peptide, beta-myosin heavy chain, osteopontin), and aryl hydrocarbon receptor (AHR) activation (cytochrome P4501A1, AHR repressor). Further, all TCDD-induced changes required the AHR since gene expression was not altered in AHR knockout fetuses. In a second study, time-pregnant mice were treated with corn oil or 6.0 microg TCDD/kg on GD 14.5, and male offspring were assessed for changes in cardiac gene expression and cardiac and renal morphology at 3 months. All TCDD-induced changes in cardiac gene expression observed fetally, except for preproET-1, remained induced in the hearts of adult male offspring. Adult male offspring of TCDD-exposed dams also displayed cardiac hypertrophy, decreased plasma volume, and mild hydronephrosis. These results demonstrate that in utero and lactational TCDD exposures alter cardiac gene expression and cardiac and renal morphology in adulthood, which may increase the susceptibility to cardiovascular dysfunction.

  6. Return of Viable Cardiac Function After Sonographic Cardiac Standstill in Pediatric Cardiac Arrest.

    PubMed

    Steffen, Katherine; Thompson, W Reid; Pustavoitau, Aliaksei; Su, Erik

    2017-01-01

    Sonographic cardiac standstill during adult cardiac arrest is associated with failure to get return to spontaneous circulation. This report documents 3 children whose cardiac function returned after standstill with extracorporeal membranous oxygenation. Sonographic cardiac standstill may not predict cardiac death in children.

  7. One-neutron knockout from 51-55 Sc

    NASA Astrophysics Data System (ADS)

    Schwertel, S.; Maierbeck, P.; Krücken, R.; Gernhäuser, R.; Kröll, T.; Alvarez-Pol, H.; Aksouh, F.; Aumann, T.; Behr, K.; Benjamim, E. A.; Benlliure, J.; Bildstein, V.; Böhmer, M.; Boretzky, K.; Borge, M. J. G.; Brünle, A.; Bürger, A.; Caamaño, M.; Casarejos, E.; Chatillon, A.; Chulkov, L. V.; Cortina-Gil, D.; Enders, J.; Eppinger, K.; Faestermann, T.; Friese, J.; Fabbietti, L.; Gascón, M.; Geissel, H.; Gerl, J.; Gorska, M.; Hansen, P. G.; Jonson, B.; Kanungo, R.; Kiselev, O.; Kojouharov, I.; Klimkiewicz, A.; Kurtukian, T.; Kurz, N.; Larsson, K.; Le Bleis, T.; Mahata, K.; Maier, L.; Nilsson, T.; Nociforo, C.; Nyman, G.; Pascual-Izarra, C.; Perea, A.; Perez, D.; Prochazka, A.; Rodriguez-Tajes, C.; Rossi, D.; Schaffner, H.; Schrieder, G.; Simon, H.; Sitar, B.; Stanoiu, M.; Sümmerer, K.; Tengblad, O.; Weick, H.; Winkler, S.; Brown, B. A.; Otsuka, T.; Tostevin, J. A.; Rae, W. D. M.

    2012-12-01

    Results are presented from a one-neutron knockout experiment at relativistic energies of ≈ 420 A MeV on 51-55Sc using the GSI Fragment Separator as a two-stage magnetic spectrometer and the MINIBALL array for gamma-ray detection. Inclusive longitudinal momentum distributions and cross-sections were measured enabling the determination of the contributions corresponding to knockout from the ν p_{1/2} , ν p_{3/2} , ( L = 1 and ν f_{7/2} , ν f_{5/2} ( L = 3 neutron orbitals. The observed L = 1 and L = 3 contributions are compared with theoretical cross-sections using eikonal knockout theory and spectroscopic factors from shell model calculations using the GXPF1A interaction. The measured inclusive knockout cross-sections generally follow the trends expected theoretically and given by the spectroscopic strength predicted from the shell model calculations. However, the deduced L = 1 cross-sections are generally 30-40% higher while the L = 3 contributions are about a factor of two smaller than predicted. This points to a promotion of neutrons from the ν f_{7/2} to the ν p_{3/2} orbital indicating a weakening of the N = 28 shell gap in these nuclei. While this is not predicted for the phenomenological GXPF1A interaction such a weakening is predicted by recent calculations using realistic low-momentum interactions V_{low k} obtained by evolving a chiral N3LO nucleon-nucleon potential.

  8. Knockout mice in understanding the mechanism of action of lithium.

    PubMed

    Agam, Galila; Bersudsky, Yuly; Berry, Gerard T; Moechars, Diederik; Lavi-Avnon, Yael; Belmaker, R H

    2009-10-01

    Lithium inhibits IMPase (inositol monophosphatase) activity, as well as inositol transporter function. To determine whether one or more of these mechanisms might underlie lithium's behavioural effects, we studied Impa1 (encoding IMPase) and Smit1 (sodium-myo-inositol transporter 1)-knockout mice. In brains of adult homozygous Impa1-knockout mice, IMPase activity was found to be decreased; however, inositol levels were not found to be altered. Behavioural analysis indicated decreased immobility in the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures. These are behaviours robustly induced by lithium. In homozygous Smit1-knockout mice, free inositol levels were decreased in the frontal cortex and hippocampus. These animals behave like lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced-swim test model of depression. In contrast with O'Brien et al. [O'Brien, Harper, Jove, Woodgett, Maretto, Piccolo and Klein (2004) J. Neurosci. 24, 6791-6798], we could not confirm that heterozygous Gsk3b (glycogen synthase kinase 3beta)-knockout mice exhibit decreased immobility in the Porsolt forced-swim test or decreased amphetamine-induced hyperactivity in a manner mimicking lithium's behavioural effects. These data support the role of inositol-related processes rather than GSK3beta in the mechanism of the therapeutic action of lithium.

  9. Central nervous system-specific knockout of steroidogenic factor 1.

    PubMed

    Kim, Ki Woo; Zhao, Liping; Parker, Keith L

    2009-03-05

    Steroidogenic factor 1 (SF-1) is a nuclear receptor that plays important roles in the hypothalamus-pituitary-steroidogenic organ axis. Global knockout studies in mice revealed the essential in vivo roles of SF-1 in the ventromedial hypothalamic (VMH) nucleus, adrenal glands, and gonads. One limitation of global SF-1 knockout mice is their early postnatal death from adrenocortical insufficiency. To overcome limitations of the global knockout mice and to delineate the roles of SF-1 in the brain, we used Cre/loxP recombination technology to genetically ablate SF-1 specifically in the central nervous system (CNS). Mice with CNS-specific knockout of SF-1 mediated by nestin-Cre showed increased anxiety-like behavior, revealing a crucial role of SF-1 in a complex behavioral phenotype. Our studies with CNS-specific SF-1 KO mice also defined roles of SF-1 in regulating the VMH expression of target genes implicated in anxiety and energy homeostasis. Therefore, this review will focus on our recent studies defining the functional roles of SF-1 in the VMH linked to anxiety and energy homeostasis.

  10. Fatty Acid Oxidation in Cardiac and Skeletal Muscle Mitochondria is Unaffected by Deletion of CD36

    PubMed Central

    King, Kristen L.; Stanley, William C.; Rosca, Mariana; Kerner, Janos; Hoppel, Charles L.; Febbraio, Maria

    2009-01-01

    Recent studies found that the plasma membrane fatty acid transport protein CD36 also resides in mitochondrial membranes in cardiac and skeletal muscle. Pharmacological studies suggest that CD36 may play an essential role in mitochondrial fatty acid oxidation. We isolated cardiac and skeletal muscle mitochondria from wild type and CD36 knock-out mice. There were no differences between wild type and CD36 knock-out mice in mitochondrial respiration with palmitoyl-CoA, palmitoyl-carnitine or glutamate as substrate. We investigated a potential alternative role for CD36 in mitochondria, ie. the export of fatty acids generated in the matrix. Palmitate export was not different between wild type and CD36 knock out mice. Taken together, CD36 does not appear to play an essential role in mitochondrial uptake of fatty acids or export of fatty acid anions. PMID:17904092

  11. Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

    PubMed

    Li, Chao; Zhang, Yu Yao; Frieler, Ryan A; Zheng, Xiao Jun; Zhang, Wu Chang; Sun, Xue Nan; Yang, Qing Zhen; Ma, Shu Min; Huang, Baozhuan; Berger, Stefan; Wang, Wang; Wu, Yong; Yu, Ying; Duan, Sheng Zhong; Mortensen, Richard M

    2014-01-01

    Mineralocorticoid receptor (MR) blockade has been shown to suppress cardiac hypertrophy and remodeling in animal models of pressure overload (POL). This study aims to determine whether MR deficiency in myeloid cells modulates aortic constriction-induced cardiovascular injuries. Myeloid MR knockout (MMRKO) mice and littermate control mice were subjected to abdominal aortic constriction (AAC) or sham operation. We found that AAC-induced cardiac hypertrophy and fibrosis were significantly attenuated in MMRKO mice. Expression of genes important in generating reactive oxygen species was decreased in MMRKO mice, while that of manganese superoxide dismutase increased. Furthermore, expression of genes important in cardiac metabolism was increased in MMRKO hearts. Macrophage infiltration in the heart was inhibited and expression of inflammatory genes was decreased in MMRKO mice. In addition, aortic fibrosis and inflammation were attenuated in MMRKO mice. Taken together, our data indicated that MR deficiency in myeloid cells effectively attenuated aortic constriction-induced cardiac hypertrophy and fibrosis, as well as aortic fibrosis and inflammation.

  12. Hepatic changes in metabolic gene expression in old ghrelin and ghrelin receptor knockout mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin knockout (GKO) and ghrelin receptor (growth hormone secretagogue receptor) knockout (GHSRKO) mice exhibit enhanced insulin sensitivity, but the mechanism is unclear. Insulin sensitivity declines with age and is inversely associated with accumulation of lipid in liver, a key glucoregulatory ...

  13. Cardiac Hegemony of Senescence

    PubMed Central

    Siddiqi, Sailay; Sussman, Mark A.

    2013-01-01

    Cardiac senescence and age-related disease development have gained general attention and recognition in the past decades due to increased accessibility and quality of health care. The advancement in global civilization is complementary to concerns regarding population aging and development of chronic degenerative diseases. Cardiac degeneration has been rigorously studied. The molecular mechanisms of cardiac senescence are on multiple cellular levels and hold a multilayer complexity level, thereby hampering development of unambiguous treatment protocols. In particular, the synergistic exchange of the senescence phenotype through a senescence secretome between myocytes and stem cells appears complicated and is of great future therapeutic value. The current review article will highlight hallmarks of senescence, cardiac myocyte and stem cell senescence, and the mutual exchange of senescent secretome. Future cardiac cell therapy approaches require a comprehensive understanding of myocardial senescence to improve therapeutic efficiency as well as efficacy. PMID:24349878

  14. Cardiac tumors: echo assessment.

    PubMed

    Mankad, Rekha; Herrmann, Joerg

    2016-12-01

    Cardiac tumors are exceedingly rare (0.001-0.03% in most autopsy series). They can be present anywhere within the heart and can be attached to any surface or be embedded in the myocardium or pericardial space. Signs and symptoms are nonspecific and highly variable related to the localization, size and composition of the cardiac mass. Echocardiography, typically performed for another indication, may be the first imaging modality alerting the clinician to the presence of a cardiac mass. Although echocardiography cannot give the histopathology, certain imaging features and adjunctive tools such as contrast imaging may aid in the differential diagnosis as do the adjunctive clinical data and the following principles: (1) thrombus or vegetations are the most likely etiology, (2) cardiac tumors are mostly secondary and (3) primary cardiac tumors are mostly benign. Although the finding of a cardiac mass on echocardiography may generate confusion, a stepwise approach may serve well practically. Herein, we will review such an approach and the role of echocardiography in the assessment of cardiac masses.

  15. Cardiac tumors: echo assessment

    PubMed Central

    Mankad, Rekha

    2016-01-01

    Cardiac tumors are exceedingly rare (0.001–0.03% in most autopsy series). They can be present anywhere within the heart and can be attached to any surface or be embedded in the myocardium or pericardial space. Signs and symptoms are nonspecific and highly variable related to the localization, size and composition of the cardiac mass. Echocardiography, typically performed for another indication, may be the first imaging modality alerting the clinician to the presence of a cardiac mass. Although echocardiography cannot give the histopathology, certain imaging features and adjunctive tools such as contrast imaging may aid in the differential diagnosis as do the adjunctive clinical data and the following principles: (1) thrombus or vegetations are the most likely etiology, (2) cardiac tumors are mostly secondary and (3) primary cardiac tumors are mostly benign. Although the finding of a cardiac mass on echocardiography may generate confusion, a stepwise approach may serve well practically. Herein, we will review such an approach and the role of echocardiography in the assessment of cardiac masses. PMID:27600455

  16. Characterization of the phospholemman knockout mouse heart: depressed left ventricular function with increased Na-K-ATPase activity.

    PubMed

    Bell, James R; Kennington, Erika; Fuller, William; Dighe, Kushal; Donoghue, Pamela; Clark, James E; Jia, Li-Guo; Tucker, Amy L; Moorman, J Randall; Marber, Michael S; Eaton, Philip; Dunn, Michael J; Shattock, Michael J

    2008-02-01

    Phospholemman (PLM, FXYD1), abundantly expressed in the heart, is the primary cardiac sarcolemmal substrate for PKA and PKC. Evidence supports the hypothesis that PLM is part of the cardiac Na-K pump complex and provides the link between kinase activity and pump modulation. PLM has also been proposed to modulate Na/Ca exchanger activity and may be involved in cell volume regulation. This study characterized the phenotype of the PLM knockout (KO) mouse heart to further our understanding of PLM function in the heart. PLM KO mice were bred on a congenic C57/BL6 background. In vivo conductance catheter measurements exhibited a mildly depressed cardiac contractile function in PLM KO mice, which was exacerbated when hearts were isolated and Langendorff perfused. There were no significant differences in action potential morphology in paced Langendorff-perfused hearts. Depressed contractile function was associated with a mild cardiac hypertrophy in PLM KO mice. Biochemical analysis of crude ventricular homogenates showed a significant increase in Na-K-ATPase activity in PLM KO hearts compared with wild-type controls. SDS-PAGE and Western blot analysis of ventricular homogenates revealed small, nonsignificant changes in Na- K-ATPase subunit expression, with two-dimensional gel (isoelectric focusing, SDS-PAGE) analysis revealing minimal changes in ventricular protein expression, indicating that deletion of PLM was the primary reason for the observed PLM KO phenotype. These studies demonstrate that PLM plays an important role in the contractile function of the normoxic mouse heart. Data are consistent with the hypothesis that PLM modulates Na-K-ATPase activity, indirectly affecting intracellular Ca and hence contractile function.

  17. [Cardiac manifestations of mitochondrial diseases].

    PubMed

    Ritzenthaler, Thomas; Luis, David; Hullin, Thomas; Fayssoil, Abdallah

    2015-05-01

    Mitochondrial diseases are multi-system disorders in relation with mitochondrial DNA and/or nuclear DNA abnormalities. Clinical pictures are heterogeneous, involving endocrine, cardiac, neurologic or sensory systems. Cardiac involvements are morphological and electrical disturbances. Prognosis is worsened in case of cardiac impairment. Treatments are related to the type of cardiac dysfunction including medication or pacemaker implantation.

  18. Knockout driven reactions in complex molecules and their clusters

    NASA Astrophysics Data System (ADS)

    Gatchell, Michael; Zettergren, Henning

    2016-08-01

    Energetic ions lose some of their kinetic energy when interacting with electrons or nuclei in matter. Here, we discuss combined experimental and theoretical studies on such impulse driven reactions in polycyclic aromatic hydrocarbons (PAHs), fullerenes, and pure or mixed clusters of these molecules. These studies show that the nature of excitation is important for how complex molecular systems respond to ion/atom impact. Rutherford-like nuclear scattering processes may lead to prompt atom knockout and formation of highly reactive fragments, while heating of the molecular electron clouds in general lead to formation of more stable and less reactive fragments. In this topical review, we focus on recent studies of knockout driven reactions, and present new calculations of the angular dependent threshold (displacement) energies for such processes in PAHs. The so-formed fragments may efficiently form covalent bonds with neighboring molecules in clusters. These unique molecular growth processes may be important in astrophysical environments such as low velocity shock waves.

  19. A STAT-1 knockout mouse model for Machupo virus pathogenesis

    PubMed Central

    2011-01-01

    Background Machupo virus (MACV), a member of the Arenaviridae, causes Bolivian hemorrhagic fever, with ~20% lethality in humans. The pathogenesis of MACV infection is poorly understood, and there are no clinically proven treatments for disease. This is due, in part, to a paucity of small animal models for MACV infection in which to discover and explore candidate therapeutics. Methods Mice lacking signal transducer and activator of transcription 1 (STAT-1) were infected with MACV. Lethality, viral replication, metabolic changes, hematology, histopathology, and systemic cytokine expression were analyzed throughout the course of infection. Results We report here that STAT-1 knockout mice succumbed to MACV infection within 7-8 days, and presented some relevant clinical and histopathological manifestations of disease. Furthermore, the model was used to validate the efficacy of ribavirin in protection against infection. Conclusions The STAT-1 knockout mouse model can be a useful small animal model for drug testing and preliminary immunological analysis of lethal MACV infection. PMID:21672221

  20. Deconstructing mammalian reproduction: using knockouts to define fertility pathways.

    PubMed

    Roy, Angshumoy; Matzuk, Martin M

    2006-02-01

    Reproduction is the sine qua non for the propagation of species and continuation of life. It is a complex biological process that is regulated by multiple factors during the reproductive life of an organism. Over the past decade, the molecular mechanisms regulating reproduction in mammals have been rapidly unraveled by the study of a vast number of mouse gene knockouts with impaired fertility. The use of reverse genetics to generate null mutants in mice through targeted disruption of specific genes has enabled researchers to identify essential regulators of spermatogenesis and oogenesis in vivo and model human disorders affecting reproduction. This review focuses on the merits, utility, and the variations of the knockout technology in studies of reproduction in mammals.

  1. Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

    PubMed Central

    2014-01-01

    Glycosaminoglycans (GAGs) are constructed through the stepwise addition of respective monosaccharides by various glycosyltransferases and maturated by epimerases and sulfotransferases. The structural diversity of GAG polysaccharides, including their sulfation patterns and sequential arrangements, is essential for a wide range of biological activities such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Studies using knockout mice of enzymes responsible for the biosynthesis of the GAG side chains of proteoglycans have revealed their physiological functions. Furthermore, mutations in the human genes encoding glycosyltransferases, sulfotransferases, and related enzymes responsible for the biosynthesis of GAGs cause a number of genetic disorders including chondrodysplasia, spondyloepiphyseal dysplasia, and Ehlers-Danlos syndromes. This review focused on the increasing number of glycobiological studies on knockout mice and genetic diseases caused by disturbances in the biosynthetic enzymes for GAGs. PMID:25126564

  2. Using engineered endonucleases to create knockout and knockin zebrafish models

    PubMed Central

    Bedell, Victoria M.; Ekker, Stephen C.

    2015-01-01

    Summary Over the last few years, the technology to create targeted knockout and knockin zebrafish animals has exploded. We have gained the ability to create targeted knockouts through the use of zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR associated system (CRISPR/Cas). Furthermore, using the high-efficiency TALEN system, we were able to create knockin zebrafish using a single-stranded DNA (ssDNA) protocol described here. Through the use of these technologies, the zebrafish has become a valuable vertebrate model and an excellent bridge between the invertebrate and mammalian model systems for the study of human disease. PMID:25408414

  3. In Silico Knockout Studies of Xenophagic Capturing of Salmonella

    PubMed Central

    Scheidel, Jennifer; Amstein, Leonie; Ackermann, Jörg; Dikic, Ivan; Koch, Ina

    2016-01-01

    The degradation of cytosol-invading pathogens by autophagy, a process known as xenophagy, is an important mechanism of the innate immune system. Inside the host, Salmonella Typhimurium invades epithelial cells and resides within a specialized intracellular compartment, the Salmonella-containing vacuole. A fraction of these bacteria does not persist inside the vacuole and enters the host cytosol. Salmonella Typhimurium that invades the host cytosol becomes a target of the autophagy machinery for degradation. The xenophagy pathway has recently been discovered, and the exact molecular processes are not entirely characterized. Complete kinetic data for each molecular process is not available, so far. We developed a mathematical model of the xenophagy pathway to investigate this key defense mechanism. In this paper, we present a Petri net model of Salmonella xenophagy in epithelial cells. The model is based on functional information derived from literature data. It comprises the molecular mechanism of galectin-8-dependent and ubiquitin-dependent autophagy, including regulatory processes, like nutrient-dependent regulation of autophagy and TBK1-dependent activation of the autophagy receptor, OPTN. To model the activation of TBK1, we proposed a new mechanism of TBK1 activation, suggesting a spatial and temporal regulation of this process. Using standard Petri net analysis techniques, we found basic functional modules, which describe different pathways of the autophagic capture of Salmonella and reflect the basic dynamics of the system. To verify the model, we performed in silico knockout experiments. We introduced a new concept of knockout analysis to systematically compute and visualize the results, using an in silico knockout matrix. The results of the in silico knockout analyses were consistent with published experimental results and provide a basis for future investigations of the Salmonella xenophagy pathway. PMID:27906974

  4. Generation of Gene Knockout Mice by ES Cell Microinjection

    PubMed Central

    Longenecker, Glenn; Kulkarni, Ashok B

    2009-01-01

    This unit lists and describes protocols used in the production of chimeric mice leading to the generation of gene knockout mice. These protocols include the collection of blastocyst embryos, ES cell injection, and uterine transfer of injected blastocysts. Support protocols in the superovulation of blastocyst donor mice, generation of pseudopregnant recipients, fabrication of glass pipettes, and generation of germline mice are also included. Practical tips and solutions are mentioned to help troubleshoot problems that may occur. PMID:19731226

  5. Constitutive phosphorylation of cardiac myosin regulatory light chain in vivo.

    PubMed

    Chang, Audrey N; Battiprolu, Pavan K; Cowley, Patrick M; Chen, Guohua; Gerard, Robert D; Pinto, Jose R; Hill, Joseph A; Baker, Anthony J; Kamm, Kristine E; Stull, James T

    2015-04-24

    In beating hearts, phosphorylation of myosin regulatory light chain (RLC) at a single site to 0.45 mol of phosphate/mol by cardiac myosin light chain kinase (cMLCK) increases Ca(2+) sensitivity of myofilament contraction necessary for normal cardiac performance. Reduction of RLC phosphorylation in conditional cMLCK knock-out mice caused cardiac dilation and loss of cardiac performance by 1 week, as shown by increased left ventricular internal diameter at end-diastole and decreased fractional shortening. Decreased RLC phosphorylation by conventional or conditional cMLCK gene ablation did not affect troponin-I or myosin-binding protein-C phosphorylation in vivo. The extent of RLC phosphorylation was not changed by prolonged infusion of dobutamine or treatment with a β-adrenergic antagonist, suggesting that RLC is constitutively phosphorylated to maintain cardiac performance. Biochemical studies with myofilaments showed that RLC phosphorylation up to 90% was a random process. RLC is slowly dephosphorylated in both noncontracting hearts and isolated cardiac myocytes from adult mice. Electrically paced ventricular trabeculae restored RLC phosphorylation, which was increased to 0.91 mol of phosphate/mol of RLC with inhibition of myosin light chain phosphatase (MLCP). The two RLCs in each myosin appear to be readily available for phosphorylation by a soluble cMLCK, but MLCP activity limits the amount of constitutive RLC phosphorylation. MLCP with its regulatory subunit MYPT2 bound tightly to myofilaments was constitutively phosphorylated in beating hearts at a site that inhibits MLCP activity. Thus, the constitutive RLC phosphorylation is limited physiologically by low cMLCK activity in balance with low MLCP activity.

  6. Knock-Out Models Reveal New Aquaporin Functions

    PubMed Central

    Verkman, Alan S.

    2013-01-01

    Knockout mice have been informative in the discovery of unexpected biological functions of aquaporins. Knockout mice have confirmed the predicted roles of aquaporins in transepithelial fluid transport, as in the urinary concentrating mechanism and glandular fluid secretion. A less obvious, though predictable role of aquaporins is in tissue swelling under stress, as in the brain in stroke, tumor and infection. Phenotype analysis of aquaporin knockout mice has revealed several unexpected cellular roles of aquaporins whose mechanisms are being elucidated. Aquaporins facilitate cell migration, as seen in aquaporin-dependent tumor angiogenesis and tumor metastasis, by a mechanism that may involve facilitated water transport in lamellipodia of migrating cells. The ‘aquaglyceroporins’, aquaporins that transport both glycerol and water, regulate glycerol content in epidermis, fat and other tissues, and lead to a multiplicity of interesting consequences of gene disruption including dry skin, resistance to skin carcinogenesis, impaired cell proliferation and altered fat metabolism. An even more surprising role of a mammalian aquaporin is in neural signal transduction in the central nervous system. The many roles of aquaporins might be exploited for clinical benefit by modulation of aquaporin expression/function – as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer. PMID:19096787

  7. The evolution of thymic lymphomas in p53 knockout mice

    PubMed Central

    Dudgeon, Crissy; Chan, Chang; Kang, Wenfeng; Sun, Yvonne; Emerson, Ryan; Robins, Harlan

    2014-01-01

    Germline deletion of the p53 gene in mice gives rise to spontaneous thymic (T-cell) lymphomas. In this study, the p53 knockout mouse was employed as a model to study the mutational evolution of tumorigenesis. The clonality of the T-cell repertoire from p53 knockout and wild-type thymic cells was analyzed at various ages employing TCRβ sequencing. These data demonstrate that p53 knockout thymic lymphomas arose in an oligoclonal fashion, with tumors evolving dominant clones over time. Exon sequencing of tumor DNA revealed that all of the independently derived oligoclonal mouse tumors had a deletion in the Pten gene prior to the formation of the TCRβ rearrangement, produced early in development. This was followed in each independent clone of the thymic lymphoma by the amplification or overexpression of cyclin Ds and Cdk6. Alterations in the expression of Ikaros were common and blocked further development of CD-4/CD-8 T cells. While the frequency of point mutations in the genome of these lymphomas was one per megabase, there were a tremendous number of copy number variations producing the tumors’ driver mutations. The initial inherited loss of p53 functions appeared to delineate an order of genetic alterations selected for during the evolution of these thymic lymphomas. PMID:25452272

  8. Cardiac Catheterization (For Kids)

    MedlinePlus

    ... done during a cardiac catheterization include: closing small holes inside the heart repairing leaky or narrow heart ... bandage. It's normal for the site to be black and blue, red, or slightly swollen for a ...

  9. Cardiac Catheterization (For Teens)

    MedlinePlus

    ... a person will have only a small puncture hole where the catheter was put in. Doctors usually ... done using a cardiac catheterization, including: closing small holes inside the heart repairing leaky or narrow heart ...

  10. Cardiac glycoside overdose

    MedlinePlus

    ... found in the leaves of the digitalis (foxglove) plant. This plant is the original source of this medicine. People ... Digitoxin (Crystodigin) Digoxin (Lanoxicaps, Lanoxin) Besides the foxglove plant, cardiac glycosides also occur naturally in plants such ...

  11. ZNF307 (Zinc Finger Protein 307) Acts as a Negative Regulator of Pressure Overload-Induced Cardiac Hypertrophy.

    PubMed

    Yu, Chang-Jiang; Liang, Chen; Li, Yu-Xia; Hu, Qing-Qing; Zheng, Wei-Wan; Niu, Na; Yang, Xu; Wang, Zi-Rui; Yu, Xiao-Di; Zhang, Bao-Long; Song, Bin-Lin; Zhang, Zhi-Ren

    2017-04-01

    Pathological cardiac hypertrophy is a key risk factor for heart failure. We found that the protein expression levels of the ZNF307 (zinc finger protein 307) were significantly increased in heart samples from both human patients with dilated cardiomyopathy and mice subjected to aortic banding. Therefore, we aimed to elucidate the role of ZNF307 in the development of cardiac hypertrophy and to explore the signal transduction events that mediate the effect of ZNF307 on cardiac hypertrophy, using cardiac-specific ZNF307 transgenic (ZNF307-TG) mice and ZNF307 global knockout (ZNF307-KO) mice. The results showed that the deletion of ZNF307 potentiated aortic banding-induced pathological cardiac hypertrophy, fibrosis, and cardiac dysfunction; however, the aortic banding-induced cardiac hypertrophic phenotype was dramatically diminished by ZNF307 overexpression in mouse heart. Mechanistically, the antihypertrophic effects mediated by ZNF307 in response to pathological stimuli were associated with the direct inactivation of NF-κB (nuclear factor-κB) signaling and blockade of the nuclear translocation of NF-κB subunit p65. Furthermore, the overexpression of a degradation-resistant mutant of IκBα (IκBα(S32A/S36A)) reversed the exacerbation of cardiac hypertrophy, fibrosis, and dysfunction shown in aortic banding-treated ZNF307-KO mice. In conclusion, our findings demonstrate that ZNF307 ameliorates pressure overload-induced cardiac hypertrophy by inhibiting the activity of NF-κB-signaling pathway.

  12. Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy.

    PubMed

    Jiang, Xi; Deng, Ke-Qiong; Luo, Yuxuan; Jiang, Ding-Sheng; Gao, Lu; Zhang, Xiao-Fei; Zhang, Peng; Zhao, Guang-Nian; Zhu, Xueyong; Li, Hongliang

    2015-08-01

    Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways. Here, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II- or phenylephrine-induced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli. This interaction between TRAF3 and TBK1 further activated AKT signaling, which ultimately promoted the development of cardiac hypertrophy. Our findings not only reveal a key role of TRAF3 in regulating the hypertrophic response but also uncover TRAF3-TBK1-AKT as a novel signaling pathway in the development of cardiac hypertrophy and heart failure. This pathway may represent a potential therapeutic target for this pathological process.

  13. Cardiac imaging in adults

    SciTech Connect

    Jaffe, C.C.

    1987-01-01

    This book approaches adult cardiac disease from the correlative imaging perspective. It includes chest X-rays and angiographs, 2-dimensional echocardiograms with explanatory diagrams for clarity, plus details on digital radiology, nuclear medicine techniques, CT and MRI. It also covers the normal heart, valvular heart disease, myocardial disease, pericardial disease, bacterial endocarditis, aortic aneurysm, cardiac tumors, and congenital heart disease of the adult. It points out those aspects where one imaging technique has significant superiority.

  14. [Intrinsic cardiac ganglia].

    PubMed

    Birand, Ahmet

    2008-12-01

    Heart has been considered as the source and the seat of emotions, passion and love. But from the dawn of XIXth century, scientists have emphasized that the heart, though life depends on its ceaseless activity, is merely a electromechanical pump, pumping oxygenated blood. Nowadays, we all know that heart pumps blood commensurate with the needs of the body and this unending toil, and its regulation depends on the intrinsic properties of the myocardium, Frank-Starling Law and neurohumoral contribution. It has been understood, though not clearly enough, that these time-tensions may cause structural or functional cardiac impairments and arrhythmias are related to the autonomic nervous system. Less well known and less taken in account in daily cardiology practice is the fact that heart has an intrinsic cardiac nervous system, or "heart brain" consisting of complex ganglia, intrinsic cardiac ganglia containing afferent (receiving), local circuit (interneurons) and efferent (transmitting) sympathetic and parasympathetic neurons. This review enlightens structural and functional aspects of intrinsic cardiac ganglia as the very first step in the regulation of cardiac function. This issue is important for targets of pharmacological treatment and techniques of cardiac surgery interventions as repair of septal defects, valvular interventions and congenital corrections.

  15. Cardiac septic pulmonary embolism

    PubMed Central

    Song, Xin yu; Li, Shan; Cao, Jian; Xu, Kai; Huang, Hui; Xu, Zuo jun

    2016-01-01

    Abstract Based on the source of the embolus, septic pulmonary embolism (SPE) can be classified as cardiac, peripheral endogenous, or exogenous. Cardiac SPEs are the most common. We conducted a retrospective analysis of 20 patients with cardiac SPE hospitalized between 1991 and 2013 at a Chinese tertiary referral hospital. The study included 14 males and 6 females with a median age of 38.1 years. Fever (100%), cough (95%), hemoptysis (80%), pleuritic chest pain (80%), heart murmur (80%), and moist rales (75%) were common clinical manifestations. Most patients had a predisposing condition: congenital heart disease (8 patients) and an immunocompromised state (5 patients) were the most common. Staphylococcal (8 patients) and Streptococcal species (4 patients) were the most common causative pathogens. Parenchymal opacities, nodules, cavitations, and pleural effusions were the most common manifestations observed via computed tomography (CT). All patients exhibited significant abnormalities by echocardiography, including 15 patients with right-sided vegetations and 4 with double-sided vegetations. All patients received parenteral antimicrobial therapy as an initial treatment. Fourteen patients received cardiac surgery, and all survived. Among the 6 patients who did not undergo surgery, only 1 survived. Most patients in our cardiac SPE cohort had predisposing conditions. Although most exhibited typical clinical manifestations and radiography, they were nonspecific. For suspected cases of SPE, blood culture, echocardiography, and CT pulmonary angiography (CTPA) are important measures to confirm an early diagnosis. Vigorous early therapy, including appropriate antibiotic treatment and timely cardiac surgery to eradicate the infective source, is critical. PMID:27336870

  16. Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy.

    PubMed

    Luo, Ji; McMullen, Julie R; Sobkiw, Cassandra L; Zhang, Li; Dorfman, Adam L; Sherwood, Megan C; Logsdon, M Nicole; Horner, James W; DePinho, Ronald A; Izumo, Seigo; Cantley, Lewis C

    2005-11-01

    Class I(A) phosphoinositide 3-kinases (PI3Ks) are activated by growth factor receptors, and they regulate, among other processes, cell growth and organ size. Studies using transgenic mice overexpressing constitutively active and dominant negative forms of the p110alpha catalytic subunit of class I(A) PI3K have implicated the role of this enzyme in regulating heart size and physiological cardiac hypertrophy. To further understand the role of class I(A) PI3K in controlling heart growth and to circumvent potential complications from the overexpression of dominant negative and constitutively active proteins, we generated mice with muscle-specific deletion of the p85alpha regulatory subunit and germ line deletion of the p85beta regulatory subunit of class I(A) PI3K. Here we show that mice with cardiac deletion of both p85 subunits exhibit attenuated Akt signaling in the heart, reduced heart size, and altered cardiac gene expression. Furthermore, exercise-induced cardiac hypertrophy is also attenuated in the p85 knockout hearts. Despite such defects in postnatal developmental growth and physiological hypertrophy, the p85 knockout hearts exhibit normal contractility and myocardial histology. Our results therefore provide strong genetic evidence that class I(A) PI3Ks are critical regulators for the developmental growth and physiological hypertrophy of the heart.

  17. Aggravated myocardial infarction-induced cardiac remodeling and heart failure in histamine-deficient mice

    PubMed Central

    Chen, Jinmiao; Hong, Tao; Ding, Suling; Deng, Long; Abudupataer, Mieradilijiang; Zhang, Weiwei; Tong, Minghong; Jia, Jianguo; Gong, Hui; Zou, Yunzeng; Wang, Timothy C.; Ge, Junbo; Yang, Xiangdong

    2017-01-01

    Histamine has pleiotropic pathophysiological effects, but its role in myocardial infarction (MI)-induced cardiac remodeling remains unclear. Histidine decarboxylase (HDC) is the main enzyme involved in histamine production. Here, we clarified the roles of HDC-expressing cells and histamine in heart failure post-MI using HDC-EGFP transgenic mice and HDC-knockout (HDC−/−) mice. HDC+CD11b+ myeloid cell numbers markedly increased in the injured hearts, and histamine levels were up-regulated in the circulation post-MI. HDC−/− mice exhibited more adverse cardiac remodeling, poorer left ventricular function and higher mortality by increasing cardiac fibrogenesis post-MI. In vitro assays further confirmed that histamine inhibited heart fibroblast proliferation. Furthermore, histamine enhanced the signal transducer and activator of transcription (STAT)-6 phosphorylation level in murine heart fibroblasts, and the inhibitive effects of histamine on fibroblast proliferation could be blocked by JAK3/STAT6 signaling selective antagonist. STAT6-knockout (STAT6−/−) mice had a phenotype similar to that of HDC−/− mice post-MI; however, in contrast to HDC−/− mice, the beneficial effects of exogenous histamine injections were abrogated in STAT6−/− mice. These data suggest that histamine exerts protective effects by modulating cardiac fibrosis and remodeling post-MI, in part through the STAT6-dependent signaling pathway. PMID:28272448

  18. [Psychosomatic aspects of cardiac arrhythmias].

    PubMed

    Siepmann, Martin; Kirch, Wilhelm

    2010-07-01

    Emotional stress facilitates the occurrence of cardiac arrhythmias including sudden cardiac death. The prevalence of anxiety and depression is increased in cardiac patients as compared to the normal population. The risk of cardiovascular mortality is enhanced in patients suffering from depression. Comorbid anxiety disorders worsen the course of cardiac arrhythmias. Disturbance of neurocardiac regulation with predominance of the sympathetic tone is hypothesized to be causative for this. The emotional reaction to cardiac arrhythmias is differing to a large extent between individuals. Emotional stress may result from coping with treatment of cardiac arrhythmias. Emotional stress and cardiac arrhythmias may influence each other in the sense of a vicious circle. Somatoform cardiac arrhythmias are predominantly of psychogenic origin. Instrumental measures and frequent contacts between physicians and patients may facilitate disease chronification. The present review is dealing with the multifaceted relationships between cardiac arrhythmias and emotional stress. The underlying mechanisms and corresponding treatment modalities are discussed.

  19. Utility of Oatp1a/1b-knockout and OATP1B1/3-humanized mice in the study of OATP-mediated pharmacokinetics and tissue distribution: case studies with pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein.

    PubMed

    Higgins, J William; Bao, Jing Q; Ke, Alice B; Manro, Jason R; Fallon, John K; Smith, Philip C; Zamek-Gliszczynski, Maciej J

    2014-01-01

    Although organic anion transporting polypeptide (OATP)-mediated hepatic uptake is generally conserved between rodents and humans at a gross pharmacokinetic level, the presence of three major hepatic OATPs with broad overlap in substrate and inhibitor affinity, and absence of rodent-human orthologs preclude clinical translation of single-gene knockout/knockin findings. At present, changes in pharmacokinetics and tissue distribution of pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein were studied in oatp1a/1b-knockout mice lacking the three major hepatic oatp isoforms, and in knockout mice with liver-specific knockin of human OATP1B1 or OATP1B3. Relative to wild-type controls, oatp1a/1b-knockout mice exhibited 1.6- to 19-fold increased intravenous and 2.1- to 115-fold increased oral drug exposure, due to 33%-75% decreased clearance, 14%-60% decreased volume of distribution, and ≤74-fold increased oral bioavailability, with the magnitude of change depending on the contribution of oatp1a/1b to pharmacokinetics. Hepatic drug distribution was 4.2- to 196-fold lower in oatp1a/1b-knockout mice; distributional attenuation was less notable in kidney, brain, cardiac, and skeletal muscle. Knockin of OATP1B1 or OATP1B3 partially restored control clearance, volume, and bioavailability values (24%-142% increase, ≤47% increase, and ≤77% decrease vs. knockout, respectively), such that knockin pharmacokinetic profiles were positioned between knockout and wild-type mice. Consistent with liver-specific humanization, only hepatic drug distribution was partially restored (1.3- to 6.5-fold increase vs. knockout). Exposure and liver distribution changes in OATP1B1-humanized versus knockout mice predicted the clinical impact of OATP1B1 on oral exposure and contribution to human hepatic uptake of statins within 1.7-fold, but only after correcting for human/humanized mouse liver relative protein expression factor (OATP1B1 = 2.2, OATP1B3 = 0.30).

  20. Cardiac radiology: centenary review.

    PubMed

    de Roos, Albert; Higgins, Charles B

    2014-11-01

    During the past century, cardiac imaging technologies have revolutionized the diagnosis and treatment of acquired and congenital heart disease. Many important contributions to the field of cardiac imaging were initially reported in Radiology. The field developed from the early stages of cardiac imaging, including the use of coronary x-ray angiography and roentgen kymography, to nowadays the widely used echocardiographic, nuclear medicine, cardiac computed tomographic (CT), and magnetic resonance (MR) applications. It is surprising how many of these techniques were not recognized for their potential during their early inception. Some techniques were described in the literature but required many years to enter the clinical arena and presently continue to expand in terms of clinical application. The application of various CT and MR contrast agents for the diagnosis of myocardial ischemia is a case in point, as the utility of contrast agents continues to expand the noninvasive characterization of myocardium. The history of cardiac imaging has included a continuous process of advances in our understanding of the anatomy and physiology of the cardiovascular system, along with advances in imaging technology that continue to the present day.

  1. Generation of TALEN-mediated FH knockout rat model.

    PubMed

    Yu, Dandan; Zhong, Yali; Li, Xiaoran; Li, Yaqing; Li, Xiaoli; Cao, Jing; Fan, Zhirui; Fan, Huijie; Yuan, Long; Xu, Benling; Yuan, Yuan; Zhang, Hongquan; Ji, Zhenyu; Wen, Jian-Guo; Zhang, Mingzhi; Nesland, Jahn M; Suo, Zhenhe

    2016-09-20

    Transcription activator-like effector nucleases (TALENs) are valuable tools for precise genome engineering of laboratory animals. Here we utilized this technique for efficient site-specific gene modification to create a fumarate hydratase (FH) gene knockout rat model, in which there was an 11 base-pair deletion in the first exon of the FH gene in 111 rats. 18 live-born targeted mutation offsprings were produced from 80 injected zygotes with 22.5% efficiency, indicating high TALEN knockout success in rat zygots. Only heterozygous deletion was observed in the offsprings. Sixteen pairs of heterozygous FH knockout (FH+/-) rats were arranged for mating experiments for six months without any homozygous KO rat identified. Sequencing from the pregnant rats embryo samples showed no homozygous FH KO, indicating that homozygous FH KO is embryonically lethal. Comparatively, the litter size was decreased in both male and female FH+/- KO rats. There was no behaviour difference between the FH+/- KO and the control rats except that the FH+/- KO male rats showed significantly higher body weight in the 16-week observation period. Clinical haematology and biochemical examinations showed hematopoietic and kidney dysfunction in the FH+/- KO rats. Small foci of anaplastic lesions of tubular epithelial cells around glomeruli were identified in the FH+/- kidney, and these anaplastic cells were comparatively positive for Ki67, p53 and Sox9, and such findings are most probably related to the kidney dysfunction reflected by the biochemical examinations of the rats. In conclusion, we have successfully established an FH+/- KO rat model, which will be useful for further functional FH studies.

  2. Generation of TALEN-mediated FH knockout rat model

    PubMed Central

    Yu, Dandan; Zhong, Yali; Li, Xiaoran; Li, Yaqing; Li, Xiaoli; Cao, Jing; Fan, Zhirui; Fan, Huijie; Yuan, Long; Xu, Benling; Yuan, Yuan; Zhang, Hongquan; Ji, Zhenyu; Wen, Jian-Guo; Zhang, Mingzhi; Nesland, Jahn M.; Suo, Zhenhe

    2016-01-01

    Transcription activator-like effector nucleases (TALENs) are valuable tools for precise genome engineering of laboratory animals. Here we utilized this technique for efficient site-specific gene modification to create a fumarate hydratase (FH) gene knockout rat model, in which there was an 11 base-pair deletion in the first exon of the FH gene in 111 rats. 18 live-born targeted mutation offsprings were produced from 80 injected zygotes with 22.5% efficiency, indicating high TALEN knockout success in rat zygots. Only heterozygous deletion was observed in the offsprings. Sixteen pairs of heterozygous FH knockout (FH+/−) rats were arranged for mating experiments for six months without any homozygous KO rat identified. Sequencing from the pregnant rats embryo samples showed no homozygous FH KO, indicating that homozygous FH KO is embryonically lethal. Comparatively, the litter size was decreased in both male and female FH+/− KO rats. There was no behaviour difference between the FH+/− KO and the control rats except that the FH+/− KO male rats showed significantly higher body weight in the 16-week observation period. Clinical haematology and biochemical examinations showed hematopoietic and kidney dysfunction in the FH+/− KO rats. Small foci of anaplastic lesions of tubular epithelial cells around glomeruli were identified in the FH+/− kidney, and these anaplastic cells were comparatively positive for Ki67, p53 and Sox9, and such findings are most probably related to the kidney dysfunction reflected by the biochemical examinations of the rats. In conclusion, we have successfully established an FH+/− KO rat model, which will be useful for further functional FH studies. PMID:27556703

  3. Pre-Equilibrium Cluster Emission with Pickup and Knockout

    SciTech Connect

    Betak, E.

    2005-05-24

    We present a generalization of the Iwamoto-Harada-Bisplinghoff pre-equilibrium model of light cluster formation and emission, which is enhanced by allowing for possible admixtures of knockout for strongly coupled ejectiles, like {alpha}'s. The model is able to attain the Weisskopf-Ewing formula for compound-nucleus decay at long-time limit; it keeps the philosophy of pre-equilibrium decay during the equilibration stage and it describes the initial phase of a reaction as direct process(es) expressed using the language of the exciton model.

  4. Normal Taste Acceptance and Preference of PANX1 Knockout Mice

    PubMed Central

    Aleman, Tiffany R.; Ellis, Hillary T.; Ohmoto, Makoto; Matsumoto, Ichiro; Shestopalov, Val I.; Mitchell, Claire H.; Foskett, J. Kevin; Poole, Rachel L.

    2015-01-01

    Taste compounds detected by G protein-coupled receptors on the apical surface of Type 2 taste cells initiate an intracellular molecular cascade culminating in the release of ATP. It has been suggested that this ATP release is accomplished by pannexin 1 (PANX1). However, we report here that PANX1 knockout mice do not differ from wild-type controls in response to representative taste solutions, measured using 5-s brief-access tests or 48-h two-bottle choice tests. This implies that PANX1 is unnecessary for taste detection and consequently that ATP release from Type 2 taste cells does not require PANX1. PMID:25987548

  5. Fetal cardiac scanning today.

    PubMed

    Allan, Lindsey

    2010-07-01

    The ability to examine the structure of the fetal heart in real-time started over 30 years ago now. The field has seen very great advances since then, both in terms of technical improvements in ultrasound equipment and in dissemination of operator skills. A great deal has been learnt about normal cardiac function in the human fetus throughout gestation and how it is affected by pathologies of pregnancy. There is increasing recognition of abnormal heart structure during routine obstetric scanning, allowing referral for specialist diagnosis and counselling. It is now possible to make accurate diagnosis of cardiac malformations as early as 12 weeks of gestation. Early diagnosis of a major cardiac malformation in the fetus can provide the parents with a comprehensive prognosis, enabling them to make the most informed choice about the management of the pregnancy.

  6. Autoantibodies and Cardiac Arrhythmias

    PubMed Central

    Lee, Hon-Chi; Huang, Kristin T. L.; Wang, Xiao-Li; Shen, Win-Kuang

    2013-01-01

    Autoimmune diseases are associated with significant morbidity and mortality, afflicting about 5% of the population of the United States. They encompass a wide range of disorders that affect all organs of the human body and have a predilection for women. In the past, autoimmune pathogenesis was not thought to be a major mechanism for cardiovascular disorders, and potential relationships remain understudied. However, accumulating evidence suggests that a number of vascular and cardiac conditions are autoimmune-mediated. Recent studies indicate that autoantibodies play an important role in the development of cardiac arrhythmias, including atrial fibrillation, modulation of autonomic influences on heart rate and rhythm, conduction system abnormalities, and ventricular arrhythmias. This manuscript will review the current evidence for the role of autoantibodies in the development of cardiac arrhythmias. PMID:21740882

  7. Toothache of cardiac origin.

    PubMed

    Kreiner, M; Okeson, J P

    1999-01-01

    Pain referred to the orofacial structures can sometimes be a diagnostic challenge for the clinician. In some instances, a patient may complain of tooth pain that is completely unrelated to any dental source. This poses a diagnostic and therapeutic problem for the dentist. Cardiac pain most commonly radiates to the left arm, shoulder, neck, and face. In rare instances, angina pectoris may present as dental pain. When this occurs, an improper diagnosis frequently leads to unnecessary dental treatment or, more significantly, a delay of proper treatment. This delay may result in the patient experiencing an acute myocardial infarction. It is the dentist's responsibility to establish a proper diagnosis so that the treatment will be directed toward the source of pain and not to the site of pain. This article reviews the literature concerning referred pain of cardiac origin and presents a case report of toothache of cardiac origin.

  8. Myoglobin-deficient mice activate a distinct cardiac gene expression program in response to isoproterenol-induced hypertrophy.

    PubMed

    Molojavyi, Andrei; Lindecke, Antje; Raupach, Annika; Moellendorf, Sarah; Köhrer, Karl; Gödecke, Axel

    2010-04-01

    Myoglobin knockout mice (myo-/-) adapt to the loss of myoglobin by the activation of a variety of compensatory mechanisms acting on the structural and functional level. To analyze to what extent myo-/- mice would tolerate cardiac stress we used the model of chronic isoproterenol application to induce cardiac hypertrophy in myo-/- mice and wild-type (WT) controls. After 14 days of isoproterenol infusion cardiac hypertrophy in WT and myo-/- mice reached a similar level. WT mice developed lung edema and left ventricular dilatation suggesting the development of heart failure. In contrast, myo-/- mice displayed conserved cardiac function and no signs of left ventricular dilatation. Analysis of the cardiac gene expression profiles using 40K mouse oligonucleotide arrays showed that isoproterenol affected the expression of 180 genes in WT but only 92 genes of myo-/- hearts. Only 40 of these genes were regulated in WT as well as in myo-/- hearts. In WT hearts a pronounced induction of genes of the extracellular matrix occurred suggesting a higher level of cardiac remodeling. myo-/- hearts showed altered transcription of genes involved in carbon metabolism, inhibition of apoptosis and muscular repair. Interestingly, a subset of genes that was altered in myo-/- mice already under basal conditions was differentially expressed in WT hearts under isoproterenol treatment. In summary, our data show a high capacity of myoglobin-deficient mice to adapt to catecholamine induced cardiac stress which is associated with activation of a distinct cardiac gene expression program.

  9. OSM mitigates post-infarction cardiac remodeling and dysfunction by up-regulating autophagy through Mst1 suppression.

    PubMed

    Hu, Jianqiang; Zhang, Lei; Zhao, Zhijing; Zhang, Mingming; Lin, Jie; Wang, Jiaxing; Yu, Wenjun; Man, Wanrong; Li, Congye; Zhang, Rongqing; Gao, Erhe; Wang, Haichang; Sun, Dongdong

    2016-11-04

    The incidence and prevalence of heart failure (HF) in the world are rapidly rising possibly attributed to the worsened HF following myocardial infarction (MI) in recent years. Here we examined the effects of oncostatin M (OSM) on postinfarction cardiac remodeling and the underlying mechanisms involved. MI model was induced using left anterior descending coronary artery (LAD) ligation. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated MI. Our results revealed that OSM alleviated left ventricular remodeling, promoted cardiac function, restored mitochondrial cristae density and architecture disorders after 4weeks of MI. Enhanced autophagic flux was indicated in cardiomyocytes transduced with Ad-GFP -LC3 in the OSM treated group as compared with the MI group. OSM receptor Oβ knockout blocked the beneficial effects of OSM in postinfarction cardiac remodeling and cardiomyocytes autophagy. OSM pretreatment significantly alleviated left ventricular remodeling and dysfunction in Mst1 transgenic mice, while it failed to reverse further the postinfarction left ventricular dilatation and cardiac function in the Mst1 knockout mice. Our data revealed that OSM alleviated postinfarction cardiac remodeling and dysfunction by enhancing cardiomyocyte autophagy. OSM holds promise as a therapeutic target in treating HF after MI through Oβ receptor by inhibiting Mst1 phosphorylation.

  10. Drug Treatment of Cardiac Failure

    PubMed Central

    Achong, M. R.; Kumana, C. R.

    1982-01-01

    Treatment of cardiac failure should first be aimed at reversing or ameliorating the underlying pathological processes. This review highlights the common problems and pitfalls in the use of digoxin, diuretics and vasodilators in patients with cardiac failure. PMID:21289849

  11. Mechanisms of cardiac arrhythmias

    PubMed Central

    Tse, Gary

    2015-01-01

    Blood circulation is the result of the beating of the heart, which provides the mechanical force to pump oxygenated blood to, and deoxygenated blood away from, the peripheral tissues. This depends critically on the preceding electrical activation. Disruptions in the orderly pattern of this propagating cardiac excitation wave can lead to arrhythmias. Understanding of the mechanisms underlying their generation and maintenance requires knowledge of the ionic contributions to the cardiac action potential, which is discussed in the first part of this review. A brief outline of the different classification systems for arrhythmogenesis is then provided, followed by a detailed discussion for each mechanism in turn, highlighting recent advances in this area. PMID:27092186

  12. Mechanisms of Cardiac Regeneration

    PubMed Central

    Uygur, Aysu; Lee, Richard T.

    2016-01-01

    Adult humans fail to regenerate their hearts following injury, and this failure to regenerate myocardium is a leading cause of heart failure and death worldwide. Although all adult mammals appear to lack significant cardiac regeneration potential, some vertebrates can regenerate myocardium throughout life. In addition, new studies indicate that mammals have cardiac regeneration potential during development and very soon after birth. The mechanisms of heart regeneration among model organisms, including neonatal mice, appear remarkably similar. Orchestrated waves of inflammation, matrix deposition and remodeling, and cardiomyocyte proliferation are commonly seen in heart regeneration models. Understanding why adult mammals develop extensive scarring instead of regeneration is a crucial goal for regenerative biology. PMID:26906733

  13. Nitric Oxide Induces Cardiac Protection by Preventing Extracellular Matrix Degradation through the Complex Caveolin-3/EMMPRIN in Cardiac Myocytes.

    PubMed

    Cuadrado, Irene; Castejon, Borja; Martin, Ana M; Saura, Marta; Reventun-Torralba, Paula; Zamorano, Jose Luis; Zaragoza, Carlos

    2016-01-01

    Inhibition of Extracellular Matrix degradation by nitric oxide (NO) induces cardiac protection against coronary ischemia/reperfusion (IR). Glycosylation of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) stimulates enzymatic activation of matrix metalloproteinases (MMPs) in the heart, although the mechanisms leading to EMMPRIN glycosylation are poorly understood. We sought to determine if NO may induce cardiac protection by preventing glycosylation of EMMPRIN in a mouse model of IR. Here we found that Caveolin-3 binds to low glycosylated EMMPRIN (LG-EMMPRIN) in cardiac cells and in the hearts of healthy mice, whereas IR disrupted the complex in nitric oxide synthase 2 (NOS2) knockout (KO) mice. By contrast, the binding was partially restored when mice were fed with an NO donor (DEA-NO) in the drinking water, showing a significant reduction on infarct size (NOS2KO: 34.6±5 vs NOS2KO+DEA-NO: 20.7±9), in expression of matrix metalloproteinases, and cardiac performance was improved (left ventricular ejection fraction (LVEF). NOS2KO: 31±4 vs NOS2KO+DEA-NO: 46±6). The role of Caveolin-3/EMMPRIN in NO-mediated cardiac protection was further assayed in Caveolin-3 KO mice, showing no significant improvement on infarct size (Caveolin-3 KO: 34.8±3 vs Caveolin-3 KO+DEA-NO:33.7±5), or in the expression of MMPs, suggesting that stabilization of the complex Caveolin-3/LG-EMMPRIN may play a significant role in the cardioprotective effect of NO against IR.

  14. Nitric Oxide Induces Cardiac Protection by Preventing Extracellular Matrix Degradation through the Complex Caveolin-3/EMMPRIN in Cardiac Myocytes

    PubMed Central

    Cuadrado, Irene; Castejon, Borja; Martin, Ana M.; Saura, Marta; Reventun-Torralba, Paula; Zamorano, Jose Luis

    2016-01-01

    Inhibition of Extracellular Matrix degradation by nitric oxide (NO) induces cardiac protection against coronary ischemia/reperfusion (IR). Glycosylation of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) stimulates enzymatic activation of matrix metalloproteinases (MMPs) in the heart, although the mechanisms leading to EMMPRIN glycosylation are poorly understood. We sought to determine if NO may induce cardiac protection by preventing glycosylation of EMMPRIN in a mouse model of IR. Here we found that Caveolin-3 binds to low glycosylated EMMPRIN (LG-EMMPRIN) in cardiac cells and in the hearts of healthy mice, whereas IR disrupted the complex in nitric oxide synthase 2 (NOS2) knockout (KO) mice. By contrast, the binding was partially restored when mice were fed with an NO donor (DEA-NO) in the drinking water, showing a significant reduction on infarct size (NOS2KO: 34.6±5 vs NOS2KO+DEA-NO: 20.7±9), in expression of matrix metalloproteinases, and cardiac performance was improved (left ventricular ejection fraction (LVEF). NOS2KO: 31±4 vs NOS2KO+DEA-NO: 46±6). The role of Caveolin-3/EMMPRIN in NO-mediated cardiac protection was further assayed in Caveolin-3 KO mice, showing no significant improvement on infarct size (Caveolin-3 KO: 34.8±3 vs Caveolin-3 KO+DEA-NO:33.7±5), or in the expression of MMPs, suggesting that stabilization of the complex Caveolin-3/LG-EMMPRIN may play a significant role in the cardioprotective effect of NO against IR. PMID:27649573

  15. Taurine depletion caused by knocking out the taurine transporter gene leads to cardiomyopathy with cardiac atrophy.

    PubMed

    Ito, Takashi; Kimura, Yasushi; Uozumi, Yoriko; Takai, Mika; Muraoka, Satoko; Matsuda, Takahisa; Ueki, Kei; Yoshiyama, Minoru; Ikawa, Masahito; Okabe, Masaru; Schaffer, Stephen W; Fujio, Yasushi; Azuma, Junichi

    2008-05-01

    The sulfur-containing beta-amino acid, taurine, is the most abundant free amino acid in cardiac and skeletal muscle. Although its physiological function has not been established, it is thought to play an important role in ion movement, calcium handling, osmoregulation and cytoprotection. To begin examining the physiological function of taurine, we generated taurine transporter- (TauT-) knockout mice (TauTKO), which exhibited a deficiency in myocardial and skeletal muscle taurine content compared with their wild-type littermates. The TauTKO heart underwent ventricular remodeling, characterized by reductions in ventricular wall thickness and cardiac atrophy accompanied with the smaller cardiomyocytes. Associated with the structural changes in the heart was a reduction in cardiac output and increased expression of heart cardiac failure (fetal) marker genes, such as ANP, BNP and beta-MHC. Moreover, ultrastructural damage to the myofilaments and mitochondria was observed. Further, the skeletal muscle of the TauTKO mice also exhibited decreased cell volume, structural defects and a reduction of exercise endurance capacity. Importantly, the expression of Hsp70, ATA2 and S100A4, which are upregulated by osmotic stress, was elevated in both heart and skeletal muscle of the TauTKO mice. Taurine depletion causes cardiomyocyte atrophy, mitochondrial and myofiber damage and cardiac dysfunction, effects likely related to the actions of taurine. Our data suggest that multiple actions of taurine, including osmoregulation, regulation of mitochondrial protein expression and inhibition of apoptosis, collectively ensure proper maintenance of cardiac and skeletal muscular structure and function.

  16. Emergency Cardiac Care: An Update

    PubMed Central

    Swanson, Richard W.

    1988-01-01

    The authors review the new guidelines for basic life support and advanced cardiac life support and the recommended changes to the standards. The changes recommended for basic life support will simplify the psychomotor skills required. The recommended changes to the guidelines for advanced cardiac life support, which include discontinuing the use of isoproterenol and limiting the use of sodium bicarbonate in cardiac arrest, are likely to improve survival rates. Controversies in the management of cardiac arrest are also discussed. PMID:21253157

  17. Hair-Cell Mechanotransduction Persists in TRP Channel Knockout Mice

    PubMed Central

    Niksch, Paul D.; Webber, Roxanna M.; Garcia-Gonzalez, Miguel; Watnick, Terry; Zhou, Jing; Vollrath, Melissa A.; Corey, David P.

    2016-01-01

    Members of the TRP superfamily of ion channels mediate mechanosensation in some organisms, and have been suggested as candidates for the mechanotransduction channel in vertebrate hair cells. Some TRP channels can be ruled out based on lack of an inner ear phenotype in knockout animals or pore properties not similar to the hair-cell channel. Such studies have excluded Trpv4, Trpa1, Trpml3, Trpm1, Trpm3, Trpc1, Trpc3, Trpc5, and Trpc6. However, others remain reasonable candidates. We used data from an RNA-seq analysis of gene expression in hair cells as well as data on TRP channel conductance to narrow the candidate group. We then characterized mice lacking functional Trpm2, Pkd2, Pkd2l1, Pkd2l2 and Pkd1l3, using scanning electron microscopy, auditory brainstem response, permeant dye accumulation, and single-cell electrophysiology. In all of these TRP-deficient mice, and in double and triple knockouts, mechanotransduction persisted. Together with published studies, these results argue against the participation of any of the 33 mouse TRP channels in hair cell transduction. PMID:27196058

  18. TALEN-based knockout library for human microRNAs.

    PubMed

    Kim, Young-Kook; Wee, Gabbine; Park, Joha; Kim, Jongkyu; Baek, Daehyun; Kim, Jin-Soo; Kim, V Narry

    2013-12-01

    Various technical tools have been developed to probe the functions of microRNAs (miRNAs), yet their application has been limited by low efficacy and specificity. To overcome the limitations, we used transcription activator-like effector nucleases (TALENs) to knock out human miRNA genes. We designed and produced a library of 540 pairs of TALENs for 274 miRNA loci, focusing on potentially important miRNAs. The knockout procedure takes only 2-4 weeks and can be applied to any cell type. As a case study, we generated knockout cells for two related miRNAs, miR-141 and miR-200c, which belong to the highly conserved miR-200 family. Interestingly, miR-141 and miR-200c, despite their overall similarity, suppress largely nonoverlapping groups of targets, thus suggesting that functional miRNA-target interaction requires strict seed-pairing. Our study illustrates the potency of TALEN technology and provides useful resources for miRNA research.

  19. Maize-targeted mutagenesis: A knockout resource for maize.

    PubMed

    May, Bruce P; Liu, Hong; Vollbrecht, Erik; Senior, Lynn; Rabinowicz, Pablo D; Roh, Donna; Pan, Xiaokang; Stein, Lincoln; Freeling, Mike; Alexander, Danny; Martienssen, Rob

    2003-09-30

    We describe an efficient system for site-selected transposon mutagenesis in maize. A total of 43,776 F1 plants were generated by using Robertson's Mutator (Mu) pollen parents and self-pollinated to establish a library of transposon-mutagenized seed. The frequency of new seed mutants was between 10-4 and 10-5 per F1 plant. As a service to the maize community, maize-targeted mutagenesis selects insertions in genes of interest from this library by using the PCR. Pedigree, knockout, sequence, phenotype, and other information is stored in a powerful interactive database (maize-targeted mutagenesis database) that enables analysis of the entire population and the handling of knockout requests. By inhibiting Mu activity in most F1 plants, we sought to reduce somatic insertions that may cause false positives selected from pooled tissue. By monitoring the remaining Mu activity in the F2, however, we demonstrate that seed phenotypes depend on it, and false positives occur in lines that appear to lack it. We conclude that more than half of all mutations arising in this population are suppressed on losing Mu activity. These results have implications for epigenetic models of inbreeding and for functional genomics.

  20. Ultrastructural analysis of megakaryocytes in GPV knockout mice.

    PubMed

    Poujol, C; Ramakrishnan, V; DeGuzman, F; Nurden, A T; Phillips, D R; Nurden, P

    2000-08-01

    Lesions in the genes for GPIb alpha, GPIb beta or GPIX result in a bleeding diathesis, the Bernard-Soulier syndrome (BSS), which associates a platelet adhesion defect with thrombocytopenia, giant platelets and abnormal megakaryocytes (MK). The role of GPV, also absent in BSS, was recently addressed by gene targeting in mice. While a negative modulator function for GPV on thrombin-induced platelet responses was found in one model, the absence of GP V had no effect on GPIb-IX expression or platelet adhesion. Our study extends previous results and reports that electron microscopy of bone marrow from the GPV knockout mice revealed a normal MK ultrastructure and development of the demarcation membrane system (DMS). There was a usual presence of MK fragments in the bone marrow vascular sinus. Immunogold labelling of MK from the knockout mice showed a normal distribution of GPIb-IX in the DMS and on the cell surface. The distribution of fibrinogen, vWF and P-selectin was unchanged with, interestingly, P-selectin also localised within the DMS in both situations. Thus GPV is not crucial to MK development and platelet production, consistent with the fact that no mutation in the GPV gene has as yet been described in BSS.

  1. Norepinephrine transporter heterozygous knockout mice exhibit altered transport and behavior.

    PubMed

    Fentress, H M; Klar, R; Krueger, J J; Sabb, T; Redmon, S N; Wallace, N M; Shirey-Rice, J K; Hahn, M K

    2013-11-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET(+/-) ), demonstrating that they display an approximately 50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET(+/-) mouse establishes an activated state of existing surface NET proteins. The NET(+/-) mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris water maze. These data suggest that recovery of near basal activity in NET(+/-) mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET(+/-) mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders.

  2. RAG1/2 knockout pigs with severe combined immunodeficiency.

    PubMed

    Huang, Jiao; Guo, Xiaogang; Fan, Nana; Song, Jun; Zhao, Bentian; Ouyang, Zhen; Liu, Zhaoming; Zhao, Yu; Yan, Quanmei; Yi, Xiaoling; Schambach, Axel; Frampton, Jon; Esteban, Miguel A; Yang, Dongshan; Yang, Huaqiang; Lai, Liangxue

    2014-08-01

    Pigs share many physiological, biochemical, and anatomical similarities with humans and have emerged as valuable large animal models for biomedical research. Considering the advantages in immune system resemblance, suitable size, and longevity for clinical practical and monitoring purpose, SCID pigs bearing dysfunctional RAG could serve as important experimental tools for regenerative medicine, allograft and xenograft transplantation, and reconstitution experiments related to the immune system. In this study, we report the generation and phenotypic characterization of RAG1 and RAG2 knockout pigs using transcription activator-like effector nucleases. Porcine fetal fibroblasts were genetically engineered using transcription activator-like effector nucleases and then used to provide donor nuclei for somatic cell nuclear transfer. We obtained 27 live cloned piglets; among these piglets, 9 were targeted with biallelic mutations in RAG1, 3 were targeted with biallelic mutations in RAG2, and 10 were targeted with a monoallelic mutation in RAG2. Piglets with biallelic mutations in either RAG1 or RAG2 exhibited hypoplasia of immune organs, failed to perform V(D)J rearrangement, and lost mature B and T cells. These immunodeficient RAG1/2 knockout pigs are promising tools for biomedical and translational research.

  3. Core features of frontotemporal dementia recapitulated in progranulin knockout mice

    PubMed Central

    Ghoshal, N.; Dearborn, J.T.; Wozniak, D.F.; Cairns, N.J.

    2011-01-01

    Frontotemporal dementia (FTD) is typified by behavioral and cognitive changes manifested as altered social comportment and impaired memory performance. To investigate the neurodegenerative consequences of progranulin gene (GRN) mutations, which cause an inherited form of FTD, we used previously generated progranulin knockout mice (Grn-/-). Specifically, we characterized two cohorts of early and later middle-age wild type and knockout mice using a battery of tests to assess neurological integrity and behavioral phenotypes analogous to FTD. The Grn-/- mice exhibited reduced social engagement and learning and memory deficits. Immunohistochemical approaches were used to demonstrate the presence of lesions characteristic of frontotemporal lobar degeneration (FTLD) with GRN mutation including ubiquitination, microgliosis, and reactive astrocytosis, the pathological substrate of FTD. Importantly, Grn-/- mice also have decreased overall survival compared to Grn+/+ mice. These data suggest that the Grn-/- mouse reproduces some core features of FTD with respect to behavior, pathology, and survival. This murine model may serve as a valuable in vivo model of FTLD with GRN mutation through which molecular mechanisms underlying the disease can be further dissected. PMID:21933710

  4. Norepinephrine Transporter Heterozygous Knockout Mice Exhibit Altered Transport and Behavior

    PubMed Central

    Fentress, HM; Klar, R; Krueger, JK; Sabb, T; Redmon, SN; Wallace, NM; Shirey-Rice, JK; Hahn, MK

    2013-01-01

    The norepinephrine (NE) transporter (NET) regulates synaptic NE availability for noradrenergic signaling in the brain and sympathetic nervous system. Although genetic variation leading to a loss of NET expression has been implicated in psychiatric and cardiovascular disorders, complete NET deficiency has not been found in people, limiting the utility of NET knockout mice as a model for genetically-driven NET dysfunction. Here, we investigate NET expression in NET heterozygous knockout male mice (NET+/−), demonstrating that they display an ~50% reduction in NET protein levels. Surprisingly, these mice display no significant deficit in NET activity, assessed in hippocampal and cortical synaptosomes. We found that this compensation in NET activity was due to enhanced activity of surface-resident transporters, as opposed to surface recruitment of NET protein or compensation through other transport mechanisms, including serotonin, dopamine or organic cation transporters. We hypothesize that loss of NET protein in the NET+/− mouse establishes an activated state of existing, surface NET proteins. NET+/− mice exhibit increased anxiety in the open field and light-dark box and display deficits in reversal learning in the Morris Water Maze. These data suggest recovery of near basal activity in NET+/− mice appears to be insufficient to limit anxiety responses or support cognitive performance that might involve noradrenergic neurotransmission. The NET+/− mice represent a unique model to study the loss and resultant compensatory changes in NET that may be relevant to behavior and physiology in human NET deficiency disorders. PMID:24102798

  5. Data analysis in cardiac arrhythmias.

    PubMed

    Rodrigo, Miguel; Pedrón-Torecilla, Jorge; Hernández, Ismael; Liberos, Alejandro; Climent, Andreu M; Guillem, María S

    2015-01-01

    Cardiac arrhythmias are an increasingly present in developed countries and represent a major health and economic burden. The occurrence of cardiac arrhythmias is closely linked to the electrical function of the heart. Consequently, the analysis of the electrical signal generated by the heart tissue, either recorded invasively or noninvasively, provides valuable information for the study of cardiac arrhythmias. In this chapter, novel cardiac signal analysis techniques that allow the study and diagnosis of cardiac arrhythmias are described, with emphasis on cardiac mapping which allows for spatiotemporal analysis of cardiac signals.Cardiac mapping can serve as a diagnostic tool by recording cardiac signals either in close contact to the heart tissue or noninvasively from the body surface, and allows the identification of cardiac sites responsible of the development or maintenance of arrhythmias. Cardiac mapping can also be used for research in cardiac arrhythmias in order to understand their mechanisms. For this purpose, both synthetic signals generated by computer simulations and animal experimental models allow for more controlled physiological conditions and complete access to the organ.

  6. Cardiac troponins and high-sensitivity cardiac troponin assays.

    PubMed

    Conrad, Michael J; Jarolim, Petr

    2014-03-01

    Measurement of circulating cardiac troponins I and T has become integral to the diagnosis of myocardial infarction. This article discusses the structure and function of the troponin complex and the release of cardiac troponin molecules from the injured cardiomyocyte into the circulation. An overview of current cardiac troponin assays and their classification according to sensitivity is presented. The diagnostic criteria, role, and usefulness of cardiac troponin for myocardial infarction are discussed. In addition, several examples are given of the usefulness of high-sensitivity cardiac troponin assays for short-term and long-term prediction of adverse events.

  7. Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis.

    PubMed

    Aherrahrou, Zouhair; Schlossarek, Saskia; Stoelting, Stephanie; Klinger, Matthias; Geertz, Birgit; Weinberger, Florian; Kessler, Thorsten; Aherrahrou, Redouane; Moreth, Kristin; Bekeredjian, Raffi; Hrabě de Angelis, Martin; Just, Steffen; Rottbauer, Wolfgang; Eschenhagen, Thomas; Schunkert, Heribert; Carrier, Lucie; Erdmann, Jeanette

    2016-01-01

    Cardiomyopathy is one of the most common causes of chronic heart failure worldwide. Mutations in the gene encoding nexilin (NEXN) occur in patients with both hypertrophic and dilated cardiomyopathy (DCM); however, little is known about the pathophysiological mechanisms and relevance of NEXN to these disorders. Here, we evaluated the functional role of NEXN using a constitutive Nexn knock-out (KO) mouse model. Heterozygous (Het) mice were inter-crossed to produce wild-type (WT), Het, and homozygous KO mice. At birth, 32, 46, and 22 % of the mice were WT, Het, and KO, respectively, which is close to the expected Mendelian ratio. After postnatal day 6, the survival of the Nexn KO mice decreased dramatically and all of the animals died by day 8. Phenotypic characterizations of the WT and KO mice were performed at postnatal days 1, 2, 4, and 6. At birth, the relative heart weights of the WT and KO mice were similar; however, at day 4, the relative heart weight of the KO group was 2.3-fold higher than of the WT group. In addition, the KO mice developed rapidly progressive cardiomyopathy with left ventricular dilation and wall thinning and decreased cardiac function. At day 6, the KO mice developed a fulminant DCM phenotype characterized by dilated ventricular chambers and systolic dysfunction. At this stage, collagen deposits and some elastin deposits were observed within the left ventricle cavity, which resembles the features of endomyocardial fibroelastosis (EFE). Overall, these results further emphasize the role of NEXN in DCM and suggest a novel role in EFE.

  8. The protective role of tacrine and donepezil in the retina of acetylcholinesterase knockout mice

    PubMed Central

    Yi, Yun-Min; Cai, Li; Shao, Yi; Xu, Man; Yi, Jing-Lin

    2015-01-01

    AIM To determine the effect of different concentrations of the acetylcholinesterase (AChE) inhibitors tacrine and donepezil on retinal protection in AChE+/− mice (AChE knockout mice) of various ages. METHODS Cultured ARPE-19 cells were treated with hydrogen peroxide (H2O2) at concentrations of 0, 250, 500, 1000 and 2000 µmol/L and protein levels were measured using Western blot. Intraperitoneal injections of tacrine and donepezil (0.1 mg/mL, 0.2 mg/mL and 0.4 mg/mL) were respectively given to AChE+/− mice aged 2mo and 4mo and wild-type S129 mice for 7d; phosphate buffered saline (PBS) was administered to the control group. The mice were sacrificed after 30d by in vitro cardiac perfusion and retinal samples were taken. AChE-deficient mice were identified by polymerase chain reaction (PCR) analysis using specific genotyping protocols obtained from the Jackson Laboratory website. H&E staining, immunofluorescence and Western blot were performed to observe AChE protein expression changes in the retinal pigment epithelial (RPE) cell layer. RESULTS Different concentrations of H2O2 induced AChE expression during RPE cell apoptosis. AChE+/− mice retina were thinner than those in wild-type mice (P<0.05); the retinal structure was still intact at 2mo but became thinner with increasing age (P<0.05); furthermore, AChE+/− mice developed more slowly than wild-type mice (P<0.05). Increased concentrations of tacrine and donepezil did not significantly improve the protection of the retina function and morphology (P>0.05). CONCLUSION In vivo, tacrine and donepezil can inhibit the expression of AChE; the decrease of AChE expression in the retina is beneficial for the development of the retina. PMID:26558196

  9. Cardiac T1 Imaging

    PubMed Central

    Jerosch-Herold, Michael; Kwong, Raymond Y.

    2014-01-01

    T1 mapping of the heart has evolved into a valuable tool to evaluate myocardial tissue properties, with or without contrast injection, including assessment of myocardial edema and free water content, extra-cellular volume (expansion), and most recently cardiomyocyte hypertrophy. The MRI pulse sequence techniques developed for these applications have had to address at least two important considerations for cardiac applications: measure magnetization inversion recoveries during cardiac motion with sufficient temporal resolution for the shortest expected T1 values, and, secondly, obtain these measurements within a time during which a patient can comfortably suspend breathing. So-called Look-Locker techniques, and variants thereof, which all sample multiple points of a magnetization recovery after each magnetization preparation have therefore become a mainstay in this field. The rapid pace of advances and new findings based on cardiac T1 mapping for assessment of diffuse fibrosis, or myocardial edema show that these techniques enrich the capabilities of MRI for myocardial tissue profiling, which is arguably unmatched by other cardiac imaging modalities. PMID:24509619

  10. Hepato-cardiac disorders

    PubMed Central

    Fouad, Yasser Mahrous; Yehia, Reem

    2014-01-01

    Understanding the mutual relationship between the liver and the heart is important for both hepatologists and cardiologists. Hepato-cardiac diseases can be classified into heart diseases affecting the liver, liver diseases affecting the heart, and conditions affecting the heart and the liver at the same time. Differential diagnoses of liver injury are extremely important in a cardiologist’s clinical practice calling for collaboration between cardiologists and hepatologists due to the many other diseases that can affect the liver and mimic haemodynamic injury. Acute and chronic heart failure may lead to acute ischemic hepatitis or chronic congestive hepatopathy. Treatment in these cases should be directed to the primary heart disease. In patients with advanced liver disease, cirrhotic cardiomyopathy may develop including hemodynamic changes, diastolic and systolic dysfunctions, reduced cardiac performance and electrophysiological abnormalities. Cardiac evaluation is important for patients with liver diseases especially before and after liver transplantation. Liver transplantation may lead to the improvement of all cardiac changes and the reversal of cirrhotic cardiomyopathy. There are systemic diseases that may affect both the liver and the heart concomitantly including congenital, metabolic and inflammatory diseases as well as alcoholism. This review highlights these hepatocardiac diseases PMID:24653793

  11. Advanced Cardiac Life Support.

    ERIC Educational Resources Information Center

    Kirkwood Community Coll., Cedar Rapids, IA.

    This document contains materials for an advanced college course in cardiac life support developed for the State of Iowa. The course syllabus lists the course title, hours, number, description, prerequisites, learning activities, instructional units, required text, six references, evaluation criteria, course objectives by units, course…

  12. Ethical Issues in Cardiac Surgery

    PubMed Central

    Kavarana, Minoo N.; Sade, Robert M.

    2012-01-01

    While ethical behavior has always been part of cardiac surgical practice, ethical deliberation has only recently become an important component of cardiac surgical practice. Issues such as informed consent, conflict of interest, and professional self-regulation, among many others, have increasingly attracted the attention of cardiac surgeons. This review covers several broad topics of interest to cardiac surgeons and cardiologists, and treats several other topics more briefly. There is much uncertainty about what the future holds for cardiac surgical practice, research, and culture, and we discuss the background of ethical issues to serve as a platform for envisioning what is to come. PMID:22642634

  13. STARS knockout attenuates hypoxia-induced pulmonary arterial hypertension by suppressing pulmonary arterial smooth muscle cell proliferation.

    PubMed

    Shi, Zhaoling; Wu, Huajie; Luo, Jianfeng; Sun, Xin

    2017-03-01

    STARS (STriated muscle Activator of Rho Signaling) is a sarcomeric protein, which expressed early in cardiac development and involved in pathological remodeling. Abundant evidence indicated that STARS could regulate cell proliferation, but it's exact function remains unclear. In this study, we aimed to investigate the role of STARS in the proliferation of pulmonary arterial smooth muscle cells (PASMC) and the potential effect on the progression of pulmonary arterial hypertension (PAH). In this study, we established a PAH mouse model through chronic hypoxia exposure as reflected by the increased RVSP and RVHI. Western blot and RT-qPCR detected the increased STARS protein and mRNA levels in PAH mice. Next, we cultured the primary PASMC from PAH mice. After STARS overexpression in PASMC, STARS, SRF and Egr-1 were up-regulated significantly. The MTT assay revealed an increase in cell proliferation. Flow cytometry showed a marked inhibition of cell apoptosis. However, STARS silence in PASMC exerted opposite effects with STARS overexpression. SRF siRNA transfection blocked the effects of STARS overexpression in PASMC. In order to further confirm the role of STARS in PAH mice in vivo, we exposed STARS knockout mice to hypoxia and found lower RVSP and RVHI in knockout mice as compared with controls. Our results not only suggest that STARS plays a crucial role in the development of PAH by increasing the proliferation of PASMC through activation of the SRF/Egr-1 pathway, but also provides a new mechanism for hypoxia-induced PAH. In addition, STARS may represent a potential treatment target.

  14. Genetics of sudden cardiac death.

    PubMed

    Bezzina, Connie R; Lahrouchi, Najim; Priori, Silvia G

    2015-06-05

    Sudden cardiac death occurs in a broad spectrum of cardiac pathologies and is an important cause of mortality in the general population. Genetic studies conducted during the past 20 years have markedly illuminated the genetic basis of the inherited cardiac disorders associated with sudden cardiac death. Here, we review the genetic basis of sudden cardiac death with a focus on the current knowledge on the genetics of the primary electric disorders caused primarily by mutations in genes encoding ion channels, and the cardiomyopathies, which have been attributed to mutations in genes encoding a broader category of proteins, including those of the sarcomere, the cytoskeleton, and desmosomes. We discuss the challenges currently faced in unraveling genetic factors that predispose to sudden cardiac death in the setting of sequela of coronary artery disease and present the genome-wide association studies conducted in recent years on electrocardiographic parameters, highlighting their potential in uncovering new biological insights into cardiac electric function.

  15. Symmetry of cardiac function assessment

    PubMed Central

    Bai, Xu-Fang; Ma, Amy X

    2016-01-01

    Both right and left ventricles are developed from two adjacent segments of the primary heart tube. Though they are different with regard to shape and power, they mirror each other in terms of behavior. This is the first level of symmetry in cardiac function assessment. Both cardiac muscle contraction and relaxation are active. This constructs the second level of symmetry in cardiac function assessment. Combination of the two levels will help to find some hidden indexes or approaches to evaluate cardiac function. In this article, four major indexes from echocardiography were analyzed under this principal, another seventeen indexes or measurement approaches came out of the shadow, which is very helpful in the assessment of cardiac function, especially for the right cardiac function and diastolic cardiac function. PMID:27582768

  16. Ablation of C/EBP homologous protein increases the acute phase mortality and doesn't attenuate cardiac remodeling in mice with myocardial infarction.

    PubMed

    Luo, Guangjin; Li, Qingman; Zhang, Xiajun; Shen, Liang; Xie, Jiahe; Zhang, Jingwen; Kitakaze, Masafumi; Huang, Xiaobo; Liao, Yulin

    2015-08-14

    Endoplasmic reticulum stress is a proapoptotic and profibrotic stimulus. Ablation of C/EBP homologous protein (CHOP) is reported to reverse cardiac dysfunction by attenuating cardiac endoplasmic reticulum stress in mice with pressure overload or ischemia/reperfusion, but it is unclear whether loss of CHOP also inhibits cardiac remodeling induced by permanent-infarction. In mice with permanent ligation of left coronary artery, we found that ablation of CHOP increased the acute phase mortality. For the mice survived to 4 weeks, left ventricular anterior (LV) wall thickness was larger in CHOP knockout mice than in the wildtype littermates, while no difference was noted on posterior wall thickness, LV dimensions, LV fractional shortening and ejection fraction. Similarly, invasive assessment of LV hemodynamics, morphological analysis of heart and lung weight indexes, myocardial fibrosis and TUNEL-assessed apoptosis showed no significant differences between CHOP knockout mice and their wildtype ones, while in mice with ischemia for 45 min and reperfusion for 1 week, myocardial fibrosis and apoptosis in the infarct area were significantly attenuated in CHOP knockout mice. These findings indicate that ablation of CHOP doesn't ameliorate cardiac remodeling induced by permanent-myocardial infarction, which implicates that early reperfusion is a prerequisite for ischemic myocardium to benefit from CHOP inhibition.

  17. Delayed liver regeneration after partial hepatectomy in adiponectin knockout mice

    SciTech Connect

    Ezaki, Hisao; Yoshida, Yuichi; Saji, Yukiko; Takemura, Takayo; Fukushima, Juichi; Matsumoto, Hitoshi; Kamada, Yoshihiro; Wada, Akira; Igura, Takumi; Kihara, Shinji; Funahashi, Tohru; Shimomura, Iichiro; Tamura, Shinji; Kiso, Shinichi Hayashi, Norio

    2009-01-02

    We previously demonstrated that adiponectin has anti-fibrogenic and anti-inflammatory effects in the liver of mouse models of various liver diseases. However, its role in liver regeneration remains unclear. The aim of this study was to determine the role of adiponectin in liver regeneration. We assessed liver regeneration after partial hepatectomy in wild-type (WT) and adiponectin knockout (KO) mice. We analyzed DNA replication and various signaling pathways involved in cell proliferation and metabolism. Adiponectin KO mice exhibited delayed DNA replication and increased lipid accumulation in the regenerating liver. The expression levels of peroxisome proliferator-activated receptor (PPAR) {alpha} and carnitine palmitoyltransferase-1 (CPT-1), a key enzyme in mitochondrial fatty acid oxidation, were decreased in adiponectin KO mice, suggesting possible contribution of altered fat metabolism to these phenomena. Collectively, the present results highlight a new role for adiponectin in the process of liver regeneration.

  18. Progranulin Knockout Accelerates Intervertebral Disc Degeneration in Aging Mice

    PubMed Central

    Zhao, Yun-peng; Tian, Qing-yun; Liu, Ben; Cuellar, Jason; Richbourgh, Brendon; Jia, Tang-hong; Liu, Chuan-ju

    2015-01-01

    Intervertebral disc (IVD) degeneration is a common degenerative disease, yet much is unknown about the mechanisms during its pathogenesis. Herein we investigated whether progranulin (PGRN), a chondroprotective growth factor, is associated with IVD degeneration. PGRN was detectable in both human and murine IVD. The levels of PGRN were upregulated in murine IVD tissue during aging process. Loss of PGRN resulted in an early onset of degenerative changes in the IVD tissue and altered expressions of the degeneration-associated molecules in the mouse IVD tissue. Moreover, PGRN knockout mice exhibited accelerated IVD matrix degeneration, abnormal bone formation and exaggerated bone resorption in vertebra with aging. The acceleration of IVD degeneration observed in PGRN null mice was probably due to the enhanced activation of NF-κB signaling and β-catenin signaling. Taken together, PGRN may play a critical role in homeostasis of IVD, and may serve as a potential molecular target for prevention and treatment of disc degenerative diseases. PMID:25777988

  19. Preaxial Polydactyly in Sost/Sostdc1 Double Knockouts

    SciTech Connect

    Yee, C M; Collette, N M; Loots, G G

    2011-07-29

    In the United States, {approx}5% are born with congenital birth defects due to abnormal function of cellular processes and interactions. Sclerosteosis, a rare autosomal recessive disease, causes hyperostosis of the axial and appendicular skeleton, and patients present radial deviation, digit syndactyly, nail dysplasia, and overall high bone mineral density. Sclerosteosis is due to a loss of function of sclerostin (Sost). Sost is a Wnt (abbrev.) antagonist; when mutated, nonfunctional Sost results in hyperactive osteoblast activity which leads to abnormal high bone mass. Previous studies have shown that Sost overexpression in transgenic mice causes reduced bone mineral density and a variety of limb phenotypes ranging from lost, fused, and split phalanges. Consistent with clinical manifestations of Sclerosteosis, Sost knockout mice exhibit increased generalized bone mineral density and syndactyly of the digits. Sostdc1 is a paralog of Sost that has also been described as an antagonist of Wnt signaling, in developing tooth buds. Unlike Sost knockouts, Sostdc1 null mice do not display any limb abnormalities. To determine if Sost and Sostdc1 have redundant functions during limb patterning, we examined Sost; Sostdc1 mice determined that they exhibit a novel preaxial polydactyly phenotype with a low penetrance. LacZ staining, skeletal preparations, and in situ hybridization experiments were used to help characterize this novel phenotype and understand how this phenotype develops. We find Sost and Sostdc1 to have complementary expression patterns during limb development, and the loss of their expression alters the transcription of several key limb regulators, such as Fgf8, Shh and Grem.

  20. Intercellular Adhesion Molecule 1 Knockout Abrogates Radiation Induced Pulmonary Inflammation

    NASA Astrophysics Data System (ADS)

    Hallahan, Dennis E.; Virudachalam, Subbulakshmi

    1997-06-01

    Increased expression of intercellular adhesion molecule 1 (ICAM-1; CD54) is induced by exposure to ionizing radiation. The lung was used as a model to study the role of ICAM-1 in the pathogenesis of the radiation-induced inflammation-like response. ICAM-1 expression increased in the pulmonary microvascular endothelium and not in the endothelium of larger pulmonary vessels following treatment of mice with thoracic irradiation. To quantify radiation-induced ICAM-1 expression, we utilized fluorescence-activated cell sorting analysis of anti-ICAM-1 antibody labeling of pulmonary microvascular endothelial cells from human cadaver donors (HMVEC-L cells). Fluorochrome conjugates and UV microscopy were used to quantify the fluorescence intensity of ICAM in the irradiated lung. These studies showed a dose- and time-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium. Peak expression occurred at 24 h, while threshold dose was as low as 2 Gy. To determine whether ICAM-1 is required for inflammatory cell infiltration into the irradiated lung, the anti-ICAM-1 blocking antibody was administered by tail vein injection to mice following thoracic irradiation. Inflammatory cells were quantified by immunofluorescence for leukocyte common antigen (CD45). Mice treated with the anti-ICAM-1 blocking antibody showed attenuation of inflammatory cell infiltration into the lung in response to ionizing radiation exposure. To verify the requirement of ICAM-1 in the inflammation-like radiation response, we utilized the ICAM-1 knockout mouse. ICAM-1 was not expressed in the lungs of ICAM-1-deficient mice following treatment with thoracic irradiation. ICAM-1 knockout mice had no increase in the inflammatory cell infiltration into the lung in response to thoracic irradiation. These studies demonstrate a radiation dose-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium, and show that ICAM-1 is required for inflammatory cell infiltration

  1. c-Myc Alters Substrate Utilization and O-GlcNAc Protein Posttranslational Modifications without Altering Cardiac Function during Early Aortic Constriction

    PubMed Central

    Ledee, Dolena; Smith, Lincoln; Bruce, Margaret; Kajimoto, Masaki; Isern, Nancy; Portman, Michael A.; Olson, Aaron K.

    2015-01-01

    Hypertrophic stimuli cause transcription of the proto-oncogene c-Myc (Myc). Prior work showed that myocardial knockout of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we assessed the interplay between Myc, substrate oxidation and cardiac function during early pressure overload hypertrophy. Mice with cardiac specific, inducible Myc knockout (MycKO-TAC) and non-transgenic littermates (Cont-TAC) were subjected to transverse aortic constriction (TAC; n = 7/group). Additional groups underwent sham surgery (Cont-Sham and MycKO-Sham, n = 5 per group). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketone bodies and unlabeled glucose and insulin. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. In sham hearts, Myc knockout did not affect cardiac function or substrate preferences for the citric acid cycle. However, Myc knockout altered fractional contributions during TAC. The unlabeled fractional contribution increased in MycKO-TAC versus Cont-TAC, whereas ketone and free fatty acid fractional contributions decreased. Additionally, protein posttranslational modifications by O-GlcNAc were significantly greater in Cont-TAC versus both Cont-Sham and MycKO-TAC. In conclusion, Myc alters substrate preferences for the citric acid cycle during early pressure overload hypertrophy without negatively affecting cardiac function. Myc also affects protein posttranslational modifications by O-GlcNAc during hypertrophy, which may regulate Myc-induced metabolic changes. PMID:26266538

  2. Reduced Extinction of Hippocampal-Dependent Memories in CPEB Knockout Mice

    ERIC Educational Resources Information Center

    Zearfoss, N. Ruth; Richter, Joel D.; Berger-Sweeney, Joanne

    2006-01-01

    CPEB is a sequence-specific RNA binding protein that regulates translation at synapses. In neurons of CPEB knockout mice, synaptic efficacy is reduced. Here, we have performed a battery of behavioral tests and find that relative to wild-type animals, CPEB knockout mice, although similar on many baseline behaviors, have reduced extinction of…

  3. Electrophysiological and Ultrastructural Characterization of Neuromuscular Junctions in Diaphragm Muscle of Acetylcholinesterase Knockout Mice

    DTIC Science & Technology

    2008-04-01

    Electrophysiological and Ultrastructural Characterization of Neuromuscular Junctions in 5a. CONTRACT NUMBER Diaphragm Muscle of Acetylcholinesterase Knockout Mice...AChE +/+) and acetylcholinesterase knockout (AChE -/-) mice to determine the compensatory mechanism manifested by the neuromuscular junction to...had smaller nerve terminals and diminished pre- and postsynaptic surface contacts relative to neuromuscular junctions of AChE +/+ mice. The

  4. Interferon Regulatory Factor 7 Functions as a Novel Negative Regulator of Pathological Cardiac Hypertrophy

    PubMed Central

    Jiang, Ding-Sheng; Liu, Yu; Zhou, Heng; Zhang, Yan; Zhang, Xiao-Dong; Zhang, Xiao-Fei; Chen, Ke; Gao, Lu; Peng, Juan; Gong, Hui; Chen, Yingjie; Yang, Qinglin; Liu, Peter P.; Fan, Guo-Chang; Zou, Yunzeng; Li, Hongliang

    2017-01-01

    Cardiac hypertrophy is a complex pathological process that involves multiple factors including inflammation and apoptosis. Interferon regulatory factor 7 (IRF7) is a multifunctional regulator that participates in immune regulation, cell differentiation, apoptosis, and oncogenesis. However, the role of IRF7 in cardiac hypertrophy remains unclear. We performed aortic banding in cardiac-specific IRF7 transgenic mice, IRF7 knockout mice, and the wild-type littermates of these mice. Our results demonstrated that IRF7 was downregulated in aortic banding–induced animal hearts and cardiomyocytes that had been treated with angiotensin II or phenylephrine for 48 hours. Accordingly, heart-specific overexpression of IRF7 significantly attenuated pressure overload–induced cardiac hypertrophy, fibrosis, and dysfunction, whereas loss of IRF7 led to opposite effects. Moreover, IRF7 protected against angiotensin II–induced cardiomyocyte hypertrophy in vitro. Mechanistically, we identified that IRF7-dependent cardioprotection was mediated through IRF7 binding to inhibitor of κB kinase-β, and subsequent nuclear factor-κB inactivation. In fact, blocking nuclear factor-κB signaling with cardiac-specific inhibitors of κBαS32A/S36A super-repressor transgene counteracted the adverse effect of IRF7 deficiency. Conversely, activation of nuclear factor-κB signaling via a cardiac-specific conditional inhibitor of κB kinase-βS177E/S181E (constitutively active) transgene negated the antihypertrophic effect of IRF7 overexpression. Our data demonstrate that IRF7 acts as a novel negative regulator of pathological cardiac hypertrophy by inhibiting nuclear factor-κB signaling and may constitute a potential therapeutic target for pathological cardiac hypertrophy. PMID:24396025

  5. The organization of adherens junctions and desmosomes at the cardiac intercalated disc is independent of gap junctions.

    PubMed

    Gutstein, David E; Liu, Fang-Yu; Meyers, Marian B; Choo, Andrew; Fishman, Glenn I

    2003-03-01

    Adherens junctions and desmosomes are responsible for mechanically coupling myocytes in the heart and are found closely apposed to gap junction plaques at the intercalated discs of cardiomyocytes. It is not known whether loss of cardiac gap junctions, such as described in cardiac disease states, may influence the expression patterns of other intercalated disc-associated proteins. We investigated whether the major cardiac gap junction protein connexin43 (Cx43) may be responsible for regulating adherens junctions, desmosomes and their associated catenins, in terms of abundance and localization at the intercalated discs of cardiomyocytes. In order to study the effect of loss of cardiac gap junctions on the intercalated disc-associated proteins, we used a combination of immunoblotting, immunofluorescence with confocal microscopy and electron microscopy to evaluate heart tissue from mice with cardiac-specific conditional knockout of Cx43. We found that the cardiac adherens junctions, desmosomes and their associated catenins, as well as vinculin and ZO-1, maintain their normal abundance, structural appearance and localization in the absence of Cx43. We conclude from these data that Cx43 is not required for the organization of the cell adhesion junctions and their associated catenins at the intercalated disc in the adult cardiac myocyte.

  6. Cardiac arrhythmias in pregnancy.

    PubMed

    Knotts, Robert J; Garan, Hasan

    2014-08-01

    As more women with repaired congenital heart disease survive to their reproductive years and many other women are delaying pregnancy until later in life, a rising concern is the risk of cardiac arrhythmias during pregnancy. Naturally occurring cardiovascular changes during pregnancy increase the likelihood that a recurrence of a previously experienced cardiac arrhythmia or a de novo arrhythmia will occur. Arrhythmias should be thoroughly investigated to determine if there is a reversible etiology, and risks/benefits of treatment options should be fully explored. We discuss the approach to working up and treating various arrhythmias during pregnancy with attention to fetal and maternal risks as well as treatment of fetal arrhythmias. Acute management in stable patients includes close monitoring and intravenous pharmacologic therapy, while DC cardioversion should be used to terminate arrhythmias in hemodynamically unstable patients. Long-term management may require continued oral antiarrhythmic therapy, with particular attention to fetal safety, to prevent complications associated with arrhythmias.

  7. Practical cardiac auscultation.

    PubMed

    Shindler, Daniel M

    2007-01-01

    This article focuses on the practical use of the stethoscope. The art of the cardiac physical examination includes skillful auscultation. The article provides the author's personal approach to the patient for the purpose of best hearing, recognizing, and interpreting heart sounds and murmurs. It should be used as a brief introduction to the art of auscultation. This article also attempts to illustrate heart sounds and murmurs by using words and letters to phonate the sounds, and by presenting practical clinical examples where auscultation clearly influences cardiac diagnosis and treatment. The clinical sections attempt to go beyond what is available in standard textbooks by providing information and stethoscope techniques that are valuable and useful at the bedside.

  8. Cardiac nuclear medicine

    SciTech Connect

    Gerson, M.C.

    1987-01-01

    The book begins with a review of the radionuclide methods available for evaluating cardiac perfusion and function. The authors discuss planar and tomographic thallium myocardial imaging, first-pass and equilibrium radionuclide angiography, and imaging with infarct-avid tracers. Several common but more specialized procedures are then reviewed: nonogemetric measurement of left ventricular volume, phase (Fourier) analysis, stroke volume ratio, right ventricular function, and diastolic function. A separate chapter is devoted to drug interventions and in particular the use of radionuclide ventriculography to monitor doxorubicin toxicity and therapy of congestive heart failure. The subsequent chapters provide a comprehensive guide to test selection, accuracy, and results in acute myocardial infarction, in postmyocardial infarction, in chronic coronary artery disease, before and after medical or surgical revascularization, in valvular heart disease, in cardiomyopathies, and in cardiac trauma.

  9. Health and population effects of rare gene knockouts in adult humans with related parents.

    PubMed

    Narasimhan, Vagheesh M; Hunt, Karen A; Mason, Dan; Baker, Christopher L; Karczewski, Konrad J; Barnes, Michael R; Barnett, Anthony H; Bates, Chris; Bellary, Srikanth; Bockett, Nicholas A; Giorda, Kristina; Griffiths, Christopher J; Hemingway, Harry; Jia, Zhilong; Kelly, M Ann; Khawaja, Hajrah A; Lek, Monkol; McCarthy, Shane; McEachan, Rosie; O'Donnell-Luria, Anne; Paigen, Kenneth; Parisinos, Constantinos A; Sheridan, Eamonn; Southgate, Laura; Tee, Louise; Thomas, Mark; Xue, Yali; Schnall-Levin, Michael; Petkov, Petko M; Tyler-Smith, Chris; Maher, Eamonn R; Trembath, Richard C; MacArthur, Daniel G; Wright, John; Durbin, Richard; van Heel, David A

    2016-04-22

    Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3222 British adults of Pakistani heritage with high parental relatedness, discovering 1111 rare-variant homozygous genotypes with predicted loss of function (knockouts) in 781 genes. We observed 13.7% fewer homozygous knockout genotypes than we expected, implying an average load of 1.6 recessive-lethal-equivalent loss-of-function (LOF) variants per adult. When genetic data were linked to the individuals' lifelong health records, we observed no significant relationship between gene knockouts and clinical consultation or prescription rate. In this data set, we identified a healthy PRDM9-knockout mother and performed phased genome sequencing on her, her child, and control individuals. Our results show that meiotic recombination sites are localized away from PRDM9-dependent hotspots. Thus, natural LOF variants inform on essential genetic loci and demonstrate PRDM9 redundancy in humans.

  10. Health and population effects of rare gene knockouts in adult humans with related parents

    PubMed Central

    Narasimhan, Vagheesh M.; Hunt, Karen A.; Mason, Dan; Baker, Christopher L.; Karczewski, Konrad J.; Barnes, Michael R.; Barnett, Anthony H.; Bates, Chris; Bellary, Srikanth; Bockett, Nicholas A.; Giorda, Kristina; Griffiths, Christopher J.; Hemingway, Harry; Jia, Zhilong; Kelly, M. Ann; Khawaja, Hajrah A.; Lek, Monkol; McCarthy, Shane; McEachan, Rosie; O’Donnell-Luria, Anne; Paigen, Kenneth; Parisinos, Constantinos A.; Sheridan, Eamonn; Southgate, Laura; Tee, Louise; Thomas, Mark; Xue, Yali; Schnall-Levin, Michael; Petkov, Petko M.; Tyler-Smith, Chris; Maher, Eamonn R.; Trembath, Richard C.; MacArthur, Daniel G.; Wright, John; Durbin, Richard; van Heel, David A.

    2016-01-01

    Examining complete gene knockouts within a viable organism can inform on gene function. We sequenced the exomes of 3,222 British Pakistani-heritage adults with high parental relatedness, discovering 1,111 rare-variant homozygous genotypes with predicted loss of gene function (knockouts) in 781 genes. We observed 13.7% fewer than expected homozygous knockout genotypes, implying an average load of 1.6 recessive-lethal-equivalent LOF variants per adult. Linking genetic data to lifelong health records, knockouts were not associated with clinical consultation or prescription rate. In this dataset we identified a healthy PRDM9 knockout mother, and performed phased genome sequencing on her, her child and controls, which showed meiotic recombination sites localised away from PRDM9-dependent hotspots. Thus, natural LOF variants inform upon essential genetic loci, and demonstrate PRDM9 redundancy in humans. PMID:26940866

  11. The Role of Cardiac Side Population Cells in Cardiac Regeneration

    PubMed Central

    Yellamilli, Amritha; van Berlo, Jop H.

    2016-01-01

    The heart has a limited ability to regenerate. It is important to identify therapeutic strategies that enhance cardiac regeneration in order to replace cardiomyocytes lost during the progression of heart failure. Cardiac progenitor cells are interesting targets for new regenerative therapies because they are self-renewing, multipotent cells located in the heart. Cardiac side population cells (cSPCs), the first cardiac progenitor cells identified in the adult heart, have the ability to differentiate into cardiomyocytes, endothelial cells, smooth muscle cells, and fibroblasts. They become activated in response to cardiac injury and transplantation of cSPCs into the injured heart improves cardiac function. In this review, we will discuss the current literature on the progenitor cell properties and therapeutic potential of cSPCs. This body of work demonstrates the great promise cSPCs hold as targets for new regenerative strategies. PMID:27679798

  12. Mechanical cardiac assistance.

    PubMed

    Sezai, Y

    1998-08-01

    In our institute, we have intensively introduced both pulsatile and non-pulsatile mechanical cardiac assist devices, such as the pneumatic ventricular assist device (VAD) and percutaneous cardiopulmonary support (PCPS), using a centrifugal pump. From various kinds of clinical views, these cases were estimated and evaluated retrospectively according to the weaning results, long-term survival rate and cause of death. Based upon our experiences and clinical results, an alternate strategy of mechanical cardiac assistance for severe heart failure is suggested as follows. In the case of post-cardiotomy cardiogenic shock or low output syndrome, PCPS system should be applied firstly under intra-aortic balloon pumping (IABP) assist for a maximum of 2-3 days. If the native cardiac function does not recover and more long-term support is needed, several types of VAD, which are more powerful and durable devices should be introduced, according to end organ function and expected support duration. In order to obtain better clinical results, we have to select an appropriate device depending on the limited availability of supporting duration. Generally speaking, centrifugal pumps can support in short-term duration, while pulsatile devices cover the broad spectrum of the supporting period. Pneumatic VADs can cover short-term to long-term support up to a year, and electric VADs can cover over 1 year, and can be used as a bridge to heart transplantation.

  13. Ultrasound in cardiac trauma.

    PubMed

    Saranteas, Theodosios; Mavrogenis, Andreas F; Mandila, Christina; Poularas, John; Panou, Fotios

    2017-04-01

    In the perioperative period, the emergency department or the intensive care unit accurate assessment of variable chest pain requires meticulous knowledge, diagnostic skills, and suitable usage of various diagnostic modalities. In addition, in polytrauma patients, cardiac injury including aortic dissection, pulmonary embolism, acute myocardial infarction, and pericardial effusion should be immediately revealed and treated. In these patients, arrhythmias, mainly tachycardia, cardiac murmurs, or hypotension must alert physicians to suspect cardiovascular trauma, which would potentially be life threatening. Ultrasound of the heart using transthoracic and transesophageal echocardiography are valuable diagnostic tools that can be used interchangeably in conjunction with other modalities such as the electrocardiogram and computed tomography for the diagnosis of cardiovascular abnormalities in trauma patients. Although ultrasound of the heart is often underused in the setting of trauma, it does have the advantages of being easily accessible, noninvasive, and rapid bedside assessment tool. This review article aims to analyze the potential cardiac injuries in trauma patients, and to provide an elaborate description of the role of echocardiography for their accurate diagnosis.

  14. Cardiac surgery 2015 reviewed.

    PubMed

    Doenst, Torsten; Strüning, Constanze; Moschovas, Alexandros; Gonzalez-Lopez, David; Essa, Yasin; Kirov, Hristo; Diab, Mahmoud; Faerber, Gloria

    2016-10-01

    For the year 2015, almost 19,000 published references can be found in PubMed when entering the search term "cardiac surgery". The last year has been again characterized by lively discussions in the fields where classic cardiac surgery and modern interventional techniques overlap. Lacking evidence in the field of coronary revascularization with either percutaneous coronary intervention or bypass surgery has been added. As in the years before, CABG remains the gold standard for the revascularization of complex stable triple-vessel disease. Plenty of new information has been presented comparing the conventional to transcatheter aortic valve implantation (TAVI) demonstrating similar short- and mid-term outcomes at high and low risk, but even a survival advantage with transfemoral TAVI at intermediate risk. In addition, there were many relevant and interesting other contributions from the purely operative arena. This review article will summarize the most pertinent publications in the fields of coronary revascularization, surgical treatment of valve disease, heart failure (i.e., transplantation and ventricular assist devices), and aortic surgery. While the article does not have the expectation of being complete and cannot be free of individual interpretation, it provides a condensed summary that is intended to give the reader "solid ground" for up-to-date decision-making in cardiac surgery.

  15. Biomechanics of Cardiac Function

    PubMed Central

    Voorhees, Andrew P.; Han, Hai-Chao

    2015-01-01

    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

  16. The Alberta Cardiac Access Collaborative: improving the cardiac patient journey.

    PubMed

    Blackadar, Robyn; Houle, Mishaela

    2009-01-01

    The Alberta Cardiac Access Collaborative (ACAC) is a joint initiative of Alberta's health system to improve access to adult cardiac services across the patient journey. ACAC has created new care delivery models and implemented best practices across Alberta in four streams across the continuum: heart attack, patient navigation, heart failure and arrhythmia. Emergency medical providers, nurses, primary care physicians, hospitals, cardiac specialists and clinicians are all working together to integrate services, bridge jurisdictions and geography with one aim--improving the patient journey for adults in need of cardiac care.

  17. Kruppel-like factor 4 protein regulates isoproterenol-induced cardiac hypertrophy by modulating myocardin expression and activity.

    PubMed

    Yoshida, Tadashi; Yamashita, Maho; Horimai, Chihiro; Hayashi, Matsuhiko

    2014-09-19

    Kruppel-like factor 4 (KLF4) plays an important role in vascular diseases, including atherosclerosis and vascular injury. Although KLF4 is expressed in the heart in addition to vascular cells, the role of KLF4 in cardiac disease has not been fully determined. The goals of this study were to investigate the role of KLF4 in cardiac hypertrophy and to determine the underlying mechanisms. Cardiomyocyte-specific Klf4 knockout (CM Klf4 KO) mice were generated by the Cre/LoxP technique. Cardiac hypertrophy was induced by chronic infusion of the β-adrenoreceptor agonist isoproterenol (ISO). Results showed that ISO-induced cardiac hypertrophy was enhanced in CM Klf4 KO mice compared with control mice. Accelerated cardiac hypertrophy in CM Klf4 KO mice was accompanied by the augmented cellular enlargement of cardiomyocytes as well as the exaggerated expression of fetal cardiac genes, including atrial natriuretic factor (Nppa). Additionally, induction of myocardin, a transcriptional cofactor regulating fetal cardiac genes, was enhanced in CM Klf4 KO mice. Interestingly, KLF4 regulated Nppa expression by modulating the expression and activity of myocardin, providing a mechanical basis for accelerated cardiac hypertrophy in CM Klf4 KO mice. Moreover, we showed that KLF4 mediated the antihypertrophic effect of trichostatin A, a histone deacetylase inhibitor, because ISO-induced cardiac hypertrophy in CM Klf4 KO mice was attenuated by olmesartan, an angiotensin II type 1 antagonist, but not by trichostatin A. These results provide novel evidence that KLF4 is a regulator of cardiac hypertrophy by modulating the expression and the activity of myocardin.

  18. Diuretics prevent thiazolidinedione-induced cardiac hypertrophy without compromising insulin-sensitizing effects in mice.

    PubMed

    Chang, Cherng-Shyang; Tsai, Pei-Jane; Sung, Junne-Ming; Chen, Ju-Yi; Ho, Li-Chun; Pandya, Kumar; Maeda, Nobuyo; Tsai, Yau-Sheng

    2014-02-01

    Much concern has arisen regarding critical adverse effects of thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, on cardiac tissue. Although TZD-induced cardiac hypertrophy (CH) has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, causative roles have not been established. To test the hypothesis that volume expansion directly mediates rosiglitazone-induced CH, mice were fed a high-fat diet with rosiglitazone, and cardiac and metabolic consequences were examined. Rosiglitazone treatment induced volume expansion and CH in wild-type and PPARγ heterozygous knockout (Pparg(+/-)) mice, but not in mice defective for ligand binding (Pparg(P465L/+)). Cotreatment with the diuretic furosemide in wild-type mice attenuated rosiglitazone-induced CH, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Similar changes were observed in mice treated with pioglitazone. The diuretics spironolactone and trichlormethiazide, but not amiloride, attenuated rosiglitazone effects on volume expansion and CH. Interestingly, expression of glucose and lipid metabolism genes in the heart was altered by rosiglitazone, but these changes were not attenuated by furosemide cotreatment. Importantly, rosiglitazone-mediated whole-body metabolic improvements were not affected by furosemide cotreatment. We conclude that releasing plasma volume reduces adverse effects of TZD-induced volume expansion and cardiac events without compromising TZD actions in metabolic switch in the heart and whole-body insulin sensitivity.

  19. Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration.

    PubMed

    Wang, E R; Jarrah, A A; Benard, L; Chen, J; Schwarzkopf, M; Hadri, L; Tarzami, S T

    2014-05-01

    Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. However, little is known regarding whether SDF-1/CXCR4 induces acute protection following pathological hypertrophy and if so, by what molecular mechanism. We have previously reported that CXCR4 physically interacts with the beta-2 adrenergic receptor and modulates its downstream signaling. Here we have shown that CXCR4 expression prevents beta-adrenergic receptor-induced hypertrophy. Cardiac beta-adrenergic receptors were stimulated with the implantation of a subcutaneous osmotic pump administrating isoproterenol and CXCR4 expression was selectively abrogated in cardiomyocytes using Cre-loxP-mediated gene recombination. CXCR4 knockout mice showed worsened fractional shortening and ejection fraction. CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases whereas fibrosis increases. In addition, CXCR4 expression was rescued with the use of cardiotropic adeno-associated viral-9 vectors. CXCR4 gene transfer reduced cardiac apoptotic signaling, improved mitochondrial function and resulted in a recovered cardiac function. Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo.

  20. Novel Protective Role of Myeloid Differentiation 1 in Pathological Cardiac Remodelling

    PubMed Central

    Xiong, Xiaojv; Liu, Yu; Mei, Yang; Peng, Jianye; Wang, Zhiqiang; Kong, Bin; Zhong, Peng; Xiong, Liang; Quan, Dajun; Li, Qi; Wang, Guangji; Huang, He

    2017-01-01

    Myeloid differentiation 1 (MD-1), a secreted protein interacting with radioprotective 105 (RP105), plays an important role in Toll-like receptor 4 (TLR4) signalling pathway. Previous studies showed that MD-1 may be restricted in the immune system. In this study, we demonstrated for the first time that MD-1 was highly expressed in both human and animal hearts. We also discovered that cardiac-specific overexpression of MD-1 significantly attenuated pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction, whereas loss of MD-1 had the opposite effects. Similar results were observed for in vitro angiotensin II-induced neonatal rat cardiomyocyte hypertrophy. The antihypertrophic effects of MD-1 under hypertrophic stimuli were associated with the blockage of MEK-ERK 1/2 and NF-κB signalling. Blocking MEK-ERK 1/2 signalling with a pharmacological inhibitor (U0126) greatly attenuated the detrimental effects observed in MD-1 knockout cardiomyocytes exposed to angiotensin II stimuli. Similar results were observed by blocking NF-κB signalling with a pharmacological inhibitor (BAY11–7082). Our data indicate that MD-1 inhibits cardiac hypertrophy and suppresses cardiac dysfunction during the remodelling process, which is dependent on its modulation of the MEK-ERK 1/2 and NF-κB signalling pathways. Thus, MD-1 might be a novel target for the treatment of pathological cardiac hypertrophy. PMID:28165494

  1. Cardiac Emergencies in Neurosurgical Patients

    PubMed Central

    Petropolis, Andrea; Cappellani, Ronald B.

    2015-01-01

    Perioperative safety concerns are a major area of interest in recent years. Severe cardiac perturbation such as cardiac arrest is one of the most dreaded complications in the intraoperative period; however, little is known about the management of these events in the patients undergoing elective neurosurgery. This special group needs further attention, as it is often neither feasible nor appropriate to apply conventional advanced cardiac life support algorithms in patients undergoing neurosurgery. Factors such as neurosurgical procedure and positioning can also have a significant effect on the occurrence of cardiac arrest. Therefore, the aim of this paper is to describe the various causes and management of cardiac emergencies with special reference to cardiac arrest during elective neurosurgical procedures, including discussion of position-related factors and resuscitative considerations in these situations. This will help to formulate possible guidelines for management of such events. PMID:25692145

  2. Sudden Cardiac Death in Athletes

    PubMed Central

    Wasfy, Meagan M.; Hutter, Adolph M.; Weiner, Rory B.

    2016-01-01

    There are clear health benefits to exercise; even so, patients with cardiac conditions who engage in exercise and athletic competition may on rare occasion experience sudden cardiac death (SCD). This article reviews the epidemiology and common causes of SCD in specific athlete populations. There is ongoing debate about the optimal mechanism for SCD prevention, specifically regarding the inclusion of the ECG and/or cardiac imaging in routine preparticipation sports evaluation. This controversy and contemporary screening recommendations are also reviewed. PMID:27486488

  3. A Comprehensive TALEN-Based Knockout Library for Generating Human Induced Pluripotent Stem Cell-Based Models for Cardiovascular Diseases.

    PubMed

    Karakikes, Ioannis; Termglinchan, Vittavat; Cepeda, Diana A; Lee, Jaecheol; Diecke, Sebastian; Hendel, Ayal; Itzhaki, Ilanit; Ameen, Mohamed; Shrestha, Rajani; Wu, Haodi; Ma, Ning; Shao, Ning-Yi; Seeger, Timon; Woo, Nicole A; Wilson, Kitchener D; Matsa, Elena; Porteus, Matthew H; Sebastiano, Vittorio; Wu, Joseph C

    2017-02-28

    Rationale: Targeted genetic engineering using programmable nucleases such as transcription activator-like effector nucleases (TALENs) is a valuable tool for precise, site-specific genetic modification in the human genome. Objective: The emergence of novel technologies such as human induced pluripotent stem cells (iPSCs) and nuclease-mediated genome editing represent a unique opportunity for studying cardiovascular diseases in vitro. Methods and Results: By incorporating extensive literature and database searches, we designed a collection of TALEN constructs to knockout (KO) eighty-eight human genes that are associated with cardiomyopathies and congenital heart diseases. The TALEN pairs were designed to induce double-strand DNA break near the starting codon of each gene that either disrupted the start codon or introduced a frameshift mutation in the early coding region, ensuring faithful gene KO. We observed that all the constructs were active and disrupted the target locus at high frequencies. To illustrate the general utility of the TALEN-mediated KO technique, six individual genes (TNNT2, LMNA/C, TBX5, MYH7, ANKRD1, and NKX2.5) were knocked out with high efficiency and specificity in human iPSCs. By selectively targeting a dilated cardiomyopathy (DCM)-causing mutation (TNNT2 p.R173W) in patient-specific iPSC-derived cardiac myocytes (iPSC-CMs), we demonstrated that the KO strategy ameliorates the DCM phenotype in vitro. In addition, we modeled the Holt-Oram syndrome (HOS) in iPSC-CMs in vitro and uncovered novel pathways regulated by TBX5 in human cardiac myocyte development. Conclusions: Collectively, our study illustrates the powerful combination of iPSCs and genome editing technology for understanding the biological function of genes and the pathological significance of genetic variants in human cardiovascular diseases. The methods, strategies, constructs and iPSC lines developed in this study provide a validated, readily available resource for cardiovascular

  4. Registry of Unexplained Cardiac Arrest

    ClinicalTrials.gov

    2016-05-16

    Cardiac Arrest; Long QT Syndrome; Brugada Syndrome; Catecholaminergi Polymorphic Ventricular Tachycardia; Idiopathic VentricularFibrillation; Early Repolarization Syndrome; Arrhythmogenic Right Ventricular Cardiomyopathy

  5. Cardiac risk stratification and protection.

    PubMed

    Halub, Meghan E; Sidwell, Richard A

    2015-04-01

    The goal of preoperative cardiac evaluation is to screen for undiagnosed cardiac disease or to find evidence of known conditions that are poorly controlled to allow management that reduces the risk of perioperative cardiac complications. A careful history and physical examination combined with the procedure-specific risk is the cornerstone of this assessment. This article reviews a brief history of prior cardiac risk stratification indexes, explores current practice guidelines by the American College of Cardiology and the American Heart Association Task Force, reviews current methods for preoperative evaluation, discusses revascularization options, and evaluates perioperative medication recommendations.

  6. Cardiac surgery for Kartagener syndrome.

    PubMed

    Tkebuchava, T; von Segesser, L K; Niederhäuser, U; Bauersfeld, U; Turina, M

    1997-01-01

    Two patients (one girl, one boy) with Kartagener syndrome (situs inversus, bronchiectasis, sinusitis), despite pulmonary problems and associated congenital cardiac anomalies, were operated on at the ages of 4 years and 7 years, respectively. They had had previous palliative treatment at the age of 3 months and 1.3 years, respectively. Both postoperative periods after total correction were without significant complications. Long-term follow-up was available for 9 and 19 years, respectively, with no manifestations of heart insufficiency. Both patients are physically active, and neither requires cardiac medication. Patients with Kartagener syndrome and associated congenital cardiac anomalies can successfully undergo multiple cardiac operations with good long-term outcome.

  7. Cardiac Dysautonomia in Huntington's Disease.

    PubMed

    Abildtrup, Mads; Shattock, Michael

    2013-01-01

    Huntington's disease is a fatal, hereditary, neurodegenerative disorder best known for its clinical triad of progressive motor impairment, cognitive deficits and psychiatric disturbances. Although a disease of the central nervous system, mortality surveys indicate that heart disease is a leading cause of death. The nature of such cardiac abnormalities remains unknown. Clinical findings indicate a high prevalence of autonomic nervous system dysfunction - dysautonomia - which may be a result of pathology of the central autonomic network. Dysautonomia can have profound effects on cardiac health, and pronounced autonomic dysfunction can be associated with neurogenic arrhythmias and sudden cardiac death. Significant advances in the knowledge of neural mechanisms in cardiac disease have recently been made which further aid our understanding of cardiac mortality in Huntington's disease. Even so, despite the evidence of aberrant autonomic activity the potential cardiac consequences of autonomic dysfunction have been somewhat ignored. In fact, underlying cardiac abnormalities such as arrhythmias have been part of the exclusion criteria in clinical autonomic Huntington's disease research. A comprehensive analysis of cardiac function in Huntington's disease patients is warranted. Further experimental and clinical studies are needed to clarify how the autonomic nervous system is controlled and regulated in higher, central areas of the brain - and how these regions may be altered in neurological pathology, such as Huntington's disease. Ultimately, research will hopefully result in an improvement of management with the aim of preventing early death in Huntington's disease from cardiac causes.

  8. MOMDIS: a Glauber model computer code for knockout reactions

    NASA Astrophysics Data System (ADS)

    Bertulani, C. A.; Gade, A.

    2006-09-01

    A computer program is described to calculate momentum distributions in stripping and diffraction dissociation reactions. A Glauber model is used with the scattering wavefunctions calculated in the eikonal approximation. The program is appropriate for knockout reactions at intermediate energy collisions ( 30 MeV⩽E/nucleon⩽2000 MeV). It is particularly useful for reactions involving unstable nuclear beams, or exotic nuclei (e.g., neutron-rich nuclei), and studies of single-particle occupancy probabilities (spectroscopic factors) and other related physical observables. Such studies are an essential part of the scientific program of radioactive beam facilities, as in for instance the proposed RIA (Rare Isotope Accelerator) facility in the US. Program summaryTitle of program: MOMDIS (MOMentum DIStributions) Catalogue identifier:ADXZ_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADXZ_v1_0 Computers: The code has been created on an IBM-PC, but also runs on UNIX or LINUX machines Operating systems: WINDOWS or UNIX Program language used: Fortran-77 Memory required to execute with typical data: 16 Mbytes of RAM memory and 2 MB of hard disk space No. of lines in distributed program, including test data, etc.: 6255 No. of bytes in distributed program, including test data, etc.: 63 568 Distribution format: tar.gz Nature of physical problem: The program calculates bound wavefunctions, eikonal S-matrices, total cross-sections and momentum distributions of interest in nuclear knockout reactions at intermediate energies. Method of solution: Solves the radial Schrödinger equation for bound states. A Numerov integration is used outwardly and inwardly and a matching at the nuclear surface is done to obtain the energy and the bound state wavefunction with good accuracy. The S-matrices are obtained using eikonal wavefunctions and the "t- ρρ" method to obtain the eikonal phase-shifts. The momentum distributions are obtained by means of a Gaussian expansion of

  9. Complementation Test of Rpe65 Knockout and Tvrm148

    PubMed Central

    Wright, Charles B.; Chrenek, Micah A.; Foster, Stephanie L.; Duncan, Todd; Redmond, T. Michael; Pardue, Machelle T.; Boatright, Jeffrey H.; Nickerson, John M.

    2013-01-01

    Purpose. A mouse mutation, tvrm148, was previously reported as resulting in retinal degeneration. Tvrm148 and Rpe65 map between markers D3Mit147 and D3Mit19 on a genetic map, but the physical map places RPE65 outside the markers. We asked if Rpe65 or perhaps another nearby gene is mutated and if the mutant reduced 11-cis-retinal levels. We studied the impact of the tvrm148 mutation on visual function, morphology, and retinoid levels. Methods. Normal phase HPLC was used to measure retinoid levels. Rpe65+/+, tvrm148/+ (T+/−), tvrm148/tvrm148 (T−/−), RPE65KO/KO (Rpe65−/−), and Rpe65T/− mice visual function was measured by optokinetic tracking (OKT) and electroretinography (ERG). Morphology was assessed by light microscopy and transmission electron microscopy (TEM). qRT-PCR was used to measure Rpe65 mRNA levels. Immunoblotting measured the size and amount of RPE65 protein. Results. The knockout and tvrm148 alleles did not complement. No 11-cis-retinal was detected in T−/− or Rpe65−/− mice. Visual acuity in Rpe65+/+ and T+/− mouse was ∼0.382 c/d, but 0.037 c/d in T−/− mice at postnatal day 210 (P210). ERG response in T−/− mice was undetectable except at bright flash intensities. Outer nuclear layer (ONL) thickness in T−/− mice was ∼70% of Rpe65+/+ by P210. Rpe65 mRNA levels in T−/− mice were unchanged, yet 14.5% of Rpe65+/+ protein levels was detected. Protein size was unchanged. Conclusions. A complementation test revealed the RPE65 knockout and tvrm148 alleles do not complement, proving that the tvrm148 mutation is in Rpe65. Behavioral, physiological, molecular, biochemical, and histological approaches indicate that tvrm148 is a null allele of Rpe65. PMID:23778877

  10. Altered Sleep Homeostasis in Rev-erbα Knockout Mice

    PubMed Central

    Mang, Géraldine M.; La Spada, Francesco; Emmenegger, Yann; Chappuis, Sylvie; Ripperger, Jürgen A.; Albrecht, Urs; Franken, Paul

    2016-01-01

    Study Objectives: The nuclear receptor REV-ERBα is a potent, constitutive transcriptional repressor critical for the regulation of key circadian and metabolic genes. Recently, REV-ERBα's involvement in learning, neurogenesis, mood, and dopamine turnover was demonstrated suggesting a specific role in central nervous system functioning. We have previously shown that the brain expression of several core clock genes, including Rev-erbα, is modulated by sleep loss. We here test the consequences of a loss of REV-ERBα on the homeostatic regulation of sleep. Methods: EEG/EMG signals were recorded in Rev-erbα knockout (KO) mice and their wild type (WT) littermates during baseline, sleep deprivation, and recovery. Cortical gene expression measurements after sleep deprivation were contrasted to baseline. Results: Although baseline sleep/wake duration was remarkably similar, KO mice showed an advance of the sleep/wake distribution relative to the light-dark cycle. After sleep onset in baseline and after sleep deprivation, both EEG delta power (1–4 Hz) and sleep consolidation were reduced in KO mice indicating a slower increase of homeostatic sleep need during wakefulness. This slower increase might relate to the smaller increase in theta and gamma power observed in the waking EEG prior to sleep onset under both conditions. Indeed, the increased theta activity during wakefulness predicted delta power in subsequent NREM sleep. Lack of Rev-erbα increased Bmal1, Npas2, Clock, and Fabp7 expression, confirming the direct regulation of these genes by REV-ERBα also in the brain. Conclusions: Our results add further proof to the notion that clock genes are involved in sleep homeostasis. Because accumulating evidence directly links REV-ERBα to dopamine signaling the altered homeostatic regulation of sleep reported here are discussed in that context. Citation: Mang GM, La Spada F, Emmenegger Y, Chappuis S, Ripperger JA, Albrecht U, Franken P. Altered sleep homeostasis in Rev

  11. [An efficient genetic knockout system based on linear DNA fragment homologous recombination for halophilic archaea].

    PubMed

    Xiaoli, Wang; Chuang, Jiang; Jianhua, Liu; Xipeng, Liu

    2015-04-01

    With the development of functional genomics, gene-knockout is becoming an important tool to elucidate gene functions in vivo. As a good model strain for archaeal genetics, Haloferax volcanii has received more attention. Although several genetic manipulation systems have been developed for some halophilic archaea, it is time-consuming because of the low percentage of positive clones during the second-recombination selection. These classical gene knockout methods are based on DNA recombination between the genomic homologous sequence and the circular suicide plasmid, which carries a pyrE selection marker and two DNA fragments homologous to the upstream and downstream fragments of the target gene. Many wild-type clones are obtained through a reverse recombination between the plasmid and genome in the classic gene knockout method. Therefore, it is necessary to develop an efficient gene knockout system to increase the positive clone percentage. Here we report an improved gene knockout method using a linear DNA cassette consisting of upstream and downstream homologous fragments, and the pyrE marker. Gene deletions were subsequently detected by colony PCR analysis. We determined the efficiency of our knockout method by deleting the xpb2 gene from the H. volcanii genome, with the percentage of positive clones higher than 50%. Our method provides an efficient gene knockout strategy for halophilic archaea.

  12. Iron regulatory protein-2 knockout increases perihematomal ferritin expression and cell viability after intracerebral hemorrhage.

    PubMed

    Chen, Mai; Awe, Olatilewa O; Chen-Roetling, Jing; Regan, Raymond F

    2010-06-14

    Iron is deposited in perihematomal tissue after an intracerebral hemorrhage (ICH), and may contribute to oxidative injury. Cell culture studies have demonstrated that enhancing ferritin expression by targeting iron regulatory protein (IRP) binding activity reduces cellular vulnerability to iron and hemoglobin. In order to assess the therapeutic potential of this approach after striatal ICH, the effect of IRP1 or IRP2 gene knockout on ferritin expression and injury was quantified. Striatal ferritin in IRP1 knockout mice was similar to that in wild-type controls 3 days after stereotactic injection of artificial CSF or autologous blood. Corresponding levels in IRP2 knockouts were increased by 11-fold and 8.4-fold, respectively, compared with wild-type. Protein carbonylation, a sensitive marker of hemoglobin neurotoxicity, was increased by 2.4-fold in blood-injected wild-type striata, was not altered by IRP1 knockout, but was reduced by approximately 60% by IRP2 knockout. Perihematomal cell viability in wild-type mice, assessed by MTT assay, was approximately half of that in contralateral striata at 3 days, and was significantly increased in IRP2 knockouts but not in IRP1 knockouts. Protection was also observed when hemorrhage was induced by collagenase injection. These results suggest that IRP2 binding activity reduces ferritin expression in the striatum after ICH, preventing an optimal response to elevated local iron concentrations. IRP2 binding activity may be a novel therapeutic target after hemorrhagic CNS injuries.

  13. Iron Regulatory Protein-2 Knockout Increases Perihematomal Ferritin Expression and Cell Viability after Intracerebral Hemorrhage

    PubMed Central

    Chen, Mai; Awe, Olatilewa O.; Chen-Roetling, Jing; Regan, Raymond F.

    2010-01-01

    Iron is deposited in perihematomal tissue after an intracerebral hemorrhage (ICH), and may contribute to oxidative injury. Cell culture studies have demonstrated that enhancing ferritin expression by targeting iron regulatory protein (IRP) binding activity reduces cellular vulnerability to iron and hemoglobin. In order to assess the therapeutic potential of this approach after striatal ICH, the effect of IRP1 or IRP2 gene knockout on ferritin expression and injury was quantified. Striatal ferritin in IRP1 knockout mice was similar to that in wild-type controls three days after stereotactic injection of artificial CSF or autologous blood. Corresponding levels in IRP2 knockouts were increased by 11-fold and 8.4-fold, respectively, compared with wild-type. Protein carbonylation, a sensitive marker of hemoglobin neurotoxicity, was increased by 2.4-fold in blood-injected wild-type striata, was not altered by IRP1 knockout, but was reduced by approximately 60% by IRP2 knockout. Perihematomal cell viability in wild-type mice, assessed by MTT assay, was approximately half of that in contralateral striata at three days, and was significantly increased in IRP2 knockouts but not in IRP1 knockouts. Protection was also observed when hemorrhage was induced by collagenase injection. These results suggest that IRP2 binding activity reduces ferritin expression in the striatum after ICH, preventing an optimal response to elevated local iron concentrations. IRP2 binding activity may be a novel therapeutic target after hemorrhagic CNS injuries. PMID:20399759

  14. Kv4.2 knockout mice demonstrate increased susceptibility to convulsant stimulation

    PubMed Central

    Barnwell, L. Forbes S.; Lugo, Joaquin N.; Lee, Wai Ling; Willis, Sarah E.; Gertz, Shira J.; Hrachovy, Richard A.; Anderson, Anne E.

    2010-01-01

    Purpose Kv4.2 subunits contribute to the pore-forming region of channels that express a transient, A-type K+ current (A-current) in hippocampal CA1 pyramidal cell dendrites. Here, the A-current plays an important role in signal processing and synaptic integration. Kv4.2 knockout mice show a near elimination of the A-current in area CA1 dendrites producing increased excitability in this region. In these studies, we evaluated young adult Kv4.2 knockout mice for spontaneous seizures and the response to convulsant stimulation in the whole animal in vivo and in hippocampal slices in vitro. Methods Electroencephalogram electrode-implanted Kv4.2 knockout and wildtype mice were observed for spontaneous behavioral and electrographic seizures. The latency to seizure and status epilepticus onset in Kv4.2 knockout and wildtype mice was assessed following intraperitoneal injection of kainate. Extracellular field potential recordings were performed in hippocampal slices from Kv4.2 knockout and wildtype mice following the bath application of bicuculline. Results No spontaneous behavioral or electrographic seizures were observed in Kv4.2 knockout mice. Following kainate, Kv4.2 knockout mice demonstrated a decreased seizure and status epilepticus latency as well as increased mortality compared to wildtype littermates. The background strain modified the seizure susceptibility phenotype in Kv4.2 knockout mice. In response to bicuculline, slices from Kv4.2 knockout mice exhibited an increase in epileptiform bursting in area CA1 as compared to wildtype littermates. Discussion These studies show that loss of Kv4.2 channels is associated with enhanced susceptibility to convulsant stimulation, supporting the concept that Kv4.2 deficiency may contribute to aberrant network excitability and regulate seizure threshold. PMID:19453702

  15. [Cardiac rehabilitation in women].

    PubMed

    Ghannem, M; Ghannem, L; Lamouchi, S; Justin, K D; Meimoun, P; Ghannem, L

    2016-12-01

    Coronary artery disease (CAD) occurs later in life in women when compared to men (10 years later). The FAST-MI study has shown that the profile of women with CAD has changed in the past 15 years, they are younger, more obese, and usually smokers. Whatever the age at which CAD occurs in women, the prognosis tends to be worse than in men, despite a higher frequency of acute coronary syndrome (ACS) with angiographically normal coronary arteries in women. In women without significant lesion at coronary angiography, the WISE study has shown abnormalities of the coronary vasomotricy. Despite its beneficial effect on morbidity and mortality, cardiac rehabilitation is underused particularly in women. Indeed, several factors do not encourage a woman to follow a cardiac rehabilitation program, even after an ACS. These factors may be cultural, domestic, familial, orthopedic, or even the fear of exercising. Therefore, physicians have to be particularly convincing in women, in order to have them participating in rehabilitation programs. Physical capacity is lower in women when compared to men. However, the weaker the physical capacity, the better the benefit of cardiac rehabilitation. Physical endurance training continuously or in interval, associated to muscle strengthening can improve the physical capacity in women. Vascular risk factors correction is also an important step for the management of women with CAD. Therapeutic education and several available workshops help women to better understand their disease and to improve their self-management when they return home. Anxiety, depression, and sexual dysfunction frequently deteriorate the quality of life of our patients. Therefore, psychological management is also essential in our departments.

  16. Dipyridamole cardiac imaging

    SciTech Connect

    Iskandrian, A.S.; Heo, J.; Askenase, A.; Segal, B.L.; Auerbach, N.

    1988-02-01

    Dipyridamole cardiac imaging is a useful alternative technique to exercise stress testing in the evaluation of patients with ischemic heart disease. Intravenous dipyridamole is still in the investigational phase, while oral dipyridamole is widely available. The hemodynamic effects of dipyridamole include an increase in coronary blood flow (due to coronary vasodilation) which is in excess of the increase in myocardial oxygen consumption and cardiac output. The disparity in the increase in coronary blood flow relative to the cardiac output results in an increase in myocardial thallium activity and an increase in the myocardial/background activity ratio. The quality of the thallium images is better or similar to that of exercise thallium images. The optimal dose of intravenous dipyridamole is 0.56 mg/kg, and of the oral dose it is 300 to 400 mg, although higher doses may be necessary in some patients. Analysis of the thallium images has been to a large extent based on visual inspection of the planar images. Delayed images are helpful to establish the nature of the perfusion abnormalities (transient or fixed). The process of redistribution is based on disparate rates of washout from the normal and abnormal zones. The sensitivity and specificity of dipyridamole thallium imaging, whether intravenous or oral, have been shown in a number of studies to be quite adequate and comparable to that achieved during exercise thallium imaging. Dipyridamole two-dimensional echocardiography has also been used in the detection of coronary artery disease; transient (new or worsening of preexisting) wall motion abnormalities have been found to be a specific marker of coronary artery disease. Transmural as well as regional coronary steal phenomena have been postulated as the mechanism for dipyridamole-induced regional wall motion abnormalities. 65 references.

  17. Cardiac Rehabilitation: MedlinePlus Health Topic

    MedlinePlus

    ... exercising are other risk factors. NIH: National Heart, Lung, and Blood Institute Start Here Cardiac Rehabilitation (Mayo Foundation for Medical Education and Research) Cardiac Rehabilitation (National Heart, Lung, and Blood Institute) What Is Cardiac Rehabilitation? (American Heart Association) - ...

  18. Accelerated retinal aging in PACAP knock-out mice.

    PubMed

    Kovács-Valasek, Andrea; Szabadfi, Krisztina; Dénes, Viktória; Szalontai, Bálint; Tamás, Andrea; Kiss, Péter; Szabó, Aliz; Setalo, Gyorgy; Reglődi, Dóra; Gábriel, Robert

    2017-02-13

    Pituitary adenylate cyclase activating polypeptide (PACAP) is a neurotrophic and neuroprotective peptide. PACAP and its receptors are widely distributed in the retina. A number of reports provided evidence that PACAP is neuroprotective in retinal degenerations. The current study compared retina cell type-specific differences in young (3-4months) and aged adults (14-16months), of wild-type (WT) mice and knock-out (KO) mice lacking endogenous PACAP production during the course of aging. Histological, immunocytochemical and Western blot examinations were performed. The staining for standard neurochemical markers (tyrosine hydroxylase for dopaminergic cells, calbindin 28 kDa for horizontal cells, protein kinase Cα for rod bipolar cells) of young adult PACAP KO retinas showed no substantial alterations compared to young adult WT retinas, except for the specific PACAP receptor (PAC1-R) staining. We could not detect PAC1-R immunoreactivity in bipolar and horizontal cells in young adult PACAP KO animals. Some other age-related changes were observed only in the PACAP KO mice only. These alterations included horizontal and rod bipolar cell dendritic sprouting into the photoreceptor layer and decreased ganglion cell number. Also, Müller glial cells showed elevated GFAP expression compared to the aging WT retinas. Furthermore, Western blot analyses revealed significant differences between the phosphorylation state of ERK1/2 and JNK in KO mice, indicating alterations in the MAPK signaling pathway. These results support the conclusion that endogenous PACAP contributes to protection against aging of the nervous system.

  19. Behavioral and neuroanatomical abnormalities in pleiotrophin knockout mice.

    PubMed

    Krellman, Jason W; Ruiz, Henry H; Marciano, Veronica A; Mondrow, Bracha; Croll, Susan D

    2014-01-01

    Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features.

  20. Immunosympathectomy as the first phenotypic knockout with antibodies

    PubMed Central

    Cattaneo, Antonino

    2013-01-01

    In a PNAS Classic Article published in 1960, Rita Levi-Montalcini offered formal and conclusive proof that endogenous NGF was responsible for the survival of sympathetic neurons in vivo. Thus ended an experimental tour de force lasting a decade, starting with the demonstration that a humoral factor, produced from a tumor transplanted in a chicken embryo, was responsible for stimulating outgrowth of nerve fibers from sympathetic and sensory neurons. From a more general methodological point of view, this work provided a breakthrough in the quest to achieve targeted loss of function and experimentally validate the function of biological molecules. Finally, this work provided an example of the ablation of a specific neuronal subpopulation in an otherwise intact nervous system, an immunological knife of unsurpassed effectiveness and precision. The novelty and the importance of the PNAS Classic Article is discussed here, collocating it within the context of the particular moment of the NGF discovery saga, of Rita Levi-Montalcini's scientific and academic career, and of the general scientific context of those years. This seminal work, involving the use of antibodies for phenotypic knockout in vivo, planted seeds that were to bear new fruit many years later with the advent of monoclonal antibodies and recombinant antibody technologies. PMID:23515328

  1. Boolean Network Model Predicts Knockout Mutant Phenotypes of Fission Yeast

    PubMed Central

    Davidich, Maria I.; Bornholdt, Stefan

    2013-01-01

    Boolean networks (or: networks of switches) are extremely simple mathematical models of biochemical signaling networks. Under certain circumstances, Boolean networks, despite their simplicity, are capable of predicting dynamical activation patterns of gene regulatory networks in living cells. For example, the temporal sequence of cell cycle activation patterns in yeasts S. pombe and S. cerevisiae are faithfully reproduced by Boolean network models. An interesting question is whether this simple model class could also predict a more complex cellular phenomenology as, for example, the cell cycle dynamics under various knockout mutants instead of the wild type dynamics, only. Here we show that a Boolean network model for the cell cycle control network of yeast S. pombe correctly predicts viability of a large number of known mutants. So far this had been left to the more detailed differential equation models of the biochemical kinetics of the yeast cell cycle network and was commonly thought to be out of reach for models as simplistic as Boolean networks. The new results support our vision that Boolean networks may complement other mathematical models in systems biology to a larger extent than expected so far, and may fill a gap where simplicity of the model and a preference for an overall dynamical blueprint of cellular regulation, instead of biochemical details, are in the focus. PMID:24069138

  2. Knockout of Foxp2 disrupts vocal development in mice

    PubMed Central

    Castellucci, Gregg A.; McGinley, Matthew J.; McCormick, David A.

    2016-01-01

    The FOXP2 gene is important for the development of proper speech motor control in humans. However, the role of the gene in general vocal behavior in other mammals, including mice, is unclear. Here, we track the vocal development of Foxp2 heterozygous knockout (Foxp2+/−) mice and their wildtype (WT) littermates from juvenile to adult ages, and observe severe abnormalities in the courtship song of Foxp2+/− mice. In comparison to their WT littermates, Foxp2+/− mice vocalized less, produced shorter syllable sequences, and possessed an abnormal syllable inventory. In addition, Foxp2+/− song also exhibited irregular rhythmic structure, and its development did not follow the consistent trajectories observed in WT vocalizations. These results demonstrate that the Foxp2 gene is critical for normal vocal behavior in juvenile and adult mice, and that Foxp2 mutant mice may provide a tractable model system for the study of the gene’s role in general vocal motor control. PMID:26980647

  3. Drop tests of the Three Mile Island knockout canister

    SciTech Connect

    Box, W.D.; Aaron, W.S.; Shappert, L.B.; Childress, P.C.; Quinn, G.J.; Smith, J.V.

    1986-09-01

    A type of Three Mile Island Unit 2 (TMI-2) defueling canister, called a ''knockout'' canister, was subjected to a series of drop tests at the Oak Ridge National Laboratory's Drop Test Facility. These tests were designed to confirm the structural integrity of internal fixed neutron poisons in support of a request for NRC licensing of this type of canister for the shipment of TMI-2 reactor fuel debris to the Idaho National Engineering Laboratory (INEL) for the Core Examination R and D Program. Work conducted at the Oak Ridge National Laboratory included (1) precise physical measurements of the internal poison rod configuration before assembly, (2) canister assembly and welding, (3) nondestructive examination (an initial hydrostatic pressure test and an x-ray profile of the internals before and after each drop test), (4) addition of a simulated fuel load, (5) instrumentation of the canister for each drop test, (6) fabrication of a cask simulation vessel with a developed and tested foam impact limiter, (7) use of refrigeration facilities to cool the canister to well below freezing prior to three of the drops, (8) recording the drop test with still, high-speed, and normal-speed photography, (9) recording the accelerometer measurements during impact, (10) disassembly and post-test examination with precise physical measurements, and (11) preparation of the final report.

  4. Modeling fragile X syndrome in the Fmr1 knockout mouse.

    PubMed

    Kazdoba, Tatiana M; Leach, Prescott T; Silverman, Jill L; Crawley, Jacqueline N

    2014-11-01

    Fragile X Syndrome (FXS) is a commonly inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. Clinical symptoms of FXS can include impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS is caused by a CGG repeat mutation which expands a region on the X chromosome containing the FMR1 gene. In FXS, a full mutation (> 200 repeats) leads to hypermethylation of FMR1, an epigenetic mechanism that effectively silences FMR1 gene expression and reduces levels of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is important for the regulation of protein expression. In an effort to further understand how loss of FMR1 and FMRP contribute to FXS symptomology, several FXS animal models have been created. The most well characterized rodent model is the Fmr1 knockout (KO) mouse, which lacks FMRP protein due to a disruption in its Fmr1 gene. Here, we review the behavioral phenotyping of the Fmr1 KO mouse to date, and discuss the clinical relevance of this mouse model to the human FXS condition. While much remains to be learned about FXS, the Fmr1 KO mouse is a valuable tool for understanding the repercussions of functional loss of FMRP and assessing the efficacy of pharmacological compounds in ameliorating the molecular and behavioral phenotypes relevant to FXS.

  5. Reduced ultrasonic vocalizations in vasopressin 1b knockout mice.

    PubMed

    Scattoni, M L; McFarlane, H G; Zhodzishsky, V; Caldwell, H K; Young, W S; Ricceri, L; Crawley, J N

    2008-03-05

    The neuropeptides oxytocin and vasopressin have been implicated in rodent social and affiliative behaviors, including social bonding, parental care, social recognition, social memory, vocalizations, territoriality, and aggression, as well as components of human social behaviors and the etiology of autism. Previous investigations of mice with various manipulations of the oxytocin and vasopressin systems reported unusual levels of ultrasonic vocalizations in social settings. We employed a vasopressin 1b receptor (Avpr1b) knockout mouse to evaluate the role of the vasopressin 1b receptor subtype in the emission of ultrasonic vocalizations in adult and infant mice. Avpr1b null mutant female mice emitted fewer ultrasonic vocalizations, and their vocalizations were generally at lower frequencies, during a resident-intruder test. Avpr1b null mutant pups emitted ultrasonic vocalizations similar to heterozygote and wildtype littermates when separated from the nest on postnatal days 3, 6, 9, and 12. However, maternal potentiation of ultrasonic vocalizations in Avpr1b null and heterozygote mutants was absent, when tested at postnatal day 9. These results indicate that Avpr1b null mutant mice are impaired in the modulation of ultrasonic vocalizations within different social contexts at infant and adult ages.

  6. Results of gal-knockout porcine thymokidney xenografts.

    PubMed

    Griesemer, A D; Hirakata, A; Shimizu, A; Moran, S; Tena, A; Iwaki, H; Ishikawa, Y; Schule, P; Arn, J S; Robson, S C; Fishman, J A; Sykes, M; Sachs, D H; Yamada, K

    2009-12-01

    Clinical transplantation for the treatment of end-stage organ disease is limited by a shortage of donor organs. Successful xenotransplantation could immediately overcome this limitation. The development of homozygous alpha1,3-galactosyltransferase knockout (GalT-KO) pigs removed hyperacute rejection as the major immunologic hurdle to xenotransplantation. Nevertheless, GalT-KO organs stimulate robust immunologic responses that are not prevented by immunosuppressive drugs. Murine studies show that recipient thymopoiesis in thymic xenografts induces xenotolerance. We transplanted life-supporting composite thymokidneys (composite thymus and kidneys) prepared in GalT-KO miniature swine to baboons in an attempt to induce tolerance in a preclinical xenotransplant model. Here, we report the results of seven xenogenic thymokidney transplants using a steroid-free immunosuppressive regimen that eliminated whole-body irradiation in all but one recipient. The regimen resulted in average recipient survival of over 50 days. This was associated with donor-specific unresponsiveness in vitro and early baboon thymopoiesis in the porcine thymus tissue of these grafts, suggesting the development of T-cell tolerance. The kidney grafts had no signs of cellular infiltration or deposition of IgG, and no grafts were lost due to rejection. These results show that xenogeneic thymus transplantation can support early primate thymopoiesis, which in turn may induce T-cell tolerance to solid organ xenografts.

  7. Results of Gal-Knockout porcine thymokidney xenografts

    PubMed Central

    Griesemer, Adam D.; Hirakata, Atsushi; Shimizu, Akira; Moran, Shannon; Tena, Aseda; Iwaki, Hideyuki; Ishikawa, Yoshinori; Schule, Patrick; Arn, J. Scott; Robson, Simon C.; Fishman, Jay A.; Sykes, Megan; Sachs, David H.; Yamada, Kazuhiko

    2009-01-01

    Clinical transplantation for the treatment of end-stage organ disease is limited by a shortage of donor organs. Successful xenotransplantation could immediately overcome this limitation. The development of homozygous α1,3-galactosyltransferase knockout (GalT-KO) pigs removed hyperacute rejection as the major immunologic hurdle to xenotransplantation. Nevertheless, GalT-KO organs stimulate robust immunologic responses that are not prevented by immunosuppressive drugs. Murine studies show that recipient thymopoiesis in thymic xenografts induces xenotolerance. We transplanted life-supporting composite thymokidneys prepared in GalT-KO miniature swine to baboons in an attempt to induce tolerance in a pre-clinical xenotransplant model. Here, we report the results of 7 xenogenic thymokidney transplants using a steroid-free immunosuppressive regimen that eliminated whole body irradiation in all but 1 recipient. The regimen resulted in average recipient survival of over 50 days. This was associated with donor-specific unresponsiveness in vitro and early baboon thymopoiesis in the porcine thymus tissue of these grafts, suggesting the development of T cell tolerance. The kidney grafts had no signs of cellular infiltration or deposition of IgG, and no grafts were lost due to rejection. These results show that xenogeneic thymus transplantation can support early human thymopoiesis, which in turn may induce T cell tolerance to solid organ xenografts. PMID:19845583

  8. Adenylate kinase 1 knockout mice have normal thiamine triphosphate levels.

    PubMed

    Makarchikov, Alexander F; Wins, Pierre; Janssen, Edwin; Wieringa, Bé; Grisar, Thierry; Bettendorff, Lucien

    2002-10-21

    Thiamine triphosphate (ThTP) is found at low concentrations in most animal tissues and it may act as a phosphate donor for the phosphorylation of proteins, suggesting a potential role in cell signaling. Two mechanisms have been proposed for the enzymatic synthesis of ThTP. A thiamine diphosphate (ThDP) kinase (ThDP+ATP if ThTP+ADP) has been purified from brewer's yeast and shown to exist in rat liver. However, other data suggest that, at least in skeletal muscle, adenylate kinase 1 (AK1) is responsible for ThTP synthesis. In this study, we show that AK1 knockout mice have normal ThTP levels in skeletal muscle, heart, brain, liver and kidney, demonstrating that AK1 is not responsible for ThTP synthesis in those tissues. We predict that the high ThTP content of particular tissues like the Electrophorus electricus electric organ, or pig and chicken skeletal muscle is more tightly correlated with high ThDP kinase activity or low soluble ThTPase activity than with non-stringent substrate specificity and high activity of adenylate kinase.

  9. Gastrointestinal Pathology in Juvenile and Adult CFTR-Knockout Ferrets

    PubMed Central

    Sun, Xingshen; Olivier, Alicia K.; Yi, Yaling; Pope, Christopher E.; Hayden, Hillary S.; Liang, Bo; Sui, Hongshu; Zhou, Weihong; Hager, Kyle R.; Zhang, Yulong; Liu, Xiaoming; Yan, Ziying; Fisher, John T.; Keiser, Nicholas W.; Song, Yi; Tyler, Scott R.; Goeken, J. Adam; Kinyon, Joann M.; Radey, Matthew C.; Fligg, Danielle; Wang, Xiaoyan; Xie, Weiliang; Lynch, Thomas J.; Kaminsky, Paul M.; Brittnacher, Mitchell J.; Miller, Samuel I.; Parekh, Kalpaj; Meyerholz, David K.; Hoffman, Lucas R.; Frana, Timothy; Stewart, Zoe A.; Engelhardt, John F.

    2015-01-01

    Cystic fibrosis (CF) is a multiorgan disease caused by loss of a functional cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel in many epithelia of the body. Here we report the pathology observed in the gastrointestinal organs of juvenile to adult CFTR-knockout ferrets. CF gastrointestinal manifestations included gastric ulceration, intestinal bacterial overgrowth with villous atrophy, and rectal prolapse. Metagenomic phylogenetic analysis of fecal microbiota by deep sequencing revealed considerable genotype-independent microbial diversity between animals, with the majority of taxa overlapping between CF and non-CF pairs. CF hepatic manifestations were variable, but included steatosis, necrosis, biliary hyperplasia, and biliary fibrosis. Gallbladder cystic mucosal hyperplasia was commonly found in 67% of CF animals. The majority of CF animals (85%) had pancreatic abnormalities, including extensive fibrosis, loss of exocrine pancreas, and islet disorganization. Interestingly, 2 of 13 CF animals retained predominantly normal pancreatic histology (84% to 94%) at time of death. Fecal elastase-1 levels from these CF animals were similar to non-CF controls, whereas all other CF animals evaluated were pancreatic insufficient (<2 μg elastase-1 per gram of feces). These findings suggest that genetic factors likely influence the extent of exocrine pancreas disease in CF ferrets and have implications for the etiology of pancreatic sufficiency in CF patients. In summary, these studies demonstrate that the CF ferret model develops gastrointestinal pathology similar to CF patients. PMID:24637292

  10. The biology of novel animal genes: Mouse APEX gene knockout

    SciTech Connect

    MacInnes, M.; Altherr, M.R.; Ludwig, D.; Pedersen, R.; Mold, C.

    1997-07-01

    This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The controlled breeding of novel genes into mice, including the gene knockout (KO), or conversely by adding back transgenes provide powerful genetic technologies that together suffice to determine in large part the biological role(s) of novel genes. Inbred mouse remains the best understood and most useful mammalian experimental system available for tackling the biology of novel genes. The major mammalian apurinic/apyrimidinic (AP) endonuclease (APE), is involved in a key step in the repair of spontaneous and induced AP sites in DNA. Efficient repair of these lesions is imperative to prevent the stable incorporation of mutations into the cellular genome which may lead to cell death or transformation. Loss or modulation of base excison repair activity in vivo may elevate the spontaneous mutation rate in cells, and may lead to a substantial increase in the incidence of cancer. Despite extensive biochemical analysis, however, the significance of these individual APE functions in vivo has not been elucidated. Mouse embryonic stem (ES) cells heterozygous for a deletion mutation in APE have been generated and whole animals containing the APE mutation have been derived from these ES cells. Animals homozygous for the APE null mutation die early in gestation, underscoring the biological significance of this DNA repair gene.

  11. Sensorimotor development in neonatal progesterone receptor knockout mice.

    PubMed

    Willing, Jari; Wagner, Christine K

    2014-01-01

    Early exposure to steroid hormones can permanently and dramatically alter neural development. This is best understood in the organizational effects of hormones during development of brain regions involved in reproductive behaviors or neuroendocrine function. However, recent evidence strongly suggests that steroid hormones play a vital role in shaping brain regions involved in cognitive behavior such as the cerebral cortex. The most abundantly expressed steroid hormone receptor in the developing rodent cortex is the progesterone receptor (PR). In the rat, PR is initially expressed in the developmentally-critical subplate at E18, and subsequently in laminas V and II/III through the first three postnatal weeks (Quadros et al. [2007] J Comp Neurol 504:42-56; Lopez & Wagner [2009]: J Comp Neurol 512:124-139), coinciding with significant periods of dendritic maturation, the arrival of afferents and synaptogenesis. In the present study, we investigated PR expression in the neonatal mouse somatosensory cortex. Additionally, to investigate the potential role of PR in developing cortex, we examined sensorimotor function in the first two postnatal weeks in PR knockout mice and their wildtype (WT) and heterozygous (HZ) counterparts. While the three genotypes were similar in most regards, PRKO and HZ mice lost the rooting reflex 2-3 days earlier than WT mice. These studies represent the first developmental behavioral assessment of PRKO mice and suggest PR expression may play an important role in the maturation of cortical connectivity and sensorimotor integration.

  12. Bone growth and turnover in progesterone receptor knockout mice.

    SciTech Connect

    Rickard, David J.; Iwaniec, Urszula T.; Evans, Glenda; Hefferan, Theresa E.; Hunter, Jaime C.; Waters, Katrina M.; Lydon, John P.; O'Malley, Bert W.; Khosla, Sundeep; Spelsberg, Thomas C.; Turner, Russell T.

    2008-05-01

    The role of progesterone receptor (PR) signaling in skeletal metabolism is controversial. To address whether signaling through the PR is necessary for normal bone growth and turnover, we performed histomorphometric and mCT analyses of bone from homozygous female PR knockout (PRKO) mice at 6, 12, and 26 weeks of age. These mice possess a null mutation of the PR locus, which blocks the gene expression of A and B isoforms of PR. Body weight gain, uterine weight gain and tibia longitudinal bone growth was normal in PRKO mice. In contrast, total and cortical bone mass were increased in long bones of post-pubertal (12 and 26-week-old) PRKO mice, whereas cancellous bone mass was normal in the tibia but increased in the humerus. The striking 57% decrease in cancellous bone from the proximal tibia metaphysis which occurred between 6 and 26 weeks in WT mice was abolished in PRKO mice. The improved bone balance in aging PRKO mice was associated with elevated bone formation and a tendency toward reduced osteoclast perimeter. Taken together, these findings suggest that PR signaling in mice attenuates the accumulation of cortical bone mass during adolescence and is required for early age-related loss of cancellous bone.

  13. Delayed wound healing in CXCR2 knockout mice.

    PubMed

    Devalaraja, R M; Nanney, L B; Du, J; Qian, Q; Yu, Y; Devalaraja, M N; Richmond, A

    2000-08-01

    Previous studies demonstrated that the CXC chemokine, MGSA/GRO-alpha and its receptor, CXCR2, are expressed during wound healing by keratinocytes and endothelial cells at areas where epithelialization and neovascularization occur. The process of wound healing is dependent on leukocyte recruitment, keratinocyte proliferation and migration, and angiogenesis. These processes may be mediated in part by CXC chemokines, such as interleukin-8 and MGSA/GRO-alpha. To examine further the significance of CXC chemokines in wound healing, full excisional wounds were created on CXCR2 wild-type (+/+), heterozygous (+/-), or knockout (-/-) mice. Wounds were histologically analyzed for neutrophil and monocyte infiltration, neovascularization and epithelialization at days 3, 5, 7, and 10 postwounding. The CXCR2 -/- mice exhibited defective neutrophil recruitment, an altered temporal pattern of monocyte recruitment, and altered secretion of interleukin-1beta. Significant delays in wound healing parameters, including epithelialization and decreased neovascularization, were also observed in CXCR2 -/- mice. In vitro wounding experiments with cultures of keratinocytes established from -/- and +/+ mice revealed a retardation in wound closure in CXCR2 -/- keratinocytes, suggesting a role for this receptor on keratinocytes in epithelial resurfacing that is independent of neutrophil recruitment. These in vitro and in vivo studies further establish a pathophysiologic role for CXCR2 during cutaneous wound repair.

  14. One-neutron knockout reaction from 20C

    NASA Astrophysics Data System (ADS)

    Hwang, Jongwon; Samurai Collaboration

    2014-09-01

    Recent researches in neutron-rich nuclei have demonstrated that the depth of each single-particle level varies from that in stable nuclei : some of the well-known magic numbers disappear and new shell closures develop. Cross-shell excitation, transition of a nucleon across a shell gap, can be exploit to probe changes in shell structure. The present work aims at exploration of neutron-unbound states of 19C, especially a hole- state populated by cross-shell excitation, via a one-neutron knockout reaction. The experiment was performed at the RIBF facility in RIKEN. A 20C secondary beam produced by BigRIPS with an energy of 280 MeV/nucleon impinged on a carbon target placed before the SAMURAI spectrometer. By taking full advantage of the analyzer system comprised of a large-acceptance super-conducting dipole magnet, associated tracking detectors, and a large volume neutron detector system, an invariant mass spectrum for the system of 18C + n was reconstructed. Three unbound excited states in 19C were identified including the unknown 1 /21+ state at 2.90 MeV in excitation energy. Details of the measurement and analysis along with results will be presented.

  15. Environmental enrichment induces behavioural disturbances in neuropeptide Y knockout mice

    PubMed Central

    Reichmann, Florian; Wegerer, Vanessa; Jain, Piyush; Mayerhofer, Raphaela; Hassan, Ahmed M.; Fröhlich, Esther E.; Bock, Elisabeth; Pritz, Elisabeth; Herzog, Herbert; Holzer, Peter; Leitinger, Gerd

    2016-01-01

    Environmental enrichment (EE) refers to the provision of a complex and stimulating housing condition which improves well-being, behaviour and brain function of laboratory animals. The mechanisms behind these beneficial effects of EE are only partially understood. In the current report, we describe a link between EE and neuropeptide Y (NPY), based on findings from NPY knockout (KO) mice exposed to EE. Relative to EE-housed wildtype (WT) animals, NPY KO mice displayed altered behaviour as well as molecular and morphological changes in amygdala and hippocampus. Exposure of WT mice to EE reduced anxiety and decreased central glucocorticoid receptor expression, effects which were absent in NPY KO mice. In addition, NPY deletion altered the preference of EE items, and EE-housed NPY KO mice responded to stress with exaggerated hyperthermia, displayed impaired spatial memory, had higher hippocampal brain-derived neurotrophic factor mRNA levels and altered hippocampal synaptic plasticity, effects which were not seen in WT mice. Accordingly, these findings suggest that NPY contributes to the anxiolytic effect of EE and that NPY deletion reverses the beneficial effects of EE into a negative experience. The NPY system could thus be a target for “enviromimetics”, therapeutics which reproduce the beneficial effects of enhanced environmental stimulation. PMID:27305846

  16. Cardiac oxidative stress in a mouse model of neutral lipid storage disease☆

    PubMed Central

    Schrammel, Astrid; Mussbacher, Marion; Winkler, Sarah; Haemmerle, Guenter; Stessel, Heike; Wölkart, Gerald; Zechner, Rudolf; Mayer, Bernd

    2013-01-01

    Cardiac oxidative stress has been implicated in the pathogenesis of hypertrophy, cardiomyopathy and heart failure. Systemic deletion of the gene encoding adipose triglyceride lipase (ATGL), the enzyme that catalyzes the rate-limiting step of triglyceride lipolysis, results in a phenotype characterized by severe steatotic cardiac dysfunction. The objective of the present study was to investigate a potential role of oxidative stress in cardiac ATGL deficiency. Hearts of mice with global ATGL knockout were compared to those of mice with cardiomyocyte-restricted overexpression of ATGL and to those of wildtype littermates. Our results demonstrate that oxidative stress, measured as lucigenin chemiluminescence, was increased ~ 6-fold in ATGL-deficient hearts. In parallel, cytosolic NADPH oxidase subunits p67phox and p47phox were upregulated 4–5-fold at the protein level. Moreover, a prominent upregulation of different inflammatory markers (tumor necrosis factor α, monocyte chemotactant protein-1, interleukin 6, and galectin-3) was observed in those hearts. Both the oxidative and inflammatory responses were abolished upon cardiomyocyte-restricted overexpression of ATGL. Investigating the effect of oxidative and inflammatory stress on nitric oxide/cGMP signal transduction we observed a ~ 2.5-fold upregulation of soluble guanylate cyclase activity and a ~ 2-fold increase in cardiac tetrahydrobiopterin levels. Systemic treatment of ATGL-deficient mice with the superoxide dismutase mimetic Mn(III)tetrakis (4-benzoic acid) porphyrin did not ameliorate but rather aggravated cardiac oxidative stress. Our data suggest that oxidative and inflammatory stress seems involved in lipotoxic heart disease. Upregulation of soluble guanylate cyclase and cardiac tetrahydrobiopterin might be regarded as counterregulatory mechanisms in cardiac ATGL deficiency. PMID:23867907

  17. c-Cbl Inhibition Improves Cardiac function and Survival in Response to Myocardial Ischemia

    PubMed Central

    Rafiq, Khadija; Kolpakov, Mikhail A; Seqqat, Rachid; Guo, Jianfen; Guo, Xinji; Qi, Zhao; Yu, Daohai; Mohapatra, Bhopal; Zutshi, Neha; An, Wei; Band, Hamid; Sanjay, Archana; Houser, Steven R; Sabri, Abdelkarim

    2014-01-01

    Background The proto-oncogene Casitas b-lineage lymphoma (c-Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor and non-receptor tyrosine kinases, resulting in their ubiquitination and down-regulation. However, the function of c-Cbl in the control of cardiac function is currently unknown. In this study, we examined the role of c-Cbl in myocyte death and cardiac function after myocardial ischemia. Methods and Results We show increased c-Cbl expression in human ischemic and dilated cardiomyopathy hearts and in response to pathological stress stimuli in mice. c-Cbl deficient mice demonstrated a more robust functional recovery after myocardial ischemia reperfusion injury, as well as significantly reduced myocyte apoptosis and improved cardiac function. Ubiquitination and downregulation of key survival c-Cbl targets, epidermal growth factor receptors and focal adhesion kinase, were significantly reduced in c-Cbl knockout mice. Inhibition of c-Cbl expression or its ubiquitin ligase activity in cardiac myocytes offered protection against H2O2 stress. Interestingly, c-Cbl deletion reduced the risk of death and increased cardiac functional recovery after chronic myocardial ischemia. This beneficial effect of c-Cbl deletion was associated with enhanced neoangiogenesis and increased expression of vascular endothelial growth factor (VEGF)-a and VEGF receptor type 2 in the infarcted region. Conclusions c-Cbl activation promotes myocyte apoptosis, inhibits angiogenesis and causes adverse cardiac remodeling after myocardial infarction. These findings point to c-Cbl as a potential therapeutic target for the maintenance of cardiac function and remodeling after myocardial ischemia. PMID:24583314

  18. Angiotensin II type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy

    PubMed Central

    Yasuno, Shinji; Kuwahara, Koichiro; Kinoshita, Hideyuki; Yamada, Chinatsu; Nakagawa, Yasuaki; Usami, Satoru; Kuwabara, Yoshihiro; Ueshima, Kenji; Harada, Masaki; Nishikimi, Toshio; Nakao, Kazuwa

    2013-01-01

    BACKGROUND AND PURPOSE Angiotensin II has been implicated in the development of various cardiovascular ailments, including cardiac hypertrophy and heart failure. The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large-scale clinical trials suggests that angiotensin II is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin II also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects. EXPERIMENTAL APPROACH We induced cardiac hypertrophy in wild-type (WT) and angiotensin II type 1a receptor knockout (AT1aR-KO) mice by transverse aortic constriction (TAC). The susceptibility to ventricular tachycardia (VT) assessed in an in vivo electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of AT1R on the incidences of arrhythmias was also assessed. KEY RESULTS As described previously, WT and AT1aR-KO mice with TAC developed cardiac hypertrophy to the same degree, but the incidence of VT was much lower in the latter. Moreover, although TAC induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in AT1aR-KO mice. Acute pharmacological blockade of AT1R also reduced the incidence of arrhythmias. CONCLUSIONS AND IMPLICATIONS Our findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling. PMID:23937445

  19. Cardiac α-actin over-expression therapy in dominant ACTA1 disease.

    PubMed

    Ravenscroft, Gianina; McNamara, Elyshia; Griffiths, Lisa M; Papadimitriou, John M; Hardeman, Edna C; Bakker, Anthony J; Davies, Kay E; Laing, Nigel G; Nowak, Kristen J

    2013-10-01

    More than 200 mutations in the skeletal muscle α-actin gene (ACTA1) cause either dominant or recessive skeletal muscle disease. Currently, there are no specific therapies. Cardiac α-actin is 99% identical to skeletal muscle α-actin and the predominant actin isoform in fetal muscle. We previously showed cardiac α-actin can substitute for skeletal muscle α-actin, preventing the early postnatal death of Acta1 knock-out mice, which model recessive ACTA1 disease. Dominant ACTA1 disease is caused by the presence of 'poison' mutant actin protein. Experimental and anecdotal evidence nevertheless indicates that the severity of dominant ACTA1 disease is modulated by the relative amount of mutant skeletal muscle α-actin protein present. Thus, we investigated whether transgenic over-expression of cardiac α-actin in postnatal skeletal muscle could ameliorate the phenotype of mouse models of severe dominant ACTA1 disease. In one model, lethality of ACTA1(D286G). Acta1(+/-) mice was reduced from ∼59% before 30 days of age to ∼12%. In the other model, Acta1(H40Y), in which ∼80% of male mice die by 5 months of age, the cardiac α-actin transgene did not significantly improve survival. Hence cardiac α-actin over-expression is likely to be therapeutic for at least some dominant ACTA1 mutations. The reason cardiac α-actin was not effective in the Acta1(H40Y) mice is uncertain. We showed that the Acta1(H40Y) mice had endogenously elevated levels of cardiac α-actin in skeletal muscles, a finding not reported in dominant ACTA1 patients.

  20. Curvature Analysis of Cardiac Excitation Wavefronts

    DTIC Science & Technology

    2013-04-01

    computational cardiac-cell network accurately reproduces a particular kind of cardiac arrhythmia , such as ventricular fibrillation. Curvature Analysis of Cardiac...network accurately reproduces a particular kind of cardiac arrhythmia , such as ventricular fibrillation. Index Terms Cardiac excitation waves...isopotentials, Bézier curves, curvature, cardiac arrhythmia and fibrillation Ç 1 INTRODUCTION AN estimated 81,000,000 American adults, more than onein three

  1. Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis.

    PubMed

    Harel, Itamar; Maezawa, Yoshiro; Avraham, Roi; Rinon, Ariel; Ma, Hsiao-Yen; Cross, Joe W; Leviatan, Noam; Hegesh, Julius; Roy, Achira; Jacob-Hirsch, Jasmine; Rechavi, Gideon; Carvajal, Jaime; Tole, Shubha; Kioussi, Chrissa; Quaggin, Susan; Tzahor, Eldad

    2012-11-13

    The search for developmental mechanisms driving vertebrate organogenesis has paved the way toward a deeper understanding of birth defects. During embryogenesis, parts of the heart and craniofacial muscles arise from pharyngeal mesoderm (PM) progenitors. Here, we reveal a hierarchical regulatory network of a set of transcription factors expressed in the PM that initiates heart and craniofacial organogenesis. Genetic perturbation of this network in mice resulted in heart and craniofacial muscle defects, revealing robust cross-regulation between its members. We identified Lhx2 as a previously undescribed player during cardiac and pharyngeal muscle development. Lhx2 and Tcf21 genetically interact with Tbx1, the major determinant in the etiology of DiGeorge/velo-cardio-facial/22q11.2 deletion syndrome. Furthermore, knockout of these genes in the mouse recapitulates specific cardiac features of this syndrome. We suggest that PM-derived cardiogenesis and myogenesis are network properties rather than properties specific to individual PM members. These findings shed new light on the developmental underpinnings of congenital defects.

  2. Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis

    PubMed Central

    Harel, Itamar; Maezawa, Yoshiro; Avraham, Roi; Rinon, Ariel; Ma, Hsiao-Yen; Cross, Joe W.; Leviatan, Noam; Hegesh, Julius; Roy, Achira; Jacob-Hirsch, Jasmine; Rechavi, Gideon; Carvajal, Jaime; Tole, Shubha; Kioussi, Chrissa; Quaggin, Susan; Tzahor, Eldad

    2012-01-01

    The search for developmental mechanisms driving vertebrate organogenesis has paved the way toward a deeper understanding of birth defects. During embryogenesis, parts of the heart and craniofacial muscles arise from pharyngeal mesoderm (PM) progenitors. Here, we reveal a hierarchical regulatory network of a set of transcription factors expressed in the PM that initiates heart and craniofacial organogenesis. Genetic perturbation of this network in mice resulted in heart and craniofacial muscle defects, revealing robust cross-regulation between its members. We identified Lhx2 as a previously undescribed player during cardiac and pharyngeal muscle development. Lhx2 and Tcf21 genetically interact with Tbx1, the major determinant in the etiology of DiGeorge/velo-cardio-facial/22q11.2 deletion syndrome. Furthermore, knockout of these genes in the mouse recapitulates specific cardiac features of this syndrome. We suggest that PM-derived cardiogenesis and myogenesis are network properties rather than properties specific to individual PM members. These findings shed new light on the developmental underpinnings of congenital defects. PMID:23112163

  3. Engineering of Conditional Class I Hdac Knockout Mice and Generation of a Time-Spatial Knockout by a Dual Recombination System.

    PubMed

    Bayer, Sieglinde; Wirth, Matthias

    2017-01-01

    The protein sequences of class I HDACs in mice and humans are 96-99 % identical. These highly conserved proteins have crucial roles in biological processes, such as proliferation and development, which is reflected in the lethality that occurs in conventional whole body knockout mice. Therefore, conditional knockouts are inevitable to investigate the functions of class I HDACs in mice. Here, we describe the generation of conditional class I Hdac knockout mice, using Hdac1 as an example. We explain a relatively quick procedure to generate the necessary target vectors by recombination-mediated genetic engineering and gateway techniques. Furthermore, we show how to culture, target, and screen for positively recombined ES cells. Additionally, we present a dual recombination system, which allows the deletion of class I Hdacs at any time by a tamoxifen inducible Cre.

  4. New Developments in Cardiac Regeneration.

    PubMed

    Le, Thi Yen Loan; Thavapalachandran, Sujitha; Kizana, Eddy; Chong, James Jh

    2017-04-01

    Numerous pharmacological and device therapies have improved adverse cardiac remodelling and mortality in heart failure. However, none are able to regenerate damaged cardiac tissue. Stem cell based therapies using multipotent (adult) stem cells and pluripotent stem cells are new approaches that could potentially achieve the elusive goal of true cardiac regeneration. Over the past two decades, various stem cell based approaches have been shown to improve left ventricular function in pre-clinical animal models. Promising results rapidly led to clinical trials, initially using bone marrow-derived mononuclear cells, then mesenchymal stromal cell populations and, more recently, progenitor cells from the adult heart itself. These have been shown to be safe and have advanced our understanding of potential suitable recipients, cell delivery routes, and possible mechanisms of action. However, efficacy in these trials has been inconsistent. Human pluripotent stem cells (hPSCs) are another potential source of stem cells for cardiac regeneration. They could theoretically provide an unlimited source of cardiomyocytes or cardiac progenitors. Pre-clinical studies in both small and large animal models have shown robust engraftment and improvements in cardiac function. The first clinical trial using hPSC-derived cardiac derivatives has now commenced and others are imminent. In this brief review article, we summarise recent developments in stem cell therapies aimed at cardiac regeneration, including discussion of types of cell and non-cell-based strategies being explored.

  5. Health Instruction Packages: Cardiac Anatomy.

    ERIC Educational Resources Information Center

    Phillips, Gwen; And Others

    Text, illustrations, and exercises are utilized in these five learning modules to instruct nurses, students, and other health care professionals in cardiac anatomy and functions and in fundamental electrocardiographic techniques. The first module, "Cardiac Anatomy and Physiology: A Review" by Gwen Phillips, teaches the learner to draw…

  6. Mitochondrial biogenesis in cardiac pathophysiology.

    PubMed

    Rimbaud, Stéphanie; Garnier, Anne; Ventura-Clapier, Renée

    2009-01-01

    Cardiac performance depends on a fine balance between the work the heart has to perform to satisfy the needs of the body and the energy that it is able to produce. Thus, energy production by oxidative metabolism, the main energy source of the cardiac muscle, has to be strictly regulated to adapt to cardiac work. Mitochondrial biogenesis is the mechanism responsible for mitochondrial component synthesis and assembly. This process controls mitochondrial content and thus correlates with energy production that, in turn, sustains cardiac contractility. Mitochondrial biogenesis should be finely controlled to match cardiac growth and cardiac work. When the heart is subjected to an increase in work in response to physiological and pathological challenges, it adapts by increasing its mass and expressing a new genetic program. In response to physiological stimuli such as endurance training, mitochondrial biogenesis seems to follow a program involving increased cardiac mass. But in the context of pathological hypertrophy, the modifications of this mechanism remain unclear. What appears clear is that mitochondrial biogenesis is altered in heart failure, and the imbalance between cardiac work demand and energy production represents a major factor in the development of heart failure.

  7. Redox Control of Cardiac Excitability

    PubMed Central

    Aggarwal, Nitin T.

    2013-01-01

    Abstract Reactive oxygen species (ROS) have been associated with various human diseases, and considerable attention has been paid to investigate their physiological effects. Various ROS are synthesized in the mitochondria and accumulate in the cytoplasm if the cellular antioxidant defense mechanism fails. The critical balance of this ROS synthesis and antioxidant defense systems is termed the redox system of the cell. Various cardiovascular diseases have also been affected by redox to different degrees. ROS have been indicated as both detrimental and protective, via different cellular pathways, for cardiac myocyte functions, electrophysiology, and pharmacology. Mostly, the ROS functions depend on the type and amount of ROS synthesized. While the literature clearly indicates ROS effects on cardiac contractility, their effects on cardiac excitability are relatively under appreciated. Cardiac excitability depends on the functions of various cardiac sarcolemal or mitochondrial ion channels carrying various depolarizing or repolarizing currents that also maintain cellular ionic homeostasis. ROS alter the functions of these ion channels to various degrees to determine excitability by affecting the cellular resting potential and the morphology of the cardiac action potential. Thus, redox balance regulates cardiac excitability, and under pathological regulation, may alter action potential propagation to cause arrhythmia. Understanding how redox affects cellular excitability may lead to potential prophylaxis or treatment for various arrhythmias. This review will focus on the studies of redox and cardiac excitation. Antioxid. Redox Signal. 18, 432–468. PMID:22897788

  8. GPCR signaling and cardiac function.

    PubMed

    Capote, Leany A; Mendez Perez, Roberto; Lymperopoulos, Anastasios

    2015-09-15

    G protein-coupled receptors (GPCRs), such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, i.e. myocytes, fibroblasts and endothelial cells, play crucial roles in regulating cardiac function and morphology. Their importance in cardiac physiology and disease is reflected by the fact that, collectively, they represent the direct targets of over a third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of their structure, function and the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart disease therapy. Here, we review these signaling modalities employed by GPCRs known to be expressed in the cardiac myocyte membranes and to directly modulate cardiac contractility. We also highlight drugs and drug classes that directly target these GPCRs to modulate cardiac function, as well as molecules involved in cardiac GPCR signaling that have the potential of becoming novel drug targets for modulation of cardiac function in the future.

  9. Revisiting Cardiac Cellular Composition

    PubMed Central

    Pinto, Alexander R.; Ilinykh, Alexei; Ivey, Malina J.; Kuwabara, Jill T.; D'Antoni, Michelle L.; Debuque, Ryan; Chandran, Anjana; Wang, Lina; Arora, Komal; Rosenthal, Nadia; Tallquist, Michelle D.

    2015-01-01

    Rationale Accurate knowledge of the cellular composition of the heart is essential to fully understand the changes that occur during pathogenesis and to devise strategies for tissue engineering and regeneration. Objective To examine the relative frequency of cardiac endothelial cells, hematopoietic-derived cells and fibroblasts in the mouse and human heart. Methods and Results Using a combination of genetic tools and cellular markers, we examined the occurrence of the most prominent cell types in the adult mouse heart. Immunohistochemistry revealed that endothelial cells constitute over 60%, hematopoietic-derived cells 5–10%, and fibroblasts under 20% of the non-myocytes in the heart. A refined cell isolation protocol and an improved flow cytometry approach provided an independent means of determining the relative abundance of non-myocytes. High dimensional analysis and unsupervised clustering of cell populations confirmed that endothelial cells are the most abundant cell population. Interestingly, fibroblast numbers are smaller than previously estimated, and two commonly assigned fibroblast markers, Sca-1 and CD90, underrepresent fibroblast numbers. We also describe an alternative fibroblast surface marker that more accurately identifies the resident cardiac fibroblast population. Conclusions This new perspective on the abundance of different cell types in the heart demonstrates that fibroblasts comprise a relatively minor population. By contrast, endothelial cells constitute the majority of non-cardiomyocytes and are likely to play a greater role in physiologic function and response to injury than previously appreciated. PMID:26635390

  10. Leadership in cardiac surgery.

    PubMed

    Rao, Christopher; Patel, Vanash; Ibrahim, Michael; Ahmed, Kamran; Wong, Kathie A; Darzi, Ara; von Segesser, Ludwig K; Athanasiou, Thanos

    2011-06-01

    Despite the efficacy of cardiac surgery, less invasive interventions with more uncertain long-term outcomes are increasingly challenging surgery as first-line treatment for several congenital, degenerative and ischemic cardiac diseases. The specialty must evolve if it is to ensure its future relevance. More importantly, it must evolve to ensure that future patients have access to treatments with proven long-term effectiveness. This cannot be achieved without dynamic leadership; however, our contention is that this is not enough. The demands of a modern surgical career and the importance of the task at hand are such that the serendipitous emergence of traditional charismatic leadership cannot be relied upon to deliver necessary change. We advocate systematic analysis and strategic leadership at a local, national and international level in four key areas: Clinical Care, Research, Education and Training, and Stakeholder Engagement. While we anticipate that exceptional individuals will continue to shape the future of our specialty, the creation of robust structures to deliver collective leadership in these key areas is of paramount importance.

  11. Decoding the Cardiac Message

    PubMed Central

    Dorn, Gerald W

    2012-01-01

    This review reflects and expands upon the contents of the author’s presentation at The Thomas W. Smith Memorial Lecture at AHA Scientific Sessions, 2011. “Decoding the cardiac message” refers to accumulating results from ongoing microRNA research that is altering longstanding concepts of the mechanisms for, and consequences of, messenger RNA (mRNA) regulation in the heart. First, I provide a brief historical perspective of the field of molecular genetics, touching upon seminal research that paved the way for modern molecular cardiovascular research and helped establish the foundation for current concepts of mRNA regulation in the heart. I follow with some interesting details about the specific research that led to the discovery and appreciation of microRNAs as highly conserved pivotal regulators of RNA expression and translation. Finally, I provide a personal viewpoint as to how agnostic genome-wide techniques for measuring microRNAs, their mRNA targets, and their protein products can be applied in an integrated multi-systems approach to uncover direct and indirect effects of microRNAs. Experimental designs integrating next-generation sequencing and global proteomics have the potential to address unanswered questions regarding microRNA-mRNA interactions in cardiac disease, how disease alters mRNA targeting by specific microRNAs, and how mutational and polymorphic nucleotide variation in microRNAs can affect end-organ function and stress-response. PMID:22383710

  12. Cardiac rehabilitation in Germany.

    PubMed

    Cantwell, J D

    1976-09-01

    The concept of cardiac reconditioning centers for the prevention and rehabilitation of coronary patients has been tremendously successful in Germany over the past 20 years. At least 40 such centers are located throughout the country. Physicians, nurses, and physical therapists work closely together in the various facets of the rehabilitation process. The financial backing for these facilities is primarily through governmental and regional insurance companies, whose officials are apparently convinced that in the long run supporting preventive measures is financially sound. Objective data supporting their convictions come from studies such as that of Brusis, who showed that such as that of 1,500 employees was diminished by nearly 70 percent during a two-year period after cardiac reconditioning, as compared to a similar time period before the rehabilitation experience. Subjective benefits, which are extremely difficult to quantitate in meaningful terms, were nonetheless expressed by nearly all the patients with whom I conversed. Perhaps they have experienced the same feelings that Mark Twain did when he observed that "all frets and worries and chafings sank to sleep in the presence of the benignant serenity of the Alps; the Great Spirit of the Mountains breathed his own peace upon their hurt minds and sore hearts and healed them."

  13. THE CHEMOTHERAPY OF CARDIAC ARREST.

    PubMed

    MINUCK, M

    1965-01-02

    Direct-air ventilation, external cardiac compression, and external defibrillation are established techniques for patients who unexpectedly develop cardiac arrest. The proper use of drugs can increase the incidence of successful resuscitation. Intracardiac adrenaline (epinephrine) acts as a powerful stimulant during cardiac standstill and, in addition, converts fine ventricular fibrillation to a coarser type, more responsive to electrical defibrillation. Routine use of intravenous sodium bicarbonate is recommended to combat the severe metabolic acidosis accompanying cardiac arrest. Lidocaine is particularly useful when ventricular fibrillation or ventricular tachycardia tends to recur. Analeptics are contraindicated, since they invariably increase oxygen requirements of already hypoxic cerebral tissues. The following acrostic is a useful mnemonic for recalling the details of the management of cardiac arrest in their proper order: A (Airway), B (Breathing), C (Circulation), D (Diagnosis of underlying cause), E (Epinephrine), F (Fibrillation), G (Glucose intravenously), pH (Sodium bicarbonate), I (Intensive care).

  14. Pediatric cardiac surgery in Indonesia.

    PubMed

    Asou, T; Rachmat, J

    1998-10-01

    Pediatric cardiac surgery in Indonesia first developed thanks to the cooperation of various cardiac centers abroad. The establishment of the 'Harapan Kita' National Cardiac Center in 1985 was one of the most important initial steps. Thereafter, the discipline advanced remarkably in terms of the number of the operations performed and the variety of the diseases treated and, as a result, the surgical outcome also improved. Numerous problems remain to be solved. Only 1% of the children with congenital heart disease are today properly treated in Indonesia. Some of the underlying problems responsible for this situation include a shortage of pediatric cardiac professionals, the lack of the information and education on the part of the patients, and a shortage of funding, both privately and publicly. It would thus be welcome for pediatric cardiac surgeons, cardiologists and nurses in Indonesia to learn about congenital heart disease from doctors and nurses in advanced countries in order to improve the outlook at home.

  15. Exacerbated cardiac fibrosis induced by β-adrenergic activation in old mice due to decreased AMPK activity.

    PubMed

    Wang, Jingjing; Song, Yao; Li, Hao; Shen, Qiang; Shen, Jing; An, Xiangbo; Wu, Jimin; Zhang, Jianshu; Wu, Yunong; Xiao, Han; Zhang, Youyi

    2016-11-01

    Senescent hearts exhibit defective responses to β-adrenergic receptor (β-AR) over-activation upon stress, leading to more severe pathological cardiac remodelling. However, the underlying mechanisms remain unclear. Here, we investigated the role of adenosine monophosphate-activated protein kinase (AMPK) in protecting against ageing-associated cardiac remodelling in mice upon β-AR over-activation. 10-week-old (young) and 18-month-old (old) mice were subcutaneously injected with the β-AR agonist isoproterenol (ISO; 5 mg/kg). More extensive cardiac fibrosis was found in old mice upon ISO exposure than in young mice. Meanwhile, ISO treatment decreased AMPK activity and increased β-arrestin 1, but not β-arrestin 2, expression, and the effects of ISO on AMPK and β-arrestin 1 were greater in old mice than in young mice. Similarly, young AMPKα2-knockout (KO) mice showed more extensive cardiac fibrosis upon ISO exposure than that was observed in age-matched wild-type (WT) littermates. The extent of cardiac fibrosis in WT old mice was similar to that in young KO mice. Additionally, AMPK activities were decreased and β-arrestin 1 expression increased in KO mice. In contrast, the AMPK activator metformin decreased β-arrestin 1 expression and attenuated cardiac fibrosis in both young and old mice upon ISO exposure. In conclusion, more severe cardiac fibrosis is induced by ISO in old mice than in young mice. A decrease in AMPK activity, which further increases β-arrestin 1 expression, is the central mechanism underlying the ageing-related cardiac fibrosis induced by ISO. The AMPK activator metformin is a promising therapeutic agent for treating ageing-related cardiac remodelling upon β-AR over-activation.

  16. Cardiac rehabilitation after myocardial infarction.

    PubMed

    Contractor, Aashish S

    2011-12-01

    Cardiac rehabilitation/secondary prevention programs are recognized as integral to the comprehensive care of patients with coronary heart disease (CHD), and as such are recommended as useful and effective (Class I) by the American Heart Association and the American College of Cardiology in the treatment of patients with CHD. The term cardiac rehabilitation refers to coordinated, multifaceted interventions designed to optimize a cardiac patient's physical, psychological, and social functioning, in addition to stabilizing, slowing, or even reversing the progression of the underlying atherosclerotic processes, thereby reducing morbidity and mortality. Cardiac rehabilitation, aims at returning the patient back to normal functioning in a safe and effective manner and to enhance the psychosocial and vocational state of the patient. The program involves education, exercise, risk factor modification and counselling. A meta-analysis based on a review of 48 randomized trials that compared outcomes of exercise-based rehabilitation with usual medical care, showed a reduction of 20% in total mortality and 26% in cardiac mortality rates, with exercise-based rehabilitation compared with usual medical care. Risk stratification helps identify patients who are at increased risk for exercise-related cardiovascular events and who may require more intensive cardiac monitoring in addition to the medical supervision provided for all cardiac rehabilitation program participants. During exercise, the patients' ECG is continuously monitored through telemetry, which serves to optimize the exercise prescription and enhance safety. The safety of cardiac rehabilitation exercise programs is well established, and the occurrence of major cardiovascular events during supervised exercise is extremely low. As hospital stays decrease, cardiac rehabilitation is assuming an increasingly important role in secondary prevention. In contrast with its growing importance internationally, there are very few

  17. INDUCTION OF MAMMARY GLAND DEVELOPMENT IN ESTROGEN RECEPTOR-ALPHA KNOCKOUT MICE

    EPA Science Inventory

    Mammary glands from the estrogen receptor knockout ( ERKO) mouse do not undergo ductal morphogenesis or alveolar development. Disrupted Er signaling may result in reduced estrogen-responsive gene products in the mammary gland or reduced mammotropic hormones that contribute t...

  18. Dcdc2 knockout mice display exacerbated developmental disruptions following knockdown of doublecortin.

    PubMed

    Wang, Y; Yin, X; Rosen, G; Gabel, L; Guadiana, S M; Sarkisian, M R; Galaburda, A M; Loturco, J J

    2011-09-08

    The dyslexia-associated gene DCDC2 is a member of the DCX family of genes known to play roles in neurogenesis, neuronal migration, and differentiation. Here we report the first phenotypic analysis of a Dcdc2 knockout mouse. Comparisons between Dcdc2 knockout mice and wild-type (wt) littermates revealed no significant differences in neuronal migration, neocortical lamination, neuronal cilliogenesis or dendritic differentiation. Considering previous studies showing genetic interactions and potential functional redundancy among members of the DCX family, we tested whether decreasing Dcx expression by RNAi would differentially impair neurodevelopment in Dcdc2 knockouts and wild-type mice. Consistent with this hypothesis, we found that deficits in neuronal migration, and dendritic growth caused by RNAi of Dcx were more severe in Dcdc2 knockouts than in wild-type mice with the same transfection. These results indicate that Dcdc2 is not required for neurogenesis, neuronal migration or differentiation in mice, but may have partial functional redundancy with Dcx.

  19. Knock-Outs, Stick-Outs, Cut-Outs: Clipping Paths Separate Objects from Background.

    ERIC Educational Resources Information Center

    Wilson, Bradley

    1998-01-01

    Outlines a six-step process that allows computer operators, using Photoshop software, to create "knock-outs" to precisely define the path that will serve to separate the object from the background. (SR)

  20. Analysis of microsatellite polymorphism in inbred knockout mice.

    PubMed

    Zuo, Baofen; Du, Xiaoyan; Zhao, Jing; Yang, Huixin; Wang, Chao; Wu, Yanhua; Lu, Jing; Wang, Ying; Chen, Zhenwen

    2012-01-01

    Previously, we found that the genotype of 42 out of 198 mouse microsatellite loci, which are distributed among all chromosomes except the Y chromosome, changed from monomorphism to polymorphism (CMP) in a genetically modified inbred mouse strain. In this study, we further examined whether CMP also relates to the homologous recombination in gene knockout (KO) mouse strains. The same 42 microsatellite loci were analyzed by polymerase chain reaction (PCR) in 29 KO inbred mouse strains via short tandem sequence repeat (STR) scanning and direct sequence cloning to justify microsatellite polymorphisms. The C57BL/6J and 129 mouse strains, from which these 29 KO mice were derived, were chosen as the background controls. The results indicated that 10 out of 42 (23.8%) loci showed CMP in some of these mouse strains. Except for the trinucleotide repeat locus of D3Mit22, which had microsatellite CMP in strain number 9, the core sequences of the remaining 41 loci were dinucleotide repeats, and 9 out of 41 (21.95%) showed CMPs among detected mouse strains. However, 11 out of 29 (37.9%) KO mice strains were recognized as having CMPs. The popular dinucleotide motifs in CMP were (TG)(n) (50%, 2/4), followed by (GT)(n) (27.27%, 3/11) and (CA)(n) (23.08%, 3/13). The microsatellite CMP in (CT)(n) and (AG)(n) repeats were 20% (1/5). According to cloning sequencing results, 6 KO mouse strains showed insertions of nucleotides whereas 1 showed a deletion. Furthermore, 2 loci (D13Mit3 and D14Mit102) revealed CMP in 2 strains, and mouse strain number 9 showed CMPs in two loci (D3Mit22 and D13Mit3) simultaneously. Collectively, these results indicated that microsatellite polymorphisms were present in the examined inbred KO mice.

  1. HFE gene knockout produces mouse model of hereditary hemochromatosis

    PubMed Central

    Zhou, Xiao Yan; Tomatsu, Shunji; Fleming, Robert E.; Parkkila, Seppo; Waheed, Abdul; Jiang, Jinxing; Fei, Ying; Brunt, Elizabeth M.; Ruddy, David A.; Prass, Cynthia E.; Schatzman, Randall C.; O’Neill, Rosemary; Britton, Robert S.; Bacon, Bruce R.; Sly, William S.

    1998-01-01

    Hereditary hemochromatosis (HH) is a common autosomal recessive disease characterized by increased iron absorption and progressive iron storage that results in damage to major organs in the body. Recently, a candidate gene for HH called HFE encoding a major histocompatibility complex class I-like protein was identified by positional cloning. Nearly 90% of Caucasian HH patients have been found to be homozygous for the same mutation (C282Y) in the HFE gene. To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, we studied the effects of a targeted disruption of the murine homologue of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates (96 ± 5% vs. 77 ± 3%, P < 0.007), and hepatic iron concentration was 8-fold higher than that of wild-type littermates (2,071 ± 450 vs. 255 ± 23 μg/g dry wt, P < 0.002). Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. This study shows that the HFE protein is involved in the regulation of iron homeostasis and that mutations in this gene are responsible for HH. The knockout mouse model of HH will facilitate investigation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for prevention or correction of iron overload. PMID:9482913

  2. Targeting cancer using KAT inhibitors to mimic lethal knockouts

    PubMed Central

    Brown, James A.L.; Bourke, Emer; Eriksson, Leif A.; Kerin, Michael J.

    2016-01-01

    Two opposing enzyme classes regulate fundamental elements of genome maintenance, gene regulation and metabolism, either through addition of an acetyl moiety by histone acetyltransferases (HATs) or its removal by histone de-acetyltransferases (HDAC), and are exciting targets for drug development. Importantly, dysfunctional acetylation has been implicated in numerous diseases, including cancer. Within the HAT superfamily the MYST family holds particular interest, as its members are directly involved in the DNA damage response and repair pathways and crucially, several members have been shown to be down-regulated in common cancers (such as breast and prostate). In the present study we focus on the development of lysine (K) acetyltransferase inhibitors (KATi) targeting the MYST family member Tip60 (Kat5), an essential protein, designed or discovered through screening libraries. Importantly, Tip60 has been demonstrated to be significantly down-regulated in many cancers which urgently require new treatment options. We highlight current and future efforts employing these KATi as cancer treatments and their ability to synergize and enhance current cancer treatments. We investigate the different methods of KATi production or discovery, their mechanisms and their validation models. Importantly, the utility of KATi is based on a key concept: using KATi to abrogate the activity of an already down-regulated essential protein (effectively creating a lethal knockout) provides another innovative mechanism for targeting cancer cells, while significantly minimizing any off-target effects to normal cells. This approach, combined with the rapidly developing interest in KATi, suggests that KATi have a bright future for providing truly personalized therapies. PMID:27528742

  3. Comprehensive behavioral analysis of cluster of differentiation 47 knockout mice.

    PubMed

    Koshimizu, Hisatsugu; Takao, Keizo; Matozaki, Takashi; Ohnishi, Hiroshi; Miyakawa, Tsuyoshi

    2014-01-01

    Cluster of differentiation 47 (CD47) is a member of the immunoglobulin superfamily which functions as a ligand for the extracellular region of signal regulatory protein α (SIRPα), a protein which is abundantly expressed in the brain. Previous studies, including ours, have demonstrated that both CD47 and SIRPα fulfill various functions in the central nervous system (CNS), such as the modulation of synaptic transmission and neuronal cell survival. We previously reported that CD47 is involved in the regulation of depression-like behavior of mice in the forced swim test through its modulation of tyrosine phosphorylation of SIRPα. However, other potential behavioral functions of CD47 remain largely unknown. In this study, in an effort to further investigate functional roles of CD47 in the CNS, CD47 knockout (KO) mice and their wild-type littermates were subjected to a battery of behavioral tests. CD47 KO mice displayed decreased prepulse inhibition, while the startle response did not differ between genotypes. The mutants exhibited slightly but significantly decreased sociability and social novelty preference in Crawley's three-chamber social approach test, whereas in social interaction tests in which experimental and stimulus mice have direct contact with each other in a freely moving setting in a novel environment or home cage, there were no significant differences between the genotypes. While previous studies suggested that CD47 regulates fear memory in the inhibitory avoidance test in rodents, our CD47 KO mice exhibited normal fear and spatial memory in the fear conditioning and the Barnes maze tests, respectively. These findings suggest that CD47 is potentially involved in the regulation of sensorimotor gating and social behavior in mice.

  4. Increased anxiety-related behaviour in Hint1 knockout mice.

    PubMed

    Varadarajulu, Jeeva; Lebar, Maria; Krishnamoorthy, Gurumoorthy; Habelt, Sonja; Lu, Jia; Bernard Weinstein, I; Li, Haiyang; Holsboer, Florian; Turck, Christoph W; Touma, Chadi

    2011-07-07

    Several reports have implicated a role for the histidine triad nucleotide-binding protein-1 (Hint1) in psychiatric disorders. We have studied the emotional behaviour of male Hint1 knockout (Hint1 KO) mice in a battery of tests and performed biochemical analyses on brain tissue. The behavioural analysis revealed that Hint1 KO mice exhibit an increased emotionality phenotype compared to wildtype (WT) mice, while no significant differences in locomotion or general exploratory activity were noted. In the elevated plus-maze (EPM) test, the Hint1 KO animals entered the open arms of the apparatus less often than WT littermates. Similarly, in the dark-light box test, Hint1 KO mice spent less time in the lit compartment and the number of entries were reduced, which further confirmed an increased anxiety-related behaviour. Moreover, the Hint1 KO animals showed significantly more struggling and less floating behaviour in the forced swim test (FST), indicating an increased emotional arousal in aversive situations. Hint1 is known as a protein kinase C (PKC) interacting protein. Western blot analysis showed that PKCγ expression was elevated in Hint1 KO compared to WT mice. Interestingly, PKCγ mRNA levels of the two groups did not show a significant difference, implying a post-transcriptional PKCγ regulation. In addition, PKC enzymatic activity was increased in Hint1 KO compared to WT mice. In summary, our results indicate a role for Hint1 and PKCγ in modulating anxiety-related and stress-coping behaviour in mice.

  5. Analysis of Microsatellite Polymorphism in Inbred Knockout Mice

    PubMed Central

    Zhao, Jing; Yang, Huixin; Wang, Chao; Wu, Yanhua; Lu, Jing; Wang, Ying; Chen, Zhenwen

    2012-01-01

    Previously, we found that the genotype of 42 out of 198 mouse microsatellite loci, which are distributed among all chromosomes except the Y chromosome, changed from monomorphism to polymorphism (CMP) in a genetically modified inbred mouse strain. In this study, we further examined whether CMP also relates to the homologous recombination in gene knockout (KO) mouse strains. The same 42 microsatellite loci were analyzed by polymerase chain reaction (PCR) in 29 KO inbred mouse strains via short tandem sequence repeat (STR) scanning and direct sequence cloning to justify microsatellite polymorphisms. The C57BL/6J and 129 mouse strains, from which these 29 KO mice were derived, were chosen as the background controls. The results indicated that 10 out of 42 (23.8%) loci showed CMP in some of these mouse strains. Except for the trinucleotide repeat locus of D3Mit22, which had microsatellite CMP in strain number 9, the core sequences of the remaining 41 loci were dinucleotide repeats, and 9 out of 41 (21.95%) showed CMPs among detected mouse strains. However, 11 out of 29 (37.9%) KO mice strains were recognized as having CMPs. The popular dinucleotide motifs in CMP were (TG)n (50%, 2/4), followed by (GT)n (27.27%, 3/11) and (CA)n (23.08%, 3/13). The microsatellite CMP in (CT)n and (AG)n repeats were 20% (1/5). According to cloning sequencing results, 6 KO mouse strains showed insertions of nucleotides whereas 1 showed a deletion. Furthermore, 2 loci (D13Mit3 and D14Mit102) revealed CMP in 2 strains, and mouse strain number 9 showed CMPs in two loci (D3Mit22 and D13Mit3) simultaneously. Collectively, these results indicated that microsatellite polymorphisms were present in the examined inbred KO mice. PMID:22509320

  6. Feeding-elicited cataplexy in orexin knockout mice.

    PubMed

    Clark, E L; Baumann, C R; Cano, G; Scammell, T E; Mochizuki, T

    2009-07-21

    Mice lacking orexin/hypocretin signaling have sudden episodes of atonia and paralysis during active wakefulness. These events strongly resemble cataplexy, episodes of sudden muscle weakness triggered by strong positive emotions in people with narcolepsy, but it remains unknown whether murine cataplexy is triggered by positive emotions. To determine whether positive emotions elicit murine cataplexy, we placed orexin knockout (KO) mice on a scheduled feeding protocol with regular or highly palatable food. Baseline sleep/wake behavior was recorded with ad libitum regular chow. Mice were then placed on a scheduled feeding protocol in which they received 60% of their normal amount of chow 3 h after dark onset for the next 10 days. Wild-type and KO mice rapidly entrained to scheduled feeding with regular chow, with more wake and locomotor activity prior to the feeding time. On day 10 of scheduled feeding, orexin KO mice had slightly more cataplexy during the food-anticipation period and more cataplexy in the second half of the dark period, when they may have been foraging for residual food. To test whether more palatable food increases cataplexy, mice were then switched to scheduled feeding with an isocaloric amount of Froot Loops, a food often used as a reward in behavioral studies. With this highly palatable food, orexin KO mice had much more cataplexy during the food-anticipation period and throughout the dark period. The increase in cataplexy with scheduled feeding, especially with highly palatable food, suggests that positive emotions may trigger cataplexy in mice, just as in people with narcolepsy. Establishing this connection helps validate orexin KO mice as an excellent model of human narcolepsy and provides an opportunity to better understand the mechanisms that trigger cataplexy.

  7. Xenobiotic transporters: ascribing function from gene knockout and mutation studies.

    PubMed

    Klaassen, Curtis D; Lu, Hong

    2008-02-01

    Transporter-mediated absorption, secretion, and reabsorption of chemicals are increasingly recognized as important determinants in the biological activities of many xenobiotics. In recent years, the rapid progress in generating and characterizing mice with targeted deletion of transporters has greatly increased our knowledge of the functions of transporters in the pharmacokinetics/toxicokinetics of xenobiotics. In this introduction, we focus on functions of transporters learned from experiments on knockout mice as well as humans and rodents with natural mutations of these transporters. We limit our discussion to transporters that either directly transport xenobiotics or are important in biliary excretion or cellular defenses, namely multidrug resistance, multidrug resistance-associated proteins, breast cancer resistance protein, organic anion transporting polypeptides, organic anion transporters, organic cation transporters, nucleoside transporters, peptide transporters, bile acid transporters, cholesterol transporters, and phospholipid transporters, as well as metal transporters. Efflux transporters in intestine, liver, kidney, brain, testes, and placenta can efflux xenobiotics out of cells and serve as barriers against the entrance of xenobiotics into cells, whereas many xenobiotics enter the biological system via uptake transporters. The functional importance of a given transporter in each tissue depends on its substrate specificity, expression level, and the presence/absence of other transporters with overlapping substrate preferences. Nevertheless, a transporter may affect a tissue independent of its local expression by altering systemic metabolism. Further studies on the gene regulation and function of transporters, as well as the interrelationship between transporters and phase I/II xenobiotic-metabolizing enzymes, will provide a complete framework for developing novel strategies to protect us from xenobiotic insults.

  8. Knockout of leucine aminopeptidase in Toxoplasma gondii using CRISPR/Cas9.

    PubMed

    Zheng, Jun; Jia, Honglin; Zheng, Yonghui

    2015-02-01

    Leucine aminopeptidases of the M17 peptidase family represent ideal drug targets for therapies directed against the pathogens Plasmodium, Babesia and Trypanosoma. Previously, we characterised Toxoplasma gondii leucine aminopeptidase and demonstrated its role in regulating the levels of free amino acids. In this study, we evaluated the potential of T. gondii leucine aminopeptidase as a drug target in T. gondii by a knockout method. Existing knockout methods for T. gondii have many drawbacks; therefore, we developed a new technique that takes advantage of the CRISPR/Cas9 system. We first chose a Cas9 target site in the gene encoding T. gondii leucine aminopeptidase and then constructed a knockout vector containing Cas9 and the single guide RNA. After transfection, single tachyzoites were cloned in 96-well plates by limiting dilution. Two transfected strains derived from a single clone were cultured in Vero cells, and then subjected to expression analysis by western blotting. The phenotypic analysis revealed that knockout of T. gondii leucine aminopeptidase resulted in inhibition of attachment/invasion and replication; both the growth and attachment/invasion capacity of knockout parasites were restored by complementation with a synonymously substituted allele of T. gondii leucine aminopeptidase. Mouse experiments demonstrated that T. gondii leucine aminopeptidase knockout somewhat reduced the pathogenicity of T. gondii. An enzymatic activity assay showed that T. gondii leucine aminopeptidase knockout reduced the processing of a leucine aminopeptidase-specific substrate in T. gondii. The absence of leucine aminopeptidase activity could be slightly compensated for in T. gondii. Overall, T. gondii leucine aminopeptidase knockout influenced the growth of T. gondii, but did not completely block parasite development, virulence or enzymatic activity. Therefore, we conclude that leucine aminopeptidase would be useful only as an adjunctive drug target in T. gondii.

  9. Normal maternal behavior, but increased pup mortality, in conditional oxytocin receptor knockout females.

    PubMed

    Macbeth, Abbe H; Stepp, Jennifer E; Lee, Heon-Jin; Young, W Scott; Caldwell, Heather K

    2010-10-01

    Oxytocin (Oxt) and the Oxt receptor (Oxtr) are implicated in the onset of maternal behavior in a variety of species. Recently, we developed two Oxtr knockout lines: a total body knockout (Oxtr-/-) and a conditional Oxtr knockout (OxtrFB/FB) in which the Oxtr is lacking only in regions of the forebrain, allowing knockout females to potentially nurse and care for their biological offspring. In the current study, we assessed maternal behavior of postpartum OxtrFB/FB females toward their own pups and maternal behavior of virgin Oxtr-/- females toward foster pups and compared knockouts of both lines to wildtype (Oxtr+/+) littermates. We found that both Oxtr-/- and OxtrFB/FB females appear to have largely normal maternal behaviors. However, with first litters, approximately 40% of the OxtrFB/FB knockout dams experienced high pup mortality, compared to fewer than 10% of the Oxtr+/+ dams. We then went on to test whether or not this phenotype occurred in subsequent litters or when the dams were exposed to an environmental disturbance. We found that regardless of the degree of external disturbance, OxtrFB/FB females lost more pups on their first and second litters compared to wildtype females. Possible reasons for higher pup mortality in OxtrFB/FB females are discussed.

  10. What do aquaporin knockout studies tell us about fluid transport in epithelia?

    PubMed

    Maclaren, Oliver J; Sneyd, James; Crampin, Edmund J

    2013-04-01

    The investigation of near-isosmotic water transport in epithelia goes back over 100 years; however, debates over mechanism and pathway remain. Aquaporin (AQP) knockouts have been used by various research groups to test the hypothesis of an osmotic mechanism as well as to explore the paracellular versus transcellular pathway debate. Nonproportional reductions in the water permeability of a water-transporting epithelial cell (e.g., a reduction of around 80-90 %) compared to the reduction in overall water transport rate in the knockout animal (e.g., a reduction of 50-60 %) are commonly found. This nonproportionality has led to controversy over whether AQP knockout studies support or contradict the osmotic mechanism. Arguments raised for and against an interpretation supporting the osmotic mechanism typically have partially specified, implicit, or incorrect assumptions. We present a simple mathematical model of the osmotic mechanism with clear assumptions and, for models based on this mechanism, establish a baseline prediction of AQP knockout studies. We allow for deviations from isotonic/isosmotic conditions and utilize dimensional analysis to reduce the number of parameters that must be considered independently. This enables a single prediction curve to be used for multiple epithelial systems. We find that a simple, transcellular-only osmotic mechanism sufficiently predicts the results of knockout studies and find criticisms of this mechanism to be overstated. We note, however, that AQP knockout studies do not give sufficient information to definitively rule out an additional paracellular pathway.

  11. What do aquaporin knockout studies tell us about fluid transport in epithelia?

    PubMed Central

    Maclaren, Oliver J; Sneyd, James; Crampin, Edmund J

    2013-01-01

    The investigation of near-isosmotic water transport in epithelia goes back over 100 years; however debates over mechanism and pathway still remain. Aquaporin (AQP) knockouts have been used by various research groups to test the hypothesis of an osmotic mechanism, as well as to explore the paracellular vs transcellular pathway debate. Non-proportional reductions in the water permeability of a water-transporting epithelial cell (e.g. a reduction of around 80–90%) compared to the reduction in overall water transport rate in the knockout animal (e.g. a reduction of 50–60%) are commonly found. This non-proportionality has led to controversy over whether AQP knockout studies support or contradict the osmotic mechanism. Arguments raised for and against an interpretation supporting the osmotic mechanism typically have partially-specified, implicit or incorrect assumptions. We present a simple mathematical model of the osmotic mechanism with clear assumptions and, for models based on this mechanism, establish a baseline prediction of AQP knockout studies. We allow for deviations from isotonic/isosmotic conditions and utilize dimensional analysis to reduce the number of parameters that must be considered independently. This enables a single prediction curve to be used for multiple epithelial systems. We find that a simple, transcellular-only osmotic mechanism sufficiently predicts the results of knockout studies and find criticisms of this mechanism to be overstated. We note, however, that AQP knockout studies do not give sufficient information to definitively rule out an additional paracellular pathway. PMID:23430220

  12. Physics of Cardiac Arrhythmogenesis

    NASA Astrophysics Data System (ADS)

    Karma, Alain

    2013-04-01

    A normal heartbeat is orchestrated by the stable propagation of an excitation wave that produces an orderly contraction. In contrast, wave turbulence in the ventricles, clinically known as ventricular fibrillation (VF), stops the heart from pumping and is lethal without prompt defibrillation. I review experimental, computational, and theoretical studies that have shed light on complex dynamical phenomena linked to the initiation, maintenance, and control of wave turbulence. I first discuss advances made to understand the precursor state to a reentrant arrhythmia where the refractory period of cardiac tissue becomes spatiotemporally disordered; this is known as an arrhythmogenic tissue substrate. I describe observed patterns of transmembrane voltage and intracellular calcium signaling that can contribute to this substrate, and symmetry breaking instabilities to explain their formation. I then survey mechanisms of wave turbulence and discuss novel methods that exploit electrical pacing stimuli to control precursor patterns and low-energy pulsed electric fields to control turbulence.

  13. [Thrombolysis in cardiac arrest].

    PubMed

    Ruiz Bailén, M; Rucabado Aguilar, L; Morante Valle, A; Castillo Rivera, A

    2006-03-01

    Both acute myocardial infarction and pulmonary thromboembolism are responsible for a great number of cardiac arrests. Both present high rates of mortality. Thrombolysis has proved to be an effective treatment for acute myocardial infarction and pulmonary thromboembolism with shock. It would be worth considering whether thrombolysis could be effective and safe during or after cardiopulmonary resuscitation (CPR). Unfortunately, too few clinical studies presenting sufficient scientific data exist in order to respond adequately to this question. However, most studies they show that thrombolysis applied during and after CPR is a therapeutic option that is not associated with greater risk of serious hemorrhaging and could possibly have beneficial effects. On the other hand, experimental data exists which show that thrombolytics can attenuate neurological damage produced after CPR. Nevertheless, clinical trials would be necessary in order to adequately establish the effectiveness and safety of thrombolysis in patients who require CPR.

  14. Cardiac action potential imaging

    NASA Astrophysics Data System (ADS)

    Tian, Qinghai; Lipp, Peter; Kaestner, Lars

    2013-06-01

    Action potentials in cardiac myocytes have durations in the order of magnitude of 100 milliseconds. In biomedical investigations the documentation of the occurrence of action potentials is often not sufficient, but a recording of the shape of an action potential allows a functional estimation of several molecular players. Therefore a temporal resolution of around 500 images per second is compulsory. In the past such measurements have been performed with photometric approaches limiting the measurement to one cell at a time. In contrast, imaging allows reading out several cells at a time with additional spatial information. Recent developments in camera technologies allow the acquisition with the required speed and sensitivity. We performed action potential imaging on isolated adult cardiomyocytes of guinea pigs utilizing the fluorescent membrane potential sensor di-8-ANEPPS and latest electron-multiplication CCD as well as scientific CMOS cameras of several manufacturers. Furthermore, we characterized the signal to noise ratio of action potential signals of varying sets of cameras, dye concentrations and objective lenses. We ensured that di-8-ANEPPS itself did not alter action potentials by avoiding concentrations above 5 μM. Based on these results we can conclude that imaging is a reliable method to read out action potentials. Compared to conventional current-clamp experiments, this optical approach allows a much higher throughput and due to its contact free concept leaving the cell to a much higher degree undisturbed. Action potential imaging based on isolated adult cardiomyocytes can be utilized in pharmacological cardiac safety screens bearing numerous advantages over approaches based on heterologous expression of hERG channels in cell lines.

  15. Trends in Cardiac Pacemaker Batteries

    PubMed Central

    Mallela, Venkateswara Sarma; Ilankumaran, V; Rao, N.Srinivasa

    2004-01-01

    Batteries used in Implantable cardiac pacemakers-present unique challenges to their developers and manufacturers in terms of high levels of safety and reliability. In addition, the batteries must have longevity to avoid frequent replacements. Technological advances in leads/electrodes have reduced energy requirements by two orders of magnitude. Micro-electronics advances sharply reduce internal current drain concurrently decreasing size and increasing functionality, reliability, and longevity. It is reported that about 600,000 pacemakers are implanted each year worldwide and the total number of people with various types of implanted pacemaker has already crossed 3 million. A cardiac pacemaker uses half of its battery power for cardiac stimulation and the other half for housekeeping tasks such as monitoring and data logging. The first implanted cardiac pacemaker used nickel-cadmium rechargeable battery, later on zinc-mercury battery was developed and used which lasted for over 2 years. Lithium iodine battery invented and used by Wilson Greatbatch and his team in 1972 made the real impact to implantable cardiac pacemakers. This battery lasts for about 10 years and even today is the power source for many manufacturers of cardiac pacemakers. This paper briefly reviews various developments of battery technologies since the inception of cardiac pacemaker and presents the alternative to lithium iodine battery for the near future. PMID:16943934

  16. Spirituality and Autonomic Cardiac Control

    PubMed Central

    Berntson, Gary G.; Norman, Greg J.; Hawkley, Louise C.; Cacioppo, John T.

    2009-01-01

    Background Spirituality has been suggested to be associated with positive health, but potential biological mediators have not been well characterized. Purpose and Methods The present study examined, in a population based sample of middle-aged and older adults, the potential relationship between spirituality and patterns of cardiac autonomic control, which may have health significance. Measures of parasympathetic (high-frequency heart rate variability) and sympathetic (pre-ejection period) cardiac control were obtained from a representative sample of 229 participants. Participants completed questionnaires to assess spirituality (closeness to and satisfactory relation with God). Personality, demographic, anthropometric, health behavior, and health status information was also obtained. A series of multivariate regression models was used to examine the relations between spirituality, the autonomic measures, and two derived indexes-- cardiac autonomic balance (CAB, reflecting parasympathetic to sympathetic balance) and cardiac autonomic regulation (CAR, reflecting total autonomic control). Results Spirituality, net of demographics or other variables, was found to be associated with enhanced parasympathetic as well as sympathetic cardiac control (yielding a higher CAR); but was not associated with CAB. Although the number of cases was small (N=11), both spirituality and CAR were significant negative predictors of the prior occurrence of a myocardial infarction. Conclusions In a population based sample, spirituality appears to be associated with a specific pattern of cardiac autonomic regulation, characterized by a high level of cardiac autonomic control, irrespective of the relative contribution of the two autonomic branches. This pattern of autonomic control may have health significance. PMID:18357497

  17. Evaluation of cardiac emboli source

    PubMed Central

    Michels, M.; Meijboom, F.J.; ten Cate, F.J.

    2005-01-01

    Background Evaluating the source of cardiac embolism is one of the most frequent reasons for cardiac consultation. Methods In 2003, 99 patients were referred for the evaluation of the source of cardiac emboli. Evaluation included history, physical examination, ECG, transoesophageal echocardiography (TOE) with contrast and 24-hour Holter electrocardiography. Results Altogether, 58 men and 41 women were studied. In 32 patients a possible source of the cardiac emboli was found. Two patients were in atrial fibrillation. Of the patients, 16 had a patent foramen ovale (PFO) and six patients a PFO and atrial septum aneurysm (ASA). Two patients had a thrombus in the left atrial appendage and 14 had severe atherosclerosis in the aortic arch. In eight patients we found two possible cardiac sources of embolism. 24-hour Holter recording did not detect any emboligenic arrhythmias. Conclusion A possible cardiac source of embolism was found in 32% of the patients referred. TOE is the ideal tool to visualise the interatrial septum, left atrial appendage and aortic arch. We advise performing a TOE with contrast in young stroke patients and in older patients with a stroke likely to be caused by an embolism of cardiac origin. 24-hour Holter recording did not detect any emboligenic arrhythmias and should only be done in selected cases. ImagesFigure 1Figure 2 PMID:25696441

  18. Trends in cardiac pacemaker batteries.

    PubMed

    Mallela, Venkateswara Sarma; Ilankumaran, V; Rao, N Srinivasa

    2004-10-01

    Batteries used in Implantable cardiac pacemakers-present unique challenges to their developers and manufacturers in terms of high levels of safety and reliability. In addition, the batteries must have longevity to avoid frequent replacements. Technological advances in leads/electrodes have reduced energy requirements by two orders of magnitude. Micro-electronics advances sharply reduce internal current drain concurrently decreasing size and increasing functionality, reliability, and longevity. It is reported that about 600,000 pacemakers are implanted each year worldwide and the total number of people with various types of implanted pacemaker has already crossed 3 million. A cardiac pacemaker uses half of its battery power for cardiac stimulation and the other half for housekeeping tasks such as monitoring and data logging. The first implanted cardiac pacemaker used nickel-cadmium rechargeable battery, later on zinc-mercury battery was developed and used which lasted for over 2 years. Lithium iodine battery invented and used by Wilson Greatbatch and his team in 1972 made the real impact to implantable cardiac pacemakers. This battery lasts for about 10 years and even today is the power source for many manufacturers of cardiac pacemakers. This paper briefly reviews various developments of battery technologies since the inception of cardiac pacemaker and presents the alternative to lithium iodine battery for the near future.

  19. Cardiac cone-beam CT

    SciTech Connect

    Manzke, Robert . E-mail: robert.manzke@philips.com

    2005-10-15

    This doctoral thesis addresses imaging of the heart with retrospectively gated helical cone-beam computed tomography (CT). A thorough review of the CT reconstruction literature is presented in combination with a historic overview of cardiac CT imaging and a brief introduction to other cardiac imaging modalities. The thesis includes a comprehensive chapter about the theory of CT reconstruction, familiarizing the reader with the problem of cone-beam reconstruction. The anatomic and dynamic properties of the heart are outlined and techniques to derive the gating information are reviewed. With the extended cardiac reconstruction (ECR) framework, a new approach is presented for the heart-rate-adaptive gated helical cardiac cone-beam CT reconstruction. Reconstruction assessment criteria such as the temporal resolution, the homogeneity in terms of the cardiac phase, and the smoothness at cycle-to-cycle transitions are developed. Several reconstruction optimization approaches are described: An approach for the heart-rate-adaptive optimization of the temporal resolution is presented. Streak artifacts at cycle-to-cycle transitions can be minimized by using an improved cardiac weighting scheme. The optimal quiescent cardiac phase for the reconstruction can be determined automatically with the motion map technique. Results for all optimization procedures applied to ECR are presented and discussed based on patient and phantom data. The ECR algorithm is analyzed for larger detector arrays of future cone-beam systems throughout an extensive simulation study based on a four-dimensional cardiac CT phantom. The results of the scientific work are summarized and an outlook proposing future directions is given. The presented thesis is available for public download at www.cardiac-ct.net.

  20. Pharmacology of cardiac potassium channels.

    PubMed

    Tamargo, Juan; Caballero, Ricardo; Gómez, Ricardo; Valenzuela, Carmen; Delpón, Eva

    2004-04-01

    Cardiac K+ channels are membrane-spanning proteins that allow the passive movement of K+ ions across the cell membrane along its electrochemical gradient. They regulate the resting membrane potential, the frequency of pacemaker cells and the shape and duration of the cardiac action potential. Additionally, they have been recognized as potential targets for the actions of neurotransmitters and hormones and class III antiarrhythmic drugs that prolong the action potential duration (APD) and refractoriness and have been found effective to prevent/suppress cardiac arrhythmias. In the human heart, K+ channels include voltage-gated channels, such as the rapidly activating and inactivating transient outward current (Ito1), the ultrarapid (IKur), rapid (IKr) and slow (IKs) components of the delayed rectifier current and the inward rectifier current (IK1), the ligand-gated channels, including the adenosine triphosphate-sensitive (IKATP) and the acetylcholine-activated (IKAch) currents and the leak channels. Changes in the expression of K+ channels explain the regional variations in the morphology and duration of the cardiac action potential among different cardiac regions and are influenced by heart rate, intracellular signalling pathways, drugs and cardiovascular disorders. A progressive number of cardiac and noncardiac drugs block cardiac K+ channels and can cause a marked prolongation of the action potential duration (i.e. an acquired long QT syndrome, LQTS) and a distinct polymorphic ventricular tachycardia termed torsades de pointes. In addition, mutations in the genes encoding IKr (KCNH2/KCNE2) and IKs (KCNQ1/KCNE1) channels have been identified in some types of the congenital long QT syndrome. This review concentrates on the function, molecular determinants, regulation and, particularly, on the mechanism of action of drugs modulating the K+ channels present in the sarcolemma of human cardiac myocytes that contribute to the different phases of the cardiac action

  1. Snf1-related kinase improves cardiac mitochondrial efficiency and decreases mitochondrial uncoupling

    PubMed Central

    Rines, Amy K.; Chang, Hsiang-Chun; Wu, Rongxue; Sato, Tatsuya; Khechaduri, Arineh; Kouzu, Hidemichi; Shapiro, Jason; Shang, Meng; Burke, Michael A.; Jiang, Xinghang; Chen, Chunlei; Rawlings, Tenley A.; Lopaschuk, Gary D.; Schumacker, Paul T.; Abel, E. Dale; Ardehali, Hossein

    2017-01-01

    Ischaemic heart disease limits oxygen and metabolic substrate availability to the heart, resulting in tissue death. Here, we demonstrate that the AMP-activated protein kinase (AMPK)-related protein Snf1-related kinase (SNRK) decreases cardiac metabolic substrate usage and mitochondrial uncoupling, and protects against ischaemia/reperfusion. Hearts from transgenic mice overexpressing SNRK have decreased glucose and palmitate metabolism and oxygen consumption, but maintained power and function. They also exhibit decreased uncoupling protein 3 (UCP3) and mitochondrial uncoupling. Conversely, Snrk knockout mouse hearts have increased glucose and palmitate oxidation and UCP3. SNRK knockdown in cardiac cells decreases mitochondrial efficiency, which is abolished with UCP3 knockdown. We show that Tribbles homologue 3 (Trib3) binds to SNRK, and downregulates UCP3 through PPARα. Finally, SNRK is increased in cardiomyopathy patients, and SNRK reduces infarct size after ischaemia/reperfusion. SNRK also decreases cardiac cell death in a UCP3-dependent manner. Our results suggest that SNRK improves cardiac mitochondrial efficiency and ischaemic protection. PMID:28117339

  2. Acupuncture therapy related cardiac injury.

    PubMed

    Li, Xue-feng; Wang, Xian

    2013-12-01

    Cardiac injury is the most serious adverse event in acupuncture therapy. The causes include needling chest points near the heart, the cardiac enlargement and pericardial effusion that will enlarge the projected area on the body surface and make the proper depth of needling shorter, and the incorrect needling method of the points. Therefore, acupuncture practitioners must be familiar with the points of the heart projected area on the chest and the correct needling methods in order to reduce the risk of acupuncture therapy related cardiac injury.

  3. Cardiac Involvement in Ankylosing Spondylitis

    PubMed Central

    Ozkan, Yasemin

    2016-01-01

    Ankylosing spondylitis is one of the subgroup of diseases called “seronegative spondyloarthropathy”. Frequently, it affects the vertebral colon and sacroiliac joint primarily and affects the peripheral joints less often. This chronic, inflammatory and rheumatic disease can also affect the extraarticular regions of the body. The extraarticular affections can be ophthalmologic, cardiac, pulmonary or neurologic. The cardiac affection can be 2-10% in all patients. Cardiac complications such as left ventricular dysfunction, aortitis, aortic regurgitation, pericarditis and cardiomegaly are reviewed. PMID:27222669

  4. Normal cardiac function in mice with supraphysiological cardiac creatine levels.

    PubMed

    Santacruz, Lucia; Hernandez, Alejandro; Nienaber, Jeffrey; Mishra, Rajashree; Pinilla, Miguel; Burchette, James; Mao, Lan; Rockman, Howard A; Jacobs, Danny O

    2014-02-01

    Creatine and phosphocreatine levels are decreased in heart failure, and reductions in myocellular phosphocreatine levels predict the severity of the disease and portend adverse outcomes. Previous studies of transgenic mouse models with increased creatine content higher than two times baseline showed the development of heart failure and shortened lifespan. Given phosphocreatine's role in buffering ATP content, we tested the hypothesis whether elevated cardiac creatine content would alter cardiac function under normal physiological conditions. Here, we report the creation of transgenic mice that overexpress the human creatine transporter (CrT) in cardiac muscle under the control of the α-myosin heavy chain promoter. Cardiac transgene expression was quantified by qRT-PCR, and human CrT protein expression was documented on Western blots and immunohistochemistry using a specific anti-CrT antibody. High-energy phosphate metabolites and cardiac function were measured in transgenic animals and compared with age-matched, wild-type controls. Adult transgenic animals showed increases of 5.7- and 4.7-fold in the content of creatine and free ADP, respectively. Phosphocreatine and ATP levels were two times as high in young transgenic animals but declined to control levels by the time the animals reached 8 wk of age. Transgenic mice appeared to be healthy and had normal life spans. Cardiac morphometry, conscious echocardiography, and pressure-volume loop studies demonstrated mild hypertrophy but normal function. Based on our characterization of the human CrT protein expression, creatine and phosphocreatine content, and cardiac morphometry and function, these transgenic mice provide an in vivo model for examining the therapeutic value of elevated creatine content for cardiac pathologies.

  5. The Scaffold Protein Muscle A-Kinase Anchoring Protein β Orchestrates Cardiac Myocyte Hypertrophic Signaling Required for the Development of Heart Failure

    PubMed Central

    Kritzer, Michael D.; Li, Jinliang; Passariello, Catherine L.; Gayanilo, Marjorie; Thakur, Hrishikesh; Dayan, Joseph; Dodge-Kafka, Kimberly; Kapiloff, Michael S.

    2014-01-01

    Background Cardiac myocyte hypertrophy is regulated by an extensive intracellular signal transduction network. In vitro evidence suggests that the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) serves as a nodal organizer of hypertrophic signaling. However, the relevance of mAKAPβ signalosomes to pathological remodeling and heart failure in vivo remains unknown. Methods and Results Using conditional, cardiac myocyte–specific gene deletion, we now demonstrate that mAKAPβ expression in mice is important for the cardiac hypertrophy induced by pressure overload and catecholamine toxicity. mAKAPβ targeting prevented the development of heart failure associated with long-term transverse aortic constriction, conferring a survival benefit. In contrast to 29% of control mice (n=24), only 6% of mAKAPβ knockout mice (n=31) died in the 16 weeks of pressure overload (P=0.02). Accordingly, mAKAPβ knockout inhibited myocardial apoptosis and the development of interstitial fibrosis, left atrial hypertrophy, and pulmonary edema. This improvement in cardiac status correlated with the attenuated activation of signaling pathways coordinated by the mAKAPβ scaffold, including the decreased phosphorylation of protein kinase D1 and histone deacetylase 4 that we reveal to participate in a new mAKAP signaling module. Furthermore, mAKAPβ knockout inhibited pathological gene expression directed by myocyte-enhancer factor-2 and nuclear factor of activated T-cell transcription factors that associate with the scaffold. Conclusions mAKAPβ orchestrates signaling that regulates pathological cardiac remodeling in mice. Targeting of the underlying physical architecture of signaling networks, including mAKAPβ signalosome formation, may constitute an effective therapeutic strategy for the prevention and treatment of pathological remodeling and heart failure. PMID:24812305

  6. Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

    PubMed Central

    Zhang, Xiaowei; Bearer, Elaine L.; Boulat, Benoit; Hall, F. Scott; Uhl, George R.; Jacobs, Russell E.

    2010-01-01

    The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn2+ into the prefrontal cortex indicated that DAT KO mice have a truncated Mn2+ distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn2+ transport into more posterior midbrain nuclei and contralateral mesolimbic structures at

  7. Use of cardiac biomarkers in neonatology.

    PubMed

    Vijlbrief, Daniel C; Benders, Manon J N L; Kemperman, Hans; van Bel, Frank; de Vries, Willem B

    2012-10-01

    Cardiac biomarkers are used to identify cardiac disease in term and preterm infants. This review discusses the roles of natriuretic peptides and cardiac troponins. Natriuretic peptide levels are elevated during atrial strain (atrial natriuretic peptide (ANP)) or ventricular strain (B-type natriuretic peptide (BNP)). These markers correspond well with cardiac function and can be used to identify cardiac disease. Cardiac troponins are used to assess cardiomyocyte compromise. Affected cardiomyocytes release troponin into the bloodstream, resulting in elevated levels of cardiac troponin. Cardiac biomarkers are being increasingly incorporated into clinical trials as indicators of myocardial strain. Furthermore, cardiac biomarkers can possibly be used to guide therapy and improve outcome. Natriuretic peptides and cardiac troponins are potential tools in the diagnosis and treatment of neonatal disease that is complicated by circulatory compromise. However, clear reference ranges need to be set and validation needs to be carried out in a population of interest.

  8. A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels.

    PubMed

    Furtado, Milena B; Wilmanns, Julia C; Chandran, Anjana; Tonta, Mary; Biben, Christine; Eichenlaub, Michael; Coleman, Harold A; Berger, Silke; Bouveret, Romaric; Singh, Reena; Harvey, Richard P; Ramialison, Mirana; Pearson, James T; Parkington, Helena C; Rosenthal, Nadia A; Costa, Mauro W

    2016-01-01

    Nkx2-5 is one of the master regulators of cardiac development, homeostasis and disease. This transcription factor has been previously associated with a suite of cardiac congenital malformations and impairment of electrical activity. When disease causative mutations in transcription factors are considered, NKX2-5 gene dysfunction is the most common abnormality found in patients. Here we describe a novel mouse model and subsequent implications of Nkx2-5 loss for aspects of myocardial electrical activity. In this work we have engineered a new Nkx2-5 conditional knockout mouse in which flox sites flank the entire Nkx2-5 locus, and validated this line for the study of heart development, differentiation and disease using a full deletion strategy. While our homozygous knockout mice show typical embryonic malformations previously described for the lack of the Nkx2-5 gene, hearts of heterozygous adult mice show moderate morphological and functional abnormalities that are sufficient to sustain blood supply demands under homeostatic conditions. This study further reveals intriguing aspects of Nkx2-5 function in the control of cardiac electrical activity. Using a combination of mouse genetics, biochemistry, molecular and cell biology, we demonstrate that Nkx2-5 regulates the gene encoding Kcnh2 channel and others, shedding light on potential mechanisms generating electrical abnormalities observed in patients bearing NKX2-5 dysfunction and opening opportunities to the study of novel therapeutic targets for anti-arrhythmogenic therapies.

  9. Radiation from Cardiac Imaging Tests

    MedlinePlus

    ... thought you would like to see the Circulation web site. Your Personal Message Send Message Share on Social Media Radiation From Cardiac Imaging Tests Andrew J. Einstein Circulation. 2013; 127: e495-e497 , ...

  10. Mitochondrial Dysfunction in Cardiac Ageing

    PubMed Central

    Tocchi, Autumn; Quarles, Ellen K.; Basisty, Nathan; Gitari, Lemuel; Rabinovitch, Peter S.

    2015-01-01

    Cardiovascular diseases are the leading cause of death in most developed nations. While it has received the least public attention, aging is the dominant risk factor for developing cardiovascular diseases, as the prevalence of cardiovascular diseases increases dramatically with increasing age. Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellular and molecular changes. Mitochondria play a great role in these processes, as cardiac function is an energetically demanding process. In this review, we examine mitochondrial dysfunction in cardiac aging. Recent research has demonstrated that mitochondrial dysfunction can disrupt morphology, signaling pathways, and protein interactions; conversely, mitochondrial homeostasis is maintained by mechanisms that include fission/fusion, autophagy, and unfolded protein responses. Finally, we describe some of the recent findings in mitochondrial targeted treatments to help meet the challenges of mitochondrial dysfunction in aging. PMID:26191650

  11. Knockout of Endothelial Cell-Derived Endothelin-1 Attenuates Skin Fibrosis but Accelerates Cutaneous Wound Healing

    PubMed Central

    Makino, Katsunari; Jinnin, Masatoshi; Aoi, Jun; Kajihara, Ikko; Makino, Takamitsu; Fukushima, Satoshi; Sakai, Keisuke; Nakayama, Kazuhiko; Emoto, Noriaki; Yanagisawa, Masashi; Ihn, Hironobu

    2014-01-01

    Endothelin (ET)-1 is known for the most potent vasoconstrictive peptide that is released mainly from endothelial cells. Several studies have reported ET-1 signaling is involved in the process of wound healing or fibrosis as well as vasodilation. However, little is known about the role of ET-1 in these processes. To clarify its mechanism, we compared skin fibrogenesis and wound repair between vascular endothelial cell-specific ET-1 knockout mice and their wild-type littermates. Bleomycin-injected fibrotic skin of the knockout mice showed significantly decreased skin thickness and collagen content compared to that of wild-type mice, indicating that bleomycin-induced skin fibrosis is attenuated in the knockout mice. The mRNA levels of transforming growth factor (TGF)-β were decreased in the bleomycin-treated skin of ET-1 knockout mice. On the other hand, skin wound healing was accelerated in ET-1 knockout mice, which was indicated by earlier granulation tissue reduction and re-epithelialization in these mice. The mRNA levels of TGF-β, tumor necrosis factor (TNF)-α and connective tissue growth factor (CTGF) were reduced in the wound of ET-1 knockout mice. In endothelial ET-1 knockout mouse, the expression of TNF-α, CTGF and TGF-β was down-regulated. Bosentan, an antagonist of dual ET receptors, is known to attenuate skin fibrosis and accelerate wound healing in systemic sclerosis, and such contradictory effect may be mediated by above molecules. The endothelial cell-derived ET-1 is the potent therapeutic target in fibrosis or wound healing, and investigations of the overall regulatory mechanisms of these pathological conditions by ET-1 may lead to a new therapeutic approach. PMID:24853267

  12. Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.

    PubMed

    Walentiny, D Matthew; Vann, Robert E; Wiley, Jenny L

    2015-06-01

    A number of studies have examined the ability of the endogenous cannabinoid anandamide to elicit Δ(9)-tetrahydrocannabinol (THC)-like subjective effects, as modeled through the THC discrimination paradigm. In the present study, we compared transgenic mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for anandamide catabolism, to wildtype counterparts in a THC discrimination procedure. THC (5.6 mg/kg) served as a discriminative stimulus in both genotypes, with similar THC dose-response curves between groups. Anandamide fully substituted for THC in FAAH knockout, but not wildtype, mice. Conversely, the metabolically stable anandamide analog O-1812 fully substituted in both groups, but was more potent in knockouts. The CB1 receptor antagonist rimonabant dose-dependently attenuated THC generalization in both groups and anandamide substitution in FAAH knockouts. Pharmacological inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), with JZL184 resulted in full substitution for THC in FAAH knockout mice and nearly full substitution in wildtypes. Quantification of brain endocannabinoid levels revealed expected elevations in anandamide in FAAH knockout mice compared to wildtypes and equipotent dose-dependent elevations in 2-AG following JZL184 administration. Dual inhibition of FAAH and MAGL with JZL195 resulted in roughly equipotent increases in THC-appropriate responding in both groups. While the notable similarity in THC's discriminative stimulus effects across genotype suggests that the increased baseline brain anandamide levels (as seen in FAAH knockout mice) do not alter THC's subjective effects, FAAH knockout mice are more sensitive to the THC-like effects of pharmacologically induced increases in anandamide and MAGL inhibition (e.g., JZL184).

  13. Cardiac transplantation in Friedreich ataxia.

    PubMed

    Yoon, Grace; Soman, Teesta; Wilson, Judith; George, Kristen; Mital, Seema; Dipchand, Anne I; McCabe, Jane; Logan, William; Kantor, Paul

    2012-09-01

    In this article, we describe a 14-year-old boy with a confirmed diagnosis of Friedreich ataxia who underwent cardiac transplantation for left ventricular failure secondary to dilated cardiomyopathy with restrictive physiology. His neurological status prior to transplantation reflected early signs of neurological disease, with evidence of dysarthria, weakness, mild gait impairment, and limb ataxia. We review the ethical issues considered during the process leading to the decision to offer cardiac transplantation.

  14. Cardiac output after burn injury.

    PubMed Central

    Porter, J. M.; Shakespeare, P. G.

    1984-01-01

    Cardiac output after burn injury has been measured by the non-invasive method of impedance plethysmography. An initial study of 143 normal subjects was undertaken in order to investigate variations in cardiac output with age. Fifteen patients were monitored during resuscitation after extensive burns. Fourteen patients showed a depression of stroke volume below the lower limits of the normal range, derived from the initial study on normal people. PMID:6691694

  15. Diuretics in cardiac edema--1969.

    PubMed

    Shanoff, H M

    1969-10-04

    New and powerful diuretics have made it possible for the physician to control cardiac edema in most patients. At the same time their potentially dangerous side effects make it mandatory for the physician to be knowledgeable and judicious in their use. The appreciation of a few simplified facts about cardiac edema and renal reabsorption of sodium makes the clinical pharmacology of the diuretics much easier to understand, remember and apply.

  16. Cardiac effects of noncardiac neoplasms

    SciTech Connect

    Schoen, F.J.; Berger, B.M.; Guerina, N.G.

    1984-11-01

    Clinically significant cardiovascular abnormalities may occur as secondary manifestations of noncardiac neoplasms. The principal cardiac effects of noncardiac tumors include the direct results of metastases to the heart or lungs, the indirect effects of circulating tumor products (causing nonbacterial thrombotic endocarditis, myeloma-associated amyloidosis, pheochromocytoma-associated cardiac hypertrophy and myofibrillar degeneration, and carcinoid heart disease), and the undesired cardiotoxicities of chemotherapy and radiotherapy. 89 references.

  17. Cardiac Regeneration and Stem Cells

    PubMed Central

    Zhang, Yiqiang; Mignone, John; MacLellan, W. Robb

    2015-01-01

    After decades of believing the heart loses the ability to regenerate soon after birth, numerous studies are now reporting that the adult heart may indeed be capable of regeneration, although the magnitude of new cardiac myocyte formation varies greatly. While this debate has energized the field of cardiac regeneration and led to a dramatic increase in our understanding of cardiac growth and repair, it has left much confusion in the field as to the prospects of regenerating the heart. Studies applying modern techniques of genetic lineage tracing and carbon-14 dating have begun to establish limits on the amount of endogenous regeneration after cardiac injury, but the underlying cellular mechanisms of this regeneration remained unclear. These same studies have also revealed an astonishing capacity for cardiac repair early in life that is largely lost with adult differentiation and maturation. Regardless, this renewed focus on cardiac regeneration as a therapeutic goal holds great promise as a novel strategy to address the leading cause of death in the developed world. PMID:26269526

  18. Exploring cardiac biophysical properties.

    PubMed

    Ait Mou, Younss; Bollensdorff, Christian; Cazorla, Olivier; Magdi, Yacoub; de Tombe, Pieter P

    2015-01-01

    The heart is subject to multiple sources of stress. To maintain its normal function, and successfully overcome these stresses, heart muscle is equipped with fine-tuned regulatory mechanisms. Some of these mechanisms are inherent within the myocardium itself and are known as intrinsic mechanisms. Over a century ago, Otto Frank and Ernest Starling described an intrinsic mechanism by which the heart, even ex vivo, regulates its function on a beat-to-beat basis. According to this phenomenon, the higher the ventricular filling is, the bigger the stroke volume. Thus, the Frank-Starling law establishes a direct relationship between the diastolic and systolic function of the heart. To observe this biophysical phenomenon and to investigate it, technologic development has been a pre-requisite to scientific knowledge. It allowed for example to observe, at the cellular level, a Frank-Starling like mechanism and has been termed: Length Dependent Activation (LDA). In this review, we summarize some experimental systems that have been developed and are currently still in use to investigate cardiac biophysical properties from the whole heart down to the single myofibril. As a scientific support, investigation of the Frank-Starling mechanism will be used as a case study.

  19. Exploring cardiac biophysical properties

    PubMed Central

    Mou, Younss Ait; Bollensdorff, Christian; Cazorla, Olivier; Magdi, Yacoub; de Tombe, Pieter P.

    2015-01-01

    The heart is subject to multiple sources of stress. To maintain its normal function, and successfully overcome these stresses, heart muscle is equipped with fine-tuned regulatory mechanisms. Some of these mechanisms are inherent within the myocardium itself and are known as intrinsic mechanisms. Over a century ago, Otto Frank and Ernest Starling described an intrinsic mechanism by which the heart, even ex vivo, regulates its function on a beat-to-beat basis. According to this phenomenon, the higher the ventricular filling is, the bigger the stroke volume. Thus, the Frank-Starling law establishes a direct relationship between the diastolic and systolic function of the heart. To observe this biophysical phenomenon and to investigate it, technologic development has been a pre-requisite to scientific knowledge. It allowed for example to observe, at the cellular level, a Frank-Starling like mechanism and has been termed: Length Dependent Activation (LDA). In this review, we summarize some experimental systems that have been developed and are currently still in use to investigate cardiac biophysical properties from the whole heart down to the single myofibril. As a scientific support, investigation of the Frank-Starling mechanism will be used as a case study. PMID:26779498

  20. Cardiac Imaging System

    NASA Technical Reports Server (NTRS)

    1990-01-01

    Although not available to all patients with narrowed arteries, balloon angioplasty has expanded dramatically since its introduction with an estimated further growth to 562,000 procedures in the U.S. alone by 1992. Growth has fueled demand for higher quality imaging systems that allow the cardiologist to be more accurate and increase the chances of a successful procedure. A major advance is the Digital Cardiac Imaging (DCI) System designed by Philips Medical Systems International, Best, The Netherlands and marketed in the U.S. by Philips Medical Systems North America Company. The key benefit is significantly improved real-time imaging and the ability to employ image enhancement techniques to bring out added details. Using a cordless control unit, the cardiologist can manipulate images to make immediate assessment, compare live x-ray and roadmap images by placing them side-by-side on monitor screens, or compare pre-procedure and post procedure conditions. The Philips DCI improves the cardiologist's precision by expanding the information available to him.

  1. Knockouts of high-ranking males have limited impact on baboon social networks.

    PubMed

    Franz, Mathias; Altmann, Jeanne; Alberts, Susan C

    Social network structures can crucially impact complex social processes such as collective behaviour or the transmission of information and diseases. However, currently it is poorly understood how social networks change over time. Previous studies on primates suggest that `knockouts' (due to death or dispersal) of high-ranking individuals might be important drivers for structural changes in animal social networks. Here we test this hypothesis using long-term data on a natural population of baboons, examining the effects of 29 natural knockouts of alpha or beta males on adult female social networks. We investigated whether and how knockouts affected (1) changes in grooming and association rates among adult females, and (2) changes in mean degree and global clustering coefficient in these networks. The only significant effect that we found was a decrease in mean degree in grooming networks in the first month after knockouts, but this decrease was rather small, and grooming networks rebounded to baseline levels by the second month after knockouts. Taken together our results indicate that the removal of high-ranking males has only limited or no lasting effects on social networks of adult female baboons. This finding calls into question the hypothesis that the removal of high-ranking individuals has a destabilizing effect on social network structures in social animals.

  2. Glutamate transporter type 3 knockout leads to decreased heart rate possibly via parasympathetic mechanism.

    PubMed

    Deng, Jiao; Li, Jiejie; Li, Liaoliao; Feng, Chenzhuo; Xiong, Lize; Zuo, Zhiyi

    2013-08-01

    Parasympathetic tone is a dominant neural regulator for basal heart rate. Glutamate transporters (EAAT) via their glutamate uptake functions regulate glutamate neurotransmission in the central nervous system. We showed that EAAT type 3 (EAAT3) knockout mice had a slower heart rate than wild-type mice when they were anesthetized. We design this study to determine whether non-anesthetized EAAT3 knockout mice have a slower heart rate and, if so, what may be the mechanism for this effect. Young adult EAAT3 knockout mice had slower heart rates than those of their littermate wild-type mice no matter whether they were awake or anesthetized. This difference was abolished by atropine, a parasympatholytic drug. Carbamylcholine chloride, a parasympathomimetic drug, equally effectively reduced the heart rates of wild-type and EAAT3 knockout mice. Positive immunostaining for EAAT3 was found in the area of nuclei deriving fibers for vagus nerve. There was no positive staining for the EAATs in the sinoatrial node. These results suggest that EAAT3 knockout mice have a slower heart rate at rest. This effect may be caused by an increased parasympathetic tone possibly due to increased glutamate neurotransmission in the central nervous system. These findings indicate that regulation of heart rate, a vital sign, is one of the EAAT biological functions.

  3. Disease phenotype of a ferret CFTR-knockout model of cystic fibrosis

    PubMed Central

    Sun, Xingshen; Sui, Hongshu; Fisher, John T.; Yan, Ziying; Liu, Xiaoming; Cho, Hyung-Ju; Joo, Nam Soo; Zhang, Yulong; Zhou, Weihong; Yi, Yaling; Kinyon, Joann M.; Lei-Butters, Diana C.; Griffin, Michelle A.; Naumann, Paul; Luo, Meihui; Ascher, Jill; Wang, Kai; Frana, Timothy; Wine, Jeffrey J.; Meyerholz, David K.; Engelhardt, John F.

    2010-01-01

    Cystic fibrosis (CF) is a recessive disease that affects multiple organs. It is caused by mutations in CFTR. Animal modeling of this disease has been challenging, with species- and strain-specific differences in organ biology and CFTR function influencing the emergence of disease pathology. Here, we report the phenotype of a CFTR-knockout ferret model of CF. Neonatal CFTR-knockout ferrets demonstrated many of the characteristics of human CF disease, including defective airway chloride transport and submucosal gland fluid secretion; variably penetrant meconium ileus (MI); pancreatic, liver, and vas deferens disease; and a predisposition to lung infection in the early postnatal period. Severe malabsorption by the gastrointestinal (GI) tract was the primary cause of death in CFTR-knockout kits that escaped MI. Elevated liver function tests in CFTR-knockout kits were corrected by oral administration of ursodeoxycholic acid, and the addition of an oral proton-pump inhibitor improved weight gain and survival. To overcome the limitations imposed by the severe intestinal phenotype, we cloned 4 gut-corrected transgenic CFTR-knockout kits that expressed ferret CFTR specifically in the intestine. One clone passed feces normally and demonstrated no detectable ferret CFTR expression in the lung or liver. The animals described in this study are likely to be useful tools for dissecting CF disease pathogenesis and developing treatments. PMID:20739752

  4. The knockout of secretin in cerebellar Purkinje cells impairs mouse motor coordination and motor learning.

    PubMed

    Zhang, Li; Chung, Sookja Kim; Chow, Billy Kwok Chong

    2014-05-01

    Secretin (SCT) was first considered to be a gut hormone regulating gastrointestinal functions when discovered. Recently, however, central actions of SCT have drawn intense research interest and are supported by the broad distribution of SCT in specific neuronal populations and by in vivo physiological studies regarding its role in water homeostasis and food intake. The direct action of SCT on a central neuron was first discovered in cerebellar Purkinje cells in which SCT from cerebellar Purkinje cells was found to potentiate GABAergic inhibitory transmission from presynaptic basket cells. Because Purkinje neurons have a major role in motor coordination and learning functions, we hypothesize a behavioral modulatory function for SCT. In this study, we successfully generated a mouse model in which the SCT gene was deleted specifically in Purkinje cells. This mouse line was tested together with SCT knockout and SCT receptor knockout mice in a full battery of behavioral tasks. We found that the knockout of SCT in Purkinje neurons did not affect general motor ability or the anxiety level in open field tests. However, knockout mice did exhibit impairments in neuromuscular strength, motor coordination, and motor learning abilities, as shown by wire hanging, vertical climbing, and rotarod tests. In addition, SCT knockout in Purkinje cells possibly led to the delayed development of motor neurons, as supported by the later occurrence of key neural reflexes. In summary, our data suggest a role in motor coordination and motor learning for SCT expressed in cerebellar Purkinje cells.

  5. Gene Knockout Identification Using an Extension of Bees Hill Flux Balance Analysis

    PubMed Central

    Choon, Yee Wen; Mohamad, Mohd Saberi; Deris, Safaai; Chong, Chuii Khim; Omatu, Sigeru; Corchado, Juan Manuel

    2015-01-01

    Microbial strain optimisation for the overproduction of a desired phenotype has been a popular topic in recent years. Gene knockout is a genetic engineering technique that can modify the metabolism of microbial cells to obtain desirable phenotypes. Optimisation algorithms have been developed to identify the effects of gene knockout. However, the complexities of metabolic networks have made the process of identifying the effects of genetic modification on desirable phenotypes challenging. Furthermore, a vast number of reactions in cellular metabolism often lead to a combinatorial problem in obtaining optimal gene knockout. The computational time increases exponentially as the size of the problem increases. This work reports an extension of Bees Hill Flux Balance Analysis (BHFBA) to identify optimal gene knockouts to maximise the production yield of desired phenotypes while sustaining the growth rate. This proposed method functions by integrating OptKnock into BHFBA for validating the results automatically. The results show that the extension of BHFBA is suitable, reliable, and applicable in predicting gene knockout. Through several experiments conducted on Escherichia coli, Bacillus subtilis, and Clostridium thermocellum as model organisms, extension of BHFBA has shown better performance in terms of computational time, stability, growth rate, and production yield of desired phenotypes. PMID:25874200

  6. Effects of morphine on pentobarbital-induced responses in mu-opioid receptor knockout mice.

    PubMed

    Park, Y; Ho, I K; Jang, C G; Tanaka, S; Ma, T; Loh, H H; Ko, K H

    2001-03-15

    Effects of morphine on the potentiation of pentobarbital-induced responses were investigated using mu-opioid receptor knockout mice. The duration of loss of righting reflex, hypothermia, and loss of motor coordination induced by pentobarbital were measured after pretreatment with either morphine or saline. Morphine pretreatment failed to show potentiation of both pentobarbital-induced loss of righting reflex and hypothermia in mu-opioid receptor knockout mice, while it significantly potentiated these responses in the wild-type controls. For motor incoordination test, morphine potentiated pentobarbital-induced motor incoordination in the wild-type mice. However, morphine may have opposite effects in the mu-opioid receptor knockout mice. These results demonstrate that synergism between morphine and pentobarbital is not detected in mu-opioid receptor knockout mice and that potentiation of pentobarbital-induced loss of righting reflex and hypothermia by morphine is mediated through mu-opioid receptor. It was interesting to note that pentobarbital-induced decrease in body temperature was less severe in mu-opioid receptor knockout mice than in wild-type mice.

  7. Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference

    PubMed Central

    Sora, Ichiro; Hall, F. Scott; Andrews, Anne M.; Itokawa, Masanari; Li, Xiao-Fei; Wei, Hong-Bing; Wichems, Christine; Lesch, Klaus-Peter; Murphy, Dennis L.; Uhl, George R.

    2001-01-01

    Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT. However, knockouts of neither DAT, SERT, or NET reduce cocaine reward/reinforcement, leaving substantial uncertainty about cocaine's molecular mechanisms for reward. Conceivably, the molecular bases of cocaine reward might display sufficient redundancy that either DAT or SERT might be able to mediate cocaine reward in the other's absence. To test this hypothesis, we examined double knockout mice with deletions of one or both copies of both the DAT and SERT genes. These mice display viability, weight gain, histologic features, neurochemical parameters, and baseline behavioral features that allow tests of cocaine influences. Mice with even a single wild-type DAT gene copy and no SERT copies retain cocaine reward/reinforcement, as measured by conditioned place-preference testing. However, mice with no DAT and either no or one SERT gene copy display no preference for places where they have previously received cocaine. The serotonin dependence of cocaine reward in DAT knockout mice is thus confirmed by the elimination of cocaine place preference in DAT/SERT double knockout mice. These results provide insights into the brain molecular targets necessary for cocaine reward in knockout mice that develop in their absence and suggest novel strategies for anticocaine medication development. PMID:11320258

  8. ECPR for Refractory Out-Of-Hospital Cardiac Arrest

    ClinicalTrials.gov

    2017-02-22

    Cardiac Arrest; Heart Arrest; Sudden Cardiac Arrest; Cardiopulmonary Arrest; Death, Sudden, Cardiac; Cardiopulmonary Resuscitation; CPR; Extracorporeal Cardiopulmonary Resuscitation; Extracorporeal Membrane Oxygenation

  9. The broken mouse: the role of development, plasticity and environment in the interpretation of phenotypic changes in knockout mice.

    PubMed

    Gingrich, J A; Hen, R

    2000-02-01

    With the advent of gene knockout technology has arisen the problem of how to interpret the resulting phenotypic changes in mice lacking specific genes. This problem is especially relevant when applied to behavioral phenotypes of knockout mice, which are difficult to interpret. Of particular interest are the roles of development and compensatory changes, as well as other factors, such as the influence of the gene knockout on nearby genes, the effect of the genetic background strain, maternal behavioral influences, and pleiotrophy.

  10. MR histology of advanced atherosclerotic lesions of ApoE- knockout mice

    NASA Astrophysics Data System (ADS)

    Naumova, A.; Yarnykh, V.; Ferguson, M.; Rosenfeld, M.; Yuan, C.

    2016-02-01

    The purposes of this study were to examine the feasibility of determining the composition of advanced atherosclerotic plaques in fixed ApoE-knockout mice and to develop a time-efficient microimaging protocol for MR histological imaging on mice. Five formalin-fixed transgenic ApoE-knockout mice were imaged at the 9.4T Bruker BioSpec MR scanner using 3D spoiled gradient-echo sequence with an isotropic field of view of 24 mm3; TR 20.8 ms; TE 2.6 ms; flip angle 20°, resulted voxel size 47 × 63 × 94 pm3. MRI examination has shown that advanced atherosclerotic lesions of aorta, innominate and carotid arteries in ApoE-knockout mice are characterized by high calcification and presence of the large fibrofatty nodules. MRI quantification of atherosclerotic lesion components corresponded to histological assessment of plaque composition with a correlation coefficient of 0.98.

  11. Direct Cardiac Reprogramming: From Developmental Biology to Cardiac Regeneration

    PubMed Central

    Qian, Li; Srivastava, Deepak

    2013-01-01

    Heart disease affects millions worldwide and is a progressive condition involving loss of cardiomyocytes. The human heart has limited endogenous regenerative capacity and is thus an important target for novel regenerative medicine approaches. While cell-based regenerative therapies hold promise, cellular reprogramming of endogenous cardiac fibroblasts, which represent more than half of the cells in the mammalian heart, may be an attractive alternative strategy for regenerating cardiac muscle. Recent advances leveraging years of developmental biology point to the feasibility of generating de novo cardiomyocyte-like cells from terminally differentiated non-myocytes in the heart in situ after ischemic damage. Here, we review the progress in cardiac reprogramming methods and consider the opportunities and challenges that lie ahead in refining this technology for regenerative medicine. PMID:24030021

  12. Effect of knockout of α2δ-1 on action potentials in mouse sensory neurons

    PubMed Central

    Margas, Wojciech; Ferron, Laurent; Nieto-Rostro, Manuela; Schwartz, Arnold; Dolphin, Annette C.

    2016-01-01

    Gene deletion of the voltage-gated calcium channel auxiliary subunit α2δ-1 has been shown previously to have a cardiovascular phenotype, and a reduction in mechano- and cold sensitivity, coupled with delayed development of neuropathic allodynia. We have also previously shown that dorsal root ganglion (DRG) neuron calcium channel currents were significantly reduced in α2δ-1 knockout mice. To extend our findings in these sensory neurons, we have examined here the properties of action potentials (APs) in DRG neurons from α2δ-1 knockout mice in comparison to their wild-type (WT) littermates, in order to dissect how the calcium channels that are affected by α2δ-1 knockout are involved in setting the duration of individual APs and their firing frequency. Our main findings are that there is reduced Ca2+ entry on single AP stimulation, particularly in the axon proximal segment, reduced AP duration and reduced firing frequency to a 400 ms stimulation in α2δ-1 knockout neurons, consistent with the expected role of voltage-gated calcium channels in these events. Furthermore, lower intracellular Ca2+ buffering also resulted in reduced AP duration, and a lower frequency of AP firing in WT neurons, mimicking the effect of α2δ-1 knockout. By contrast, we did not obtain any consistent evidence for the involvement of Ca2+-activation of large conductance calcium-activated potassium (BK) and small conductance calcium-activated potassium (SK) channels in these events. In conclusion, the reduced Ca2+ elevation as a result of single AP stimulation is likely to result from the reduced duration of the AP in α2δ-1 knockout sensory neurons. This article is part of the themed issue ‘Evolution brings Ca2+ and ATP together to control life and death’. PMID:27377724

  13. Effects of HAb18G/CD147 knockout on hepatocellular carcinoma cells in vitro using a novel zinc-finger nuclease-targeted gene knockout approach.

    PubMed

    Li, Hong-Wei; Yang, Xiang-Min; Tang, Juan; Wang, Shi-Jie; Chen, Zhi-Nan; Jiang, Jian-Li

    2015-03-01

    HAb18G/CD147 belongs to the immunoglobulin superfamily and predominantly functions as an inducer of matrix metalloproteinase secretion for tumor invasion and metastasis. This study was designed to investigate the effects of HAb18G/CD147 knockout on hepatocellular carcinoma cells using zinc-finger nuclease (ZFNs)-targeted gene knockout approach. The HCC cell line SMMC-7721 was used for ZFNs-targeted cleavage of the HAb18G/CD147 gene. RT-PCR and Western blot assays were used to detect HAb18G/CD147 expression. HAb18G phenotypic changes following HAb18G/CD147 knockout in SMMC-K7721 cells were assessed using tumor cell adhesion, invasion, migration and colony formation and flow cytometric assays. These data demonstrated that tumor cell adhesion, invasion, migration, and colony formation capabilities of SMMC-K7721 were significantly reduced compared to parental cells or SMMC-7721 with re-expression of HAb18G/CD147 protein transfected with HAb18G/CD147 cDNA. Moreover, knockout of HAb18G/CD147 expression also induced SMMC-K7721 cells to undergo apoptosis compared to SMMC-7721 and SMMC-R7721 (P < 0.01). Molecularly, protein expression of p53 was induced in these cells, but re-expression of HAb18G/CD147 reduced p53 levels in SMMC-R7721 cells, possibly through inhibition of the PI3K-Akt-MDM2 signaling pathway. The findings provide a novel insight into the mechanisms underlying HAb18G/CD147-induced progression of HCC cells.

  14. Sudden cardiac death: A reappraisal.

    PubMed

    Steinberg, Christian; Laksman, Zachary W M; Krahn, Andrew D

    2016-11-01

    Sudden cardiac death (SCD) is still among the leading causes of death in women and men, accounting for over 50% of all fatal cardiovascular events in the United States. Two arrhythmia mechanisms of SCD can be distinguished as follows: shockable rhythms (ventricular fibrillation and pulseless ventricular tachycardia) and non-shockable rhythms including asystole or pulseless electrical activity. The overall prognosis of cardiac arrest due to shockable rhythms is significantly better. While the majority of SCDs is attributed to coronary artery disease or other structural heart disease, no obvious cause can be identified in 5% of all events, and those events are labeled as sudden unexplained deaths (SUD). Those unexplained events are typically caused by rare hereditary electrical disorders or arrhythmogenic cardiomyopathies. A systematic approach to the diagnosis of cardiac arrest followed by tailored therapy based on etiology has emerged in the last 10-15 years, with significant changes of medical practice and risk management of cardiac arrest victims. The aim of this review is to summarize our contemporary understanding of SCD/SUD in adults and to discuss current concepts of management and secondary prevention in cardiac arrest victims. A full discussion of the topic of primary prevention of SCD is beyond the scope of this article.

  15. Pharmacology of cardiac potassium channels.

    PubMed

    Li, Gui-Rong; Dong, Ming-Qing

    2010-01-01

    Cardiac K(+) channels are cardiomyocyte membrane proteins that regulate K(+) ion flow across the cell membrane on the electrochemical gradient and determine the resting membrane potential and the cardiac action potential morphology and duration. Several K(+) channels have been well studied in the human heart. They include the transient outward K(+) current I(to1), the ultra-rapidly activating delayed rectifier current I(Kur), the rapidly and slowly activating delayed rectifier currents I(Kr) and I(Ks), the inward rectifier K(+) current I(K1), and ligand-gated K(+) channels, including adenosine-5'-triphosphate (ATP)-sensitive K(+) current (I(KATP)) and acetylcholine-activated current (I(KACh)). Regional differences of K(+) channel expression contribute to the variable morphologies and durations of cardiac action potentials from sinus node and atrial to ventricular myocytes, and different ventricular layers from endocardium and midmyocardium to epicardium. They also show different responses to endogenous regulators and/or pharmacological agents. K(+) channels are well-known targets for developing novel anti-arrhythmic drugs that can effectively prevent/inhibit cardiac arrhythmias. Especially, atrial-specific K(+) channel currents (I(Kur) and I(KACh)) are the targets for developing atrial-selective anti-atrial fibrillation drugs, which has been greatly progressed in recent years. This chapter concentrates on recent advances in intracellular signaling regulation and pharmacology of cardiac K(+) channels under physiological and pathophysiological conditions.

  16. [Cardiac surgery in the elderly].

    PubMed

    Wiegmann, B; Ismail, I; Haverich, A

    2017-02-01

    Due to the increasing demographic changes and the fact that cardiovascular diseases are still the leading cause of death, the mean chronological age of patients undergoing cardiac surgery is steadily increasing. In 2015, 14.8% of these patients were aged 80 years and older. This meta-analysis reviewed if and under what circumstances elderly patients benefit from cardiac surgical procedures without running the risk of limitations in the quality of life and high rates of morbidity and mortality. Generally, the chronological age was not a risk factor for higher perioperative and postoperative morbidity and mortality but the biological age was the critical factor, in particular the associated comorbidities of patients and the timing of the surgical procedure in the course of the disease. The result is that elective operations resulted in a better outcome than operations in a symptomatic or decompensated stage of a disease. Compared to patients receiving conventional medicinal therapy, elderly patients undergoing cardiac surgery had an improved life expectancy. A significant increase in the quality of life could also be identified and was ultimately comparable to those of younger patients after cardiac surgery; therefore, elderly patients even those over 80 years old benefit in all aspects of cardiac surgery, as long as individually adapted operative techniques are considered.

  17. Analysis of Cardiac Myocyte Maturation Using CASAAV, A Platform for Rapid Dissection of Cardiac Myocyte Gene Function In Vivo.

    PubMed

    Guo, Yuxuan; VanDusen, Nathan J; Zhang, Lina; Gu, Weiliang; Sethi, Isha; Guatimosim, Silvia; Ma, Qing; Jardin, Blake D; Ai, Yulan; Zhang, Donghui; Chen, Biyi; Guo, Ang; Yuan, Guo-Cheng; Song, Long-Sheng; Pu, William T

    2017-03-29

    Rationale: Loss-of-function studies in cardiac myocytes (CMs) are currently limited by the need for appropriate conditional knockout alleles. The factors that regulate CM maturation are poorly understood. Prior studies on CM maturation have been confounded by heart dysfunction caused by whole organ gene inactivation. Objective: To develop a new technical platform to rapidly characterize cell-autonomous gene function in postnatal murine CMs and apply it to identify genes that regulate T-tubules, a hallmark of mature cardiac myocytes. Methods and Results: We developed CASAAV (CRISPR/Cas9-AAV9-based somatic mutagenesis), a platform in which AAV9 delivers tandem guide RNAs targeting a gene of interest and cardiac troponin T promoter (cTNT)-driven Cre to Rosa(Cas9GFP/Cas9GFP) neonatal mice. When directed against junctophilin-2 (Jph2), a gene previously implicated in T-tubule maturation, we achieved efficient, rapid, and CM-specific JPH2 depletion. High-dose AAV9 ablated JPH2 in 64% CMs and caused lethal heart failure, whereas low-dose AAV9 ablated JPH2 in 22% CMs and preserved normal heart function. In the context of preserved heart function, CMs lacking JPH2 developed T-tubules that were nearly morphologically normal, indicating that JPH2 does not have a major, cell-autonomous role in T-tubule maturation. However, in hearts with severe dysfunction, both AAV-transduced and non-transduced CMs exhibited T-tubule disruption, which was more severe in the transduced subset. These data indicate that cardiac dysfunction disrupts T-tubule structure, and that JPH2 protects T-tubules in this context. We then used CASAAV to screen 8 additional genes for required, cell-autonomous roles in T-tubule formation. We identified ryanodine receptor 2 (RYR2) as a novel, cell-autonomously required T-tubule maturation factor. Conclusions: CASAAV is a powerful tool to study cell-autonomous gene functions. Genetic mosaics are invaluable to accurately define cell-autonomous gene function. JPH2

  18. Camkii-Dependent Phosphorylation of Cardiac Ryanodine Receptors Regulates Cell Death In Cardiac Ischemia/Reperfusion Injury

    PubMed Central

    Di Carlo, Mariano N.; Said, Matilde; Ling, Haiyun; Valverde, Carlos A.; De Giusti, Verónica; Sommese, Leandro; Palomeque, Julieta; Aiello, Alejandro E.; Skapura, Darlene G.; Rinaldi, Gustavo; Respress, Jonathan L.; Brown, Joan Heller; Wehrens, Xander H.T.; Salas, Margarita A.; Mattiazzi, Alicia

    2014-01-01

    Ca2+-Calmodulin kinase II (CaMKII) activation is deleterious in cardiac ischemia/reperfusion (I/R). Moreover, inhibition of CaMKII-dependent phosphorylations at the sarcoplasmic reticulum (SR) prevents CaMKII-induced I/R damage. However, the downstream targets of CaMKII at the SR level, responsible for this detrimental effect, remain unclear. In the present study we aimed to dissect the role of the two main substrates of CaMKII at the SR level, phospholamban (PLN) and ryanodine receptors (RyR2), in CaMKII-dependent I/R injury. In mouse hearts subjected to global I/R (45/120 min), phosphorylation of the primary CaMKII sites, S2814 on cardiac RyR2 and of T17 on PLN, significantly increased at the onset of reperfusion whereas PKA-dependent phosphorylation of RyR2 and PLN did not change. Similar results were obtained in vivo, in mice subjected to regional myocardial I/R (1/24 hrs). Knock-in mice with an inactivated serine 2814 phosphorylation site on RyR2 (S2814A), significantly improved post-ischemic mechanical recovery, reduced infarct size and decreased apoptosis. Conversely, knock-in mice, in which CaMKII site of RyR2 is constitutively activated (S2814D), significantly increased infarct size and exacerbated apoptosis. In S2814A and S2814D mice subjected to regional myocardial ischemia, infarct size was also decreased and increased respectively. Transgenic mice with double-mutant non-phosphorylatable PLN (S16A/T17A) in the PLN knockout background (PLNDM) also showed significantly increased post-ischemic cardiac damage. This effect cannot be attributed to PKA-dependent PLN phosphorylation and was not due to the enhanced L-type Ca2+ current, present in these mice. Our results reveal a major role for the phosphorylation of S2814 site on RyR2 in CaMKII-dependent I/R cardiac damage. In contrast, they showed that CaMKII-dependent increase in PLN phosphorylation during reperfusion opposes rather than contributes to I/R damage. PMID:24949568

  19. Differential cytokine expression in skin graft healing in inducible nitric oxide synthase knockout mice.

    PubMed

    Most, D; Efron, D T; Shi, H P; Tantry, U S; Barbul, A

    2001-10-01

    Inducible nitric oxide synthase (iNOS) and its product, nitric oxide, have been shown to play important roles in wound biology. The present study was performed to investigate the role of iNOS in modulating the cytokine cascade during the complex process of skin graft wound healing.Fifteen iNOS-knockout mice and 15 wild-type C57BL/6J mice were subjected to autogenous 1-cm2 intrascapular full-thickness skin grafts. Three animals in each group were killed on postoperative days 3, 5, 7, 10, and 14. Specimens were then analyzed using nonisotopic in situ hybridization versus mRNA of tumor growth factor-beta1, vascular endothelial growth factor, iNOS, endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha, and basic fibroblast growth factor, as well as positive and negative control probes. Positive cells in both grafts and wound beds were counted using a Leica microgrid. Scar thickness was measured with a Leica micrometer. Data were analyzed using the unpaired Student's t test. Expression of iNOS was 2- to 4-fold higher in knockout mice than in wild-type mice on postoperative days 5, 7, and 14. Expression of eNOS was 2- to 2.5-fold higher in knockout mice than in wild-type mice on postoperative days 5 and 7. Tumor necrosis factor-alpha expression was 2- to 7-fold higher in knockout mice than in wild-type mice on all postoperative days. In contrast, expression levels of angiogenic/fibrogenic cytokines (vascular endothelial growth factor, basis fibroblast growth factor, and tumor growth factor-beta1) were 2.5- to 4-fold higher in wild-type mice than in knockout mice. Scars were 1.5- to 2.5-fold thicker in knockout mice than in wild-type mice at all time points. All of the above results represent statistically significant differences (p < 0.05). Significantly different patterns of cytokine expression were seen in knockout and wild-type mice. Although the scar layer was thicker in knockout mice, it showed much greater infiltration with inflammatory cells. These

  20. Invariant Mass Spectroscopy of 17C via One-Neutron Knockout Reaction of 18C

    NASA Astrophysics Data System (ADS)

    Kim, Sunji; Hwang, Jongwon; Satou, Yoshiteru; Orr, Nigel A.; Nakamura, Takashi; Kondo, Yosuke; Gibelin, Julien; Achouri, N. Lynda; Aumann, Thomas; Baba, Hidetada; Delaunay, Franck; Doornenbal, Pieter; Fukuda, Naoki; Inabe, Naohito; Isobe, Tadaaki; Kameda, Daisuke; Kanno, Daiki; Kobayashi, Nobuyuki; Kobayashi, Toshio; Kubo, Toshiyuki; Leblond, Sylvain; Lee, Jenny; Marqués, F. Miguel; Minakata, Ryogo; Motobayashi, Tohru; Murai, Daichi; Murakami, Tetsuya; Muto, Kotomi; Nakashima, Tomohiro; Nakatsuka, Noritsugu; Navin, Alahari; Nishi, Seijiro; Ogoshi, Shun; Otsu, Hideaki; Sato, Hiromi; Shimizu, Yohei; Suzuki, Hiroshi; Takahashi, Kento; Takeda, Hiroyuki; Takeuchi, Satoshi; Tanaka, Ryuki; Togano, Yasuhiro; Tuff, Adam G.; Vandebrouck, Marine; Yoneda, Ken-ichiro

    Unbound states in 17C were investigated via one-neutron knockout of 18C. The experiment was performed using SAMURAI spectrometer in RIBF at RIKEN. By invariant mass spectroscopy, three resonances were measured at excitation energies of 3.03(12), 2.74(3), and 4.03(6) MeV as preliminary results. For the excited state at 2.74(3) MeV, the parallel momentum distribution was satisfactorily described by the distribution calculated for p-wave knockout from 18C.

  1. Out-of-hospital Cardiac Arrest (OHCA) Biomarkers

    ClinicalTrials.gov

    2017-04-07

    Neurological Outcome; Cardiac Arrest; Out-Of-Hospital Cardiac Arrest; Brain Anoxia Ischemia; Hypoxia, Brain; Hypoxia-Ischemia, Brain; Cardiac Arrest With Successful Resuscitation; Cardiac Arrest, Out-Of-Hospital; Brain Injuries

  2. Cardiac hypertrophy is associated with altered thioredoxin and ASK-1 signaling in a mouse model of menopause.

    PubMed

    Ebrahimian, Talin; Sairam, M Ram; Schiffrin, Ernesto L; Touyz, Rhian M

    2008-10-01

    Oxidative stress is implicated in menopause-associated hypertension and cardiovascular disease. The role of antioxidants in this process is unclear. We questioned whether the downregulation of thioredoxin (TRX) is associated with oxidative stress and the development of hypertension and target-organ damage (cardiac hypertrophy) in a menopause model. TRX is an endogenous antioxidant that also interacts with signaling molecules, such as apoptosis signal-regulated kinase 1 (ASK-1), independently of its antioxidant function. Aged female wild-type (WT) and follitropin receptor knockout (FORKO) mice (20-24 wk), with hormonal imbalances, were studied. Mice were infused with ANG II (400 ng x kg(-1) x min(-1); 14 days). Systolic blood pressure was increased by ANG II in WT (166+/-8 vs. 121+/-5 mmHg) and FORKO (176+/-7 vs. 115+/-5 mmHg; P<0.0001; n=9/group) mice. In ANG II-infused FORKO mice, cardiac mass was increased by 42% (P<0.001). This was associated with increased collagen content and augmented ERK1/2 phosphorylation (2-fold). Cardiac TRX expression and activity were decreased by ANG II in FORKO but not in WT (P<0.01) mice. ASK-1 expression, cleaved caspase III content, and Bax/Bcl-2 content were increased in ANG II-infused FORKO (P<0.05). ANG II had no effect on cardiac NAD(P)H oxidase activity or on O(2)(*-) levels in WT or FORKO. Cardiac ANG II type 1 receptor expression was similar in FORKO and WT. These findings indicate that in female FORKO, ANG II-induced cardiac hypertrophy and fibrosis are associated with the TRX downregulation and upregulation of ASK-1/caspase signaling. Our data suggest that in a model of menopause, protective actions of TRX may be blunted, which could contribute to cardiac remodeling independently of oxidative stress and hypertension.

  3. Exercise-induced cardiac remodeling.

    PubMed

    Weiner, Rory B; Baggish, Aaron L

    2012-01-01

    Early investigations in the late 1890s and early 1900s documented cardiac enlargement in athletes with above-normal exercise capacity and no evidence of cardiovascular disease. Such findings have been reported for more than a century and continue to intrigue scientists and clinicians. It is well recognized that repetitive participation in vigorous physical exercise results in significant changes in myocardial structure and function. This process, termed exercise-induced cardiac remodeling (EICR), is characterized by structural cardiac changes including left ventricular hypertrophy with sport-specific geometry (eccentric vs concentric). Associated alterations in both systolic and diastolic functions are emerging as recognized components of EICR. The increasing popularity of recreational exercise and competitive athletics has led to a growing number of individuals exhibiting these findings in routine clinical practice. This review will provide an overview of EICR in athletes.

  4. [Ectopia cordis and cardiac anomalies].

    PubMed

    Cabrera, Alberto; Rodrigo, David; Luis, María Teresa; Pastor, Esteban; Galdeano, José Miguel; Esteban, Susana

    2002-11-01

    Ectopia cordis is a rare disease that occurs in 5.5 to 7.9 per million live births. Only 267 cases had been reported as of 2001, most (95%) associated with other cardiac anomalies. We studied the cardiac malformations associated in 6 patients with ectopia cordis. Depending on where the defect was located, the cases of ectopia were classified into four groups: cervical, thoracic, thoraco-abdominal, and abdominal. All 6 patients died before the third day of life, 4 during delivery. Three of the patients were included in the thoracic group, whereas the other 3 belonged to the thoraco-abdominal group. All the patients had associated ventricular septal defects, 3 double-outlet right ventricle (50%) and the rest (50%) tetralogy of Fallot-pulmonary atresia. Two patients with double-outlet right ventricle presented mitral-valve pathology, a parachute valve and an atresic mitral valve. None of these cardiac anomalies have been reported to date.

  5. Cardiac manifestations in Behcet's disease

    PubMed Central

    Demirelli, Selami; Degirmenci, Husnu; Inci, Sinan; Arisoy, Arif

    2015-01-01

    Summary Behcet's disease (BD) is a chronic inflammatory disorder, with vasculitis underlying the pathophysiology of its multisystemic effects. Venous pathology and thrombotic complications are hallmarks of BD. However, it has been increasingly recognised that cardiac involvement and arterial complications are also important aspects of the course of the disease. Cardiac lesions include pericarditis, endocarditis, intracardiac thrombosis, myocardial infarction, endomyocardial fibrosis, and myocardial aneurysm. Treatment of cardiovascular involvement in BD is largely empirical, and is aimed towards suppressing the vasculitis. The most challenging aspect seems to be the treatment of arterial aneurysms and thromboses due to the associated risk of bleeding. When the prognosis of cardiac involvement in BD is not good, recovery can be achieved through oral anticoagulation, immunosuppressive therapy, and colchicine use. In this review, we summarise the cardiovascular involvement, different manifestations, and treatment of BD. PMID:25984424

  6. Cardiac myofilaments: mechanics and regulation

    NASA Technical Reports Server (NTRS)

    de Tombe, Pieter P.; Bers, D. M. (Principal Investigator)

    2003-01-01

    The mechanical properties of the cardiac myofilament are an important determinant of pump function of the heart. This report is focused on the regulation of myofilament function in cardiac muscle. Calcium ions form the trigger that induces activation of the thin filament which, in turn, allows for cross-bridge formation, ATP hydrolysis, and force development. The structure and protein-protein interactions of the cardiac sarcomere that are responsible for these processes will be reviewed. The molecular mechanism that underlies myofilament activation is incompletely understood. Recent experimental approaches have been employed to unravel the mechanism and regulation of myofilament mechanics and energetics by activator calcium and sarcomere length, as well as contractile protein phosphorylation mediated by protein kinase A. Central to these studies is the question whether such factors impact on muscle function simply by altering thin filament activation state, or whether modulation of cross-bridge cycling also plays a part in the responses of muscle to these stimuli.

  7. Current trends in cardiac rehabilitation

    PubMed Central

    Dafoe, W; Huston, P

    1997-01-01

    Cardiac rehabilitation can reduce mortality and morbidity for patients with many types of cardiac disease cost-effectively, yet is generally underutilized. Rehabilitation is helpful not only for patients who have had a myocardial infarction but also for those with stable angina or congestive heart failure or those who have undergone myocardial revascularization procedures, a heart transplant or heart valve surgery. The beneficial effects of rehabilitation include a reduction in the rate of death from cardiovascular disease, improved exercise tolerance, fewer cardiac symptoms, improved lipid levels, decreased cigarette smoking, improvement in psychosocial well-being and increased likelihood of return to work. Rehabilitation involves a multidisciplinary team that focuses on education, individually tailored exercise, risk-factor modification and the optimization of functional status and mental health. Current research trends in this area include the evaluation of new secondary-prevention modalities and alternative program options, such as home-based rehabilitation. PMID:9054823

  8. Cardiac Fibrosis: The Fibroblast Awakens

    PubMed Central

    Travers, Joshua G.; Kamal, Fadia A.; Robbins, Jeffrey; Yutzey, Katherine E.; Blaxall, Burns C.

    2016-01-01

    Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of this cell population impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis. PMID:26987915

  9. β-Arrestin mediates the Frank-Starling mechanism of cardiac contractility.

    PubMed

    Abraham, Dennis M; Davis, Robert T; Warren, Chad M; Mao, Lan; Wolska, Beata M; Solaro, R John; Rockman, Howard A

    2016-12-13

    The Frank-Starling law of the heart is a physiological phenomenon that describes an intrinsic property of heart muscle in which increased cardiac filling leads to enhanced cardiac contractility. Identified more than a century ago, the Frank-Starling relationship is currently known to involve length-dependent enhancement of cardiac myofilament Ca(2+) sensitivity. However, the upstream molecular events that link cellular stretch to the length-dependent myofilament Ca(2+) sensitivity are poorly understood. Because the angiotensin II type 1 receptor (AT1R) and the multifunctional transducer protein β-arrestin have been shown to mediate mechanosensitive cellular signaling, we tested the hypothesis that these two proteins are involved in the Frank-Starling mechanism of the heart. Using invasive hemodynamics, we found that mice lacking β-arrestin 1, β-arrestin 2, or AT1R were unable to generate a Frank-Starling force in response to changes in cardiac volume. Although wild-type mice pretreated with the conventional AT1R blocker losartan were unable to enhance cardiac contractility with volume loading, treatment with a β-arrestin-biased AT1R ligand to selectively activate β-arrestin signaling preserved the Frank-Starling relationship. Importantly, in skinned muscle fiber preparations, we found markedly impaired length-dependent myofilament Ca(2+) sensitivity in β-arrestin 1, β-arrestin 2, and AT1R knockout mice. Our data reveal β-arrestin 1, β-arrestin 2, and AT1R as key regulatory molecules in the Frank-Starling mechanism, which potentially can be targeted therapeutically with β-arrestin-biased AT1R ligands.

  10. Sudden Cardiac Arrest (SCA) Risk Assessment

    MedlinePlus

    ... HRS Find a Specialist Share Twitter Facebook SCA Risk Assessment Sudden Cardiac Arrest (SCA) occurs abruptly and without ... people of all ages and health conditions. Start Risk Assessment The Sudden Cardiac Arrest (SCA) Risk Assessment Tool ...

  11. MR and CT appearance of cardiac hemangioma

    SciTech Connect

    Kemp, J.L.; Kessler, R.M.; Raizada, V.; Williamson, M.R.

    1996-05-01

    We present a case of cardiac hemangioma in a symptomatic patient. MR and CT each have specific characteristics that should make one consider including or excluding this in the differential diagnosis of a cardiac tumor. 7 refs., 3 figs.

  12. Cardiac Arrest: MedlinePlus Health Topic

    MedlinePlus

    ... dying from a second SCA. NIH: National Heart, Lung, and Blood Institute Start Here About Cardiac Arrest (American Heart ... Society) What Is Sudden Cardiac Arrest? (National Heart, Lung, and Blood Institute) Latest News How Devices in Public Places ...

  13. A cardiac cause for deafness

    PubMed Central

    Naha, Kushal; Vivek, G; Shetty, Ranjan K; Dias, Lorraine Simone

    2013-01-01

    We describe a case of a 49-year-old diabetic man with a history of myocardial infarction, presenting with deafness for 2 weeks. Initial assessment by otorhinolaryngologists was suggestive of sensorineural hearing loss. Subsequently, the cardiac evaluation showed an apical clot in the left ventricle. Careful neurological reassessment and a cranial MRI yielded a diagnosis of cortical deafness with auditory agnosia secondary to bilateral temporal infarcts. Doppler and MRI ruled out carotid artery thrombosis. The temporal infarcts were therefore considered to be cardioembolic in origin. Cardioembolic stroke is an important differential diagnosis for patients presenting with neurological symptoms on a background of cardiac disease. PMID:24165506

  14. Redox regulation of cardiac hypertrophy.

    PubMed

    Sag, Can M; Santos, Celio X C; Shah, Ajay M

    2014-08-01

    It is increasingly evident that redox-dependent modifications in cellular proteins and signaling pathways (or redox signaling) play important roles in many aspects of cardiac hypertrophy. Indeed, these redox modifications may be intricately linked with the process of hypertrophy wherein there is not only a significant increase in myocardial O2 consumption but also important alterations in metabolic processes and in the local generation of O2-derived reactive species (ROS) that modulate and/or amplify cell signaling pathways. This article reviews our current knowledge of redox signaling pathways and their roles in cardiac hypertrophy. This article is part of a Special Issue entitled "Redox Signalling in the Cardiovascular System".

  15. PGD for inherited cardiac diseases.

    PubMed

    Kuliev, Anver; Pomerantseva, Ekaterina; Polling, Dana; Verlinsky, Oleg; Rechitsky, Svetlana

    2012-04-01

    Preimplantation genetic diagnosis (PGD) has been applied for more than 200 different inherited conditions, with expanding application to common disorders with genetic predisposition. One of the recent indications for PGD has been inherited cardiac disease, for which no preclinical diagnosis and preventive management may exist and which may lead to premature or sudden death. This paper presents the first, as far as is known, cumulative experience of PGD for inherited cardiac diseases, including familial hypertrophic and dilated cardiomyopathy, cardioencephalomyopathy and Emery-Dreifuss muscular dystrophy. A total of 18 PGD cycles were performed, resulting in transfer in 15 of them, which yielded nine unaffected pregnancies and the births of seven disease- or disease predisposition-free children. The data open the prospect of PGD for inherited cardiac diseases, allowing couples carrying cardiac disease predisposing genes to reproduce without much fear of having offspring with these genes, which are at risk for premature or sudden death. Preimplantation genetic diagnosis (PGD) is currently an established clinical procedure in assisted reproduction and genetic practices. Its application has been expanding beyond traditional indications of prenatal diagnosis and currently includes common disorders with genetic predisposition, such as inherited forms of cancer. This applies also to the diseases with no current prospect of treatment, which may manifest despite presymptomatic diagnosis and follow up, when PGD may provide the only relief for the at-risk couples to reproduce. One of the recent indications for PGD has been inherited cardiac disease, for which no preclinical diagnosis and preventive management may exist and which may lead to premature or sudden death. We present here our first cumulative experience of PGD for inherited cardiac diseases, including familial hypertrophic and dilated cardiomyopathy, cardioencephalomyopathy and Emery-Dreifuss muscular dystrophy. A

  16. Neurological complications of cardiac surgery.

    PubMed

    McDonagh, David L; Berger, Miles; Mathew, Joseph P; Graffagnino, Carmelo; Milano, Carmelo A; Newman, Mark F

    2014-05-01

    As increasing numbers of elderly people undergo cardiac surgery, neurologists are frequently called upon to assess patients with neurological complications from the procedure. Some complications mandate acute intervention, whereas others need longer term observation and management. A large amount of published literature exists about these complications and guidance on best practice is constantly changing. Similarly, despite technological advances in surgical intervention and modifications in surgical technique to make cardiac procedures safer, these advances often create new avenues for neurological injury. Accordingly, rapid and precise neurological assessment and therapeutic intervention rests on a solid understanding of the evidence base and procedural variables.

  17. Cardiac 4D Ultrasound Imaging

    NASA Astrophysics Data System (ADS)

    D'hooge, Jan

    Volumetric cardiac ultrasound imaging has steadily evolved over the last 20 years from an electrocardiography (ECC) gated imaging technique to a true real-time imaging modality. Although the clinical use of echocardiography is still to a large extent based on conventional 2D ultrasound imaging it can be anticipated that the further developments in image quality, data visualization and interaction and image quantification of three-dimensional cardiac ultrasound will gradually make volumetric ultrasound the modality of choice. In this chapter, an overview is given of the technological developments that allow for volumetric imaging of the beating heart by ultrasound.

  18. Cardiac Involvement in Peripheral Neuropathies.

    PubMed

    Burakgazi, Ahmet Z; AlMahameed, Soufian

    2016-03-01

    Cardiac autonomic neuropathy (CAN) is the least recognized and understood complication of peripheral neuropathy. However, because of its potential adverse effects including sudden death, CAN is one of the most important forms of autonomic neuropathies. CAN presents with different clinical manifestations including postural hypotension, exercise intolerance, fluctuation of blood pressure and heart rate, arrhythmia, and increased risk of myocardial infarction. In this article, the prevalence, clinical presentations, and management of cardiac involvement in certain peripheral neuropathies, including diabetic neuropathy, Guillain-Barré syndrome, chronic inflammatory polyneuropathy, human immunodeficiency virus-associated neuropathy, hereditary neuropathies, and amyloid neuropathy are examined in detail.

  19. [Cardiac rehabilitation after myocardial infarction].

    PubMed

    Ghannem, M; Ghannem, L; Ghannem, L

    2015-12-01

    Although the proofs of the benefits of cardiac rehabilitation accumulate, many patients are not sent to rehabilitation units, especially younger and very elderly patients. As the length of stay in acute care units decreases, rehabilitation offers more time to fully assess the patients' conditions and needs. Meta-analyses of randomised trials suggest that mortality can be improved by as much as 20-30%. In addition, rehabilitation helps managing risk factors, including hyperlipidemia, diabetes, smoking and sedentary behaviours. Physical training also helps improving exercise capacity. Because of all of these effects, cardiac rehabilitation for post-myocardial infarction patients has been given a class IA recommendation in current guidelines.

  20. Systemic therapy for cardiac sarcomas.

    PubMed

    Ravi, Vinod; Benjamin, Robert S

    2010-01-01

    Cardiac sarcomas create 2 risks: local problems and metastatic disease. Most frequently, the histologies are angiosarcoma and high-grade pleomorphic unclassified sarcoma (formerly called MFH or malignant fibrous histiocytoma). There is also a clinical-pathological entity without distinctive histological features of tumors that originate in the pulmonary artery and are referred to as pulmonary artery sarcomas or intimal sarcomas of the pulmonary artery. Conventional wisdom indicates that soft-tissue sarcomas are poorly responsive to chemotherapy. Luckily, that is not the case. Attempts to concentrate on the local problem only with therapies up to and including cardiac transplantation have been unsuccessful due to the high rate of fatal metastatic disease.

  1. Cardiac Metastasis from Invasive Thymoma Via the Superior Vena Cava: Cardiac MRI Findings

    SciTech Connect

    Dursun, Memduh Sarvar, Sadik; Cekrezi, Bledi; Kaba, Erkan; Bakir, Baris; Toker, Alper

    2008-07-15

    Cardiac tumors are rare, and metastatic deposits are more common than primary cardiac tumors. We present cardiac magnetic resonance imaging (MRI) findings of a 50-year-old woman with invasive thymoma. Cardiac MRI revealed a heterogeneous, lobulated anterior mediastinal mass invading the superior vena cava and extending to the right atrium. In cine images there was no invasion to the right atrial wall.

  2. Health Literacy Predicts Cardiac Knowledge Gains in Cardiac Rehabilitation Participants

    ERIC Educational Resources Information Center

    Mattson, Colleen C.; Rawson, Katherine; Hughes, Joel W.; Waechter, Donna; Rosneck, James

    2015-01-01

    Objective: Health literacy is increasingly recognised as a potentially important patient characteristic related to patient education efforts. We evaluated whether health literacy would predict gains in knowledge after completion of patient education in cardiac rehabilitation. Method: This was a re-post observational analysis study design based on…

  3. Cardiac CaM Kinase II Genes δ and γ Contribute to Adverse Remodeling but Redundantly Inhibit Calcineurin-Induced Myocardial Hypertrophy

    PubMed Central

    Kreusser, Michael M.; Lehmann, Lorenz H.; Keranov, Stanislav; Hoting, Marc-Oscar; Oehl, Ulrike; Kohlhaas, Michael; Reil, Jan-Christian; Neumann, Kay; Schneider, Michael D.; Hill, Joseph A.; Dobrev, Dobromir; Maack, Christoph; Maier, Lars S.; Gröne, Hermann-Josef; Katus, Hugo A.; Olson, Eric N.; Backs, Johannes

    2014-01-01

    Background Ca2+-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. Methods and Results We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca2+ handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. Conclusions We established a mouse model in which CaMKII’s activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure. PMID:25124496

  4. Bifid cardiac apex in a 25-year-old male with sudden cardiac death.

    PubMed

    Wu, Annie; Kay, Deborah; Fishbein, Michael C

    2014-01-01

    Although a bifid cardiac apex is common in certain marine animals, it is an uncommon finding in humans. When present, bifid cardiac apex is usually associated with other congenital heart anomalies. We present a case of bifid cardiac apex that was an incidental finding in a 25-year-old male with sudden cardiac death from combined drug toxicity. On gross examination, there was a bifid cardiac apex with a 2-cm long cleft. There were no other significant gross or microscopic abnormalities. This case represents the very rare occurrence of a bifid cardiac apex as an isolated cardiac anomaly.

  5. Neonatal cardiac dysfunction and transcriptome changes caused by the absence of Celf1

    PubMed Central

    Giudice, Jimena; Xia, Zheng; Li, Wei; Cooper, Thomas A.

    2016-01-01

    The RNA binding protein Celf1 regulates alternative splicing in the nucleus and mRNA stability and translation in the cytoplasm. Celf1 is strongly down-regulated during mouse postnatal heart development. Its re-induction in adults induced severe heart failure and reversion to fetal splicing and gene expression patterns. However, the impact of Celf1 depletion on cardiac transcriptional and posttranscriptional dynamics in neonates has not been addressed. We found that homozygous Celf1 knock-out neonates exhibited cardiac dysfunction not observed in older homozygous animals, although homozygous mice are smaller than wild type littermates throughout development. RNA-sequencing of mRNA from homozygous neonatal hearts identified a network of cell cycle genes significantly up-regulated and down-regulation of ion transport and circadian genes. Cell cycle genes are enriched for Celf1 binding sites supporting a regulatory role in mRNA stability of these transcripts. We also identified a cardiac splicing network coordinated by Celf1 depletion. Target events contain multiple Celf1 binding sites and enrichment in GU-rich motifs. Identification of direct Celf1 targets will advance our knowledge in the mechanisms behind developmental networks regulated by Celf1 and diseases where Celf1 is mis-regulated. PMID:27759042

  6. Targeted Deletion of MicroRNA-22 Promotes Stress-Induced Cardiac Dilation and Contractile Dysfunction

    PubMed Central

    Gurha, Priyatansh; Abreu-Goodger, Cei; Wang, Tiannan; Ramirez, Maricela O.; Drumond, Ana L.; van Dongen, Stijn; Chen, Yuqing; Bartonicek, Nenad; Enright, Anton J.; Lee, Brendan; Kelm, Robert J.; Reddy, Anilkumar K.; Taffet, George E.; Bradley, Allan; Wehrens, Xander H.; Entman, Mark L.; Rodriguez, Antony

    2012-01-01

    Background Delineating the role of microRNAs (miRNAs) in the posttranscriptional gene regulation offers new insights into how the heart adapts to pathological stress. We developed a knockout of miR-22 in mice and investigated its function in the heart. Methods and Results Here, we show that miR-22–deficient mice are impaired in inotropic and lusitropic response to acute stress by dobutamine. Furthermore, the absence of miR-22 sensitized mice to cardiac decompensation and left ventricular dilation after long-term stimulation by pressure overload. Calcium transient analysis revealed reduced sarcoplasmic reticulum Ca2+ load in association with repressed sarcoplasmic reticulum Ca2+ ATPase activity in mutant myocytes. Genetic ablation of miR-22 also led to a decrease in cardiac expression levels for Serca2a and muscle-restricted genes encoding proteins in the vicinity of the cardiac Z disk/titin cytoskeleton. These phenotypes were attributed in part to inappropriate repression of serum response factor activity in stressed hearts. Global analysis revealed increased expression of the transcriptional/translational repressor purine-rich element binding protein B, a highly conserved miR-22 target implicated in the negative control of muscle expression. Conclusion These data indicate that miR-22 functions as an integrator of Ca2+ homeostasis and myofibrillar protein content during stress in the heart and shed light on the mechanisms that enhance propensity toward heart failure. PMID:22570371

  7. Ah Receptor Signaling Controls the Expression of Cardiac Development and Homeostasis Genes

    PubMed Central

    Carreira, Vinicius S.; Fan, Yunxia; Wang, Qing; Zhang, Xiang; Kurita, Hisaka; Ko, Chia-I.; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

    2015-01-01

    Congenital heart disease (CHD) is the most common congenital abnormality and one of the leading causes of newborn death throughout the world. Despite much emerging scientific information, the precise etiology of this disease remains elusive. Here, we show that the aryl hydrocarbon receptor (AHR) regulates the expression of crucial cardiogenesis genes and that interference with endogenous AHR functions, either by gene ablation or by agonist exposure during early development, causes overlapping structural and functional cardiac abnormalities that lead to altered fetal heart physiology, including higher heart rates, right and left ventricle dilation, higher stroke volume, and reduced ejection fraction. With striking similarity between AHR knockout (Ahr−/−) and agonist-exposed wild type (Ahr+/+) embryos, in utero disruption of endogenous AHR functions converge into dysregulation of molecular mechanisms needed for attainment and maintenance of cardiac differentiation, including the pivotal signals regulated by the cardiogenic transcription factor NKH2.5, energy balance via oxidative phosphorylation and TCA cycle and global mitochondrial function and homeostasis. Our findings suggest that AHR signaling in the developing mammalian heart is central to the regulation of pathways crucial for cellular metabolism, cardiogenesis, and cardiac function, which are potential targets of environmental factors associated with CHD. PMID:26139165

  8. The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development.

    PubMed

    Robson, Andrew; Allinson, Kathleen R; Anderson, Robert H; Henderson, Deborah J; Arthur, Helen M

    2010-09-01

    TGFβ signalling is required for normal cardiac development. To investigate which cell types are involved, we used mice carrying a floxed Type II TGFβ receptor (Tgfbr2fl) allele and Cre-lox genetics to deplete this receptor in different regions of the heart. The three target tissues and corresponding Cre transgenic lines were atrioventricular myocardium (using cGata6-Cre), ventricular myocardium (using Mlc2v-Cre), and vascular endothelium (using tamoxifen-activated Cdh5(PAC)-CreERT2). Spatio-temporal Cre activity in each case was tracked via lacZ activation from the Rosa26R locus. Atrioventricular-myocardial-specific Tgfbr2 knockout (KO) embryos had short septal leaflets of the tricuspid valve, whereas ventricular myocardial-specific KO embryos mainly exhibited a normal cardiac phenotype. Inactivation of Tgfbr2 in endothelial cells from E11.5 resulted in deficient ventricular septation, accompanied by haemorrhage from cerebral blood vessels. We conclude that TGFβ signalling through the Tgfbr2 receptor, in endothelial cells, plays an important role in cardiac development, and is essential for cerebral vascular integrity.

  9. Mathematics and the Heart: Understanding Cardiac Output

    ERIC Educational Resources Information Center

    Champanerkar, Jyoti

    2013-01-01

    This paper illustrates a biological application of the concepts of relative change and area under a curve, from mathematics. We study two biological measures "relative change in cardiac output" and "cardiac output", which are predictors of heart blockages and other related ailments. Cardiac output refers to the quantity of…

  10. Discovery and progress of direct cardiac reprogramming.

    PubMed

    Kojima, Hidenori; Ieda, Masaki

    2017-02-14

    Cardiac disease remains a major cause of death worldwide. Direct cardiac reprogramming has emerged as a promising approach for cardiac regenerative therapy. After the discovery of MyoD, a master regulator for skeletal muscle, other single cardiac reprogramming factors (master regulators) have been sought. Discovery of cardiac reprogramming factors was inspired by the finding that multiple, but not single, transcription factors were needed to generate induced pluripotent stem cells (iPSCs) from fibroblasts. We first reported a combination of cardiac-specific transcription factors, Gata4, Mef2c, and Tbx5 (GMT), that could convert mouse fibroblasts into cardiomyocyte-like cells, which were designated as induced cardiomyocyte-like cells (iCMs). Following our first report of cardiac reprogramming, many researchers, including ourselves, demonstrated an improvement in cardiac reprogramming efficiency, in vivo direct cardiac reprogramming for heart regeneration, and cardiac reprogramming in human cells. However, cardiac reprogramming in human cells and adult fibroblasts remains inefficient, and further efforts are needed. We believe that future research elucidating epigenetic barriers and molecular mechanisms of direct cardiac reprogramming will improve the reprogramming efficiency, and that this new technology has great potential for clinical applications.

  11. Cardiac anatomy and physiology: a review.

    PubMed

    Gavaghan, M

    1998-04-01

    This article reviews the normal anatomy and physiology of the heart. Understanding the normal anatomic and physiologic relationships described in this article will help perioperative nurses care for patients who are undergoing cardiac procedures. Such knowledge also assists nurses in educating patients about cardiac procedures and about activities that can prevent, reverse, or improve cardiac illness.

  12. Heart Failure Induced by Perinatal Ablation of Cardiac Myosin Light Chain Kinase.

    PubMed

    Islam, Yasmin F K; Joseph, Ryan; Chowdhury, Rajib R; Anderson, Robert H; Kasahara, Hideko

    2016-01-01

    Background: Germline knockout mice are invaluable in understanding the function of the targeted genes. Sometimes, however, unexpected phenotypes are encountered, due in part to the activation of compensatory mechanisms. Germline ablation of cardiac myosin light chain kinase (cMLCK) causes mild cardiac dysfunction with cardiomyocyte hypertrophy, whereas ablation in adult hearts results in acute heart failure with cardiomyocyte atrophy. We hypothesized that compensation after ablation of cMLCK is dependent on developmental staging and perinatal-onset of cMLCK ablation will result in more evident heart failure than germline ablation, but less profound when compared to adult-onset ablation. Methods and Results: The floxed-Mylk3 gene was ablated at the beginning of the perinatal stage using a single intra-peritoneal tamoxifen injection of 50 mg/kg into pregnant mice on the 19th day of gestation, this being the final day of gestation. The level of cMLCK protein level could no longer be detected 3 days after the injection, with these mice hereafter denoted as the perinatal Mylk3-KO. At postnatal day 19, shortly before weaning age, these mice showed reduced cardiac contractility with a fractional shortening 22.8 ± 1.0% (n = 7) as opposed to 31.4 ± 1.0% (n = 11) in controls. The ratio of the heart weight relative to body weight was significantly increased at 6.68 ± 0.28 mg/g (n = 12) relative to the two control groups, 5.90 ± 0.16 (flox/flox, n = 11) and 5.81 ± 0.33 (wild/wild/Cre, n = 5), accompanied by reduced body weight. Furthermore, their cardiomyocytes were elongated without thickening, with a long-axis of 101.8 ± 2.4 μm (n = 320) as opposed to 87.1 ± 1.6 μm (n = 360) in the controls. Conclusion: Perinatal ablation of cMLCK produces an increase of heart weight/body weight ratio, a reduction of contractility, and an increase in the expression of fetal genes. The perinatal Mylk3-KO cardiomyocytes were elongated in the absence of thickening, differing from the

  13. Serotonin Transporter Knockout Rats Show Improved Strategy Set-Shifting and Reduced Latent Inhibition

    ERIC Educational Resources Information Center

    Nonkes, Lourens J. P.; van de Vondervoort, Ilse I. G. M.; de Leeuw, Mark J. C.; Wijlaars, Linda P.; Maes, Joseph H. R.; Homberg, Judith R.

    2012-01-01

    Behavioral flexibility is a cognitive process depending on prefrontal areas allowing adaptive responses to environmental changes. Serotonin transporter knockout (5-HTT[superscript -/-]) rodents show improved reversal learning in addition to orbitofrontal cortex changes. Another form of behavioral flexibility, extradimensional strategy set-shifting…

  14. Altered Expression of EPO Might Underlie Hepatic Hemangiomas in LRRK2 Knockout Mice

    PubMed Central

    Xiao, Kaifu; Zhang, Zhuohua

    2016-01-01

    Parkinson's disease (PD) is a severe neurodegenerative disorder caused by progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. The molecular mechanism of PD pathogenesis is unclear. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common genetic cause of familial and sporadic PD. However, studies on LRRK2 mutant mice revealed no visible dopaminergic neuronal loss in the midbrain. While surveying a LRRK2 knockout mouse strain, we found that old animals developed age-dependent hepatic vascular growths similar to cavernous hemangiomas. In livers of these hemangioma-positive LRRK2 knockout mice, we detected an increased expression of the HIF-2α protein and significant reactivation of the expression of the HIF-2α target gene erythropoietin (EPO), a finding consistent with a role of the HIF-2α pathway in blood vessel vascularization. We also found that the kidney EPO expression was reduced to 20% of the wild-type level in 18-month-old LRRK2 knockout mice. Unexpectedly, this reduction was restored to wild-type levels when the knockout mice were 22 months to 23 months old, implying a feedback mechanism regulating kidney EPO expression. Our findings reveal a novel function of LRRK2 in regulating EPO expression and imply a potentially novel relationship between PD genes and hematopoiesis. PMID:27872856

  15. Altered Expression of EPO Might Underlie Hepatic Hemangiomas in LRRK2 Knockout Mice.

    PubMed

    Wu, Ben; Xiao, Kaifu; Zhang, Zhuohua; Ma, Long

    2016-01-01

    Parkinson's disease (PD) is a severe neurodegenerative disorder caused by progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. The molecular mechanism of PD pathogenesis is unclear. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common genetic cause of familial and sporadic PD. However, studies on LRRK2 mutant mice revealed no visible dopaminergic neuronal loss in the midbrain. While surveying a LRRK2 knockout mouse strain, we found that old animals developed age-dependent hepatic vascular growths similar to cavernous hemangiomas. In livers of these hemangioma-positive LRRK2 knockout mice, we detected an increased expression of the HIF-2α protein and significant reactivation of the expression of the HIF-2α target gene erythropoietin (EPO), a finding consistent with a role of the HIF-2α pathway in blood vessel vascularization. We also found that the kidney EPO expression was reduced to 20% of the wild-type level in 18-month-old LRRK2 knockout mice. Unexpectedly, this reduction was restored to wild-type levels when the knockout mice were 22 months to 23 months old, implying a feedback mechanism regulating kidney EPO expression. Our findings reveal a novel function of LRRK2 in regulating EPO expression and imply a potentially novel relationship between PD genes and hematopoiesis.

  16. Increased Renal Proximal Convoluted Tubule Transport Contributes to Hypertension in Cyp4a14 Knockout Mice

    PubMed Central

    Quigley, Raymond; Chakravarty, Sumana; Zhao, Xueying; Imig, John D.; Capdevila, Jorge H.

    2009-01-01

    Background/Aims Disrupting the enzyme Cyp4a14 in mice leads to hypertension, which is more severe in the male mice and appears to be due to androgen excess. Because the Cyp4a14 enzyme is located in the proximal tubule of the kidney, we hypothesized that there could be dysregulation of transport in this segment that could contribute to the hypertension. Methods Wild-type (SV/129) mice and mice that had targeted disruption of the Cyp4a14 gene were studied. Proximal convoluted tubules (PCT) from knockout and wild-type mice were dissected and perfused in vitrofor measurement of volume absorption (JV). Expression of the sodium-hydrogen exchanger 3 (NHE3), the predominant transporter responsible for sodium transport in this segment, was measured by immunoblot. Renal vascular (afferent arteriole) responses to angiotensin and endothelin were also measured. Results PCT volume absorption was elevated in tubules from the Cyp4a14 knockout mice as compared to the wild-type mice. Brush border membrane NHE3 expression was almost 2-fold higher in Cyp4a14 knockout mice than in wild-type mice. No difference was found in the afferent arteriolar response. Conclusion Thus, hypertension in the Cyp4a14 knockout mice appears to be driven by excessive fluid reabsorption in the proximal tubule, which is secondary to overexpression of NHE3. PMID:19713718

  17. SPERM MOTILITY IN HSF1 KNOCKOUT MICE AFTER HEAT SHOCK IS ASSOCIATED WITH FERTILITY DEFICITS

    EPA Science Inventory

    SPERM MOTILITY IN HSF1 KNOCKOUT MICE AFTER HEAT SHOCK IS ASSOCIATED WITH FERTILITY DEFICITS. L.F. Strader*, S.D. Perreault, J.C. Luft*, and D.J. Dix*. US EPA/ORD, Reproductive Toxicology Div., Research Triangle Park, NC
    Heat shock proteins (HSPs) protect cells from environm...

  18. Targeted gene knockout in mammalian cells by using engineered zinc-finger nucleases

    PubMed Central

    Santiago, Yolanda; Chan, Edmond; Liu, Pei-Qi; Orlando, Salvatore; Zhang, Lin; Urnov, Fyodor D.; Holmes, Michael C.; Guschin, Dmitry; Waite, Adam; Miller, Jeffrey C.; Rebar, Edward J.; Gregory, Philip D.; Klug, Aaron; Collingwood, Trevor N.

    2008-01-01

    Gene knockout is the most powerful tool for determining gene function or permanently modifying the phenotypic characteristics of a cell. Existing methods for gene disruption are limited by their efficiency, time to completion, and/or the potential for confounding off-target effects. Here, we demonstrate a rapid single-step approach to targeted gene knockout in mammalian cells, using engineered zinc-finger nucleases (ZFNs). ZFNs can be designed to target a chosen locus with high specificity. Upon transient expression of these nucleases the target gene is first cleaved by the ZFNs and then repaired by a natural—but imperfect—DNA repair process, nonhomologous end joining. This often results in the generation of mutant (null) alleles. As proof of concept for this approach we designed ZFNs to target the dihydrofolate reductase (DHFR) gene in a Chinese hamster ovary (CHO) cell line. We observed biallelic gene disruption at frequencies >1%, thus obviating the need for selection markers. Three new genetically distinct DHFR−/− cell lines were generated. Each new line exhibited growth and functional properties consistent with the specific knockout of the DHFR gene. Importantly, target gene disruption is complete within 2–3 days of transient ZFN delivery, thus enabling the isolation of the resultant DHFR−/− cell lines within 1 month. These data demonstrate further the utility of ZFNs for rapid mammalian cell line engineering and establish a new method for gene knockout with application to reverse genetics, functional genomics, drug discovery, and therapeutic recombinant protein production. PMID:18359850

  19. Glutamate transporter type 3 knockout reduces brain tolerance to focal brain ischemia in mice.

    PubMed

    Li, Liaoliao; Zuo, Zhiyi

    2011-05-01

    Excitatory amino-acid transporters (EAATs) transport glutamate into cells under physiologic conditions. Excitatory amino-acid transporter type 3 (EAAT3) is the major neuronal EAAT and also uptakes cysteine, the rate-limiting substrate for synthesis of glutathione. Thus, we hypothesize that EAAT3 contributes to providing brain ischemic tolerance. Male 8-week-old EAAT3 knockout mice on CD-1 mouse gene background and wild-type CD-1 mice were subjected to right middle cerebral artery occlusion for 90 minutes. Their brain infarct volumes, neurologic functions, and brain levels of glutathione, nitrotyrosine, and 4-hydroxy-2-nonenal (HNE) were evaluated. The EAAT3 knockout mice had bigger brain infarct volumes and worse neurologic deficit scores and motor coordination functions than did wild-type mice, no matter whether these neurologic outcome parameters were evaluated at 24 hours or at 4 weeks after brain ischemia. The EAAT3 knockout mice contained higher levels of HNE in the ischemic penumbral cortex and in the nonischemic cerebral cortex than did wild-type mice. Glutathione levels in the ischemic and nonischemic cortices of EAAT3 knockout mice tended to be lower than those of wild-type mice. Our results suggest that EAAT3 is important in limiting ischemic brain injury after focal brain ischemia. This effect may involve attenuating brain oxidative stress.

  20. Brief Report: Altered Social Behavior in Isolation-Reared "Fmr1" Knockout Mice

    ERIC Educational Resources Information Center

    Heitzer, Andrew M.; Roth, Alexandra K.; Nawrocki, Lauren; Wrenn, Craige C.; Valdovinos, Maria G.

    2013-01-01

    Social behavior abnormalities in Fragile X syndrome (FXS) are characterized by social withdrawal, anxiety, and deficits in social cognition. To assess these deficits, a model of FXS, the "Fmr1" knockout mouse ("Fmr1" KO), has been utilized. This mouse model has a null mutation in the fragile X mental retardation 1 gene ("Fmr1") and displays…

  1. IdealKnock: A framework for efficiently identifying knockout strategies leading to targeted overproduction.

    PubMed

    Gu, Deqing; Zhang, Cheng; Zhou, Shengguo; Wei, Liujing; Hua, Qiang

    2016-04-01

    In recent years, computer aided redesigning methods based on genome-scale metabolic network models (GEMs) have played important roles in metabolic engineering studies; however, most of these methods are hindered by intractable computing times. In particular, methods that predict knockout strategies leading to overproduction of desired biochemical are generally unable to do high level prediction because the computational time will increase exponentially. In this study, we propose a new framework named IdealKnock, which is able to efficiently evaluate potentials of the production for different biochemical in a system by merely knocking out pathways. In addition, it is also capable of searching knockout strategies when combined with the OptKnock or OptGene framework. Furthermore, unlike other methods, IdealKnock suggests a series of mutants with targeted overproduction, which enables researchers to select the one of greatest interest for experimental validation. By testing the overproduction of a large number of native metabolites, IdealKnock showed its advantage in successfully breaking through the limitation of maximum knockout number in reasonable time and suggesting knockout strategies with better performance than other methods. In addition, gene-reaction relationship is well considered in the proposed framework.

  2. Highly Efficient Genome Editing via CRISPR/Cas9 to Create Clock Gene Knockout Cells.

    PubMed

    Korge, Sandra; Grudziecki, Astrid; Kramer, Achim

    2015-10-01

    Targeted genome editing using CRISPR/Cas9 is a relatively new, revolutionary technology allowing for efficient and directed alterations of the genome. It has been widely used for loss-of-function studies in animals and cell lines but has not yet been used to study circadian rhythms. Here, we describe the application of CRISPR/Cas9 genome editing for the generation of an F-box and leucine-rich repeat protein 3 (Fbxl3) knockout in a human cell line. Genomic alterations at the Fbxl3 locus occurred with very high efficiency (70%-100%) and specificity at both alleles, resulting in insertions and deletions that led to premature stop codons and hence FBXL3 knockout. Fbxl3 knockout cells displayed low amplitude and long period oscillations of Bmal1-luciferase reporter activity as well as increased CRY1 protein stability in line with previously published phenotypes for Fbxl3 knockout in mice. Thus, CRISPR/Cas9 genome editing should be highly valuable for studying circadian rhythms not only in human cells but also in classic model systems as well as nonmodel organisms.

  3. Simultaneous paralogue knockout using a CRISPR-concatemer in mouse small intestinal organoids.

    PubMed

    Andersson-Rolf, Amanda; Merenda, Alessandra; Mustata, Roxana C; Li, Taibo; Dietmann, Sabine; Koo, Bon-Kyoung

    2016-10-27

    Approaches based on genetic modification have been invaluable for investigating a wide array of biological processes, with gain- and loss-of-function approaches frequently used to investigate gene function. However, the presence of paralogues, and hence possible genetic compensation, for many genes necessitates the knockout (KO) of all paralogous genes in order to observe clear phenotypic change. CRISPR technology, the most recently described tool for gene editing, can generate KOs with unprecedented ease and speed and has been used in adult stem cell-derived organoids for single gene knockout, gene knock-in and gene correction. However, the simultaneous targeting of multiple genes in organoids by CRISPR technology has not previously been described. Here we describe a rapid, scalable and cost effective method for generating double knockouts in organoids. By concatemerizing multiple gRNA expression cassettes, we generated a 'gRNA concatemer vector'. Our method allows the rapid assembly of annealed synthetic DNA oligos into the final vector in a single step. This approach facilitates simultaneous delivery of multiple gRNAs to allow up to 4 gene KO in one step, or potentially to increase the efficiency of gene knockout by providing multiple gRNAs targeting one gene. As a proof of concept, we knocked out negative regulators of the Wnt pathway in small intestinal organoids, thereby removing their growth dependence on the exogenous Wnt enhancer, R-spondin1.

  4. Generation and Behavioral Characterization of β-catenin Forebrain-Specific Conditional Knock-Out Mice

    PubMed Central

    Gould, Todd D.; O'Donnell, Kelley C.; Picchini, Alyssa M.; Dow, Eliot R.; Chen, Guang; Manji, Husseini K.

    2009-01-01

    The canonical Wnt pathway and β-catenin have been implicated in the pathophysiology of mood disorders. We generated forebrain-specific CRE-mediated conditional β-catenin knockout mice to begin exploring the behavioral implications of decreased Wnt pathway signaling in the central nervous system. In situ hybridization revealed a progressive knockout of β-catenin that began between 2 and 4 weeks of age, and by 12 weeks resulted in considerably decreased β-catenin expression in regions of the forebrain, including the frontal cortex, hippocampus, and striatum. A significant decrease in protein levels of β-catenin in these brain regions was observed by western blot. Behavioral characterization of these mice in several tests (including the forced swim test, tail suspension test (TST), learned helplessness, response and sensitization to stimulants, and light/dark box among other tests) revealed relatively circumscribed alterations. In the TST, knockout mice spent significantly less time struggling (a depression-like phenotype). However, knockout mice did not differ from their wild-type littermates in the other behavioral tests of mood-related or anxiety-related behaviors. These results suggest that a considerable β-catenin reserve exists, and that a 50-70% β-catenin reduction in circumscribed brain regions is only capable of inducing subtle behavioral changes. Alternatively, regulating β-catenin may modulate drug effects rather than being a model of mood disorder pathophysiology per se. PMID:18299155

  5. The Importance of Immunohistochemical Analyses in Evaluating the Phenotype of Kv Channel Knockout Mice

    PubMed Central

    Menegola, Milena; Clark, Eliana; Trimmer, James S.

    2012-01-01

    Summary To gain insights into the phenotype of Kv1.1 and Kv4.2 knockout mice, we used immunohistochemistry to analyze expression of component principal or α subunits and auxiliary subunits of neuronal Kv channels in knockout mouse brains. Genetic ablation of the Kv1.1 α subunit did not result in compensatory changes in the expression levels or subcellular distribution of related ion channel subunits in hippocampal medial perforant path and mossy fiber nerve terminals, where high levels of Kv1.1 are normally expressed. Genetic ablation of the Kv4.2 α subunit did not result in altered neuronal cytoarchitecture of the hippocampus. While Kv4.2 knockout mice did not exhibit compensatory changes in the expression levels or subcellular distribution of the related Kv4.3 α subunit, we found dramatic decreases in the cellular and subcellular expression of specific KChIPs that reflected their degree of association and colocalization with Kv4.2 in wild-type mouse and rat brains. These studies highlight the insights that can be gained by performing detailed immunohistochemical analyses of Kv channel knockout mouse brains. PMID:22612819

  6. Bifurcation theory and cardiac arrhythmias

    PubMed Central

    Karagueuzian, Hrayr S; Stepanyan, Hayk; Mandel, William J

    2013-01-01

    In this paper we review two types of dynamic behaviors defined by the bifurcation theory that are found to be particularly useful in describing two forms of cardiac electrical instabilities that are of considerable importance in cardiac arrhythmogenesis. The first is action potential duration (APD) alternans with an underlying dynamics consistent with the period doubling bifurcation theory. This form of electrical instability could lead to spatially discordant APD alternans leading to wavebreak and reentrant form of tachyarrhythmias. Factors that modulate the APD alternans are discussed. The second form of bifurcation of importance to cardiac arrhythmogenesis is the Hopf-homoclinic bifurcation that adequately describes the dynamics of the onset of early afterdepolarization (EAD)-mediated triggered activity (Hopf) that may cause ventricular tachycardia and ventricular fibrillation (VT/VF respectively). The self-termination of the triggered activity is compatible with the homoclinic bifurcation. Ionic and intracellular calcium dynamics underlying these dynamics are discussed using available experimental and simulation data. The dynamic analysis provides novel insights into the mechanisms of VT/VF, a major cause of sudden cardiac death in the US. PMID:23459417

  7. Device Assists Cardiac Chest Compression

    NASA Technical Reports Server (NTRS)

    Eichstadt, Frank T.

    1995-01-01

    Portable device facilitates effective and prolonged cardiac resuscitation by chest compression. Developed originally for use in absence of gravitation, also useful in terrestrial environments and situations (confined spaces, water rescue, medical transport) not conducive to standard manual cardiopulmonary resuscitation (CPR) techniques.

  8. Cardiac arrest during dipyridamole imaging

    SciTech Connect

    Blumenthal, M.S.; McCauley, C.S.

    1988-05-01

    A case of cardiac arrest and subsequent acute myocardial infarction occurring during thallium-201 imaging with oral dipyridamole augmentation is presented. Previous reports emphasizing the safety of this procedure are briefly reviewed and a recommendation for close hemodynamic and arrhythmia monitoring during the study is made. Large doses of oral dipyridamole may be contraindicated in patients with unstable angina.

  9. Guide to prosthetic cardiac valves

    SciTech Connect

    Morse, D.; Steiner, R.M.; Fernandez, J.

    1985-01-01

    This book contains 10 chapters. Some of the chapter titles are: The development of artificial heart valves: Introduction and historical perspective; The radiology of prosthetic heart valves; The evaluation of patients for prosthetic valve implantation; Pathology of cardiac valve replacement; and Bioengineering of mechanical and biological heart valve substitutes.

  10. Cardiac sarcoidosis: diagnosis and management.

    PubMed

    Dubrey, S W; Sharma, R; Underwood, R; Mittal, T

    2015-07-01

    Cardiac sarcoidosis is one of the most serious and unpredictable aspects of this disease state. Heart involvement frequently presents with arrhythmias or conduction disease, although myocardial infiltration resulting in congestive heart failure may also occur. The prognosis in cardiac sarcoidosis is highly variable, which relates to the heterogeneous nature of heart involvement and marked differences between racial groups. Electrocardiography and echocardiography often provide the first clue to the diagnosis, but advanced imaging studies using positron emission tomography and MRI, in combination with nuclear isotope perfusion scanning are now essential to the diagnosis and management of this condition. The identification of clinically occult cardiac sarcoidosis and the management of isolated and/or asymptomatic heart involvement remain both challenging and contentious. Corticosteroids remain the first treatment choice with the later substitution of immunosuppressive and steroid-sparing therapies. Heart transplantation is an unusual outcome, but when performed, the results are comparable or better than heart transplantation for other disease states. We review the epidemiology, developments in diagnostic techniques and the management of cardiac sarcoidosis.

  11. Cardiac arrhythmias in paediatric practice.

    PubMed

    Chan, K Y; Loke, K Y; Yip, W C; Tay, J S

    1989-01-01

    Clinical data of patients with cardiac arrhythmias managed between May 1986 and March 1988 were reviewed to determine their mode of presentation and clinical course. Of the 5,768 admissions, 62 (1.07%) patients had arrhythmias. During the same period, 21 patients were managed as outpatients with 13 being new referrals. Thirty-eight patients had undergone corrective cardiac procedures, 8 others had congenital heart lesions, 3 were associated with acquired cardiac pathology and the remaining had isolated arrhythmias. The cardiac arrhythmias were: right bundle branch block 36, premature atrial and ventricular contractions 15, supraventricular tachycardia (SVT) 15, atrioventricular (AV) block 7, sinus bradycardia 3, atrial fibrillation 2, ventricular tachycardia and fibrillation 2, Wolff-Parkinson-White syndrome without SVT 2, bradytachyarrhythmia 1. There were 3 patients with foetal SVT, one persisting till day 1. High grade AV block occurred in 2 patients post-surgically and needed pacing. Only 2 others were symptomatic. Other than the 38 patients who underwent corrective procedures (2 had balloon valvuloplasty for pulmonary stenosis), 8 others had structural heart disease. There was 1 sudden death and 5 died from their primary heart disease.

  12. Automatic referral to cardiac rehabilitation.

    PubMed

    Fischer, Jane P

    2008-01-01

    The pervasive negative impact of cardiovascular disease in the United States is well documented. Although advances have been made, the campaign to reduce the occurrence, progression, and mortality continues. Determining evidence-based data is only half the battle. Implementing new and updated clinical guidelines into daily practice is a challenging task. Cardiac rehabilitation is an example of a proven intervention whose benefit is hindered through erratic implementation. The American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR), the American College of Cardiology (ACC), and the American Heart Association (AHA) have responded to this problem by publishing the AACVPR/ACC/AHA 2007 Performance Measures on Cardiac Rehabilitation for Referral to and Delivery of Cardiac Rehabilitation/Secondary Prevention Services. This new national guideline recommends automatic referral to cardiac rehabilitation for every eligible patient (performance measure A-1). This article offers guidance for the initiation of an automatic referral system, including individualizing your protocol with regard to electronic or paper-based order entry structures.

  13. Molecular Modeling of Cardiac Troponin

    NASA Astrophysics Data System (ADS)

    Manning, Edward P.

    The cardiac thin filament regulates interactions of actin and myosin, the force-generating elements of muscular contraction. Over the past several decades many details have been discovered regarding the structure and function of the cardiac thin filament and its components, including cardiac troponin (cTn). My hypothesis is that signal propagation occurs between distant ends of the cardiac troponin complex through calcium-dependent alterations in the dynamics of cTn and tropomyosin (Tm). I propose a model of the thin filament that encompasses known structures of cTn, Tm and actin to gain insight into cardiac troponin's allosteric regulation of thin filament dynamics. By performing molecular dynamics simulations of cTn in conjunction with overlapping Tm in two conditions, with and without calcium bound to site II of cardiac troponin C (cTnC), I found a combination of calcium-dependent changes in secondary structure and dynamics throughout the cTn-Tm complex. I then applied this model to investigate familial hypertrophic cardiomyopathy (FHC), a disease of the sarcomere that is one of the most commonly occurring genetic causes of heart disease. Approximately 15% of known FHC-related mutations are found in cardiac troponin T (cTnT), most of which are in or flank the alpha-helical N-tail domain TNT1. TNT1 directly interacts with overlapping Tm coiled coils. Using this model I identified effects of TNT1 mutations that propagate to the cTn core where site II of cTnC, the regulatory site of calcium binding in the thin filament, is located. Specifically, I found that mutations in TNT1 alter the flexibility of TNT1 and that the flexibility of TNT1 is inversely proportional to the cooperativity of calcium activation of the thin filament. Further, I identified a pathway of propagation of structural and dynamic changes linking TNT1 to site II of cTnC. Mutation-induced changes at site II cTnC alter calcium coordination which corresponds to biophysical measurements of calcium

  14. Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain.

    PubMed

    Gingras, Jacinthe; Smith, Sarah; Matson, David J; Johnson, Danielle; Nye, Kim; Couture, Lauren; Feric, Elma; Yin, Ruoyuan; Moyer, Bryan D; Peterson, Matthew L; Rottman, James B; Beiler, Rudolph J; Malmberg, Annika B; McDonough, Stefan I

    2014-01-01

    Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund's adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain.

  15. FMR1 Knockout mice: A model to study fragile X mental retardation

    SciTech Connect

    Oostra, B.A.; Bakker, C.E.; Reyniers, E.

    1994-09-01

    The fragile X syndrome is the most frequent form of inherited mental retardation in humans with an incidence of 1 in 1250 males and 1 in 2500 females. The clinical syndrome includes moderate to severe mental retardation, autistic behavior, macroorchidism, and facial features, such as long face with mandibular prognathism and large, everted ears. The molecular basis for this disease is a large expansion of a triplet repeat (CGG){sub n} in the 5{prime} untranslated region of the FMR1 gene. Due to this large expansion of the CGG repeat, the promoter region becomes methylated and the FMR1 gene is subsequently silenced. Hardly anything is known about the physiologic function of FMR1 and the pathologic mechanisms leading to these symptoms. Since the FMR1 gene is highly conserved in the mouse, we used the mouse to design a knockout model for the fragile X syndrome. These knockout mice lacking Fmrp have normal litter size suggesting that FMR1 is not essential in human gametogenesis and embryonic development. The knockout mice show the abnormalities also seen in the affected organs of human patients. Mutant mice show a gradual development through time of macroorchidism. In the knockout mice we observed cognitive defects in the form of deficits in learning (as shown by the hidden platform Morris water maze task) and behavioral abnormalities such as increased exploratory behavior and hyperactivity. Therefore this knockout mouse may serve as a valuable tool in studying the role of FMR1 in the fragile X syndrome and may serve as a model to elucidate the mechanisms involved in macroorchidism, abnormal behavior, and mental retardation.

  16. Knockout mutations of insulin-like peptide genes enhance sexual receptivity in Drosophila virgin females.

    PubMed

    Watanabe, Kazuki; Sakai, Takaomi

    2016-01-01

    In the fruitfly Drosophila melanogaster, females take the initiative to mate successfully because they decide whether to mate or not. However, little is known about the molecular and neuronal mechanisms regulating sexual receptivity in virgin females. Genetic tools available in Drosophila are useful for identifying molecules and neural circuits involved in the regulation of sexual receptivity. We previously demonstrated that insulin-producing cells (IPCs) in the female brain are critical to the regulation of female sexual receptivity. Ablation and inactivation of IPCs enhance female sexual receptivity, suggesting that neurosecretion from IPCs inhibits female sexual receptivity. IPCs produce and release insulin-like peptides (Ilps) that modulate various biological processes such as metabolism, growth, lifespan and behaviors. Here, we report a novel role of the Ilps in sexual behavior in Drosophila virgin females. Compared with wild-type females, females with knockout mutations of Ilps showed a high mating success rate toward wild-type males, whereas wild-type males courted wild-type and Ilp-knockout females to the same extent. Wild-type receptive females retard their movement during male courtship and this reduced female mobility allows males to copulate. Thus, it was anticipated that knockout mutations of Ilps would reduce general locomotion. However, the locomotor activity in Ilp-knockout females was significantly higher than that in wild-type females. Thus, our findings indicate that the high mating success rate in Ilp-knockout females is caused by their enhanced sexual receptivity, but not by improvement of their sex appeal or by general sluggishness.

  17. Global Nav1.7 Knockout Mice Recapitulate the Phenotype of Human Congenital Indifference to Pain

    PubMed Central

    Gingras, Jacinthe; Smith, Sarah; Matson, David J.; Johnson, Danielle; Nye, Kim; Couture, Lauren; Feric, Elma; Yin, Ruoyuan; Moyer, Bryan D.; Peterson, Matthew L.; Rottman, James B.; Beiler, Rudolph J.; Malmberg, Annika B.; McDonough, Stefan I.

    2014-01-01

    Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund’s adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain. PMID:25188265

  18. Cardiac ablation of Rheb1 induces impaired heart growth, endoplasmic reticulum-associated apoptosis and heart failure in infant mice.

    PubMed

    Cao, Yunshan; Tao, Lichan; Shen, Shutong; Xiao, Junjie; Wu, Hang; Li, Beibei; Wu, Xiangqi; Luo, Wen; Xiao, Qi; Hu, Xiaoshan; Liu, Hailang; Nie, Junwei; Lu, Shuangshuang; Yuan, Baiyin; Han, Zhonglin; Xiao, Bo; Yang, Zhongzhou; Li, Xinli

    2013-12-13

    Ras homologue enriched in brain 1 (Rheb1) plays an important role in a variety of cellular processes. In this study, we investigate the role of Rheb1 in the post-natal heart. We found that deletion of the gene responsible for production of Rheb1 from cardiomyocytes of post-natal mice resulted in malignant arrhythmias, heart failure, and premature death of these mice. In addition, heart growth impairment, aberrant metabolism relative gene expression, and increased cardiomyocyte apoptosis were observed in Rheb1-knockout mice prior to the development of heart failure and arrhythmias. Also, protein kinase B (PKB/Akt) signaling was enhanced in Rheb1-knockout mice, and removal of phosphatase and tensin homolog (Pten) significantly prolonged the survival of Rheb1-knockouts. Furthermore, signaling via the mammalian target of rapamycin complex 1 (mTORC1) was abolished and C/EBP homologous protein (CHOP) and phosphorylation levels of c-Jun N-terminal kinase (JNK) were increased in Rheb1 mutant mice. In conclusion, this study demonstrates that Rheb1 is important for maintaining cardiac function in post-natal mice via regulation of mTORC1 activity and stress on the endoplasmic reticulum. Moreover, activation of Akt signaling helps to improve the survival of mice with advanced heart failure. Thus, this study provides direct evidence that Rheb1 performs multiple important functions in the heart of the post-natal mouse. Enhancing Akt activity improves the survival of infant mice with advanced heart failure.

  19. Cardiac arrest: resuscitation and reperfusion.

    PubMed

    Patil, Kaustubha D; Halperin, Henry R; Becker, Lance B

    2015-06-05

    The modern treatment of cardiac arrest is an increasingly complex medical procedure with a rapidly changing array of therapeutic approaches designed to restore life to victims of sudden death. The 2 primary goals of providing artificial circulation and defibrillation to halt ventricular fibrillation remain of paramount importance for saving lives. They have undergone significant improvements in technology and dissemination into the community subsequent to their establishment 60 years ago. The evolution of artificial circulation includes efforts to optimize manual cardiopulmonary resuscitation, external mechanical cardiopulmonary resuscitation devices designed to augment circulation, and may soon advance further into the rapid deployment of specially designed internal emergency cardiopulmonary bypass devices. The development of defibrillation technologies has progressed from bulky internal defibrillators paddles applied directly to the heart, to manually controlled external defibrillators, to automatic external defibrillators that can now be obtained over-the-counter for widespread use in the community or home. But the modern treatment of cardiac arrest now involves more than merely providing circulation and defibrillation. As suggested by a 3-phase model of treatment, newer approaches targeting patients who have had a more prolonged cardiac arrest include treatment of the metabolic phase of cardiac arrest with therapeutic hypothermia, agents to treat or prevent reperfusion injury, new strategies specifically focused on pulseless electric activity, which is the presenting rhythm in at least one third of cardiac arrests, and aggressive post resuscitation care. There are discoveries at the cellular and molecular level about ischemia and reperfusion pathobiology that may be translated into future new therapies. On the near horizon is the combination of advanced cardiopulmonary bypass plus a cocktail of multiple agents targeted at restoration of normal metabolism and

  20. Cardiac energetics: sense and nonsense.

    PubMed

    Gibbs, Colin L

    2003-08-01

    1. The background to current ideas in cardiac energetics is outlined and, in the genomic era, the need is stressed for detailed knowledge of mouse heart mechanics and energetics. 2. The mouse heart is clearly different to the rat in terms of its excitation-contraction (EC) coupling and the common assumption that heart rate difference between mice and humans will account for the eightfold difference in myocardial oxygen consumption is wrong, because the energy per beat of the mouse heart is approximately one-third that of the human heart. 3. In vivo evidence suggests that there may well be an eightfold species difference in the non-beating metabolism of mice and human hearts. It is speculated that the magnitude of basal metabolism in the heart is regulatable and that, in the absence of perfusion, it falls to approximately one-quarter of its in vivo rate and that in clinical conditions, such as hibernation, it probably decreases; its magnitude may be controlled by the endothelium. 4. The active energy balance sheet is briefly discussed and it is suggested that the activation heat accounts for 20-25% of the active energy per beat and cross-bridge turnover accounts for the balance. It is argued that force, not shortening, is the major determinant of cardiac energy usage. 5. The outcome of recent cardiac modelling with variants of the Huxley and Hill/Eisenberg models is described. It has been necessary to invoke 'loose coupling' to replicate the low cardiac energy flux measured at low afterloads (medium to high velocities of shortening). 6. Lastly, some of the unexplained or 'nonsense' energetic data are outlined and eight unsolved problems in cardiac energetics are discussed.

  1. Advances in cardiac processing software.

    PubMed

    Gordon DePuey, Ernest

    2014-07-01

    New software methods that incorporate iterative reconstruction, resolution recovery, and noise compensation now provide the ability to maintain or improve myocardial perfusion SPECT image quality with conventional sodium iodide cameras. Despite lower image counting statistics associated with significantly decreased injected radiopharmaceutical doses or shortened acquisition times or both, image quality is preserved or even improved compared with conventional processing methods. The ability to prescribe a desired myocardial count density by preselecting a SPECT acquisition time now avoids additional patient radiation exposure associated with "weight-based" dosing. More recent advancements, including temporal correlation among the gated perfusion frames and higher resolution SPECT acquisitions, hold promise to further improve image quality and diagnostic accuracy. Phase analysis of gated perfusion SPECT provides the ability to assess cardiac dyssynchrony and to select those patients who will most benefit from resynchronization therapy. In combination with the higher counting statistics afforded by the new solid-state dedicated cardiac cameras, these software advancements allow for even further decreased patient radiation doses or acquisition times or both. List-mode software allows for refinement of myocardial perfusion SPECT by interrogating particular data from selected cardiac cycles. Rejection of frames degraded by arrhythmic cardiac cycles or excessive extracardiac uptake can be excluded for reconstruction. Respiratory gating, which diminishes cardiac motion and potentially decreases diaphragmatic attenuation, has been demonstrated to improve diagnostic specificity. With high-count first-pass list-mode acquisitions at rest and during pharmacologic vasodilatation, it may be possible to measure global and regional myocardial perfusion reserve to more accurately diagnose coronary artery disease and avoid false-negative studies owing to balanced ischemia.

  2. Can cardiac surgery cause hypopituitarism?

    PubMed

    Francis, Flverly; Burger, Ines; Poll, Eva Maria; Reineke, Andrea; Strasburger, Christian J; Dohmen, Guido; Gilsbach, Joachim M; Kreitschmann-Andermahr, Ilonka

    2012-03-01

    Apoplexy of pituitary adenomas with subsequent hypopituitarism is a rare but well recognized complication following cardiac surgery. The nature of cardiac on-pump surgery provides a risk of damage to the pituitary because the vascular supply of the pituitary is not included in the cerebral autoregulation. Thus, pituitary tissue may exhibit an increased susceptibility to hypoperfusion, ischemia or intraoperative embolism. After on-pump procedures, patients often present with physical and psychosocial impairments which resemble symptoms of hypopituitarism. Therefore, we analyzed whether on-pump cardiac surgery may cause pituitary dysfunction also in the absence of pre-existing pituitary disease. Twenty-five patients were examined 3-12 months after on-pump cardiac surgery. Basal hormone levels for all four anterior pituitary hormone axes were measured and a short synacthen test and a growth hormone releasing hormone plus arginine (GHRH-ARG)-test were performed. Quality of life (QoL), depression, subjective distress for a specific life event, sleep quality and fatigue were assessed by means of self-rating questionnaires. Hormonal alterations were only slight and no signs of anterior hypopituitarism were found except for an insufficient growth hormone rise in two overweight patients in the GHRH-ARG-test. Psychosocial impairment was pronounced, including symptoms of moderate to severe depression in 9, reduced mental QoL in 8, dysfunctional coping in 6 and pronounced sleep disturbances in 16 patients. Hormone levels did not correlate with psychosocial impairment. On-pump cardiac surgery did not cause relevant hypopituitarism in our sample of patients and does not serve to explain the psychosocial symptoms of these patients.

  3. Using cardiac biomarkers in veterinary practice.

    PubMed

    Oyama, Mark A

    2013-11-01

    Blood-based assays for various cardiac biomarkers can assist in the diagnosis of heart disease in dogs and cats. The two most common markers are cardiac troponin-I and N-terminal pro-B-type natriuretic peptide. Biomarker assays can assist in differentiating cardiac from noncardiac causes of respiratory signs and detection of preclinical cardiomyopathy. Increasingly, studies indicate that cardiac biomarker testing can help assess the risk of morbidity and mortality in animals with heart disease. Usage of cardiac biomarker testing in clinical practice relies on proper patient selection, correct interpretation of test results, and incorporation of biomarker testing into existing diagnostic methods.

  4. Using Cardiac Biomarkers in Veterinary Practice.

    PubMed

    Oyama, Mark A

    2015-09-01

    Blood-based assays for various cardiac biomarkers can assist in the diagnosis of heart disease in dogs and cats. The two most common markers are cardiac troponin-I and N-terminal pro-B-type natriuretic peptide. Biomarker assays can assist in differentiating cardiac from noncardiac causes of respiratory signs and detection of preclinical cardiomyopathy. Increasingly, studies indicate that cardiac biomarker testing can help assess the risk of morbidity and mortality in animals with heart disease. Usage of cardiac biomarker testing in clinical practice relies on proper patient selection, correct interpretation of test results, and incorporation of biomarker testing into existing diagnostic methods.

  5. Cardiac deficiency of single cytochrome oxidase assembly factor scox induces p53-dependent apoptosis in a Drosophila cardiomyopathy model.

    PubMed

    Martínez-Morentin, Leticia; Martínez, Lidia; Piloto, Sarah; Yang, Hua; Schon, Eric A; Garesse, Rafael; Bodmer, Rolf; Ocorr, Karen; Cervera, Margarita; Arredondo, Juan J

    2015-07-01

    The heart is a muscle with high energy demands. Hence, most patients with mitochondrial disease produced by defects in the oxidative phosphorylation (OXPHOS) system are susceptible to cardiac involvement. The presentation of mitochondrial cardiomyopathy includes hypertrophic, dilated and left ventricular noncompaction, but the molecular mechanisms involved in cardiac impairment are unknown. One of the most frequent OXPHOS defects in humans frequently associated with cardiomyopathy is cytochrome c oxidase (COX) deficiency caused by mutations in COX assembly factors such as Sco1 and Sco2. To investigate the molecular mechanisms that underlie the cardiomyopathy associated with Sco deficiency, we have heart specifically interfered scox expression, the single Drosophila Sco orthologue. Cardiac-specific knockdown of scox reduces fly lifespan, and it severely compromises heart function and structure, producing dilated cardiomyopathy. Cardiomyocytes with low levels of scox have a significant reduction in COX activity and they undergo a metabolic switch from OXPHOS to glycolysis, mimicking the clinical features found in patients harbouring Sco mutations. The major cardiac defects observed are produced by a significant increase in apoptosis, which is dp53-dependent. Genetic and molecular evidence strongly suggest that dp53 is directly involved in the development of the cardiomyopathy induced by scox deficiency. Remarkably, apoptosis is enhanced in the muscle and liver of Sco2 knock-out mice, clearly suggesting that cell death is a key feature of the COX deficiencies produced by mutations in Sco genes in humans.

  6. Cardiac catheterization laboratory imaging quality assurance program.

    PubMed

    Wondrow, M A; Laskey, W K; Hildner, F J; Cusma, J; Holmes, D R

    2001-01-01

    With the recent approval of the National Electrical Manufacturers Association (NEMA) standard for "Characteristics of and Test Procedures for a Phantom to Benchmark Cardiac Fluoroscopic and Photographic Performance," comprehensive cardiac image assurance control programs are now possible. This standard was developed by a joint NEMA/Society for Cardiac Angiography and Interventions (SCA&I) working group of imaging manufacturers and cardiology society professionals over the past 4 years. This article details a cardiac catheterization laboratory image quality assurance and control program that includes the new standard along with current regulatory requirements for cardiac imaging. Because of the recent proliferation of digital imaging equipment, quality assurance for cardiac imaging fluoroscopy and digital imaging are critical. Included are the previous works recommended by the American College of Cardiology (ACC) and American Heart Association (AHA), Society for Cardiac Angiographers and Interventions (SCA&I), and authors of previous image quality subjects.

  7. Cardiac rehabilitation improves the blood plasma properties of cardiac patients.

    PubMed

    Gwoździński, Krzysztof; Pieniążek, Anna; Czepas, Jan; Brzeszczyńska, Joanna; Jegier, Anna; Pawlicki, Lucjan

    2016-11-01

    Cardiac rehabilitation (CR) improves exercise tolerance and general function. However, its effects on blood plasma in cardiac patients remain uncertain. Our aim was to examine the effect of comprehensive CR on the oxidative stress parameters and antioxidant plasma status in patients with coronary artery disease (CAD) after cardiac interventions. Exercise-based rehabilitation was established as ergometer training, adjusted for individual patients' physical efficiency. Training was repeated three times a week for two months. The standard biochemical (total cholesterol, HDL, LDL, triglycerides and erythrocyte sedimentation rate) and metabolic parameters (peak oxygen uptake [VO2] and peak workload) were determined. We assessed plasma viscosity, lipid peroxidation, carbonyl compounds levels, glutathione (GSH) and ascorbate (ASC) levels and the non-enzymatic antioxidant capacity of plasma in 12 patients with CAD before and after CR. Parameters were examined before exercise, immediately after exercise, and 1 h later. We also compared morphological and biochemical parameters of blood, as well as other parameters such as heart rate and blood pressure (resting and exercise), VO2max and peak workload (W) before and after CR. Before CR, a significant decrease in GSH concentration was observed 1 h after exercise. Conversely, after CR, GSH, and ASC levels remained unchanged immediately after exercise. However, ASC increased after CR after exercise and 1 h later in comparison to before CR. There was a significant increase in ferric reduction ability of plasma immediately after exercise after CR, when compared with before CR. CR improved several blood biochemical parameters, peak VO2, induced an increase in systolic blood pressure peak, and patients' peak workload. After CR, improvements were detected in oxidative stress parameters, except in the level of carbonyls. These changes may contribute to the increased functional heart capacity and better tolerance to exercise and

  8. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by β-Adrenergic Stimulation

    PubMed Central

    Shawl, Asif Iqbal; Im, Soo-Yeul; Nam, Tae-Sik; Lee, Sun-Hwa; Ko, Jae-Ki; Jang, Kyu Yoon; Kim, Donghee; Kim, Uh-Hyun

    2016-01-01

    Ca2+ signaling plays a fundamental role in cardiac hypertrophic remodeling, but the underlying mechanisms remain poorly understood. We investigated the role of Ca2+-mobilizing second messengers, NAADP and cADPR, in the cardiac hypertrophy induced by β-adrenergic stimulation by isoproterenol. Isoproterenol induced an initial Ca2+ transients followed by sustained Ca2+ rises. Inhibition of the cADPR pathway with 8-Br-cADPR abolished only the sustained Ca2+ increase, whereas inhibition of the NAADP pathway with bafilomycin-A1 abolished both rapid and sustained phases of the isoproterenol-mediated signal, indicating that the Ca2+ signal is mediated by a sequential action of NAADP and cADPR. The sequential production of NAADP and cADPR was confirmed biochemically. The isoproterenol-mediated Ca2+ increase and cADPR production, but not NAADP production, were markedly reduced in cardiomyocytes obtained from CD38 knockout mice. CD38 knockout mice were rescued from chronic isoproterenol infusion-induced myocardial hypertrophy, interstitial fibrosis, and decrease in fractional shortening and ejection fraction. Thus, our findings indicate that β-adrenergic stimulation contributes to the development of maladaptive cardiac hypertrophy via Ca2+ signaling mediated by NAADP-synthesizing enzyme and CD38 that produce NAADP and cADPR, respectively. PMID:26959359

  9. Cyclosporine A Treatment Inhibits Abcc6-Dependent Cardiac Necrosis and Calcification following Coxsackievirus B3 Infection in Mice

    PubMed Central

    Marton, Jennifer; Albert, Danica; Wiltshire, Sean A.; Park, Robin; Bergen, Arthur; Qureshi, Salman; Malo, Danielle; Burelle, Yan; Vidal, Silvia M.

    2015-01-01

    Coxsackievirus type B3 (CVB3) is a cardiotropic enterovirus. Infection causes cardiomyocyte necrosis and myocardial inflammation. The damaged tissue that results is replaced with fibrotic or calcified tissue, which can lead to permanently altered cardiac function. The extent of pathogenesis among individuals exposed to CVB3 is dictated by a combination of host genetics, viral virulence, and the environment. Here, we aimed to identify genes that modulate cardiopathology following CVB3 infection. 129S1 mice infected with CVB3 developed increased cardiac pathology compared to 129X1 substrain mice despite no difference in viral burden. Linkage analysis identified a major locus on chromosome 7 (LOD: 8.307, P<0.0001) that controlled the severity of cardiac calcification and necrosis following infection. Sub-phenotyping and genetic complementation assays identified Abcc6 as the underlying gene. Microarray expression profiling identified genotype-dependent regulation of genes associated with mitochondria. Electron microscopy examination showed elevated deposition of hydroxyapatite-like material in the mitochondrial matrices of infected Abcc6 knockout (Abcc6-/-) mice but not in wildtype littermates. Cyclosporine A (CsA) inhibits mitochondrial permeability transition pore opening by inhibiting cyclophilin D (CypD). Treatment of Abcc6 -/- mice with CsA reduced cardiac necrosis and calcification by more than half. Furthermore, CsA had no effect on the CVB3-induced phenotype of doubly deficient CypD-/-Abcc6-/- mice. Altogether, our work demonstrates that mutations in Abcc6 render mice more susceptible to cardiac calcification following CVB3 infection. Moreover, we implicate CypD in the control of cardiac necrosis and calcification in Abcc6-deficient mice, whereby CypD inhibition is required for cardioprotection. PMID:26375467

  10. Maltodextrin and fat preference deficits in "taste-blind" P2X2/P2X3 knockout mice.

    PubMed

    Sclafani, Anthony; Ackroff, Karen

    2014-07-01

    Adenosine triphosphate is a critical neurotransmitter in the gustatory response to the 5 primary tastes in mice. Genetic deletion of the purinergic P2X2/P2X3 receptor greatly reduces the neural and behavioral response to prototypical primary taste stimuli. In this study, we examined the behavioral response of P2X double knockout mice to maltodextrin and fat stimuli, which appear to activate additional taste channels. P2X double knockout and wild-type mice were given 24-h choice tests (vs. water) with ascending concentrations of Polycose and Intralipid. In Experiment 1, naive double knockout mice, unlike wild-type mice, were indifferent to dilute (0.5-4%) Polycose solutions but preferred concentrated (8-32%) Polycose to water. In a retest, the Polycose-experienced double knockout mice, like wild-type mice, preferred all Polycose concentrations. In Experiment 2, naive double knockout mice, unlike wild-type mice, were indifferent to dilute (0.313-2.5%) Intralipid emulsions but preferred concentrated (5-20%) Intralipid to water. In a retest, the fat-experienced double knockout mice, like wild-type mice, strongly preferred 0.313-5% Intralipid to water. These results indicate that the inherent preferences of mice for maltodextrin and fat are dependent upon adenosine triphosphate taste cell signaling. With experience, however, P2X double knockout mice develop strong preferences for the nontaste flavor qualities of maltodextrin and fat conditioned by the postoral actions of these nutrients.

  11. Cerebellar defects in Pdss2 conditional knockout mice during embryonic development and in adulthood.

    PubMed

    Lu, Song; Lu, Lin-Yu; Liu, Meng-Fei; Yuan, Qiu-Ju; Sham, Mai-Har; Guan, Xin-Yuan; Huang, Jian-Dong

    2012-01-01

    PDSS2 is a gene that encodes one of the two subunits of trans-prenyl diphosphate synthase that is essential for ubiquinone biosynthesis. It is known that mutations in PDSS2 can cause primary ubiquinone deficiency in humans and a similar disease in mice. Cerebellum is the most often affected organ in ubiquinone deficiency, and cerebellar atrophy has been diagnosed in many infants with this disease. In this study, two Pdss2 conditional knockout mouse lines directed by Pax2-cre and Pcp2-cre were generated to investigate the effect of ubiquinone deficiency on cerebellum during embryonic development and in adulthood, respectively. The Pdss2(f/-); Pax2-cre mouse recapitulates some symptoms of ubiquinone deficiency in infants, including severe cerebellum hypoplasia and lipid accumulation in skeletal muscles at birth. During early cerebellum development (E12.5-14.5), Pdss2 knockout initially causes the delay of radial glial cell growth and neuron progenitor migration, so the growth of mutant cerebellum is retarded. During later development (E15.5-P0), increased ectopic apoptosis of neuroblasts and impaired cell proliferation result in the progression of cerebellum hypoplasia in the mutant. Thus, the mutant cerebellum contains fewer neurons at birth, and the cells are disorganized. The developmental defect of mutant cerebellum does not result from reduced Fgf8 expression before E12.5. Electron microscopy reveals mitochondrial defects and increased autophagic-like vacuolization that may arise in response to abnormal mitochondria in the mutant cerebellum. Nevertheless, the mutant mice die soon after birth probably due to cleft palate and micrognathia, which may result from Pdss2 knockout caused by ectopic Pax2-cre expression in the first branchial arch. On the other hand, the Pdss2(f/-); Pcp2-cre mouse is healthy at birth but gradually loses cerebellar Purkinje cells and develops ataxia-like symptoms at 9.5 months; thus this conditional knockout mouse may serve as a model for

  12. Characterisation of iunH gene knockout strain from Mycobacterium tuberculosis

    PubMed Central

    Villela, Anne Drumond; Rodrigues, Valnês da Silva; Pinto, Antônio Frederico Michel; Wink, Priscila Lamb; Sánchez-Quitian, Zilpa Adriana; Petersen, Guilherme Oliveira; Campos, Maria Martha; Basso, Luiz Augusto; Santos, Diógenes Santiago

    2017-01-01

    BACKGROUND Tuberculosis (TB) is an infectious disease caused mainly by the bacillus Mycobacterium tuberculosis. The better understanding of important metabolic pathways from M. tuberculosis can contribute to the development of novel therapeutic and prophylactic strategies to combat TB. Nucleoside hydrolase (MtIAGU-NH), encoded by iunH gene (Rv3393), is an enzyme from purine salvage pathway in M. tuberculosis. MtIAGU-NH accepts inosine, adenosine, guanosine, and uridine as substrates, which may point to a pivotal metabolic role. OBJECTIVES Our aim was to construct a M. tuberculosis knockout strain for iunH gene, to evaluate in vitro growth and the effect of iunH deletion in M. tuberculosis in non-activated and activated macrophages models of infection. METHODS A M. tuberculosis knockout strain for iunH gene was obtained by allelic replacement, using pPR27xylE plasmid. The complemented strain was constructed by the transformation of the knockout strain with pNIP40::iunH. MtIAGU-NH expression was analysed by Western blot and LC-MS/MS. In vitro growth was evaluated in Sauton’s medium. Bacterial load of non-activated and interferon-γ activated RAW 264.7 cells infected with knockout strain was compared with wild-type and complemented strains. FINDINGS Western blot and LC-MS/MS validated iunH deletion at protein level. The iunH knockout led to a delay in M. tuberculosis growth kinetics in Sauton’s medium during log phase, but did not affect bases and nucleosides pool in vitro. No significant difference in bacterial load of knockout strain was observed when compared with both wild-type and complemented strains after infection of non-activated and interferon-γ activated RAW 264.7 cells. MAIN CONCLUSION The disruption of iunH gene does not influence M. tuberculosis growth in both non-activated and activated RAW 264.7 cells, which show that iunH gene is not important for macrophage invasion and virulence. Our results indicated that MtIAGU-NH is not a target for drug

  13. Charge-to-Mass Dispersion Methods in Knockout-Ablation Fragmentation Models

    NASA Astrophysics Data System (ADS)

    Townsend, Lawrence; Burton, Krista; de Wet, Wouter

    2014-09-01

    Breakup of high-energy heavy ions in nuclear collisions is an important process in space radiation transport, shielding and risk assessment since the secondary particles produced by these collisions have ranges greater than their parent nucleus, and are damaging to humans and spacecraft components. This work uses a quantum-mechanical optical potential knockout-ablation model to estimate these collision cross sections in order to investigate differences in isotope and element production cross sections as a result of utilizing two different models of charge-to mass ratios for the projectile prefragments produced by the abrasion/knockout process. One model commonly used, a hypergeometric model, assumes that the distribution of abraded nucleons is completely uncorrelated. However, it permits some unrealistic distributions, such as removing all neutrons in the knockout stage, while leaving all protons intact. Another model, developed for use with a classical geometric, clean-cut abrasion model, is based upon the zero point vibrations of the giant dipole resonance of the fragmenting nucleus. In this work we compare fragment production cross section predictions using the two charge dispersion models with published experimental data. Breakup of high-energy heavy ions in nuclear collisions is an important process in space radiation transport, shielding and risk assessment since the secondary particles produced by these collisions have ranges greater than their parent nucleus, and are damaging to humans and spacecraft components. This work uses a quantum-mechanical optical potential knockout-ablation model to estimate these collision cross sections in order to investigate differences in isotope and element production cross sections as a result of utilizing two different models of charge-to mass ratios for the projectile prefragments produced by the abrasion/knockout process. One model commonly used, a hypergeometric model, assumes that the distribution of abraded nucleons is

  14. Phenotypes Associated with Knockouts of Eight Dense Granule Gene Loci (GRA2-9) in Virulent Toxoplasma gondii.

    PubMed

    Rommereim, Leah M; Bellini, Valeria; Fox, Barbara A; Pètre, Graciane; Rak, Camille; Touquet, Bastien; Aldebert, Delphine; Dubremetz, Jean-François; Cesbron-Delauw, Marie-France; Mercier, Corinne; Bzik, David J

    2016-01-01

    Toxoplasma gondii actively invades host cells and establishes a parasitophorous vacuole (PV) that accumulates many proteins secreted by the dense granules (GRA proteins). To date, at least 23 GRA proteins have been reported, though the function(s) of most of these proteins still remains unknown. We targeted gene knockouts at ten GRA gene loci (GRA1-10) to investigate the cellular roles and essentiality of these classical GRA proteins during acute infection in the virulent type I RH strain. While eight of these genes (GRA2-9) were successfully knocked out, targeted knockouts at the GRA1 and GRA10 loci were not obtained, suggesting these GRA proteins may be essential. As expected, the Δgra2 and Δgra6 knockouts failed to form an intravacuolar network (IVN). Surprisingly, Δgra7 exhibited hyper-formation of the IVN in both normal and lipid-free growth conditions. No morphological alterations were identified in parasite or PV structures in the Δgra3, Δgra4, Δgra5, Δgra8, or Δgra9 knockouts. With the exception of the Δgra3 and Δgra8 knockouts, all of the GRA knockouts exhibited defects in their infection rate in vitro. While the single GRA knockouts did not exhibit reduced replication rates in vitro, replication rate defects were observed in three double GRA knockout strains (Δgra4Δgra6, Δgra3Δgra5 and Δgra3Δgra7). However, the virulence of single or double GRA knockout strains in CD1 mice was not affected. Collectively, our results suggest that while the eight individual GRA proteins investigated in this study (GRA2-9) are not essential, several GRA proteins may provide redundant and potentially important functions during acute infection.

  15. Phenotypes Associated with Knockouts of Eight Dense Granule Gene Loci (GRA2-9) in Virulent Toxoplasma gondii

    PubMed Central

    Fox, Barbara A.; Pètre, Graciane; Rak, Camille; Touquet, Bastien; Aldebert, Delphine; Dubremetz, Jean-François; Cesbron-Delauw, Marie-France; Mercier, Corinne; Bzik, David J.

    2016-01-01

    Toxoplasma gondii actively invades host cells and establishes a parasitophorous vacuole (PV) that accumulates many proteins secreted by the dense granules (GRA proteins). To date, at least 23 GRA proteins have been reported, though the function(s) of most of these proteins still remains unknown. We targeted gene knockouts at ten GRA gene loci (GRA1-10) to investigate the cellular roles and essentiality of these classical GRA proteins during acute infection in the virulent type I RH strain. While eight of these genes (GRA2-9) were successfully knocked out, targeted knockouts at the GRA1 and GRA10 loci were not obtained, suggesting these GRA proteins may be essential. As expected, the Δgra2 and Δgra6 knockouts failed to form an intravacuolar network (IVN). Surprisingly, Δgra7 exhibited hyper-formation of the IVN in both normal and lipid-free growth conditions. No morphological alterations were identified in parasite or PV structures in the Δgra3, Δgra4, Δgra5, Δgra8, or Δgra9 knockouts. With the exception of the Δgra3 and Δgra8 knockouts, all of the GRA knockouts exhibited defects in their infection rate in vitro. While the single GRA knockouts did not exhibit reduced replication rates in vitro, replication rate defects were observed in three double GRA knockout strains (Δgra4Δgra6, Δgra3Δgra5 and Δgra3Δgra7). However, the virulence of single or double GRA knockout strains in CD1 mice was not affected. Collectively, our results suggest that while the eight individual GRA proteins investigated in this study (GRA2-9) are not essential, several GRA proteins may provide redundant and potentially important functions during acute infection. PMID:27458822

  16. Progeria syndrome with cardiac complications.

    PubMed

    Ilyas, Saadia; Ilyas, Hajira; Hameed, Abdul; Ilyas, Muhammad

    2013-09-01

    A case report of 6-year-old boy with progeria syndrome, with marked cardiac complications is presented. The boy had cardiorespiratory failure. Discoloured purpuric skin patches, alopecia, prominent forehead, protuberant eyes, flattened nasal cartilage, malformed mandible, hypodentition, and deformed rigid fingers and toes were observed on examination. The boy was unable to speak. A sclerotic systolic murmur was audible over the mitral and aortic areas. Chest x-rays showed cardiac enlargement and the electrocardiogram (ECG) showed giant peaked P waves (right atrial hypertrophy) and right ventricular hypertrophy. Atherosclerotic dilated ascending aorta, thickened sclerotic aortic, mitral, and tricuspid valves with increased echo texture, left and right atrial and right ventricular dilatation, reduced left ventricular cavity, and thickened speckled atrial and ventricular septa were observed on echocardiography.

  17. A new cardiac auscultation simulator.

    PubMed

    Takashina, T; Masuzawa, T; Fukui, Y

    1990-12-01

    We have successfully developed a new cardiac auscultation simulator by applying recently developed digital and computer technology, which digitally records, stores, modifies, and plays back heart sounds and murmurs characteristic of various heart diseases. The simulator is capable of playing back different heart sounds or murmurs at each auscultatory site (aortic, pulmonic, tricuspid, and mitral) of a human chest-sized mannequin (made of urethane foam), through four built-in speakers. We were able to listen to accurate reproductions of heart sounds and murmurs at the same timing as in real patients by any type of stethoscope used in routine medical practice. This compact and portable educational apparatus, which simulates realistic auscultatory sounds, will impact greatly on the medical training of cardiac auscultation for physicians, medical students, nurses, and paramedicals.

  18. Systems biology and cardiac arrhythmias.

    PubMed

    Grace, Andrew A; Roden, Dan M

    2012-10-27

    During the past few years, the development of effective, empirical technologies for treatment of cardiac arrhythmias has exceeded the pace at which detailed knowledge of the underlying biology has accumulated. As a result, although some clinical arrhythmias can be cured with techniques such as catheter ablation, drug treatment and prediction of the risk of sudden death remain fairly primitive. The identification of key candidate genes for monogenic arrhythmia syndromes shows that to bring basic biology to the clinic is a powerful approach. Increasingly sophisticated experimental models and methods of measurement, including stem cell-based models of human cardiac arrhythmias, are being deployed to study how perturbations in several biologic pathways can result in an arrhythmia-prone heart. The biology of arrhythmia is largely quantifiable, which allows for systematic analysis that could transform treatment strategies that are often still empirical into management based on molecular evidence.

  19. [Cardiac toxicity of 5-fluorouracil].

    PubMed

    Fournier, C; Benahmed, M; Blondeau, M

    1989-02-01

    A 67 year-old patient receives 5-fluorouracil for vocal chord cancer. During the perfusion, atypical angina pain occurs, accompanied with offset of ST above the baseline in standard leads and in V4 through V6. The pain subsides spontaneously in 45 minutes. These ECG alterations are followed 48 hours later by diffuse inverted T waves with lengthened QT. Cardiac ultrasonography and isotopic angiography do not show any abnormality of the left ventricular function, but myocardial tomoscintigraphy with labelled thallium show a lower hypofixation on exertion. The cardiac toxicity of 5-fluorouracil is in frequent. It is usually believed that it involves a coronary spasm, as suggested by the ECG tracing in the reported cases. The incident, which may be painful or painless, may result in a myocardial infarction or even sudden death during the perfusion. Therefore, it is advisable to discontinue the treatment as soon as an angina-type pain occurs.

  20. Chaos control of cardiac arrhythmias.

    PubMed

    Garfinkel, A; Weiss, J N; Ditto, W L; Spano, M L

    1995-01-01

    Chaos theory has shown that many disordered and erratic phenomena are in fact deterministic, and can be understood causally and controlled. The prospect that cardiac arrhythmias might be instances of deterministic chaos is therefore intriguing. We used a recently developed method of chaos control to stabilize a ouabain-induced arrhythmia in rabbit ventricular tissue in vitro. Extension of these results to clinically significant arrhythmias such as fibrillation will require overcoming the additional obstacles of spatiotemporal complexity.

  1. Strategic Planning for Cardiac Services

    DTIC Science & Technology

    2008-04-13

    under a process review. 15. SUBJECT TERMS Strategy, Cardiac Services, DDEAMC, Dwight D. Eisenhower Army Medical Center 16. SECURITY CLASSIFICATION OF...each factor under a process review. CT Strategy Plan Table of Contents 1. Introduction 6 Conditions Which Prompted the Study 7 Statement of the...awareness of the program. Legal and administrative issues were seen in the consult process with Humana, the Tricare contractor for region South. Tricare

  2. Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females.

    PubMed

    Jia, Guanghong; Habibi, Javad; DeMarco, Vincent G; Martinez-Lemus, Luis A; Ma, Lixin; Whaley-Connell, Adam T; Aroor, Annayya R; Domeier, Timothy L; Zhu, Yi; Meininger, Gerald A; Barrett Mueller, Katelee; Jaffe, Iris Z; Sowers, James R

    2015-12-01

    Overnutrition and insulin resistance are especially prominent risk factors for the development of cardiac diastolic dysfunction in females. We recently reported that consumption of a Western diet (WD) containing excess fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) for 16 weeks resulted in cardiac diastolic dysfunction and aortic stiffening in young female mice and that these abnormalities were prevented by mineralocorticoid receptor blockade. Herein, we extend those studies by testing whether WD-induced diastolic dysfunction and factors contributing to diastolic impairment, such as cardiac fibrosis, hypertrophy, inflammation, and impaired insulin signaling, are modulated by excess endothelial cell mineralocorticoid receptor signaling. Four-week-old female endothelial cell mineralocorticoid receptor knockout and wild-type mice were fed mouse chow or WD for 4 months. WD feeding resulted in prolonged relaxation time, impaired diastolic septal wall motion, and increased left ventricular filling pressure indicative of diastolic dysfunction. This occurred in concert with myocardial interstitial fibrosis and cardiomyocyte hypertrophy that were associated with enhanced profibrotic (transforming growth factor β1/Smad) and progrowth (S6 kinase-1) signaling, as well as myocardial oxidative stress and a proinflammatory immune response. WD also induced cardiomyocyte stiffening, assessed ex vivo using atomic force microscopy. Conversely, endothelial cell mineralocorticoid receptor deficiency prevented WD-induced diastolic dysfunction, profibrotic, and progrowth signaling, in conjunction with reductions in macrophage proinflammatory polarization and improvements in insulin metabolic signaling. Therefore, our findings indicate that increased endothelial cell mineralocorticoid receptor signaling associated with consumption of a WD plays a key role in the activation of cardiac profibrotic, inflammatory, and growth pathways that lead to diastolic dysfunction in

  3. Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy.

    PubMed

    Abdullah, Chowdhury S; Li, Zhao; Wang, Xiuqing; Jin, Zhu-Qiu

    2016-10-01

    T cell infiltration has been associated with increased coronary heart disease risk in patients with diabetes mellitus. Effect of modulation of T cell trafficking on diabetes-induced cardiac fibrosis has yet to be determined. Therefore, our aim was to investigate the circulatory T cell depletion-mediated cardioprotection in streptozotocin-induced diabetic cardiomyopathy. Fingolimod (FTY720), an immunomodulatory drug, was tested in wild-type (WT) C57BL/6 and recombination activating gene 1 (Rag1) knockout (KO) mice without mature lymphocytes in streptozotocin-induced type 1 diabetic model. FTY720 (0.3mg/kg/day) was administered intraperitoneally daily for the first 4weeks with interim 3weeks then resumed for another 4weeks in 11weeks study period. T lymphocyte counts, cardiac histology, function, and fibrosis were examined in diabetic both WT and KO mice. FTY720 reduced both CD4(+) and CD8(+) T cells in diabetic WT mice. FTY720-treated diabetic WT mouse myocardium showed reduction in CD3 T cell infiltration and decreased expression of S1P1 and TGF-β1 in cardiac tissue. Fibrosis was reduced after FTY720 treatment in diabetic WT mice. Rag1 KO mice exhibited no CD4(+) and CD8(+) T cells in the blood and CD3 T cells in the heart. Diabetic Rag1 KO mouse hearts appeared no fibrosis and exhibited preserved myocardial contractility. FTY720-induced antifibrosis was abolished in diabetic Rag1 KO mice. These findings demonstrate that chronic administration with FTY720 induces lymphopenia and protects diabetic hearts in WT mice whereas FTY720 increases cardiac fibrosis and myocardial dysfunction in diabetic Rag1 KO mice without mature lymphocytes.

  4. Cardiac autonomic nerve distribution and arrhythmia☆

    PubMed Central

    Liu, Quan; Chen, Dongmei; Wang, Yonggang; Zhao, Xin; Zheng, Yang

    2012-01-01

    OBJECTIVE: To analyze the distribution characteristics of cardiac autonomic nerves and to explore the correlation between cardiac autonomic nerve distribution and arrhythmia. DATA RETRIEVAL: A computer-based retrieval was performed for papers examining the distribution of cardiac autonomic nerves, using heart, autonomic nerve, sympathetic nerve, vagus nerve, nerve distribution, rhythm and atrial fibrillation as the key words. SELECTION CRITERIA: A total of 165 studies examining the distribution of cardiac autonomic nerve were screened, and 46 of them were eventually included. MAIN OUTCOME MEASURES: The distribution and characteristics of cardiac autonomic nerves were observed, and immunohistochemical staining was applied to determine the levels of tyrosine hydroxylase and acetylcholine transferase (main markers of cardiac autonomic nerve distribution). In addition, the correlation between cardiac autonomic nerve distribution and cardiac arrhythmia was investigated. RESULTS: Cardiac autonomic nerves were reported to exhibit a disordered distribution in different sites, mainly at the surface of the cardiac atrium and pulmonary vein, forming a ganglia plexus. The distribution of the pulmonary vein autonomic nerve was prominent at the proximal end rather than the distal end, at the upper left rather than the lower right, at the epicardial membrane rather than the endocardial membrane, at the left atrium rather than the right atrium, and at the posterior wall rather than the anterior wall. The main markers used for cardiac autonomic nerves were tyrosine hydroxylase and acetylcholine transferase. Protein gene product 9.5 was used to label the immunoreactive nerve distribution, and the distribution density of autonomic nerves was determined using a computer-aided morphometric analysis system. CONCLUSION: The uneven distribution of the cardiac autonomic nerves is the leading cause of the occurrence of arrhythmia, and the cardiac autonomic nerves play an important role in

  5. Mastocytosis presenting as cardiac emergency.

    PubMed

    Ridolo, Erminia; Triggiani, Massimo; Montagni, Marcello; Olivieri, Elisa; Ticinesi, Andrea; Nouvenne, Antonio; Magliacane, Diomira; de Crescenzo, Gennaro; Meschi, Tiziana

    2013-12-01

    Mastocytosis is characterised by clonal proliferation of mast cells in the skin and in various internal organs, and by symptoms related to an acute release of mast cell-derived mediators. In 20-30 % of patients, mastocytosis occurs without the typical skin lesions of urticaria pigmentosa that are usually the first clinical sign of the disease. In these patients, anaphylaxis is often the presenting sign of the disease. We report three cases in which a cardiac emergency (cardiac arrest or ventricular fibrillation) was the first clinical manifestation of anaphylaxis associated with systemic mastocytosis. All patients were men, none of them had previous episodes of anaphylaxis or other mediator-related symptoms, and none had major pre-existing cardiovascular condition. An eliciting factor was identified in one case (a wasp sting), but one was found in the other two. Elevation of the serum tryptase suggested a mastocytosis, which was confirmed by bone marrow biopsy. This case series demonstrates that cardiovascular emergencies may be presenting signs of mastocytosis, and that elevation of serum tryptase after an acute cardiac event, if confirmed under basal conditions, may be useful for diagnosing this disease.

  6. Prospectively gated cardiac computed tomography.

    PubMed

    Moore, S C; Judy, P F; Garnic, J D; Kambic, G X; Bonk, F; Cochran, G; Margosian, P; McCroskey, W; Foote, F

    1983-01-01

    A fourth-generation scanner has been modified to perform prospectively gated cardiac computed tomography (CT). A computer program monitors the electrocardiogram (ECG) and predicts when to initiate the next scan in a gated series in order to acquire all projection data for a desired phase of the heart cycle. The system has been tested with dogs and has produced cross-sectional images of all phases of the cardiac cycle. Eight to ten scans per series were sufficient to obtain reproducible images of each transverse section in the end-diastolic and end-systolic phases. The radiation dose to the skin was approximately 1.4 cGy per scan. The prospectively gated system is more than twice as efficient as a retrospectively gated system in obtaining complete angular projection data for a 10% heart cycle window. A temporal smoothing technique to suppress reconstruction artifacts due to sorting inconsistent projection data was developed and evaluated. Image noise was reduced by averaging together any overlapping projection data. Prospectively gated cardiac CT has also been used to demonstrate that the error in attenuation measured with a single nongated CT scan through the heart can be as large as 50-60 CT numbers outside the heart in the lung field.

  7. Inherited arrhythmias: The cardiac channelopathies

    PubMed Central

    Behere, Shashank P; Weindling, Steven N

    2015-01-01

    Ion channels in the myocardial cellular membrane are responsible for allowing the cardiac action potential. Genetic abnormalities in these channels can predispose to life-threatening arrhythmias. We discuss the basic science of the cardiac action potential; outline the different clinical entities, including information regarding overlapping diagnoses, touching upon relevant genetics, new innovations in screening, diagnosis, risk stratification, and management. The special considerations of sudden unexplained death and sudden infant death syndrome are discussed. Scientists and clinicians continue to reconcile the rapidly growing body of knowledge regarding the molecular mechanisms and genetics while continuing to improve our understanding of the various clinical entities and their diagnosis and management in clinical setting. Two separate searches were run on the National Center for Biotechnology Information's website. The first using the term cardiac channelopathies was run on the PubMed database using filters for time (published in past 5 years) and age (birth-18 years), yielding 47 results. The second search using the medical subject headings (MeSH) database with the search terms “Long QT Syndrome” (MeSH) and “Short QT Syndrome” (MeSH) and “Brugada Syndrome” (MeSH) and “Catecholaminergic Polymorphic Ventricular Tachycardia” (MeSH), applying the same filters yielded 467 results. The abstracts of these articles were studied, and the articles were categorized and organized. Articles of relevance were read in full. As and where applicable, relevant references and citations from the primary articles where further explored and read in full. PMID:26556967

  8. Sudden cardiac death risk stratification.

    PubMed

    Deyell, Marc W; Krahn, Andrew D; Goldberger, Jeffrey J

    2015-06-05

    Arrhythmic sudden cardiac death (SCD) may be caused by ventricular tachycardia/fibrillation or pulseless electric activity/asystole. Effective risk stratification to identify patients at risk of arrhythmic SCD is essential for targeting our healthcare and research resources to tackle this important public health issue. Although our understanding of SCD because of pulseless electric activity/asystole is growing, the overwhelming majority of research in risk stratification has focused on SCD-ventricular tachycardia/ventricular fibrillation. This review focuses on existing and novel risk stratification tools for SCD-ventricular tachycardia/ventricular fibrillation. For patients with left ventricular dysfunction or myocardial infarction, advances in imaging, measures of cardiac autonomic function, and measures of repolarization have shown considerable promise in refining risk. Yet the majority of SCD-ventricular tachycardia/ventricular fibrillation occurs in patients without known cardiac disease. Biomarkers and novel imaging techniques may provide further risk stratification in the general population beyond traditional risk stratification for coronary artery disease alone. Despite these advances, significant challenges in risk stratification remain that must be overcome before a meaningful impact on SCD can be realized.

  9. Cardiac MRI in restrictive cardiomyopathy.

    PubMed

    Gupta, A; Singh Gulati, G; Seth, S; Sharma, S

    2012-02-01

    Restrictive cardiomyopathy (RCM) is a specific group of heart muscle disorders characterized by inadequate ventricular relaxation during diastole. This leads to diastolic dysfunction with relative preservation of systolic function. Although short axis systolic function is usually preserved in RCM, the long axis systolic function may be severely impaired. Confirmation of diagnosis and information regarding aetiology, extent of myocardial damage, and response to treatment requires imaging. Importantly, differentiation from constrictive pericarditis (CCP) is needed, as only the latter is managed surgically. Echocardiography is the initial cardiac imaging technique but cannot reliably suggest a tissue diagnosis; although recent advances, especially tissue Doppler imaging and spectral tracking, have improved its ability to differentiate RCM from CCP. Cardiac catheterization is the reference standard, but is invasive, two-dimensional, and does not aid myocardial characterization. Cardiac magnetic resonance (CMR) is a versatile technique providing anatomical, morphological and functional information. In recent years, it has been shown to provide important information regarding disease mechanisms, and also been found useful to guide treatment, assess its outcome and predict patient prognosis. This review describes the CMR features of RCM, appearances in various diseases, its overall role in patient management, and how it compares with other imaging techniques.

  10. The history of cardiac catheterization.

    PubMed

    Bourassa, Martial G

    2005-10-01

    The evolution of cardiac catheterization has occurred over at least four centuries. One of the first major steps was the description of the circulation of the blood by William Harvey in 1628. The next milestone was the measurement of arterial pressure by Stephen Hales, one century later. However, the 19th century represented the golden age of cardiovascular physiology, highlighted by the achievements of Carl Ludwig, Etienne-Jules Marey and Claude Bernard, among others. Human cardiac catheterization developed during the 20th century. The first right heart catheterization in a human was performed by Werner Forssmann on himself in 1929. Diagnostic cardiac catheterization was introduced by André Cournand and Dickinson Richards in the early 1940s, and selective coronary angiography was described by Mason Sones in the early 1960s. More recently, with the advent of catheter-based interventions, pioneered by Andreas Gruentzig in the late 1970s, there has been considerable progress in the refinement and expansion of these techniques. Currently, the Sones technique is used only infrequently, and coronary angiography and percutaneous coronary intervention rely mainly on percutaneous femoral and percutaneous radial artery approaches. On the occasion of the 50th anniversary of the Montreal Heart Institute, it seems appropriate to highlight the contribution of this institution in these two areas.

  11. Neutron knockout of {sup 12}Be populating neutron-unbound states in {sup 11}Be

    SciTech Connect

    Peters, W. A.; Baumann, T.; Lecouey, J.-L.; Schiller, A.; Yoneda, K.; Brown, B. A.; Frank, N.; Thoennessen, M.; Brown, J.; DeYoung, P. A.; Peaslee, G. F.; Finck, J. E.; Jones, K. L.; Luther, B.; Rogers, W. F.; Tostevin, J. A.

    2011-05-15

    Neutron-unbound resonant states of {sup 11}Be were populated in neutron knockout reactions from {sup 12}Be and identified by {sup 10}Be-n coincidence measurements. A resonance in the decay-energy spectrum at 80(2) keV was attributed to a highly excited unbound state in {sup 11}Be at 3.949(2) MeV decaying to the 2{sup +} excited state in {sup 10}Be. A knockout cross section of 15(3) mb was inferred for this 3.949(2) MeV state, suggesting a spectroscopic factor near unity for this 0p3/2{sup -} level, consistent with the detailed shell model calculations.

  12. Generation of knockout rabbits using transcription activator-like effector nucleases.

    PubMed

    Wang, Yu; Fan, Nana; Song, Jun; Zhong, Juan; Guo, Xiaogang; Tian, Weihua; Zhang, Quanjun; Cui, Fenggong; Li, Li; Newsome, Philip N; Frampton, Jon; Esteban, Miguel A; Lai, Liangxue

    2014-01-01

    Zinc-finger nucleases and transcription activator-like effector nucleases are novel gene-editing platforms contributing to redefine the boundaries of modern biological research. They are composed of a non-specific cleavage domain and a tailor made DNA-binding module, which enables a broad range of genetic modifications by inducing efficient DNA double-strand breaks at desired loci. Among other remarkable uses, these nucleases have been employed to produce gene knockouts in mid-size and large animals, such as rabbits and pigs, respectively. This approach is cost effective, relatively quick, and can produce invaluable models for human disease studies, biotechnology or agricultural purposes. Here we describe a protocol for the efficient generation of knockout rabbits using transcription activator-like effector nucleases, and a perspective of the field.

  13. Metabolic flux analysis of Escherichia coli knockouts: lessons from the Keio collection and future outlook.

    PubMed

    Long, Christopher P; Antoniewicz, Maciek R

    2014-08-01

    Cellular metabolic and regulatory systems are of fundamental interest to biologists and engineers. Incomplete understanding of these complex systems remains an obstacle to progress in biotechnology and metabolic engineering. An established method for obtaining new information on network structure, regulation and dynamics is to study the cellular system following a perturbation such as a genetic knockout. The Keio collection of all viable Escherichia coli single-gene knockouts is facilitating a systematic investigation of the regulation and metabolism of E. coli. Of all omics measurements available, the metabolic flux profile (the fluxome) provides the most direct and relevant representation of the cellular phenotype. Recent advances in (13)C-metabolic flux analysis are now permitting highly precise and accurate flux measurements for investigating cellular systems and guiding metabolic engineering efforts.

  14. A norm knockout method on indirect reciprocity to reveal indispensable norms

    PubMed Central

    Yamamoto, Hitoshi; Okada, Isamu; Uchida, Satoshi; Sasaki, Tatsuya

    2017-01-01

    Although various norms for reciprocity-based cooperation have been suggested that are evolutionarily stable against invasion from free riders, the process of alternation of norms and the role of diversified norms remain unclear in the evolution of cooperation. We clarify the co-evolutionary dynamics of norms and cooperation in indirect reciprocity and also identify the indispensable norms for the evolution of cooperation. Inspired by the gene knockout method, a genetic engineering technique, we developed the norm knockout method and clarified the norms necessary for the establishment of cooperation. The results of numerical investigations revealed that the majority of norms gradually transitioned to tolerant norms after defectors are eliminated by strict norms. Furthermore, no cooperation emerges when specific norms that are intolerant to defectors are knocked out. PMID:28276485

  15. Reveromycin A Administration Prevents Alveolar Bone Loss in Osteoprotegerin Knockout Mice with Periodontal Disease

    PubMed Central

    Mizuno, Manami; Miyazawa, Ken; Tabuchi, Masako; Tanaka, Miyuki; Yoshizako, Mamoru; Minamoto, Chisato; Torii, Yasuyoshi; Tamaoka, Yusuke; Kawatani, Makoto; Osada, Hiroyuki; Maeda, Hatsuhiko; Goto, Shigemi

    2015-01-01

    Chronic periodontal disease is characterized by alveolar bone loss and inflammatory changes. Reveromycin A (RMA) was recently developed and is a unique agent for inhibiting osteoclast activity. This study analysed the effects of RMA in an experimental mouse model of periodontitis involving osteoprotegerin (OPG)-knockout mice, specifically, whether it could control osteoclasts and reduce inflammation in periodontal tissue. We examined wild-type (WT) and OPG knockout mice (OPG KO) ligated with wire around contact points on the left first and second molars. RMA was administered twice a day to half of the mice. Using micro-computed tomography, we measured the volume of alveolar bone loss between the first and second molars, and also performed histological analysis. The OPG KO RMA+ group had significantly decreased osteoclast counts, alveolar bone loss, attachment loss, and inflammatory cytokine expression 8 weeks after ligation. Thus, RMA may reduce alveolar bone loss and inflamed periodontal tissues in patients with periodontitis. PMID:26561427

  16. Rapid phenotyping of knockout mice to identify genetic determinants of bone strength

    PubMed Central

    Freudenthal, Bernard; Logan, John; Croucher, Peter I

    2016-01-01

    The genetic determinants of osteoporosis remain poorly understood, and there is a large unmet need for new treatments in our ageing society. Thus, new approaches for gene discovery in skeletal disease are required to complement the current genome-wide association studies in human populations. The International Knockout Mouse Consortium (IKMC) and the International Mouse Phenotyping Consortium (IMPC) provide such an opportunity. The IKMC generates knockout mice representing each of the known protein-coding genes in C57BL/6 mice and, as part of the IMPC initiative, the Origins of Bone and Cartilage Disease project identifies mutants with significant outlier skeletal phenotypes. This initiative will add value to data from large human cohorts and provide a new understanding of bone and cartilage pathophysiology, ultimately leading to the identification of novel drug targets for the treatment of skeletal disease. PMID:27535945

  17. Reveromycin A Administration Prevents Alveolar Bone Loss in Osteoprotegerin Knockout Mice with Periodontal Disease.

    PubMed

    Mizuno, Manami; Miyazawa, Ken; Tabuchi, Masako; Tanaka, Miyuki; Yoshizako, Mamoru; Minamoto, Chisato; Torii, Yasuyoshi; Tamaoka, Yusuke; Kawatani, Makoto; Osada, Hiroyuki; Maeda, Hatsuhiko; Goto, Shigemi

    2015-11-12

    Chronic periodontal disease is characterized by alveolar bone loss and inflammatory changes. Reveromycin A (RMA) was recently developed and is a unique agent for inhibiting osteoclast activity. This study analysed the effects of RMA in an experimental mouse model of periodontitis involving osteoprotegerin (OPG)-knockout mice, specifically, whether it could control osteoclasts and reduce inflammation in periodontal tissue. We examined wild-type (WT) and OPG knockout mice (OPG KO) ligated with wire around contact points on the left first and second molars. RMA was administered twice a day to half of the mice. Using micro-computed tomography, we measured the volume of alveolar bone loss between the first and second molars, and also performed histological analysis. The OPG KO RMA+ group had significantly decreased osteoclast counts, alveolar bone loss, attachment loss, and inflammatory cytokine expression 8 weeks after ligation. Thus, RMA may reduce alveolar bone loss and inflamed periodontal tissues in patients with periodontitis.

  18. Cnga2 Knockout Mice Display Alzheimer's-Like Behavior Abnormities and Pathological Changes.

    PubMed

    Xie, Ao-Ji; Liu, En-Jie; Huang, He-Zhou; Hu, Yu; Li, Ke; Lu, Youming; Wang, Jian-Zhi; Zhu, Ling-Qiang

    2016-09-01

    Olfactory dysfunction is recognized as a potential risk factor for Alzheimer's disease (AD). We have reported previously that olfactory deprivation by olfactory bulbectomy (OBX) induced Alzheimer's-like pathological changes and behavioral abnormalities. However, the acute OBX model undergoes surgical-induced brain parenchyma loss and unexpected massive hemorrhage so that it cannot fully mimic the progressive olfactory loss and neurodegeneration in AD. Here, we employed the mice loss of cyclic nucleotide-gated channel alpha 2 (Cnga2) which is critical for olfactory sensory transduction, to investigate the role of olfactory dysfunction in AD pathological process. We found that impaired learning and memory abilities, loss of dendrite spines, as well as decrement of synaptic proteins were displayed in Cnga2 knockout mice. Moreover, Aβ overproduction, tau hyperphosphorylation, and somatodendritic translocation were also found in Cnga2 knockout mice. Our findings suggest that progressive olfactory loss leads to Alzheimer's-like behavior abnormities and pathological changes.

  19. Validation of microinjection methods for generating knockout mice by CRISPR/Cas-mediated genome engineering

    PubMed Central

    Horii, Takuro; Arai, Yuji; Yamazaki, Miho; Morita, Sumiyo; Kimura, Mika; Itoh, Masahiro; Abe, Yumiko; Hatada, Izuho

    2014-01-01

    The CRISPR/Cas system, in which the Cas9 endonuclease and a guide RNA complementary to the target are sufficient for RNA-guided cleavage of the target DNA, is a powerful new approach recently developed for targeted gene disruption in various animal models. However, there is little verification of microinjection methods for generating knockout mice using this approach. Here, we report the verification of microinjection methods of the CRISPR/Cas system. We compared three methods for injection: (1) injection of DNA into the pronucleus, (2) injection of RNA into the pronucleus, and (3) injection of RNA into the cytoplasm. We found that injection of RNA into the cytoplasm was the most efficient method in terms of the numbers of viable blastocyst stage embryos and full-term pups generated. This method also showed the best overall knockout efficiency. PMID:24675426

  20. A norm knockout method on indirect reciprocity to reveal indispensable norms

    NASA Astrophysics Data System (ADS)

    Yamamoto, Hitoshi; Okada, Isamu; Uchida, Satoshi; Sasaki, Tatsuya

    2017-03-01

    Although various norms for reciprocity-based cooperation have been suggested that are evolutionarily stable against invasion from free riders, the process of alternation of norms and the role of diversified norms remain unclear in the evolution of cooperation. We clarify the co-evolutionary dynamics of norms and cooperation in indirect reciprocity and also identify the indispensable norms for the evolution of cooperation. Inspired by the gene knockout method, a genetic engineering technique, we developed the norm knockout method and clarified the norms necessary for the establishment of cooperation. The results of numerical investigations revealed that the majority of norms gradually transitioned to tolerant norms after defectors are eliminated by strict norms. Furthermore, no cooperation emerges when specific norms that are intolerant to defectors are knocked out.

  1. Validation of microinjection methods for generating knockout mice by CRISPR/Cas-mediated genome engineering.

    PubMed

    Horii, Takuro; Arai, Yuji; Yamazaki, Miho; Morita, Sumiyo; Kimura, Mika; Itoh, Masahiro; Abe, Yumiko; Hatada, Izuho

    2014-03-28

    The CRISPR/Cas system, in which the Cas9 endonuclease and a guide RNA complementary to the target are sufficient for RNA-guided cleavage of the target DNA, is a powerful new approach recently developed for targeted gene disruption in various animal models. However, there is little verification of microinjection methods for generating knockout mice using this approach. Here, we report the verification of microinjection methods of the CRISPR/Cas system. We compared three methods for injection: (1) injection of DNA into the pronucleus, (2) injection of RNA into the pronucleus, and (3) injection of RNA into the cytoplasm. We found that injection of RNA into the cytoplasm was the most efficient method in terms of the numbers of viable blastocyst stage embryos and full-term pups generated. This method also showed the best overall knockout efficiency.

  2. Kv4.2 Knockout Mice Have Hippocampal-Dependent Learning and Memory Deficits

    ERIC Educational Resources Information Center

    Lugo, Joaquin N.; Brewster, Amy L.; Spencer, Corinne M.; Anderson, Anne E.

    2012-01-01

    Kv4.2 channels contribute to the transient, outward K[superscript +] current (A-type current) in hippocampal dendrites, and modulation of this current substantially alters dendritic excitability. Using Kv4.2 knockout (KO) mice, we examined the role of Kv4.2 in hippocampal-dependent learning and memory. We found that Kv4.2 KO mice showed a deficit…

  3. Transgenic knockout mice with exclusively human sickle hemoglobinand sickle cell disease

    SciTech Connect

    Paszty, C.; Brion, C.; Manci, E.; Witkowska, E.; Stevens, M.; Narla, M.; Rubin, E.

    1997-06-13

    To create mice expressing exclusively human sicklehemoglobin (HbS), transgenic mice expressing human alpha-, gamma-, andbeta[S]-globin were generated and bred with knockout mice that haddeletions of the murine alpha- and beta-globin genes. These sickle cellmice have the major features (irreversibly sickled red cells, anemia,multiorgan pathology) found in humans with sickle cell disease and, assuch, represent a useful in vivo system to accelerate the development ofimproved therapies for this common genetic disease.

  4. Selection-independent generation of gene knockout mouse embryonic stem cells using zinc-finger nucleases.

    PubMed

    Osiak, Anna; Radecke, Frank; Guhl, Eva; Radecke, Sarah; Dannemann, Nadine; Lütge, Fabienne; Glage, Silke; Rudolph, Cornelia; Cantz, Tobias; Schwarz, Klaus; Heilbronn, Regine; Cathomen, Toni

    2011-01-01

    Gene knockout in murine embryonic stem cells (ESCs) has been an invaluable tool to study gene function in vitro or to generate animal models with altered phenotypes. Gene targeting using standard techniques, however, is rather inefficient and typically does not exceed frequencies of 10(-6). In consequence, the usage of complex positive/negative selection strategies to isolate targeted clones has been necessary. Here, we present a rapid single-step approach to generate a gene knockout in mouse ESCs using engineered zinc-finger nucleases (ZFNs). Upon transient expression of ZFNs, the target gene is cleaved by the designer nucleases and then repaired by non-homologous end-joining, an error-prone DNA repair process that introduces insertions/deletions at the break site and therefore leads to functional null mutations. To explore and quantify the potential of ZFNs to generate a gene knockout in pluripotent stem cells, we generated a mouse ESC line containing an X-chromosomally integrated EGFP marker gene. Applying optimized conditions, the EGFP locus was disrupted in up to 8% of ESCs after transfection of the ZFN expression vectors, thus obviating the need of selection markers to identify targeted cells, which may impede or complicate downstream applications. Both activity and ZFN-associated cytotoxicity was dependent on vector dose and the architecture of the nuclease domain. Importantly, teratoma formation assays of selected ESC clones confirmed that ZFN-treated ESCs maintained pluripotency. In conclusion, the described ZFN-based approach represents a fast strategy for generating gene knockouts in ESCs in a selection-independent fashion that should be easily transferrable to other pluripotent stem cells.

  5. Uterine-Specific Knockout of Tsc-2: A Mouse Model for Lymphangioleiomyomatosis

    DTIC Science & Technology

    2013-10-01

    wild-type) were used as controls. In the mouse uterus, low-level PR pro- moter activity occurs in luminal and glandular epithe- lium (reflecting less...and irregular luminal epithelium in uteri of uterine-specific Tsc2 knockout mice (Figure 2C). In addition, histological analysis and measurement of...absence of Tsc2 expression. Finally, treatment of OVX wild-type mice with estradiol plus progesterone decreased proliferation of epithelial and glandular

  6. Changes in signaling pathways regulating neuroplasticity induced by neurokinin 1 receptor knockout.

    PubMed

    Musazzi, Laura; Perez, Jorge; Hunt, Stephen P; Racagni, Giorgio; Popoli, Maurizio

    2005-03-01

    Neurokinin 1 (NK-1) receptor knockout mice showed behavioral responses similar to animals chronically treated with antidepressants. The aim of this study was to analyse, in NK-1 receptor knockout, the molecular modifications of signaling pathways involved in the pathophysiology of depression and antidepressant mechanism. We found, in total cell cytosol from the prefrontal/frontal cortex, hippocampus and striatum, a marked up-regulation of Ca(2+)-independent enzymatic activity and Thr(286) autophosphorylation of Ca(2+)/calmodulin-dependent protein kinase (CaMK) II. Similar changes in CaMKII regulation were previously observed in rats chronically treated with antidepressants. In striatum, up-regulation of the activity and phosphorylation of CaMKII was also found in the homogenate and synaptosomes. No major changes were observed in the Ca(2+)-dependent kinase activity, with the exception of homogenate from the prefrontal/frontal cortex. We also analysed the expression and phosphorylation of presynaptic proteins, which modulate synaptic vesicle trafficking and exocytosis, and found a marked decrease in synapsin I total expression and basal phosphorylation of Ser(603) (the phosphorylation site for CaMKII) in the prefrontal/frontal cortex. Accordingly, the Ca(2+)/calmodulin-dependent posthoc endogenous phosphorylation of synapsin I in the same area was increased. The knockout of NK-1 receptor had no consequences on the expression or phosphorylation levels of the transcription factor cAMP-responsive element-binding protein and its regulating kinase CaMKIV. However, phosphorylation of ERK1/2-mitogen-activated protein kinases was reduced in the hippocampus and striatum, again resembling an effect previously observed in antidepressant-treated rats. These results show similarities between NK-1 knockouts and animals chronically treated with antidepressants and support the putative antidepressant activity of NK-1 receptor antagonists.

  7. Social status and day-to-day behaviour of male serotonin transporter knockout mice.

    PubMed

    Lewejohann, Lars; Kloke, Vanessa; Heiming, Rebecca S; Jansen, Friederike; Kaiser, Sylvia; Schmitt, Angelika; Lesch, Klaus Peter; Sachser, Norbert

    2010-08-25

    Humans differing in the amount of serotonin transporter (5-HTT) are known to be differentially prone to neuropsychiatric disorders. Genetically modified mice eliciting abrogated transporter function display a number of corresponding phenotypic changes in behavioural tests. However, a characterisation of the effects of serotonergic malfunction on the day-to-day life is still missing. Yet, this is precisely what an animal model is needed for in order to be meaningful for translation into human anxiety disorders. Homozygous 5-HTT knockout mice, heterozygous 5-HTT mice, and wild-type controls were housed in groups of males of the same genotype in spacious and richly structured cages. This enriched environment allowed the animals to show a wide variety of spontaneous behavioural patterns quantified by a trained experimenter. Additionally the mice could emigrate from the cages through a tunnel and a water basin. The results revealed unaltered daily behaviour in heterozygous mice. In knockouts, however, reduced locomotion, increased socio-positive behaviour, and reduced aggressive behaviour were observed. Nevertheless, all groups showed a significant amount of aggressive behaviour and there were no differences regarding the establishment of dominance relationships, emigration, and the number of animals remaining in their groups. In a second step, pairs of heterozygous and wild-type males and pairs of knockout and wild-type males were brought together in order to assess their ability to obtain a dominant social position in a direct encounter. Heterozygous mice did not differ from wild-type mice but knockout mice were significantly inferior in obtaining the dominant position. In addition to confirming multiple effects of abolished 5-HTT function in a real life situation, this study supports the central role of the 5-HTT in the control of social interactions.

  8. Selection-Independent Generation of Gene Knockout Mouse Embryonic Stem Cells Using Zinc-Finger Nucleases

    PubMed Central

    Osiak, Anna; Radecke, Frank; Guhl, Eva; Radecke, Sarah; Dannemann, Nadine; Lütge, Fabienne; Glage, Silke; Rudolph, Cornelia; Cantz, Tobias; Schwarz, Klaus; Heilbronn, Regine; Cathomen, Toni

    2011-01-01

    Gene knockout in murine embryonic stem cells (ESCs) has been an invaluable tool to study gene function in vitro or to generate animal models with altered phenotypes. Gene targeting using standard techniques, however, is rather inefficient and typically does not exceed frequencies of 10−6. In consequence, the usage of complex positive/negative selection strategies to isolate targeted clones has been necessary. Here, we present a rapid single-step approach to generate a gene knockout in mouse ESCs using engineered zinc-finger nucleases (ZFNs). Upon transient expression of ZFNs, the target gene is cleaved by the designer nucleases and then repaired by non-homologous end-joining, an error-prone DNA repair process that introduces insertions/deletions at the break site and therefore leads to functional null mutations. To explore and quantify the potential of ZFNs to generate a gene knockout in pluripotent stem cells, we generated a mouse ESC line containing an X-chromosomally integrated EGFP marker gene. Applying optimized conditions, the EGFP locus was disrupted in up to 8% of ESCs after transfection of the ZFN expression vectors, thus obviating the need of selection markers to identify targeted cells, which may impede or complicate downstream applications. Both activity and ZFN-associated cytotoxicity was dependent on vector dose and the architecture of the nuclease domain. Importantly, teratoma formation assays of selected ESC clones confirmed that ZFN-treated ESCs maintained pluripotency. In conclusion, the described ZFN-based approach represents a fast strategy for generating gene knockouts in ESCs in a selection-independent fashion that should be easily transferrable to other pluripotent stem cells. PMID:22194948

  9. Robotic cardiac surgery in Brazil

    PubMed Central

    Toschi, Alisson P.; Pope, Renato B.; Montanhesi, Paola K.; Santos, Ricardo S.; Teruya, Alexandre; Hatanaka, Dina M.; Rusca, Gabriel F.; Fischer, Claudio H.; Vieira, Marcelo C.; Makdisse, Marcia R.

    2017-01-01

    Background Brazil, the largest country and economy in South America, is a major driving force behind the development of new medical technologies in the region. Robotic cardiac surgery (RCS) has been evolving rapidly since 2010, when the first surgery using the DaVinci® robotic system was performed in Latin America. The aim of this article is to evaluate short and mid-term results in patients undergoing robotic cardiac surgery in Brazil. Methods From March 2010 to December 2015, 39 consecutive patients underwent robotic cardiac surgery. Twenty-seven patients were male (69.2%), with the mean age of 51.3±17.9 years. Participants had a mean ejection fraction of 62±5%. The procedures included in this study were mitral valve surgery, surgical treatment of atrial fibrillation, atrial septal defect closure, resection of intra-cardiac tumors, totally endoscopic coronary artery bypass and pericardiectomy. Results The mean time spent on cardiopulmonary bypass (CPB) during RCS was 154.9±94.2 minutes and the mean aortic cross-clamp time was 114.48±75.66 minutes. Thirty-two patients (82%) were extubated in the operating room immediately after surgery. The median intensive care unit (ICU) length of stay was 1 day (ranging from 0 to 25) and the median hospital length of stay was 5 days (ranging from 3 to 25). For each type of procedure, endpoints were individually reported. There were no conversions to sternotomy and no intra-operative complications. Patient follow-up was complete in 100% of the participants, with two early deaths unrelated to the procedures and no re-operations at mid-term. Conclusions Despite the heterogeneity of this series, RCS appears to be feasible, safe and effective when used for the correction of various intra- and extra-cardiac pathologies. Adopting the robotic system has been a challenge in Brazil, where its limited clinical application may be related to the lack of specific training and the high cost of technology. PMID:28203537

  10. Positron emission tomography and functional characterization of a complete PBR/TSPO knockout

    PubMed Central

    Banati, Richard B.; Middleton, Ryan J.; Chan, Ronald; Hatty, Claire R.; Wai-Ying Kam, Winnie; Quin, Candice; Graeber, Manuel B.; Parmar, Arvind; Zahra, David; Callaghan, Paul; Fok, Sandra; Howell, Nicholas R.; Gregoire, Marie; Szabo, Alexander; Pham, Tien; Davis, Emma; Liu, Guo-Jun

    2014-01-01

    The evolutionarily conserved peripheral benzodiazepine receptor (PBR), or 18-kDa translocator protein (TSPO), is thought to be essential for cholesterol transport and steroidogenesis, and thus life. TSPO has been proposed as a biomarker of neuroinflammation and a new drug target in neurological diseases ranging from Alzheimer’s disease to anxiety. Here we show that global C57BL/6-Tspotm1GuWu(GuwiyangWurra)-knockout mice are viable with normal growth, lifespan, cholesterol transport, blood pregnenolone concentration, protoporphyrin IX metabolism, fertility and behaviour. However, while the activation of microglia after neuronal injury appears to be unimpaired, microglia from GuwiyangWurraTSPO knockouts produce significantly less ATP, suggesting reduced metabolic activity. Using the isoquinoline PK11195, the ligand originally used for the pharmacological and structural characterization of the PBR/TSPO, and the imidazopyridines CLINDE and PBR111, we demonstrate the utility of GuwiyangWurraTSPO knockouts to provide robust data on drug specificity and selectivity, both in vitro and in vivo, as well as the mechanism of action of putative TSPO-targeting drugs. PMID:25406832

  11. The effect of PDIA3 gene knockout on the mucosal immune function in IBS rats

    PubMed Central

    Zhuang, Zhao-Meng; Wang, Xiao-Teng; Zhang, Lu; Tao, Li-Yuan; Lv, Bin

    2015-01-01

    Objective: To observe the changes of intestinal inflammation on PDIA3 gene knockout IBS rats and its effect on immune function. Methods: 36 SD rats were randomly divided into four groups: the control group (n = 8); IBS- empty virus group (IBS-GFP, which); IBS-PDIA3 knockout group (n = 12); IBS- the control group (n = 12). After modeling, colon and ileocecal tissue pathology in each group were observed separately. Changes of immune and inflammatory markers were measured. At the same time, ultrastructural changes in each group were observed by electron microscopy. Results: Compared with the IBS control group, inflammation was reduced significantly in IBS-PDIA3 knockout group. IgE, IL-4 and IL-9 and the level of intestinal trypsin type were decreased significantly. Furthermore, mast cell degranulation and PAR 2 receptor reduced significantly. Conclusion: PDIA3 may play an important role in the development of IBS by mediating through immune responses of mucosal abnormalities. However, the mechanism needs to be confirmed in further study. PMID:26221224

  12. Identification of Novel Knockout Targets for Improving Terpenoids Biosynthesis in Saccharomyces cerevisiae

    PubMed Central

    Li, Jing; Wang, Jianfeng; Li, Qian; Wang, Yong; Zhang, Yansheng

    2014-01-01

    Many terpenoids have important pharmacological activity and commercial value; however, application of these terpenoids is often limited by problems associated with the production of sufficient amounts of these molecules. The use of Saccharomyces cerevisiae (S. cerevisiae) for the production of heterologous terpenoids has achieved some success. The objective of this study was to identify S. cerevisiae knockout targets for improving the synthesis of heterologous terpeniods. On the basis of computational analysis of the S. cerevisiae metabolic network, we identified the knockout sites with the potential to promote terpenoid production and the corresponding single mutant was constructed by molecular manipulations. The growth rates of these strains were measured and the results indicated that the gene deletion had no adverse effects. Using the expression of amorphadiene biosynthesis as a testing model, the gene deletion was assessed for its effect on the production of exogenous terpenoids. The results showed that the dysfunction of most genes led to increased production of amorphadiene. The yield of amorphadiene produced by most single mutants was 8–10-fold greater compared to the wild type, indicating that the knockout sites can be engineered to promote the synthesis of exogenous terpenoids. PMID:25386654

  13. Myo5b knockout mice as a model of microvillus inclusion disease.

    PubMed

    Cartón-García, Fernando; Overeem, Arend W; Nieto, Rocio; Bazzocco, Sarah; Dopeso, Higinio; Macaya, Irati; Bilic, Josipa; Landolfi, Stefania; Hernandez-Losa, Javier; Schwartz, Simo; Ramon y Cajal, Santiago; van Ijzendoorn, Sven C D; Arango, Diego

    2015-07-23

    Inherited MYO5B mutations have recently been associated with microvillus inclusion disease (MVID), an autosomal recessive syndrome characterized by intractable, life-threatening, watery diarrhea appearing shortly after birth. Characterization of the molecular mechanisms underlying this disease and development of novel therapeutic approaches is hampered by the lack of animal models. In this study we describe the phenotype of a novel mouse model with targeted inactivation of Myo5b. Myo5b knockout mice show perinatal mortality, diarrhea and the characteristic mislocalization of apical and basolateral plasma membrane markers in enterocytes. Moreover, in transmission electron preparations, we observed microvillus atrophy and the presence of microvillus inclusion bodies. Importantly, Myo5b knockout embryos at day 20 of gestation already display all these structural defects, indicating that they are tissue autonomous rather than secondary to environmental cues, such as the long-term absence of nutrients in the intestine. Myo5b knockout mice closely resemble the phenotype of MVID patients and constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches.

  14. Development and Characterization of Uterine Glandular Epithelium Specific Androgen Receptor Knockout Mouse Model.

    PubMed

    Choi, Jaesung Peter; Zheng, Yu; Skulte, Katherine A; Handelsman, David J; Simanainen, Ulla

    2015-11-01

    While estrogen action is the major driver of uterine development, androgens acting via the androgen receptor (AR) may also promote uterine growth as suggested by uterine phenotypes in global AR knockout (ARKO) female mice. Because AR is expressed in uterine endometrial glands, we generated (Cre/loxP) uterine gland epithelium-specific ARKO (ugeARKO) to determine the role of endometrial gland-specific androgen actions. However, AR in uterine gland epithelium may not be required for normal uterine development and function because ugeARKO females had normal uterine development and fertility. To determine if exogenous androgens acting via AR can fully support uterine growth in the absence of estrogens, the ARKO and ugeARKO females were ovariectomized and treated with supraphysiological doses of testosterone or dihydrotestosterone (nonaromatizable androgen). Both dihydrotestosterone and testosterone supported full uterine regrowth in wild-type females while ARKO females had no regrowth (comparable to ovariectomized only). These findings suggest that androgens acting via AR can promote full uterine regrowth in the absence of estrogens. The ugeARKO had 50% regrowth when compared to intact uterine glands, and histomorphologically, both the endometrial and myometrial areas were significantly (P < 0.05) reduced, suggesting glandular epithelial AR located in the endometrium may indirectly modify myometrial development. Additionally, to confirm Cre function in endometrial glands, we generated uge-specific PTEN knockout mouse model. The ugePTEN knockout females developed severe endometrial hyperplasia and therefore present a novel model for future research.

  15. Retinoid-related orphan receptor γ (RORγ) adult induced knockout mice develop lymphoblastic lymphoma.

    PubMed

    Liljevald, Maria; Rehnberg, Maria; Söderberg, Magnus; Ramnegård, Marie; Börjesson, Jenny; Luciani, Donatella; Krutrök, Nina; Brändén, Lena; Johansson, Camilla; Xu, Xiufeng; Bjursell, Mikael; Sjögren, Anna-Karin; Hornberg, Jorrit; Andersson, Ulf; Keeling, David; Jirholt, Johan

    2016-11-01

    RORγ is a nuclear hormone receptor which controls polarization of naive CD4(+) T-cells into proinflammatory Th17 cells. Pharmacological antagonism of RORγ has therapeutic potential for autoimmune diseases; however, this mechanism may potentially carry target-related safety risks, as mice deficient in Rorc, the gene encoding RORγ, develop T-cell lymphoma with 50% frequency. Due to the requirement of RORγ during development, the Rorc knockout (KO) animals lack secondary lymphoid organs and have a dysregulation in the generation of CD4+ and CD8+ T cells. We wanted to extend the evaluation of RORγ deficiency to address the question whether lymphomas, similar to those observed in the Rorc KO, would develop in an animal with an otherwise intact adult immune system. Accordingly, we designed a conditional RORγ knockout mouse (Rorc CKO) where the Rorc locus could be deleted in adult animals. Based on these studies we can confirm that these animals also develop lymphoma in a similar time frame as embryonic Rorc knockouts. This study also suggests that in animals where the gene deletion is incomplete, the thymus undergoes a rapid selection process replacing Rorc deficient cells with remnant thymocytes carrying a functional Rorc locus and that subsequently, these animals do not develop lymphoblastic lymphoma.

  16. Generation of RUNX3 knockout pigs using CRISPR/Cas9-mediated gene targeting.

    PubMed

    Kang, J-T; Ryu, J; Cho, B; Lee, E-J; Yun, Y-J; Ahn, S; Lee, J; Ji, D-Y; Lee, K; Park, K-W

    2016-12-01

    Pigs are an attractive animal model to study the progression of cancer because of their anatomical and physiological similarities to human. However, the use of pig models for cancer research has been limited by availability of genetically engineered pigs which can recapitulate human cancer progression. Utilizing genome editing technologies such as CRISPR/Cas9 system allows us to generate genetically engineered pigs at a higher efficiency. In this study, specific CRISPR/Cas9 systems were used to target RUNX3, a known tumour suppressor gene, to generate a pig model that can induce gastric cancer in human. First, RUNX3 knockout cell lines carrying genetic modification (monoallelic or biallelic) of RUNX3 were generated by introducing engineered CRISPR/Cas9 system specific to RUNX3 into foetal fibroblast cells. Then, the genetically modified foetal fibroblast cells were used as donor cells for somatic cell nuclear transfer, followed by embryo transfer. We successfully obtained four live RUNX3 knockout piglets from two surrogates. The piglets showed the lack of RUNX3 protein in their internal organ system. Our results demonstrate that the CRISPR/Cas9 system is effective in inducing mutations on a specific locus of genome and the RUNX3 knockout pigs can be useful resources for human cancer research and to develop novel cancer therapies.

  17. Myo5b knockout mice as a model of microvillus inclusion disease

    PubMed Central

    Cartón-García, Fernando; Overeem, Arend W.; Nieto, Rocio; Bazzocco, Sarah; Dopeso, Higinio; Macaya, Irati; Bilic, Josipa; Landolfi, Stefania; Hernandez-Losa, Javier; Schwartz, Simo; Ramon y Cajal, Santiago; van Ijzendoorn, Sven C. D.; Arango, Diego

    2015-01-01

    Inherited MYO5B mutations have recently been associated with microvillus inclusion disease (MVID), an autosomal recessive syndrome characterized by intractable, life-threatening, watery diarrhea appearing shortly after birth. Characterization of the molecular mechanisms underlying this disease and development of novel therapeutic approaches is hampered by the lack of animal models. In this study we describe the phenotype of a novel mouse model with targeted inactivation of Myo5b. Myo5b knockout mice show perinatal mortality, diarrhea and the characteristic mislocalization of apical and basolateral plasma membrane markers in enterocytes. Moreover, in transmission electron preparations, we observed microvillus atrophy and the presence of microvillus inclusion bodies. Importantly, Myo5b knockout embryos at day 20 of gestation already display all these structural defects, indicating that they are tissue autonomous rather than secondary to environmental cues, such as the long-term absence of nutrients in the intestine. Myo5b knockout mice closely resemble the phenotype of MVID patients and constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches. PMID:26201991

  18. Identification of novel knockout targets for improving terpenoids biosynthesis in Saccharomyces cerevisiae.

    PubMed

    Sun, Zhiqiang; Meng, Hailin; Li, Jing; Wang, Jianfeng; Li, Qian; Wang, Yong; Zhang, Yansheng

    2014-01-01

    Many terpenoids have important pharmacological activity and commercial value; however, application of these terpenoids is often limited by problems associated with the production of sufficient amounts of these molecules. The use of Saccharomyces cerevisiae (S. cerevisiae) for the production of heterologous terpenoids has achieved some success. The objective of this study was to identify S. cerevisiae knockout targets for improving the synthesis of heterologous terpeniods. On the basis of computational analysis of the S. cerevisiae metabolic network, we identified the knockout sites with the potential to promote terpenoid production and the corresponding single mutant was constructed by molecular manipulations. The growth rates of these strains were measured and the results indicated that the gene deletion had no adverse effects. Using the expression of amorphadiene biosynthesis as a testing model, the gene deletion was assessed for its effect on the production of exogenous terpenoids. The results showed that the dysfunction of most genes led to increased production of amorphadiene. The yield of amorphadiene produced by most single mutants was 8-10-fold greater compared to the wild type, indicating that the knockout sites can be engineered to promote the synthesis of exogenous terpenoids.

  19. Rapid construction of a whole-genome transposon insertion collection for Shewanella oneidensis by Knockout Sudoku

    PubMed Central

    Baym, Michael; Shaket, Lev; Anzai, Isao A.; Adesina, Oluwakemi; Barstow, Buz

    2016-01-01

    Whole-genome knockout collections are invaluable for connecting gene sequence to function, yet traditionally, their construction has required an extraordinary technical effort. Here we report a method for the construction and purification of a curated whole-genome collection of single-gene transposon disruption mutants termed Knockout Sudoku. Using simple combinatorial pooling, a highly oversampled collection of mutants is condensed into a next-generation sequencing library in a single day, a 30- to 100-fold improvement over prior methods. The identities of the mutants in the collection are then solved by a probabilistic algorithm that uses internal self-consistency within the sequencing data set, followed by rapid algorithmically guided condensation to a minimal representative set of mutants, validation, and curation. Starting from a progenitor collection of 39,918 mutants, we compile a quality-controlled knockout collection of the electroactive microbe Shewanella oneidensis MR-1 containing representatives for 3,667 genes that is functionally validated by high-throughput kinetic measurements of quinone reduction. PMID:27830751

  20. Generation of Recombinant Capripoxvirus Vectors for Vaccines and Gene Knockout Function Studies.

    PubMed

    Boshra, Hani; Cao, Jingxin; Babiuk, Shawn

    2016-01-01

    The ability to manipulate capripoxvirus through gene knockouts and gene insertions has become an increasingly valuable research tool in elucidating the function of individual genes of capripoxvirus, as well as in the development of capripoxvirus-based recombinant vaccines. The homologous recombination technique is used to generate capripoxvirus knockout viruses (KO), and is based on the targeting a particular viral gene of interest. This technique can also be used to insert a gene of interest. A protocol for the generation of a viral gene knockout is described. This technique involves the use of a plasmid which encodes the flanking sequences of the regions where the homologous recombination will occur, and will result in the insertion of an EGFP reporter gene for visualization of recombinant virus, as well as the E. coli gpt gene as a positive selection marker. If an additional gene is to be incorporated, this can be achieved by inserting a gene of interest for expression under a poxvirus promoter into the plasmid between the flanking regions for insertion. This chapter describes a protocol for generating such recombinant capripoxviruses.

  1. Less is More: unveiling the functional core of hematopoietic stem cells through knockout mice

    PubMed Central

    Rossi, Lara; Lin, Kuanyin K.; Boles, Nathan C.; Yang, Liubin; King, Katherine Y.; Jeong, Mira; Mayle, Allison; Goodell, Margaret A.

    2012-01-01

    Summary Hematopoietic stem cells (HSCs) represent one of the first recognized somatic stem cells. As such, nearly 200 genes have been examined for roles in HSC function in knockout mice. In this review, we compile the majority of these reports to provide a broad overview of the functional modules revealed by these genetic analyses and highlight some key regulatory pathways involved, including cell cycle control, TGF-β signaling, Pten/AKT signaling, Wnt signaling, and cytokine signaling. Finally, we propose recommendations for characterization of HSC function in knockout mice to facilitate cross-study comparisons that would generate a more cohesive picture of HSC biology. In the field of design, the minimalist movement stripped down buildings and objects to their most basic features, a sentiment that architect Ludwig Mies van der Rohe summarized in his motto “less is more”. By depleting HSCs of specific genes, knockout studies transpose the minimalist approach into research biology, providing insights into the essential core of genetic features that is indispensable for a well-functioning hematopoietic system. PMID:22958929

  2. Locomotor activity, ultrasonic vocalization and oxytocin levels in infant CD38 knockout mice.

    PubMed

    Liu, Hong-Xiang; Lopatina, Olga; Higashida, Chiharu; Tsuji, Takahiro; Kato, Ichiro; Takasawa, Shin; Okamoto, Hiroshi; Yokoyama, Shigeru; Higashida, Haruhiro

    2008-12-19

    Oxytocin (OT), a neurohormone involved in reproduction, plays a critical role in social behavior in a wide range of mammalian species from rodents to humans. The role of CD38 in regulating OT secretion for social behavior has been demonstrated in adult mice, but has not been examined in pups or during development. Separation from the dam induces stress in 7-day-old mouse pups. During such isolation, locomotor activity was higher in CD38 knockout (CD38(-/-)) pups than in wild-type (CD38(+/+)) or heterozygous (CD38(+/-)) controls. The number of ultrasonic vocalizations was lower in CD38(-/-) pups than in CD38(+/+) pups. However, the difference between the two genotypes was less severe than that in OT knockout or OT receptor knockout mice. To explain this, we measured plasma OT levels. The level was not lower in CD38(-/-) pups during the period 1-3 weeks after birth, but was significantly reduced after weaning (>3 weeks). ADP-ribosyl cyclase activities in the hypothalamus and pituitary were markedly lower from 1 week after birth in CD38(-/-) mice and were consistently lower thereafter to the adult stage (2 months old). These results showed that the reduced severity of behavioral abnormalities in CD38(-/-) pups was due to partial compensation by the high level of plasma OT.

  3. Axonal regeneration of optic nerve after crush in Nogo66 receptor knockout mice.

    PubMed

    Su, Ying; Wang, Feng; Teng, Yan; Zhao, Shi-Guang; Cui, Hao; Pan, Shang-Ha

    2009-09-04

    Mature retinal ganglion cells (RGCs) cannot regenerate injured axons because some neurite growth inhibitors, including the C-terminal of Nogo-A (Nogo66), myelin-associated glycoprotein (MAG) and Omgp, exert their effects on neuron regeneration through the Nogo receptor (NgR). In this study, the axonal regeneration of retinal ganglion cells (RGCs) after optic nerve (ON) crush was investigated both in vivo and in vitro in NgR knockout mice. We used NgR knockout mice as the experimental group, and C57BL/6 mice as the control group. Partial ON injury was induced by using a specially designed ON clip to pinch the ON 1mm behind the mouse eyeball with 40g pressure for 9s. NgR mRNA was studied by in situ hybridization (ISH). NgR protein was studied by Western blot. Growth Associated Protein 43 (GAP-43), a plasticity protein expressed highly during axon regeneration, was studied by immunofluorescence staining on the frozen sections. RGCs were cultured and purified. The axonal growth of RGCs was calculated by a computerized image analyzer. We found that compared with the control group, the GAP-43 expression was significantly higher and the axonal growth was significantly more active at every observation time point in the experimental group. These results indicate that NgR genes play an important role in the axonal regeneration after ON injury, while knockout of NgR is effective for eliminating this inhibition and enhancing axonal regeneration.

  4. Neutron Knockout to Probe 3N Forces in the Ca Isotopes

    NASA Astrophysics Data System (ADS)

    Crawford, Heather; NSCL Experiment e12029 Collaboration

    2013-10-01

    Recent calculations by Holt et al. have suggested that the inclusion of 3N forces to describe the structure of neutron-rich Ca isotopes provides a more realistic description of the nuclear structure. Mass measurements have confirmed the importance of including 3N forces compared to NN-only interactions, but cannot discriminate between the predictions of phenomenological interactions and the NN+3N microscopic calculations. Neutron knockout along the Z = 20 isotopes provides an opportunity to test the results of NN+3N calculations against phenomenological interactions. The calculations of Holt et al. predict a fragmentation of the 1f7 / 2 neutron strength from the first 7/2- state in 49Ca into higher lying states, in contrast to the predictions of both GXPF1 and KB3G which concentrate the strength in the lowest lying 7/2- state. Differences are also observed in the summed f7 / 2 strength to bound nuclear states in both 50Ca and 49Ca neutron knockout. We will report on a systematic study of one-neutron knockout along the Ca isotopes using GRETINA+S800. Comparison of experimental spectroscopic factors to calculations will provide insight into the role of 3N forces in describing the Z = 20 isotopes. With collaborators from LBNL, NSCL/MSU, ANL, Central Michigan University, TRIUMF/UBC and TU-Darmstadt.

  5. Deletion of JAM-C, a candidate gene for heart defects in Jacobsen syndrome, results in a normal cardiac phenotype in mice.

    PubMed

    Ye, Maoqing; Hamzeh, Rabih; Geddis, Amy; Varki, Nissi; Perryman, M Benjamin; Grossfeld, Paul

    2009-07-01

    The 11q terminal deletion disorder (11q-) is a rare chromosomal disorder caused by a deletion in distal 11q. Fifty-six percent of patients have clinically significant congenital heart defects. A cardiac "critical region" has been identified in distal 11q that contains over 40 annotated genes. In this study, we identify the distal breakpoint of a patient with a paracentric inversion in distal 11q who had hypoplastic left heart and congenital thrombocytopenia. The distal breakpoint mapped to JAM-3, a gene previously identified as a candidate gene for causing HLHS in 11q-. To determine the role of JAM-3 in cardiac development, we performed a comprehensive cardiac phenotypic assessment in which the mouse homolog for JAM-3, JAM-C, has been deleted. These mice have normal cardiac structure and function, indicating that haplo-insufficiency of JAM-3 is unlikely to cause the congenital heart defects that occur in 11q- patients. Notably, we identified a previously undescribed phenotype, jitteriness, in most of the sick or dying adult JAM-C knockout mice. These data provide further insights into the identification of the putative disease-causing cardiac gene(s) in distal 11q, as well as the functions of JAM-C in normal organ development.

  6. Mitochondria in cardiac hypertrophy and heart failure

    PubMed Central

    Rosca, Mariana G.; Tandler, Bernard; Hoppel, Charles L.

    2013-01-01

    Heart failure (HF) frequently is the unfavorable outcome of pathological heart hypertrophy. In contrast to physiological cardiac hypertrophy, which occurs in response to exercise and leads to full adaptation of contractility to the increased wall stress, pathological hypertrophy occurs in response to volume or pressure overload, ultimately leading to contractile dysfunction and HF. Because cardiac hypertrophy impairs the relationship between ATP demand and production, mitochondrial bioenergetics must keep up with the cardiac hypertrophic phenotype. We review data regarding the mitochondrial proteomic and energetic remodeling in cardiac hypertrophy, as well as the temporal and causal relationship between mitochondrial failure to match the increased energy demand and progression to cardiac decompensation. We suggest that the maladaptive effect of sustained neuroendocrine signals on mitochondria leads to bioenergetic fading which contributes to the progression from cardiac hypertrophy to failure. PMID:22982369

  7. Cardiac mechanics: Physiological, clinical, and mathematical considerations

    NASA Technical Reports Server (NTRS)

    Mirsky, I. (Editor); Ghista, D. N.; Sandler, H.

    1974-01-01

    Recent studies concerning the basic physiological and biochemical principles underlying cardiac muscle contraction, methods for the assessment of cardiac function in the clinical situation, and mathematical approaches to cardiac mechanics are presented. Some of the topics covered include: cardiac ultrastructure and function in the normal and failing heart, myocardial energetics, clinical applications of angiocardiography, use of echocardiography for evaluating cardiac performance, systolic time intervals in the noninvasive assessment of left ventricular performance in man, evaluation of passive elastic stiffness for the left ventricle and isolated heart muscle, a conceptual model of myocardial infarction and cardiogenic shock, application of Huxley's sliding-filament theory to the mechanics of normal and hypertrophied cardiac muscle, and a rheological modeling of the intact left ventricle. Individual items are announced in this issue.

  8. Quality Control Systems in Cardiac Aging

    PubMed Central

    Quarles, Ellen K; Dai, Dao-Fu; Tocchi, Autumn; Basisty, Nathan; Gitari, Lemuel; Rabinovitch, Peter S

    2015-01-01

    Cardiac aging is an intrinsic process that results in impaired cardiac function, along with cellular and molecular changes. These degenerative changes are intimately associated with quality control mechanisms. This review provides a general overview of the clinical and cellular changes which manifest in cardiac aging, and the quality control mechanisms involved in maintaining homeostasis and retarding aging. These mechanisms include autophagy, ubiquitin-mediated turnover, apoptosis, mitochondrial quality control and cardiac matrix homeostasis. Finally, we discuss aging interventions that have been observed to impact cardiac health outcomes. These include caloric restriction, rapamycin, resveratrol, GDF11, mitochondrial antioxidants and cardiolipin-targeted therapeutics. A greater understanding of the quality control mechanisms that promote cardiac homeostasis will help to understand the benefits of these interventions, and hopefully lead to further improved therapeutic modalities. PMID:25702865

  9. 42 CFR 410.49 - Cardiac rehabilitation program and intensive cardiac rehabilitation program: Conditions of coverage.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...) Body mass index. (iv) Systolic blood pressure. (v) Diastolic blood pressure. (vi) The need for cholesterol, blood pressure, and diabetes medications. (3) A list of approved intensive cardiac rehabilitation... prescribed exercise, cardiac risk factor modification, psychosocial assessment, and outcomes...

  10. 42 CFR 410.49 - Cardiac rehabilitation program and intensive cardiac rehabilitation program: Conditions of coverage.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...) Body mass index. (iv) Systolic blood pressure. (v) Diastolic blood pressure. (vi) The need for cholesterol, blood pressure, and diabetes medications. (3) A list of approved intensive cardiac rehabilitation... prescribed exercise, cardiac risk factor modification, psychosocial assessment, and outcomes...

  11. 42 CFR 410.49 - Cardiac rehabilitation program and intensive cardiac rehabilitation program: Conditions of coverage.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...) Body mass index. (iv) Systolic blood pressure. (v) Diastolic blood pressure. (vi) The need for cholesterol, blood pressure, and diabetes medications. (3) A list of approved intensive cardiac rehabilitation... prescribed exercise, cardiac risk factor modification, psychosocial assessment, and outcomes...

  12. Enhanced sympathetic cardiac modulation in bruxism patients.

    PubMed

    Marthol, Harald; Reich, Sven; Jacke, Julia; Lechner, Karl-Heinz; Wichmann, Manfred; Hilz, Max Josef

    2006-08-01

    Sleep bruxism, an oral parafunction including teeth clenching and grinding, might be related to increased stress. To evaluate sympathetic cardiac activity in bruxism patients, we monitored cardiac autonomic modulation using spectral analysis of heart rate variability and compared results to those of age-matched healthy volunteers. In bruxism patients, sympathetic cardiac activity was higher than in volunteers. The increased sympathetic tone suggests increased stress and might be related to occlusal disharmonies.

  13. Cardiac Arrhythmias: Diagnosis, Symptoms, and Treatments.

    PubMed

    Fu, Du-Guan

    2015-11-01

    The cardiac arrhythmia is characterized by irregular rhythm of heartbeat which could be either too slow (<60 beats/min) or too fast (>100 beats/min) and can happen at any age. The use of pacemaker and defibrillators devices has been suggested for heart arrhythmias patients. The antiarrhythmic medications have been reported for the treatment of cardiac arrhythmias or irregular heartbeats. The diagnosis, symptoms, and treatments of cardiac arrhythmias as well as the radiofrequency ablation, tachycardia, Brugada syndrome, arterial fibrillation, and recent research on the genetics of cardiac arrhythmias have been described here.

  14. Sudden cardiac death – Historical perspectives

    PubMed Central

    Abhilash, S.P.; Namboodiri, Narayanan

    2014-01-01

    Sudden cardiac death (SCD) is an unexpected death due to cardiac causes that occurs in a short time period (generally within 1 h of symptom onset) in a person with known or unknown cardiac disease. It is believed to be involved in nearly a quarter of human deaths, with ventricular fibrillation being the most common mechanism. It is estimated that more than 7 million lives per year are lost to SCD worldwide. Historical perspectives of SCD are analyzed with a brief description on how the developments in the management of sudden cardiac arrest evolved over time. PMID:24568828

  15. Cardiac tissue engineering in magnetically actuated scaffolds

    NASA Astrophysics Data System (ADS)

    Sapir, Yulia; Polyak, Boris; Cohen, Smadar

    2014-01-01

    Cardiac tissue engineering offers new possibilities for the functional and structural restoration of damaged or lost heart tissue by applying cardiac patches created in vitro. Engineering such functional cardiac patches is a complex mission, involving material design on the nano- and microscale as well as the application of biological cues and stimulation patterns to promote cell survival and organization into a functional cardiac tissue. Herein, we present a novel strategy for creating a functional cardiac patch by combining the use of a macroporous alginate scaffold impregnated with magnetically responsive nanoparticles (MNPs) and the application of external magnetic stimulation. Neonatal rat cardiac cells seeded within the magnetically responsive scaffolds and stimulated by an alternating magnetic field of 5 Hz developed into matured myocardial tissue characterized by anisotropically organized striated cardiac fibers, which preserved its features for longer times than non-stimulated constructs. A greater activation of AKT phosphorylation in cardiac cell constructs after applying a short-term (20 min) external magnetic field indicated the efficacy of magnetic stimulation to actuate at a distance and provided a possible mechanism for its action. Our results point to a synergistic effect of magnetic field stimulation together with nanoparticulate features of the scaffold surface as providing the regenerating environment for cardiac cells driving their organization into functionally mature tissue.

  16. Preload Sensitivity in Cardiac Assist Devices

    PubMed Central

    Fukamachi, Kiyotaka; Shiose, Akira; Massiello, Alex; Horvath, David J.; Golding, Leonard A. R.; Lee, Sangjin; Starling, Randall C.

    2013-01-01

    With implantable cardiac assist devices increasingly proving their effectiveness as therapeutic options for end-stage heart failure, it is important for clinicians to understand the unique physiology of device-assisted circulation. Preload sensitivity as it relates to cardiac assist devices is derived from the Frank-Starling relationship between human ventricular filling pressures and ventricular stroke volume. In this review, we stratify the preload sensitivity of 17 implantable cardiac assist devices relative to the native heart and discuss the effect of preload sensitivity on left ventricular volume unloading, levels of cardiac support, and the future development of continuous-flow total artificial heart technology. PMID:23272869

  17. Multimodality imaging for resuscitated sudden cardiac death.

    PubMed

    Chen, Yingming Amy; Deva, Djeven; Kirpalani, Anish; Prabhudesai, Vikram; Marcuzzi, Danny W; Graham, John J; Verma, Subodh; Jimenez-Juan, Laura; Yan, Andrew T

    2015-01-01

    We present a case that elegantly illustrates the utility of two novel noninvasive imaging techniques, computed tomography (CT) coronary angiography and cardiac MRI, in the diagnosis and management of a 27-year-old man with exertion-induced cardiac arrest caused by an anomalous right coronary artery. CT coronary angiography with 3D reformatting delineated the interarterial course of an anomalous right coronary artery compressed between the aorta and pulmonary artery, whereas cardiac MRI showed a small myocardial infarction in the right coronary artery territory not detected on echocardiography. This case highlights the value of novel multimodality imaging techniques in the risk stratification and management of patients with resuscitated cardiac arrest.

  18. Comparison of intestinal warm ischemic injury in PACAP knockout and wild-type mice.

    PubMed

    Ferencz, Andrea; Kiss, Peter; Weber, Gyorgy; Helyes, Zsuzsanna; Shintani, Norihito; Baba, Akemichi; Reglodi, Dora

    2010-11-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is present in the gastrointestinal tract and plays a central role in the intestinal physiology, mainly in the secretion and motility. The aim of our study was to compare the ischemic injury in wild-type and PACAP-38 knockout mice following warm mesenteric small bowel ischemia. Warm ischemia groups were designed with occlusion of superior mesenteric artery for 1, 3, and 6 h in wild-type (n = 10 in each group) and PACAP-38 knockout (n = 10 in each group) mice. Small bowel biopsies were collected after laparotomy (control) and at the end of the ischemia periods. To determine oxidative stress parameters, malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) were measured. Tissue damage was analyzed by qualitative and quantitative methods on hematoxylin/eosin-stained sections. In PACAP-38 knockout animals, tissue MDA increased significantly after 3 and 6 h ischemia (133.97 ± 6,2; 141.86 ± 5,8) compared to sham-operated (100.92 ± 3,6) and compared to wild-type results (112.8 ± 2,1; 118.4 ± 1.03 μmol/g, p < 0.05). Meanwhile, tissue concentration of GSH and activity of SOD decreased significantly in knockout mice compared to wild-type form (GSH, 795.97 ± 10.4; 665.1 ± 8,8 vs. 893.23 ± μmol/g; SOD, 94.4 ± 1.4; 81.2 ± 3.9 vs. 208.09 ± 3,7 IU/g). Qualitative and quantitative histological results showed destruction of the mucous, submucous layers, and crypts in knockout mice compared to wild-type tissues. These processes correlated with the warm ischemia periods. Our present results propose an important protective effect of endogenous PACAP-38 against intestinal warm ischemia, which provides basis for further investigation to elucidate the mechanism of this protective effect.

  19. Improving the efficiency of CHO cell line generation using glutamine synthetase gene knockout cells.

    PubMed

    Fan, Lianchun; Kadura, Ibrahim; Krebs, Lara E; Hatfield, Christopher C; Shaw, Margaret M; Frye, Christopher C

    2012-04-01

    Although Chinese hamster ovary (CHO) cells, with their unique characteristics, have become a major workhorse for the manufacture of therapeutic recombinant proteins, one of the major challenges in CHO cell line generation (CLG) is how to efficiently identify those rare, high-producing clones among a large population of low- and non-productive clones. It is not unusual that several hundred individual clones need to be screened for the identification of a commercial clonal cell line with acceptable productivity and growth profile making the cell line appropriate for commercial application. This inefficiency makes the process of CLG both time consuming and laborious. Currently, there are two main CHO expression systems, dihydrofolate reductase (DHFR)-based methotrexate (MTX) selection and glutamine synthetase (GS)-based methionine sulfoximine (MSX) selection, that have been in wide industrial use. Since selection of recombinant cell lines in the GS-CHO system is based on the balance between the expression of the GS gene introduced by the expression plasmid and the addition of the GS inhibitor, L-MSX, the expression of GS from the endogenous GS gene in parental CHOK1SV cells will likely interfere with the selection process. To study endogenous GS expression's potential impact on selection efficiency, GS-knockout CHOK1SV cell lines were generated using the zinc finger nuclease (ZFN) technology designed to specifically target the endogenous CHO GS gene. The high efficiency (∼2%) of bi-allelic modification on the CHO GS gene supports the unique advantages of the ZFN technology, especially in CHO cells. GS enzyme function disruption was confirmed by the observation of glutamine-dependent growth of all GS-knockout cell lines. Full evaluation of the GS-knockout cell lines in a standard industrial cell culture process was performed. Bulk culture productivity improved two- to three-fold through the use of GS-knockout cells as parent cells. The selection stringency was

  20. Phosphorylation of 4EBP by oral leucine administration was suppressed in the skeletal muscle of PGC-1α knockout mice.

    PubMed

    Yoshimura, Ryoji; Minami, Kimiko; Matsuda, Junichiro; Sawada, Naoki; Miura, Shinji; Kamei, Yasutomi

    2016-01-01

    Leucine is known to increase mTOR-mediated phosphorylation of 4EBP. In this study, leucine was administered to skeletal muscle-PGC-1α knockout mice. We observed attenuated 4EBP phosphorylation in the skeletal muscle, but not in the liver, of the PGC-1α knockout mice. These data suggest that skeletal muscle-PGC-1α is important for leucine-mediated mTOR activation and protein biosynthesis.

  1. Cardiac aetiology of cardiac arrest: percutaneous coronary interventions during and after cardiopulmonary resuscitation.

    PubMed

    Nikolaou, Nikolaos I; Christou, Apostolos H

    2013-09-01

    Management and prevention of cardiac arrest in the setting of heart disease is a challenge for modern cardiology. After reviewing the aetiology of sudden cardiac death and discussing the way to identify candidates at risk, we emphasise the role of percutaneous coronary interventions during and after cardiopulmonary resuscitation in the treatment of patients with return of spontaneous circulation after cardiac arrest.

  2. Brain responses to cardiac electrical stimulation: a new EEG method for evaluating cardiac sensation.

    PubMed

    Suzuki, Hideaki; Hirose, Masanori; Watanabe, Satoshi; Fukuda, Koji; Fukudo, Shin; Shimokawa, Hiroaki

    2012-01-01

    Although cardiac sensation, such as palpitation or chest pain, is common and is sometimes a malignant sign of heart diseases, the mechanism by which the human brain responds to afferent signals from the heart remains unclear. In this study, we investigated whether electrical stimulation of the heart provokes brain responses in humans. We examined 15 patients (age: 65.4 ± 3.1 years old, 11 males and 4 females) implanted with either a cardiac pacemaker or cardiac resynchronization therapy (CRT) device. Electroencephalogram (EEG) was simultaneously recorded from the vertex during right ventricular pacing at 70-100 beats/min at baseline (1.5 V) and intense (6-8 V) stimulation sessions. We evaluated brain responses to cardiac electrical stimulation by measuring cerebral potentials that were obtained by subtracting the average of 100 EEG waves triggered by cardiac pacing during baseline stimulation from those during the intense stimulation. Intense stimulation of the cardiac pacemaker or CRT device reproducibly induced cardiac sensation in 6 out of the 15 patients; namely, the remaining 9 patients showed no reproducible response. Brain responses were evident by averaging cerebral potentials from all of the 15 patients and those from 6 patients with reproducible cardiac sensation. To the best our knowledge, this is the first report that demonstrates the brain responses to cardiac electrical stimulation in humans. This new method should be useful for examining pathophysiology of cardiac diseases with pathological cardiac sensation, including cardiac anxiety and silent myocardial ischemia.

  3. 42 CFR 410.49 - Cardiac rehabilitation program and intensive cardiac rehabilitation program: Conditions of coverage.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... heart-lung transplant. (vii) For cardiac rehabilitation only, other cardiac conditions as specified...) Body mass index. (iv) Systolic blood pressure. (v) Diastolic blood pressure. (vi) The need for cholesterol, blood pressure, and diabetes medications. (3) A list of approved intensive cardiac...

  4. 42 CFR 410.49 - Cardiac rehabilitation program and intensive cardiac rehabilitation program: Conditions of coverage.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... heart-lung transplant. (vii) For cardiac rehabilitation only, other cardiac conditions as specified...) Body mass index. (iv) Systolic blood pressure. (v) Diastolic blood pressure. (vi) The need for cholesterol, blood pressure, and diabetes medications. (3) A list of approved intensive cardiac...

  5. An In Silico Knockout Model for Gastrointestinal Absorption Using a Systems Pharmacology Approach - Development and Application for Ketones

    PubMed Central

    Shivva, Vittal; Tucker, Ian G.; Duffull, Stephen B.

    2016-01-01

    Gastrointestinal absorption and disposition of ketones is complex. Recent work describing the pharmacokinetics (PK) of d-β-hydroxybutyrate (BHB) following oral ingestion of a ketone monoester ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) found multiple input sites, nonlinear disposition and feedback on endogenous production. In the current work, a human systems pharmacology model for gastrointestinal absorption and subsequent disposition of small molecules (monocarboxylic acids with molecular weight < 200 Da) was developed with an application to a ketone monoester. The systems model was developed by collating the information from the literature and knowledge gained from empirical population modelling of the clinical data. In silico knockout variants of this systems model were used to explore the mechanism of gastrointestinal absorption of ketones. The knockouts included active absorption across different regions in the gut and also a passive diffusion knockout, giving 10 gut knockouts in total. Exploration of knockout variants has suggested that there are at least three distinct regions in the gut that contribute to absorption of ketones. Passive diffusion predominates in the proximal gut and active processes contribute to the absorption of ketones in the distal gut. Low doses are predominantly absorbed from the proximal gut by passive diffusion whereas high doses are absorbed across all sites in the gut. This work has provided mechanistic insight into the absorption process of ketones, in the form of unique in silico knockouts that have potential for application with other therapeutics. Future studies on absorption process of ketones are suggested to substantiate findings in this study. PMID:27685985

  6. ECLS in Pediatric Cardiac Patients

    PubMed Central

    Di Nardo, Matteo; MacLaren, Graeme; Marano, Marco; Cecchetti, Corrado; Bernaschi, Paola; Amodeo, Antonio

    2016-01-01

    Extracorporeal life support (ECLS) is an important device in the management of children with severe refractory cardiac and or pulmonary failure. Actually, two forms of ECLS are available for neonates and children: extracorporeal membrane oxygenation (ECMO) and use of a ventricular assist device (VAD). Both these techniques have their own advantages and disadvantages. The intra-aortic balloon pump is another ECLS device that has been successfully used in larger children, adolescents, and adults, but has found limited applicability in smaller children. In this review, we will present the “state of art” of ECMO in neonate and children with heart failure. ECMO is commonly used in a variety of settings to provide support to critically ill patients with cardiac disease. However, a strict selection of patients and timing of intervention should be performed to avoid the increase in mortality and morbidity of these patients. Therefore, every attempt should be done to start ECLS “urgently” rather than “emergently,” before the presence of dysfunction of end organs or circulatory collapse. Even though exciting progress is being made in the development of VADs for long-term mechanical support in children, ECMO remains the mainstay of mechanical circulatory support in children with complex anatomy, particularly those needing rapid resuscitation and those with a functionally univentricular circulation. With the increase in familiarity with ECMO, new indications have been added, such as extracorporeal cardiopulmonary resuscitation (ECPR). The literature supporting ECPR is increasing in children. Reasonable survival rates have been achieved after initiation of support during active compressions of the chest following in-hospital cardiac arrest. Contraindications to ECLS have reduced in the last 5 years and many centers support patients with functionally univentricular circulations. Improved results have been recently achieved in this complex subset of patients. PMID

  7. Cardiac imaging: does radiation matter?

    PubMed Central

    Einstein, Andrew J.; Knuuti, Juhani

    2012-01-01

    The use of ionizing radiation in cardiovascular imaging has generated considerable discussion. Radiation should not be considered in isolation, but rather in the context of a careful examination of the benefits, risks, and costs of cardiovascular imaging. Such consideration requires an understanding of some fundamental aspects of the biology, physics, epidemiology, and terminology germane to radiation, as well as principles of radiological protection. This paper offers a concise, contemporary perspective on these areas by addressing pertinent questions relating to radiation and its application to cardiac imaging. PMID:21828062

  8. CARDIAC OPERATIONS WITH EXTRACORPOREAL CIRCULATION

    PubMed Central

    Kay, Jerome Harold; Anderson, Robert M.; Lewis, Reuben R.; Meihaus, John; Magidson, Oscar; Snyder, Edward N.; Bennett, Louis C.; Bernstein, Sol; Amsden, Neal

    1959-01-01

    In a series of 50 patients for whom a heart-lung machine was used for periods as long as 70 minutes during operations to correct structural defects of the heart, there were no deaths attributable to the machine. Seven patients died. Two of them had high pressure ventricular septal defects with bidirectional shunts; a third patient with the same lesion recovered after repair. One patient died of cardiac tamponade when a large blood clot formed about the entire heart in a loosely closed pericardial sac. Others died of various causes. The development of subacute bacterial endocarditis in one patient led to a change in sterilization of apparatus. PMID:13662856

  9. Cardiac Resynchronization Therapy in Women.

    PubMed

    Costanzo, Maria Rosa

    2017-01-01

    The benefits of cardiac resynchronization therapy (CRT) on the outcomes of patients with heart failure are unquestionable. Women are under-represented in all CRT studies. Most of the available data show that CRT produces a greater clinical benefit in women than men. In several studies, women have left bundle branch block more frequently than men. Women have a remarkably high (90%) CRT response over a wide range of QRS lengths (130-175 milliseconds). Use of a QRS duration of 150 milliseconds as the threshold for CRT prescription may deny a life-saving therapy to many women likely to benefit from CRT.

  10. Cardiac Resynchronization Therapy in Women.

    PubMed

    Costanzo, Maria Rosa

    2015-12-01

    The benefits of cardiac resynchronization therapy (CRT) on the outcomes of patients with heart failure are unquestionable. Women are under-represented in all CRT studies. Most of the available data show that CRT produces a greater clinical benefit in women than men. In several studies, women have left bundle branch block more frequently than men. Women have a remarkably high (90%) CRT response over a wide range of QRS lengths (130-175 milliseconds). Use of a QRS duration of 150 milliseconds as the threshold for CRT prescription may deny a life-saving therapy to many women likely to benefit from CRT.

  11. [Morgagni hernia causing cardiac tamponade].

    PubMed

    S Breinig; Paranon, S; Le Mandat, A; Galinier, P; Dulac, Y; Acar, P

    2010-10-01

    Morgagni hernia is a rare malformation (3% of diaphragmatic hernias). This hernia is usually asymptomatic in children. We report on a case revealed by an unusual complication. Severe cyanosis was due to right-to-left atrial shunt through the foramen ovale assessed by 2D echocardiography. Diagnosis of the Morgagni hernia was made with CT scan. The intrathoracic liver compressed the right chambers of the heart causing tamponade. Cardiac compression was reversed after surgery and replacement of the liver in the abdomen. Six months after the surgery, the infant was symptom-free with normal size right chambers of the heart.

  12. Echocardiographic assessment of cardiac disease

    NASA Technical Reports Server (NTRS)

    Popp, R. L.

    1976-01-01

    The physical principles and current applications of echocardiography in assessment of heart diseases are reviewed. Technical considerations and unresolved points relative to the use of echocardiography in various disease states are stressed. The discussion covers normal mitral valve motion, mitral stenosis, aortic regurgitation, atrial masses, mitral valve prolapse, and idiopathic hypertrophic subaortic stenosis. Other topics concern tricuspic valve abnormalities, aortic valve disease, pulmonic valve, pericardial effusion, intraventricular septal motion, and left ventricular function. The application of echocardiography to congenital heart disease diagnosis is discussed along with promising ultrasonic imaging systems. The utility of echocardiography in quantitative evaluation of cardiac disease is demonstrated.

  13. [Carney's Complex: familial cardiac myxoma].

    PubMed

    Guerra, Miguel S; Santos, Nelson; Neves, Fátima; Carlos Mota, João; Miranda, José António; Vouga, Luis

    2006-01-01

    The Carney Complex is a very rare autosomal dominant disease including multiple neoplasia syndrome. This syndrome was initially described in 1985 under the rubric "...the complex of myxomas, spotty pigmentation, and endocrine overactivity". We present a case report of an old woman with Carney Complex who had the characteristic features of facial hirsutism and acromegalic facies, a large pigmented swelling over the face and a cardiac myxoma arising from the left atrium. We emphasize the need for periodic echocardiographic screening of patients and family members.

  14. Cardiac dysfunctions following spinal cord injury

    PubMed Central

    Sandu, AM; Popescu, M; Iacobini, MA; Stoian, R; Neascu, C; Popa, F

    2009-01-01

    The aim of this article is to analyze cardiac dysfunctions occurring after spinal cord injury (SCI). Cardiac dysfunctions are common complications following SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI. We reviewed epidemiology of cardiac disturbances after SCI, and neuroanatomy and pathophysiology of autonomic nervous system, sympathetic and parasympathetic. SCI causes disruption of descendent pathways from central control centers to spinal sympathetic neurons, originating into intermediolateral nuclei of T1–L2 spinal cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve. SCI associates significant cardiac dysfunction. Impairment of autonomic nervous control system, mostly in patients with cervical or high thoracic SCI, causes cardiac dysrrhythmias, especially bradycardia and, rarely, cardiac arrest, or tachyarrhytmias and hypotension. Specific complication dependent on the period of time after trauma like spinal shock and autonomic dysreflexia are also reviewed. Spinal shock occurs during the acute phase following SCI and is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe bradycardia and hypotension. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Besides all this, additional cardiac complications, such as cardiac deconditioning and coronary heart disease may also occur. Proper prophylaxis, including nonpharmacologic and pharmacological strategies and cardiac rehabilitation diminish occurrence of the cardiac dysfunction following

  15. CXCR6 deficiency attenuates pressure overload-induced monocytes migration and cardiac fibrosis through downregulating TNF-α-dependent MMP9 pathway.

    PubMed

    Wang, Jia-Hong; Su, Feng; Wang, Shijun; Lu, Xian-Cheng; Zhang, Shao-Heng; Chen, De; Chen, Nan-Nan; Zhong, Jing-Quan

    2014-01-01

    An immerging role of TNF-α in collagen synthesis and cardiac fibrosis implies the significance of TNF-α production in the development of myocardial remodeling. Our previous study showed a reduction of TNF-α and attenuated cardiac remodeling in CXCR6 knockout (KO) mice after ischemia/reperfusion injury. However, the potential mechanism of TNF-α-mediated cardiac fibrosis with pressure overload has not been well elucidated. In the present study, we aim to investigate the role of CXCR6 in TNF-α release and myocardial remodeling in response to pressure overload. Pressure overload was performed by constriction of transverse aorta (TAC) surgery on CXCR6 KO mice and C57 wild-type (WT) counterparts. At 6 weeks after TAC, cardiac remodeling was assessed by echocardiography, cardiac TNF-α release and its type I receptor (TNFRI), were detected by ELISA and western blot, collagen genes Col1a1 (type I) and Col3a1 (type III) were examined by real-time PCR. Compared with CXCR6 WT mice, CXCR6 KO mice exhibited less cardiac dysfunction, reduced expression of TNFRI, Col1a1 and Col3a. In vitro, we confirmed that CXCR6 deficiency led to reduced homing and infiltration of CD11b(+) monocytes, which contributed to attenuated TNF-α release in myocardium. Furthermore, TNFRI antagonist pretreatment blocked AT1 receptor signaling and NOX4 expression, reduced collagen synthesis, and blunted the activity of MMP9 in CXCR6 WT mice after TAC, but these were not observed in CXCR6 KO mice. In the present work, we propose a mechanism that CXCR6 is essential for pressure overload-mediated myocardial recruitment of monocytes, which contributes to cardiac fibrosis through TNF-α-dependent MMP9 activation and collagen synthesis.

  16. Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling.

    PubMed

    Li, Yulin; Li, Zhenya; Zhang, Congcong; Li, Ping; Wu, Yina; Wang, Chunxiao; Lau, Wayne Bond; Ma, Xin-Liang; Du, Jie

    2017-03-01

    Background -Hypertensive ventricular remodeling is a common cause of heart failure. However, the molecular mechanisms regulating ventricular remodeling remain poorly understood. Methods -We used a discovery-driven/nonbiased approach to indentify increased ATF3 expression in hypertensive heart. We employed loss/gain of function approaches to understand the role of ATF3 in heart failure. We also examine the mechanisms through transcriptome, CHIP-seq analysis and in vivo and vitro experiments. Results -ATF3 expression increased in murine hypertensive heart and human hypertrophic heart. Cardiac fibroblast cells are the primary cell type expressing high ATF3 levels in response to hypertensive stimuli. ATF3 knockout (ATF3KO) markedly exaggerated hypertensive ventricular remodeling, a state rescued by lentivirus-mediated/miRNA-aided cardiac fibroblast-selective ATF3 overexpression. Conversely, conditional cardiac fibroblast cell-specific ATF3 transgenic overexpression significantly ameliorated ventricular remodeling and heart failure. We identified Map2K3 as a novel ATF3 target. ATF3 binds with the Map2K3 promoter, recruiting HDAC1, resulting in Map2K3 gene-associated histone deacetylation, thereby inhibiting Map2K3 expression. Genetic Map2K3 knockdown rescued the pro-fibrotic/hypertrophic phenotype in ATF3KO cells. Finally, we demonstrated that p38 is the downstream molecule of Map2K3 mediating the pro-fibrotic/hypertrophic effects in ATF3KO animals. Inhibition of p38 signaling reduced TGF-β signaling-related pro-fibrotic and hypertrophic gene expression, and blocked exaggerated cardiac remodeling in ATF3KO cells. Conclusions -Our study provides the first evidence that ATF3 upregulation in cardiac fibroblasts in response to hypertensive stimuli protects heart by suppressing Map2K3 expression and subsequent p38-TGF-β signaling. These results suggest that positive modulation of cardiac fibroblast ATF3 may represent a novel therapeutic approach against hypertensive

  17. Postoperative atrial fibrillation in non-cardiac and cardiac surgery: an overview.

    PubMed

    Bessissow, A; Khan, J; Devereaux, P J; Alvarez-Garcia, J; Alonso-Coello, P

    2015-06-01

    Postoperative atrial fibrillation (POAF) is the most common perioperative cardiac arrhythmia. A major risk factor for POAF is advanced age, both in non-cardiac and cardiac surgery. Following non-cardiac surgery, it is important to correct reversible conditions such as electrolytes imbalances to prevent the occurrence of POAF. Management of POAF consists of rate control and therapeutic anticoagulation if POAF persists for > 48 h and CHADS2 score > 2. After cardiac surgery, POAF affects a larger amount of patients. In addition to age, valve surgery carries the greatest risk for new AF. Rate control is the mainstay therapy in these patients. Prediction, prevention, and management of POAF should be further studied.

  18. Embryonic caffeine exposure acts via A1 adenosine receptors to alter adult cardiac function and DNA methylation in mice.

    PubMed

    Buscariollo, Daniela L; Fang, Xiefan; Greenwood, Victoria; Xue, Huiling; Rivkees, Scott A; Wendler, Christopher C

    2014-01-01

    Evidence indicates that disruption of normal prenatal development influences an individual's risk of developing obesity and cardiovascular disease as an adult. Thus, understanding how in utero exposure to chemical agents leads to increased susceptibility to adult diseases is a critical health related issue. Our aim was to determine whether adenosine A1 receptors (A1ARs) mediate the long-term effects of in utero caffeine exposure on cardiac function and whether these long-term effects are the result of changes in DNA methylation patterns in adult hearts. Pregnant A1AR knockout mice were treated with caffeine (20 mg/kg) or vehicle (0.09% NaCl) i.p. at embryonic day 8.5. This caffeine treatment results in serum levels equivalent to the consumption of 2-4 cups of coffee in humans. After dams gave birth, offspring were examined at 8-10 weeks of age. A1AR+/+ offspring treated in utero with caffeine were 10% heavier than vehicle controls. Using echocardiography, we observed altered cardiac function and morphology in adult mice exposed to caffeine in utero. Caffeine treatment decreased cardiac output by 11% and increased left ventricular wall thickness by 29% during diastole. Using DNA methylation arrays, we identified altered DNA methylation patterns in A1AR+/+ caffeine treated hearts, including 7719 differentially methylated regions (DMRs) within the genome and an overall decrease in DNA methylation of 26%. Analysis of genes associated with DMRs revealed that many are associated with cardiac hypertrophy. These data demonstrate that A1ARs mediate in utero caffeine effects on cardiac function and growth and that caffeine exposure leads to changes in DNA methylation.

  19. Imminent Cardiac Risk Assessment via Optical Intravascular Biochemical Analysis

    SciTech Connect

    Wetzel, D.; Wetzel, L; Wetzel, M; Lodder, R

    2009-01-01

    Heart disease is by far the biggest killer in the United States, and type II diabetes, which affects 8% of the U.S. population, is on the rise. In many cases, the acute coronary syndrome and/or sudden cardiac death occurs without warning. Atherosclerosis has known behavioral, genetic and dietary risk factors. However, our laboratory studies with animal models and human post-mortem tissue using FT-IR microspectroscopy reveal the chemical microstructure within arteries and in the arterial walls themselves. These include spectra obtained from the aortas of ApoE-/- knockout mice on sucrose and normal diets showing lipid deposition in the former case. Also pre-aneurysm chemical images of knockout mouse aorta walls, and spectra of plaque excised from a living human patient are shown for comparison. In keeping with the theme of the SPEC 2008 conference Spectroscopic Diagnosis of Disease this paper describes the background and potential value of a new catheter-based system to provide in vivo biochemical analysis of plaque in human coronary arteries. We report the following: (1) results of FT-IR microspectroscopy on animal models of vascular disease to illustrate the localized chemical distinctions between pathological and normal tissue, (2) current diagnostic techniques used for risk assessment of patients with potential unstable coronary syndromes, and (3) the advantages and limitations of each of these techniques illustrated with patent care histories, related in the first person, by the physician coauthors. Note that the physician comments clarify the contribution of each diagnostic technique to imminent cardiac risk assessment in a clinical setting, leading to the appreciation of what localized intravascular chemical analysis can contribute as an add-on diagnostic tool. The quality of medical imaging has improved dramatically since the turn of the century. Among clinical non-invasive diagnostic tools, laboratory tests of body fluids, EKG, and physical examination are

  20. Brain penetration of WEB 2086 (Apafant) and dantrolene in Mdr1a (P-glycoprotein) and Bcrp knockout rats.

    PubMed

    Fuchs, Holger; Kishimoto, Wataru; Gansser, Dietmar; Tanswell, Paul; Ishiguro, Naoki

    2014-10-01

    Transporter gene knockout rat models are attracting increasing interest for mechanistic studies of new drugs as transporter substrates or inhibitors in vivo. However, limited data are available on the functional validity of such models at the blood-brain barrier. Therefore, the present study evaluated Mdr1a [P-glycoprotein (P-gp)], Bcrp, and combined Mdr1a/Bcrp knockout rat strains for the influence of P-gp and breast cancer resistance protein (BCRP) transport proteins on brain penetration of the selective test substrates [(14)C]WEB 2086 (3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]-diazepin-2-yl]-1-(4-morpholinyl)-1-propanon) for P-gp and dantrolene for BCRP. Brain-to-plasma concentration ratios (BPR) were measured after intravenous coinfusions of 5.5 µmol/kg per hour [(14)C]WEB 2086 and 2 µmol/kg per hour dantrolene for 2 hours in groups of knockout or wild-type rats. Compared with wild-type controls, mean BPR of [(14)C]WEB 2086 increased 8-fold in Mdr1a knockouts, 9.5-fold in double Mdr1a/Bcrp knockouts, and 7.3-fold in zosuquidar-treated wild-type rats, but was unchanged in Bcrp knockout rats. Mean BPR of dantrolene increased 3.3-fold in Bcrp knockouts and 3.9-fold in double Mdr1a/Bcrp knockouts compared with wild type, but was unchanged in the Mdr1a knockouts. The human intestinal CaCo-2 cell bidirectional transport system in vitro confirmed the in vivo finding that [(14)C]WEB 2086 is a substrate of P-gp but not of BCRP. Therefore, Mdr1a, Bcrp, and combined Mdr1a/Bcrp knockout rats provide functional absence of these efflux transporters at the blood-brain barrier and are a suitable model for mechanistic studies on the brain penetration of drug candidates.

  1. The potential impact of new generation transgenic methods on creating rabbit models of cardiac diseases.

    PubMed

    Bősze, Z; Major, P; Baczkó, I; Odening, K E; Bodrogi, L; Hiripi, L; Varró, A

    2016-07-01

    Since the creation of the first transgenic rabbit thirty years ago, pronuclear microinjection remained the single applied method and resulted in numerous important rabbit models of human diseases, including cardiac deficiencies, albeit with low efficiency. For additive transgenesis a novel transposon mediated method, e.g., the Sleeping Beauty transgenesis, increased the efficiency, and its application to create cardiac disease models is expected in the near future. The targeted genome engineering nuclease family, e.g., the zink finger nuclease (ZFN), the transcription activator-like effector nuclease (TALEN) and the newest, clustered regularly interspaced short palindromic repeats (CRISPR) with the CRISPR associated effector protein (CAS), revolutionized the non-mouse transgenesis. The latest gene-targeting technology, the CRISPR/CAS system, was proven to be efficient in rabbit to create multi-gene knockout models. In the future, the number of tailor-made rabbit models produced with one of the above mentioned methods is expected to exponentially increase and to provide adequate models of heart diseases.

  2. Vinculin variant M94I identified in sudden unexplained nocturnal death syndrome decreases cardiac sodium current

    PubMed Central

    Cheng, Jianding; Kyle, John W.; Wiedmeyer, Brandi; Lang, Di; Vaidyanathan, Ravi; Makielski, Jonathan C.

    2017-01-01

    Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative disorder with unclear etiology. Vinculin (VCL) was linked to sudden arrhythmia death in VCL knockout mice prior to the appearance of cardiomyopathy. We hypothesized VCL mutations underlie risk for SUNDS. A rare heterozygous variant VCL-M94I was found in a SUNDS victim who suffered sudden nocturnal tachypnea and lacked pathogenic variants in known arrhythmia-causing genes. VCL was identified to interact with SCN5A in vitro/vivo. The VCL-M94I was co-expressed with the cardiac sodium channel in HEK293 cells and also overexpressed in induced pluripotent stem cells derived cardiomyocytes (iPSCs-CM). In HEK293 cells with pH 7.4, VCL-M94I caused ~30% decrease in peak sodium current (INa) amplitude compared to WT; under acidotic conditions (pH 7.0) typically found with hypoxia during sleep apnea, M94I resulted in 37% reduction in peak INa compared to WT and the combination of VCL-M94I and pH 7.0 decreased peak INa by ~56% compared to WT at pH 7.4. In iPSCs-CM, similar effects of M94I on reduction of peak INa were observed. This study initially shows both physical and functional interaction between VCL and cardiac sodium channel, and suggests an important role for respiratory acidosis in triggering the fatal arrhythmia underlying SUNDS. PMID:28218286

  3. Cardiac cell proliferation assessed by EdU, a novel analysis of cardiac regeneration.

    PubMed

    Zeng, Bin; Tong, Suiyang; Ren, Xiaofeng; Xia, Hao

    2016-08-01

    Emerging evidence suggests that mammalian hearts maintain the capacity for cardiac regeneration. Rapid and sensitive identification of cardiac cellular proliferation is prerequisite for understanding the underlying mechanisms and strategies of cardiac regeneration. The following immunologically related markers of cardiac cells were analyzed: cardiac transcription factors Nkx2.5 and Gata 4; specific marker of cardiomyocytes TnT; endothelial cell marker CD31; vascular smooth muscle marker smooth muscle myosin IgG; cardiac resident stem cells markers IsL1, Tbx18, and Wt1. Markers were co-localized in cardiac tissues of embryonic, neonatal, adult, and pathological samples by 5-ethynyl-2'-deoxyuridine (EdU) staining. EdU was also used to label isolated neonatal cardiomyocytes in vitro. EdU robustly labeled proliferating cells in vitro and in vivo, co-immunostaining with different cardiac cells markers. EdU can rapidly and sensitively label proliferating cardiac cells in developmental and pathological states. Cardiac cell proliferation assessed by EdU is a novel analytical tool for investigating the mechanism and strategies of cardiac regeneration in response to injury.

  4. Mechanoregulation of cardiac myofibroblast differentiation: implications for cardiac fibrosis and therapy.

    PubMed

    Yong, Kar Wey; Li, YuHui; Huang, GuoYou; Lu, Tian Jian; Safwani, Wan Kamarul Zaman Wan; Pingguan-Murphy, Belinda; Xu, Feng

    2015-08-15

    Cardiac myofibroblast differentiation, as one of the most important cellular responses to heart injury, plays a critical role in cardiac remodeling and failure. While biochemical cues for this have been extensively investigated, the role of mechanical cues, e.g., extracellular matrix stiffness and mechanical strain, has also been found to mediate cardiac myofibroblast differentiation. Cardiac fibroblasts in vivo are typically subjected to a specific spatiotemporally changed mechanical microenvironment. When exposed to abnormal mechanical conditions (e.g., increased extracellular matrix stiffness or strain), cardiac fibroblasts can undergo myofibroblast differentiation. To date, the impact of mechanical cues on cardiac myofibroblast differentiation has been studied both in vitro and in vivo. Most of the related in vitro research into this has been mainly undertaken in two-dimensional cell culture systems, although a few three-dimensional studies that exist revealed an important role of dimensionality. However, despite remarkable advances, the comprehensive mechanisms for mechanoregulation of cardiac myofibroblast differentiation remain elusive. In this review, we introduce important parameters for evaluating cardiac myofibroblast differentiation and then discuss the development of both in vitro (two and three dimensional) and in vivo studies on mechanoregulation of cardiac myofibroblast differentiation. An understanding of the development of cardiac myofibroblast differentiation in response to changing mechanical microenvironment will underlie potential targets for future therapy of cardiac fibrosis and failure.

  5. [Cardiac Pacemakers, implantable defibrillators and IRM].

    PubMed

    Frank, R; Hidden-Lucet, F; Himbert, C; Petitot, J C; Fontaine, G

    2003-04-01

    The IRM is formally contraindicated to the pacemaker and cardiac defibrillator wearers because of the risk of inhibition or inappropriate stimulations during the examination. However if the examination is essential, suitable programming of the apparatus and a constant monitoring of the heartbeat rate by a qualified doctor in cardiac stimulation must make it possible to avoid any accident.

  6. Fetal cardiac interventions: clinical and experimental research

    PubMed Central

    Humuruola, Gulimila

    2016-01-01

    Fetal cardiac interventions for congenital heart diseases may alleviate heart dysfunction, prevent them evolving into hypoplastic left heart syndrome, achieve biventricular outcome and improve fetal survival. Candidates for clinical fetal cardiac interventions are now restricted to cases of critical aortic valve stenosis with evolving hypoplastic left heart syndrome, pulmonary atresia with an intact ventricular septum and evolving hypoplastic right heart syndrome, and hypoplastic left heart syndrome with an intact or highly restrictive atrial septum as well as fetal heart block. The therapeutic options are advocated as prenatal aortic valvuloplasty, pulmonary valvuloplasty, creation of interatrial communication and fetal cardiac pacing. Experimental research on fetal cardiac intervention involves technical modifications of catheter-based cardiac clinical interventions and open fetal cardiac bypass that cannot be applied in human fetuses for the time being. Clinical fetal cardiac interventions are plausible for midgestation fetuses with the above-mentioned congenital heart defects. The technical success, biventricular outcome and fetal survival are continuously being improved in the conditions of the sophisticated multidisciplinary team, equipment, techniques and postnatal care. Experimental research is laying the foundations and may open new fields for catheter-based clinical techniques. In the present article, the clinical therapeutic options and experimental fetal cardiac interventions are described. PMID:27279868

  7. Cardiac Vagal Regulation and Early Peer Status

    ERIC Educational Resources Information Center

    Graziano, Paulo A.; Keane, Susan P.; Calkins, Susan D.

    2007-01-01

    A sample of 341 5 1/2-year-old children participating in an ongoing longitudinal study was the focus of a study on the relation between cardiac vagal regulation and peer status. To assess cardiac vagal regulation, resting measures of respiratory sinus arrhythmia (RSA) and RSA change (suppression) to 3 cognitively and emotionally challenging tasks…

  8. Ultrasound Imaging in Teaching Cardiac Physiology

    ERIC Educational Resources Information Center

    Johnson, Christopher D.; Montgomery, Laura E. A.; Quinn, Joe G.; Roe, Sean M.; Stewart, Michael T.; Tansey, Etain A.

    2016-01-01

    This laboratory session provides hands-on experience for students to visualize the beating human heart with ultrasound imaging. Simple views are obtained from which students can directly measure important cardiac dimensions in systole and diastole. This allows students to derive, from first principles, important measures of cardiac function, such…

  9. MicroRNAs and cardiac regeneration

    PubMed Central

    Hodgkinson, Conrad P.; Kang, Martin H.; Dal-Pra, Sophie; Mirotsou, Maria; Dzau, Victor J.

    2015-01-01

    The human heart has a very limited capacity to regenerate lost or damaged cardiomyocytes following cardiac insult. Instead, myocardial injury is characterized by extensive cardiac remodeling by fibroblasts, resulting in the eventual deterioration of cardiac structure and function. Cardiac function would be improved if these fibroblasts could be converted into cardiomyocytes. MicroRNAs (miRNAs), small non-coding RNAs that promote mRNA degradation and inhibit mRNA translation, have been shown to be important in cardiac development. Using this information various researchers have utilized miRNAs to promote the formation of cardiomyocytes through a number of approaches. Several miRNAs acting in combination promote the direct conversion of cardiac fibroblasts into cardiomyocytes. Moreover, a number of miRNAs have been identified that aid the formation of iPS cells and miRNAs also induce these cells to adopt a cardiac fate. MiRNAs have also been implicated in resident cardiac progenitor cell differentiation. In this review we will discuss the current literature as it pertains to these processes as well as discussing the therapeutic implications of these findings. PMID:25953925

  10. Slow inactivation in human cardiac sodium channels.

    PubMed Central

    Richmond, J E; Featherstone, D E; Hartmann, H A; Ruben, P C

    1998-01-01

    The available pool of sodium channels, and thus cell excitability, is regulated by both fast and slow inactivation. In cardiac tissue, the requirement for sustained firing of long-duration action potentials suggests that slow inactivation in cardiac sodium channels may differ from slow inactivation in skeletal muscle sodium channels. To test this hypothesis, we used the macropatch technique to characterize slow inactivation in human cardiac sodium channels heterologously expressed in Xenopus oocytes. Slow inactivation was isolated from fast inactivation kinetically (by selectively recovering channels from fast inactivation before measurement of slow inactivation) and structurally (by modification of fast inactivation by mutation of IFM1488QQQ). Time constants of slow inactivation in cardiac sodium channels were larger than previously reported for skeletal muscle sodium channels. In addition, steady-state slow inactivation was only 40% complete in cardiac sodium channels, compared to 80% in skeletal muscle channels. These results suggest that cardiac sodium channel slow inactivation is adapted for the sustained depolarizations found in normally functioning cardiac tissue. Complete slow inactivation in the fast inactivation modified IFM1488QQQ cardiac channel mutant suggests that this impairment of slow inactivation may result from an interaction between fast and slow inactivation. PMID:9635748

  11. Seasonal variations of cardiac output in rats.

    PubMed

    Back, G; Strubelt, O

    1975-11-15

    Cardiac output of rats shows seasonal variations with low values in spring and summer and high ones in autumn and winter. The stroke volume was much more implicated in these changes than the heart rate. The seasonal changes of cardiac output are probably due to changes of thyroid function.

  12. Athletes at Risk for Sudden Cardiac Death

    ERIC Educational Resources Information Center

    Subasic, Kim

    2010-01-01

    High school athletes represent the largest group of individuals affected by sudden cardiac death, with an estimated incidence of once or twice per week. Structural cardiovascular abnormalities are the most frequent cause of sudden cardiac death. Athletes participating in basketball, football, track, soccer, baseball, and swimming were found to…

  13. Tissue Doppler imaging in cardiac sarcoidosis.

    PubMed

    Smedema, J P

    2008-07-01

    A middle-aged African lady, who presented with ventricular tachycardias, mitral valve regurgitation and congestive heart failure, was diagnosed with cardiac sarcoidosis. Tissue Doppler imaging demonstrated abnormalities suggestive of myocardial scar, which was confirmed by contrast-enhanced cardiac magnetic resonance.

  14. Epicardial origin of cardiac CFU-Fs.

    PubMed

    Slukvin, Igor I

    2011-12-02

    The epicardium has been recognized as a source of cardiovascular progenitors during embryogenesis and postnatal life. In this issue of Cell Stem Cell, Chong et al. (2011) identify cardiac CFU-Fs as cardiac-resident cells of epicardial origin with broad multilineage differentiation potential.

  15. Update in cardiac arrhythmias and pacing.

    PubMed

    García-Bolao, Ignacio; Ruiz-Mateas, Francisco; Bazan, Victor; Berruezo, Antonio; Alcalde, Oscar; Leal del Ojo, Juan; Acosta, Juan; Martínez Sellés, Manuel; Mosquera, Ignacio

    2015-03-01

    This article discusses the main advances in cardiac arrhythmias and pacing published between 2013 and 2014. Special attention is given to the interventional treatment of atrial fibrillation and ventricular arrhythmias, and on advances in cardiac pacing and implantable cardioverter defibrillators, with particular reference to the elderly patient.

  16. Paradoxical hypertension with cardiac tamponade.

    PubMed

    Argulian, Edgar; Herzog, Eyal; Halpern, Dan G; Messerli, Franz H

    2012-10-01

    Subacute (medical) tamponade develops over a period of days or even weeks. Previous studies have shown that subacute tamponade is uncommonly associated with hypotension. On the contrary, many of those patients are indeed hypertensive at initial presentation. We sought to determine the prevalence and predictors of hypertensive cardiac tamponade and hemodynamic response to pericardial effusion drainage. We conducted a retrospective study of patients who underwent pericardial effusion drainage for subacute pericardial tamponade. Diagnosis of pericardial tamponade was established by the treating physician based on clinical data and supportive echocardiographic findings. Patients were defined as hypertensive if initial systolic blood pressure (BP) was ≥140 mm Hg. Thirty patients with subacute tamponade who underwent pericardial effusion drainage were included in the analysis. Eight patients (27%) were hypertensive with a mean systolic BP of 167 compared to 116 mm Hg in 22 nonhypertensive patients. Hypertensive patients with tamponade were more likely to have advanced renal disease (63% vs 14%, p <0.05) and pre-existing hypertension (88% vs 46, p <0.05) and less likely to have systemic malignancy (0 vs 41%, p <0.05). Systolic BP decreased significantly in patients with hypertensive tamponade after pericardial effusion drainage. Those results are consistent with previous studies with an estimated prevalence of hypertensive tamponade from 27% to 43%. In conclusion, a hypertensive response was observed in approximately 1/3 of patients with subacute pericardial tamponade. Relief of cardiac tamponade commonly resulted in a decrease in BP.

  17. Glucose metabolism and cardiac hypertrophy

    PubMed Central

    Kolwicz, Stephen C.; Tian, Rong

    2011-01-01

    The most notable change in the metabolic profile of hypertrophied hearts is an increased reliance on glucose with an overall reduced oxidative metabolism, i.e. a reappearance of the foetal metabolic pattern. In animal models, this change is attributed to the down-regulation of the transcriptional cascades promoting gene expression for fatty acid oxidation and mitochondrial oxidative phosphorylation in adult hearts. Impaired myocardial energetics in cardiac hypertrophy also triggers AMP-activated protein kinase (AMPK), leading to increased glucose uptake and glycolysis. Aside from increased reliance on glucose as an energy source, changes in other glucose metabolism pathways, e.g. the pentose phosphate pathway, the glucosamine biosynthesis pathway, and anaplerosis, are also noted in the hypertrophied hearts. Studies using transgenic mouse models and pharmacological compounds to mimic or counter the switch of substrate preference in cardiac hypertrophy have demonstrated that increased glucose metabolism in adult heart is not harmful and can be beneficial when it provides sufficient fuel for oxidative metabolism. However, improvement in the oxidative capacity and efficiency rather than the selection of the substrate is likely the ultimate goal for metabolic therapies. PMID:21502371

  18. Cardiac cachexia: hic et nunc.

    PubMed

    Loncar, Goran; Springer, Jochen; Anker, Markus; Doehner, Wolfram; Lainscak, Mitja

    2016-06-01

    Cardiac cachexia (CC) is the clinical entity at the end of the chronic natural course of heart failure (HF). Despite the efforts, even the most recent definition of cardiac cachexia has been challenged, more precisely, the addition of new criteria on top of obligatory weight loss. The pathophysiology of CC is complex and multifactorial. A better understanding of pathophysiological pathways in body wasting will contribute to establish potentially novel treatment strategies. The complex biochemical network related with CC and HF pathophysiology underlines that a single biomarker cannot reflect all of the features of the disease. Biomarkers that could pick up the changes in body composition before they convey into clinical manifestations of CC would be of great importance. The development of preventive and therapeutic strategies against cachexia, sarcopenia, and wasting disorders is perceived as an urgent need by healthcare professionals. The treatment of body wasting remains an unresolved challenge to this day. As CC is a multifactorial disorder, it is unlikely that any single agent will be completely effective in treating this condition. Among all investigated therapeutic strategies, aerobic exercise training in HF patients is the most proved to counteract skeletal muscle wasting and is recommended by treatment guidelines for HF.

  19. Cardiac manifestations of parasitic diseases.

    PubMed

    Nunes, Maria Carmo P; Guimarães Júnior, Milton Henriques; Diamantino, Adriana Costa; Gelape, Claudio Leo; Ferrari, Teresa Cristina Abreu

    2017-03-11

    The heart may be affected directly or indirectly by a variety of protozoa and helminths. This involvement may manifest in different ways, but the syndromes resulting from impairment of the myocardium and pericardium are the most frequent. The myocardium may be invaded by parasites that trigger local inflammatory response with subsequent myocarditis or cardiomyopathy, as occurs in Chagas disease, African trypanosomiasis, toxoplasmosis, trichinellosis and infection with free-living amoebae. In amoebiasis and echinococcosis, the pericardium is the structure most frequently involved with consequent pericardial effusion, acute pericarditis, cardiac tamponade or constrictive pericarditis. Chronic hypereosinophilia due to helminth infections, especially filarial infections, has been associated with the development of tropical endomyocardial fibrosis, a severe form of restrictive cardiomyopathy. Schistosomiasis-associated lung vasculature involvement may cause pulmonary hypertension (PH) and cor pulmonale Tropical pulmonary eosinophilia, which is characterised by progressive interstitial fibrosis and restrictive lung disease, may lead to PH and its consequences may occur in the course of filarial infections. Intracardiac rupture of an Echinococcus cyst can cause membrane or secondary cysts embolisation to the lungs or organs supplied by the systemic circulation. Although unusual causes of cardiac disease outside the endemic areas, heart involvement by parasites should be considered in the differential diagnosis especially of myocardial and/or pericardial diseases of unknown aetiology in both immunocompetent and immunocompromised individuals. In this review, we updated and summarised the current knowledge on the major heart diseases caused by protozoan and metazoan parasites, which either involve the heart directly or otherwise influence the heart adversely.

  20. Cardiac cachexia: hic et nunc

    PubMed Central

    Loncar, Goran; Springer, Jochen; Anker, Markus; Doehner, Wolfram

    2016-01-01

    Abstract Cardiac cachexia (CC) is the clinical entity at the end of the chronic natural course of heart failure (HF). Despite the efforts, even the most recent definition of cardiac cachexia has been challenged, more precisely, the addition of new criteria on top of obligatory weight loss. The pathophysiology of CC is complex and multifactorial. A better understanding of pathophysiological pathways in body wasting will contribute to establish potentially novel treatment strategies. The complex biochemical network related with CC and HF pathophysiology underlines that a single biomarker cannot reflect all of the features of the disease. Biomarkers that could pick up the changes in body composition before they convey into clinical manifestations of CC would be of great importance. The development of preventive and therapeutic strategies against cachexia, sarcopenia, and wasting disorders is perceived as an urgent need by healthcare professionals. The treatment of body wasting remains an unresolved challenge to this day. As CC is a multifactorial disorder, it is unlikely that any single agent will be completely effective in treating this condition. Among all investigated therapeutic strategies, aerobic exercise training in HF patients is the most proved to counteract skeletal muscle wasting and is recommended by treatment guidelines for HF. PMID:27386168

  1. Clofibrate, calcium and cardiac muscle.

    PubMed

    Fairhurst, A S; Wickie, G; Peabody, T

    1982-03-01

    The anti-hyperlipidemic drug clofibrate produces negative inotropic effects and arrythmias in isolated perfused rabbit heart Langendorff preparations. In electrically stimulated rat left atria, clofibrate produces negative inotropic effects, the speed of onset and extent of which are decreased by raising the Ca concentration of the bathing medium. Sensitivity of isolated rat atria to clofibrate is not increased when the tissues are stimulated under slow Ca channel conditions, in which the tissues are activated by either isoproterenol or dibutyryl cyclic AMP, although sensitivity to clofibrate is decreased when atria are exposed to increasing concentrations of norepinephrine. Increasing the stimulation frequency of isolated guinea-pig atria to produce a positive treppe also decreases the inhibitory effect of clofibrate, while in rat atria the typical negative treppe is altered towards a positive treppe in presence of clofibrate. The effects of paired electrical stimulation are not diminished by the drug, suggesting that Ca release from the sarcoplasmic reticulum is not affected by clofibrate, although the drug inhibits the rate of Ca uptake by isolated cardiac sarcoplasmic reticulum and mitochondria. These results suggest that clofibrate has multiple effects on Ca functions in cardiac muscle.

  2. Cardiac Rehabilitation in Older Adults.

    PubMed

    Schopfer, David W; Forman, Daniel E

    2016-09-01

    The biology of aging and the pathophysiology of cardiovascular disease (CVD) overlap, with the effect that CVD is endemic in the growing population of older adults. Moreover, CVD in older adults is usually complicated by age-related complexities, including multimorbidity, polypharmacy, frailty, and other intricacies that add to the risks of ambiguous symptoms, deconditioning, iatrogenesis, falls, disability, and other challenges. Cardiac rehabilitation (CR) is a comprehensive lifestyle program that can have particular benefit for older patients with cardiovascular conditions. Although CR was originally designed primarily as an exercise training program for younger adults after a myocardial infarction or coronary artery bypass surgery, it has evolved as a comprehensive lifestyle program (promoting physical activity as well as education, diet, risk reduction, and adherence) for a broader range of CVD (coronary heart disease, heart failure, and valvular heart disease). It provides a valuable opportunity to address and moderate many of the challenges pertinent for the large and growing population of older adults with CVD. Cardiac rehabilitation promotes physical function (cardiorespiratory fitness as well as strength and balance) that helps overcome disease and deconditioning as well as related vulnerabilities such as disability, frailty, and falls. Similarly, CR facilitates education, monitoring, and guidance to reduce iatrogenesis and promote adherence. Furthermore, CR fosters cognition, socialization, and independence in older patients. Yet despite all its conceptual benefits, CR is significantly underused in older populations. This review discusses benefits and the paradoxical underuse of CR, as well as evolving models of care that may achieve greater application and efficacy.

  3. AKI Associated with Cardiac Surgery

    PubMed Central

    Thiele, Robert H.; Isbell, James M.

    2015-01-01

    Approximately 18% of patients undergoing cardiac surgery experience AKI (on the basis of modern standardized definitions of AKI), and approximately 2%–6% will require hemodialysis. The development of AKI after cardiac surgery portends poor short- and long-term prognoses, with those developing RIFLE failure or AKI Network stage III having an almost 2-fold increase in the risk of death. AKI is caused by a variety of factors, including nephrotoxins, hypoxia, mechanical trauma, inflammation, cardiopulmonary bypass, and hemodynamic instability, and it may be affected by the clinician’s choice of fluids and vasoactive agents as well as the transfusion strategy used. The risk of AKI may be ameliorated by avoidance of nephrotoxins, achievement of adequate glucose control preoperatively, and use of goal-directed therapy hemodynamic strategies. Remote ischemic preconditioning is an exciting future strategy, but more work is needed before widespread implementation. Unfortunately, there are no pharmacologic agents known to reduce the risk of AKI or treat established AKI. PMID:25376763

  4. Predictive Modeling of Cardiac Ischemia

    NASA Technical Reports Server (NTRS)

    Anderson, Gary T.

    1996-01-01

    The goal of the Contextual Alarms Management System (CALMS) project is to develop sophisticated models to predict the onset of clinical cardiac ischemia before it occurs. The system will continuously monitor cardiac patients and set off an alarm when they appear about to suffer an ischemic episode. The models take as inputs information from patient history and combine it with continuously updated information extracted from blood pressure, oxygen saturation and ECG lines. Expert system, statistical, neural network and rough set methodologies are then used to forecast the onset of clinical ischemia before it transpires, thus allowing early intervention aimed at preventing morbid complications from occurring. The models will differ from previous attempts by including combinations of continuous and discrete inputs. A commercial medical instrumentation and software company has invested funds in the project with a goal of commercialization of the technology. The end product will be a system that analyzes physiologic parameters and produces an alarm when myocardial ischemia is present. If proven feasible, a CALMS-based system will be added to existing heart monitoring hardware.

  5. Mycobacterium chimaera and cardiac surgery.

    PubMed

    Stewardson, Andrew J; Stuart, Rhonda L; Cheng, Allen C; Johnson, Paul Dr

    2017-02-20

    There is an ongoing investigation into infections with non-tuberculous mycobacteria associated with contaminated heater-cooler units used in cardiac surgery. The overall risk is low, but surgical site and disseminated infections have been reported, including one possible case in Australia, mainly with surgery involving implantation of prosthetic material. Mycobacterium chimaera infection should be considered in patients who have previously undergone surgery with cardiopulmonary bypass and who present with cardiac or disseminated infection or sternal wound infection unresponsive to standard antibiotic therapy. Where cases are suspected, patients should be investigated and managed in consultation with an infectious diseases physician and/or clinical microbiologist. If cases are confirmed or heater-cooler devices are found to be contaminated, details should be reported to the hospital infection control team, the jurisdictional health department, the Therapeutic Goods Administration and the Australian distributor of the affected heater-cooler unit(s). Measures to manage risk should include communicating with relevant hospital departments, ensuring that the manufacturer's updated instructions for use are followed, regular testing of machines, and reviewing the location of machines when in use.

  6. [Maternal cardiac arrhythmias in pregnancy].

    PubMed

    Facchini, M; Bauersfeld, U; Fasnacht, M; Candinas, R

    2000-12-23

    During pregnancy an increased incidence of maternal cardiac arrhythmias is observed. These include a wide spectrum, from clinically irrelevant isolated premature beats to debilitating supraventricular and ventricular tachycardias. In principle, management of arrhythmias during pregnancy is similar to that in non-pregnant patients. However, special consideration should be given to foetal age and potential teratogenic and haemodynamic adverse drug effects on the foetus. Therapeutic strategy should be guided by interdisciplinary consulting (i.e. cardiology, obstetrics, neonatology). Diagnostic evaluation must rule out underlying cardiovascular, pulmonary, endocrine or metabolic diseases. Additionally, precipitating factors such as excessive caffeine and/or alcohol ingestion and cigarette smoking should be avoided. For benign arrhythmias a conservative approach is appropriate. Antiarrhythmic drug selection depends on the specific arrhythmia being treated and the cardiac condition of the mother and the foetus. Some antiarrhythmic agents, such as propranolol, metoprolol, digoxin and quinidine, have been extensively tested during pregnancy and have proven to be safe; they should therefore, whenever possible, be used as firstline. For supraventricular tachycardia, intravenous adenosine may be used to terminate the arrhythmia if vagal manoeuvres fail. In emergency situations cardioversion may be performed with relative safety. Implantable cardioverter defibrillators as a preventive measure for life-threatening arrhythmias in pregnant patients do not seem to increase the risk of major complications.

  7. Cardiac safety of liposomal anthracyclines.

    PubMed

    Ewer, Michael S; Martin, Francis J; Henderson, Craig; Shapiro, Charles L; Benjamin, Robert S; Gabizon, Alberto A

    2004-12-01

    Conventional anthracyclines are active against many tumor types, but cardiotoxicity related to the cumulative dose may limit their use; this is particularly problematic for patients with risk factors for increased toxicity, for those who have received any anthracycline in the past, or for those who are to receive other cardiotoxic agents. Preclinical studies determined that encapsulating conventional anthracyclines in liposomes reduced the incidence and severity of cumulative dose-related cardiomyopathy while preserving antitumor activity. In controlled clinical trials, the risk of cardiotoxicity was significantly lower when nonpegylated liposomal doxorubicin (Myocet [NPLD]) was substituted for conventional doxorubicin, but the risk was not significantly different when NPLD was used in place of conventional epirubicin. Direct comparisons to conventional doxorubicin therapy showed comparable efficacy but significantly lower risk of cardiotoxicity with pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) therapy. Retrospective and prospective trials have not identified a maximum "cardiac safe" dose of PLD, despite use of cumulative doses exceeding 2,000 mg/m2 in some patients. Liposomal daunorubicin (DaunoXome [DNX]) may be associated with a lower risk of cardiotoxicity than conventional anthracyclines, but comparative trials are not available. With respect to combination chemotherapy, early results of clinical trials suggest that combining trastuzumab or a taxane with NPLD or PLD instead of a conventional anthracycline significantly reduces cardiotoxicity risk without reducing chemotherapeutic efficacy. Further results are eagerly awaited from ongoing controlled trials of cardiac safety with long-term liposomal anthracycline therapy, either alone or in combination with other potentially cardiotoxic agents.

  8. Integrative modeling of the cardiac ventricular myocyte

    PubMed Central

    Winslow, Raimond L.; Cortassa, Sonia; O'Rourke, Brian; Hashambhoy, Yasmin L.; Rice, John Jeremy; Greenstein, Joseph L.

    2011-01-01

    Cardiac electrophysiology is a discipline with a rich 50-year history of experimental research coupled with integrative modeling which has enabled us to achieve a quantitative understanding of the relationships between molecular function and the integrated behavior of the cardiac myocyte in health and disease. In this paper, we review the development of integrative computational models of the cardiac myocyte. We begin with a historical overview of key cardiac cell models that helped shape the field. We then narrow our focus to models of the cardiac ventricular myocyte and describe these models in the context of their subcellular functional systems including dynamic models of voltage-gated ion channels, mitochondrial energy production, ATP-dependent and electrogenic membrane transporters, intracellular Ca dynamics, mechanical contraction, and regulatory signal transduction pathways. We describe key advances and limitations of the models as well as point to new directions for future modeling research. PMID:20865780

  9. Cardiac tamponade, constrictive pericarditis, and restrictive cardiomyopathy.

    PubMed

    Goldstein, James A

    2004-09-01

    The pericardium envelopes the cardiac chambers and under physiological conditions exerts subtle functions, including mechanical effects that enhance normal ventricular interactions that contribute to balancing left and right cardiac outputs. Because the pericardium is non-compliant, conditions that cause intrapericardial crowding elevate intrapericardial pressure, which may be the mediator of adverse cardiac compressive effects. Elevated intrapericardial pressure may result from primary disease of the pericardium itself (tamponade or constriction) or from abrupt chamber dilatation (eg, right ventricular infarction). Regardless of the mechanism leading to increased intrapericardial pressure, the resultant pericardial constraint exerts adverse effects on cardiac filling and output. Constriction and restrictive cardiomyopathy share common pathophysiological and clinical features; their differentiation can be quite challenging. This review will consider the physiology of the normal pericardium and its dynamic interactions with the heart and review in detail the pathophysiology and clinical manifestations of cardiac tamponade, constrictive pericarditis, and restrictive cardiomyopathy.

  10. Cardiac emergencies in neonates and young infants

    PubMed Central

    Kabbani, Nasib; Kabbani, Mohamed S.; Al Taweel, Hayan

    2017-01-01

    Cardiac emergencies in children are not infrequent. Early recognition and management are essential to save life and prevent any comorbidity. The presentation of cardiac emergencies and etiologies is variable depending on the age of child at the time of presentation and type of cardiac lesion. Cyanotic and noncyanotic congenital heart diseases are the main causes in neonates and infants. Acquired heart diseases and dysrhythmia are more common causes for cardiac emergencies in toddler and childhood. In this review, we discuss the most common causes for cardiac emergencies in neonates and young infants highlighting important points in the presentation and management that are essential for early recognition and timely management of infants presenting with these conditions. PMID:28182035

  11. Applications of Computational Modeling in Cardiac Surgery

    PubMed Central

    Lee, Lik Chuan; Genet, Martin; Dang, Alan B.; Ge, Liang; Guccione, Julius M.; Ratcliffe, Mark B.

    2014-01-01

    Although computational modeling is common in many areas of science and engineering, only recently have advances in experimental techniques and medical imaging allowed this tool to be applied in cardiac surgery. Despite its infancy in cardiac surgery, computational modeling has been useful in calculating the effects of clinical devices and surgical procedures. In this review, we present several examples that demonstrate the capabilities of computational cardiac modeling in cardiac surgery. Specifically, we demonstrate its ability to simulate surgery, predict myofiber stress and pump function, and quantify changes to regional myocardial material properties. In addition, issues that would need to be resolved in order for computational modeling to play a greater role in cardiac surgery are discussed. PMID:24708036

  12. Interspecies Differences in Virus Uptake versus Cardiac Function of the Coxsackievirus and Adenovirus Receptor

    PubMed Central

    Freiberg, Fabian; Sauter, Martina; Pinkert, Sandra; Govindarajan, Thirupugal; Kaldrack, Joanna; Thakkar, Meghna; Fechner, Henry; Klingel, Karin

    2014-01-01

    ABSTRACT The coxsackievirus and adenovirus receptor (CAR) is a cell contact protein with an important role in virus uptake. Its extracellular immunoglobulin domains mediate the binding to coxsackievirus and adenovirus as well as homophilic and heterophilic interactions between cells. The cytoplasmic tail links CAR to the cytoskeleton and intracellular signaling cascades. In the heart, CAR is crucial for embryonic development, electrophysiology, and c