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Sample records for adverse lv remodeling

  1. Cardiac restricted overexpression of membrane type-1 matrix metalloproteinase causes adverse myocardial remodeling following myocardial infarction.

    PubMed

    Spinale, Francis G; Mukherjee, Rupak; Zavadzkas, Juozas A; Koval, Christine N; Bouges, Shenikqua; Stroud, Robert E; Dobrucki, Lawrence W; Sinusas, Albert J

    2010-09-24

    The membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the MMP family, but induction patterns and consequences of MT1-MMP overexpression (MT1-MMPexp), in a left ventricular (LV) remodeling process such as myocardial infarction (MI), have not been explored. MT1-MMP promoter activity (murine luciferase reporter) increased 20-fold at 3 days and 50-fold at 14 days post-MI. MI was then induced in mice with cardiac restricted MT1-MMPexp (n = 58) and wild type (WT, n = 60). Post-MI survival was reduced (67% versus 46%, p < 0.05), and LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT (41 ± 2 versus 32 ± 2%,p < 0.05). In the post-MI MT1-MMPexp mice, LV myocardial MMP activity, as assessed by radiotracer uptake, and MT1-MMP-specific proteolytic activity using a specific fluorogenic assay were both increased by 2-fold. LV collagen content was increased by nearly 2-fold in the post-MI MT1-MMPexp compared with WT. Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor-1 binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by 4-fold in the post-MI MT1-MMPexp group. Early and persistent MT1-MMP promoter activity occurred post-MI, and increased myocardial MT1-MMP levels resulted in poor survival, worsening of LV function, and significant fibrosis. A molecular mechanism for the adverse LV matrix remodeling with MT1-MMP induction is increased processing of pro-fibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and likely plays a mechanistic role in adverse LV remodeling.

  2. Residual Myocardial Iron Following Intramyocardial Hemorrhage During the Convalescent Phase of Reperfused ST-Segment–Elevation Myocardial Infarction and Adverse Left Ventricular Remodeling

    PubMed Central

    Bulluck, Heerajnarain; Rosmini, Stefania; Abdel-Gadir, Amna; White, Steven K.; Bhuva, Anish N.; Treibel, Thomas A.; Fontana, Marianna; Ramlall, Manish; Hamarneh, Ashraf; Sirker, Alex; Herrey, Anna S.; Manisty, Charlotte; Yellon, Derek M.; Kellman, Peter; Moon, James C.

    2016-01-01

    Background— The presence of intramyocardial hemorrhage (IMH) in ST-segment–elevation myocardial infarction patients reperfused by primary percutaneous coronary intervention has been associated with residual myocardial iron at follow-up, and its impact on adverse left ventricular (LV) remodeling is incompletely understood and is investigated here. Methods and Results— Forty-eight ST-segment–elevation myocardial infarction patients underwent cardiovascular magnetic resonance at 4±2 days post primary percutaneous coronary intervention, of whom 40 had a follow-up scan at 5±2 months. Native T1, T2, and T2* maps were acquired. Eight out of 40 (20%) patients developed adverse LV remodeling. A subset of 28 patients had matching T2* maps, of which 15/28 patients (54%) had IMH. Eighteen of 28 (64%) patients had microvascular obstruction on the acute scan, of whom 15/18 (83%) patients had microvascular obstruction with IMH. On the follow-up scan, 13/15 patients (87%) had evidence of residual iron within the infarct zone. Patients with residual iron had higher T2 in the infarct zone surrounding the residual iron when compared with those without. In patients with adverse LV remodeling, T2 in the infarct zone surrounding the residual iron was also higher than in those without (60 [54–64] ms versus 53 [51–56] ms; P=0.025). Acute myocardial infarct size, extent of microvascular obstruction, and IMH correlated with the change in LV end-diastolic volume (Pearson’s rho of 0.64, 0.59, and 0.66, respectively; P=0.18 and 0.62, respectively, for correlation coefficient comparison) and performed equally well on receiver operating characteristic curve for predicting adverse LV remodeling (area under the curve: 0.99, 0.94, and 0.95, respectively; P=0.19 for receiver operating characteristic curve comparison). Conclusions— The majority of ST-segment–elevation myocardial infarction patients with IMH had residual myocardial iron at follow-up. This was associated with

  3. Tumor Necrosis Factor Receptor Associated Factor 2 Signaling Provokes Adverse Cardiac Remodeling in the Adult Mammalian Heart

    PubMed Central

    Divakaran, Vijay G.; Evans, Sarah; Topkara, Veli K.; Diwan, Abhinav; Burchfield, Jana; Gao, Feng; Dong, Jianwen; Tzeng, Huei-Ping; Sivasubramanian, Natarajan; Barger, Philip M.; Mann, Douglas L.

    2013-01-01

    Background Tumor necrosis factor (TNF) superfamily ligands that provoke a dilated cardiac phenotype signal through a common scaffolding protein termed TNF receptor associated factor 2 (TRAF2); however, virtually nothing is known with regard to TRAF2 signaling in the adult mammalian heart. Methods and Results We generated multiple founder lines of mice with cardiac restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (MHC-TRAF2HC). MHC-TRAF2HC transgenic mice developed a time-dependent increase in cardiac hypertrophy, LV dilation and adverse LV remodeling, and a significant decrease in LV +dP/dt and −dP/dt when compared to littermate (LM) controls (p < 0.05 compared to LM). During the early phases of LV remodeling there was a significant increase in total matrix metalloproteinase (MMP) activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2HC mice aged, there was a significant decrease in total MMP activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in NF-κB activation at 4 – 12 weeks and JNK activation at 4 weeks in the MHCs TRAF2HC mice. Transciptional profiling revealed that > 95% of the hypertrophic/dilated cardiomyopathy-related genes that were significantly upregulated genes in the MHC-TRAF2HC hearts contained κB elements in their promoters. Conclusions These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart. PMID:23493088

  4. Circulating Endothelial Cells and Endothelial Function predict Major Adverse Cardiac Events and Early Adverse Left Ventricular Remodeling in Patients with ST-Segment Elevation Myocardial Infarction

    PubMed Central

    Magdy, Abdel Hamid; Bakhoum, Sameh; Sharaf, Yasser; Sabry, Dina; El-Gengehe, Ahmed T; Abdel-Latif, Ahmed

    2016-01-01

    Endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) are mobilized from the bone marrow and increase in the early phase after ST-elevation myocardial infarction (STEMI). The aim of this study was to assess the prognostic significance of CECs and indices of endothelial dysfunction in patients with STEMI. In 78 patients with acute STEMI, characterization of CD34+/VEGFR2+ CECs, and indices of endothelial damage/dysfunction such as brachial artery flow mediated dilatation (FMD) were determined. Blood samples for CECs assessment and quantification were obtained within 24 hours of admission and FMD was assessed during the index hospitalization. At 30 days follow up, the primary composite end point of major cardiac adverse events (MACE) consisting of all-cause mortality, recurrent non-fatal MI, or heart failure and the secondary endpoint of early adverse left ventricular (LV) remodeling were analyzed. The 17 patients (22%) who developed MACE had significantly higher CEC level (P = 0.004), vWF level (P =0.028), and significantly lower FMD (P = 0.006) compared to the remaining patients. Logistic regression analysis showed that CECs level and LV ejection fraction were independent predictors of MACE. The areas under the receiver operating characteristic curves (ROC) for CEC level, FMD, and the logistic model with both markers were 0.73, 0.75, and 0.82 respectively for prediction of the MACE. The 16 patients who developed the secondary endpoint had significantly higher CEC level compared to remaining patients (p =0.038). In conclusion, increased circulating endothelial cells and endothelial dysfunction predicted the occurrence of major adverse cardiac events and adverse cardiac remodeling in patients with STEMI. PMID:26864952

  5. Angiotensin receptor blockade and angiotensin-converting-enzyme inhibition limit adverse remodeling of infarct zone collagens and global diastolic dysfunction during healing after reperfused ST-elevation myocardial infarction.

    PubMed

    Jugdutt, Bodh I; Idikio, Halliday; Uwiera, Richard R E

    2007-09-01

    To determine whether therapy with the angiotensin II type 1 receptor blocker (ARB) candesartan and the comparator angiotensin-converting-enzyme inhibitor (ACEI) enalapril during healing after reperfused ST-elevation myocardial infarction (RSTEMI) limit adverse remodeling of infarct zone (IZ) collagens and left ventricular (LV) diastolic dysfunction, we randomized 24 dogs surviving anterior RSTEMI (90-min coronary occlusion) to placebo, candesartan, and enalapril therapy between day 2 and 42. Six other dogs were sham. We measured regional IZ and non-infarct zone (NIZ) collagens (hydroxyproline; types I/III; cross-linking), transforming growth factor-beta (TGF-beta) and topography at 6 weeks, and hemodynamics, LV diastolic and systolic function, and remodeling over 6 weeks. Compared to sham, placebo-RSTEMI differentially altered regional collagens, with more pronounced increase in TGF-beta, hydroxyproline, and type I, insoluble, and cross-linked collagens in the IZ than NIZ, and increased IZ soluble and type III collagens at 6 weeks, and induced persistent LV filling pressure elevation, diastolic and systolic dysfunction, and LV remodeling over 6 weeks. Compared to placebo-RSTEMI, candesartan and enalapril limited adverse regional collagen remodeling, with normalization of type III, soluble and insoluble collagens and decrease in pyridinoline cross-linking in the IZ at 6 weeks, and attenuation of LV filling pressure, diastolic dysfunction, and remodeling over 6 weeks. The results suggest that candesartan and enalapril during healing after RSTEMI prevent rather than worsen adverse remodeling of IZ collagens and LV diastolic dysfunction, supporting the clinical use of ARBs and ACEIs during subacute RSTEMI.

  6. Sustained myocardial production of stromal cell-derived factor-1α was associated with left ventricular adverse remodeling in patients with myocardial infarction.

    PubMed

    Uematsu, Manabu; Yoshizaki, Toru; Shimizu, Takuya; Obata, Jun-ei; Nakamura, Takamitsu; Fujioka, Daisuke; Watanabe, Kazuhiro; Watanabe, Yosuke; Kugiyama, Kiyotaka

    2015-11-15

    The role of stromal cell-derived factor-1α (SDF-1α) expressed in infarcted myocardium is unknown in humans. We examined whether SDF-1α produced in an infarcted myocardial lesion may play a role in left ventricle (LV) remodeling and dysfunction in patients with acute myocardial infarction (AMI). We measured SDF-1α levels in plasma obtained from aortic root (AO) and anterior interventricular vein (AIV) in the early phase (2 wk after MI) and the chronic phase (6 mo after MI) in 80 patients with anterior MI. An increment in SDF-1α level from AO to AIV, reflecting SDF-1α release from infarcted myocardium, was more frequent in patients with MI in the early phase of MI [n = 52 (65%), P = 0.03] but not in the chronic phase of MI [n = 46 (58%), P = 0.11] compared with that in control patients [n = 6/17 (35%)]. On linear regression analysis, the transmyocardial gradient in SDF-1α level in the chronic phase of MI was correlated with percentage changes in LV end-diastolic volume index (r = 0.39, P < 0.001), LV end-systolic volume index (r = 0.38, P < 0.001), and LV ejection fraction (r = -0.26, P = 0.01) 6 mo after AMI. By contrast, the transmyocardial gradient of SDF-1α in the early phase of MI had no significant correlations. In conclusion, the production of SDF-1α in infarcted myocardium in the chronic phase of MI was associated with LV adverse remodeling and progressive dysfunction in AMI survivors.

  7. Reversibility of Adverse, Calcineurin-Dependent Cardiac Remodeling

    PubMed Central

    Berry, Jeff M.; Le, Vien; Rotter, David; Battiprolu, Pavan K.; Grinsfelder, Bennett; Tannous, Paul; Burchfield, Jana S.; Czubryt, Michael; Backs, Johannes; Olson, Eric N.; Rothermel, Beverly A.; Hill, Joseph A.

    2011-01-01

    Background Studies to dissect the role of calcineurin in pathological cardiac remodeling have relied heavily on murine models, where genetic gain- and loss-of-function manipulations are initiated at or before birth. However, the great majority of clinical cardiac pathology occurs in adults. Yet, nothing is known about the effects of calcineurin when its activation commences in adulthood. Further, despite the fact that ventricular hypertrophy is a well established risk factor for heart failure, the relative pace and progression of these two major phenotypic features of heart disease are unknown. Methods and Results We engineered mice harboring in cardiomyocytes a constitutively active calcineurin transgene driven by a tetracycline-responsive promoter element. Expression of the mutant calcineurin transgene was initiated for variable lengths of time to determine the natural history of disease pathogenesis, and to determine when, if ever, these events are reversible. Activation of the calcineurin transgene in adult mice triggered rapid and robust cardiac growth with features characteristic of pathological hypertrophy. Concentric hypertrophy preceded the development of systolic dysfunction, fetal gene activation, fibrosis, and clinical heart failure. Further, cardiac hypertrophy reversed spontaneously when calcineurin activity was turned off, and expression of fetal genes reverted to baseline. Fibrosis, a prominent feature of pathological cardiac remodeling, manifested partial reversibility. Conclusions Together, these data establish and define the deleterious effects of calcineurin signaling in adult heart and reveal that calcineurin-dependent hypertrophy with concentric geometry precedes systolic dysfunction and heart failure. Furthermore, these findings demonstrate that during much of the disease process, calcineurin-dependent remodeling remains reversible. PMID:21700928

  8. The Structural Basis of Functional Improvement in Response to Human Umbilical Cord Blood Stem Cell Transplantation in Hearts with Post-Infarct LV Remodeling

    PubMed Central

    Chen, Yong; Ye, Lei; Zhong, Jia; Li, Xin; Yan, Chen; Chandler, Margaret P.; Calvin, Steve; Xiao, Feng; Negia, Mesfin; Low, Walter C.; Zhang, Jianyi; Yu, Xin

    2015-01-01

    Cellular therapy for myocardial repair has been one of the most intensely investigated interventional strategies for acute myocardium infarction. Although the therapeutic potential of stem cells has been demonstrated in various studies, the underlying mechanisms for such improvement are poorly understood. In the present study, we investigated the long-term effects of stem cell therapy on both myocardial fiber organization and regional contractile function using a rat model of post-infarct remodeling. Human non-hematopoietic umbilical cord blood stem cells (nh-UCBSCs) were administered via tail vein to rats 2 days after infarct surgery. Animals were maintained without immunosuppressive therapy. In vivo and ex vivo MR imaging was performed on infarct hearts ten months after cell transplantation. Compared to the age-matched rats exposed to the identical surgery, both global and regional cardiac function of the nh-UCBSC-treated hearts, such as ejection fraction, ventricular strain and torsion, were significantly improved. More importantly, the treated hearts exhibited preserved fiber orientation and water diffusivities that were similar to those in sham-operated control hearts. These data provide the first evidence that nh-UCBSC treatment may prevent/delay untoward structural remodeling in post-infarct hearts, which supports the improved LV function observed in vivo in the absence of immunosuppression, suggesting a beneficial paracrine effect that occurred with the cellular therapy. PMID:24332083

  9. Air pollution and adverse cardiac remodeling: clinical effects and basic mechanisms.

    PubMed

    Liu, Yonggang; Goodson, Jamie M; Zhang, Bo; Chin, Michael T

    2015-01-01

    Exposure to air pollution has long been known to trigger cardiovascular events, primarily through activation of local and systemic inflammatory pathways that affect the vasculature. Detrimental effects of air pollution exposure on heart failure and cardiac remodeling have also been described in human populations. Recent studies in both human subjects and animal models have provided insights into the basic physiological, cellular and molecular mechanisms that play a role in adverse cardiac remodeling. This review will give a brief overview of the relationship between air pollution and cardiovascular disease, describe the clinical effects of air pollution exposure on cardiac remodeling, describe the basic mechanisms that affect remodeling as described in human and animal systems and will discuss future areas of investigation.

  10. Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction.

    PubMed

    Sonnenberg, Sonya B; Rane, Aboli A; Liu, Cassie J; Rao, Nikhil; Agmon, Gillie; Suarez, Sophia; Wang, Raymond; Munoz, Adam; Bajaj, Vaibhav; Zhang, Shirley; Braden, Rebecca; Schup-Magoffin, Pamela J; Kwan, Oi Ling; DeMaria, Anthony N; Cochran, Jennifer R; Christman, Karen L

    2015-03-01

    Hepatocyte growth factor (HGF) has been shown to have anti-fibrotic, pro-angiogenic, and cardioprotective effects; however, it is highly unstable and expensive to manufacture, hindering its clinical translation. Recently, a HGF fragment (HGF-f), an alternative c-MET agonist, was engineered to possess increased stability and recombinant expression yields. In this study, we assessed the potential of HGF-f, delivered in an extracellular matrix (ECM)-derived hydrogel, as a potential treatment for myocardial infarction (MI). HGF-f protected cardiomyocytes from serum-starvation and induced down-regulation of fibrotic markers in whole cardiac cell isolate compared to the untreated control. The ECM hydrogel prolonged release of HGF-f compared to collagen gels, and in vivo delivery of HGF-f from ECM hydrogels mitigated negative left ventricular (LV) remodeling, improved fractional area change (FAC), and increased arteriole density in a rat myocardial infarction model. These results indicate that HGF-f may be a viable alternative to using recombinant HGF, and that an ECM hydrogel can be employed to increase growth factor retention and efficacy.

  11. Vagus nerve stimulation mitigates intrinsic cardiac neuronal and adverse myocyte remodeling postmyocardial infarction

    PubMed Central

    Beaumont, Eric; Southerland, Elizabeth M.; Hardwick, Jean C.; Wright, Gary L.; Ryan, Shannon; Li, Ying; KenKnight, Bruce H.; Armour, J. Andrew

    2015-01-01

    This paper aims to determine whether chronic vagus nerve stimulation (VNS) mitigates myocardial infarction (MI)-induced remodeling of the intrinsic cardiac nervous system (ICNS), along with the cardiac tissue it regulates. Guinea pigs underwent VNS implantation on the right cervical vagus. Two weeks later, MI was produced by ligating the ventral descending coronary artery. VNS stimulation started 7 days post-MI (20 Hz, 0.9 ± 0.2 mA, 14 s on, 48 s off; VNS-MI, n = 7) and was compared with time-matched MI animals with sham VNS (MI n = 7) vs. untreated controls (n = 8). Echocardiograms were performed before and at 90 days post-MI. At termination, IC neuronal intracellular voltage recordings were obtained from whole-mount neuronal plexuses. MI increased left ventricular end systolic volume (LVESV) 30% (P = 0.027) and reduced LV ejection fraction (LVEF) 6.5% (P < 0.001) at 90 days post-MI compared with baseline. In the VNS-MI group, LVESV and LVEF did not differ from baseline. IC neurons showed depolarization of resting membrane potentials and increased input resistance in MI compared with VNS-MI and sham controls (P < 0.05). Neuronal excitability and sensitivity to norepinephrine increased in MI and VNS-MI groups compared with controls (P < 0.05). Synaptic efficacy, as determined by evoked responses to stimulating input axons, was reduced in VNS-MI compared with MI or controls (P < 0.05). VNS induced changes in myocytes, consistent with enhanced glycogenolysis, and blunted the MI-induced increase in the proapoptotic Bcl-2-associated X protein (P < 0.05). VNS mitigates MI-induced remodeling of the ICNS, correspondingly preserving ventricular function via both neural and cardiomyocyte-dependent actions. PMID:26276818

  12. Estrogen Inhibits Mast Cell Chymase Release to Prevent Pressure Overload-Induced Adverse Cardiac Remodeling

    PubMed Central

    Li, Jianping; Jubair, Shaiban; Janicki, Joseph S.

    2014-01-01

    Estrogen regulation of myocardial chymase and chymase effects on cardiac remodeling are unknown. To test the hypothesis that estrogen prevents pressure overload-induced adverse cardiac remodeling by inhibiting mast cell chymase release, transverse aortic constriction or sham surgery was performed in 7-week-old intact and ovariectomized rats. Three days prior to creating the constriction, additional groups of ovariectomized rats began receiving 17β-Estradiol, a chymase inhibitor, or a mast cell stabilizer. Left ventricular function, cardiomyocyte size, collagen volume fraction, mast cell density and degranulation, and myocardial and plasma chymase levels were assessed 18 days post-surgery. Aortic constriction resulted in ventricular hypertrophy in intact and ovariectomized groups while collagen volume fraction was increased only in ovariectomized rats. Chymase protein content was increased by aortic constriction in the intact and ovariectomized groups with the magnitude of the increase being greater in ovariectomized rats. Mast cell density and degranulation, plasma chymase levels and myocardial active transforming growth factor- 1 levels were increased by aortic constriction only in ovariectomized rats. Estrogen replacement markedly attenuated the constriction-increased myocardial chymase, mast cell density and degranulation, plasma chymase and myocardial active transforming growth factor- 1 as well as prevented ventricular hypertrophy and increased collagen volume fraction. Chymostatin attenuated the aortic constriction induced ventricular hypertrophy and collagen volume fraction in the ovariectomized rats similar to that achieved by estrogen replacement. Nedocromil yielded similar effects except for the reduction of chymase content. We conclude that the estrogen-inhibited release of mast cell chymase is responsible for the cardioprotection against transverse aortic constriction-induced adverse cardiac remodeling. PMID:25403608

  13. Estrogen inhibits mast cell chymase release to prevent pressure overload-induced adverse cardiac remodeling.

    PubMed

    Li, Jianping; Jubair, Shaiban; Janicki, Joseph S

    2015-02-01

    Estrogen regulation of myocardial chymase and chymase effects on cardiac remodeling are unknown. To test the hypothesis that estrogen prevents pressure overload-induced adverse cardiac remodeling by inhibiting mast cell (MC) chymase release, transverse aortic constriction or sham surgery was performed in 7-week-old intact and ovariectomized (OVX) rats. Three days before creating the constriction, additional groups of OVX rats began receiving 17β-estradiol, a chymase inhibitor, or a MC stabilizer. Left ventricular function, cardiomyocyte size, collagen volume fraction, MC density and degranulation, and myocardial and plasma chymase levels were assessed 18 days postsurgery. Aortic constriction resulted in ventricular hypertrophy in intact and OVX groups, whereas collagen volume fraction was increased only in OVX rats. Chymase protein content was increased by aortic constriction in the intact and OVX groups, with the magnitude of the increase being greater in OVX rats. MC density and degranulation, plasma chymase levels, and myocardial active transforming growth factor-β1 levels were increased by aortic constriction only in OVX rats. Estrogen replacement markedly attenuated the constriction-increased myocardial chymase, MC density and degranulation, plasma chymase, and myocardial active transforming growth factor-β1, as well as prevented ventricular hypertrophy and increased collagen volume fraction. Chymostatin attenuated the aortic constriction-induced ventricular hypertrophy and collagen volume fraction in the OVX rats similar to that achieved by estrogen replacement. Nedocromil yielded similar effects, except for the reduction of chymase content. We conclude that the estrogen-inhibited release of MC chymase is responsible for the cardioprotection against transverse aortic constriction-induced adverse cardiac remodeling.

  14. Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats.

    PubMed

    Kang, Kyu-Tae; Coggins, Matthew; Xiao, Chunyang; Rosenzweig, Anthony; Bischoff, Joyce

    2013-10-01

    Cell-based therapies to restore heart function after infarction have been tested in pre-clinical models and clinical trials with mixed results, and will likely require both contractile cells and a vascular network to support them. We and others have shown that human endothelial colony forming cells (ECFC) combined with mesenchymal progenitor cells (MPC) can be used to "bio-engineer" functional human blood vessels. Here we investigated whether ECFC + MPC form functional vessels in ischemic myocardium and whether this affects cardiac function or remodeling. Myocardial ischemia/reperfusion injury (IRI) was induced in 12-week-old immunodeficient rats by ligation of the left anterior descending coronary artery. After 40 min, myocardium was reperfused and ECFC + MPC (2 × 10(6) cells, 2:3 ratio) or PBS was injected. Luciferase assays after injection of luciferase-labeled ECFC + MPC showed that 1,500 ECFC were present at day 14. Human ECFC-lined perfused vessels were directly visualized by femoral vein injection of a fluorescently-tagged human-specific lectin in hearts injected with ECFC + MPC but not PBS alone. While infarct size at day 1 was no different, LV dimensions and heart weight to tibia length ratios were lower in cell-treated hearts compared with PBS at 4 months, suggesting post-infarction remodeling was ameliorated by local cell injection. Fractional shortening, LV wall motion score, and fibrotic area were not different between groups at 4 months. However, pressure-volume loops demonstrated improved cardiac function and reduced volumes in cell-treated animals. These data suggest that myocardial delivery of ECFC + MPC at reperfusion may provide a therapeutic strategy to mitigate LV remodeling and cardiac dysfunction after IRI.

  15. The Emerging Prominence of the Cardiac Mast Cell as a Potent Mediator of Adverse Myocardial Remodeling

    PubMed Central

    Janicki, Joseph S.; Brower, Gregory L.; Levick, Scott P.

    2015-01-01

    Cardiac mast cells store and release a variety of biologically active mediators, several of which have been implicated in the activation of matrix metalloproteinases in the volume-overloaded heart, while others are involved in the fibrotic process in pressure-overloaded hearts. Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic cardiac volume overload. Also, there is evolving evidence implicating the cardiac mast cell as having a major role in the adverse remodeling underlying these cardiovascular disorders. Thus, the cardiac mast cell is the focus of this chapter that begins with a historical background, followed by sections on methods for their isolation and characterization, endogenous secretagogues, phenotype, and ability of estrogen to alter their phenotype so as to provide cardioprotection. Finally the role of mast cells in myocardial remodeling secondary to a sustained cardiac volume overload, hypertension, and ischemic injury and future research directions are discussed. PMID:25388248

  16. Pathological Role of Serum- and Glucocorticoid-Regulated Kinase 1 in Adverse Ventricular Remodeling

    PubMed Central

    Das, Saumya; Aiba, Takeshi; Rosenberg, Michael; Hessler, Katherine; Xiao, Chunyang; Quintero, Pablo A.; Ottaviano, Filomena G.; Knight, Ashley C.; Graham, Evan L.; Boström, Pontus; Morissette, Michael R.; del Monte, Federica; Begley, Michael J.; Cantley, Lewis C.; Ellinor, Patrick T.; Tomaselli, Gordon F.; Rosenzweig, Anthony

    2012-01-01

    Background Heart failure is a growing cause of morbidity and mortality. Cardiac PI3-kinase signaling promotes cardiomyocyte survival and function but is paradoxically activated in heart failure, suggesting chronic activation of this pathway may become maladaptive. Here we investigated the downstream PI3-kinase effector, SGK1 (serum- and glucocorticoid-regulated kinase-1), in heart failure and its complications. Methods and Results We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart using cardiac-specific expression of constitutively-active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The pro-arrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations. Conclusions SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease. PMID:23019294

  17. Echocardiographic Predictors for Left Ventricular Remodeling after Acute ST Elevation Myocardial Infarction with Low Risk Group: Speckle Tracking Analysis

    PubMed Central

    Na, Hyun-Min; Lee, Joo Myung; Cha, Myung-Jin; Yoon, Yeonyee E.; Lee, Seung-Pyo; Kim, Hyung-Kwan; Kim, Yong-Jin; Sohn, Dae-Won

    2016-01-01

    Background We sought to assess echocardiographic predictors of left ventricular (LV) adverse remodeling after successfully reperfused acute ST elevation myocardial infarction (STEMI). LV remodeling is commonly found in STEMI patients and it may suggest adverse outcome in acute myocardial infarction. We sought to identify whether 2D strain and torsion be independent parameters for prediction of LV adverse remodeling. Methods We investigated 208 patients with low-risk STEMI patients who had follow up echocardiography at 6 or more months. After clinical assessments, all patients received revascularization according to current guideline. LV remodeling was defined as > 20% increase in end-diastolic volume (EDV) at follow up. Results During the follow-up (11.9 ± 5.3 months), 53 patients (25.5%) showed LV remodeling. In univariate analysis, EDV, end-systolic volume, deceleration time (DT), CK-MB, and global longitudinal strain (GLS) were associated with LV remodeling. In multivariate analysis, EDV [hazard ratio (HR): 0.922, 95% confidence interval (CI): 0.897–0.948, p< 0.001], GLS (HR: 0.842, 95% CI: 0.728–0.974, p = 0.020), DT (HR: 0.989, 95% CI: 0.980–0.998, p = 0.023) and CK-MB (HR: 1.003, 95% CI: 1.000–1.005, p = 0.033) independently predicted LV remodeling. However, global circumferential strain, net twist, and twist or untwist rate were not associated with remodeling. Conclusion Of various parameters of speckle strain, only GLS predicted adverse remodeling in STEMI patients. PMID:27358705

  18. Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

    PubMed Central

    Lehmann, Lorenz H.; Rostosky, Julia S.; Buss, Sebastian J.; Kreusser, Michael M.; Krebs, Jutta; Mier, Walter; Enseleit, Frank; Spiger, Katharina; Hardt, Stefan E.; Wieland, Thomas; Haass, Markus; Lüscher, Thomas F.; Schneider, Michael D.; Parlato, Rosanna; Gröne, Hermann-Josef; Haberkorn, Uwe; Yanagisawa, Masashi; Katus, Hugo A.; Backs, Johannes

    2014-01-01

    In preclinical studies, endothelin receptor A (ETA) antagonists (ETAi) attenuated the progression of heart failure (HF). However, clinical HF trials failed to demonstrate beneficial effects of ETAi. These conflicting data may be explained by the possibility that established HF drugs such as adrenergic receptor blockers interfered with the mechanism of ETAi action in clinical trials. Here we report that mice lacking ETA only in sympathetic neurons (SN-KO) showed less adverse structural remodeling and cardiac dysfunction in response to pathological pressure overload induced by transverse aortic constriction (TAC). In contrast, mice lacking ETA only in cardiomyocytes (CM-KO) were not protected. TAC led to a disturbed sympathetic nerve function as measured by cardiac norepinephrine (NE) tissue levels and [124I]-metaiodobenzylguanidine-PET, which was prevented in SN-KO. In a rat model of HF, ETAi improved cardiac and sympathetic nerve function. In cocultures of cardiomyocytes (CMs) and sympathetic neurons (SNs), endothelin-1 (ET1) led to a massive NE release and exaggerated CM hypertrophy compared with CM monocultures. ETA-deficient CMs gained a hypertrophic response through wild-type SNs, but ETA-deficient SNs failed to mediate exaggerated CM hypertrophy. Furthermore, ET1 mediated its effects indirectly via NE in CM-SN cocultures through adrenergic receptors and histone deacetylases, resulting in activation of the prohypertrophic transcription factor myocyte enhancer factor 2. In conclusion, sympathetic ETA amplifies ET1 effects on CMs through adrenergic signaling pathways. Thus, antiadrenergic therapies may blunt potentially beneficial effects of ETAi. Taken together, this may indicate that patients with β blocker intolerance or disturbed sympathetic nerve function could be evaluated for a potential benefit from ETAi. PMID:25197047

  19. Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction

    PubMed Central

    Sonnenberg, Sonya; Rane, Aboli A.; Liu, Cassie J.; Rao, Nikhil; Agmon, Gillie; Suarez, Sophia; Wang, Raymond; Munoz, Adam; Bajaj, Vaibhav; Zhang, Shirley; Braden, Rebecca; Schup-Magoffin, Pamela J.; Kwan, Oi Ling; DeMaria, Anthony N.; Cochran, Jennifer R.; Christman, Karen L.

    2015-01-01

    Hepatocyte growth factor (HGF) has been shown to have anti-fibrotic, pro-angiogenic, and cardioprotective effects; however, it is highly unstable and expensive to manufacture, hindering its clinical translation. Recently, a HGF fragment (HGF-f), an alternative c-MET agonist, was engineered to possess increased stability and recombinant expression yields. In this study, we assessed the potential of HGF-f, delivered in an extracellular matrix (ECM)-derived hydrogel, as a potential treatment for myocardial infarction (MI). HGF-f protected cardiomyocytes from serum-starvation and induced down-regulation of fibrotic markers in whole cardiac cell isolate compared to the untreated control. The ECM hydrogel prolonged release of HGF-f compared to collagen gels, and in vivo delivery of HGF-f from ECM hydrogels mitigated negative remodeling, improved fractional area change (FAC), and increased arteriole density in rat myocardial infarction model. These results indicate that HGF-f may be a viable alternative to using recombinant HGF, and that an ECM hydrogel can be employed to increase growth factor retention and efficacy. PMID:25662495

  20. Cardiac oxytocin receptor blockade stimulates adverse cardiac remodeling in ovariectomized spontaneously hypertensive rats.

    PubMed

    Jankowski, Marek; Wang, Donghao; Danalache, Bogdan; Gangal, Marius; Gutkowska, Jolanta

    2010-08-01

    An increasing amount of evidence demonstrates the beneficial role of oxytocin (OT) in the cardiovascular system. Similar actions are attributed to genistein, an isoflavonic phytoestrogen. The treatment with genistein activates the OT system in the aorta of ovariectomized (OVX) Sprague-Dawley (SD) rats. The objective of this study was to determine the effects of low doses of genistein on the OT-induced effects in rat hypertension. The hypothesis tested was that treatment of OVX spontaneously hypertensive rats (SHRs) with genistein improves heart structure and heart work through a mechanism involving the specific OT receptor (OTR). OVX SHRs or SD rats were treated with genistein (in microg/g body wt sc, 10 days) in the presence or absence of an OT antagonist (OTA) [d(CH(2))(5), Tyr(Me)(2), Orn(8)]-vasotocin or a nonspecific estrogen receptor antagonist (ICI-182780). Vehicle-treated OVX rats served as controls. RT-PCR and Western blot analysis demonstrated that left ventricular (LV) OTR, downregulated by ovariectomy, increased in response to genistein. In SHRs or SD rats, this effect was blocked by OTA or ICI-182780 administration. The OTR was mainly localized in microvessels expressing the CD31 marker and colocalized with endothelial nitric oxide synthase. In SHRs, the genistein-stimulated OTR increases were associated with improved fractional shortening, decreased blood pressure (12 mmHg), decreased heart weight-to-body weight ratio, decreased fibrosis, and lowered brain natriuretic peptide in the LV. The prominent finding of the study is the detrimental effect of OTA treatment on the LV of SHRs. OTA treatment of OVX SHRs resulted in a dramatic worsening of ejection fractions and an augmented fibrosis. In conclusion, these results demonstrate that cardiac OTRs are involved in the regulation of cardiac function of OVX SHRs. The decreases of OTRs may contribute to cardiac pathology following menopause.

  1. Deficiency of MAPK-activated protein kinase 2 (MK2) prevents adverse remodelling and promotes endothelial healing after arterial injury.

    PubMed

    Kapopara, P R; von Felden, J; Soehnlein, O; Wang, Y; Napp, L C; Sonnenschein, K; Wollert, K C; Schieffer, B; Gaestel, M; Bauersachs, J; Bavendiek, U

    2014-12-01

    Maladaptive remodelling of the arterial wall after mechanical injury (e. g. angioplasty) is characterised by inflammation, neointima formation and media hypertrophy, resulting in narrowing of the affected artery. Moreover, mechanical injury of the arterial wall causes loss of the vessel protecting endothelial cell monolayer. Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), a major downstream target of p38 MAPK, regulates inflammation, cell migration and proliferation, essential processes for vascular remodelling and re-endothelialisation. Therefore, we investigated the role of MK2 in remodelling and re-endothelialisation after arterial injury in genetically modified mice in vivo. Hypercholesterolaemic low-density-lipoprotein-receptor-deficient mice (ldlr-/-) were subjected to wire injury of the common carotid artery. MK2-deficiency (ldlr-/-/mk2-/-) nearly completely prevented neointima formation, media hypertrophy, and lumen loss after injury. This was accompanied by reduced proliferation and migration of MK2-deficient smooth muscle cells. In addition, MK2-deficiency severely reduced monocyte adhesion to the arterial wall (day 3 after injury, intravital microscopy), which may be attributed to reduced expression of the chemokine ligands CCL2 and CCL5. In line, MK2-deficiency significantly reduced the content of monocytes, neutrophiles and lymphocytes of the arterial wall (day 7 after injury, flow cytometry). In conclusion, in a model of endothelial injury (electric injury), MK2-deficiency strongly increased proliferation of endothelial cells and improved re-endothelialisation of the arterial wall after injury. Deficiency of MK2 prevents adverse remodelling and promotes endothelial healing of the arterial wall after injury, suggesting that MK2-inhibition is a very attractive intervention to prevent restenosis after percutaneous therapeutic angioplasty. PMID:25120198

  2. Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling.

    PubMed

    Lindsey, Merry L; Iyer, Rugmani Padmanabhan; Jung, Mira; DeLeon-Pennell, Kristine Y; Ma, Yonggang

    2016-02-01

    Despite current optimal therapeutic regimens, approximately one in four patients diagnosed with myocardial infarction (MI) will go on to develop congestive heart failure, and heart failure has a high five-year mortality rate of 50%. Elucidating mechanisms whereby heart failure develops post-MI, therefore, is highly needed. Matrix metalloproteinases (MMPs) are key enzymes involved in post-MI remodeling of the left ventricle (LV). While MMPs process cytokine and extracellular matrix (ECM) substrates to regulate the inflammatory and fibrotic components of the wound healing response to MI, MMPs also serve as upstream signaling initiators with direct actions on cell signaling cascades. In this review, we summarize the current literature regarding MMP roles in post-MI LV remodeling. We also identify the current knowledge gaps and provide templates for experiments to fill these gaps. A more complete understanding of MMP roles, particularly with regards to upstream signaling roles, may provide new strategies to limit adverse LV remodeling.

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

    PubMed Central

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

    2015-01-01

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

  4. Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction.

    PubMed

    Kuznetsova, Tatiana; Haddad, Francois; Knez, Judita; Rosenberg-Hasson, Yael; Sung, Janine; Cauwenberghs, Nicholas; Thijs, Lutgarde; Karakikes, Ioannis; Maecker, Holden; Mahaffey, Kenneth W; Wu, Joseph C; Staessen, Jan A

    2015-12-01

    There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN. PMID:26565110

  5. Featured Article: Cardioprotective effects of lysyl oxidase inhibition against volume overload-induced extracellular matrix remodeling

    PubMed Central

    El Hajj, Elia C; El Hajj, Milad C; Ninh, Van K

    2015-01-01

    A hallmark of heart failure (HF) is adverse extracellular matrix (ECM) remodeling, which is regulated by the collagen cross-linking enzyme, lysyl oxidase (LOX). In this study, we evaluate the efficacy of LOX inhibition to prevent adverse left ventricular (LV) remodeling and dysfunction using an experimental model of HF. Sprague–Dawley rats were subjected to surgically induced volume overload (VO) by creation of aortocaval fistula (ACF). A LOX inhibitor, beta-aminopropionitrile (BAPN; 100 mg/kg/day), was administered to rats with ACF or sham surgery at eight weeks postsurgery. Echocardiography was used to assess progressive alterations in cardiac ventricular structure and function. Left ventricular (LV) catheterization was used to assess alterations in contractility, stiffness, LV pressure and volume, and other indices of cardiac function. The LV ECM alterations were assessed by: (a) histological staining of collagen, (b) protein expression of collagen types I and III, (c) hydroxyproline assay, and (d) cross-linking assay. LOX inhibition attenuated VO-induced increases in cardiac stress, and attenuated increases in interstitial myocardial collagen, total collagen, and protein levels of collagens I and III. Both echocardiography and catheterization measurements indicated improved cardiac function post-VO in BAPN treated rats vs. untreated. Inhibition of LOX attenuated VO-induced decreases in LV stiffness and cardiac function. Overall, our data indicate that LOX inhibition was cardioprotective in the volume overloaded heart. PMID:26582054

  6. Biodegradable elastic patch plasty ameliorates left ventricular adverse remodeling after ischemia–reperfusion injury: A preclinical study of a porous polyurethane material in a porcine model

    PubMed Central

    Hashizume, Ryotaro; Fujimoto, Kazuro L.; Hong, Yi; Guan, Jianjun; Toma, Catalin; Tobita, Kimimasa; Wagner, William R.

    2013-01-01

    Objective Myocardial infarction (MI) can lead to irreversible adverse left ventricular remodeling resulting in subsequent severe dysfunction. The objective of this study was to investigate the potential for biodegradable, elastomeric patch implantation to positively alter the remodeling process after MI in a porcine model. Methods Yorkshire pigs underwent a 60-minute catheter balloon occlusion of the left circumflex artery. Two weeks after MI animals underwent epicardial placement of a biodegradable, porous polyurethane (poly(ester urethane)urea; PEUU) patch (MI+PEUU, n = 7) or sham surgery (MI+sham, n = 8). Echocardiography before surgery and at 4 and 8 weeks after surgery measured the end-diastolic area (EDA) and fractional area change (% FAC). All animals were humanely killed 8 weeks after surgery and hearts were histologically assessed. Results At 8 weeks, echocardiography revealed greater EDA values in the MI+sham group (23.6 ± 6.6 cm2 , mean ± standard deviaation) than in the MI+PEUU group (15.9 ± 2.5 cm2) (P < .05) and a lower %FAC in the MI+sham group (24.8 ± 7.6) than in the MI+PEUU group (35.9 ± 7.8) (P < .05). The infarcted ventricular wall was thicker in the MI+PEUU group (1.56 ± 0.5 cm) than in the MI+sham group (0.91 ± 0.24 cm) (P < .01). Conclusions Biodegradable elastomeric PEUU patch implantation onto the porcine heart 2 weeks post-MI attenuated left ventricular adverse remodeling and functional deterioration and was accompanied by increased neovascularization. These findings, although limited to a 2-month follow-up, may suggest an attractive clinical option to moderate post-MI cardiac failure. PMID:23219497

  7. Exercise intensity-dependent reverse and adverse remodeling of voltage-gated Ca(2+) channels in mesenteric arteries from spontaneously hypertensive rats.

    PubMed

    Chen, Yu; Zhang, Hanmeng; Zhang, Yanyan; Lu, Ni; Zhang, Lin; Shi, Lijun

    2015-10-01

    Exercise can be regarded as a drug for treating hypertension, and the 'dosage' (intensity/volume) is therefore of great importance. L-type voltage-gated Ca(2+) (Cav1.2) channels on the plasma membrane of vascular smooth muscle cells have a pivotal role in modulating the vascular tone, and the upregulation of Cav1.2 channels is a hallmark feature of hypertension. The present study investigated the beneficial and adverse effects of exercise at different intensities on the remodeling of the Cav1.2 channel in mesenteric arteries (MAs) of spontaneously hypertensive rats (SHRs). Moderate- (SHR-M, 18-20 m min(-1)) and high-intensity (SHR-H, 26-28 m min(-1)) aerobic exercise training groups were created for SHRs and lasted for 8 weeks (1 h per day, 5 d per week). Age-matched sedentary SHRs and normotensive Wistar-Kyoto rats (WKY) were used as controls. The mesenteric arterial mechanical and functional properties were evaluated. Moderate-intensity exercise training induced a lower systolic blood pressure and heart rate in these rats compared with sedentary SHRs. BayK 8644 and nifedipine induced vasoconstriction and dose-dependent vasorelaxation, respectively, in the mesenteric arterial rings. Moderate-intensity exercise significantly suppressed the increase in BayK 8644-induced vasoconstriction, tissue sensitivity to nifedipine, Cav1.2 channel current density and Cav1.2 α1C-subunit protein expression in MAs from SHRs. However, high-intensity exercise training aggravated all of these hypertension-associated functional and molecular alterations of Cav1.2 channels. These results indicate that moderate-intensity aerobic training may act as a drug and effectively reverse the remodeling of Cav1.2 channels in hypertension to restore the vascular function in MAs, but that high-intensity exercise exaggerates the adverse remodeling of Cav1.2 channels and worsens the vascular function. PMID:25902901

  8. IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

    PubMed Central

    Tejada, Thor; Tan, Lin; Torres, Rebecca A.; Calvert, John W.; Lambert, Jonathan P.; Zaidi, Madiha; Husain, Murtaza; Berce, Maria D.; Naib, Hussain; Pejler, Gunnar; Abrink, Magnus; Graham, Robert M.; Lefer, David J.; Naqvi, Nawazish; Husain, Ahsan

    2016-01-01

    Heart disease is a leading cause of death in adults. Here, we show that a few days after coronary artery ligation and reperfusion, the ischemia-injured heart elaborates the cardioprotective polypeptide, insulin-like growth factor-1 (IGF-1), which activates IGF-1 receptor prosurvival signaling and improves cardiac left ventricular systolic function. However, this signaling is antagonized by the chymase, mouse mast cell protease 4 (MMCP-4), which degrades IGF-1. We found that deletion of the gene encoding MMCP-4 (Mcpt4), markedly reduced late, but not early, infarct size by suppressing IGF-1 degradation and, consequently, diminished cardiac dysfunction and adverse structural remodeling. Our findings represent the first demonstration to our knowledge of tissue IGF-1 regulation through proteolytic degradation and suggest that chymase inhibition may be a viable therapeutic approach to enhance late cardioprotection in postischemic heart disease. PMID:27274047

  9. Inhalation of hydrogen gas attenuates left ventricular remodeling induced by intermittent hypoxia in mice.

    PubMed

    Hayashi, Tetsuya; Yoshioka, Toshitaka; Hasegawa, Kenichi; Miyamura, Masatoshi; Mori, Tatsuhiko; Ukimura, Akira; Matsumura, Yasuo; Ishizaka, Nobukazu

    2011-09-01

    Sleep apnea syndrome increases the risk of cardiovascular morbidity and mortality. We previously reported that intermittent hypoxia increases superoxide production in a manner dependent on nicotinamide adenine dinucleotide phosphate and accelerates adverse left ventricular (LV) remodeling. Recent studies have suggested that hydrogen (H(2)) may have an antioxidant effect by reducing hydroxyl radicals. In this study, we investigated the effects of H(2) gas inhalation on lipid metabolism and LV remodeling induced by intermittent hypoxia in mice. Male C57BL/6J mice (n = 62) were exposed to intermittent hypoxia (repetitive cycle of 1-min periods of 5 and 21% oxygen for 8 h during daytime) for 7 days. H(2) gas (1.3 vol/100 vol) was given either at the time of reoxygenation, during hypoxic conditions, or throughout the experimental period. Mice kept under normoxic conditions served as controls (n = 13). Intermittent hypoxia significantly increased plasma levels of low- and very low-density cholesterol and the amount of 4-hydroxy-2-nonenal-modified protein adducts in the LV myocardium. It also upregulated mRNA expression of tissue necrosis factor-α, interleukin-6, and brain natriuretic peptide, increased production of superoxide, and induced cardiomyocyte hypertrophy, nuclear deformity, mitochondrial degeneration, and interstitial fibrosis. H(2) gas inhalation significantly suppressed these changes induced by intermittent hypoxia. In particular, H(2) gas inhaled at the timing of reoxygenation or throughout the experiment was effective in preventing dyslipidemia and suppressing superoxide production in the LV myocardium. These results suggest that inhalation of H(2) gas was effective for reducing oxidative stress and preventing LV remodeling induced by intermittent hypoxia relevant to sleep apnea.

  10. The effect of long-term amiodarone administration on myocardial fibrosis and evolution of left ventricular remodeling in a porcine model of ischemic cardiomyopathy.

    PubMed

    Zagorianou, Anastasia; Marougkas, Meletios; Drakos, Stavros G; Diakos, Nikolaos; Konstantopoulos, Panagiotis; Perrea, Despina N; Anastasiou-Nana, Maria; Malliaras, Konstantinos

    2016-01-01

    Amiodarone is effective in suppressing arrhythmias in heart failure patients. We investigated the effect of long-term amiodarone administration on myocardial fibrosis and left ventricular (LV) remodeling in a porcine model of ischemic cardiomyopathy. Eighteen infarcted farm pigs were randomized to receive long-term amiodarone administration for 3 months (n = 9) or conventional follow-up (n = 9). Evolution of LV remodeling over 3 months post-myocardial infarction was examined at tissue level (myocyte size, myocardial fibrosis and vascular density assessed by whole-field digital histopathology), organ level (LV structure and function assessed by echocardiography), and systemic level (BNP and MMP-9 levels). Long-term administration of the standard anti-arrhythmic doses of amiodarone was not associated with adverse effects on myocardial fibrosis and other features of adverse cardiac remodeling. This favorable safety profile suggests that long-term anti-arrhythmic therapy with amiodarone warrants further clinical investigation in the subpopulation of heart failure patients with significantly increased burden of arrhythmias. PMID:27652141

  11. LV software support for supersonic flow analysis

    NASA Technical Reports Server (NTRS)

    Bell, William A.

    1991-01-01

    During 1991, the software developed allowed an operator to configure and checkout the TSI, Inc. laser velocimeter (LV) system prior to a run. This setup procedure established the operating conditions for the TSI MI-990 multichannel interface and the RMR-1989 rotating machinery resolver. In addition to initializing the instruments, the software package provides a means of specifying LV calibration constants, controlling the sampling process, and identifying the test parameters.

  12. Heavy chain (LvH) and light chain (LvL) of lipovitellin (Lv) of zebrafish can both bind to bacteria and enhance phagocytosis.

    PubMed

    Liang, Xue; Hu, Yu; Feng, Shuoqi; Zhang, Shicui; Zhang, Yu; Sun, Chen

    2016-10-01

    Lipovitellin (Lv) is an apoprotein in oviparous animals. Lv consists of a heavy chain (LvH) and a light chain (LvL) which are traditionally regarded as energy reserves for developing embryos. Recently, Lv has been shown to be involved in immune defense of developing embryos in fish. However, it remains unknown if each of LvH and LvL possesses immune activity; and if so, whether or not they function similarly. Here we clearly demonstrated that recombinant LvH (rLvH) and LvL (rLvL) from zebrafish vg1 gene bound to both the Gram-negative bacteria Escherichia coli and Vibrio anguillarum and the Gram-positive bacteria Staphylococcus aureus and Micrococcus luteus as well as the pathogen-associated molecular patterns LPS, LTA and PGN. In addition, both rLvH and rLvL were able to enhance the phagocytosis of bacteria E. coli and S. aureus by macrophages. All these data suggest that both LvH and LvL, in addition to being energy reserves, are also maternal immune-relevant factors capable of interacting with invading bacteria in zebrafish embryos/larvae. PMID:27185202

  13. Connective tissue growth factor inhibition attenuates left ventricular remodeling and dysfunction in pressure overload-induced heart failure.

    PubMed

    Szabó, Zoltán; Magga, Johanna; Alakoski, Tarja; Ulvila, Johanna; Piuhola, Jarkko; Vainio, Laura; Kivirikko, Kari I; Vuolteenaho, Olli; Ruskoaho, Heikki; Lipson, Kenneth E; Signore, Pierre; Kerkelä, Risto

    2014-06-01

    Connective tissue growth factor (CTGF) is involved in the pathogenesis of various fibrotic disorders. However, its role in the heart is not clear. To investigate the role of CTGF in regulating the development of cardiac fibrosis and heart failure, we subjected mice to thoracic aortic constriction (TAC) or angiotensin II infusion, and antagonized the function of CTGF with CTGF monoclonal antibody (mAb). After 8 weeks of TAC, mice treated with CTGF mAb had significantly better preserved left ventricular (LV) systolic function and reduced LV dilatation compared with mice treated with control immunoglobulin G. CTGF mAb-treated mice exhibited significantly smaller cardiomyocyte cross-sectional area and reduced expression of hypertrophic marker genes. CTGF mAb treatment reduced the TAC-induced production of collagen 1 but did not significantly attenuate TAC-induced accumulation of interstitial fibrosis. Analysis of genes regulating extracellular matrix proteolysis showed decreased expression of plasminogen activator inhibitor-1 and matrix metalloproteinase-2 in mice treated with CTGF mAb. In contrast to TAC, antagonizing the function of CTGF had no effect on LV dysfunction or LV hypertrophy in mice subjected to 4-week angiotensin II infusion. Further analysis showed that angiotensin II-induced expression of hypertrophic marker genes or collagens was not affected by treatment with CTGF mAb. In conclusion, CTGF mAb protects from adverse LV remodeling and LV dysfunction in hearts subjected to pressure overload by TAC. Antagonizing the function of CTGF may offer protection from cardiac end-organ damage in patients with hypertension.

  14. LV software for supersonic flow analysis

    NASA Technical Reports Server (NTRS)

    Bell, William A.

    1992-01-01

    The NASA Lewis Research Center (LeRC) maintains a leadership position in research into advanced aerospace propulsion systems. For the next generation of aircraft, engine designs continue to involve complex, high-speed flows. Performing the detailed flow diagnostics to properly evaluate these designs requires advanced instrumentation to probe these highly turbulent flows. The hostile flow environment often requires nonintrusive measurement techniques such as the laser velocimeter (LV). Since the LV is a proven instrument for nonintrusive flow measurement, it can provide quantitative velocity data with minimal interference to the flow. Based on anticipated flow conditions, laser velocimeter systems were procured from TSI, Inc. The initial system utilized counter processor technology, but later procurements this past year include a more advanced, correlator-based processor, which significantly improves the overall LV performance. To meet the needs of advanced research into propulsion, this instrument must be integrated into an existing VAX/VMS computer system for data acquisition, processing, and presentation. The work done under this grant before this period concentrated on developing the software required to setup and acquire data from the TSI MI-990 multichannel interface, and the RMR 1989 rotating machinery resolver. With the basis established for controlling the operation of the LV system, software development this past year shifted in emphasis from instrumentation control and data acquisition to data analysis and presentation. The progress of the program is reported.

  15. Optimized Local Infarct Restraint Improves Left Ventricular Function and Limits Remodeling

    PubMed Central

    Koomalsingh, Kevin J.; Witschey, Walter R.T.; McGarvey, Jeremy R.; Shuto, Takashi; Kondo, Norihiro; Xu, Chun; Jackson, Benjamin M.; Gorman, Joseph H.; Gorman, Robert C.; Pilla, James J.

    2013-01-01

    Background Preventing expansion and dyskinetic movement of a myocardial infarction (MI) can limit left ventricular (LV) remodeling. Using a device designed to produce variable alteration of infarct stiffness and geometry, we sought to understand how these parameters affect LV function and remodeling early after MI. Methods Ten pigs had posterolateral infarctions. An unexpanded device was placed in 5 animals at the time of infarction, and 5 animals served as untreated controls. One week after MI animals underwent MRI to assess LV size and regional function. In the treatment group, after initial imaging, the device was expanded with 2ml, 4ml, 6ml, 8ml and 10ml of saline. The optimal degree of inflation was defined as that which maximized stroke volume (SV). The device was left optimally inflated in the treatment animals for three additional weeks. Results One week after MI, device inflation to ≥6ml significantly (p<0.05) decreased endsystolic volume (ESV) (0ml:59.9ml±3.8, 6ml:54.0ml≥±3.1, 8ml:50.5ml±4.8, 10ml:46.1ml±2.2) and increased ejection fraction (EF) (0ml:34.6%±1.6, 6ml:39.7%±0.9, 8ml:43.1%±2.7, 10ml:44.1%±0.9). SV significantly (p<0.05) improved for the 6ml and 8ml volumes (0ml: 31.2ml±2.6, 6ml: 35.7ml±2.0, 8ml: 37.5ml±1.9) but trended downward for 10ml (36.6ml±2.8). At four-weeks after MI, end-diastolic volume and ESV were unchanged from one-week values in the treatment group while the control group continued to dilate. SV (38.2±4.4ml vs. 34.0.1±4.8ml, p=0.08) and EF (36.0±2.6% vs. 27.6±1.4%, p=0.04) were also better in the treatment animals. Conclusions Optimized isolated infarct restraint can limit adverse LV remodeling after MI. The tested device affords the potential for a patient-specific therapy to preserve cardiac function after MI. PMID:23146279

  16. Evaluation of Long Term Effect of RV Apical Pacing on Global LV Function by Echocardiography

    PubMed Central

    Tilkar, Mahendra; Jain, Siddhant; Mondal, Subrata; Sarkar, Piyabi; Modi, Nitin

    2016-01-01

    Introduction We very often face pacemaker implanted patients during follow-up with shortness of breath and effort intolerance inspite of normal clinical parameters. Aim The aim of our study is to evaluate the cause of effort intolerance and probable cause of sub-clinical Congestive Cardiac Failure (CCF) in a case of long term Right Ventricular (RV) apical pacing on global Left Ventricular (LV) function non- invasively by echocardiography. Materials and Methods We studied 54 patients (Male 42, Female 12) of complete heart block (CHB) with RV apical pacing (40 VVI and 14 DCP). Mean duration of pacing was 58+4 months. All patients underwent 24 hours Holter monitoring to determine the percentage of ventricular pacing beats. 2-D Echocardiography was done to assess the regional wall motion of abnormality and global LV ejection fraction by modified Simpson’s rule. These methods were coupled with the Doppler derived Myocardial Performance Index (MPI), tissue Doppler imaging, and mechanical regional dyssynchrony with 3-D Echocardiography. Data were analysed from 54 RV- apical paced patients and compared with age and body surface area of 60 controlled subjects (Male 46, Female 14). Results Evaluation of LV function in 54 patients demonstrated regional wall motion abnormality and Doppler study revealed both LV systolic and diastolic dysfunction compare with control subjects (regional wall motion abnormality 80±6% vs 30±3% with p-value<0.0001) which is proportional to the percentage of ventricular pacing beats (mean paced beat 78%). Global LVEF 50±4% vs 60±2% (p-valve <0.0001) and MPI 0.46 ±0.12 v/s 0.36±0.09 (p-value <0.0001). Conclusion RV–apical pacing induces iatrogenic electrical dyssynchrony which leads to remodeling of LV and produces mechanical dyssynchrony which is responsible for LV dysfunction. Alternate site of RV pacing and/or biventricular pacing should be done to maintain biventricular electrical synchrony which will preserve the LV function. PMID

  17. LV305, a dendritic cell-targeting integration-deficient ZVexTM-based lentiviral vector encoding NY-ESO-1, induces potent anti-tumor immune response

    PubMed Central

    Albershardt, Tina Chang; Campbell, David James; Parsons, Andrea Jean; Slough, Megan Merrill; ter Meulen, Jan; Berglund, Peter

    2016-01-01

    We have engineered an integration-deficient lentiviral vector, LV305, to deliver the tumor antigen NY-ESO-1 to human dendritic cells in vivo through pseudotyping with a modified Sindbis virus envelop protein. Mice immunized once with LV305 developed strong, dose-dependent, multifunctional, and cytotoxic NY-ESO-1-specific cluster of differentiation 8 (CD8) T cells within 14 days post-immunization and could be boosted with LV305 at least twice to recall peak-level CD8 T-cell responses. Immunization with LV305 protected mice against tumor growth in an NY-ESO-1-expressing CT26 lung metastasis model, with the protective effect abrogated upon depletion of CD8 T cells. Adoptive transfer of CD8 T cells, alone or together with CD4 T cells or natural killer cells, from LV305-immunized donor mice to tumor-bearing recipient mice conferred significant protection against metastatic tumor growth. Biodistribution of injected LV305 in mice was limited to the site of injection and the draining lymph node, and injected LV305 exhibited minimal excretion. Mice injected with LV305 developed little to no adverse effects, as evaluated by toxicology studies adherent to good laboratory practices. Taken together, these data support the development of LV305 as a clinical candidate for treatment against tumors expressing NY-ESO-1. PMID:27626061

  18. LV305, a dendritic cell-targeting integration-deficient ZVex(TM)-based lentiviral vector encoding NY-ESO-1, induces potent anti-tumor immune response.

    PubMed

    Albershardt, Tina Chang; Campbell, David James; Parsons, Andrea Jean; Slough, Megan Merrill; Ter Meulen, Jan; Berglund, Peter

    2016-01-01

    We have engineered an integration-deficient lentiviral vector, LV305, to deliver the tumor antigen NY-ESO-1 to human dendritic cells in vivo through pseudotyping with a modified Sindbis virus envelop protein. Mice immunized once with LV305 developed strong, dose-dependent, multifunctional, and cytotoxic NY-ESO-1-specific cluster of differentiation 8 (CD8) T cells within 14 days post-immunization and could be boosted with LV305 at least twice to recall peak-level CD8 T-cell responses. Immunization with LV305 protected mice against tumor growth in an NY-ESO-1-expressing CT26 lung metastasis model, with the protective effect abrogated upon depletion of CD8 T cells. Adoptive transfer of CD8 T cells, alone or together with CD4 T cells or natural killer cells, from LV305-immunized donor mice to tumor-bearing recipient mice conferred significant protection against metastatic tumor growth. Biodistribution of injected LV305 in mice was limited to the site of injection and the draining lymph node, and injected LV305 exhibited minimal excretion. Mice injected with LV305 developed little to no adverse effects, as evaluated by toxicology studies adherent to good laboratory practices. Taken together, these data support the development of LV305 as a clinical candidate for treatment against tumors expressing NY-ESO-1. PMID:27626061

  19. LV305, a dendritic cell-targeting integration-deficient ZVex(TM)-based lentiviral vector encoding NY-ESO-1, induces potent anti-tumor immune response.

    PubMed

    Albershardt, Tina Chang; Campbell, David James; Parsons, Andrea Jean; Slough, Megan Merrill; Ter Meulen, Jan; Berglund, Peter

    2016-01-01

    We have engineered an integration-deficient lentiviral vector, LV305, to deliver the tumor antigen NY-ESO-1 to human dendritic cells in vivo through pseudotyping with a modified Sindbis virus envelop protein. Mice immunized once with LV305 developed strong, dose-dependent, multifunctional, and cytotoxic NY-ESO-1-specific cluster of differentiation 8 (CD8) T cells within 14 days post-immunization and could be boosted with LV305 at least twice to recall peak-level CD8 T-cell responses. Immunization with LV305 protected mice against tumor growth in an NY-ESO-1-expressing CT26 lung metastasis model, with the protective effect abrogated upon depletion of CD8 T cells. Adoptive transfer of CD8 T cells, alone or together with CD4 T cells or natural killer cells, from LV305-immunized donor mice to tumor-bearing recipient mice conferred significant protection against metastatic tumor growth. Biodistribution of injected LV305 in mice was limited to the site of injection and the draining lymph node, and injected LV305 exhibited minimal excretion. Mice injected with LV305 developed little to no adverse effects, as evaluated by toxicology studies adherent to good laboratory practices. Taken together, these data support the development of LV305 as a clinical candidate for treatment against tumors expressing NY-ESO-1.

  20. New lv Mutants of Pea Are Deficient in Phytochrome B.

    PubMed Central

    Weller, J. L.; Nagatani, A.; Kendrick, R. E.; Murfet, I. C.; Reid, J. B.

    1995-01-01

    The lv-1 mutant of pea (Pisum sativum L.) is deficient in responses regulated by phytochrome B (phyB) in other species but has normal levels of spectrally active phyB. We have characterized three further lv mutants (lv-2, lv-3, and lv-4), which are all elongated under red (R) and white light but are indistinguishable from wild type under far-red light. The phyB apoprotein present in the lv-1 mutant was undetectable in all three new lv mutants. The identification of allelic mutants with and without phyB apoprotein suggests that Lv may be a structural gene for a B-type phytochrome. Furthermore, it indicates that the lv-1 mutation results specifically in the loss of normal biological activity of this phytochrome. Red-light-pulse and fluence-rate-response experiments suggest that lv plants are deficient in the low-fluence response (LFR) but retain a normal very-low-fluence-rate-dependent response for leaflet expansion and inhibition of stem elongation. Comparison of lv alleles of differing severity indicates that the LFR for stem elongation can be mediated by a lower level of phyB than the LFR for leaflet expansion. The retention of a strong response to continuous low-fluence-rate R in all four lv mutants suggests that there may be an additional phytochrome controlling responses to R in pea. The kinetics of phytochrome destruction and reaccumulation in the lv mutant indicate that phyB may be involved in the light regulation of phyA levels. PMID:12228490

  1. Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation.

    PubMed

    Bernardo, Bianca C; Sapra, Geeta; Patterson, Natalie L; Cemerlang, Nelly; Kiriazis, Helen; Ueyama, Tomomi; Febbraio, Mark A; McMullen, Julie R

    2015-01-01

    Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions. PMID:26660322

  2. Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation

    PubMed Central

    Bernardo, Bianca C.; Sapra, Geeta; Patterson, Natalie L.; Cemerlang, Nelly; Kiriazis, Helen; Ueyama, Tomomi; Febbraio, Mark A.; McMullen, Julie R.

    2015-01-01

    Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions. PMID:26660322

  3. Role of reactive oxygen species in myocardial remodeling.

    PubMed

    Zhang, Min; Shah, Ajay M

    2007-03-01

    Adverse cardiac remodeling is a fundamental process in the progression to chronic heart failure. Although the mechanisms underlying cardiac remodeling are multi-factorial, a significant body of evidence points to the crucial roles of increased reactive oxygen species. This article reviews recent advances in delineating the different sources of production for reactive oxygen species (namely mitochondria, xanthine oxidase, uncoupled nitric oxide synthases, and NADPH oxidases) that may be involved in cardiac remodeling and the aspects of the remodeling process that they affect. These data could suggest new ways of targeting redox pathways for the prevention and treatment of adverse cardiac remodeling.

  4. Role of reactive oxygen species in myocardial remodeling.

    PubMed

    Zhang, Min; Shah, Ajay M

    2007-03-01

    Adverse cardiac remodeling is a fundamental process in the progression to chronic heart failure. Although the mechanisms underlying cardiac remodeling are multi-factorial, a significant body of evidence points to the crucial roles of increased reactive oxygen species. This article reviews recent advances in delineating the different sources of production for reactive oxygen species (namely mitochondria, xanthine oxidase, uncoupled nitric oxide synthases, and NADPH oxidases) that may be involved in cardiac remodeling and the aspects of the remodeling process that they affect. These data could suggest new ways of targeting redox pathways for the prevention and treatment of adverse cardiac remodeling. PMID:17386182

  5. Gender differences in cardiac hypertrophic remodeling.

    PubMed

    Patrizio, Mario; Marano, Giuseppe

    2016-01-01

    Cardiac remodeling is a complex process that occurs in response to different types of cardiac injury such as ischemia and hypertension, and that involves cardiomyocytes, fibroblasts, vascular smooth muscle cells, vascular endothelial cells, and inflammatory cells. The end result is cardiomyocyte hypertrophy, fibrosis, inflammation, vascular, and electrophysiological remodeling. This paper reviews a large number of studies on the influence of gender on pathological cardiac remodeling and shows how sex differences result in different clinical outcomes and therapeutic responses, with males which generally develop greater cardiac remodeling responses than females. Although estrogens appear to have an important role in attenuating adverse cardiac remodeling, the mechanisms through which gender modulates myocardial remodeling remain to be identified. PMID:27364397

  6. Prognostic heterogeneity of diastolic abnormalities along left ventricular remodeling continuum according to survival rates and laser polarimetry of blood

    NASA Astrophysics Data System (ADS)

    Boychuk, T. M.; Ivashchuk, O. I.; Kolomoiets, M. Y.; Mikhaliev, K. O.; Chursina, T. Y.

    2011-09-01

    The results of examination of 35 arterial hypertension and coronary heart disease patients are presented. The clinical, paraclinical and echocardiographic examinations were performed, and the parameters of prognosis (survival) according to Seattle Heart Failure Model, as well as the optical (polarimetric) properties of erythrocytic suspension were determined. The group of patients under examination was stratified by patterns of remodeling of left ventricle (LV). It was determined that increasing of anisotropy of erythrocytic suspension along LV remodeling patterns continuum correlates with aggravation of structural and functional state of LV and is associated with unfavorable prognosis.

  7. Prognostic heterogeneity of diastolic abnormalities along left ventricular remodeling continuum according to survival rates and laser polarimetry of blood

    NASA Astrophysics Data System (ADS)

    Boychuk, T. M.; Ivashchuk, O. I.; Kolomoiets, M. Y.; Mikhaliev, K. O.; Chursina, T. Y.

    2012-01-01

    The results of examination of 35 arterial hypertension and coronary heart disease patients are presented. The clinical, paraclinical and echocardiographic examinations were performed, and the parameters of prognosis (survival) according to Seattle Heart Failure Model, as well as the optical (polarimetric) properties of erythrocytic suspension were determined. The group of patients under examination was stratified by patterns of remodeling of left ventricle (LV). It was determined that increasing of anisotropy of erythrocytic suspension along LV remodeling patterns continuum correlates with aggravation of structural and functional state of LV and is associated with unfavorable prognosis.

  8. Safe Oral Triiodo-L-Thyronine Therapy Protects from Post-Infarct Cardiac Dysfunction and Arrhythmias without Cardiovascular Adverse Effects

    PubMed Central

    Rajagopalan, Viswanathan; Zhang, Youhua; Ojamaa, Kaie; Chen, Yue-feng; Pingitore, Alessandro; Pol, Christine J.; Saunders, Debra; Balasubramanian, Krithika; Towner, Rheal A.; Gerdes, A. Martin

    2016-01-01

    Background A large body of evidence suggests that thyroid hormones (THs) are beneficial for the treatment of cardiovascular disorders. We have shown that 3 days of triiodo-L-thyronine (T3) treatment in myocardial infarction (MI) rats increased left ventricular (LV) contractility and decreased myocyte apoptosis. However, no clinically translatable protocol is established for T3 treatment of ischemic heart disease. We hypothesized that low-dose oral T3 will offer safe therapeutic benefits in MI. Methods and Results Adult female rats underwent left coronary artery ligation or sham surgeries. T3 (~6 μg/kg/day) was available in drinking water ad libitum immediately following MI and continuing for 2 month(s) (mo). Compared to vehicle-treated MI, the oral T3-treated MI group at 2 mo had markedly improved anesthetized Magnetic Resonance Imaging-based LV ejection fraction and volumes without significant negative changes in heart rate, serum TH levels or heart weight, indicating safe therapy. Remarkably, T3 decreased the incidence of inducible atrial tachyarrhythmias by 88% and improved remodeling. These were accompanied by restoration of gene expression involving several key pathways including thyroid, ion channels, fibrosis, sympathetic, mitochondria and autophagy. Conclusions Low-dose oral T3 dramatically improved post-MI cardiac performance, decreased atrial arrhythmias and cardiac remodeling, and reversed many adverse changes in gene expression with no observable negative effects. This study also provides a safe and effective treatment/monitoring protocol that should readily translate to humans. PMID:26981865

  9. Bacteriocin production by Carnobacterium piscicola LV 61.

    PubMed

    Schillinger, U; Stiles, M E; Holzapfel, W H

    1993-11-26

    Carnobacterium piscicola LV 61 produces a bacteriocin designated piscicolin 61, that is heat resistant, active over a wide pH range and inactivated by alpha-chymotrypsin, pepsin, trypsin and papain. It is effective against strains of the genera Carnobacterium, Enterococcus and Listeria. Other lactic acid bacteria tested were less sensitive or resistant to piscicolin. It is produced at temperatures from 1 to 30 degrees C. Maximum bacteriocin activity was detected after the culture had entered the stationary phase of growth and when the culture was grown in a medium with an initial pH between 8.0 and 9.0. The same high amounts of bacteriocin could be obtained in a culture at a constant pH of 6.5. No bacteriocin was produced at pH 5.0. Peptone in the growth medium promotes bacteriocin production, whereas meat and yeast extract did not influence the amounts of bacteriocin produced. Bacteriocin production and immunity are probably encoded by a 22 kb plasmid. PMID:8312140

  10. Simulated Microgravity and Recovery-Induced Remodeling of the Left and Right Ventricle.

    PubMed

    Zhong, Guohui; Li, Yuheng; Li, Hongxing; Sun, Weijia; Cao, Dengchao; Li, Jianwei; Zhao, Dingsheng; Song, Jinping; Jin, Xiaoyan; Song, Hailin; Yuan, Xinxin; Wu, Xiaorui; Li, Qi; Xu, Qing; Kan, Guanghan; Cao, Hongqing; Ling, Shukuan; Li, Yingxian

    2016-01-01

    Physiological adaptations to microgravity involve alterations in cardiovascular systems. These adaptations result in cardiac remodeling and orthostatic hypotension. However, the response of the left ventricle (LV) and right ventricle (RV) following hindlimb unloading (HU) and hindlimb reloading (HR) is not clear and the underlying mechanism remains to be understood. In this study, three groups of mice were subjected to HU by tail suspension for 28 days. Following this, two groups were allowed to recover for 7 or 14 days. The control group was treated equally, with the exception of tail suspension. Echocardiography was performed to detect the structure and function changes of heart. Compared with the control, the HU group of mice showed reduced LV-EF (ejection fraction), and LV-FS (fractional shortening). However, mice that were allowed to recover for 7 days after HU (HR-7d) showed increased LVIDs (systolic LV internal diameter) and LV Vols (systolic LV volume). Mice that recovered for 14 days (HR-14d) returned to the normal state. In comparison, RV-EF and RV-FS didn't recover to the normal conditions till being reloaded for 14 days. Compared with the control, RVIDd (diastolic RV internal diameter), and RV Vold (diastolic RV volume) were reduced in HU group and recovered to the normal conditions in HR-7d and HR-14d groups, in which groups RVIDs (systolic RV internal diameter) and RV Vols (systolic RV volume) were increased. Histological analysis and cardiac remodeling gene expression results indicated that HU induces left and right ventricular remodeling. Western blot demonstrated that the phosphorylation of HDAC4 and ERK1/2 and the ratio of LC3-II / LC3-I, were increased following HU and recovered following HR in both LV and RV, and the phosphorylation of AMPK was inhibited in both LV and RV following HU, but only restored in LV following HR for 14 days. These results indicate that simulated microgravity leads to cardiac remodeling, and the remodeling changes can

  11. Simulated Microgravity and Recovery-Induced Remodeling of the Left and Right Ventricle

    PubMed Central

    Zhong, Guohui; Li, Yuheng; Li, Hongxing; Sun, Weijia; Cao, Dengchao; Li, Jianwei; Zhao, Dingsheng; Song, Jinping; Jin, Xiaoyan; Song, Hailin; Yuan, Xinxin; Wu, Xiaorui; Li, Qi; Xu, Qing; Kan, Guanghan; Cao, Hongqing; Ling, Shukuan; Li, Yingxian

    2016-01-01

    Physiological adaptations to microgravity involve alterations in cardiovascular systems. These adaptations result in cardiac remodeling and orthostatic hypotension. However, the response of the left ventricle (LV) and right ventricle (RV) following hindlimb unloading (HU) and hindlimb reloading (HR) is not clear and the underlying mechanism remains to be understood. In this study, three groups of mice were subjected to HU by tail suspension for 28 days. Following this, two groups were allowed to recover for 7 or 14 days. The control group was treated equally, with the exception of tail suspension. Echocardiography was performed to detect the structure and function changes of heart. Compared with the control, the HU group of mice showed reduced LV-EF (ejection fraction), and LV-FS (fractional shortening). However, mice that were allowed to recover for 7 days after HU (HR-7d) showed increased LVIDs (systolic LV internal diameter) and LV Vols (systolic LV volume). Mice that recovered for 14 days (HR-14d) returned to the normal state. In comparison, RV-EF and RV-FS didn't recover to the normal conditions till being reloaded for 14 days. Compared with the control, RVIDd (diastolic RV internal diameter), and RV Vold (diastolic RV volume) were reduced in HU group and recovered to the normal conditions in HR-7d and HR-14d groups, in which groups RVIDs (systolic RV internal diameter) and RV Vols (systolic RV volume) were increased. Histological analysis and cardiac remodeling gene expression results indicated that HU induces left and right ventricular remodeling. Western blot demonstrated that the phosphorylation of HDAC4 and ERK1/2 and the ratio of LC3-II / LC3-I, were increased following HU and recovered following HR in both LV and RV, and the phosphorylation of AMPK was inhibited in both LV and RV following HU, but only restored in LV following HR for 14 days. These results indicate that simulated microgravity leads to cardiac remodeling, and the remodeling changes can

  12. Subclinical LV Dysfunction Detection Using Speckle Tracking Echocardiography in Hypertensive Patients with Preserved LV Ejection Fraction

    PubMed Central

    Ayoub, Amal Mohamed; Keddeas, Viola William; Ali, Yasmin Abdelrazek; El Okl, Reham Atef

    2016-01-01

    BACKGROUND Early detection of subclinical left ventricular (LV) systolic dysfunction in hypertensive patients is important for the prevention of progression of hypertensive heart disease. METHODS We studied 60 hypertensive patients (age ranged from 21 to 49 years, the duration of hypertension ranged from 1 to 18 years) and 30 healthy controls, all had preserved left ventricular ejection fraction (LVEF), detected by two-dimensional speckle tracking echocardiography (2D-STE). RESULTS There was no significant difference between the two groups regarding ejection fraction (EF) by Simpson’s method. Systolic velocity was significantly higher in the control group, and global longitudinal strain was significantly higher in the control group compared with the hypertensive group. In the hypertensive group, 23 of 60 patients had less negative global longitudinal strain than −19.1, defined as reduced systolic function, which is detected by 2D-STE (subclinical systolic dysfunction), when compared with 3 of 30 control subjects. CONCLUSION 2D-STE detected substantial impairment of LV systolic function in hypertensive patients with preserved LVEF, which identifies higher risk subgroups for earlier medical intervention. PMID:27385916

  13. Low-intensity aerobic interval training attenuates pathological left ventricular remodeling and mitochondrial dysfunction in aortic-banded miniature swine

    PubMed Central

    Baines, Christopher P.

    2010-01-01

    Cardiac hypertrophy in response to hypertension or myocardial infarction is a pathological indicator associated with heart failure (HF). A central component of the remodeling process is the loss of cardiomyocytes via cell death pathways regulated by the mitochondrion. Recent evidence has indicated that exercise training can attenuate or reverse pathological remodeling, creating a physiological phenotype. The purpose of this study was to examine left ventricular (LV) function, remodeling, and cardiomyocyte mitochondrial function in aortic-banded (AB) sedentary (HFSED; n = 6), AB exercise-trained (HFTR, n = 5), and control sedentary (n = 5) male Yucatan miniature swine. LV hypertrophy was present in both AB groups before the start of training, as indicated by increases in LV end-diastolic volume, LV end-systolic volume (LVESV), and LV end-systolic dimension (LVESD). Exercise training (15 wk) prevented further increases in LVESV and LVESD (P < 0.05). The heart weight-to-body weight ratio, LV + septum-to-body weight ratio, LV + septum-to-right ventricle ratio, and cardiomyocyte cross-sectional area were increased in both AB groups postmortem regardless of training status. Preservation of LV function after exercise training, as indicated by the maintenance of fractional shortening, ejection fraction, and mean wall shortening and increased stroke volume, was associated with an attenuation of the increased LV fibrosis (23%) and collagen (36%) observed in HFSED animals. LV mitochondrial dysfunction, as measured by Ca2+-induced mitochondrial permeability transition, was increased in HFSED (P < 0.05) but not HFTR animals. In conclusion, low-intensity interval exercise training preserved LV function as exemplified by an attenuation of fibrosis, maintenance of a positive inotropic state, and inhibition of mitochondrial dysfunction, providing further evidence of the therapeutic potential of exercise in a clinical setting. PMID:20817828

  14. Induction, structural characterization, and genome sequence of Lv1, a prophage from a human vaginal Lactobacillus jensenii strain.

    PubMed

    Martín, Rebeca; Escobedo, Susana; Suárez, Juan E

    2010-09-01

    The prophage Lv1, harbored by a vaginal Lactobacillus jensenii isolate, was induced by several different anticancer, antimicrobial, and antiseptic agents, suggesting that they contribute to the adverse vaginal effects associated with their therapeutic use. Of special interest with respect to its novelty was the inducing effect of nonoxynol-9, a non-ionic detergent commonly used as a spermicide. The Lv1 genome consists of a 38,934-bp dsDNA molecule with cohesive ends, in which 48 ORFs were recognized, and is organized into functional modules. Lv1 belongs to the family Siphoviridae and, more precisely, to the proposed Sfi21-like genus. The capsid-tail junction of the Lv1 virions is fragile such that most particles become disrupted, suggesting that the virus is defective and thus unable to generate fertile progeny. However, genome analysis did not provide evidence of the defective nature of the prophage, other than the finding that its genome is shorter than those of other, related, phages. Further analysis indicated that prophage Lv1 suffered deletions in its right half to the extent that it no longer fulfill the minimum packaging limits, thereby generating the observed unstable particles. PMID:20890845

  15. Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model

    PubMed Central

    Huang, Chun-kai; Chen, Bi-yi; Guo, Ang; Chen, Rong; Zhu, Yan-qi; Kutschke, William; Hong, Jiang; Song, Long-sheng

    2016-01-01

    Aim: Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits. Methods: A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg·kg−1·d−1, sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes. Results: TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T-tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R2=0.74, P<0.01) and global LV function (R2=0.47, P<0.01). Conclusion: Sildenafil effectively ameliorates LV T-tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure. PMID:26972492

  16. Prognosis parameters and polarimetric properties of erythrocytes of the patients suffering from arterial hypertension and coronary heart disease at various patterns of left ventricular remodeling

    NASA Astrophysics Data System (ADS)

    Ivaschuk, Oleg I.; Kolomoiets, M. Y.; Mikhaliev, K. O.; Chursina, T. Ya.

    2012-01-01

    The results of examination of 35 arterial hypertension and coronary heart disease patients are presented. The clinical, paraclinical and echocardiographic examinations were performed, and the parameters of prognosis (survival) according to Seattle Heart Failure Model, as well as the optical (polarimetric) properties of erythrocytic suspension were determined. The group of patients under examination was stratified by patterns of remodeling of left ventricle (LV). It was determined that increasing of anisotropy of erythrocytic suspension along LV remodeling patterns continuum correlates with aggravation of structural and functional state of LV and is associated with unfavorable prognosis.

  17. Myocardial Connective Tissue Growth Factor (CCN2/CTGF) Attenuates Left Ventricular Remodeling after Myocardial Infarction

    PubMed Central

    Gravning, Jørgen; Ørn, Stein; Kaasbøll, Ole Jørgen; Martinov, Vladimir N.; Manhenke, Cord; Dickstein, Kenneth; Edvardsen, Thor; Attramadal, Håvard; Ahmed, Mohammed Shakil

    2012-01-01

    Aims Myocardial CCN2/CTGF is induced in heart failure of various etiologies. However, its role in the pathophysiology of left ventricular (LV) remodeling after myocardial infarction (MI) remains unresolved. The current study explores the role of CTGF in infarct healing and LV remodeling in an animal model and in patients admitted for acute ST-elevation MI. Methods and Results Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate controls (NLC) were subjected to permanent ligation of the left anterior descending coronary artery. Despite similar infarct size (area of infarction relative to area at risk) 24 hours after ligation of the coronary artery in Tg-CTGF and NLC mice, Tg-CTGF mice disclosed smaller area of scar tissue, smaller increase of cardiac hypertrophy, and less LV dilatation and deterioration of LV function 4 weeks after MI. Tg-CTGF mice also revealed substantially reduced mortality after MI. Remote/peri-infarct tissue of Tg-CTGF mice contained reduced numbers of leucocytes, macrophages, and cells undergoing apoptosis as compared with NLC mice. In a cohort of patients with acute ST-elevation MI (n = 42) admitted to hospital for percutaneous coronary intervention (PCI) serum-CTGF levels (s-CTGF) were monitored and related to infarct size and LV function assessed by cardiac MRI. Increase in s-CTGF levels after MI was associated with reduced infarct size and improved LV ejection fraction one year after MI, as well as attenuated levels of CRP and GDF-15. Conclusion Increased myocardial CTGF activities after MI are associated with attenuation of LV remodeling and improved LV function mediated by attenuation of inflammatory responses and inhibition of apoptosis. PMID:23284892

  18. Anti‐Remodeling and Anti‐Fibrotic Effects of the Neuregulin‐1β Glial Growth Factor 2 in a Large Animal Model of Heart Failure

    PubMed Central

    Galindo, Cristi L.; Kasasbeh, Ehab; Murphy, Abigail; Ryzhov, Sergey; Lenihan, Sean; Ahmad, Farhaan A.; Williams, Philip; Nunnally, Amy; Adcock, Jamie; Song, Yanna; Harrell, Frank E.; Tran, Truc‐Linh; Parry, Tom J.; Iaci, Jen; Ganguly, Anindita; Feoktistov, Igor; Stephenson, Matthew K.; Caggiano, Anthony O.; Sawyer, Douglas B.; Cleator, John H.

    2014-01-01

    Background Neuregulin‐1β (NRG‐1β) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 (GGF2) isoform of NRG‐1β improves cardiac function in rodents after myocardial infarction (MI), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF2 on ventricular remodeling, cardiac function, and global transcription in post‐MI swine, as well as potential mechanisms for anti‐remodeling effects. Methods and Results MI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post‐MI, survivors (n=13) received GGF2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post‐MI, fractional shortening was higher (32.8% versus 25.3%, P=0.019), and left ventricular (LV) end‐diastolic dimension lower (4.5 versus 5.3 cm, P=0.003) in GGF2‐treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF2‐treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG‐1β reduces myoFbs, and suppresses TGFβ‐induced phospho‐SMAD3 as well as αSMA expression. Conclusions These results suggest that GGF2/NRG‐1β prevents adverse remodeling after injury in part via anti‐fibrotic effects in the heart. PMID:25341890

  19. Multiscale Characterization of Impact of Infarct Size on Myocardial Remodeling in an Ovine Infarct Model.

    PubMed

    Zhang, Pei; Li, Tielou; Griffith, Bartley P; Wu, Zhongjun J

    2015-01-01

    The surviving myocardium initially compensates the loss of injured myocardium after myocardial infarction (MI) and gradually becomes progressively dysfunctional. There have been limited studies on the effect of infarct size on temporal and spatial alterations in the myocardium during progressive myocardial remodeling. MI with three infarct sizes, i.e. 15, 25 and 35% of the left ventricular (LV) wall, was created in an ovine infarction model. The progressive LV remodeling over a 12-week period was studied. Echocardiography, sonomicrometry, and histological and molecular analyses were carried out to evaluate cardiac function, regional tissue contractile function, structural remodeling and cardiomyocyte hypertrophy, and calcium handling proteins. Twelve weeks after MI, the 15, 25 and 35% MI groups had normalized LV end diastole volumes of 1.4 ± 0.2, 1.7 ± 0.3 and 2.0 ± 0.4 ml/kg, normalized end systole volumes of 1.0 ± 0.1, 1.0 ± 0.2 and 1.3 ± 0.3 ml/kg and LV ejection fractions of 43 ± 3, 42 ± 6 and 34 ± 4%, respectively. They all differed from the sham group (p < 0.05). All the three MI groups exhibited larger wall areal expansion (remodeling strain), larger cardiomyocyte size and altered expression of calcium handing proteins in the adjacent myocardium compared to the remote counterpart from the infarct. A significant correlation was found between cardiomyocyte size and remodeling strain in the adjacent zone. A comparative analysis among the three MI groups showed that a larger infarct size (35 vs. 15% MI) was associated with larger remodeling strain, more serious impairment in the cellular structure and composition, and regional contractile function at regional tissue level and LV function at organ level.

  20. Hyperinsulinemia improves ischemic LV function in insulin resistant subjects

    PubMed Central

    2010-01-01

    Background Glucose is a more efficient substrate for ATP production than free fatty acid (FFA). Insulin resistance (IR) results in higher FFA concentrations and impaired myocardial glucose use, potentially worsening ischemia. We hypothesized that metabolic manipulation with a hyperinsulinemic euglycemic clamp (HEC) would affect a greater improvement in left ventricular (LV) performance during dobutamine stress echo (DSE) in subjects with IR. Methods 24 subjects with normal LV function and coronary disease (CAD) awaiting revascularization underwent 2 DSEs. Prior to one DSEs they underwent an HEC, where a primed infusion of insulin (rate 43 mU/m 2/min) was co-administered with 20% dextrose at variable rates to maintain euglycemia. At steady-state the DSE was performed and images of the LV were acquired with tissue Doppler at each stage for offline analysis. Segmental peak systolic velocities (Vs) were recorded, as well as LV ejection fraction (EF). Subjects were then divided into two groups based on their insulin sensitivity during the HEC. Results HEC changed the metabolic environment, suppressing FFAs and thereby increasing glucose use. This resulted in improved LV performance at peak stress, measured by EF (IS group mean difference 5.3 (95% CI 2.5-8) %, p = 0.002; IR group mean difference 8.7 (95% CI 5.8-11.6) %, p < 0.0001) and peak V s in ischemic segments (IS group mean improvement 0.7(95% CI 0.07-1.58) cm/s, p = 0.07; IR group mean improvement 1.0 (95% CI 0.54-1.5) cm/s, p < 0.0001) , that was greater in the subjects with IR. Conclusions Increased myocardial glucose use induced by HEC improves LV function under stress in subjects with CAD and IR. Cardiac metabolic manipulation in subjects with IR is a promising target for future therapy. PMID:20576156

  1. [An Elderly Patient with Multiple Lung Metastases after Colectomy Successfully Treated with a Combination Oral UFT/LV Chemotherapy Regimen].

    PubMed

    Shiraishi, Takehiro; Moriya, Tomoyuki; Ueno, Hideki; Shinto, Eiji; Kajiwara, Yoshiki; Sueyama, Takahiro; Watanabe, Tomoki; Yamadera, Masato; Yamamoto, Junji; Hase, Kazuo

    2016-07-01

    We report an 84-year-old woman with multiple lung metastases from sigmoid colon cancer successfully treated with an oral combination chemotherapeutic agent regimen(UFT/LV).The patient had undergone colectomy for sigmoid colon cancer. Histological examination confirmed a pT4a, pN3, pM1a(LYM), pStage IV tumor.The patient refused adjuvant chemotherapy. However, approximately 9 months postoperatively, she developed a severe cough.Chest radiography and computed tomography(CT)revealed multiple progressive lung metastases.Thereafter, considering her advanced age and general condition, an oral UFT/LV regimen(UFT 300mg/LV 75mg for 7 days every 14 days)was initiated.Two and a half months after initiating chemotherapy, symptom amelioration was observed.Chest radiography and CT showed disappearance of several of the lung metastases, indicating a Partial Response(PR).For the nearly one year to date since diagnosis, she has remained free of cough and the PR has been maintained without chemotherapy-associated adverse events.She is currently being managed on an outpatient basis.The oral UFT/LV regimen is considered to be among the potentially effective and safe treatments for elderly patients with postoperative metastases from colon cancer.

  2. Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs. short-term lowlander adaptation.

    PubMed

    Stembridge, Mike; Ainslie, Philip N; Hughes, Michael G; Stöhr, Eric J; Cotter, James D; Nio, Amanda Q X; Shave, Rob

    2014-08-01

    Short-term, high-altitude (HA) exposure raises pulmonary artery systolic pressure (PASP) and decreases left-ventricular (LV) volumes. However, relatively little is known of the long-term cardiac consequences of prolonged exposure in Sherpa, a highly adapted HA population. To investigate short-term adaptation and potential long-term cardiac remodeling, we studied ventricular structure and function in Sherpa at 5,050 m (n = 11; 31 ± 13 yr; mass 68 ± 10 kg; height 169 ± 6 cm) and lowlanders at sea level (SL) and following 10 ± 3 days at 5,050 m (n = 9; 34 ± 7 yr; mass 82 ± 10 kg; height 177 ± 6 cm) using conventional and speckle-tracking echocardiography. At HA, PASP was higher in Sherpa and lowlanders compared with lowlanders at SL (both P < 0.05). Sherpa had smaller right-ventricular (RV) and LV stroke volumes than lowlanders at SL with lower RV systolic strain (P < 0.05) but similar LV systolic mechanics. In contrast to LV systolic mechanics, LV diastolic, untwisting velocity was significantly lower in Sherpa compared with lowlanders at both SL and HA. After partial acclimatization, lowlanders demonstrated no change in the RV end-diastolic area; however, both RV strain and LV end-diastolic volume were reduced. In conclusion, short-term hypoxia induced a reduction in RV systolic function that was also evident in Sherpa following chronic exposure. We propose that this was consequent to a persistently higher PASP. In contrast to the RV, remodeling of LV volumes and normalization of systolic mechanics indicate structural and functional adaptation to HA. However, altered LV diastolic relaxation after chronic hypoxic exposure may reflect differential remodeling of systolic and diastolic LV function.

  3. Functional significance of the discordance between transcriptional profile and left ventricular structure/function during reverse remodeling

    PubMed Central

    Topkara, Veli K.; Chambers, Kari T.; Yang, Kai-Chien; Tzeng, Huei-Ping; Evans, Sarah; Weinheimer, Carla; Kovacs, Attila; Robbins, Jeffrey; Barger, Philip; Mann, Douglas L.

    2016-01-01

    To elucidate the mechanisms for reverse LV remodeling, we generated a conditional (doxycycline [dox] off) transgenic mouse tetracycline transactivating factor–TRAF2 (tTA-TRAF2) that develops a dilated heart failure (HF) phenotype upon expression of a proinflammatory transgene, TNF receptor–associated factor 2 (TRAF2), and complete normalization of LV structure and function when the transgene is suppressed. tTA-TRAF2 mice developed a significant increase in LV dimension with decreased contractile function, which was completely normalized in the tTA-TRAF2 mice fed dox for 4 weeks (tTA-TRAF2dox4W). Normalization of LV structure and function was accompanied by partial normalization (~60%) of gene expression associated with incident HF. Similar findings were observed in patients with dilated cardiomyopathy who underwent reverse LV remodeling following mechanical circulatory support. Persistence of the HF gene program was associated with an exaggerated hypertrophic response and increased mortality in tTA-TRAF2dox4W mice following transaortic constriction (TAC). These effects were no longer observed following TAC in tTA-TRAF2dox8W, wherein there was a more complete (88%) reversal of the incident HF genes. These results demonstrate that reverse LV remodeling is associated with improvements in cardiac myocyte biology; however, the persistence of the abnormal HF gene program may be maladaptive following perturbations in hemodynamic loading conditions. PMID:27158672

  4. In vitro comparison tests of three LV vent valves.

    PubMed

    Lewis, G S; Czaplicka, C

    1990-01-01

    Many surgical teams employ a sump pump to vent the left ventricle (LV). The problems associated with this technique are related to safety and convenience. If the flow is accidentally reversed in the LV vent line, air embolism accidents and subsequent litigation may be the result. If the cannula is occluded, it is inconvenient to juggle pump speed to prevent the line from collapsing while maintaining gentle but adequate suction. In this study we in vitro tested three commercially available LV vent valves (RLV-2100 "B," VRV-200 B, H-130) (GLV did not wish to send samples for comparison at the time of this study). Each valve was designed to: regulate suction in the LV vent line; prevent the flow of air towards the heart; and vent downstream pressure to the atmosphere. Each valve was tested for suction at various flow rates, pressure heads, and for the presence of air leakage during reversed flow conditions. The results of pressure and suction tests during normal flow and occluded line conditions have been tabulated. We found the RLV-2100 "B" offers the safest combination of suction control and pressure relief. The most astonishing fact learned was the RLV-2100 "B" was the only valve which prevented the flow of air towards the heart during reversed flow. As a result, we elected to use only this valve in our clinical practice.

  5. Weight loss and progressive left ventricular remodelling: The Multi-Ethnic Study of Atherosclerosis (MESA)

    PubMed Central

    Shah, Ravi V; Murthy, Venkatesh L; Abbasi, Siddique A; Eng, John; Wu, Colin; Ouyang, Pamela; Kwong, Raymond Y; Goldfine, Allison; Bluemke, David A; Lima, Joao; Jerosch-Herold, Michael

    2016-01-01

    Aims Impact of weight loss on cardiac structure has not been extensively investigated in large, multi-ethnic, community-based populations. We investigated the longitudinal impact of weight loss on cardiac structure by cardiac magnetic resonance (CMR). Methods and results 2351 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent CMR at Exam 1 (2002) and Exam 5 (2011) were included. Primary outcomes were percentage change in LV mass (indexed to height) and LV mass-to-volume ratio (concentric LV remodelling). Multivariable linear regression was used to measure the association between outcomes and weight change. At median 9.4 years' follow-up, 639 individuals (27%) experienced >5% weight loss (median 6.9 kg) and 511 (22%) had >5% weight gain (median 6.4 kg). A >5% weight gain was associated with the greatest increase in LV mass (+5.4% median) and LV mass-to-volume ratio (+12.2% median). Adjusting for medications, hypertension/diabetes (and change in these risk factors), age, race and other risk factors, every 5% weight loss was associated with a 1.3% decrease in height-indexed LV mass and 1.3% decrease in LV mass-to-volume ratio (p <0.0001). There was no effect modification/confounding by age, race, gender or baseline BMI. Change in LV mass-to-volume ratio was roughly linear, specifically for modest degrees of weight loss (−10% to +10%). Change in LV mass was linear with weight loss, suggesting no threshold of weight loss is needed for LV mass regression. Conclusions In a large multi-ethnic population, weight loss is associated with beneficial effects on cardiac structure, independent of age, race, gender, BMI and obesity-related cardiometabolic risk. There is no threshold of weight loss required to produce these effects. PMID:25009171

  6. Multiscale Characterization of Impact of Infarct Size on Myocardial Remodeling in an Ovine Infarct Model

    PubMed Central

    Zhang, Pei; Li, Tielou; Griffith, Bartley P; Wu, Zhongjun J

    2015-01-01

    The surviving myocardium initially compensates the loss of injured myocardium after myocardial infarction (MI) and gradually becomes progressively dysfunctional. There have been limited studies of the influence of infarct size on temporal and spatial alteration of myocardium during progressive myocardial remodeling. MI with three infarct sizes (15%, 25% and 35% of left ventricular wall) was created in an ovine infarction model. The progressive LV remodeling over a 12 week period was studied. Echocardiography, sonomicrometry, histological and molecular analyses were carried out to evaluate cardiac function, regional tissue contractile function and structural remodeling, and regional cardiomycyte hypertrophy and calcium handling proteins. The 15%, 25% and 35% MI groups at 12 weeks after MI had normalized LV end diastole volumes of 1.4±0.2, 1.7±0.3 and 2.0±0.4 mL/Kg, normalized end systole volumes of 1.0±0.1, 1.0±0.2 and 1.3±0.3 mL/Kg and LV ejection fractions of 43%±3%, 42%±6% and 34%±4%, respectively. They all differed from a sham group (p<0.05). All the three MI groups exhibited larger wall areal expansion (remodeling strain), larger cardiomyocyte size and altered expression of calcium handing proteins in the adjacent myocardium compared to the remote counterpart from the infarct. Significant correlation was found between myocardiocyte size and remodeling strain in the adjacent zone. A comparative analysis among the three MI groups showed that a larger infarct size (35% vs. 15% MI) was associated with larger remodeling strain, impairment severity of cellular structure and composition, and regional contractile function at regional tissue level and LV cardiac function at organ level. PMID:26540290

  7. Correcting For Seed-Particle Lag In LV Measurements

    NASA Technical Reports Server (NTRS)

    Jones, Gregory S.; Gartrell, Luther R.; Kamemoto, Derek Y.

    1994-01-01

    Two experiments conducted to evaluate effects of sizes of seed particles on errors in LV measurements of mean flows. Both theoretical and conventional experimental methods used to evaluate errors. First experiment focused on measurement of decelerating stagnation streamline of low-speed flow around circular cylinder with two-dimensional afterbody. Second performed in transonic flow and involved measurement of decelerating stagnation streamline of hemisphere with cylindrical afterbody. Concluded, mean-quantity LV measurements subject to large errors directly attributable to sizes of particles. Predictions of particle-response theory showed good agreement with experimental results, indicating velocity-error-correction technique used in study viable for increasing accuracy of laser velocimetry measurements. Technique simple and useful in any research facility in which flow velocities measured.

  8. Endocardial Remodeling in Heart Failure Patients with Impaired and Preserved Left Ventricular Systolic Function--A Magnetic Resonance Image Study.

    PubMed

    Lin, Lian-Yu; Su, Mao-Yuan M; Pham, Van-Truong; Tran, Thi-Thao; Wang, Yung-Hung; Tseng, Wen-Yih I; Lo, Men-Tzung; Lin, Jiunn-Lee

    2016-01-01

    Left ventricular (LV) trabeculation has been studied in certain forms of cardiomyopathy. However, the changes of LV endocardial trabeculation during the remodeling process leading to heart failure (HF) are unclear. Seventy-four patients with systolic heart failure (SHF), 65 with heart failure with preserved ejection fraction (HFpEF) and 61 without HF were prospectively enrolled. All subjects received magnetic resonance imaging (MRI) study including cine, T1 and late gadolinium enhancement (LGE) images. Trabecular-papillary muscle (TPM) mass, fractal dimension (FD) and extracellular volume (ECV) were derived. The results showed that TPM mass index was higher in patients with SHF than that in patients with HFpEF and non-HF. The TPM mass-LV mass ratio (TPMm/LVM) was higher in SHF group than that in HFpEF and non-HF. FD was not different among groups. The presence of LGE was inversely associated with TPM mass index and TPMm/LVM while the ECV were positively associated with TPMm/LVM. The FD was positively associated with LV chamber size. In conclusion, TPM increases in patients with SHF and are probably related to myocardial cell hypertrophy and fibrotic repair during remodeling. The FD increases with the dilatation of LV chamber but remain unchanged with the deterioration of LV function. PMID:26876005

  9. Endocardial Remodeling in Heart Failure Patients with Impaired and Preserved Left Ventricular Systolic Function-A Magnetic Resonance Image Study

    PubMed Central

    Lin, Lian-Yu; Su, Mao-Yuan M.; Pham, Van-Truong; Tran, Thi-Thao; Wang, Yung-Hung; Tseng, Wen-Yih I.; Lo, Men-Tzung; Lin, Jiunn-Lee

    2016-01-01

    Left ventricular (LV) trabeculation has been studied in certain forms of cardiomyopathy. However, the changes of LV endocardial trabeculation during the remodeling process leading to heart failure (HF) are unclear. Seventy-four patients with systolic heart failure (SHF), 65 with heart failure with preserved ejection fraction (HFpEF) and 61 without HF were prospectively enrolled. All subjects received magnetic resonance imaging (MRI) study including cine, T1 and late gadolinium enhancement (LGE) images. Trabecular-papillary muscle (TPM) mass, fractal dimension (FD) and extracellular volume (ECV) were derived. The results showed that TPM mass index was higher in patients with SHF than that in patients with HFpEF and non-HF. The TPM mass-LV mass ratio (TPMm/LVM) was higher in SHF group than that in HFpEF and non-HF. FD was not different among groups. The presence of LGE was inversely associated with TPM mass index and TPMm/LVM while the ECV were positively associated with TPMm/LVM. The FD was positively associated with LV chamber size. In conclusion, TPM increases in patients with SHF and are probably related to myocardial cell hypertrophy and fibrotic repair during remodeling. The FD increases with the dilatation of LV chamber but remain unchanged with the deterioration of LV function. PMID:26876005

  10. Left ventricular structure and remodeling in patients with COPD

    PubMed Central

    Pelà, Giovanna; Li Calzi, Mauro; Pinelli, Silvana; Andreoli, Roberta; Sverzellati, Nicola; Bertorelli, Giuseppina; Goldoni, Matteo; Chetta, Alfredo

    2016-01-01

    Background Data on cardiac alterations such as left ventricular (LV) hypertrophy, diastolic dysfunction, and lower stroke volume in patients with COPD are discordant. In this study, we investigated whether early structural and functional cardiac changes occur in patients with COPD devoid of manifest cardiovascular disease, and we assessed their associations with clinical and functional features. Methods Forty-nine patients with COPD belonging to all Global Initiative for Chronic Obstructive Lung Disease (GOLD) classes were enrolled and compared with 36 controls. All subjects underwent clinical history assessment, lung function testing, blood pressure measurement, electrocardiography, and conventional and Doppler tissue echocardiography. Patients were also subjected to computed tomography to quantify emphysema score. Results Patients with COPD had lower LV cavity associated with a marked increase in relative wall thickness (RWT), suggesting concentric remodeling without significant changes in LV mass. RWT was significantly associated with ratio of the forced expiratory volume in 1 second to the forced vital capacity and emphysema score and was the only cardiac parameter that – after multivariate analysis – significantly correlated with COPD conditions in all individuals. Receiver operating characteristic curve analysis showed that RWT (with a cutoff point of 0.42) predicted the severity of COPD with 83% specificity and 56% sensitivity (area under the curve =0.69, 95% confidence interval =0.59–0.81). Patients with COPD showed right ventricular to be functional but no structural changes. Conclusion Patients with COPD without evident cardiovascular disease exhibit significant changes in LV geometry, resulting in concentric remodeling. In all individuals, RWT was significantly and independently related to COPD. However, its prognostic role should be determined in future studies. PMID:27257378

  11. Protein remodeling of the heart ventricles in hereditary hypertriglyceridemic rat: effect of ACE-inhibition.

    PubMed

    Simko, Fedor; Pelouch, Václav; Torok, Jozef; Luptak, Ivan; Matuskova, Jana; Pechanova, Olga; Babal, Pavel

    2005-01-01

    The aim of this study was to determine whether protein remodeling of the heart ventricles and remodeling of the aorta were present in hereditary hypertriglyceridemic (hHTG) rats and whether treatment with the angiotensin-converting enzyme inhibitor, captopril could prevent these alterations. Three groups of rats were investigated in a four week experiment control Wistar /C/rats, hHTg rats, hHTg rats given captopril (100 mg/kg/day) (hHTg + CAP). In the hHTg group, the increased systolic blood pressure (SBP) was associated with hypertrophy of the LV and RV. Protein profile analysis revealed an enhancement of metabolic protein concentration in both ventricles. The concentration of total collagenous proteins was not changed in either ventricles. However, alterations in composition of cardiac collagen were detected, characterized by higher concentration of hydroxyproline in pepsin-insoluble fraction and lower concentration of hydroxyproline in pepsin soluble faction in the LV. Hypertrophy of aorta, associated with the reduction of nitric oxide dependent relaxation, was also present in hHTG rats. Captopril normalized SBP, reduced left ventricular hypertrophy (LVH), diminished metabolic protein concentration in both ventricles, and improved NO-dependent relaxation of the aorta. Furthermore, captopril partially reversed alterations in hydroxyproline concentration in soluble and insoluble collagenous fractions of the LV. We conclude that hypertrophy of both ventricles and the aorta are present in hHTG rats, along with protein remodeling of both ventricles. Captopril partially prevented left ventricular hypertrophy development and protein remodeling of the myocardium.

  12. A Targeted Mutation within the Feline Leukemia Virus (FeLV) Envelope Protein Immunosuppressive Domain To Improve a Canarypox Virus-Vectored FeLV Vaccine

    PubMed Central

    Schlecht-Louf, Géraldine; Mangeney, Marianne; El-Garch, Hanane; Lacombe, Valérie; Poulet, Hervé

    2014-01-01

    We previously delineated a highly conserved immunosuppressive (IS) domain within murine and primate retroviral envelope proteins that is critical for virus propagation in vivo. The envelope-mediated immunosuppression was assessed by the ability of the proteins, when expressed by allogeneic tumor cells normally rejected by engrafted mice, to allow these cells to escape, at least transiently, immune rejection. Using this approach, we identified key residues whose mutation (i) specifically abolishes immunosuppressive activity without affecting the “mechanical” function of the envelope protein and (ii) significantly enhances humoral and cellular immune responses elicited against the virus. The objective of this work was to study the immunosuppressive activity of the envelope protein (p15E) of feline leukemia virus (FeLV) and evaluate the effect of its abolition on the efficacy of a vaccine against FeLV. Here we demonstrate that the FeLV envelope protein is immunosuppressive in vivo and that this immunosuppressive activity can be “switched off” by targeted mutation of a specific amino acid. As a result of the introduction of the mutated envelope sequence into a previously well characterized canarypox virus-vectored vaccine (ALVAC-FeLV), the frequency of vaccine-induced FeLV-specific gamma interferon (IFN-γ)-producing cells was increased, whereas conversely, the frequency of vaccine-induced FeLV-specific interleukin-10 (IL-10)-producing cells was reduced. This shift in the IFN-γ/IL-10 response was associated with a higher efficacy of ALVAC-FeLV against FeLV infection. This study demonstrates that FeLV p15E is immunosuppressive in vivo, that the immunosuppressive domain of p15E can modulate the FeLV-specific immune response, and that the efficacy of FeLV vaccines can be enhanced by inhibiting the immunosuppressive activity of the IS domain through an appropriate mutation. PMID:24198407

  13. Role of HIV-2 envelope in Lv2-mediated restriction

    SciTech Connect

    Reuter, Sandra; Kaumanns, Patrick; Buschhorn, Sabine B.; Dittmar, Matthias T. . E-mail: Matthias_Dittmar@med.uni-heidelberg.de

    2005-02-05

    We have characterized envelope protein pseudotyped HIV-2 particles derived from two HIV-2 isolates termed prCBL23 and CBL23 in order to define the role of the envelope protein for the Lv2-mediated restriction to infection. Previously, it has been described that the primary isolate prCBL23 is restricted to infection of several human cell types, whereas the T cell line adapted isolate CBL23 is not restricted in these cell types. Molecular cloning of the two isolates revealed that the env and the gag gene are responsible for the observed phenotype and that this restriction is mediated by Lv2, which is distinct from Ref1/Lv1 (Schmitz, C., Marchant, D., Neil, S.J., Aubin, K., Reuter, S., Dittmar, M.T., McKnight, A., Kizhatil, K., Albritton, L.M., 2004. Lv2, a novel postentry restriction, is mediated by both capsid and envelope. J. Virol. 78 (4), 2006-2016). We generated pseudotyped viruses consisting of HIV-2 (ROD-A{delta}env-GFP, ROD-A{delta}env-RFP, or ROD-A{delta}env-REN) and the prCBL23 or CBL23 envelope proteins as well as chimeric proteins between these envelopes. We demonstrate that a single amino acid exchange at position 74 in the surface unit of CBL23-Env confers restriction to infection. This single point mutation causes tighter CD4 binding, resulting in a less efficient fusion into the cytosol of the restricted cell line. Prevention of endosome formation and prevention of endosome acidification enhance infectivity of the restricted particles for GHOST/X4 cells indicating a degradative lysosomal pathway as a cause for the reduced cytosolic entry. The described restriction to infection of the primary isolate prCBL23 is therefore largely caused by an entry defect. A remaining restriction to infection (19-fold) is preserved when endosomal acidification is prevented. This restriction to infection is also dependent on the presence of the point mutation at position 74 (G74E)

  14. Structural remodeling of the heart and its premotor cardioinhibitory vagal neurons following T5 spinal cord transection

    PubMed Central

    Lujan, Heidi L.; Janbaih, Hussein

    2014-01-01

    Midthoracic spinal cord injury (SCI) is associated with enhanced cardiac sympathetic activity and reduced cardiac parasympathetic activity. The enhanced cardiac sympathetic activity is associated with sympathetic structural plasticity within the stellate ganglia, spinal cord segments T1–T4, and heart. However, changes to cardiac parasympathetic centers rostral to an experimental SCI are relatively unknown. Importantly, reduced vagal activity is a predictor of high mortality. Furthermore, this autonomic dysregulation promotes progressive left ventricular (LV) structural remodeling. Accordingly, we hypothesized that midthoracic spinal cord injury is associated with structural plasticity in premotor (preganglionic parasympathetic neurons) cardioinhibitory vagal neurons located within the nucleus ambiguus as well as LV structural remodeling. To test this hypothesis, dendritic arborization and morphology (cholera toxin B immunohistochemistry and Sholl analysis) of cardiac projecting premotor cardioinhibitory vagal neurons located within the nucleus ambiguus were determined in intact (sham transected) and thoracic level 5 transected (T5X) rats. In addition, LV chamber size, wall thickness, and collagen content (Masson trichrome stain and structural analysis) were determined. Midthoracic SCI was associated with structural changes within the nucleus ambiguus and heart. Specifically, following T5 spinal cord transection, there was a significant increase in cardiac parasympathetic preganglionic neuron dendritic arborization, soma area, maximum dendritic length, and number of intersections/animal. This parasympathetic structural remodeling was associated with a profound LV structural remodeling. Specifically, T5 spinal cord transection increased LV chamber area, reduced LV wall thickness, and increased collagen content. Accordingly, results document a dynamic interaction between the heart and its parasympathetic innervation. PMID:24610530

  15. How molecular methods change our views of FeLV infection and vaccination.

    PubMed

    Hofmann-Lehmann, Regina; Cattori, Valentino; Tandon, Ravi; Boretti, Felicitas S; Meli, Marina L; Riond, Barbara; Lutz, Hans

    2008-05-15

    FeLV was discovered 40 years ago and vaccines have been commercially available for almost two decades. So far, most FeLV pathogenesis and vaccine studies were conducted assaying parameters, such as virus isolation and antigen detection. Accordingly, regressive infection was characterized by transient or undetectable viremia, while persistent viremia is typically observed in cats with progressive infection. Using real-time polymerase chain reaction assays, the spectrum of host response categories to FeLV infection was recently refined by investigating proviral and plasma viral RNA loads. Cats believed to be immune to FeLV infection were found to turn provirus-positive after virus exposure. Moreover, efficacious FeLV vaccines were found unable to prevent provirus-integration and minimal viral replication. Remarkably, no difference was found in initial proviral and plasma viral RNA loads between cats with different infection outcomes. Only subsequently, the infection outcome is associated with FeLV loads. FeLV provirus was found to persist for years; reoccurrence of viremia and disease development was observed in some cats. Thus, aviremic provirus-positive cats are FeLV carriers and, following reactivation, may act as an infection source. However, integrated viral DNA may also be essential for solid protection and long-lasting maintenance of protective immunity. In conclusion, real-time TaqMan PCR and RT-PCR assays are highly sensitive and specific. They yield a more sensitive measure for FeLV exposure than antigen detection, virus isolation or immunofluoresence assays. We recommend the use of real-time PCR assays to identify FeLV exposed cats, particularly in catteries, and investigate obscure clinical cases that may be FeLV-associated. The use of sensitive molecular methods will contribute to a more in-depth understanding of the FeLV pathogenesis.

  16. Diseases associated with spontaneous feline leukemia virus (FeLV) infection in cats.

    PubMed

    Reinacher, M

    1989-05-01

    More than 2000 cats sent for necropsy in order to provide a diagnosis were investigated immunohistologically using paraffin sections for the presence of a persistent infection with feline leukemia virus (FeLV). The spectrum of neoplastic and non-neoplastic diseases associated significantly with FeLV infection was determined statistically. Three-quarters of the cats with persistent FeLV infections died of non-neoplastic diseases and about 23% died of tumors, nearly exclusively those of the leukemia/lymphoma disease complex. A strong association with liver degeneration, icterus and a FeLV-associated enteritis was found in addition to the known association with non-neoplastic diseases and conditions such as anemia, bacterial secondary infections and respiratory tract inflammations due to the immunosuppressive effect of FeLV, hemorrhages and feline infectious peritonitis. Surprisingly, diseases and conditions like feline infectious panleukopenia, enteritis (of other types than FeLV-associated enteritis and feline infectious panleukopenia), glomerulonephritis, uremia and hemorrhagic cystitis were not associated with persistent FeLV infection. Another unexpected finding was that most pathogenic infectious agents demonstrated in the cats were not FeLV-associated either. Thus, immunosuppression due to FeLV infection seems to make the animals susceptible to certain pathogenic infectious agents, but not to the majority. PMID:2549696

  17. Electrical remodeling contributes to complex tachyarrhythmias in connexin43-deficient mouse hearts

    PubMed Central

    Danik, Stephan B.; Rosner, Gregg; Lader, Joshua; Gutstein, David E.; Fishman, Glenn I.; Morley, Gregory E.

    2009-01-01

    Loss of connexin43 (Cx43) gap junction channels in the heart results in a marked increase in the incidence of spontaneous and inducible polymorphic ventricular tachyarrhythmias (PVTs). The mechanisms resulting in this phenotype remain unclear. We hypothesized that uncoupling promotes regional ion channel remodeling, thereby increasing electrical heterogeneity and facilitating the development of PVT. In isolated-perfused control hearts, programmed electrical stimulation elicited infrequent monomorphic ventricular tachyarrhythmias (MVT), and dominant frequencies (DFs) during MVT were similar in the right ventricle (RV) and left ventricle (LV). Moreover, conduction properties, action potential durations (APDs), and repolarizing current densities were similar in RV and LV myocytes. In contrast, PVT was common in Cx43 conditional knockout (OCKO) hearts, and arrhythmias were characterized by significantly higher DFs in the RV compared to the LV. APDs in OCKO myocytes were significantly shorter than those from chamber-matched controls, with RV OCKO myocytes being most affected. APD shortening was associated with higher levels of sustained current in myocytes from both chambers as well as higher levels of the inward rectifier current only in RV myocytes. Thus, alterations in cell-cell coupling lead to regional changes in potassium current expression, which in this case facilitates the development of reentrant arrhythmias. We propose a new mechanistic link between electrical uncoupling and ion channel remodeling. These findings may be relevant not only in cardiac tissue but also to other organ systems where gap junction remodeling is known to occur. PMID:17984180

  18. Electrical remodeling contributes to complex tachyarrhythmias in connexin43-deficient mouse hearts.

    PubMed

    Danik, Stephan B; Rosner, Gregg; Lader, Joshua; Gutstein, David E; Fishman, Glenn I; Morley, Gregory E

    2008-04-01

    Loss of connexin43 (Cx43) gap junction channels in the heart results in a marked increase in the incidence of spontaneous and inducible polymorphic ventricular tachyarrhythmias (PVTs). The mechanisms resulting in this phenotype remain unclear. We hypothesized that uncoupling promotes regional ion channel remodeling, thereby increasing electrical heterogeneity and facilitating the development of PVT. In isolated-perfused control hearts, programmed electrical stimulation elicited infrequent monomorphic ventricular tachyarrhythmias (MVT), and dominant frequencies (DFs) during MVT were similar in the right ventricle (RV) and left ventricle (LV). Moreover, conduction properties, action potential durations (APDs), and repolarizing current densities were similar in RV and LV myocytes. In contrast, PVT was common in Cx43 conditional knockout (OCKO) hearts, and arrhythmias were characterized by significantly higher DFs in the RV compared to the LV. APDs in OCKO myocytes were significantly shorter than those from chamber-matched controls, with RV OCKO myocytes being most affected. APD shortening was associated with higher levels of sustained current in myocytes from both chambers as well as higher levels of the inward rectifier current only in RV myocytes. Thus, alterations in cell-cell coupling lead to regional changes in potassium current expression, which in this case facilitates the development of reentrant arrhythmias. We propose a new mechanistic link between electrical uncoupling and ion channel remodeling. These findings may be relevant not only in cardiac tissue but also to other organ systems where gap junction remodeling is known to occur. PMID:17984180

  19. Epigenetic regulation of aortic remodeling in hyperhomocysteinemia

    PubMed Central

    Narayanan, Nithya; Pushpakumar, Sathnur Basappa; Givvimani, Srikanth; Kundu, Sourav; Metreveli, Naira; James, Dexter; Bratcher, Adrienne P.; Tyagi, Suresh C.

    2014-01-01

    Hyperhomocysteinemia (HHcy) is prevalent in patients with hypertension and is an independent risk factor for aortic pathologies. HHcy is known to cause an imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), leading to the accumulation of collagen in the aorta and resulting in stiffness and development of hypertension. Although the exact mechanism of extracellular matrix (ECM) remodeling is unclear, emerging evidence implicates epigenetic regulation involving DNA methylation. Our purpose was to investigate whether 5-aza-2′-deoxycytidine (Aza), a DNA methyltransferase (DNMT1) inhibitor, reduces high blood pressure (BP) by regulating aortic ECM remodeling in HHcy. Wild-type and cystathionine β-synthase (CBS)+/− HHcy mice were treated with Aza (0.5 mg/kg body weight). In HHcy mice, Aza treatment normalized the plasma homocysteine (Hcy) level and BP. Thoracic and abdominal aorta ultrasound revealed a reduction in the resistive index and wall-to-lumen ratio. Vascular response to phenylephrine, acetylcholine, and sodium nitroprusside improved after Aza in HHcy mice. Histology showed a marked reduction in collagen deposition in the aorta. Aza treatment decreased the expression of DNMT1, MMP9, TIMP1, and S-adenosyl homocysteine hydrolase (SAHH) and upregulated methylene tetrahydrofolate reductase (MTHFR). We conclude that reduction of DNA methylation by Aza in HHcy reduces adverse aortic remodeling to mitigate hypertension.—Narayanan, N., Pushpakumar, S. B., Givvimani, S., Kundu, S., Metreveli, N., James, D., Bratcher, A. P., Tyagi, S. C. Epigenetic regulation of aortic remodeling in hyperhomocysteinemia. PMID:24739303

  20. Assessment of the LV-S2 & LV-S3 Stack Sampling Probe Locations for Compliance with ANSI/HPS N13.1-1999

    SciTech Connect

    Glissmeyer, John A.; Antonio, Ernest J.; Flaherty, Julia E.; Amidan, Brett G.

    2014-09-30

    This document reports on a series of tests conducted to assess the proposed air sampling locations for the Hanford Tank Waste Treatment and Immobilization Plant (WTP) Group 1-2A exhaust stacks with respect to the applicable criteria regarding the placement of an air sampling probe. The LV-C2, LV-S2, and LV-S3 exhaust stacks were tested together as a group (Test Group 1-2A). This report only covers the results of LV-S2 and LV-S3; LV-C2 will be reported on separately. Federal regulations1 require that a sampling probe be located in the exhaust stack according to the criteria established by the American National Standards Institute/Health Physics Society (ANSI/HPS) N13.1-1999, Sampling and Monitoring Releases of Airborne Radioactive Substances from the Stack and Ducts of Nuclear Facilities. 2 These criteria address the capability of the sampling probe to extract a sample that represents the effluent stream.

  1. Surgical ventricular reconstruction has a role in surgical remodeling in patients with LV systolic dysfunction even post-STICH?

    PubMed

    Balsam, Leora B; Grossi, Eugene A

    2013-01-01

    The Hypothesis 2 arm of the STICH trial compared outcomes in ischemic cardiomyopathy patients undergoing CABG plus SVR vs. CABG alone. Although the trial results suggest equivalency of these therapies, important trial flaws have been identified which cast critical doubt regarding the generalizability of the trial findings.

  2. Impact of Valvuloarterial Impedance on Concentric Remodeling in Aortic Stenosis and Its Regression after Valve Replacement

    PubMed Central

    Jang, Jeong Yoon; Seo, Jeong-Sook; Sun, Byung Joo; Kim, Dae-Hee; Song, Jong-Min; Kang, Duk-Hyun

    2016-01-01

    Background Left ventricle (LV) in patients with aortic stenosis (AS) faces a double hemodynamic load incorporating both valvular stenosis and reduced systemic arterial compliance (SAC). This study aimed to evaluate the impact of global LV afterload on LV hypertrophy (LVH) before and after aortic valve replacement (AVR). Methods The study cohort included 453 patients (247 males; mean age, 64 ± 11 years) who underwent AVR. Pre- and post-AVR echocardiographic examinations were retrospectively analyzed including an index of valvuloarterial impedance (ZVA) and LV mass index/LV end-diastolic volume index (LVMI/LVEDVI) as a parameter of LVH. Results Pre-AVR LVMI/LVEDVI was 2.7 ± 0.9 g/mL with an aortic valve area (AVA) of 0.6 ± 0.2 cm2. ZVA was 5.9 ± 1.9 mm Hg/mL/m2 and showed a stronger correlation (β = 0.601, p < 0.001) with pre-AVR LVMI/LVEDVI than indexed AVA (β = 0.061, p = 0.19), transvalvular peak velocity (β = 0.211, p < 0.001). During a median follow-up of 3.5 years, patients had a 18.8 ± 10.4% decrease in the LV geometry index with a decrease in SAC from 1.20 ± 0.48 to 1.00 ± 0.38 mL/m2/mm Hg (p < 0.001). Pre-AVR LV ejection fraction (r = 0.284, p < 0.001) and ZVA (r = 0.523, p < 0.001) were independent factors associated with LVH regression in 322 patients with follow-up duration >1 year after AVR. Conclusion ZVA is a major determinant of concentric remodeling in AS before AVR and LVH regression after AVR, which should be incorporated in routine evaluation of AS. PMID:27721950

  3. Mechanoelectrical remodeling and arrhythmias during progression of hypertrophy

    PubMed Central

    Jin, Hongwei; Chemaly, Elie R.; Lee, Ahyoung; Kho, Changwon; Hadri, Lahouaria; Hajjar, Roger J.; Akar, Fadi G.

    2010-01-01

    Despite a clear association between left ventricular (LV) mechanical dysfunction in end-stage heart failure and the incidence of arrhythmias, the majority of sudden cardiac deaths occur at earlier stages of disease development. The mechanisms by which structural, mechanical, and molecular alterations predispose to arrhythmias at the tissue level before the onset of LV dysfunction remain unclear. In a rat model of pressure overload hypertrophy (PoH) produced by ascending aortic banding, we correlated mechanical and structural changes measured in vivo with key electrophysiological changes measured ex vivo in the same animals. We found that action potential prolongation, a hallmark of electrical remodeling at the tissue level, is highly correlated with changes in LV wall thickness but not mechanical function. In contrast, conduction delays are not predicted by either mechanical or structural changes during disease development. Moreover, disrupted Cx43 phosphorylation at intermediate (increased) and late (decreased) stages of PoH are associated with moderate and severe conduction delays, respectively. Interestingly, the level of interaction between Cx43 and the cytoskeletal protein ZO-1 is exclusively decreased at the late stage of PoH. Closely coupled action potentials consistent with afterdepolarization-mediated triggered beats were readily observed in 6 of 15 PoH hearts but never in controls. Similarly, PoH (8/15) but not control hearts exhibited sustained episodes of ventricular tachycardia after rapid stimulation. The initiation and early maintenance of arrhythmias in PoH were formed by rapid and highly uniform activation wavefronts emanating from sites distal to the former site of stimulation. In conclusion, repolarization but not conduction delays are predicted by structural remodeling in PoH. Cx43 phosphorylation is disrupted at intermediate (increased) and late (decreased) stages, which are associated with conduction delays. Dephosphorylation of Cx43 is

  4. SERIAL ULTRASOUND EVALUATION OF INTRAMYOCARDIAL STRAIN AFTER REPERFUSED MYOCARDIAL INFARCTION REVEALS THAT REMOTE ZONE DYSSYNCHRONY DEVELOPS IN CONCERT WITH LEFT VENTRICULAR REMODELING

    PubMed Central

    Li, Yinbo; Garson, Christopher D.; Xu, Yaqin; Helm, Patrick A.; Hossack, John A.; French, Brent A.

    2011-01-01

    This study noninvasively evaluated the development of left ventricular (LV) dyssynchrony following reperfused myocardial infarction (MI) in mice using an ultrasonic speckle-tracking method. Eight C57BL/6J mice were assessed by high-resolution echocardiography at baseline and at eight time-points following MI. Images were acquired at 1mm elevational intervals encompassing the entire LV to determine chamber volumes and radial strain. Receiver-operating characteristic (ROC) analysis of regional radial strain was used to segment the three-dimensional (3-D) LV into infarct, adjacent and remote zones. This in vivo segmentation was correlated to histologic infarct size (R = 0.89, p < 0.01) in a short-axis, slice-by-slice comparison. The onset of dyssynchrony during LV remodeling was assessed by standard deviation of time to peak radial strain in the infarct, adjacent and remote zones. It was discovered that the form of LV dyssynchrony that develops in the remote zone late after MI does so in concert with the progression of LV remodeling (R = 0.70, p < 0.05). PMID:21640480

  5. 77 FR 21620 - Notice of the Buy America Waiver Request for Vossloh 101-LV Concrete Ties

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-10

    ... Register published on April 11, 2000 (65 FR 19477), or you may visit http://www.dot.gov/privacy.html... Federal Railroad Administration Notice of the Buy America Waiver Request for Vossloh 101-LV Concrete Ties... requirements for the purchase of Vossloh 101-LV concrete ties, which contain certain components...

  6. Recombinant Expression and Characterization of α-Conotoxin LvIA in Escherichia coli

    PubMed Central

    Zhu, Xiaopeng; Bi, Jianpeng; Yu, Jinpeng; Li, Xiaodan; Zhang, Yaning; Zhangsun, Dongting; Luo, Sulan

    2016-01-01

    α-Conotoxin LvIA is derived from Conus lividus, native to Hainan, and is the most selective inhibitor of α3β2 nicotinic acetylcholine receptors (nAChRs) known to date. In this study, an efficient approach for the production of recombinant α-Conotoxin LvIA is described. Tandem repeats of a LvIA gene fragment were constructed and fused with a KSI gene and a His6 tag in a Escherichia coli (E. coli) expression vector pET-31b(+). The recombinant plasmids were transformed into E. coli and were found to express well. The KSI-(LvIA)n-His6 fusion protein was purified by metal affinity chromatography and then cleaved with CNBr to release recombinant LvIA (rLvIA). High yields of fusion protein ranging from 100 to 500 mg/L culture were obtained. The pharmacological profile of rLvIA was determined by two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes expressing rat nAChR subtypes. The rLvIA antagonized the α3β2 nAChR subtype selectively with a nano-molar IC50. The rLvIA was analgesic in a mouse hot-plate test model of pain. Overall, this study provides an effective method to synthesize α-conotoxin LvIA in an E. coli recombinant expression system, and this approach could be useful to obtain active conopeptides in large quantity and at low cost. PMID:26742048

  7. Relation of reduced preclinical left ventricular diastolic function and cardiac remodeling in overweight youth to insulin resistance and inflammation.

    PubMed

    Dahiya, Rachana; Shultz, Sarah P; Dahiya, Arun; Fu, Jinlin; Flatley, Christopher; Duncan, Danusia; Cardinal, John; Kostner, Karam M; Byrne, Nuala M; Hills, Andrew P; Harris, Mark; Conwell, Louise S; Leong, Gary M

    2015-05-01

    Insulin resistance (IR) and inflammation are associated with an increased risk of cardiovascular disease and may contribute to obesity cardiomyopathy. The earliest sign of obesity cardiomyopathy is impaired left ventricular (LV) diastolic function, which may be evident in obese children and adolescents. However, the precise metabolic basis of the impaired LV diastolic function remains unknown. The aims of this study were to evaluate cardiac structure and LV diastolic function by tissue Doppler imaging in overweight and obese (OW) youth and to assess the relative individual contributions of adiposity, IR, and inflammation to alterations in cardiac structure and function. We studied 35 OW (body mass index standard deviation score 2.0±0.8; non-IR n=19, IR n=16) and 34 non-OW youth (body mass index standard deviation score 0.1±0.7). LV diastolic function was reduced in OW youth compared with non-OW controls, as indicated by lower peak myocardial relaxation velocities (p<0.001) and greater filling pressures (p<0.001). OW youth also had greater LV mass index (p<0.001), left atrial volume index, and LV interventricular septal thickness (LV-IVS; both p=0.02). IR-OW youth had the highest LV filling pressures, LV-IVS, and relative wall thickness (all p<0.05). Homeostasis model of assessment-insulin resistance and C-reactive protein were negative determinants of peak myocardial relaxation velocity and positive predictors of filling pressure. Adiponectin was a negative determinant of LV-IVS, independent of obesity. In conclusion, OW youth with IR and inflammation are more likely to have adverse changes to cardiovascular structure and function which may predispose to premature cardiovascular disease in adulthood.

  8. Assessment of Left Ventricular Structural Remodelling in Patients with Diabetic Cardiomyopathy by Cardiovascular Magnetic Resonance.

    PubMed

    Shang, Yongning; Zhang, Xiaochun; Chen, Liu; Leng, Weiling; Lei, Xiaotian; Yang, Qi; Liang, Ziwen; Wang, Jian

    2016-01-01

    Background. Diabetic cardiomyopathy (DCM) is always accompanied with alteration of left ventricular structure and function. The aims of this study were to assess the structural remodelling in patients with DCM by cardiovascular magnetic resonance (CMR) and correlation of structural remodelling with severity of DCM. Methods. Twenty-five patients (53.8 ± 8.8 years, 52.0% males) with DCM and thirty-one normal healthy controls (51.9 ± 13.6 years, 45.2% males) were scanned by CMR cine to assess function and structure of left ventricular. Length of diabetic history and results of cardiac echocardiography (E', A', and E'/A') were also measured. Results. Compared with normal controls group, DCM group was associated with significantly increased ratio of left ventricular mass at end diastole to end-diastolic volume (MVR) (P < 0.05) and no significant difference was in mass at end diastole (P > 0.05). The ratio correlated with both length of diabetic history and echocardiographic Doppler tissue imaging E' (all P < 0.05). Conclusions. CMR can be a powerful technique to assess LV remodelling, and MVR may be considered as an imaging marker to evaluate the severity of LV remodelling in patients with DCM. PMID:27419144

  9. Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart.

    PubMed

    Matsushima, Shouji; Kinugawa, Shintaro; Ide, Tomomi; Matsusaka, Hidenori; Inoue, Naoki; Ohta, Yukihiro; Yokota, Takashi; Sunagawa, Kenji; Tsutsui, Hiroyuki

    2006-11-01

    Oxidative stress plays an important role in the structural and functional abnormalities of diabetic heart. Glutathione peroxidase (GSHPx) is a critical antioxidant enzyme that removes H(2)O(2) in both the cytosol and mitochondia. We hypothesized that the overexpression of GSHPx gene could attenuate left ventricular (LV) remodeling in diabetes mellitus (DM). We induced DM by injection of streptozotocin (160 mg/kg ip) in male GSHPx transgenic mice (TG+DM) and nontransgenic wildtype littermates (WT+DM). GSHPx activity was higher in the hearts of TG mice compared with WT mice, with no significant changes in other antioxidant enzymes. LV thiobarbituric acid-reactive substances measured in TG+DM at 8 wk were significantly lower than those in WT+DM (58 +/- 3 vs. 71 +/- 5 nmol/g, P < 0.05). Heart rate and aortic blood pressure were comparable between groups. Systolic function was preserved normal in WT+DM and TG+DM mice. In contrast, diastolic function was impaired in WT+DM and was improved in TG+DM as assessed by the deceleration time of peak velocity of transmitral diastolic flow and the time needed for relaxation of 50% maximal LV pressure to baseline value (tau; 13.5 +/- 1.2 vs. 8.9 +/- 0.7 ms, P < 0.01). The TG+DM values were comparable with those of WT+Control (tau; 7.8 +/- 0.2 ms). Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis, and apoptosis. Overexpression of GSHPx gene ameliorated LV remodeling and diastolic dysfunction in DM. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac abnormalities in DM. PMID:16844917

  10. Comparative Efficacy of Feline Leukemia Virus (FeLV) Inactivated Whole-Virus Vaccine and Canarypox Virus-Vectored Vaccine during Virulent FeLV Challenge and Immunosuppression

    PubMed Central

    Patel, M.; Carritt, K.; Lane, J.; Jayappa, H.; Stahl, M.

    2015-01-01

    Four vaccines for feline leukemia virus (FeLV) are available in the United States. This study's purpose was to compare the efficacy of Nobivac feline 2-FeLV (an inactivated, adjuvanted whole-virus vaccine) and PureVax recombinant FeLV (a live, canarypox virus-vectored vaccine) following FeLV challenge. Cats were vaccinated at 9 and 12 weeks with Nobivac feline 2-FeLV (group A, n = 11) or PureVax recombinant FeLV (group B, n = 10). Group C (n = 11) comprised unvaccinated controls. At 3 months postvaccination, cats were immunosuppressed and challenged with FeLV-A/61E. The outcomes measured were persistent antigenemia at 12 weeks postchallenge (PC) and proviral DNA and viral RNA at 3 to 9 weeks PC. Persistent antigenemia was observed in 0 of 11 cats in group A, 5 of 10 cats in group B, and 10 of 11 cats in group C. Group A was significantly protected compared to those in groups B (P < 0.013) and C (P < 0.0001). No difference was found between groups B and C (P > 0.063). The preventable fraction was 100% for group A and 45% for group B. At 9 weeks PC, proviral DNA and viral RNA were detected 1 of 11 cats in group A, 6 of 10 cats in group B, and 9 of 11 cats in group C. Nucleic acid loads were significantly lower in group A than in group C (P < 0.01). Group A had significantly lower proviral DNA loads than group B at weeks 6 to 9 (P < 0.02). The viral RNA loads were significantly lower in group A than in group B at weeks 7 to 9 (P < 0.01). The results demonstrate that Nobivac feline 2-FeLV-vaccinated cats were fully protected against persistent antigenemia and had significantly smaller amounts of proviral DNA and plasma viral RNA loads than PureVax recombinant FeLV-vaccinated cats and unvaccinated controls. PMID:25972402

  11. Intravenous myocardial contrast echocardiography predicts regional and global left ventricular remodelling after acute myocardial infarction: comparison with low dose dobutamine stress echocardiography

    PubMed Central

    Abe, Y; Muro, T; Sakanoue, Y; Komatsu, R; Otsuka, M; Naruko, T; Itoh, A; Yoshiyama, M; Haze, K; Yoshikawa, J

    2005-01-01

    Objective: To assess the role of intravenous myocardial contrast echocardiography (MCE) in predicting functional recovery and regional or global left ventricular (LV) remodelling after acute myocardial infarction (AMI) compared with low dose dobutamine stress echocardiography (LDSE). Methods: 21 patients with anterior AMI and successful primary angioplasty underwent MCE and LDSE during the subacute stage (2–4 weeks after AMI). Myocardial perfusion and contractile reserve were assessed in each segment (12 segment model) with MCE and LDSE. The 118 dyssynergic segments in the subacute stage were classified as recovered, unchanged, or remodelled according to wall motion at six months’ follow up. Percentage increase in LV end diastolic volume (%ΔEDV) was also calculated. Results: The presence of perfusion was less accurate than the presence of contractile reserve in predicting regional recovery (55% v 81%, p < 0.0001). However, the absence of perfusion was more accurate than the absence of contractile reserve in predicting regional remodelling (83% v 48%, p < 0.0001). The number of segments without perfusion was an independent predictor of %ΔEDV, whereas the number of segments without contractile reserve was not. The area under the receiver operating characteristic curve showed that the number of segments without perfusion predicted substantial LV dilatation (%ΔEDV > 20%) more accurately than did the number of segments without contractile reserve (0.88 v 0.72). Conclusion: In successfully revascularised patients with AMI, myocardial perfusion assessed by MCE is predictive of regional and global LV remodelling rather than of functional recovery, whereas contractile reserve assessed by LDSE is predictive of functional recovery rather than of LV remodelling. PMID:15797931

  12. Nucleosome Remodeling and Epigenetics

    PubMed Central

    Becker, Peter B.; Workman, Jerry L.

    2013-01-01

    Eukaryotic chromatin is kept flexible and dynamic to respond to environmental, metabolic, and developmental cues through the action of a family of so-called “nucleosome remodeling” ATPases. Consistent with their helicase ancestry, these enzymes experience conformation changes as they bind and hydrolyze ATP. At the same time they interact with DNA and histones, which alters histone–DNA interactions in target nucleosomes. Their action may lead to complete or partial disassembly of nucleosomes, the exchange of histones for variants, the assembly of nucleosomes, or the movement of histone octamers on DNA. “Remodeling” may render DNA sequences accessible to interacting proteins or, conversely, promote packing into tightly folded structures. Remodeling processes participate in every aspect of genome function. Remodeling activities are commonly integrated with other mechanisms such as histone modifications or RNA metabolism to assemble stable, epigenetic states. PMID:24003213

  13. Altered Diastolic Flow Patterns and Kinetic Energy in Subtle Left Ventricular Remodeling and Dysfunction Detected by 4D Flow MRI

    PubMed Central

    Fredriksson, Alexandru; Eriksson, Jonatan; Dyverfeldt, Petter; Ebbers, Tino; Bolger, Ann F.; Engvall, Jan; Carlhäll, Carl-Johan

    2016-01-01

    Aims 4D flow magnetic resonance imaging (MRI) allows quantitative assessment of left ventricular (LV) function according to characteristics of the dynamic flow in the chamber. Marked abnormalities in flow components’ volume and kinetic energy (KE) have previously been demonstrated in moderately dilated and depressed LV’s compared to healthy subjects. We hypothesized that these 4D flow-based measures would detect even subtle LV dysfunction and remodeling. Methods and Results We acquired 4D flow and morphological MRI data from 26 patients with chronic ischemic heart disease with New York Heart Association (NYHA) class I and II and with no to mild LV systolic dysfunction and remodeling, and from 10 healthy controls. A previously validated method was used to separate the LV end-diastolic volume (LVEDV) into functional components: direct flow, which passes directly to ejection, and non-ejecting flow, which remains in the LV for at least 1 cycle. The direct flow and non-ejecting flow proportions of end-diastolic volume and KE were assessed. The proportions of direct flow volume and KE fell with increasing LVEDV-index (LVEDVI) and LVESV-index (LVESVI) (direct flow volume r = -0.64 and r = -0.74, both P<0.001; direct flow KE r = -0.48, P = 0.013, and r = -0.56, P = 0.003). The proportions of non-ejecting flow volume and KE rose with increasing LVEDVI and LVESVI (non-ejecting flow volume: r = 0.67 and r = 0.76, both P<0.001; non-ejecting flow KE: r = 0.53, P = 0.005 and r = 0.52, P = 0.006). The proportion of direct flow volume correlated moderately to LVEF (r = 0.68, P < 0.001) and was higher in a sub-group of patients with LVEDVI >74 ml/m2 compared to patients with LVEDVI <74 ml/m2 and controls (both P<0.05). Conclusion Direct flow volume and KE proportions diminish with increased LV volumes, while non-ejecting flow proportions increase. A decrease in direct flow volume and KE at end-diastole proposes that alterations in these novel 4D flow-specific markers may detect

  14. Remodeling and Shuttling

    PubMed Central

    Rodrigueza, Wendi V.; Williams, Kevin Jon; Rothblat, George H.; Phillips, Michael C.

    2016-01-01

    In normal physiology, cells are exposed to cholesterol acceptors of different sizes simultaneously. The current study examined the possible interactions between two different classes of acceptors, one large (large unilamellar phospholipid vesicles, LUVs) and one small (HDL or other small acceptors), added separately or in combination to Fu5AH rat hepatoma cells. During a 24-hour incubation, LUVs of palmitoyl-oleoyl phosphatidylcholine at 1 mg phospholipid (PL) per milliliter extracted ≈20% of cellular unesterified cholesterol (UC) label and mass in a slow, continuous fashion (half-time [t½] for UC efflux was ≈50 hours) and human HDL3 at 25 μg PL per milliliter extracted ≈15% cellular UC label with no change in cellular cholesterol mass (t½ of ≈8 hours). In contrast, the combination of LUVs and HDL3 extracted over 90% of UC label (t½ of ≈4 hours) and ≈50% of the UC mass, indicating synergy. To explain this synergy, specific particle interactions were examined, namely, remodeling, in which the two acceptors alter each other’s composition and thus the ability to mobilize cellular cholesterol, and shuttling, in which the small acceptor ferries cholesterol from cells to the large acceptor. To examine remodeling, LUVs and HDL were coincubated and reisolated before application to cells. This HDL became UC depleted, PL enriched, and lost a small amount of apolipoprotein A-I. Compared with equivalent numbers of control HDL particles, remodeled HDL caused faster efflux (t½ ≈4 hours) and exhibited a greater capacity to sequester cellular cholesterol over 24 hours (≈38% versus ≈15% for control HDL), consistent with their enrichment in PL. Remodeled LUVs still extracted ≈20% of cellular UC. Thus, remodeling accounted for some but not all of the synergy between LUVs and HDL. To examine shuttling, several approaches were used. First, reisolation of particles after an 8-hour exposure to cells revealed that HDL contained very little of the cellular UC

  15. FGF23 Modifies the Relationship between Vitamin D and Cardiac Remodeling

    PubMed Central

    Ky, Bonnie; Shults, Justine; Keane, Martin G.; St. John Sutton, Martin; Wolf, Myles; Feldman, Harold; Reese, Peter; Anderson, Cheryl; Townsend, Raymond; Deo, Rajat; Lo, Joan; Gadegbeku, Crystal; Carlow, Dean; Sulik, Michael J.; Leonard, Mary B.

    2013-01-01

    Background There is growing evidence to support an important role for vitamin D and related hormones PTH and FGF23 on cardiac remodeling in chronic kidney disease (CKD). Our objective was to determine the relationships between vitamin D and cardiac remodeling in CKD and the effects of PTH and FGF23 on these associations. Methods and Results In 1,431 participants from the Chronic Renal Insufficiency Cohort (CRIC) study, we measured 25(OH)D, 1,25(OH)2D, FGF23, and PTH, and performed quantitative echocardiography. Using linear regression methods, we determined significant negative interactions between 25(OH)D and FGF23 on LV mass (p=0.016); end-diastolic ([EDV], p=0.029); and end-systolic volumes ([ESV], p=0.021). In participants with an FGF23 level >the median of 123.5 RU/ml, each doubling of 25(OH)D was associated with a 2.5% (95%CI −4.8,−0.2) lower LV mass. This association was less pronounced with FGF23 levels LV mass compared to only a 1.6% (95%CI −0.2,3.5) difference in participants with sufficient 25(OH)D. Similar findings were observed with 25(OH)D and volumes (p<0.05), and 1,25(OH)2D and LV mass and volumes (p<0.005). There was no effect modification by PTH. Conclusions We identified significant interactions between 25(OH)D, 1,25(OH)2D, and FGF23 on cardiac remodeling. Increased LV mass and cavity dilatation were observed with low 25(OH)D and high FGF23. Our findings suggest that consideration of both hormones is crucial to understanding the role of either in cardiac remodeling, and may have important therapeutic implications. PMID:23748358

  16. [Complete response to CPT-11 and UFT/LV combination therapy in a case with simultaneous multiple lung metastases from colon cancer].

    PubMed

    Ishida, Hideyuki; Akita, Hirofumi; Watanabe, Yasunori; Nakaguchi, Kazunori; Kabuto, Toshiyuki

    2006-06-01

    We report the complete response for one year of a patient with simultaneous multiple lung metastases from colon cancer who was treated using a combination of irinotecan (CPT-11) and uracil/tegafur (UFT)/Leucovorin (LV) using a schedule reported overseas. A 61-year-old woman was admitted to our hospital and diagnosed with ascending colon cancer and simultaneous multiple lung metastases. The patient underwent a right hemicolectomy and was treated with CPT-11 (150 mg/m(2)) on day 1 and oral UFT and oral LV on days 1-14. This treatment cycle was repeated every 3 weeks. A CT examination after 4 cycles of chemotherapy revealed a partial response of multiple lung metastases, and the next examination after 6 cycles revealed a complete response. The adverse effects observed during this chemotherapy regimen were leucopenia (grade 1), neutropenia (grade 2), vomiting (grade 2) and hair loss (grade 1). The patient is now receiving her 22nd cycle of chemotherapy, and her multiple metastases have shown a complete response for one year. The CPT-11 and UFT/LV combination therapy was well tolerated and was covered by the national health insurance system in Japan. This treatment may enable prolonged survival and improve quality of life in patients with metastatic colorectal cancer.

  17. MRI evaluation of injectable hyaluronic acid-based hydrogel therapy to limit ventricular remodeling after myocardial infarction.

    PubMed

    Dorsey, Shauna M; McGarvey, Jeremy R; Wang, Hua; Nikou, Amir; Arama, Leron; Koomalsingh, Kevin J; Kondo, Norihiro; Gorman, Joseph H; Pilla, James J; Gorman, Robert C; Wenk, Jonathan F; Burdick, Jason A

    2015-11-01

    Injectable biomaterials are an attractive therapy to attenuate left ventricular (LV) remodeling after myocardial infarction (MI). Although studies have shown that injectable hydrogels improve cardiac structure and function in vivo, temporal changes in infarct material properties after treatment have not been assessed. Emerging imaging and modeling techniques now allow for serial, non-invasive estimation of infarct material properties. Specifically, cine magnetic resonance imaging (MRI) assesses global LV structure and function, late-gadolinium enhancement (LGE) MRI enables visualization of infarcted tissue to quantify infarct expansion, and spatial modulation of magnetization (SPAMM) tagging provides passive wall motion assessment as a measure of tissue strain, which can all be used to evaluate infarct properties when combined with finite element (FE) models. In this work, we investigated the temporal effects of degradable hyaluronic acid (HA) hydrogels on global LV remodeling, infarct thinning and expansion, and infarct stiffness in a porcine infarct model for 12 weeks post-MI using MRI and FE modeling. Hydrogel treatment led to decreased LV volumes, improved ejection fraction, and increased wall thickness when compared to controls. FE model simulations demonstrated that hydrogel therapy increased infarct stiffness for 12 weeks post-MI. Thus, evaluation of myocardial tissue properties through MRI and FE modeling provides insight into the influence of injectable hydrogel therapies on myocardial structure and function post-MI.

  18. Salvianolic acid B functioned as a competitive inhibitor of matrix metalloproteinase-9 and efficiently prevented cardiac remodeling

    PubMed Central

    2010-01-01

    Background Infarct-induced left ventricular (LV) remodeling is a deleterious consequence after acute myocardial infarction (MI) which may further advance to congestive heart failure. Therefore, new therapeutic strategies to attenuate the effects of LV remodeling are urgently needed. Salvianolic acid B (SalB) from Salviae mitiorrhizae, which has been widely used in China for the treatment of cardiovascular diseases, is a potential candidate for therapeutic intervention of LV remodeling targeting matrix metalloproteinase-9 (MMP-9). Results Molecular modeling and LIGPLOT analysis revealed in silico docking of SalB at the catalytic site of MMP-9. Following this lead, we expressed truncated MMP-9 which contains only the catalytic domain, and used this active protein for in-gel gelatin zymography, enzymatic analysis, and SalB binding by Biacore. Data generated from these assays indicated that SalB functioned as a competitive inhibitor of MMP-9. In our rat model for cardiac remodeling, western blot, echocardiography, hemodynamic measurement and histopathological detection were used to detect the effects and mechanism of SalB on cardio-protection. Our results showed that in MI rat, SalB selectively inhibited MMP-9 activities without affecting MMP-9 expression while no effect of SalB was seen on MMP-2. Moreover, SalB treatment in MI rat could efficiently increase left ventricle wall thickness, improve heart contractility, and decrease heart fibrosis. Conclusions As a competitive inhibitor of MMP-9, SalB presents significant effects on preventing LV structural damage and preserving cardiac function. Further studies to develop SalB and its analogues for their potential for cardioprotection in clinic are warranted. PMID:20735854

  19. Left ventricular epicardial admittance measurement for detection of acute LV dilation

    PubMed Central

    Porterfield, John E.; Larson, Erik R.; Jenkins, James T.; Escobedo, Daniel; Valvano, Jonathan W.; Pearce, John A.

    2011-01-01

    There are two implanted heart failure warning systems incorporated into biventricular pacemakers/automatic implantable cardiac defibrillators and tested in clinical trials: right heart pressures, and lung conductance measurements. However, both warning systems postdate measures of the earliest indicator of impending heart failure: left ventricular (LV) volume. There are currently no proposed implanted technologies that can perform LV blood volume measurements in humans. We propose to solve this problem by incorporating an admittance measurement system onto currently deployed biventricular and automatic implantable cardiac defibrillator leads. This study will demonstrate that an admittance measurement system can detect LV blood conductance from the epicardial position, despite the current generating and sensing electrodes being in constant motion with the heart, and with dynamic removal of the myocardial component of the returning voltage signal. Specifically, in 11 pigs, it will be demonstrated that 1) a physiological LV blood conductance signal can be derived; 2) LV dilation in response to dose-response intravenous neosynephrine can be detected by blood conductance in a similar fashion to the standard of endocardial crystals when admittance is used, but not when only traditional conductance is used; 3) the physiological impact of acute left anterior descending coronary artery occlusion and resultant LV dilation can be detected by blood conductance, before the anticipated secondary rise in right ventricular systolic pressure; and 4) a pleural effusion simulated by placing saline outside the pericardium does not serve as a source of artifact for blood conductance measurements. PMID:21148342

  20. Adapting extracellular matrix proteomics for clinical studies on cardiac remodeling post-myocardial infarction.

    PubMed

    Lindsey, Merry L; Hall, Michael E; Harmancey, Romain; Ma, Yonggang

    2016-01-01

    Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of cardiac wound healing responses that involve stimulation of robust inflammation to clear necrotic myocytes and tissue debris and induction of extracellular matrix (ECM) protein synthesis to generate a scar. Proteomic strategies provide us with a means to index the ECM proteins expressed in the LV, quantify amounts, determine functions, and explore interactions. This review will focus on the efforts taken in the proteomics research field that have expanded our understanding of post-MI LV remodeling, concentrating on the strengths and limitations of different proteomic approaches to glean information that is specific to ECM turnover in the post-MI setting. We will discuss how recent advances in sample preparation and labeling protocols increase our successes at detecting components of the cardiac ECM proteome. We will summarize how proteomic approaches, focusing on the ECM compartment, have progressed over time to current gel-free methods using decellularized fractions or labeling strategies that will be useful for clinical applications. This review will provide an overview of how cardiac ECM proteomics has evolved over the last decade and will provide insight into future directions that will drive forward our understanding of cardiac ECM turnover in the post-MI LV. PMID:27651752

  1. Remodeling with the sun

    SciTech Connect

    Bodzin, S.

    1997-05-01

    Remodeling is the perfect time to improve daylighting, direct gain heating and shading with passive solar techniques. It can also provide the best opportunity to add solar water heating or even photoboltaics to a home. This article describes addition of such energy efficient plans to a home in terms of what is needed and what the benefits are: adding windows, North glass, east and west glass, south glass, daylighting, the roof, shingles and roofing tiles, walls and floors, solar hot water, photovoltaics. Two side bars discuss the sunplace: a passive solar room and angles and overhangs.

  2. Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy.

    PubMed

    Koshman, Yevgeniya E; Sternlicht, Mark D; Kim, Taehoon; O'Hara, Christopher P; Koczor, Christopher A; Lewis, William; Seeley, Todd W; Lipson, Kenneth E; Samarel, Allen M

    2015-12-01

    Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective tissue growth factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. Our aim was to test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase Cε (PKCε) mouse model of DCM. Transgenic mice expressing constitutively active PKCε in cardiomyocytes develop cardiac dysfunction that was evident by 3 months of age, and that progressed to cardiac fibrosis, heart failure, and increased mortality. Beginning at 3 months of age, PKCε mice were treated with a neutralizing monoclonal antibody to CTGF (FG-3149) for an additional 3 months. CTGF inhibition significantly improved left ventricular (LV) systolic and diastolic functions in PKCε mice, and slowed the progression of LV dilatation. Using gene arrays and quantitative PCR, the expression of many genes associated with tissue remodeling was elevated in PKCε mice, but significantly decreased by CTGF inhibition. However total collagen deposition was not attenuated. The observation of significantly improved LV function by CTGF inhibition in PKCε mice suggests that CTGF inhibition may benefit patients with DCM. Additional studies to explore this potential are warranted.

  3. A novel cardiac muscle-derived biomaterial reduces dyskinesia and postinfarct left ventricular remodeling in a mouse model of myocardial infarction

    PubMed Central

    O'Connor, Daniel M; Naresh, Nivedita K; Piras, Bryan A; Xu, Yaqin; Smith, Robert S; Epstein, Frederick H; Hossack, John A; Ogle, Roy C; French, Brent A

    2015-01-01

    Extracellular matrix (ECM) degradation after myocardial infarction (MI) leaves the myocardium structurally weakened and, as a result, susceptible to early infarct zone dyskinesia and left ventricular (LV) remodeling. While various cellular and biomaterial preparations have been transplanted into the infarct zone in hopes of improving post-MI LV remodeling, an allogeneic cardiac muscle-derived ECM extract has yet to be developed and tested in the setting of reperfused MI. We sought to determine the effects of injecting a novel cardiac muscle-derived ECM into the infarct zone on early dyskinesia and LV remodeling in a mouse model of MI. Cardiac muscle ECM was extracted from frozen mouse heart tissue by a protocol that enriches for basement membrane constituents. The extract was injected into the infarct zone immediately after ischemia/reperfusion injury (n = 6). Echocardiography was performed at baseline and at days 2, 7, 14, and 28 post-MI to assess 3D LV volumes and cardiac function, as compared to infarcted controls (n = 9). Early infarct zone dyskinesia was measured on day 2 post-MI using a novel metric, the dyskinesia index. End-systolic volume was significantly reduced in the ECM-treated group compared to controls by day 14. Ejection fraction and stroke volume were also significantly improved in the ECM-treated group. ECM-treated hearts showed a significant (P < 0.005) reduction in dyskinetic motion on day 2. Thus, using high-frequency ultrasound, it was shown that treatment with a cardiac-derived ECM preparation reduced early infarct zone dyskinesia and post-MI LV remodeling in a mouse model of reperfused MI. PMID:25825543

  4. Significance of myocardial tenascin‐C expression in left ventricular remodelling and long‐term outcome in patients with dilated cardiomyopathy

    PubMed Central

    Yokokawa, Tetsuro; Nakayama, Takafumi; Nagai, Toshiyuki; Matsuyama, Taka‐aki; Ohta‐Ogo, Keiko; Ikeda, Yoshihiko; Ishibashi‐Ueda, Hatsue; Nakatani, Takeshi; Yasuda, Satoshi; Takeishi, Yasuchika; Ogawa, Hisao; Anzai, Toshihisa

    2016-01-01

    Aim Dilated cardiomyopathy (DCM) has a variety of causes, and no useful approach to predict left ventricular (LV) remodelling and long‐term outcome has yet been established. Myocardial tenascin‐C (TNC) is known to appear under pathological conditions, possibly to regulate cardiac remodelling. The aim of this study was to clarify the significance of myocardial TNC expression in LV remodelling and the long‐term outcome in DCM. Methods and results One hundred and twenty‐three consecutive DCM patients who underwent endomyocardial biopsy for initial diagnosis were studied. Expression of TNC in biopsy sections was analysed immunohistochemically to quantify the ratio of the TNC‐positive area to the whole myocardial tissue area (TNC area). Clinical parameters associated with TNC area were investigated. The patients were divided into two groups based on receiver operating characteristic analysis of TNC area to predict death: high TNC group with TNC area ≥2.3% (22 patients) and low TNC group with TNC area <2.3% (101 patients). High TNC was associated with diabetes mellitus. Comparing echocardiographic findings between before and 9 months after endomyocardial biopsy, the low TNC group was associated with decreased LV end‐diastolic diameter and increased LV ejection fraction, whereas the high TNC group was not. Survival analysis revealed a worse outcome in the high TNC group than in the low TNC group (P < 0.001). Multivariable Cox regression analysis revealed that TNC area was independently associated with poor outcome (HR = 1.347, P = 0.032). Conclusions Increased myocardial TNC expression was associated with worse LV remodeling and long‐term outcome in DCM. PMID:26763891

  5. Exogenous midkine administration prevents cardiac remodeling in pacing-induced congestive heart failure of rabbits.

    PubMed

    Harada, Masahide; Hojo, Mayumi; Kamiya, Kaichiro; Kadomatsu, Kenji; Murohara, Toyoaki; Kodama, Itsuo; Horiba, Mitsuru

    2016-01-01

    Midkine (MK), a heparin-binding growth factor, has been shown to prevent cardiac remodeling after ischemic injury through its anti-apoptotic effect. Cell apoptosis is central to the pathophysiology of cardiac remodeling in congestive heart failure (CHF) of ischemic as well as non-ischemic origin. We hypothesized that MK exerts the anti-apoptotic cardioprotective effect in CHF of non-ischemic etiology. MK protein or vehicle (normal saline) was subcutaneously administered in tachycardia-induced CHF rabbits (right ventricular pacing, 350 beats/min, 4 weeks). The vehicle-treated rabbits (n = 19, control) demonstrated severe CHF and high mortality rate, whereas MK (n = 16) demonstrated a well-compensated state and a lower mortality rate. In echocardiography, left ventricular (LV) end-diastolic dimension decreased in MK versus control, whereas LV systolic function increased. In histological analysis (picrosirius red staining), MK decreased collagen deposition area compared with control. TUNEL staining showed that MK prevented cell apoptosis and minimized myocyte loss in the CHF rabbit ventricle, associated with activation of PI3-K/Akt signaling, producing a parallel decrease of Bax/Bcl-2 ratio. MK prevented progression of cardiac remodeling in the CHF rabbit, likely by activation of anti-apoptotic signaling. Exogenous MK application might be a novel therapeutic strategy for CHF due to non-ischemic origin.

  6. To Remodel or To Build?

    ERIC Educational Resources Information Center

    Rosenblum, Todd

    2009-01-01

    The question of remodeling an existing house to make it wheelchair accessible or building a new barrier-free house is a difficult decision. This article presents some initial questions and considerations followed by a list of pros and cons for remodeling an existing house vs. building a new house.

  7. Plasma Levels of Transforming Growth Factor-β1 Reflect Left Ventricular Remodeling in Aortic Stenosis

    PubMed Central

    Villar, Ana V.; Cobo, Manuel; Llano, Miguel; Montalvo, Cecilia; González-Vílchez, Francisco; Martín-Durán, Rafael; Hurlé, María A.; Nistal, J. Francisco

    2009-01-01

    Background TGF-β1 is involved in cardiac remodeling through an auto/paracrine mechanism. The contribution of TGF-β1 from plasmatic source to pressure overload myocardial remodeling has not been analyzed. We investigated, in patients with valvular aortic stenosis (AS), and in mice subjected to transverse aortic arch constriction (TAC), whether plasma TGF-β1 relates with myocardial remodeling, reflected by LV transcriptional adaptations of genes linked to myocardial hypertrophy and fibrosis, and by heart morphology and function. Methodology/Principal Findings The subjects of the study were: 39 patients operated of AS; 27 healthy volunteers; 12 mice subjected to TAC; and 6 mice sham-operated. Myocardial samples were subjected to quantitative PCR. Plasma TGF-β1 was determined by ELISA. Under pressure overload, TGF-β1 plasma levels were significantly increased both in AS patients and TAC mice. In AS patients, plasma TGF-β1 correlated directly with aortic transvalvular gradients and LV mass surrogate variables, both preoperatively and 1 year after surgery. Plasma TGF-β1 correlated positively with the myocardial expression of genes encoding extracellular matrix (collagens I and III, fibronectin) and sarcomeric (myosin light chain-2, β-myosin heavy chain) remodelling targets of TGF-β1, in TAC mice and in AS patients. Conclusions/Significance A circulating TGF-β1-mediated mechanism is involved, in both mice and humans, in the excessive deposition of ECM elements and hypertrophic growth of cardiomyocytes under pressure overload. The possible value of plasma TGF-β1 as a marker reflecting preoperative myocardial remodeling status in AS patients deserves further analysis in larger patient cohorts. PMID:20041033

  8. Heterologous expression of the lactacin F peptides by Carnobacterium piscicola LV17.

    PubMed Central

    Allison, G E; Worobo, R W; Stiles, M E; Klaenhammer, T R

    1995-01-01

    The lactacin F complex, composed of LafA and LafX peptides, is produced by Lactobacillus johnsonii VPI 11088 and is active against five other Lactobacillus species and Enterococcus faecalis. The genetic determinants encoding the lactacin F complex are organized in a 1-kb polycistronic operon which comprises three genes, lafA, lafX, and ORFZ (encoding the putative immunity protein). The lafA and lafX genes encode the bacteriocin precursors with N-terminal extensions characterized by a Gly-Gly-1*Xaa+1 cleavage site (*). The Gly-Gly motif is conserved in several other bacteriocins, including carnobacteriocins A, BM1, and B2. Carnobacterium piscicola LV17 produces carnobacteriocins which are active against Listeria monocytogenes and other lactic acid bacteria. In this study, the lactacin F operon was introduced into C. piscicola LV17. The transformants produced lactacin F concurrently with the carnobacteriocins. When the lafA and lafX genes were separated and cloned individually into LV17, production of either LafA or LafX by C. piscicola LV17 was detected by complementation with L. johnsonii clones producing LafX or LafA, respectively. Transformants of C. piscicola LV17 which produced lactacin F, LafA, or LafX, in combination with the carnobacteriocins, were assayed for an increased and expanded inhibitory spectrum. The recombinant organisms were only active against lactacin F- and carnobacteriocin-sensitive strains. A plasmidless derivative of LV17 which does not produce the carnobacteriocins failed to produce lactacin F, LafA, or LafX when transformed with the appropriate recombinant plasmids. The ability of C. piscicola LV17 to produce lactacin F demonstrates that the machinery for the carnobacteriocins is capable of processing and exporting bacteriocins from both systems. PMID:7747957

  9. No-Regrets Remodeling, 2nd Edition

    SciTech Connect

    2013-12-01

    No-Regrets Remodeling, sponsored by Oak Ridge National Laboratory, is an informative publication that walks homeowners and/or remodelers through various home remodeling projects. In addition to remodeling information, the publication provides instruction on how to incorporate energy efficiency into the remodeling process. The goal of the publication is to improve homeowner satisfaction after completing a remodeling project and to provide the homeowner with a home that saves energy and is comfortable and healthy.

  10. Assessment of the Utility of the Septal E/(E′ × S′) Ratio and Tissue Doppler Index in Predicting Left Ventricular Remodeling after Acute Myocardial Infarction

    PubMed Central

    Kenar Tiryakioglu, Selma; Yalin, Kıvanc; Coskun, Senol

    2016-01-01

    Background. The aim of this study is to show whether the septal E/(E′ × S′) ratio assessed by tissue Doppler echocardiography can predict left ventricular remodeling after first ST segment elevation myocardial infarction treated successfully with primary percutaneous intervention. Methods. Consecutive patients (n = 111) presenting with acute anterior myocardial infarction for the first time in their life were enrolled. All patients underwent successful primary percutaneous coronary intervention. Standard and tissue Doppler echocardiography were performed in the first 24-36 hours of admission. Echocardiographic examination was repeated after 6 months to reassess left ventricular volumes. Septal E/(E′ × S′) ratio was assessed by pulsed Doppler echocardiography. Results. Group 1 consisted of 33 patients with left ventricular (LV) remodeling, and Group 2 had 78 patients without LV remodeling. E/(E′ × S′) was significantly higher in Group 1 (4.1 ± 1.9 versus 1.65 ± 1.32, p = 0.001). The optimal cutoff value for E/(E′ × S′) ratio was 2.34 with 87.0% sensitivity and 82.1% specificity. Conclusion. Septal E/(E′ × S′) values measured after the acute anterior myocardial infarction can strongly predict LV remodeling in the 6-month follow-up. In the risk assessment, the septal E/(E′ × S′) can be evaluated together with the conventional echocardiographic techniques. PMID:27703973

  11. MuLV IN Mutants Responsive to HDAC Inhibitors Enhance Transcription from Unintegrated Retroviral DNA

    PubMed Central

    Schneider, William M.; Wu, Dai-tze; Amin, Vaibhav; Aiyer, Sriram; Roth, Monica J.

    2012-01-01

    For Moloney murine leukemia virus (M-MuLV), sustained viral infections require expression from an integrated provirus. For many applications, non-integrating retroviral vectors have been utilized to avoid the unwanted effects of integration, however, the level of expression from unintegrated DNA is significantly less than that of integrated provirus. We find that unintegrated DNA expression can be increased in the presence of HDAC inhibitors, such as TSA, when applied in combination with integrase (IN) mutations. These mutants include an active site mutation as well as catalytically active INs bearing mutations of K376 in the MuLV C-terminal domain of IN. MuLV IN K376 is homologous to K266 in HIV-1 IN, a known substrate for acetylation. The MuLV IN protein is acetylated by p300 in vitro, however, the effect of HDAC inhibitors on gene expression from unintegrated DNA is not dependent on the acetylation state of MuLV IN K376. PMID:22365328

  12. IL-17A promotes ventricular remodeling after myocardial infarction.

    PubMed

    Zhou, Su-Feng; Yuan, Jing; Liao, Meng-Yang; Xia, Ni; Tang, Ting-Ting; Li, Jing-Jing; Jiao, Jiao; Dong, Wen-Yong; Nie, Shao-Fang; Zhu, Zheng-Feng; Zhang, Wen-Cai; Lv, Bing-Jie; Xiao, Hong; Wang, Qing; Tu, Xin; Liao, Yu-Hua; Shi, Guo-Ping; Cheng, Xiang

    2014-10-01

    Inflammatory responses play an important role in the pathogenesis of adverse ventricular remodeling after myocardial infarction (MI). We previously demonstrated that interleukin (IL)-17A plays a pathogenic role in myocardial ischemia/reperfusion injury and viral myocarditis. However, the role of IL-17A in post-MI remodeling and the related mechanisms have not been fully elucidated. Acute MI was induced by permanent ligation of the left anterior descending coronary artery in C57BL/6 mice. Repletion of IL-17A significantly aggravated both early- and late-phase ventricular remodeling, as demonstrated by increased infarct size, deteriorated cardiac function, increased myocardial fibrosis, and cardiomyocyte apoptosis. By contrast, genetic IL-17A deficiency had the opposite effect. Additional studies in vitro indicated that IL-17A induces neonatal cardiomyocyte (from C57BL/6 mice) apoptosis through the activation of p38, p53 phosphorylation, and Bax redistribution. These data demonstrate that IL-17A induces cardiomyocyte apoptosis through the p38 mitogen-activated protein kinase (MAPK)-p53-Bax signaling pathway and promotes both early- and late-phase post-MI ventricular remodeling. IL-17A might be an important target in preventing heart failure after MI. Key message: We demonstrated that IL-17A plays a pathogenic role both in the early and late stages of post-MI remodeling. IL-17A induces murine cardiomyocyte apoptosis. IL-17A induces murine cardiomyocyte apoptosis through the p38 MAPK-p53-Bax signaling pathway.

  13. Moderate Physical Activity in Healthy Adults Is Associated With Cardiac Remodeling

    PubMed Central

    Dawes, Timothy J.W.; Corden, Ben; Cotter, Sorcha; de Marvao, Antonio; Walsh, Roddy; Ware, James S.; Cook, Stuart A.

    2016-01-01

    Background— Cardiac mass and volumes are often elevated in athletes, but it is not known whether moderate physical activity is also associated with cardiac dilatation and hypertrophy in a healthy adult population. Methods and Results— In total, 1096 adults (54% female, median age 39 years) without cardiovascular disease or cardiomyopathy-associated genetic variants underwent cardiac magnetic resonance imaging to determine biventricular volumes and function. Physical activity was assessed using a validated activity questionnaire. The relationship between cardiac parameters and activity was assessed using multiple linear regression adjusting for age, sex, race, and systolic blood pressure. Logistic regression was performed to determine the effect of activity on the likelihood of subjects having cardiac dilatation or hypertrophy according to standard cardiac magnetic resonance normal ranges. Increasing physical activity was associated with greater left ventricular (LV) mass (β=0.23; P<0.0001) and elevated LV and right ventricular volumes (LV: β=0.26, P<0.0001; right ventricular: β=0.26, P<0.0001). Physical activity had a larger effect on cardiac parameters than systolic blood pressure (0.06≤β≤0.21) and a similar effect to age (−0.20≤β≤−0.31). Increasing physical activity was a risk factor for meeting imaging criteria for LV hypertrophy (adjusted odds ratio 2.1; P<0.0001), LV dilatation (adjusted odds ratio 2.2; P<0.0001), and right ventricular dilatation (adjusted odds ratio 2.2; P<0.0001). Conclusions— Exercise-related cardiac remodeling is not confined to athletes, and there is a risk of overdiagnosing cardiac dilatation or hypertrophy in a proportion of active, healthy adults. PMID:27502059

  14. Nocturnal Blood Pressure Pattern Affects Left Ventricular Remodeling and Late Gadolinium Enhancement in Patients with Hypertension and Left Ventricular Hypertrophy

    PubMed Central

    Yokota, Hajime; Imai, Yasuko; Tsuboko, Yusuke; Tokumaru, Aya M.; Fujimoto, Hajime; Harada, Kazumasa

    2013-01-01

    Background Left ventricular hypertrophy (LVH) is an independent predictor of cardiac mortality, regardless of its etiology. Previous studies have shown that high nocturnal blood pressure (BP) affects LV geometry in hypertensive patients. It has been suggested that continuous pressure overload affects the development of LVH, but it is unknown whether persistent pressure influences myocardial fibrosis or whether the etiology of LVH is associated with myocardial fibrosis. Comprehensive cardiac magnetic resonance (CMR) including the late gadolinium enhancement (LGE) technique can evaluate both the severity of changes in LV geometry and myocardial fibrosis. We tested the hypothesis that the nocturnal non-dipper BP pattern causes LV remodeling and fibrosis in patients with hypertension and LVH. Methods Forty-seven hypertensive patients with LVH evaluated by echocardiography (29 men, age 73.0±10.4 years) were examined by comprehensive CMR and 24-h ambulatory blood pressure monitoring (ABPM). Results and Conclusions Among the 47 patients, twenty-four had nocturnal non-dipper BP patterns. Patients with nocturnal non-dipper BP patterns had larger LV masses and scar volumes independent of etiologies than those in patients with dipper BP patterns (p = 0.035 and p = 0.015, respectively). There was no significant difference in mean 24-h systolic BP between patients with and without nocturnal dipper BP patterns (p = 0.367). Among hypertensive patients with LVH, the nocturnal non-dipper blood pressure pattern is associated with both LV remodeling and myocardial fibrosis independent of LVH etiology. PMID:23840777

  15. Residual stress impairs pump function after surgical ventricular remodeling: A finite element analysis

    PubMed Central

    Pantoja, Joe Luis; Zhang, Zhihong; Tartibi, Mehrzad; Sun, Kay; Macmillan, Warrick; Guccione, Julius M.; Ge, Liang; Ratcliffe, Mark B.

    2016-01-01

    Objectives Surgical ventricular restoration (Dor procedure) is generally thought to reduce left ventricular (LV) myofiber stress (FS) but to adversely affect pump function. However, the underlying mechanism is unclear. The goal of this study was to determine the effect of residual stress (RS) on LV FS and pump function after the Dor procedure. Methods Previously described finite element models of the LV based on MRI data obtained in five sheep 16 weeks after antero-apical myocardial infarction were used. Simulated Dacron patches that were elliptical and 25% of the infarct opening area were implanted using a virtual suture technique (VIRTUAL-DOR). In each case, diastole and systole were simulated and RS, FS, LV volumes, systolic and diastolic function, and pump (Starling) function were calculated. Results VIRTUAL-DOR was associated with significant RS that was tensile (2.89±1.31 kPa) in the remote myocardium and compressive (234.15±65.53 kPa) in the borderzone (BZ). VIRTUAL-DOR+RS (compared to VIRTUAL-DOR-NO-RS) was associated with further reduction in regional diastolic and systolic FS with the greatest change in the BZ (43.5-fold and 7.1-fold respectively, p<0.0001). VIRTUAL-DOR+RS was also associated with further reduction in systolic and diastolic volumes (7.9%, p=0.0606 and 10.6%, p=0.0630, respectively). The resultant effect was a further reduction in pump function after VIRTUAL-DOR+RS. Conclusion Residual stress that occurs after the Dor procedure is positive (tensile) in the remote myocardium and negative (compressive) in the BZ and associated with reductions in fiber stress and LV volumes. The resultant effect is a further reduction in LV pump (Starling) function. PMID:26341601

  16. Addition of substitution of simian virus 40 enhancer sequences into the Moloney murine leukemia virus (M-MuLV) long terminal repeat yields infectious M-MuLV with altered biological properties.

    PubMed

    Hanecak, R; Pattengale, P K; Fan, H

    1988-07-01

    Moloney murine leukemia virus (M-MuLV) is a replication-competent retrovirus which induces T-cell lymphoma in mice. The enhancer sequences present within the M-MuLV long terminal repeat (LTR) region of the proviral genome have been shown to influence the disease specificity of the virus strongly. We examined the contribution of the M-MuLV enhancers to the transcriptional activity and pathogenesis of M-MuLV by constructing LTRs containing heterologous enhancer elements. The simian virus 40 enhancer region (72- and 21-base-pair repeats) was inserted into the U3 region (at -150 base pairs) of the M-MuLV LTR (Mo + SV) and also into a deleted form of the LTR which lacks the M-MuLV enhancer sequences (delta Mo + SV). These chimeric LTRs were used to generate infectious M-MuLVs by transfection of corresponding proviral plasmids into mouse fibroblasts. The relative infectivities of Mo + SV and delta Mo + SV recombinant viruses as determined by rat XC cell plaque assay and reverse transcriptase assay were 60 to 70% of wild-type M-MuLV levels. To study the pathogenicity of these two recombinant viruses, we inoculated newborn NIH Swiss mice with either Mo + SV or delta Mo + SV M-MuLV. Both viruses induced disease more slowly than M-MuLV, which induces disease 2 to 4 months postinoculation. Mo + SV M-MuLV-inoculated animals became moribund at 3 to 13 months postinoculation, whereas delta Mo + SV M-MuLV-inoculated animals became moribund at 6 to 24 months postinoculation. The tumors induced by the two viruses were characterized histologically and molecularly. Mo + SV M-MuLV-induced tumors were primarily T-cell-derived lymphoblastic lymphomas containing extensive rearrangements of the T-cell receptor beta gene. In contrast, delta Mo + SV M-MuLV induced pre-B- and B-cell lymphoblastic lymphomas, B-cell-derived follicular-center cell lymphomas, and acute myeloid leukemia. The delta Mo + SV tumor DNAs from B-lineage tumors were typically rearranged at the immunoglobulin gene loci

  17. Relationship between self-reported residential indoor remodeling and semen quality: a case-control study

    PubMed Central

    Miao, Mao-Hua; Li, Zheng; Li, De-Kun; Yan, Bei; Liang, Hong; Zhi, Er-Lei; Du, Hong-Wei; Yuan, Wei

    2015-01-01

    The present study examined the association between residential indoor remodeling and poor semen quality. Sperm donors aged 18–45 years old were recruited in Shanghai, China. Semen specimens were collected and analyzed. An in-person interview was conducted to obtain information on the history of indoor remodeling and potential confounders. A total of 70 participants with abnormal semen quality (case group) and 68 controls were examined. A total of 20 subjects reported indoor remodeling in the recent 24 months, and among them 17 subjects reported indoor remodeling in the recent 12 months. Compared with participants with no history of indoor remodeling, participants with a history of indoor remodeling in the recent 24 months were more than three times as likely to have poor sperm quality (adjusted odds ratio = 3.8, 95% confidence interval: 1.3–12.0) after controlling for potential confounders. The association was strengthened when the analysis was restricted to those who had indoor remodeling in the recent 12 months. Our findings provide preliminary evidence that indoor remodeling has an adverse effect on semen quality. PMID:25432500

  18. 3D quantitative visualization of altered LV wall thickening dynamics caused by coronary microembolization

    NASA Astrophysics Data System (ADS)

    Eusemann, Christian D.; Mohlenkamp, Stefan; Ritman, Erik L.; Robb, Richard A.

    2001-05-01

    Regional heart wall dynamics has been shown to be a sensitive indicator of LV wall ischemia. Rates of local LV wall thickening during a cardiac cycle can be measured and illustrated using functional parametric mappings. This display conveys the spatial distribution of dynamic strain in the myocardium and thereby provides a rapid qualitative appreciation of the severity and extent of the ischemic region. 3D reconstructions were obtained in an anesthetized pig from 8 adjacent, shortaxis, slices of the left ventricle imaged with an Electron Beam Computer Tomograph at 11 time points through one complete cardiac cycle. The 3D reconstructions were obtained before and after injection of 100 micrometer microspheres into the Left Anterior Descending (LAD) coronary artery. This injection causes microembolization of LAD artery branches within the heart wall. The image processing involved radially dividing the tomographic images of the myocardium into small subdivisions with color encoding of the local magnitude of regional thickness or regional velocities of LV wall thickening throughout the cardiac cycle. We compared the effectiveness of animation of wall thickness encoded in color versus a static image of computed rate of wall thickness change in color. The location, extent and severity of regional wall akinesis or dyskinesis, as determined from these displays, can then be compared to the region of embolization as indicated by the distribution of altered LV wall perfusion.

  19. Right ventricular septal pacing- clinical and electrical predictors for LV contraction asynchrony

    PubMed Central

    Iorgulescu, C; Radu, DA; Constantinescu, D; Caldararu, C; Dorobantu, M

    2014-01-01

    Purpose: Prolonged pacing from the right ventricular apex (RV) is associated with the LV dyssynchrony leading to progressive left ventricular dysfunction and increased morbidity and mortality. Alternate RV pacing sites-in particular the mid- RV septum and the RV outflow tract (RVOT) septum were considered, but no clear benefit was proven till now for this pacing sites. This may be due to the heterogeneity of the RV septal positions and to the significant number of leads placed on the RV free wall. The aim of this study is to find a reliable method of septal lead placement and to identify those pacing sites which provide better LV electrical activation Methods: 50 consecutive patients referred for pacemaker implants due to AV block were included. Patients with history of heart failure or LVEF < 50% at the implant were excluded. All patients had RV leads placed in septal position. This was achieved with a double curved stilet with the distal curve aimed posteriorly. RV septum and RVOT were mapped during implant aiming for a narrow paced QRS with an axis as close to normal as possible. Pacing lead position was evaluated during the implant using fluoroscopy (AP and LAO 40 °) and than by 12 lead ECG and echo. IntraLV dyssynchrony was evaluated during pacing using SPWMD in short axis parasternal view and the TDI septal to lateral ∆ t. Paced QRS duration and axis were also recorded. The correlation was sought between lead position evaluated by Rx and by echo and between paced QRS duration and axis and LV dyssynchrony. Results: 92%(46) of the patients had the lead in septal position RV (32 in the mid-septal RV and 14 in RVOT), while 8% (4 pts) had the lead on the RVOT RV free wall as shown by echo. An anterior-oriented lead in the left anterior oblique fluoroscopic projection was specific for free wall position while positive QRS in DI in RVOT position was suggestive for free wall position on the ECG. No correlation was made between paced QRS axis and LV dyssynchrony

  20. Vaccine Adverse Events

    MedlinePlus

    ... Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products Vaccines, Blood & Biologics Home Vaccines, Blood & Biologics Safety & Availability ( ... Center for Biologics Evaluation & Research Vaccine Adverse Events Vaccine Adverse Events Share Tweet Linkedin Pin it More ...

  1. 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.

  2. Insertional activation of myb by F-MuLV in SCID mice induces myeloid leukemia.

    PubMed

    Haeri, Mehran; Li, Youjun; Li, Yanmei; Li, Qi; Spaner, David E; Ben-David, Yaacov

    2013-07-01

    Identification of retrovirus integration sites is a powerful method to identify cancer-related genes. This approach led to the discovery of the Friend murine leukemia virus (F-MuLV) integration site-1 (fli-1). Viral insertion at the fli-1 locus induces erythroleukemia in susceptible strains of mice. Our recent data demonstrated that, F-MuLV-infected SCID mice, in contrast to wt CB17 controls, developed a non‑erythroleukemic leukemia without viral integration at the fli-1 locus. Using ligation-mediated polymerase chain reaction (LM-PCR) approach we identified a total of 15 viral integration sites in F-MuLV-infected SCID mice. One of the identified insertion sites was located about 62 kb upstream of the myeloblastosis (myb) gene. While integration within or surrounding the myb gene has been reported before for murine leukemia viruses, the location of the viral integration site identified in F-MuLV‑infected SCID mice is novel and has never been reported. Using PCR analysis we showed that viral integration at the myb locus occurs with a frequency of 35% and therefore is considered as a common integration site. Integration of F-MuLV in this locus resulted in upregulation of the MYB protein. Flow cytometry analysis and methylcellulose culture of leukemic cells isolated from tumors with viral integration close to the myb indicated tumors of myeloid origin. Our findings indicate that, in contrast to wt CB17 mice, F-MuLV-infected SCID mice display viral integration within myeloid specific gene loci that result in the development of myelogenous leukemia.

  3. Attenuation of increased secretory leukocyte protease inhibitor, matricellular proteins and angiotensin II and left ventricular remodeling by candesartan and omapatrilat during healing after reperfused myocardial infarction.

    PubMed

    Palaniyappan, Ariv; Uwiera, Richard R E; Idikio, Halliday; Menon, Vijay; Jugdutt, Catherine; Jugdutt, Bodh I

    2013-04-01

    While secretory-leukocyte-protease-inhibitor (SLPI) may promote skin wound healing, its role in infarct healing after reperfused myocardial infarction (RMI) remains unclear. Short-term intravenous angiotensin II (AngII) receptor blocker therapy with candesartan (CN) attenuates increased SLPI and markers of early matrix/left ventricular (LV) in acute RMI. To determine whether reducing effects of AngII with CN or the vasopeptidase inhibitor omapatrilat (OMA) during the healing phase after RMI attenuates SLPI and other mediators of healing and matrix/LV remodeling, we measured these in Sprague-Dawley rats randomized to oral placebo, CN (30 mg/kg/day) or OMA (10 mg/kg/day) therapy during healing between days 2 and 23 after RMI and sham. On day-25, RMI-placebo showed significant LV remodeling, systolic/diastolic dysfunction and impaired passive compliance, and ischemic zone increases in SLPI, secreted-protein-acidic-and-rich-in-cysteine (SPARC) and osteopontin (OPN) mRNA and protein. In addition, metalloproteinase (MMP)-9 and -2, a-disintegrin-and-metalloproteinase (ADAM)-10 and -17, inducible-nitric-oxide-synthase (iNOS), pro-inflammatory cytokines interleukin (IL)-6, and tumor necrosis factor-α, transforming growth factor (TGF)-β(1) and its signaling molecule p-Smad-2, myeloperoxidase (MPO), AngII, MPO-positive granulocytes, MAC387-positive macrophages and monocytes, scar collagens, cardiomyocyte and fibroblast apoptosis, and microvascular no-reflow also increased whereas anti-inflammatory cytokine IL-10 decreased. Both CN and OMA attenuated all the changes except IL-10, which normalized. Thus, CN or OMA treatment during healing after RMI results in attenuation of SLPI as well as tissue AngII and mediators of inflammation and matrix/LV remodeling including SPARC, OPN, and ADAMs. Whether increasing SLPI on top of background AngII inhibition or therapy such as CN or OMA might produce added remodeling benefit needs study.

  4. The complete nucleotide sequence and genomic organization of Citrus Leprosis associated Virus, Cytoplasmatic type (CiLV-C).

    PubMed

    Pascon, Renata C; Kitajima, João Paulo; Breton, Michèle C; Assumpção, Laura; Greggio, Christian; Zanca, Almir S; Okura, Vagner Katsumi; Alegria, Marcos C; Camargo, Maria E; Silva, Giovana G C; Cardozo, Jussara C; Vallim, Marcelo A; Franco, Sulamita F; Silva, Vitor H; Jordão, Hamilton; Oliveira, Fernanda; Giachetto, Poliana F; Ferrari, Fernanda; Aguilar-Vildoso, Carlos I; Franchiscini, Fabrício J B; Silva, José M F; Arruda, Paulo; Ferro, Jesus A; Reinach, Fernando; da Silva, Ana Cláudia Rasera

    2006-06-01

    The Citrus leprosis disease (CiL) is associated to a virus (CiLV) transmitted by Brevipalpus spp. mites (Acari: Tenuipalpidae). CiL is endemic in Brazil and its recently spreading to Central America represents a threat to citrus industry in the USA. Electron microscopy images show two forms of CiLV: a rare nuclear form, characterized by rod-shaped naked particle (CiLV-N) and a common cytoplasmic form (CiLV-C) associated with bacilliform-enveloped particle and cytoplasmic viroplasm. Due to this morphological feature, CiLV-C has been treated as Rhabdovirus-like. In this paper we present the complete nucleotide sequence and genomic organization of CiLV-C. It is a bipartite virus with sequence similarity to ssRNA positive plant virus. RNA1 encodes a putative replicase polyprotein and an ORF with no known function. RNA2 encodes 4 ORFs. pl5, p24 and p61 have no significant similarity to any known proteins and p32 encodes a protein with similarity to a viral movement protein. The CiLV-C sequences are associated with typical symptoms of CiL by RT-PCR. Phylogenetic analysis suggests that CiLV-C is probably a member of a new family of plant virus evolutionarily related to Tobamovirus. PMID:16732481

  5. microRNAs and Cardiovascular Remodeling.

    PubMed

    Ono, Koh

    2015-01-01

    Heart failure (HF) is associated with significant morbidity and mortality attributable largely to structural changes in the heart and with associated cardiac dysfunction. Remodeling is defined as alteration of the mass, dimensions, or shape of the heart (termed cardiac or ventricular remodeling) and vessels (vascular remodeling) in response to hemodynamic load and/or cardiovascular injury in association with neurohormonal activation. Remodeling may be described as physiologic or pathologic; alternatively, remodeling may be classified as adaptive or maladaptive. The importance of remodeling as a pathogenic mechanism has been controversial because factors leading to remodeling as well as the remodeling itself may be major determinants of patients' prognosis. The basic mechanisms of cardiovascular remodeling, and especially the roles of microRNAs in HF progression and vascular diseases, will be reviewed here.

  6. Quantitative computed tomography–derived clusters: Redefining airway remodeling in asthmatic patients☆

    PubMed Central

    Gupta, Sumit; Hartley, Ruth; Khan, Umair T.; Singapuri, Amisha; Hargadon, Beverly; Monteiro, William; Pavord, Ian D.; Sousa, Ana R.; Marshall, Richard P.; Subramanian, Deepak; Parr, David; Entwisle, James J.; Siddiqui, Salman; Raj, Vimal; Brightling, Christopher E.

    2014-01-01

    Background Asthma heterogeneity is multidimensional and requires additional tools to unravel its complexity. Computed tomography (CT)–assessed proximal airway remodeling and air trapping in asthmatic patients might provide new insights into underlying disease mechanisms. Objectives The aim of this study was to explore novel, quantitative, CT-determined asthma phenotypes. Methods Sixty-five asthmatic patients and 30 healthy subjects underwent detailed clinical, physiologic characterization and quantitative CT analysis. Factor and cluster analysis techniques were used to determine 3 novel, quantitative, CT-based asthma phenotypes. Results Patients with severe and mild-to-moderate asthma demonstrated smaller mean right upper lobe apical segmental bronchus (RB1) lumen volume (LV) in comparison with healthy control subjects (272.3 mm3 [SD, 112.6 mm3], 259.0 mm3 [SD, 53.3 mm3], 366.4 mm3 [SD, 195.3 mm3], respectively; P = .007) but no difference in RB1 wall volume (WV). Air trapping measured based on mean lung density expiratory/inspiratory ratio was greater in patients with severe and mild-to-moderate asthma compared with that seen in healthy control subjects (0.861 [SD, 0.05)], 0.866 [SD, 0.07], and 0.830 [SD, 0.06], respectively; P = .04). The fractal dimension of the segmented airway tree was less in asthmatic patients compared with that seen in control subjects (P = .007). Three novel, quantitative, CT-based asthma clusters were identified, all of which demonstrated air trapping. Cluster 1 demonstrates increased RB1 WV and RB1 LV but decreased RB1 percentage WV. On the contrary, cluster 3 subjects have the smallest RB1 WV and LV values but the highest RB1 percentage WV values. There is a lack of proximal airway remodeling in cluster 2 subjects. Conclusions Quantitative CT analysis provides a new perspective in asthma phenotyping, which might prove useful in patient selection for novel therapies. PMID:24238646

  7. Tolerance to ischaemic injury in remodelled mouse hearts: less ischaemic glycogenolysis and preserved metabolic efficiency

    PubMed Central

    Masoud, Waleed G.T.; Abo Al-Rob, Osama; Yang, Yang; Lopaschuk, Gary D.; Clanachan, Alexander S.

    2015-01-01

    Aims Post-infarction remodelled failing hearts have reduced metabolic efficiency. Paradoxically, they have increased tolerance to further ischaemic injury. This study was designed to investigate the metabolic mechanisms that may contribute to this phenomenon and to examine the relationship between ischaemic tolerance and metabolic efficiency during post-ischaemic reperfusion. Methods and results Male C57BL/6 mice were subjected to coronary artery ligation (CAL) or SHAM surgery. After 4 weeks, in vivo mechanical function was assessed by echocardiography, and then isolated working hearts were perfused in this sequence: 45 min aerobic, 15 min global no-flow ischaemia, and 30 min aerobic reperfusion. Left ventricular (LV) function, metabolic rates, and metabolic efficiency were measured. Relative to SHAM, both in vivo and in vitro CAL hearts had depressed cardiac function under aerobic conditions (45 and 36%, respectively), but they had a greater recovery of LV function during post-ischaemic reperfusion (67 vs. 49%, P < 0.05). While metabolic efficiency (LV work per ATP produced) was 50% lower during reperfusion of SHAM hearts, metabolic efficiency in CAL hearts did not decrease. During ischaemia, glycogenolysis was 28% lower in CAL hearts, indicative of lower ischaemic proton production. There were no differences in mitochondrial abundance, calcium handling proteins, or key metabolic enzymes. Conclusion Compared with SHAM, remodelled CAL hearts are more tolerant to ischaemic injury and undergo no further deterioration of metabolic efficiency during reperfusion. Less glycogen utilization in CAL hearts during ischaemia may contribute to increased ischaemic tolerance by limiting ischaemic proton production that may improve ion homeostasis during early reperfusion. PMID:26150203

  8. Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs

    PubMed Central

    Fernandes, Tiago; Baraúna, Valério G.; Negrão, Carlos E.; Phillips, M. Ian

    2015-01-01

    Left ventricular (LV) hypertrophy is an important physiological compensatory mechanism in response to chronic increase in hemodynamic overload. There are two different forms of LV hypertrophy, one physiological and another pathological. Aerobic exercise induces beneficial physiological LV remodeling. The molecular/cellular mechanisms for this effect are not totally known, and here we review various mechanisms including the role of microRNA (miRNA). Studies in the heart, have identified antihypertrophic miRNA-1, -133, -26, -9, -98, -29, -378, and -145 and prohypertrophic miRNA-143, -103, -130a, -146a, -21, -210, -221, -222, -27a/b, -199a/b, -208, -195, -499, -34a/b/c, -497, -23a, and -15a/b. Four miRNAs are recognized as cardiac-specific: miRNA-1, -133a/b, -208a/b, and -499 and called myomiRs. In our studies we have shown that miRNAs respond to swimming aerobic exercise by 1) decreasing cardiac fibrosis through miRNA-29 increasing and inhibiting collagen, 2) increasing angiogenesis through miRNA-126 by inhibiting negative regulators of the VEGF pathway, and 3) modulating the renin-angiotensin system through the miRNAs-27a/b and -143. Exercise training also increases cardiomyocyte growth and survival by swimming-regulated miRNA-1, -21, -27a/b, -29a/c, -30e, -99b, -100, -124, -126, -133a/b, -143, -144, -145, -208a, and -222 and running-regulated miRNA-1, -26, -27a, -133, -143, -150, and -222, which influence genes associated with the heart remodeling and angiogenesis. We conclude that there is a potential role of these miRNAs in promoting cardioprotective effects on physiological growth. PMID:26071549

  9. Bi-layered polyurethane - Extracellular matrix cardiac patch improves ischemic ventricular wall remodeling in a rat model.

    PubMed

    D'Amore, Antonio; Yoshizumi, Tomo; Luketich, Samuel K; Wolf, Matthew T; Gu, Xinzhu; Cammarata, Marcello; Hoff, Richard; Badylak, Stephen F; Wagner, William R

    2016-11-01

    As an intervention to abrogate ischemic cardiomyopathy, the concept of applying a temporary, local patch to the surface of the recently infarcted ventricle has been explored from a number of design perspectives. Two important features considered for such a cardiac patch include the provision of appropriate mechanical support and the capacity to influence the remodeling pathway by providing cellular or biomolecule delivery. The objective of this report was to focus on these two features by first evaluating the incorporation of a cardiac extracellular matrix (ECM) component, and second by evaluating the impact of patch anisotropy on the pathological remodeling process initiated by myocardial infarction. The functional outcomes of microfibrous, elastomeric, biodegradable cardiac patches have been evaluated in a rat chronic infarction model. Ten weeks after infarction and 8 wk after patch epicardial placement, echocardiographic function, tissue-level structural remodeling (e.g., biaxial mechanical response and microstructural analysis), and cellular level remodeling were assessed. The results showed that the incorporation of a cardiac ECM altered the progression of several keys aspects of maladaptive remodeling following myocardial infarction. This included decreasing LV global mechanical compliance, inhibiting echocardiographically-measured functional deterioration, mitigating scar formation and LV wall thinning, and promoting angiogenesis. In evaluating the impact of patch anisotropy, no effects from the altered patch mechanics were detected after 8 wk, possibly due to patch fibrous encapsulation. Overall, this study demonstrates the benefit of a cardiac patch design that combines both ventricle mechanical support, through a biodegradable, fibrillary elastomeric component, and the incorporation of ECM-based hydrogel components. PMID:27579776

  10. Alterations in vasomotor control of coronary resistance vessels in remodelled myocardium of swine with a recent myocardial infarction.

    PubMed

    Duncker, Dirk J; de Beer, Vincent J; Merkus, Daphne

    2008-05-01

    The mechanism underlying the progressive deterioration of left ventricular (LV) dysfunction after myocardial infarction (MI) towards overt heart failure remains incompletely understood, but may involve impairments in coronary blood flow regulation within remodelled myocardium leading to intermittent myocardial ischemia. Blood flow to the remodelled myocardium is hampered as the coronary vasculature does not grow commensurate with the increase in LV mass and because extravascular compression of the coronary vasculature is increased. In addition to these factors, an increase in coronary vasomotor tone, secondary to neurohumoral activation and endothelial dysfunction, could also contribute to the impaired myocardial oxygen supply. Consequently, we explored, in a series of studies, the alterations in regulation of coronary resistance vessel tone in remodelled myocardium of swine with a 2 to 3-week-old MI. These studies indicate that myocardial oxygen balance is perturbed in remodelled myocardium, thereby forcing the myocardium to increase its oxygen extraction. These perturbations do not appear to be the result of blunted beta-adrenergic or endothelial NO-mediated coronary vasodilator influences, and are opposed by an increased vasodilator influence through opening of K(ATP) channels. Unexpectedly, we observed that despite increased circulating levels of noradrenaline, angiotensin II and endothelin-1, alpha-adrenergic tone remained negligible, while the coronary vasoconstrictor influences of endogenous endothelin and angiotensin II were virtually abolished. We conclude that, early after MI, perturbations in myocardial oxygen balance are observed in remodelled myocardium. However, adaptive alterations in coronary resistance vessel control, consisting of increased vasodilator influences in conjunction with blunted vasoconstrictor influences, act to minimize the impairments of myocardial oxygen balance.

  11. Design and rationale of a multicentre, randomised, double-blind, placebo-controlled clinical trial to evaluate the effect of vitamin D on ventricular remodelling in patients with anterior myocardial infarction: the VITamin D in Acute Myocardial Infarction (VITDAMI) trial

    PubMed Central

    Tuñón, José; González-Hernández, Ignacio; Llanos-Jiménez, Lucía; Alonso-Martín, Joaquín; Escudier-Villa, Juan M; Tarín, Nieves; Cristóbal, Carmen; Sanz, Petra; Pello, Ana M; Aceña, Álvaro; Carda, Rocío; Orejas, Miguel; Tomás, Marta; Beltrán, Paula; Calero Rueda, Marta; Marcos, Esther; Serrano-Antolín, José María; Gutiérrez-Landaluce, Carlos; Jiménez, Rosa; Cabezudo, Jorge; Curcio, Alejandro; Peces-Barba, Germán; González-Parra, Emilio; Muñoz-Siscart, Raquel; González-Casaus, María Luisa; Lorenzo, Antonio; Huelmos, Ana; Goicolea, Javier; Ibáñez, Borja; Hernández, Gonzalo; Alonso-Pulpón, Luis M; Farré, Jerónimo; Lorenzo, Óscar; Mahíllo-Fernández, Ignacio; Egido, Jesús

    2016-01-01

    Introduction Decreased plasma vitamin D (VD) levels are linked to cardiovascular damage. However, clinical trials have not demonstrated a benefit of VD supplements on left ventricular (LV) remodelling. Anterior ST-elevation acute myocardial infarction (STEMI) is the best human model to study the effect of treatments on LV remodelling. We present a proof-of-concept study that aims to investigate whether VD improves LV remodelling in patients with anterior STEMI. Methods and analysis The VITamin D in Acute Myocardial Infarction (VITDAMI) trial is a multicentre, randomised, double-blind, placebo-controlled trial. 144 patients with anterior STEMI will be assigned to receive calcifediol 0.266 mg capsules (Hidroferol SGC)/15 days or placebo on a 2:1 basis during 12 months. Primary objective: to evaluate the effect of calcifediol on LV remodelling defined as an increase in LV end-diastolic volume ≥10% (MRI). Secondary objectives: change in LV end-diastolic and end-systolic volumes, ejection fraction, LV mass, diastolic function, sphericity index and size of fibrotic area; endothelial function; plasma levels of aminoterminal fragment of B-type natriuretic peptide, galectin-3 and monocyte chemoattractant protein-1; levels of calcidiol (VD metabolite) and other components of mineral metabolism (fibroblast growth factor-23 (FGF-23), the soluble form of its receptor klotho, parathormone and phosphate). Differences in the effect of VD will be investigated according to the plasma levels of FGF-23 and klotho. Treatment safety and tolerability will be assessed. This is the first study to evaluate the effect of VD on cardiac remodelling in patients with STEMI. Ethics and dissemination This trial has been approved by the corresponding Institutional Review Board (IRB) and National Competent Authority (Agencia Española de Medicamentos y Productos Sanitarios (AEMPS)). It will be conducted in accordance with good clinical practice (International Council for Harmonisation of

  12. Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes.

    PubMed

    Mehta, Nishaki; Chacko, Paul; Jin, James; Tran, Tam; Prior, Thomas W; He, Xin; Agarwal, Gunjan; Raman, Subha V

    2016-08-01

    Patients with Friedreich ataxia typically die of cardiomyopathy, marked by myocardial fibrosis and abnormal left ventricular (LV) geometry. We measured procollagen I carboxyterminal propeptide (PICP), a serum biomarker of collagen production, and characterized genotypes, phenotypes, and outcomes in these patients. Twenty-nine patients with Friedreich ataxia (mean age, 34.2 ± 2.2 yr) and 29 healthy subjects (mean age, 32.5 ± 1.1 yr) underwent serum PICP measurements. Patients underwent cardiac magnetic resonance imaging and outcome evaluations at baseline and 12 months. Baseline PICP values were significantly higher in the patients than in the control group (1,048 ± 77 vs 614 ± 23 ng/mL; P <0.001); severity of genetic abnormality did not indicate severity of PICP elevation. Higher PICP levels corresponded to greater LV concentric remodeling only at baseline (r=0.37, P <0.05). Higher baseline PICP strongly indicated subsequent increases in LV end-diastolic volume (r=0.52, P=0.02). The PICP levels did not distinguish between 14 patients with evident myocardial fibrosis identified through positive late gadolinium enhancement and 15 who had no enhancement (1,067 ± 125 vs 1,030 ± 98 ng/mL; P=0.82). At 12 months, cardiac events had occurred in 3 of 14 fibrosis-positive and none of 15 fibrosis-negative patients (P=0.1); their baseline PICP levels were similar. We conclude that PICP, a serum marker of collagen synthesis, is elevated in Friedreich ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy. PMID:27547137

  13. Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes

    PubMed Central

    Chacko, Paul; Jin, James; Tran, Tam; Prior, Thomas W.; He, Xin; Agarwal, Gunjan; Raman, Subha V.

    2016-01-01

    Patients with Friedreich ataxia typically die of cardiomyopathy, marked by myocardial fibrosis and abnormal left ventricular (LV) geometry. We measured procollagen I carboxyterminal propeptide (PICP), a serum biomarker of collagen production, and characterized genotypes, phenotypes, and outcomes in these patients. Twenty-nine patients with Friedreich ataxia (mean age, 34.2 ± 2.2 yr) and 29 healthy subjects (mean age, 32.5 ± 1.1 yr) underwent serum PICP measurements. Patients underwent cardiac magnetic resonance imaging and outcome evaluations at baseline and 12 months. Baseline PICP values were significantly higher in the patients than in the control group (1,048 ± 77 vs 614 ± 23 ng/mL; P <0.001); severity of genetic abnormality did not indicate severity of PICP elevation. Higher PICP levels corresponded to greater LV concentric remodeling only at baseline (r=0.37, P <0.05). Higher baseline PICP strongly indicated subsequent increases in LV end-diastolic volume (r=0.52, P=0.02). The PICP levels did not distinguish between 14 patients with evident myocardial fibrosis identified through positive late gadolinium enhancement and 15 who had no enhancement (1,067 ± 125 vs 1,030 ± 98 ng/mL; P=0.82). At 12 months, cardiac events had occurred in 3 of 14 fibrosis-positive and none of 15 fibrosis-negative patients (P=0.1); their baseline PICP levels were similar. We conclude that PICP, a serum marker of collagen synthesis, is elevated in Friedreich ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy. PMID:27547137

  14. Endocardial versus epicardial electrical synchrony during LV free-wall pacing

    PubMed Central

    Faris, Owen P.; Evans, Frank J.; Dick, Alexander J.; Raman, Venkatesh K.; Ennis, Daniel B.; Kass, David A.; McVeigh, Elliot R.

    2007-01-01

    Cardiac resynchronization therapy has been most typically achieved by biventricular stimulation. However, left ventricular (LV) free-wall pacing appears equally effective in acute and chronic clinical studies. Recent data suggest electrical synchrony measured epicardially is not required to yield effective mechanical synchronization, whereas endocardial mapping data suggest synchrony (fusion with intrinsic conduction) is important. To better understand this disparity, we simultaneously mapped both endocardial and epicardial electrical activation during LV free-wall pacing at varying atrioventricular delays (AV delay 0–150 ms) in six normal dogs with the use of a 64-electrode LV endocardial basket and a 128-electrode epicardial sock. The transition from dyssynchronous LV-paced activation to synchronous RA-paced activation was studied by constructing activation time maps for both endo- and epicardial surfaces as a function of increasing AV delay. The AV delay at the transition from dyssynchronous to synchronous activation was defined as the transition delay (AVt). AVt was variable among experiments, in the range of 44–93 ms on the epicardium and 47–105 ms on the endocardium. Differences in endo- and epicardial AVt were smaller (−17 to +12 ms) and not significant on average (−5.0 ± 5.2 ms). In no instance was the transition to synchrony complete on one surface without substantial concurrent transition on the other surface. We conclude that both epicardial and endocardial synchrony due to fusion of native with ventricular stimulation occur nearly concurrently. Assessment of electrical epicardial delay, as often used clinically during cardiac resynchronization therapy lead placement, should provide adequate assessment of stimulation delay for inner wall layers as well. PMID:12855422

  15. Special Report: The Rush to Remodel

    ERIC Educational Resources Information Center

    Nation's Schools, 1973

    1973-01-01

    As more and more districts scurry to remodel outdated buildings and individual rooms, the detailed how-to-do-it sometimes gets lost in the overall planning. This article furnishes specific help in ways to remodel economically. (Author/JN)

  16. Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction.

    PubMed

    Morimoto, Hajime; Takahashi, Masafumi; Izawa, Atsushi; Ise, Hirohiko; Hongo, Minoru; Kolattukudy, Pappachan E; Ikeda, Uichi

    2006-10-13

    Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. Because monocyte chemoattractant protein-1 (MCP-1) (also known as CCL2) regulates monocytic inflammatory responses, we investigated the effect of cardiac MCP-1 overexpression on left ventricular (LV) dysfunction and remodeling in a murine MI model. Transgenic mice expressing the mouse JE-MCP-1 gene under the control of the alpha-cardiac myosin heavy chain promoter (MHC/MCP-1 mice) were used for this purpose. MHC/MCP-1 mice had reduced infarct area and scar formation and improved LV dysfunction after MI. These mice also showed induction of macrophage infiltration and neovascularization; however, few bone marrow-derived endothelial cells were detected in MHC/MCP-1 mice whose bone marrow was replaced with that of Tie2/LacZ transgenic mice. Flow cytometry analysis showed no increase in endothelial progenitor cells (CD34+/Flk-1+ cells) in MHC/MCP-1 mice. Marked myocardial interleukin (IL)-6 secretion, STAT3 activation, and LV hypertrophy were observed after MI in MHC/MCP-1 mice. Furthermore, cardiac myofibroblasts accumulated after MI in MHC/MCP-1 mice. In vitro experiments revealed that a combination of IL-6 with MCP-1 synergistically stimulated and sustained STAT3 activation in cardiomyocytes. MCP-1, IL-6, and hypoxia directly promoted the differentiation of cardiac fibroblasts into myofibroblasts. Our results suggest that cardiac overexpression of MCP-1 induced macrophage infiltration, neovascularization, myocardial IL-6 secretion, and accumulation of cardiac myofibroblasts, thereby resulting in the prevention of LV dysfunction and remodeling after MI. They also provide a new insight into the role of cardiac MCP-1 in the pathophysiology of MI. PMID:16990567

  17. Envelope Proteins of White Spot Syndrome Virus (WSSV) Interact with Litopenaeus vannamei Peritrophin-Like Protein (LvPT)

    PubMed Central

    Xie, Shijun; Zhang, Xiaojun; Zhang, Jiquan; Li, Fuhua; Xiang, Jianhai

    2015-01-01

    White spot syndrome virus (WSSV) is a major pathogen in shrimp cultures. The interactions between viral proteins and their receptors on the surface of cells in a frontier target tissue are crucial for triggering an infection. In this study, a yeast two-hybrid (Y2H) library was constructed using cDNA obtained from the stomach and gut of Litopenaeus vannamei, to ascertain the role of envelope proteins in WSSV infection. For this purpose, VP37 was used as the bait in the Y2H library screening. Forty positive clones were detected after screening. The positive clones were analyzed and discriminated, and two clones belonging to the peritrophin family were subsequently confirmed as genuine positive clones. Sequence analysis revealed that both clones could be considered as the same gene, LV-peritrophin (LvPT). Co-immunoprecipitation confirmed the interaction between LvPT and VP37. Further studies in the Y2H system revealed that LvPT could also interact with other WSSV envelope proteins such as VP32, VP38A, VP39B, and VP41A. The distribution of LvPT in tissues revealed that LvPT was mainly expressed in the stomach than in other tissues. In addition, LvPT was found to be a secretory protein, and its chitin-binding ability was also confirmed. PMID:26692362

  18. Envelope Proteins of White Spot Syndrome Virus (WSSV) Interact with Litopenaeus vannamei Peritrophin-Like Protein (LvPT).

    PubMed

    Xie, Shijun; Zhang, Xiaojun; Zhang, Jiquan; Li, Fuhua; Xiang, Jianhai

    2015-01-01

    White spot syndrome virus (WSSV) is a major pathogen in shrimp cultures. The interactions between viral proteins and their receptors on the surface of cells in a frontier target tissue are crucial for triggering an infection. In this study, a yeast two-hybrid (Y2H) library was constructed using cDNA obtained from the stomach and gut of Litopenaeus vannamei, to ascertain the role of envelope proteins in WSSV infection. For this purpose, VP37 was used as the bait in the Y2H library screening. Forty positive clones were detected after screening. The positive clones were analyzed and discriminated, and two clones belonging to the peritrophin family were subsequently confirmed as genuine positive clones. Sequence analysis revealed that both clones could be considered as the same gene, LV-peritrophin (LvPT). Co-immunoprecipitation confirmed the interaction between LvPT and VP37. Further studies in the Y2H system revealed that LvPT could also interact with other WSSV envelope proteins such as VP32, VP38A, VP39B, and VP41A. The distribution of LvPT in tissues revealed that LvPT was mainly expressed in the stomach than in other tissues. In addition, LvPT was found to be a secretory protein, and its chitin-binding ability was also confirmed.

  19. Partial LVAD restores ventricular outputs and normalizes LV but not RV stress distributions in the acutely failing heart in silico

    PubMed Central

    Sack, Kevin L.; Baillargeon, Brian; Acevedo-Bolton, Gabriel; Genet, Martin; Rebelo, Nuno; Kuhl, Ellen; Klein, Liviu; Weiselthaler, Georg M.; Burkhoff, Daniel; Franz, Thomas; Guccione, Julius M.

    2016-01-01

    Purpose Heart failure is a worldwide epidemic that is unlikely to change as the population ages and life expectancy increases. We sought to detail significant recent improvements to the Dassault Systèmes Living Heart Model (LHM) and use the LHM to compute left ventricular (LV) and right ventricular (RV) myofiber stress distributions under the following 4 conditions: (1) normal cardiac function; (2) acute left heart failure (ALHF); (3) ALHF treated using an LV assist device (LVAD) flow rate of 2 L/min; and (4) ALHF treated using an LVAD flow rate of 4.5 L/min. Methods and Results Incorporating improved systolic myocardial material properties in the LHM resulted in its ability to simulate the Frank-Starling law of the heart. We decreased myocardial contractility in the LV myocardium so that LV ejection fraction decreased from 56% to 28%. This caused mean LV end diastolic (ED) stress to increase to 508% of normal, mean LV end systolic (ES) stress to increase to 113% of normal, mean RV ED stress to decrease to 94% of normal and RV ES to increase to 570% of normal. When ALHF in the model was treated with an LVAD flow rate of 4.5 L/min, most stress results normalized. Mean LV ED stress became 85% of normal, mean LV ES stress became 109% of normal and mean RV ED stress became 95% of normal. However, mean RV ES stress improved less dramatically (to 342% of normal values). Conclusions These simulations strongly suggest that an LVAD is effective in normalizing LV stresses but not RV stresses that become elevated as a result of ALHF. PMID:27646633

  20. Adverse Stress, Hippocampal Networks, and Alzheimer's Disease

    PubMed Central

    Rothman, Sarah M.; Mattson, Mark P.

    2009-01-01

    Recent clinical data have implicated chronic adverse stress as a potential risk factor in the development of Alzheimer's disease (AD) and data also suggest that normal, physiological stress responses may be impaired in AD. It is possible that pathology associated with AD causes aberrant responses to chronic stress, due to potential alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Recent work in rodent models of AD suggests that chronic adverse stress exacerbates the cognitive deficits and hippocampal pathology that are present in the AD brain. This review summarizes recent findings obtained in experimental AD models regarding the influence of chronic adverse stress on the underlying cellular and molecular disease processes including the potential role of glucocorticoids. Emerging findings suggest that both AD and chronic adverse stress affect hippocampal neural networks in a similar fashion. We describe alterations in hippocampal plasticity that occur in both chronic stress and AD including dendritic remodeling, neurogenesis and long-term potentiation. Finally, we outline potential roles for oxidative stress and neurotrophic factor signaling as key determinants of the impact of chronic stress on the plasticity of neural networks and AD pathogenesis. PMID:19943124

  1. Asiatic acid alleviates cardiovascular remodelling in rats with L-NAME-induced hypertension.

    PubMed

    Bunbupha, Sarawoot; Prachaney, Parichat; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Welbat, Jariya Umka; Pakdeechote, Poungrat

    2015-11-01

    A previous study demonstrated the antihypertensive effect of asiatic acid. The current study investigates the effect of asiatic acid on cardiovascular remodelling and possible mechanisms involved in Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats were treated with L-NAME (40 mg/kg per day) for 3 weeks in order to induce hypertension. Hypertensive rats were administered asiatic acid (20 mg/kg per day) or vehicle for a further 2 weeks. It was found that hypertensive rats showed high systolic blood pressure, left ventricular (LV) hypertrophy, increases in LV fibrosis, aortic wall thickness and aortic collagen deposition (P < 0.05). Moreover, decreased plasma nitrate and nitrite (NOx) and increased plasma tumor necrosis factor alpha (TNF-α) were observed in hypertensive rats (P < 0.05). This was consistent with downregulation of endothelial nitric oxide synthase (eNOS) expression and upregulation of inducible nitric oxide synthase (iNOS) expression in heart and aortic tissues (P < 0.05). Levels of malondialdehyde (MDA) in plasma, aortic and heart tissues were significantly increased in hypertensive rats (P < 0.05). Asiatic acid markedly reduced blood pressure, alleviated cardiovascular remodelling, and restored plasma NOx and TNF-α as well as eNOS/iNOS expression in heart and aortic tissues (P < 0.05). Additionally, there was a significant reduction of MDA levels in the tissues of treated hypertensive rats. In conclusion, this study demonstrates the therapeutic effects of asiatic acid on blood pressure and cardiovascular remodelling, which is possibly related to the restoration of eNOS/iNOS expression, and the resulting anti-inflammatory and antioxidant activities. PMID:26234646

  2. Regulatory role of CARD3 in left ventricular remodelling and dysfunction after myocardial infarction.

    PubMed

    Li, Liangpeng; Wang, Xiaodi; Chen, Wen; Qi, Haoyu; Jiang, Ding-Sheng; Huang, Ling; Huang, Fuhua; Wang, Liming; Li, Hongliang; Chen, Xin

    2015-11-01

    Caspase activation and recruitment domain 3 (CARD3) is a caspase recruitment domain (CARD)-containing serine/threonine kinase and plays a pivotal role in apoptosis, immunity, tissue development and proliferation. To date, the causal relationship between CARD3 and myocardial infarction (MI) remains largely unexplored. This study aimed to identify the functional significance of CARD3 in the regulation of cardiac remodelling after MI and the underlying mechanisms of its effects. The levels of CARD3 expression were up-regulated in failing human and mouse post-infarction hearts. In addition, CARD3-knockout (KO) mice and transgenic mice overexpressing CARD3 in the heart were then generated and subjected to MI. Compared with wild-type (WT) control mice, CARD3-KO mice developed smaller infarct sizes, improved survival rates, and preserved left ventricle (LV) function after MI. Significantly, CARD3-KO hearts had less cardiomyocyte apoptosis and inflammatory cell infiltration in the infarct border zone. Attenuated LV remodelling was also observed in the KO hearts following MI, with reduced cardiac hypertrophy and fibrosis. Conversely, CARD3 overexpression resulted in the opposite MI-induced phenotype. Similar results were observed in ex vivo-cultured neonatal rat cardiomyocytes exposed to hypoxia. Mechanistically, we discovered that the CARD3-mediated detrimental effects of MI were associated with the activation of the NF-κB and p38 signalling cascades. Taken together, these data demonstrate that CARD3 serves as a novel positive modulator of ventricular remodelling after MI via the regulation of the NF-κB and p38 signalling. Thus, CARD3 may be a promising therapeutic target for the treatment of heart failure after MI.

  3. Impact on Left Ventricular Function and Remodeling and on 1-Year Outcome in Patients With Left Bundle Branch Block After Transcatheter Aortic Valve Implantation.

    PubMed

    Carrabba, Nazario; Valenti, Renato; Migliorini, Angela; Marrani, Marco; Cantini, Giulia; Parodi, Guido; Dovellini, Emilio Vincenzo; Antoniucci, David

    2015-07-01

    Conflicting results have been reported about the prognostic impact of left bundle branch block (LBBB) after transcatheter aortic valve implantation (TAVI). The aim of this study was to evaluate the impact of LBBB after TAVI on left ventricular (LV) function and remodeling and on 1-year outcomes. Of 101 TAVI patients, 9 were excluded. All complications were evaluated according to the Valve Academic Research Consortium 2 definition. Of 92 patients, 34 developed LBBB without more advanced myocardial damage or inflammation biomarkers in comparison with patients without LBBB. The only predictor of new LBBB was larger baseline LV end-diastolic volume. LBBB plus advanced atrioventricular block was strongly correlated with permanent pacemaker implantation (p <0.0001). Patients with LBBB had a higher rate of permanent pacemaker implantation at 30 days (59% vs 19%, p <0.0001) and less recovery of LV systolic function and a trend toward a lower rate of LV reverse remodeling at 1 year. The development of acute kidney injury and the logistic European System for Cardiac Operative Risk Evaluation score were associated with poor outcomes (all-cause mortality and heart failure) (hazard ratio 6.86, 95% confidence interval 2.51 to 18.74, p <0.0001, and hazard ratio 1.04, 95% confidence interval 1.01 to 1.08, p = 0.021, respectively), but not LBBB. In conclusion, after TAVI, 37% of patients developed new LBBB without more advanced myocardial damage or inflammation biomarkers. LBBB was associated with a higher rate of permanent pacemaker implantation, which negatively affected the recovery of LV systolic function. The development of acute kidney injury, rather than LBBB, increases the 1-year risk for mortality and hospitalization for heart failure. PMID:25937352

  4. Remodeling of ribosomal genes in somatic cells by Xenopus egg extract

    SciTech Connect

    Ostrup, Olga; Hyttel, Poul; Klaerke, Dan A.; Collas, Philippe

    2011-09-02

    Highlights: {yields} Xenopus egg extract remodels nuclei and alter cell growth characteristics. {yields} Ribosomal genes are reprogrammed within 6 h after extract exposure. {yields} rDNA reprogramming involves promoter targeting of SNF2H remodeling complex. {yields} Xenopus egg extract does not initiate stress-related response in somatic cells. {yields} Aza-cytidine elicits a stress-induced response in reprogrammed cells. -- Abstract: Extracts from Xenopus eggs can reprogram gene expression in somatic nuclei, however little is known about the earliest processes associated with the switch in the transcriptional program. We show here that an early reprogramming event is the remodeling of ribosomal chromatin and gene expression. This occurs within hours of extract treatment and is distinct from a stress response. Egg extract elicits remodeling of the nuclear envelope, chromatin and nucleolus. Nucleolar remodeling involves a rapid and stable decrease in ribosomal gene transcription, and promoter targeting of the nucleolar remodeling complex component SNF2H without affecting occupancy of the transcription factor UBF and the stress silencers SUV39H1 and SIRT1. During this process, nucleolar localization of UBF and SIRT1 is not altered. On contrary, azacytidine pre-treatment has an adverse effect on rDNA remodeling induced by extract and elicits a stress-type nuclear response. Thus, an early event of Xenopus egg extract-mediated nuclear reprogramming is the remodeling of ribosomal genes involving nucleolar remodeling complex. Condition-specific and rapid silencing of ribosomal genes may serve as a sensitive marker for evaluation of various reprogramming methods.

  5. Cellular entry via an actin and clathrin-dependent route is required for Lv2 restriction of HIV-2

    SciTech Connect

    Harrison, I.P.; McKnight, A.

    2011-06-20

    Lv2 is a human factor that restricts infection of some HIV-2 viruses after entry into particular target cells. HIV-2 MCR is highly susceptible to Lv2 whereas HIV-2 MCN is not. The block is after reverse transcription but prior to nuclear entry. The viral determinants for this restriction have been mapped to the HIV-2 envelope and the capsid genes. Our model of Lv2 restriction suggests that the route taken into a cell is important in determining whether a productive infection occurs. Here we characterised the infectious routes used by MCN and MCR using chemical compounds and molecular techniques to distinguish between potential pathways. Our results suggest that susceptible MCR can enter restrictive HeLa{sup CD4} cells via two pathways; a clathrin/AP2 mediated endocytic route that is sensitive to Lv2 restriction and an alternative, non-clathrin mediated route, which results in more efficient infection.

  6. Neural remodeling in retinal degeneration.

    PubMed

    Marc, Robert E; Jones, Bryan W; Watt, Carl B; Strettoi, Enrica

    2003-09-01

    Mammalian retinal degenerations initiated by gene defects in rods, cones or the retinal pigmented epithelium (RPE) often trigger loss of the sensory retina, effectively leaving the neural retina deafferented. The neural retina responds to this challenge by remodeling, first by subtle changes in neuronal structure and later by large-scale reorganization. Retinal degenerations in the mammalian retina generally progress through three phases. Phase 1 initiates with expression of a primary insult, followed by phase 2 photoreceptor death that ablates the sensory retina via initial photoreceptor stress, phenotype deconstruction, irreversible stress and cell death, including bystander effects or loss of trophic support. The loss of cones heralds phase 3: a protracted period of global remodeling of the remnant neural retina. Remodeling resembles the responses of many CNS assemblies to deafferentation or trauma, and includes neuronal cell death, neuronal and glial migration, elaboration of new neurites and synapses, rewiring of retinal circuits, glial hypertrophy and the evolution of a fibrotic glial seal that isolates the remnant neural retina from the surviving RPE and choroid. In early phase 2, stressed photoreceptors sprout anomalous neurites that often reach the inner plexiform and ganglion cell layers. As death of rods and cones progresses, bipolar and horizontal cells are deafferented and retract most of their dendrites. Horizontal cells develop anomalous axonal processes and dendritic stalks that enter the inner plexiform layer. Dendrite truncation in rod bipolar cells is accompanied by revision of their macromolecular phenotype, including the loss of functioning mGluR6 transduction. After ablation of the sensory retina, Müller cells increase intermediate filament synthesis, forming a dense fibrotic layer in the remnant subretinal space. This layer invests the remnant retina and seals it from access via the choroidal route. Evidence of bipolar cell death begins in

  7. Incomplete RV Remodeling After Transcatheter ASD Closure in Pediatric Age.

    PubMed

    Agha, Hala M; El-Saiedi, Sonia A; Shaltout, Mohamed F; Hamza, Hala S; Nassar, Hayat H; Abdel-Aziz, Doaa M; Tantawy, Amira Esmat El

    2015-10-01

    Published data showing the intermediate effect of transcatheter device closure of atrial septal defect (ASD) in the pediatric age-group are scarce. The objective of the study was to assess the effects of transcatheter ASD closure on right and left ventricular functions by tissue Doppler imaging (TDI). The study included 37 consecutive patients diagnosed as ASD secundum by transthoracic echocardiography and TEE and referred for transcatheter closure at Cairo University Specialized Pediatric Hospital, Egypt, from October 2010 to July 2013. Thirty-seven age- and sex-matched controls were selected. TDI was obtained using the pulsed Doppler mode, interrogating the right cardiac border (the tricuspid annulus) and lateral mitral annulus, and myocardial performance index (MPI) was calculated at 1-, 3-, 6- and 12-month post-device closure. Transcatheter closure of ASD and echocardiographic examinations were successfully performed in all patients. There were no significant differences between two groups as regards the age, gender, weight or BSA. TDI showed that patients with ASD had significantly prolonged isovolumetric contraction, relaxation time and MPI compared with control group. Decreased tissue Doppler velocities of RV and LV began at one-month post-closure compared with the controls. Improvement in RVMPI and LVMPI began at 1-month post-closure, but they are still prolonged till 1 year. Reverse remodeling of right and left ventricles began 1 month after transcatheter ASD closure, but did not completely normalize even after 1 year of follow-up by tissue Doppler imaging.

  8. Haptoglobin genotype is a determinant of survival and cardiac remodeling after myocardial infarction in diabetic mice

    PubMed Central

    Asaf, Roy; Blum, Shany; Roguin, Ariel; Kalet-Litman, Shiri; Kheir, Jad; Frisch, Avi; Miller-Lotan, Rachel; Levy, Andrew P

    2009-01-01

    Background We have recently demonstrated in man that a functional allelic polymorphism in the Haptoglobin (Hp) gene plays a major role in determining survival and congestive heart failure after myocardial infarction (MI). We sought to recapitulate the effect of Hp type on outcomes and cardiac remodeling after MI in transgenic mice. Methods The Hp 2 allele exists only in man. Wild type C57Bl/6 mice carry the Hp 1 allele with high homology to the human Hp 1 allele. We genetically engineered a murine Hp 2 allele and targeted its insertion by homologous recombination to the murine Hp locus to create Hp 2 mice. Diabetes Mellitus (DM) was induced with streptozotocin. MI was produced by occlusion of the left anterior descending artery in DM C57Bl/6 mice carrying the Hp 1 or Hp 2 allele. MI size was determined with TTC staining. Left ventricular (LV) function and dimensions were assessed by 2-dimensional echocardiography. Results In the absence of DM, Hp 1-1 and Hp 2-2 mice had similar LV dimensions and LV function. MI size was similar in DM Hp 1-1 and 2-2 mice 24 hours after MI (50.2 ± 2.1%and 46.9 ± 5.5%, respectively, p = 0.6). However, DM Hp 1-1 mice had a significantly lower mortality rate than DM Hp 2-2 mice 30 days after MI (HR 0.41, 95% CI (0.19–0.95), p = 0.037 by log rank). LV chamber dimensions were significantly increased in DM Hp 2-2 mice compared to DM Hp 1-1 mice 30 days after MI (0.196 ± 0.01 cm2 vs. 0.163 ± 0.01 cm2, respectively; p = 0.029). Conclusion In DM mice the Hp 2-2 genotype is associated with increased mortality and more severe cardiac remodeling 30 days after MI. PMID:19490627

  9. Frontiers in growth and remodeling

    PubMed Central

    Menzel, Andreas; Kuhl, Ellen

    2012-01-01

    Unlike common engineering materials, living matter can autonomously respond to environmental changes. Living structures can grow stronger, weaker, larger, or smaller within months, weeks, or days as a result of a continuous microstructural turnover and renewal. Hard tissues can adapt by increasing their density and grow strong. Soft tissues can adapt by increasing their volume and grow large. For more than three decades, the mechanics community has actively contributed to understand the phenomena of growth and remodeling from a mechanistic point of view. However, to date, there is no single, unified characterization of growth, which is equally accepted by all scientists in the field. Here we shed light on the continuum modeling of growth and remodeling of living matter, and give a comprehensive overview of historical developments and trends. We provide a state-of-the-art review of current research highlights, and discuss challenges and potential future directions. Using the example of volumetric growth, we illustrate how we can establish and utilize growth theories to characterize the functional adaptation of soft living matter. We anticipate this review to be the starting point for critical discussions and future research in growth and remodeling, with a potential impact on life science and medicine. PMID:22919118

  10. Vascular Remodeling in Pulmonary Hypertension

    PubMed Central

    Shimoda, Larissa A; Laurie, Steven S.

    2013-01-01

    Pulmonary hypertension is a complex, progressive condition arising from a variety of genetic and pathogenic causes. Patients present with a spectrum of histologic and pathophysiological features, likely reflecting the diversity in underlying pathogenesis. It is widely recognized that structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions and the appearance of cells expressing smooth muscle specific markers in normally non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular trans-differentiation. The development of several animal models of pulmonary hypertension has provided the means to explore the mechanistic underpinnings of pulmonary vascular remodeling, although none of the experimental models currently used entirely replicates the pulmonary arterial hypertension observed in patients. Herein, we provide an overview of the histological abnormalities observed in humans with pulmonary hypertension and in preclinical models and discuss insights gained regarding several key signaling pathways contributing to the remodeling process. In particular, we will focus on the roles of ion homeostasis, endothelin-1, serotonin, bone morphogenetic proteins, Rho kinase and hypoxia-inducible factor 1 in pulmonary arterial smooth muscle and endothelial cells, highlighting areas of cross-talk between these pathways and potentials for therapeutic targeting. PMID:23334338

  11. Frontiers in growth and remodeling.

    PubMed

    Menzel, Andreas; Kuhl, Ellen

    2012-06-01

    Unlike common engineering materials, living matter can autonomously respond to environmental changes. Living structures can grow stronger, weaker, larger, or smaller within months, weeks, or days as a result of a continuous microstructural turnover and renewal. Hard tissues can adapt by increasing their density and grow strong. Soft tissues can adapt by increasing their volume and grow large. For more than three decades, the mechanics community has actively contributed to understand the phenomena of growth and remodeling from a mechanistic point of view. However, to date, there is no single, unified characterization of growth, which is equally accepted by all scientists in the field. Here we shed light on the continuum modeling of growth and remodeling of living matter, and give a comprehensive overview of historical developments and trends. We provide a state-of-the-art review of current research highlights, and discuss challenges and potential future directions. Using the example of volumetric growth, we illustrate how we can establish and utilize growth theories to characterize the functional adaptation of soft living matter. We anticipate this review to be the starting point for critical discussions and future research in growth and remodeling, with a potential impact on life science and medicine. PMID:22919118

  12. Chromatin remodeling in plant development.

    PubMed

    Jarillo, José A; Piñeiro, Manuel; Cubas, Pilar; Martínez-Zapater, José M

    2009-01-01

    Plant development results from specific patterns of gene expression that are tightly regulated in a spatio-temporal manner. Chromatin remodeling plays a central role in establishing these expression patterns and maintaining epigenetic transcriptional states through successive rounds of mitosis that take place within a cell lineage. Plant epigenetic switches occur not only at the embryo stage, but also during postembryonic developmental transitions, suggesting that chromatin remodeling activities in plants can provide a higher degree of regulatory flexibility which probably underlies their developmental plasticity. Here, we highlight recent progress in the understanding of plant chromatin dynamic organization, facilitating the activation or repression of specific sets of genes involved in different developmental programs and integrating them with the response to environmental signals. Chromatin conformation controls gene expression both in actively dividing undifferentiated cells and in those already fate-determined. In this context, we first describe chromatin reorganization activities required to maintain meristem function stable through DNA replication and cell division. Organ initiation at the apex, with emphasis on reproductive development, is next discussed to uncover the chromatin events involved in the establishment and maintenance of expression patterns associated with differentiating cells; this is illustrated with the complex epigenetic regulation of the Arabidopsis floral repressor FLOWERING LOCUS C (FLC). Finally, we discuss the involvement of chromatin remodeling in plant responses to environmental cues and to different types of stress conditions.

  13. Rodent Biocompatibility Test Using the NASA Foodbar and Epoxy EP21LV

    NASA Technical Reports Server (NTRS)

    Tillman, J.; Steele, M.; Dumars, P.; Vasques, M.; Girten, B.; Sun, S. (Technical Monitor)

    2002-01-01

    Epoxy has been used successfully to affix NASA foodbars to the inner walls of the Animal Enclosure Module for past space flight experiments utilizing rodents. The epoxy used on past missions was discontinued, making it necessary to identify a new epoxy for use on the STS-108 and STS-107 missions. This experiment was designed to test the basic biocompatibility of epoxy EP21LV with male rats (Sprague Dawley) and mice (Swiss Webster) when applied to NASA foodbars. For each species, the test was conducted with a control group fed untreated foodbars and an experimental group fed foodbars applied with EP21LV. For each species, there were no group differences in animal health and no statistical differences (P<0.05) in body weights throughout the study. In mice, there was a 16% increase in heart weight in the epoxy group; this result was not found in rats. For both species, there were no statistical differences found in other organ weights measured. In rats, blood glucose levels were 15% higher and both total protein and globulin were 10% lower in the epoxy group. Statistical differences in these parameters were not found in mice. For both species, no statistical differences were found in other blood parameters tested. Food consumption was not different in rats but water consumption was significantly decreased 10 to 15% in the epoxy group. The difference in water consumption is likely due to an increased water content of the epoxy-treated foodbars. Finally, both species avoided consumption of the epoxy material. Based on the global analysis of the results, the few parameters found to be statistically different do not appear to be a physiologically relevant effect of the epoxy material, We conclude that the EP21LV epoxy is biocompatible with rodents.

  14. Cardiac fibroblast GSK-3β regulates ventricular remodeling and dysfunction in ischemic heart

    PubMed Central

    Lal, Hind; Ahmad, Firdos; Zhou, Jibin; Yu, Justine E.; Vagnozzi, Ronald J.; Guo, Yuanjun; Yu, Daohai; Tsai, Emily J.; Woodgett, James; Gao, Erhe; Force, Thomas

    2014-01-01

    Background Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. Following MI, activated cardiac fibroblasts (CFs) deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate and new molecular targets are needed. Methods and Results Herein we report that GSK-3β is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using two fibroblast-specific GSK-3β knockout mouse models, we show that deletion of GSK-3β in CFs leads to fibrogenesis, left ventricular dysfunction and excessive scarring in the ischemic heart. Deletion of GSK-3β induces a pro-fibrotic myofibroblast phenotype in isolated CFs, in post-MI hearts, and in MEFs deleted for GSK-3β. Mechanistically, GSK-3β inhibits pro-fibrotic TGF-β1-SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3β resulted in the suppression of SMAD-3 transcriptional activity. This pathway is central to the pathology since a small molecule inhibitor of SMAD-3 largely prevented fibrosis and limited LV remodeling. Conclusion These studies support targeting GSK-3β in myocardial fibrotic disorders and establish critical roles of CFs in remodeling and ventricular dysfunction. PMID:24899689

  15. LV Dyssynchrony Is Helpful in Predicting Ventricular Arrhythmia in Ischemic Cardiomyopathy After Cardiac Resynchronization Therapy

    PubMed Central

    Tsai, Shih-Chuan; Chang, Yu-Cheng; Chiang, Kuo-Feng; Lin, Wan-Yu; Huang, Jin-Long; Hung, Guang-Uei; Kao, Chia-Hung; Chen, Ji

    2016-01-01

    Abstract For patients with coronary artery disease, larger scar burdens are associated with higher risk of ventricular arrhythmia. Left ventricular (LV) dyssynchrony is associated with increased risk of sudden cardiac death in patients with heart failure. The purpose of this study was to assess the values of LV dyssynchrony and myocardial scar assessed by myocardial perfusion SPECT (MPS) in predicting the development of ventricular arrhythmia in ischemic cardiomyopathy. Twenty-two patients (16 males, mean age: 66 ± 13) with irreversible ischemic cardiomyopathy received cardiac resynchronization therapy (CRT) for at least 12 months were enrolled for MPS. Quantitative parameters, including LV dyssynchrony with phase standard deviation (phase SD) and bandwidth, left ventricular ejection fraction (LVEF), and scar (% of total areas), were generated by Emory Cardiac Toolbox. Ventricular tachycardia (VT) and ventricular fibrillation (VF) recorded in the CRT device during follow-up were used as the reference standard of diagnosing ventricular arrhythmia. Stepwise logistic regression analysis was performed for determining the independent predictors of VT/VF and receiver operating characteristic (ROC) curve analysis was used for generating the optimal cut-off values for predicting VT/VF. Nine (41%) of the 22 patients developed VT/VF during the follow-up periods. Patients with VT/VF had significantly lower LVEF, larger scar, larger phase SD, and larger bandwidth (all P < 0.05). Logistic regression analysis showed LVEF and bandwidth were independent predictors of VT/VF. ROC curve analysis showed the areas under the curves were 0.71 and 0.83 for LVEF and bandwidth, respectively. The optimal cut-off values were <36% and > 139° for LVEF and bandwidth, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 39%, 53%, and 100%, respectively, for LVEF; and were 78%, 92%, 88%, and 86%, respectively, for bandwidth. LV

  16. Development and evaluation of a semiautomatic segmentation method for the estimation of LV parameters on cine MR images

    NASA Astrophysics Data System (ADS)

    Mazonakis, Michalis; Grinias, Elias; Pagonidis, Konstantin; Tziritas, George; Damilakis, John

    2010-02-01

    The purpose of this study was to develop and evaluate a semiautomatic method for left ventricular (LV) segmentation on cine MR images and subsequent estimation of cardiac parameters. The study group comprised cardiac MR examinations of 18 consecutive patients with known or suspected coronary artery disease. The new method allowed the automatic detection of the LV endocardial and epicardial boundaries on each short-axis cine MR image using a Bayesian flooding segmentation algorithm and weighted least-squares B-splines minimization. Manual editing of the automatic contours could be performed for unsatisfactory segmentation results. The end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF) and LV mass estimated by the new method were compared with the reference values obtained by manually tracing the LV cavity borders. The reproducibility of the new method was determined using data from two independent observers. The mean number of endocardial and epicardial outlines not requiring any manual adjustment was more than 80% and 76% of the total contour number per study, respectively. The mean segmentation time including the required manual corrections was 2.3 ± 0.7 min per patient. LV volumes estimated by the semiautomatic method were significantly lower than those by manual tracing (P < 0.05), whereas no difference was found for EF and LV mass (P > 0.05). LV indices estimated by the two methods were well correlated (r >= 0.80). The mean difference between manual and semiautomatic method for estimating EDV, ESV, EF and LV mass was 6.1 ± 7.2 ml, 3.0 ± 5.2 ml, -0.6 ± 4.3% and -6.2 ± 12.2 g, respectively. The intraobserver and interobserver variability associated with the semiautomatic determination of LV indices was 0.5-1.2% and 0.8-3.9%, respectively. The estimation of LV parameters with the new semiautomatic segmentation method is technically feasible, highly reproducible and time effective.

  17. Key Residues in the Nicotinic Acetylcholine Receptor β2 Subunit Contribute to α-Conotoxin LvIA Binding*

    PubMed Central

    Zhangsun, Dongting; Zhu, Xiaopeng; Wu, Yong; Hu, Yuanyan; Kaas, Quentin; Craik, David J.; McIntosh, J. Michael; Luo, Sulan

    2015-01-01

    α-Conotoxin LvIA (α-CTx LvIA) is a small peptide from the venom of the carnivorous marine gastropod Conus lividus and is the most selective inhibitor of α3β2 nicotinic acetylcholine receptors (nAChRs) known to date. It can distinguish the α3β2 nAChR subtype from the α6β2* (* indicates the other subunit) and α3β4 nAChR subtypes. In this study, we performed mutational studies to assess the influence of residues of the β2 subunit versus those of the β4 subunit on the binding of α-CTx LvIA. Although two β2 mutations, α3β2[F119Q] and α3β2[T59K], strongly enhanced the affinity of LvIA, the β2 mutation α3β2[V111I] substantially reduced the binding of LvIA. Increased activity of LvIA was also observed when the β2-T59L mutant was combined with the α3 subunit. There were no significant difference in inhibition of α3β2[T59I], α3β2[Q34A], and α3β2[K79A] nAChRs when compared with wild-type α3β2 nAChR. α-CTx LvIA displayed slower off-rate kinetics at α3β2[F119Q] and α3β2[T59K] than at the wild-type receptor, with the latter mutant having the most pronounced effect. Taken together, these data provide evidence that the β2 subunit contributes to α-CTx LvIA binding and selectivity. The results demonstrate that Val111 is critical and facilitates LvIA binding; this position has not previously been identified as important to binding of other 4/7 framework α-conotoxins. Thr59 and Phe119 of the β2 subunit appear to interfere with LvIA binding, and their replacement by the corresponding residues of the β4 subunit leads to increased affinity. PMID:25713061

  18. Erythrocyte stiffness during morphological remodeling induced by carbon ion radiation.

    PubMed

    Zhang, Baoping; Liu, Bin; Zhang, Hong; Wang, Jizeng

    2014-01-01

    The adverse effect induced by carbon ion radiation (CIR) is still an unavoidable hazard to the treatment object. Thus, evaluation of its adverse effects on the body is a critical problem with respect to radiation therapy. We aimed to investigate the change between the configuration and mechanical properties of erythrocytes induced by radiation and found differences in both the configuration and the mechanical properties with involving in morphological remodeling process. Syrian hamsters were subjected to whole-body irradiation with carbon ion beams (1, 2, 4, and 6 Gy) or X-rays (2, 4, 6, and 12 Gy) for 3, 14 and 28 days. Erythrocytes in peripheral blood and bone marrow were collected for cytomorphological analysis. The mechanical properties of the erythrocytes were determined using atomic force microscopy, and the expression of the cytoskeletal protein spectrin-α1 was analyzed via western blotting. The results showed that dynamic changes were evident in erythrocytes exposed to different doses of carbon ion beams compared with X-rays and the control (0 Gy). The magnitude of impairment of the cell number and cellular morphology manifested the subtle variation according to the irradiation dose. In particular, the differences in the size, shape and mechanical properties of the erythrocytes were well exhibited. Furthermore, immunoblot data showed that the expression of the cytoskeletal protein spectrin-α1 was changed after irradiation, and there was a common pattern among its substantive characteristics in the irradiated group. Based on these findings, the present study concluded that CIR could induce a change in mechanical properties during morphological remodeling of erythrocytes. According to the unique characteristics of the biomechanical categories, we deduce that changes in cytomorphology and mechanical properties can be measured to evaluate the adverse effects generated by tumor radiotherapy. Additionally, for the first time, the current study provides a new

  19. Erythrocyte Stiffness during Morphological Remodeling Induced by Carbon Ion Radiation

    PubMed Central

    Zhang, Baoping; Liu, Bin; Zhang, Hong; Wang, Jizeng

    2014-01-01

    The adverse effect induced by carbon ion radiation (CIR) is still an unavoidable hazard to the treatment object. Thus, evaluation of its adverse effects on the body is a critical problem with respect to radiation therapy. We aimed to investigate the change between the configuration and mechanical properties of erythrocytes induced by radiation and found differences in both the configuration and the mechanical properties with involving in morphological remodeling process. Syrian hamsters were subjected to whole-body irradiation with carbon ion beams (1, 2, 4, and 6 Gy) or X-rays (2, 4, 6, and 12 Gy) for 3, 14 and 28 days. Erythrocytes in peripheral blood and bone marrow were collected for cytomorphological analysis. The mechanical properties of the erythrocytes were determined using atomic force microscopy, and the expression of the cytoskeletal protein spectrin-α1 was analyzed via western blotting. The results showed that dynamic changes were evident in erythrocytes exposed to different doses of carbon ion beams compared with X-rays and the control (0 Gy). The magnitude of impairment of the cell number and cellular morphology manifested the subtle variation according to the irradiation dose. In particular, the differences in the size, shape and mechanical properties of the erythrocytes were well exhibited. Furthermore, immunoblot data showed that the expression of the cytoskeletal protein spectrin-α1 was changed after irradiation, and there was a common pattern among its substantive characteristics in the irradiated group. Based on these findings, the present study concluded that CIR could induce a change in mechanical properties during morphological remodeling of erythrocytes. According to the unique characteristics of the biomechanical categories, we deduce that changes in cytomorphology and mechanical properties can be measured to evaluate the adverse effects generated by tumor radiotherapy. Additionally, for the first time, the current study provides a new

  20. Simulation of LV pacemaker lead in marginal vein: potential risk factors for acute dislodgement.

    PubMed

    Zhao, Xuefeng; Burger, Mike; Liu, Yi; Das, Mithilesh K; Combs, William; Wenk, Jonathan F; Guccione, Julius M; Kassab, Ghassan S

    2011-03-01

    Although left ventricular (LV) coronary sinus lead dislodgement remains a problem, the risk factors for dislodgement have not been clearly defined. In order to identify potential risk factors for acute lead dislodgement, we conducted dynamic finite element simulations of pacemaker lead dislodgement in marginal LV vein. We considered factors such as mismatch in lead and vein diameters, velocity of myocardial motion, branch angle between the insertion vein and the coronary sinus, degree of slack, and depth of insertion. The results show that large lead-to-vein diameter mismatch, rapid myocardial motion, and superficial insertion are potential risk factors for lead dislodgement. In addition, the degree of slack presents either a positive or negative effect on dislodgement risk depending on the branch angle. The prevention of acute lead dislodgment can be enforced by inducing as much static friction force as possible at the lead-vein interface, while reducing the external force. If the latter exceeds the former, dislodgement will occur. The present findings underscore the major risk factors for lead dislodgment, which may improve implantation criterion and future lead design. PMID:21303182

  1. Motion corrected LV quantification based on 3D modelling for improved functional assessment in cardiac MRI

    NASA Astrophysics Data System (ADS)

    Liew, Y. M.; McLaughlin, R. A.; Chan, B. T.; Aziz, Y. F. Abdul; Chee, K. H.; Ung, N. M.; Tan, L. K.; Lai, K. W.; Ng, S.; Lim, E.

    2015-04-01

    Cine MRI is a clinical reference standard for the quantitative assessment of cardiac function, but reproducibility is confounded by motion artefacts. We explore the feasibility of a motion corrected 3D left ventricle (LV) quantification method, incorporating multislice image registration into the 3D model reconstruction, to improve reproducibility of 3D LV functional quantification. Multi-breath-hold short-axis and radial long-axis images were acquired from 10 patients and 10 healthy subjects. The proposed framework reduced misalignment between slices to subpixel accuracy (2.88 to 1.21 mm), and improved interstudy reproducibility for 5 important clinical functional measures, i.e. end-diastolic volume, end-systolic volume, ejection fraction, myocardial mass and 3D-sphericity index, as reflected in a reduction in the sample size required to detect statistically significant cardiac changes: a reduction of 21-66%. Our investigation on the optimum registration parameters, including both cardiac time frames and number of long-axis (LA) slices, suggested that a single time frame is adequate for motion correction whereas integrating more LA slices can improve registration and model reconstruction accuracy for improved functional quantification especially on datasets with severe motion artefacts.

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

    NASA Astrophysics Data System (ADS)

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

    2016-03-01

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

  3. Seeding considerations for an LV system in a large transonic wind tunnel

    NASA Technical Reports Server (NTRS)

    Freedman, R. J.

    1982-01-01

    When it was decided to use a laser velocimeter to measure the properties of propellers, seeding was a great concern since large particles fail to flow and small ones are too small to be seen. Many methods were tried and weeded out by using a Malvern particle sizer. The most promising ones were tested in the tunnel and the laser velocimeter (LV) measurements compared to theoretical values of veocity as the particle approached a blunt nose body along a stagnation streamline. Data obtained from the LV system were compared with the one dimensional particle lag calculation. This figure showed the theoretical velocity over the blunt nose and a velocity profile for 5 um particles. This indicated the particles were approximately 5 um. The seeding method is shown. The seed was atomized by 2 seeders run with all 12 available atomizer jets on. The atomizer seed traveled from these two seeders through four 1 inch tubes 20 feet long to the plenum chamber where this cluster of tubes injected the seed into the air stream. The tubes were located 60 feet from the model and could be moved only by shutting the tunnel down. Future seeding plans are shown.

  4. Surface glycosaminoglycans mediate adherence between HeLa cells and Lactobacillus salivarius Lv72

    PubMed Central

    2013-01-01

    Background The adhesion of lactobacilli to the vaginal surface is of paramount importance to develop their probiotic functions. For this reason, the role of HeLa cell surface proteoglycans in the attachment of Lactobacillus salivarius Lv72, a mutualistic strain of vaginal origin, was investigated. Results Incubation of cultures with a variety of glycosaminoglycans (chondroitin sulfate A and C, heparin and heparan sulfate) resulted in marked binding interference. However, no single glycosaminoglycan was able to completely abolish cell binding, the sum of all having an additive effect that suggests cooperation between them and recognition of specific adhesins on the bacterial surface. In contrast, chondroitin sulfate B enhanced cell to cell attachment, showing the relevance of the stereochemistry of the uronic acid and the sulfation pattern on binding. Elimination of the HeLa surface glycosaminoglycans with lyases also resulted in severe adherence impairment. Advantage was taken of the Lactobacillus-glycosaminoglycans interaction to identify an adhesin from the bacterial surface. This protein, identify as a soluble binding protein of an ABC transporter system (OppA) by MALDI-TOF/(MS), was overproduced in Escherichia coli, purified and shown to interfere with L. salivarius Lv72 adhesion to HeLa cells. Conclusions These data suggest that glycosaminoglycans play a fundamental role in attachment of mutualistic bacteria to the epithelium that lines the cavities where the normal microbiota thrives, OppA being a bacterial adhesin involved in the process. PMID:24044741

  5. MicroRNA-214 Inhibits Left Ventricular Remodeling in an Acute Myocardial Infarction Rat Model by Suppressing Cellular Apoptosis via the Phosphatase and Tensin Homolog (PTEN).

    PubMed

    Yang, Xingwei; Qin, Yanjun; Shao, Suxia; Yu, Yueqing; Zhang, Chongyang; Dong, Hua; Lv, Guangwei; Dong, Shimin

    2016-01-01

    The aims of the present study were to determine the role of miR-214 on left ventricular remodeling of rat heart with acute myocardial infarction (AMI) and to further investigate the underlying mechanism of miR-214-mediated myocardial protection. AMI was induced in which adenovirus-expressing miR-214 (Ad-miR-214), anti-miR-214, or Ad-GFP had been delivered into rats hearts 4 days prior, while a phosphatase and tensin homolog (PTEN) inhibitor was administered via intra-peritoneal injection 30 minutes prior to AMI. Changes in hemodynamic parameters were detected and recorded. Left ventricular (LV) dimensions and LV/BW were measured. Quantitative RT-PCR was used to determine the miR-214 expression levels of the myocytes in the infarcted, border, and non-infarcted areas of the LV. Myocardial infarct size was also measured. Flow cytometry analysis was performed to examine cellular apoptosis. Western blot analysis was performed to examine PTEN expression. The results showed that miR-214 was upregulated in both border and infarcted areas. Myocardial cell apoptosis was decreased in the Ad-miR-214 group, but was increased in the anti-miR-214 group, while there were no differences among the Ad-GFP-group, PTEN-ad-miR-214 group, or PTEN-anti-miR-214 group. Myocardial infarct size, LV dimensions, heart rate (HR), and LV end-diastolic pressure (LVEDP) were decreased while the maximal rates of rise or decline in blood pressure in the ventricular chamber (± dp/dt) and LV systolic pressure (LVSP) were increased in the Ad-miR-214 group, all of which exhibited opposite changes in the anti-miR-214 group. PTEN was downregulated in the Ad-miR-214 group and upregulated in the anti-miR-214 group. PTEN was decreased in both the border and infarcted areas compared with non-infarcted areas. The study results suggest that Ad-miR-214 improves LV remodeling and decreases the apoptosis of myocardial cells through PTEN, suggesting a possible mechanism by which Ad-miR-214 functions in protecting

  6. Pulsatile Fluid Shear in Bone Remodeling

    NASA Technical Reports Server (NTRS)

    Frangos, John A.

    1997-01-01

    The objective of this investigation was to elucidate the sensitivity to transients in fluid shear stress in bone remodeling. Bone remodeling is clearly a function of the local mechanical environment which includes interstitial fluid flow. Traditionally, load-induced remodeling has been associated with low frequency (1-2 Hz) signals attributed to normal locomotion. McLeod and Rubin, however, demonstrated in vivo remodeling events associated with high frequency (15-30 Hz) loading. Likewise, other in vivo studies demonstrated that slowly applied strains did not trigger remodeling events. We therefore hypothesized that the mechanosensitive pathways which control bone maintenance and remodeling are differentially sensitive to varying rates of applied fluid shear stress.

  7. Exposure of cats to low doses of FeLV: seroconversion as the sole parameter of infection.

    PubMed

    Major, Andrea; Cattori, Valentino; Boenzli, Eva; Riond, Barbara; Ossent, Peter; Meli, Marina Luisa; Hofmann-Lehmann, Regina; Lutz, Hans

    2010-01-01

    In felids, feline leukemia virus (FeLV) infection results in a variety of outcomes that range from abortive (virus readily eliminated and never detectable) to progressive infection (persistent viremia and viral shedding). Recently, a novel outcome was postulated for low FeLV infectious doses. Naïve cats exposed to faeces of persistently infected cats seroconverted, indicating infection, but remained negative for provirus and p27 antigen in blood. FeLV provirus was found in some tissues but not in the bone marrow, infection of which is usually considered a necessary stage for disease progression. To investigate the impact of low FeLV doses on young cats and to test the hypothesis that low dose exposure may lead to an unknown pathogenesis of infection without involvement of the bone marrow, 21 cats were infected oronasally with variable viral doses. Blood p27, proviral and viral loads were followed until week 20 post-infection. Tissue proviral loads were determined as well. The immune response was monitored by measuring FeLV whole virus and p45 antibodies; and feline oncornavirus-associated cell membrane antigen (FOCMA) assay. One cat showed regressive infection (transient antigenemia, persistent provirus-positivity, and seroconversion) with provirus only found in some organs at sacrifice. In 7 of the 20 remaining cats FOCMA assay positivity was the only sign of infection, while all other tests were negative. Overall, the results show that FeLV low dose exposure can result in seroconversion during a presumed abortive infection. Therefore, commonly used detection methods do not detect all FeLV-infected animals, possibly leading to an underestimation of the prevalence of infection.

  8. Exposure of cats to low doses of FeLV: seroconversion as the sole parameter of infection

    PubMed Central

    Major, Andrea; Cattori, Valentino; Boenzli, Eva; Riond, Barbara; Ossent, Peter; Meli, Marina Luisa; Hofmann-Lehmann, Regina; Lutz, Hans

    2009-01-01

    In felids, feline leukemia virus (FeLV) infection results in a variety of outcomes that range from abortive (virus readily eliminated and never detectable) to progressive infection (persistent viremia and viral shedding). Recently, a novel outcome was postulated for low FeLV infectious doses. Naïve cats exposed to faeces of persistently infected cats seroconverted, indicating infection, but remained negative for provirus and p27 antigen in blood. FeLV provirus was found in some tissues but not in the bone marrow, infection of which is usually considered a necessary stage for disease progression. To investigate the impact of low FeLV doses on young cats and to test the hypothesis that low dose exposure may lead to an unknown pathogenesis of infection without involvement of the bone marrow, 21 cats were infected oronasally with variable viral doses. Blood p27, proviral and viral loads were followed until week 20 post-infection. Tissue proviral loads were determined as well. The immune response was monitored by measuring FeLV whole virus and p45 antibodies; and feline oncornavirus-associated cell membrane antigen (FOCMA) assay. One cat showed regressive infection (transient antigenemia, persistent provirus-positivity, and seroconversion) with provirus only found in some organs at sacrifice. In 7 of the 20 remaining cats FOCMA assay positivity was the only sign of infection, while all other tests were negative. Overall, the results show that FeLV low dose exposure can result in seroconversion during a presumed abortive infection. Therefore, commonly used detection methods do not detect all FeLV-infected animals, possibly leading to an underestimation of the prevalence of infection. PMID:19861115

  9. Prolongation of atrio-ventricular node conduction in a rabbit model of ischaemic cardiomyopathy: Role of fibrosis and connexin remodelling.

    PubMed

    Nisbet, Ashley M; Camelliti, Patrizia; Walker, Nicola L; Burton, Francis L; Cobbe, Stuart M; Kohl, Peter; Smith, Godfrey L

    2016-05-01

    Conduction abnormalities are frequently associated with cardiac disease, though the mechanisms underlying the commonly associated increases in PQ interval are not known. This study uses a chronic left ventricular (LV) apex myocardial infarction (MI) model in the rabbit to create significant left ventricular dysfunction (LVD) 8weeks post-MI. In vivo studies established that the PQ interval increases by approximately 7ms (10%) with no significant change in average heart rate. Optical mapping of isolated Langendorff perfused rabbit hearts recapitulated this result: time to earliest activation of the LV was increased by 14ms (16%) in the LVD group. Intra-atrial and LV transmural conduction times were not altered in the LVD group. Isolated AVN preparations from the LVD group demonstrated a significantly longer conduction time (by approximately 20ms) between atrial and His electrograms than sham controls across a range of pacing cycle lengths. This difference was accompanied by increased effective refractory period and Wenckebach cycle length, suggesting significantly altered AVN electrophysiology post-MI. The AVN origin of abnormality was further highlighted by optical mapping of the isolated AVN. Immunohistochemistry of AVN preparations revealed increased fibrosis and gap junction protein (connexin43 and 40) remodelling in the AVN of LVD animals compared to sham. A significant increase in myocyte-non-myocyte connexin co-localization was also observed after LVD. These changes may increase the electrotonic load experienced by AVN muscle cells and contribute to slowed conduction velocity within the AVN.

  10. Comprehensive Annular and Subvalvular Repair of Chronic Ischemic Mitral Regurgitation Improves Long-Term Results With the Least Ventricular Remodeling

    PubMed Central

    Szymanski, Catherine; Bel, Alain; Cohen, Iris; Touchot, Bernard; Handschumacher, Mark D.; Desnos, Michel; Carpentier, Alain; Menasché, Philippe; Hagège, Albert A.; Levine, Robert A.; Messas, Emmanuel

    2012-01-01

    Background Undersized ring annuloplasty for ischemic mitral regurgitation (MR) is associated with variable results and >30% MR recurrence. We tested whether subvalvular repair by severing second-order mitral chordae can improve annuloplasty by reducing papillary muscle tethering. Methods and Results Posterolateral myocardial infarction known to produce chronic remodeling and MR was created in 28 sheep. At 3 months, sheep were randomized to sham surgery versus isolated undersized annuloplasty versus isolated bileaflet chordal cutting versus the combined therapy (n=7 each). At baseline, chronic myocardial infarction (3 months), and euthanasia (6.6 months), we measured left ventricular (LV) volumes and ejection fraction, wall motion score index, MR regurgitation fraction and vena contracta, mitral annulus area, and posterior leaflet restriction angle (posterior leaflet to mitral annulus area) by 2-dimensional and 3-dimensional echocardiography. All groups were comparable at baseline and chronic myocardial infarction, with mild to moderate MR (MR vena contracta, 4.6±0.1 mm; MR regurgitation fraction, 24.2±2.9%) and mitral annulus dilatation (P<0.01). At euthanasia, MR progressed to moderate to severe in controls but decreased to trace with ring plus chordal cutting versus trace to mild with chordal cutting alone versus mild to moderate with ring alone (MR vena contracta, 5.9±1.1 mm in controls, 0.5±0.08 with both, 1.0±0.9 with chordal cutting alone, 2.0±0.7 with ring alone; P<0.01). In addition, LV end-systolic volume increased by 108% in controls versus 28% with ring plus chordal cutting, less than with each intervention alone (P<0.01). In multivariate analysis, LV end-systolic volume and mitral annulus area most strongly predicted MR (r2=0.82, P<0.01). Conclusions Comprehensive annular and subvalvular repair improves long-term reduction of both chronic ischemic MR and LV remodeling without decreasing global or segmental LV function at follow-up. PMID:23139296

  11. Design and rationale of the Reduction of Infarct Expansion and Ventricular Remodeling with Erythropoietin After Large Myocardial Infarction (REVEAL) trial

    PubMed Central

    Melloni, Chiara; Rao, Sunil V.; Povsic, Thomas J.; Melton, Laura; Kim, Raymond J.; Kilaru, Rakhi; Patel, Manesh; Talan, Mark; Ferrucci, Luigi; Longo, Dan L.; Lakatta, Edward G.; Najjar, Samer S.; Harrington, Robert A.

    2010-01-01

    Background Acute myocardial infarction (MI) remains a leading cause of death despite advances in pharmacologic and percutaneous therapies. Animal models of ischemia/reperfusion have demonstrated that single-dose erythropoietin (EPO) may reduce infarct size, decrease apoptosis, and increase neovascularization, possibly through mobilization of endothelial progenitor cells (EPCs). Study Design REVEAL is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the effects of epoetin alfa on infarct size and left ventricular (LV) remodeling in patients with large MIs. The trial comprises a dose-escalation safety phase and a single-dose efficacy phase using the highest acceptable epoetin alfa dose up to 60,000 units. Up to 250 STEMI patients undergoing primary or rescue percutaneous coronary intervention (PCI) will be randomized to intravenous epoetin alfa or placebo within 4 hours of successful reperfusion. The primary study endpoint is infarct size expressed as a percentage of LV mass, as measured by cardiac magnetic resonance imaging 2–6 days post study medication administration. Secondary endpoints will assess changes in EPC numbers and changes in indices of ventricular remodeling. Conclusion The REVEAL trial will evaluate the safety and efficacy of the highest tolerated single dose of epoetin alfa in patients who have undergone successful rescue or primary PCI for acute STEMI. PMID:21095264

  12. Adverse reactions to cosmetics.

    PubMed

    Gendler, E

    1987-06-01

    Adverse reactions to cosmetics can be irritant or allergic and are most often caused by fragrances or preservatives. Preservatives include formaldehyde, formaldehyde releasers, and parabens. Other agents that cause allergy are paraphenylenediamine in hair dyes and toluene sulfonamide formaldehyde resin in nail polishes.

  13. Scientists Trace Adversity's Toll

    ERIC Educational Resources Information Center

    Sparks, Sarah D.

    2012-01-01

    The stress of a spelling bee or a challenging science project can enhance a student's focus and promote learning. But the stress of a dysfunctional or unstable home life can poison a child's cognitive ability for a lifetime, according to new research. Those studies show that stress forms the link between childhood adversity and poor academic…

  14. Endothelial cells overexpressing IL-8 receptor reduce cardiac remodeling and dysfunction following myocardial infarction.

    PubMed

    Zhao, Xiangmin; Zhang, Wei; Xing, Dongqi; Li, Peng; Fu, Jinyan; Gong, Kaizheng; Hage, Fadi G; Oparil, Suzanne; Chen, Yiu-Fai

    2013-08-15

    The endothelium is a dynamic component of the cardiovascular system that plays an important role in health and disease. This study tested the hypothesis that targeted delivery of endothelial cells (ECs) overexpressing neutrophil membrane IL-8 receptors IL8RA and IL8RB reduces acute myocardial infarction (MI)-induced left ventricular (LV) remodeling and dysfunction and increases neovascularization in the area at risk surrounding the infarcted tissue. MI was created by ligating the left anterior descending coronary artery in 12-wk-old male Sprague-Dawley rats. Four groups of rats were studied: group 1: sham-operated rats without MI or EC transfusion; group 2: MI rats with intravenous vehicle; group 3: MI rats with transfused ECs transduced with empty adenoviral vector (Null-EC); and group 4: MI rats with transfused ECs overexpressing IL8RA/RB (1.5 × 10⁶ cells post-MI). Two weeks after MI, LV function was assessed by echocardiography; infarct size was assessed by triphenyltetrazolium chloride (live tissue) and picrosirus red (collagen) staining, and capillary density and neutrophil infiltration in the area at risk were measured by CD31 and MPO immunohistochemical staining, respectively. When compared with the MI + vehicle and MI-Null-EC groups, transfusion of IL8RA/RB-ECs decreased neutrophil infiltration and pro-inflammatory cytokine expression and increased capillary density in the area at risk, decreased infarct size, and reduced MI-induced LV dysfunction. These findings provide proof of principle that targeted delivery of ECs is effective in repairing injured cardiac tissue. Targeted delivery of ECs to infarcted hearts provides a potential novel strategy for the treatment of acute MI in humans.

  15. Low Intensity Physical Exercise Attenuates Cardiac Remodeling and Myocardial Oxidative Stress and Dysfunction in Diabetic Rats

    PubMed Central

    Gimenes, C.; Gimenes, R.; Rosa, C. M.; Xavier, N. P.; Campos, D. H. S.; Fernandes, A. A. H.; Cezar, M. D. M.; Guirado, G. N.; Cicogna, A. C.; Takamoto, A. H. R.; Okoshi, M. P.; Okoshi, K.

    2015-01-01

    We evaluated the effects of a low intensity aerobic exercise protocol on cardiac remodeling and myocardial function in diabetic rats. Wistar rats were assigned into four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary diabetes (DM-Sed), and exercised diabetes (DM-Ex). Diabetes was induced by intraperitoneal injection of streptozotocin. Rats exercised for 9 weeks in treadmill at 11 m/min, 18 min/day. Myocardial function was evaluated in left ventricular (LV) papillary muscles and oxidative stress in LV tissue. Statistical analysis was given by ANOVA or Kruskal-Wallis. Echocardiogram showed diabetic groups with higher LV diastolic diameter-to-body weight ratio and lower posterior wall shortening velocity than controls. Left atrium diameter was lower in DM-Ex than DM-Sed (C-Sed: 5.73 ± 0.49; C-Ex: 5.67 ± 0.53; DM-Sed: 6.41 ± 0.54; DM-Ex: 5.81 ± 0.50 mm; P < 0.05 DM-Sed vs C-Sed and DM-Ex). Papillary muscle function was depressed in DM-Sed compared to C-Sed. Exercise attenuated this change in DM-Ex. Lipid hydroperoxide concentration was higher in DM-Sed than C-Sed and DM-Ex. Catalase and superoxide dismutase activities were lower in diabetics than controls and higher in DM-Ex than DM-Sed. Glutathione peroxidase activity was lower in DM-Sed than C-Sed and DM-Ex. Conclusion. Low intensity exercise attenuates left atrium dilation and myocardial oxidative stress and dysfunction in type 1 diabetic rats. PMID:26509175

  16. Intracranial pressure and skull remodeling

    PubMed Central

    McCulley, Timothy J.; Jordan Piluek, W.; Chang, Jessica

    2014-01-01

    In this article we review bony changes resulting from alterations in intracranial pressure (ICP) and the implications for ophthalmologists and the patients for whom we care. Before addressing ophthalmic implications, we will begin with a brief overview of bone remodeling. Bony changes seen with chronic intracranial hypotension and hypertension will be discussed. The primary objective of this review was to bring attention to bony changes seen with chronic intracranial hypotension. Intracranial hypotension skull remodeling can result in enophthalmos. In advanced disease enophthalmos develops to a degree that is truly disfiguring. The most common finding for which subjects are referred is ocular surface disease, related to loss of contact between the eyelids and the cornea. Other abnormalities seen include abnormal ocular motility and optic atrophy. Recognition of such changes is important to allow for diagnosis and treatment prior to advanced clinical deterioration. Routine radiographic assessment of bony changes may allow for the identification of patient with abnormal ICP prior to the development of clinically significant disease. PMID:25859141

  17. Adrenocortical Zonation, Renewal, and Remodeling

    PubMed Central

    Pihlajoki, Marjut; Dörner, Julia; Cochran, Rebecca S.; Heikinheimo, Markku; Wilson, David B.

    2015-01-01

    The adrenal cortex is divided into concentric zones. In humans the major cortical zones are the zona glomerulosa, zona fasciculata, and zona reticularis. The adrenal cortex is a dynamic organ in which senescent cells are replaced by newly differentiated ones. This constant renewal facilitates organ remodeling in response to physiological demand for steroids. Cortical zones can reversibly expand, contract, or alter their biochemical profiles to accommodate needs. Pools of stem/progenitor cells in the adrenal capsule, subcapsular region, and juxtamedullary region can differentiate to repopulate or expand zones. Some of these pools appear to be activated only during specific developmental windows or in response to extreme physiological demand. Senescent cells can also be replenished through direct lineage conversion; for example, cells in the zona glomerulosa can transform into cells of the zona fasciculata. Adrenocortical cell differentiation, renewal, and function are regulated by a variety of endocrine/paracrine factors including adrenocorticotropin, angiotensin II, insulin-related growth hormones, luteinizing hormone, activin, and inhibin. Additionally, zonation and regeneration of the adrenal cortex are controlled by developmental signaling pathways, such as the sonic hedgehog, delta-like homolog 1, fibroblast growth factor, and WNT/β-catenin pathways. The mechanisms involved in adrenocortical remodeling are complex and redundant so as to fulfill the offsetting goals of organ homeostasis and stress adaptation. PMID:25798129

  18. HDL biogenesis, remodeling, and catabolism.

    PubMed

    Zannis, Vassilis I; Fotakis, Panagiotis; Koukos, Georgios; Kardassis, Dimitris; Ehnholm, Christian; Jauhiainen, Matti; Chroni, Angeliki

    2015-01-01

    In this chapter, we review how HDL is generated, remodeled, and catabolized in plasma. We describe key features of the proteins that participate in these processes, emphasizing how mutations in apolipoprotein A-I (apoA-I) and the other proteins affect HDL metabolism. The biogenesis of HDL initially requires functional interaction of apoA-I with the ATP-binding cassette transporter A1 (ABCA1) and subsequently interactions of the lipidated apoA-I forms with lecithin/cholesterol acyltransferase (LCAT). Mutations in these proteins either prevent or impair the formation and possibly the functionality of HDL. Remodeling and catabolism of HDL is the result of interactions of HDL with cell receptors and other membrane and plasma proteins including hepatic lipase (HL), endothelial lipase (EL), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), apolipoprotein M (apoM), scavenger receptor class B type I (SR-BI), ATP-binding cassette transporter G1 (ABCG1), the F1 subunit of ATPase (Ecto F1-ATPase), and the cubulin/megalin receptor. Similarly to apoA-I, apolipoprotein E and apolipoprotein A-IV were shown to form discrete HDL particles containing these apolipoproteins which may have important but still unexplored functions. Furthermore, several plasma proteins were found associated with HDL and may modulate its biological functions. The effect of these proteins on the functionality of HDL is the topic of ongoing research. PMID:25522986

  19. The effect of enalapril on the cardiac remodelling in ovariectomized spontaneously hypertensive rats.

    PubMed

    Santos, Wellington V; Pereira, Leila M M; Mandarim-de-Lacerda, Carlos A

    2004-10-01

    Angiotensin-converting enzyme inhibitors reduce the blood pressure (BP) and inhibit the generation of the angiotensin II from the inactive angiotensin I. Ten 28-week-old spontaneously hypertensive rats (SHRs) had their ovaries bilaterally removed and five rats were left intact and studied for 7 additional weeks: intact group, ovariectomized group (ovx SHRs) and ovariectomized + enalapril group (ovx + en). BP was higher in ovx SHRs and lower in treated ovx SHRs. Left ventricular (LV) mass index was greater in untreated ovx SHRs and smaller in ovx + en group. The LV cardiomyocyte (cmy) mean cross-sectional area, measured by stereology, was greater in ovx SHRs and smaller in both intact and ovx + en SHRs. Ovx significantly decreased the density of intramyocardial blood vessels (ive), but administration of enalapril was able to restore the density of the ive to that seen in intact group. The worst ive:cmy ratio was found in untreated ovx SHRs, the intact group showed a 90% greater ratio, and the treated ovx group showed a 150% greater ratio than the untreated ovx group. In conclusion, ovariectomy, in SHRs, causes cardiac hypertrophy and an unfavourable myocardial remodelling. Of the spectrum of changes seen, the major effect of enalapril appears to be mediated via an increase in the density of ive.

  20. The response of the pulmonary circulation and right ventricle to exercise: exercise-induced right ventricular dysfunction and structural remodeling in endurance athletes (2013 Grover Conference series).

    PubMed

    La Gerche, André; Roberts, Timothy; Claessen, Guido

    2014-09-01

    There is unequivocal evidence that exercise results in considerable health benefits. These are the result of positive hormonal, metabolic, neuronal, and structural changes brought about by the intermittent physiological challenge of exercise. However, there is evolving evidence that intense exercise may place disproportionate physiological stress on the right ventricle (RV) and the pulmonary circulation. Both echocardiographic and invasive studies are consistent in demonstrating that pulmonary arterial pressures increase progressively with exercise intensity, such that the harder one exercises, the greater the load on the RV. This disproportionate load can result in fatigue or damage of the RV if the intensity and duration of exercise is sufficiently prolonged. This is distinctly different from the load imposed by exercise on the left ventricle (LV), which is moderated by a greater capacity for reductions in systemic afterload. Finally, given the increasing RV demand during exercise, it may be hypothesized that chronic exercise-induced cardiac remodeling (the so-called athlete's heart) may also disproportionately affect the RV. Indeed, there is evidence, although somewhat inconsistent, that RV volume increases may be relatively greater than those for the LV. Perhaps more importantly, there is a suggestion that chronic endurance exercise may cause electrical remodeling, predisposing some athletes to serious arrhythmias originating from the RV. Thus, a relatively consistent picture is emerging of acute stress, prolonged fatigue, and long-term remodeling, which all disproportionately affect the RV. Thus, we contend that the RV should be considered a potential Achilles' heel of the exercising heart. PMID:25621154

  1. Comparative cardiac toxicity in two treatment schedules of 5-FU/LV for colorectal carcinoma.

    PubMed

    Najam, Rahila; Bano, Nusrat; Mateen, Ahmed

    2013-09-01

    The purpose of the study is evaluation and assessment of parameters of cardiac toxicity in patients subjected to 5-FU based chemotherapy. Cardiac morbidity is a reported outcome in different 5FU/LV regimens; however none of them are definite or proximate. The bimonthly regimen of high dose leucovorin is reported to be less toxic and more effective as compared to the monthly regimen of low dose leucovorin. We report the detailed assessment of few cardiac parameter of toxicity in patients of advanced colorectal carcinoma subjected to two Schedules of high and low dose Folinic Acid, 5-Fluorouracil, bolus and continuous infusion. The correlation of elevated cardiac biomarkers, angina and hypertension is comparatively assessed in patients with normal general status, hyperglycemia and known cardiac disorders subjected to two different 5FU based chemotherapeutic regimen.

  2. Curva de rotação óptica de ESO-LV 5100550

    NASA Astrophysics Data System (ADS)

    Carvalho, D. B.; Soares, D. S. L.

    2003-08-01

    ESO-LV 5100550 é o membro mais fraco do par de galáxias austral SBG 357 (Soares et al. 1995). É classificada no catálogo RC3 como uma espiral ordinária de tipo inicial (early-type); porém, uma análise morfológica sugere que ela tenha uma grande barra. O objetivo do estudo é determinar sua cinemática de tal modo que possamos inferir mais a respeito de sua dinâmica, provavelmente perturbada, já que se espera que esteja sob forte influência da companheira ESO-LV 5100560. Apresentarei resultados parciais determinados a partir de espectros obtidos com o instrumento Double Spectrograph montado no telescópio Hale do Monte Palomar, EUA. As observações foram realizadas por D.S.L. Soares, P.M.V. Veiga e T.E. Nordgren, em 1998. Foram tomados espectros de fenda longa posicionada sobre a linha dos nodos do disco e ao longo da suposta barra. Os dados foram reduzidos com uso do pacote IRAF. Obtivemos o perfil de velocidades radiais na linha de visada ao longo das fendas e calculamos o desvio para o vermelho cosmológico do sistema, com base no espectro central. Determinamos as curvas de rotação deprojetadas, com base em cálculos para os valores teóricos esperados das componentes de velocidades puramente circulares em um disco inclinado. A inclinação do disco, dado fundamental nesta deprojeção, foi estimada através da média das elipticidades das isofotas mais externas.

  3. ATP synthase subunit alpha and LV mass in ischaemic human hearts

    PubMed Central

    Roselló-Lletí, Esther; Tarazón, Estefanía; Barderas, María G; Ortega, Ana; Molina-Navarro, Maria Micaela; Martínez, Alba; Lago, Francisca; Martínez-Dolz, Luis; González-Juanatey, Jose Ramón; Salvador, Antonio; Portolés, Manuel; Rivera, Miguel

    2015-01-01

    Mitochondrial dysfunction plays a critical role in the development of ischaemic cardiomyopathy (ICM). In this study, the mitochondrial proteome in the cardiac tissue of ICM patients was analysed by quantitative differential electrophoresis (2D-DIGE) and mass spectrometry (MS) for the first time to provide new insights into cardiac dysfunction in this cardiomyopathy. We isolated mitochondria from LV samples of explanted hearts of ICM patients (n = 8) and control donors (n = 8) and used a proteomic approach to investigate the variations in mitochondrial protein expression. We found that most of the altered proteins were involved in cardiac energy metabolism (82%). We focused on ATPA, which is involved in energy production, and dihydrolipoyl dehydrogenase, implicated in substrate utilization, and observed that these molecules were overexpressed and that the changes detected in the processes mediated by these proteins were closely related. Notably, we found that ATPA overexpression was associated with reduction in LV mass (r = −0.74, P < 0.01). We also found a substantial increase in the expression of elongation factor Tu, a molecule implicated in protein synthesis, and PRDX3, involved in the stress response. All of these changes were validated using classical techniques and by using novel and precise selected reaction monitoring analysis and an RNA sequencing approach, with the total heart samples being increased to 24. This study provides key insights that enhance our understanding of the cellular mechanisms related to the pathophysiology of ICM and could lead to the development of aetiology-specific heart failure therapies. ATPA could serve as a molecular target suitable for new therapeutic interventions. PMID:25382018

  4. Bone remodeling and silicon deficiency in rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Alveolar bone undergoes continuous remodeling to meet physiologic and functional demands. The aim of the present work was to evaluate histologically and histomorphometrically the effect of silicon deficiency on bone modeling and remodeling in the periodontal cortical plate. Two groups of weaning mal...

  5. Chromatin Remodelers: From Function to Dysfunction.

    PubMed

    Längst, Gernot; Manelyte, Laura

    2015-01-01

    Chromatin remodelers are key players in the regulation of chromatin accessibility and nucleosome positioning on the eukaryotic DNA, thereby essential for all DNA dependent biological processes. Thus, it is not surprising that upon of deregulation of those molecular machines healthy cells can turn into cancerous cells. Even though the remodeling enzymes are very abundant and a multitude of different enzymes and chromatin remodeling complexes exist in the cell, the particular remodeling complex with its specific nucleosome positioning features must be at the right place at the right time in order to ensure the proper regulation of the DNA dependent processes. To achieve this, chromatin remodeling complexes harbor protein domains that specifically read chromatin targeting signals, such as histone modifications, DNA sequence/structure, non-coding RNAs, histone variants or DNA bound interacting proteins. Recent studies reveal the interaction between non-coding RNAs and chromatin remodeling complexes showing importance of RNA in remodeling enzyme targeting, scaffolding and regulation. In this review, we summarize current understanding of chromatin remodeling enzyme targeting to chromatin and their role in cancer development. PMID:26075616

  6. The non-specificity of the left/right ventricular amplitude ratio (LV/RV) for mitral insufficiency

    SciTech Connect

    Preston, D.F.; Reinsel, M.S.; Martin, N.L.; Robinson, R.G.

    1984-01-01

    The purpose of this study was to determine the specificity of the LV/RV for mitral insufficiency. One hundred and sixty patients underwent MUGA studies as part of their diagnostic evaluation. Phase analysis was performed. In the amplitude image, the LV/RV was measured. Patients were divided into 11 clinical groups based on chart review after adequate follow-up. The groups were compared by Duncan's Multiple Comparsion Test. Patients with mitral insufficiency (N = 12, mean LV/RV = 2.36), those with idiopathic myocardiopathy (8, 2.29) and those with normal hearts having lung disease on chest x-ray (22, 1.78) formed a group which at the p < .05 level were not different from one another. Patients with idiopathic myocardiography, normal hearts with lung disease on chest x-ray, normal hearts with lung disease (23, 1.71) formed a second group which partially overlapped with both the first and third groups. The third group consisted of normal hearts with lung disease, normal hearts not taking adriamycin (18, 1.53), normal hearts taking adriamycin (22, 1.50), congestive heart failure (19, 1.50), arteriosclerotic heart disease, normal hearts (15, 1.29), chronic obstructive pulmonary disease and acute myocardial infarction. The LV/RV is not specific for mitral insufficiency. Idiopathic myocardiography, and normal hearts with lung disease on chest x-ray (metastases, cancer of the lung, infiltrates, fibrosis, and/or COPD) cannot be differentiated on a statistical basis. The mitral insufficiency group had the greatest values of LV/RV. It appears that decreased RV amplitude seen with diseases causing strain on the right ventricle will result in elevated LV/RV ratios.

  7. Both enalapril and losartan attenuate sarcolemmal Na+-K+-ATPase remodeling in failing rat heart due to myocardial infarction.

    PubMed

    Guo, Xiaobing; Wang, Jingwei; Elimban, Vijayan; Dhalla, Naranjan S

    2008-04-01

    To investigate the mechanisms underlying the depressed sarcolemmal (SL) Na(+)-K(+)-ATPase activity in congestive heart failure (CHF), different isoforms and gene expression of Na(+)-K(+)-ATPase were examined in the failing left ventricle (LV) at 8 weeks after myocardial infarction (MI). In view of the increased activity of renin-angiotensin system (RAS) in CHF, these parameters were also studied after 5 weeks of treatment with enalapril (10 mg x kg-1 x day-1), an angiotensin-converting enzyme inhibitor, and losartan (20 mg.kg-1.day-1), an angiotensin II type 1 receptor antagonist, starting at 3 weeks after the coronary ligation in rats. The infarcted animals showed LV dysfunction and depressed SL Na(+)-K(+)-ATPase activity. Protein content and mRNA levels for Na(+)-K(+)-ATPase alpha2 isoform were decreased whereas those for Na(+)-K(+)-ATPase alpha3 isoform were increased in the failing LV. On the other hand, no significant changes were observed in protein content or mRNA levels for Na(+)-K(+)-ATPase alpha1 and beta1 isoforms. The treatment of infarcted animals with enalapril or losartan improved LV function and attenuated the depression in Na(+)-K(+)-ATPase alpha2 isoform as well as the increase in alpha3 isoform, at both the protein and mRNA levels; however, combination therapy with enalapril and losartan did not produce any additive effects. These results provide further evidence that CHF due to MI is associated with remodeling of SL membrane and suggest that the blockade of RAS plays an important role in preventing these alterations in the failing heart.

  8. Nucleosome dynamics during chromatin remodeling in vivo

    PubMed Central

    Ramachandran, Srinivas; Henikoff, Steven

    2016-01-01

    ABSTRACT Precise positioning of nucleosomes around regulatory sites is achieved by the action of chromatin remodelers, which use the energy of ATP to slide, evict or change the composition of nucleosomes. Chromatin remodelers act to bind nucleosomes, disrupt histone-DNA interactions and translocate the DNA around the histone core to reposition nucleosomes. Hence, remodeling is expected to involve nucleosomal intermediates with a structural organization that is distinct from intact nucleosomes. We describe the identification of a partially unwrapped nucleosome structure using methods that map histone-DNA contacts genome-wide. This alternative nucleosome structure is likely formed as an intermediate or by-product during nucleosome remodeling by the RSC complex. Identification of the loss of histone-DNA contacts during chromatin remodeling by RSC in vivo has implications for the regulation of transcriptional initiation. PMID:26933790

  9. Lipid Acyl Chain Remodeling in Yeast

    PubMed Central

    Renne, Mike F.; Bao, Xue; De Smet, Cedric H.; de Kroon, Anton I. P. M.

    2015-01-01

    Membrane lipid homeostasis is maintained by de novo synthesis, intracellular transport, remodeling, and degradation of lipid molecules. Glycerophospholipids, the most abundant structural component of eukaryotic membranes, are subject to acyl chain remodeling, which is defined as the post-synthetic process in which one or both acyl chains are exchanged. Here, we review studies addressing acyl chain remodeling of membrane glycerophospholipids in Saccharomyces cerevisiae, a model organism that has been successfully used to investigate lipid synthesis and its regulation. Experimental evidence for the occurrence of phospholipid acyl chain exchange in cardiolipin, phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine is summarized, including methods and tools that have been used for detecting remodeling. Progress in the identification of the enzymes involved is reported, and putative functions of acyl chain remodeling in yeast are discussed. PMID:26819558

  10. Adverse reactions to cosmetics.

    PubMed

    Dogra, A; Minocha, Y C; Kaur, S

    2003-01-01

    Adverse reaction to cosmetics constitute a small but significant number of cases of contact dermatitis with varied appearances. These can present as contact allergic dermatitis, photodermatitis, contact irritant dermatitis, contact urticaria, hypopigmentation, hyperpigmentation or depigmentation, hair and nail breakage. Fifty patients were included for the study to assess the role of commonly used cosmetics in causing adverse reactions. It was found that hair dyes, lipsticks and surprisingly shaving creams caused more reaction as compared to other cosmetics. Overall incidence of contact allergic dermatitis seen was 3.3% with patients own cosmetics. Patch testing was also done with the basic ingredients and showed positive results in few cases where casual link could be established. It is recommended that labeling of the cosmetics should be done to help the dermatologists and the patients to identify the causative allergen in cosmetic preparation.

  11. Chromatin remodeling in nuclear cloning.

    PubMed

    Wade, Paul A; Kikyo, Nobuaki

    2002-05-01

    Nuclear cloning is a procedure to create new animals by injecting somatic nuclei into unfertilized oocytes. Recent successes in mammalian cloning with differentiated adult nuclei strongly indicate that oocyte cytoplasm contains unidentified remarkable reprogramming activities with the capacity to erase the previous memory of cell differentiation. At the heart of this nuclear reprogramming lies chromatin remodeling as chromatin structure and function define cell differentiation through regulation of the transcriptional activities of the cells. Studies involving the modification of chromatin elements such as selective uptake or release of binding proteins, covalent histone modifications including acetylation and methylation, and DNA methylation should provide significant insight into the molecular mechanisms of nuclear dedifferentiation and redifferentiation in oocyte cytoplasm.

  12. Thyroid Hormone and Vascular Remodeling.

    PubMed

    Ichiki, Toshihiro

    2016-01-01

    Both hyperthyroidism and hypothyroidism affect the cardiovascular system. Hypothyroidism is known to be associated with enhanced atherosclerosis and ischemic heart diseases. The accelerated atherosclerosis in the hypothyroid state has been traditionally ascribed to atherogenic lipid profile, diastolic hypertension, and impaired endothelial function. However, recent studies indicate that thyroid hormone has direct anti-atherosclerotic effects, such as production of nitric oxide and suppression of smooth muscle cell proliferation. These data suggest that thyroid hormone inhibits atherogenesis through direct effects on the vasculature as well as modification of risk factors for atherosclerosis. This review summarizes the basic and clinical studies on the role of thyroid hormone in vascular remodeling. The possible application of thyroid hormone mimetics to the therapy of hypercholesterolemia and atherosclerosis is also discussed. PMID:26558400

  13. Seroprevalence of feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) in shelter cats on the island of Newfoundland, Canada.

    PubMed

    Munro, Hannah J; Berghuis, Lesley; Lang, Andrew S; Rogers, Laura; Whitney, Hugh

    2014-04-01

    Feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) are retroviruses found within domestic and wild cat populations. These viruses cause severe illnesses that eventually lead to death. Housing cats communally for long periods of time makes shelters at high risk for virus transmission among cats. We tested 548 cats from 5 different sites across the island of Newfoundland for FIV and FeLV. The overall seroprevalence was 2.2% and 6.2% for FIV and FeLV, respectively. Two sites had significantly higher seroprevalence of FeLV infection than the other 3 sites. Analysis of sequences from the FeLV env gene (envelope gene) from 6 positive cats showed that 4 fell within the FeLV subtype-A, while 2 sequences were most closely related to FeLV subtype-B and endogenous feline leukemia virus (en FeLV). Varying seroprevalence and the variation in sequences at different sites demonstrate that some shelters are at greater risk of FeLV infections and recombination can occur at sites of high seroprevalence.

  14. 31P NMR 2D Mapping of Creatine Kinase Forward Flux Rate in Hearts with Postinfarction Left Ventricular Remodeling in Response to Cell Therapy

    PubMed Central

    Gao, Ling; Cui, Weina; Zhang, Pengyuan; Jang, Albert; Zhu, Wuqiang; Zhang, Jianyi

    2016-01-01

    Utilizing a fast 31P magnetic resonance spectroscopy (MRS) 2-dimensional chemical shift imaging (2D-CSI) method, this study examined the heterogeneity of creatine kinase (CK) forward flux rate of hearts with postinfarction left ventricular (LV) remodeling. Immunosuppressed Yorkshire pigs were assigned to 4 groups: 1) A sham-operated normal group (SHAM, n = 6); 2) A 60 minutes distal left anterior descending coronary artery ligation and reperfusion (MI, n = 6); 3) Open patch group; ligation injury plus open fibrin patch over the site of injury (Patch, n = 6); and 4) Cell group, hiPSCs-cardiomyocytes, -endothelial cells, and -smooth muscle cells (2 million, each) were injected into the injured myocardium pass through a fibrin patch (Cell+Patch, n = 5). At 4 weeks, the creatine phosphate (PCr)/ATP ratio, CK forward flux rate (Flux PCr→ATP), and k constant of CK forward flux rate (kPCr→ATP) were severely decreased at border zone myocardium (BZ) adjacent to MI. Cell treatment results in significantly increase of PCr/ATP ratio and improve the value of kPCr→ATP and Flux PCr→ATP in BZ myocardium. Moreover, the BZ myocardial CK total activity and protein expression of CK mitochondria isozyme and CK myocardial isozyme were significantly reduced, but recovered in response to cell treatment. Thus, cell therapy results in improvement of BZ bioenergetic abnormality in hearts with postinfarction LV remodeling, which is accompanied by significantly improvements in BZ CK activity and CK isozyme expression. The fast 2D 31P MR CSI mapping can reliably measure the heterogeneity of bioenergetics in hearts with post infarction LV remodeling. PMID:27606901

  15. 31P NMR 2D Mapping of Creatine Kinase Forward Flux Rate in Hearts with Postinfarction Left Ventricular Remodeling in Response to Cell Therapy.

    PubMed

    Gao, Ling; Cui, Weina; Zhang, Pengyuan; Jang, Albert; Zhu, Wuqiang; Zhang, Jianyi

    2016-01-01

    Utilizing a fast 31P magnetic resonance spectroscopy (MRS) 2-dimensional chemical shift imaging (2D-CSI) method, this study examined the heterogeneity of creatine kinase (CK) forward flux rate of hearts with postinfarction left ventricular (LV) remodeling. Immunosuppressed Yorkshire pigs were assigned to 4 groups: 1) A sham-operated normal group (SHAM, n = 6); 2) A 60 minutes distal left anterior descending coronary artery ligation and reperfusion (MI, n = 6); 3) Open patch group; ligation injury plus open fibrin patch over the site of injury (Patch, n = 6); and 4) Cell group, hiPSCs-cardiomyocytes, -endothelial cells, and -smooth muscle cells (2 million, each) were injected into the injured myocardium pass through a fibrin patch (Cell+Patch, n = 5). At 4 weeks, the creatine phosphate (PCr)/ATP ratio, CK forward flux rate (Flux PCr→ATP), and k constant of CK forward flux rate (kPCr→ATP) were severely decreased at border zone myocardium (BZ) adjacent to MI. Cell treatment results in significantly increase of PCr/ATP ratio and improve the value of kPCr→ATP and Flux PCr→ATP in BZ myocardium. Moreover, the BZ myocardial CK total activity and protein expression of CK mitochondria isozyme and CK myocardial isozyme were significantly reduced, but recovered in response to cell treatment. Thus, cell therapy results in improvement of BZ bioenergetic abnormality in hearts with postinfarction LV remodeling, which is accompanied by significantly improvements in BZ CK activity and CK isozyme expression. The fast 2D 31P MR CSI mapping can reliably measure the heterogeneity of bioenergetics in hearts with post infarction LV remodeling. PMID:27606901

  16. Deficiency of Smad7 Enhances Cardiac Remodeling Induced by Angiotensin II Infusion in a Mouse Model of Hypertension

    PubMed Central

    Wei, Li Hua; Huang, Xiao Ru; Zhang, Yang; Li, You Qi; Chen, Hai-yong; Heuchel, Rainer; Yan, Bryan P.; Yu, Cheuk-Man; Lan, Hui Yao

    2013-01-01

    Smad7 has been shown to negatively regulate fibrosis and inflammation, but its role in angiotensin II (Ang II)-induced hypertensive cardiac remodeling remains unknown. Therefore, the present study investigated the role of Smad7 in hypertensive cardiopathy induced by angiotensin II infusion. Hypertensive cardiac disease was induced in Smad7 gene knockout (KO) and wild-type (WT) mice by subcutaneous infusion of Ang II (1.46 mg/kg/day) for 28 days. Although equal levels of high blood pressure were developed in both Smad7 KO and WT mice, Smad7 KO mice developed more severe cardiac injury as demonstrated by impairing cardiac function including a significant increase in left ventricular (LV) mass (P<0.01),reduction of LV ejection fraction(P<0.001) and fractional shortening(P<0.001). Real-time PCR, Western blot and immunohistochemistry detected that deletion of Smad7 significantly enhanced Ang II-induced cardiac fibrosis and inflammation, including upregulation of collagen I, α-SMA, interleukin-1β, TNF-α, and infiltration of CD3+ T cells and F4/80+ macrophages. Further studies revealed that enhanced activation of the Sp1-TGFβ/Smad3-NF-κB pathways and downregulation of miR-29 were mechanisms though which deletion of Smad7 promoted Ang II-mediated cardiac remodeling. In conclusions, Smad7 plays a protective role in AngII-mediated cardiac remodeling via mechanisms involving the Sp1-TGF-β/Smad3-NF.κB-miR-29 regulatory network. PMID:23894614

  17. Adverse effects of cannabis.

    PubMed

    2011-01-01

    Cannabis, Cannabis sativa L., is used to produce a resin that contains high levels of cannabinoids, particularly delta9-tetrahydrocannabinol (THC), which are psychoactive substances. Although cannabis use is illegal in France and in many other countries, it is widely used for its relaxing or euphoric effects, especially by adolescents and young adults. What are the adverse effects of cannabis on health? During consumption? And in the long term? Does cannabis predispose users to the development of psychotic disorders? To answer these questions, we reviewed the available evidence using the standard Prescrire methodology. The long-term adverse effects of cannabis are difficult to evaluate. Since and associated substances, with or without the user's knowledge. Tobacco and alcohol consumption, and particular lifestyles and behaviours are often associated with cannabis use. Some traits predispose individuals to the use of psychoactive substances in general. The effects of cannabis are dosedependent.The most frequently report-ed adverse effects are mental slowness, impaired reaction times, and sometimes accentuation of anxiety. Serious psychological disorders have been reported with high levels of intoxication. The relationship between poor school performance and early, regular, and frequent cannabis use seems to be a vicious circle, in which each sustains the other. Many studies have focused on the long-term effects of cannabis on memory, but their results have been inconclusive. There do not * About fifteen longitudinal cohort studies that examined the influence of cannabis on depressive thoughts or suicidal ideation have yielded conflicting results and are inconclusive. Several longitudinal cohort studies have shown a statistical association between psychotic illness and self-reported cannabis use. However, the results are difficult to interpret due to methodological problems, particularly the unknown reliability of self-reported data. It has not been possible to

  18. Adverse effects of cannabis.

    PubMed

    2011-01-01

    Cannabis, Cannabis sativa L., is used to produce a resin that contains high levels of cannabinoids, particularly delta9-tetrahydrocannabinol (THC), which are psychoactive substances. Although cannabis use is illegal in France and in many other countries, it is widely used for its relaxing or euphoric effects, especially by adolescents and young adults. What are the adverse effects of cannabis on health? During consumption? And in the long term? Does cannabis predispose users to the development of psychotic disorders? To answer these questions, we reviewed the available evidence using the standard Prescrire methodology. The long-term adverse effects of cannabis are difficult to evaluate. Since and associated substances, with or without the user's knowledge. Tobacco and alcohol consumption, and particular lifestyles and behaviours are often associated with cannabis use. Some traits predispose individuals to the use of psychoactive substances in general. The effects of cannabis are dosedependent.The most frequently report-ed adverse effects are mental slowness, impaired reaction times, and sometimes accentuation of anxiety. Serious psychological disorders have been reported with high levels of intoxication. The relationship between poor school performance and early, regular, and frequent cannabis use seems to be a vicious circle, in which each sustains the other. Many studies have focused on the long-term effects of cannabis on memory, but their results have been inconclusive. There do not * About fifteen longitudinal cohort studies that examined the influence of cannabis on depressive thoughts or suicidal ideation have yielded conflicting results and are inconclusive. Several longitudinal cohort studies have shown a statistical association between psychotic illness and self-reported cannabis use. However, the results are difficult to interpret due to methodological problems, particularly the unknown reliability of self-reported data. It has not been possible to

  19. DEVELOPMENT AND USE OF IMMUNOCHEMICAL METHODS FOR ENVIRONMENTAL CONTAMINANTS AT THE U.S. EPA, NERL, HERB-LV

    EPA Science Inventory

    The HERB-LV has developed several immunoassay methods for environmental and human exposure studies. Immunoassays to detect low levels (<10 ng/mL) chlorpyrifos in track-in dirt and house dust have been developed for indoor exposure surveys. An immunoassay for the urinary metabol...

  20. LV wall segmentation using the variational level set method (LSM) with additional shape constraint for oedema quantification

    NASA Astrophysics Data System (ADS)

    Kadir, K.; Gao, H.; Payne, A.; Soraghan, J.; Berry, C.

    2012-10-01

    In this paper an automatic algorithm for the left ventricle (LV) wall segmentation and oedema quantification from T2-weighted cardiac magnetic resonance (CMR) images is presented. The extent of myocardial oedema delineates the ischaemic area-at-risk (AAR) after myocardial infarction (MI). Since AAR can be used to estimate the amount of salvageable myocardial post-MI, oedema imaging has potential clinical utility in the management of acute MI patients. This paper presents a new scheme based on the variational level set method (LSM) with additional shape constraint for the segmentation of T2-weighted CMR image. In our approach, shape information of the myocardial wall is utilized to introduce a shape feature of the myocardial wall into the variational level set formulation. The performance of the method is tested using real CMR images (12 patients) and the results of the automatic system are compared to manual segmentation. The mean perpendicular distances between the automatic and manual LV wall boundaries are in the range of 1-2 mm. Bland-Altman analysis on LV wall area indicates there is no consistent bias as a function of LV wall area, with a mean bias of -121 mm2 between individual investigator one (IV1) and LSM, and -122 mm2 between individual investigator two (IV2) and LSM when compared to two investigators. Furthermore, the oedema quantification demonstrates good correlation when compared to an expert with an average error of 9.3% for 69 slices of short axis CMR image from 12 patients.

  1. Vaccine adverse events.

    PubMed

    Follows, Jill

    2012-01-01

    Millions of adults are vaccinated annually against the seasonal influenza virus. An undetermined number of individuals will develop adverse events to the influenza vaccination. Those who suffer substantiated vaccine injuries, disabilities, and aggravated conditions may file a timely, no-fault and no-cost petition for financial compensation under the National Vaccine Act in the Vaccine Court. The elements of a successful vaccine injury claim are described in the context of a claim showing the seasonal influenza vaccination was the cause of Guillain-Barré syndrome.

  2. [Adverse events prevention ability].

    PubMed

    Aparo, Ugo Luigi; Aparo, Andrea

    2007-03-01

    The issue of how to address medical errors is the key to improve the health care system performances. Operational evidence collected in the last five years shows that the solution is only partially linked to future technological developments. Cultural and organisational changes are mandatory to help to manage and drastically reduce the adverse events in health care organisations. Classical management, merely based on coordination and control, is inadequate. Proactive, self-organising network based structures must be put in place and managed using adaptive, fast evolving management tools. PMID:17484160

  3. [Adverse events prevention ability].

    PubMed

    Aparo, Ugo Luigi; Aparo, Andrea

    2007-03-01

    The issue of how to address medical errors is the key to improve the health care system performances. Operational evidence collected in the last five years shows that the solution is only partially linked to future technological developments. Cultural and organisational changes are mandatory to help to manage and drastically reduce the adverse events in health care organisations. Classical management, merely based on coordination and control, is inadequate. Proactive, self-organising network based structures must be put in place and managed using adaptive, fast evolving management tools.

  4. Maternal uterine vascular remodeling during pregnancy.

    PubMed

    Osol, George; Mandala, Maurizio

    2009-02-01

    Sufficient uteroplacental blood flow is essential for normal pregnancy outcome and is accomplished by the coordinated growth and remodeling of the entire uterine circulation, as well as the creation of a new fetal vascular organ: the placenta. The process of remodeling involves a number of cellular processes, including hyperplasia and hypertrophy, rearrangement of existing elements, and changes in extracellular matrix. In this review, we provide information on uterine blood flow increases during pregnancy, the influence of placentation type on the distribution of uterine vascular resistance, consideration of the patterns, nature, and extent of maternal uterine vascular remodeling during pregnancy, and what is known about the underlying cellular mechanisms.

  5. Modelling wetland-groundwater interactions in the boreal Kälväsvaara esker, Northern Finland

    NASA Astrophysics Data System (ADS)

    Jaros, Anna; Rossi, Pekka; Ronkanen, Anna-Kaisa; Kløve, Bjørn

    2016-04-01

    Many types of boreal peatland ecosystems such as alkaline fens, aapa mires and Fennoscandia spring fens rely on the presence of groundwater. In these ecosystems groundwater creates unique conditions for flora and fauna by providing water, nutrients and constant water temperature enriching local biodiversity. The groundwater-peatland interactions and their dynamics are not, however, in many cases fully understood and their measurement and quantification is difficult due to highly heterogeneous structure of peatlands and large spatial extend of these ecosystems. Understanding of these interactions and their changes due to anthropogenic impact on groundwater resources would benefit the protection of the groundwater dependent peatlands. The groundwater-peatland interactions were investigated using the fully-integrated physically-based groundwater-surface water code HydroGeoSphere in a case study of the Kälväsvaara esker aquifer, Northern Finland. The Kälväsvaara is a geologically complex esker and it is surrounded by vast aapa mire system including alkaline and springs fens. In addition, numerous small springs occur in the discharge zone of the esker. In order to quantify groundwater-peatland interactions a simple steady-state model was built and results were evaluated using expected trends and field measurements. The employed model reproduced relatively well spatially distributed hydrological variables such as soil water content, water depths and groundwater-surface water exchange fluxes within the wetland and esker areas. The wetlands emerged in simulations as a result of geological and topographical conditions. They could be identified by high saturation levels at ground surface and by presence of shallow ponded water over some areas. The model outputs exhibited also strong surface water-groundwater interactions in some parts of the aapa system. These areas were noted to be regions of substantial diffusive groundwater discharge by the earlier studies. In

  6. Shrimp with knockdown of LvSOCS2, a negative feedback loop regulator of JAK/STAT pathway in Litopenaeus vannamei, exhibit enhanced resistance against WSSV.

    PubMed

    Wang, Sheng; Song, Xuan; Zhang, Zijian; Li, Haoyang; L, Kai; Yin, Bin; He, Jianguo; Li, Chaozheng

    2016-12-01

    JAK/STAT pathway is one of cytokine signaling pathways and mediates diversity immune responses to protect host from viral infection. In this study, LvSOCS2, a member of suppressor of cytokine signaling (SOCS) families, has been cloned and identified from Litopenaeus vannamei. The full length of LvSOCS2 is 1601 bp, including an 1194 bp open reading frame (ORF) coding for a putative protein of 397 amino acids with a calculated molecular weight of ∼42.3 kDa. LvSOCS2 expression was most abundant in gills and could respond to the challenge of LPS, Vibrio parahaemolyticus, Staphhylococcus aureus, Poly (I: C) and white spot syndrome virus (WSSV). There are several STAT binding motifs presented in the proximal promoter region of LvSOCS2 and its expression was induced by LvJAK or LvSTAT protein in a dose dependent manner, suggesting LvSOCS2 could be the transcriptional target gene of JAK/STAT pathway. Moreover, the transcription of DmVir-1, a read out of the activation of JAK/STAT pathway in Drosophila, was promoted by LvJAK but inhibited by LvSOCS2, indicating that LvSOCS2 could be a negative regulator in this pathway and thus can form a negative feedback loop. Our previous study indicated that shrimp JAK/STAT pathway played a positive role against WSSV. In this study, RNAi-mediated knockdown of LvSOCS2 shrimps showed lower susceptibility to WSSV infection and caused lessened virus loads, which further demonstrated that the JAK/STAT pathway could function as an anti-viral immunity in shrimp. PMID:27497874

  7. Shrimp with knockdown of LvSOCS2, a negative feedback loop regulator of JAK/STAT pathway in Litopenaeus vannamei, exhibit enhanced resistance against WSSV.

    PubMed

    Wang, Sheng; Song, Xuan; Zhang, Zijian; Li, Haoyang; L, Kai; Yin, Bin; He, Jianguo; Li, Chaozheng

    2016-12-01

    JAK/STAT pathway is one of cytokine signaling pathways and mediates diversity immune responses to protect host from viral infection. In this study, LvSOCS2, a member of suppressor of cytokine signaling (SOCS) families, has been cloned and identified from Litopenaeus vannamei. The full length of LvSOCS2 is 1601 bp, including an 1194 bp open reading frame (ORF) coding for a putative protein of 397 amino acids with a calculated molecular weight of ∼42.3 kDa. LvSOCS2 expression was most abundant in gills and could respond to the challenge of LPS, Vibrio parahaemolyticus, Staphhylococcus aureus, Poly (I: C) and white spot syndrome virus (WSSV). There are several STAT binding motifs presented in the proximal promoter region of LvSOCS2 and its expression was induced by LvJAK or LvSTAT protein in a dose dependent manner, suggesting LvSOCS2 could be the transcriptional target gene of JAK/STAT pathway. Moreover, the transcription of DmVir-1, a read out of the activation of JAK/STAT pathway in Drosophila, was promoted by LvJAK but inhibited by LvSOCS2, indicating that LvSOCS2 could be a negative regulator in this pathway and thus can form a negative feedback loop. Our previous study indicated that shrimp JAK/STAT pathway played a positive role against WSSV. In this study, RNAi-mediated knockdown of LvSOCS2 shrimps showed lower susceptibility to WSSV infection and caused lessened virus loads, which further demonstrated that the JAK/STAT pathway could function as an anti-viral immunity in shrimp.

  8. Abrogation of CC chemokine receptor 9 ameliorates ventricular remodeling in mice after myocardial infarction.

    PubMed

    Huang, Yan; Wang, Dandan; Wang, Xin; Zhang, Yijie; Liu, Tao; Chen, Yuting; Tang, Yanhong; Wang, Teng; Hu, Dan; Huang, Congxin

    2016-01-01

    CC chemokine receptor 9 (CCR9), which is a unique receptor for CC chemokine ligand (CCL25), is mainly expressed on lymphocytes, dendritic cells (DCs) and monocytes/macrophages. CCR9 mediates the chemotaxis of inflammatory cells and participates in the pathological progression of inflammatory diseases. However, the role of CCR9 in the pathological process of myocardial infarction (MI) remains unexplored; inflammation plays a key role in this process. Here, we used CCR9 knockout mice to determine the functional significance of CCR9 in regulating post-MI cardiac remodeling and its underlying mechanism. MI was induced by surgical ligation of the left anterior descending coronary artery in CCR9 knockout mice and their CCR9+/+ littermates. Our results showed that the CCR9 expression levels were up-regulated in the hearts of the MI mice. Abrogation of CCR9 improved the post-MI survival rate and left ventricular (LV) dysfunction and decreased the infarct size. In addition, the CCR9 knockout mice exhibited attenuated inflammation, apoptosis, structural and electrical remodeling compared with the CCR9+/+ MI mice. Mechanistically, CCR9 mainly regulated the pathological response by interfering with the NF-κB and MAPK signaling pathways. In conclusion, the data reveal that CCR9 serves as a novel modulator of pathological progression following MI through NF-κB and MAPK signaling.

  9. Abrogation of CC chemokine receptor 9 ameliorates ventricular remodeling in mice after myocardial infarction

    PubMed Central

    Huang, Yan; Wang, Dandan; Wang, Xin; Zhang, Yijie; Liu, Tao; Chen, Yuting; Tang, Yanhong; Wang, Teng; Hu, Dan; Huang, Congxin

    2016-01-01

    CC chemokine receptor 9 (CCR9), which is a unique receptor for CC chemokine ligand (CCL25), is mainly expressed on lymphocytes, dendritic cells (DCs) and monocytes/macrophages. CCR9 mediates the chemotaxis of inflammatory cells and participates in the pathological progression of inflammatory diseases. However, the role of CCR9 in the pathological process of myocardial infarction (MI) remains unexplored; inflammation plays a key role in this process. Here, we used CCR9 knockout mice to determine the functional significance of CCR9 in regulating post-MI cardiac remodeling and its underlying mechanism. MI was induced by surgical ligation of the left anterior descending coronary artery in CCR9 knockout mice and their CCR9+/+ littermates. Our results showed that the CCR9 expression levels were up-regulated in the hearts of the MI mice. Abrogation of CCR9 improved the post-MI survival rate and left ventricular (LV) dysfunction and decreased the infarct size. In addition, the CCR9 knockout mice exhibited attenuated inflammation, apoptosis, structural and electrical remodeling compared with the CCR9+/+ MI mice. Mechanistically, CCR9 mainly regulated the pathological response by interfering with the NF-κB and MAPK signaling pathways. In conclusion, the data reveal that CCR9 serves as a novel modulator of pathological progression following MI through NF-κB and MAPK signaling. PMID:27585634

  10. Abrogation of CC chemokine receptor 9 ameliorates ventricular remodeling in mice after myocardial infarction.

    PubMed

    Huang, Yan; Wang, Dandan; Wang, Xin; Zhang, Yijie; Liu, Tao; Chen, Yuting; Tang, Yanhong; Wang, Teng; Hu, Dan; Huang, Congxin

    2016-01-01

    CC chemokine receptor 9 (CCR9), which is a unique receptor for CC chemokine ligand (CCL25), is mainly expressed on lymphocytes, dendritic cells (DCs) and monocytes/macrophages. CCR9 mediates the chemotaxis of inflammatory cells and participates in the pathological progression of inflammatory diseases. However, the role of CCR9 in the pathological process of myocardial infarction (MI) remains unexplored; inflammation plays a key role in this process. Here, we used CCR9 knockout mice to determine the functional significance of CCR9 in regulating post-MI cardiac remodeling and its underlying mechanism. MI was induced by surgical ligation of the left anterior descending coronary artery in CCR9 knockout mice and their CCR9+/+ littermates. Our results showed that the CCR9 expression levels were up-regulated in the hearts of the MI mice. Abrogation of CCR9 improved the post-MI survival rate and left ventricular (LV) dysfunction and decreased the infarct size. In addition, the CCR9 knockout mice exhibited attenuated inflammation, apoptosis, structural and electrical remodeling compared with the CCR9+/+ MI mice. Mechanistically, CCR9 mainly regulated the pathological response by interfering with the NF-κB and MAPK signaling pathways. In conclusion, the data reveal that CCR9 serves as a novel modulator of pathological progression following MI through NF-κB and MAPK signaling. PMID:27585634

  11. Screening for adverse events.

    PubMed

    Karson, A S; Bates, D W

    1999-02-01

    Adverse events (AEs) in medical patients are common, costly, and often preventable. Development of quality improvement programs to decrease the number and impact of AEs demands effective methods for screening for AEs on a routine basis. Here we describe the impact, types, and potential causes of AEs and review various techniques for identifying AEs. We evaluate the use of generic screening criteria in detail and describe a recent study of the sensitivity and specificity of individual generic screening criteria and combinations of these criteria. In general, the most sensitive screens were the least specific and no small sub-set of screens identified a large percentage of adverse events. Combinations of screens that were limited to administrative data were the least expensive, but none were particularly sensitive, although in practice they might be effective since routine screening is currently rarely done. As computer systems increase in sophistication sensitivity will improve. We also discuss recent studies that suggest that programs that screen for and identify AEs can be useful in reducing AE rates. While tools for identifying AEs have strengths and weaknesses, they can play an important role in organizations' quality improvement portfolios. PMID:10468381

  12. Pay attention to cardiac remodeling in cancer cachexia.

    PubMed

    Zheng, Yawen; Chen, Han; Li, Xiaoqing; Sun, Yuping

    2016-07-01

    Cancer cachexia is a complex and multifaceted disease state characterized by fatigue, weakness, and loss of skeletal muscle and adipose tissue. Recently, the profound negative effects of cancer cachexia on cardiac tissue draw much attention, which is likely to contribute to mortality in tumor-bearing animals. The mechanism of cardiac remodeling is not so clear and involved with a series of molecular alterations. In cancer cachexia model, progressive loss of left ventricular mass and decrease in myocardial function is observed and cardiac autonomic functions are altered. Levels of several emerging cardiovascular neurohormones are found elevating in patients with cancer, but it is still controversial whether the changes could reflect the heart injury accurately. The remedy for cardiac remodeling has been explored. It is showed that exercise can modulate signaling pathways activated by wasting cytokines and impact on the resulting outcomes on heart adaptation. Some drugs, such as bisoprolol, spironolactone, perindopril, tandospirone, and simvastatin, can mitigate adverse effects of the tumor on the heart and prolong survival. PMID:27108265

  13. Impact of biogenic nanoscale metals Fe, Cu, Zn and Se on reproductive LV chickens

    NASA Astrophysics Data System (ADS)

    Khiem Nguyen, Quy; Dieu Nguyen, Duy; Kien Nguyen, Van; Thinh Nguyen, Khac; Chau Nguyen, Hoai; Tin Tran, Xuan; Nguyen, Huu Cuong; Tien Phung, Duc

    2015-09-01

    Using biogenic nanoscale metals (Fe, Cu, ZnO, Se) to supplement into diet premix of reproductive LV (a Vietnamese Luong Phuong chicken breed) chickens resulted in certain improvement of poultry farming. The experimental data obtained showed that the farming indices depend mainly on the quantity of nanocrystalline metals which replaced the inorganic mineral component in the feed premix. All four experimental groups with different quantities of the replacement nano component grew and developed normally with livability reaching 91 to 94%, hen’s bodyweight at 38 weeks of age and egg weight ranged from 2.53-2.60 kg/hen and 50.86-51.55 g/egg, respectively. All these farming indices together with laying rate, egg productivity and chick hatchability peaked at group 5 with 25% of nanoscale metals compared to the standard inorganic mineral supplement, while feed consumption was lowest. The results also confirmed that nanocrystalline metals Fe, Cu, ZnO and Se supplemented to chicken feed were able to decrease inorganic minerals in the diet premixes at least four times, allowing animals to more effectively absorb feed minerals, consequently decreasing environmental pollution risks.

  14. Raise the Floor When Remodeling Science Labs

    ERIC Educational Resources Information Center

    Nation's Schools, 1972

    1972-01-01

    A new remodeling idea adopts the concept of raised floor covering gas, water, electrical, and drain lines. The accessible floor has removable panels set into an adjustable support frame 24 inches above a concrete subfloor. (Author)

  15. Lead Poisoning in Remodeling of Old Homes

    ERIC Educational Resources Information Center

    Barnes, Bart

    1973-01-01

    An article based on Dr. Muriel D. Wolf's study of elevated blood lead levels in children and adults present during the remodeling of old homes. Lead poisoning examples, symptoms, and precautions are given. (ST)

  16. Bone Remodeling Under Pathological Conditions.

    PubMed

    Xiao, Wenmei; Li, Shuai; Pacios, Sandra; Wang, Yu; Graves, Dana T

    2016-01-01

    Bone is masterfully programmed to repair itself through the coupling of bone formation following bone resorption, a process referred to as coupling. In inflammatory or other conditions, the balance between bone resorption and bone formation shifts so that a net bone loss results. This review focuses on four pathologic conditions in which remodeling leads to net loss of bone, postmenopausal osteoporosis, arthritis, periodontal disease, and disuse bone loss, which is similar to bone loss associated with microgravity. In most of these there is an acceleration of the resorptive process due to increased formation of bone metabolic units. This initially leads to a net bone loss since the time period of resorption is much faster than the time needed for bone formation that follows. In addition, each of these processes is characterized by an uncoupling that leads to net bone loss. Mechanisms responsible for increased rates of bone resorption, i.e. the formation of more bone metabolic units, involve enhanced expression of inflammatory cytokines and increased expression of RANKL. Moreover, the reasons for uncoupling are discussed which range from a decrease in expression of growth factors and bone morphogenetic proteins to increased expression of factors that inhibit Wnt signaling. PMID:26599114

  17. Remodeling kitchens: A smorgasbord of energy savings

    SciTech Connect

    Sullivan, B.

    1995-09-01

    The kitchen is often the busiest room in the house and is most likely to remodeled repeatedly over the life of a house. The kitchen also represents a concentration of household energy use. Remodeling a kitchen can mean introducing a host of new energy-saving features or making major energy blunders. This article discusses ways to utilized the best features: layout and design; appliances; lighting; windows and skylights; ventilation; insulation and air sealing; water; household recycling; green building materials.

  18. [Bone remodelling using the boundary element method].

    PubMed

    Martínez, Gabriela; Cerrolaza, Miguel

    2003-01-01

    An algorithm for the mathematical representation of external bone remodeling is proposed. The Boundary element method is used for the numerical analysis of trabecular bone, together with the remodeling algorithm presented by Fridez. The versatility and power of the algorithm discussed herein are shown by some numerical examples. As well, the method converges very fast to the solution, which is one of the main advantages of the proposed numerical scheme.

  19. Biomechanics of vascular mechanosensation and remodeling

    PubMed Central

    Baeyens, Nicolas; Schwartz, Martin A.

    2016-01-01

    Flowing blood exerts a frictional force, fluid shear stress (FSS), on the endothelial cells that line the blood and lymphatic vessels. The magnitude, pulsatility, and directional characteristics of FSS are constantly sensed by the endothelium. Sustained increases or decreases in FSS induce vessel remodeling to maintain proper perfusion of tissue. In this review, we discuss these mechanisms and their relevance to physiology and disease, and propose a model for how information from different mechanosensors might be integrated to govern remodeling. PMID:26715421

  20. ISMP Adverse Drug Reactions

    PubMed Central

    2013-01-01

    The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration’s (FDA’s) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA’s MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID:24421544

  1. Mitochondria, myocardial remodeling, and cardiovascular disease.

    PubMed

    Verdejo, Hugo E; del Campo, Andrea; Troncoso, Rodrigo; Gutierrez, Tomás; Toro, Barbra; Quiroga, Clara; Pedrozo, Zully; Munoz, Juan Pablo; Garcia, Lorena; Castro, Pablo F; Lavandero, Sergio

    2012-12-01

    The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload is associated with a complex molecular change in cardiomyocytes which leads to anatomic remodeling of the heart muscle. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. One of the features of cardiac remodeling is a progressive impairment in mitochondrial function. The heart has the highest oxygen uptake in the human body and accordingly it has a large number of mitochondria, which form a complex network under constant remodeling in order to sustain the high metabolic rate of cardiac cells and serve as Ca(2+) buffers acting together with the endoplasmic reticulum (ER). However, this high dependence on mitochondrial metabolism has its costs: when oxygen supply is threatened, high leak of electrons from the electron transport chain leads to oxidative stress and mitochondrial failure. These three aspects of mitochondrial function (Reactive oxygen species signaling, Ca(2+) handling and mitochondrial dynamics) are critical for normal muscle homeostasis. In this article, we will review the latest evidence linking mitochondrial morphology and function with the process of myocardial remodeling and cardiovascular disease.

  2. Physiology and pathophysiology of bone remodeling.

    PubMed

    Raisz, L G

    1999-08-01

    The skeleton is a metabolically active organ that undergoes continuous remodeling throughout life. This remodeling is necessary both to maintain the structural integrity of the skeleton and to subserve its metabolic functions as a storehouse of calcium and phosphorus. These dual functions often come into conflict under conditions of changing mechanical forces or metabolic and nutritional stress. The bone remodeling cycle involves a complex series of sequential steps that are highly regulated. The "activation" phase of remodeling is dependent on the effects of local and systemic factors on mesenchymal cells of the osteoblast lineage. These cells interact with hematopoietic precursors to form osteoclasts in the "resorption" phase. Subsequently, there is a "reversal" phase during which mononuclear cells are present on the bone surface. They may complete the resorption process and produce the signals that initiate formation. Finally, successive waves of mesenchymal cells differentiate into functional osteoblasts, which lay down matrix in the "formation" phase. The effects of calcium-regulating hormones on this remodeling cycle subserve the metabolic functions of the skeleton. Other systemic hormones control overall skeletal growth. The responses to changes in mechanical force and repair of microfractures, as well as the maintenance of the remodeling cycle, are determined locally by cytokines, prostaglandins, and growth factors. Interactions between systemic and local factors are important in the pathogenesis of osteoporosis as well as the skeletal changes in hyperparathyroidism and hyperthyroidism. Local factors are implicated in the pathogenesis of the skeletal changes associated with immobilization, inflammation, and Paget disease of bone. PMID:10430818

  3. Epigenomic regulation of oncogenesis by chromatin remodeling.

    PubMed

    Kumar, R; Li, D-Q; Müller, S; Knapp, S

    2016-08-25

    Disruption of the intricate gene expression program represents one of major driving factors for the development, progression and maintenance of human cancer, and is often associated with acquired therapeutic resistance. At the molecular level, cancerous phenotypes are the outcome of cellular functions of critical genes, regulatory interactions of histones and chromatin remodeling complexes in response to dynamic and persistent upstream signals. A large body of genetic and biochemical evidence suggests that the chromatin remodelers integrate the extracellular and cytoplasmic signals to control gene activity. Consequently, widespread dysregulation of chromatin remodelers and the resulting inappropriate expression of regulatory genes, together, lead to oncogenesis. We summarize the recent developments and current state of the dysregulation of the chromatin remodeling components as the driving mechanism underlying the growth and progression of human tumors. Because chromatin remodelers, modifying enzymes and protein-protein interactions participate in interpreting the epigenetic code, selective chromatin remodelers and bromodomains have emerged as new frontiers for pharmacological intervention to develop future anti-cancer strategies to be used either as single-agent or in combination therapies with chemotherapeutics or radiotherapy. PMID:26804164

  4. Mitochondria, myocardial remodeling, and cardiovascular disease.

    PubMed

    Verdejo, Hugo E; del Campo, Andrea; Troncoso, Rodrigo; Gutierrez, Tomás; Toro, Barbra; Quiroga, Clara; Pedrozo, Zully; Munoz, Juan Pablo; Garcia, Lorena; Castro, Pablo F; Lavandero, Sergio

    2012-12-01

    The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload is associated with a complex molecular change in cardiomyocytes which leads to anatomic remodeling of the heart muscle. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. One of the features of cardiac remodeling is a progressive impairment in mitochondrial function. The heart has the highest oxygen uptake in the human body and accordingly it has a large number of mitochondria, which form a complex network under constant remodeling in order to sustain the high metabolic rate of cardiac cells and serve as Ca(2+) buffers acting together with the endoplasmic reticulum (ER). However, this high dependence on mitochondrial metabolism has its costs: when oxygen supply is threatened, high leak of electrons from the electron transport chain leads to oxidative stress and mitochondrial failure. These three aspects of mitochondrial function (Reactive oxygen species signaling, Ca(2+) handling and mitochondrial dynamics) are critical for normal muscle homeostasis. In this article, we will review the latest evidence linking mitochondrial morphology and function with the process of myocardial remodeling and cardiovascular disease. PMID:22972531

  5. Zygotic LvBMP5-8 is required for skeletal patterning and for left-right but not dorsal-ventral specification in the sea urchin embryo.

    PubMed

    Piacentino, Michael L; Chung, Oliver; Ramachandran, Janani; Zuch, Daniel T; Yu, Jia; Conaway, Evan A; Reyna, Arlene E; Bradham, Cynthia A

    2016-04-01

    Skeletal patterning in the sea urchin embryo requires coordinated signaling between the pattern-dictating ectoderm and the skeletogenic primary mesenchyme cells (PMCs); recent studies have begun to uncover the molecular basis for this process. Using an unbiased RNA-Seq-based screen, we have previously identified the TGF-ß superfamily ligand, LvBMP5-8, as a skeletal patterning gene in Lytechinus variegatus embryos. This result is surprising, since both BMP5-8 and BMP2/4 ligands have been implicated in sea urchin dorsal-ventral (DV) and left-right (LR) axis specification. Here, we demonstrate that zygotic LvBMP5-8 is required for normal skeletal patterning on the left side, as well as for normal PMC positioning during gastrulation. Zygotic LvBMP5-8 is required for expression of the left-side marker soxE, suggesting that LvBMP5-8 is required for left-side specification. Interestingly, we also find that LvBMP5-8 knockdown suppresses serotonergic neurogenesis on the left side. While LvBMP5-8 overexpression is sufficient to dorsalize embryos, we find that zygotic LvBMP5-8 is not required for normal DV specification or development. In addition, ectopic LvBMP5-8 does not dorsalize LvBMP2/4 morphant embryos, indicating that, in the absence of BMP2/4, BMP5-8 is insufficient to specify dorsal. Taken together, our data demonstrate that zygotic LvBMP5-8 signaling is essential for left-side specification, and for normal left-side skeletal and neural patterning, but not for DV specification. Thus, while both BMP2/4 and BMP5-8 regulate LR axis specification, BMP2/4 but not zygotic BMP5-8 regulates DV axis specification in sea urchin embryos. PMID:26905309

  6. Zygotic LvBMP5-8 is required for skeletal patterning and for left-right but not dorsal-ventral specification in the sea urchin embryo.

    PubMed

    Piacentino, Michael L; Chung, Oliver; Ramachandran, Janani; Zuch, Daniel T; Yu, Jia; Conaway, Evan A; Reyna, Arlene E; Bradham, Cynthia A

    2016-04-01

    Skeletal patterning in the sea urchin embryo requires coordinated signaling between the pattern-dictating ectoderm and the skeletogenic primary mesenchyme cells (PMCs); recent studies have begun to uncover the molecular basis for this process. Using an unbiased RNA-Seq-based screen, we have previously identified the TGF-ß superfamily ligand, LvBMP5-8, as a skeletal patterning gene in Lytechinus variegatus embryos. This result is surprising, since both BMP5-8 and BMP2/4 ligands have been implicated in sea urchin dorsal-ventral (DV) and left-right (LR) axis specification. Here, we demonstrate that zygotic LvBMP5-8 is required for normal skeletal patterning on the left side, as well as for normal PMC positioning during gastrulation. Zygotic LvBMP5-8 is required for expression of the left-side marker soxE, suggesting that LvBMP5-8 is required for left-side specification. Interestingly, we also find that LvBMP5-8 knockdown suppresses serotonergic neurogenesis on the left side. While LvBMP5-8 overexpression is sufficient to dorsalize embryos, we find that zygotic LvBMP5-8 is not required for normal DV specification or development. In addition, ectopic LvBMP5-8 does not dorsalize LvBMP2/4 morphant embryos, indicating that, in the absence of BMP2/4, BMP5-8 is insufficient to specify dorsal. Taken together, our data demonstrate that zygotic LvBMP5-8 signaling is essential for left-side specification, and for normal left-side skeletal and neural patterning, but not for DV specification. Thus, while both BMP2/4 and BMP5-8 regulate LR axis specification, BMP2/4 but not zygotic BMP5-8 regulates DV axis specification in sea urchin embryos.

  7. Chemical abundances in the protoplanetary disc LV 2 (Orion) - II. High-dispersion VLT observations and microjet properties

    NASA Astrophysics Data System (ADS)

    Tsamis, Y. G.; Walsh, J. R.

    2011-11-01

    Integral field spectroscopy of the LV 2 proplyd is presented taken with the Very Large Telescope (VLT)/FLAMES Argus array at an angular resolution of 0.31 × 0.31 arcsec2 and velocity resolutions down to 2 km s-1 pixel-1. Following subtraction of the local M42 emission, the spectrum of LV 2 is isolated from the surrounding nebula. We measured the heliocentric velocities and widths of a number of lines detected in the intrinsic spectrum of the proplyd, as well as in the adjacent Orion nebula falling within a 6.6 × 4.2 arcsec2 field of view. It is found that far-ultraviolet to optical collisional lines with critical densities, Ncr, ranging from 103 to 109 cm-3 suffer collisional de-excitation near the rest velocity of the proplyd correlating tightly with their critical densities. Lines of low Ncr are suppressed the most. The bipolar jet arising from LV 2 is spectrally and spatially well detected in several emission lines. We compute the [O III] electron temperature profile across LV 2 in velocity space and measure steep temperature variations associated with the red-shifted lobe of the jet, possibly being due to a shock discontinuity. From the velocity-resolved analysis the ionized gas near the rest frame of LV 2 has Te= 9200 ± 800 K and Ne˜ 106 cm-3, while the red-shifted jet lobe has Te≈ 9000-104 K and Ne˜ 106-107 cm-3. The jet flow is highly ionized but contains dense semineutral clumps emitting neutral oxygen lines. The abundances of N+, O2 +, Ne2 +, Fe2 +, S+and S2 +are measured for the strong red-shifted jet lobe. Iron in the core of LV 2 is depleted by 2.54 dex with respect to solar as a result of sedimentation on dust, whereas the efficient destruction of dust grains in the fast microjet raises its Fe abundance to at least 30 per cent solar. Sulphur does not show evidence of significant depletion on dust, but its abundance both in the core and the jet is only about half solar. Based on observations made with ESO telescopes at the Paranal Observatory

  8. Cardiac remodelling and RAS inhibition.

    PubMed

    Ferrario, Carlos M

    2016-06-01

    Risk factors such as hypertension and diabetes are known to augment the activity and tissue expression of angiotensin II (Ang II), the major effector peptide of the renin-angiotensin system (RAS). Overstimulation of the RAS has been implicated in a chain of events that contribute to the pathogenesis of cardiovascular (CV) disease, including the development of cardiac remodelling. This chain of events has been termed the CV continuum. The concept of CV disease existing as a continuum was first proposed in 1991 and it is believed that intervention at any point within the continuum can modify disease progression. Treatment with antihypertensive agents may result in regression of left ventricular hypertrophy, with different drug classes exhibiting different degrees of efficacy. The greatest decrease in left ventricular mass is observed following treatment with angiotensin converting enzyme inhibitors (ACE-Is), which inhibit Ang II formation. Although ACE-Is and angiotensin receptor blockers (ARBs) provide significant benefits in terms of CV events and stroke, mortality remains high. This is partly due to a failure to completely suppress the RAS, and, as our knowledge has increased, an escape phenomenon has been proposed whereby the human sequence of the 12 amino acid substrate angiotensin-(1-12) is converted to Ang II by the mast cell protease, chymase. Angiotensin-(1-12) is abundant in a wide range of organs and has been shown to increase blood pressure in animal models, an effect abolished by the presence of ACE-Is or ARBs. This review explores the CV continuum, in addition to examining the influence of the RAS. We also consider novel pathways within the RAS and how new therapeutic approaches that target this are required to further reduce Ang II formation, and so provide patients with additional benefits from a more complete blockade of the RAS. PMID:27105891

  9. 10A1-MuLV but not the related amphotropic 4070A MuLV is highly neurovirulent: importance of sequences upstream of the structural Gag coding region.

    PubMed

    Münk, Carsten; Prassolov, Vladimir; Rodenburg, Michaela; Kalinin, Viacheslav; Löhler, Jürgen; Stocking, Carol

    2003-08-15

    Recombinants of Moloney murine leukemia virus (MoMuLV) with either an amphotropic (MoAmphoV) or 10A1-tropic host range (Mo10A1V) induce a spongiform neurodegenerative disease in susceptible mice. To test whether MoMuLV -derived sequences are required for induction of neuropathology, mice were inoculated with either the original 10A1 or the amphotropic (4070A) MuLV isolate. Strikingly, wild-type 10A1 was more neurovirulent than Mo10A1V, inducing severe neurological clinical symptoms with a median latency of 99 days in 100% of infected mice. In contrast, no motor disturbances were detected in any of the 4070A-infected mice, although limited central nervous system lesions were observed. A viral determinant conferring high neurovirulence to 10A1 was mapped to a region encompassing the first 676 bases of the viral genome, including the U5 LTR and encoding the amino-terminus of glycosylated Gag (glycoGag). In contrast to studies with the highly neurovirulent CasFr(KP) virus, an inverse correlation between surface expression levels of glycoGag and neurovirulence was not observed; however, this does not rule out a common underlying mechanism regulating virus pathogenicity.

  10. SVM-based classification of LV wall motion in cardiac MRI with the assessment of STE

    NASA Astrophysics Data System (ADS)

    Mantilla, Juan; Garreau, Mireille; Bellanger, Jean-Jacques; Paredes, José Luis

    2015-01-01

    In this paper, we propose an automated method to classify normal/abnormal wall motion in Left Ventricle (LV) function in cardiac cine-Magnetic Resonance Imaging (MRI), taking as reference, strain information obtained from 2D Speckle Tracking Echocardiography (STE). Without the need of pre-processing and by exploiting all the images acquired during a cardiac cycle, spatio-temporal profiles are extracted from a subset of radial lines from the ventricle centroid to points outside the epicardial border. Classical Support Vector Machines (SVM) are used to classify features extracted from gray levels of the spatio-temporal profile as well as their representations in the Wavelet domain under the assumption that the data may be sparse in that domain. Based on information obtained from radial strain curves in 2D-STE studies, we label all the spatio-temporal profiles that belong to a particular segment as normal if the peak systolic radial strain curve of this segment presents normal kinesis, or abnormal if the peak systolic radial strain curve presents hypokinesis or akinesis. For this study, short-axis cine- MR images are collected from 9 patients with cardiac dyssynchrony for which we have the radial strain tracings at the mid-papilary muscle obtained by 2D STE; and from one control group formed by 9 healthy subjects. The best classification performance is obtained with the gray level information of the spatio-temporal profiles using a RBF kernel with 91.88% of accuracy, 92.75% of sensitivity and 91.52% of specificity.

  11. Chromatin remodelling initiation during human spermiogenesis

    PubMed Central

    De Vries, Marieke; Ramos, Liliana; Housein, Zjwan; De Boer, Peter

    2012-01-01

    Summary During the last phase of spermatogenesis, spermiogenesis, haploid round spermatids metamorphose towards spermatozoa. Extensive cytoplasmic reduction and chromatin remodelling together allow a dramatic decrease of cellular, notably nuclear volume. DNA packing by a nucleosome based chromatin structure is largely replaced by a protamine based one. At the cytoplasmic level among others the acrosome and perinuclear theca (PNT) are formed. In this study we describe the onset of chromatin remodelling to occur concomitantly with acrosome and PNT development. In spread human round spermatid nuclei, we show development of a DAPI-intense doughnut-like structure co-localizing with the acrosomal sac and sub acrosomal PNT. At this structure we observe the first gradual decrease of nucleosomes and several histones. Histone post-translational modifications linked to chromatin remodelling such as H4K8ac and H4K16ac also delineate the doughnut, that is furthermore marked by H3K9me2. During the capping phase of acrosome development, the size of the doughnut-like chromatin domain increases, and this area often is marked by uniform nucleosome loss and the first appearance of transition protein 2 and protamine 1. In the acrosome phase at nuclear elongation, chromatin remodelling follows the downward movement of the marginal ring of the acrosome. Our results indicate that acrosome development and chromatin remodelling are interacting processes. In the discussion we relate chromatin remodelling to the available data on the nuclear envelope and the linker of nucleoskeleton and cytoskeleton (LINC) complex of spermatids, suggesting a signalling route for triggering chromatin remodelling. PMID:23213436

  12. Periprosthetic Bone Remodelling in Total Knee Arthroplasty

    PubMed Central

    GEORGEANU, Vlad; ATASIEI, Tudor; GRUIONU, Lucian

    2014-01-01

    Introduction: The clinical studies have shown that the displacement of the prosthesis components, especially of the tibial one is higher during the first year, after which it reaches an equilibrum position compatible with a good long term functioning. This displacement takes place due to bone remodelling close to the implant secondary to different loading concentrations over different areas of bone. Material and Method: Our study implies a simulation on a computational model using the finite element analysis. The simulation started taking into account arbitrary points because of non-linear conditions of bone-prosthesis interface and it was iterative.. A hundred consecutive situations corresponding to intermediate bone remodelling phases have been calculated according to given loadings. Bone remodelling was appreciated as a function of time and bone density for each constitutive element of the computational model created by finite element method. For each constitutive element a medium value of stress during the walking cycle was applied. Results: Analyse of proximal epiphysis-prosthesis complex slices showed that bone density increase is maintained all over the stem in the immediately post-operative period. At 10 months, the moment considered to be the end of bone remodelling, areas with increased bone density are fewer and smaller. Meanwhile, their distribution with a concentration toward the internal compartment in the distal metaphysis is preserved. Conclusions: After the total knee arthroplasty the tibial bone suffered a process of remodelling adapted to the new stress conditions. This bone remodelling can influence, sometimes negatively, especially in the cases with tibial component varus malposition, the fixation, respectively the survival of the prosthesis. This process has been demonstrated both by clinical trials and by simulation, using the finite elements method of periprosthetic bone remodelling. PMID:25553127

  13. Free gp70 from FeLV: enrichment from cell culture fluid by ferric oxide-agarose chromatography.

    PubMed

    Zelikman, I; Akerblom, L; Hjertèn, S; Morein, B

    1989-04-01

    A new chromatographic material based on beads of macroporous crosslinked agarose containing ferric oxide particles was used for enrichment of gp70--the envelope glycoprotein of feline leukemia virus (FeLV). Free gp70 was purified from cell culture fluid in one step with a recovery of 50 to 60% and a purification of about 60 times. The described procedure is a suitable first step for the purification of gp70 from large volumes of cell culture fluid.

  14. LV wall segmentation using the variational level set method (LSM) with additional shape constraint for oedema quantification.

    PubMed

    Kadir, K; Gao, H; Payne, A; Soraghan, J; Berry, C

    2012-10-01

    In this paper an automatic algorithm for the left ventricle (LV) wall segmentation and oedema quantification from T2-weighted cardiac magnetic resonance (CMR) images is presented. The extent of myocardial oedema delineates the ischaemic area-at-risk (AAR) after myocardial infarction (MI). Since AAR can be used to estimate the amount of salvageable myocardial post-MI, oedema imaging has potential clinical utility in the management of acute MI patients. This paper presents a new scheme based on the variational level set method (LSM) with additional shape constraint for the segmentation of T2-weighted CMR image. In our approach, shape information of the myocardial wall is utilized to introduce a shape feature of the myocardial wall into the variational level set formulation. The performance of the method is tested using real CMR images (12 patients) and the results of the automatic system are compared to manual segmentation. The mean perpendicular distances between the automatic and manual LV wall boundaries are in the range of 1-2 mm. Bland-Altman analysis on LV wall area indicates there is no consistent bias as a function of LV wall area, with a mean bias of -121 mm(2) between individual investigator one (IV1) and LSM, and -122 mm(2) between individual investigator two (IV2) and LSM when compared to two investigators. Furthermore, the oedema quantification demonstrates good correlation when compared to an expert with an average error of 9.3% for 69 slices of short axis CMR image from 12 patients.

  15. HIGH RESOLUTION H{alpha} IMAGES OF THE BINARY LOW-MASS PROPLYD LV 1 WITH THE MAGELLAN AO SYSTEM

    SciTech Connect

    Wu, Y.-L.; Close, L. M.; Males, J. R.; Follette, K.; Morzinski, K.; Kopon, D.; Rodigas, T. J.; Hinz, P.; Puglisi, A.; Esposito, S.; Pinna, E.; Riccardi, A.; Xompero, M.; Briguglio, R.

    2013-09-01

    We utilize the new Magellan adaptive optics system (MagAO) to image the binary proplyd LV 1 in the Orion Trapezium at H{alpha}. This is among the first AO results in visible wavelengths. The H{alpha} image clearly shows the ionization fronts, the interproplyd shell, and the cometary tails. Our astrometric measurements find no significant relative motion between components over {approx}18 yr, implying that LV 1 is a low-mass system. We also analyze Large Binocular Telescope AO observations, and find a point source which may be the embedded protostar's photosphere in the continuum. Converting the H magnitudes to mass, we show that the LV 1 binary may consist of one very-low-mass star with a likely brown dwarf secondary, or even plausibly a double brown dwarf. Finally, the magnetopause of the minor proplyd is estimated to have a radius of 110 AU, consistent with the location of the bow shock seen in H{alpha}.

  16. Viral DNA tethering domains complement replication-defective mutations in the p12 protein of MuLV Gag.

    PubMed

    Schneider, William M; Brzezinski, Jonathon D; Aiyer, Sriram; Malani, Nirav; Gyuricza, Mercedes; Bushman, Frederic D; Roth, Monica J

    2013-06-01

    The p12 protein of murine leukemia virus (MuLV) group-specific antigen (Gag) is associated with the preintegration complex, and mutants of p12 (PM14) show defects in nuclear entry or retention. Here we show that p12 proteins engineered to encode peptide sequences derived from known viral tethering proteins can direct chromatin binding during the early phase of viral replication and rescue a lethal p12-PM14 mutant. Peptides studied included segments of Kaposi sarcoma herpesvirus latency-associated nuclear antigen (LANA)(1-23), human papillomavirus 8 E2, and prototype foamy virus chromatin-binding sequences. Amino acid substitutions in Kaposi sarcoma herpesvirus LANA and prototype foamy virus chromatin-binding sequences that blocked nucleosome association failed to rescue MuLV p12-PM14. Rescue by a larger LANA peptide, LANA(1-32), required second-site mutations that are predicted to reduce peptide binding affinity to chromosomes, suggesting that excessively high binding affinity interfered with Gag/p12 function. This is supported by confocal microscopy of chimeric p12-GFP fusion constructs showing the reverted proteins had weaker association to condensed mitotic chromosomes. Analysis of the integration-site selection of these chimeric viruses showed no significant change in integration profile compared with wild-type MuLV, suggesting release of the tethered p12 post mitosis, before viral integration. PMID:23661057

  17. Viral DNA tethering domains complement replication-defective mutations in the p12 protein of MuLV Gag

    PubMed Central

    Schneider, William M.; Brzezinski, Jonathon D.; Aiyer, Sriram; Malani, Nirav; Gyuricza, Mercedes; Bushman, Frederic D.; Roth, Monica J.

    2013-01-01

    The p12 protein of murine leukemia virus (MuLV) group-specific antigen (Gag) is associated with the preintegration complex, and mutants of p12 (PM14) show defects in nuclear entry or retention. Here we show that p12 proteins engineered to encode peptide sequences derived from known viral tethering proteins can direct chromatin binding during the early phase of viral replication and rescue a lethal p12-PM14 mutant. Peptides studied included segments of Kaposi sarcoma herpesvirus latency-associated nuclear antigen (LANA)1–23, human papillomavirus 8 E2, and prototype foamy virus chromatin-binding sequences. Amino acid substitutions in Kaposi sarcoma herpesvirus LANA and prototype foamy virus chromatin-binding sequences that blocked nucleosome association failed to rescue MuLV p12-PM14. Rescue by a larger LANA peptide, LANA1–32, required second-site mutations that are predicted to reduce peptide binding affinity to chromosomes, suggesting that excessively high binding affinity interfered with Gag/p12 function. This is supported by confocal microscopy of chimeric p12-GFP fusion constructs showing the reverted proteins had weaker association to condensed mitotic chromosomes. Analysis of the integration-site selection of these chimeric viruses showed no significant change in integration profile compared with wild-type MuLV, suggesting release of the tethered p12 post mitosis, before viral integration. PMID:23661057

  18. Obesity and carotid artery remodeling

    PubMed Central

    Kozakova, M; Palombo, C; Morizzo, C; Højlund, K; Hatunic, M; Balkau, B; Nilsson, P M; Ferrannini, E

    2015-01-01

    Background/Objective: The present study tested the hypothesis that obesity-related changes in carotid intima-media thickness (IMT) might represent not only preclinical atherosclerosis but an adaptive remodeling meant to preserve circumferential wall stress (CWS) in altered hemodynamic conditions characterized by body size-dependent increase in stroke volume (SV) and blood pressure (BP). Subjects/Methods: Common carotid artery (CCA) luminal diameter (LD), IMT and CWS were measured in three different populations in order to study: (A) cross-sectional associations between SV, BP, anthropometric parameters and CCA LD (266 healthy subjects with wide range of body weight (24–159 kg)); (B) longitudinal associations between CCA LD and 3-year IMT progression rate (ΔIMT; 571 healthy non-obese subjects without increased cardiovascular (CV) risk); (C) the impact of obesity on CCA geometry and CWS (88 obese subjects without CV complications and 88 non-obese subjects matched for gender and age). Results: CCA LD was independently associated with SV that was determined by body size. In the longitudinal study, baseline LD was an independent determinant of ΔIMT, and ΔIMT of subjects in the highest LD quartile was significantly higher (28±3 μm) as compared with those in the lower quartiles (8±3, 16±4 and 16±3 μm, P=0.001, P<0.05 and P=0.01, respectively). In addition, CCA CWS decreased during the observational period in the highest LD quartile (from 54.2±8.6 to 51.6±7.4 kPa, P<0.0001). As compared with gender- and age-matched lean individuals, obese subjects had highly increased CCA LD and BP (P<0.0001 for both), but only slightly higher CWS (P=0.05) due to a significant increase in IMT (P=0.005 after adjustment for confounders). Conclusions: Our findings suggest that in obese subjects, the CCA wall thickens to compensate the luminal enlargement caused by body size-induced increase in SV, and therefore, to normalize the wall stress. CCA diameter in obesity could

  19. A fly's view of neuronal remodeling.

    PubMed

    Yaniv, Shiri P; Schuldiner, Oren

    2016-09-01

    Developmental neuronal remodeling is a crucial step in sculpting the final and mature brain connectivity in both vertebrates and invertebrates. Remodeling includes degenerative events, such as neurite pruning, that may be followed by regeneration to form novel connections during normal development. Drosophila provides an excellent model to study both steps of remodeling since its nervous system undergoes massive and stereotypic remodeling during metamorphosis. Although pruning has been widely studied, our knowledge of the molecular and cellular mechanisms is far from complete. Our understanding of the processes underlying regrowth is even more fragmentary. In this review, we discuss recent progress by focusing on three groups of neurons that undergo stereotypic pruning and regrowth during metamorphosis, the mushroom body γ neurons, the dendritic arborization neurons and the crustacean cardioactive peptide peptidergic neurons. By comparing and contrasting the mechanisms involved in remodeling of these three neuronal types, we highlight the common themes and differences as well as raise key questions for future investigation in the field. WIREs Dev Biol 2016, 5:618-635. doi: 10.1002/wdev.241 For further resources related to this article, please visit the WIREs website. PMID:27351747

  20. STIM1-dependent Ca2+ microdomains are required for myofilament remodeling and signaling in the heart

    PubMed Central

    Parks, Cory; Alam, Mohammad Afaque; Sullivan, Ryan; Mancarella, Salvatore

    2016-01-01

    In non-excitable cells stromal interaction molecule 1 (STIM1) is a key element in the generation of Ca2+ signals that lead to gene expression, migration and cell proliferation. A growing body of literature suggests that STIM1 plays a key role in the development of pathological cardiac hypertrophy. However, the precise mechanisms involving STIM-dependent Ca2+ signaling in the heart are not clearly established. Here, we have investigated the STIM1-associated Ca2+ signals in cardiomyocytes and their relevance to pathological cardiac remodeling. We show that mice with inducible, cardiac-restricted, ablation of STIM1 exhibited left ventricular reduced contractility, which was corroborated by impaired single cell contractility. The spatial properties of STIM1-dependent Ca2+ signals determine restricted Ca2+ microdomains that regulate myofilament remodeling and activate spatially segregated pro-hypertrophic factors. Indeed, mice lacking STIM1 showed less adverse structural remodeling in response to pressure overload-induced cardiac hypertrophy. These results highlight how STIM1-dependent Ca2+ microdomains have a major impact on intracellular Ca2+ homeostasis, cytoskeletal remodeling and cellular signaling, even when excitation-contraction coupling is present. PMID:27150728

  1. Anti-lipopolysaccharide factor in Litopenaeus vannamei (LvALF): a broad spectrum antimicrobial peptide essential for shrimp immunity against bacterial and fungal infection.

    PubMed

    de la Vega, Enrique; O'Leary, Nuala A; Shockey, Jessica E; Robalino, Javier; Payne, Caroline; Browdy, Craig L; Warr, Gregory W; Gross, Paul S

    2008-04-01

    Antimicrobial peptides are an essential component of the innate immune system of most organisms. Expressed sequence tag analysis from various shrimp (Litopenaeus vannamei) tissues revealed transcripts corresponding to two distinct sequences (LvALF1 and LvALF2) with strong sequence similarity to anti-lipopolysaccharide factor (ALF), an antimicrobial peptide originally isolated from the horseshoe crab Limulus polyphemus. Full-length clones contained a 528bp transcript with a predicted open reading frame coding for 120 amino acids in LvALF1, and a 623bp transcript with a predicted open reading frame coding for 93 amino acids in LvALF2. A reverse genetic approach was implemented to study the in vivo role of LvALF1 in protecting shrimp from bacterial, fungal and viral infections. Injection of double-stranded RNA (dsRNA) corresponding to the LvALF1 message resulted in a significant reduction of LvALF1 mRNA transcript abundance as determined by qPCR. Following knockdown, shrimp were challenged with low pathogenic doses of Vibrio penaeicida, Fusarium oxysporum or white spot syndrome virus (WSSV) and the resulting mortality curves were compared with controls. A significant increase of mortality in the LvALF1 knockdown shrimp was observed in the V. penaeicida and F. oxysporum infections when compared to controls, showing that this gene has a role in protecting shrimp from both bacterial and fungal infections. In contrast, LvALF1 dsRNA activated the sequence-independent innate anti-viral immune response giving increased protection from WSSV infection.

  2. CT-1-CP-induced ventricular electrical remodeling in mice.

    PubMed

    Chen, Shu-fen; Wei, Tao-zhi; Rao, Li-ya; Xu, Ming-guang; Dong, Zhan-ling

    2015-02-01

    The chronic effects of carboxyl-terminal polypeptide of Cardiotrophin-1 (CT-1-CP) on ventricular electrical remodeling were investigated. CT-1-CP, which contains 16 amino acids in sequence of the C-terminal of Cardiotrophin-1, was selected and synthesized, and then administered to Kunming mice (aged 5 weeks) by intraperitoneal injection (500 ng·g⁻¹·day⁻¹) (4 groups, n=10 and female: male=1:1 in each group) for 1, 2, 3 and 4 weeks, respectively. The control group (n=10, female: male=1:1) was injected by physiological saline for 4 weeks. The epicardial monophasic action potential (MAP) was recorded by using a contact-type MAP electrode placed vertically on the left ventricular (LV) epicardium surface, and the electrocardiogram (ECG) signal in lead II was monitored synchronously. ECG intervals (RR, PR, QRS and QT) and the amplitude of MAP (Am), the maximum upstroke velocity (Vmax), as well as action potential durations (APDs) at different repolarization levels (APD30, APD50, APD70, and APD90) of MAP were determined and analyzed in detail. There were no significant differences in RR and P intervals between CT-1-CP-treated groups and control group, but the PR segment and the QRS complex were greater in the former than in the latter (F=2.681 and 5.462 respectively, P<0.05). Though QT interval and the corrected QT interval (QTc) were shorter in CT-1-CP-treated groups than in control group, the QT dispersion (QTd) of them was greater in the latter than in the former (F=3.090, P<0.05) and increased with the time. The ECG monitoring synchronously with the MAP showed that the compression of MAP electrode on the left ventricular epicardium induced performance similar to myocardium ischemia. As compared with those before chest-opening, the PR segment and QT intervals remained basically unchanged in control group, but prolonged significantly in all CT-1-CP-treated groups and the prolongation of QT intervals increased gradually along with the time of exposure to CT-1-CP

  3. Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters.

    PubMed

    Kato, Ryuji; Nomura, Atsuo; Sakamoto, Aiji; Yasuda, Yuki; Amatani, Koyuha; Nagai, Sayuri; Sen, Yoko; Ijiri, Yoshio; Okada, Yoshikatsu; Yamaguchi, Takehiro; Izumi, Yasukatsu; Yoshiyama, Minoru; Tanaka, Kazuhiko; Hayashi, Tetsuya

    2014-12-01

    The prevalence of sleep apnea is very high in patients with heart failure (HF). The aims of this study were to investigate the influence of intermittent hypoxia (IH) on the failing heart and to evaluate the antioxidant effect of hydrogen gas. Normal male Syrian hamsters (n = 22) and cardiomyopathic (CM) hamsters (n = 33) were exposed to IH (repeated cycles of 1.5 min of 5% oxygen and 5 min of 21% oxygen for 8 h during the daytime) or normoxia for 14 days. Hydrogen gas (3.05 vol/100 vol) was inhaled by some CM hamsters during hypoxia. IH increased the ratio of early diastolic mitral inflow velocity to mitral annulus velocity (E/e', 21.8 vs. 16.9) but did not affect the LV ejection fraction (EF) in normal Syrian hamsters. However, IH increased E/e' (29.4 vs. 21.5) and significantly decreased the EF (37.2 vs. 47.2%) in CM hamsters. IH also increased the cardiomyocyte cross-sectional area (672 vs. 443 μm(2)) and interstitial fibrosis (29.9 vs. 9.6%), along with elevation of oxidative stress and superoxide production in the left ventricular (LV) myocardium. Furthermore, IH significantly increased the expression of brain natriuretic peptide, β-myosin heavy chain, c-fos, and c-jun mRNA in CM hamsters. Hydrogen gas inhalation significantly decreased both oxidative stress and embryonic gene expression, thus preserving cardiac function in CM hamsters. In conclusion, IH accelerated LV remodeling in CM hamsters, at least partly by increasing oxidative stress in the failing heart. These findings might explain the poor prognosis of patients with HF and sleep apnea.

  4. Prenatal programming: adverse cardiac programming by gestational testosterone excess.

    PubMed

    Vyas, Arpita K; Hoang, Vanessa; Padmanabhan, Vasantha; Gilbreath, Ebony; Mietelka, Kristy A

    2016-01-01

    Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30-90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells -c3 (NFATc3), and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess.

  5. Prenatal programming: adverse cardiac programming by gestational testosterone excess.

    PubMed

    Vyas, Arpita K; Hoang, Vanessa; Padmanabhan, Vasantha; Gilbreath, Ebony; Mietelka, Kristy A

    2016-01-01

    Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30-90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells -c3 (NFATc3), and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess. PMID:27328820

  6. Prenatal programming: adverse cardiac programming by gestational testosterone excess

    PubMed Central

    Vyas, Arpita K.; Hoang, Vanessa; Padmanabhan, Vasantha; Gilbreath, Ebony; Mietelka, Kristy A.

    2016-01-01

    Adverse events during the prenatal and early postnatal period of life are associated with development of cardiovascular disease in adulthood. Prenatal exposure to excess testosterone (T) in sheep induces adverse reproductive and metabolic programming leading to polycystic ovarian syndrome, insulin resistance and hypertension in the female offspring. We hypothesized that prenatal T excess disrupts insulin signaling in the cardiac left ventricle leading to adverse cardiac programming. Left ventricular tissues were obtained from 2-year-old female sheep treated prenatally with T or oil (control) from days 30–90 of gestation. Molecular markers of insulin signaling and cardiac hypertrophy were analyzed. Prenatal T excess increased the gene expression of molecular markers involved in insulin signaling and those associated with cardiac hypertrophy and stress including insulin receptor substrate-1 (IRS-1), phosphatidyl inositol-3 kinase (PI3K), Mammalian target of rapamycin complex 1 (mTORC1), nuclear factor of activated T cells –c3 (NFATc3), and brain natriuretic peptide (BNP) compared to controls. Furthermore, prenatal T excess increased the phosphorylation of PI3K, AKT and mTOR. Myocardial disarray (multifocal) and increase in cardiomyocyte diameter was evident on histological investigation in T-treated females. These findings support adverse left ventricular remodeling by prenatal T excess. PMID:27328820

  7. Repeated sauna therapy attenuates ventricular remodeling after myocardial infarction in rats by increasing coronary vascularity of noninfarcted myocardium.

    PubMed

    Sobajima, Mitsuo; Nozawa, Takashi; Shida, Takuya; Ohori, Takashi; Suzuki, Takayuki; Matsuki, Akira; Inoue, Hiroshi

    2011-08-01

    Repeated sauna therapy (ST) increases endothelial nitric oxide synthase (eNOS) activity and improves cardiac function in heart failure as well as peripheral blood flow in ischemic limbs. The present study investigates whether ST can increase coronary vascularity and thus attenuate cardiac remodeling after myocardial infarction (MI). We induced MI by ligating the left coronary artery of Wistar rats. The rats were placed in a far-infrared dry sauna at 41°C for 15 min and then at 34°C for 20 min once daily for 4 wk. Cardiac hemodynamic, histopathological, and gene analyses were performed. Despite the similar sizes of MI between the ST and non-ST groups (51.4 ± 0.3 vs. 51.1 ± 0.2%), ST reduced left ventricular (LV) end-diastolic (9.7 ± 0.4 vs. 10.7 ± 0.5 mm, P < 0.01) and end-systolic (8.6 ± 0.5 vs. 9.6 ± 0.6 mm, P < 0.01) dimensions and attenuated MI-induced increases in LV end-diastolic pressure. Cross-sectional areas of cardiomyocytes were smaller in ST rats and associated with a significant reduction in myocardial atrial natriuretic peptide mRNA levels. Vascular density was reduced in the noninfarcted myocardium of non-ST rats, and the density of cells positive for CD31 and for α-smooth muscle actin was decreased. These decreases were attenuated in ST rats compared with non-ST rats and associated with increases in myocardial eNOS and vascular endothelial growth factor mRNA levels. In conclusion, ST attenuates cardiac remodeling after MI, at least in part, through improving coronary vascularity in the noninfarcted myocardium. Repeated ST might serve as a novel noninvasive therapy for patients with MI.

  8. Cardiovascular magnetic resonance in pregnancy: Insights from the cardiac hemodynamic imaging and remodeling in pregnancy (CHIRP) study

    PubMed Central

    2014-01-01

    Background Cardiovascular disease in pregnancy is the leading cause of maternal mortality in North America. Although transthoracic echocardiography (TTE) is the most widely used imaging modality for the assessment of cardiovascular function during pregnancy, little is known on the role of cardiovascular magnetic resonance (CMR). The objective of the Cardiac Hemodynamic Imaging and Remodeling in Pregnancy (CHIRP) study was to compare TTE and CMR in the non-invasive assessment of maternal cardiac remodeling during the peripartum period. Methods Between 2010–2012, healthy pregnant women aged 18 to 35 years were prospectively enrolled. All women underwent TTE and CMR during the third trimester and at least 3 months postpartum (surrogate for non-pregnant state). Results The study population included a total of 34 women (mean age 29 ± 3 years). During the third trimester, TTE and CMR demonstrated an increase in left ventricular end-diastolic volume from 95 ± 11 mL to 115 ± 14 mL and 98 ± 6 mL to 125 ± 5 mL, respectively (p < 0.05). By TTE and CMR, there was also an increase in left ventricular (LV) mass during pregnancy from 111 ± 10 g to 163 ± 11 g and 121 ± 5 g to 179 ± 5 g, respectively (p < 0.05). Although there was good correlation between both imaging modalities for LV mass, stroke volume, and cardiac output, the values were consistently underestimated by TTE. Conclusion This CMR study provides reference values for cardiac indices during normal pregnancy and the postpartum state. PMID:24387349

  9. Scar remodeling after strabismus surgery.

    PubMed Central

    Ludwig, I H

    1999-01-01

    limitation of versions, less separation of the tendons from sclera, and thicker appearance of the scar segments. The use of nonabsorbable sutures in the repair procedure reduced the recurrence rate. Histologic examination of the clinical stretched scar specimens showed dense connective tissue that was less well organized compared with normal tendon. In the tissue culture studies, cells cultured from the stretched scar specimens grew rapidly and were irregularly shaped. A high-molecular-weight protein was identified in the culture medium. By contrast, cells cultured from normal tendon (controls) grew more slowly and regularly, stopped growing at 4 days, and produced less total protein than cultured stretched scar specimens. In the animal model studies, the collagenase-treated sites showed elongated scars with increased collagen between the muscle and the sclera, as well as increased collagen creep rates, compared with the saline-treated controls. The use of nonabsorbable sutures in collagenase-treated animal model surgery sites was associated with shorter, thicker scars compared with similar sites sutured with absorbable sutures. CONCLUSIONS: A lengthened or stretched, remodeled scar between an operated muscle tendon and sclera is a common occurrence and is a factor contributing to the variability of outcome after strabismus repair, even years later. This abnormality may be revealed by careful exploration of previously operated muscles. Definitive repair requires firm reattachment of tendon to sclera with nonabsorbable suture support. Images FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 FIGURE 9 FIGURE 10 FIGURE 11 FIGURE 12 FIGURE 13 FIGURE 14 FIGURE 15 FIGURE 16 FIGURE 17 FIGURE 18 FIGURE 19 FIGURE 20 FIGURE 21 FIGURE 22 FIGURE 23 FIGURE 24 FIGURE 25 FIGURE 26 FIGURE 27 FIGURE 28 FIGURE 29 FIGURE 30 FIGURE 31 FIGURE 32 FIGURE 33 FIGURE 34 FIGURE 35 FIGURE 36 FIGURE 37 FIGURE 38 FIGURE 39 FIGURE 40 FIGURE 41 FIGURE 42 FIGURE 43 FIGURE 44 FIGURE 45 FIGURE 46 FIGURE 52

  10. Adverse Reactions to Hallucinogenic Drugs.

    ERIC Educational Resources Information Center

    Meyer, Roger E. , Ed.

    This reports a conference of psychologists, psychiatrists, geneticists and others concerned with the biological and psychological effects of lysergic acid diethylamide and other hallucinogenic drugs. Clinical data are presented on adverse drug reactions. The difficulty of determining the causes of adverse reactions is discussed, as are different…

  11. Sustained augmentation of cardiac alpha1A-adrenergic drive results in pathological remodeling with contractile dysfunction, progressive fibrosis and reactivation of matricellular protein genes.

    PubMed

    Chaulet, H; Lin, F; Guo, J; Owens, W A; Michalicek, J; Kesteven, S H; Guan, Z; Prall, O W; Mearns, B M; Feneley, M P; Steinberg, S F; Graham, R M

    2006-04-01

    We previously reported that transgenic (TG) mice with cardiac-restricted alpha(1A)-adrenergic receptor (alpha(1A)-AR)-overexpression showed enhanced contractility, but no hypertrophy. Since chronic inotropic enhancement may be deleterious, we investigated if long-term, cardiac function and longevity are compromised. alpha(1A)-TG mice, but not their non-TG littermates (NTLs), showed progressive loss of left ventricular (LV) hypercontractility (dP/dt(max): 14,567+/-603 to 11,610+/-915 mmHg/s, P<0.05, A1A1 line: 170-fold overexpression; and 13,625+/-826 to 8322+/-682 mmHg/s, respectively, P<0.05, A1A4 line: 112-fold overexpression, at 2 and 6 months, respectively). Both TG lines developed LV fibrosis, but not LV dilatation or hypertrophy, despite activation of hypertrophic signaling pathways. Microarray and real time RT-PCR analyses revealed activation of matricellular protein genes, including those for thrombospondin 1, connective tissue growth factor and tenascin C, but not transforming growth factor beta1. Life-span was markedly shortened (mean age at death: 155 days, A1A1 line; 224 days, A1A4 line compared with NTLs: >300 days). Telemetric electrocardiography revealed that death in the alpha(1A)-AR TG mice was due to cardiac standstill preceded by a progressive diminution in QRS amplitude, but not by arrhythmias. The QRS changes and sudden death could be mimicked by alpha(1)-AR activation, and reversed preterminally by alpha(1)-AR blockade, suggesting a relationship to stress- or activity-associated catecholamine release. Thus, long-term augmentation of cardiac alpha(1A)-adrenergic drive leads to premature death and progressive LV fibrosis with reactivation of matricellular protein genes. To our knowledge this is the first evidence in vivo for a role of the alpha(1A)-AR in ventricular fibrosis and in pathological cardiac remodeling.

  12. Sex-related differences in intrinsic myocardial properties influence cardiac function in middle-aged rats during infarction-induced left ventricular remodeling.

    PubMed

    Dedkov, Eduard I; Bogatyryov, Yevgen; Pavliak, Kristina; Santos, Adora T; Chen, Yue-Feng; Zhang, Youhua; Pingitore, Alessandro

    2016-06-01

    We previously determined that residual left ventricular (LV) myocardium of middle-aged rats had sex-related differences in regional tissue properties 4 weeks after a large myocardial infarction (MI). However, the impact of such differences on cardiac performance remained unclear. Therefore, our current study aimed to elucidate whether sex-related changes in MI-induced myocardial remodeling can influence cardiac function. A similar-sized MI was induced in 12-month-old male (M-MI) and female (F-MI) Sprague-Dawley rats by ligation of the left coronary artery. The cardiac function was monitored for 2 months after MI and then various LV parameters were compared between sexes. We found that although two sex groups had a similar pattern of MI-induced decline in LV function, F-MI rats had greater cardiac performance compared to M-MI rats, considering the higher values of EF (39.9 ± 3.4% vs. 26.7 ± 7.7%, P < 0.05), SW index (40.4 ± 2.1 mmHg • mL/kg vs. 20.2 ± 3.3 mmHg • mL/kg, P < 0.001), and CI (139.2 ± 7.9 mL/min/kg vs. 74.9 ± 14.7 mL/min/kg, P < 0.01). The poorer pumping capacity in M-MI hearts was associated with markedly reduced LV compliance and prolonged relaxation. On the tissue level, F-MI rats revealed a higher, than in M-MI rats, density of cardiac myocytes in the LV free wall (2383.8 ± 242.6 cells/mm(2) vs. 1785.7 ± 55.9 cells/mm(2), P < 0.05). The latter finding correlated with a lower density of apoptotic cardiac myocytes in residual LV myocardium of F-MI rats (0.18 ± 0.08 cells/mm(2) vs. 0.91 ± 0.30 cells/mm(2) in males, P < 0.01). Thus, our data suggested that F-MI rats had markedly attenuated decline in cardiac performance compared to males due to ability of female rats to better retain functionally favorable intrinsic myocardial properties.

  13. Strategies for Energy Efficient Remodeling: SEER 2003 Case Study Report

    SciTech Connect

    2004-11-01

    The goal of the Strategies for Energy Efficiency in Remodeling (SEER) project is to provide information, based on research and case studies, to remodelers and consumers about opportunities to increase home energy performance.

  14. Progesterone inhibits vascular remodeling and attenuates monocrotaline-induced pulmonary hypertension in estrogen-deficient rats.

    PubMed

    Tofovic, P S; Zhang, X; Petrusevska, G

    2009-07-01

    (Full text is available at http://www.manu.edu.mk/prilozi). Pulmonary arterial hypertension (PH) is predominantly a disease of young females. Yet, little is known regarding the effects of female sex hormones in PH. Female rats develop less severe PH compared to male rats, and ovariectomy (OVX) exacerbates PH. Although OVX rats treated with estradiol develop less severe disease, the role of progesterone in OVX-induced exacerbation of disease has not been examined. Progesterone was shown to dilate pulmonary vessels and to inhibit proliferation of endothelial and vascular smooth muscle cells. Therefore, we hypothesized that progesterone may confer protective effects in experimental PH. A total of 30 female rats were ovariectomized and OVX rats were randomly administered either saline (OVX-Control group, n = 7), monocrotaline (60mg/kg i.p.; OVX-MCT group; n = 12), or MCT plus progesterone (30microg/kg/h via osmotic minipumps; OVX-MCT+P group; n = 11). After 32 days animals were instrumented for in situ (open chest) measurements of right ventricle (RV) peak systolic (RVSP) and end diastolic (RVEDP) pressures, and tissue samples were obtained for morphometric and histological analysis. Administration of MCT elevated RVSP (22.2 +/- 1.1 vs. 46.7 +/- 2.4 mmHg) and RVEDP (1.51 +/- 0.86 vs. 11.9+/-2.2 mmHg), increased RV/left ventricle + septum (RV/LV+S) ratio (0.256 +/- 0.010 vs. 0.582 +/- 0.033, OVX vs. OVX-MCT), and induced media hypertrophy of small size pulmonary arteries. In ovariectomized pulmonary hypertensive rats, treatment with progesterone attenuated the severity of disease (OVX-MCT+P group: RVSP = 36.6 +/- 2.3 mmHg; RV/LV+S = 0.468 +/- 0.025; RVEDP = 7.5 +/-1.5 mmHg), attenuated vascular remodeling (media % index: 28.2 +/- 1.1 vs. 34.2 +/- 1.3), and reduced mortality (9% vs. 25%; OVX-MCT+P vs. OVX-MCT). This study provides the first evidence that in estrogen-deficient rats, progesterone has protective effects in MCT-induced PH. Further evaluation of the role of

  15. A hemocyte-expressed fibrinogen-related protein gene (LvFrep) from the shrimp Litopenaeus vannamei: Expression analysis after microbial infection and during larval development.

    PubMed

    Coelho, Jaqueline da Rosa; Barreto, Cairé; Silveira, Amanda da Silva; Vieira, Graziela Cleusa; Rosa, Rafael Diego; Perazzolo, Luciane Maria

    2016-09-01

    Fibrinogen-related proteins (FREPs) comprise a large family of microbial recognition proteins involved in many biological functions in both vertebrate and invertebrate animals. By taking advantage of publicly accessible databases, we have identified a FREP-like homolog in the most cultivated penaeid shrimp, Litopenaeus vannamei (LvFrep). The obtained sequence showed a conserved fibrinogen-related domain (FReD) and displayed significant similarities to FREP-like proteins from other invertebrates and to ficolins from crustaceans. The expression of LvFrep appeared to be limited to circulating hemocytes. Interestingly, LvFrep gene expression was induced in shrimp hemocytes only in response to a Vibrio infection but not to the White spot syndrome virus (WSSV). Moreover, LvFrep transcript levels were detected early in fertilized eggs, suggesting the participation of this immune-related gene in the antimicrobial defenses during shrimp development.

  16. Retinal remodeling in human retinitis pigmentosa.

    PubMed

    Jones, B W; Pfeiffer, R L; Ferrell, W D; Watt, C B; Marmor, M; Marc, R E

    2016-09-01

    Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies. PMID:27020758

  17. Revealing remodeler function: Varied and unique

    NASA Astrophysics Data System (ADS)

    Eastlund, Allen

    Chromatin remodelers perform a necessary and required function for the successful expression of our genetic code. By modifying, shifting, or ejecting nucleosomes from the chromatin structure they allow access to the underlying DNA to the rest of the cell's machinery. This research has focused on two major remodeler motors from major families of chromatin remodelers: the trimeric motor domain of RSC and the motor domain of the ISWI family, ISWI. Using primarily stopped-flow spectrofluorometry, I have categorized the time-dependent motions of these motor domains along their preferred substrate, double-stranded DNA. Combined with collected ATP utilization data, I present the subsequent analysis and associated conclusions that stem from the underlying assumptions and models. Interestingly, there is little in common between the investigated proteins aside from their favored medium. While RSC exhibits modest translocation characteristics and highly effective motion with the ability for large molecular forces, ISWI is not only structurally different but highly inefficient in its motion leading to difficulties in determining its specific translocation mechanics. While chromatin remodeling is a ubiquitous facet of eukaryotic life, there remains much to be understood about their general mechanisms.

  18. Chromatin remodelers: We are the drivers!!

    PubMed

    Tyagi, Monica; Imam, Nasir; Verma, Kirtika; Patel, Ashok K

    2016-07-01

    Chromatin is a highly dynamic structure that imparts structural organization to the genome and regulates the gene expression underneath. The decade long research in deciphering the significance of epigenetics in maintaining cellular integrity has embarked the focus on chromatin remodeling enzymes. These drivers have been categorized as readers, writers and erasers with each having significance of their own. Largely, on the basis of structure, ATP dependent chromatin remodelers have been grouped into 4 families; SWI/SNF, ISWI, IN080 and CHD. It is still unclear to what degree these enzymes are swayed by local DNA sequences when shifting a nucleosome to different positions. The ability of regulating active and repressive transcriptional state via open and close chromatin architecture has been well studied however, the significance of chromatin remodelers in regulating transcription at each step i.e. initiation, elongation and termination require further attention. The authors have highlighted the significance and role of different chromatin remodelers in transcription, DNA repair and histone variant deposition. PMID:27429206

  19. Challenging Modernization: Remodelling the Education Workforce

    ERIC Educational Resources Information Center

    Butt, Graham; Gunter, Helen

    2005-01-01

    This special edition enables an in-depth look at the process of modernization of education in England, in relation to other international developments. In particular we focus on the reform of teachers? work by examining the antecedence of the current policy of remodelling through three articles based on the Evaluation of the Department for…

  20. Arterial Remodeling Associates with CKD Progression

    PubMed Central

    Collin, Cédric; Karras, Alexandre; Laurent, Stéphane; Bozec, Erwan; Jacquot, Christian; Stengel, Bénédicte; Houillier, Pascal; Froissart, Marc; Boutouyrie, Pierre

    2011-01-01

    In CKD, large arteries remodel and become increasingly stiff. The greater pulsatile pressure reaching the glomerulus as a result of increased aortic stiffness could induce renal damage, suggesting that the stiffening and remodeling of large arteries could affect the progression of CKD. We measured carotid-femoral pulse wave velocity, aortic pressure and carotid remodeling and stiffness parameters in 180 patients with CKD (mean measured GFR, 32 ml/min per 1.73 m2) and followed them prospectively for a mean of 3.1 years. During follow-up, carotid stiffness significantly increased (+0.28 ± 0.05 m/s; P < 0.0001) but aortic stiffness did not. Carotid intima-media thickness decreased significantly during follow-up and the internal diameter of the carotid increased, producing increased circumferential wall stress (+2.08 ± 0.43 kPa/yr; P < 0.0001). In a linear mixed model, circumferential wall stress significantly associated with faster GFR decline after adjustment for risk factors of cardiovascular disease and progression of CKD. In a multivariable Cox model, carotid circumferential wall stress and pulse pressure independently associated with higher risk for ESRD. None of the arterial stiffness parameters associated with progression of CKD. In conclusion, maladaptive remodeling of the carotid artery and increased pulse pressure independently associate with faster decline of renal function and progression to ESRD. PMID:21493771

  1. Effect of culprit-lesion remodeling versus plaque rupture on three-year outcome in patients with acute coronary syndrome.

    PubMed

    Okura, Hiroyuki; Kobayashi, Yoshio; Sumitsuji, Satoru; Terashima, Mitsuyasu; Kataoka, Toru; Masutani, Motomaru; Ohyanagi, Mitsumasa; Shimada, Kenei; Taguchi, Haruyuki; Yasuga, Yuji; Takeda, Yoshihiro; Ohashi, Yoshitaka; Awano, Kojiro; Fujii, Kenichi; Mintz, Gary S

    2009-03-15

    To investigate intravascular ultrasound predictors of long-term clinical outcome in patients with acute coronary syndrome, 94 patients with a first acute coronary syndrome with both preintervention intravascular ultrasound imaging and long-term follow-up were enrolled in this study. Remodeling index was defined as external elastic membrane cross-sectional area at the target lesion divided by that at the proximal reference. Arterial remodeling was defined as either positive (PR: remodeling index >1.05) or intermediate/negative remodeling (remodeling index < or =1.05). Clinical events were death, myocardial infarction, and target-lesion revascularization. Patients were followed up for a mean of 3 years. PR was observed in 50 (53%), and intermediate/negative remodeling, in 44 (47%). During the 3-year follow-up, there were 20 target-lesion revascularization events and 5 deaths (2 cardiac and 3 noncardiac), but no myocardial infarctions. Patients with PR showed significantly lower major adverse cardiac event (MACE; death, myocardial infarction, and target-lesion revascularization)-free survival (log-rank p = 0.03). However, patients with plaque rupture showed a nonsignificant trend toward lower MACE-free survival (p = 0.13), but there were no significant differences in MACE-free survival between those with single versus multiple plaque ruptures. Using multivariate logistic regression analysis, only culprit lesion PR was an independent predictor of MACEs (p = 0.04). In conclusion, culprit-lesion remodeling rather than the presence or absence of culprit-lesion plaque rupture was a strong predictor of long-term (3-year) clinical outcome in patients with acute coronary syndrome. PMID:19268733

  2. Remodeling and vascular spaces in bone.

    PubMed

    Eriksen, Erik Fink; Eghbali-Fatourechi, Guiti Z; Khosla, Sundeep

    2007-01-01

    In recent years, we have come to appreciate that the close association between bone and vasculature plays a pivotal role in the regulation of bone remodeling and fracture repair. In 2001, Hauge et al. characterized a specialized vascular structure, the bone remodeling compartment (BRC), and showed that the outer lining of this compartment was made up of flattened cells, displaying all the characteristics of lining cells in bone. A decrease in bone turnover leads to a decrease in surfaces covered with remodeling compartments, whereas increased turnover causes an increase. Immunoreactivity for all major osteotropic growth factors and cytokines including osteoprotegerin (OPG) and RANKL has been shown in the cells lining the BRC, which makes the BRC the structure of choice for coupling between resorption and formation. The secretion of these factors inside a confined space separated from the bone marrow would facilitate local regulation of the remodeling process without interference from growth factors secreted by blood cells in the marrow space. The BRC creates an environment where cells inside the structure are exposed to denuded bone, which may enable direct cellular interactions with integrins and other matrix factors known to regulate osteoclast/osteoblast activity. However, the denuded bone surface inside the BRC also constitutes an ideal environment for the seeding of bone metastases, known to have high affinity for bone matrix. Reduction in BRC space brought about by antiresorptive therapies such as bisphosphonates reduce the number of skeletal events in advanced cancer, whereas an increase in BRC space induced by remodeling activators like PTH may increase the bone metastatic burden. The BRC has only been characterized in detail in trabecular bone; there is, however, evidence that a similar structure may exist in cortical bone, but further characterization is needed.

  3. Automated classification of LV regional wall motion based on spatio-temporal profiles from cardiac cine magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Mantilla, Juan; Garreau, Mireille; Bellanger, Jean-Jacques; Paredes, José Luis

    2013-11-01

    Assessment of the cardiac Left Ventricle (LV) wall motion is generally based on visual inspection or quantitative analysis of 2D+t sequences acquired in short-axis cardiac cine-Magnetic Resonance Imaging (MRI). Most often, cardiac dynamic is globally analized from two particular phases of the cardiac cycle. In this paper, we propose an automated method to classify regional wall motion in LV function based on spatio-temporal pro les and Support Vector Machines (SVM). This approach allows to obtain a binary classi cation between normal and abnormal motion, without the need of pre-processing and by exploiting all the images of the cardiac cycle. In each short- axis MRI slice level (basal, median, and apical), the spatio-temporal pro les are extracted from the selection of a subset of diametrical lines crossing opposites LV segments. Initialized at end-diastole phase, the pro les are concatenated with their corresponding projections into the succesive temporal phases of the cardiac cycle. These pro les are associated to di erent types of information that derive from the image (gray levels), Fourier, Wavelet or Curvelet domains. The approach has been tested on a set of 14 abnormal and 6 healthy patients by using a leave-one-out cross validation and two kernel functions for SVM classi er. The best classi cation performance is yielded by using four-level db4 wavelet transform and SVM with a linear kernel. At each slice level the results provided a classi cation rate of 87.14% in apical level, 95.48% in median level and 93.65% in basal level.

  4. LV Dyssynchrony Is Helpful in Predicting Ventricular Arrhythmia in Ischemic Cardiomyopathy After Cardiac Resynchronization Therapy: A Preliminary Study.

    PubMed

    Tsai, Shih-Chuan; Chang, Yu-Cheng; Chiang, Kuo-Feng; Lin, Wan-Yu; Huang, Jin-Long; Hung, Guang-Uei; Kao, Chia-Hung; Chen, Ji

    2016-02-01

    For patients with coronary artery disease, larger scar burdens are associated with higher risk of ventricular arrhythmia. Left ventricular (LV) dyssynchrony is associated with increased risk of sudden cardiac death in patients with heart failure. The purpose of this study was to assess the values of LV dyssynchrony and myocardial scar assessed by myocardial perfusion SPECT (MPS) in predicting the development of ventricular arrhythmia in ischemic cardiomyopathy. Twenty-two patients (16 males, mean age: 66 ± 13) with irreversible ischemic cardiomyopathy received cardiac resynchronization therapy (CRT) for at least 12 months were enrolled for MPS. Quantitative parameters, including LV dyssynchrony with phase standard deviation (phase SD) and bandwidth, left ventricular ejection fraction (LVEF), and scar (% of total areas), were generated by Emory Cardiac Toolbox. Ventricular tachycardia (VT) and ventricular fibrillation (VF) recorded in the CRT device during follow-up were used as the reference standard of diagnosing ventricular arrhythmia. Stepwise logistic regression analysis was performed for determining the independent predictors of VT/VF and receiver operating characteristic (ROC) curve analysis was used for generating the optimal cut-off values for predicting VT/VF. Nine (41%) of the 22 patients developed VT/VF during the follow-up periods. Patients with VT/VF had significantly lower LVEF, larger scar, larger phase SD, and larger bandwidth (all P < 0.05). Logistic regression analysis showed LVEF and bandwidth were independent predictors of VT/VF. ROC curve analysis showed the areas under the curves were 0.71 and 0.83 for LVEF and bandwidth, respectively. The optimal cut-off values were <36% and > 139° for LVEF and bandwidth, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value were 100%, 39%, 53%, and 100%, respectively, for LVEF; and were 78%, 92%, 88%, and 86%, respectively, for bandwidth. LV

  5. The RSC chromatin remodeling complex has a crucial role in the complete remodeler set for yeast PHO5 promoter opening.

    PubMed

    Musladin, Sanja; Krietenstein, Nils; Korber, Philipp; Barbaric, Slobodan

    2014-04-01

    Although yeast PHO5 promoter chromatin opening is a founding model for chromatin remodeling, the complete set of involved remodelers remained unknown for a long time. The SWI/SNF and INO80 remodelers cooperate here, but nonessentially, and none of the many tested single or combined remodeler gene mutations could prevent PHO5 promoter opening. RSC, the most abundant and only remodeler essential for viability, was a controversial candidate for the unrecognized remodeling activity but unassessed in vivo. Now we show that remodels the structure of chromatin (RSC) is crucially involved in PHO5 promoter opening. Further, the isw1 chd1 double deletion also delayed chromatin remodeling. Strikingly, combined absence of RSC and Isw1/Chd1 or Snf2 abolished for the first time promoter opening on otherwise sufficient induction in vivo. Together with previous findings, we recognize now a surprisingly complex network of five remodelers (RSC, SWI/SNF, INO80, Isw1 and Chd1) from four subfamilies (SWI/SNF, INO80, ISWI and CHD) as involved in PHO5 promoter chromatin remodeling. This is likely the first described complete remodeler set for a physiological chromatin transition. RSC was hardly involved at the coregulated PHO8 or PHO84 promoters despite cofactor recruitment by the same transactivator and RSC's presence at all three promoters. Therefore, promoter-specific chromatin rather than transactivators determine remodeler requirements.

  6. THE IMPACT OF CHEMOTHERAPY AND RADIATION ON THE REMODELING OF ACELLULAR DERMAL MATRICES IN STAGED, PROSTHETIC BREAST RECONSTRUCTION

    PubMed Central

    Myckatyn, Terence M.; Cavallo, Jaime A.; Sharma, Ketan; Gangopadhyay, Noopur; Dudas, Jason R.; Roma, Andres A.; Baalman, Sara; Tenenbaum, Marissa M.; Matthews, Brent D.; Deeken, Corey R.

    2015-01-01

    Background An acellular dermal matrix (ADM) used in prosthetic breast reconstruction will typically incorporate, in time, with the overlying mastectomy skin flap. This remodeling process may be adversely impacted in patients that require chemotherapy and radiation therapies that influence neovascularization and cellular proliferation. Methods Multiple biopsies of the submuscular capsule and ADM were procured from 86 women (N=94 breasts) undergoing exchange of a tissue expander for a breast implant. These were divided by biopsy location : submuscular capsule (control) as well as superiorly, centrally and inferiorly along the ADM. Specimens were assessed grossly for incorporation and semi-quantitatively for cellular infiltration, cell type, fibrous encapsulation, scaffold degradation, extracellular matrix deposition, neovascularization, mean composite remodeling score, as well as Type I and III collagen area and ratio. Five oncologic treatment groups were compared : no adjuvant therapy (untreated), neoadjuvant chemotherapy ± radiation ; and chemotherapy ± radiation. Results ADM and submuscular capsule biopsies were procured 45 to 1805 days after ADM insertion and demonstrated a significant reduction in Type I collagen over time. Chemotherapy adversely impacted fibrous encapsulation relative to the untreated group (p=0.03). Chemotherapy with or without radiation adversely impacted Type I collagen area (p=0.02), cellular infiltration (p<0.01), extracellular matrix deposition (p<0.04), and neovascularization (p<0.01). Radiation exacerbated the adverse impact of chemotherapy for gross incorporation as well as several remodeling parameters. Neoadjuvant chemotherapy also caused a reduction in Type I (p=0.01) and III collagen (p=0.05), extracellular matrix deposition (p=0.03), and scaffold degradation (p=0.02). Conclusions Chemotherapy and radiation therapy limit ADM remodeling. PMID:25539350

  7. Metformin and its effects on myocardial dimension and left ventricular hypertrophy in normotensive patients with coronary heart disease (the MET-REMODEL study): rationale and design of the MET-REMODEL study.

    PubMed

    Mohan, Mohapradeep; McSwiggan, Stephen; Baig, Fatima; Rutherford, Lynn; Lang, Chim C

    2015-02-01

    Left ventricular hypertrophy (LVH) is a common and independent risk factor for cardiovascular events in patients with coronary artery disease (CAD). Controlling blood pressure is the standard approach to the management of LVH, but this is only partially effective as LVH also persists in normotensive patients. Apart from blood pressure (BP), other main risk factors associated with LVH are insulin resistance (IR) and central obesity. The diabetic medication, Metformin, reduces IR and aids weight loss and may therefore regress LVH. The MET REMODEL study will investigate the ability of Metformin to regress LVH in 64 patients with CAD. The MET-REMODEL trial is a single-center, phase IV, double blind, randomized, placebo-controlled trial to investigate the efficacy of Metformin in regression of the independent cardiac risk factor of LVH in patients with CAD who are insulin resistant. A minimum of 64 adults with a history of CAD with LVH and IR will be randomized into two groups to receive, either Metformin XL or placebo. The primary endpoint of this trial is to investigate any change in left ventricular mass index. Secondary endpoints include changes to insulin resistance measured using fasting insulin resistance index (FIRI), obesity, LV size, and function and improvement in endothelial function. A positive result will assist clinicians to identify a new mechanism for LVH regression by administering Metformin XL. This may also lead to investigating the mortality benefit of Metformin in patients with CAD and LVH.

  8. Time Course of Atrophic Remodeling: Effects of Exercise on Cardiac Morpology and Function

    NASA Technical Reports Server (NTRS)

    Scott, J. M.; Martin, D.; Caine, T.; Matz, T.; Ploutz-Snyder, L. L.

    2014-01-01

    Early and consistent evaluation of cardiac morphology and function throughout an atrophic stimulus is critically important for the design and optimization of interventions. Exercise training is one intervention that has been shown to confer favorable improvements in LV mass and function during unloading. However, the format and intensity of exercise required to induce optimal cardiac improvements has not been investigated. PURPOSE: This randomized, controlled trial was designed to 1) comprehensively characterize the time course of unloading-induced morpho-functional remodeling, and 2) examine the effects of high intensity exercise training on cardiac structural and functional parameters during unloading. METHODS: Twenty six subjects completed 70 days of head down tilt bed rest (HDBR): 17 were randomized to exercise training (ExBR) and 9 remained sedentary. Exercise consisted of integrated high intensity, continuous, and resistance exercise. We assessed cardiac morphology (left ventricular mass; LVM) and function (speckle-tracking assessment of longitudinal, radial, and circumferential strain and twist) before (BR-2), during (BR7,21,31,70), and following (BR+0, +3) HDBR. Cardiorespiratory fitness (VO2max) was evaluated before (BR- 3), during (BR4,25,46,68) and following (BR+0) HDBR. RESULTS: Sedentary HDBR resulted in a progressive decline in LVM, longitudinal, radial, and circumferential strain, and an increase in twist. ExBR mitigated decreases in LVM and function. Change in twist was significantly related to change in VO2max (R=0.68, p<0.01). CONCLUSIONS: Alterations in cardiac morphology and function begin early during unloading. High-intensity exercise attenuates atrophic morphological and functional remodeling.

  9. A novel lectin domain-containing protein (LvCTLD) associated with response of the whiteleg shrimp Penaeus (Litopenaeus) vannamei to yellow head virus (YHV).

    PubMed

    Junkunlo, Kingkamon; Prachumwat, Anuphap; Tangprasittipap, Amornrat; Senapin, Saengchan; Borwornpinyo, Suparerk; Flegel, Timothy W; Sritunyalucksana, Kallaya

    2012-07-01

    When using mRNA from gills of normal whiteleg shrimp Penaeus (Litopenaeus) vannamei as the tester and mRNA from yellow head virus (YHV)-infected shrimp as the driver, subtractive suppression hybridization (SSH) revealed that a novel EST clone of 198 bp with a putative C-type lectin-like domain (CTLD) was downregulated in YHV-infected shrimp. The clone nucleotide sequence had 99% identity with one contig MGID1052359 (1,380 bp) reported in an EST database of P. vannamei, and the presence of this target in normal shrimp was confirmed by RT-PCR using primers designed from the MGID1052359 sequence. Analysis of the primary structure of the deduced amino acid (a.a.) sequence of the contig revealed a short portion (40 a.a. residues) at its N-terminus with high similarity to a low density lipoprotein receptor (LDLR) class A domain and another 152 a.a. residues at its C-terminus with high similarity to a C-type lectin domain. Thus, the clone was named LvCTLD and three recombinant proteins (LvCTLD, the LDLR domain and the CTLD domain) were synthesized in a bacterial system based on its sequence. An in vitro encapsulation assay revealed that Sepharose 4B beads coated with rLvCTLD were encapsulated by shrimp hemocytes and that melanization followed by 24 h post-encapsulation. The encapsulation activity of rLvCTLD was inhibited by 100 mM galactose, but not mannose or EDTA. In vivo injection of rLvCTLD or rLvCTLD plus YHV resulted in a significant elevation of PO activity in the hemolymph of the challenged shrimp when compared to shrimp injected with buffer, suggesting that rLvCTLD could activate the proPO system. An ELISA test revealed that rLvCTLD could bind to YHV particles in the presence of shrimp hemolymph. Phylogenetic analysis suggested that the LvCTLD sequence was more closely related to an antiviral gene found in Penaeus monodon (PmAV) than to other reported shrimp lectins. Taken together, we conclude that a novel shrimp LvCTLD is a host recognition molecule involved in

  10. Reverse Engineering Adverse Outcome Pathways

    SciTech Connect

    Perkins, Edward; Chipman, J.K.; Edwards, Stephen; Habib, Tanwir; Falciani, Francesco; Taylor, Ronald C.; Van Aggelen, Graham; Vulpe, Chris; Antczak, Philipp; Loguinov, Alexandre

    2011-01-30

    The toxicological effects of many stressors are mediated through unknown, or poorly characterized, mechanisms of action. We describe the application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, metabolic, signaling) to characterize adverse outcome pathways (AOPs) for chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis in fathead minnows. Gene expression changes in fathead minnow ovaries in response to 7 different chemicals, over different times, doses, and in vivo versus in vitro conditions were captured in a large data set of 868 arrays. We examined potential AOPs of the antiandrogen flutamide using two mutual information theory methods, ARACNE and CLR to infer gene regulatory networks and potential adverse outcome pathways. Representative networks from these studies were used to predict a network path from stressor to adverse outcome as a candidate AOP. The relationship of individual chemicals to an adverse outcome can be determined by following perturbations through the network in response to chemical treatment leading to the nodes associated with the adverse outcome. Identification of candidate pathways allows for formation of testable hypotheses about key biologic processes, biomarkers or alternative endpoints, which could be used to monitor an adverse outcome pathway. Finally, we identify the unique challenges facing the application of this approach in ecotoxicology, and attempt to provide a road map for the utilization of these tools. Key Words: mechanism of action, toxicology, microarray, network inference

  11. Adverse effects of anabolic steroids.

    PubMed

    Hickson, R C; Ball, K L; Falduto, M T

    1989-01-01

    Anabolic steroids are used therapeutically for various disorders and as ergogenic aids by athletes to augment strength, muscular development, and to enhance performance. There is a wide range of concomitant temporary and permanent adverse effects with steroid administration. Several well-documented adverse actions of these hormones may develop rapidly within several weeks or less (i.e. altered reproductive function) or require up to several years of steroid intake (i.e. liver carcinoma). More recent studies indicate that glucose intolerance, insulin resistance, increased cardiovascular disease risk profiles, cerebral dangers, musculoskeletal injuries, prostate cancer, psychosis and schizophrenic episodes, among others, accompany anabolic steroid intake. There is, at present, no evidence to support the claim that athletes are less susceptible to adverse effects than those individuals receiving hormone treatment in a clinical setting. Based on the available information which has accumulated primarily from cross-sectional, short term longitudinal, and case studies, there is a need: (a) to develop a comprehensive battery of specific and sensitive markers of adverse effects, particularly those that would be able to detect the onset of adverse actions; and (b) to conduct controlled long term longitudinal studies in order to fully understand the extensiveness and mechanisms involved in the occurrence of adverse effects.

  12. Project of Ariane 5 LV family advancement by use of reusable fly-back boosters (named “Bargouzine”)

    NASA Astrophysics Data System (ADS)

    Sumin, Yu.; Bonnal, Ch.; Kostromin, S.; Panichkin, N.

    2007-12-01

    The paper concerns possible concept variants of a partially reusable Heavy-Lift Launch Vehicle derived from the advanced basic launcher (Ariane-2010) by means of substitution of the EAP Solid Rocket Boosters for a Reusable Starting Stage consisting two Liquid-propellant Reusable Fly-Back Boosters called "Bargouzin". This paper describes the status of the presently studied RFBB concepts during its three phases. The first project phase was dedicated to feasibility expertise of liquid-rocket reusable fly-back boosters ("Baikal" type) utilization for heavy-lift space launch vehicle. The design features and main conclusions are presented. The second phase has been performed with the purpose of selection of preferable concept among the alternative ones for the future Ariane LV modernization by using RFBB instead of EAP Boosters. The main requirements, logic of work, possible configuration and conclusion are presented. Initial aerodynamic, ballistic, thermoloading, dynamic loading, trade-off and comparison analysis have been performed on these concepts. The third phase consists in performing a more detailed expertise of the chosen LV concept. This part summarizes some of the more detailed results related to flight performance, system mass, thermoprotection system, aspects of technologies, ground complex modification, comparison analyses and conclusion.

  13. Specific identification of Lachesis muta muta snake venom using antibodies against the plasminogen activator enzyme, LV-PA.

    PubMed

    Felicori, Liza F; Chávez-Olórtegui, Carlos; Sánchez, Eladio F

    2005-05-01

    Sandwich-type enzyme linked immunosorbent assays (ELISA) were developed to detect Lachesis muta muta (bushmaster) snake venom using antibodies against the plasminogen activator enzyme (LV-PA). Antibodies to LV-PA were obtained by immunization of one rabbit with the purified enzyme. The IgG fraction was purified from rabbit blood in a single step on a column of Sepharose-L. m. muta venom and used to coat the microtiter plates. The specificity of the assay was demonstrated by its capacity to correctly discriminate between the circulating antigens in mice that were experimentally inoculated with L. m. muta venom from those in mice inoculated with venoms from Bothrops atrox, B. brazili, B. castelnaudi, Bothriopsis taeniata, B. bilineata, Crotalus durissus ruruima and the antigenic Bothrops (AgB) and Crotalus (AgC) pools venoms used to produce Bothropic and Crotalic antivenoms at Fundacao Ezequiel Dias (FUNED). Measurable absorbance signals were obtained with 1.5 ng of venom per assay. The ELISA was used to follow the kinetic distribution of antigens in experimentally envenomed mice. PMID:15804530

  14. Immunopathology of B-cell lymphomas induced in C57BL/6 mice by dualtropic murine leukemia virus (MuLV).

    PubMed Central

    Pattengale, P. K.; Taylor, C. R.; Twomey, P.; Hill, S.; Jonasson, J.; Beardsley, T.; Haas, M.

    1982-01-01

    Combined clinicopathologic and immunomorphologic evidence is presented that would indicate that a murine leukemia virus (MuLV) with the dualtropic host range is capable of producing a clinically malignant lesion composed of immunoblasts and associated plasma cells in C57BL/6 mice. This process, morphologically diagnosed as an immunoblastic lymphoma of B cells using standard histopathologic criteria, was found to be distinctly polyclonal with regard to immunoglobulin (Ig) isotype when analyzed for both surface and cytoplasmic Ig. Further studies demonstrated that this clinicopathologically malignant, dualtropic MuLV-induced, polyclonal immunoblastic lymphoma of B cells in C57BL/6 mice was normal diploid and unable to be successfully transplanted to nonimmunosuppressed syngeneic recipients. Although all serum heavy and light chain components were found to be progressively elevated as the tumor load increased, the polyclonal increase in serum immunoglobulins was most pronounced for mu heavy and kappa light chains (ie, mu greater than gamma 2A greater than alpha greater than gamma 2B greater than gamma 1; kappa greater than lamba). The dissociation of clinicopathologic and biologic criteria for malignancy in the presently described dualtropic (RadLV) MuLV-induced B-cell lesion is sharply contrasted with the thymotropic (RadLV), MuLV-induced T-cell lymphoblastic lymphoma in C57BL/6 mice. This process is also a clinicopathologically malignant lesion but, when one uses biologic criteria, is found to be distinctly monoclonal, aneuploid, and easily transplanted to nonimmunosuppressed syngeneic recipients. The close clinicopathologic and biologic similarities of the dualtropic MuLV-induced animal model to corresponding human B-cell lymphoproliferative diseases are stressed. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 7 PMID:6282131

  15. Serological survey of Toxoplasma gondii, Dirofilaria immitis, Feline Immunodeficiency Virus (FIV) and Feline Leukemia Virus (FeLV) infections in pet cats in Bangkok and vicinities, Thailand.

    PubMed

    Sukhumavasi, Woraporn; Bellosa, Mary L; Lucio-Forster, Araceli; Liotta, Janice L; Lee, Alice C Y; Pornmingmas, Pitcha; Chungpivat, Sudchit; Mohammed, Hussni O; Lorentzen, Leif; Dubey, J P; Bowman, Dwight D

    2012-08-13

    The seroprevalence of Toxoplasma gondii, Dirofilaria immitis (heartworm), feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) infections was examined using serum or plasma samples from 746 pet cats collected between May and July 2009 from clinics and hospitals located in and around Bangkok, Thailand. The samples were tested for heartworm, FIV, and FeLV using a commercial ELISA. Of the 746 samples, 4.6% (34/746) were positive for heartworm antigen, 24.5% (183/746) had circulating FeLV antigen, and 20.1% (150/746) had antibodies against FIV. In addition, the first 348 submitted samples were tested for T. gondii antibodies using a modified agglutination test (MAT, cut off 1:25); 10.1% (35/348) were seropositive. Of the 348 cats sampled for all four pathogens, 11, 10, and 1 were positive for T. gondii antibodies and FIV antibodies, FeLV antigen, or D. immitis antigen, respectively. Of the 35 T. gondii-seropositive cats, 42.9% (15/35) were co-infected with at least one of the other three pathogens. The presence of antibodies to FIV was significantly associated with both age and gender, while FeLV antigen presence was only associated with age. In the case of FIV, males were twice as likely to be infected as females, and cats over 10 years of age were 13.5 times more likely to be infected than cats less than 1 year of age. FeLV antigen was more common in younger cats, with cats over 10 years of age being 10 times less likely to be FeLV positive than cats under 1 year of age. This is the first survey for these four pathogens affecting feline health in Thailand. PMID:22497870

  16. [Remodeling of Cardiovascular System: Causes and Consequences].

    PubMed

    Lopatina, E V; Kipenko, A V; Penniyaynen, V A; Pasatetckaia, N A; Tsyrline, V A

    2016-01-01

    Literature and our data suggest the regulatory action of a number of biologically active substances (catecholamines, cardiac glycosides, β-blockers, angiotensin-converting-enzyme inhibitor) on the growth and proliferation of heart cells. By using of organotypic tissue culture has proved that the basis of this regulation is the ability of test substances, receptor- or transducer-mediated signaling to modulate the function of Na⁺, K⁺-ATPase. There is a delay in the development of vascular smooth muscle in the late postnatal period in rats with the blockade of the sympathetic nervous system in the prenatal period. The relationship between vascular remodeling and contractile activity is described. It seems that one of the causes of high blood pressure is a remodeling of the cardiovascular system, which precedes the development of hypertension. PMID:27530043

  17. Chromatin Remodeling, DNA Damage Repair and Aging

    PubMed Central

    Liu, Baohua; Yip, Raymond KH; Zhou, Zhongjun

    2012-01-01

    Cells are constantly exposed to a variety of environmental and endogenous conditions causing DNA damage, which is detected and repaired by conserved DNA repair pathways to maintain genomic integrity. Chromatin remodeling is critical in this process, as the organization of eukaryotic DNA into compact chromatin presents a natural barrier to all DNA-related events. Studies on human premature aging syndromes together with normal aging have suggested that accumulated damages might lead to exhaustion of resources that are required for physiological functions and thus accelerate aging. In this manuscript, combining the present understandings and latest findings, we focus mainly on discussing the role of chromatin remodeling in the repair of DNA double-strand breaks (DSBs) and regulation of aging. PMID:23633913

  18. Metabolic remodeling in chronic heart failure.

    PubMed

    Wang, Jing; Guo, Tao

    2013-08-01

    Although the management of chronic heart failure (CHF) has made enormous progress over the past decades, CHF is still a tremendous medical and societal burden. Metabolic remodeling might play a crucial role in the pathophysiology of CHF. The characteristics and mechanisms of metabolic remodeling remained unclear, and the main hypothesis might include the changes in the availability of metabolic substrate and the decline of metabolic capability. In the early phases of the disease, metabolism shifts toward carbohydrate utilization from fatty acids (FAs) oxidation. Along with the progress of the disease, the increasing level of the hyperadrenergic state and insulin resistance cause the changes that shift back to a greater FA uptake and oxidation. In addition, a growing body of experimental and clinical evidence suggests that the improvement in the metabolic capability is likely to be more significant than the selection of the substrate.

  19. [Remodeling of Cardiovascular System: Causes and Consequences].

    PubMed

    Lopatina, E V; Kipenko, A V; Penniyaynen, V A; Pasatetckaia, N A; Tsyrline, V A

    2016-01-01

    Literature and our data suggest the regulatory action of a number of biologically active substances (catecholamines, cardiac glycosides, β-blockers, angiotensin-converting-enzyme inhibitor) on the growth and proliferation of heart cells. By using of organotypic tissue culture has proved that the basis of this regulation is the ability of test substances, receptor- or transducer-mediated signaling to modulate the function of Na⁺, K⁺-ATPase. There is a delay in the development of vascular smooth muscle in the late postnatal period in rats with the blockade of the sympathetic nervous system in the prenatal period. The relationship between vascular remodeling and contractile activity is described. It seems that one of the causes of high blood pressure is a remodeling of the cardiovascular system, which precedes the development of hypertension.

  20. Remodeling of Calcium Entry Pathways in Cancer.

    PubMed

    Villalobos, Carlos; Sobradillo, Diego; Hernández-Morales, Miriam; Núñez, Lucía

    2016-01-01

    Ca(2+) entry pathways play important roles in control of many cellular functions, including long-term proliferation, migration and cell death. In recent years, it is becoming increasingly clear that, in some types of tumors, remodeling of Ca(2+) entry pathways could contribute to cancer hallmarks such as excessive proliferation, cell migration and invasion as well as resistance to cell death or survival. In this chapter we briefly review findings related to remodeling of Ca(2+) entry pathways in cancer with emphasis on the mechanisms that contribute to increased store-operated Ca(2+) entry (SOCE) and store-operated currents (SOCs) in colorectal cancer cells. Finally, since SOCE appears critically involved in colon tumorogenesis, the inhibition of SOCE by aspirin and other NSAIDs and its possible contribution to colon cancer chemoprevention is reviewed.

  1. Remodeling of Calcium Entry Pathways in Cancer.

    PubMed

    Villalobos, Carlos; Sobradillo, Diego; Hernández-Morales, Miriam; Núñez, Lucía

    2016-01-01

    Ca(2+) entry pathways play important roles in control of many cellular functions, including long-term proliferation, migration and cell death. In recent years, it is becoming increasingly clear that, in some types of tumors, remodeling of Ca(2+) entry pathways could contribute to cancer hallmarks such as excessive proliferation, cell migration and invasion as well as resistance to cell death or survival. In this chapter we briefly review findings related to remodeling of Ca(2+) entry pathways in cancer with emphasis on the mechanisms that contribute to increased store-operated Ca(2+) entry (SOCE) and store-operated currents (SOCs) in colorectal cancer cells. Finally, since SOCE appears critically involved in colon tumorogenesis, the inhibition of SOCE by aspirin and other NSAIDs and its possible contribution to colon cancer chemoprevention is reviewed. PMID:27161240

  2. Cardiac Remodeling, Adaptations and Associated Myocardial Mechanics in Hypertensive Heart Diseases

    PubMed Central

    Lai, Yau-Huei; Lo, Chi-In; Wu, Yih-Jer; Hung, Chung-Lieh; Yeh, Hung-I

    2013-01-01

    Hypertension is the leading cause of heart failure and cardiovascular comorbidities in developed countries. Left ventricular structural/functional alterations such as concentric remodeling or hypertrophy have been extensively studied in hypertensive heart diseases. Furthermore, it is also well-recognized that diastolic function actually deteriorates in hypertensive subjects prior to overt heart failure. Novel imaging modality techniques such as myocardial deformation have allowed for early detection of regional/global myocardial contractile dysfunction. Myocardial deformation, which can be quantified by measuring the systolic strain and strain rate in three different directions (longitudinal, circumferential and radial), has facilitated new insights into the understanding of cardiac systolic mechanics in subjects with early stage myocardial damage. Previous studies had shown that longitudinal function remains the most sensitive parameter in identifying hypertension-related myocardial dysfunction, particularly for those patients who had developed LV hypertrophy. Instead, preserved or enhanced short-axis function, when presented as circumferential or radial strains, may remain relatively preserved or enhanced in order to compensate for longitudinal functional decline. In this manner, global cardiac pumping in terms of ejection fraction may remain relatively unchanged. The early recognition of subclinical systolic dysfunction and associated mechanical compensation in the context of hypertension is crucial, which potentially helps to identify a disease stage that is still responsive to therapeutic intervention. PMID:27122686

  3. REACTIVE OXYGEN SPECIES IN PULMONARY VASCULAR REMODELING

    PubMed Central

    Aggarwal, Saurabh; Gross, Christine M.; Sharma, Shruti; Fineman, Jeffrey R.; Black, Stephen M.

    2014-01-01

    The pathogenesis of pulmonary hypertension is a complex multifactorial process that involves the remodeling of pulmonary arteries. This remodeling process encompasses concentric medial thickening of small arterioles, neomuscularization of previously nonmuscular capillary-like vessels, and structural wall changes in larger pulmonary arteries. The pulmonary arterial muscularization is characterized by vascular smooth muscle cell (SMC) hyperplasia and hypertrophy. In addition, in uncontrolled pulmonary hypertension, the clonal expansion of apoptosis-resistant endothelial cells leads to the formation of plexiform lesions. Based upon a large number of studies in animal models, the three major stimuli that drive the vascular remodeling process are inflammation, shear stress and hypoxia. Although, the precise mechanisms by which these stimuli impair pulmonary vascular function and structure are unknown, reactive oxygen species (ROS)-mediated oxidative damage appears to play an important role. ROS are highly reactive due to their unpaired valence shell electron. Oxidative damage occurs when the production of ROS exceeds the quenching capacity of the anti-oxidant mechanisms of the cell. ROS can be produced from complexes in the cell membrane (nicotinamide adenine dinucleotide phosphate-oxidase), cellular organelles (peroxisomes and mitochondria), and in the cytoplasm (xanthine oxidase). Furthermore, low levels of tetrahydrobiopterin (BH4) and L-arginine the rate limiting co-factor and substrate for endothelial nitric oxide synthase (eNOS), can cause the uncoupling of eNOS, resulting in decreased NO production and increased ROS production. This review will focus on the ROS generation systems, scavenger antioxidants, and oxidative stress associated alterations in vascular remodeling in pulmonary hypertension. PMID:23897679

  4. Perspectives on biological growth and remodeling

    PubMed Central

    Ambrosi, D.; Ateshian, G. A.; Arruda, E. M.; Cowin, S. C.; Dumais, J.; Goriely, A.; Holzapfel, G. A.; Humphrey, J. D.; Kemkemer, R.; Kuhl, E.; Olberding, J. E.; Taber, L. A.; Garikipati, K.

    2011-01-01

    The continuum mechanical treatment of biological growth and remodeling has attracted considerable attention over the past fifteen years. Many aspects of these problems are now well-understood, yet there remain areas in need of significant development from the standpoint of experiments, theory, and computation. In this perspective paper we review the state of the field and highlight open questions, challenges, and avenues for further development. PMID:21532929

  5. Application of Petri Nets in Bone Remodeling

    PubMed Central

    Li, Lingxi; Yokota, Hiroki

    2009-01-01

    Understanding a mechanism of bone remodeling is a challenging task for both life scientists and model builders, since this highly interactive and nonlinear process can seldom be grasped by simple intuition. A set of ordinary differential equations (ODEs) have been built for simulating bone formation as well as bone resorption. Although solving ODEs numerically can provide useful predictions for dynamical behaviors in a continuous time frame, an actual bone remodeling process in living tissues is driven by discrete events of molecular and cellular interactions. Thus, an event-driven tool such as Petri nets (PNs), which may dynamically and graphically mimic individual molecular collisions or cellular interactions, seems to augment the existing ODE-based systems analysis. Here, we applied PNs to expand the ODE-based approach and examined discrete, dynamical behaviors of key regulatory molecules and bone cells. PNs have been used in many engineering areas, but their application to biological systems needs to be explored. Our PN model was based on 8 ODEs that described an osteoprotegerin linked molecular pathway consisting of 4 types of bone cells. The models allowed us to conduct both qualitative and quantitative evaluations and evaluate homeostatic equilibrium states. The results support that application of PN models assists understanding of an event-driven bone remodeling mechanism using PN-specific procedures such as places, transitions, and firings. PMID:19838338

  6. Stepwise nucleosome translocation by RSC remodeling complexes

    PubMed Central

    Harada, Bryan T; Hwang, William L; Deindl, Sebastian; Chatterjee, Nilanjana; Bartholomew, Blaine; Zhuang, Xiaowei

    2016-01-01

    The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP hydrolysis to the repositioning and restructuring of nucleosomes, but how the ATPase activity of these enzymes drives the motion of DNA across the nucleosome remains unclear. Here, we used single-molecule FRET to monitor the remodeling of mononucleosomes by the yeast SWI/SNF remodeler, RSC. We observed that RSC primarily translocates DNA around the nucleosome without substantial displacement of the H2A-H2B dimer. At the sites where DNA enters and exits the nucleosome, the DNA moves largely along or near its canonical wrapping path. The translocation of DNA occurs in a stepwise manner, and at both sites where DNA enters and exits the nucleosome, the step size distributions exhibit a peak at approximately 1–2 bp. These results suggest that the movement of DNA across the nucleosome is likely coupled directly to DNA translocation by the ATPase at its binding site inside the nucleosome. DOI: http://dx.doi.org/10.7554/eLife.10051.001 PMID:26895087

  7. Stepwise nucleosome translocation by RSC remodeling complexes.

    PubMed

    Harada, Bryan T; Hwang, William L; Deindl, Sebastian; Chatterjee, Nilanjana; Bartholomew, Blaine; Zhuang, Xiaowei

    2016-02-19

    The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP hydrolysis to the repositioning and restructuring of nucleosomes, but how the ATPase activity of these enzymes drives the motion of DNA across the nucleosome remains unclear. Here, we used single-molecule FRET to monitor the remodeling of mononucleosomes by the yeast SWI/SNF remodeler, RSC. We observed that RSC primarily translocates DNA around the nucleosome without substantial displacement of the H2A-H2B dimer. At the sites where DNA enters and exits the nucleosome, the DNA moves largely along or near its canonical wrapping path. The translocation of DNA occurs in a stepwise manner, and at both sites where DNA enters and exits the nucleosome, the step size distributions exhibit a peak at approximately 1-2 bp. These results suggest that the movement of DNA across the nucleosome is likely coupled directly to DNA translocation by the ATPase at its binding site inside the nucleosome.

  8. The reduced virulence of the thymotropic Moloney murine leukemia virus derivative MoMuLV-TB is mapped to 11 mutations within the U3 region of the long terminal repeat.

    PubMed Central

    Yuen, P H; Szurek, P F

    1989-01-01

    Chimeric constructs were generated by exchanging genomic fragments between the potent T-cell lymphoma inducer Moloney murine leukemia virus (MoMuLV) and its derivative MoMuLV-TB, which induces T-cell lymphoma after a relatively longer latent period. Analysis of the T-cell lymphoma-inducing potential of the hybrid viruses that were obtained localized the primary determinant critical to efficient T-cell lymphoma induction to the MoMuLV ClaI-XbaI fragment which comprises 48 nucleotides (nt) of p15E, p2E, the 3'-noncoding sequence, and 298 nt of U3. The 438-base-pair ClaI-XbaI fragments of MoMuLV and MoMuLV-TB differed in only 11 nt. Nine mutations were found within the enhancer. These mutations occurred within the two CORE, the two GRE-LVa, and two of the four NF1 nuclear factor-binding motifs. MoMuLV-TB replicated better than MoMuLV in thymus-bone marrow (TB) cells, a cultured cell line of lymphoid origin. In addition, MoMuLV-TB and NwtTB-2, a recombinant virus with the ClaI-SmaI fragment of MoMuLV-TB in a MoMuLV background, replicated in thymocytes as efficiently as did MoMuLV or TBNwt-2, the reciprocal recombinant virus, with the ClaI-SmaI fragment of MoMuLV in a MoMuLV-TB background. Like NwtTB-4, a recombinant virus with the ClaI-XbaI fragment of MoMuLV-TB in a MoMuLV background, NwtTB-2 induced lymphoma after a long latent period. The finding given above suggests that thymotropism is not the only factor that determines the T-cell lymphoma-inducing potential of MoMuLV. It appears likely that mutations in one or more of the MoMuLV-TB nuclear factor-binding motifs may have altered the interaction of the enhancer with specific nuclear factors; this, in turn, may affect the T-cell lymphoma-inducing potential of MoMuLV-TB. PMID:2783465

  9. No Evidence of XMRV or MuLV Sequences in Prostate Cancer, Diffuse Large B-Cell Lymphoma, or the UK Blood Donor Population

    PubMed Central

    Robinson, Mark James; Tuke, Philip William; Erlwein, Otto; Tettmar, Kate I.; Kaye, Steve; Naresh, Kikkeri N.; Patel, Anup; Walker, Marjorie M.; Kimura, Takahiro; Gopalakrishnan, Ganesh; Tedder, Richard S.; McClure, Myra O.

    2011-01-01

    Xenotropic murine leukaemia virus-related virus (XMRV) is a recently described retrovirus which has been claimed to infect humans and cause associated pathology. Initially identified in the US in patients with prostate cancer and subsequently in patients with chronic fatigue syndrome, doubt now exists that XMRV is a human pathogen. We studied the prevalence of genetic sequences of XMRV and related MuLV sequences in human prostate cancer, from B cell lymphoma patients and from UK blood donors. Nucleic acid was extracted from fresh prostate tissue biopsies, formalin-fixed paraffin-embedded (FFPE) prostate tissue and FFPE B-cell lymphoma. The presence of XMRV-specific LTR or MuLV generic gag-like sequences was investigated by nested PCR. To control for mouse DNA contamination, a PCR that detected intracisternal A-type particle (IAP) sequences was included. In addition, DNA and RNA were extracted from whole blood taken from UK blood donors and screened for XMRV sequences by real-time PCR. XMRV or MuLV-like sequences were not amplified from tissue samples. Occasionally MuLV gag and XMRV-LTR sequences were amplified from Indian prostate cancer samples, but were always detected in conjunction with contaminating murine genomic DNA. We found no evidence of XMRV or MuLV infection in the UK blood donors. PMID:22312352

  10. Accumulation and activation of natural killer cells in local intraperitoneal HIV-1/MuLV infection results in early control of virus infected cells.

    PubMed

    Johansson, Susanne E; Brauner, Hanna; Hinkula, Jorma; Wahren, Britta; Berg, Louise; Johansson, Maria H

    2011-01-01

    Natural killer (NK) cells are important effectors in resistance to viral infections. The role of NK cells in the acute response to human immunodeficiency virus 1 (HIV-1) infected cells was investigated in a mouse model based on a HIV-1/murine leukemia virus (MuLV) pseudovirus. Splenocytes infected with HIV-1/MuLV were injected intraperitoneally and local immunologic responses and persistence of infected cells were investigated. In vivo depletion with an anti-NK1.1 antibody showed that NK cells are important in resistance to virus infected cells. Moreover, NK cell frequency in the peritoneal cavity increased in response to infected cells and these NK cells had a more mature phenotype, as determined by CD27 and Mac-1 expression. Interestingly, after injection of HIV-1/MuLV infected cells, but not MuLV infected cells, peritoneal NK cells had an increased cytotoxic activity. In conclusion, NK cells play a role in the early control of HIV-1/MuLV infected cells in vivo.

  11. No Evidence of XMRV or MuLV Sequences in Prostate Cancer, Diffuse Large B-Cell Lymphoma, or the UK Blood Donor Population.

    PubMed

    Robinson, Mark James; Tuke, Philip William; Erlwein, Otto; Tettmar, Kate I; Kaye, Steve; Naresh, Kikkeri N; Patel, Anup; Walker, Marjorie M; Kimura, Takahiro; Gopalakrishnan, Ganesh; Tedder, Richard S; McClure, Myra O

    2011-01-01

    Xenotropic murine leukaemia virus-related virus (XMRV) is a recently described retrovirus which has been claimed to infect humans and cause associated pathology. Initially identified in the US in patients with prostate cancer and subsequently in patients with chronic fatigue syndrome, doubt now exists that XMRV is a human pathogen. We studied the prevalence of genetic sequences of XMRV and related MuLV sequences in human prostate cancer, from B cell lymphoma patients and from UK blood donors. Nucleic acid was extracted from fresh prostate tissue biopsies, formalin-fixed paraffin-embedded (FFPE) prostate tissue and FFPE B-cell lymphoma. The presence of XMRV-specific LTR or MuLV generic gag-like sequences was investigated by nested PCR. To control for mouse DNA contamination, a PCR that detected intracisternal A-type particle (IAP) sequences was included. In addition, DNA and RNA were extracted from whole blood taken from UK blood donors and screened for XMRV sequences by real-time PCR. XMRV or MuLV-like sequences were not amplified from tissue samples. Occasionally MuLV gag and XMRV-LTR sequences were amplified from Indian prostate cancer samples, but were always detected in conjunction with contaminating murine genomic DNA. We found no evidence of XMRV or MuLV infection in the UK blood donors. PMID:22312352

  12. The Mus cervicolor MuLV isolate M813 is highly fusogenic and induces a T-cell lymphoma associated with large multinucleated cells.

    PubMed

    Prassolov, V; Ivanov, D; Hein, S; Rutter, G; Münk, C; Löhler, J; Stocking, C

    2001-11-10

    M813 is a type-C murine leukemia virus (MuLV) isolated from the Asian rodent Mus cervicolor. We have recently demonstrated that M813 defines a distinct MuLV receptor interference group. Here we show that M813 rapidly induces fusion of MuLV-expressing fibroblasts from "without," with syncytia being observed within 1 h after exposure to virus. Infection of fibroblasts with MuLV from all tested receptor-interference groups imparts susceptibility to M813-induced fusion, provided the cells also express the M813 receptor. Syncytium induction is also observed in vivo; mice infected with M813 develop a peripheral T-cell lymphoma, which is associated with large multinucleated cells of macrophage origin. A recombinant Moloney MuLV/M813 chimeric virus demonstrated that syncytium induction is a function of the Env SU protein. We postulate that the highly fusogenic property of M813 is attributable to either its unique receptor usage or sequences in the proline-rich domain of the Env protein.

  13. Are there gender differences in left ventricular remodeling after myocardial infarction in rats?

    PubMed Central

    Antonio, Ednei Luiz; Serra, Andrey Jorge; dos Santos, Alexandra Alberta; Vieira, Stella Sousa; Silva, Jairo Montemor Augusto; Yoshizaki, Amanda; Sofia, Renato Rodrigues; Tucci, Paulo José Ferreira

    2015-01-01

    Objective An unclear issue is whether gender may influence at cardiac remodeling after myocardial infarction (MI). We evaluated left ventricle remodeling in female and male rats post-MI. Methods Rats were submitted to anterior descending coronary occlusion. Echocardiographic evaluations were performed on the first and sixth week post-occlusion to determine myocardial infarction size and left ventricle systolic function (FAC, fractional area change). Pulsed Doppler was applied to analyze left ventricle diastolic function using the following parameters: E wave, A wave, E/A ratio. Two-way ANOVA was applied for comparisons, complemented by the Bonferroni test. A P≤=0.05 was considered significant. Results There were no significant differences between genders for morphometric parameters on first (MI [Female (FE): 44.0±5.0 vs. Male (MA): 42.0±3.0%]; diastolic [FE: 0.04±0.003 vs. MA: 0.037±0.005, mm/g] and systolic [FE: 0.03±0.0004 vs. MA: 0.028±0.005, mm/g] diameters of left ventricle) and sixth (MI [FE: 44.0±5.0 vs. MA: 42.0±3.0, %]; diastolic [FE: 0.043±0.01 vs. MA: 0.034±0.005, mm/g] and systolic [FE: 0.035±0.01 vs. MA: 0.027±0.005, mm/g] of LV) week. Similar findings were reported for left ventricle functional parameters on first (FAC [FE: 34.0±6.0 vs. MA: 32.0±4.0, %]; wave E [FE: 70.0±18.0 vs. MA: 73.0±14.0, cm/s]; wave A [FE: 20.0±12.0 vs. MA: 28.0±13.0, cm/s]; E/A [FE: 4.9±3.4 vs. MA: 3.3±1.8]) and sixth (FAC [FE: 29.0±7.0 vs. MA: 31.0±7.0, %]; wave E [FE: 85.0±18.0 vs. MA: 87.0±20.0, cm/s]; wave A [FE: 20.0±11.0 vs. MA: 28.0±17.0, cm/s]; E/A [FE: 6.2±4.0 vs. MA: 4.6±3.4]) week. Conclusion Gender does not influence left ventricle remodeling post-MI in rats. PMID:25859870

  14. Targeted disruption of the heat shock protein 20–phosphodiesterase 4D (PDE4D) interaction protects against pathological cardiac remodelling in a mouse model of hypertrophy

    PubMed Central

    Martin, Tamara P.; Hortigon-Vinagre, Maria P.; Findlay, Jane E.; Elliott, Christina; Currie, Susan; Baillie, George S.

    2014-01-01

    Phosphorylated heat shock protein 20 (HSP20) is cardioprotective. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model of pressure overload mediated hypertrophy, we show that peptide disruption of the HSP20–phosphodiesterase 4D (PDE4D) complex results in attenuation of action potential prolongation and protection against adverse cardiac remodelling. The later was evidenced by improved contractility, decreased heart weight to body weight ratio, and reduced interstitial and perivascular fibrosis. This study demonstrates that disruption of the specific HSP20–PDE4D interaction leads to attenuation of pathological cardiac remodelling. PMID:25426411

  15. Adverse ocular reactions to drugs.

    PubMed Central

    Spiteri, M. A.; James, D. G.

    1983-01-01

    Drugs acting on various parts of the body may also affect the eye insidiously. Increased awareness of such drug toxicity by the prescribing doctor should encourage him to consider effects on the cornea, lens, retina, optic nerve and elsewhere when checking the patient's progress. The following review concerns adverse ocular effects of systemic drug administration. PMID:6356101

  16. Urbanicity, social adversity and psychosis

    PubMed Central

    Heinz, Andreas; Deserno, Lorenz; Reininghaus, Ulrich

    2013-01-01

    In recent years, there has been increasing interest in research on geographical variation in the incidence of schizophrenia and other psychoses. In this paper, we review the evidence on variation in incidence of schizophrenia and other psychoses in terms of place, as well as the individual- and area-level factors that account for this variation. We further review findings on potential mechanisms that link adverse urban environment and psychosis. There is evidence from earlier and more recent studies that urbanicity is associated with an increased incidence of schizophrenia and non-affective psychosis. In addition, considerable variation in incidence across neighbourhoods has been observed for these disorders. Findings suggest it is unlikely that social drift alone can fully account for geographical variation in incidence. Evidence further suggests that the impact of adverse social contexts – indexed by area-level exposures such as population density, social fragmentation and deprivation – on risk of psychosis is explained (confounding) or modified (interaction) by environmental exposures at the individual level (i.e., cannabis use, social adversity, exclusion and discrimination). On a neurobiological level, several studies suggest a close link between social adversity, isolation and stress on the one hand, and monoamine dysfunction on the other, which resembles findings in schizophrenia patients. However, studies directly assessing correlations between urban stress or discrimination and neurobiological alterations in schizophrenia are lacking to date. PMID:24096775

  17. Adverse Childhood Experiences and Hallucinations

    ERIC Educational Resources Information Center

    Whitfield, C.L.; Dube, S.R.; Felitti, V.J.; Anda, R.F.

    2005-01-01

    Objective:: Little information is available about the contribution of multiple adverse childhood experiences (ACEs) to the likelihood of reporting hallucinations. We used data from the ACE study to assess this relationship. Methods:: We conducted a survey about childhood abuse and household dysfunction while growing up, with questions about health…

  18. Maladaptive matrix remodeling and regional biomechanical dysfunction in a mouse model of aortic valve disease.

    PubMed

    Krishnamurthy, Varun K; Opoka, Amy M; Kern, Christine B; Guilak, Farshid; Narmoneva, Daria A; Hinton, Robert B

    2012-04-01

    Aortic valve disease (AVD) occurs in 2.5% of the general population and often requires surgical intervention. Aortic valve malformation (AVM) underlies the majority of cases, suggesting a developmental etiology. Elastin haploinsufficiency results in complex cardiovascular problems, and 20-45% of patients have AVM and/or AVD. Elastin insufficient (Eln+/-) mice demonstrate AVM and latent AVD due to abnormalities in the valve annulus region. The objective of this study was to examine extracellular matrix (ECM) remodeling and biomechanical properties in regional aortic valve tissue and determine the impact of early AVM on late AVD in the Eln+/- mouse model. Aortic valve ECM composition and remodeling from juvenile, adult, and aged stages were evaluated in Eln+/- mice using histology, ELISA, immunohistochemistry and gelatin zymography. Aortic valve tissue biomechanical properties were determined using micropipette aspiration. Cartilage-like nodules were demonstrated within the valve annulus region at all stages identifying a developmental abnormality preceding AVD. Interestingly, maladaptive ECM remodeling was observed in early AVM without AVD and worsened with late AVD, as evidenced by increased MMP-2 and MMP-9 expression and activity, as well as abnormalities in ADAMTS-mediated versican processing. Cleaved versican was increased in the valve annulus region of aged Eln+/- mice, and this abnormality correlated temporally with adverse alterations in valve tissue biomechanical properties and the manifestation of AVD. These findings identify maladaptive ECM remodeling in functional AVM as an early disease process with a progressive natural history, similar to that seen in human AVD, emphasizing the importance of the annulus region in pathogenesis. Combining molecular and engineering approaches provides complementary mechanistic insights that may be informative in the search for new therapeutic targets and durable valve bioprostheses.

  19. Alexa Fluor 546-ArIB[V11L;V16A] is a potent ligand for selectively labeling alpha 7 nicotinic acetylcholine receptors.

    PubMed

    Hone, Arik J; Whiteaker, Paul; Mohn, Jesse L; Jacob, Michele H; McIntosh, J Michael

    2010-08-01

    The alpha7* (*denotes the possible presence of additional subunits) nicotinic acetylcholine receptor (nAChR) subtype is widely expressed in the vertebrate nervous system and implicated in neuropsychiatric disorders that compromise thought and cognition. In this report, we demonstrate that the recently developed fluorescent ligand Cy3-ArIB[V11L;V16A] labels alpha7 nAChRs in cultured hippocampal neurons. However, photobleaching of this ligand during long image acquisition times prompted us to develop a new derivative. In photostability studies, this new ligand, Alexa Fluor 546-ArIB[V11L;V16A], was significantly more resistant to bleaching than the Cy3 derivative. The classic alpha7 ligand alpha-bungarotoxin binds to alpha1* and alpha9* nAChRs. In contrast, Alexa Fluor 546-ArIB[V11L;V16A] potently (IC(50) 1.8 nM) and selectively blocked alpha7 nAChRs but not alpha1* or alpha9* nAChRs expressed in Xenopus oocytes. Selectivity was further confirmed by competition binding studies of native nAChRs in rat brain membranes. The fluorescence properties of Alexa Fluor 546-ArIB[V11L;V16A] were assessed using human embryonic kidney-293 cells stably transfected with nAChRs; labeling was observed on cells expressing alpha7 but not cells expressing alpha3beta2, alpha3beta4, or alpha4beta2 nAChRs. Further imaging studies demonstrate that Alexa Fluor 546-ArIB[V11L;V16A] labels hippocampal neurons from wild-type mice but not from nAChR alpha7 subunit-null mice. Thus, Alexa Fluor 546-ArIB[V11L;V16A] represents a potent and selective ligand for imaging alpha7 nAChRs.

  20. Control of bone remodelling by applied dynamic loads

    NASA Technical Reports Server (NTRS)

    Lanyon, L. E.; Rubin, C. T.

    1984-01-01

    The data showing the relationship between bone mass and peak strain magnitude prepared and submitted for publication. The data from experiments relating remodelling activity with static or dynamic loads were prepared and submitted for publication. Development of programs to relate the location of remodelling activity with he natural and artificial dynamic strain distributions continued. Experiments on the effect of different strain rates on the remodelling response continued.

  1. Pregnancy-induced remodeling of heart valves.

    PubMed

    Pierlot, Caitlin M; Moeller, Andrew D; Lee, J Michael; Wells, Sarah M

    2015-11-01

    Recent studies have demonstrated remodeling of aortic and mitral valves leaflets under the volume loading and cardiac expansion of pregnancy. Those valves' leaflets enlarge with altered collagen fiber architecture, content, and cross-linking and biphasic changes (decreases, then increases) in extensibility during gestation. This study extends our analyses to right-sided valves, with additional compositional measurements for all valves. Valve leaflets were harvested from nonpregnant heifers and pregnant cows. Leaflet structure was characterized by leaflet dimensions, and ECM composition was determined using standard biochemical assays. Histological studies assessed changes in cellular and ECM components. Leaflet mechanical properties were assessed using equibiaxial mechanical testing. Collagen thermal stability and cross-linking were assessed using denaturation and hydrothermal isometric tension tests. Pulmonary and tricuspid leaflet areas increased during pregnancy by 35 and 55%, respectively. Leaflet thickness increased by 20% only in the pulmonary valve and largely in the fibrosa (30% thickening). Collagen crimp length was reduced in both the tricuspid (61%) and pulmonary (42%) valves, with loss of crimped area in the pulmonary valve. Thermomechanics showed decreased collagen thermal stability with surprisingly maintained cross-link maturity. The pulmonary leaflet exhibited the biphasic change in extensibility seen in left side valves, whereas the tricuspid leaflet mechanics remained largely unchanged throughout pregnancy. The tricuspid valve exhibits a remodeling response during pregnancy that is significantly diminished from the other three valves. All valves of the heart remodel in pregnancy in a manner distinct from cardiac pathology, with much similarity valve to valve, but with interesting valve-specific responses in the aortic and tricuspid valves.

  2. Chromatin remodelling: the industrial revolution of DNA around histones.

    PubMed

    Saha, Anjanabha; Wittmeyer, Jacqueline; Cairns, Bradley R

    2006-06-01

    Chromatin remodellers are specialized multi-protein machines that enable access to nucleosomal DNA by altering the structure, composition and positioning of nucleosomes. All remodellers have a catalytic ATPase subunit that is similar to known DNA-translocating motor proteins, suggesting DNA translocation as a unifying aspect of their mechanism. Here, we explore the diversity and specialization of chromatin remodellers, discuss how nucleosome modifications regulate remodeller activity and consider a model for the exposure of nucleosomal DNA that involves the use of directional DNA translocation to pump 'DNA waves' around the nucleosome.

  3. CHD chromatin remodelers and the transcription cycle.

    PubMed

    Murawska, Magdalena; Brehm, Alexander

    2011-01-01

    It is well established that ATP-dependent chromatin remodelers modulate DNA access of transcription factors and RNA polymerases by "opening" or "closing" chromatin structure. However, this view is far too simplistic. Recent findings have demonstrated that these enzymes not only set the stage for the transcription machinery to act but are actively involved at every step of the transcription process. As a consequence, they affect initiation, elongation, termination and RNA processing. In this review we will use the CHD family as a paradigm to illustrate the progress that has been made in revealing these new concepts.

  4. Bacterial genome remodeling through bacteriophage recombination.

    PubMed

    Menouni, Rachid; Hutinet, Geoffrey; Petit, Marie-Agnès; Ansaldi, Mireille

    2015-01-01

    Bacteriophages co-exist and co-evolve with their hosts in natural environments. Virulent phages lyse infected cells through lytic cycles, whereas temperate phages often remain dormant and can undergo lysogenic or lytic cycles. In their lysogenic state, prophages are actually part of the host genome and replicate passively in rhythm with host division. However, prophages are far from being passive residents: they can modify or bring new properties to their host. In this review, we focus on two important phage-encoded recombination mechanisms, i.e. site-specific recombination and homologous recombination, and how they remodel bacterial genomes. PMID:25790500

  5. Bacterial genome remodeling through bacteriophage recombination.

    PubMed

    Menouni, Rachid; Hutinet, Geoffrey; Petit, Marie-Agnès; Ansaldi, Mireille

    2015-01-01

    Bacteriophages co-exist and co-evolve with their hosts in natural environments. Virulent phages lyse infected cells through lytic cycles, whereas temperate phages often remain dormant and can undergo lysogenic or lytic cycles. In their lysogenic state, prophages are actually part of the host genome and replicate passively in rhythm with host division. However, prophages are far from being passive residents: they can modify or bring new properties to their host. In this review, we focus on two important phage-encoded recombination mechanisms, i.e. site-specific recombination and homologous recombination, and how they remodel bacterial genomes.

  6. The Effect of Rosuvastatin on Inflammation, Matrix Turnover and Left Ventricular Remodeling in Dilated Cardiomyopathy: A Randomized, Controlled Trial

    PubMed Central

    Gjertsen, Erik; Ueland, Thor; Yndestad, Arne; Godang, Kristin; Stueflotten, Wenche; Andreassen, Johanna; Svendsmark, Rolf; Smith, Hans-Jørgen; Aakhus, Svend; Aukrust, Pål; Gullestad, Lars

    2014-01-01

    Background Dilated cardiomyopathy is characterized by left ventricular dilatation and dysfunction. Inflammation and adverse remodeling of the extracellular matrix may be involved in the pathogenesis. Statins reduce levels of low density lipoprotein cholesterol, but may also attenuate inflammation and affect matrix remodeling. We hypothesized that treatment with rosuvastatin would reduce or even reverse left ventricular remodeling in dilated cardiomyopathy. Materials and Methods In this multicenter, randomized, double blind, placebo-controlled study, 71 patients were randomized to 10 mg of rosuvastatin or matching placebo. Physical examination, blood sampling, echocardiography and cardiac magnetic resonance imaging were performed at baseline and at six months’ follow-up. The pre-specified primary end point was the change in left ventricular ejection fraction from baseline to six months. Results Over all, left ventricular ejection fraction improved 5 percentage points over the duration of the study, but there was no difference in the change in left ventricular ejection fraction between patients allocated to rosuvastatin and those allocated to placebo. Whereas serum low density lipoprotein cholesterol concentration fell significantly in the treatment arm, rosuvastatin did not affect plasma or serum levels of a wide range of inflammatory variables, including C-reactive protein. The effect on markers of extracellular matrix remodeling was modest. Conclusion Treatment with rosuvastatin does not improve left ventricular ejection fraction in patients with dilated cardiomyopathy. Trial Registration ClinicalTrials.gov NCT00505154 PMID:24586994

  7. Pharmacogenomics of adverse drug reactions

    PubMed Central

    2013-01-01

    Considerable progress has been made in identifying genetic risk factors for idiosyncratic adverse drug reactions in the past 30 years. These reactions can affect various tissues and organs, including liver, skin, muscle and heart, in a drug-dependent manner. Using both candidate gene and genome-wide association studies, various genes that make contributions of varying extents to each of these forms of reactions have been identified. Many of the associations identified for reactions affecting the liver and skin involve human leukocyte antigen (HLA) genes and for reactions relating to the drugs abacavir and carbamazepine, HLA genotyping is now in routine use prior to drug prescription. Other HLA associations are not sufficiently specific for translation but are still of interest in relation to underlying mechanisms for the reactions. Progress on non-HLA genes affecting adverse drug reactions has been less, but some important associations, such as those of SLCO1B1 and statin myopathy, KCNE1 and drug-induced QT prolongation and NAT2 and isoniazid-induced liver injury, are considered. Future prospects for identification of additional genetic risk factors for the various adverse drug reactions are discussed. PMID:23360680

  8. ECG manifestations of left ventricular electrical remodeling.

    PubMed

    Estes, E Harvey

    2012-01-01

    Research and thinking about the electrocardiographic manifestations of left ventricular hypertrophy has been constrained by a limited conceptual model of the process: heart disease produces chamber enlargement (increased mass), which in turn produces an altered electrocardiogram. The process is much more complex than can be represented in this simple model. A more robust and intricate model is proposed, in which heart (and vascular) disease causes structural changes, electrical changes, biochemical changes, and others, all of which interact to produce electrical remodeling of ventricular myocardium. This electrical remodeling results in a variety of ECG changes. All of these changes interact, leading to an altered clinical course, and to premature death. It is suggested that research, based on this model, can provide new clues to the processes involved, and improve the prediction of clinical outcomes. New directions in research, in recording equipment, and in organizational activities are suggested to test this new model, and to improve the usefulness of the electrocardiogram as a research and diagnostic tool.

  9. Remodeling of cardiolipin by phospholipid transacylation.

    PubMed

    Xu, Yang; Kelley, Richard I; Blanck, Thomas J J; Schlame, Michael

    2003-12-19

    Mitochondrial cardiolipin (CL) contains unique fatty acid patterns, but it is not known how the characteristic molecular species of CL are formed. We found a novel reaction that transfers acyl groups from phosphatidylcholine or phosphatidylethanolamine to CL in mitochondria of rat liver and human lymphoblasts. Acyl transfer was stimulated by ADP, ATP, and ATP gamma S, but not by other nucleotides. Coenzyme A stimulated the reaction only in the absence of adenine nucleotides. Free fatty acids were not incorporated into CL under the same incubation condition. The transacylation required addition of exogenous CL or monolyso-CL, whereas dilyso-CL was not a substrate. Transacylase activity was decreased in lymphoblasts from patients with Barth syndrome (tafazzin deletion), and this was accompanied by drastic changes in the molecular composition of CL. In rat liver, where linoleic acid was the most abundant residue of CL, only linoleoyl groups were transferred into CL, but not oleoyl or arachidonoyl groups. We demonstrated complete remodeling of tetraoleoyl-CL to tetralinoleoyl-CL in rat liver mitochondria and identified the intermediates linoleoyl-trioleoyl-CL, dilinoleoyl-dioleoyl-CL, and trilinoleoyl-oleoyl-CL by high-performance liquid chromatography. The data suggest that CL is remodeled by acyl specific phospholipid transacylation and that tafazzin is an acyltransferase involved in this mechanism.

  10. PARP inhibition and postinfarction myocardial remodeling.

    PubMed

    Halmosi, Robert; Deres, Laszlo; Gal, Roland; Eros, Krisztian; Sumegi, Balazs; Toth, Kalman

    2016-08-01

    Coronary artery disease accounts for the greatest proportion of cardiovascular diseases therefore it is the major cause of death worldwide. Its therapeutic importance is indicated by still high mortality of myocardial infarction, which is one of the most severe forms of CVDs. Moreover, the risk of developing heart failure is very high among survivors. Heart failure is accompanied by high morbidity and mortality rate, therefore this topic is in the focus of researchers' interest. After a myocardial infarct, at first ventricular hypertrophy develops as a compensatory mechanism to decrease wall stress but finally leads to left ventricular dilation. This phenomenon is termed as myocardial remodeling. The main characteristics of underlying mechanisms involve cardiomyocyte growth, vessel changes and increased collagen production, in all of which several mechanical stress induced neurohumoral agents, oxidative stress and signal transduction pathways are involved. The long term activation of these processes ultimately leads to left ventricular dilation and heart failure with decreased systolic function. Oxidative stress causes DNA breaks producing the activation of nuclear poly(ADP-ribose) polymerase-1 (PARP-1) enzyme that leads to energy depletion and unfavorable modulation of different kinase cascades (Akt-1/GSK-3β, MAPKs, various PKC isoforms) and thus it promotes the development of heart failure. Therefore inhibition of PARP enzyme could offer a promising new therapeutical approach to prevent the onset of heart failure among postinfarction patients. The purpose of this review is to give a comprehensive summary about the most significant experimental results and mechanisms in postinfarction remodeling. PMID:27392900

  11. Densitometric evaluation of periprosthetic bone remodeling

    PubMed Central

    Parchi, Paolo Domenico; Cervi, Valentina; Piolanti, Nicola; Ciapini, Gianluca; Andreani, Lorenzo; Castellini, Iacopo; Poggetti, Andrea; Lisanti, Michele

    2014-01-01

    Summary The application of Dual-energy X-ray absorptiometry (DEXA) in orthopaedic surgery gradually has been extended from the study of osteoporosis to different areas of interest like the study of the relation between bone and prosthetic implants. Aim of this review is to analyze changes that occur in periprosthetic bone after the implantation of a total hip arthroplasty (THA) or a total knee arthroplasty (TKA). In THA the pattern of adaptive bone remodeling with different cementless femoral stems varies and it appears to be strictly related to the design and more specifically to where the femoral stem is fixed on bone. Short stems with metaphyseal fixation allow the maintenance of a more physiologic load transfer to the proximal femur decreasing the entity of bone loss. Femoral bone loss after TKA seems to be related to the stress shielding induced by the implants while tibial bone remodeling seems to be related to postoperative changes in knee alignment (varus/valgus) and consequently in tibial load transfer. After both THA and TKA stress shielding seems to be an inevitable phenomenon that occurs mainly in the first year after surgery. PMID:25568658

  12. Overexpression of microRNA-99a attenuates heart remodelling and improves cardiac performance after myocardial infarction.

    PubMed

    Li, Qiaoling; Xie, Jun; Li, Ruotian; Shi, Jian; Sun, Jiayin; Gu, Rong; Ding, Liang; Wang, Lian; Xu, Biao

    2014-05-01

    MicroRNAs are involved in the regulation of various cellular processes, including cell apoptosis and autophagy. Expression of microRNA-99a (miR-99a) is reduced in apoptotic neonatal mice ventricular myocytes (NMVMs) subjected to hypoxia. We hypothesize that miR-99a might restore cardiac function after myocardial infarction (MI) by up-regulation of myocyte autophagy and apoptosis. We observed down-regulated miR-99a expression in NMVMs exposed to hypoxia using TaqMan quantitative reverse transcriptase-polymerase chain reaction analysis (RT-PCR). We also observed that miR-99a overexpression decreased hypoxia-mediated apoptosis in cultured NMVMs. To investigate whether overexpression of miR-99a in vivo could improve cardiac function in ischaemic heart, adult C57/BL6 mice undergoing MI were randomized into two groups and were intra-myocardially injected with lenti-99a-green fluorescent protein (GFP) or lenti-GFP (control). Four weeks after MI, lenti-99a-GFP group showed significant improvement in both left ventricular (LV) function and survival ratio, as compared to the lenti-GFP group. Histological analysis, western blotting analysis and electron microscopy revealed decreased cellular apoptosis and increased autophagy in cardiomyocytes of lenti-99a-GFP group. Furthermore, western blotting analysis showed inhibited mammalian target of rapamycin (mTOR) expression in the border zones of hearts in miR-99a-treated group. Our results demonstrate that miR-99a overexpression improves both cardiac function and survival ratio in a murine model of MI by preventing cell apoptosis and increasing autophagy via an mTOR/P70/S6K signalling pathway. These findings suggest that miR-99a plays a cardioprotective role in post-infarction LV remodelling and increased expression of miR-99a may have a therapeutic potential in ischaemic heart disease.

  13. Xenotransplantation of Bone Marrow-Derived Human Mesenchymal Stem Cell Sheets Attenuates Left Ventricular Remodeling in a Porcine Ischemic Cardiomyopathy Model

    PubMed Central

    Kawamura, Masashi; Miyagawa, Shigeru; Fukushima, Satsuki; Saito, Atsuhiro; Toda, Koichi; Daimon, Takashi; Shimizu, Tatsuya; Okano, Teruo

    2015-01-01

    Introduction: Bone marrow-derived autologous human mesenchymal stem cells (MSCs) are one of the most promising cell sources for cell therapy to treat heart failure. The cell sheet technique has allowed transplantation of a large number of cells and enhanced the efficacy of cell therapy. We hypothesized that the transplantation of MSC sheets may be a feasible, safe, and effective treatment for ischemic cardiomyopathy (ICM). Methods and Results: Human MSCs acquired from bone marrow were positive for CD73, CD90, and CD105 and negative for CD11b and CD45 by flow cytometry. Ten MSC sheets were created from a total cell number of 1×108 MSCs using temperature-responsive culture dishes. These were successfully transplanted over the infarct myocardium of porcine ICM models induced by placing an ameroid constrictor on the left anterior descending coronary artery without any procedural-related complications (MSC group=6: sheet transplantation; sham group=6, oral intake of tacrolimus in both groups). Premature ventricular contractions were rarely detected by Holter electrocardiogram (ECG) in the MSC group in the first week after transplantation. On echocardiography, the cardiac performance of the MSC group was significantly better than that of the sham group at 8 weeks after transplantation. On histological examination 8 weeks after transplantation, left ventricular (LV) remodeling was significantly attenuated compared with the sham group (cardiomyocyte size and interstitial fibrosis were measured). Immunohistochemistry of the von Willebrand factor showed that the vascular density in the infarct border area was significantly greater in the MSC group than the sham group. Expression of angiogenesis-related factors in the infarct border area of the MSC group was significantly greater than that of the sham group, as measured by real-time polymerase chain reaction. Conclusions: Bone marrow-derived MSC sheets improved cardiac function and attenuated LV remodeling in ICM without

  14. Serological survey of Toxoplasma gondii, Dirofilaria immitis, Feline Immunodeficiency Virus (FIV) and Feline Leukemia Virus (FeLV) infections in pet cats in Bangkok and vicinities, Thailand

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The seroprevalence of Toxoplasma gondii, Dirofilaria immitis (heartworm), feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) infections was examined using serum or plasma samples from 746 pet cats collected between May and July 2009 from clinics and hospitals located in and around ...

  15. ISOLATION OF AN ACTIVE LV1 GENE FROM CATTLE INDICATES THAT TRIPARTITE MOTIF PROTEIN-MEDIATED INNATE IMMUNITY TO RETROVIRAL INFECTION IS WIDESPREAD AMONG MAMMALS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lv1/TRIM5alpha (tripartite motif 5alpha) has recently emerged as an important factor influencing species-specific permissivity to retroviral infection in a range of primates, including humans. Old World monkey TRIM5alpha blocks human immunodeficiency virus type 1 (HIV-1) infectivity, and the human a...

  16. In vivo MRI-Based 3D FSI RV/LV Models for Human Right Ventricle and Patch Design for Potential Computer-Aided Surgery Optimization.

    PubMed

    Yang, Chun; Tang, Dalin; Haber, Idith; Geva, Tal; Del Nido, Pedro J

    2007-01-01

    Right ventricular dysfunction is one of the more common causes of heart failure in patients with congenital heart defects. Use of computer-assisted procedures is becoming more popular in clinical decision making process and computer-aided surgeries. A 3D in vivo MRI-based RV/LV combination model with fluid-structure interaction (FSI), RV-LV interaction, and RV-patch interaction was introduced to perform mechanical analysis for human right ventricle with potential clinical applications. Patient-specific RV/LV morphologies were acquired by using planar tagged MRI. The 3D RV/LV FSI model was solved using a commercial finite element package ADINA. Our results indicated that flow and stress/strain distributions in the right ventricle are closely related to RV morphology, material properties and blood pressure conditions. Patches with material properties better matching RV tissue properties and smaller size lead to better RV function recoveries. Computational RV volumes showed very good agreement with MRI data (error < 3%). More patient studies are needed to establish baseline database so that computational simulations can be used to replace empirical and often risky clinical experimentation to examine the efficiency and suitability of various reconstructive procedures in diseased hearts and optimal design can be found.

  17. Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats

    PubMed Central

    Gu, Ye; Zou, Wusong; Zhang, Mingjing; Zhu, Pengfei; Hu, Shao

    2015-01-01

    Background Aortocaval fistula (AV) in rat is a unique model of volume-overload congestive heart failure and cardiac hypertrophy. Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Impact of AV on animals with mild renal dysfunction is not fully understood. In this study, we explored the effects of AV in unilateral nephrectomized (UNX) rats. Methods Adult male Sprague-Dawley (SD) rats were divided into Sham (n = 10), UNX (right kidney remove, n = 10), AV (AV established between the levels of renal arteries and iliac bifurcation, n = 18) and UNX+AV (AV at one week after UNX, n = 22), respectively. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, fractional excretion of sodium, albuminuria, plasma creatinine, and cystatin C. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function was measured by echocardiography and hemodynamic measurements. Results UNX alone induced compensatory left kidney enlargement, increased plasma creatinine and cystatin C levels, and slightly reduced glomerular filtration rate and increased FGS. AV induced significant cardiac enlargement and hypertrophy and reduced cardiac function and increased FGS, these changes were aggravated in UNX+AV rats. Conclusions Although UNX only induces minor renal dysfunction, additional chronic volume overload placement during the adaptation phase of the remaining kidney is associated with aggravated cardiac dysfunction and remodeling in UNX rats, suggesting special medical care is required for UNX or congenital monokidney subjects in case of chronic volume overload as in the case of pregnancy and hyperthyroidism to prevent further adverse cardiorenal events in these individuals. PMID:26252578

  18. The effect of stress concentration on bone remodeling: theoretical predictions.

    PubMed

    Firoozbakhsh, K; Aleyaasin, M

    1989-11-01

    Theoretical predictions of internal bone remodeling around an elliptical hole are studied. The internal remodeling theory due to Cowin and Hegedus is employed. The bone is modeled as an initially homogeneous adaptive elastic plate with an elliptical hole under a superposed steady compressive load. It is shown that there will exist a final inhomogeneous remodeling distribution around the hole that will disappear away from the hole. The remodeling is such that the compressive stress concentration causes the bone structure to evolve to one of greater density and stiffer elastic coefficients. The speed of remodeling around the hole and its variation with respect to distance is investigated and discussed. It is shown that the rate of bone reinforcement in the area of compressive stress concentration is much higher than the rate of bone resorption in the area of existing tensile stress. Special cases of a circular hole and vertical and horizontal slots are studied and discussed.

  19. Sustained cardiac remodeling after a short-term very low calorie diet in type 2 diabetes mellitus patients.

    PubMed

    Jonker, Jacqueline T; Snel, Marieke; Hammer, Sebastiaan; Jazet, Ingrid M; van der Meer, Rutger W; Pijl, Hanno; Meinders, A Edo; de Roos, Albert; Smit, Johannes W A; Romijn, Johannes A; Lamb, Hildo J

    2014-01-01

    A very low calorie diet (VLCD) results in cardiac remodeling and improved diastolic function. It is unknown how long these effects sustain after reintroduction of a regular diet. We aimed to assess the long-term effects of initial weight loss by VLCD on cardiac dimensions and function in type 2 diabetes mellitus (T2DM) patients. Fourteen insulin-dependent T2DM patients (mean ± SEM: age 53 ± 2 years; BMI 35 ± 1 kg/m(2)) were treated by a VLCD (450 kcal/day) during 16 weeks. Cardiac function and myocardial triglyceride (TG) content were measured by magnetic resonance imaging and spectroscopy at baseline, after a 16-week VLCD and after 14 months of follow-up on a regular diet. BMI decreased from 35 ± 1 to 28 ± 1 kg/m(2) after VLCD and increased again to 32 ± 1 kg/m(2) at 18 months (both P < 0.05 vs. baseline). Left ventricular (LV) end-diastolic volume index increased after the 16-week VLCD (80 ± 3 to 89 ± 4 ml/m(2), P < 0.05) and remained increased after follow-up (90 ± 3 ml/m(2); P < 0.05 vs. baseline) at comparable filling pressures. The improvement in LV diastolic function after the 16-week VLCD, was sustained at 18 months [early (E)/atrial (A) diastolic filling phase ratio: 0.96 ± 0.07 (baseline); 1.12 ± 0.06 (after VLCD); 1.06 ± 0.07 (18 months, P < 0.05 vs. baseline)]. Myocardial TG content decreased after the 16-week VLCD [0.74 (0.41-1.10) to 0.45 (0.31-0.54) %, P < 0.05], but returned to baseline levels at 18 months [0.76 (0.65-1.32) %]. Weight reduction by a 16-week VLCD in T2DM patients results in sustained cardiac remodeling and improved diastolic function after 14 months of follow-up, despite weight regain on a regular diet.

  20. [Adverse ocular effects of vaccinations].

    PubMed

    Ness, T; Hengel, H

    2016-07-01

    Vaccinations are very effective measures for prevention of infections but are also associated with a long list of possible side effects. Adverse ocular effects following vaccination have been rarely reported or considered to be related to vaccinations. Conjunctivitis is a frequent sequel of various vaccinations. Oculorespiratory syndrome and serum sickness syndrome are considered to be related to influenza vaccinations. The risk of reactivation or initiation of autoimmune diseases (e. g. uveitis) cannot be excluded but has not yet been proven. Overall the benefit of vaccination outweighs the possible but very low risk of ocular side effects.

  1. [Adverse ocular effects of vaccinations].

    PubMed

    Ness, T; Hengel, H

    2016-07-01

    Vaccinations are very effective measures for prevention of infections but are also associated with a long list of possible side effects. Adverse ocular effects following vaccination have been rarely reported or considered to be related to vaccinations. Conjunctivitis is a frequent sequel of various vaccinations. Oculorespiratory syndrome and serum sickness syndrome are considered to be related to influenza vaccinations. The risk of reactivation or initiation of autoimmune diseases (e. g. uveitis) cannot be excluded but has not yet been proven. Overall the benefit of vaccination outweighs the possible but very low risk of ocular side effects. PMID:27357302

  2. Adverse Effects of Electroconvulsive Therapy.

    PubMed

    Andrade, Chittaranjan; Arumugham, Shyam Sundar; Thirthalli, Jagadisha

    2016-09-01

    Electroconvulsive therapy (ECT) is an effective treatment commonly used for depression and other major psychiatric disorders. We discuss potential adverse effects (AEs) associated with ECT and strategies for their prevention and management. Common acute AEs include headache, nausea, myalgia, and confusion; these are self-limiting and are managed symptomatically. Serious but uncommon AEs include cardiovascular, pulmonary, and cerebrovascular events; these may be minimized with screening for risk factors and by physiologic monitoring. Although most cognitive AEs of ECT are short-lasting, troublesome retrograde amnesia may rarely persist. Modifications of and improvements in treatment techniques minimize cognitive and other AEs. PMID:27514303

  3. Multimodality Imaging of Myocardial Injury and Remodeling

    PubMed Central

    Kramer, Christopher M.; Sinusas, Albert J.; Sosnovik, David E.; French, Brent A.; Bengel, Frank M.

    2011-01-01

    Advances in cardiovascular molecular imaging have come at a rapid pace over the last several years. Multiple approaches have been taken to better understand the structural, molecular, and cellular events that underlie the progression from myocardial injury to myocardial infarction (MI) and, ultimately, to congestive heart failure. Multimodality molecular imaging including SPECT, PET, cardiac MRI, and optical approaches is offering new insights into the pathophysiology of MI and left ventricular remodeling in small-animal models. Targets that are being probed include, among others, angiotensin receptors, matrix metalloproteinases, integrins, apoptosis, macrophages, and sympathetic innervation. It is only a matter of time before these advances are applied in the clinical setting to improve post-MI prognostication and identify appropriate therapies in patients to prevent the onset of congestive heart failure. PMID:20395347

  4. Cell wall remodeling under abiotic stress

    PubMed Central

    Tenhaken, Raimund

    2015-01-01

    Plants exposed to abiotic stress respond to unfavorable conditions on multiple levels. One challenge under drought stress is to reduce shoot growth while maintaining root growth, a process requiring differential cell wall synthesis and remodeling. Key players in this process are the formation of reactive oxygen species (ROS) and peroxidases, which initially cross-link phenolic compounds and glycoproteins of the cell walls causing stiffening. The function of ROS shifts after having converted all the peroxidase substrates in the cell wall. If ROS-levels remain high during prolonged stress, OH°-radicals are formed which lead to polymer cleavage. In concert with xyloglucan modifying enzymes and expansins, the resulting cell wall loosening allows further growth of stressed organs. PMID:25709610

  5. Organelle remodeling at membrane contact sites.

    PubMed

    Henne, W Mike

    2016-10-01

    Cellular organelles must execute sophisticated biological processes to persist, and often communicate with one another to exchange metabolites and information. Recent studies suggest inter-organelle membrane contact sites (MCSs) are hubs for this cellular cross-talk. MCSs also govern membrane remodeling, thus controlling aspects of organelle shape, identity, and function. Here, we summarize three emerging phenomena that MCSs appear to govern: 1) organelle identity via the non-vesicular exchange of lipids, 2) mitochondrial shape and division, and 3) endosomal migration in response to sterol trafficking. We also discuss the role for ER-endolysosomal contact sites in cholesterol metabolism, and the potential biomedical importance this holds. Indeed, the emerging field inter-organellar cross-talk promises substantial advances in the fields of lipid metabolism and cell signaling.

  6. Molecular mechanisms of synaptic remodeling in alcoholism.

    PubMed

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-01

    Alcohol use and alcohol addiction represent dysfunctional brain circuits resulting from neuroadaptive changes during protracted alcohol exposure and its withdrawal. Alcohol exerts a potent effect on synaptic plasticity and dendritic spine formation in specific brain regions, providing a neuroanatomical substrate for the pathophysiology of alcoholism. Epigenetics has recently emerged as a critical regulator of gene expression and synaptic plasticity-related events in the brain. Alcohol exposure and withdrawal induce changes in crucial epigenetic processes in the emotional brain circuitry (amygdala) that may be relevant to the negative affective state defined as the "dark side" of addiction. Here, we review the literature concerning synaptic plasticity and epigenetics, with a particular focus on molecular events related to dendritic remodeling during alcohol abuse and alcoholism. Targeting epigenetic processes that modulate synaptic plasticity may yield novel treatments for alcoholism.

  7. Protective effects of Ping-Lv-Mixture (PLM), a medicinal formula on arrhythmias induced by myocardial ischemia-reperfusion.

    PubMed

    An, Wei; Yang, Jing

    2006-11-01

    Ping-Lv-Mixture (PLM) is a Chinese medicinal formula. The present study aimed to determine the effects of PLM on myocardial ischemia-reperfusion (MI/R) induced arrhythmias in rats. Arrhythmia model was established by occlusion of the left arterial descending coronary artery and thereafter reperfusion. A lead II electrocardiogram was monitored throughout the experiment. The results showed that pretreatment of PLM to MI/R rats significantly reduced the incidence and duration of ventricular tachycardia and ventricular fibrillation. On induction of MI/R, the activities of creatine kinase and lactate dehydrogenase were increased in vehicle group. PLM (0.04-1.00 g/kg) administration prevented the increase of these enzymes. Moreover, a significant increase of myocardium superoxide dismutase and decrease of malondialdehyde contents were observed in rats of PLM groups. On the other hand, the expressions of platelet activating factor (PAF) receptor mRNA was down-regulated in a dose-dependent manner in the PLM-treated groups by RT-PCR. Thus, it can be concluded that pretreatment with PLM inhibited lipid peroxidation in rats through suppressing the expression of PAF receptor, which may contribute to its preventive effect on myocardial ischemia-reperfusion induced arrhythmias.

  8. Myocardial Tissue Remodeling in Adolescent Obesity

    PubMed Central

    Shah, Ravi V.; Abbasi, Siddique A.; Neilan, Tomas G.; Hulten, Edward; Coelho‐Filho, Otavio; Hoppin, Alison; Levitsky, Lynne; de Ferranti, Sarah; Rhodes, Erinn T.; Traum, Avram; Goodman, Elizabeth; Feng, Henry; Heydari, Bobak; Harris, William S.; Hoefner, Daniel M.; McConnell, Joseph P.; Seethamraju, Ravi; Rickers, Carsten; Kwong, Raymond Y.; Jerosch‐Herold, Michael

    2013-01-01

    Background Childhood obesity is a significant risk factor for cardiovascular disease in adulthood. Although ventricular remodeling has been reported in obese youth, early tissue‐level markers within the myocardium that precede organ‐level alterations have not been described. Methods and Results We studied 21 obese adolescents (mean age, 17.7±2.6 years; mean body mass index [BMI], 41.9±9.5 kg/m2, including 11 patients with type 2 diabetes [T2D]) and 12 healthy volunteers (age, 15.1±4.5 years; BMI, 20.1±3.5 kg/m2) using biomarkers of cardiometabolic risk and cardiac magnetic resonance imaging (CMR) to phenotype cardiac structure, function, and interstitial matrix remodeling by standard techniques. Although left ventricular ejection fraction and left atrial volumes were similar in healthy volunteers and obese patients (and within normal body size‐adjusted limits), interstitial matrix expansion by CMR extracellular volume fraction (ECV) was significantly different between healthy volunteers (median, 0.264; interquartile range [IQR], 0.253 to 0.271), obese adolescents without T2D (median, 0.328; IQR, 0.278 to 0.345), and obese adolescents with T2D (median, 0.376; IQR, 0.336 to 0.407; P=0.0001). ECV was associated with BMI for the entire population (r=0.58, P<0.001) and with high‐sensitivity C‐reactive protein (r=0.47, P<0.05), serum triglycerides (r=0.51, P<0.05), and hemoglobin A1c (r=0.76, P<0.0001) in the obese stratum. Conclusions Obese adolescents (particularly those with T2D) have subclinical alterations in myocardial tissue architecture associated with inflammation and insulin resistance. These alterations precede significant left ventricular hypertrophy or decreased cardiac function. PMID:23963758

  9. Progenitor cells in pulmonary vascular remodeling.

    PubMed

    Yeager, Michael E; Frid, Maria G; Stenmark, Kurt R

    2011-01-01

    Pulmonary hypertension is characterized by cellular and structural changes in the walls of pulmonary arteries. Intimal thickening and fibrosis, medial hypertrophy and fibroproliferative changes in the adventitia are commonly observed, as is the extension of smooth muscle into the previously non-muscularized vessels. A majority of these changes are associated with the enhanced presence of α-SM-actin+ cells and inflammatory cells. Atypical abundances of functionally distinct endothelial cells, particularly in the intima (plexiform lesions), and also in the perivascular regions, are also described. At present, neither the origin(s) of these cells nor the molecular mechanisms responsible for their accumulation, in any of the three compartments of the vessel wall, have been fully elucidated. The possibility that they arise from either resident vascular progenitors or bone marrow-derived progenitor cells is now well established. Resident vascular progenitor cells have been demonstrated to exist within the vessel wall, and in response to certain stimuli, to expand and express myofibroblastic, endothelial or even hematopoietic markers. Bone marrow-derived or circulating progenitor cells have also been shown to be recruited to sites of vascular injury and to assume both endothelial and SM-like phenotypes. Here, we review the data supporting the contributory role of vascular progenitors (including endothelial progenitor cells, smooth muscle progenitor cells, pericytes, and fibrocytes) in vascular remodeling. A more complete understanding of the processes by which progenitor cells modulate pulmonary vascular remodeling will undoubtedly herald a renaissance of therapies extending beyond the control of vascular tonicity and reduction of pulmonary artery pressure. PMID:22034593

  10. A randomized, double-blind, placebo-controlled trial to evaluate the safety and effectiveness of intracoronary application of a novel bioabsorbable cardiac matrix for the prevention of ventricular remodeling after large ST-segment elevation myocardial infarction: Rationale and design of the PRESERVATION I trial.

    PubMed

    Rao, Sunil V; Zeymer, Uwe; Douglas, Pamela S; Al-Khalidi, Hussein; Liu, Jingyu; Gibson, C Michael; Harrison, Robert W; Joseph, Diane S; Heyrman, Reinilde; Krucoff, Mitchell W

    2015-11-01

    Postinfarction left ventricular (LV) remodeling can result in chronic heart failure and functional impairment. Although pharmacological strategies for established heart failure can be beneficial, preventing remodeling remains a challenge. Injectable bioabsorbable alginate or "bioabsorbable cardiac matrix" (BCM), composed of an aqueous mixture of sodium alginate and calcium gluconate, is a sterile colorless liquid that is a polysaccharide polymer produced from brown seaweed. When exposed to excess ionized calcium present in infarcted myocardium, BCM assembles to form a flexible gel, structurally resembling extracellular matrix, which provides temporary structural support to the infarct zone through and beyond the time needed for mature fibrotic tissue to develop. The PRESERVATION I trial is an early phase randomized, double-blind, placebo-controlled trial comparing intracoronary application of 4 mL of BCM with saline control in patients who develop large infarctions after successful reperfusion of large ST-segment elevation myocardial infarction (MI). Subjects will be randomized 2:1 to either BCM or saline control and will have the study device deployed through an intracoronary microcatheter in the infarct-related artery 2 to 5 days after index ST-segment elevation MI treated with successful primary or rescue percutaneous coronary intervention. The primary effectiveness end point is the absolute change in LV diastolic volume index as measured by 3-dimensional echocardiography from baseline to 6 months after BCM deployment. Secondary effectiveness end points include clinical outcomes, patient-reported quality of life, additional echocardiographic measures, and functional status measures. In summary, the PRESERVATION I trial is a randomized double-blind trial evaluating the effectiveness and safety of the novel device BCM in preventing LV remodeling patients who have large MIs despite undergoing successful primary or rescue percutaneous coronary intervention.

  11. Intermediate monocytes lead to enhanced myocardial remodelling in STEMI patients with diabetes.

    PubMed

    Lu, Wenbin; Zhang, Ziwei; Fu, Cong; Ma, Genshan

    2015-01-01

    revealed that counts of the intermediate monocytes according to median showed statistical significance in STEMI patients with diabetes (P = 0.010). After full adjustment for confounding factors, the cells were found to remain independently related to recurrent cardiovascular events or death in this group (P = 0.004, 95% CI: 1.62-12.49).Intermediate monocytes were associated with LV remodelling in STEMI patients with diabetes. The cells were predictive for recurrent cardiovascular events or death in these patients. A low level of D6 mRNA in the intermediate monocytes of STEMI patients with diabetes and high level of CCL2 in these patients may partially explain the causality.

  12. Classically and alternatively activated macrophages contribute to tissue remodelling after myocardial infarction

    PubMed Central

    Troidl, C; Möllmann, H; Nef, H; Masseli, F; Voss, S; Szardien, S; Willmer, M; Rolf, A; Rixe, J; Troidl, K; Kostin, S; Hamm, C; Elsässer, A

    2009-01-01

    An important goal in cardiology is to minimize myocardial necrosis and to support a discrete but resilient scar formation after myocardial infarction (MI). Macrophages are a type of cells that influence cardiac remodelling during MI. Therefore, the goal of the present study was to investigate their transcriptional profile and to identify the type of activation during scar tissue formation. Ligature of the left anterior descending coronary artery was performed in mice. Macrophages were isolated from infarcted tissue using magnetic cell sorting after 5 days. The total RNA of macrophages was subjected to microarray analysis and compared with RNA from MI and LV-control. mRNA abundance of relevant targets was validated by quantitative real-time PCR 2, 5 and 10 days after MI (qRT-PCR). Immunohistochemistry was performed to localize activation type-specific proteins. The genome scan revealed 68 targets predominantly expressed by macrophages after MI. Among these targets, an increased mRNA abundance of genes, involved in both the classically (tumour necrosis factor α, interleukin 6, interleukin 1β) and the alternatively (arginase 1 and 2, mannose receptor C type 1, chitinase 3-like 3) activated phenotype of macrophages, was found 5 days after MI. This observation was confirmed by qRT-PCR. Using immunohistochemistry, we confirmed that tumour necrosis factor α, representing the classical activation, is strongly transcribed early after ligature (2 days). It was decreased after 5 and 10 days. Five days after MI, we found a fundamental change towards alternative activation of macrophages with up-regulation of arginase 1. Our results demonstrate that macrophages are differentially activated during different phases of scar tissue formation after MI. During the early inflammatory phase, macrophages are predominantly classically activated, whereas their phenotype changes during the important transition from inflammation to scar tissue formation into an alternatively activated

  13. Remodeling of Endogenous Mammary Epithelium by Breast Cancer Stem Cells

    PubMed Central

    Parashurama, Natesh; Lobo, Neethan A.; Ito, Ken; Mosley, Adriane R.; Habte, Frezghi G.; Zabala, Maider; Smith, Bryan R.; Lam, Jessica; Weissman, Irving L.; Clarke, Michael F.; Gambhir, Sanjiv S.

    2014-01-01

    Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. We find that normal, regenerating, and developing gland maintain a specific branching pattern. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Furthermore, we identify unique, CSC-specific, remodeling events. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC. PMID:22899386

  14. Remodeling of endogenous mammary epithelium by breast cancer stem cells.

    PubMed

    Parashurama, Natesh; Lobo, Neethan A; Ito, Ken; Mosley, Adriane R; Habte, Frezghi G; Zabala, Maider; Smith, Bryan R; Lam, Jessica; Weissman, Irving L; Clarke, Michael F; Gambhir, Sanjiv S

    2012-10-01

    Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. We find that normal, regenerating, and developing gland maintain a specific branching pattern. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Furthermore, we identify unique, CSC-specific, remodeling events. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC. PMID:22899386

  15. Adverse reactions to food additives.

    PubMed

    Simon, R A

    1986-01-01

    There are thousands of agents that are intentionally added to the food that we consume. These include preservatives, stabilizers, conditioners, thickeners, colorings, flavorings, sweeteners, antioxidants, etc. etc. Yet only a surprisingly small number have been associated with hypersensitivity reactions. Amongst all the additives, FD&C dyes have been most frequently associated with adverse reactions. Tartrazine is the most notorious of them all; however, critical review of the medical literature and current Scripps Clinic studies would indicate that tartrazine has been confirmed to be at best only occasionally associated with flares of urticaria or asthma. There is no convincing evidence in the literature of reactivity to the other azo or nonazo dyes. This can also be said of BHA/BHT, nitrites/nitrates and sorbates. Parabens have been shown to elicit IgE mediated hypersensitivity reactions when used as pharmaceutical preservatives; however, as with the other additives noted above, ingested parabens have only occasionally been associated with adverse reactions. MSG, the cause of the 'Chinese restaurant syndrome' has only been linked to asthma in one report. Sulfiting agents used primarily as food fresheners and to control microbial growth in fermented beverages have been established as the cause of any where from mild to severe and even fatal reactions in at least 5% of the asthmatic population. Other reactions reported to follow sulfite ingestion include anaphylaxis, gastro intestinal complaints and dermatological eruptions. The prevalence of these non asthmatic reactions is unknown. The mechanism of sulfite sensitive asthma is also unknown but most likely involves hyperreactivity to inhale SO2 in the great majority of cases; however, there are reports of IgE mediated reactions and other sulfite sensitive asthmatics have been found with low levels of sulfite oxidase; necessary to oxidize endogenous sulfite to sulfate.

  16. Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

    PubMed Central

    Fu, Xuebin; Segiser, Adrian; Carrel, Thierry P.; Tevaearai Stahel, Hendrik T.; Most, Henriette

    2016-01-01

    Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation (hHTX) in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery. We herein review the current knowledge on the effects of volume unloading the left ventricle via different methods of hHTX in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under “reloaded” conditions. While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced changes in the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further improve our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients. PMID:27807535

  17. Pathological Ventricular Remodeling: Mechanisms: Part 1 of 2

    PubMed Central

    Xie, Min; Burchfield, Jana S.; Hill, Joseph A.

    2013-01-01

    Despite declines in heart failure morbidity and mortality with current therapies, re-hospitalization rates remain distressingly high, impacting substantially on individuals, society, and the economy. As a result, the need for new therapeutic advances and novel medical devices is urgent. Disease-related left ventricular remodeling is a complex process involving cardiac myocyte growth and death, vascular rarefaction, fibrosis, inflammation, and electrophysiological remodeling. As these events are highly inter-related, targeting one single molecule or process may not be sufficient. Here, we review molecular and cellular mechanisms governing pathological ventricular remodeling. PMID:23877061

  18. Cardiac Remodeling: Concepts, Clinical Impact, Pathophysiological Mechanisms and Pharmacologic Treatment

    PubMed Central

    Azevedo, Paula S.; Polegato, Bertha F.; Minicucci, Marcos F.; Paiva, Sergio A. R.; Zornoff, Leonardo A. M.

    2016-01-01

    Cardiac remodeling is defined as a group of molecular, cellular and interstitial changes that manifest clinically as changes in size, mass, geometry and function of the heart after injury. The process results in poor prognosis because of its association with ventricular dysfunction and malignant arrhythmias. Here, we discuss the concepts and clinical implications of cardiac remodeling, and the pathophysiological role of different factors, including cell death, energy metabolism, oxidative stress, inflammation, collagen, contractile proteins, calcium transport, geometry and neurohormonal activation. Finally, the article describes the pharmacological treatment of cardiac remodeling, which can be divided into three different stages of strategies: consolidated, promising and potential strategies. PMID:26647721

  19. Lymphoid Tissue Mesenchymal Stromal Cells in Development and Tissue Remodeling

    PubMed Central

    2016-01-01

    Secondary lymphoid organs (SLOs) are sites that facilitate cell-cell interactions required for generating adaptive immune responses. Nonhematopoietic mesenchymal stromal cells have been shown to play a critical role in SLO function, organization, and tissue homeostasis. The stromal microenvironment undergoes profound remodeling to support immune responses. However, chronic inflammatory conditions can promote uncontrolled stromal cell activation and aberrant tissue remodeling including fibrosis, thus leading to tissue damage. Despite recent advancements, the origin and role of mesenchymal stromal cells involved in SLO development and remodeling remain unclear. PMID:27190524

  20. Arabidopsis FORGETTER1 mediates stress-induced chromatin memory through nucleosome remodeling

    PubMed Central

    Brzezinka, Krzysztof; Altmann, Simone; Czesnick, Hjördis; Nicolas, Philippe; Gorka, Michal; Benke, Eileen; Kabelitz, Tina; Jähne, Felix; Graf, Alexander; Kappel, Christian; Bäurle, Isabel

    2016-01-01

    Plants as sessile organisms can adapt to environmental stress to mitigate its adverse effects. As part of such adaptation they maintain an active memory of heat stress for several days that promotes a more efficient response to recurring stress. We show that this heat stress memory requires the activity of the FORGETTER1 (FGT1) locus, with fgt1 mutants displaying reduced maintenance of heat-induced gene expression. FGT1 encodes the Arabidopsis thaliana orthologue of Strawberry notch (Sno), and the protein globally associates with the promoter regions of actively expressed genes in a heat-dependent fashion. FGT1 interacts with chromatin remodelers of the SWI/SNF and ISWI families, which also display reduced heat stress memory. Genomic targets of the BRM remodeler overlap significantly with FGT1 targets. Accordingly, nucleosome dynamics at loci with altered maintenance of heat-induced expression are affected in fgt1. Together, our results suggest that by modulating nucleosome occupancy, FGT1 mediates stress-induced chromatin memory. DOI: http://dx.doi.org/10.7554/eLife.17061.001 PMID:27680998

  1. Scar prevention and remodeling: a review of the medical, surgical, topical and light treatment approaches.

    PubMed

    Kerwin, Leonard Y; El Tal, Abdel Kader; Stiff, Mark A; Fakhouri, Tarek M

    2014-08-01

    Cosmetic, functional, and structural sequelae of scarring are innumerable, and measures exist to optimize and ultimately minimize these sequelae. To evaluate the innumerable methods available to decrease the cosmetic, functional, and structural repercussions of scarring, pubMed search of the English literature with key words scar, scar revision, scar prevention, scar treatment, scar remodeling, cicatrix, cicatrix treatment, and cicatrix remodeling was done. Original articles and reviews were examined and included. Seventy-nine manuscripts were reviewed. Techniques, comparisons, and results were reviewed and tabulated. Overall, though topical modalities are easier to use and are usually more attractive to the patient, the surgical approaches still prove to be superior and more reliable. However, advances in topical medications for scar modification are on the rise and a change towards medical treatment of scars may emerge as the next best approach. Comparison studies of the innumerable specific modalities for scar revision and prevention are impossible. Standardization of techniques is lacking. Scarring, the body's natural response to a wound, can create many adverse effects. At this point, the practice of sound, surgical fundamentals still trump the most advanced preventative methods and revision techniques. Advances in medical approaches are available, however, to assist the scarring process, which even the most advanced surgical fundamentals will ultimately lead to. Whether through newer topical therapies, light treatment, or classical surgical intervention, our treatment armamentarium of scars has expanded and will allow us to maximize scar prevention and to minimize scar morbidity.

  2. Metallothioneins 1 and 2 Modulate Inflammation and Support Remodeling in Ischemic Cardiomyopathy in Mice.

    PubMed

    Duerr, Georg D; Dewald, Daniela; Schmitz, Eva J; Verfuerth, Luise; Keppel, Katharina; Peigney, Christine; Ghanem, Alexander; Welz, Armin; Dewald, Oliver

    2016-01-01

    Aims. Repetitive brief ischemia and reperfusion (I/R) is associated with left ventricular dysfunction during development of ischemic cardiomyopathy. We investigated the role of zinc-donor proteins metallothionein MT1 and MT2 in a closed-chest murine model of I/R. Methods. Daily 15-minute LAD-occlusion was performed for 1, 3, and 7 days in SV129 (WT)- and MT1/2 knockout (MT(-/-))-mice (n = 8-10/group). Hearts were examined with M-mode echocardiography and processed for histological and mRNA studies. Results. Expression of MT1/2 mRNA was transiently induced during repetitive I/R in WT-mice, accompanied by a transient inflammation, leading to interstitial fibrosis with left ventricular dysfunction without infarction. In contrast, MT(-/-)-hearts presented with enhanced apoptosis and small infarctions leading to impaired global and regional pump function. Molecular analysis revealed maladaptation of myosin heavy chain isoforms and antioxidative enzymes in MT1/2(-/-)-hearts. Despite their postponed chemokine induction we found a higher total neutrophil density and macrophage infiltration in small infarctions in MT(-/-)-hearts. Subsequently, higher expression of osteopontin 1 and tenascin C was associated with increased myofibroblast density resulting in predominately nonreversible fibrosis and adverse remodeling in MT1/2(-/-)-hearts. Conclusion. Cardioprotective effects of MT1/2 seem to be exerted via modulation of contractile elements, antioxidative enzymes, inflammatory response, and myocardial remodeling. PMID:27403038

  3. Scar prevention and remodeling: a review of the medical, surgical, topical and light treatment approaches.

    PubMed

    Kerwin, Leonard Y; El Tal, Abdel Kader; Stiff, Mark A; Fakhouri, Tarek M

    2014-08-01

    Cosmetic, functional, and structural sequelae of scarring are innumerable, and measures exist to optimize and ultimately minimize these sequelae. To evaluate the innumerable methods available to decrease the cosmetic, functional, and structural repercussions of scarring, pubMed search of the English literature with key words scar, scar revision, scar prevention, scar treatment, scar remodeling, cicatrix, cicatrix treatment, and cicatrix remodeling was done. Original articles and reviews were examined and included. Seventy-nine manuscripts were reviewed. Techniques, comparisons, and results were reviewed and tabulated. Overall, though topical modalities are easier to use and are usually more attractive to the patient, the surgical approaches still prove to be superior and more reliable. However, advances in topical medications for scar modification are on the rise and a change towards medical treatment of scars may emerge as the next best approach. Comparison studies of the innumerable specific modalities for scar revision and prevention are impossible. Standardization of techniques is lacking. Scarring, the body's natural response to a wound, can create many adverse effects. At this point, the practice of sound, surgical fundamentals still trump the most advanced preventative methods and revision techniques. Advances in medical approaches are available, however, to assist the scarring process, which even the most advanced surgical fundamentals will ultimately lead to. Whether through newer topical therapies, light treatment, or classical surgical intervention, our treatment armamentarium of scars has expanded and will allow us to maximize scar prevention and to minimize scar morbidity. PMID:24697346

  4. Adverse events in healthcare: learning from mistakes.

    PubMed

    Rafter, N; Hickey, A; Condell, S; Conroy, R; O'Connor, P; Vaughan, D; Williams, D

    2015-04-01

    Large national reviews of patient charts estimate that approximately 10% of hospital admissions are associated with an adverse event (defined as an injury resulting in prolonged hospitalization, disability or death, caused by healthcare management). Apart from having a significant impact on patient morbidity and mortality, adverse events also result in increased healthcare costs due to longer hospital stays. Furthermore, a substantial proportion of adverse events are preventable. Through identifying the nature and rate of adverse events, initiatives to improve care can be developed. A variety of methods exist to gather adverse event data both retrospectively and prospectively but these do not necessarily capture the same events and there is variability in the definition of an adverse event. For example, hospital incident reporting collects only a very small fraction of the adverse events found in retrospective chart reviews. Until there are systematic methods to identify adverse events, progress in patient safety cannot be reliably measured. This review aims to discuss the need for a safety culture that can learn from adverse events, describe ways to measure adverse events, and comment on why current adverse event monitoring is unable to demonstrate trends in patient safety.

  5. Landslide risk assessment in the Göta Älv river valley to limit consequences of climate change on society

    NASA Astrophysics Data System (ADS)

    Hedlund, Jonas; Lind, Bo; Tremblay, Marius; Zackrisson, Peter; Cederbom, Charlotte

    2010-05-01

    Higher temperatures, higher average precipitation and increased occurrence of extreme rainfall events are some expected climate changes in Sweden during the coming 70-100 years. Due to the changing climate the risk for floods, erosion and landslides are expected to increase. in large parts of the country. To prevent extensive floodings and damages of cities and infrastructure around Lake Vänern, it is necessary to allow controlled overflow from Lake Vänern through the river Göta Älv. An overflow in the river, in turn, leads to increased risk for erosion and landslides along the Göta Älv valley. In order to meet the upcoming climate changes and to handle the increasing flows through the river, we need to improve the knowledge of the stability of the entire river bank. The Swedish Government has commissioned the Swedish Geotechnical Institute (SGI) to investigate the landslide potential of the Göta Älv valley, taking the predicted climate changes into consideration. The investigated area includes the parts of Göta Älv that could be affected by the increased flows from Lake Vänern; areas where the increased flow will affect stability and where landslides could cause serious damages or damming of the river. The investigation area includes c. 90 km of the Göta Älv river plus tributaries in connection to Göta Älv. In the landslide risk analyses developed for Göta Älv, the likelihood of landslides and estimation of the subsequent consequences are included. The methodology involves mapping of landslide hazards and a judgement of the risk area on the basis of a risk matrix. The landslide risk analysis allows for an assessment of where geotechnical reinforcements would be necessary. A cost estimation for the required reinforcement measures is also provided. In areas where the estimated risk for a landslide is low (e.g. limited consequences), stability mapping in accordance with the model used by the Swedish Civil Contingencies Agency (MSB) is developed

  6. Molecular Imaging of Angiogenesis and Vascular Remodeling in Cardiovascular Pathology

    PubMed Central

    Golestani, Reza; Jung, Jae-Joon; Sadeghi, Mehran M.

    2016-01-01

    Angiogenesis and vascular remodeling are involved in a wide array of cardiovascular diseases, from myocardial ischemia and peripheral arterial disease, to atherosclerosis and aortic aneurysm. Molecular imaging techniques to detect and quantify key molecular and cellular players in angiogenesis and vascular remodeling (e.g., vascular endothelial growth factor and its receptors, αvβ3 integrin, and matrix metalloproteinases) can advance vascular biology research and serve as clinical tools for early diagnosis, risk stratification, and selection of patients who would benefit most from therapeutic interventions. To target these key mediators, a number of molecular imaging techniques have been developed and evaluated in animal models of angiogenesis and vascular remodeling. This review of the state of the art molecular imaging of angiogenesis and vascular (and valvular) remodeling, will focus mostly on nuclear imaging techniques (positron emission tomography and single photon emission tomography) that offer high potential for clinical translation. PMID:27275836

  7. ATP-dependent chromatin remodeling shapes the DNA replication landscape

    PubMed Central

    Vincent, Jack A.; Kwong, Tracey J.; Tsukiyama, Toshio

    2009-01-01

    Summary The eukaryotic DNA replication machinery must traverse every nucleosome in the genome during S phase. As nucleosomes are generally inhibitory to DNA-dependent processes, chromatin structure must undergo extensive reorganization to facilitate DNA synthesis. However, the identity of chromatin-remodeling factors involved in replication and how they affect DNA synthesis is largely unknown. Here we show that two highly conserved ATP-dependent chromatin-remodeling complexes in Saccharomyces cerevisiae, Isw2 and Ino80, function in parallel to promote replication fork progression. As a result, Isw2 and Ino80 play especially important roles for replication of late-replicating regions during periods of replication stress. Both Isw2 and Ino80 complexes are enriched at sites of replication, suggesting that these complexes act directly to promote fork progression. These findings identify ATP-dependent chromatin-remodeling complexes promoting DNA replication, and define a specific stage of replication that requires remodeling for normal function. PMID:18408730

  8. Postinfarct Left Ventricular Remodelling: A Prevailing Cause of Heart Failure

    PubMed Central

    Galli, Alessio; Lombardi, Federico

    2016-01-01

    Heart failure is a chronic disease with high morbidity and mortality, which represents a growing challenge in medicine. A major risk factor for heart failure with reduced ejection fraction is a history of myocardial infarction. The expansion of a large infarct scar and subsequent regional ventricular dilatation can cause postinfarct remodelling, leading to significant enlargement of the left ventricular chamber. It has a negative prognostic value, because it precedes the clinical manifestations of heart failure. The characteristics of the infarcted myocardium predicting postinfarct remodelling can be studied with cardiac magnetic resonance and experimental imaging modalities such as diffusion tensor imaging can identify the changes in the architecture of myocardial fibers. This review discusses all the aspects related to postinfarct left ventricular remodelling: definition, pathogenesis, diagnosis, consequences, and available therapies, together with experimental interventions that show promising results against postinfarct remodelling and heart failure. PMID:26989555

  9. Aliskiren and valsartan mediate left ventricular remodeling post-myocardial infarction in mice through MMP-9 effects.

    PubMed

    Ramirez, Trevi A; Iyer, Rugmani Padmanabhan; Ghasemi, Omid; Lopez, Elizabeth F; Levin, Daniel B; Zhang, Jianhua; Zamilpa, Rogelio; Chou, Youn-Min; Jin, Yu-Fang; Lindsey, Merry L

    2014-07-01

    We evaluated whether aliskiren, valsartan, or a combination of both was protective following myocardial infarction (MI) through effects on matrix metalloproteinase (MMP)-9. C57BL/6J wild type (WT, n=94) and MMP-9 null (null, n=85) mice were divided into 4 groups at 3h post-MI: saline (S), aliskiren (A; 50mg/kg/day), valsartan (V; 40mg/kg/day), or A+V and compared to no MI controls at 28days post-MI. All groups had similar infarct areas, and survival rates were higher in the null mice. The treatments influenced systolic function and hypertrophy index, as well as extracellular matrix (ECM) and inflammatory genes in the remote region, indicating that primary effects were on the viable myocardium. Saline treated WT mice showed increased end systolic and diastolic volumes and hypertrophy index, along with reduced ejection fraction. MMP-9 deletion improved LV function post-MI. Aliskiren attenuated the increase in end systolic volume and hypertrophy index, while valsartan improved end diastolic volumes and aliskiren+valsartan improved the hypertrophy index only when MMP-9 was absent. Extracellular matrix and inflammatory gene expression showed distinct patterns among the treatment groups, indicating a divergence in mechanisms of remodeling. This study shows that MMP-9 regulates aliskiren and valsartan effects in mice. These results in mice provide mechanistic insight to help translate these findings to post-MI patients.

  10. Tissue remodeling investigation in varicose veins

    PubMed Central

    Ghaderian, Sayyed Mohammad Hossein; Khodaii, Zohreh

    2012-01-01

    Although the etiology of varicose veins remains unknown, recent studies have focused on endothelial cell integrity and function because the endothelium regulates vessel tone and synthesizes many pro- and anti-inflammatory factors. The aim of this study was to investigate the evidence involving the endothelium in the development of varicose vein disease. In addition, tissue remodeling was investigated in varicose veins to determine the expression of different types of collagen. Tissue specimens of superficial varicose veins and control saphenous vein were used for immunohistochemical and transmission electron microscope (TEM). α-smooth muscle actin, and collagen I, III, IV antibodies were applied for immunohistochemical investigation. Findings of this study showed alterations of the intima, such as focal intimal discontinuity and denudation of endothelium; and the media, such as irregular arrangements of smooth muscle cells and collagen fibres in varicose veins. Our findings showed some changes in terms of distribution of types I, III and IV collagen in the intima and media of varicose vein walls compared with controls. These alterations to the media suggest that the pathological abnormality in varicose veins may be due to the loss of muscle tone as a result of the breakup of its regular structure by the collagen fibres. These findings only described some changes in terms of distribution of these types of collagen in the intima and media of varicose vein walls which may result in venous wall dysfunction in varicosis. PMID:24551759

  11. Shape Remodeling Assemblies in Biologically Inspired Materials

    NASA Astrophysics Data System (ADS)

    Safinya, Cyrus

    2013-03-01

    Much of our research is inspired by, and directed at, understanding the formation of novel structures (both relatively static and highly dynamic) with distinct shapes and morphologies observed in charged biological systems. The structures, in turn, often correlate to specific functions. For example, charged nanoscale tubules and rods and their assemblies are of interest in a range of applications, including as templates for hierarchical nanostructures, encapsulation systems, and biosensors. A series of studies will be described on charged biological assemblies exhibiting ``molecularly-triggered'' dynamical shape changes. In particular, we will focus on protein and lipid based nanotubule formation through small molecule stimuli-induced shape remodeling events. The systems include invertible protein nanotubes from two-state tubulin-protein building blocks and lipid nanotubes and nanorods from curvature stabilizing lipids (mimicking membrane curvature generating proteins). Funded by DOE-BES grant number DOE-DE-FG02-06ER46314 (protein and lipid assembly, lipid synthesis, structure-function) and NSF-DMR-1101900 (phase behavior).

  12. Chromatin modifications remodel cardiac gene expression.

    PubMed

    Mathiyalagan, Prabhu; Keating, Samuel T; Du, Xiao-Jun; El-Osta, Assam

    2014-07-01

    Signalling and transcriptional control involve precise programmes of gene activation and suppression necessary for cardiovascular physiology. Deep sequencing of DNA-bound transcription factors reveals a remarkable complexity of co-activators or co-repressors that serve to alter chromatin modification and regulate gene expression. The regulated complexes characterized by genome-wide mapping implicate the recruitment and exchange of proteins with specific enzymatic activities that include roles for histone acetylation and methylation in key developmental programmes of the heart. As for transcriptional changes in response to pathological stress, co-regulatory complexes are also differentially utilized to regulate genes in cardiac disease. Members of the histone deacetylase (HDAC) family catalyse the removal of acetyl groups from proteins whose pharmacological inhibition has profound effects preventing heart failure. HDACs interact with a complex co-regulatory network of transcription factors, chromatin-remodelling complexes, and specific histone modifiers to regulate gene expression in the heart. For example, the histone methyltransferase (HMT), enhancer of zeste homolog 2 (Ezh2), is regulated by HDAC inhibition and associated with pathological cardiac hypertrophy. The challenge now is to target the activity of enzymes involved in protein modification to prevent or reverse the expression of genes implicated with cardiac hypertrophy. In this review, we discuss the role of HDACs and HMTs with a focus on chromatin modification and gene function as well as the clinical treatment of heart failure. PMID:24812277

  13. Speckle-tracking and tissue-Doppler stress echocardiography in arterial hypertension: a sensitive tool for detection of subclinical LV impairment.

    PubMed

    Hensel, Kai O; Jenke, Andreas; Leischik, Roman

    2014-01-01

    Early diagnosis of cardiac alterations in hypertensive heart disease is still challenging. Since such patients might have depressed global LV systolic strain or strain rate when EF is still normal, speckle-tracking echocardiography (STE) and tissue-Doppler imaging (TDI) combined with stress echocardiography might improve early diagnosis of cardiac alterations. In this prospective study standard 2D Doppler echocardiography, STE, and TDI were performed at rest and during bicycle exercise in 92 consecutive patients--46 hypertensive subjects with normal ejection fraction and 46 healthy controls. STE and TDI were used to measure global peak systolic LV circumferential strain (CS), longitudinal strain (LS), and longitudinal strain rate (SR). Mean arterial blood pressure was significantly higher in hypertensive patients at rest (100.8 mmHg SD 13.5 mmHg; P=0.002) and during physical exercise testing (124.2 mmHg SD 13.4 mmHg; P=0.003). Hypertensive patients had significantly reduced values of systolic CS (P=0.001), LS (P=0.014), and SR (P<0.001) at rest as well as during physical exercise-CS (P<0.001), LS (P<0.001), and SR (P<0.001). Using STE and TDI, reduced LV systolic strain and strain rate consistent with early cardiac alterations can be detected in patients with arterial hypertension. These findings were evident at rest and markedly pronounced during exercise echocardiography. PMID:25389528

  14. TOWARDS A NEW SPATIAL REPRESENTATION OF BONE REMODELING

    PubMed Central

    Graham, Jason M.; Ayati, Bruce P.; Ramakrishnan, Prem S.; Martin, James A.

    2013-01-01

    Irregular bone remodeling is associated with a number of bone diseases such as osteoporosis and multiple myeloma. Computational and mathematical modeling can aid in therapy and treatment as well as understanding fundamental biology. Different approaches to modeling give insight into different aspects of a phenomena so it is useful to have an arsenal of various computational and mathematical models. Here we develop a mathematical representation of bone remodeling that can effectively describe many aspects of the complicated geometries and spatial behavior observed. There is a sharp interface between bone and marrow regions. Also the surface of bone moves in and out, i.e. in the normal direction, due to remodeling. Based on these observations we employ the use of a level-set function to represent the spatial behavior of remodeling. We elaborate on a temporal model for osteoclast and osteoblast population dynamics to determine the change in bone mass which influences how the interface between bone and marrow changes. We exhibit simulations based on our computational model that show the motion of the interface between bone and marrow as a consequence of bone remodeling. The simulations show that it is possible to capture spatial behavior of bone remodeling in complicated geometries as they occur in vitro and in vivo. By employing the level set approach it is possible to develop computational and mathematical representations of the spatial behavior of bone remodeling. By including in this formalism further details, such as more complex cytokine interactions and accurate parameter values, it is possible to obtain simulations of phenomena related to bone remodeling with spatial behavior much as in vitro and in vivo. This makes it possible to perform in silica experiments more closely resembling experimental observations. PMID:22901065

  15. Exercise hypertension: an adverse prognosis?

    PubMed

    Smith, Ryan G; Rubin, Stanley A; Ellestad, Myrvin H

    2009-01-01

    We sought to clarify the prognostic importance of an "exaggerated" or "hypertensive" systolic blood pressure response to exercise during an exercise test. Studies evaluating the prognosis for cardiovascular events and cardiovascular mortality in those with hypertension during exercise testing were systematically reviewed. Fourteen studies were identified. Six studies were of healthy volunteers or hypertensives. Eight studies were in subjects with known or suspected heart disease. Without established heart disease, exercise hypertension predicted cardiovascular events and cardiovascular death. However, two of the six studies included a multivariate analysis; both demonstrated no independent association. Studies in subjects with known or suspected heart disease demonstrated that exercise hypertension predicted fewer cardiac events and lesser mortality or, after multivariate adjustment, no associated risk. In a healthy population, a higher exercise blood pressure may indicate hypertension or prehypertension, instead of normal vascular function, and an associated long-term adverse prognosis. In a population with a high burden of heart disease, the highest risk subjects with the most extensive cardiac disease may not be capable of generating pressure or workload to allow the manifestation of exercise systolic hypertension. By comparison, therefore, those with exercise hypertension have a better prognosis. PMID:20409979

  16. Adverse effects of antihypertensive drugs.

    PubMed

    Husserl, F E; Messerli, F H

    1981-09-01

    Early essential hypertension is asymptomatic and should remain so throughout treatment. In view of the increasing number of available antihypertensive agents, clinicians need to become familiar with the potential side effects of these drugs. By placing more emphasis on non-pharmacological treatment (sodium restriction, weight loss, exercise) and thoroughly evaluating each case in particular, the pharmacological regimen can be optimally tailored to the patient's needs. Potential side effects should be predicted and can often be avoided; if they become clinically significant they should be rapidly recognised and corrected. These side effects can be easily remembered in most instances, as they fall into 3 broad categories: (a) those caused by an exaggerated therapeutic effect; (b) those due to a non-therapeutic pharmacological effect; and (c) those caused by a non-therapeutic, non-pharmacological effect probably representing idiosyncratic reactions. This review focuses mainly on adverse effects of the second and third kind. Each group of drugs in general shares the common side effects of the first two categories, while each individual drug has its own idiosyncratic side effects.

  17. Novel concepts in airway inflammation and remodelling in asthma.

    PubMed

    Saglani, Sejal; Lloyd, Clare M

    2015-12-01

    The hallmark pathological features of asthma include airway eosinophilic inflammation and structural changes (remodelling) which are associated with an irreversible loss in lung function that tracks from childhood to adulthood. In parallel with changes in function, pathological abnormalities occur early, during the pre-school years, are established by school age and subsequently remain (even though symptoms may remit for periods during adulthood). Given the equal importance of inflammation and remodelling in asthma pathogenesis, there is a significant disparity in studies undertaken to investigate the contribution of each. The majority focus on the role of inflammation, and although novel therapeutics such as those targeted against T-helper cell type 2 (Th2) mediators have arisen, it is apparent that targeting inflammation alone has not allowed disease modification. Therefore, unless airway remodelling is addressed for future therapeutic strategies, it is unlikely that we will progress towards a cure for asthma. Having acknowledged these limitations, the focus of this review is to highlight the gaps in our current knowledge about the mechanisms underlying airway remodelling, the relationships between remodelling, inflammation and function, remodelling and clinical phenotypes, and the importance of utilising innovative and realistic pre-clinical models to uncover effective, disease-modifying therapeutic strategies. PMID:26541520

  18. Clinical Implications and Pathogenesis of Esophageal Remodeling in Eosinophilic Esophagitis

    PubMed Central

    Hirano, Ikuo; Aceves, Seema S.

    2014-01-01

    In eosinophilic esophagitis (EoE), remodeling changes are manifest histologically in both the epithelium as well as in the subepithelium where lamina propria (LP) fibrosis, expansion of the muscularis propria and increased vascularity occur. The major clinical symptoms and complications of EoE are largely consequences of esophageal remodeling. Important mediators of the process include IL-5, IL-13, TGFβ1, mast cells, fibroblasts and eosinophils. Methods to detect remodeling effects include upper endoscopy, histopathology, barium esophagram, endoscopic ultrasonography, esophageal manometry, and functional luminal imaging. These modalities provide evidence of organ dysfunction that include focal and diffuse esophageal strictures, expansion of the mucosa and subepithelium, esophageal motor abnormalities and reduced esophageal distensibility. Complications of food impaction and perforations of the esophageal wall have been associated with reduction in esophageal caliber and increased esophageal mural stiffness. The therapeutic benefits of topical corticosteroids and elimination diet therapy in resolving mucosal eosinophilic inflammation of the esophagus are evident. Available therapies, however, have demonstrated variable ability to reverse existing remodeling changes of the esophagus. Systemic therapies that include novel, targeted biologic agents have the potential of addressing subepithelial remodeling. Esophageal dilation remains a useful, adjunctive therapeutic maneuver in symptomatic adults with esophageal stricture. As novel treatments emerge, it is essential that therapeutic endpoints account for the fundamental contributions of esophageal remodeling to overall disease activity. PMID:24813517

  19. RELATION OF LEFT VENTRICULAR MASS AND CONCENTRIC REMODELING TO EXTENT OF CORONARY ARTERY DISEASE BY COMPUTED TOMOGRAPHY IN PATIENTS WITHOUT LEFT VENTRICULAR HYPERTROPHY: ROMICAT STUDY

    PubMed Central

    Truong, Quynh A.; Toepker, Michael; Mahabadi, Amir A.; Bamberg, Fabian; Rogers, Ian S.; Blankstein, Ron; Brady, Thomas J.; Nagurney, John T.; Hoffmann, Udo

    2010-01-01

    Objective Cardiac computed tomography (CT) allows for simultaneous assessment of left ventricular mass (LVM) and coronary artery disease (CAD). We aimed to determine whether LVM, LVM index (LVMi), and the left ventricular (LV) geometric pattern of concentric remodeling are associated with the extent of CAD in patients without left ventricular hypertrophy (LVH). Methods In 348 patients from the ROMICAT trial, 64-slice CT was performed and LVM measured at end-diastole. We used 3 LVM indexation criteria to obtain 3 cohorts: LVM indexed to body surface area by echocardiography (n=337) and CT criteria (n=325), and by height2.7 (n=326). The cohorts were subdivided into concentric remodeling and normal geometry. Extent of coronary plaque was classified based on a 17-segment model, treated as a continuous variable, and stratified into 3 groups: 0 segments, 1–4 segments, >4 segments. Results Patients with >4 segments of coronary plaque had higher LVM (Δ12.8–15.1g) and LVMi (Δ4.0–5.5g/m2 and Δ2.2g/m2.7) than those without CAD (all p≤0.03). After multivariable adjustment, LVM and LVMi remained independent predictors of extent of coronary plaque, with 0.27–0.29 segments more plaque per 20 g increase of LVM (all p=0.02), 0.32–0.34 segments more plaque per 10 g/m2 increase of LVMi (both p=0.02), and 0.80 segments more plaque per 10 g/m2.7 increase of LVMi (p=0.008). Concentric remodeling patients had 1.1–1.3 segments more plaque than those with normal geometry (all p≤0.05). Patients with >4 segments of plaque had 2-fold increase odds (all p≤0.05) of having concentric remodeling as compared to those without CAD. Conclusion Increased LVM, LVMi, and concentric remodeling are associated with a greater degree of coronary plaque burden in patients without LVH. These findings could provide an indication to intensify medical therapy in patients with subclinical CAD and hypertension. PMID:19696685

  20. Adverse effects of general anaesthetics.

    PubMed

    Berthoud, M C; Reilly, C S

    1992-01-01

    This review deals with the adverse reactions associated with general anaesthetic agents in current use. These reactions fall into 2 categories; those which are more common, predictable and often closely related, and those which are rare, unpredictable and carry a high mortality. Both inhalational and intravenous anaesthetic agents affect the central nervous and cardio-respiratory systems in a dose-related manner. Neuronal inhibition results in decreasing levels of consciousness and depression of the medullary vital centres which can lead to cardiorespiratory failure. Both groups of agents have some depressant effect on the myocardium and vascular smooth muscle leading to a fall in cardiac output and hypotension. Centrally-mediated respiratory depression is common to both groups and the inhalational agents have a direct effect on lung physiology. The most important idiosyncratic reactions to the volatile agents are malignant hyperpyrexia and 'halothane hepatitis'. Malignant hyperpyrexia has an incidence of 1:12,000 with a mortality of about 24%. It is triggered most often by halothane together with suxamethonium. Post halothane hepatic necrosis is rare. Evidence points to 2 distinct syndromes; direct toxicity from the products of reductive metabolism, and a more serious illness, immunologically mediated via haptens formed by liver proteins and the products of oxidative metabolism. Prolonged nitrous oxide exposure can cause bone marrow depression and life-threatening pressure effects by expansion of air-filled spaces within the body. The idiosyncratic reactions to the intravenous agents include anaphylactoid reactions (which are rare) and triggering of acute porphyria. Etomidate is immunologically 'clean', but it inhibits cortisol synthesis. PMID:1418699

  1. Early adversity, neural development, and inflammation.

    PubMed

    Chiang, Jessica J; Taylor, Shelley E; Bower, Julienne E

    2015-12-01

    Early adversity is a risk factor for poor mental and physical health. Although altered neural development is believed to be one pathway linking early adversity to psychopathology, it has rarely been considered a pathway linking early adversity to poor physical health. However, this is a viable pathway because the central nervous system is known to interact with the immune system via the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). In support of this pathway, early adversity has been linked to changes in neural development (particularly of the amygdala, hippocampus, and prefrontal cortex), HPA axis and ANS dysregulation, and higher levels of inflammation. Inflammation, in turn, can be detrimental to physical health when prolonged. In this review, we present these studies and consider how altered neural development may be a pathway by which early adversity increases inflammation and thus risk for adverse physical health outcomes.

  2. [Cutaneous adverse effects of TNFalpha antagonists].

    PubMed

    Failla, V; Sabatiello, M; Lebas, E; de Schaetzen, V; Dezfoulian, B; Nikkels, A F

    2012-01-01

    The TNFalpha antagonists, including adalimumab, etanercept and infliximab, represent a class of anti-inflammatory and immunosuppressive drugs. Although cutaneous adverse effects are uncommon, they are varied. There is no particular risk profile to develop cutaneous adverse effects. The principal acute side effects are injection site reactions and pruritus. The major long term cutaneous side effects are infectious and inflammatory conditions. Neoplastic skin diseases are exceptional. The association with other immunosuppressive agents can increase the risk of developing cutaneous adverse effects. Some adverse effects, such as lupus erythematosus, require immediate withdrawal of the biological treatment, while in other cases temporary withdrawal is sufficient. The majority of the other cutaneous adverse effects can be dealt without interrupting biologic treatment. Preclinical and clinical investigations revealed that the new biologics, aiming IL12/23, IL23 and IL17, present a similar profile of cutaneous adverse effects, although inflammatory skin reactions may be less often encountered compared to TNFalpha antagonists.

  3. Adaptive scapula bone remodeling computational simulation: Relevance to regenerative medicine

    SciTech Connect

    Sharma, Gulshan B.; Robertson, Douglas D.

    2013-07-01

    Shoulder arthroplasty success has been attributed to many factors including, bone quality, soft tissue balancing, surgeon experience, and implant design. Improved long-term success is primarily limited by glenoid implant loosening. Prosthesis design examines materials and shape and determines whether the design should withstand a lifetime of use. Finite element (FE) analyses have been extensively used to study stresses and strains produced in implants and bone. However, these static analyses only measure a moment in time and not the adaptive response to the altered environment produced by the therapeutic intervention. Computational analyses that integrate remodeling rules predict how bone will respond over time. Recent work has shown that subject-specific two- and three dimensional adaptive bone remodeling models are feasible and valid. Feasibility and validation were achieved computationally, simulating bone remodeling using an intact human scapula, initially resetting the scapular bone material properties to be uniform, numerically simulating sequential loading, and comparing the bone remodeling simulation results to the actual scapula’s material properties. Three-dimensional scapula FE bone model was created using volumetric computed tomography images. Muscle and joint load and boundary conditions were applied based on values reported in the literature. Internal bone remodeling was based on element strain-energy density. Initially, all bone elements were assigned a homogeneous density. All loads were applied for 10 iterations. After every iteration, each bone element’s remodeling stimulus was compared to its corresponding reference stimulus and its material properties modified. The simulation achieved convergence. At the end of the simulation the predicted and actual specimen bone apparent density were plotted and compared. Location of high and low predicted bone density was comparable to the actual specimen. High predicted bone density was greater than

  4. Adaptive scapula bone remodeling computational simulation: Relevance to regenerative medicine

    NASA Astrophysics Data System (ADS)

    Sharma, Gulshan B.; Robertson, Douglas D.

    2013-07-01

    Shoulder arthroplasty success has been attributed to many factors including, bone quality, soft tissue balancing, surgeon experience, and implant design. Improved long-term success is primarily limited by glenoid implant loosening. Prosthesis design examines materials and shape and determines whether the design should withstand a lifetime of use. Finite element (FE) analyses have been extensively used to study stresses and strains produced in implants and bone. However, these static analyses only measure a moment in time and not the adaptive response to the altered environment produced by the therapeutic intervention. Computational analyses that integrate remodeling rules predict how bone will respond over time. Recent work has shown that subject-specific two- and three dimensional adaptive bone remodeling models are feasible and valid. Feasibility and validation were achieved computationally, simulating bone remodeling using an intact human scapula, initially resetting the scapular bone material properties to be uniform, numerically simulating sequential loading, and comparing the bone remodeling simulation results to the actual scapula's material properties. Three-dimensional scapula FE bone model was created using volumetric computed tomography images. Muscle and joint load and boundary conditions were applied based on values reported in the literature. Internal bone remodeling was based on element strain-energy density. Initially, all bone elements were assigned a homogeneous density. All loads were applied for 10 iterations. After every iteration, each bone element's remodeling stimulus was compared to its corresponding reference stimulus and its material properties modified. The simulation achieved convergence. At the end of the simulation the predicted and actual specimen bone apparent density were plotted and compared. Location of high and low predicted bone density was comparable to the actual specimen. High predicted bone density was greater than actual

  5. Obstruction-induced pulmonary vascular remodeling.

    PubMed

    Chow, Ming-Jay; Zou, Yu; He, Huamei; McGowan, Francis X; Zurakowski, David; Zhang, Yanhang

    2011-11-01

    Pulmonary obstruction occurs in many common forms of congenital heart disease. In this study, pulmonary artery (PA) banding is used as a model for pulmonary stenosis. Significant remodeling of the vascular bed occurs as a result of a prolonged narrowing of the PAs, and here we quantify the biophysical and molecular changes proximal and distal to the obstruction. Main and branch PAs are harvested from banded and sham rabbits and their mechanical properties are assessed using a biaxial tensile tester. Measurements defined as initial and stiff slopes are taken, assuming a linear region at the start and end of the J-shaped stress-strain curves, along with a transitional knee point. Collagen, elastin assays, Movat's pentachrome staining, and Doppler protocols are used to quantify biochemical, structural, and physiological differences. The banded main PAs have significantly greater initial slopes while banded branch PAs have lower initial slopes; however, this change in mechanical behavior cannot be explained by the assay results as the elastin content in both main and branch PAs is not significantly different. The stiff slopes of the banded main PAs are higher, which is attributed to the significantly greater amounts of insoluble collagen. Shifting of the knee points reveals a decreased toe region in the main PAs but an opposite trend in the branch PAs. The histology results show a loss of integrity of the media, increase in ground substance, and dispersion of collagen in the banded tissue samples. This indicates other structural changes could have led to the mechanical differences in banded and normal tissue. PMID:22168741

  6. Remodeling of alveolar septa after murine pneumonectomy

    PubMed Central

    Ysasi, Alexandra B.; Wagner, Willi L.; Bennett, Robert D.; Ackermann, Maximilian; Valenzuela, Cristian D.; Belle, Janeil; Tsuda, Akira; Konerding, Moritz A.

    2015-01-01

    In most mammals, removing one lung (pneumonectomy) results in the compensatory growth of the remaining lung. In mice, stereological observations have demonstrated an increase in the number of mature alveoli; however, anatomic evidence of the early phases of alveolar growth has remained elusive. To identify changes in the lung microstructure associated with neoalveolarization, we used tissue histology, electron microscopy, and synchrotron imaging to examine the configuration of the alveolar duct after murine pneumonectomy. Systematic histological examination of the cardiac lobe demonstrated no change in the relative frequency of dihedral angle components (Ends, Bends, and Junctions) (P > 0.05), but a significant decrease in the length of a subset of septal ends (“E”). Septal retraction, observed in 20–30% of the alveolar ducts, was maximal on day 3 after pneumonectomy (P < 0.01) and returned to baseline levels within 3 wk. Consistent with septal retraction, the postpneumonectomy alveolar duct diameter ratio (Dout:Din) was significantly lower 3 days after pneumonectomy compared to all controls except for the detergent-treated lung (P < 0.001). To identify clumped capillaries predicted by septal retraction, vascular casting, analyzed by both scanning electron microscopy and synchrotron imaging, demonstrated matted capillaries that were most prominent 3 days after pneumonectomy. Numerical simulations suggested that septal retraction could reflect increased surface tension within the alveolar duct, resulting in a new equilibrium at a higher total energy and lower surface area. The spatial and temporal association of these microstructural changes with postpneumonectomy lung growth suggests that these changes represent an early phase of alveolar duct remodeling. PMID:26078396

  7. Chronic Juvenile Stress Produces Corticolimbic Dendritic Architectural Remodeling and Modulates Emotional Behavior in Male and Female Rats

    PubMed Central

    Eiland, Lisa; Ramroop, Johnny; Hill, Matthew N.; Manley, Jasmine; McEwen, Bruce S.

    2011-01-01

    Nearly 12% of US children are exposed to intense adverse experiences. Research has demonstrated that these experiences can negatively impact adult health, often resulting in psychopathology. Less attention, however, is given to the impact of childhood adverse experiences on childhood health and wellbeing. Using a rodent model of chronic juvenile stress (restraint 6h daily from postnatal day 20–41), we report that chronic stress has significant immediate morbidities in both males and females during this developmental window. Specifically, we demonstrate that chronic juvenile stress produces depressive-like behavior and significant neuronal remodeling of brain regions likely involved in these behavioral alterations: the hippocampus, prefrontal cortex and amygdala. Chronically stressed males and females exhibit anhedonia, increased locomotion when exposed to novelty, and altered coping strategies when exposed to acute stress. Coincident with these behavioral changes, we report simplification of dendrites in the hippocampus and prefrontal cortex and concurrent hypertrophy of dendrites in the amygdala. Taken together, these results demonstrate that chronically stressed juveniles exhibit aberrant behavioral responses to acute challenges that occur in conjunction with stress-induced remodeling of brain regions intimately involved in regulating emotionality and stress reactivity. Further, the absence of sex differences in our reported stress responses, likely speaks to the decreased sensitivity of immature HPA regulating brain regions to sex hormones. PMID:21658845

  8. Chronic juvenile stress produces corticolimbic dendritic architectural remodeling and modulates emotional behavior in male and female rats.

    PubMed

    Eiland, Lisa; Ramroop, Johnny; Hill, Matthew N; Manley, Jasmine; McEwen, Bruce S

    2012-01-01

    Nearly 12% of US children are exposed to intense adverse experiences. Research has demonstrated that these experiences can negatively impact adult health, often resulting in psychopathology. Less attention, however, is given to the impact of childhood adverse experiences on childhood health and wellbeing. Using a rodent model of chronic juvenile stress (restraint 6 h daily from postnatal day 20 to 41), we report that chronic stress has significant immediate morbidities in both males and females during this developmental window. Specifically, we demonstrate that chronic juvenile stress produces depressive-like behavior and significant neuronal remodeling of brain regions likely involved in these behavioral alterations: the hippocampus, prefrontal cortex and amygdala. Chronically stressed males and females exhibit anhedonia, increased locomotion when exposed to novelty, and altered coping strategies when exposed to acute stress. Coincident with these behavioral changes, we report simplification of dendrites in the hippocampus and prefrontal cortex and concurrent hypertrophy of dendrites in the amygdala. Taken together, these results demonstrate that chronically stressed juveniles exhibit aberrant behavioral responses to acute challenges that occur in conjunction with stress-induced remodeling of brain regions intimately involved in regulating emotionality and stress reactivity. Further, the absence of sex differences in our reported stress responses, likely speaks to the decreased sensitivity of immature HPA regulating brain regions to sex hormones.

  9. Strategic approaches to adverse outcome pathway development

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are conceptual frameworks for organizing biological and toxicological knowledge in a manner that supports extrapolation of data pertaining to the initiation or early progression of toxicity to an apical adverse outcome that occurs at a level of org...

  10. Understanding adverse events: human factors.

    PubMed Central

    Reason, J

    1995-01-01

    (1) Human rather than technical failures now represent the greatest threat to complex and potentially hazardous systems. This includes healthcare systems. (2) Managing the human risks will never be 100% effective. Human fallibility can be moderated, but it cannot be eliminated. (3) Different error types have different underlying mechanisms, occur in different parts of the organisation, and require different methods of risk management. The basic distinctions are between: Slips, lapses, trips, and fumbles (execution failures) and mistakes (planning or problem solving failures). Mistakes are divided into rule based mistakes and knowledge based mistakes. Errors (information-handling problems) and violations (motivational problems) Active versus latent failures. Active failures are committed by those in direct contact with the patient, latent failures arise in organisational and managerial spheres and their adverse effects may take a long time to become evident. (4) Safety significant errors occur at all levels of the system, not just at the sharp end. Decisions made in the upper echelons of the organisation create the conditions in the workplace that subsequently promote individual errors and violations. Latent failures are present long before an accident and are hence prime candidates for principled risk management. (5) Measures that involve sanctions and exhortations (that is, moralistic measures directed to those at the sharp end) have only very limited effectiveness, especially so in the case of highly trained professionals. (6) Human factors problems are a product of a chain of causes in which the individual psychological factors (that is, momentary inattention, forgetting, etc) are the last and least manageable links. Attentional "capture" (preoccupation or distraction) is a necessary condition for the commission of slips and lapses. Yet, its occurrence is almost impossible to predict or control effectively. The same is true of the factors associated with

  11. Understanding adverse events: human factors.

    PubMed

    Reason, J

    1995-06-01

    (1) Human rather than technical failures now represent the greatest threat to complex and potentially hazardous systems. This includes healthcare systems. (2) Managing the human risks will never be 100% effective. Human fallibility can be moderated, but it cannot be eliminated. (3) Different error types have different underlying mechanisms, occur in different parts of the organisation, and require different methods of risk management. The basic distinctions are between: Slips, lapses, trips, and fumbles (execution failures) and mistakes (planning or problem solving failures). Mistakes are divided into rule based mistakes and knowledge based mistakes. Errors (information-handling problems) and violations (motivational problems) Active versus latent failures. Active failures are committed by those in direct contact with the patient, latent failures arise in organisational and managerial spheres and their adverse effects may take a long time to become evident. (4) Safety significant errors occur at all levels of the system, not just at the sharp end. Decisions made in the upper echelons of the organisation create the conditions in the workplace that subsequently promote individual errors and violations. Latent failures are present long before an accident and are hence prime candidates for principled risk management. (5) Measures that involve sanctions and exhortations (that is, moralistic measures directed to those at the sharp end) have only very limited effectiveness, especially so in the case of highly trained professionals. (6) Human factors problems are a product of a chain of causes in which the individual psychological factors (that is, momentary inattention, forgetting, etc) are the last and least manageable links. Attentional "capture" (preoccupation or distraction) is a necessary condition for the commission of slips and lapses. Yet, its occurrence is almost impossible to predict or control effectively. The same is true of the factors associated with

  12. Chromatin remodeling facilitates DNA incision in UV-damaged nucleosomes.

    PubMed

    Lee, Kyungeun; Kim, Deok Ryong; Ahn, Byungchan

    2004-08-31

    The DNA repair machinery must locate and repair DNA damage all over the genome. As nucleosomes inhibit DNA repair in vitro, it has been suggested that chromatin remodeling might be required for efficient repair in vivo. To investigate a possible contribution of nucleosome dynamics and chromatin remodeling to the repair of UV-photoproducts in nucleosomes, we examined the effect of a chromatin remodeling complex on the repair of UV-lesions by Micrococcus luteus UV endonuclease (ML-UV endo) and T4-endonuclease V (T4-endoV) in reconstituted mononucleosomes positioned at one end of a 175-bp long DNA fragment. Repair by ML-UV endo and T4-endoV was inefficient in mononucleosomes compared with naked DNA. However, the human nucleosome remodeling complex, hSWI/SNF, promoted more homogeneous repair by ML-UV endo and T4-endo V in reconstituted nucleosomes. This result suggests that recognition of DNA damage could be facilitated by a fluid state of the chromatin resulting from chromatin remodeling activities. PMID:15359130

  13. Chemistry of bone remodelling preserved in extant and fossil Sirenia.

    PubMed

    Anné, Jennifer; Wogelius, Roy A; Edwards, Nicholas P; van Veelen, Arjen; Ignatyev, Konstantin; Manning, Phillip L

    2016-05-01

    Bone remodelling is a crucial biological process needed to maintain elemental homeostasis. It is important to understand the trace elemental inventories that govern these processes as malfunctions in bone remodelling can have devastating effects on an organism. In this study, we use a combination of X-ray techniques to map, quantify, and characterise the coordination chemistry of trace elements within the highly remodelled bone tissues of extant and extinct Sirenia (manatees and dugongs). The dense bone structure and unique body chemistry of sirenians represent ideal tissues for studying both high remodelling rates as well as unique fossilisation pathways. Here, elemental maps revealed uncorrelated patterning of Ca and Zn within secondary osteons in both extant and fossil sirenians, as well as elevated Sr within the connecting canals of fossil sirenians. Concentrations of these elements are comparable between extant and fossil material indicating geochemical processing of the fossil bone has been minimal. Zn was found to be bound in the same coordination within the apatite structure in both extant and fossil bone. Accurate quantification of trace elements in extant material was only possible when the organic constituents of the bone were included. The comparable distributions, concentrations, and chemical coordination of these physiologically important trace elements indicate the chemistry of bone remodelling has been preserved for 19 million years. This study signifies the powerful potential of merging histological and chemical techniques in the understanding of physiological processes in both extant and extinct vertebrates. PMID:26923825

  14. Role of nucleosome remodeling in neurodevelopmental and intellectual disability disorders.

    PubMed

    López, Alberto J; Wood, Marcelo A

    2015-01-01

    It is becoming increasingly important to understand how epigenetic mechanisms control gene expression during neurodevelopment. Two epigenetic mechanisms that have received considerable attention are DNA methylation and histone acetylation. Human exome sequencing and genome-wide association studies have linked several neurobiological disorders to genes whose products actively regulate DNA methylation and histone acetylation. More recently, a third major epigenetic mechanism, nucleosome remodeling, has been implicated in human developmental and intellectual disability (ID) disorders. Nucleosome remodeling is driven primarily through nucleosome remodeling complexes with specialized ATP-dependent enzymes. These enzymes directly interact with DNA or chromatin structure, as well as histone subunits, to restructure the shape and organization of nucleosome positioning to ultimately regulate gene expression. Of particular interest is the neuron-specific Brg1/hBrm Associated Factor (nBAF) complex. Mutations in nBAF subunit genes have so far been linked to Coffin-Siris syndrome (CSS), Nicolaides-Baraitser syndrome (NBS), schizophrenia, and Autism Spectrum Disorder (ASD). Together, these human developmental and ID disorders are powerful examples of the impact of epigenetic modulation on gene expression. This review focuses on the new and emerging role of nucleosome remodeling in neurodevelopmental and ID disorders and whether nucleosome remodeling affects gene expression required for cognition independently of its role in regulating gene expression required for development. PMID:25954173

  15. Physiological remodelling of the maternal uterine circulation during pregnancy.

    PubMed

    Mandala, Maurizio; Osol, George

    2012-01-01

    Sufficient uteroplacental blood flow is essential for normal pregnancy outcome and is accomplished by the coordinated growth and remodelling of the entire maternal uterine vasculature. The main focus of this MiniReview is to provide information on upstream (pre-placental) maternal uterine vascular remodelling that facilitates gestational increases in uterine blood flow. Consideration of the three-dimensional pattern of remodelling (circumferential enlargement versus axial elongation), changes in vessel biomechanical properties, and underlying mechanisms [shear stress, nitric oxide, vascular endothelial growth factor (VEGF)/placental growth factor (PlGF), the renin-angiotensin system] and pathways (local versus systemic; venoarterial exchange) are provided using the rat as the principal animal model, although findings from other species are incorporated wherever possible to provide a comparative perspective. The process of maternal gestational uterine vascular remodelling involves a number of cellular processes and mechanisms, including trophoblast invasion, hyperplasia and hypertrophy, and changes in extracellular matrix composition. In addition, changes in cellular function, e.g. the secretory and contractile properties of smooth muscle and an up-regulation of endothelial vasodilatory influences may contribute to uteroplacental blood flow increases through changes in tone as well as in structure. Future studies aimed at better understanding the inter-relationship between changes in vessel structure (remodelling) and function (reactivity) would likely generate new mechanistic insights into the fascinating process of maternal gestational uterine vascular adaptation and provide a more physiological perspective of the underlying cellular processes involved in its regulation.

  16. Auditory cortex directs the input-specific remodeling of thalamus.

    PubMed

    Nelson, Sultan L; Kong, Lingzhi; Liu, Xiuping; Yan, Jun

    2015-10-01

    Input-specific remodeling is observed both in the primary auditory cortex (AI) and the ventral division of the medial geniculate body of the thalamus (MGBv) through motivation such as learning. Here, we show the role of AI in the MGBv remodeling induced by the electrical stimulation (ES) of the central division of the inferior colliculus (ICc). For the MGBv neurons with frequency tunings different from those of electrically stimulated ICc neurons, their frequency tunings shifted towards the tunings of the ICc neurons. AI neurons also showed this input-specific remodeling after ES of the ICc (ESICc). Interestingly, the input-specific remodeling of MGBv was eliminated when the AI was inactivated using cortical application of muscimol. For the MGBv neurons tuned to the same frequency as the stimulated ICc neurons, their tunings were kept but their responses were facilitated after the ESICc. In contrast to the input-specific tuning shifts, this facilitation was rarely impacted by the AI inactivation. Thus, we conclude that AI directs the input-specific remodeling of MGBv induced by ESICc. It is suggested that the tuning shift in the MGBv primarily takes place in the AI and is relayed to the MGBv through the corticofugal system while the MGBv mainly highlights the frequency information emphasized in ICc.

  17. Multiple adverse experiences and child cognitive development.

    PubMed

    Guinosso, Stephanie A; Johnson, Sara B; Riley, Anne W

    2016-01-01

    During childhood and adolescence, children's social environments shape their cognitive development. Children exposed to multiple adversities in their social environment are more likely to have poorer cognitive outcomes. These findings have prompted interest among pediatric and public health communities to screen and connect youth to appropriate interventions that ameliorate the detrimental effects of adverse exposures. Such intervention efforts can be improved with a stronger conceptual understanding of the relationship between multiple adverse exposures and child cognitive development. This includes disentangling adverse exposures from other risk factors or underlying mechanisms, specifying mechanisms of action, and determining when adverse exposures are most detrimental. This review summarizes findings from the literature on each of these areas and proposes a conceptual model to guide further research and intervention.

  18. Adverse effects of anabolic steroids in athletes.

    PubMed

    Kibble, M W; Ross, M B

    1987-09-01

    The effects of anabolic steroid use on athletic performance and the adverse effects associated with the use of anabolic steroids are reviewed. Anabolic steroids increase protein synthesis in skeletal muscles and reverse catabolic processes. Because of these properties, some athletes use anabolic steroids in an attempt to improve their athletic performance. However, studies indicate that increases in muscle mass and strength during anabolic steroid administration are observed only in athletes who already are weight-trained and who continue intensive training while maintaining high-protein, high-calorie diets. Adverse effects attributed to anabolic steroid use occur frequently. Serious adverse effects include hepatic and endocrine dysfunction; cardiovascular and behavioral changes also are reported. Some of the adverse effects associated with the use of these agents are irreversible, particularly in women. The use of anabolic steroids to improve athletic performance has become prevalent. However, the reported benefits are tempered by numerous adverse reactions.

  19. Adulthood personality correlates of childhood adversity

    PubMed Central

    Carver, Charles S.; Johnson, Sheri L.; McCullough, Michael E.; Forster, Daniel E.; Joormann, Jutta

    2014-01-01

    Objective: Childhood adversity has been linked to internalizing and externalizing disorders and personality disorders in adulthood. This study extends that research by examining several personality measures as correlates of childhood adversity. Method: In a college sample self-reports were collected of childhood adversity, several scales relating to personality, and current depression symptoms as a control variable. The personality-related scales were reduced to four latent variables, which we termed anger/aggression, extrinsic focus, agreeableness, and engagement. Results: Controlling for concurrent depressive symptoms and gender, higher levels of reported childhood adversity related to lower agreeableness and to higher anger/aggression and extrinsic focus. Conclusions: Findings suggest that early adversity is linked to personality variables relevant to the building of social connection. PMID:25484874

  20. Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context

    PubMed Central

    Ajijola, Olujimi A.; Yagishita, Daigo; Patel, Krishan J.; Vaseghi, Marmar; Zhou, Wei; Yamakawa, Kentaro; So, Eileen; Lux, Robert L.; Mahajan, Aman

    2013-01-01

    Myocardial infarction (MI) induces neural and electrical remodeling at scar border zones. The impact of focal MI on global functional neural remodeling is not well understood. Sympathetic stimulation was performed in swine with anteroapical infarcts (MI; n = 9) and control swine (n = 9). A 56-electrode sock was placed over both ventricles to record electrograms at baseline and during left, right, and bilateral stellate ganglion stimulation. Activation recovery intervals (ARIs) were measured from electrograms. Global and regional ARI shortening, dispersion of repolarization, and activation propagation were assessed before and during sympathetic stimulation. At baseline, mean ARI was shorter in MI hearts than control hearts (365 ± 8 vs. 436 ± 9 ms, P < 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 ± 123 vs. 362 ± 32 ms2, P = 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 ± 14 vs. 365 ± 8 ms, P = 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation (P = 0.0001), whereas left stellate ganglion stimulation showed the reverse (P = 0.0003). In infarcted animals, this pattern was completely lost. In 50% of the animals studied, sympathetic stimulation, compared with baseline, significantly altered the direction of activation propagation emanating from the intramyocardial scar during pacing. In conclusion, focal distal anterior MI alters regional and global pattern of sympathetic innervation, resulting in shorter ARIs in infarcted hearts, greater repolarization dispersion, and altered activation propagation. These conditions may underlie the mechanisms by which arrhythmias are initiated when sympathetic tone is enhanced. PMID:23893167

  1. Managing adverse effects of glaucoma medications

    PubMed Central

    Inoue, Kenji

    2014-01-01

    Glaucoma is a chronic, progressive disease in which retinal ganglion cells disappear and subsequent, gradual reductions in the visual field ensues. Glaucoma eye drops have hypotensive effects and like all other medications are associated with adverse effects. Adverse reactions may either result from the main agent or from preservatives used in the drug vehicle. The preservative benzalkonium chloride, is one such compound that causes frequent adverse reactions such as superficial punctate keratitis, corneal erosion, conjunctival allergy, and conjunctival injection. Adverse reactions related to main hypotensive agents have been divided into those affecting the eye and those affecting the entire body. In particular, β-blockers frequently cause systematic adverse reactions, including bradycardia, decrease in blood pressure, irregular pulse and asthma attacks. Prostaglandin analogs have distinctive local adverse reactions, including eyelash bristling/lengthening, eyelid pigmentation, iris pigmentation, and upper eyelid deepening. No systemic adverse reactions have been linked to prostaglandin analog eye drop usage. These adverse reactions may be minimized when they are detected early and prevented by reducing the number of different eye drops used (via fixed combination eye drops), reducing the number of times eye drops are administered, using benzalkonium chloride-free eye drops, using lower concentration eye drops, and providing proper drop instillation training. Additionally, a one-time topical medication can be given to patients to allow observation of any adverse reactions, thereafter the preparation of a topical medication with the fewest known adverse reactions can be prescribed. This does require precise patient monitoring and inquiries about patient symptoms following medication use. PMID:24872675

  2. Finite element prediction of endosteal and periosteal bone remodelling in the turkey ulna: effect of remodelling signal and dead-zone definition.

    PubMed

    Taylor, W R; Warner, M D; Clift, S E

    2003-01-01

    Bone remodelling is the adaptation of bone mass in response to localized changes in loading conditions. The nature of the mechanical signal governing remodelling, however, remains the subject of continued investigation. The aims of this study were to use an iterative finite element (FE) bone remodelling technique to explore the effect of different remodelling signals in the prediction of bone remodelling behaviour. A finite element model of the turkey ulna, following that of Brown et al., was analysed using the ABAQUS package. The model was validated against the static predictions of the Brown et al. study. A bone remodelling technique, based on swelling algorithms given by Taylor and Clift, was then applied to predict the dramatic change in loading conditions imposed. The resulting changes in FE mid-shaft bone geometry were compared with the remodelling observed experimentally and showed good agreement. The tensile principal stress was found to be the best remodelling signal under the imposed conditions. Localized sensitivities in the remodelling patterns were found, however, and the definition of the dead zone was modified as a result. Remodelling with the new dead-zone definition showed that both the tensile principal stress and the tensile principal strain produced the remodelling patterns that agreed most closely with experiment.

  3. Chromatin Remodeling by Imitation Switch (ISWI) Class ATP-dependent Remodelers Is Stimulated by Histone Variant H2A.Z

    PubMed Central

    Goldman, Joseph A.; Garlick, Joseph D.; Kingston, Robert E.

    2010-01-01

    ATP-dependent chromatin remodeling complexes rearrange nucleosomes by altering the position of DNA around the histone octamer. Although chromatin remodelers and the histone variant H2A.Z colocalize on transcriptional control regions, whether H2A.Z directly affects remodeler association or activity is unclear. We determined the relative association of remodelers with H2A.Z chromatin and tested whether replacement of H2A.Z in a nucleosome altered the activity of remodeling enzymes. Many families of remodelers showed increased association with H2A.Z chromatin, but only the ISWI family of chromatin remodelers showed stimulated activity in vitro. An acidic patch on the nucleosome surface, extended by inclusion of H2A.Z in nucleosomes and essential for viability, is required for ISWI stimulation. We conclude that H2A.Z incorporation increases nucleosome remodeling activity of the largest class of mammalian remodelers (ISWI) and that it correlates with increased association of other remodelers to chromatin. This reveals two possible modes for regulation of a remodeler by a histone variant. PMID:19940112

  4. Chemical abundances in the protoplanetary disc LV 2 (Orion): clues to the causes of the abundance anomaly in H II regions

    NASA Astrophysics Data System (ADS)

    Tsamis, Y. G.; Walsh, J. R.; Vílchez, J. M.; Péquignot, D.

    2011-04-01

    Optical integral field spectroscopy of the archetype protoplanetary disc LV 2 in the Orion nebula is presented, taken with the Very Large Telescope (VLT) FLAMES/Argus fibre array. The detection of recombination lines (RLs) of C II and O II from this class of objects is reported, and the lines are utilized as abundance diagnostics. The study is complemented with the analysis of Hubble Space Telescope (HST) Faint Object Spectrograph ultraviolet and optical spectra of the target contained within the Argus field of view. By subtracting the local nebula background the intrinsic spectrum of the proplyd is obtained and its elemental composition is derived for the first time. The proplyd is found to be overabundant in carbon, oxygen and neon compared to the Orion nebula and the Sun. The simultaneous coverage over LV 2 of the C III]λ1908 and [O III]λ5007 collisionally excited lines (CELs) and C II and O II RLs has enabled us to measure the abundances of C2 + and O2 + for LV 2 with both sets of lines. The two methods yield consistent results for the intrinsic proplyd spectrum, but not for the proplyd spectrum contaminated by the generic nebula spectrum, thus providing one example where the long-standing abundance anomaly plaguing metallicity studies of H II regions has been resolved. These results would indicate that the standard forbidden-line methods used in the derivation of light metal abundances in H II regions in our own and other galaxies underestimate the true gas metallicity.

  5. Regulation of the Golgi Complex by Phospholipid Remodeling Enzymes

    PubMed Central

    Ha, Kevin D.; Clarke, Benjamin A.; Brown, William J.

    2012-01-01

    The mammalian Golgi complex is a highly dynamic organelle consisting of stacks of flattened cisternae with associated coated vesicles and membrane tubules that contribute to cargo import and export, intra-cisternal trafficking, and overall Golgi architecture. At the morphological level, all of these structures are continuously remodeled to carry out these trafficking functions. Recent advances have shown that continual phospholipid remodeling by phospholipase A (PLA) and lysophospholipid acyltransferase (LPAT) enzymes, which deacylate and reacylate Golgi phospholipids, respectively, contributes to this morphological remodeling. Here we review the identification and characterization of four cytoplasmic PLA enzymes and one integral membrane LPAT that participate in the dynamic functional organization of the Golgi complex, and how some of these enzymes are integrated to determine the relative abundance of COPI vesicle and membrane tubule formation. PMID:22562055

  6. Remodeling of legacy systems in health care using UML.

    PubMed

    Garde, Sebastian; Knaup, Petra; Herold, Ralf

    2002-01-01

    Research projects in the field of Medical Informatics often involve the development of application systems. Usually they are developed over a longer period of time, so that at a certain point of time a systematically planned reimplementation is necessary. The first step of reimplementation should be a systematic and comprehensive remodeling. When using UML for this task a systematic approach for remodeling activities is missing. Therefore, we developed a method for remodeling of legacy systems (Qumquad) and applied it to DOSPO, a documentation and therapy planning system for pediatric oncology. Qumquad helps to systematically carry out three steps: the modeling of the current actual state of the application system, the systematic identification of weak points and the development of a target concept for reimplementation considering the identified weak points. Results show that this approach is valuable and feasible and could be applied to various application systems in health care.

  7. Remodelling the extracellular matrix in development and disease

    PubMed Central

    Bonnans, Caroline; Chou, Jonathan; Werb, Zena

    2015-01-01

    The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics. PMID:25415508

  8. Computational Study of Growth and Remodeling in the Aortic Arch

    PubMed Central

    Alford, Patrick W.; Taber, Larry A.

    2009-01-01

    Opening angles (OAs) are associated with growth and remodeling in arteries. One curiosity has been the relatively large OAs found in the aortic arch of some animals. Here, we use computational models to explore the reasons behind this phenomenon. The artery is assumed to contain a smooth muscle/collagen phase and an elastin phase. In the models, growth and remodeling of smooth muscle/collagen depends on wall stress and fluid shear stress. Remodeling of elastin, which normally turns over very slowly, is neglected. The results indicate that OAs generally increase with longitudinal curvature (torus model), earlier elastin production during development, and decreased wall stiffness. Correlating these results with available experimental data suggests that all of these effects may contribute to the large OAs in the aortic arch. The models also suggest that the slow turnover rate of elastin limits longitudinal growth. These results should promote increased understanding of the causes of residual stress in arteries. PMID:18792831

  9. Remodeling of legacy systems in health care using UML.

    PubMed

    Garde, Sebastian; Knaup, Petra; Herold, Ralf

    2002-01-01

    Research projects in the field of Medical Informatics often involve the development of application systems. Usually they are developed over a longer period of time, so that at a certain point of time a systematically planned reimplementation is necessary. The first step of reimplementation should be a systematic and comprehensive remodeling. When using UML for this task a systematic approach for remodeling activities is missing. Therefore, we developed a method for remodeling of legacy systems (Qumquad) and applied it to DOSPO, a documentation and therapy planning system for pediatric oncology. Qumquad helps to systematically carry out three steps: the modeling of the current actual state of the application system, the systematic identification of weak points and the development of a target concept for reimplementation considering the identified weak points. Results show that this approach is valuable and feasible and could be applied to various application systems in health care. PMID:15460740

  10. Iron chelation inhibits the development of pulmonary vascular remodeling.

    PubMed

    Wong, Chi-Ming; Preston, Ioana R; Hill, Nicholas S; Suzuki, Yuichiro J

    2012-11-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. Because iron is an important regulator of ROS biology, this study examined the effects of iron chelation on the development of pulmonary vascular remodeling. The administration of an iron chelator, deferoxamine, to rats prevented chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. Various iron chelators inhibited the growth of cultured pulmonary artery smooth muscle cells. Protein carbonylation, an important iron-dependent biological event, was promoted in association with pulmonary vascular remodeling and cell growth. A proteomic approach identified that Rho GDP-dissociation inhibitor (a negative regulator of RhoA) is carbonylated. In human plasma, the protein carbonyl content was significantly higher in patients with idiopathic pulmonary arterial hypertension than in healthy controls. These results suggest that iron plays an important role in the ROS-dependent mechanism underlying the development of pulmonary hypertension.

  11. Iron chelation inhibits the development of pulmonary vascular remodeling

    PubMed Central

    Wong, Chi-Ming; Preston, Ioana R.; Hill, Nicholas S.; Suzuki, Yuichiro J.

    2012-01-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. Since iron is an important regulator of ROS biology, the present study examined the effect of iron chelation on the development of pulmonary vascular remodeling. The administration of an iron chelator, deferoxamine, to rats prevented chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. Various iron chelators inhibited growth of cultured pulmonary artery smooth muscle cells. Protein carbonylation, an important iron-dependent biological event, was promoted in association with pulmonary vascular remodeling and cell growth. A proteomic approach identified that Rho GDP-dissociation inhibitor (a negative regulator of RhoA) is carbonylated. In human plasma, the protein carbonyl content was significantly higher in patients with idiopathic pulmonary arterial hypertension than in healthy controls. These results suggest that iron plays an important role in the ROS-dependent mechanism underlying the development of pulmonary hypertension. PMID:22974762

  12. Dynamic regulation of transcription factors by nucleosome remodeling.

    PubMed

    Li, Ming; Hada, Arjan; Sen, Payel; Olufemi, Lola; Hall, Michael A; Smith, Benjamin Y; Forth, Scott; McKnight, Jeffrey N; Patel, Ashok; Bowman, Gregory D; Bartholomew, Blaine; Wang, Michelle D

    2015-06-05

    The chromatin landscape and promoter architecture are dominated by the interplay of nucleosome and transcription factor (TF) binding to crucial DNA sequence elements. However, it remains unclear whether nucleosomes mobilized by chromatin remodelers can influence TFs that are already present on the DNA template. In this study, we investigated the interplay between nucleosome remodeling, by either yeast ISW1a or SWI/SNF, and a bound TF. We found that a TF serves as a major barrier to ISW1a remodeling, and acts as a boundary for nucleosome repositioning. In contrast, SWI/SNF was able to slide a nucleosome past a TF, with concurrent eviction of the TF from the DNA, and the TF did not significantly impact the nucleosome positioning. Our results provide direct evidence for a novel mechanism for both nucleosome positioning regulation by bound TFs and TF regulation via dynamic repositioning of nucleosomes.

  13. Dynamical DNA accessibility induced by chromatin remodeling and protein binding

    NASA Astrophysics Data System (ADS)

    Montel, F.; Faivre-Moskalenko, C.; Castelnovo, M.

    2014-11-01

    Chromatin remodeling factors are enzymes being able to alter locally chromatin structure at the nucleosomal level and they actively participate in the regulation of gene expression. Using simple rules for individual nucleosome motion induced by a remodeling factor, we designed simulations of the remodeling of oligomeric chromatin, in order to address quantitatively collective effects in DNA accessibility upon nucleosome mobilization. Our results suggest that accessibility profiles are inhomogeneous thanks to borders effects like protein binding. Remarkably, we show that the accessibility lifetime of DNA sequence is roughly doubled in the vicinity of borders as compared to its value in bulk regions far from the borders. These results are quantitatively interpreted as resulting from the confined diffusion of a large nucleosome depleted region.

  14. Passive ventricular remodeling in cardiac disease: focus on heterogeneity

    PubMed Central

    Kessler, Elise L.; Boulaksil, Mohamed; van Rijen, Harold V. M.; Vos, Marc A.; van Veen, Toon A. B.

    2014-01-01

    Passive ventricular remodeling is defined by the process of molecular ventricular adaptation to different forms of cardiac pathophysiology. It includes changes in tissue architecture, such as hypertrophy, fiber disarray, alterations in cell size and fibrosis. Besides that, it also includes molecular remodeling of gap junctions, especially those composed by Connexin43 proteins (Cx43) in the ventricles that affect cell-to-cell propagation of the electrical impulse, and changes in the sodium channels that modify excitability. All those alterations appear mainly in a heterogeneous manner, creating irregular and inhomogeneous electrical and mechanical coupling throughout the heart. This can predispose to reentry arrhythmias and adds to a further deterioration into heart failure. In this review, passive ventricular remodeling is described in Hypertrophic Cardiomyopathy (HCM), Dilated Cardiomyopathy (DCM), Ischemic Cardiomyopathy (ICM), and Arrhythmogenic Cardiomyopathy (ACM), with a main focus on the heterogeneity of those alterations mentioned above. PMID:25566084

  15. Anisotropic stress orients remodelling of mammalian limb bud ectoderm

    PubMed Central

    Lau, Kimberly; Tao, Hirotaka; Liu, Haijiao; Wen, Jun; Sturgeon, Kendra; Sorfazlian, Natalie; Lazic, Savo; Burrows, Jeffrey T. A.; Wong, Michael D.; Li, Danyi; Deimling, Steven; Ciruna, Brian; Scott, Ian; Simmons, Craig; Henkelman, R. Mark; Williams, Trevor; Hadjantonakis, Anna-Katerina; Fernandez-Gonzalez, Rodrigo; Sun, Yu; Hopyan, Sevan

    2016-01-01

    The physical forces that drive morphogenesis are not well characterized in vivo, especially among vertebrates. In the early limb bud, dorsal and ventral ectoderm converge to form the apical ectodermal ridge (AER), although the underlying mechanisms are unclear. By live imaging mouse embryos, we show that prospective AER progenitors intercalate at the dorsoventral boundary and that ectoderm remodels by concomitant cell division and neighbour exchange. Mesodermal expansion and ectodermal tension together generate a dorsoventrally biased stress pattern that orients ectodermal remodelling. Polarized distribution of cortical actin reflects this stress pattern in a β-catenin- and Fgfr2-dependent manner. Intercalation of AER progenitors generates a tensile gradient that reorients resolution of multicellular rosettes on adjacent surfaces, a process facilitated by β-catenin-dependent attachment of cortex to membrane. Therefore, feedback between tissue stress pattern and cell intercalations remodels mammalian ectoderm. PMID:25893915

  16. [Determinants of bone quality and strength independent of bone remodeling].

    PubMed

    Saito, Mitsuru; Marumo, Keishi

    2016-01-01

    Bone mineral density(BMD)and bone microstructure are regulated mainly by bone remodeling. In contrast, bone collagen enzymatic immature and mature cross-links and advanced glycation end products such as pentosidine and carboxyl methyl lysine are affected by various factors. Aging bone tissue is repaired in the process of bone remodeling. However, deterioration of bone material properties markedly advances due to increases in oxidative stress, glycation stress, reactive oxygen species, carbonyl stress associated with aging and reduced sex hormone levels, and glucocorticoid use. To improve bone material properties in osteoporosis, we should use different drug (Saito M, Calcif Tissue Int, REVIEW, 97;242-261, 2015). In this review, we summarized determinants of bone quality and strength independent of bone remodeling. PMID:26728528

  17. [Focus on the effect of orthognathic surgery on condylar remodeling].

    PubMed

    Boulétreau, P; Frey, R; Breton, P; Freidel, M

    2004-11-01

    Condylar remodeling is a physiologic process that aims to adapt the structure of the temporo-mandibular joint (TMJ) to meet the functional demands. It is based on an interaction between the mechanical forces sustained by the TMJ and the adaptative capacities of the condyle. Orthognathic surgery can sometimes be responsible for an excessive physical stress to the articular surfaces. In these cases, normal functional condylar remodelling shifts to the process of progressive condylar resorption. Effect of orthognathic surgery on condylar remodeling is a poorly understood and controversial issue. It is however considered as an etiology of postoperative skeletal relapse following orthognathic surgery. Based on two case reports, etiopathogenic hypotheses of this process are discussed as well as predisposing factors to condylar resorption following orthognathic surgery.

  18. Bone marrow mononuclear cells induce beneficial remodeling and reduce diastolic dysfunction in the left ventricle of hypertensive SS/MCWi rats.

    PubMed

    Parker, Sarah J; Didier, Daniela N; Karcher, Jamie R; Stodola, Timothy J; Endres, Bradley; Greene, Andrew S

    2012-10-01

    Bone marrow mononuclear cells (BMMNCs) increase capillary density and reduce fibrosis in rodents after myocardial infarction, resulting in an overall improvement in left ventricular function. Little is known about the effectiveness of BMMNC therapy in hypertensive heart disease. In the current study, we show that delivery of BMMNCs from hypertension protected SS-13(BN)/MCWi donor rats, but not BMMNC from hypertension susceptible SS/MCWi donor rats, resulted in 57.2 and 83.4% reductions in perivascular and interstitial fibrosis, respectively, as well as a 60% increase in capillary-to-myocyte count in the left ventricles (LV) of hypertensive SS/MCWi recipients. These histological changes were associated with improvements in LV compliance and relaxation (103 and 46.4% improvements, respectively). Furthermore, improved diastolic function in hypertensive SS/MCWi rats receiving SS-13(BN)/MCWi derived BMMNCs was associated with lower clinical indicators of heart failure, including reductions in end diastolic pressure (65%) and serum brain natriuretic peptide levels (49.9%) with no improvements observed in rats receiving SS/MCWi BMMNCs. SS/MCWi rats had a lower percentage of endothelial progenitor cells in their bone marrow relative to SS-13(BN)/MCWi rats. These results suggest that administration of BMMNCs can prevent or reverse pathological remodeling in hypertensive heart disease, which contributes to ameliorating diastolic dysfunction and associated symptomology. Furthermore, the health and hypertension susceptibility of the BMMNC donor are important factors influencing therapeutic efficacy, possibly via differences in the cellular composition of bone marrow.

  19. Parallel mechanisms suppress cochlear bone remodeling to protect hearing.

    PubMed

    Jáuregui, Emmanuel J; Akil, Omar; Acevedo, Claire; Hall-Glenn, Faith; Tsai, Betty S; Bale, Hrishikesh A; Liebenberg, Ellen; Humphrey, Mary Beth; Ritchie, Robert O; Lustig, Lawrence R; Alliston, Tamara

    2016-08-01

    Bone remodeling, a combination of bone resorption and formation, requires precise regulation of cellular and molecular signaling to maintain proper bone quality. Whereas osteoblasts deposit and osteoclasts resorb bone matrix, osteocytes both dynamically resorb and replace perilacunar bone matrix. Osteocytes secrete proteases like matrix metalloproteinase-13 (MMP13) to maintain the material quality of bone matrix through perilacunar remodeling (PLR). Deregulated bone remodeling impairs bone quality and can compromise hearing since the auditory transduction mechanism is within bone. Understanding the mechanisms regulating cochlear bone provides unique ways to assess bone quality independent of other aspects that contribute to bone mechanical behavior. Cochlear bone is singular in its regulation of remodeling by expressing high levels of osteoprotegerin. Since cochlear bone expresses a key PLR enzyme, MMP13, we examined whether cochlear bone relies on, or is protected from, osteocyte-mediated PLR to maintain hearing and bone quality using a mouse model lacking MMP13 (MMP13(-/-)). We investigated the canalicular network, collagen organization, lacunar volume via micro-computed tomography, and dynamic histomorphometry. Despite finding defects in these hallmarks of PLR in MMP13(-/-) long bones, cochlear bone revealed no differences in these markers, nor hearing loss as measured by auditory brainstem response (ABR) or distortion product oto-acoustic emissions (DPOAEs), between wild type and MMP13(-/-) mice. Dynamic histomorphometry revealed abundant PLR by tibial osteocytes, but near absence in cochlear bone. Cochlear suppression of PLR corresponds to repression of several key PLR genes in the cochlea relative to long bones. These data suggest that cochlear bone uniquely maintains bone quality and hearing independent of MMP13-mediated osteocytic PLR. Furthermore, the cochlea employs parallel mechanisms to inhibit remodeling by osteoclasts and osteoblasts, and by

  20. Synaptic activity and connective tissue remodeling in denervated frog muscle

    PubMed Central

    1994-01-01

    Denervation of skeletal muscle results in dramatic remodeling of the cellular and molecular composition of the muscle connective tissue. This remodeling is concentrated in muscle near neuromuscular junctions and involves the accumulation of interstitial cells and several extracellular matrix molecules. Given the role of extracellular matrix in neurite outgrowth and synaptogenesis, we predict that this remodeling of the junctional connective tissue directly influences the regeneration of the neuromuscular junction. As one step toward understanding the role of this denervation-induced remodeling in synapse formation, we have begun to look for the signals that are involved in initiating the junctional accumulations of interstitial cells and matrix molecules. Here, the role of muscle inactivity as a signal was examined. The distributions of interstitial cells, fibronectin, and tenascin were determined in muscles inactivated by presynaptic blockade of muscle activity with tetrodotoxin. We found that blockade of muscle activity for up to 4 wk produced neither the junctional accumulation of interstitial cells nor the junctional concentrations of tenascin and fibronectin normally present in denervated frog muscle. In contrast, the muscle inactivity induced the extrajunctional appearance of two synapse-specific molecules, the acetylcholine receptor and a muscle fiber antigen, mAb 3B6. These results demonstrate that the remodeling of the junctional connective tissue in response to nerve injury is a unique response of muscle to denervation in that it is initiated by a mechanism that is independent of muscle activity. Thus connective tissue remodeling in denervated skeletal muscle may be induced by signals released from or associated with the nerve other than the evoked release of neurotransmitter. PMID:7525607

  1. Collateral Adverse Outcomes After Lumbar Spine Surgery.

    PubMed

    Daniels, Alan H; Gundle, Kenneth; Hart, Robert A

    2016-01-01

    Collateral adverse outcomes are the expected or unavoidable results of a procedure that is performed in a standard manner and typically experienced by the patient. Collateral adverse outcomes do not result from errors, nor are they rare. Collateral adverse outcomes occur as the direct result of a surgical procedure and must be accepted as a trade-off to attain the intended benefits of the surgical procedure. As such, collateral adverse outcomes do not fit into the traditional definition of a complication or adverse event. Examples of collateral adverse outcomes after lumbar spine arthrodesis include lumbar stiffness, postoperative psychological stress, postoperative pain, peri-incisional numbness, paraspinal muscle denervation, and adjacent-level degeneration. Ideally, a comparison of interventions for the treatment of a clinical condition should include information on both the negative consequences (expected and unexpected) and potential benefits of the treatment options. The objective evaluation and reporting of collateral adverse outcomes will provide surgeons with a more complete picture of invasive interventions and, thus, the improved ability to assess alternative treatment options. PMID:27049197

  2. Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling.

    PubMed

    Yang, Kai-Chien; Nerbonne, Jeanne M

    2016-04-01

    In the mammalian heart, multiple types of K(+) channels contribute to the control of cardiac electrical and mechanical functioning through the regulation of resting membrane potentials, action potential waveforms and refractoriness. There are similarly vast arrays of K(+) channel pore-forming and accessory subunits that contribute to the generation of functional myocardial K(+) channel diversity. Maladaptive remodeling of K(+) channels associated with cardiac and systemic diseases results in impaired repolarization and increased propensity for arrhythmias. Here, we review the diverse transcriptional, post-transcriptional, post-translational, and epigenetic mechanisms contributing to regulating the expression, distribution, and remodeling of cardiac K(+) channels under physiological and pathological conditions. PMID:26391345

  3. Efficient computational simulation of actin stress fiber remodeling.

    PubMed

    Ristori, T; Obbink-Huizer, C; Oomens, C W J; Baaijens, F P T; Loerakker, S

    2016-09-01

    Understanding collagen and stress fiber remodeling is essential for the development of engineered tissues with good functionality. These processes are complex, highly interrelated, and occur over different time scales. As a result, excessive computational costs are required to computationally predict the final organization of these fibers in response to dynamic mechanical conditions. In this study, an analytical approximation of a stress fiber remodeling evolution law was derived. A comparison of the developed technique with the direct numerical integration of the evolution law showed relatively small differences in results, and the proposed method is one to two orders of magnitude faster.

  4. Mechanisms of ATP-Dependent Chromatin Remodeling Motors.

    PubMed

    Zhou, Coral Y; Johnson, Stephanie L; Gamarra, Nathan I; Narlikar, Geeta J

    2016-07-01

    Chromatin remodeling motors play essential roles in all DNA-based processes. These motors catalyze diverse outcomes ranging from sliding the smallest units of chromatin, known as nucleosomes, to completely disassembling chromatin. The broad range of actions carried out by these motors on the complex template presented by chromatin raises many stimulating mechanistic questions. Other well-studied nucleic acid motors provide examples of the depth of mechanistic understanding that is achievable from detailed biophysical studies. We use these studies as a guiding framework to discuss the current state of knowledge of chromatin remodeling mechanisms and highlight exciting open questions that would continue to benefit from biophysical analyses. PMID:27391925

  5. Remodeling of Cell-Cell Junctions in Arrhythmogenic Cardiomyopathy

    PubMed Central

    Asimaki, Angeliki; Saffitz, Jeffrey E.

    2015-01-01

    Arrhythmogenic cardiomyopathy (AC) is a primary myocardial disorder characterized by a high incidence of ventricular arrhythmias often preceding the onset of ventricular remodeling and dysfunction. Approximately 50% of patients diagnosed with AC have one or more mutations in genes encoding desmosomal proteins, although non-desmosomal genes have also been associated with the disease. Increasing evidence implicates remodeling of intercalated disk proteins reflecting abnormal responses to mechanical load and aberrant cell signaling pathways in the pathogenesis of AC. This review summarizes recent advances in understanding disease mechanisms in AC that have come from studies of human myocardium and experimental models. PMID:24460198

  6. [Bone quality and strength relating with bone remodeling].

    PubMed

    Mori, Satoshi

    2016-01-01

    The bone has the functions of mineral reservoir and mechanical support as skeleton. Bone remodeling is the adult mode of bone metabolism, replacing old bone tissue to new one. Bone strength is determined by bone volume, structure and quality such as micro damage, degree of mineralization and collagen cross linkage, which are all controlled by bone remodeling. Bone strength decreases under high turn-over condition by decreasing bone volume and deterioration of bone structure, which also decreases under low turn-over condition by increased micro damage, increasing mineralization and AGE collagen cross linkage.

  7. Efficient computational simulation of actin stress fiber remodeling.

    PubMed

    Ristori, T; Obbink-Huizer, C; Oomens, C W J; Baaijens, F P T; Loerakker, S

    2016-09-01

    Understanding collagen and stress fiber remodeling is essential for the development of engineered tissues with good functionality. These processes are complex, highly interrelated, and occur over different time scales. As a result, excessive computational costs are required to computationally predict the final organization of these fibers in response to dynamic mechanical conditions. In this study, an analytical approximation of a stress fiber remodeling evolution law was derived. A comparison of the developed technique with the direct numerical integration of the evolution law showed relatively small differences in results, and the proposed method is one to two orders of magnitude faster. PMID:26823159

  8. Silent Synapse-Based Circuitry Remodeling in Drug Addiction

    PubMed Central

    2016-01-01

    Exposure to cocaine, and likely other drugs of abuse, generates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-silent glutamatergic synapses in the nucleus accumbens. These immature synaptic contacts evolve after drug withdrawal to redefine the neurocircuital properties. These results raise at least three critical questions: (1) what are the molecular and cellular mechanisms that mediate drug-induced generation of silent synapses; (2) how are neurocircuits remodeled upon generation and evolution of drug-generated silent synapses; and (3) what behavioral consequences are produced by silent synapse-based circuitry remodeling? This short review analyzes related experimental results, and extends them to some speculations. PMID:26721952

  9. Childhood adversities and psychosis: evidence, challenges, implications

    PubMed Central

    Morgan, Craig; Gayer‐Anderson, Charlotte

    2016-01-01

    There is a substantial body of research reporting evidence of associations between various forms of childhood adversity and psychosis, across the spectrum from experiences to disorder. This has been extended, more recently, to include studies of cumulative effects, of interactions with other factors, of specific effects, and of putative biological and psychological mechanisms. In this paper we evaluate this research and highlight the remaining methodological issues and gaps that temper, but do not dismiss, conclusions about the causal role of childhood adversity. We also consider the emerging work on cumulative, synergistic, and specific effects and on mechanisms; and discuss the broader implications of this line of research for our understanding of psychosis. We conclude that the current balance of evidence is that childhood adversities – particularly exposure to multiple adversities involving hostility and threat – do, in some people, contribute to the onset of psychotic experiences and psychotic disorders. PMID:27265690

  10. RACIAL RESIDENTIAL SEGREGATION AND ADVERSE BIRTH OUTCOMES

    EPA Science Inventory

    INTRODUCTION. The disparity between black and white women's adverse birth outcomes has been subject to much investigation, yet the factors underlying its persistence remain elusive, which has encouraged research on neighborhood-level influences, including racial residential segr...

  11. Encouraging spontaneous reporting of adverse effects.

    PubMed

    2015-02-01

    One priority when organising surveillance of health products is to remove barriers to reporting adverse effects. One way to encourage reporting is by providing regular feedback, as practised by the German drug bulletin arznei-telegramm, for example. PMID:25802925

  12. Adverse Outcome Pathways: From Definition to Application

    EPA Science Inventory

    A challenge for both human health and ecological toxicologists is the transparent application of mechanistic (e.g., molecular, biochemical, histological) data to risk assessments. The adverse outcome pathway (AOP) is a conceptual framework designed to meet this need. Specifical...

  13. PPAR-pan activation induces hepatic oxidative stress and lipidomic remodelling.

    PubMed

    Ament, Zsuzsanna; West, James A; Stanley, Elizabeth; Ashmore, Tom; Roberts, Lee D; Wright, Jayne; Nicholls, Andrew W; Griffin, Julian L

    2016-06-01

    The peroxisome proliferator-activated receptors (PPARs) are ligand activated nuclear receptors that regulate cellular homoeostasis and metabolism. PPARs control the expression of genes involved in fatty-acid and lipid metabolism. Despite evidence showing beneficial effects of their activation in the treatment of metabolic diseases, particularly dyslipidaemias and type 2 diabetes, PPAR agonists have also been associated with a variety of side effects and adverse pathological changes. Agonists have been developed that simultaneously activate the three PPAR receptors (PPARα, γ and δ) in the hope that the beneficial effects can be harnessed while avoiding some of the negative side effects. In this study, the hepatic effects of a discontinued PPAR-pan agonist (a triple agonist of PPAR-α, -γ, and -δ), was investigated after dietary treatment of male Sprague-Dawley (SD) rats. The agonist induced liver enlargement in conjunction with metabolomic and lipidomic remodelling. Increased concentrations of several metabolites related to processes of oxidation, such as oxo-methionine, methyl-cytosine and adenosyl-methionine indicated increased stress and immune status. These changes are reflected in lipidomic changes, and increased energy demands as determined by free fatty acid (decreased 18:3 n-3, 20:5 n-3 and increased ratios of n-6/n-3 fatty acids) triacylglycerol, phospholipid (decreased and increased bulk changes respectively) and eicosanoid content (increases in PGB2 and 15-deoxy PGJ2). We conclude that the investigated PPAR agonist, GW625019, induces liver enlargement, accompanied by lipidomic remodelling, oxidative stress and increases in several pro-inflammatory eicosanoids. This suggests that such pathways should be monitored in the drug development process and also outline how PPAR agonists induce liver proliferation. PMID:26654758

  14. Metallothioneins 1 and 2 Modulate Inflammation and Support Remodeling in Ischemic Cardiomyopathy in Mice

    PubMed Central

    Dewald, Daniela; Schmitz, Eva J.; Verfuerth, Luise; Keppel, Katharina; Peigney, Christine; Ghanem, Alexander; Welz, Armin; Dewald, Oliver

    2016-01-01

    Aims. Repetitive brief ischemia and reperfusion (I/R) is associated with left ventricular dysfunction during development of ischemic cardiomyopathy. We investigated the role of zinc-donor proteins metallothionein MT1 and MT2 in a closed-chest murine model of I/R. Methods. Daily 15-minute LAD-occlusion was performed for 1, 3, and 7 days in SV129 (WT)- and MT1/2 knockout (MT−/−)-mice (n = 8–10/group). Hearts were examined with M-mode echocardiography and processed for histological and mRNA studies. Results. Expression of MT1/2 mRNA was transiently induced during repetitive I/R in WT-mice, accompanied by a transient inflammation, leading to interstitial fibrosis with left ventricular dysfunction without infarction. In contrast, MT−/−-hearts presented with enhanced apoptosis and small infarctions leading to impaired global and regional pump function. Molecular analysis revealed maladaptation of myosin heavy chain isoforms and antioxidative enzymes in MT1/2−/−-hearts. Despite their postponed chemokine induction we found a higher total neutrophil density and macrophage infiltration in small infarctions in MT−/−-hearts. Subsequently, higher expression of osteopontin 1 and tenascin C was associated with increased myofibroblast density resulting in predominately nonreversible fibrosis and adverse remodeling in MT1/2−/−-hearts. Conclusion. Cardioprotective effects of MT1/2 seem to be exerted via modulation of contractile elements, antioxidative enzymes, inflammatory response, and myocardial remodeling. PMID:27403038

  15. FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism.

    PubMed

    Joki, Yusuke; Ohashi, Koji; Yuasa, Daisuke; Shibata, Rei; Ito, Masanori; Matsuo, Kazuhiro; Kambara, Takahiro; Uemura, Yusuke; Hayakawa, Satoko; Hiramatsu-Ito, Mizuho; Kanemura, Noriyoshi; Ogawa, Hayato; Daida, Hiroyuki; Murohara, Toyoaki; Ouchi, Noriyuki

    2015-03-27

    Ischemic heart disease is one of the leading causes of death. Fibroblast growth factor 21 (FGF21) is a circulating factor with an anti-diabetic property. Skeletal muscle is an important source of FGF21 production. Here, we investigated whether skeletal muscle-derived FGF21 modulates cardiac remodeling in a murine model of myocardial infarction. Myocardial infarction was produced in C57BL/6J wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery (LAD). Adenoviral vectors expressing FGF21 (Ad-FGF21) or control β-galactosidase were intramuscularly injected into mice at 3 days before permanent LAD ligation. Intramuscular injection of Ad-FGF21 increased plasma FGF21 levels in WT mice compared with control. Treatment of WT mice with Ad-FGF21 led to improvement of left ventricular systolic dysfunction and dilatation at 2 weeks after LAD ligation. Ad-FGF21 administration to WT mice also led to enhancement of capillary density in the infarct border zone, and reduction of myocyte apoptosis in the remote zone, which were accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, treatment of WT mice with Ad-FGF21 increased plasma levels of adiponectin, which is a cardioprotective adipokine. The beneficial effects of Ad-FGF21 on cardiac dysfunction and inflammatory response after myocardial infarction were diminished in adiponectin-knockout mice. These data suggest that muscle-derived FGF21 ameliorates adverse cardiac remodeling after myocardial infarction, at least in part, through an adiponectin-dependent mechanism.

  16. Assessment of the LV-C2 Stack Sampling Probe Location for Compliance with ANSI/HPS N13.1-1999

    SciTech Connect

    Glissmeyer, John A.; Antonio, Ernest J.; Flaherty, Julia E.

    2015-09-01

    This document reports on a series of tests conducted to assess the proposed air sampling location for the Hanford Tank Waste Treatment and Immobilization Plant (WTP) Low-Activity Waste (LAW) C2V (LV-C2) exhaust stack with respect to the applicable criteria regarding the placement of an air sampling probe. Federal regulations require that a sampling probe be located in the exhaust stack according to the criteria established by the American National Standards Institute/Health Physics Society (ANSI/HPS) N13.1-1999, Sampling and Monitoring Releases of Airborne Radioactive Substances from the Stack and Ducts of Nuclear Facilities. These criteria address the capability of the sampling probe to extract a sample that represents the effluent stream. The tests were conducted on the LV-C2 scale model system. Based on the scale model tests, the location proposed for the air sampling probe in the scale model stack meets the requirements of the ANSI/HPS N13.1-1999 standard for velocity uniformity, flow angle, gas tracer and particle tracer uniformity. Additional velocity uniformity and flow angle tests on the actual stack will be necessary during cold startup to confirm the validity of the scale model results in representing the actual stack.

  17. School Buildings: Remodeling; Rehabilitation; Modernization; Repair. Bulletin, 1950, No. 17

    ERIC Educational Resources Information Center

    Yiles, Nelson E.

    1950-01-01

    Adequate school plants are essential to a modern educational program. The school plant that is not properly maintained soon fails to provide the service for which it was intended. The total program of maintenance, including repairs, renovation, remodeling, rehabilitation, and modernization should be carefully planned. Some tasks will recur at…

  18. Remodelling the School Workforce in England: A Study in Tyranny

    ERIC Educational Resources Information Center

    Gunter, Helen

    2007-01-01

    Remodelling the school workforce is being rolled out across England with official purposes articulated around work-life balance, improving standards, and the need to efficiently and effectively deploy staffing. This is not new and can be related to ongoing policy thrusts designed to restructure the state as manifest in the haphazard construction…

  19. Regulator of calcineurin 1 mediates pathological vascular wall remodeling

    PubMed Central

    Esteban, Vanesa; Méndez-Barbero, Nerea; Jesús Jiménez-Borreguero, Luis; Roqué, Mercè; Novensá, Laura; Belén García-Redondo, Ana; Salaices, Mercedes; Vila, Luis; Arbonés, María L.

    2011-01-01

    Artery wall remodeling, a major feature of diseases such as hypertension, restenosis, atherosclerosis, and aneurysm, involves changes in the tunica media mass that reduce or increase the vessel lumen. The identification of molecules involved in vessel remodeling could aid the development of improved treatments for these pathologies. Angiotensin II (AngII) is a key effector of aortic wall remodeling that contributes to aneurysm formation and restenosis through incompletely defined signaling pathways. We show that AngII induces vascular smooth muscle cell (VSMC) migration and vessel remodeling in mouse models of restenosis and aneurysm. These effects were prevented by pharmacological inhibition of calcineurin (CN) or lentiviral delivery of CN-inhibitory peptides. Whole-genome analysis revealed >1,500 AngII-regulated genes in VSMCs, with just 11 of them requiring CN activation. Of these, the most sensitive to CN activation was regulator of CN 1 (Rcan1). Rcan1 was strongly activated by AngII in vitro and in vivo and was required for AngII-induced VSMC migration. Remarkably, Rcan1−/− mice were resistant to AngII-induced aneurysm and restenosis. Our results indicate that aneurysm formation and restenosis share mechanistic elements and identify Rcan1 as a potential therapeutic target for prevention of aneurysm and restenosis progression. PMID:21930771

  20. CREB Selectively Controls Learning-Induced Structural Remodeling of Neurons

    ERIC Educational Resources Information Center

    Middei, Silvia; Spalloni, Alida; Longone, Patrizia; Pittenger, Christopher; O'Mara, Shane M.; Marie, Helene; Ammassari-Teule, Martine

    2012-01-01

    The modulation of synaptic strength associated with learning is post-synaptically regulated by changes in density and shape of dendritic spines. The transcription factor CREB (cAMP response element binding protein) is required for memory formation and in vitro dendritic spine rearrangements, but its role in learning-induced remodeling of neurons…

  1. Minor Groove Binder Distamycin Remodels Chromatin but Inhibits Transcription

    PubMed Central

    Majumder, Parijat; Banerjee, Amrita; Shandilya, Jayasha; Senapati, Parijat; Chatterjee, Snehajyoti; Kundu, Tapas K.; Dasgupta, Dipak

    2013-01-01

    The condensed structure of chromatin limits access of cellular machinery towards template DNA. This in turn represses essential processes like transcription, replication, repair and recombination. The repression is alleviated by a variety of energy dependent processes, collectively known as “chromatin remodeling”. In a eukaryotic cell, a fine balance between condensed and de-condensed states of chromatin helps to maintain an optimum level of gene expression. DNA binding small molecules have the potential to perturb such equilibrium. We present herein the study of an oligopeptide antibiotic distamycin, which binds to the minor groove of B-DNA. Chromatin mobility assays and circular dichroism spectroscopy have been employed to study the effect of distamycin on chromatosomes, isolated from the liver of Sprague-Dawley rats. Our results show that distamycin is capable of remodeling both chromatosomes and reconstituted nucleosomes, and the remodeling takes place in an ATP-independent manner. Binding of distamycin to the linker and nucleosomal DNA culminates in eviction of the linker histone and the formation of a population of off-centered nucleosomes. This hints at a possible corkscrew type motion of the DNA with respect to the histone octamer. Our results indicate that distamycin in spite of remodeling chromatin, inhibits transcription from both DNA and chromatin templates. Therefore, the DNA that is made accessible due to remodeling is either structurally incompetent for transcription, or bound distamycin poses a roadblock for the transcription machinery to advance. PMID:23460895

  2. Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

    PubMed Central

    Leopold, Jane A.; Maron, Bradley A.

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype. PMID:27213345

  3. The Remodeling Conjecture and the Faber-Pandharipande Formula

    NASA Astrophysics Data System (ADS)

    Bouchard, Vincent; Catuneanu, Andrei; Marchal, Olivier; Sułkowski, Piotr

    2013-01-01

    In this note, we prove that the free energies F g constructed from the Eynard-Orantin topological recursion applied to the curve mirror to {{C}^3} reproduce the Faber-Pandharipande formula for genus g Gromov-Witten invariants of {{C}^3} . This completes the proof of the remodeling conjecture for {{C}^3}.

  4. Bone remodeling induced by dental implants of functionally graded materials.

    PubMed

    Lin, Daniel; Li, Qing; Li, Wei; Swain, Michael

    2010-02-01

    Functionally graded material (FGM) had been developed as a potential implant material to replace titanium for its improved capability of initial osseointegration. The idea behind FGM dental implant is that its properties can be tailored in accordance with the biomechanical needs at different regions adapting to its hosting bony tissues, therefore creating an improved overall integration and stability in the entire restoration. However, there have been very few reports available so far on predicting bone remodeling induced by FGM dental implants. This article aims to evaluate bone remodeling when replacing the titanium with a hydroxyapatite/collagen (HAP/Col) FGM model. A finite element model was constructed in the buccal-lingual section of a dental implant-bone structure generated from in vivo CT scan images. The remodeling simulation was performed over a 4 year healing period. Comparisons were made between the titanium implant and various FGM implants of this model. The FGM implants showed an improved bone remodeling outcome. The study is expected to provide a basis for future development of FGM implants.

  5. Analgesic Drugs Alter Connective Tissue Remodeling and Mechanical Properties.

    PubMed

    Carroll, Chad C

    2016-01-01

    Exercising individuals commonly consume analgesics, but these medications alter tendon and skeletal muscle connective tissue properties, possibly limiting a person from realizing the full benefits of exercise training. I detail the novel hypothesis that analgesic medications alter connective tissue structure and mechanical properties by modifying fibroblast production of growth factors and matrix enzymes, which are responsible for extracellular matrix remodeling.

  6. Energy Efficiency Measures to Incorporate into Remodeling Projects

    SciTech Connect

    Liaukus, C.

    2014-12-01

    Energy improvements in a home are often approached as one concerted effort, beginning with a simple walk-through assessment or more in-depth energy audit and followed by the installation of recommended energy measures. While this approach allows for systems thinking to guide the efforts, comprehensive energy improvements of this nature are undertaken by a relatively small number of U.S. households compared to piecemeal remodeling efforts. In this report, the U.S Department of Energy Building America Retrofit Alliance research team examines the improvement of a home’s energy performance in an opportunistic way by examining what can be done to incorporate energy efficiency measures into general remodeling work and home repair projects. This allows for energy efficiency upgrades to occur at the same time as remodeling proejcts. There are challenges to this approach, not the least of which being that the work will take place over time in potentially many separate projects. The opportunity to improve a home’s energy efficiency at one time expands or contracts with the scope of the remodel. As such, guidance on how to do each piece thoughtfully and with consideration for potential future projects, is critical.

  7. Energy Efficiency Measures to Incorporate into Remodeling Projects

    SciTech Connect

    Liaukus, C.

    2014-12-01

    Energy improvements in a home are often approached as one concerted effort, beginning with a simple walk-through assessment or more in-depth energy audit and followed by the installation of recommended energy measures. While this approach allows for systems thinking to guide the efforts, comprehensive energy improvements of this nature are undertaken by a relatively small number of the households in our nation compared to more piecemeal remodeling efforts. Even when programs like the Weatherization Assistance Program and Home Performance with ENERGY STAR are considered, homes that have had a comprehensive energy makeover still represent a small fraction of the 111.1 million households. In this report, the U.S Department of Energy Building America Retrofit Alliance research team looks at the improvement of a home's energy performance in an opportunistic way: it examines what can be done to incorporate energy efficiency measures into general remodeling work and home repair projects. This allows for the possibility for people who would not normally pursue energy efficiency but will remodel their kitchen or re-side their home to improve their home's performance at the same time. There are challenges to this approach, not the least of which being that the work will take place over time in potentially many separate projects. The opportunity to improve a home's energy efficiency at one time expands or contracts with the scope of the remodel. As such, guidance on how to do each piece thoughtfully and with consideration for potential future projects, is critical.

  8. 19. 'Southern Pacific Company, Pacific Lines, Remodeling of Piers For ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    19. 'Southern Pacific Company, Pacific Lines, Remodeling of Piers For Renewal of Br. 210-C Near Tehama, Sac. Division, Scale 1' = 40' & 1/4' = 1'-0', Sept. 1927, M.W.D., Drawing 5935, Sheet 2.' - Southern Pacific Railroad Shasta Route, Bridge No. 210.52, Milepost 210.52, Tehama, Tehama County, CA

  9. "New Professionalism," Workforce Remodeling and the Restructuring of Teachers' Work

    ERIC Educational Resources Information Center

    Stevenson, Howard; Carter, Bob; Passy, Rowena

    2007-01-01

    Since its election in 1997 the Labour government's policy has sought to promote a "new professionalism" amongst teachers. First mooted at the time when new performance management arrangements were introduced, the discourse of new professionalism has now become closely associated with the "workforce remodeling" agenda in which teachers' work is…

  10. Pentoxifylline Attenuates Cardiac Remodeling Induced by Tobacco Smoke Exposure

    PubMed Central

    Minicucci, Marcos; Oliveira, Fernando; Santos, Priscila; Polegato, Bertha; Roscani, Meliza; Fernandes, Ana Angelica; Lustosa, Beatriz; Paiva, Sergio; Zornoff, Leonardo; Azevedo, Paula

    2016-01-01

    Background Tobacco smoke exposure is an important risk factor for cardiac remodeling. Under this condition, inflammation, oxidative stress, energy metabolism abnormalities, apoptosis, and hypertrophy are present. Pentoxifylline has anti‑inflammatory, anti-apoptotic, anti-thrombotic and anti-proliferative properties. Objective The present study tested the hypothesis that pentoxifylline would attenuate cardiac remodeling induced by smoking. Methods Wistar rats were distributed in four groups: Control (C), Pentoxifylline (PX), Tobacco Smoke (TS), and PX-TS. After two months, echocardiography, invasive blood pressure measurement, biochemical, and histological studies were performed. The groups were compared by two-way ANOVA with a significance level of 5%. Results TS increased left atrium diameter and area, which was attenuated by PX. In the isolated heart study, TS lowered the positive derivate (+dp/dt), and this was attenuated by PX. The antioxidants enzyme superoxide dismutase and glutathione peroxidase were decreased in the TS group; PX recovered these activities. TS increased lactate dehydrogenase (LDH) and decreased 3-hydroxyacyl Coenzyme A dehydrogenases (OH-DHA) and citrate synthase (CS). PX attenuated LDH, 3-OH-DHA and CS alterations in TS-PX group. TS increased IL-10, ICAM-1, and caspase-3. PX did not influence these variables. Conclusion TS induced cardiac remodeling, associated with increased inflammation, oxidative stress, apoptosis, and changed energy metabolism. PX attenuated cardiac remodeling by reducing oxidative stress and improving cardiac bioenergetics, but did not act upon cardiac cytokines and apoptosis. PMID:27096523

  11. Remodeling of University of Minnesota President's House and Office.

    ERIC Educational Resources Information Center

    Minnesota State Office of the Legislative Auditor, St. Paul. Program Evaluation Div.

    A report on the remodeling projects at the University of Minnesota president's house and office is presented, noting significant shortcomings in the way the projects were managed and in the reporting relationship that existed between the Board of Regents and the university's administration. Recommendations are offered to the university on how…

  12. 17. Photographic copy of original remodeling drawings dated July 8, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    17. Photographic copy of original remodeling drawings dated July 8, 1988 (original sepia in plan room of Base Civil Engineer, Scott AFB) First and second floor plans - Scott Air Force Base, General Officer Quarters, 229 Birchard Street, O'Fallon, St. Clair County, IL

  13. 18. Photographic copy of original remodeling drawings dated July 8, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    18. Photographic copy of original remodeling drawings dated July 8, 1988 (original sepia in plan room of Base Civil Engineer, Scott AFB) First and second floor demolition and framing plan - Scott Air Force Base, General Officer Quarters, 229 Birchard Street, O'Fallon, St. Clair County, IL

  14. Transcriptional coactivator PGC-1alpha promotes peroxisomal remodeling and biogenesis.

    PubMed

    Bagattin, Alessia; Hugendubler, Lynne; Mueller, Elisabetta

    2010-11-23

    Mitochondria and peroxisomes execute some analogous, nonredundant functions including fatty acid oxidation and detoxification of reactive oxygen species, and, in response to select metabolic cues, undergo rapid remodeling and division. Although these organelles share some components of their division machinery, it is not known whether a common regulator coordinates their remodeling and biogenesis. Here we show that in response to thermogenic stimuli, peroxisomes in brown fat tissue (BAT) undergo selective remodeling and expand in number and demonstrate that ectopic expression of the transcriptional coactivator PGC-1α recapitulates these effects on the peroxisomal compartment, both in vitro and in vivo. Conversely, β-adrenergic stimulation of PGC-1α(-/-) cells results in blunted induction of peroxisomal gene expression. Surprisingly, PPARα was not required for the induction of critical biogenesis factors, suggesting that PGC-1α orchestrates peroxisomal remodeling through a PPARα-independent mechanism. Our data suggest that PGC-1α is critical to peroxisomal physiology, establishing a role for this factor as a fundamental orchestrator of cellular adaptation to energy demands.

  15. Effects of Electrical and Structural Remodeling on Atrial Fibrillation Maintenance: A Simulation Study

    PubMed Central

    Krogh-Madsen, Trine; Abbott, Geoffrey W.; Christini, David J.

    2012-01-01

    Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength - electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely. PMID:22383869

  16. Protective role of heme oxygenase-1 in atrial remodeling.

    PubMed

    Yeh, Yung-Hsin; Hsu, Lung-An; Chen, Ying-Hwa; Kuo, Chi-Tai; Chang, Gwo-Jyh; Chen, Wei-Jan

    2016-09-01

    Structural and electrical remodeling in the atrium constitutes the main feature of atrial fibrillation (AF), which is characterized by increased oxidative stress. Heme oxygenase-1 (HO-1) is a potent anti-oxidant system that may provide protection against various oxidative stress-related diseases. The aim of this study is to investigate whether HO-1 has a protective effect on AF-related remodeling. Cultured atrium-derived myocytes (HL-1 cell line) were used to evaluate tachypacing-induced oxidative stress, structural, and electrical remodeling. Transforming growth factor-β (TGF-β) was utilized to assess collagen (a main fibrosis-related protein) expression in atrial fibroblasts. Tachypacing in HL-1 myocytes and treatment of atrial fibroblasts with TGF-β enhanced the expression of HO-1, both of which were mediated by the activation of nuclear factor erythroid-2-related factor 2. Over-expression of HO-1 in HL-1 cells attenuated tachypacing-induced oxidative stress, myofibril degradation, down-regulation of L-type calcium channel, and shortening of action potential duration. Furthermore, HO-1 over-expression in atrial fibroblasts blocked the up-regulation of collagen by TGF-β, implicating a protective role of HO-1 in structural and electrical remodeling in the atrium. In vivo, HO-1(-/-) mice exhibited a higher degree of oxidative stress, myofibril degradation, and collagen deposit in their atria than wild-type mice. Moreover, burst atrial pacing induced a greater susceptibility to AF in HO-1(-/-) mice than in wild-type mice. In conclusion, a negative-feedback regulation of HO-1 in activated atrial myocytes and fibroblasts may provide protection against AF-related remodeling and AF development. PMID:27562817

  17. Toxoplasma gondii, Dirofilaria immitis, feline immunodeficiency virus (FIV), and feline leukemia virus (FeLV) infections in stray and pet cats (Felis catus) in northwest China: co-infections and risk factors.

    PubMed

    Cong, Wei; Meng, Qing-Feng; Blaga, Radu; Villena, Isabelle; Zhu, Xing-Quan; Qian, Ai-Dong

    2016-01-01

    This study was conducted to estimate the prevalence of Toxoplasma gondii, Dirofilaria immitis, feline immunodeficiency virus (FIV), and feline leukemia virus (FeLV) infections among stray and pet cats in Lanzhou, northwest China, and to identify the influence of age, gender, and regions on seropositivity. T. gondii antibodies were examined in cat sera by the modified agglutination test (MAT). The circulating antigens of D. immitis and FeLV and specific antibodies to FIV were examined using kits commercially available. The overall prevalence of T. gondii, FIV, FeLV, and D. immitis was 19.34, 9.12, 11.33, and 3.04 %, respectively. For the genetic characterization of T. gondii genotypes in cats, genomic DNA was extracted from the seropositive cats and the T. gondii B1 gene was amplified using a semi-nested PCR. DNA samples giving positive B1 amplification were then genotyped using multilocus PCR-RFLP. Two T. gondii genotypes (ToxoDB#9 and ToxoDB#1) were identified. Results of the multivariate logistic regression analysis showed that older cats are more likely to be seropositive than juveniles for T. gondii, FIV, FeLV, and D. immitis. This is the first report of T. gondii genotypes in cats in northwest China. Moreover, the present study is the first study of retrovirus and D. immitis seroprevalence in cats in China. The results revealed that T. gondii, FIV, and FeLV infections are common in stray and pet cats in northwest China.

  18. The Complement System and Adverse Pregnancy Outcomes

    PubMed Central

    Regal, Jean F.; Gilbert, Jeffrey S.; Burwick, Richard M.

    2015-01-01

    Adverse pregnancy outcomes significantly contribute to morbidity and mortality for mother and child, with lifelong health consequences for both. The innate and adaptive immune system must be regulated to insure survival of the feta allograft, and the complement system is no exception. An intact complement system optimizes placental development and function and is essential to maintain host defense and fetal survival. Complement regulation is apparent at the placental interface from early pregnancy with some degree of complement activation occurring normally throughout gestation. However, a number of pregnancy complications including early pregnancy loss, fetal growth restriction, hypertensive disorders of pregnancy and preterm birth are associated with excessive or misdirected complement activation, and are more frequent in women with inherited or acquired complement system disorders or complement gene mutations. Clinical studies employing complement biomarkers in plasma and urine implicate dysregulated complement activation in components of each of the adverse pregnancy outcomes. In addition, mechanistic studies in rat and mouse models of adverse pregnancy outcomes address the complement pathways or activation products of importance and allow critical analysis of the pathophysiology. Targeted complement therapeutics are already in use to control adverse pregnancy outcomes in select situations. A clearer understanding of the role of the complement system in both normal pregnancy and complicated or failed pregnancy will allow a rational approach to future therapeutic strategies for manipulating complement with the goal of mitigating adverse pregnancy outcomes, preserving host defense, and improving long term outcomes for both mother and child. PMID:25802092

  19. ADVERSE DRUG REACTIONS IN THE ORAL CAVITY.

    PubMed

    Boras, Vanja Vučićević; Andabak-Rogulj, Ana; Brailo, Vlaho; Šimunković, Sonja Kraljević; Gabrić, Dragana; Vrdoljak, Danko Velimir

    2015-06-01

    Every medication may lead to adverse effects, even when used in standard doses and mode of application. In the oral cavity, adverse effects may affect every part of oral mucosa and are the result of medications taken either locally or systemically. Oral adverse reactions to drugs are not typical and therefore sometimes not easy to recognize. On diagnosing adverse side effects in the oral cavity, experienced clinician will usually diagnose the condition on the basis of detailed medical history and clinical finding. However, the only objective evidence for the offending drug is 're-challenge', i.e. exposure to the drug after its discontinuation. It carries a huge risk of anaphylactic reaction; therefore it has to be performed in a controlled hospital setting. Therapy is based on immediate exclusion of the offending drug and, if lesions are present in the oral cavity, topical or systemic corticosteroid therapy is prescribed. This article gives a review of patients with oral adverse drug reactions referred to the Department of Oral Medicine in Zagreb.

  20. Putative adverse outcome pathways relevant to neurotoxicity

    PubMed Central

    Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

    2016-01-01

    The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

  1. The complement system and adverse pregnancy outcomes.

    PubMed

    Regal, Jean F; Gilbert, Jeffrey S; Burwick, Richard M

    2015-09-01

    Adverse pregnancy outcomes significantly contribute to morbidity and mortality for mother and child, with lifelong health consequences for both. The innate and adaptive immune system must be regulated to insure survival of the fetal allograft, and the complement system is no exception. An intact complement system optimizes placental development and function and is essential to maintain host defense and fetal survival. Complement regulation is apparent at the placental interface from early pregnancy with some degree of complement activation occurring normally throughout gestation. However, a number of pregnancy complications including early pregnancy loss, fetal growth restriction, hypertensive disorders of pregnancy and preterm birth are associated with excessive or misdirected complement activation, and are more frequent in women with inherited or acquired complement system disorders or complement gene mutations. Clinical studies employing complement biomarkers in plasma and urine implicate dysregulated complement activation in components of each of the adverse pregnancy outcomes. In addition, mechanistic studies in rat and mouse models of adverse pregnancy outcomes address the complement pathways or activation products of importance and allow critical analysis of the pathophysiology. Targeted complement therapeutics are already in use to control adverse pregnancy outcomes in select situations. A clearer understanding of the role of the complement system in both normal pregnancy and complicated or failed pregnancy will allow a rational approach to future therapeutic strategies for manipulating complement with the goal of mitigating adverse pregnancy outcomes, preserving host defense, and improving long term outcomes for both mother and child.

  2. Effective chromosome pairing requires chromatin remodeling at the onset of meiosis

    PubMed Central

    Colas, Isabelle; Shaw, Peter; Prieto, Pilar; Wanous, Michael; Spielmeyer, Wolfgang; Mago, Rohit; Moore, Graham

    2008-01-01

    During meiosis, homologous chromosomes (homologues) recognize each other and then intimately associate. Studies exploiting species with large chromosomes reveal that chromatin is remodeled at the onset of meiosis before this intimate association. However, little is known about the effect the remodeling has on pairing. We show here in wheat that chromatin remodeling of homologues can only occur if they are identical or nearly identical. Moreover, a failure to undergo remodeling results in reduced pairing between the homologues. Thus, chromatin remodeling at the onset of meiosis enables the chromosomes to become competent to pair and recombine efficiently. PMID:18417451

  3. Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart

    PubMed Central

    Webb, Ian G.; Nishino, Yasuhiro; Clark, James E.; Murdoch, Colin; Walker, Simon J.; Makowski, Marcus R.; Botnar, Rene M.; Redwood, Simon R.; Shah, Ajay M.; Marber, Michael S.

    2010-01-01

    Aims Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3α and 9 of GSK-3β respectively, required for inactivation by upstream kinases. Methods and results Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts. Conclusion Expression of inactivation-resistant GSK-3α/β does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3α/β, may enable a sustained cardiac response to chronic β-agonist stimulation while preventing pathological remodelling. PMID:20299330

  4. Adverse reaction; patent blue turning patient blue.

    PubMed

    Joshi, Meera; Hart, Matthew; Ahmed, Farid; McPherson, Sandy

    2012-11-30

    The authors report a severe anaphylactic reaction to Patent Blue V dye used in sentinel node biopsy for lymphatic mapping during breast cancer surgery to stage the axilla. Patent Blue dye is the most widely used in the UK; however, adverse reactions have been reported with the blue dye previously. This case highlights that reactions may not always be immediately evident and to be vigilant in all patients that have undergone procedures using blue dye. If the patients are not responding appropriately particularly during an anaesthetic, one must always think of a possible adverse reaction to the dye. All surgical patients should give consent for adverse reactions to patent blue dye preoperatively. Alternative agents such as methylene blue are considered.

  5. The multisystem adverse effects of NSAID therapy.

    PubMed

    James, D S

    1999-11-01

    The clinical utility of nonsteroidal anti-inflammatory drugs (NSAIDs) to manage pain and inflammation is limited by adverse side effects. Although effective analgesic and anti-inflammatory agents, NSAIDs are associated with side effects that are a consequence of nonspecific inhibition of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The primary adverse events associated with NSAID therapy are upper gastrointestinal (GI) ulceration, perforation, or bleeding, all of which involve mucosal damage of varying severity and can be asymptomatic and occur with little warning. Clinicians who prescribe NSAIDs should be able to identify patients who are at risk of an NSAID-induced GI adverse event and to detect and manage the event should one occur. The use of COX-2-specific inhibitors to manage pain and inflammation may minimize the risks of NSAID-associated toxicities.

  6. Adverse events related to blood transfusion

    PubMed Central

    Sahu, Sandeep; Hemlata; Verma, Anupam

    2014-01-01

    The acute blood transfusion reactions are responsible for causing most serious adverse events. Awareness about various clinical features of acute and delayed transfusion reactions with an ability to assess the serious reactions on time can lead to a better prognosis. Evidence-based medicine has changed today's scenario of clinical practice to decrease adverse transfusion reactions. New evidence-based algorithms of transfusion and improved haemovigilance lead to avoidance of unnecessary transfusions perioperatively. The recognition of adverse events under anaesthesia is always challenging. The unnecessary blood transfusions can be avoided with better blood conservation techniques during surgery and with anaesthesia techniques that reduce blood loss. Better and newer blood screening methods have decreased the infectious complications to almost negligible levels. With universal leukoreduction of red blood cells (RBCs), selection of potential donors such as use of male donors only plasma and restriction of RBC storage, most of the non-infectious complications can be avoided. PMID:25535415

  7. Adverse health consequences of the Iraq War.

    PubMed

    Levy, Barry S; Sidel, Victor W

    2013-03-16

    The adverse health consequences of the Iraq War (2003-11) were profound. We conclude that at least 116,903 Iraqi non-combatants and more than 4800 coalition military personnel died over the 8-year course. Many Iraqi civilians were injured or became ill because of damage to the health-supporting infrastructure of the country, and about 5 million were displaced. More than 31,000 US military personnel were injured and a substantial percentage of those deployed suffered post-traumatic stress disorder, traumatic brain injury, and other neuropsychological disorders and their concomitant psychosocial problems. Many family members of military personnel had psychological problems. Further review of the adverse health consequences of this war could help to minimise the adverse health consequences of, and help to prevent, future wars.

  8. Identifying Adverse Drug Events by Relational Learning.

    PubMed

    Page, David; Costa, Vítor Santos; Natarajan, Sriraam; Barnard, Aubrey; Peissig, Peggy; Caldwell, Michael

    2012-07-01

    The pharmaceutical industry, consumer protection groups, users of medications and government oversight agencies are all strongly interested in identifying adverse reactions to drugs. While a clinical trial of a drug may use only a thousand patients, once a drug is released on the market it may be taken by millions of patients. As a result, in many cases adverse drug events (ADEs) are observed in the broader population that were not identified during clinical trials. Therefore, there is a need for continued, post-marketing surveillance of drugs to identify previously-unanticipated ADEs. This paper casts this problem as a reverse machine learning task, related to relational subgroup discovery and provides an initial evaluation of this approach based on experiments with an actual EMR/EHR and known adverse drug events. PMID:24955289

  9. The MuLV 4070A G541R Env mutation decreases the stability and alters the conformation of the TM ectodomain

    SciTech Connect

    Schneider, William M. Zheng, Haiyan Cote, Marie L. Roth, Monica J.

    2008-02-05

    Virus-cell and cell-cell fusion events are affected by various properties of the fusogenic Env protein on the cell surface. The G541R mutation within the TM ectodomain of murine leukemia virus (MuLV) 4070A arose by positive selection in viral passage and results in a reduction of cell-cell fusion events while maintaining viral titer. Size exclusion chromatography shows that the multimerization properties are similar among expressed wild-type and mutant ectodomain peptides. Circular dichroism measurements reveal decreased thermal stability of the G541R mutant as compared to wild type. The G541R mutant also renders the peptide more susceptible to Lys-C protease cleavage. The 42-114 monoclonal antibody does not bind to the G541R mutant peptides, suggesting a structural difference from wild type. These altered physical properties result in productive viral infection of G541R bearing virus with decreased syncytia.

  10. The MuLV 4070A G541R Env mutation decreases the stability and alters the conformation of the TM ectodomain

    PubMed Central

    Schneider, William M.; Zheng, Haiyan; Coté, Marie L.; Roth, Monica J.

    2008-01-01

    Virus-cell and cell-cell fusion events are affected by various properties of the fusogenic Env protein on the cell surface. The G541R mutation within the TM ectodomain of murine leukemia virus (MuLV) 4070A arose by positive selection in viral passage and results in a reduction of cell-cell fusion events while maintaining viral titer. Size exclusion chromatography shows that the multimerization properties are similar among expressed wild-type and mutant ectodomain peptides. Circular dichroism measurements reveal decreased thermal stability of the G541R mutant as compared to wild-type. The G541R mutant also renders the peptide more susceptible to Lys-C protease cleavage. The 42-114 monoclonal antibody does not bind to the G541R mutant peptides, suggesting a structural difference from wildtype. These altered physical properties result in productive viral infection of G541R bearing virus with decreased syncytia. PMID:17961622

  11. Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

    PubMed Central

    Quinton, Lee J.; Mizgerd, Joseph P.

    2015-01-01

    Pneumonia is initiated by microbes in the lung, but physiological processes integrating responses across diverse cell types and organ systems dictate the outcome of respiratory infection. Resistance, or actions of the host to eradicate living microbes, in the lungs involves a combination of innate and adaptive immune responses triggered by air-space infection. Resilience, or the ability of the host tissues to withstand the physiologically damaging effects of microbial and immune activities, is equally complex, precisely regulated, and determinative. Both immune resistance and tissue resilience are dynamic and change throughout the lifetime, but we are only beginning to understand such remodeling and how it contributes to the incidence of severe pneumonias, which diminishes as childhood progresses and then increases again among the elderly. Here, we review the concepts of resistance, resilience, and remodeling as they apply to pneumonia, highlighting recent advances and current significant knowledge gaps. PMID:25148693

  12. Perspectives on biomechanical growth and remodeling mechanisms in glaucoma⋆

    PubMed Central

    Grytz, Rafael; Girkin, Christopher A.; Libertiaux, Vincent; Downs, J. Crawford

    2012-01-01

    Glaucoma is a blinding diseases in which damage to the axons results in loss of retinal ganglion cells. Experimental evidence indicates that chronic intraocular pressure elevation initiates axonal insult at the level of the lamina cribrosa. The lamina cribrosa is a porous collagen structure through which the axons pass on their path from the retina to the brain. Recent experimental studies revealed the extensive structural changes of the lamina cribrosa and its surrounding tissues during the development and progression of glaucoma. In this perspective paper we review the experimental evidence for growth and remodeling mechanisms in glaucoma including adaptation of tissue anisotropy, tissue thickening/thinning, tissue elongation/shortening and tissue migration. We discuss the existing predictive computational approaches that try to elucidate the potential biomechanical basis of theses growth and remodeling mechanisms and highlight open questions, challenges, and avenues for further development. PMID:23109748

  13. Physical principles of membrane remodelling during cell mechanoadaptation

    PubMed Central

    Kosmalska, Anita Joanna; Casares, Laura; Elosegui-Artola, Alberto; Thottacherry, Joseph Jose; Moreno-Vicente, Roberto; González-Tarragó, Víctor; del Pozo, Miguel Ángel; Mayor, Satyajit; Arroyo, Marino; Navajas, Daniel; Trepat, Xavier; Gauthier, Nils C.; Roca-Cusachs, Pere

    2015-01-01

    Biological processes in any physiological environment involve changes in cell shape, which must be accommodated by their physical envelope—the bilayer membrane. However, the fundamental biophysical principles by which the cell membrane allows for and responds to shape changes remain unclear. Here we show that the 3D remodelling of the membrane in response to a broad diversity of physiological perturbations can be explained by a purely mechanical process. This process is passive, local, almost instantaneous, before any active remodelling and generates different types of membrane invaginations that can repeatedly store and release large fractions of the cell membrane. We further demonstrate that the shape of those invaginations is determined by the minimum elastic and adhesive energy required to store both membrane area and liquid volume at the cell–substrate interface. Once formed, cells reabsorb the invaginations through an active process with duration of the order of minutes. PMID:26073653

  14. ATP Dependent Chromatin Remodeling Enzymes in Embryonic Stem Cells

    PubMed Central

    Saladi, Srinivas Vinod

    2010-01-01

    Embryonic stem (ES) cells are pluripotent cells that can self renew or be induced to differentiate into multiple cell lineages, and thus have the potential to be utilized in regenerative medicine. Key pluripotency specific factors (Oct 4/Sox2/Nanog/Klf4) maintain the pluripotent state by activating expression of pluripotency specific genes and by inhibiting the expression of developmental regulators. Pluripotent ES cells are distinguished from differentiated cells by a specialized chromatin state that is required to epigenetically regulate the ES cell phenotype. Recent studies show that in addition to pluripotency specific factors, chromatin remodeling enzymes play an important role in regulating ES cell chromatin and the capacity to self-renew and to differentiate. Here we review recent studies that delineate the role of ATP dependent chromatin remodeling enzymes in regulating ES cell chromatin structure. PMID:20148317

  15. The role of microRNAs in bone remodeling

    PubMed Central

    Jing, Dian; Hao, Jin; Shen, Yu; Tang, Ge; Li, Mei-Le; Huang, Shi-Hu; Zhao, Zhi-He

    2015-01-01

    Bone remodeling is balanced by bone formation and bone resorption as well as by alterations in the quantities and functions of seed cells, leading to either the maintenance or deterioration of bone status. The existing evidence indicates that microRNAs (miRNAs), known as a family of short non-coding RNAs, are the key post-transcriptional repressors of gene expression, and growing numbers of novel miRNAs have been verified to play vital roles in the regulation of osteogenesis, osteoclastogenesis, and adipogenesis, revealing how they interact with signaling molecules to control these processes. This review summarizes the current knowledge of the roles of miRNAs in regulating bone remodeling as well as novel applications for miRNAs in biomaterials for therapeutic purposes. PMID:26208037

  16. Dental implant design--effect on bone remodeling.

    PubMed

    Pilliar, R M; Deporter, D A; Watson, P A; Valiquette, N

    1991-04-01

    Bone remodeling around three different endosseous dental implant designs placed in dog mandibles was studied using radiography during lengthy periods of function and by histology after animal sacrifice. The three designs investigated were (a) threaded (c.p. titanium), (b) fully porous-coated (titanium alloy), and (c) partially porous-coated (titanium alloy). The implants were kept in function for either 32 weeks (fully porous-coated) or 73 to 77 weeks (partially porous-coated and threaded). The studies indicated that some crestal bone loss occurred for both the threaded and partially porous-coated implants while no significant bone loss was seen with fully porous-coated implants in the absence of plaque-associated infection. It is suggested that these observed differences are a result of the different stress states that develop in bone surrounding the three designs underlying the importance of implant design on bone remodeling.

  17. The solid state environment orchestrates embryonic development and tissue remodeling

    NASA Technical Reports Server (NTRS)

    Damsky, C. H.; Moursi, A.; Zhou, Y.; Fisher, S. J.; Globus, R. K.

    1997-01-01

    Cell interactions with extracellular matrix and with other cells play critical roles in morphogenesis during development and in tissue homeostasis and remodeling throughout life. Extracellular matrix is information-rich, not only because it is comprised of multifunctional structural ligands for cell surface adhesion receptors, but also because it contains peptide signaling factors, and proteinases and their inhibitors. The functions of these groups of molecules are extensively interrelated. In this review, three primary cell culture models are described that focus on adhesion receptors and their roles in complex aspects of morphogenesis and remodeling: the regulation of proteinase expression by fibronectin and integrins in synovial fibroblasts; the regulation of osteoblast differentiation and survival by fibronectin, and the regulation of trophoblast differentiation and invasion by integrins, cadherins and immunoglobulin family adhesion receptors.

  18. Design stars: how small DNA viruses remodel the host nucleus.

    PubMed

    Jiang, Mengxi; Imperiale, Michael J

    2012-05-01

    Numerous host components are encountered by viruses during the infection process. While some of these host structures are left unchanged, others may go through dramatic remodeling processes. In this review, we summarize these host changes that occur during small DNA virus infections, with a focus on host nuclear components and pathways. Although these viruses differ significantly in their genome structures and infectious pathways, there are common nuclear targets that are altered by various viral factors. Accumulating evidence suggests that these nuclear remodeling processes are often essential for productive viral infections and/or viral-induced transformation. Understanding the complex interactions between viruses and these host structures and pathways will help to build a more integrated network of how the virus completes its life cycle and point toward the design of novel therapeutic regimens that either prevent harmful viral infections or employ viruses as nontraditional treatment options or molecular tools.

  19. Frequent mutations in chromatin-remodeling genes in pulmonary carcinoids

    PubMed Central

    Lu, Xin; Sun, Ruping; Ozretić, Luka; Seidal, Danila; Zander, Thomas; Leenders, Frauke; George, Julie; Müller, Christian; Dahmen, Ilona; Pinther, Berit; Bosco, Graziella; Konrad, Kathryn; Altmüller, Janine; Nürnberg, Peter; Achter, Viktor; Lang, Ulrich; Schneider, Peter M; Bogus, Magdalena; Soltermann, Alex; Brustugun, Odd Terje; Helland, Åslaug; Solberg, Steinar; Lund-Iversen, Marius; Ansén, Sascha; Stoelben, Erich; Wright, Gavin M.; Russell, Prudence; Wainer, Zoe; Solomon, Benjamin; Field, John K; Hyde, Russell; Davies, Michael PA.; Heukamp, Lukas C; Petersen, Iver; Perner, Sven; Lovly, Christine; Cappuzzo, Federico; Travis, William D; Wolf, Jürgen; Vingron, Martin; Brambilla, Elisabeth; Haas, Stefan A.; Buettner, Reinhard; Thomas, Roman K

    2014-01-01

    Pulmonary carcinoids are rare neuroendocrine tumors of the lung. The molecular alterations underlying the pathogenesis of these tumors have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodeling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40% and 22.2% of the cases respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumors, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin remodeling genes is sufficient to drive transformation in pulmonary carcinoids. PMID:24670920

  20. Probabilistic Study of Bone Remodeling Using Finite Element Analysis

    NASA Astrophysics Data System (ADS)

    Werner, C.; Gorla, R. S. R.

    2013-08-01

    The dynamic bone remodeling process is a computationally challenging research area that struggles to understand the actual mechanisms. It has been observed that a mechanical stimulus in the bone greatly affects the remodeling process. A 3D finite element model of a femur is created and a probabilistic analysis is performed on the model. The probabilistic analysis measures the sensitivities of various parameters related to the material properties, geometric properties, and the three load cases defined as Single Leg Stance, Abduction, and Adduction. The sensitivity of each parameter is based on the calculated maximum mechanical stimulus and analyzed at various values of probabilities ranging from 0.001 to 0.999. The analysis showed that the parameters associated with the Single Leg Stance load case had the highest sensitivity with a probability of 0.99 and the angle of the force applied to the joint of the proximal femur had the overall highest sensitivity

  1. The population model of bone remodelling employed the optimal control.

    PubMed

    Moroz, Adam

    2012-11-01

    Several models have been developed in recent years which apply population dynamics methods to describe the mechanisms of bone remodelling. This study incorporates the population kinetics model of bone turnover (including the osteocyte loop regulation) with the optimal control technique. Model simulations have been performed with a wide range of rate parameters using the Monte Carlo method. The regression method has also been used to investigate the interdependence of the location of equilibrium and the characteristics of the equilibrium/relaxation time on the rate parameters employed. The dynamic optimal control outlook for the regulation of bone remodelling processes, in the context of the osteocyte-control population model, has been discussed. Optimisation criteria have been formulated from the perspective of the energetic and metabolic losses in the tissue, with respect to the performance of the bone multicellular unit.

  2. Remodeling myelination: implications for mechanisms of neural plasticity.

    PubMed

    Chang, Kae-Jiun; Redmond, Stephanie A; Chan, Jonah R

    2016-02-01

    One of the most significant paradigm shifts in membrane remodeling is the emerging view that membrane transformation is not exclusively controlled by cytoskeletal rearrangement, but also by biophysical constraints, adhesive forces, membrane curvature and compaction. One of the most exquisite examples of membrane remodeling is myelination. The advent of myelin was instrumental in advancing the nervous system during vertebrate evolution. With more rapid and efficient communication between neurons, faster and more complex computations could be performed in a given time and space. Our knowledge of how myelin-forming oligodendrocytes select and wrap axons has been limited by insufficient spatial and temporal resolution. By virtue of recent technological advances, progress has clarified longstanding controversies in the field. Here we review insights into myelination, from target selection to axon wrapping and membrane compaction, and discuss how understanding these processes has unexpectedly opened new avenues of insight into myelination-centered mechanisms of neural plasticity.

  3. Osteocyte Remodeling of the Perilacunar and Pericanalicular Matrix

    PubMed Central

    Qing, Hai; Bonewald, Lynda F

    2009-01-01

    With additional functions of osteocytes being identified, the concept that osteocytes are just “static lacunar-dwelling cells” is no longer accepted. We reviewed most of the relevant literature on osteocyte's function in the direct remodeling of the perilucunar matrix, discussing the advantages and disadvantages. Special attention was paid to how the negative researchers argue about the “osteocytic osteolysis” principle, and how the positive side addressed the arguments. We also discussed the newly found data of osteocytic remodeling function from our group. With more biotechnology in hand, there is increased excitement in the prospect of now being able to answer the two important questions: do osteocytes have the capability to remove mineral from the perilacunar matrix and if so what are the molecular and cellular mechanisms? do osteocytes have the capability to deposit new mineral on the perilacunar matrix and if so what are the cellular and molecular mechanisms? PMID:20687297

  4. ISWI chromatin remodeling complexes in the DNA damage response

    PubMed Central

    Aydin, Özge Z; Vermeulen, Wim; Lans, Hannes

    2014-01-01

    Regulation of chromatin structure is an essential component of the DNA damage response (DDR), which effectively preserves the integrity of DNA by a network of multiple DNA repair and associated signaling pathways. Within the DDR, chromatin is modified and remodeled to facilitate efficient DNA access, to control the activity of repair proteins and to mediate signaling. The mammalian ISWI family has recently emerged as one of the major ATP-dependent chromatin remodeling complex families that function in the DDR, as it is implicated in at least 3 major DNA repair pathways: homologous recombination, non-homologous end-joining and nucleotide excision repair. In this review, we discuss the various manners through which different ISWI complexes regulate DNA repair and how they are targeted to chromatin containing damaged DNA. PMID:25486562

  5. SUN4 is essential for nuclear remodeling during mammalian spermiogenesis.

    PubMed

    Calvi, Alessandra; Wong, Arnette Shi Wei; Wright, Graham; Wong, Esther Sook Miin; Loo, Tsui Han; Stewart, Colin L; Burke, Brian

    2015-11-15

    One of the more dramatic examples of cellular reorganization occurs during spermiogenesis in which a roughly spherical spermatid is transformed into a mature sperm cell. A highlight of this process involves nuclear remodeling whereby the round spermatid nucleus is sculpted into an elongated and polar structure. This transformation in nuclear architecture features chromatin condensation, changes in the composition and organization of the nuclear lamina and redistribution and elimination of nuclear pore complexes. The manchette, a cytoplasmic microtubule-based structure is thought to play a crucial role in the remodeling process. Here we show that SUN4, a spermatid nuclear membrane protein has an essential function in coupling the manchette to the nuclear periphery. In the absence of SUN4, manchette microtubules appear highly disorganized and the nucleus itself fails to elongate. Consequently, mice deficient in SUN4 display globozoospermia with associated infertility.

  6. ISWI chromatin remodeling complexes in the DNA damage response.

    PubMed

    Aydin, Özge Z; Vermeulen, Wim; Lans, Hannes

    2014-01-01

    Regulation of chromatin structure is an essential component of the DNA damage response (DDR), which effectively preserves the integrity of DNA by a network of multiple DNA repair and associated signaling pathways. Within the DDR, chromatin is modified and remodeled to facilitate efficient DNA access, to control the activity of repair proteins and to mediate signaling. The mammalian ISWI family has recently emerged as one of the major ATP-dependent chromatin remodeling complex families that function in the DDR, as it is implicated in at least 3 major DNA repair pathways: homologous recombination, non-homologous end-joining and nucleotide excision repair. In this review, we discuss the various manners through which different ISWI complexes regulate DNA repair and how they are targeted to chromatin containing damaged DNA.

  7. Nucleosome breathing and remodeling constrain CRISPR-Cas9 function.

    PubMed

    Isaac, R Stefan; Jiang, Fuguo; Doudna, Jennifer A; Lim, Wendell A; Narlikar, Geeta J; Almeida, Ricardo

    2016-04-28

    The CRISPR-Cas9 bacterial surveillance system has become a versatile tool for genome editing and gene regulation in eukaryotic cells, yet how CRISPR-Cas9 contends with the barriers presented by eukaryotic chromatin is poorly understood. Here we investigate how the smallest unit of chromatin, a nucleosome, constrains the activity of the CRISPR-Cas9 system. We find that nucleosomes assembled on native DNA sequences are permissive to Cas9 action. However, the accessibility of nucleosomal DNA to Cas9 is variable over several orders of magnitude depending on dynamic properties of the DNA sequence and the distance of the PAM site from the nucleosome dyad. We further find that chromatin remodeling enzymes stimulate Cas9 activity on nucleosomal templates. Our findings imply that the spontaneous breathing of nucleosomal DNA together with the action of chromatin remodelers allow Cas9 to effectively act on chromatin in vivo.

  8. Remodelling the vascular microenvironment of glioblastoma with alpha-particles

    PubMed Central

    Behling, Katja; Maguire, William F.; Di Gialleonardo, Valentina; Heeb, Lukas E.M.; Hassan, Iman F.; Veach, Darren R.; Keshari, Kayvan R.; Gutin, Philip H.; Scheinberg, David A.; McDevitt, Michael R.

    2016-01-01

    Rationale Tumors escape anti-angiogenic therapy by activation of pro-angiogenic signaling pathways. Bevacizumab is approved for the treatment of recurrent glioblastoma, but patients inevitably develop resistance to this angiogenic inhibitor. We investigated targeted α-particle therapy with 225Ac-E4G10 as an anti-vascular approach and previously showed increased survival and tumor control in a high-grade transgenic orthotopic glioblastoma model. Here we investigate changes in tumor-vascular morphology and functionality caused by 225Ac-E4G10. Methods We investigated remodeling of tumor microenvironment in transgenic Ntva glioblastoma mice using a therapeutic 7.4 kBq dose of 225Ac-E4G10. Immunofluorescence and immunohistochemical analyses imaged morphological changes in the tumor blood brain barrier microenvironment. Multi-color flow cytometry quantified the endothelial progenitor cell population in the bone marrow. Diffusion-weighted magnetic resonance imaged functional changes of the tumor vascular network. Results The mechanism of drug action is a combination of glioblastoma vascular microenvironment remodeling, edema relief, and depletion of regulatory T and endothelial progenitor cells. The primary remodeling event is the reduction of both endothelial and perivascular cell populations. Tumor-associated edema and necrosis was lessened and resulted in increased perfusion and reduced diffusion. Pharmacological uptake of dasatinib into tumor was enhanced following α-particle therapy. Conclusion Targeted anti-vascular α-particle radiation remodels the glioblastoma vascular microenvironment via a multimodal mechanism of action and provides insight into the vascular architecture of Platelet-derived growth factor driven glioblastoma. PMID:27261519

  9. Adverse outcome pathway (AOP) development and evaluation

    EPA Science Inventory

    The Adverse Outcome Pathway provides a construct for assembling mechanistic information at different levels of biological organization in a form designed to support regulatory decision making. In particular, it frames the link between molecular and cellular events that can be mea...

  10. The adverse outcome pathway knowledge base

    EPA Science Inventory

    The rapid advancement of the Adverse Outcome Pathway (AOP) framework has been paralleled by the development of tools to store, analyse, and explore AOPs. The AOP Knowledge Base (AOP-KB) project has brought three independently developed platforms (Effectopedia, AOP-Wiki, and AOP-X...

  11. Linezolid Induced Adverse Drug Reactions - An Update.

    PubMed

    Kishor, Kamal; Dhasmana, Neha; Kamble, Shashank Shivaji; Sahu, Roshan Kumar

    2015-01-01

    Treatment regimen recommended for resistant tuberculosis consists of various drugs and these drugs are prescribed for at least 12-15 months. Such a long duration therapy and high dose of antibiotics result in adverse drug reactions (ADRs). ADRs may lead to various complications in disease management like replacement of drugs, dose increment, therapy withdrawal, etc. Linezolid is one of those drugs, practiced as an anti-mycobacterial agent and it is an important member of drug regimen for MDR and XDR tuberculosis. Linezolid is a broad spectrum antibiotic known for its unique mechanism of inhibition of resistant pathogenic strains. However, it causes serious adverse effects like thrombocytopenia, optic neuropathy, peripheral neuropathy, lactic acidosis, etc. Literature suggests that Linezolid can cause severe ADRs which affect patient compliance and hinder in therapy to a larger extent. Recent studies confirm the possibility of ADRs to be predicted with genetic make-up of individuals. To effectively deliver the available treatment regimen and ensure patient compliance, it is important to manage ADRs more efficiently. The role of pharmacogenomics in reducing adverse drug effects has been recently explored. In the present review, we discussed about Linezolid induced adverse drug reactions, mechanisms and genetic associations. PMID:26424176

  12. Enduring psychobiological effects of childhood adversity.

    PubMed

    Ehlert, Ulrike

    2013-09-01

    This mini-review refers to recent findings on psychobiological long-term consequences of childhood trauma and adverse living conditions. The continuum of trauma-provoked aftermath reaches from healthy adaptation with high resilience, to severe maladjustment with co-occurring psychiatric and physical pathologies in children, adolescents and adults. There is increasing evidence of a strong interconnectivity between genetic dispositions, epigenetic processes, stress-related hormonal systems and immune parameters in all forms of (mal)-adjustment to adverse living conditions. Unfavorable constellations of these dispositions and systems, such as low cortisol levels and elevated markers of inflammation in maltreated children, seem to promote the (co)-occurrence of psychiatric and physical pathologies such as posttraumatic stress disorder, obesity, or diabetes. Although findings from prospective study designs support a deepened understanding of causal relations between adverse living conditions, including traumatic experiences, during childhood and its psychobiological effects, so far, little is known about the temporal coincidence of stress-sensitive developmental stages during childhood and adolescence and trauma consequences. Taken together, childhood adversity is a severe risk factor for the onset of psychobiological (mal)-adjustment, which has to be explained under consideration of diverse physiological systems and developmental stages of childhood and adolescence.

  13. Pharmacogenomics and adverse drug reactions in children

    PubMed Central

    Rieder, Michael J.; Carleton, Bruce

    2014-01-01

    Adverse drug reactions are a common and important complication of drug therapy in children. Over the past decade it has become increasingly apparent that genetically controlled variations in drug disposition and response are important determinants of adverse events for many important adverse events associated with drug therapy in children. While this research has been difficult to conduct over the past decade technical and ethical evolution has greatly facilitated the ability of investigators to conduct pharmacogenomic studies in children. Some of this research has already resulted in changes in public policy and clinical practice, for example in the case of codeine use by mothers and children. It is likely that the use of pharmacogenomics to enhance drug safety will first be realized among selected groups of children with high rates of drug use such as children with cancer, but it also likely that this research will be extended to other groups of children who have high rates of drug utilization and as well as providing insights into the mechanisms and pathophysiology of adverse drug reactions in children. PMID:24795743

  14. Adverse Effects of Common Drugs: Dietary Supplements.

    PubMed

    Felix, Todd Matthew; Karpa, Kelly Dowhower; Lewis, Peter R

    2015-09-01

    Dietary supplement-induced adverse effects often resolve quickly after discontinuation of the offending product, especially in younger patients. The potential for unwanted outcomes can be amplified in elderly patients or those taking multiple prescription drugs, especially where interactions exist with drugs metabolized by cytochrome P450 enzymes. Attributing injury or illness to a specific supplement can be challenging, especially in light of multi-ingredient products, product variability, and variability in reporting, as well as the vast underreporting of adverse drug reactions. Clinicians prescribing a new drug or evaluating a patient with a new symptom complex should inquire about use of herbal and dietary supplements as part of a comprehensive evaluation. Clinicians should report suspected supplement-related adverse effects to the local or state health department, as well as the Food and Drug Administration's MedWatch program (available at https://www.safetyreporting.hhs.gov). Clinicians should consider discussing suspected adverse effects involving drugs, herbal products, or dietary supplements with their community- and hospital-based pharmacists, and explore patient management options with medical or clinical toxicology subspecialists.

  15. Reducing Adverse Impact: One City's Efforts.

    ERIC Educational Resources Information Center

    Prewitt, Jeff

    Following a workshop on "Innovations in Employment Testing that Improve Validity and Reduce Adverse Impact," the City of Louisville (Kentucky) implemented a strategy to develop a comprehensive testing and recruiting program for police recruits. To improve candidate expectations and preparation, the following activities were undertaken: intense…

  16. Helping Student Teachers Avoid Adverse Legal Actions.

    ERIC Educational Resources Information Center

    Peach, Larry; Reddick, Thomas L.

    1984-01-01

    Discusses five areas of the school environment lending themselves to the possibility of teacher and student teacher liability: negligence, malpractice, rights to privacy, field trips, and search of students and school property. Suggests specific guidelines for decreasing the possibility of adverse legal action. (NEC)

  17. Adverse effects of fillers and their histopathology.

    PubMed

    Haneke, Eckart

    2014-12-01

    Injectable fillers nowadays represent a pillar in facial rejuvenation and make a significant contribution to the success of the treatment. Despite their obvious benefits, a wide range of possible complications such as immediate, late, delayed, temporary, or irreversible adverse effects have to be respected. Differentiating the various filler materials, these effects are assigned to histopathology findings and currently available treatment options.

  18. Resilience in the Face of Adversity.

    ERIC Educational Resources Information Center

    Patterson, Jerry

    2001-01-01

    "Resilience" is the capacity for moving ahead under adverse circumstances. School superintendents are advised to stay upbeat and mindful of "both-and" opportunities; stay focused on what they care about; remain flexible and tolerant of ambiguity; be proactive, not reactive; and apply resilience-conserving strategies during tough times. (MLH)

  19. Adverse Effects of Psychotropic Medications on Sleep.

    PubMed

    Doghramji, Karl; Jangro, William C

    2016-09-01

    Psychotropic medications such as antidepressants, antipsychotics, stimulants, and benzodiazepines are widely prescribed. Most of these medications are thought to exert their effects through modulation of various monoamines as well as interactions with receptors such as histamine and muscarinic cholinergic receptors. Through these interactions, psychotropics can also have a significant impact on sleep physiology, resulting in both beneficial and adverse effects on sleep. PMID:27514301

  20. [Analysis of Spontaneously Reported Adverse Events].

    PubMed

    Nakamura, Mitsuhiro

    2016-01-01

    Observational study is necessary for the evaluation of drug effectiveness in clinical practice. In recent years, the use of spontaneous reporting systems (SRS) for adverse drug reactions has increased and they have become an important resource for regulatory science. SRS, being the largest and most well-known databases worldwide, are one of the primary tools used for postmarketing surveillance and pharmacovigilance. To analyze SRS, the US Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report Database (JADER) are reviewed. Authorized pharmacovigilance algorithms were used for signal detection, including the reporting odds ratio. An SRS is a passive reporting database and is therefore subject to numerous sources of selection bias, including overreporting, underreporting, and a lack of a denominator. Despite the inherent limitations of spontaneous reporting, SRS databases are a rich resource and data mining index that provide powerful means of identifying potential associations between drugs and their adverse effects. Our results, which are based on the evaluation of SRS databases, provide essential knowledge that could improve our understanding of clinical issues.