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Sample records for adverse lv remodeling

  1. Effect of Microvascular Obstruction and Intramyocardial Hemorrhage by CMR on LV Remodeling and Outcomes After Myocardial Infarction

    PubMed Central

    Hamirani, Yasmin S.; Wong, Andrew; Kramer, Christopher M.; Salerno, Michael

    2015-01-01

    The goal of this systematic analysis is to provide a comprehensive review of the current cardiac magnetic resonance data on microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH). Data related to the association of MVO and IMH in patients with acute myocardial infarction (MI) with left ventricular (LV) function, volumes, adverse LV remodeling, and major adverse cardiac events (MACE) were critically analyzed. MVO is associated with a lower ejection fraction, increased ventricular volumes and infarct size, and a greater risk of MACE. Late MVO is shown to be a stronger prognostic marker for MACE and cardiac death, recurrent MI, congestive heart failure/heart failure hospitalization, and follow-up LV end-systolic volumes than early MVO. IMH is associated with LV remodeling and MACE on pooled analysis, but because of limited data and heterogeneity in study methodology, the effects of IMH on remodeling require further investigation. PMID:25212800

  2. Pathophysiology of LV Remodeling in Survivors of STEMI

    PubMed Central

    Carrick, David; Haig, Caroline; Rauhalammi, Sam; Ahmed, Nadeem; Mordi, Ify; McEntegart, Margaret; Petrie, Mark C.; Eteiba, Hany; Lindsay, Mitchell; Watkins, Stuart; Hood, Stuart; Davie, Andrew; Mahrous, Ahmed; Sattar, Naveed; Welsh, Paul; Tzemos, Niko; Radjenovic, Aleksandra; Ford, Ian; Oldroyd, Keith G.; Berry, Colin

    2015-01-01

    .049). Conclusions Reperfusion injury and inflammation early post-MI was associated with remote zone T1, which in turn was independently associated with LV remodeling and adverse cardiac events post-STEMI. (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI]; NCT02072850) PMID:26093923

  3. The Adverse Impact of Diabetes Mellitus on Left Ventricular Remodeling and Function in Patients with Severe Aortic Stenosis

    PubMed Central

    Lindman, Brian R.; Arnold, Suzanne V.; Madrazo, José A.; Zajarias, Alan; Johnson, Stephanie N.; Pérez, Julio E.; Mann, Douglas L.

    2011-01-01

    Background The diabetic heart exhibits increased left ventricular (LV) mass and reduced ventricular function. However, this relationship has not been studied in patients with aortic stenosis (AS), a disease process that causes LV hypertrophy and dysfunction through a distinct mechanism of pressure overload. The aim of this study was to determine how diabetes mellitus (DM) impacts LV remodeling and function in patients with severe AS. Methods and Results Echocardiograms were performed on 114 patients with severe AS [mean aortic valve area (AVA) 0.6 cm2] and included measures of LV remodeling and function. Multivariable linear regression models investigated the independent effect of DM on these aspects of LV structure and function. Compared to non-diabetics (n=60), diabetics (n=54) had increased LV mass, LV end-systolic dimension, LV end-diastolic dimension, and decreased LV ejection fraction (EF) and longitudinal systolic strain (p<0.01 for all). In multivariable analyses adjusting for age, sex, systolic BP, AVA, BSA, and coronary disease, DM was an independent predictor of increased LV mass (β=26g, p=0.01), LV end-systolic dimension (β=0.5cm, p=0.008), and LV end-diastolic dimension (β=0.3cm, p=0.025). After additionally adjusting for LV mass, DM was associated with reduced longitudinal systolic strain (β=1.9%, p=0.023) and a trend toward reduced EF (β=−5%, p=0.09). Among diabetics, insulin use (as a marker of disease severity) was associated with larger LV end-systolic dimension and worse LV function. LV mass was a strong predictor of reduced EF and systolic strain (p<0.001 for both). Conclusions DM has an additive adverse effect on hypertrophic remodeling—increased LV mass and larger cavity dimensions—and is associated with reduced systolic function in patients with AS beyond known factors of pressure overload. PMID:21357546

  4. Cardiac interstitial bradykinin and mast cells modulate pattern of LV remodeling in volume overload in rats.

    PubMed

    Wei, Chih-Chang; Lucchesi, Pamela A; Tallaj, Jose; Bradley, Wayne E; Powell, Pamela C; Dell'Italia, Louis J

    2003-08-01

    In the current study, interstitial fluid (ISF), bradykinin (BK), and angiotensin II (ANG II) levels were measured using cardiac microdialysis in conscious, nonsedated rats at baseline and at 48 h and 5 days after each of the following: sham surgery (sham, n = 6), sham + administration of ANG-converting enzyme inhibitor ramipril (R, n = 6), creation of aortocaval fistula (ACF, n = 6), ACF + R (n = 6), and ACF + R + BK2 receptor antagonist (HOE-140) administration (n = 6). At 5 days, both ISF ANG II and BK increased in ACF rats (P < 0.05); however, in ACF + R rats, ISF ANG II did not differ from basal levels and ISF BK increased greater than threefold above baseline at 2 and 5 days (P < 0.05). Five days after ACF, the left ventricular (LV) weight-to-body weight ratio increased 30% (P < 0.05) in ACF but did not differ from sham in ACF + R and ACF + R + HOE-140 rats despite similar systemic arterial pressures across all ACF groups. However, ACF + R + HOE-140 rats had greater postmortem wall thickness-to-diameter ratio and smaller cross-sectional diameter compared with ACF + R rats. There was a significant increase in mast cell density in ACF and ACF + R rats that decreased below sham in ACF + R + HOE-140 rats. These results suggest a potentially important interaction of mast cells and BK in the cardiac interstitium that modulates the pattern of LV remodeling in the acute phase of volume overload. PMID:12663259

  5. Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy.

    PubMed

    Thoonen, Robrecht; Ernande, Laura; Cheng, Juan; Nagasaka, Yasuko; Yao, Vincent; Miranda-Bezerra, Alexandre; Chen, Chan; Chao, Wei; Panagia, Marcello; Sosnovik, David E; Puppala, Dheeraj; Armoundas, Antonis A; Hindle, Allyson; Bloch, Kenneth D; Buys, Emmanuel S; Scherrer-Crosbie, Marielle

    2015-07-01

    Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1(-/-)) mice, which have dysfunctional BAT, were subjected to catecholamine-induced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1(-/-) mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1(-/-) mice. UCP1(-/-) mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1(-/-) mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1(-/-) BAT transplanted to either UCP1(-/-) or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1(-/-) mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1(-/-) mice, suggesting a systemic cardioprotective role of functional BAT. BAT is also activated in chronic ischemic cardiomyopathy. PMID:25968336

  6. 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

  7. Beneficial effect of simvastatin and pravastatin treatment on adverse cardiac remodelling and glomeruli loss in spontaneously hypertensive rats.

    PubMed

    Bezerra, Daniele G; Mandarim-de-Lacerda, Carlos A

    2005-04-01

    The aim of the present study was to investigate the possibility of different effects of the hydrophobic statin simvastatin and the hydrophilic statin pravastatin on the remodelling process in the overloaded left ventricle and renal cortex of SHRs (spontaneously hypertensive rats). Fifteen SHRs were treated for 40 days with simvastatin, pravastatin or placebo (water) via orogastric administration. Left ventricle and renal cortex were examined by light microscopy and stereology. LV (left ventricular) cardiomyocyte nuclei (N[cmn]) and glomeruli (N[gl]) numbers were estimated by the dissector method. BP (blood pressure) and serum triacylglycerols (triglycerides) were lower in the statin-treated groups than in the untreated control group. The volume density of the interstitial connective tissue was smaller and length density of the intramyocardial arteries, as well as the arteries/cardiomyocyte ratio, was greater in the statin-treated groups than in the control group. No difference was observed between the two statin-treated groups. The cross-sectional cardiomyocyte area was significantly smaller in the simvastatin-treated group than in the control or pravastatin-treated groups, and it was smaller in the pravastatin-treated group than in the control group. N[cmn] and N[gl] were greater in the two statin-treated groups than in the control group, but no significant difference was observed between the two statin-treated groups. In conclusion, administration of the statins simvastatin and pravastatin to SHRs effectively prevented the elevation in BP and serum triaclyglycerols, and also attenuated adverse cardiac and kidney remodelling by preventing LV hypertrophy, enhancing myocardial vascularization with the decrease in interstitial fibrosis and attenuating cardiomyocyte and glomerular loss. PMID:15610072

  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 Central

    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. PMID:26042051

  10. Rapid Surface Cooling by ThermoSuit System Dramatically Reduces Scar Size, Prevents Post-Infarction Adverse Left Ventricular Remodeling, and Improves Cardiac Function in Rats

    PubMed Central

    Dai, Wangde; Herring, Michael J; Hale, Sharon L; Kloner, Robert A

    2015-01-01

    Background The long-term effects of transient hypothermia by the non-invasive ThermoSuit apparatus on myocardial infarct (MI) scar size, left ventricular (LV) remodeling, and LV function were assessed in rat MI model. Methods and Results Rats were randomized to normothermic or hypothermic groups (n=14 in each group) and subjected to 30 minutes coronary artery occlusion and 6 weeks of reperfusion. For hypothermia therapy, rats were placed into the ThermoSuit apparatus at 2 minutes after the onset of coronary artery occlusion, were taken out of the apparatus when the core body temperature reached 32°C (in ≈8 minutes), and were then allowed to rewarm. After 6 weeks of recovery, rats treated with hypothermia demonstrated markedly reduced scar size (expressed as % of left ventricular area: hypothermia, 6.5±1.1%; normothermia, 19.4±1.7%; P=1.3×10−6); and thicker anterior LV wall (hypothermia, 1.57±0.09 mm; normothermia, 1.07±0.05 mm; P=3.4×10−5); decreased postmortem left ventricular volume (hypothermia, 0.45±0.04 mL; normothermia, 0.6±0.03 mL; P=0.028); and better LV fractional shortening by echocardiography (hypothermia, 37.2±2.8%; normothermia, 18.9±2.3%; P=0.0002) and LV ejection fraction by LV contrast ventriculography (hypothermia, 66.8±2.3%; normothermia, 56.0±2.0%; P=0.0014). Conclusions Rapid, transient non-invasive surface cooling with the ThermoSuit apparatus in the acute phase of MI decreased scar size by 66.5%, attenuated adverse post-infarct left ventricular dilation and remodeling, and improved cardiac function in the chronic phase of experimental MI. PMID:26116692

  11. Association of the Frontal QRS-T Angle with Adverse Cardiac Remodeling, Impaired Left and Right Ventricular Function, and Worse Outcomes in Heart Failure with Preserved Ejection Fraction

    PubMed Central

    Selvaraj, Senthil; Ilkhanoff, Leonard; Burke, Michael A.; Freed, Benjamin H.; Lang, Roberto M.; Martinez, Eva E.; Shah, Sanjiv J.

    2013-01-01

    Background No prior studies have investigated the association of QRS-T angle with cardiac structure/function and outcomes in heart failure with preserved ejection fraction (HFpEF). We hypothesized that increased frontal QRS-T angle is associated with worse cardiac function/remodeling and adverse outcomes in HFpEF. Methods We prospectively studied 376 patients with HFpEF (i.e. symptomatic HF with left ventricular [LV] ejection fraction >50%.) The frontal QRS-T angle was calculated from the 12-lead electrocardiogram. Patients were divided into tertiles by frontal QRS-T angle (0–26°, 27–75°, and 76–179°), and clinical, laboratory, and echocardiographic data were compared among groups. Cox proportional hazards analyses were performed to determine the association between QRS-T angle and outcomes. Results The mean age of the cohort was 64±13 years, 65% were women, and the mean QRS-T angle was 61±51°. Patients with increased QRS-T angle were older, had a lower body-mass index, more frequently had coronary artery disease, diabetes, chronic kidney disease, and atrial fibrillation, and had higher B-type natriuretic peptide (BNP) levels (P<0.05 for all comparisons). After multivariable adjustment, patients with increased QRS-T angle had higher BNP levels in addition to higher LV mass index, worse diastolic function parameters, more right ventricular (RV) remodeling, and worse RV systolic function (P<0.05 for all associations). QRS-T angle was independently associated with the composite outcome of cardiovascular hospitalization or death on multivariable analysis, even after adjusting for BNP (HR for the highest QRS-T tertile = 2.0, 95% CI 1.2–3.4; P=0.008). Conclusions In HFpEF, increased QRS-T angle is independently associated with worse left and right ventricular function/remodeling and adverse outcomes. PMID:24075945

  12. Orphan nuclear receptor Nur77 affects cardiomyocyte calcium homeostasis and adverse cardiac remodelling

    PubMed Central

    Medzikovic, Lejla; Schumacher, Cees A.; Verkerk, Arie O.; van Deel, Elza D.; Wolswinkel, Rianne; van der Made, Ingeborg; Bleeker, Natascha; Cakici, Daniella; van den Hoogenhof, Maarten M. G.; Meggouh, Farid; Creemers, Esther E.; Ann Remme, Carol; Baartscheer, Antonius; de Winter, Robbert J.; de Vries, Carlie J. M.; Arkenbout, E. Karin; de Waard, Vivian

    2015-01-01

    Distinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca2+ ([Ca2+]i). However, chronic β-adrenergic stimulation promotes adverse cardiac remodelling. Cardiac expression of nuclear receptor Nur77 is enhanced by β-adrenergic stimulation, but its role in cardiac remodelling is still unclear. We show high and rapid Nur77 upregulation in cardiomyocytes stimulated with β-adrenergic agonist isoproterenol. Nur77 knockdown in culture resulted in hypertrophic cardiomyocytes. Ventricular cardiomyocytes from Nur77-deficient (Nur77-KO) mice exhibited elevated diastolic and systolic [Ca2+]i and prolonged action potentials compared to wild type (WT). In vivo, these differences resulted in larger cardiomyocytes, increased expression of hypertrophic genes, and more cardiac fibrosis in Nur77-KO mice upon chronic isoproterenol stimulation. In line with the observed elevated [Ca2+]i, Ca2+-activated phosphatase calcineurin was more active in Nur77-KO mice compared to WT. In contrast, after cardiac pressure overload by aortic constriction, Nur77-KO mice exhibited attenuated remodelling compared to WT. Concluding, Nur77-deficiency results in significantly altered cardiac Ca2+ homeostasis and distinct remodelling outcome depending on the type of insult. Detailed knowledge on the role of Nur77 in maintaining cardiomyocyte Ca2+ homeostasis and the dual role Nur77 plays in cardiac remodelling will aid in developing personalized therapies against heart failure. PMID:26486271

  13. Intracoronary Delivery of Self-Assembling Heart-Derived Microtissues (“Cardiospheres”) for Prevention of Adverse Remodeling in a Pig Model of Convalescent Myocardial Infarction

    PubMed Central

    Gallet, Romain; Tseliou, Eleni; Dawkins, James; Middleton, Ryan; Valle, Jackelyn; Angert, David; Reich, Heidi; Luthringer, Daniel; Kreke, Michelle; Smith, Rachel; Marbán, Linda; Marbán, Eduardo

    2015-01-01

    Background Preclinical studies in rodents and pigs indicate that the self-assembling microtissues known as cardiospheres (CSp) may be more effective than dispersed CSp-derived cells (CDCs). However, the more desirable intracoronary (IC) route has been assumed to be unsafe for CSp delivery: CSp are large (30-150 μm), raising concerns about likely micro-embolization. We questioned these negative assumptions by evaluating the safety and efficacy of optimized IC delivery of CSp in a porcine model of convalescent MI. Methods and Results First, we standardized the size of CSp by modifying culture conditions. Then, dosage was determined by infusing escalating doses of CSp in the LAD of naïve pigs, looking for acute adverse effects. Finally in a randomized efficacy study, 14 mini-pigs received allogeneic CSp (1.3×106) or vehicle one month following MI. Animals underwent MRI before infusion and 1 month later to assess left ventricular (LV) ejection fraction (EF), scar mass and viable mass. In the dosing study, we did not observe any evidence of micro-embolization after CSp infusion. In the post-MI study, CSp preserved LV function, reduced scar mass and increased viable mass whereas placebo did not. Moreover, CSp decreased collagen content, and increased vessel densities and myocardial perfusion. Importantly, IC CSp decreased LV end diastolic pressure and increased cardiac output. Conclusions Intracoronary delivery of CSp is safe. Intracoronary CSp are also remarkably effective in decreasing scar, halting adverse remodeling, increasing myocardial perfusion and improving hemodynamic status post-MI in pigs. Thus, CSp may be viable therapeutic candidates for IC infusion in selected myocardial disorders. PMID:25953823

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

    PubMed

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

    2015-10-01

    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

  15. TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload

    PubMed Central

    Jobe, Lynetta J.; Meléndez, Giselle C.; Levick, Scott P.; Du, Yan; Brower, Gregory L.

    2009-01-01

    Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-α are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-α with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-α inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-α antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-α has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure. PMID:19666842

  16. Relationship between Left Ventricular Structural and Metabolic Remodelling in Type 2 Diabetes Mellitus

    PubMed Central

    Levelt, Eylem; Mahmod, Masliza; Piechnik, Stefan K.; Ariga, Rina; Francis, Jane M.; Rodgers, Christopher T.; Clarke, William T.; Sabharwal, Nikant; Schneider, Jurgen E.; Karamitsos, Theodoros D.; Clarke, Kieran; Rider, Oliver J.; Neubauer, Stefan

    2016-01-01

    Concentric left ventricular (LV) remodelling is associated with adverse cardiovascular events and is frequently observed in patients with type 2 diabetes mellitus (T2DM). Despite this, the cause of concentric remodelling in diabetes, per se, is unclear, but may be related to cardiac steatosis and impaired myocardial energetics. Thus, we investigated the relationship amongst myocardial metabolic changes and LV remodelling in T2DM. Forty-six non-hypertensive T2DM patients and twenty matched controls underwent cardiovascular magnetic resonance to assess LV remodelling (LV mass to LV end diastolic volume ratio-LVMVR), function, pre- and post-contrast tissue characterisation using T1 mapping, 1H-, 31P-magnetic resonance spectroscopy for myocardial triglyceride content (MTG) and phosphocreatine to ATP ratio (PCr/ATP) respectively. When compared to body mass index and blood pressure matched controls, diabetes was associated with: concentric LV remodelling, higher MTG, impaired myocardial energetics and impaired systolic strain indicating a subtle contractile dysfunction. Importantly, cardiac steatosis independently predicted concentric remodelling and systolic strain. Extracellular volume fraction was unchanged, indicating absence of fibrosis. In conclusion, cardiac steatosis may contribute to LV concentric remodelling and contractile dysfunction in diabetes. As cardiac steatosis is modifiable, strategies aimed at reducing myocardial triglyceride may be beneficial in reversing concentric remodelling and improving contractile function in the diabetic heart. PMID:26438611

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. Increased systolic load causes adverse remodeling of fetal aortic and mitral valves.

    PubMed

    Tibayan, Frederick A; Louey, Samantha; Jonker, Sonnet; Espinoza, Herbert; Chattergoon, Natasha; You, Fanglei; Thornburg, Kent L; Giraud, George

    2015-12-15

    While abnormal hemodynamic forces alter fetal myocardial growth, little is known about whether such insults affect fetal cardiac valve development. We hypothesized that chronically elevated systolic load would detrimentally alter fetal valve growth. Chronically instrumented fetal sheep received either a continuous infusion of adult sheep plasma to increase fetal blood pressure, or a lactated Ringer's infusion as a volume control beginning on day 126 ± 4 of gestation. After 8 days, mean arterial pressure was higher in the plasma infusion group (63.0 mmHg vs. 41.8 mmHg, P < 0.05). Mitral annular septal-lateral diameter (11.9 mm vs. 9.1 mm, P < 0.05), anterior leaflet length (7.7 mm vs. 6.4 mm, P < 0.05), and posterior leaflet length (P2; 4.0 mm vs. 3.0 mm, P < 0.05) were greater in the elevated load group. mRNA levels of Notch-1, TGF-β2, Wnt-2b, BMP-1, and versican were suppressed in aortic and mitral valve leaflets; elastin and α1 type I collagen mRNA levels were suppressed in the aortic valves only. We conclude that sustained elevated arterial pressure load on the fetal heart valve leads to anatomic remodeling and, surprisingly, suppression of signaling and extracellular matrix genes that are important to valve development. These novel findings have important implications on the developmental origins of valve disease and may have long-term consequences on valve function and durability. PMID:26354842

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

    PubMed Central

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

    2014-01-01

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

  4. 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

  5. Atorvastatin Therapy during the Peri-Infarct Period Attenuates Left Ventricular Dysfunction and Remodeling after Myocardial Infarction

    PubMed Central

    Sato, Hiroshi; Bi, Qiuli; Hunt, Greg; Vincent, Robert J.; Peng, Yong; Shirk, Gregg; Dawn, Buddhadeb; Bolli, Roberto

    2011-01-01

    Although statins impart a number of cardiovascular benefits, whether statin therapy during the peri-infarct period improves subsequent myocardial structure and function remains unclear. Thus, we evaluated the effects of atorvastatin on cardiac function, remodeling, fibrosis, and apoptosis after myocardial infarction (MI). Two groups of rats were subjected to permanent coronary occlusion. Group II (n = 14) received oral atorvastatin (10 mg/kg/d) daily for 3 wk before and 4 wk after MI, while group I (n = 12) received equivalent doses of vehicle. Infarct size (Masson's trichrome-stained sections) was similar in both groups. Compared with group I, echocardiographic left ventricular ejection fraction (LVEF) and fractional area change (FAC) were higher while LV end-diastolic volume (LVEDV) and LV end-systolic and end-diastolic diameters (LVESD and LVEDD) were lower in treated rats. Hemodynamically, atorvastatin-treated rats exhibited significantly higher dP/dtmax, end-systolic elastance (Ees), and preload recruitable stroke work (PRSW) and lower LV end-diastolic pressure (LVEDP). Morphometrically, infarct wall thickness was greater in treated rats. The improvement of LV function by atorvastatin was associated with a decrease in hydroxyproline content and in the number of apoptotic cardiomyocyte nuclei. We conclude that atorvastatin therapy during the peri-infarct period significantly improves LV function and limits adverse LV remodeling following MI independent of a reduction in infarct size. These salubrious effects may be due in part to a decrease in myocardial fibrosis and apoptosis. PMID:21980426

  6. Exendin-4 attenuates adverse cardiac remodelling in streptozocin-induced diabetes via specific actions on infiltrating macrophages.

    PubMed

    Tate, Mitchel; Robinson, Emma; Green, Brian D; McDermott, Barbara J; Grieve, David J

    2016-01-01

    In addition to its' established metabolic and cardioprotective effects, glucagon-like peptide-1 (GLP-1) reduces post-infarction heart failure via preferential actions on the extracellular matrix (ECM). Here, we investigated whether the GLP-1 mimetic, exendin-4, modulates cardiac remodelling in experimental diabetes by specifically targeting inflammatory/ECM pathways, which are characteristically dysregulated in this setting. Adult mice were subjected to streptozotocin (STZ) diabetes and infused with exendin-4/insulin/saline from 0 to 4 or 4-12 weeks. Exendin-4 and insulin improved metabolic parameters in diabetic mice after 12 weeks, but only exendin-4 reduced cardiac diastolic dysfunction and interstitial fibrosis in parallel with altered ECM gene expression. Whilst myocardial inflammation was not evident at 12 weeks, CD11b-F4/80(++) macrophage infiltration at 4 weeks was increased and reduced by exendin-4, together with an improved cytokine profile. Notably, media collected from high glucose-treated macrophages induced cardiac fibroblast differentiation, which was prevented by exendin-4, whilst several cytokines/chemokines were differentially expressed/secreted by exendin-4-treated macrophages, some of which were modulated in STZ exendin-4-treated hearts. Our findings suggest that exendin-4 preferentially protects against ECM remodelling and diastolic dysfunction in experimental diabetes via glucose-dependent modulation of paracrine communication between infiltrating macrophages and resident fibroblasts, thereby indicating that cell-specific targeting of GLP-1 signalling may be a viable therapeutic strategy in this setting. PMID:26597728

  7. 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

  8. TIMP-2 mutant decreases MMP-2 activity and augments pressure overload induced LV dysfunction and heart failure.

    PubMed

    Givvimani, S; Kundu, S; Narayanan, N; Armaghan, F; Qipshidze, N; Pushpakumar, S; Vacek, T P; Tyagi, S C

    2013-05-01

    Pressure overload induces cardiac extracellular matrix (ECM) remodelling and results in heart failure. ECM remodelling by matrix metalloproteinases (MMPs) is primarily regulated by their target inhibitors, tissue inhibitor of matrix metalloproteinases (TIMPs). It is known that TIMP-2 is highly expressed in myocardium and is required for cell surface activation of pro-MMP-2. We and others have reported that imbalance between angiogenic growth factors and anti-angiogenic factors results in transition from compensatory cardiac hypertrophy to heart failure. We previously reported the pro-angiogenic role of MMP-2 in cardiac compensation, however, the specific role of TIMP-2 during pressure overload is yet unclear. We hypothesize that genetic ablation of TIMP-2 exacerbates the adverse cardiac matrix remodelling due to lack of pro-angiogenic MMP-2 and increase in anti-angiogenic factors during pressure overload stress and results in severe heart failure. To verify this, ascending aortic banding (AB) was created to mimic pressure overload, in wild type C57BL6/J and TIMP-2-/- (model of MMP-2 deficiency) mice. Left ventricular (LV) function assessed by echocardiography and pressure-volume loop studies showed severe LV dysfunction in TIMP-2-/- AB mice compared to controls. Expression of MMP-2, vascular endothelial growth factor (VEGF) was decreased and expression of MMP-9, anti-angiogenic factors endostatin and angiostatin was increased in TIMP-2-/- AB mice compared with wild type AB mice. Connexins (Cx) are the gap junction proteins that are widely present in the myocardium and play an important role in endothelial-myocyte coupling. Our results showed that expression of Cx 37 and 43 was decreased in TIMP-2-/- AB mice compared with corresponding wild type controls. These results suggest that genetic ablation of TIMP-2 decrease the expression of pro-angiogenic MMP-2, VEGF and increases anti-angiogenic factors that results in exacerbated abnormal ventricular remodelling leading

  9. Targeted Regional Injection of Biocomposite Microspheres Alters Post Myocardial Infarction Remodeling and Matrix Proteolytic Pathways

    PubMed Central

    Dixon, Jennifer A.; Gorman, Robert C.; Stroud, Robert E.; Mukherjee, Rupak; Meyer, Evan C.; Baker, Nathaniel L.; Morita, Masato; Hamamoto, Hirotsugu; Ryan, Liam P.; Gorman, Joseph H.; Spinale, Francis G.

    2011-01-01

    Background While localized delivery of biocomposite materials, such as calcium hydroxyapatite (CHAM), have been demonstrated to potentially attenuate adverse LV remodeling post-myocardial infarction (MI), the underlying biological mechanisms for this effect remain unclear. This study tested the hypothesis that targeted CHAM injections would alter proteolytic pathways (matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs)), and be associated with parameters of post-MI LV remodeling. Methods and Results MI was induced in adult sheep followed by 20 targeted injections of a total volume of 1.3 mL (n=6) or 2.6 mL of CHAM (n=5), or saline (n=13), and LV end-diastolic volume (EDV) and MMP/TIMP profiles in the MI region were measured at 8 weeks post-MI. LV EDV decreased with 2.6 mL CHAM vs MI Only (105.4±7.5 vs 80.6±4.2 respectively, p<0.05) but not with 1.3 mL CHAM (94.5±5.0, p=0.32). However, MI thickness increased by 2-fold in both CHAM groups compared to MI Only (p<0.05). MMP-13 increased 40-fold in the MI Only group (p<0.05) but fell by over 6-fold in both CHAM groups (p<0.05). MMP-7 increased approximately 1.5-fold in the MI Only group (p<0.05) but decreased to referent control values in both CHAM groups in the MI region (p<0.05). Collagen content was reduced by approximately 30% in the CHAM groups compared to MI Only (p<0.05). Conclusions Differential effects on LV remodeling and MMP/TIMP profiles occurred with CHAM. Thus, targeted injections of a biocomposite material can favorably affect the post-MI remodeling process and therefore holds promise as a treatment strategy in and of itself, or as a matrix with potentially synergistic effects with localized pharmacologic or cellular therapies. PMID:21911817

  10. 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.

  11. Heterogeneous fate of perfusion and contraction after anterior wall acute myocardial infarction and effects on left ventricular remodeling.

    PubMed

    Marcassa, C; Galli, M; Bolli, R; Temporelli, P L; Campini, R; Giannuzzi, P

    1998-12-15

    After acute myocardial infarction, patency of infarct vessel and extent of left venticular (LV) dysfunction are major determinants of ventricular remodeling. Spontaneous, delayed reperfusion in the infarct zone occurs in a sizeable number of patients well after the subacute phase. The aim of this study was to determine the relation between the occurrence of this spontaneous, delayed reperfusion and LV remodeling. In 84 patients, resting LV volumes, topography, regional function, and perfusion were quantitatively evaluated by 2-dimensional echocardiography and sestamibi tomography 5 weeks (study 1) and 7 months (study 2) after anterior Q-wave infarction. At study 2, LV end-diastolic volume increased by > 15% in 17 patients (20%, LV remodeling); they had already had at study 1 significantly larger LV volumes, more severe hypoperfusion and wall motion abnormalities, and greater regional dilation than patients with stable LV volumes. Delayed reperfusion occurred in 8 of 17 patients with and in 42 of 67 patients without LV remodeling (47% vs 63%; p=NS). At study 2, LV regional dilation and end-diastolic volumes were stable in patients with, but increased in patients without, spontaneous reperfusion (from 25+/-24% to 29+/-26% at study 2 [p<0.05] and from 65+/-14 to 68+/-18 ml/m2 [p <0.05]). At multivariate analysis, however, regional ventricular dilation at study 1 was the sole predictor of further LV remodeling. Thus, after acute myocardial infarction, spontaneous reperfusion occurring after 5 weeks plays only a minor role in influencing LV remodeling. Benefits from delayed reperfusion seem limited to patients with preserved LV volumes; patients with an enlarged left ventricle 5 weeks after acute infarction are prone to further LV remodeling, irrespective of delayed reperfusion. PMID:9874047

  12. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: Functional recovery and reverse remodeling

    PubMed Central

    Williams, Adam R.; Trachtenberg, Barry; Velazquez, Darcy L.; McNiece, Ian; Altman, Peter; Rouy, Didier; Mendizabal, Adam M.; Pattany, Pradip M.; Lopera, Gustavo A.; Fishman, Joel; Zambrano, Juan P.; Heldman, Alan W.; Hare, Joshua M.

    2012-01-01

    Rationale Transcatheter, intramyocardial injections of bone marrow derived cell therapy produces reverse remodeling in large animal models of ischemic cardiomyopathy. Objective We used cardiac magnetic resonance imaging (CMR) in patients with LV dysfunction related to remote myocardial infarction (MI) to test the hypothesis that bone marrow progenitor cell injection cause functional recovery of scarred myocardium and reverse remodeling. Methods and Results Eight patients (age 57.2±13.3) received transendocardial, intramyocardial injection of autologous bone marrow progenitor cells (mononuclear or mesenchymal stem cells) in LV scar and border zone. All patients tolerated the procedure with no serious adverse events. CMR at 1-year demonstrated a decrease in end-diastolic volume (208.7±20.4 vs. 167.4±7.32mL; p=0.03), a trend towards decreased end-systolic volume (142.4±16.5 vs. 107.6±7.4mL; p=0.06), decreased infarct size (p<0.05), and improved regional LV function by peak Ecc in the treated infarct zone (-8.1±1.0 vs. -11.4±1.3; p=0.04). Improvements in regional function were evident at 3 months, while the changes in chamber dimensions were not significant until 6 months. Improved regional function in the infarct zone strongly correlated with reduction of EDV (r2=0.69, p=0.04) and ESV (r2=0.83, p=0.01). Conclusions These data suggest that transcatheter, intramyocardial injections of autologous bone marrow progenitor cells improve regional contractility of a chronic myocardial scar and these changes predict subsequent reverse remodeling. The findings support the potential clinical benefits of this new treatment strategy and ongoing randomized clinical trials. PMID:21415390

  13. 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

  14. Moderate mitral regurgitation accelerates left ventricular remodeling after postero-lateral myocardial infarction

    PubMed Central

    Soleimani, Mehrdad; Khazalpour, Michael; Cheng, Guangming; Zhang, Zhihong; Acevedo-Bolton, Gabriel; Saloner, David A.; Mishra, Rakesh; Wallace, Arthur W.; Guccione, Julius M.; Ge, Liang; Ratcliffe, Mark B.

    2012-01-01

    Background Chronic ischemic mitral regurgitation (CIMR: MR) is associated with poor outcome. However, the effect of CIMR on left ventricular (LV) remodeling after postero-lateral myocardial infarction (MI) remains controversial. We tested the hypothesis that moderate MR accelerates LV remodeling after postero-lateral MI. Methods/Results Postero-lateral MI was created in 10 sheep. Cardiac MRI was performed 2 weeks before and 2, 8 and 16 weeks after MI. LV and right ventricular (RV) volumes were measured and regurgitant volume (RegurgVolume) calculated as the difference between LV and RV stroke volumes. Multivariate mixed effect regression showed that LV volumes at end-diastole (ED) and end-systole (ES) and LV sphericity were strongly correlated with both RegurgVolume (p<0.0001, p=0.0086 and p=0.0007 respectively) and %Infarct area (p=0.0156, 0=0.0307, and p<0.0001 respectively). On the other hand, while LV hypertrophy (LV wall volume) increased from 2 to 16 weeks post-MI there was no effect of either RegurgVolume or %Infarct. Conclusions Moderate mitral regurgitation accelerates LV remodeling after postero-lateral MI. Further studies are needed to determine whether mitral valve repair is able to slow or reverse MI remodeling after postero-lateral MI. PMID:21945222

  15. LV software support for supersonic flow analysis

    NASA Technical Reports Server (NTRS)

    Bell, William A.

    1992-01-01

    The software for configuring a Laser Velocimeter (LV) counter processor system was developed using structured design. The LV system includes up to three counter processors and a rotary encoder. The software for configuring and testing the LV system was developed, tested, and included in an overall software package for data acquisition, analysis, and reduction. Error handling routines respond to both operator and instrument errors which often arise in the course of measuring complex, high-speed flows. The use of networking capabilities greatly facilitates the software development process by allowing software development and testing from a remote site. In addition, high-speed transfers allow graphics files or commands to provide viewing of the data from a remote site. Further advances in data analysis require corresponding advances in procedures for statistical and time series analysis of nonuniformly sampled data.

  16. Interleukin-2/Anti-Interleukin-2 Immune Complex Attenuates Cardiac Remodeling after Myocardial Infarction through Expansion of Regulatory T Cells

    PubMed Central

    Zeng, Zhipeng; Yu, Kunwu; Chen, Long; Li, Weihua; Xiao, Hong; Huang, Zhengrong

    2016-01-01

    CD4+CD25+Foxp3+ regulatory T cells (Treg cells) have protective effects in wound healing and adverse ventricular remodeling after myocardial infarction (MI). We hypothesize that the interleukin- (IL-) 2 complex comprising the recombinant mouse IL-2/anti-IL-2 mAb (JES6-1) attenuates cardiac remodeling after MI through the expansion of Treg. Mice were subjected to surgical left anterior descending coronary artery ligation and treated with either PBS or IL-2 complex. The IL-2 complex significantly attenuates ventricular remodeling, as demonstrated by reduced infarct size, improved left ventricular (LV) function, and attenuated cardiomyocyte apoptosis. The IL-2 complex increased the percentage of CD4+CD25+Foxp3+ Treg cells, which may be recruited to the infarcted heart, and decreased the frequencies of IFN-γ- and IL-17-producing CD4+ T helper (Th) cells among the CD4+Foxp3− T cells in the spleen. Furthermore, the IL-2 complex inhibited the gene expression of proinflammatory cytokines as well as macrophage infiltrates in the infarcted myocardium and induced the differentiation of macrophages from M1 to M2 phenotype in border zone of infarcted myocardium. Our studies indicate that the IL-2 complex may serve as a promising therapeutic approach to attenuate adverse remodeling after MI through expanding Treg cells specifically. PMID:27144181

  17. Efficacy of an inactivated FeLV vaccine compared to a recombinant FeLV vaccine in minimum age cats following virulent FeLV challenge.

    PubMed

    Stuke, Kristin; King, Vickie; Southwick, Kendra; Stoeva, Mira I; Thomas, Anne; Winkler, M Teresa C

    2014-05-01

    The aim of the study was to determine the efficacy of an inactivated feline leukemia virus (FeLV) vaccine (Versifel(®) FeLV, Zoetis.) compared to a recombinant FeLV vaccine (Purevax(®) FeLV, Merial Animal Health) in young cats, exposed under laboratory conditions to a highly virulent challenge model. The study was designed to be consistent with the general immunogenicity requirements of the European Pharmacopoeia 6.0 Monograph 01/2008:1321-Feline Leukaemia Vaccine (Inactivated) with the exception that commercial-strength vaccines were assessed. Fifty seronegative cats (8-9 weeks old) were vaccinated subcutaneously on two occasions, three weeks apart, with either placebo (treatment group T01), Versifel FeLV Vaccine (treatment group T02), or Purevax FeLV Vaccine (treatment group T03) according to the manufacturer's directions. Cats were challenged three weeks after the second vaccination with a virulent FeLV isolate (61E strain). Persistent FeLV antigenemia was determined from 3 to 15 weeks postchallenge. Bone marrow samples were tested for the presence of FeLV proviral DNA to determine FeLV latent infection. At week 15 after challenge with the virulent FeLV 61E strain, the Versifel FeLV Vaccine conferred 89.5% protection against FeLV persistent antigenemia and 94.7% protection against FeLV proviral DNA integration in bone marrow cells. In comparison, the Purevax FeLV Vaccine conferred 20% protection against FeLV persistent antigenemia and 35% protection against FeLV proviral DNA integration in bone marrow cells following challenge. The data from this study show that the Versifel FeLV Vaccine was efficacious in preventing both FeLV persistent p27 antigenemia and FeLV proviral DNA integration in bone marrow cells of cats challenged with this particular challenge model under laboratory conditions and provided better protection than Purevax FeLV in this experimental challenge model with highly virulent FeLV. PMID:24662705

  18. 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.

  19. Roles of ghrelin in left-ventricular remodelling after acute myocardial infarction

    PubMed Central

    Kondo, Hideyuki; Hojo, Yukihiro; Takahashi, Nozomu; Ikemoto, Tomokazu; Aoki, Hirotaka; Dezaki, Katsuya; Kario, Kazuomi; Katsuki, Takaaki; Yada, Toshihiko; Shimada, Kazuyuki

    2010-01-01

    Objective The purpose of this study was to elucidate the role of ghrelin after acute myocardial infarction (AMI) in left ventricular (LV) remodelling. Design Prospective observational study. Setting Jichi Medical University Hospital. Patients Fifty consecutive patients experiencing their first AMI. Interventions Ghrelin was measured on the day of admission, day 7, day 14 and 6 months after AMI. Patients were treated by percutaneous coronary intervention, and successful myocardial reperfusion was accomplished within 12 h after onset. To analyse LV remodelling, the authors performed left ventriculographies on the day of admission and 6 months after AMI. Main outcome measures Changes in LV volume. Results Plasma ghrelin increased significantly after AMI (admission: 40.9±7.3; day 7: 89.5±11.0; day 14: 92.6±11.8 fmol/ml, p<0.0001). There was a significant correlation between ghrelin on day 14 and changes in LV volume over 6 months (r=+0.46, p<0.001). Multivariate regression analysis showed that ghrelin on day 14 is a significant predictor of LV remodelling after AMI (β=+0.44, p=0.001). Conclusion To our knowledge, this is the first report that shows a relation between circulating ghrelin after AMI and the progression of LV remodelling in the chronic phase. The elevation of ghrelin after AMI might be a compensatory mechanism to attenuate LV remodelling.

  20. Myocardial Remodeling: Cellular and Extracellular Events and Targets

    PubMed Central

    Dixon, Jennifer A.; Spinale, Francis G.

    2011-01-01

    The focus of this review is on translational studies utilizing large-animal models and clinical studies that provide fundamental insight into cellular and extracellular pathways contributing to post–myocardial infarction (MI) left ventricle (LV) remodeling. Specifically, both large-animal and clinical studies have examined the potential role of endogenous and exogenous stem cells to alter the course of LV remodeling. Interestingly, there have been alterations in LV remodeling with stem cell treatment despite a lack of long-term cell engraftment. The translation of the full potential of stem cell treatments to clinical studies has yet to be realized. The modulation of proteolytic pathways that contribute to the post-MI remodeling process has also been examined. On the basis of recent large-animal studies, there appears to be a relationship between stem cell treatment post-MI and the modification of proteolytic pathways, generating the hypothesis that stem cells leave an echo effect that moderates LV remodeling. PMID:21314431

  1. 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

  2. Mast Cell Inhibition Attenuates Cardiac Remodeling and Diastolic Dysfunction in Middle-aged, Ovariectomized Fischer 344 × Brown Norway Rats.

    PubMed

    Wang, Hao; da Silva, Jaqueline; Alencar, Allan; Zapata-Sudo, Gisele; Lin, Marina R; Sun, Xuming; Ahmad, Sarfaraz; Ferrario, Carlos M; Groban, Leanne

    2016-07-01

    The incidence of left ventricular diastolic dysfunction (LVDD) increases in women after menopause, yet the mechanisms are unclear. Because mast cells participate in the pathological processes of various cardiac diseases, we hypothesized that mast cell inhibition would protect against estrogen loss-induced LVDD. The mast cell stabilizer, cromolyn sodium (30 mg·kg·d), or vehicle was administered subcutaneously by osmotic minipump to ovariectomized (OVX) female Fischer 344 × Brown Norway (F344BN) rats starting at 4 weeks after surgery. Eight weeks after OVX, systolic blood pressure increased by 20% in OVX versus sham rats, and this effect was attenuated after 4 weeks of cromolyn treatment. Also, cromolyn mitigated the adverse reductions in myocardial relaxation (e') and increases in left ventricle (LV) filling pressures (E/e'), LV mass, wall thicknesses, and interstitial fibrosis from OVX. Although cardiac mast cell number was increased after OVX, cardiac chymase activity was not overtly altered by estrogen status and tended to decrease by cromolyn. Contrariwise, Ang II content was greater in hearts of OVX versus sham rats, and cromolyn attenuated this effect. Taken together, mast cell inhibition with cromolyn attenuates LV remodeling and LVDD in OVX-Fischer 344 × Brown Norway rats possibly through actions on the heart level and/or through vasodilatory effects at the vascular level. PMID:26981683

  3. Two cases of FeLV-associated dermatoses.

    PubMed

    Favrot, C; Wilhelm, S; Grest, P; Meli, M L; Hofmann-Lehmann, R; Kipar, A

    2005-12-01

    Two cases of feline leukaemia virus (FeLV)-associated dermatosis are described. The first cat was affected by an ulcerative dermatitis identified as a giant-cell dermatosis. The second case was a cutaneous lymphoma. In both cases, FeLV antigens and FeLV genome were demonstrated in the affected skin immunologically and with polymerase chain reaction, respectively. The first case suggests that, like other retroviruses, at least some strains of FeLV can induce syncytium formation. As FeLV antigens and genome were demonstrated in a serologically negative cat, the second case suggests that focal skin FeLV replication may occur. FeLV-associated dermatoses are rare skin conditions that may be under-diagnosed. PMID:16359309

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. Activation of GPR30 attenuates diastolic dysfunction and left ventricle remodelling in oophorectomized mRen2.Lewis rats

    PubMed Central

    Wang, Hao; Jessup, Jewell A.; Lin, Marina S.; Chagas, Clarissa; Lindsey, Sarah H.; Groban, Leanne

    2012-01-01

    Aims GPR30 is a novel oestrogen receptor expressed in various tissues, including the heart. We determined the role of GPR30 in the maintenance of left ventricular (LV) structure and diastolic function after the surgical loss of ovarian hormones in the female mRen2.Lewis rat, a model emulating the cardiac phenotype of the post-menopausal woman. Methods and results Bilateral oophorectomy (OVX) or sham surgery was performed in study rats; the selective GPR30 agonist, G-1 (50 µg/kg/day), or vehicle was given subcutaneously to OVX rats from 13–15 weeks of age. Similar to the cardiac phenotype of sham rats, G-1 preserved diastolic function and structure relative to vehicle-treated OVX littermates independent of changes in blood pressure. G-1 limited the OVX-induced increase in LV filling pressure, LV mass, wall thickness, interstitial collagen deposition, atrial natriuretic factor and brain natriuretic peptide mRNA levels, and cardiac NAD(P)H oxidase 4 (NOX4) expression. In vitro studies showed that G-1 inhibited angiotensin II-induced hypertrophy in H9c2 cardiomyocytes, evidenced by reductions in cell size, protein content per cell, and atrial natriuretic factor mRNA levels. The GPR30 antagonist, G15, inhibited the protective effects of both oestradiol and G-1 on this hypertrophy. Conclusion These data show that the GPR30 agonist G-1 mitigates the adverse effects of oestrogen loss on LV remodelling and the development of diastolic dysfunction in the study rats. This expands our knowledge of the sex-specific mechanisms underlying diastolic dysfunction and provides a potential therapeutic target for reducing the progression of this cardiovascular disease process in post-menopausal women. PMID:22328091

  11. 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

  12. 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

  13. Human relaxin gene expression delivered by bioreducible dendrimer polymer for post-infarct cardiac remodeling in rats.

    PubMed

    Lee, Young Sook; Choi, Joung-Woo; Oh, Jung-Eun; Yun, Chae-Ok; Kim, Sung Wan

    2016-08-01

    In consensus, myocardial infarction (MI) is defined as irreversible cell death secondary to prolonged ischemia in heart. The aim of our study was to evaluate the therapeutic potential of anti-fibrotic human Relaxin-expressing plasmid DNA with hypoxia response element (HRE) 12 copies (HR1) delivered by a dendrimer type PAM-ABP polymer G0 (HR1/G0) after MI on functional, hemodynamic, geometric, and cardiac extracellular matrix (ECM) remodeling in rats. HR1/G0 demonstrated significantly improved LV systolic function, hemodynamic parameters, and geometry on 1 wk and 4 wks after MI in rats, compared with I/R group. The resolution of regional wall motional abnormalities and the increased blood flow of infarct-related coronary artery supported functional improvements of HR1/G0. Furthermore, HR1/G0 polyplex showed favorable post-infarct cardiac ECM remodeling reflected on the favorable cardiac ECM compositions. Overall, this is the first study, which presented an advanced platform for the gene therapy that reverses adverse cardiac remodeling after MI with a HR1 gene delivered by a bioreducible dendrimer polymer in the cardiac ECM. PMID:27174688

  14. Visceral Adiposity and Left Ventricular Remodeling: the Multi-Ethnic Study of Atherosclerosis

    PubMed Central

    Abbasi, Siddique A.; Hundley, W. Gregory; Bluemke, David A.; Blankstein, Ron; Jerosch-Herold, Michael; Lima, Joao A.C.; Allison, Matthew A.; Murthy, Venkatesh L.; Shah, Ravi V.

    2015-01-01

    Background and Aims Visceral fat (VF) is a source of pro-inflammatory adipokines implicated in cardiac remodeling. We sought to determine the impact of visceral fat (VF) and subcutaneous fat (SQ) depots on left ventricular (LV) structure, function, and geometry in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods and Results We performed a post-hoc analysis on 1,151 participants from MESA with cardiac magnetic resonance quantification of LV mass and LV mass-to-volume ratio (LVMV, an index of concentricity) and computed tomographic-derived SQ and VF area. Multivariable regression models to estimate association between height-indexed SQ and VF area (per cm2/m) with height-indexed LV mass (per height2.7) and LVMV were constructed, adjusted for clinical, biochemical, and demographic covariates. We found that both VF and SQ area were associated with height-indexed LV mass (ρ =0.36 and 0.12, P<0.0001, respectively), while only VF area was associated with LVMV (ρ =0.28, P<0.0001). Individuals with above-median VF had lower LV ejection fraction, greater indexed LV volumes and mass, and higher LVMV (all P < 0.001). In multivariable models adjusted for weight, VF (but not SQ) area was associated with LV concentricity and LV mass index, across both sexes. Conclusion Visceral adiposity is independently associated with LV concentricity, a precursor to heart failure. Further study into the role of VF in LV remodeling as a potential therapeutic target is warranted. PMID:26033394

  15. Cardiac remodeling in rats with renal failure shows interventricular differences.

    PubMed

    Svíglerová, Jitka; Kuncová, Jitka; Nalos, Lukás; Holas, Jaromír; Tonar, Zbynek; Rajdl, Daniel; Stengl, Milan

    2012-09-01

    Chronic renal failure (CRF) is associated with an increased incidence of cardiovascular diseases. Intensive research revealed a number of alterations in the heart during CRF; however, possible interventricular differences in CRF-induced cardiac remodeling have so far not been addressed. CRF was induced by two-stage surgical 5/6 nephrectomy (NX) in male Wistar rats. Cellular hypertrophy was quantified using immunohistological morphometric analysis. Contraction force and membrane potential were recorded in left and right ventricle papillary muscles with an isometric force transducer and high-resistance glass microelectrodes. Hypertrophy was present in the left ventricle (LV) of NX animals, but not in the right ventricle (RV) of NX animals, as documented by both ventricle/body weight ratios and cellular morphometric analysis of the cross-sectional area of myocytes. The contraction force was reduced in the LV of NX animals but increased in the RV of NX animals compared with sham-operated rats. Rest potentiation of contraction force was relatively more pronounced in the LV of NX rats. Fifty percent substitution of extracellular sodium with lithium significantly increased the contraction force only in the LV of NX animals. Action potential durations were shortened in both ventricles of CRF animals. Cardiac structural and contractile remodeling in CRF shows significant interventricular differences. CRF induces hypertrophy of the LV but not of the RV. LV hypertrophy was associated with a reduction of contraction force, whereas in the RV, the contraction force was enhanced. Partial recovery of contractile function of the LV by rest potentiation or lithium substitution indicates a role of the Na(+)/Ca(2+) exchanger in this phenomenon. PMID:22929800

  16. 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

  17. 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

  18. 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

  19. 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

  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. Stem cell mechanisms during left ventricular remodeling post-myocardial infarction: Repair and regeneration

    PubMed Central

    Zamilpa, Rogelio; Navarro, Mary M; Flores, Iris; Griffey, Sy

    2014-01-01

    Post-myocardial infarction (MI), the left ventricle (LV) undergoes a series of events collectively referred to as remodeling. As a result, damaged myocardium is replaced with fibrotic tissue consequently leading to contractile dysfunction and ultimately heart failure. LV remodeling post-MI includes inflammatory, fibrotic, and neovascularization responses that involve regulated cell recruitment and function. Stem cells (SCs) have been transplanted post-MI for treatment of LV remodeling and shown to improve LV function by reduction in scar tissue formation in humans and animal models of MI. The promising results obtained from the application of SCs post-MI have sparked a massive effort to identify the optimal SC for regeneration of cardiomyocytes and the paradigm for clinical applications. Although SC transplantations are generally associated with new tissue formation, SCs also secrete cytokines, chemokines and growth factors that robustly regulate cell behavior in a paracrine fashion during the remodeling process. In this review, the different types of SCs used for cardiomyogenesis, markers of differentiation, paracrine factor secretion, and strategies for cell recruitment and delivery are addressed. PMID:25068021

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

    PubMed Central

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

    2014-01-01

    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. PMID:24876358

  3. 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. PMID:24876358

  4. 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

  5. Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial

    PubMed Central

    Cassidy, J; Douillard, J-Y; Twelves, C; McKendrick, J J; Scheithauer, W; Bustová, I; Johnston, P G; Lesniewski-Kmak, K; Jelic, S; Fountzilas, G; Coxon, F; Díaz-Rubio, E; Maughan, T S; Malzyner, A; Bertetto, O; Beham, A; Figer, A; Dufour, P; Patel, K K; Cowell, W; Garrison, L P

    2006-01-01

    Oral capecitabine (Xeloda®) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings £3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings £1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK. PMID:16622438

  6. 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

  7. 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

  8. Mechanism of chromatin remodeling.

    PubMed

    Lorch, Yahli; Maier-Davis, Barbara; Kornberg, Roger D

    2010-02-23

    Results from biochemical and structural studies of the RSC chromatin-remodeling complex prompt a proposal for the remodeling mechanism: RSC binding to the nucleosome releases the DNA from the histone surface and initiates DNA translocation (through one or a small number of DNA base pairs); ATP binding completes translocation, and ATP hydrolysis resets the system. Binding energy thus plays a central role in the remodeling process. RSC may disrupt histone-DNA contacts by affecting histone octamer conformation and through extensive interaction with the DNA. Bulging of the DNA from the octamer surface is possible, and twisting is unavoidable, but neither is the basis of remodeling. PMID:20142505

  9. 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.

  10. The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy

    PubMed Central

    Gold, Michael R.; Birgersdotter-Green, Ulrika; Singh, Jagmeet P.; Ellenbogen, Kenneth A.; Yu, Yinghong; Meyer, Timothy E.; Seth, Milan; Tchou, Patrick J.

    2011-01-01

    Aims The aim of the present study was to evaluate the relationship between left ventricular (LV) electrical delay, as measured by the QLV interval, and outcomes in a prospectively designed substudy of the SMART-AV Trial. Methods and results This was a multicentre study of patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) defibrillator implantation. In 426 subjects, QLV was measured as the interval from the onset of the QRS from the surface ECG to the first large peak of the LV electrogram. Left ventricular volumes were measured by echocardiography at baseline and after 6 months of CRT by a blinded core laboratory. Quality of life (QOL) was assessed by a standardized questionnaire. When separated by quartiles based on QLV duration, reverse remodelling response rates (>15% reduction in LV end systolic volume) increased progressively from 38.7 to 68.4% and QOL response rate (>10 points reduction) increased from 50 to 72%. Patients in the highest quartile of QLV had a 3.21-fold increase (1.58–6.50, P = 0.001) in their odds of a reverse remodelling response after correcting for QRS duration, bundle branch block type, and clinical characteristics by multivariate logistic regression analysis. Conclusion Electrical dyssynchrony, as measured by QLV, was strongly and independently associated with reverse remodelling and QOL with CRT. Acute measurements of QLV may be useful to guide LV lead placement. PMID:21875862

  11. Albuminuria is Independently Associated with Cardiac Remodeling, Abnormal Right and Left Ventricular Function, and Worse Outcomes in Heart Failure with Preserved Ejection Fraction

    PubMed Central

    Katz, Daniel H.; Burns, Jacob A.; Aguilar, Frank G.; Beussink, Lauren; Shah, Sanjiv J.

    2014-01-01

    Objectives To determine the relationship between albuminuria and cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). Background Albuminuria, a marker of endothelial dysfunction, has been associated with adverse cardiovascular outcomes in HFpEF. However, the relationship between albuminuria and cardiac structure/function in HFpEF has not been well studied. Methods We measured urinary albumin-to-creatinine ratio (UACR) and performed comprehensive echocardiography, including tissue Doppler imaging and right ventricular (RV) evaluation, in a prospective study of 144 patients with HFpEF. Multivariable-adjusted linear regression was used to determine the association between UACR and echocardiographic parameters. Cox proportional hazards analyses were used to determine the association between UACR and outcomes. Results The mean age was 66±11 years, 62% were female, and 42% were African-American. Higher UACR was associated with greater left ventricular (LV) mass, lower preload-recruitable stroke work, and lower global longitudinal strain. Higher UACR was also significantly associated with RV remodeling (for each doubling of UACR, RV wall thickness was 0.9 mm higher [95% confidence interval (CI) 0.05–0.14 mm; P=0.001, adjusted P=0.01]) and worse RV systolic function (for each doubling of UACR, RV fractional area change was 0.56% lower [95% CI 0.14–0.98%; P=0.01, adjusted P=0.03]. The association between UACR and RV parameters persisted after excluding patients with macroalbuminuria (UACR > 300 mg/g). Increased UACR was also independently associated with worse outcomes. Conclusions In HFpEF, increased UACR is a prognostic marker and is associated with increased RV and LV remodeling, and longitudinal systolic dysfunction. PMID:25282032

  12. Ventricular Remodeling in Heart Failure with Preserved Ejection Fraction

    PubMed Central

    Shah, Amil M.

    2014-01-01

    Heart failure with preserved ejection fraction (HFpEF) is common, increasing in prevalence, and causes substantial morbidity and mortality. HFpEF has commonly been viewed as an expression of advanced hypertensive heart disease, with a cardiac phenotype characterized by an increase in wall thickness-to-chamber radius ratio (concentric hypertrophy). However, marked clinical heterogeneity within this syndrome is now well appreciated, and is mirrored in the variability in left ventricular structure. A review of larger imaging studies from epidemiology and clinical trial cohorts demonstrate that while concentric LV remodeling is common, it is by no means universal and many patients demonstrate normal LV geometry or even an eccentric pattern. More detailed assessment of cardiac structure and function in broader HFpEF populations will be necessary to better define the prevalence, determinants, and prognostic relevance of these measures, which may in turn serve as a foundation to identify pathophysiologically relevant sub-phenotypes within this diverse syndrome. PMID:24097113

  13. Hypercholesterolaemia exacerbates ventricular remodelling after myocardial infarction in the rat: role of angiotensin II type 1 receptors

    PubMed Central

    Mączewski, M; Mączewska, J; Duda, M

    2008-01-01

    Background and purpose: Diet-induced hypercholesterolaemia exacerbates post-myocardial infarction (MI) ventricular remodelling and heart failure, but the mechanism of this phenomenon remains unknown. This study examined whether worsening of post-MI ventricular remodelling induced by dietary hypercholesterolaemia was related to upregulation of angiotensin II type 1 (AT1) receptor in the rat heart. Experimental approach: MI was induced surgically in rats fed normal or high cholesterol diet. Both groups of rats were then assigned to control, atorvastatin, losartan or atorvastatin+losartan-treated subgroups and followed for 8 weeks. Left ventricular (LV) function was assessed with echocardiography. In isolated hearts, LV pressures were measured with a latex balloon and a tip catheter. AT1-receptor density was assessed in LV membranes with radioligand-binding assays. Key results: High cholesterol diet exacerbated LV dilation and dysfunction in post-MI hearts. Atorvastatin or losartan prevented these hypercholesterolaemia-induced effects, whereas their combination was not more effective than each drug alone. AT1 receptors were upregulated 8 weeks after MI, this was further increased by hypercholesterolaemia and restored to baseline levels by atorvastatin. Conclusions and implications: Hypercholesterolaemia exacerbated LV remodelling and dysfunction in post-MI rat hearts and upregulated cardiac AT1 receptors. All these effects were effectively prevented by atorvastatin. Thus, the pleiotropic statin effects may include interference with the renin-angiotensin system through downregulation of AT1 receptors. PMID:18536757

  14. 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

  15. 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

  16. 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

  17. 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)

  18. 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

  19. LV motion tracking from 3D echocardiography using textural and structural information.

    PubMed

    Myronenko, Andriy; Song, Xubo; Sahn, David J

    2007-01-01

    Automated motion reconstruction of the left ventricle (LV) from 3D echocardiography provides insight into myocardium architecture and function. Low image quality and artifacts make 3D ultrasound image processing a challenging problem. We introduce a LV tracking method, which combines textural and structural information to overcome the image quality limitations. Our method automatically reconstructs the motion of the LV contour (endocardium and epicardium) from a sequence of 3D ultrasound images. PMID:18044597

  20. 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

  1. 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.

  2. 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...

  3. 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

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

    PubMed Central

    Zhang, Xiaochun; Leng, Weiling

    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

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

    PubMed

    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

  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. Immunoregulation of bone remodelling

    PubMed Central

    Singh, Ajai; Mehdi, Abbass A; Srivastava, Rajeshwer N; Verma, Nar Singh

    2012-01-01

    Remodeling, a continuous physiological process maintains the strength of the bones, which maintains a delicate balance between bone formation and resorption process. This review gives an insight to the complex interaction and correlation between the bone remodeling and the corresponding changes in host immunological environment and also summarises the most recent developments occuring in the understanding of this complex field. T cells, both directly and indirectly increase the expression of receptor activator of nuclear factor kB ligand (RANKL); a vital step in the activation of osteoclasts, thus positively regulates the osteoclastogenesis. Though various cytokines, chemikines, transcription factors and co-stimulatory molecules are shared by both skeletal and immune systems, but researches are being conducted to establish and analyse their role and / or control on this complex but vital process. The understanding of this part of research may open new horizons in the management of inflammatory and autoimmune diseases, resulting into bone loss and that of osteoporosis also. PMID:22837895

  8. Prevention of increases in blood pressure and left ventricular mass and remodeling of resistance arteries in young New Zealand genetically hypertensive rats: the effects of chronic treatment with valsartan, enalapril and felodipine.

    PubMed

    Ledingham, J M; Phelan, E L; Cross, M A; Laverty, R

    2000-01-01

    The relative efficacy of three antihypertensive drugs in the prevention of further elevation of blood pressure (BP) and cardiovascular structural remodeling in 4-week-old genetically hypertensive (GH) rats was studied by means of two complementary methods, stereology and myography. Four to 10-week-old GH rats were treated with valsartan (10 mg/kg/day), enalapril (10 mg/kg/day) or felodipine (30 mg/kg/day). Untreated GH and normotensive control rats of Wistar origin served as controls. Tail-cuff systolic SBP was measured weekly and left ventricular (LV) mass determined at the end of the experiment. Mesenteric resistance arteries (MRA) were either fixed by perfusion, embedded in Technovit and sections stained for stereological analysis, or mounted on a wire myograph for structural and functional measurements. BP and LV mass were significantly reduced by all drugs; decreases in BP and LV mass were smaller after felodipine treatment. Valsartan and enalapril caused a decrease in BP to normotensive control values. Felodipine kept BP at the 4-week level and prevented further rise with age. Valsartan caused hypotrophic outward remodeling of MRA, enalapril eutrophic outward remodeling and felodipine hypotrophic remodeling. Myograph measurements showed remodeling of the same order. While all drugs lowered the media/lumen ratio in GH to normal, the outward remodeling after valsartan and enalapril indicates that valsartan and enalapril might be more effective in reversing the inward remodeling of resistance arteries found in essential hypertension. PMID:10754398

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

    PubMed

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

    2015-07-01

    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

  10. 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

  11. 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

  12. Characterization of Thiobacillus thioparus LV43 and its distribution in a chemoautotrophically based groundwater ecosystem.

    PubMed Central

    Vlasceanu, L; Popa, R; Kinkle, B K

    1997-01-01

    Bacterial strain LV43 was previously isolated from a floating microbial mat located in Movile Cave, the access point to a chemoautotrophically based groundwater ecosystem in southern Romania. This gram-negative, rod-shaped organism grows autotrophically through the oxidation of thiosulfate and sulfide, but it does not grow heterotrophically. Strain LV43 grows over a pH range of 5.0 to 9.0, with an optimum near 7.5 at 28 degrees C. The pH of the medium decreased from 7.5 to 6.5 during growth on thiosulfate. Carbon isotope fractionation values for strain LV43 were within the previously reported range of fractionation values for the overall floating microbial mat in Movile Cave and were similar to values reported for chemoautotrophic sulfur-oxidizing strains of Thiobacillus neapolitanus and Thiomicrospira sp. The 16S rRNA gene sequence of strain LV43 was determined, and phylogenetic analysis indicated that strain LV43 was most closely related to Thiobacillus thioparus and the uncultured bacterial strain Strip2, which is represented by a 16S rRNA clone obtained by direct PCR from the Stripa research mine in Sweden. This identification of strain LV43 is supported by its G+C content of 62%, which is within the range reported for strains of T. thioparus. Fluorescently labeled polyclonal antibodies specific for strain LV43 were used to locate and enumerate this strain at different locations in Movile Cave and in nearby surface-water and groundwater sources. Strain LV43 was found only at aerobic, neutral-pH sites within the cave. Strain LV43 was also found outside Movile Cave in surface waters and in groundwater believed to intercept the same sulfurous aquifer as Movile Cave. PMID:9251199

  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. 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

  15. 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.

  16. Ocular disease in FeLV-positive cats: 11 cases (1981-1986).

    PubMed

    Brightman, A H; Ogilvie, G K; Tompkins, M

    1991-03-15

    A total of 147 cats positive for FeLV were retrospectively studied to determine the incidence of ocular disease. Of those cats, 97 had clinical cases of the disease and 50 were artificially infected with the virus. The incidence of ocular disease among FeLV-positive cats with clinical signs of disease was less than 2%, and represented less than 0.1% of the total feline cases for the 5-year period studied. The only ocular findings that could be associated with FeLV were pupillary and motility abnormalities. Retinal hemorrhage and subsequent degeneration found in experimentally infected and naturally infected cats were secondary to profound anemia, which was secondary to FeLV infection. On the basis of the literature and our findings, FeLV is not a major cause of primary or secondary ocular disease in the cat. Anterior uveal disease (iris bombé) was detected in 1 of 147 FeLV-positive cats, and the incidence of secondary infectious disease was zero. PMID:1851738

  17. 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

  18. 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.

  19. 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.

  20. Using Extracellular Matrix Proteomics: To Understand Left Ventricular Remodeling

    PubMed Central

    Lindsey, Merry L.; Weintraub, Susan T.; Lange, Richard A.

    2011-01-01

    Survival following myocardial infarction (MI) has improved substantially over the last 40 years; however, the incidence of subsequent congestive heart failure has dramatically increased as a consequence. Discovering plasma markers that signify adverse cardiac remodeling may allow high-risk patients to be recognized earlier and may provide an improved way to assess treatment efficacy. Alterations in extracellular matrix (ECM) regulate cardiac remodeling following MI and potentially provide a large array of candidate indicators. The field of cardiac proteomics has progressed rapidly over the past 20 years, since publication of the first two-dimensional electrophoretic gels of left ventricle proteins. Proteomic approaches are now routinely utilized to better understand how the left ventricle responds to injury. In this review, we will discuss how methods have developed to allow comprehensive evaluation of the ECM proteome. We will explain how ECM proteomic data can be used to predict adverse remodeling for an individual patient and highlight future directions. Although this review will focus on the use of ECM proteomics to better understand post-MI remodeling responses, these approaches have applicability to a wide-range of cardiac pathologies, including pressure overload hypertrophy, viral myocarditis, and non-ischemic heart failure. PMID:22337931

  1. Age, Gender and Load-Related Influences on Left Ventricular Geometric Remodeling, Systolic Mid-Wall Function, and NT-ProBNP in Asymptomatic Asian Population

    PubMed Central

    Chen, Chi; Sung, Kuo-Tzu; Shih, Shou-Chuan; Liu, Chuan-Chuan; Kuo, Jen-Yuan; Hou, Charles Jia-Yin; Hung, Chung-Lieh; Yeh, Hung-I

    2016-01-01

    Background Advanced age is associated with left ventricle (LV) remodeling and impaired cardiac function that may increase the risk of heart failure. Even so, studies regarding age-related cardiac remodeling in a large, asymptomatic Asian population remain limited. Materials and Methods We studied 8,410 asymptomatic participants (49.7 ±11.7 y, 38.9% women) in a health evaluation cohort (2004–2012) at a tertiary center in Northern Taiwan. We analyzed age-related alterations for all echocardiography-derived cardiac structures/functions and the associations with circulating N-terminal prohormone of brain natriuretic peptide (NT-proBNP). We also explored sex-related differences in these measures. Results In our cohort of 8,410 participants, advanced age was associated with greater LV wall thickness, larger LV total mass (+5.08 g/decade), and greater LV mass index (4.41 g/m2/decade), as well as increased serum NT-proBNP level (+18.89 pg/mL/decade). An accompanying reduction of stress-corrected midwall fractional shortening (–0.1%/decade) with aging was apparent in women after multi-variate adjustment (–0.09%/decade, p = 0.001). Furthermore, women demonstrated greater overall increase in LV wall thickness, LV mass index, and NT-proBNP compared to men (p for interaction: <0.001). All blood pressure components, including systolic, diastolic, and pulse pressures were independently associated with greater wall thickness and LV mass index after adjustment for confounders (all p <0.001). The associations between age and cardiac remodeling or mid-wall functions were further confirmed in a subset of study subjects with repeated follow up by GEE model. Conclusions Significant associations of unfavorable LV remodeling and advanced age in our asymptomatic Asian population were observed, along with sex differences. These data may help explain the incidence of some diverse gender-related cardiovascular diseases, especially heart failure. PMID:27280886

  2. Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function.

    PubMed

    Liu, Xiaoli; Pachori, Alok S; Ward, Christopher A; Davis, J Paul; Gnecchi, Massimiliano; Kong, Deling; Zhang, Lunan; Murduck, Jared; Yet, Shaw-Fang; Perrella, Mark A; Pratt, Richard E; Dzau, Victor J; Melo, Luis G

    2006-02-01

    We reported previously that predelivery of the anti-oxidant gene heme oxygenase-1 (HO-1) to the heart by adeno associated virus (AAV) markedly reduces injury after acute myocardial infarction (MI). However, the effect of HO-1 gene delivery on postinfarction recovery has not been investigated. In the current study, we assessed the effect of HO-1 gene delivery on post-MI left ventricle (LV) remodeling and function using echocardiographic imaging and histomorphometric approaches. Two groups of Sprague-Dawley rats were injected with 4 x 10(11) particles of AAV-LacZ (control) or AAV-hHO-1 in the LV wall. Eight wk after gene transfer, the animals were subjected to 30 min of ischemia by ligation of left anterior descending artery (LAD) followed by reperfusion. Echocardiographic measurements were obtained in a blinded fashion prior and at 1.5 and 3 months after I/R. Ejection fraction (EF) was reduced by 13% and 40% in the HO-1 and LacZ groups, respectively at 1.5 months after MI. Three months after MI, EF recovered fully in the HO-1, but only partially in the LacZ-treated animals. Post-MI LV dimensions were markedly increased and the anterior wall was markedly thinned in the LacZ-treated animals compared with the HO-1-treated animals. Significant myocardial scarring and fibrosis were observed in the LacZ-group in association with elevated levels of interstitial collagen I and III and MMP-2 activity. Post-MI myofibroblast accumulation was reduced in the HO-1-treated animals, and retroviral overexpression of HO-1 reduced proliferation of isolated cardiac fibroblasts. Our data indicate that rAAV-HO-1 gene transfer markedly reduces fibrosis and ventricular remodeling and restores LV function and chamber dimensions after myocardial infarction. PMID:16449792

  3. Assessment of LV systolic function in atrial fibrillation using an index of preceding cardiac cycles.

    PubMed

    Tabata, T; Grimm, R A; Greenberg, N L; Agler, D A; Mowrey, K A; Wallick, D W; Zhang, Y; Zhuang, S; Mazgalev, T N; Thomas, J D

    2001-08-01

    The clinical assessment of left ventricular (LV) systolic function during atrial fibrillation (AF) is unreliable and difficult because of beat-to-beat variability. We evaluated an index for the estimation of LV systolic function in AF that is based on the relationship between the preceding (R-R1) and prepreceding (R-R2) R-R intervals. LV Doppler stroke volume (SV), ejection fraction (EF), peak aortic flow rate (AoF) and the maximum value of the first derivative of the LV pressure curve (dP/dt(max)) were evaluated in 13 healthy open-chest dogs during triggered AF. All parameters showed a significantly strong positive linear relationship with the ratio of R-R1/R-R2 (r = 0.65, 0.74, 0.75, and 0.70 for SV, EF, AoF, and dP/dt(max), respectively). The calculated value of LV systolic parameters at R-R1/R-R2 = 1 in the linear regression line showed a good relationship and an agreement with the measured average value of the parameter over all cardiac cycles (SV, 12.1 vs. 12.8 ml; EF, 49.6 vs. 51.2%; AoF, 1.37 vs. 1.48 l/min; and dP/dt(max), 2,323 vs. 2,454 mmHg/s). Using the LV systolic parameters estimated at R-R1/R-R2 = 1 in the linear regression line allows the LV contractile function to be accurately and reproducibly evaluated during AF and obviates the less-reliable process of averaging multiple cardiac cycles. PMID:11454559

  4. 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

  5. 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

  6. 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

  7. Muscle RING Finger-1 Promotes a Maladaptive Phenotype in Chronic Hypoxia-Induced Right Ventricular Remodeling

    PubMed Central

    Campen, Matthew J.; Paffett, Michael L.; Colombo, E. Sage; Lucas, Selita N.; Anderson, Tamara; Nysus, Monique; Norenberg, Jeffrey P.; Gershman, Ben; Hesterman, Jacob; Hoppin, Jack; Willis, Monte

    2014-01-01

    Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while cardiac-specific overexpression would reduce hypertrophy following CH-induced pulmonary hypertension. We assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3-wk isobaric CH exposure. Additionally, we conducted dual-isotope SPECT/CT imaging with cardiac function agent 201Tl-chloride and cell death agent 99mTc-annexin V. Predictably, CH induced pulmonary hypertension, measured by increased RVSP, RV/LV+S and Hct in WT mice compared to normoxic WT mice. Normoxic WT and MuRF1-null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH-induced increases in RVSP were also similar between WT and MuRF1-null mice; however, RV/LV+S and Hct were significantly elevated in CH-exposed MuRF1-null mice compared to WT. In cardiac-specific MuRF1 overexpressing mice, RV/LV+S increased significantly due to CH exposure, even greater than in WT mice. This remodeling appeared eccentric, maladaptive and led to reduced systemic perfusion. In conclusion, these results are consistent with an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy following CH-induction of pulmonary hypertension. PMID:24811453

  8. Muscle RING finger-1 promotes a maladaptive phenotype in chronic hypoxia-induced right ventricular remodeling.

    PubMed

    Campen, Matthew J; Paffett, Michael L; Colombo, E Sage; Lucas, Selita N; Anderson, Tamara; Nysus, Monique; Norenberg, Jeffrey P; Gershman, Ben; Hesterman, Jacob; Hoppin, Jack; Willis, Monte

    2014-01-01

    Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while cardiac-specific overexpression would reduce hypertrophy following CH-induced pulmonary hypertension. We assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3-wk isobaric CH exposure. Additionally, we conducted dual-isotope SPECT/CT imaging with cardiac function agent 201Tl-chloride and cell death agent 99mTc-annexin V. Predictably, CH induced pulmonary hypertension, measured by increased RVSP, RV/LV+S and Hct in WT mice compared to normoxic WT mice. Normoxic WT and MuRF1-null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH-induced increases in RVSP were also similar between WT and MuRF1-null mice; however, RV/LV+S and Hct were significantly elevated in CH-exposed MuRF1-null mice compared to WT. In cardiac-specific MuRF1 overexpressing mice, RV/LV+S increased significantly due to CH exposure, even greater than in WT mice. This remodeling appeared eccentric, maladaptive and led to reduced systemic perfusion. In conclusion, these results are consistent with an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy following CH-induction of pulmonary hypertension. PMID:24811453

  9. Therapeutic effects of recombinant feline interferon-omega on feline leukemia virus (FeLV)-infected and FeLV/feline immunodeficiency virus (FIV)-coinfected symptomatic cats.

    PubMed

    de Mari, Karine; Maynard, Laurence; Sanquer, Annaelle; Lebreux, Bernard; Eun, Hyone-Myong

    2004-01-01

    The clinical efficacy of a recombinant feline interferon, rFeIFN-omega, was evaluated for the treatment of cats presented with clinical signs associated with feline leukemia virus (FeLV) infection and FeLV/feline immunodeficiency virus (FIV) coinfection in the field. In this multicentric, double-blind, placebo-controlled trial, 81 cats meeting the inclusion criteria were randomly placed into 2 groups and treated subcutaneously with rFelFN-omega (1 million [M]U/kg per day) or placebo once daily for 5 consecutive days in 3 series (day 0, 14, 60). The cats were monitored for up to 1 year for clinical signs and mortality. During the initial 4-month period, interferon (IFN)-treated cats (n = 39) had significantly reduced clinical scores compared with placebo (n = 42), with all cats having received concomitant supportive therapies. Compared with the control, the IFN-treated group showed significantly lower rates of mortality: 39% versus 59% (1.7-fold higher risk of death for controls) at the 9-month time point and 47% versus 59% (1.4-fold higher risk of death for controls) at the 12-month time point. The IFN treatment was associated with minor but consistent improvement in abnormal hematologic parameters (red blood cell count, packed cell volume, and white blood cell count), apparently underlying the positive effects of IFN on clinical parameters. These data demonstrate that rFeIFN-omega initially has statistically significant therapeutic effects on clinical signs and later on survival of cats with clinical signs associated with FeLV infection and FeLV/FIV coinfection. PMID:15320583

  10. 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

  11. Redox regulation of vascular remodeling.

    PubMed

    Karimi Galougahi, Keyvan; Ashley, Euan A; Ali, Ziad A

    2016-01-01

    Vascular remodeling is a dynamic process of structural and functional changes in response to biochemical and biomechanical signals in a complex in vivo milieu. While inherently adaptive, dysregulation leads to maladaptive remodeling. Reactive oxygen species participate in homeostatic cell signaling in tightly regulated- and compartmentalized cellular circuits. It is well established that perturbations in oxidation-reduction (redox) homeostasis can lead to a state of oxidative-, and more recently, reductive stress. We provide an overview of the redox signaling in the vasculature and review the role of oxidative- and reductive stress in maladaptive vascular remodeling. Particular emphasis has been placed on essential processes that determine phenotype modulation, migration and fate of the main cell types in the vessel wall. Recent advances in systems biology and the translational opportunities they may provide to specifically target the redox pathways driving pathological vascular remodeling are discussed. PMID:26483132

  12. Plant cell remodeling by autophagy

    PubMed Central

    Kim, Jimi; Lee, Han Nim; Chung, Taijoon

    2014-01-01

    Plant seedlings are not photoautotrophs until they are equipped with photosynthetic machinery. Some plant cells are remodeled after being exposed to light, and a group of peroxisomal proteins are degraded during the remodeling. Autophagy was proposed as one of the mechanisms for the degradation of peroxisomal proteins. We recently showed that ATG7-dependent autophagy is partially responsible for the degradation of obsolete peroxisomal proteins during Arabidopsis seedling growth. PMID:24492493

  13. 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

  14. 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

  15. 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 ...

  16. Partially Silencing Brain Toll-Like Receptor 4 Prevents in Part Left Ventricular Remodeling with Sympathoinhibition in Rats with Myocardial Infarction-Induced Heart Failure

    PubMed Central

    Ogawa, Kiyohiro; Hirooka, Yoshitaka; Kishi, Takuya; Ide, Tomomi; Sunagawa, Kenji

    2013-01-01

    Background Left ventricular (LV) remodeling and activation of sympathetic nervous system (SNS) are cardinal features of heart failure. We previously demonstrated that enhanced central sympathetic outflow is associated with brain toll-like receptor 4 (TLR4) probably mediated by brain angiotensin II type 1 receptor in mice with myocardial infarction (MI)-induced heart failure. The purpose of the present study was to examine whether silencing brain TLR4 could prevent LV remodeling with sympathoinhibition in MI-induced heart failure. Methodology/Principal Findings MI-induced heart failure model rats were created by ligation of left coronary artery. The expression level of TLR4 in brainstem was significantly higher in MI-induced heart failure treated with intracerebroventricular (ICV) injection of hGAPDH-SiRNA than in sham. TLR4 in brainstem was significantly lower in MI-induced heart failure treated with ICV injection of TLR4-SiRNA than in that treated with ICV injection of hGAPDH-SiRNA. Lung weight, urinary norepinephrine excretion, and LV end-diastolic pressure were significantly lower and LV dimension was significantly smaller in MI-induced heart failure treated with TLR4-SiRNA than in that treated with hGAPDH-SiRNA for 2 weeks. Conclusions Partially silencing brain TLR4 by ICV injection of TLR4-SiRNA for 2 weeks could in part prevent LV remodeling with sympathoinhibition in rats with MI-induced heart failure. Brain TLR4 has a potential to be a target of the treatment for MI-induced heart failure. PMID:23874864

  17. Identification and function analysis of a novel vascular endothelial growth factor, LvVEGF3, in the Pacific whiteleg shrimp Litopenaeus vannamei.

    PubMed

    Wang, Zhiwei; Li, Shihao; Li, Fuhua; Xie, Shijun; Xiang, Jianhai

    2016-10-01

    VEGF signaling pathway is first discovered in mammals and proved to play important roles in the biological processes of angiogenesis, tumor migration, cell differentiation, apoptosis, host-virus interaction etc. Three members in the VEGF signaling pathway, including LvVEGFR, LvVEGF1 and LvVEGF2 in shrimp have been proved to be related with WSSV infection in our previous studies. Currently, another member of VEGF family, LvVEGF3, was isolated and its function during the WSSV infection of shrimp was studied. The deduced amino acid sequence of LvVEGF3 contained a signal peptide, a typical PDGF/VEGF domain and a cysteine-knot motif (CXCXC). Tissue distribution analysis showed that LvVEGF3 was predominantly expressed in hemocytes. The transcriptional level of LvVEGF3 in hemocytes was apparently up-regulated during WSSV infection. Silencing of LvVEGF3 with double-stranded RNA caused a reduction of the cumulative mortality rate of shrimp during WSSV infection. The expression of LvVEGFR was apparently down-regulated after LvVEGF3 silencing and up-regulated after injection of recombinant LvVEGF3 protein, suggesting an interaction between LvVEGF3 and LvVEGFR. Furthermore, the interaction between LvVEGFR and LvVEGF3 was confirmed using the yeast two-hybrid system. The results provided new insights into understanding the role of VEGF signaling pathway during virus infection. PMID:27241034

  18. Effects of buyang huanwu decoction on ventricular remodeling and differential protein profile in a rat model of myocardial infarction.

    PubMed

    Zhou, Ying Chun; Liu, Bin; Li, Ying Jia; Jing, Lin Lin; Wen, Ge; Tang, Jing; Xu, Xin; Lv, Zhi Ping; Sun, Xue Gang

    2012-01-01

    Buyang Huanwu decoction (BYHWD) is a well-known and canonical Chinese medicine formula from "Correction on Errors in Medical Classics" in Qing dynasty. Here, we show that BYHWD could alleviate the ventricular remodeling induced by left anterior descending (LAD) artery ligation in rats. BYHWD treatment (18 g/kg/day) decreased heart weight/body weight (HW/BW), left ventricle (LV) dimension at end diastole (LVDd) and increased LV ejection fraction (LVEF) and LV fractional shortening (LVFS) significantly compared to model group at the end of 12 weeks. The collagen volume of BYHWD group was more significantly decreased than that of model group. Proteomic analysis showed that atrial natriuretic factor (ANF) was downregulated; heat shock protein beta-6 (HSPB6) and peroxiredoxin-6 (PRDX6) were upregulated in BYHWD-treated group among successfully identified proteins. The apoptotic index (AI) was reduced by BYHWD accompanied by decreased expression of Bax and caspase 3 activity, increased Bcl-2/Bax ratio, and phosphorylation of HSPB6 compared to that of model group. Taken together, these results suggest that BYHWD can alleviate ventricular remodeling induced by LAD artery ligation. The antiremodeling effects of BYHWD are conferred by decreasing AI through affecting multiple targets including increased Bcl-2/Bax ratio and decreased caspase 3 activity that might be via upregulated PRDX6, phosphorylation of HSPB6 and subsequently reduction of ANF. PMID:23049607

  19. [Diagnostic image (128). A boy who refused to walk. Spondylodiscitis LIV-LV].

    PubMed

    van Reisen, M T; van der Meer, S B

    2003-03-01

    One week after a fall from his buggy, a 2-year-old boy was seen at the first-aid department because he refused to walk. A bone scan and MRI revealed spondylodiscitis at the left side of the discus Liv-Lv and a psoas abscess. PMID:12661457

  20. 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

  1. Detection of Antibodies to the Feline Leukemia Virus (FeLV) Transmembrane Protein p15E: an Alternative Approach for Serological FeLV Detection Based on Antibodies to p15E

    PubMed Central

    Boenzli, Eva; Hadorn, Maik; Hartnack, Sonja; Huder, Jon; Hofmann-Lehmann, Regina

    2014-01-01

    The aim of this report was to investigate whether the diagnosis of feline leukemia virus (FeLV) infection by serology might be feasible and useful. Among the various viral proteins, the FeLV env-gene product (SU) and the envelope transmembrane protein p15E were considered promising candidates for the serological diagnosis of FeLV infection. Thus, we evaluated p15E and three other FeLV antigens, namely, a recombinant env-gene product, whole FeLV, and a short peptide from the FeLV transmembrane protein, for their potential to detect FeLV infection. To evaluate possible exposure of cats to FeLV, we tested serum and plasma samples from experimentally and naturally infected and vaccinated cats for the presence of antibodies to these antigens by enzyme-linked immunosorbent assays (ELISAs). The serological results were compared with the p27 and proviral real-time PCR results. We found that p15E displayed a diagnostic sensitivity of 95.7% and a specificity of 100% in experimentally infected cats. In naturally infected cats, p15E showed a diagnostic sensitivity of 77.1% and a specificity of 85.6%. Vaccinated cats displayed minimal antibody levels to p15E, suggesting that anti-p15E antibodies indicate infection rather than vaccination. The other antigens turned out to be too unspecific. The lower specificity in cats exposed to FeLV under field conditions may be explained by the fact that some cats become infected and seroconvert in the absence of detectable viral nucleic acids in plasma. We conclude that p15E serology may become a valuable tool for diagnosing FeLV infection; in some cases, it may replace PCR. PMID:24696026

  2. Detection of antibodies to the feline leukemia Virus (FeLV) transmembrane protein p15E: an alternative approach for serological FeLV detection based on antibodies to p15E.

    PubMed

    Boenzli, Eva; Hadorn, Maik; Hartnack, Sonja; Huder, Jon; Hofmann-Lehmann, Regina; Lutz, Hans

    2014-06-01

    The aim of this report was to investigate whether the diagnosis of feline leukemia virus (FeLV) infection by serology might be feasible and useful. Among the various viral proteins, the FeLV env-gene product (SU) and the envelope transmembrane protein p15E were considered promising candidates for the serological diagnosis of FeLV infection. Thus, we evaluated p15E and three other FeLV antigens, namely, a recombinant env-gene product, whole FeLV, and a short peptide from the FeLV transmembrane protein, for their potential to detect FeLV infection. To evaluate possible exposure of cats to FeLV, we tested serum and plasma samples from experimentally and naturally infected and vaccinated cats for the presence of antibodies to these antigens by enzyme-linked immunosorbent assays (ELISAs). The serological results were compared with the p27 and proviral real-time PCR results. We found that p15E displayed a diagnostic sensitivity of 95.7% and a specificity of 100% in experimentally infected cats. In naturally infected cats, p15E showed a diagnostic sensitivity of 77.1% and a specificity of 85.6%. Vaccinated cats displayed minimal antibody levels to p15E, suggesting that anti-p15E antibodies indicate infection rather than vaccination. The other antigens turned out to be too unspecific. The lower specificity in cats exposed to FeLV under field conditions may be explained by the fact that some cats become infected and seroconvert in the absence of detectable viral nucleic acids in plasma. We conclude that p15E serology may become a valuable tool for diagnosing FeLV infection; in some cases, it may replace PCR. PMID:24696026

  3. 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

  4. Effects of liraglutide, a glucagon-like peptide-1 analog, on left ventricular remodeling assessed by cardiac magnetic resonance imaging in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention.

    PubMed

    Nozue, Tsuyoshi; Yamada, Masayo; Tsunoda, Tetsuji; Katoh, Hiromasa; Ito, Shimpei; Iwaki, Taku; Michishita, Ichiro

    2016-08-01

    The clinical efficacy of glucagon-like peptide-1 (GLP-1) analogs in patients with acute myocardial infarction (AMI) is uncertain. The purpose of the present study was to evaluate the effects of the GLP-1 analog liraglutide on left ventricular (LV) remodeling in patients with AMI. We retrospectively evaluated the effects of liraglutide on LV remodeling assessed by cardiac magnetic resonance imaging (CMRI) in 15 patients with type 2 diabetes who were successfully treated with primary percutaneous coronary intervention (PCI) for AMI. Patients were divided into two groups based on their hypoglycemic medication: liraglutide use (group L; n = 6) or standard therapy (group S; n = 9). The CMRI findings in the early phase and at the 6-month follow-up were compared. At the 6-month follow-up, group S showed increases in LV end-diastolic (from 64 to 74 mL/m(2), p = 0.08) and end-systolic (from 38 to 45 mL/m(2), p = 0.13) volume indexes, whereas no such increase was observed in group L. The LV mass index (LVMI) was significantly smaller in group L than in group S at baseline (64 vs. 75 g/m(2), p = 0.05) and at follow-up (56 vs. 78 g/m(2), p = 0.009). Multivariate regression analysis showed that liraglutide use was an independent negative predictor of LVMI (β = -0.720, p = 0.003). In conclusion, liraglutide may be able to prevent the progression of LV remodeling and is associated with a lower LV mass in diabetic patients with AMI undergoing primary PCI. PMID:26293570

  5. 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

  6. Ataxia telangiectasia-mutated kinase deficiency exacerbates left ventricular dysfunction and remodeling late after myocardial infarction.

    PubMed

    Daniel, Laura L; Scofield, Stephanie L C; Thrasher, Patsy; Dalal, Suman; Daniels, Christopher R; Foster, Cerrone R; Singh, Mahipal; Singh, Krishna

    2016-08-01

    Ataxia telangiectasia-mutated kinase (ATM), a cell cycle checkpoint protein, is activated in response to DNA damage and oxidative stress. We have previously shown that ATM deficiency is associated with increased apoptosis and fibrosis and attenuation of cardiac dysfunction early (1-7 days) following myocardial infarction (MI). Here, we tested the hypothesis that enhanced fibrosis and apoptosis, as observed early post-MI during ATM deficiency, exacerbate cardiac dysfunction and remodeling in ATM-deficient mice late post-MI. MIs were induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Left ventricular (LV) structural and functional parameters were assessed by echocardiography 14 and 28 days post-MI, whereas biochemical parameters were measured 28 days post-MI. hKO-MI mice exhibited exacerbated LV dysfunction as observed by increased LV end-systolic volume and decreased percent fractional shortening and ejection fraction. Infarct size and thickness were not different between the two genotypes. Myocyte cross-sectional area was greater in hKO-MI group. The hKO-MI group exhibited increased fibrosis in the noninfarct and higher expression of α-smooth muscle actin (myofibroblast marker) in the infarct region. Apoptosis and activation of GSK-3β (proapoptotic kinase) were significantly lower in the infarct region of hKO-MI group. Matrix metalloproteinase 2 (MMP-2) expression was not different between the two genotypes. However, MMP-9 expression was significantly lower in the noninfarct region of hKO-MI group. Thus ATM deficiency exacerbates cardiac remodeling late post-MI with effects on cardiac function, fibrosis, apoptosis, and myocyte hypertrophy. PMID:27288435

  7. 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

  8. 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

  9. 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

  10. Rho Kinases and Cardiac Remodeling.

    PubMed

    Shimizu, Toru; Liao, James K

    2016-06-24

    Hypertensive cardiac remodeling is characterized by left ventricular hypertrophy and interstitial fibrosis, which can lead to heart failure with preserved ejection fraction. The Rho-associated coiled-coil containing kinases (ROCKs) are members of the serine/threonine protein kinase family, which mediates the downstream effects of the small GTP-binding protein RhoA. There are 2 isoforms: ROCK1 and ROCK2. They have different functions in different types of cells and tissues. There is growing evidence that ROCKs contribute to the development of cardiovascular diseases, including cardiac fibrosis, hypertrophy, and subsequent heart failure. Recent experimental studies using ROCK inhibitors, such as fasudil, have shown the benefits of ROCK inhibition in cardiac remodeling. Mice lacking each ROCK isoform also exhibit reduced myocardial fibrosis in a variety of pathological models of cardiac remodeling. Indeed, clinical studies with fasudil have suggested that ROCKs could be potential novel therapeutic targets for cardiovascular diseases. In this review, we summarize the current understanding of the roles of ROCKs in the development of cardiac fibrosis and hypertrophy and discuss their therapeutic potential for deleterious cardiac remodeling. (Circ J 2016; 80: 1491-1498). PMID:27251065

  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. Impact of Atrial Fibrillation Ablation on Left Ventricular Filling Pressure and Left Atrial Remodeling

    PubMed Central

    dos Santos, Simone Nascimento; Henz, Benhur Davi; Zanatta, André Rodrigues; Barreto, José Roberto; Loureiro, Kelly Bianca; Novakoski, Clarissa; dos Santos, Marcus Vinícius Nascimento; Giuseppin, Fabio F.; Oliveira, Edna Maria; Leite, Luiz Roberto

    2014-01-01

    Background Left ventricular (LV) diastolic dysfunction is associated with new-onset atrial fibrillation (AF), and the estimation of elevated LV filling pressures by E/e' ratio is related to worse outcomes in patients with AF. However, it is unknown if restoring sinus rhythm reverses this process. Objective To evaluate the impact of AF ablation on estimated LV filling pressure. Methods A total of 141 patients underwent radiofrequency (RF) ablation to treat drug-refractory AF. Transthoracic echocardiography was performed 30 days before and 12 months after ablation. LV functional parameters, left atrial volume index (LAVind), and transmitral pulsed and mitral annulus tissue Doppler (e' and E/e') were assessed. Paroxysmal AF was present in 18 patients, persistent AF was present in 102 patients, and long-standing persistent AF in 21 patients. Follow-up included electrocardiographic examination and 24-h Holter monitoring at 3, 6, and 12 months after ablation. Results One hundred seventeen patients (82.9%) were free of AF during the follow-up (average, 18 ± 5 months). LAVind reduced in the successful group (30.2 mL/m2 ± 10.6 mL/m2 to 22.6 mL/m2 ± 1.1 mL/m2, p < 0.001) compared to the non-successful group (37.7 mL/m2 ± 14.3 mL/m2 to 37.5 mL/m2 ± 14.5 mL/m2, p = ns). Improvement of LV filling pressure assessed by a reduction in the E/e' ratio was observed only after successful ablation (11.5 ± 4.5 vs. 7.1 ± 3.7, p < 0.001) but not in patients with recurrent AF (12.7 ± 4.4 vs. 12 ± 3.3, p = ns). The success rate was lower in the long-standing persistent AF patient group (57% vs. 87%, p = 0.001). Conclusion Successful AF ablation is associated with LA reverse remodeling and an improvement in LV filling pressure. PMID:25590928

  13. 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

  14. FIV, FeLV, and FIPV: interpretation and misinterpretation of serological test results.

    PubMed

    Barr, M C

    1996-08-01

    Serological testing is a common method of diagnosis of felina viral infections, including feline immunodeficiency virus (FIV), feline leukemia virus (FeLV), and feline infectious peritonitis virus (FIPV). Infections with these viruses can be difficult to diagnose by clinical signs alone and are sometimes clinically inapparent for months after initial exposure. Serological testing to confirm a tentative diagnosis or as a screening tool for infection can be invaluable. However, serological tests must be used only with a thorough understanding of the mechanisms and abilities of the tests, and with recognition of their potential inadequacies and misinterpretations. This report summarizes the assays available for FIV, FeLV, and FIPV, and discusses merits and pitfalls associated with each test. PMID:8942210

  15. Dynamics of a feline retrovirus (FeLV) in host populations with variable spatial structure.

    PubMed Central

    Fromont, E; Pontier, D; Langlais, M

    1998-01-01

    The predictions of epidemic models are remarkably affected by the underlying assumptions concerning host population dynamics and the relation between host density and disease transmission. Furthermore, hypotheses underlying distinct models are rarely tested. Domestic cats (Felis catus) can be used to compare models and test their predictions, because cat populations show variable spatial structure that probably results in variability in the relation between density and disease transmission. Cat populations also exhibit various dynamics. We compare four epidemiological models of Feline Leukaemia Virus (FeLV). We use two different incidence terms, i.e. proportionate mixing and pseudo-mass action. Population dynamics are modelled as logistic or exponential growth. Compared with proportionate mixing, mass action incidence with logistic growth results in a threshold population size under which the virus cannot persist in the population. Exponential growth of host populations results in systems where FeLV persistence at a steady prevalence and depression of host population growth are biologically unlikely to occur. Predictions of our models account for presently available data on FeLV dynamics in various populations of cats. Thus, host population dynamics and spatial structure can be determinant parameters in parasite transmission, host population depression, and disease control. PMID:9684375

  16. 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

  17. 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

  18. TRPV1 gene deletion exacerbates inflammation and atypical cardiac remodeling after myocardial infarction

    PubMed Central

    Huang, Wei; Rubinstein, Jack; Prieto, Alejandro R.; Thang, Loc Vinh; Wang, Donna H.

    2009-01-01

    The transient receptor potential vanilloid (TRPV1) channels expressed in sensory afferent fibers innervating the heart may be activated by proton or endovanilloids released during myocardial ischemia (MI), leading to angina. Although our previous in vitro data indicate that TRPV1 activation may preserve cardiac function after ischemia-reperfusion (I/R) injury, the underlying mechanisms are largely unknown. To test the hypothesis that TRPV1 modulates inflammatory and early remodeling processes to prevent cardiac functional deterioration after myocardial infarction, TRPV1-null mutant (TRPV1-/-) and wild-type (WT) mice were subjected to left anterior descending coronary ligation or sham operation. The infarct size was greater in TRPV1-/- than in WT mice (P < 0.001) 3 days after MI, and the mortality rate was higher in TRPV1-/- than in WT mice (P < 0.05) 7 days after MI. The levels of plasma cardiac troponin I; cytokines including TNF-α, IL-1β, and IL-6; chemokines including MCP-1 and MIP-2; infiltration of inflammatory cells including neutrophil, macrophage, and myofibroblast; as well as collagen contents were greater in TRPV1-/- than in WT mice (P < 0.05) in the infarct area on day 3 and 7 after MI. Changes in left ventricular (LV) geometry led to increased end-systolic and -diastolic diameters and reduced contractile function in TRPV1-/- compared to WT mice. These data show that TRPV1 gene deletion results in excessive inflammation, disproportional LV remodeling, and deteriorated cardiac function after MI, indicating that TRPV1 may prevent infarct expansion and cardiac injury by inhibiting inflammation and abnormal tissue remodeling. PMID:19114647

  19. 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.

  20. 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

  1. Left Ventricle: Fully Automated Segmentation Based on Spatiotemporal Continuity and Myocardium Information in Cine Cardiac Magnetic Resonance Imaging (LV-FAST)

    PubMed Central

    Wang, Lijia; Pei, Mengchao; Codella, Noel C. F.; Kochar, Minisha; Weinsaft, Jonathan W.; Li, Jianqi; Prince, Martin R.

    2015-01-01

    CMR quantification of LV chamber volumes typically and manually defines the basal-most LV, which adds processing time and user-dependence. This study developed an LV segmentation method that is fully automated based on the spatiotemporal continuity of the LV (LV-FAST). An iteratively decreasing threshold region growing approach was used first from the midventricle to the apex, until the LV area and shape discontinued, and then from midventricle to the base, until less than 50% of the myocardium circumference was observable. Region growth was constrained by LV spatiotemporal continuity to improve robustness of apical and basal segmentations. The LV-FAST method was compared with manual tracing on cardiac cine MRI data of 45 consecutive patients. Of the 45 patients, LV-FAST and manual selection identified the same apical slices at both ED and ES and the same basal slices at both ED and ES in 38, 38, 38, and 41 cases, respectively, and their measurements agreed within −1.6 ± 8.7 mL, −1.4 ± 7.8 mL, and 1.0 ± 5.8% for EDV, ESV, and EF, respectively. LV-FAST allowed LV volume-time course quantitatively measured within 3 seconds on a standard desktop computer, which is fast and accurate for processing the cine volumetric cardiac MRI data, and enables LV filling course quantification over the cardiac cycle. PMID:25738153

  2. 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

  3. 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

  4. Advances in understanding cartilage remodeling

    PubMed Central

    Li, Yefu; Xu, Lin

    2015-01-01

    Cartilage remodeling is currently among the most popular topics in osteoarthritis research. Remodeling includes removal of the existing cartilage and replacement by neo-cartilage. As a loss of balance between removal and replacement of articular cartilage develops (particularly, the rate of removal surpasses the rate of replacement), joints will begin to degrade. In the last few years, significant progress in molecular understanding of the cartilage remodeling process has been made. In this brief review, we focus on the discussion of some current “controversial” observations in articular cartilage degeneration: (1) the biological effect of transforming growth factor-beta 1 on developing and mature articular cartilages, (2) the question of whether aggrecanase 1 (ADAMTS4) and aggrecanase 2 (ADAMTS5) are key enzymes in articular cartilage destruction, and (3) chondrocytes versus chondron in the development of osteoarthritis. It is hoped that continued discussion and investigation will follow to better clarify these topics. Clarification will be critical for those in search of novel therapeutic targets for the treatment of osteoarthritis. PMID:26380073

  5. 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. PMID:25981566

  6. Acute versus chronic exercise-induced left-ventricular remodeling.

    PubMed

    Weiner, Rory B; Baggish, Aaron L

    2014-11-01

    Exercise-induced cardiac remodeling (EICR) is the process by which the heart adapts to the physiologic stress of exercise. Non-invasive cardiovascular imaging has led to advances in the understanding of EICR, with sport-specific changes in left-ventricular (LV) structure and function being described; however, the majority of data stem from cross-sectional and short-duration longitudinal studies. Due to the paucity of long-term longitudinal EICR studies, the time course of this process and any distinct differentiation between acute and chronic adaptations remain largely unexplored. In order to clarify the natural history of EICR, longer duration longitudinal study is required. Such work will determine whether exercise-induced changes in myocardial structure and function occur in discrete stages. Examination of prolonged exposures to exercise training will also be necessary to determine normative values across the age and training spectrums of athletic patients. This information will help to distinguish the boundary between physiology and pathology in athletic patients. PMID:25300444

  7. Myofibroblast-mediated mechanisms of pathological remodelling of the heart.

    PubMed

    Weber, Karl T; Sun, Yao; Bhattacharya, Syamal K; Ahokas, Robert A; Gerling, Ivan C

    2013-01-01

    The syncytium of cardiomyocytes in the heart is tethered within a matrix composed principally of type I fibrillar collagen. The matrix has diverse mechanical functions that ensure the optimal contractile efficiency of this muscular pump. In the diseased heart, cardiomyocytes are lost to necrotic cell death, and phenotypically transformed fibroblast-like cells-termed 'myofibroblasts'-are activated to initiate a 'reparative' fibrosis. The structural integrity of the myocardium is preserved by this scar tissue, although at the expense of its remodelled architecture, which has increased tissue stiffness and propensity to arrhythmias. A persisting population of activated myofibroblasts turns this fibrous tissue into a living 'secretome' that generates angiotensin II and its type 1 receptor, and fibrogenic growth factors (such as transforming growth factor-β), all of which collectively act as a signal-transducer-effector signalling pathway to type I collagen synthesis and, therefore, fibrosis. Persistent myofibroblasts, and the resultant fibrous tissue they produce, cause progressive adverse myocardial remodelling, a pathological hallmark of the failing heart irrespective of its etiologic origin. Herein, we review relevant cellular, subcellular, and molecular mechanisms integral to cardiac fibrosis and consequent remodelling of atria and ventricles with a heterogeneity in cardiomyocyte size. Signalling pathways that antagonize collagen fibrillogenesis provide novel strategies for cardioprotection. PMID:23207731

  8. 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.

  9. 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

  10. 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

  11. 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

  12. Rutaecarpine attenuates hypoxia-induced right ventricular remodeling in rats.

    PubMed

    Li, Wen-Qun; Li, Xiao-Hui; Du, Jie; Zhang, Wang; Li, Dai; Xiong, Xiao-Ming; Li, Yuan-Jian

    2016-07-01

    Rutaecarpine has been shown to exhibit wide pharmacological effects in the cardiovascular system via stimulation of calcitonin gene-related peptide (CGRP) release. In the present study, the effect of rutaecarpine on hypoxia-induced right ventricular (RV) remodeling and the underlying mechanisms were evaluated. RV remodeling was induced by hypoxia (10 % O2, 3 weeks) in rats. Rats were treated with rutaecarpine (20 or 40 mg/kg) by intragastric administration. Proliferation of cardiac fibroblasts was induced by TGF-β1 (5 ng/mL) and determined by MTS and EdU incorporation method. Cardiac fibroblasts were treated with exogenous CGRP (10 or 100 nM). The concentrations of CGRP and TGF-β1 in plasma were measured by ELISA. The expression of eIF3a, p27, α-SMA, collagen-I/III, ANP, and BNP were measured by real-time PCR or western blot. Hypoxia induced an increase of right ventricle systolic pressure (RVSP), ration of RV/LV+S, and RV/tibial length in rats, while cardiac hypertrophy, apoptosis, and fibrosis were detected. The expression of ANP, BNP, α-SMA, collagen-I, collagen-III, eIF3a, and TGF-β1 was up-regulated, and the expression of p27 was down-regulated in the right ventricle of hypoxia-treated rats. The plasma concentration of CGRP was decreased and TGF-β1 was increased in hypoxia-treated rats. All of these effects induced by hypoxia were attenuated by rutaecarpine in a dose-dependent manner. In cultured cardiac fibroblasts, TGF-β1 significantly promoted the proliferation and up-regulated the expression of α-SMA and collagen-I/III, while the expression of eIF3a was up-regulated and the expression of p27 was down-regulated. The effects of TGF-β1 were attenuated by CGRP. CGRP8-37, a selective CGRP receptor antagonist, abolished the effects of CGRP. Rutaecarpine attenuates hypoxia-induced RV remodeling via stimulation of CGRP release, and the effects of rutaecarpine involve the eIF3a/p27 pathway. PMID:27052575

  13. Durable Scar Size Reduction Due to Allogeneic Mesenchymal Stem Cell Therapy Regulates Whole‐Chamber Remodeling

    PubMed Central

    Williams, Adam R.; Suncion, Viky Y.; McCall, Frederic; Guerra, Danny; Mather, Jacques; Zambrano, Juan P.; Heldman, Alan W.; Hare, Joshua M.

    2013-01-01

    Background Intramyocardial injection of mesenchymal stem cells (MSCs) in chronic ischemic cardiomyopathy is associated with reverse remodeling in experimental models and humans. Here, we tested the hypothesis that allogeneic MSC therapy drives ventricular remodeling by producing durable and progressive scar size reduction in ischemic cardiomyopathy. Methods and Results Gottingen swine (n=12) underwent left anterior descending coronary artery myocardial infarction (MI), and 3 months post‐MI animals received either intramyocardial allogeneic MSC injection (200 mol/L cells; n=6) or left ventricle (LV) catheterization without injection (n=6). Swine were followed with serial cardiac magnetic resonance imaging for 9 months to assess structural and functional changes of the LV. Intramyocardial injection was performed using an integrated imaging platform combining electroanatomical mapping unipolar voltage and 3‐dimensional cardiac magnetic resonance imaging angiography–derived anatomy to accurately target infarct border zone injections. MSC‐treated animals had a 19.62±2.86% reduction in scar size at 3 months postinjection, which progressed to 28.09±2.31% from 3 to 6 months postinjection (P<0.0001). MSC‐treated animals had unchanged end‐diastolic volume (EDV; P=0.08) and end‐systolic volume (ESV; P=0.28) from preinjection to 6 months postinjection, whereas controls had progressive dilatation in both EDV (P=0.0002) and ESV (P=0.0002). In addition, MSC‐treated animals had improved LV sphericity index. Percentage change in infarct size correlated with percentage change in EDV (r=0.68; P=0.01) and ESV (r=0.77; P=0.001). Ejection fraction increased from 29.69±1.68% to 35.85±2.74% at 3 months post‐MSC injection and progressed to 39.02±2.42% 6 months postinjection (P=0.0001), whereas controls had a persistently depressed ejection fraction during follow‐up (P=0.33). Conclusion Intramyocardial injection of allogeneic MSCs leads to a sustained and

  14. 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.

  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. 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.

  17. Adverse reactions to sulfites

    PubMed Central

    Yang, William H.; Purchase, Emerson C.R.

    1985-01-01

    Sulfites are widely used as preservatives in the food and pharmaceutical industries. In the United States more than 250 cases of sulfite-related adverse reactions, including anaphylactic shock, asthmatic attacks, urticaria and angioedema, nausea, abdominal pain and diarrhea, seizures and death, have been reported, including 6 deaths allegedly associated with restaurant food containing sulfites. In Canada 10 sulfite-related adverse reactions have been documented, and 1 death suspected to be sulfite-related has occurred. The exact mechanism of sulfite-induced reactions is unknown. Practising physicians should be aware of the clinical manifestations of sulfite-related adverse reactions as well as which foods and pharmaceuticals contain sulfites. Cases should be reported to health officials and proper advice given to the victims to prevent further exposure to sulfites. The food industry, including beer and wine manufacturers, and the pharmaceutical industry should consider using alternative preservatives. In the interim, they should list any sulfites in their products. PMID:4052897

  18. Cost-effectiveness of adjuvant FOLFOX and 5FU/LV chemotherapy for patients with stage II colon cancer

    PubMed Central

    Ayvaci, Mehmet U.S.; Shi, Jinghua; Alagoz, Oguzhan; Lubner, Sam

    2014-01-01

    Purpose We evaluated the cost-effectiveness of adjuvant chemotherapy using 5-fluorouracil, leucovorin (5FU/LV), and oxaliplatin (FOLFOX) compared with 5FU/LV alone and 5FU/LV compared with observation alone for patients who had resected stage II colon cancer. Methods We developed two Markov models to represent the adjuvant chemotherapy and follow-up periods and a single Markov model to represent the observation group. We used calibration to estimate the transition probabilities among different toxicity levels. The base-case considered 60-year-old patients who had undergone an uncomplicated hemicolectomy for stage II colon cancer and was medically fit to receive 6 months of adjuvant chemotherapy. We measured health outcomes in quality-adjusted life-years (QALYs) and estimated costs using 2007 US$. Results In the base-case, adjuvant chemotherapy of FOLFOX regimen had an incremental cost-effectiveness ratio (ICER) of $54,359/QALY compared with the 5FU/LV regimen and the 5FU/LV regimen had an ICER of $14,584/QALY compared with the observation group from the third-party payer perspective. The ICER values were most sensitive to 5-year relapse probability, cost of adjuvant chemotherapy, and the discount rate for the FOLFOX arm, whereas the ICER value of 5FU/LV was most sensitive to the 5-year relapse probability, 5-year survival probability, and the relapse cost. The probabilistic sensitivity analysis indicate that the ICER of 5FU/LV is less than $50,000/QALY with a probability of 99.62% and the ICER of FOLFOX as compared to 5FU/LV is less than $50,000/QALY and $100,000/QALY with a probability of 44.48% and 97.24%, respectively. Conclusion While adjuvant chemotherapy with 5FU/LV is cost-effective at all ages for patients who had undergone an uncomplicated hemicolectomy for stage II colon cancer, FOLFOX is not likely to be cost-effective as compared to 5FU/LV. PMID:23313932

  19. Key residues in the nicotinic acetylcholine receptor β2 subunit contribute to α-conotoxin LvIA binding.

    PubMed

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

    2015-04-10

    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 Val(111) is critical and facilitates LvIA binding; this position has not previously been identified as important to binding of other 4/7 framework α-conotoxins. Thr(59) and Phe(119) 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

  20. Dynamin, a membrane remodelling GTPase

    PubMed Central

    Ferguson, Shawn M.; De Camilli, Pietro

    2012-01-01

    Dynamin, the founding member of a family of dynamin-like GTPases (DLPs) implicated in membrane remodelling, has a critical role in endocytic membrane fission events. The use of complementary approaches, including live cell imaging, cell free-studies, X-ray crystallography and genetic studies in mice has greatly advanced our understanding of the mechanisms by which dynamin acts, its essential roles in cell physiology and the specific function of different dynamin isoforms. In addition, several connections between dynamin and human disease have also emerged that highlight specific contributions of this GTPase to the physiology of different tissues. PMID:22233676

  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. 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

  4. 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. PMID:27021518

  5. 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…

  6. 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

  7. Osteocyte-Driven Bone Remodeling

    PubMed Central

    Bellido, Teresita

    2013-01-01

    Osteocytes, the most abundant cells in bone, have been long postulated to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. The discovery that the inhibitor of bone formation sclerostin is primarily expressed in osteocytes in bone and it is downregulated by anabolic stimuli provided a mechanism by which osteocytes influence the activity of osteoblasts. Advances of the last few years provided experimental evidence demonstrating that osteocytes also participate in the recruitment of osteoclasts and the initiation of bone remodeling. Apoptotic osteocytes trigger yet to be identified signals that attract osteoclast precursors to specific areas of bone, which in turn differentiate to mature, bone resorbing osteoclasts. Osteocytes are also the source of molecules that regulate generation and activity of osteoclasts, such as OPG and RANKL; and genetic manipulations of the mouse genome leading to loss or gain of function, or to altered expression of either molecule in osteocytes, markedly affect bone resorption. This review highlights these investigations and discusses how the novel concept of osteocyte-driven bone resorption and formation impacts our understanding of the mechanisms by which current therapies control bone remodeling. PMID:24002178

  8. 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

  9. 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

  10. 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

  11. A morphological control for ventricular pathology in man: a morphometric and morphologic assessment of LV myofibres in secundum ASD.

    PubMed Central

    Gregory, M. A.; Whitton, I. D.

    1990-01-01

    Ethical considerations preclude the biopsy of normal human myocardium. As a consequence, morphological investigations of diseased human heart muscle are hampered by a lack of suitable normal control tissue. The left ventricular (LV) myocardium of patients with isolated secundum atrial septal defect (ASD) is considered to be normal. This study was designed to investigate the possibility that the fine-structure of LV myofibres in hearts with ASD could be used as normal controls for myofibre pathomorphology. Wedge biopsies from the LV of four adults undergoing elective surgery for the repair of ASD were examined by light and electron microscopy. Bivariant myofibre morphometry showed that the LV myocardium of one specimen was 'normal' while three specimens exhibited varying degrees of hypertrophy. There was a correlation between the diameter (FD) and morphology of individual myofibres within and between specimens. In general, myofibres with FD less than 25 microns were similar in fine-structural appearance to those described as morphologically normal in animal models whereas those with FD greater than 25 microns exhibited hypertrophic features that increased in 'severity' with increase in myofibre size. It is proposed that although the LV myocardium in ASD may be mildly hypertrophied, myofibres with FD less than 25 microns are probably normal and may be used as fine-structural controls for myofibre pathomorphology in hearts suspected of disease. Images Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 PMID:2278821

  12. Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice

    PubMed Central

    Tolonen, Anna-Maria; Magga, Johanna; Szabó, Zoltán; Viitala, Pirkko; Gao, Erhe; Moilanen, Anne-Mari; Ohukainen, Pauli; Vainio, Laura; Koch, Walter J; Kerkelä, Risto; Ruskoaho, Heikki; Serpi, Raisa

    2014-01-01

    The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined the effect of inhibiting the function of Let-7c miRNA on the progression of postinfarction left ventricular (LV) remodeling in mice. Myocardial infarction was induced with permanent ligation of left anterior descending coronary artery with a 4-week follow-up period. Let-7c miRNA was inhibited with a specific antagomir administered intravenously. The inhibition of Let-7c miRNA downregulated the levels of mature Let-7c miRNA and its other closely related members of Let-7 family in the heart and resulted in increased expression of pluripotency-associated genes Oct4 and Sox2 in cardiac fibroblasts in vitro and in adult mouse heart in vivo. Importantly, Let-7c inhibitor prevented the deterioration of cardiac function postinfarction, as demonstrated by preserved LV ejection fraction and elevated cardiac output. Improvement in cardiac function by Let-7c inhibitor postinfarction was associated with decreased apoptosis, reduced fibrosis, and reduction in the number of discoidin domain receptor 2–positive fibroblasts, while the number of c-kit+ cardiac stem cells and Ki-67+ proliferating cells remained unaltered. In conclusion, inhibition of Let-7 miRNA may be beneficial for the prevention of postinfarction LV remodeling and progression of heart failure. PMID:25505600

  13. 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. PMID:15379961

  14. An Analysis of the Residential Remodeling Occupation.

    ERIC Educational Resources Information Center

    Scruggs, Kenneth

    The general purpose of the occupational analysis is to provide workable, basic information dealing with the many and varied duties performed in the residential remodeling occupation. The analysis only briefly covers the many areas of residential remodeling. The document opens with a brief introduction followed by a job description. The bulk of the…

  15. 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...

  16. Chromatin Remodelers: From Function to Dysfunction

    PubMed Central

    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

  17. Multiscale Simulation of Protein Mediated Membrane Remodeling

    PubMed Central

    Ayton, Gary S.; Voth, Gregory A.

    2009-01-01

    Proteins interacting with membranes can result in substantial membrane deformations and curvatures. This effect is known in its broadest terms as membrane remodeling. This review article will survey current multiscale simulation methodologies that have been employed to examine protein-mediated membrane remodeling. PMID:19922811

  18. 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 Central

    Roberts, Timothy; Claessen, Guido

    2014-01-01

    Abstract 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

  19. 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

  20. 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

  1. 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

  2. Nucleosome dynamics during chromatin remodeling in vivo.

    PubMed

    Ramachandran, Srinivas; Henikoff, Steven

    2016-01-01

    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

  3. Gas-generator pressurization system experimental development method of the LV propellant tanks

    NASA Astrophysics Data System (ADS)

    Logvinenko, A.

    2009-01-01

    The approved efficient method of experimental development is given in the example of accumulated experience in the gas-generator pressurization system development of the LV propellant tanks. To the present time, acceptable calculated methods has not been created from complexity of thermo-mass-transfer processes. Therefore, under the development of similar systems the main attention is centered to its ground experimental development which requires special benches, corresponding competent structures, great time and material expenditure. The approved method of gas-generator pressurization system experimental development is proposed. It is based on the energy analysis of influenced factors and selection of its limit-possible operation modes. Practical use is allowed to decrease significantly the test volume, to decrease material expenditure and time for pressurization system experimental development under complex assurance of its optimal main characteristics.

  4. Renal denervation mitigates cardiac remodeling and renal damage in Dahl rats: a comparison with β-receptor blockade.

    PubMed

    Watanabe, Heitaro; Iwanaga, Yoshitaka; Miyaji, Yuki; Yamamoto, Hiromi; Miyazaki, Shunichi

    2016-04-01

    Chronic activation of the sympathetic nervous system (SNS) contributes to cardiac remodeling and the transition to heart failure (HF). Renal sympathetic denervation (RDN) may ameliorate this damage by improving renal function and sympathetic cardioregulation in hypertensive HF patients with renal injury. The efficacy may be comparable to that of chronic β-blocker treatment. Dahl salt-sensitive hypertensive rats were subjected to RDN in the hypertrophic stage. Another group of Dahl rats were subjected to sham operations and treated chronically with vehicle (CONT) or β-blocker bisoprolol (BISO). Neither RDN nor BISO altered the blood pressure; however, BISO significantly reduced the heart rate (HR). Both RDN and BISO significantly prolonged survival (22.2 and 22.4 weeks, respectively) compared with CONT (18.3 weeks). Echocardiography revealed reduced left ventricular (LV) hypertrophy and improved LV function, and histological analysis demonstrated the amelioration of LV myocyte hypertrophy and fibrosis in the RDN and BISO rats at the HF stage. Tyrosine hydroxylase and β1-adrenergic receptor (ADR) expression levels in the LV myocardium significantly increased only in the RDN rats, whereas the α1b-, α1d- and α2c-ADR expression levels increased only in the BISO rats. In both groups, renal damage and dysfunction were also reduced, and this reduction was accompanied by the suppression of endothelin-1, renin and angiotensin-converting enzyme mRNAs. RDN ameliorated the progression of both myocardial and renal damage in the hypertensive rats independent of blood pressure changes. The overall effects were similar to those of β-receptor blockade with favorable effects on HR and α-ADR expression. These findings may be associated with the restoration of the myocardial SNS and renal protection. PMID:26631854

  5. 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.

  6. Feline upper respiratory tract lymphoma: site, cyto-histology, phenotype, FeLV expression, and prognosis.

    PubMed

    Santagostino, S F; Mortellaro, C M; Boracchi, P; Avallone, G; Caniatti, M; Forlani, A; Roccabianca, P

    2015-03-01

    Lymphoma is the most common feline upper respiratory tract (URT) tumor. Primary nasal and nasopharyngeal lymphomas have been evaluated as distinct pathological entities; however, data on their differing clinical behavior are missing. A total of 164 endoscopic- guided URT pinch biopsies were formalin fixed and routinely processed. Imprint cytological specimens were stained with May Grünwald-Giemsa. Immunohistochemistry for anti-CD20, CD3, FeLVp27, and FeLVgp70 was performed. Prognostic significance of clinicopathological variables was investigated by univariate and multivariate analysis. Lymphoma was diagnosed in 39 cats (24%). Most cats with lymphoma were domestic shorthair (32 [82%]), were male (F/M = 0.56), and had a mean age of 10.3 years (range, 1-16 years). Lymphomas were primary nasal in 26 cats (67%), nasopharyngeal in 6 (15%), and in both locations (combined lymphomas) in 7 cats (18%). Neoplastic growth pattern was diffuse in 35 cases (90%) and nodular in 4 (10%). Epitheliotropism was observed in 10 cases (26%). Tumor cells were large in 15 cases, were small and medium in 11 cases each, and 2 had mixed cell size. Submucosal lymphoplasmacytic inflammation was observed in 23 cases (59%). Cytology was diagnostic for lymphoma in 12 of 25 cases (48%). A B-cell origin prevailed (34 [87%]). Feline leukemia virus (FeLV) p27 or gp70 antigen was detected in 21 lymphomas (54%). URT lymphomas were aggressive, with survival varying from 0 to 301 days (mean, 53 days). Epitheliotropism in 8 B-cell lymphomas (80%) and in 2 T-cell lymphomas (20%) correlated with prolonged survival. Age younger or older than 10 years had a negative prognostic value. Lymphoplasmacytic inflammation and FeLV infection may represent favoring factors for URT lymphoma development. PMID:24903757

  7. 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

  8. Calcium signalling remodelling and disease.

    PubMed

    Berridge, Michael J

    2012-04-01

    A wide range of Ca2+ signalling systems deliver the spatial and temporal Ca2+ signals necessary to control the specific functions of different cell types. Release of Ca2+ by InsP3 (inositol 1,4,5-trisphosphate) plays a central role in many of these signalling systems. Ongoing transcriptional processes maintain the integrity and stability of these cell-specific signalling systems. However, these homoeostatic systems are highly plastic and can undergo a process of phenotypic remodelling, resulting in the Ca2+ signals being set either too high or too low. Such subtle dysregulation of Ca2+ signals have been linked to some of the major diseases in humans such as cardiac disease, schizophrenia, bipolar disorder and Alzheimer's disease. PMID:22435804

  9. 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.

  10. 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

  11. [Adverse reaction of pseudoephedrine].

    PubMed

    López Lois, G; Gómez Carrasco, J A; García de Frías, E

    2005-04-01

    We present a case of a 7 years old girl who developed an episode of myoclonic movements and tremors after being medicated with a not well quantified amount of a pseudoephedrine/antihistamine combination. We want to highlight the potential toxicity of pseudoephedrine, usually administered as part of cold-syrup preparations which are used for symptomatic treatment of upper respiratory tract cough and congestion associated with the common cold and allergic rhinitis. Although these products are generally considered to be safe either by physicians and parents, we can't underestimate the potential adverse events and toxic effects that can occur when administering these medications. PMID:15826569

  12. 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. PMID:24688176

  13. 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

  14. 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

  15. Gender Differences in Non-Ischemic Myocardial Remodeling: Are They Due to Estrogen Modulation of Cardiac Mast Cells and/or Membrane Type 1 Matrix Metalloproteinase

    PubMed Central

    Janicki, Joseph S.; Spinale, Francis G.; Levick, Scott P.

    2013-01-01

    SUMMARY This review is focused on gender differences in cardiac remodeling secondary to sustained increases in cardiac volume (VO) and generated pressure (PO). Estrogen has been shown to favorably alter the course of VO-induced remodeling. That is, the VO-induced increased extracellular matrix proteolytic activity and mast cell degranulation responsible for the adverse cardiac remodeling in males and ovariectomized rodents do not occur in intact premenopausal females. While less is known regarding the mechanisms responsible for female cardioprotection in PO-induced stress, gender differences in remodeling have been reported indicating the ability of premenopausal females to adequately compensate. In view of the fact that, in male mice with PO, mast cells have been shown to play a role in the adverse remodeling suggests favorable estrogen modification of mast cell phenotype may also be responsible for cardioprotection in females with PO. Thus, while evidence is accumulating regarding premenopausal females being cardioprotected; there remains the need for in-depth studies to identify critical downstream molecular targets that are under the regulation of estrogen and relevant to cardiac remodeling. Such studies would result in the development of therapy which provides cardioprotection while avoiding the adverse effects of systemic estrogen delivery. PMID:23417570

  16. 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

  17. 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

  18. 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.

  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. 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

  1. 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)

  2. 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

  3. 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.

  4. Effect of material damping on bone remodelling.

    PubMed

    Misra, J C; Samanta, S

    1987-01-01

    This paper considers the effect of internal material damping on the stresses, strains, and surface and internal remodelling behaviour in a section of axisymmetrical bone with a force-fitted axially oriented medullary pin. The bone response to several loading situations is modelled using visco-elastic equations. An approximate method is developed to analyse the proposed mathematical model. By considering a numerical example, the effect of material damping on the remodelling stresses is quantified. PMID:3584150

  5. Chromatin remodeling by nucleosome disassembly in vitro.

    PubMed

    Lorch, Yahli; Maier-Davis, Barbara; Kornberg, Roger D

    2006-02-28

    The RSC chromatin-remodeling complex completely disassembles a nucleosome in the presence of the histone chaperone Nap1 and ATP. Disassembly occurs in a stepwise manner, with the removal of H2A/H2B dimers, followed by the rest of the histones and the release of naked DNA. RSC and related chromatin-remodeling complexes may be responsible for the removal of promoter nucleosomes during transcriptional activation in vivo. PMID:16492771

  6. 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

  7. 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

  8. [Cutaneous adverse drug reactions].

    PubMed

    Lebrun-Vignes, B; Valeyrie-Allanore, L

    2015-04-01

    Cutaneous adverse drug reactions (CADR) represent a heterogeneous field including various clinical patterns without specific features suggesting drug causality. Exanthematous eruptions, urticaria and vasculitis are the most common forms of CADR. Fixed eruption is uncommon in western countries. Serious reactions (fatal outcome, sequelae) represent 2% of CADR: bullous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), DRESS (drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome) and acute generalized exanthematous pustulosis (AGEP). These forms must be quickly diagnosed to guide their management. The main risk factors are immunosuppression, autoimmunity and some HLA alleles in bullous reactions and DRESS. Most systemic drugs may induce cutaneous adverse reactions, especially antibiotics, anticonvulsivants, antineoplastic drugs, non-steroidal anti-inflammatory drugs, allopurinol and contrast media. Pathogenesis includes immediate or delayed immunologic mechanism, usually not related to dose, and pharmacologic/toxic mechanism, commonly dose-dependent or time-dependent. In case of immunologic mechanism, allergologic exploration is possible to clarify drug causality, with a variable sensitivity according to the drug and to the CADR type. It includes epicutaneous patch testing, prick test and intradermal test. However, no in vivo or in vitro test can confirm the drug causality. To determine the cause of the eruption, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis is required, completed with a literature search. A reporting to pharmacovigilance network is essential in case of a serious CADR whatever the suspected drug and in any case if the involved drug is a newly marketed one or unusually related to cutaneous reactions. PMID:25458866

  9. Dynamics of the Ethanolamine Glycerophospholipid Remodeling Network

    PubMed Central

    Hermansson, Martin; Somerharju, Pentti; Chuang, Jeffrey

    2012-01-01

    Acyl chain remodeling in lipids is a critical biochemical process that plays a central role in disease. However, remodeling remains poorly understood, despite massive increases in lipidomic data. In this work, we determine the dynamic network of ethanolamine glycerophospholipid (PE) remodeling, using data from pulse-chase experiments and a novel bioinformatic network inference approach. The model uses a set of ordinary differential equations based on the assumptions that (1) sn1 and sn2 acyl positions are independently remodeled; (2) remodeling reaction rates are constant over time; and (3) acyl donor concentrations are constant. We use a novel fast and accurate two-step algorithm to automatically infer model parameters and their values. This is the first such method applicable to dynamic phospholipid lipidomic data. Our inference procedure closely fits experimental measurements and shows strong cross-validation across six independent experiments with distinct deuterium-labeled PE precursors, demonstrating the validity of our assumptions. In constrast, fits of randomized data or fits using random model parameters are worse. A key outcome is that we are able to robustly distinguish deacylation and reacylation kinetics of individual acyl chain types at the sn1 and sn2 positions, explaining the established prevalence of saturated and unsaturated chains in the respective positions. The present study thus demonstrates that dynamic acyl chain remodeling processes can be reliably determined from dynamic lipidomic data. PMID:23251394

  10. 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

  11. 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

  12. 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.

  13. Complete set of mitochondrial pan-edited mRNAs in Leishmania mexicana amazonensis LV78

    PubMed Central

    Maslov, Dmitri A.

    2010-01-01

    Editing of mRNA transcribed from the mitochondrial cryptogenes ND8 (G1), ND9 (G2), G3, G4, ND3 (G5), RPS12 (G6) was investigated in Leishmania mexicana amazonensis, strain LV78, by amplification of the cDNA, cloning and sequencing. For each of these genes, extensively and partially edited transcripts were found to be relatively abundant compared to the respective pre-edited molecules. Moreover, the editing patterns observed in a majority of transcripts of each gene were consistent among themselves which allowed for inferring consensus editing sequences. The open reading frames contained in the consensus sequences were predicted to encode polypeptides that were highly similar to their counterparts in other species of Trypanosomatidae. Several kinetoplast DNA minicircles from this species available in the public domain were found to contain genes for guide RNAs which mediate editing of some of the mRNAs. The results indicate that the investigated strain of L. m. amazonensis has preserved its full editing capacity in spite of the long-term maintenance in culture. This property differs drastically from the other Leishmania species which lost some or all of the G1–G5 mRNA editing ability in culture. PMID:20546801

  14. Influence of site of regional ischemia on LV cavity shape change in dogs

    SciTech Connect

    Marino, P.; Kass, D.; Lima, J.; Maughan, W.L.; Graves, W.; Weiss, J.L. )

    1988-03-01

    The authors assessed whether altering the location of acute ischemia produced differing and consistent changes in cavity shape in the canine left ventricle. Twenty anesthetized open-chest dogs underwent transient occlusion of the left anterior descending (LAD) or circumflex (Circ) artery, and cavity shape change was recorded in two-dimensional short-axis echocardiograms. The extent of injury was assessed by radiolabeled microspheres. Shape was analyzed by converting digitized endocardial contours into polar form and expressing the results as a Fourier series. Series terms reflected specific shape deformations. Normal ventricular shape became more circular during ejection indicated by a reduction in the power in nearly all of the Fourier spectra components. During Circ occlusion, the chamber became more elongated and overall shape significantly less circular at end systole than at end diastole. LAD occlusion produced an entirely different pattern, one with no significant elongation but the development of a more triangular shape by end systole. They conclude that there are characteristic and contrasting shape deformations in LV short-axis contours that depend on the site of ischemic injury. These changes may relate to site-specific geometry and loading, and they point to potential limitations of left ventricular models that no not account for regional inhomogeneity.

  15. 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

  16. Adverse antibiotic drug interactions.

    PubMed

    Bint, A J; Burtt, I

    1980-07-01

    There is enormous potential for drug interactions in patients who, today, often receive many drugs. Antibiotics are prominent amongst the groups of drugs commonly prescribed. Many interactions take place at the absorption stage. Antacids and antidiarrhoeal preparations, in particular, can delay and reduce the absorption of antibiotics such as tetracyclines and clindamycin, by combining with them in the gastrointestinal tract to form chelates or complexes. Other drugs can affect gastric motility, which in turn often controls the rate at which antibiotics are absorbed. Some broad spectrum antibiotics can alter the bacterial flora of the gut which may be related to malabsorption states. The potentiation of toxic side effects of one drug by another is a common type of interaction. Antibiotics which are implicated in this type of interaction are those which themselves possess some toxicity such as aminoglycosides, some cephalosporins, tetracyclines and colistin. Some of the most important adverse interactions with antibiotics are those which involve other drugs which have a low toxicity/efficacy ratio. These include anticoagulants such as warfarin, anticonvulsants such as phenytoin and phenobarbitone and oral antidiabetic drugs like tolbutamide. Risk of interaction arises when the metabolism of these drugs is inhibited by liver microsomal enzyme inhibitors such as some sulphonamides and chloramphenicol, or is enhanced by enzyme inducers such as rifampicin. PMID:6995091

  17. ADVERSE CUTANEOUS DRUG REACTION

    PubMed Central

    Nayak, Surajit; Acharjya, Basanti

    2008-01-01

    In everyday clinical practice, almost all physicians come across many instances of suspected adverse cutaneous drug reactions (ACDR) in different forms. Although such cutaneous reactions are common, comprehensive information regarding their incidence, severity and ultimate health effects are often not available as many cases go unreported. It is also a fact that in the present world, almost everyday a new drug enters market; therefore, a chance of a new drug reaction manifesting somewhere in some form in any corner of world is unknown or unreported. Although many a times, presentation is too trivial and benign, the early identification of the condition and identifying the culprit drug and omit it at earliest holds the keystone in management and prevention of a more severe drug rash. Therefore, not only the dermatologists, but all practicing physicians should be familiar with these conditions to diagnose them early and to be prepared to handle them adequately. However, we all know it is most challenging and practically difficult when patient is on multiple medicines because of myriad clinical symptoms, poorly understood multiple mechanisms of drug-host interaction, relative paucity of laboratory testing that is available for any definitive and confirmatory drug-specific testing. Therefore, in practice, the diagnosis of ACDR is purely based on clinical judgment. In this discussion, we will be primarily focusing on pathomechanism and approach to reach a diagnosis, which is the vital pillar to manage any case of ACDR. PMID:19967009

  18. 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

  19. 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

  20. Simulated 3D ultrasound LV cardiac images for active shape model training

    NASA Astrophysics Data System (ADS)

    Butakoff, Constantine; Balocco, Simone; Ordas, Sebastian; Frangi, Alejandro F.

    2007-03-01

    In this paper a study of 3D ultrasound cardiac segmentation using Active Shape Models (ASM) is presented. The proposed approach is based on a combination of a point distribution model constructed from a multitude of high resolution MRI scans and the appearance model obtained from simulated 3D ultrasound images. Usually the appearance model is learnt from a set of landmarked images. The significant level of noise, the low resolution of 3D ultrasound images (3D US) and the frequent failure to capture the complete wall of the left ventricle (LV) makes automatic or manual landmarking difficult. One possible solution is to use artificially simulated 3D US images since the generated images will match exactly the shape in question. In this way, by varying simulation parameters and generating corresponding images, it is possible to obtain a training set where the image matches the shape exactly. In this work the simulation of ultrasound images is performed by a convolutional approach. The evaluation of segmentation accuracy is performed on both simulated and in vivo images. The results obtained on 567 simulated images had an average error of 1.9 mm (1.73 +/- 0.05 mm for epicardium and 2 +/- 0.07 mm for endocardium, with 95% confidence) with voxel size being 1.1 × 1.1 × 0.7 mm. The error on 20 in vivo data was 3.5 mm (3.44 +/- 0.4 mm for epicardium and 3.73 +/- 0.4 mm for endocardium). In most images the model was able to approximate the borders of myocardium even when the latter was indistinguishable from the surrounding tissues.

  1. 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.

  2. 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

  3. 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

  4. 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

  5. The role of midkine in skeletal remodelling

    PubMed Central

    Liedert, A; Schinke, T; Ignatius, A; Amling, M

    2014-01-01

    Bone tissue is subjected to continuous remodelling, replacing old or damaged bone throughout life. In bone remodelling, the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts ensure the maintenance of bone mass and strength. In early life, the balance of these cellular activities is tightly regulated by various factors, including systemic hormones, the mechanical environment and locally released growth factors. Age-related changes in the activity of these factors in bone remodelling can result in diseases with low bone mass, such as osteoporosis. Osteoporosis is a systemic and age-related skeletal disease characterized by low bone mass and structural degeneration of bone tissue, predisposing the patient to an increased fracture risk. The growth factor midkine (Mdk) plays a key role in bone remodelling and it is expressed during bone formation and fracture repair. Using a mouse deficient in Mdk, our group have identified this protein as a negative regulator of bone formation and mechanically induced bone remodelling. Thus, specific Mdk antagonists might represent a therapeutic option for diseases characterized by low bone mass, such as osteoporosis. Linked Articles This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4 PMID:24102259

  6. 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

  7. 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

  8. 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

  9. 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}.

  10. Atomic force microscopy investigation of fibroblasts infected with wild-type and mutant murine leukemia virus (MuLV).

    PubMed Central

    Kuznetsov, Yurii G; Datta, Shoibal; Kothari, Natantara H; Greenwood, Aaron; Fan, Hung; McPherson, Alexander

    2002-01-01

    NIH 3T3 cells were infected in culture with the oncogenic retrovirus, mouse leukemia virus (MuLV), and studied using atomic force microscopy (AFM). Cells fixed with glutaraldehyde alone, and those postfixed with osmium tetroxide, were imaged under ethanol according to procedures that largely preserved their structures. With glutaraldehyde fixation alone, the lipid bilayer was removed and maturing virions were seen emerging from the cytoskeletal matrix. With osmium tetroxide postfixation, the lipid bilayer was maintained and virions were observable still attached to the cell surfaces. The virions on the cell surfaces were imaged at high resolution and considerable detail of the arrangement of protein assemblies on their surfaces was evident. Infected cells were also labeled with primary antibodies against the virus env surface protein, followed by secondary antibodies conjugated with colloidal gold particles. Other 3T3 cells in culture were infected with MuLV containing a mutation in the gPr80(gag) gene. Those cells were observed by AFM not to produce normal MuLV on their surfaces, or at best, only at very low levels. The cell surfaces, however, became covered with tubelike structures that appear to result from a failure of the virions to properly undergo morphogenesis, and to fail in budding completely from the cell's surfaces. PMID:12496133

  11. 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

  12. 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…

  13. Gender differences in adiponectin modulation of cardiac remodeling in mice deficient in endothelial nitric oxide synthase.

    PubMed

    Durand, Jorge L; Nawrocki, Andrea R; Scherer, Philipp E; Jelicks, Linda A

    2012-10-01

    Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular disease, a leading cause of death. Alterations in endothelial nitric oxide synthase (eNOS), an enzyme involved in regulating vascular tone, and in adiponectin, an adipocyte-derived secretory factor, are associated with cardiac remodeling. Deficiency of eNOS is associated with hypertension and LVH. Adiponectin exhibits vaso-protective, anti-inflammatory, and anti-atherogenic properties. We hypothesized that increased levels of adiponectin would alleviate cardiac pathology resulting from eNOS deficiency, while decreased levels of adiponectin would exacerbate the pathology. Male and female mice, deficient in eNOS, and either lacking or over-expressing adiponectin, were fed high fat diet (HFD) or normal chow. Cardiac magnetic resonance imaging was performed to serially assess heart morphology and function up to 40 weeks of age. Thirty-two weeks of HFD feeding led to significantly greater LV mass in male mice deficient in eNOS and either lacking or over-expressing adiponectin. Heart function was significantly reduced when the mice were deficient in either eNOS, adiponectin or both eNOS and adiponectin; for female mice, heart function was only reduced when both eNOS and adiponectin were lacking. Thus, while over-expression of adiponectin in the eNOS deficient HFD fed male mice preserved function at the expense of significantly increased LV mass, female mice were protected from decreased function and increased LVH by over-expression of adiponectin. Our results demonstrate a sexual dimorphism in response of the heart to alterations in eNOS and adiponectin during high fat feeding and suggest that adiponectin might require eNOS for some of its metabolic effects. PMID:22644792

  14. Post-Infarct biomaterials, left ventricular remodeling, and heart failure: Is good good enough?

    PubMed Central

    Zouein, Fouad A.; Zgheib, Carlos; Liechty, Kenneth W.; Booz, George W.

    2012-01-01

    Infarct expansion and extension of the border zone play a key role in the progression of heart failure after myocardial infarction. Increased wall stress, along with complex cellular and extracellular changes in the surviving myocardium, underlie these events and contributes to the adverse cardiac remodeling that drives ventricular dilation and progression of heart failure. Recently, there has been much interest in the development of biopolymers that can be injected into the infarcted myocardium in order to increase its stiffness and thus reduce mechanical stress on the surrounding myocardium. Here we discuss the findings of recent animal studies that have noted improvements in contractile function or cardiac remodeling using either natural or synthetic biomaterials, as well as several that did not. Besides offering physical support to the injured myocardium, injectable biomaterials could also serve the purpose of fostering cardiac repair by functioning as a protective scaffold for stem cell or drug delivery. PMID:22612796

  15. The proposed role of plasma NT pro-brain natriuretic peptide in assessing cardiac remodelling in hypertensive African subjects

    PubMed Central

    Ojji, Dike B; Opie, Lionel H; Lecour, Sandrine; Lacerda, Lydia; Sliwa, Karen; Adeyemi, Olusoji M

    2014-01-01

    Summary Aim Although plasma NT-proBNP differentiates hypertension (HT) with or without left ventricular hypertrophy (LVH) from hypertensive heart failure (HHF), most of the published data are based on studies in Western populations. Also, most previous studies did not consider left ventricular (LV) diastolic function and right ventricular (RV) function. We therefore examined the relation between NT-proBNP on LV and RV remodelling in an African hypertensive cohort. Methods Subjects were subdivided into three groups after echocardiography: hypertensives without LVH (HT) (n = 83); hypertensives with LVH (HT+LVH) (n = 50); and those with hypertensive heart failure (HHF) (n = 77). Results Subjects with HHF had significantly higher NT-proBNP levels compared to the HT+LVH group (p < 0.0002). NT-proBNP correlated positively with right atrial area, an indirect measure of RV function. Conclusions NT-proBNP is proposed as a useful biomarker in differentiating hypertension with or without LVH from hypertensive heart failure in black hypertensive subjects. PMID:25629540

  16. 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

  17. Reverse remodeling and recovery from cachexia in rats with aldosteronism.

    PubMed

    Cheema, Yaser; Zhao, Wenyuan; Zhao, Tieqiang; Khan, M Usman; Green, Kelly D; Ahokas, Robert A; Gerling, Ivan C; Bhattacharya, Syamal K; Weber, Karl T

    2012-08-15

    The congestive heart failure (CHF) syndrome with soft tissue wasting, or cachexia, has its pathophysiologic origins rooted in neurohormonal activation. Mechanical cardiocirculatory assistance reveals the potential for reverse remodeling and recovery from CHF, which has been attributed to device-based hemodynamic unloading whereas the influence of hormonal withdrawal remains uncertain. This study addresses the signaling pathways induced by chronic aldosteronism in normal heart and skeletal muscle at organ, cellular/subcellular, and molecular levels, together with their potential for recovery (Recov) after its withdrawal. Eight-week-old male Sprague-Dawley rats were examined at 4 wk of aldosterone/salt treatment (ALDOST) and following 4-wk Recov. Compared with untreated, age-/sex-/strain-matched controls, ALDOST was accompanied by 1) a failure to gain weight, reduced muscle mass with atrophy, and a heterogeneity in cardiomyocyte size across the ventricles, including hypertrophy and atrophy at sites of microscopic scarring; 2) increased cardiomyocyte and mitochondrial free Ca(2+), coupled to oxidative stress with increased H(2)O(2) production and 8-isoprostane content, and increased opening potential of the mitochondrial permeability transition pore; 3) differentially expressed genes reflecting proinflammatory myocardial and catabolic muscle phenotypes; and 4) reversal to or toward recovery of these responses with 4-wk Recov. Aldosteronism in rats is accompanied by cachexia and leads to an adverse remodeling of the heart and skeletal muscle at organ, cellular/subcellular, and molecular levels. However, evidence presented herein implicates that these tissues retain their inherent potential for recovery after complete hormone withdrawal. PMID:22730385

  18. Reverse remodeling and recovery from cachexia in rats with aldosteronism

    PubMed Central

    Cheema, Yaser; Zhao, Wenyuan; Zhao, Tieqiang; Khan, M. Usman; Green, Kelly D.; Ahokas, Robert A.; Gerling, Ivan C.; Bhattacharya, Syamal K.

    2012-01-01

    The congestive heart failure (CHF) syndrome with soft tissue wasting, or cachexia, has its pathophysiologic origins rooted in neurohormonal activation. Mechanical cardiocirculatory assistance reveals the potential for reverse remodeling and recovery from CHF, which has been attributed to device-based hemodynamic unloading whereas the influence of hormonal withdrawal remains uncertain. This study addresses the signaling pathways induced by chronic aldosteronism in normal heart and skeletal muscle at organ, cellular/subcellular, and molecular levels, together with their potential for recovery (Recov) after its withdrawal. Eight-week-old male Sprague-Dawley rats were examined at 4 wk of aldosterone/salt treatment (ALDOST) and following 4-wk Recov. Compared with untreated, age-/sex-/strain-matched controls, ALDOST was accompanied by 1) a failure to gain weight, reduced muscle mass with atrophy, and a heterogeneity in cardiomyocyte size across the ventricles, including hypertrophy and atrophy at sites of microscopic scarring; 2) increased cardiomyocyte and mitochondrial free Ca2+, coupled to oxidative stress with increased H2O2 production and 8-isoprostane content, and increased opening potential of the mitochondrial permeability transition pore; 3) differentially expressed genes reflecting proinflammatory myocardial and catabolic muscle phenotypes; and 4) reversal to or toward recovery of these responses with 4-wk Recov. Aldosteronism in rats is accompanied by cachexia and leads to an adverse remodeling of the heart and skeletal muscle at organ, cellular/subcellular, and molecular levels. However, evidence presented herein implicates that these tissues retain their inherent potential for recovery after complete hormone withdrawal. PMID:22730385

  19. Dual infections with low virulent chicken infectious anaemia virus (lvCIAV) and intermediate infectious bursal disease virus (iIBDV) in young chicks increase lvCIAV in thymus and bursa while decreasing lymphocyte disorders induced by iIBDV.

    PubMed

    Vaziry, Asaad; Silim, Amer; Bleau, Christian; Frenette, Diane; Lamontagne, Lucie

    2013-04-01

    The use of attenuated vaccines or the occurrence of low virulent T-lymphotropic or B-lymphotropic viruses in flocks may alter the immune responses of young chicks in spite of the absence of clinical signs. Infections with a low virulent T-lymphotropic chicken infectious anaemia virus (lvCIAV) followed by infection with an intermediate B-lymphotropic infectious bursal disease virus (iIBDV) were conducted in specific pathogen free chicks. Thirty-six 1-day-old chicks were infected with the lvCIAV strain (CAV-VAC®) and a similar number of chicks were inoculated with phosphate-buffered saline. At 14 days after lvCIAV infection, one group of 18 lvCIAV-infected chicks and one group of 18 uninfected chicks were infected with an iIBDV strain. At 4, 7 and 14 days post infection with iIBDV, six chicks from each group were euthanized and lymphoid organs were collected. Detection of lvCIAV and iIBDV genomes was conducted by polymerase chain reaction and reverse transcriptase-polymerase chain reaction, respectively. Double-labelled lymphoid subsets from the thymus, spleen and bursa were studied by cytofluorometric analysis. The results reveal that previous infection with lvCIAV increases the occurrence of the lvCIAV and iIBDV genome in thymus and/or bursa without the occurrence of clinical signs in dually lvCIAV/iIBDV-infected chicks. However, the decreases of B cells in spleen and bursa and increases of T-cell subsets in bursa observed in chicks infected with iIBDV did not occur in chicks previously infected with lvCIAV. Taken together, these results suggest that previous infection of young chicks with lvCIAV decreases lymphoid disorders induced by iIBDV while subsequent iIBDV infection increases the lvCIAV genome in lymphoid organs. PMID:23581435

  20. 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.

  1. Echocardiographic assessment of subclinical left ventricular eccentric hypertrophy in adult-onset GHD patients by geometric remodeling: an observational case-control study

    PubMed Central

    de Gregorio, Cesare; Curtò, Lorenzo; Recupero, Antonino; Grimaldi, Patrizia; Almoto, Barbara; Venturino, Marilena; Cento, Domenico; Narbone, Maria Carola; Trimarchi, Francesco; Coglitore, Sebastiano; Cannavò, Salvatore

    2006-01-01

    Background Most patients with growth hormone deficiency (GHD) show high body mass index. Overweight subjects, but GHD patients, were demonstrated to have high left ventricular mass index (LVMi) and abnormal LV geometric remodeling. We sought to study these characteristics in a group of GHD patients, in an attempt to establish the BMI-independent role of GHD. Methods Fifty-four patients, 28 F and 26 M, aged 45.9 ± 13.1, with adult-onset GHD (pituitary adenomas 48.2%, empty sella 27.8%, pituitary inflammation 5.5%, cranio-pharyngioma 3.7%, not identified pathogenesis 14.8%) were enrolled. To minimize any possible interferences of BMI on the aim of this study, the control group included 20 age- and weight-matched healthy subjects. The LV geometry was identified by the relationship between LVMi (cut-off 125 g/m2) and relative wall thickness (cut-off 0.45) at echocardiography. Results There was no significant between-group difference in resting cardiac morphology and function, nor when considering age-related discrepancy. The majority of patients had normal-low LVM/LVMi, but about one fourth of them showed higher values. These findings correlated to relatively high circulating IGF-1 and systolic blood pressure at rest. The main LV geometric pattern was eccentric hypertrophy in 22% of GHD population (26% of with severe GHD) and in 15% of controls (p = NS). Conclusion Though the lack of significant differences in resting LV morphology and function, about 25% of GHD patients showed high LVMi (consisting of eccentric hypertrophy), not dissimilarly to overweight controls. This finding, which prognostic role is well known in obese and hypertensive patients, is worthy to be investigated in GHD patients through wider controlled trials. PMID:16507109

  2. Subdural hygroma after craniosynostosis remodeling surgery.

    PubMed

    Ganesh, Praveen; Nagarjuna, Muralidhara; Shetty, Samarth; Salins, Paul C

    2015-01-01

    Craniosynostosis is defined as the premature fusion of the cranial sutures and can cause functional impairment or cosmetic deformity. Surgical techniques for the correction of craniosynostosis have changed overtime, as so have the intraoperative and postoperative complications. Extensive surgeries involving fronto-orbital unit repositioning and cranial vault remodeling are associated with various complications. Intraoperative and postoperative hemorrhage, venous infarct, air embolism, hydrocephalus, cerebrospinal fluid leak, as well as meningitis are a few complications associated with cranial vault remodeling surgery. Postoperative complications can increase the morbidity and mortality associated with these procedures. Identification of the complications and their timely management should be a part of every craniofacial reconstruction team's training program.In this article, we report a case of subdural hygroma in an infant after cranial vault remodeling procedure. Subdural hygroma is a known complication following head injuries and represents 5% to 20% of posttraumatic intracranial mass lesions. However, subdural hygroma developing after a cranial procedure is rare and has not been reported in the literature. Identification of the complication, close monitoring of the change in subdural fluid volume, and tapping of the fluid through the craniotomy site if indicated form the mainstay of management of subdural hygroma that develops after cranial vault remodeling surgery. PMID:25469899

  3. Interleukin-20 promotes airway remodeling in asthma.

    PubMed

    Gong, Wenbin; Wang, Xin; Zhang, Yuguo; Hao, Junqing; Xing, Chunyan; Chu, Qi; Wang, Guicheng; Zhao, Jiping; Wang, Junfei; Dong, Qian; Liu, Tian; Zhang, Yuanyuan; Dong, Liang

    2014-12-01

    Previous studies have demonstrated that interleukin-20 (IL-20) is a pro-inflammatory cytokine, and it has been implicated in psoriasis, lupus nephritis, rheumatoid arthritis, atherosclerosis, and ulcerative colitis. Little is known about the effects of IL-20 in airway remodeling in asthma. The aim of our study was to demonstrate the function of IL-20 in airway remodeling in asthma. To identify the expression of IL-20 and its receptor, IL-20R1/IL-20R2, in the airway epithelium in bronchial tissues, bronchial biopsy specimens were collected from patients and mice with asthma and healthy subjects and stained with specific antibodies. To characterize the effects of IL-20 in asthmatic airway remodeling, we silenced and stimulated IL-20 in cell lines isolated from mice by shRNA and recombinant protein approaches, respectively, and detected the expression of α-SMA and FN-1 by Western blot analysis. First, overexpression of IL-20 and its receptor, IL-20R1/IL-20R2, was detected in the airway epithelium collected from patients and mice with asthma. Second, IL-20 increased the expression of fibronectin-1 and α-SMA, and silencing of IL-20 in mouse lung epithelial (MLE)-12 cells decreased the expression of fibronectin-1 and α-SMA. IL-20 may be a critical cytokine in airway remodeling in asthma. This study indicates that targeting IL-20 and/or its receptors may be a new therapeutic strategy for asthma. PMID:25028099

  4. Chromatin-modifying and -remodeling complexes.

    PubMed

    Kornberg, R D; Lorch, Y

    1999-04-01

    Nucleosomes have long been known to inhibit DNA transactions on chromosomes and a remarkable abundance of multiprotein complexes that either enhance or relieve this inhibition have been described. Most is known about chromatin-remodeling complexes that perturb nucleosome structure. PMID:10322131

  5. 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…

  6. Re-Modelling as De-Professionalisation

    ERIC Educational Resources Information Center

    Thompson, Meryl

    2006-01-01

    The article sets out the consequences of the British Government's remodelling agenda and its emphasis on less demarcation, for the professional status of teachers in England. It describes how the National Agreement on Raising Standards and Tackling Workload, reached between five of the six trade unions for teachers and headteachers paves the way…

  7. 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

  8. 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.

  9. 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

  10. The Effects of Chemotherapeutic Agents, Bleomycin, Etoposide, and Cisplatin, on Chromatin Remodeling in Male Rat Germ Cells.

    PubMed

    Bagheri-Sereshki, Negar; Hales, Barbara F; Robaire, Bernard

    2016-04-01

    The coadministration of bleomycin, etoposide, and cisplatin (BEP) has increased the survival rate of testicular cancer patients to over 90%. Previous studies have demonstrated that BEP induces germ cell damage during the final stages of spermatogenesis, when major chromatin remodeling occurs. Chromatin remodeling permits histone-protamine exchange, resulting in sperm head chromatin compaction. This process involves different epigenetic modifications of the core histones. The objective of these studies was to investigate the effects of BEP on epigenetic modifications to histones involved in chromatin remodeling. Brown Norway rats were treated with BEP, and their testes were removed to isolate pachytene spermatocytes and round spermatids by unit gravity sedimentation. Western blot analyses were conducted on extracted proteins to detect the expression of key modified histones. In a second cohort testes were prepared for immunohistochemical analysis. The stage-specific expression of each modified histone mark in rat spermatogenesis suggests the involvement of these modifications in chromatin remodeling. BEP treatment significantly increased expression of H3K9m and decreased that of tH2B (or Hist1h2ba) in pachytene spermatocytes, suggesting that nucleosomes were not destabilized to allow for transcription of genes involved in chromatin remodeling. Moreover, BEP treatment altered the expression of H4K8ac in round and elongating spermatids, suggesting that histone eviction was compromised, leading to a looser chromatin structure in mature spermatozoa. Less-compacted sperm chromatin, with alterations to the sperm epigenome, may have an adverse effect on male fertility. PMID:26911428

  11. 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. PMID:27380968

  12. 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

  13. Adverse possession of subsurface minerals

    SciTech Connect

    Bowles, P.N.

    1983-01-01

    Concepts applicable to adverse possession of subsurface minerals are generally the same as those that apply to adverse possession of all real estate. However, special requirements must be satisfied in order to perfect title to subsurface minerals by adverse possession, particularly when there has been a severance of the true title between surface and subsurface minerals. In those jurisdictions where senior and junior grants came from the state or commonwealth covering the same or some of the same land and in those areas where descriptions of land were vague or not carefully drawn, adverse possession serves to solidify land and mineral ownership. There may be some public, social, and economic justification in rewarding, with good title, those who take possession and use real estate for its intended use, including the extraction of subsurface minerals. 96 refernces.

  14. 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

  15. Litopenaeus vannamei sterile-alpha and armadillo motif containing protein (LvSARM) is involved in regulation of Penaeidins and antilipopolysaccharide factors.

    PubMed

    Wang, Pei-Hui; Gu, Zhi-Hua; Wan, Ding-Hui; Zhu, Wei-Bin; Qiu, Wei; Weng, Shao-Ping; Yu, Xiao-Qiang; He, Jian-Guo

    2013-01-01

    The Toll-like receptor (TLR)-mediated NF-κB pathway is tightly controlled because overactivation may result in severe damage to the host, such as in the case of chronic inflammatory diseases and cancer. In mammals, sterile-alpha and armadillo motif-containing protein (SARM) plays an important role in negatively regulating this pathway. While Caenorhabditis elegans SARM is crucial for an efficient immune response against bacterial and fungal infections, it is still unknown whether Drosophila SARM participates in immune responses. Here, Litopenaeus vannamei SARM (LvSARM) was cloned and functionally characterized. LvSARM shared signature domains with and exhibited significant similarities to mammalian SARM. Real-time quantitative PCR analysis indicated that the expression of LvSARM was responsive to Vibrio alginolyticus and white spot syndrome virus (WSSV) infections in the hemocyte, gill, hepatopancreas and intestine. In Drosophila S2 cells, LvSARM was widely distributed in the cytoplasm and could significantly inhibit the promoters of the NF-κB pathway-controlled antimicrobial peptide genes (AMPs). Silencing of LvSARM using dsRNA-mediated RNA interference increased the expression levels of Penaeidins and antilipopolysaccharide factors, which are L.vannamei AMPs, and increased the mortality rate after V. alginolyticus infection. Taken together, our results reveal that LvSARM may be a novel component of the shrimp Toll pathway that negatively regulates shrimp AMPs, particularly Penaeidins and antilipopolysaccharide factors. PMID:23405063

  16. Relationship of basal-septal fibrosis with LV outflow tract obstruction in hypertrophic cardiomyopathy: insights from cardiac magnetic resonance analysis.

    PubMed

    Nakamura, Takashi; Iwanaga, Yoshitaka; Yasuda, Masakazu; Kawamura, Takayuki; Miyaji, Yuki; Morooka, Hanako; Miyazaki, Shunichi

    2016-04-01

    Myocardial fibrosis is frequently observed and may be associated with the prognosis in patients with hypertrophic cardiomyopathy (HCM); however, the clinical pathophysiological features, particularly in terms of fibrosis, of hypertrophic obstructive cardiomyopathy (HOCM) remain unclear. This study aimed to determine a role of local fibrosis in HOCM using cardiac magnetic resonance (CMR). 108 consecutive HCM patients underwent CMR. HOCM was defined as a left ventricular outflow tract (LVOT) pressure gradient ≥30 mmHg at rest. Myocardial mass and fibrosis mass by late gadolinium-enhancement CMR (LGE-CMR) were calculated and the distribution/pattern was analyzed using the AHA 17-segment model. LV ejection fraction (LVEF) was significantly higher in patients with HOCM (n = 19) than in those with nonobstructive HCM (n = 89) (P < 0.05). Both total myocardial and fibrosis masses in LV were similar in the two groups (P = 0.385 and P = 0.859, respectively). However, fibrosis in the basal septum was significantly less frequent in the HOCM group than in the nonobstructive HCM group (P < 0.01). The LVOT pressure gradient was significantly higher in the basal-septal non-fibrosis group than in the fibrosis group (23.6 ± 37.3 vs. 4.8 ± 11.4 mmHg, P < 0.01). Multivariate analysis revealed that basal-septal fibrosis was an independent negative predictor of LVOT obstruction in addition to the local wall thickness and LVEF as positive predictors in HCM patients. In conclusion, a significant association was observed between LVOT obstruction and basal septal fibrosis by LGE-CMR in HCM patients. In addition to negative impact of basal-septal fibrosis, basal-septal hypertrophy and preserved global LV contractility may be associated with the pathophysiological features of LVOT obstruction. PMID:26589516

  17. 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.

  18. 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.

  19. Human Mesenchymal Stem Cell Delivery System Modulates Ischemic Cardiac Remodeling With an Increase of Coronary Artery Blood Flow.

    PubMed

    Lee, Young Sook; Joo, Wan Seok; Kim, Hyun Soo; Kim, Sung Wan

    2016-04-01

    Ways for extending the longevity of stem cells are imperative to attain diverse expected therapeutic effects. Here, we constructed a three-dimentional (3D) scaffold system for human mesenchymal stem cell (hMSC) delivery. Intramyocardial injections of porous PEI1.8k blended with poly(lactic-co-glycolic acid) (PLGA) (PLGA/PEI1.8k) (PPP) microparticles by physical electrostatic conjugation and structural entrapment of hMSCs demonstrated enhanced functional and geometric improvements on post-infarct cardiac remodeling in rats. In the hMSC-loaded PPP delivery, increases of coronary artery blood flow rate and in vivo engraftment rate as well as time-dependent functional, geometric, and pathologic findings reversing post-infarct cardiac remodeling account for improved left ventricular (LV) systolic function up to the level of sham thoracotomy group. This study expands our understanding by proving that increase of coronary artery blood flow augmented functional recovery of hMSC-loaded PPP delivery system after myocardial infarction (MI). PMID:26782638

  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. PMID:27161240

  1. 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

  2. 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

  3. 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

  4. Link between vitamin D and airway remodeling

    PubMed Central

    Berraies, Anissa; Hamzaoui, Kamel; Hamzaoui, Agnes

    2014-01-01

    In the last decade, many epidemiologic studies have investigated the link between vitamin D deficiency and asthma. Most studies have shown that vitamin D deficiency increases the risk of asthma and allergies. Low levels of vitamin D have been associated with asthma severity and loss of control, together with recurrent exacerbations. Remodeling is an early event in asthma described as a consequence of production of mediators and growth factors by inflammatory and resident bronchial cells. Consequently, lung function is altered, with a decrease in forced expiratory volume in one second and exacerbated airway hyperresponsiveness. Subepithelial fibrosis and airway smooth muscle cell hypertrophy are typical features of structural changes in the airways. In animal models, vitamin D deficiency enhances inflammation and bronchial anomalies. In severe asthma of childhood, major remodeling is observed in patients with low vitamin D levels. Conversely, the antifibrotic and antiproliferative effects of vitamin D in smooth muscle cells have been described in several experiments. In this review, we briefly summarize the current knowledge regarding the relationship between vitamin D and asthma, and focus on its effect on airway remodeling and its potential therapeutic impact for asthma. PMID:24729717

  5. Tissue Remodelling following Resection of Porcine Liver

    PubMed Central

    Nygård, Ingvild Engdal; Mortensen, Kim Erlend; Hedegaard, Jakob; Conley, Lene Nagstrup; Bendixen, Christian; Sveinbjørnsson, Baldur; Revhaug, Arthur

    2015-01-01

    Aim. To study genes regulating the extracellular matrix (ECM) and investigate the tissue remodelling following liver resection in porcine. Methods. Four pigs with 60% partial hepatectomy- (PHx-) induced liver regeneration were studied over six weeks. Four pigs underwent sham surgery and another four pigs were used as controls of the normal liver growth. Liver biopsies were taken upon laparotomy, after three and six weeks. Gene expression profiles were obtained using porcine-specific oligonucleotide microarrays. Immunohistochemical staining was performed and a proliferative index was assessed. Results. More differentially expressed genes were associated with the regulation of ECM in the resection group compared to the sham and control groups. Secreted protein acidic and rich in cysteine (SPARC) and collagen 1, alpha 2 (COL1A2) were both upregulated in the early phase of liver regeneration, validated by immunopositive cells during the remodelling phase of liver regeneration. A broadened connective tissue was demonstrated by Masson's Trichrome staining, and an immunohistochemical staining against pan-Cytokeratin (pan-CK) demonstrated a distinct pattern of migrating cells, followed by proliferating cell nuclear antigen (PCNA) positive nuclei. Conclusions. The present study demonstrates both a distinct pattern of PCNA positive nuclei and a deposition of ECM proteins in the remodelling phase of liver regeneration. PMID:26240819

  6. Stepwise nucleosome translocation by RSC remodeling complexes.

    PubMed

    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. PMID:26895087

  7. 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

  8. The effects and mechanism of ginsenoside Rg1 on myocardial remodeling in an animal model of chronic thromboembolic pulmonary hypertension

    PubMed Central

    2013-01-01

    Background Recent studies haveshown that ginsenoside Rg1, extracted from the dry roots of Panax notoginseng as a traditional Asian medicine, plays an anti-fibrosis role in myocardial remodeling. However, the mechanism still remains unclear. In the present study, we investigate the effect of ginsenoside Rg1on the collagenic remodeling of myocardium in chronic thromboembolic pulmonary hypertension (CTEPH), and its potential mechanism. Methods A rat model of CTEPH was established by injecting thrombi through the jugular vein wice in2 weeks. Four weeks later, four groups (Group A: normal rats + normal saline; Group B: normal rats + Rg1; Group C: CTEPH model + normal saline; Group D: CTEPH model + Rg1) were established. Normal saline and Rg1 were administrated by intraperitoneal injection. Ineach group, we measured the hemodynamic parameters, as well as the right ventricle to left ventricle (RV/LV) thickness ratio. Myocardial tissue sections of the RV were stained by hematoxylin-eosin +gentian violet and the morphological characteristics were observed by light microscopy. The matrix metalloproteinases (MMP) -2 and −9 were detected by the western blot. Results Compared with Group A and Group B, the right ventricular systolic pressure was significantly increased in Group C and significantly decreased in Group D. Compared with Group A and Group B, the RV/LV thickness ratio of the rats was significantly higher in Group C and Group D. There was significant fibrosis with collagen in Group C compared with Group A and Group B, and less significant changes in Group D were observed compared with those in Group C. The expression of MMP-2 and MMP-9 exhibited a significant decrease in Group C and was also significantly decreased in Group D compared withGroup A and Group B. Also, a negative linear relationship was shown between collagen-I and the expression of MMP-2 and MMP-9. Conclusions Our animal study showed that ginsenoside Rg1 positively affects myocardial remodeling and

  9. MicroRNA and vascular remodelling in acute vascular injury and pulmonary vascular remodelling

    PubMed Central

    McDonald, Robert A.; Hata, Akiko; MacLean, Margaret R.; Morrell, Nicholas W.; Baker, Andrew H.

    2012-01-01

    Vascular remodelling is an integral pathological process central to a number of cardiovascular diseases. The complex interplay between distinct cell populations in the vessel wall following vascular injury leads to inflammation, cellular dysfunction, pro-growth signals in the smooth muscle cell (SMC) compartment, and the acquisition of a synthetic phenotype. Although the signals for vascular remodelling are diverse in different pathological contexts, SMC proliferation and migration are consistently observed. It is therefore critical to elucidate key mechanisms central to these processes. MicroRNAs (miRNAs) are small non-coding sequences of RNA that have the capacity to regulate many genes, pathways, and complex biological networks within cells, acting either alone or in concert with one another. In diseases such as cancer and cardiac disease, the role of miRNA in disease pathogenesis has been documented in detail. In contrast, despite a great deal of interest in miRNA, relatively few studies have directly assessed the role of miRNA in vascular remodelling. The potential for modulation of miRNA to achieve therapeutic benefits in this setting is attractive. Here, we focus on the role of miRNA in vascular inflammation and remodelling associated with acute vascular injury (vein graft disease, angioplasty restenosis, and in-stent restenosis) as well as in vascular remodelling associated with the development of pulmonary arterial hypertension. PMID:22065733

  10. Adverse ventricular-ventricular interactions in right ventricular pressure load: Insights from pediatric pulmonary hypertension versus pulmonary stenosis.

    PubMed

    Driessen, Mieke M P; Hui, Wei; Bijnens, Bart H; Dragulescu, Andreea; Mertens, Luc; Meijboom, Folkert J; Friedberg, Mark K

    2016-06-01

    Right ventricular (RV) pressure overload has a vastly different clinical course in children with idiopathic pulmonary arterial hypertension (iPAH) than in children with pulmonary stenosis (PS). While RV function is well recognized as a key prognostic factor in iPAH, adverse ventricular-ventricular interactions and LV dysfunction are less well characterized and the pathophysiology is incompletely understood. We compared ventricular-ventricular interactions as hypothesized drivers of biventricular dysfunction in pediatric iPAH versus PS Eighteen iPAH, 16 PS patients and 18 age- and size-matched controls were retrospectively studied. Cardiac cycle events were measured by M-mode and Doppler echocardiography. Measurements were compared between groups using ANOVA with post hoc Dunnet's or ANCOVA including RV systolic pressure (RVSP; iPAH 96.8 ± 25.4 mmHg vs. PS 75.4 ± 18.9 mmHg; P = 0.011) as a covariate. RV-free wall thickening was prolonged in iPAH versus PS, extending beyond pulmonary valve closure (638 ± 76 msec vs. 562 ± 76 msec vs. 473 ± 59 msec controls). LV and RV isovolumetric relaxation were prolonged in iPAH (P < 0.001; LV 102.8 ± 24.1 msec vs. 63.1 ± 13.7 msec; RV 95 [61-165] vs. 28 [0-43]), associated with adverse septal kinetics; characterized by rightward displacement in early systole and leftward displacement in late RV systole (i.e., early LV diastole). Early LV diastolic filling was decreased in iPAH (73 ± 15.9 vs. PS 87.4 ± 14.4 vs. controls 95.8 ± 12.5 cm/sec; P = 0.004). Prolonged RVFW thickening, prolonged RVFW isovolumetric times, and profound septal dyskinesia are associated with interventricular mechanical discoordination and decreased early LV filling in pediatric iPAH much more than PS These adverse mechanics affect systolic and diastolic biventricular efficiency in iPAH and may form the basis for worse clinical outcomes. We used clinically derived data to study the pathophysiology of ventricular

  11. [The effect of prosthesis-patient mismatchon early myocardial remodeling after aortic valve replacement].

    PubMed

    Belov, Iu V; Katkov, A I; Seslavinskaia, T V; Vinokurov, I A; Salagaev, G I

    2015-01-01

    The reductionofan effective orifice area is associated with the development of the phenomenon of prosthesis-patient mismatch (PPM). The purpose of this study was to evaluate the impact of PPM on the immediate results of surgical treatment in patients with aortic valve stenosis. The study included 50 patients who underwent aortic valve replacement. All patients were divided into 2 groups: with PPM (27 patients) and without it (23 patients). Immediate postoperative results were not statistically different. Analysis of echocardiographic data showed worse results in patients with PPM. It was marked reduction of LV EDV on 23.43 ± 8.93 ml in the group without PPM and on 16.5 ± 1.76 ml in patients with PPM (p<0.05). Also it was noted a greater decrease of pulmonary artery pressure (16.56 ± 12.94 mm Hg) compared with the group with PPM (8.44 ± 7.38 mm Hg), p<0.05. The presence of PPM in patients after aortic valve replacement leads to a slower reverse remodeling of the myocardium. PMID:26031944

  12. Vagal Nerve Stimulation Evoked Heart Rate Changes and Protection from Cardiac Remodeling.

    PubMed

    Agarwal, Rahul; Mokelke, Eric; Ruble, Stephen B; Stolen, Craig M

    2016-02-01

    This study investigated whether vagal nerve stimulation (VNS) leads to improvements in ischemic heart failure via heart rate modulation. At 7 ± 1 days post left anterior descending artery (LAD) ligation, 63 rats with myocardial infarctions (MI) were implanted with ECG transmitters and VNS devices (MI + VNS, N = 44) or just ECG transmitters (MI, N = 17). VNS stimulation was active from 14 ± 1 days to 8 ± 1 weeks post MI. The average left ventricular (LV) end diastolic volumes at 8 ± 1 weeks were MI = 672.40 μl and MI + VNS = 519.35 μl, p = 0.03. The average heart weights, normalized to body weight (± std) at 14 ± 1 weeks were MI = 3.2 ± 0.6 g*kg(-1) and MI + VNS = 2.9 ± 0.3 g*kg(-1), p = 0.03. The degree of cardiac remodeling was correlated with the magnitude of acute VNS-evoked heart rate (HR) changes. Further research is required to determine if the acute heart rate response to VNS activation is useful as a heart failure biomarker or as a tool for VNS therapy characterization. PMID:26746408

  13. Depression Increases Sympathetic Activity and Exacerbates Myocardial Remodeling after Myocardial Infarction: Evidence from an Animal Experiment

    PubMed Central

    Liu, Tao; Yuan, Xiaoran; Ruan, Bing; Sun, Lifang; Tang, Yanhong; Yang, Bo; Hu, Dan; Huang, Congxin

    2014-01-01

    Depression is an independent risk factor for cardiovascular events and mortality in patients with myocardial infarction (MI). Excessive sympathetic activation and serious myocardial remodeling may contribute to this association. The aim of this study was to discuss the effect of depression on sympathetic activity and myocardial remodeling after MI. Wild-type (WT) rats were divided into a sham group (Sham), a myocardial infarction group (MI), a depression group (D), and a myocardial infarction plus depression group (MI+D). Compared with controls, the MI+D animals displayed depression-like behaviors and attenuated body weight gain. The evaluation of sympathetic activity showed an increased level in plasma concentrations of epinephrine and norepinephrine and higher expression of myocardial tyrosine hydroxylase in the MI+D group than the control groups (p<0.05 for all). Cardiac function and morphologic analyses revealed a decreased fractional shortening accompanied by increased left ventricular dimensions, thinning myocardium wall, and reduced collagen repair in the MI+D group compared with the MI group (p<0.05 for all). Frequent premature ventricular contractions, prolonged QT duration and ventricular repolarization duration, shorted effective refractory period, and increased susceptibility to ventricular arrhythmia were displayed in MI+D rats. These results indicate that sympathetic hyperactivation and exacerbated myocardial remodeling may be a plausible mechanism linking depression to an adverse prognosis after MI. PMID:25036781

  14. Biologics in dermatology: adverse effects.

    PubMed

    Sehgal, Virendra N; Pandhi, Deepika; Khurana, Ananta

    2015-12-01

    Biologics are a group of drugs that precisely affect certain specific steps in the immune response and are an extremely useful group when used in an appropriate setting. However, their use can often be a double-edged sword. Careful patient selection and thorough knowledge of adverse effects is a key to their successful use in various disorders. The initial enthusiasm has gradually given way to a more cautious approach wherein a balance is sought between clinical usefulness and expected side effects. The adverse effects of the biologics most commonly used in dermatology have been carefully listed for ready reference. The plausible causes of the adverse reactions are succinctly outlined along with their incriminating factor(s). Besides, in brief, the attention has been focused on their management. The content should provide an essential didactic content for educating the practitioner. PMID:26147909

  15. Arterial remodeling of basilar atherosclerosis in isolated pontine infarction.

    PubMed

    Feng, Chao; Hua, Ting; Xu, Yu; Liu, Xue-Yuan; Huang, Jing

    2015-04-01

    Isolated pontine infarctions are usually classified as paramedian pontine infarction (PPI) and lacunar pontine infarction (LPI). Although they have different shapes and locations, some recent studies proved that they might both be associated with basilar artery atherosclerosis in pathogenesis. This study aimed to explore the difference of basilar artery remodeling between two subtypes of pontine infarctions. Patients with PPI or LPI were scanned by High-resolution MRI (HR-MRI). The MR images of patients with basilar artery atherosclerosis were further analyzed to measure the vessel, lumen and wall areas at different segments of basilar arteries. Stenosis rate and remodeling index were calculated according to which arterial remodeling was divided into positive, intermediate and negative remodeling. Vascular risk factors and remodeling-related features were compared between PPI and LPI, and also between patients with and without positive remodeling. 34 patients with PPI and 21 patients with LPI had basilar artery atherosclerosis identified by HR-MRI. Positive remodeling was dominant in LPI group while in PPI group, three subtypes of remodeling were equal. Patients with positive remodeling had higher levels of low-density lipoprotein and homocysteine. Positive remodeling of basilar artery might reflect the low stability of basilar atherosclerotic plaques, which was more closely associated with LPI than PPI. PMID:25367406

  16. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling

    PubMed Central

    Broide, David H.

    2008-01-01

    Although histologic features of airway remodeling have been well characterized in asthma, the immunologic and inflammatory mechanisms that drive progression of asthma to remodeling are still incompletely understood. Conceptually, airway remodeling may be due to persistent inflammation and/or aberrant tissue repair mechanisms. It is likely that several immune and inflammatory cell types and mediators are involved in mediating airway remodeling. In addition, different features of airway remodeling are likely mediated by different inflammatory pathways. Several important candidate mediators of remodeling have been identified including TGF-β and Th2 cytokines (including IL-5 and IL-13), as well as VEGF, ADAM-33, and MMP-9. Mouse models of airway remodeling have provided important insight into potential mechanisms by which TGF-β activation of the Smad 2/3 signaling pathway may contribute to airway remodeling. Human studies have demonstrated that anti-IL-5 reduces levels of airway eosinophils expressing TGF-β, as well as levels of airway remodeling as assessed by bronchial biopsies. Further such studies confirming these observations, as well as alternate studies targeting additional individual cell types, cytokines, and mediators are needed in human subjects with asthma to determine the role of candidate mediators of inflammation on the development and progression of airway remodeling. PMID:18328887

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

    PubMed

    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

  18. 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

  19. Adversity and advancing nursing knowledge.

    PubMed

    Reed, Pamela G

    2008-04-01

    This column reports the theme of adversity addressed in reference to theoretical and metatheoretical considerations for advancing nursing knowledge. The development and content of three classic nursing theories are presented by Neuman representatives, and by theorists King and Roy. Topics for continued dialogue are identified as derived from the interface between philosophy of science issues and these theories. PMID:18378823

  20. 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…

  1. 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

  2. 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

  3. Estrogen attenuates chronic volume overload induced structural and functional remodeling in male rat hearts

    PubMed Central

    Murray, David B.; Voloshenyuk, Tetyana G.; Brower, Gregory L.; Bradley, Jessica M.; Janicki, Joseph S.

    2010-01-01

    We have previously reported gender differences in ventricular remodeling and development of heart failure using the aortocaval fistula model of chronic volume overload in rats. In contrast to males, female rats exhibited no adverse ventricular remodeling and less mortality in response to volume overload. This gender-specific cardioprotection was lost following ovariectomy and was partially restored using estrogen replacement. However, it is not known if estrogen treatment would be as effective in males. The purpose of this study was to evaluate the structural and functional effects of estrogen in male rats subjected to chronic volume overload. Four groups of male rats were studied at 3 days and 8 wk postsurgery as follows: fistula and sham-operated controls, with and without estrogen treatment. Biochemical and histological studies were performed at 3 days postsurgery, with chronic structural and functional effects studied at 8 wk. Measurement of systolic and diastolic pressure-volume relationships was obtained using a blood-perfused isolated heart preparation. Both fistula groups developed significant ventricular hypertrophy after 8 wk of volume overload. Untreated rats with fistula exhibited extensive ventricular dilatation, which was coupled with a loss of systolic function. Estrogen attenuated left ventricular dilatation and maintained function in treated rats. Estrogen treatment was also associated with a reduction in oxidative stress and circulating endothelin-1 levels, as well as prevention of matrix metalloproteinase-2 and -9 activation and breakdown of ventricular collagen in the early stage of remodeling. These data demonstrate that estrogen attenuates ventricular remodeling and disease progression in male rats subjected to chronic volume overload. PMID:19933421

  4. Pyrvinium, a Potent Small Molecule Wnt Inhibitor, Promotes Wound Repair and Post-MI Cardiac Remodeling

    PubMed Central

    Saraswati, Sarika; Alfaro, Maria P.; Thorne, Curtis A.; Atkinson, James; Lee, Ethan; Young, Pampee P.

    2010-01-01

    Wnt signaling plays an important role in developmental and stem cell biology. To test the hypothesis that temporary inhibition of Wnt signaling will enhance granulation tissue and promote angiogenesis in tissue repair, we employed a recently characterized small molecule Wnt inhibitor. Pyrvinium is an FDA-approved drug that we identified as a Wnt inhibitor in a chemical screen for small molecules that stabilize β-catenin and inhibit Axin degradation. Our subsequent characterization of pyrvinium has revealed that its critical cellular target in the Wnt pathway is Casein Kinase 1α. Daily administration of pyrvinium directly into polyvinyl alcohol (PVA) sponges implanted subcutaneously in mice generated better organized and vascularized granulation tissue; this compound also increased the proliferative index of the tissue within the sponges. To evaluate its effect in myocardial repair, we induced a myocardial infarction (MI) by coronary artery ligation and administered a single intramyocardial dose of pyrvinium. Mice were evaluated by echocardiography at 7 and 30 days post-MI and treatment; post mortem hearts were evaluated by histology at 30 days. Pyrvinium reduced adverse cardiac remodeling demonstrated by decreased left ventricular internal diameter in diastole (LVIDD) as compared to a control compound. Increased Ki-67+ cells were observed in peri-infarct and distal myocardium of pyrvinium-treated animals. These results need to be further followed-up to determine if therapeutic inhibition of canonical Wnt may avert adverse remodeling after ischemic injury and its impact on myocardial repair and regeneration. PMID:21170416

  5. [Two cases of recurrent colorectal cancer treated successfully with folinate/tegafur/uracil (UFT/LV) chemotherapy on an outpatient basis].

    PubMed

    Hosotaki, Kiyoshi; Tabira, Yoichi; Shimamoto, Masato; Tamori, Yasuhiro

    2008-04-01

    We report two cases of recurrent colorectal cancer in two patients who were treated successfully with a combined oral chemotherapeutic agent folinate/tegafur/uracil (UFT/LV) dosage. The first case was a 74-year-old woman who underwent Hartmann operation for colon cancer perforation. One year and 7 months after surgery, a local recurrence was found on the CT scan and endoscopy. It ended in exploratory laparotomy though we were operated on. Chemotherapy using 5-fluorouracil/Leucovorin (5-FU/LV) was performed six times. Sequentially, UFT/LV internal use was managed at our outpatient clinic. This patient has been living without side effects in the first three postoperative years, and without increase in tumors. The second case was a 65-year-old woman who underwent abdominoperineal resection of the rectum for rectal cancer. The histologic stage of disease aggravation of the patient was stageI. Post operatively, 2 years and 6 months later, we recognized a metastasis node on the lung upper right lobe of the patient and her CA19-9 value climbed dramatically. The patient took UFT/LV during outpatient visits to the hospital, the lung node shadow disappeared two months later, and CA19-9 decreased, too. The patient is living without a cancer recurrence now. UFT/LV treatment is one of the effective modalities against recurrence of colorectal cancer from outpatient treatment while maintaining QOL. PMID:18408440

  6. Association of Increased Epicardial Adipose Tissue Thickness With Adverse Cardiovascular Outcomes in Patients With Atrial Fibrillation

    PubMed Central

    Chu, Chun-Yuan; Lee, Wen-Hsien; Hsu, Po-Chao; Lee, Meng-Kuang; Lee, Hung-Hao; Chiu, Cheng-An; Lin, Tsung-Hsien; Lee, Chee-Siong; Yen, Hsueh-Wei; Voon, Wen-Chol; Lai, Wen-Ter; Sheu, Sheng-Hsiung; Su, Ho-Ming

    2016-01-01

    Abstract The thickness of epicardial adipose tissue (EAT) was reported to be highly associated with the incidence and severity of atrial fibrillation (AF). This study was conducted to analyze the ability of EAT thickness in predicting adverse cardiovascular (CV) events in AF. In 190 persistent AF patients, we performed a comprehensive transthoracic echocardiographic examination with assessment of EAT thickness. The definition of CV events included CV mortality, hospitalization for heart failure, myocardial infarction, and stroke. There were 69 CV events including 19 CV deaths, 32 hospitalizations for heart failure, 3 myocardial infarctions, and 15 strokes during a mean follow-up of 29 (25th–75th percentile: 17–36) months. The multivariable analysis demonstrates that chronic heart failure, increased left ventricular (LV) mass index and the ratio of transmitral E-wave velocity to early diastolic mitral annulus velocity, decreased body mass index, and increased EAT thickness (per 1-mm increase, odds ratio 1.224, 95% confidence interval [CI] 1.096–1.368, P < 0.001) were associated with adverse CV events. Additionally, the addition of EAT thickness to a model containing CHA2DS2-VASc score, left atrial volume index, and LV systolic and diastolic function significantly improved the values in predicting CV events (global χ2 increase 14.65, P < 0.001 and integrated discrimination improvement 0.10, 95% CI 0.04–0.16, P < 0.001). In AF, EAT thickness was useful in predicting adverse CV events. Additionally, EAT thickness could provide incremental value for CV outcome prediction over traditional clinical and echocardiographic parameters in AF. PMID:26986099

  7. Association of Increased Epicardial Adipose Tissue Thickness With Adverse Cardiovascular Outcomes in Patients With Atrial Fibrillation.

    PubMed

    Chu, Chun-Yuan; Lee, Wen-Hsien; Hsu, Po-Chao; Lee, Meng-Kuang; Lee, Hung-Hao; Chiu, Cheng-An; Lin, Tsung-Hsien; Lee, Chee-Siong; Yen, Hsueh-Wei; Voon, Wen-Chol; Lai, Wen-Ter; Sheu, Sheng-Hsiung; Su, Ho-Ming

    2016-03-01

    The thickness of epicardial adipose tissue (EAT) was reported to be highly associated with the incidence and severity of atrial fibrillation (AF). This study was conducted to analyze the ability of EAT thickness in predicting adverse cardiovascular (CV) events in AF.In 190 persistent AF patients, we performed a comprehensive transthoracic echocardiographic examination with assessment of EAT thickness. The definition of CV events included CV mortality, hospitalization for heart failure, myocardial infarction, and stroke.There were 69 CV events including 19 CV deaths, 32 hospitalizations for heart failure, 3 myocardial infarctions, and 15 strokes during a mean follow-up of 29 (25th-75th percentile: 17-36) months. The multivariable analysis demonstrates that chronic heart failure, increased left ventricular (LV) mass index and the ratio of transmitral E-wave velocity to early diastolic mitral annulus velocity, decreased body mass index, and increased EAT thickness (per 1-mm increase, odds ratio 1.224, 95% confidence interval [CI] 1.096-1.368, P < 0.001) were associated with adverse CV events. Additionally, the addition of EAT thickness to a model containing CHA2DS2-VASc score, left atrial volume index, and LV systolic and diastolic function significantly improved the values in predicting CV events (global χ increase 14.65, P < 0.001 and integrated discrimination improvement 0.10, 95% CI 0.04-0.16, P < 0.001).In AF, EAT thickness was useful in predicting adverse CV events. Additionally, EAT thickness could provide incremental value for CV outcome prediction over traditional clinical and echocardiographic parameters in AF. PMID:26986099

  8. A dynamic zone defines interneuron remodeling in the adult neocortex

    PubMed Central

    Lee, Wei-Chung Allen; Chen, Jerry L.; Huang, Hayden; Leslie, Jennifer H.; Amitai, Yael; So, Peter T.; Nedivi, Elly

    2008-01-01

    The contribution of structural remodeling to long-term adult brain plasticity is unclear. Here, we investigate features of GABAergic interneuron dendrite dynamics and extract clues regarding its potential role in cortical function and circuit plasticity. We show that remodeling interneurons are contained within a “dynamic zone” corresponding to a superficial strip of layers 2/3, and remodeling dendrites respect the lower border of this zone. Remodeling occurs primarily at the periphery of dendritic fields with addition and retraction of new branch tips. We further show that dendrite remodeling is not intrinsic to a specific interneuron class. These data suggest that interneuron remodeling is not a feature predetermined by genetic lineage, but rather, it is imposed by cortical laminar circuitry. Our findings are consistent with dynamic GABAergic modulation of feedforward and recurrent connections in response to top-down feedback and suggest a structural component to functional plasticity of supragranular neocortical laminae. PMID:19066223

  9. In Brief: Picturing the complex world of chromatin remodelling families.

    PubMed

    Witkowski, Leora; Foulkes, William D

    2015-12-01

    Over the past decade, chromatin remodelling emerged as one of the most important causes of both abnormal development and cancer. Although much has been written about one or another of the complexes, no recent concise summary of the chromatin remodelling families as a whole is available. In this short review, we introduce the family members, briefly summarize their role in developmental abnormalities and neoplasia, and outline the different ways in which these families remodel chromatin. PMID:26174723

  10. 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.

  11. 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. PMID:26371175

  12. MoMuLV-ts-1: A Unique Mouse Model of Retrovirus-Induced Lymphoma Transmitted by Breast Milk

    PubMed Central

    Chakraborty, J.; Okonta, H.; Bagalb, H.; Duggan, J.

    2011-01-01

    Our laboratory has developed a murine model of lymphoma via breast milk transmission of MoMuLV-ts-1 (Moloney murine leukemia virus-temperature sensitive mutant-1). Uninfected offspring suckled from infected surrogate mothers become infected and develop lymphoma. Multiple gene integration sites of ts-1 into the infected mouse genome including tacc3, aurka, ndel1, tpx2, p53, and rhamm were identified, and mRNA expressions were quantitated. These genes produce centrosomal proteins, which may be involved in abnormal chromosomal segregation leading to aneuploidy or multiploidy, thus causing lymphoma. Since there is no report to date on this retroviral model leading to centrosomal abnormality, and causing lymphoma development, this is a valuable and unique model to study the centrosomal involvement in lymphomagenesis. PMID:22312355

  13. 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

  14. The putative invertebrate adaptive immune protein Litopenaeus vannamei Dscam (LvDscam) is the first reported Dscam to lack a transmembrane domain and cytoplasmic tail.

    PubMed

    Chou, Pin-Hsiang; Chang, Hao-Shuo; Chen, I-Tung; Lin, Han-You; Chen, Yi-Min; Yang, Huey-Lang; Wang, K C Han-Ching

    2009-12-01

    It has recently been suggested that Dscam (Down syndrome cell adhesion molecule), a member of the immunoglobulin superfamily (IgSF), plays an essential role in the alternative adaptive immune system of invertebrates. Here, we isolated and characterized the first shrimp Dscam from Litopenaeus vannamei. The LvDscam protein had an extracellular domain but lacked the expected transmembrane domain and cytoplasmic tail, both of which are found in all other members of the Dscam family (and may also be found in other L. vannamei Dscams that have not yet been isolated). In nervous tissue, expression levels of LvDscam were unexpectedly low. Phylogenetic analysis suggests that LvDscam is far from the Dscams found in other invertebrates. Nevertheless, the domain architecture of the extracellular region of LvDscam is similar to other invertebrate Dscams, and it exhibits the typical configuration of 10 immunoglobulin (Ig) domains, 6 fibronectin type 3 domains (FNIII) and one cell attachment sequence (RGD). Cloning and characterization of a total of 62 cDNAs from hemocytes collected from WSSV-free, WSSV-persistent and WSSV-acute-infected shrimp revealed 23 alternative amino acid sequences in the N-terminal of Ig2, 30 in the N-terminal of Ig3 and 13 in the Ig7 domain. This implies that LvDscam can potentially encode at least 8970 unique isoforms. Further analysis suggested that the LvDscam Ig2 and Ig3 regions are more functionally important than Ig7 in the shrimp's specific immune response against WSSV. We discuss how this tail-less, soluble Dscam can still play an active role in alternative adaptive immune response even while its axonal guidance functionality may be impaired. PMID:19635499

  15. Cardiovascular adverse effects of phenytoin.

    PubMed

    Guldiken, B; Rémi, J; Noachtar, Soheyl

    2016-05-01

    Phenytoin is an established drug in the treatment of acute repetitive seizures and status epilepticus. One of its main advantages over benzodiazepines is the less sedative effect. However, the possibility of cardiovascular adverse effects with the intravenous use of phenytoin cause a reluctance to its usage, and this has lead to a search for safer anticonvulsant drugs. In this study, we aimed to review the studies which evaluated the safety of phenytoin with respect to cardiovascular adverse effects. The original clinical trials and case reports listed in PUBMED in English language between the years of 1946-2014 were evaluated. As the key words, "phenytoin, diphenylhydantoin, epilepsy, seizure, cardiac toxicity, asystole, arrhythmia, respiratory arrest, hypotension, death" were used. Thirty-two clinical trials and ten case reports were identified. In the case reports, a rapid infusion rate (>50 mg/min) of phenytoin appeared as the major cause of increased mortality. In contrast, no serious cardiovascular adverse effects leading to death were met in the clinical trials which applied the recommended infusion rate and dosages. An infusion rate of 50 mg/min was reported to be safe for young patients. For old patients and patients with a cardiovascular co-morbidity, a slower infusion rate was recommended with a careful follow-up of heart rhythm and blood pressure. No cardiovascular adverse effect was reported in oral phenytoin overdoses except one case with a very high serum phenytoin level and hypoalbuminemia. Phenytoin is an effective and well tolerated drug in the treatment of epilepsy. Intravenous phenytoin is safe when given at recommended infusion rates and doses. PMID:26645393

  16. [Adverse events of psychotropic drugs].

    PubMed

    Watanabe, Koichiro; Kikuchi, Toshiaki

    2014-01-01

    The authors discuss adverse events which are often missed but clinicians should pay attention to in order to preserve patients'quality of life(QOL). Among mood stabilizers, lithium may cause a urinary volume increase, hyperparathyroidism, and serum calcium elevation; sodium valproate possibly increases androgenic hormone levels and the risk of polycystic ovary syndrome (PCOS) as well as hypothyroidism. Moreover, in addition to teratogenesis, it has been reported that fetal exposure to a higher dose of valproate is associated with a lower intelligence quotient and higher incidence of autism spectrum disorders in children. Antidepressants with a higher affinity for serotonin transporters might induce gastrointestinal bleeding, and some antidepressants cause sexual dysfunction more frequently than others. Activation syndrome is still a key side effect which should be noted. Regarding the adverse events of antipsychotics, subjective side effects unpleasant to patients such as dysphoria and a lower subjective well-being should not be overlooked. We clinicians have to cope with adverse events worsening the QOL of patients with psychiatric disorders and, therefore, we need to adopt appropriate counter-measures. PMID:24864567

  17. [Histamine in regulation of bone remodeling processes].

    PubMed

    Wiercigroch, Marek; Folwarczna, Joanna

    2013-01-01

    Bone remodeling is under autocrine, paracrine, endocrine and central nervous system control. One of the potential endogenous factors affecting bone remodeling is histamine, an endogenous amine which acts as a mediator of allergic reactions and neuromediator, and induces production of gastric acid. Histamine H₁ receptor antagonists are widely used in the treatment of allergic conditions, H₂ receptor antagonists in peptic ulcer disease, and betahistine (an H₃ receptor antagonist and H₁ receptor agonist) is used in the treatment of Ménière's disease. Excess histamine release in mastocytosis and allergic diseases may lead to development of osteoporosis. Clinical and population-based studies on the effects of histamine receptor antagonists on the skeletal system have not delivered unequivocal results. Expression of mRNA of histamine receptors has been discovered in bone cells (osteoblasts and osteoclasts). Histamine synthesis has been demonstrated in osteoclast precursors. Histamine increases bone resorption both by direct effects on osteoclast precursors and osteoclasts, and indirectly, by increasing the expression of RANKL in osteoblasts. In in vivo studies, H₁ and H₂ receptor antagonists exerted protective effects on the bone tissue, although not in all experimental models. In the present article, in vitro and in vivo studies conducted so far, concerning the effects of histamine and drugs modifying its activity on the skeletal system, have been reviewed. PMID:24018454

  18. 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

  19. 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

  20. Remodeling of the Fetal Collecting Duct Epithelium

    PubMed Central

    Hiatt, Michael J.; Ivanova, Larissa; Toran, Nuria; Tarantal, Alice F.; Matsell, Douglas G.

    2010-01-01

    Congenital urinary tract obstruction induces changes to the renal collecting duct epithelium, including alteration and depletion of intercalated cells. To study the effects of obstruction on the ontogeny of intercalated cell development, we examined normal and obstructed human fetal and postnatal kidneys. In the normal human fetal kidney, intercalated cells originated in the medullary collecting duct at 8 weeks gestation and remained most abundant in the inner medulla throughout gestation. In the cortex, intercalated cells were rare at 18 and 26 weeks gestation and observed at low abundance at 36 weeks gestation. Although early intercalated cells exhibit an immature phenotype, Type A intercalated cells predominated in the inner and outer medullae at 26 and 36 weeks gestation with other intercalated cell subtypes observed rarely. Postnatally, the collecting duct epithelium underwent a remodeling whereby intercalated cells become abundant in the cortex yet absent from the inner medulla. In 18-week obstructed kidneys with mild to moderate injury, the intercalated cells became more abundant and differentiated than the equivalent age-matched normal kidney. In contrast, more severely injured ducts of the late obstructed kidney exhibited a significant reduction in intercalated cells. These studies characterize the normal ontogeny of human intercalated cell development and suggest that obstruction induces premature remodeling and differentiation of the fetal collecting duct epithelium. PMID:20035053

  1. Abnormal bone remodelling in inflammatory arthritis

    PubMed Central

    Bogoch, Earl R.; Moran, Erica

    1998-01-01

    Osteopenia is responsible for substantial comorbidity in patients suffering from rheumatoid arthritis and is an important factor in the surgical management of joint disease. In animal models of bone loss stimulated by inflammatory arthritis, increased bone remodelling and altered microstructure of bone have been documented. The subchondral bone plate near the joint surface is narrow and perforated by vascular inflammatory invasion, and in the shaft the thin cortices are weakened by giant resorption defects. Biomechanical tests and a mathematical model of bone strength suggest that cortical defects, much larger than those found in normal osteonal remodelling, are principally responsible for the experimentally observed loss of strength. Similarly, these defects may explain the increased femoral fracture risk in rheumatoid arthritis. The osteoclast, the cell resorbing bone, is demonstrated in increased number and activity in rheumatoid arthritis and in animal models. Bisphosphonates, drugs that inhibit osteoclast function, have been shown experimentally to reduce both focal and generalized osteopenia and to prevent loss of bone strength. Bisphosphonates also protect articular cartilage from damage characteristic of inflammatory arthritis. The mechanism of chondroprotection may be prevention of subchondral bone resorption by the osteoclast and also an altered distribution of bone marrow cells. Thus, bisphosphonates, currently in clinical use for other bone metabolic diseases, appear to have potential as prophylaxis and treatment for osteopenia and joint damage in inflammatory arthritis. PMID:9711159

  2. Hard tissue remodeling using biofabricated coralline biomaterials.

    PubMed

    Vago, Razi; Plotquin, Daniel; Bunin, Alex; Sinelnikov, Igor; Atar, Dan; Itzhak, David

    2002-01-01

    Biotechnical and biomedical approaches were combined in an attempt to identify potential uses of biofabricated marine carbonate materials in biomedical applications, particularly as biomatrices for remodeling bone and cartilage tissue. After grafting, it is desirable for bone ingrowth to proceed as quickly as possible because the strength of the implanted region depends on a good mechanical bond forming between the implant and surrounding regions in the body. Ingrowth can take place as a result of growth of tissue and cells into the implanted porous material, or it may be promoted by transplanting cells seeded onto such a material. The rate at which ingrowth occurs is dependent on many factors, including pore size and the interconnectivity of the implanted structure. In vivo graftings into osteochondral defects demonstrated that our biofabricated porous material is highly biocompatible with cartilage and bone tissue. The biofabricated matrix was well incorporated into the biphasic osteochondral area. Resorption was followed by bone and cartilage formation, and after 4 months, the biomaterial had been replaced by new tissue. Ossification was induced and enhanced without introduction of additional factors. We believe that this is the first time that such biofabricated materials have been used for biomedical purposes. In face of the obvious environmental disadvantages of harvesting from limited natural resources, we propose the use of bioengineered coralline and other materials such as those cultured by our group under field and laboratory conditions as a possible biomatrix for hard tissue remodeling. PMID:11741712

  3. Chromatin remodeling in cardiovascular development and physiology

    PubMed Central

    Han, Pei; Hang, Calvin T.; Yang, Jin; Chang, Ching-Pin

    2010-01-01

    Chromatin regulation provides an important means of controlling cardiac gene expression under different physiological and pathological conditions. Processes that direct the development of normal embryonic hearts and pathology of stressed adult hearts may share general mechanisms that govern cardiac gene expression by chromatin-regulating factors. These common mechanisms may provide a framework for us to investigate the interactions among diverse chromatin remodelers/modifiers and various transcription factors in the fine regulation of gene expression, essential for all aspects of cardiovascular biology. Aberrant cardiac gene expression, triggered by a variety of pathological insults, can cause heart diseases in both animals and humans. The severity of cardiomyopathy and heart failure correlates strongly with abnormal cardiac gene expression. Therefore, controlling cardiac gene expression presents a promising approach to the treatment of human cardiomyopathy. This review focuses on the roles of ATP-dependent chromatin-remodeling factors and chromatin-modifying enzymes in the control of gene expression during cardiovascular development and disease. PMID:21293009

  4. Atrial remodeling, fibrosis, and atrial fibrillation.

    PubMed

    Jalife, José; Kaur, Kuljeet

    2015-08-01

    The fundamental mechanisms governing the perpetuation of atrial fibrillation (AF), the most common arrhythmia seen in clinical practice, are poorly understood, which explains in part why AF prevention and treatment remain suboptimal. Although some clinical parameters have been identified as predicting a transition from paroxysmal to persistent AF in some patients, the molecular, electrophysiological, and inflammation changes leading to such a progression have not been described in detail. Oxidative stress, atrial dilatation, calcium overload, inflammation, microRNAs, and myofibroblast activation are all thought to be involved in AF-induced atrial remodeling. However, it is unknown to what extent and at which time points such alterations influence the remodeling process that perpetuates AF. Here we postulate a working model that might open new pathways for future investigation into mechanisms of AF perpetuation. We start from the premise that the progression to AF perpetuation is the result of interplay among manifold signaling pathways with differing kinetics. Some such pathways have relatively fast kinetics (e.g., oxidative stress-mediated shortening of refractory period); others likely depend on molecular processes with slower kinetics (e.g., transcriptional changes in myocyte ion channel protein expression mediated through inflammation and fibroblast activation). We stress the need to fully understand the relationships among such pathways should one hope to identify novel, truly effective targets for AF therapy and prevention. PMID:25661032

  5. Impact of septal flash and left ventricle contractile reserve on positive remodeling during 1 year cardiac resynchronization therapy: the multicenter ViaCRT study

    PubMed Central

    Gąsior, Zbigniew; Płońska-Gościniak, Edyta; Wita, Krystian; Mizia-Stec, Katarzyna; Szwed, Hanna; Kasprzak, Jarosław; Tomaszewski, Andrzej; Sinkiewicz, Władysław; Wojciechowska, Celina

    2016-01-01

    Introduction Cardiac resynchronization therapy (CRT) has been shown to improve outcomes in patients with systolic heart failure (HFREF). However, the relatively high non-responder rate results in a need for more precise qualification for CRT. The ViaCRT study was designed to determine the role of contractile reserve and dyssynchrony parameters in predicting CRT response. The purpose of this analysis was to determine the effect of baseline septal flash and contractile reserve (CR) on clinical and echocardiographic parameters of response to CRT in 12-month follow-up. Material and methods One hundred thirty-three guideline-selected CRT candidates (both ischemic and non-ischemic heart failure with reduced ejection fraction) were enrolled in the study. Baseline study population characteristics were: left ventricle ejection fraction (LVEF) 25 ±6%, QRS 165 ±25 ms, NYHA class III (90%) and IV (10%). Results In subjects with septal flash (SF) registered before CRT implantation improvement in LVEF (14 ±2% vs. 8 ±1%, p < 0.05) and left ventricle (LV) systolic (63 ±10 ml vs. 36 ±6 ml, p < 0.05) and diastolic (46 ±10 ml vs. 32 ±7, p < 0.05) volumes was more pronounced than in patients without SF. In patients with CR (defined as LVEF increase by 20% or 4 viable segments) improvement in echo parameters was not significantly different then in the CR– group. Neither SF nor CR was associated with improvement in NYHA class. Subgroup analysis revealed that only in non-ischemic HF patients is presence of septal flash associated with LV function improvement after CRT. Conclusions In non-ischemic HF patients septal flash is a helpful parameter in prediction of LV remodeling after 12 months of resynchronization therapy. PMID:27186179

  6. Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

    PubMed Central

    Kiriazis, Helen; Tugiono, Niquita; Xu, Qi; Gao, Xiao-Ming; Jennings, Nicole L; Ming, Ziqui; Su, Yidan; Klenowski, Paul; Summers, Roger J; Kaumann, Alberto; Molenaar, Peter; Du, Xiao-Jun

    2013-01-01

    BACKGROUND AND PURPOSE The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. EXPERIMENTAL APPROACH C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4–8 or 4–12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. CONCLUSIONS AND IMPLICATIONS β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure. PMID:23750586

  7. Detecting Adverse Events Using Information Technology

    PubMed Central

    Bates, David W.; Evans, R. Scott; Murff, Harvey; Stetson, Peter D.; Pizziferri, Lisa; Hripcsak, George

    2003-01-01

    Context: Although patient safety is a major problem, most health care organizations rely on spontaneous reporting, which detects only a small minority of adverse events. As a result, problems with safety have remained hidden. Chart review can detect adverse events in research settings, but it is too expensive for routine use. Information technology techniques can detect some adverse events in a timely and cost-effective way, in some cases early enough to prevent patient harm. Objective: To review methodologies of detecting adverse events using information technology, reports of studies that used these techniques to detect adverse events, and study results for specific types of adverse events. Design: Structured review. Methodology: English-language studies that reported using information technology to detect adverse events were identified using standard techniques. Only studies that contained original data were included. Main Outcome Measures: Adverse events, with specific focus on nosocomial infections, adverse drug events, and injurious falls. Results: Tools such as event monitoring and natural language processing can inexpensively detect certain types of adverse events in clinical databases. These approaches already work well for some types of adverse events, including adverse drug events and nosocomial infections, and are in routine use in a few hospitals. In addition, it appears likely that these techniques will be adaptable in ways that allow detection of a broad array of adverse events, especially as more medical information becomes computerized. Conclusion: Computerized detection of adverse events will soon be practical on a widespread basis. PMID:12595401

  8. 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

  9. National Remodelling Team: Evaluation Study (Year 2). Final Report

    ERIC Educational Resources Information Center

    Easton, Claire; Wilson, Rebekah; Sharp, Caroline

    2005-01-01

    This report sets out to provide the National Remodelling Team (NRT) with comprehensive details on stakeholders' views about the second year of the remodelling programme. This report is divided into nine chapters: (1) Introduction; (2) outlines the aims of the evaluation and the methodology used; (3) describes the findings from the survey of local…

  10. Chromatin-remodeling and the initiation of transcription.

    PubMed

    Lorch, Yahli; Kornberg, Roger D

    2015-11-01

    The nucleosome serves as a general gene repressor by the occlusion of regulatory and promoter DNA sequences. Repression is relieved by the SWI/SNF-RSC family of chromatin-remodeling complexes. Research reviewed here has revealed the essential features of the remodeling process. PMID:26537406

  11. Macrophage plasticity and polarization in tissue repair and remodelling.

    PubMed

    Mantovani, Alberto; Biswas, Subhra K; Galdiero, Maria Rosaria; Sica, Antonio; Locati, Massimo

    2013-01-01

    Mononuclear phagocyte plasticity includes the expression of functions related to the resolution of inflammation, tissue repair and remodelling, particularly when these cells are set in an M2 or an M2-like activation mode. Macrophages are credited with an essential role in remodelling during ontogenesis. In extraembryonic life, under homeostatic conditions, the macrophage trophic and remodelling functions are recapitulated in tissues such as bone, mammary gland, decidua and placenta. In pathology, macrophages are key components of tissue repair and remodelling that occur during wound healing, allergy, parasite infection and cancer. Interaction with cells bearing stem or progenitor cell properties is likely an important component of the role of macrophages in repair and remodelling. These properties of cells of the monocyte-macrophage lineage may represent a tool and a target for therapeutic exploitation. PMID:23096265

  12. [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

  13. 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

  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. Left atrial remodelling in patients undergoing transcatheter aortic valve implantation: a speckle-tracking prospective, longitudinal study.

    PubMed

    D'Ascenzi, Flavio; Cameli, Matteo; Henein, Michael; Iadanza, Alessandro; Reccia, Rosanna; Lisi, Matteo; Curci, Valeria; Sinicropi, Giuseppe; Torrisi, Andrea; Pierli, Carlo; Mondillo, Sergio

    2013-12-01

    Aortic stenosis (AS) results in several left ventricular (LV) disturbances as well as progressive left atrial (LA) enlargement and dysfunction. Transcatheter aortic valve implantation (TAVI) reverses LV remodelling and improves overall systolic function but its effect on LA function remains undetermined. The aim of this prospective, longitudinal study was to investigate the effects of TAVI on LA structure and function. We studied thirty-two patients with severe symptomatic AS who underwent TAVI, using standard and 2-dimensional speckle-tracking echocardiography before, at 40-day and at 3-month follow-up. Following TAVI, mean transvalvular gradient decreased (p < 0.001). Both LA area index and LA volume index decreased at 40-day follow-up (16.2 ± 6.4 vs. 12.5 ± 2.9 cm2/m2, and 47.3 ± 12.0 vs. 42.8 ± 12.5 mL/m2, respectively, p < 0.05) and values remained unchanged at 3 months. The reduction of LA size was accompanied by a significant increase in global peak atrial longitudinal strain (14.4 ± 3.9 vs. 19.1 ± 4.7%, p < 0.001) and in global peak atrial contraction strain (8.4 ± 2.5 vs. 11.0 ± 4.1%, p < 0.05) at 3-month follow-up. LA stiffness measurements significantly decreased 3 months after TAVI (0.93 ± 0.59 vs. 0.65 ± 0.37, respectively, p < 0.001). Trans-aortic mean gradient change and pre-procedural LA volume were identified as predictors of global peak atrial longitudinal strain increase (β = -0.41, β = -0.35, respectively, p < 0.0001) while pre-procedural LA volume and trans-aortic mean gradient change as predictor of LA volume index reduction 3 months after TAVI (β = -0.37, β = -0.28, respectively, p < 0.0001). TAVI is associated with significant recovery of LA structure and function suggesting a reverse cavity remodelling. Such functional recovery is primarily determined by the severity of pre-procedural valve stenosis. PMID:23852277

  17. Matrix Remodeling in Pulmonary Fibrosis and Emphysema.

    PubMed

    Kulkarni, Tejaswini; O'Reilly, Philip; Antony, Veena B; Gaggar, Amit; Thannickal, Victor J

    2016-06-01

    Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-β1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema. PMID:26741177

  18. 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

  19. Osteocytes: The master cells in bone remodelling.

    PubMed

    Prideaux, Matthew; Findlay, David M; Atkins, Gerald J

    2016-06-01

    Bone remodelling is an essential process for shaping and maintaining bone mass in the mature skeleton. During our lifetime bone is constantly being removed by osteoclasts and new bone is formed by osteoblasts. The activities of osteoclasts and osteoblasts must be regulated under a strict balance to ensure that bone homeostasis is maintained. Osteocytes, which form an extensive, multi-functional syncytium throughout the bone, are increasingly considered to be the cells that maintain this balance. Current research is elucidating key signalling pathways by which the osteocyte exerts control over the other cell types in bone and over its own activities, and potential ways in which these pathways may be exploited therapeutically. PMID:26927500

  20. Bone Remodeling and Energy Metabolism: New Perspectives

    PubMed Central

    de Paula, Francisco J. A.; Rosen, Clifford J.

    2013-01-01

    Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. Adipose tissue store lipids and cholecalciferol, which, in turn, can influence calcium balance and energy expenditure. Hormones long-thought to solely modulate energy and mineral homeostasis may influence adipocytic function. Osteoblasts are a target of insulin action in bone. Moreover, endocrine mediators, such as osteocalcin, are synthesized in the skeleton but regulate carbohydrate disposal and insulin secretion. Finally, osteoblasts and adipocytes originate from the same mesenchymal progenitor. The mutual crosstalk between osteoblasts and adipocytes within the bone marrow microenvironment plays a crucial role in bone remodeling. In the present review we provide an overview of the reciprocal control between bone and energy metabolism and its clinical implications. PMID:26273493

  1. Adverse drug reactions in dermatology.

    PubMed

    Ferner, R E

    2015-03-01

    Adverse drug reactions (ADRs) - that is, unintended and harmful responses to medicines - are important to dermatologists because many present with cutaneous signs and because dermatological treatments can cause serious ADRs. The detection of ADRs to new drugs is often delayed because they have a long latency or are rare or unexpected. This means that ADRs to newer agents emerge only slowly after marketing. ADRs are part of the differential diagnosis of unusual rashes. A good drug history that includes details of drug dose, time-course of the reaction and factors that may make the patient more susceptible, will help. For example, Stevens-Johnson syndrome with abacavir is much commoner in patients with HLA-B*5701, and has a characteristic time course. Newer agents have brought newer reactions; for example, acneiform rashes associated with epidermal growth factor receptor inhibitors such as erlotinib. Older systemic agents used to treat skin disease, including corticosteroids and methotrexate, cause important ADRs. The adverse effects of newer biological agents used in dermatology are becoming clearer; for example, hypersensitivity reactions or loss of efficacy from antibody formation and progressive multifocal leucoencephalopathy due to reactivation of latent JC (John Cunningham) virus infections during efalizumab treatment. Unusual or serious harm from medicines, including ADRs, medication errors and overdose, should be reported. The UK Yellow Card scheme is online, and patients can report their own ADRs. PMID:25622648

  2. [Recipients adverse reactions: guidance supports].

    PubMed

    Bazin, A

    2010-12-01

    Since 1994, adverse effects of transfusion transmitted to the French haemovigilance network are registered on "e-fit", the database of the French agency for the safety of health products (Afssaps). In order to improve their analysis, guidance supports have been made by Afssaps working groups. Each support deals with a blood transfusion side effect and is composed of five parts including pathophysiological mechanisms, diagnostic criteria, management recommendations, etiologic investigations and rules of filing the notification form on e-fit. The major characteristics of sheets published or soon-to-be published are presented: transfusion-related acute lung injury, transfusion-transmitted bacterial infection, non-haemolytic febrile reaction, allergic reaction, transfusion-associated circulatory overload, hypotensive transfusion reaction, alloimmunization, erythrocyte incompatibility reaction and hemosiderosis. These new supports give relevant guidelines allowing a better analysis and evaluation of recipients' adverse reactions, particularly their diagnosis, gravity and accountability. They could also initiate studies in European and international haemovigilance and transfusion networks. PMID:21051267

  3. Adverse effects of plasma transfusion.

    PubMed

    Pandey, Suchitra; Vyas, Girish N

    2012-05-01

    Plasma utilization has increased over the past two decades, and there is a growing concern that many plasma transfusions are inappropriate. Plasma transfusion is not without risk, and certain complications are more likely with plasma than other blood components. Clinical and laboratory investigations of the patients suffering reactions after infusion of fresh-frozen plasma (FFP) define the etiology and pathogenesis of the panoply of adverse effects. We review here the pathogenesis, diagnosis, and management of the risks associated with plasma transfusion. Risks commonly associated with FFP include: 1) transfusion-related acute lung injury, 2) transfusion-associated circulatory overload, and 3) allergic and/or anaphylactic reactions. Other less common risks include 1) transmission of infections, 2) febrile nonhemolytic transfusion reactions, 3) red blood cell alloimmunization, and 4) hemolytic transfusion reactions. The effects of pathogen inactivation or reduction methods on these risks are also discussed. Fortunately, a majority of the adverse effects are not lethal and are adequately treated in clinical practice. PMID:22578374

  4. PNPLA3 mediates hepatocyte triacylglycerol remodeling.

    PubMed

    Ruhanen, Hanna; Perttilä, Julia; Hölttä-Vuori, Maarit; Zhou, You; Yki-Järvinen, Hannele; Ikonen, Elina; Käkelä, Reijo; Olkkonen, Vesa M

    2014-04-01

    The I148M substitution in patatin-like phospholipase domain containing 3 (PNPLA3(I148M)) determines a genetic form of nonalcoholic fatty liver disease. To elucidate the mode of PNPLA3 action in human hepatocytes, we studied effects of WT PNPLA3 (PNPLA3(WT)) and PNPLA3(I148M) on HuH7 cell lipidome after [(13)C]glycerol labeling, cellular turnover of oleic acid labeled with 17 deuterium atoms ([D17]oleic acid) in triacylglycerols (TAGs), and subcellular distribution of the protein variants. PNPLA3(I148M) induced a net accumulation of unlabeled TAGs, but not newly synthesized total [(13)C]TAGs. Principal component analysis (PCA) revealed that both PNPLA3(WT) and PNPLA3(I148M) induced a relative enrichment of TAGs with saturated FAs or MUFAs, with concurrent enrichment of polyunsaturated phosphatidylcholines. PNPLA3(WT) associated in PCA with newly synthesized [(13)C]TAGs, particularly 52:1 and 50:1, while PNPLA3(I148M) associated with similar preexisting TAGs. PNPLA3(WT) overexpression resulted in increased [D17]oleic acid labeling of TAGs during 24 h, and after longer incubations their turnover was accelerated, effects not detected with PNPLA3(I148M). PNPLA3(I148M) localized more extensively to lipid droplets (LDs) than PNPLA3(WT), suggesting that the substitution alters distribution of PNPLA3 between LDs and endoplasmic reticulum/cytosol. This study reveals a function of PNPLA3 in FA-selective TAG remodeling, resulting in increased TAG saturation. A defect in TAG remodeling activity likely contributes to the TAG accumulation observed in cells expressing PNPLA3(I148M). PMID:24511104

  5. "Adversative Conjunction": The Poetics of Linguistic Opposition.

    ERIC Educational Resources Information Center

    Wallerstein, Nicholas

    1992-01-01

    The general use of adversative conjunction in (primarily) English and U.S. poetry is outlined. The contention is that the adversative is not merely a grammatical convenience but sometimes a highly functional tool of rhetorical strategy. (36 references) (LB)

  6. Determination of early diastolic LV vortex formation time (T*) via the PDF formalism: a kinematic model of filling.

    PubMed

    Ghosh, Erina; Shmuylovich, Leonid; Kovacs, Sandor J

    2009-01-01

    The filling (diastolic) function of the human left ventricle is most commonly assessed by echocardiography, a non-invasive imaging modality. To quantify diastolic function (DF) empiric indices are obtained from the features (height, duration, area) of transmitral flow velocity contour, obtained by echocardiography. The parameterized diastolic filling (PDF) formalism is a kinematic model developed by Kovács et. al. which incorporates the suction pump attribute of the left ventricle and facilitates DF quantitation by analysis of echocardiographic transmitral flow velocity contours in terms of stiffness (k), relaxation (c) and load (x(0)). A complementary approach developed by Gharib et. al., uses fluid mechanics and characterizes DF in terms of vortex formation time (T*) derived from streamline features formed by the jet of blood aspirated into the ventricle. Both of these methods characterize DF using a causality-based approach. In this paper, we derive T*'s kinematic analogue T*(kinematic) in terms of k, c and x(0). A comparison between T*(kinematic) and T*(fluid) (mechanic) obtained from averaged transmitral velocity and mitral annulus diameter, is presented. We found that T* calculated by the two methods were comparable and T*(kinematic) correlated with the peak LV recoil driving force kx(0). PMID:19964049

  7. 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. PMID

  8. The Redox State of Transglutaminase 2 Controls Arterial Remodeling

    PubMed Central

    van den Akker, Jeroen; VanBavel, Ed; van Geel, Remon; Matlung, Hanke L.; Guvenc Tuna, Bilge; Janssen, George M. C.; van Veelen, Peter A.; Boelens, Wilbert C.; De Mey, Jo G. R.; Bakker, Erik N. T. P.

    2011-01-01

    While inward remodeling of small arteries in response to low blood flow, hypertension, and chronic vasoconstriction depends on type 2 transglutaminase (TG2), the mechanisms of action have remained unresolved. We studied the regulation of TG2 activity, its (sub) cellular localization, substrates, and its specific mode of action during small artery inward remodeling. We found that inward remodeling of isolated mouse mesenteric arteries by exogenous TG2 required the presence of a reducing agent. The effect of TG2 depended on its cross-linking activity, as indicated by the lack of effect of mutant TG2. The cell-permeable reducing agent DTT, but not the cell-impermeable reducing agent TCEP, induced translocation of endogenous TG2 and high membrane-bound transglutaminase activity. This coincided with inward remodeling, characterized by a stiffening of the artery. The remodeling could be inhibited by a TG2 inhibitor and by the nitric oxide donor, SNAP. Using a pull-down assay and mass spectrometry, 21 proteins were identified as TG2 cross-linking substrates, including fibronectin, collagen and nidogen. Inward remodeling induced by low blood flow was associated with the upregulation of several anti-oxidant proteins, notably glutathione-S-transferase, and selenoprotein P. In conclusion, these results show that a reduced state induces smooth muscle membrane-bound TG2 activity. Inward remodeling results from the cross-linking of vicinal matrix proteins, causing a stiffening of the arterial wall. PMID:21901120

  9. Fiber optics in adverse environments

    SciTech Connect

    Lyous, P.B.

    1982-01-01

    Radiation effects in optical fibers are considered, taking into account recent progress in the investigation of radiation resistant optical fibers, radiation damage in optical fibers, radiation-induced transient absorption in optical fibers, X-ray-induced transient attenuation at low temperatures in polymer clad silica (PCS) fibers, optical fiber composition and radiation hardness, the response of irradiated optical waveguides at low temperatures, and the effect of ionizing radiation on fiber-optic waveguides. Other topics explored are related to environmental effects on components of fiber optic systems, and radiation detection systems using optical fibers. Fiber optic systems in adverse environments are also discussed, giving attention to the survivability of Army fiber optics systems, space application of fiber optics systems, fiber optic wavelength multiplexing for civil aviation applications, a new fiber optic data bus topology, fiber optics for aircraft engine/inlet control, and application of fiber optics in high voltage substations.

  10. The multifactorial nature of microRNAs in vascular remodelling.

    PubMed

    Welten, S M J; Goossens, E A C; Quax, P H A; Nossent, A Y

    2016-05-01

    Vascular remodelling is a multifactorial process that involves both adaptive and maladaptive changes of the vessel wall through, among others, cell proliferation and migration, but also apoptosis and necrosis of the various cell types in the vessel wall. Vascular remodelling can be beneficial, e.g. during neovascularization after ischaemia, as well as pathological, e.g. during atherosclerosis and aneurysm formation. In recent years, it has become clear that microRNAs are able to target many genes that are involved in vascular remodelling processes and either can promote or inhibit structural changes of the vessel wall. Since many different processes of vascular remodelling are regulated by similar mechanisms and factors, both positive and negative vascular remodelling can be affected by the same microRNAs. A large number of microRNAs has been linked to various aspects of vascular remodelling and indeed, several of these microRNAs regulate multiple vascular remodelling processes, including both the adaptive processes angiogenesis and arteriogenesis as well as maladaptive processes of atherosclerosis, restenosis and aneurysm formation. Here, we discuss the multifactorial role of microRNAs and microRNA clusters that were reported to play a role in multiple forms of vascular remodelling and are clearly linked to cardiovascular disease (CVD). The microRNAs reviewed are miR-126, miR-155 and the microRNA gene clusters 17-92, 23/24/27, 143/145 and 14q32. Understanding the contribution of these microRNAs to the entire spectrum of vascular remodelling processes is important, especially as these microRNAs may have great potential as therapeutic targets for treatment of various CVDs. PMID:26912672

  11. Intratracheal Bleomycin Causes Airway Remodeling and Airflow Obstruction in Mice

    PubMed Central

    Polosukhin, Vasiliy V.; Degryse, Amber L.; Newcomb, Dawn C.; Jones, Brittany R.; Ware, Lorraine B.; Lee, Jae Woo; Loyd, James E.; Blackwell, Timothy S.; Lawson, William E.

    2014-01-01

    Introduction In addition to parenchymal fibrosis, fibrotic remodeling of the distal airways has been reported in interstitial lung diseases. Mechanisms of airway wall remodeling, which occurs in a variety of chronic lung diseases, are not well defined and current animal models are limited. Methods We quantified airway remodeling in lung sections from subjects with idiopathic pulmonary fibrosis (IPF) and controls. To investigate intratracheal bleomycin as a potential animal model for fibrotic airway remodeling, we evaluated lungs from C57BL/6 mice after bleomycin treatment by histologic scoring for fibrosis and peribronchial inflammation, morphometric evaluation of subepithelial connective tissue volume density, TUNEL assay, and immunohistochemistry for transforming growth factor β1 (TGFβ1), TGFβ2, and the fibroblast marker S100A4. Lung mechanics were determined at 3 weeks post-bleomycin. Results IPF lungs had small airway remodeling with increased bronchial wall thickness compared to controls. Similarly, bleomycin treated mice developed dose-dependent airway wall inflammation and fibrosis and greater airflow resistance after high dose bleomycin. Increased TUNEL+ bronchial epithelial cells and peribronchial inflammation were noted by 1 week, and expression of TGFβ1 and TGFβ2 and accumulation of S100A4+ fibroblasts correlated with airway remodeling in a bleomycin dose-dependent fashion. Conclusions IPF is characterized by small airway remodeling in addition to parenchymal fibrosis, a pattern also seen with intratracheal bleomycin. Bronchial remodeling from intratracheal bleomycin follows a cascade of events including epithelial cell injury, airway inflammation, pro-fibrotic cytokine expression, fibroblast accumulation, and peribronchial fibrosis. Thus, this model can be utilized to investigate mechanisms of airway remodeling. PMID:22394287

  12. 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

  13. 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

  14. 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. PMID:3302664

  15. Effect of Right Ventricular versus Biventricular Pacing on Electrical Remodeling in the Normal Heart

    PubMed Central

    Saba, Samir; Mehdi, Haider; Mathier, Michael A.; Islam, M. Zahadul; Salama, Guy; London, Barry

    2010-01-01

    Background Biventricular (BIV) pacing can improve cardiac function in heart failure by altering the mechanical and electrical substrates. We investigated the effect of BIV versus right ventricular (RV) pacing on the normal heart. Methods and Results Male New Zealand White rabbits (n=33) were divided into 3 groups: sham-operated (control), RV pacing, and BIV pacing groups. Four weeks after surgery, the native QT (p=0.004) interval was significantly shorter in the BIV group compared to the RV or sham-operated groups. Also, compared to rabbits in the RV group, rabbits in the BIV group had shorter RV ventricular effective refractory period (VERP) at all cycle lengths, and shorter LV paced QT interval during the drive train of stimuli and close to refractoriness (p<0.001 for all comparisons). Protein expression of the KVLQT1 was significantly increased in the BIV group compared to the RV and control groups, while protein expression of SCN5A and connexin43 was significantly decreased in the RV compared to the other study groups. Erg protein expression was significantly increased in both pacing groups compared to the controls. Conclusions In this rabbit model, we demonstrate a direct effect of BIV but not RV pacing on shortening the native QT interval as well as the paced QT interval during burst pacing and close to the VERP. These findings underscore the fact that the effect of BIV pacing is partially mediated through direct electrical remodeling and may have implications as to the effect of BIV pacing on arrhythmia incidence and burden. PMID:20042767

  16. Tetrahydrocurcumin Protects against Cadmium-Induced Hypertension, Raised Arterial Stiffness and Vascular Remodeling in Mice

    PubMed Central

    Sangartit, Weerapon; Kukongviriyapan, Upa; Donpunha, Wanida; Pakdeechote, Poungrat; Kukongviriyapan, Veerapol; Surawattanawan, Praphassorn; Greenwald, Stephen E.

    2014-01-01

    Background Cadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti-diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice. Methods Male ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment. Results Administration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues. Conclusions Our results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure. PMID:25502771

  17. 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

  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

    Genovese, Luca; Brendolan, Andrea

    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. 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. PMID:25078411

  1. 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

  2. Tissue Inhibitor of Metalloproteinase-2 Gene Delivery Ameliorates Post-Infarction Cardiac Remodeling

    PubMed Central

    Ramani, Ravi; Nilles, Kathleen; Gibson, Gregory; Burkhead, Benjamin; Mathier, Michael; McNamara, Dennis; McTiernan, Charles F.

    2011-01-01

    Hypothesis Adenoviral-mediated (AdV-T2) overexpression of TIMP-2 would blunt ventricular remodeling and improve survival in a murine model of chronic ischemic injury. Methods Male mice (n=124) aged 10–14 weeks underwent either 1) left coronary artery ligation to induce myocardial infarction (MI group, n=36), 2) myocardial injection of 6×1010 viral particles of AdV-T2 immediately post-MI (MI+T2 group, n=30), 3) myocardial injection of 6×1010 viral particles of a control adenovirus (MI+Ct, n=38), or 4) received no intervention (controls, n=20). On post-MI day 7, surviving mice (n=79) underwent echocardiographic, immunohistochemical and biochemical analysis. Results In infarcted animals, the MI+T2 group demonstrated improved survival (p< 0.02), better preservation of developed pressure and ventricular diameter (p<0.04), and the lowest expression and activity of MMP-2 and MMP-9 (P<0.04) compared with MI and MI+Ct groups.. All infarcted hearts displayed significantly increased inflammatory cell infiltration (p<0.04 versus control, MI, or MI+T2), with infiltration highest in the MI+Ct group and lowest in the MI+T2 group (p<0.04). Conclusions Adenoviral mediated myocardial delivery of the TIMP-2 gene improves post-MI survival and limits adverse remodeling in a murine model of myocardial infarction. PMID:21348952

  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. Transplantation of expanded bone marrow-derived very small embryonic-like stem cells (VSEL-SCs) improves left ventricular function and remodelling after myocardial infarction

    PubMed Central

    Zuba-Surma, Ewa K; Guo, Yiru; Taher, Hisham; Sanganalmath, Santosh K; Hunt, Greg; Vincent, Robert J; Kucia, Magda; Abdel-Latif, Ahmed; Tang, Xian-Liang; Ratajczak, Mariusz Z; Dawn, Buddhadeb; Bolli, Roberto

    2011-01-01

    Abstract Adult bone marrow-derived very small embryonic-like stem cells (VSEL-SCs) exhibit a Sca-1+/Lin–/CD45– phenotype and can differentiate into various cell types, including cardiomyocytes and endothelial cells. We have previously reported that transplantation of a small number (1 × 106) of freshly isolated, non-expanded VSEL-SCs into infarcted mouse hearts resulted in improved left ventricular (LV) function and anatomy. Clinical translation, however, will require large numbers of cells. Because the frequency of VSEL-SCs in the marrow is very low, we examined whether VSEL-SCs can be expanded in culture without loss of therapeutic efficacy. Mice underwent a 30 min. coronary occlusion followed by reperfusion and, 48 hrs later, received an intramyocardial injection of vehicle (group I, n= 11), 1 × 105 enhanced green fluorescent protein (EGFP)-labelled expanded untreated VSEL-SCs (group II, n= 7), or 1 × 105 EGFP-labelled expanded VSEL-SCs pre-incubated in a cardiogenic medium (group III, n= 8). At 35 days after myocardial infarction (MI), mice treated with pre-incubated VSEL-SCs exhibited better global and regional LV systolic function and less LV hypertrophy compared with vehicle-treated controls. In contrast, transplantation of expanded but untreated VSEL-SCs did not produce appreciable reparative benefits. Scattered EGFP+ cells expressing α-sarcomeric actin, platelet endothelial cell adhesion molecule (PECAM)-1, or von Willebrand factor were present in VSEL-SC-treated mice, but their numbers were very small. No tumour formation was observed. We conclude that VSEL-SCs expanded in culture retain the ability to alleviate LV dysfunction and remodelling after a reperfused MI provided that they are exposed to a combination of cardiomyogenic growth factors and cytokines prior to transplantation. Counter intuitively, the mechanism whereby such pre-incubation confers therapeutic efficacy does not involve differentiation into new cardiac cells. These results

  5. 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

  6. 65. (Credit JTL) Filter room looking WSW across remodelled New ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    65. (Credit JTL) Filter room looking WSW across remodelled New York horizontal pressure filters (in foreground). - McNeil Street Pumping Station, McNeil Street & Cross Bayou, Shreveport, Caddo Parish, LA

  7. 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

  8. Emerging mechanisms of mRNP remodeling regulation

    PubMed Central

    Chen, Chyi-Ying A.

    2015-01-01

    The assembly and remodeling of the components of messenger ribonucleoprotein particles (mRNPs) are important in determining the fate of an mRNA. A combination of biochemical and cell biology research, recently complemented by genome-wide high-throughput approaches, has led to significant progress on understanding the formation, dynamics and function of mRNPs. These studies also advanced the challenging process of identifying the evolving constituents of individual mRNPs at various stages during an mRNA’s lifetime. While research on mRNP remodeling in general has been gaining momentum, there has been relatively little attention paid to the regulatory aspect of mRNP remodeling. Here, we discuss the results of some new studies and potential mechanisms for regulation of mRNP remodeling. PMID:24923990

  9. Remodeled second floor with stairs and stacks. This was formerly ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Remodeled second floor with stairs and stacks. This was formerly the upper part of the original two story reading room. View to southwest. - San Bernardino Valley College, Library, 701 South Mount Vernon Avenue, San Bernardino, San Bernardino County, CA

  10. Restricting Fermentative Potential by Proteome Remodeling

    PubMed Central

    Clair, Gérémy; Armengaud, Jean; Duport, Catherine

    2012-01-01

    Pathogenesis hinges on successful colonization of the gastrointestinal (GI) tract by pathogenic facultative anaerobes. The GI tract is a carbohydrate-limited environment with varying oxygen availability and oxidoreduction potential (ORP). How pathogenic bacteria are able to adapt and grow in these varying conditions remains a key fundamental question. Here, we designed a system biology-inspired approach to pinpoint the key regulators allowing Bacillus cereus to survive and grow efficiently under low ORP anoxic conditions mimicking those encountered in the intestinal lumen. We assessed the proteome components using high throughput nanoLC-MS/MS techniques, reconstituted the main metabolic circuits, constructed ΔohrA and ΔohrR mutants, and analyzed the impacts of ohrA and ohrR disruptions by a novel round of shotgun proteomics. Our study revealed that OhrR and OhrA are crucial to the successful adaptation of B. cereus to the GI tract environment. Specifically, we showed that B. cereus restricts its fermentative growth under low ORP anaerobiosis and sustains efficient aerobic respiratory metabolism, motility, and stress response via OhrRA-dependent proteome remodeling. Finally, our results introduced a new adaptive strategy where facultative anaerobes prefer to restrict their fermentative potential for a long term benefit. PMID:22232490

  11. Chromatin remodeling effects on enhancer activity.

    PubMed

    García-González, Estela; Escamilla-Del-Arenal, Martín; Arzate-Mejía, Rodrigo; Recillas-Targa, Félix

    2016-08-01

    During organism development, a diversity of cell types emerges with disparate, yet stable profiles of gene expression with distinctive cellular functions. In addition to gene promoters, the genome contains enhancer regulatory sequences, which are implicated in cellular specialization by facilitating cell-type and tissue-specific gene expression. Enhancers are DNA binding elements characterized by highly sophisticated and various mechanisms of action allowing for the specific interaction of general and tissue-specific transcription factors (TFs). However, eukaryotic organisms package their genetic material into chromatin, generating a physical barrier for TFs to interact with their cognate sequences. The ability of TFs to bind DNA regulatory elements is also modulated by changes in the chromatin structure, including histone modifications, histone variants, ATP-dependent chromatin remodeling, and the methylation status of DNA. Furthermore, it has recently been revealed that enhancer sequences are also transcribed into a set of enhancer RNAs with regulatory potential. These interdependent processes act in the context of a complex network of chromatin interactions, which together contributes to a renewed vision of how gene activation is coordinated in a cell-type-dependent manner. In this review, we describe the interplay between genetic and epigenetic aspects associated with enhancers and discuss their possible roles on enhancer function. PMID:27026300

  12. Effects of long term treatment with high doses of odanacatib on bone mass, bone strength, and remodeling/modeling in newly ovariectomized monkeys.

    PubMed

    Duong, L T; Pickarski, M; Cusick, T; Chen, C M; Zhuo, Y; Scott, K; Samadfam, R; Smith, S Y; Pennypacker, B L

    2016-07-01

    The objectives here were to evaluate the effects of odanacatib (ODN) at doses exceeding the clinical exposure on biomechanical properties of lumbar vertebrae (LV), hip and central femur (CF), and compare ODN to alendronate (ALN) on bone remodeling/modeling in ovariectomized (OVX) monkeys. Ten days post-surgery, animals were treated with vehicle (VEH), ODN-L (2mg/kg/day, p.o.), ODN-H (8/4mg/kg/day), or ALN (30μg/kg/week, s.c.) for 20months. An intact group was also included. ODN-L provided systemic exposures of 1.8-fold of clinical exposure. ODN-H started at 20-fold for 5.5months, and then reduced to 7.8-fold of clinical exposure, compared to ALN at approximated clinical exposure. From cross sectional analyses, LV density and peak load in ODN at both doses or ALN were not different from VEH or Intact. However, cortical thickness of femoral neck (FN) and CF in ODN were higher (21-34%, p<0.05) than VEH, due to smaller endocortical (Ec) perimeter of FN (10-11%; p<0.05) and CF (9-12%; ODN-L, p<0.05), and larger CF periosteal (Ps) perimeter (2-12%; ODN-H, p<0.001) versus VEH. ODN groups also showed slightly higher cortical porosity and Ps non-lamellar bone in CF. ODN-H treatment resulted in higher CF peak load (p<0.05) versus VEH. For all bone sites analyzed, a positive, linear relationship (r(2)=0.46-0.69, p<0.0001) of peak load to density or structural parameters was demonstrated. No treatment-related differences in the derived intrinsic strength properties were evidenced as compared between groups. ALN reduced all remodeling surfaces without affecting Ps modeling. Trabecular and intracortical remodeling were reduced in ODN groups, similar to ALN. Ec mineralizing surface in ODN-H trended to be lower than VEH by month 20, but Ec bone formation indices in ODN groups generally were not different from VEH. Ps modeling in ODN groups was significantly higher than other treatment groups. This study overall demonstrated the bone safety profile of ODN and its unique mechanism

  13. 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

  14. OAE: The Ontology of Adverse Events

    PubMed Central

    2014-01-01

    Background A medical intervention is a medical procedure or application intended to relieve or prevent illness or injury. Examples of medical interventions include vaccination and drug administration. After a medical intervention, adverse events (AEs) may occur which lie outside the intended consequences of the intervention. The representation and analysis of AEs are critical to the improvement of public health. Description The Ontology of Adverse Events (OAE), previously named Adverse Event Ontology (AEO), is a community-driven ontology developed to standardize and integrate data relating to AEs arising subsequent to medical interventions, as well as to support computer-assisted reasoning. OAE has over 3,000 terms with unique identifiers, including terms imported from existing ontologies and more than 1,800 OAE-specific terms. In OAE, the term ‘adverse event’ denotes a pathological bodily process in a patient that occurs after a medical intervention. Causal adverse events are defined by OAE as those events that are causal consequences of a medical intervention. OAE represents various adverse events based on patient anatomic regions and clinical outcomes, including symptoms, signs, and abnormal processes. OAE has been used in the analysis of several different sorts of vaccine and drug adverse event data. For example, using the data extracted from the Vaccine Adverse Event Reporting System (VAERS), OAE was used to analyse vaccine adverse events associated with the administrations of different types of influenza vaccines. OAE has also been used to represent and classify the vaccine adverse events cited in package inserts of FDA-licensed human vaccines in the USA. Conclusion OAE is a biomedical ontology that logically defines and classifies various adverse events occurring after medical interventions. OAE has successfully been applied in several adverse event studies. The OAE ontological framework provides a platform for systematic representation and analysis of

  15. Remodeling of the bone material containing microcracks: A theoretical analysis

    NASA Astrophysics Data System (ADS)

    Ramtani, S.; Zidi, M.

    1999-12-01

    The question is, what happens when the bone loses its ability for load-driven adaptation, when damage is no longer repaired as it seems to be the case for bone loss associated with age, medication or disease? In this study, we tempt to show how damage can influence the remodeling process. A thermodynamic theoretical framework is therefore provided as a basis for a consistent formulation of bone remodeling involving a chemical reaction and mass transfer between two constituents in presence of microcracks.

  16. Aliskiren and Valsartan Mediate Left Ventricular Remodeling Post-Myocardial Infarction in Mice through MMP-9 Effects

    PubMed Central

    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.

    2014-01-01

    Background We evaluated whether aliskiren, valsartan, or the combination was protective following myocardial infarction (MI) through effects on matrix metalloproteinase (MMP)-9. Methods and Results C57BL/6J wild type (WT, n=94) and MMP-9 null (null, n=85) mice were divided into 4 groups at 3 h post-MI: saline (S), aliskiren (A; 50 mg/kg/d), valsartan (V; 40 mg/kg/d), or A+V and compared to no MI controls at 28 d 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. Conclusions 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. PMID:24768766

  17. Numerical evaluation of bone remodelling associated with trans-femoral osseointegration implant--A 68 month follow-up study.

    PubMed

    Xu, D H; Crocombe, A D; Xu, W

    2016-02-01

    Osseointegrated trans-femoral implant is a relatively new orthopaedic anchoring method for connecting a stump with a prosthesis. Through a follow-up study of a patient over six years, significant bone remodelling has been observed. Finite element (FE) simulations were carried out to investigate the relationship between the bone remodelling and the strain re-distribution around the trans-femoral osseointegrated implant system. An initial FE model representing the original status of the femur-implant assembly was created from CT scans of the subject prior to osseointegration. Follow-up X-ray images were acquired at various stages post-surgery, which allowed the changes in bone wall thickness to be measured. By updating the bone thickness in the initial model, a series of follow-up FE models were created. Representative load associated with the subject's body weight was applied to the models, and the strain re-distributions were calculated. The results showed that in order to minimise the adverse effect of bone remodelling, an osseointegration implant made by functionally gradient materials are preferred over homogeneous materials. PMID:26776932

  18. The role of the epithelium in airway remodeling in asthma.

    PubMed

    Davies, Donna E

    2009-12-01

    The bronchial epithelium is the barrier to the external environment and plays a vital role in protection of the internal milieu of the lung. It functions within the epithelial-mesenchymal trophic unit to control the local microenvironment and help maintain tissue homeostasis. However, in asthma, chronic perturbation of these homeostatic mechanisms leads to alterations in the structure of the airways, termed remodeling. Damage to the epithelium is now recognized to play a key role in driving airway remodeling. We have postulated that epithelial susceptibility to environmental stress and injury together with impaired repair responses results in generation of signals that act on the underlying mesenchyme to propagate and amplify inflammatory and remodeling responses in the submucosa. Many types of challenges to the epithelium, including pathogens, allergens, environmental pollutants, cigarette smoke, and even mechanical forces, can elicit production of mediators by the epithelium, which can be translated into remodeling responses by the mesenchyme. Several important mediators of remodeling have been identified, most notably transforming growth factor-beta, which is released from damaged/repairing epithelium or in response to inflammatory mediators, such as IL-13. The cross talk between the epithelium and the underlying mesenchyme to drive remodeling responses is considered in the context of subepithelial fibrosis and potential pathogenetic mechanisms linked to the asthma susceptibility gene, a disintegrin and metalloprotease (ADAM)33. PMID:20008875

  19. 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

  20. Fstl1 Promotes Asthmatic Airway Remodeling by Inducing Oncostatin M.

    PubMed

    Miller, Marina; Beppu, Andrew; Rosenthal, Peter; Pham, Alexa; Das, Sudipta; Karta, Maya; Song, Dae Jin; Vuong, Christine; Doherty, Taylor; Croft, Michael; Zuraw, Bruce; Zhang, Xu; Gao, Xiang; Aceves, Seema; Chouiali, Fazila; Hamid, Qutayba; Broide, David H

    2015-10-15

    Chronic asthma is associated with airway remodeling and decline in lung function. In this article, we show that follistatin-like 1 (Fstl1), a mediator not previously associated with asthma, is highly expressed by macrophages in the lungs of humans with severe asthma. Chronic allergen-challenged Lys-Cre(tg) /Fstl1(Δ/Δ) mice in whom Fstl1 is inactivated in macrophages/myeloid cells had significantly reduced airway remodeling and reduced levels of oncostatin M (OSM), a cytokine previously not known to be regulated by Fstl1. The importance of the Fstl1 induction of OSM to airway remodeling was demonstrated in murine studies in which administration of Fstl1 induced airway remodeling and increased OSM, whereas administration of an anti-OSM Ab blocked the effect of Fstl1 on inducing airway remodeling, eosinophilic airway inflammation, and airway hyperresponsiveness, all cardinal features of asthma. Overall, these studies demonstrate that the Fstl1/OSM pathway may be a novel pathway to inhibit airway remodeling in severe human asthma. PMID:26355153

  1. Left ventricular remodeling during and after 60 days of sedentary head-down bed rest.

    PubMed

    Westby, Christian M; Martin, David S; Lee, Stuart M C; Stenger, Michael B; Platts, Steven H

    2016-04-15

    Short periods of weightlessness are associated with reduced stroke volume and left ventricular (LV) mass that appear rapidly and are thought to be largely dependent on plasma volume. The magnitude of these cardiac adaptations are even greater after prolonged periods of simulated weightlessness, but the time course during and the recovery from bed rest has not been previously described. We collected serial measures of plasma volume (PV, carbon monoxide rebreathing) and LV structure and function [tissue Doppler imaging, three-dimensional (3-D) and 2-D echocardiography] before, during, and up to 2 wk after 60 days of 6° head down tilt bed rest (HDTBR) in seven healthy subjects (four men, three women). By 60 days of HDTBR, PV was markedly reduced (2.7 ± 0.3 vs. 2.3 ± 0.3 liters,P< 0.001). Resting measures of LV volume and mass were ∼15% (P< 0.001) and ∼14% lower (P< 0.001), respectively, compared with pre-HDTBR values. After 3 days of reambulation, both PV and LV volumes were not different than pre-HDTBR values. However, LV mass did not recover with normalization of PV and remained 12 ± 4% lower than pre-bed rest values (P< 0.001). As previously reported, decreased PV and LV volume precede and likely contribute to cardiac atrophy during prolonged LV unloading. Although PV and LV volume recover rapidly after HDTBR, there is no concomitant normalization of LV mass. These results demonstrate that reduced LV mass in response to prolonged simulated weightlessness is not a simple effect of tissue dehydration, but rather true LV muscle atrophy that persists well into recovery. PMID:26494448

  2. Loss of Apelin Exacerbates Myocardial Infarction Adverse Remodeling and Ischemia‐reperfusion Injury: Therapeutic Potential of Synthetic Apelin Analogues

    PubMed Central

    Wang, Wang; McKinnie, Shaun M.K.; Patel, Vaibhav B.; Haddad, George; Wang, Zuocheng; Zhabyeyev, Pavel; Das, Subhash K.; Basu, Ratnadeep; McLean, Brent; Kandalam, Vijay; Penninger, Josef M.; Kassiri, Zamaneh; Vederas, John C.; Murray, Allan G.; Oudit, Gavin Y.

    2013-01-01

    Background Coronary artery disease leading to myocardial ischemia is the most common cause of heart failure. Apelin (APLN), the endogenous peptide ligand of the APJ receptor, has emerged as a novel regulator of the cardiovascular system. Methods and Results Here we show a critical role of APLN in myocardial infarction (MI) and ischemia‐reperfusion (IR) injury in patients and animal models. Myocardial APLN levels were reduced in patients with ischemic heart failure. Loss of APLN increased MI‐related mortality, infarct size, and inflammation with drastic reductions in prosurvival pathways resulting in greater systolic dysfunction and heart failure. APLN deficiency decreased vascular sprouting, impaired sprouting of human endothelial progenitor cells, and compromised in vivo myocardial angiogenesis. Lack of APLN enhanced susceptibility to ischemic injury and compromised functional recovery following ex vivo and in vivo IR injury. We designed and synthesized two novel APLN analogues resistant to angiotensin converting enzyme 2 cleavage and identified one analogue, which mimicked the function of APLN, to be markedly protective against ex vivo and in vivo myocardial IR injury linked to greater activation of survival pathways and promotion of angiogenesis. Conclusions APLN is a critical regulator of the myocardial response to infarction and ischemia and pharmacologically targeting this pathway is feasible and represents a new class of potential therapeutic agents. PMID:23817469

  3. Severe cutaneous adverse drug reactions.

    PubMed

    Chung, Wen-Hung; Wang, Chuang-Wei; Dao, Ro-Lan

    2016-07-01

    The clinical manifestations of drug eruptions can range from mild maculopapular exanthema to severe cutaneous adverse drug reactions (SCAR), including drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which are rare but occasionally fatal. Some pathogens may induce skin reactions mimicking SCAR. There are several models to explain the interaction of human leukocyte antigen (HLA), drug and T-cell receptor (TCR): (i) the "hapten/prohapten" theory; (ii) the "p-i concept"; (iii) the "altered peptide repertoire"; and (iv) the "altered TCR repertoire". The checkpoints of molecular mechanisms of SCAR include specific drug antigens interacting with the specific HLA loci (e.g. HLA-B*15:02 for carbamazepine-induced SJS/TEN and HLA-B*58:01 for allopurinol-induced SCAR), involvement of specific TCR, induction of T-cell-mediated responses (e.g. granulysin, Fas ligand, perforin/granzyme B and T-helper 1/2-associated cytokines) and cell death mechanism (e.g. miR-18a-5p-induced apoptosis; annexin A1 and formyl peptide receptor 1-induced necroptosis in keratinocytes). In addition to immune mechanism, metabolism has been found to play a role in the pathogenesis of SCAR, such as recent findings of strong association of CYP2C9*3 with phenytoin-induced SCAR and impaired renal function with allopurinol SCAR. With a better understanding of the mechanisms, effective therapeutics and prevention for SCAR can be improved. PMID:27154258

  4. 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

  5. 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

  6. 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

  7. 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

  8. PTH signaling mediates perilacunar remodeling during exercise.

    PubMed

    Gardinier, Joseph D; Al-Omaishi, Salam; Morris, Michael D; Kohn, David H

    2016-01-01

    Mechanical loading and release of endogenous parathyroid hormone (PTH) during exercise facilitate the adaptation of bone. However, it remains unclear how exercise and PTH influence the composition of bone and how exercise and PTH-mediated compositional changes influence the mechanical properties of bone. Thus, the primary purpose of this study was to establish compositional changes within osteocytes' perilacunar region of cortical bone following exercise, and evaluate the influence of endogenous PTH signaling on this perilacunar adaptation. Raman spectroscopy, scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDS) were used to evaluate tissue composition surrounding individual lacuna within the tibia of 19week old male mice exposed to treadmill running for 3weeks. As a result of exercise, tissue within the perilacunar region (within 0-5μm of the lacuna wall) had a lower mineral-to-matrix ratio (MMR) compared to sedentary controls. In addition, exercise also increased the carbonate-to-phosphate ratio (CPR) across both perilacunar and non-perilacunar regions (5-10μm and 10-15μm from the lacuna walls). Tibial post-yield work had a significant negative correlation with perilacunar MMR. Inhibition of PTH activity with PTH(7-34) demonstrated that perilacunar remodeling during exercise was dependent on the cellular response to endogenous PTH. The osteocytes' response to endogenous PTH during exercise was characterized by a significant reduction in SOST expression and significant increase in FGF-23 expression. The potential reduction in phosphate levels due to FGF-23 expression may explain the increase in carbonate substitution. Overall, this is the first study to demonstrate that adaptation in tissue composition is localized around individual osteocytes, may contribute to the changes in whole bone mechanics during exercise, and that PTH signaling during exercise contributes to these adaptations. PMID:26924474

  9. Remodeling of alveolar septa after murine pneumonectomy.

    PubMed

    Ysasi, Alexandra B; Wagner, Willi L; Bennett, Robert D; Ackermann, Maximilian; Valenzuela, Cristian D; Belle, Janeil; Tsuda, Akira; Konerding, Moritz A; Mentzer, Steven J

    2015-06-15

    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

  10. Mechanisms of Cardiovascular Remodeling in Hyperhomocysteinemia

    PubMed Central

    Steed, Mesia M.

    2011-01-01

    Abstract In hypertension, an increase in arterial wall thickness and loss of elasticity over time result in an increase in pulse wave velocity, a direct measure of arterial stiffness. This change is reflected in gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers in the media that occurs independently of atherosclerosis. Similar results are seen with an elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), which increases vascular thickness, elastin fragmentation, and arterial blood pressure. Studies from our laboratory have demonstrated a decrease in elasticity and an increase in pulse wave velocity in HHcy cystathionine β synthase heterozygote knockout (CBS−/+) mice. Nitric oxide (NO) is a potential regulator of matrix metalloproteinase (MMP) activity in MMP-NO-TIMP (tissue inhibitor of metalloproteinase) inhibitory tertiary complex. We have demonstrated the contribustion of the NO synthase (NOS) isoforms, endothelial NOS and inducible NOS, in the activation of latent MMP. The differential production of NO contributes to oxidative stress and increased oxidative/nitrative activation of MMP resulting in vascular remodeling in response to HHcy. The contribution of the NOS isoforms, endothelial and inducible in the collagen/elastin switch, has been demonstrated. We have showed that an increase in inducible NOS activity is a key contributor to HHcy-mediated collagen/elastin switch and resulting decline in aortic compliance. In addition, increased levels of Hcy compete and suppress the γ-amino butyric acid-receptor, N-methyl-d-aspartame-receptor, and peroxisome proliferator-activated receptor. The HHcy causes oxidative stress by generating nitrotyrosine, activating the latent MMPs and decreasing the endothelial NO concentration. The HHcy causes elastinolysis and decrease elastic complicance of the vessel wall. The treatment with γ-amino butyric acid-receptor agonist (muscimol), N

  11. 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

  12. [Acute adverse effects of dialysis].

    PubMed

    Opatrný, K

    2003-02-01

    Adverse reactions to dialyzers are a not very frequent, but because of the serious, sometimes fatal course, a dreaded complication of haemodialysis treatment. Most important among these reactions are hypersensitive reactions (anaphylactoid, reaction type A to dialyzer), which develop as a rule within the 10th minute of the procedure, and the reaction caused by the action of perfluorohydrocarbon which develop hours after onset or even completion of haemodialysis. Explanation of the development of hypersensitive reactions (HSR) by complement activation and formation of anaphylatoxins C3a and C5a during contact of blood with the bioincompatible dialysis membrane has been abandoned. Evidence of the etiological role of ethylene oxide (ETO) in the development of HSR influenced the selection of materials for the production of dialyzers and sterilization during manufacture, it emphasized the importance of rinsing of the dialyzer in the dialysis centre and led to the wide application of alternative methods of sterilization by gamma radiation and steam. HSR may be also caused by overproduction of bradykinin and inhibition of its degradation or degradation of its metabolites. Excessive bradykinin production caused by dialysis membranes with a negative charge is potentiated e.g. by a lower pH and increased plasma dilution in the initial stage of haemodialysis. Inhibition of bradykinin degradation develops during treatment with angiotensin converting enzyme inhibitors (ACEI). In prevention of HSR associated with bradykinin in addition to elimination of a combination of a negatively charged dialysis membrane and ACEI treatment a part is played also by rinsing of the dialyzer before haemodialysis with a bicarbonate solution and the modification of the membrane surface (implemented by the manufacturer) which reduces its negative charge. The first reaction to the dialyzer in conjunction with perfluorohydrocarbon (PF-5070), used in production of some dialyzers for testing the

  13. The role of microRNAs in arterial remodelling.

    PubMed

    Nazari-Jahantigh, M; Wei, Y; Schober, A

    2012-04-01

    Adaptive alterations of the vessel wall architecture, called vascular remodelling, can be found in arterial hypertension, during the formation of aneurysms, in restenosis after vascular interventions, and in atherosclerosis. MicroRNAs (miR) critically affect the main cellular players in arterial remodelling and may either promote or inhibit the structural changes in the vessel wall. They regulate the phenotype of smooth muscle cells (SMCs) and control the inflammatory response in endothelial cells and macrophages. In SMCs, different sets of miRs induce either a synthetic or contractile phenotype, respectively. The conversion into a synthetic SMC phenotype is a crucial event in arterial remodelling. Therefore, reprogramming of the SMC phenotype by miR targeting can modulate the remodelling process. Furthermore, the effects of stimuli that induce remodelling, such as shear stress, angiotensin II, oxidised low-density lipoprotein, or apoptosis, on endothelial cells are mediated by miRs. The endothelial cell-specific miR-126, for example, is transferred in microvesicles from apoptotic endothelial cells and plays a protective role in atherogenesis. The inflammatory response of the innate immune system, especially through macrophages, promotes arterial remodelling. miR-155 induces the expression of inflammatory cytokines, whereas miR-146a and miR-147 are involved in the resolution phase of inflammation. However, in vivo data on the role of miRs in vascular remodelling are still scarce, which are required to test the therapeutic potential of the available, highly effective miR inhibitors. PMID:22371089

  14. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling.

    PubMed

    Hu, Ming Chang; Shi, Mingjun; Cho, Han Jun; Adams-Huet, Beverley; Paek, Jean; Hill, Kathy; Shelton, John; Amaral, Ansel P; Faul, Christian; Taniguchi, Masatomo; Wolf, Myles; Brand, Markus; Takahashi, Masaya; Kuro-O, Makoto; Hill, Joseph A; Moe, Orson W

    2015-06-01

    Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiency-genetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor-23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-β1-, angiotensin II-, or high phosphate-induced fibrosis and abolished TGF-β1- or angiotensin II-induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor-23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging. PMID:25326585

  15. 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...

  16. Adverse Drug Reactions in Dental Practice

    PubMed Central

    Becker, Daniel E.

    2014-01-01

    Adverse reactions may occur with any of the medications prescribed or administered in dental practice. Most of these reactions are somewhat predictable based on the pharmacodynamic properties of the drug. Others, such as allergic and pseudoallergic reactions, are less common and unrelated to normal drug action. This article will review the most common adverse reactions that are unrelated to drug allergy. PMID:24697823

  17. Nurses must report adverse drug reactions.

    PubMed

    Griffith, Richard

    There is renewed determination throughout the European Union (EU) to reduce the economic cost and high death rate associated with adverse drug reactions through better pharmacovigilance. Timely reporting and sharing of information concerning adverse drug reactions is vital to the success of this initiative. In the UK, the reporting of serious adverse drug reactions is facilitated by the Yellow Card Scheme, yet despite being well placed to monitor the effect of medicines on patients, nurses do not make full use of the scheme. This article sets out the impact of adverse drug reactions in the EU and argues that it is essential that nurses must be at the vanguard of adverse reaction reporting if the EU's pharmacovigilance initiative is to be a success. PMID:23905231

  18. 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

  19. 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

  20. Myocardial reverse remodeling: how far can we rewind?

    PubMed

    Rodrigues, Patrícia G; Leite-Moreira, Adelino F; Falcão-Pires, Inês

    2016-06-01

    Heart failure (HF) is a systemic disease that can be divided into HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). HFpEF accounts for over 50% of all HF patients and is typically associated with high prevalence of several comorbidities, including hypertension, diabetes mellitus, pulmonary hypertension, obesity, and atrial fibrillation. Myocardial remodeling occurs both in HFrEF and HFpEF and it involves changes in cardiac structure, myocardial composition, and myocyte deformation and multiple biochemical and molecular alterations that impact heart function and its reserve capacity. Understanding the features of myocardial remodeling has become a major objective for limiting or reversing its progression, the latter known as reverse remodeling (RR). Research on HFrEF RR process is broader and has delivered effective therapeutic strategies, which have been employed for some decades. However, the RR process in HFpEF is less clear partly due to the lack of information on HFpEF pathophysiology and to the long list of failed standard HF therapeutics strategies in these patient's outcomes. Nevertheless, new proteins, protein-protein interactions, and signaling pathways are being explored as potential new targets for HFpEF remodeling and RR. Here, we review recent translational and clinical research in HFpEF myocardial remodeling to provide an overview on the most important features of RR, comparing HFpEF with HFrEF conditions. PMID:26993225

  1. Chromatin dynamics: Interplay between remodeling enzymes and histone modifications

    PubMed Central

    Swygert, Sarah G.; Peterson, Craig L.

    2014-01-01

    Chromatin dynamics play an essential role in regulating the accessibility of genomic DNA for a variety of nuclear processes, including gene transcription and DNA repair. The posttranslational modification of the core histones and the action of ATP-dependent chromatin remodeling enzymes represent two primary mechanisms by which chromatin dynamics are controlled and linked to nuclear events. Although there are examples in which a histone modification or a remodeling enzyme may be sufficient to drive a chromatin transition, these mechanisms typically work in concert to integrate regulatory inputs, leading to a coordinated alteration in chromatin structure and function. Indeed, site-specific histone modifications can facilitate the recruitment of chromatin remodeling enzymes to particular genomic regions, or they can regulate the efficiency or the outcome of a chromatin remodeling reaction. Conversely, chromatin remodeling enzymes can also influence, and sometimes directly modulate, the modification state of histones. These functional interactions are generally complex, frequently transient, and often require the association of myriad additional factors. PMID:24583555

  2. Hydrogen sulfide depletion contributes to microvascular remodeling in obesity.

    PubMed

    Candela, Joseph; Velmurugan, Gopal V; White, Carl

    2016-05-01

    Structural remodeling of the microvasculature occurs during obesity. Based on observations that impaired H2S signaling is associated with cardiovascular pathologies, the current study was designed to test the hypothesis that altered H2S homeostasis is involved in driving the remodeling process in a diet-induced mouse model of obesity. The structural and passive mechanical properties of mesenteric resistance arterioles isolated from 30-wk-old lean and obese mice were assessed using pressure myography, and vessel H2S levels were quantified using the H2S indicator sulfidefluor 7-AM. Remodeling gene expression was assessed using quantitative RT-PCR, and histological staining was used to quantify vessel collagen and elastin. Obesity was found to be associated with decreased vessel H2S concentration, inward hypertrophic remodeling, altered collagen-to-elastin ratio, and reduced vessel stiffness. In addition, mRNA levels of fibronectin, collagen types I and III, matrix metalloproteinases 2 and 9, and tissue inhibitor of metalloproteinase 1 were increased and elastin was decreased by obesity. Evidence that decreased H2S was responsible for the genetic changes was provided by experiments in which H2S levels were manipulated, either by inhibition of the H2S-generating enzyme cystathionine γ-lyase with dl-propargylglycine or by incubation with the H2S donor GYY4137. These data suggest that, during obesity, depletion of H2S is involved in orchestrating the genetic changes underpinning inward hypertrophic remodeling in the microvasculature. PMID:26993223

  3. 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

  4. Role of nucleosome remodeling in neurodevelopmental and intellectual disability disorders

    PubMed Central

    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

  5. 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

  6. Unremodeled and remodeled cardiolipin are functionally indistinguishable in yeast.

    PubMed

    Baile, Matthew G; Sathappa, Murugappan; Lu, Ya-Wen; Pryce, Erin; Whited, Kevin; McCaffery, J Michael; Han, Xianlin; Alder, Nathan N; Claypool, Steven M

    2014-01-17

    After biosynthesis, an evolutionarily conserved acyl chain remodeling process generates a final highly homogeneous and yet tissue-specific molecular form of the mitochondrial lipid cardiolipin. Hence, cardiolipin molecules in different organisms, and even different tissues within the same organism, contain a distinct collection of attached acyl chains. This observation is the basis for the widely accepted paradigm that the acyl chain composition of cardiolipin is matched to the unique mitochondrial demands of a tissue. For this hypothesis to be correct, cardiolipin molecules with different acyl chain compositions should have distinct functional capacities, and cardiolipin that has been remodeled should promote cardiolipin-dependent mitochondrial processes better than its unremodeled form. However, functional disparities between different molecular forms of cardiolipin have never been established. Here, we interrogate this simple but crucial prediction utilizing the best available model to do so, Saccharomyces cerevisiae. Specifically, we compare the ability of unremodeled and remodeled cardiolipin, which differ markedly in their acyl chain composition, to support mitochondrial activities known to require cardiolipin. Surprisingly, defined changes in the acyl chain composition of cardiolipin do not alter either mitochondrial morphology or oxidative phosphorylation. Importantly, preventing cardiolipin remodeling initiation in yeast lacking TAZ1, an ortholog of the causative gene in Barth syndrome, ameliorates mitochondrial dysfunction. Thus, our data do not support the prevailing hypothesis that unremodeled cardiolipin is functionally distinct from remodeled cardiolipin, at least for the functions examined, suggesting alternative physiological roles for this conserved pathway. PMID:24285538

  7. 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

  8. 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

  9. 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

  10. ATP-dependent chromatin remodeling in T cells

    PubMed Central

    Wurster, Andrea L.; Pazin, Michael J.

    2012-01-01

    One of the best studied systems for mammalian chromatin remodeling is transcriptional regulation during T cell development. The variety of these studies have led to important findings in T cell gene regulation and cell fate determination. Importantly, these findings have also advanced our knowledge of the function of remodeling enzymes in mammalian gene regulation. In this review, first we briefly present biochemical/cell-free analysis of 3 types of ATP dependent remodeling enzymes (SWI/SNF, Mi2, and ISWI), to construct an intellectual framework to understand how these enzymes might be working. Second, we compare and contrast the function of these enzymes, during early (thymic) and late (peripheral) T cell development. Finally, we examine some of the gaps in our present understanding. PMID:21999456

  11. [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

  12. 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. PMID:22974762

  13. Subject-specific bone remodelling of the scapula.

    PubMed

    Quental, Carlos; Folgado, João; Fernandes, Paulo R; Monteiro, Jacinto

    2014-08-01

    Finite element analyses, with increasing levels of detail and complexity, are becoming effective tools to evaluate the performance of joint replacement prostheses and to predict the behaviour of bone. As a first step towards the study of the complications of shoulder arthroplasty, the aim of this work was the development and validation of a 3D finite element model of an intact scapula for the prediction of the bone remodelling process based on a previously published model that attempts to follow Wolff's law. The boundary conditions applied include full muscle and joint loads taken from a multibody system of the upper limb based on the same subject whose scapula was here analysed. To validate the bone remodelling simulations, qualitative and quantitative comparisons between the predicted and the specimen's bone density distribution were performed. The results showed that the bone remodelling model was able to successfully reproduce the actual bone density distribution of the analysed scapula. PMID:23210487

  14. Anisotropic stress orients remodelling of mammalian limb bud ectoderm.

    PubMed

    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

    2015-05-01

    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

  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. Physiological bases of bone regeneration II. The remodeling process.

    PubMed

    Fernández-Tresguerres-Hernández-Gil, Isabel; Alobera-Gracia, Miguel Angel; del-Canto-Pingarrón, Mariano; Blanco-Jerez, Luis

    2006-03-01

    Bone remodeling is the restructuring process of existing bone, which is in constant resorption and formation. Under normal conditions, this balanced process allows the renewal of 5-10% of bone volume per year. At the microscopic level, bone remodeling is produced in basic multicellular units, where osteoclasts resorb a certain quantity of bone and osteoblasts form the osteoid matrix and mineralize it to fill the previously created cavity. These units contain osteoclasts, macrophages, preosteoblasts and osteoblasts, and are controlled by a series of factors, both general and local, allowing normal bone function and maintaining the bone mass. When this process becomes unbalanced then bone pathology appears, either in excess (osteopetrosis) or deficit (osteoporosis). The purpose of this study is to undertake a revision of current knowledge on the physiological and biological mechanisms of the bone remodeling process; highlighting the role played by the regulating factors, in particular that of the growth factors. PMID:16505794

  17. 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

  18. 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.

  19. The Role of Reactive Oxygen Species in Microvascular Remodeling

    PubMed Central

    Staiculescu, Marius C.; Foote, Christopher; Meininger, Gerald A.; Martinez-Lemus, Luis A.

    2014-01-01

    The microcirculation is a portion of the vascular circulatory system that consists of resistance arteries, arterioles, capillaries and venules. It is the place where gases and nutrients are exchanged between blood and tissues. In addition the microcirculation is the major contributor to blood flow resistance and consequently to regulation of blood pressure. Therefore, structural remodeling of this section of the vascular tree has profound implications on cardiovascular pathophysiology. This review is focused on the role that reactive oxygen species (ROS) play on changing the structural characteristics of vessels within the microcirculation. Particular attention is given to the resistance arteries and the functional pathways that are affected by ROS in these vessels and subsequently induce vascular remodeling. The primary sources of ROS in the microcirculation are identified and the effects of ROS on other microcirculatory remodeling phenomena such as rarefaction and collateralization are briefly reviewed. PMID:25535075

  20. 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

  1. Myocardial repair/remodelling following infarction: roles of local factors

    PubMed Central

    Sun, Yao

    2009-01-01

    Heart failure is a global health problem, appearing most commonly in patients with previous myocardial infarction (MI). Cardiac remodelling, particularly fibrosis, seen in both the infarcted and non-infarcted myocardium is recognized to be a major determinant of the development of impaired ventricular function, leading to a poor prognosis. Elucidating cellular and molecular mechanisms responsible for the accumulation of extracellular matrix is essential for designing cardioprotective and reparative strategies that could regress fibrosis after infarction. Multiple factors contribute to left ventricular remodelling at different stages post-MI. This review will discuss the role of oxidative stress and locally produced angiotensin II in the pathogenesis of myocardial repair/remodelling after MI. PMID:19050008

  2. Uptake and remodeling of exogenous phosphatidylethanolamine in E. coli.

    PubMed

    Kol, Matthijs A; Kuster, Diederik W D; Boumann, Henry A; de Cock, Hans; Heck, Albert J R; de Kruijff, Ben; de Kroon, Anton I P M

    2004-03-22

    The fate of exogenous short-chain analogues of phosphatidylethanolamine and phosphatidylserine was studied in a deep-rough derivative of E. coli mutant strain AD93 that cannot synthesize phosphatidylethanolamine de novo. Using mass spectrometry, it was shown that dicaproyl(di 6:0)-phosphatidylethanolamine is extensively remodeled, eventually adopting the phosphatidylethanolamine species profile of the parental wild-type strain of AD93. Dicaproyl-phosphatidylserine was decarboxylated to form phosphatidylethanolamine, and yielded a species profile, which strongly resembled that of the introduced phosphatidylethanolamine. This demonstrates transport of phosphatidylserine to the cytosolic leaflet of the inner membrane. The changes of the species profile of phosphatidylethanolamine indicate that the short-chain phospholipids are most likely remodeled via two consecutive acyl chain substitutions, and at least part of this remodeling involves transport to the inner membrane. PMID:15164768

  3. Assessment of bone vascularization and its role in bone remodeling

    PubMed Central

    Lafage-Proust, Marie-Hélène; Roche, Bernard; Langer, Max; Cleret, Damien; Vanden Bossche, Arnaud; Olivier, Thomas; Vico, Laurence

    2015-01-01

    Bone is a composite organ that fulfils several interconnected functions, which may conflict with each other in pathological conditions. Bone vascularization is at the interface between these functions. The roles of bone vascularization are better documented in bone development, growth and modeling than in bone remodeling. However, every bone remodeling unit is associated with a capillary in both cortical and trabecular envelopes. Here we summarize the most recent data on vessel involvement in bone remodeling, and we present the characteristics of bone vascularization. Finally, we describe the various techniques used for bone vessel imaging and quantitative assessment, including histology, immunohistochemistry, microtomography and intravital microscopy. Studying the role of vascularization in adult bone should provide benefits for the understanding and treatment of metabolic bone diseases. PMID:25861447

  4. 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

  5. Adverse event recording post hip fracture surgery.

    PubMed

    Doody, K; Mohamed, K M S; Butler, A; Street, J; Lenehan, B

    2013-01-01

    Accurate recording of adverse events post hip fracture surgery is vital for planning and allocating resources. The purpose of this study was to compare adverse events recorded prospectively at point of care with adverse recorded by the Hospital In-Patient Enquiry (HIPE) System. The study examined a two month period from August to September 2011 at University Hospital Limerick. Out of a sample size of 39, there were 7 males (17.9%) and 32 females (82.1%) with an age range of between 53 and 98 years. The mean age was 80.5 years. 55 adverse events were recorded, in contrast to the HIPE record of 13 (23.6%) adverse events. The most common complications included constipation 10 (18.2%), anaemia 8 (14.5%), urinary retention 8 (14.50%), pneumonia 5 (9.1%) and delirium 5 (9.1%). Of the female cohort, 24 (68.8%) suffered an adverse event, while only 4 (57%) males suffered an adverse event. PMID:24579408

  6. 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

  7. Learning from adverse incidents involving medical devices.

    PubMed

    Amoore, John; Ingram, Paula

    While an adverse event involving a medical device is often ascribed to either user error or device failure, the causes are typically multifactorial. A number of incidents involving medical devices are explored using this approach to investigate the various causes of the incident and the protective barriers that minimised or prevented adverse consequences. User factors, including mistakes, omissions and lack of training, conspired with background factors--device controls and device design, storage conditions, hidden device damage and physical layout of equipment when in use--to cause the adverse events. Protective barriers that prevented or minimised the consequences included staff vigilance, operating procedures and alarms. PMID:12715578

  8. 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

  9. Structural remodeling of unweighted soleus myotendinous junction in monkey.

    PubMed

    Roffino, Sandrine; Carnino, Alain; Chopard, Angèle; Mutin, Murielle; Marini, Jean-François

    2006-03-01

    This study describes the morphology of the soleus myotendinous junction (MTJ) in the Rhesus monkey. Ultrastructural observations revealed a structural complexity that probably reflects functional adaptations. We also studied ultrastructural modifications of the MTJ in response to 14 days of hypokinesia and microgravity (Bion 11 mission). The reduced limb mobility of the animals, placed in a safety seat aboard the satellite, induced a sarcolemmal remodeling that was enhanced by the microgravity conditions. Signs of MTJ remodeling such as alterations of contractile apparatus and myofilament-anchoring structures, T-tubule dilation, and autophagic vacuoles could be ascribed to the microgravity. PMID:16545758

  10. 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

  11. 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

  12. Synaptic circuit remodelling by matrix metalloproteinases in health and disease

    PubMed Central

    Huntley, George W.

    2016-01-01

    Matrix metalloproteinases (MMPs) are extracellularly acting enzymes that have long been known to have deleterious roles in brain injury and disease. In particular, widespread and protracted MMP activity can contribute to neuronal loss and synaptic dysfunction. However, recent studies show that rapid and focal MMP-mediated proteolysis proactively drives synaptic structural and functional remodelling that is crucial for ongoing cognitive processes. Deficits in synaptic remodelling are associated with psychiatric and neurological disorders, and aberrant MMP expression or function may contribute to the molecular mechanisms underlying these deficits. This Review explores the paradigm shift in our understanding of the contribution of MMPs to normal and abnormal synaptic plasticity and function. PMID:23047773

  13. 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

  14. [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. PMID:26728527

  15. Silent Synapse-Based Circuitry Remodeling in Drug Addiction.

    PubMed

    Dong, Yan

    2016-05-01

    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

  16. Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure

    PubMed Central

    2010-01-01

    Background Accumulating evidence suggests glucagon-like peptide-1 (GLP-1) exerts cardioprotective effects in animal models of myocardial infarction (MI). We hypothesized that chronic treatment with GLP-1 or the exenatide analog AC3174 would improve cardiac function, cardiac remodeling, insulin sensitivity, and exercise capacity (EC) in rats with MI-induced chronic heart failure (CHF) caused by coronary artery ligation. Methods Two weeks post-MI, male Sprague-Dawley rats were treated with GLP-1 (2.5 or 25 pmol/kg/min), AC3174 (1.7 or 5 pmol/kg/min) or vehicle via subcutaneous infusion for 11 weeks. Cardiac function and morphology were assessed by echocardiography during treatment. Metabolic, hemodynamic, exercise-capacity, and body composition measurements were made at study end. Results Compared with vehicle-treated rats with CHF, GLP-1 or AC3174 significantly improved cardiac function, including left ventricular (LV) ejection fraction, and end diastolic pressure. Cardiac dimensions also improved as evidenced by reduced LV end diastolic and systolic volumes and reduced left atrial volume. Vehicle-treated CHF rats exhibited fasting hyperglycemia and hyperinsulinemia. In contrast, GLP-1 or AC3174 normalized fasting plasma insulin and glucose levels. GLP-1 or AC3174 also significantly reduced body fat and fluid mass and improved exercise capacity and respiratory efficiency. Four of 16 vehicle control CHF rats died during the study compared with 1 of 44 rats treated with GLP-1 or AC3174. The cellular mechanism by which GLP-1 or AC3174 exert cardioprotective effects appears unrelated to changes in GLUT1 or GLUT4 translocation or expression. Conclusions Chronic treatment with either GLP-1 or AC3174 showed promising cardioprotective effects in a rat model of CHF. Hence, GLP-1 receptor agonists may represent a novel approach for the treatment of patients with CHF or cardiovascular disease associated with type 2 diabetes. PMID:21080957

  17. Comparative effects of valsartan in combination with cilnidipine or amlodipine on cardiac remodeling and diastolic dysfunction in Dahl salt-sensitive rats.

    PubMed

    Nagasawa, Kai; Takahashi, Keiji; Matsuura, Natsumi; Takatsu, Miwa; Hattori, Takuya; Watanabe, Shogo; Harada, Eri; Niinuma, Kazumi; Murohara, Toyoaki; Nagata, Kohzo

    2015-01-01

    Angiotensin receptor blockers (ARBs) are often supplemented with calcium channel blockers (CCBs) for treatment of hypertension. We recently showed that the L/N-type CCB cilnidipine has superior cardioprotective effects compared with the L-type CCB amlodipine in Dahl salt-sensitive (DS) rats. We have now compared the effects of the ARB valsartan combined with cilnidipine or amlodipine on cardiac pathophysiology in DS rats. DS rats fed a high-salt diet from 6 weeks of age were treated with vehicle, valsartan alone (10 mg kg(-1) per day), or valsartan combined with either cilnidipine (1 mg kg(-1) per day) or amlodipine (1 mg kg(-1) per day) from 7 to 11 weeks. The salt-induced increase in systolic blood pressure apparent in the vehicle group was attenuated similarly in the three drug treatment groups. Valsartan-cilnidipine attenuated left ventricular (LV) fibrosis and diastolic dysfunction as well as cardiac oxidative stress and inflammation to a greater extent than did valsartan alone or valsartan-amlodipine. In addition, the increases in urinary excretion of dopamine and epinephrine as well as in cardiac renin-angiotensin-aldosterone-system (RAAS) gene expression apparent in vehicle-treated rats were attenuated to a greater extent by valsartan-cilnidipine than by the other two treatments. Valsartan-cilnidipine thus attenuated LV remodeling and diastolic dysfunction more effectively than did valsartan or valsartan-amlodipine in rats with salt-sensitive hypertension, and this superior cardioprotective action of valsartan-cilnidipine compared with valsartan-amlodipine is likely attributable, at least in part, to the greater antioxidant and antiinflammatory effects associated with both greater inhibition of cardiac RAAS gene expression and N-type calcium channel blockade. PMID:25209105

  18. Effects of dipeptidyl peptidase-4 inhibitor in insulin-resistant rats with myocardial infarction.

    PubMed

    Apaijai, Nattayaporn; Inthachai, Tharnwimol; Lekawanvijit, Suree; Chattipakorn, Siriporn C; Chattipakorn, Nipon

    2016-06-01

    Adverse cardiac remodeling after myocardial infarction (MI) leads to progressive heart failure. Obese-insulin resistance increases risks of MI and heart failure. Although dipeptidyl peptidase-4 (DPP4) inhibitor is known to exert cardioprotection, its effects on adverse remodeling after MI in obese-insulin-resistant rats are unclear. We hypothesized that DPP4 inhibitor reduces adverse left ventricular (LV) remodeling and LV dysfunction in obese-insulin-resistant rats with MI. Rats were fed either normal diet (ND) or high-fat diet (HFD) for 12 weeks to induce obese-insulin resistance, followed by left anterior descending coronary artery ligation to induce MI. Then, rats in each dietary group were divided into five subgroups to receive vehicle, enalapril (10mg/kg/day), metformin (30mg/kg/day), DPP4 inhibitor vildagliptin (3mg/kg/day), or combined metformin and vildagliptin for 8 weeks. Heart rate variability (HRV), LV function, pathological and biochemical studies for LV remodeling, and cardiomyocyte apoptosis were determined. Obese-insulin-resistant rats had severe insulin resistance and LV dysfunction. HFD rats had a higher mortality rate than ND rats, and all treatments reduced the mortality rate in obese-insulin-resistant rats. Although all drugs improved insulin resistance, HRV, LV function as well as reduced cardiac hypertrophy and fibrosis, vildagliptin effectively reduced cardiomyocyte cross-sectional areas more than enalapril and was related to markedly decreased ERK1/2 phosphorylation. In ND rats with MI, metformin neither improved LV ejection fraction nor reduced cardiac fibrosis. The infarct size and transforming growth factor-β expression were not different among groups. In obese-insulin-resistant rats with chronic MI, DPP4 inhibitor vildagliptin exerts better cardioprotection than enalapril in attenuating adverse LV remodeling. PMID:27044778

  19. 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.

  20. 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...

  1. Adverse cutaneous drug eruptions: current understanding.

    PubMed

    Hoetzenecker, W; Nägeli, M; Mehra, E T; Jensen, A N; Saulite, I; Schmid-Grendelmeier, P; Guenova, E; Cozzio, A; French, L E

    2016-01-01

    Adverse cutaneous drug reactions are recognized as being major health problems worldwide causing considerable costs for health care systems. Most adverse cutaneous drug reactions follow a benign course; however, up to 2% of all adverse cutaneous drug eruptions are severe and life-threatening. These include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Physicians should be aware of specific red flags to rapidly identify these severe cutaneous drug eruptions and initiate appropriate treatment. Besides significant progress in clinical classification and treatment, recent studies have greatly enhanced our understanding in the pathophysiology of adverse cutaneous drug reactions. Genetic susceptibilities to certain drugs have been identified in SJS/TEN patients, viral reactivation in DRESS has been elucidated, and the discovery of tissue resident memory T cells helps to better understand the recurrent site-specific inflammation in patients with fixed drug eruption. PMID:26553194

  2. 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

  3. 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...

  4. 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

  5. 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

  6. 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

  7. 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

  8. "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…

  9. 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…

  10. Role of microRNAs in Vascular Remodeling.

    PubMed

    Fang, Y-C; Yeh, C-H

    2015-01-01

    Besides being involved in the gradual formation of blood vessels during embryonic development, vascular remodeling also contributes to the progression of various cardiovascular diseases, such as; myocardial infarction, heart failure, atherosclerosis, pulmonary artery hypertension, restenosis, aneurysm, etc. The integrated mechanisms; proliferation of medial smooth muscle cell, dysregulation of intimal endothelial cell, activation of adventitial fibroblast, inflammation of macrophage, and the participation of extracellular matrix proteins are important factors in vascular remodeling. In the recent studies, microRNAs (miRs) have been shown to be expressed in all of these cell-types and play important roles in the mechanisms of vascular remodeling. Therefore, some miRs may be involved in prevention and others in the aggravation of the vascular lesions. miRs are small, endogenous, conserved, single-stranded, non-coding RNAs; which degrade target RNAs or inhibit translation post-transcriptionally. In this paper, we reviewed the function and mechanisms of miRs, which are highly expressed in various cells types, especially endothelial and smooth muscle cells, which are closely involved in the process of vascular remodeling. We also assess the functions of these miRs in the hope that they may provide new possibilities of diagnosis and treatment choices for the related diseases. PMID:26391551

  11. 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

  12. 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.

  13. Differential remodeling of extracellular matrices by breast cancer initiating cells.

    PubMed

    Raja, Anju M; Xu, Shuoyu; Zhuo, Shuangmu; Tai, Dean C S; Sun, Wanxin; So, Peter T C; Welsch, Roy E; Chen, Chien-Shing; Yu, Hanry

    2015-10-01

    Cancer initiating cells (CICs) have been the focus of recent anti-cancer therapies, exhibiting strong invasion capability via potentially enhanced ability to remodel extracellular matrices (ECM). We have identified CICs in a human breast cancer cell line, MX-1, and developed a xenograft model in SCID mice. We investigated the CICs' matrix-remodeling effects using Second Harmonic Generation (SHG) microscopy to identify potential phenotypic signatures of the CIC-rich tumors. The isolated CICs exhibit higher proliferation, drug efflux and drug resistant properties in vitro; were more tumorigenic than non-CICs, resulting in more and larger tumors in the xenograft model. The CIC-rich tumors have less collagen in the tumor interior than in the CIC-poor tumors supporting the idea that the CICs can remodel the collagen more effectively. The collagen fibers were preferentially aligned perpendicular to the CIC-rich tumor boundary while parallel to the CIC-poor tumor boundary suggesting more invasive behavior of the CIC-rich tumors. These findings would provide potential translational values in quantifying and monitoring CIC-rich tumors in future anti-cancer therapies. CIC-rich tumors remodel the collagen matrix more than CIC-poor tumors. PMID:25597396

  14. Bioresorbable vascular scaffolds: Biodegradation, drug delivery and vascular remodeling.

    PubMed

    Tesfamariam, Belay

    2016-05-01

    The metallic stents with durable polymers have been effective in reducing the need for revascularization, but the permanent presence of the metal and polymer have been associated with persistent inflammation, hypersensitivity reactions and incidence of thrombosis. Recent innovations of bioresorbable polymers are in development which could serve as temporary scaffolds that degrade into molecules and eventually resorb overtime, and leave the artery free of any permanent prosthetic constraints. The transient scaffolding has the advantages of restoring blood vessel to natural state, improve vasomotor tone and increase lumen enlargement because of expansive remodeling following completion of polymer resorption. The success of bioresorbable vascular scaffolds will depend on the degradation timeline, such that the elastic recoil of the blood vessel and negative remodeling which could potentially lead to restenosis are prevented. Bioresorbable scaffolds with bulky backbone and thick struts could lead to prolonged biodegradation, alter blood flow dynamics and increase thrombogenicity. The development of bioresorbable scaffolds is challenging because of the complexity of finding an ideal balance of polymer biodegradation and controlled drug release over time, such that the fractional drug released achieves optimal inhibitory concentration until the blood vessel remodels to a stable set point. This review discusses the various types of biodegradable materials, factors affecting biodegradation, drug release kinetics, vascular biocompatibility, adaptive vascular remodeling, and challenges in the development of bioresorbable scaffolds to treat vascular restenosis. PMID:27001225

  15. 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.

  16. DNA Looping Facilitates Targeting of a Chromatin Remodeling Enzyme

    PubMed Central

    Yadon, Adam N; Singh, Badri Nath; Hampsey, Michael; Tsukiyama, Toshio

    2013-01-01

    Summary ATP-dependent chromatin remodeling enzymes are highly abundant and play pivotal roles regulating DNA-dependent processes. The mechanisms by which they are targeted to specific loci have not been well understood on a genome-wide scale. Here we present evidence that a major targeting mechanism for the Isw2 chromatin remodeling enzyme to specific genomic loci is through sequence-specific transcription factor (TF)-dependent recruitment. Unexpectedly, Isw2 is recruited in a TF-dependent fashion to a large number of loci without TF binding sites. Using the 3C assay, we show that Isw2 can be targeted by Ume6- and TFIIB-dependent DNA looping. These results identify DNA looping as a previously unknown mechanism for the recruitment of a chromatin remodeling enzyme and defines a novel function for DNA looping. We also present evidence suggesting that Ume6-dependent DNA looping is involved in chromatin remodeling and transcriptional repression, revealing a mechanism by which the three-dimensional folding of chromatin affects DNA-dependent processes. PMID:23478442

  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. 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…

  19. Probing Nucleosome Remodeling by Unzipping Single DNA Molecules

    NASA Astrophysics Data System (ADS)

    Wang, Michelle

    2006-03-01

    At the core of eukaryotic chromatin is the nucleosome, which consists of 147 bp of DNA wrapped 1.65 turns around an octamer of histone proteins. Even this lowest level of genomic compaction presents a strong barrier to DNA-binding cellular factors that are required for essential processes such as transcription, DNA replication, recombination and repair. Chromatin remodeling enzymes use the energy of ATP hydrolysis to regulate accessibility of the genetic code by altering chromatin structure. While remodeling enzymes have been the subject of extensive research in recent years, their precise mechanism remains unclear. In order to probe the structure of individual nucleosomes and their remodeling, we assembled a histone octamer onto a DNA segment containing a strong nucleosome positioning sequence. As the DNA double helix was unzipped through the nucleosome using a feedback-enhanced optical trap, the presence of the nucleosome was detected as a series of dramatic increases in the tension in the DNA, followed by sudden tension reductions. Analysis of the unzipping force throughout the disruption accurately revealed the spatial location and fine structure of the nucleosome to near base pair precision. Using this approach, we investigate how remodeling enzymes may alter the location and structure of a nucleosome.

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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.

  5. MuLV-related endogenous retroviral elements and Flt3 participate in aberrant end-joining events that promote B-cell leukemogenesis

    PubMed Central

    Johnson, Radia M.; Papp, Eniko; Grandal, Ildiko; Kowalski, Paul E.; Nutter, Lauryl; Wong, Raymond C.C.; Joseph-George, Ann M.; Danska, Jayne S.; Guidos, Cynthia J.

    2014-01-01

    During V(D)J recombination of immunoglobulin genes, p53 and nonhomologous end-joining (NHEJ) suppress aberrant rejoining of DNA double-strand breaks induced by recombinase-activating genes (Rags)-1/2, thus maintaining genomic stability and limiting malignant transformation during B-cell development. However, Rag deficiency does not prevent B-cell leukemogenesis in p53/NHEJ mutant mice, revealing that p53 and NHEJ also suppress Rag-independent mechanisms of B-cell leukemogenesis. Using several cytogenomic approaches, we identified a novel class of activating mutations in Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase important for normal hematopoiesis in Rag/p53/NHEJ triple-mutant (TM) B-cell leukemias. These mutant Flt3 alleles were created by complex genomic rearrangements with Moloney leukemia virus (MuLV)-related endogenous retroviral (ERV) elements, generating ERV-Flt3 fusion genes encoding an N-terminally truncated mutant form of Flt3 (trFlt3) that was transcribed from ERV long terminal repeats. trFlt3 protein lacked most of the Flt3 extracellular domain and induced ligand-independent STAT5 phosphorylation and proliferation of hematopoietic progenitor cells. Furthermore, expression of trFlt3 in p53/NHEJ mutant hematopoietic progenitor cells promoted development of clinically aggressive B-cell leukemia. Thus, repetitive MuLV-related ERV sequences can participate in aberrant end-joining events that promote development of aggressive B-cell leukemia. PMID:24888589

  6. Obliterative airway remodelling in transplanted and non-transplanted lungs.

    PubMed

    Jonigk, Danny; Theophile, Katharina; Hussein, Kais; Bock, Oliver; Lehmann, Ulrich; Bockmeyer, Clemens L; Gottlieb, Jens; Fischer, Stefan; Simon, Andre; Welte, Tobias; Maegel, Lavinia; Kreipe, Hans; Laenger, Florian

    2010-09-01

    Obliterative airway remodelling is a morphological sequence in a variety of pulmonary diseases. Notably, bronchiolitis obliterans represents one of the key complications of lung transplantation, induced by (immigrating) myofibroblasts. A comparative expression analysis of obliterative airway remodelling in transplanted and non-transplanted patients has not been reported so far. Obliterated and unremodelled airways from explanted lungs (n = 19) from patients suffering from chronic allograft dysfunction, infection, graft-versus-host disease and toxic exposure were isolated by laser-assisted microdissection. Airways from lung allografts harvested shortly before and after transplantation (n = 4) as well as fibroblastic foci from lungs with interstitial pulmonary fibrosis (n = 4) served as references. Pre-amplified cDNA was analysed by quantitative real-time RT-PCR for expression of fibrosis, inflammation and apoptosis-associated genes. Composition of infiltrating cells and protein expression were assessed by conventional histology and immunohistochemistry. Bronchiolitis obliterans in transplanted patients showed a significant increase of BMP-7 expression (p = 0.0141 compared with controls), while TGF-beta1 and FGF-2 as well as BMP-4 and BMP-7 were up-regulated in fibroblastic foci in interstitial pulmonary fibrosis (p < 0.0424 compared with controls). Regarding other fibrosis-associated genes (BMP-6, SMAD-3, CASP-3 and CASP-9, FASLG, NF-KB1, IL-1 and IL-2) as well as cellularity and cellular composition, no significant differences between obliterative airway remodelling in transplanted and non-transplanted patients could be shown. Obliterative airway remodelling in lung allografts and in non-transplanted patients share many morphological and genetic traits. BMPs, especially BMP-7, warrant further investigation as possible markers for the aggravation of airway remodelling. PMID:20632031

  7. Urokinase plasminogen activator gene deficiency inhibits fracture cartilage remodeling.

    PubMed

    Popa, Nicoleta L; Wergedal, Jon E; Lau, K-H William; Mohan, Subburaman; Rundle, Charles H

    2014-03-01

    Urokinase plasminogen activator (uPA) regulates a proteolytic cascade of extracellular matrix degradation that functions in tissue development and tissue repair. The development and remodeling of the skeletal extracellular matrix during wound healing suggests that uPA might regulate bone development and repair. To determine whether uPA functions regulate bone development and repair, we examined the basal skeletal phenotype and endochondral bone fracture repair in uPA-deficient mice. The skeletal phenotype of uPA knockout mice was compared with that of control mice under basal conditions by dual-energy X-ray absorptiometry and micro-CT analysis, and during femur fracture repair by micro-CT and histological examination of the fracture callus. No effects of uPA gene deficiency were observed in the basal skeletal phenotype of the whole body or the femur. However, uPA gene deficiency resulted in increased fracture callus cartilage abundance during femur fracture repair at 14 days healing. The increase in cartilage corresponded to reduced tartrate-resistant acid phosphatase (TRAP) staining for osteoclasts in the uPA knockout fracture callus at this time, consistent with impaired osteoclast-mediated remodeling of the fracture cartilage. CD31 staining was reduced in the knockout fracture tissues at this time, suggesting that angiogenesis was also reduced. Osteoclasts also colocalized with CD31 expression in the endothelial cells of the fracture tissues during callus remodeling. These results indicate that uPA promotes remodeling of the fracture cartilage by osteoclasts that are associated with angiogenesis and suggest that uPA promotes angiogenesis and remodeling of the fracture cartilage at this time of bone fracture repair. PMID:23700285

  8. 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

  9. Characterizing matrix remodeling in collagen gels using optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Levitz, David; Hinds, Monica T.; Hanson, Stephen R.; Jacques, Steven L.

    2010-02-01

    Optical coherence tomography (OCT) has shown promise at non-destructively characterizing engineered tissues such as collagen gels. However, as the collagen gels develop, the OCT images lose contrast of structures as the gels develop, making visual assessment difficult. Our group proposed quantitatively characterizing these gels by fitting the optical properties from the OCT signals. In this paper, we imaged collagen gels seeded with smooth muscle cells (SMCs) over a 5-day period and used the data to measure their optical properties. Our results showed that over time, the reflectivity of the samples increased 10-fold, corresponding to a decrease in anisotropy factor g, without much change in the scattering coefficient μs. Overall, the optical properties appeared to be dominated by scattering from the collagen matrix, not the cells. However, SMCs remodeled the collagen matrix, and this collagen remodeling by the cells is what causes the observed changes in optical properties. Moreover, the data showed that the optical properties were sensitive to the activity of matrix metalloproteinases (MMPs), enzymes that break down local collagen fibrils into smaller fragments. Blocking MMPs in the SMC gels greatly impeded both the remodeling process and change in optical properties at day 5. Treating day 1 acellular gels with MMP-8 for 3 hr managed to partially reproduce the remodeling observed in SMC gels at day 5. Altogether, we conclude that matrix remodeling in general, and MMPs specifically, greatly affect the local optical properties of the sample, and OCT is a unique tool that can assess MMP activity in collagen gels both non-destructively and label free.

  10. The SWI/SNF chromatin-remodeling gene AtCHR12 mediates temporary growth arrest in Arabidopsis thaliana upon perceiving environmental stress.

    PubMed

    Mlynárová, Ludmila; Nap, Jan-Peter; Bisseling, Ton

    2007-09-01

    One of the earliest responses of plants to environmental stress is establishing a temporary growth arrest that allows adaptation to adverse conditions. The response to abiotic stress requires the modulation of gene expression, which may be mediated by the alteration of chromatin structures. This alteration can be accomplished with the help of chromatin-remodeling enzymes, such as the various SWI/SNF classes of ATPases. Here, we investigate the role of the Arabidopsis SNF2/Brahma-type AtCHR12 chromatin-remodeling gene in plant growth and development in reaction to adverse environmental conditions. We show that the AtCHR12 chromatin-remodeling gene plays a vital role in mediating the temporary growth arrest of Arabidopsis that is induced upon perception of stress. Exposing an AtCHR12 overexpressing mutant to stress conditions leads to growth arrest of normally active primary buds, as well as to reduced growth of the primary stem. In contrast, the AtCHR12 knockout mutant shows less growth arrest than the wild-type when exposed to moderate stress. Without stress, mutant plants are indistinguishable from the wild-type, and the growth arrest response seems to depend on the severity of the stress applied. Modulation of AtCHR12 expression correlates with changes in expression of dormancy-associated genes. This is in agreement with the concept of AtCHR12 participation in priming the plants for the growth arrest response. Our data indicate that AtCHR12-associated growth arrest differs from DELLA-mediated growth restraint. This establishes AtCHR12 as a novel gene involved in the response repertoire of plants that permits flexible modulation of growth in adverse and/or otherwise limiting environments. PMID:17605754

  11. Adverse events temporally associated with meningococcal vaccines.

    PubMed Central

    Yergeau, A; Alain, L; Pless, R; Robert, Y

    1996-01-01

    OBJECTIVE: To determine the incidence of severe adverse events temporally associated with meningococcal vaccines administered as part of a mass vaccination program. DESIGN: Retrospective descriptive study of events reported to a passive provincial surveillance system. SETTING: The province of Quebec. PARTICIPANTS: The 1,198,751 individuals aged 6 months to 20 years who were vaccinated against meningococcal disease between Dec. 27, 1992, and Mar. 31, 1993. OUTCOME MEASURES: Total numbers and rates of severe adverse events, including allergic reactions, anaphylactic reactions, neurological events (other than abnormal crying and screaming) and other serious or unusual events. RESULTS: A total of 118 reports of severe adverse events were selected from the surveillance system. The most frequent were allergic reactions (9.2 per 100,000 doses). Few anaphylactic or neurologic reactions were reported (0.1 and 0.5 per 100,000 doses respectively). There were no reports of sequelae or of encephalopathy, meningitis or encephalitis. CONCLUSION: Meningococcal vaccines seem to be associated with fewer adverse events than have previously been reported. Existing surveillance programs are useful for determining the incidence of adverse events temporally associated with vaccines. PMID:8630839

  12. 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. PMID:25802092

  13. Identifying Adverse Drug Events by Relational Learning

    PubMed Central

    Page, David; Costa, Vítor Santos; Natarajan, Sriraam; Barnard, Aubrey; Peissig, Peggy; Caldwell, Michael

    2013-01-01

    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

  14. Standardizing drug adverse event reporting data.

    PubMed

    Wang, Liwei; Jiang, Guoqian; Li, Dingcheng; Liu, Hongfang

    2013-01-01

    Normalizing data in the Adverse Event Reporting System (AERS), an FDA database, would improve the mining capacity of AERS for drug safety signal detection. In this study, we aim to normalize AERS and build a publicly available normalized Adverse drug events (ADE) data source.he drug information in AERS is normalized to RxNorm, a standard terminology source for medication. Drug class information is then obtained from the National Drug File - Reference Terminology (NDF-RT). Adverse drug events (ADE) are aggregated through mapping with the PT (Preferred Term) and SOC (System Organ Class) codes of MedDRA. Our study yields an aggregated knowledge-enhanced AERS data mining set (AERS-DM). The AERS-DM could provide more perspectives to mine AERS database for drug safety signal detection and could be used by research community in the data mining field. PMID:23920875

  15. A revised inventory of Adverse Childhood Experiences.

    PubMed

    Finkelhor, David; Shattuck, Anne; Turner, Heather; Hamby, Sherry

    2015-10-01

    This study examines whether the items from the original Adverse Childhood Experiences (ACE) scale can be improved in their prediction of health outcomes by adding some additional widely recognized childhood adversities. The analyses come from the National Survey of Children's Exposure to Violence 2014, a telephone survey conducted from August 2013 through April 2014 with a nationally representative sample of 1,949 children and adolescents aged 10-17 and their caregivers who were asked about adversities, physical health conditions and mental health symptoms. The addition of measures of peer victimization, peer isolation/rejection, and community violence exposure added significantly to the prediction of mental health symptoms, and the addition of a measure of low socioeconomic status (SES) added significantly to the prediction of physical health problems. A revised version of the ACES scale is proposed. PMID:26259971

  16. 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. PMID:23499043

  17. 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

  18. Follistatin-like 1 in Chronic Systolic Heart Failure: A Marker of Left Ventricular Remodeling

    PubMed Central

    El-Armouche, Ali; Ouchi, Noriyuki; Tanaka, Komei; Doros, Gheorghe; Wittköpper, Katrin; Schulze, Thomas; Eschenhagen, Thomas; Walsh, Kenneth; Sam, Flora

    2011-01-01

    Background Follistatin-like 1 (FSTL1) is an extracellular glycoprotein that is found in human serum. Recent work suggests that FSTL1 is secreted in response to ischemic injuries and that its overexpression is protective in the heart and vasculature. Methods and Results Here, we examined serum FSTL1 levels in patients with chronic heart failure with left ventricular (LV) ejection fraction <40% (n=86). The distribution of the sample, from these chronic heart failure patients, was separated into three tertiles of low, medium and high FSTL1 levels. Serum FSTL1 levels were increased 56% above age- and gender-matched, healthy controls. Diabetes mellitus, brain natriuretic peptide level, left atrial size, LV posterior wall thickness, LV end-diastolic diameter and LV mass were significant determinants of FSTL1 serum levels by bivariate analysis. After controlling for significant covariates, FSTL1 levels predicted LV hypertrophy (as measured by LV mass index) by multivariate linear regression analysis (P<0.001). Unadjusted survival analysis demonstrated increased mortality in patients with increasing FSTL1 levels (P=0.09). After adjusting for significant parameters, patients with increased FSTL1 remained at the highest risk of death [hazard ratio (95% confidence limits) 1.028, (0.98 and 1.78)]; (P=0.26). To determine whether elevated FSTL1 may be derived from the myocardium, FSTL1 protein expression was measured in samples from explanted, failing (n=18) and non-failing human hearts (n=7). LV failing hearts showed 2.5-fold higher FSTL1 protein levels than non-failing control hearts (P<0.05). Conclusions Elevated serum FSTL1 in human heart failure patients was associated with LV hypertrophy. Further studies on the role of FSTL1 as a biomarker in chronic systolic heart failure are warranted. PMID:21622850

  19. Adverse Drug Reactions of the Lower Extremities.

    PubMed

    Adigun, Chris G

    2016-07-01

    Adverse drug reactions (ADRs) are a common cause of dermatologic consultation, involving 2 to 3 per 100 medical inpatients in the United States. Female patients are 1.3 to 1.5 times more likely to develop ADRs, except in children less than 3 years of age, among whom boys are more often affected. Certain drugs are more frequent causes, including aminopenicillins, trimethoprim-sulfamethoxazole, and nonsteroidal antiinflammatory drugs. Chemotherapeutic agents commonly cause adverse reactions to the skin and nails, with certain agents causing particular patterns of reactions. ADRs can involve any area of the skin; the appendages, including hair and nails; as well as mucosa. PMID:27215159

  20. Bone Marrow-Derived Multipotent Stromal Cells Promote Myocardial Fibrosis and Reverse Remodeling of the Left Ventricle

    PubMed Central

    Fatkhudinov, Timur; Bolshakova, Galina; Arutyunyan, Irina; Elchaninov, Andrey; Makarov, Andrey; Kananykhina, Evgeniya; Khokhlova, Oksana; Murashev, Arkady; Glinkina, Valeria; Goldshtein, Dmitry; Sukhikh, Gennady

    2015-01-01

    Cell therapy is increasingly recognized as a beneficial practice in various cardiac conditions, but its fundamentals remain largely unclear. The fates of transplanted multipotent stromal cells in postinfarction cardiac microenvironments are particularly understudied. To address this issue, labeled multipotent stromal cells were infused into rat myocardium at day 30 after myocardial infarction, against the background of postinfarction cardiosclerosis. Therapeutic effects of the transplantation were assessed by an exercise tolerance test. Histological examination at 14 or 30 days after the transplantation was conducted by means of immunostaining and quantitative image analysis. An improvement in the functional status of the cardiovascular system was observed after both the autologous and the allogeneic transplantations. Location of the label-positive cells within the heart was restricted to the affected part of myocardium. The transplanted cells could give rise to fibroblasts or myofibroblasts but not to cardiac myocytes or blood vessel cells. Both types of transplantation positively influenced scarring processes, and no expansion of fibrosis to border myocardium was observed. Left ventricular wall thickening associated with reduced dilatation index was promoted by transplantation of the autologous cells. According to the results, multipotent stromal cell transplantation prevents adverse remodeling and stimulates left ventricular reverse remodeling. PMID:25685158

  1. Original Rehabilitation Programme after Anatomical ACL Reconstruction Based on MRI Evaluated Graft Remodelling

    PubMed Central

    Plenzler, Marcin; Straszewski, Dariusz; Ciszkowska-Łysoń, Beata; Śmigielski, Robert; Popieluch, Marcin

    2014-01-01

    Objectives: This study was carried out to design a rehabilitation program allowing for complete functional post-surgical recovery of the limb, that would not affect the remodelling process of the transplanted graft evaluated on MRI imaging. The main reason for changing the rehabilitation protocol was the 14 months of observation of the MRI images (a series of 9 MRIs performed over a two year period) among the patients after ACL reconstruction, in whom the adverse characteristics in remodelling of the graft were observed in line with the implementation of the traditional rehabilitation program. Methods: A 23 years old patient, a professional hi-rank skateboarder, took part in this pilot study. He had a torsion injury of the left knee joint. The main concepts of the rehabilitation program were: functional training in CKC that would involve muscles of the entire kinetic chain of the operated limb; the co-contraction training under the axial load, active extension training, the avoidance of static flexor stretching for at least 24 weeks after the surgery, no passive movements while exercising, the use of posterior translation of the tibia while doing the exercises, and no knee joint extensor strengthening activities in OKC for at least six months after the surgery. In order to evaluate the remodelling of the graft, seven oblique axial MR images (DOA) were taken, on which the graft’s cross-sectional area was measured. The MRI's were performed in the second, sixth, and twelfth week; then in the fourth, sixth, and ninth month, and, finally a year after the surgery. The angle of the graft and PCL was also measured. Additionally, the quality of tendon signal was assessed. For the functional evaluation, isokinetic and isometric tests of the knee extensor and the flexor muscles, along with the tibial rotator functions were performed using Humac Norm device. Postural stability based on COP parameter was established, as well, using the stabilometric platform HUR. For the

  2. Systems Toxicology of Male Reproductive Development: Profiling 774 Chemicals for Molecular Targets and Adverse Outcomes

    PubMed Central

    Leung, Maxwell C.K.; Phuong, Jimmy; Baker, Nancy C.; Sipes, Nisha S.; Klinefelter, Gary R.; Martin, Matthew T.; McLaurin, Keith W.; Setzer, R. Woodrow; Darney, Sally Perreault; Judson, Richard S.; Knudsen, Thomas B.

    2015-01-01

    Background: Trends in male reproductive health have been reported for increased rates of testicular germ cell tumors, low semen quality, cryptorchidism, and hypospadias, which have been associated with prenatal environmental chemical exposure based on human and animal studies. Objective: In the present study we aimed to identify significant correlations between environmental chemicals, molecular targets, and adverse outcomes across a broad chemical landscape with emphasis on developmental toxicity of the male reproductive system. Methods: We used U.S. EPA’s animal study database (ToxRefDB) and a comprehensive literature analysis to identify 774 chemicals that have been evaluated for adverse effects on male reproductive parameters, and then used U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB) to profile their bioactivity across approximately 800 molecular and cellular features. Results: A phenotypic hierarchy of testicular atrophy, sperm effects, tumors, and malformations, a composite resembling the human testicular dysgenesis syndrome (TDS) hypothesis, was observed in 281 chemicals. A subset of 54 chemicals with male developmental consequences had in vitro bioactivity on molecular targets that could be condensed into 156 gene annotations in a bipartite network. Conclusion: Computational modeling of available in vivo and in vitro data for chemicals that produce adverse effects on male reproductive end points revealed a phenotypic hierarchy across animal studies consistent with the human TDS hypothesis. We confirmed the known role of estrogen and androgen signaling pathways in rodent TDS, and importantly, broadened the list of molecular targets to include retinoic acid signaling, vascular remodeling proteins, G-protein coupled receptors (GPCRs), and cytochrome P450s. Citation: Leung MC, Phuong J, Baker NC, Sipes NS, Klinefelter GR, Martin MT, McLaurin KW, Setzer RW, Darney SP, Judson RS, Knudsen TB. 2016. Systems toxicology of male

  3. 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

  4. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer.

    PubMed

    Malik, Ruchi; Lelkes, Peter I; Cukierman, Edna

    2015-04-01

    The extracellular matrix (ECM) provides structural and biochemical signals that regulate cell function. A well-controlled balance between cells and surroundings (i.e., dynamic reciprocity) is crucial for regulating ECM architecture. During cancer progression, epithelial cells undergo genetic alterations which, together with stromal changes including ECM remodeling, disturb the homeostatic dynamics of the epithelium. A parallel organization of stromal ECM fibrils is associated with tumorigenic responses. In an emerging paradigm, continuous and progressive regulation via mechanical forces and aberrant signaling are believed to be responsible for tumor-associated ECM remodeling. In this review we discuss the discrete biomechanical and biochemical mechanisms that underlie these architectural changes and highlight their particular relevance to the regulation of the alignment of ECM in the mesenchymal stroma. PMID:25708906

  5. Compensatory Effect between Aortic Stiffening and Remodelling during Ageing

    PubMed Central

    Guala, Andrea; Camporeale, Carlo; Ridolfi, Luca

    2015-01-01

    The arterial tree exhibits a complex spatio-temporal wave pattern, whose healthy behaviour depends on a subtle balance between mechanical and geometrical properties. Several clinical studies demonstrated that such a balance progressively breaks down during ageing, when the aorta stiffens and remodels by increasing its diameter. These two degenerative processes however, have different impacts on the arterial wave pattern. They both tend to compensate for each other, thus reducing the detrimental effect they would have had if they had arisen individually. This remarkable compensatory mechanism is investigated by a validated multi-scale model, with the aim to elucidate how aortic stiffening and remodelling quantitatively impact the complex interplay between forward and reflected backward waves in the arterial network. We focus on the aorta and on the pressure at the ventricular-aortic interface, which epidemiological studies demonstrate to play a key role in cardiovascular diseases. PMID:26426360

  6. Dynamics of lung defense in pneumonia: resistance, resilience, and remodeling.

    PubMed

    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

  7. 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

  8. 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

  9. BIOMECHANICAL and BIOCHEMICAL REMODELING of STROMAL EXTRACELLULAR MATRIX IN CANCER

    PubMed Central

    Malik, Ruchi; Lelkes, Peter I; Cukierman, Edna

    2015-01-01

    The extracellular matrix (ECM) provides structural and biochemical signals that regulate cell function. A well-controlled balance between cells and surroundings (i.e., Dynamic Reciprocity) is crucial for regulating ECM architecture. During cancer progression, epithelial cells undergo genetic alterations, which together with stromal changes, including ECM remodeling, disturb the homeostatic dynamics of the epithelium. A parallel organization of stromal ECM fibrils is associated with tumorigenic responses. In an emerging paradigm, continuous and progressive regulation via mechanical forces and aberrant signaling are believed to be responsible for tumor-associated ECM remodeling. In this review, we discuss the discrete biomechanical and biochemical mechanisms that underlie these architectural changes and highlight their particular relevance to the regulation of the alignment of ECM in the mesenchymal stroma. PMID:25708906

  10. Physical principles of membrane remodelling during cell mechanoadaptation

    NASA Astrophysics Data System (ADS)

    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

    2015-06-01

    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.

  11. 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

  12. 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

  13. 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

  14. Physical principles of membrane remodelling during cell mechanoadaptation.

    PubMed

    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

  15. Microvascular remodelling in chronic airway inflammation in mice.

    PubMed

    Thurston, G; Maas, K; Labarbara, A; Mclean, J W; McDonald, D M

    2000-10-01

    1. Chronic inflammation is associated with blood vessel remodelling, including vessel proliferation and enlargement, and changes in vessel phenotype. We sought to characterize these changes in chronic airway inflammation and to determine whether corticosteroids that inhibit inflammation, such as dexamethasone, can also reduce microvascular remodelling. 2. Chronic airway inflammation was induced in C3H mice by infection with Mycoplasmapulmonis and the tracheal vessels treatment also decreased the immunoreactivity for P-selectin and the number of adherent leucocytes (595 +/- 203 vs 2,024 +/- 393 cells/ mm2 in treated and non-treated infected mice, respectively). 6. We conclude that microvascular enlargement and changes in vessel phenotype are features of some types of chronic inflammation and, furthermore, that dexamethasone reverses the microvascular enlargement, changes in vessel phenotype and leucocyte influx associated with chronic inflammatory airway disease. PMID:11022979

  16. Remodeling myelination: implications for mechanisms of neural plasticity

    PubMed Central

    Chang, Kae-Jiun; Redmond, Stephanie A; Chan, Jonah R

    2016-01-01

    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. PMID:26814588

  17. 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

  18. Synaptic remodeling of neuronal circuits in early retinal degeneration

    PubMed Central

    Soto, Florentina; Kerschensteiner, Daniel

    2015-01-01

    Photoreceptor degenerations are a major cause of blindness and among the most common forms of neurodegeneration in humans. Studies of mouse models revealed that synaptic dysfunction often precedes photoreceptor degeneration, and that abnormal synaptic input from photoreceptors to bipolar cells causes circuits in the inner retina to become hyperactive. Here, we provide a brief overview of frequently used mouse models of photoreceptor degenerations. We then discuss insights into circuit remodeling triggered by early synaptic dysfunction in the outer and hyperactivity in the inner retina. We discuss these insights in the context of other experimental manipulations of synaptic function and activity. Knowledge of the plasticity and early remodeling of retinal circuits will be critical for the design of successful vision rescue strategies. PMID:26500497

  19. 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.

  20. Intradialytic Hypotension and Cardiac Remodeling: A Vicious Cycle

    PubMed Central

    Huang, Jenq-Wen; Yen, Chung-Jen

    2015-01-01

    Hemodynamic instability during hemodialysis is a common but often underestimated issue in the nephrologist practice. Intradialytic hypotension, namely, a decrease of systolic or mean blood pressure to a certain level, prohibits the safe and smooth achievement of ultrafiltration and solute removal goal in chronic dialysis patients. Studies have elucidated the potential mechanisms involved in the development of Intradialytic hypotension, including excessive ultrafiltration and loss of compensatory mechanisms for blood pressure maintenance. Cardiac remodeling could also be one important piece of the puzzle. In this review, we intend to discuss the role of cardiac remodeling, including left ventricular hypertrophy, in the development of Intradialytic hypotension. In addition, we will also provide evidence that a bidirectional relationship might exist between Intradialytic hypotension and left ventricular hypertrophy in chronic dialysis patients. A more complete understanding of the complex interactions in between could assist the readers in formulating potential solutions for the reduction of both phenomena. PMID:25654122