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Sample records for adverse lv remodeling

  1. Association Between Myocardial Mechanics and Ischemic LV Remodeling.

    PubMed

    D'Elia, Nicholas; D'hooge, Jan; Marwick, Thomas H

    2015-12-01

    The outcomes associated with heart failure after myocardial infarction are still poor. Both global and regional left ventricular (LV) remodeling are associated with the progression of the post-infarct patient to heart failure, but although global remodeling can be accurately measured, regional LV remodeling has been more difficult to investigate. Preliminary evidence suggests that post-MI assessment of LV mechanics using stress and strain may predict global (and possibly regional) LV remodeling. A method of predicting both global and regional LV remodeling might facilitate earlier, targeted, and more extensive clinical intervention in those most likely to benefit from novel interventions such as cell therapy.

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

    PubMed Central

    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

    2015-01-01

    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

  3. Mast Cell Inhibition Attenuates Myocardial Damage, Adverse Remodeling and Dysfunction during Fulminant Myocarditis in Rat

    PubMed Central

    Mina, Yair; Rinkevich-Shop, Shunit; Konen, Eli; Goitein, Orly; Kushnir, Tammar; Epstein, Frederick H.; Feinberg, Micha S.; Leor, Jonathan; Landa-Rouben, Natalie

    2013-01-01

    Background Myocarditis is a life-threatening heart disease characterized by myocardial inflammation, necrosis and chronic fibrosis. While mast cell inhibition has been suggested to prevents fibrosis in rat myocarditis, little is known about its effectiveness in attenuating cardiac remodeling and dysfunction in myocarditis. Thus, we sought to test the hypothesis that mast cell inhibition will attenuate the inflammatory reaction and associated left ventricular (LV) remodeling and dysfunction after fulminant autoimmune myocarditis. Methods and Results To induce experimental autoimmune myocarditis, we immunized 30 rats with porcine cardiac myosin twice at a 7-day interval. On day 8 animals were randomized into treatment either with an intraperitoneal (IP) injection of 25mg/kg of cromolyn sodium (n=13), or an equivalent volume (~0.5ml IP) of normal saline (n=11). All animals were scanned by serial echocardiography studies before treatment (baseline echocardiogram) and after 20 days of cromolyn sodium (28 days after immunization). Furthermore, serial cardiac magnetic resonance was performed in a subgroup of 12 animals. After 20 days of treatment (28 days from first immunization), hearts were harvested for histopathological analysis. By echocardiography, cromolyn sodium prevented LV dilatation and attenuated LV dysfunction, compared with controls. Postmortem analysis of hearts showed that cromolyn sodium reduced myocardial fibrosis, as well as the number and size of cardiac mast cells in the inflamed myocardium, compared with controls. Conclusions Our study suggests that mast cell inhibition with cromolyn sodium attenuates adverse LV remodeling and dysfunction in myocarditis. This mechanism-based therapy is clinically relevant and could improve the outcome of patients at risk for inflammatory cardiomyopathy and heart failure. PMID:23172937

  4. Endothelial progenitor cell transplantation decreases lymphangiogenesis and adverse myocardial remodeling in a mouse model of acute myocardial infarction.

    PubMed

    Park, Jae-Hyeong; Yoon, Jung Yeon; Ko, Seon Mi; Jin, Seon Ah; Kim, Jun Hyung; Cho, Chung-Hyun; Kim, Jin-Man; Lee, Jae-Hwan; Choi, Si Wan; Seong, In-Whan; Jeong, Jin Ok

    2011-08-31

    Cardiac lymphatic system in the remodeling after acute myocardial infarction (AMI) has been overlooked. We wanted to investigate the role of bone marrow-derived endothelial progenitor cells (EPCs) and their contribution to lymphatic distribution in myocardial remodeling after AMI. Mouse (C57bl/6J) MI models were created by ligation of the left anterior descending coronary artery and were treated with phosphate buffered saline (PBS) or EPCs. Real-time RT-PCR with 2- to 4-week myocardial tissue samples revealed that lymphangiogenetic factors such as vascular endothelial growth factor (VEGF)-C (8.5 fold, P < 0.05), VEGF-D (6.1 fold, P < 0.05), Lyve-1 (15 fold, P < 0.05), and Prox-1 (11 fold, P < 0.05) were expressed at significantly higher levels in the PBS group than the EPC group. The PBS group also showed a significantly higher density of lymphatic vessels in the peri-infarction area. Echocardiography showed that from 2 weeks after the treatment, left ventricle (LV) dimensions at both systole and diastole were significantly smaller in the EPC group than in the PBS group (P < 0.01) and LV fractional shortening was higher in the EPC group accordingly (P < 0.01). Lymphangiogenic markers increased in a mouse MI model. EPC transplantation decreased lymphangiogenesis and adverse ventricular remodeling after AMI. These novel findings suggest that new lymphatic vessels may be formed in severely damaged myocardium, and may be involved in adverse myocardial remodeling after AMI.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  7. 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

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

    PubMed

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

    2007-09-01

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

  9. Persistent Microvascular Obstruction After Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse RemodelingCLINICAL PERSPECTIVE

    SciTech Connect

    Kali, Avinash; Cokic, Ivan; Tang, Richard; Dohnalkova, Alice; Kovarik, Libor; Yang, Hsin-Jung; Kumar, Andreas; Prato, Frank S.; Wood, John C.; Underhill, David; Marbán, Eduardo; Dharmakumar, Rohan

    2016-11-01

    Emerging evidence now supports the notion that persistent microvascular obstruction (PMO) may be more predictive of major adverse cardiovascular events than MI size itself. But, how PMO, a phenomenon limited to the acute/sub-acute period of MI, imparts adverse remodeling throughout the post MI period, particularly after its resolution, is incompletely understood. We hypothesized that PMOs resolve into chronic iron crystals within MI territories and actively impart a proinflammatory burden and adverse remodeling of infarction and LV in the chronic phase of MI. Canine models reperfused (n=20) and non-reperfused (n=20) with and without PMO were studied with serial cardiac MRI to characterize the spatiotemporal relationships between PMO, iron deposition, and infarct and LV remodeling indices between acute (day 7, post MI) and chronic (week 8, post MI). Histopathology and immunohistochemistry were used to validate the iron deposition, microscopically map and quantify the relationship between iron-rich chronic MI regions against pro-inflammatory macrophages, proinflammatory cytokines and matrix metalloproteinase. Atomic resolution transmission electron microscopy (TEM) was used to determine the crystallinity of iron and assess the physical effects of iron on lysosomes within macrophages, and energy-dispersive X-ray spectroscopy (EDS) to identify the chemical composition of the iron composite. Results showed that PMOs lead to iron deposition within chronic MI and that the extent of chronic iron deposition is strongly related to PMO Volume (r>0.6, p<0.001). TEM and EDS analysis showed that iron within chronic MI is found within macrophages as aggregates of nanocrystals of ~2.5 nm diameter in ferric state. Correlative histological studies showed that iron content, proinflammatory burden and collagen degrading enzyme were highly correlated (r >0.7, p<0.001). Iron within chronic MI was significantly associated with infarct resorption (r>0.5, p<0.001) and adverse structural (r

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

    PubMed

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

    2015-11-15

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

  11. 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

  12. Targeting TRAF3IP2 by Genetic and Interventional Approaches Inhibits Ischemia/Reperfusion-induced Myocardial Injury and Adverse Remodeling.

    PubMed

    Erikson, John M; Valente, Anthony J; Mummidi, Srinivas; Kandikattu, Hemanth Kumar; DeMarco, Vincent G; Bender, Shawn B; Fay, William P; Siebenlist, Ulrich; Chandrasekar, Bysani

    2017-02-10

    Re-establishing blood supply is the primary goal for reducing myocardial injury in subjects with ischemic heart disease. Paradoxically, reperfusion results in nitroxidative stress and a marked inflammatory response in the heart. TRAF3IP2 (TRAF3 Interacting Protein 2; previously known as CIKS or Act1) is an oxidative stress-responsive cytoplasmic adapter molecule that is an upstream regulator of both IκB kinase (IKK) and c-Jun N-terminal kinase (JNK), and an important mediator of autoimmune and inflammatory responses. Here we investigated the role of TRAF3IP2 in ischemia/reperfusion (I/R)-induced nitroxidative stress, inflammation, myocardial dysfunction, injury, and adverse remodeling. Our data show that I/R up-regulates TRAF3IP2 expression in the heart, and its gene deletion, in a conditional cardiomyocyte-specific manner, significantly attenuates I/R-induced nitroxidative stress, IKK/NF-κB and JNK/AP-1 activation, inflammatory cytokine, chemokine, and adhesion molecule expression, immune cell infiltration, myocardial injury, and contractile dysfunction. Furthermore, Traf3ip2 gene deletion blunts adverse remodeling 12 weeks post-I/R, as evidenced by reduced hypertrophy, fibrosis, and contractile dysfunction. Supporting the genetic approach, an interventional approach using ultrasound-targeted microbubble destruction-mediated delivery of phosphorothioated TRAF3IP2 antisense oligonucleotides into the LV in a clinically relevant time frame significantly inhibits TRAF3IP2 expression and myocardial injury in wild type mice post-I/R. Furthermore, ameliorating myocardial damage by targeting TRAF3IP2 appears to be more effective to inhibiting its downstream signaling intermediates NF-κB and JNK. Therefore, TRAF3IP2 could be a potential therapeutic target in ischemic heart disease.

  13. 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

  14. Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium

    PubMed Central

    Weber, Karl T.; Weglicki, William B.; Simpson, Robert U.

    2009-01-01

    Hypertension and heart failure are worldwide health problems of ever-increasing proportions. A failure of the heart, during either systolic and/or diastolic phases of the cardiac cycle, has its origins rooted in an adverse structural, biochemical, and molecular remodelling of myocardium that involves its cellular constituents, extracellular matrix, and intramural coronary vasculature. Herein we focus on the pathogenic role of a dyshomeostasis of several macro- (i.e. Ca2+ and Mg2+) and micronutrients (i.e. Zn2+, Se2+, and vitamin D) in contributing to adverse remodelling of the myocardium and its failure as a pulsatile muscular pump. An improved understanding of how these macro- and micronutrients account for the causes and consequences of adverse myocardial remodelling carries with it the potential of identifying new biomarkers predictive of risk, onset and progression, and response to intervention(s), which could be monitored non-invasively and serially over time. Moreover, such incremental knowledge will serve as the underpinning to the development of novel strategies aimed at preventing and/or regressing the ongoing adverse remodelling of myocardium. The time is at hand to recognize the importance of macro- and micronutrient dyshomeostasis in the evaluation and management of hypertension and heart failure. PMID:18835843

  15. 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

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

    PubMed

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

    2015-03-01

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

  17. Intra-Myocardial Injection of Both Growth Factors and Heart Derived Sca-1+/CD31− Cells Attenuates Post-MI LV Remodeling More Than Does Cell Transplantation Alone: Neither Intervention Enhances Functionally Significant Cardiomyocyte Regeneration

    PubMed Central

    Wang, Xiaohong; Li, Qinglu; Hu, Qingsong; Suntharalingam, Piradeep; From, Arthur H. L.; Zhang, Jianyi

    2014-01-01

    Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are two potent cell survival and regenerative factors in response to myocardial injury (MI). We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1+/CD31− cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1+/CD31− cells were injected into the peri-infarction area after left anterior descending coronary artery (LAD) ligation in mice. Recombinant mouse IGF-1+HGF was added to the cell suspension prior to the injection. The left ventricular (LV) function was assessed by echocardiography 4 weeks after the transplantation. The cell engraftment, differentiation and cardiomyocyte regeneration were evaluated by histological analysis. Sca-1+/CD31− cells formed viable grafts and improved LV ejection fraction (EF) (Control, 54.5+/−2.4; MI, 17.6+/−3.1; Cell, 28.2+/−4.2, n = 9, P<0.01). IGF+HGF significantly enhanced the benefits of cell transplantation as evidenced by increased EF (38.8+/−2.2; n = 9, P<0.01) and attenuated adverse structural remodeling. Furthermore, IGF+HGF supplementation increased the cell engraftment rate, promoted the transplanted cell survival, enhanced angiogenesis, and minimally stimulated endogenous cardiomyocyte regeneration in vivo. The in vitro experiments showed that IGF+HGF treatment stimulated Sca-1+/CD31− cell proliferation and inhibited serum free medium induced apoptosis. Supperarray profiling of Sca-1+/CD31− cells revealed that Sca-1+/CD31− cells highly expressed various trophic factor mRNAs and IGF+HGF treatment altered the mRNAs expression patterns of these cells. These data indicate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial repair by stimulating donor cell and endogenous cardiac stem cell survival, regeneration and promoting angiogenesis. PMID:24919180

  18. UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine.

    PubMed

    Uitterdijk, André; Hermans, Kevin C M; de Wijs-Meijler, Daphne P M; Daskalopoulos, Evangelos P; Reiss, Irwin K; Duncker, Dirk J; Matthijs Blankesteijn, W; Merkus, Daphne

    2016-02-01

    Modulation of Wnt/Frizzled signaling with UM206 reduced infarct expansion and prevented heart failure development in mice, an effect that was accompanied by increased myofibroblast presence in the infarct, suggesting that Wnt/Frizzled signaling has a key role in cardiac remodeling following myocardial infarction (MI). This study investigated the effects of modulation of Wnt/Frizzled signaling with UM206 in a swine model of reperfused MI. For this purpose, seven swine with MI were treated with continuous infusion of UM206 for 5 weeks. Six control swine were treated with vehicle. Another eight swine were sham-operated. Cardiac function was determined by echo in awake swine. Infarct mass was estimated at baseline by heart-specific fatty acid-binding protein ELISA and at follow-up using planimetry. Components of Wnt/Frizzled signaling, myofibroblast presence, and extracellular matrix were measured at follow-up with qPCR and/or histology. Results show that UM206 treatment resulted in a significant decrease in infarct mass compared with baseline (-41±10%), whereas infarct mass remained stable in the Control-MI group (+3±17%). Progressive dilation of the left ventricle occurred in the Control-MI group between 3 and 5 weeks after MI, while adverse remodeling was halted in the UM206-treated group. mRNA expression for Frizzled-4 and the Frizzled co-receptor LRP5 was increased in UM206-treated swine as compared with Control-MI swine. Myofibroblast presence was significantly lower in infarcted tissue of the UM206-treated animals (1.53±0.43% vs 3.38±0.61%) at 5 weeks follow-up. This study demonstrates that UM206 treatment attenuates adverse remodeling in a swine model of reperfused MI, indicating that Wnt/Frizzled signaling is a promising target to improve infarct healing and limit post-MI remodeling.

  19. 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.

  20. Interleukin-1 Blockade With Anakinra to Prevent Adverse Cardiac Remodeling After Acute Myocardial Infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot Study)

    PubMed Central

    Abbate, Antonio; Kontos, Michael C.; Grizzard, John D.; Biondi-Zoccai, Giuseppe G. L.; Van Tassell, Benjamin W.; Robati, Roshanak; Roach, Lenore M.; Arena, Ross A.; Roberts, Charlotte S.; Varma, Amit; Gelwix, Christopher C.; Salloum, Fadi N.; Hastillo, Andrea; Dinarello, Charles A.; Vetrovec, George W.

    2013-01-01

    Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m2 median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a –3.2 ml/m2 median decrease (interquartile range –4.5, –1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m2. On echocardiography, the median difference in the LVESVi change was 13.4 ml/m2 (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m2, p = 0.033) and echocardiography (9.4 ml/m2, p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R =+0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI. PMID:23453459

  1. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study).

    PubMed

    Abbate, Antonio; Kontos, Michael C; Grizzard, John D; Biondi-Zoccai, Giuseppe G L; Van Tassell, Benjamin W; Robati, Roshanak; Roach, Lenore M; Arena, Ross A; Roberts, Charlotte S; Varma, Amit; Gelwix, Christopher C; Salloum, Fadi N; Hastillo, Andrea; Dinarello, Charles A; Vetrovec, George W

    2010-05-15

    Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m(2) median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a -3.2 ml/m(2) median decrease (interquartile range -4.5, -1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m(2). On echocardiography, the median difference in the LVESVi change was 13.4 ml/m(2) (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m(2), p = 0.033) and echocardiography (9.4 ml/m(2), p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R = +0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI.

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

    PubMed

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

    2015-02-01

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

  3. 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

  4. Relationship Between Left Ventricular Structural and Metabolic Remodeling in Type 2 Diabetes.

    PubMed

    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) remodeling is associated with adverse cardiovascular events and is frequently observed in patients with type 2 diabetes mellitus (T2DM). Despite this, the cause of concentric remodeling in diabetes per se is unclear, but it may be related to cardiac steatosis and impaired myocardial energetics. Thus, we investigated the relationship between myocardial metabolic changes and LV remodeling in T2DM. Forty-six nonhypertensive patients with T2DM and 20 matched control subjects underwent cardiovascular magnetic resonance to assess LV remodeling (LV mass-to-LV end diastolic volume ratio), function, tissue characterization before and after contrast using T1 mapping, and (1)H and (31)P magnetic resonance spectroscopy for myocardial triglyceride content (MTG) and phosphocreatine-to-ATP ratio, respectively. When compared with BMI- and blood pressure-matched control subjects, subjects with diabetes were associated with concentric LV remodeling, higher MTG, impaired myocardial energetics, and impaired systolic strain indicating a subtle contractile dysfunction. Importantly, cardiac steatosis independently predicted concentric remodeling and systolic strain. Extracellular volume fraction was unchanged, indicating the absence of fibrosis. In conclusion, cardiac steatosis may contribute to concentric remodeling and contractile dysfunction of the LV in diabetes. Because cardiac steatosis is modifiable, strategies aimed at reducing MTG may be beneficial in reversing concentric remodeling and improving contractile function in the hearts of patients with diabetes.

  5. Overexpression of TIMP-1 in embryonic stem cells attenuates adverse cardiac remodeling following myocardial infarction.

    PubMed

    Glass, Carley; Singla, Dinender K

    2012-01-01

    Transplanted embryonic stem (ES) cells, following myocardial infarction (MI), contribute to limited cardiac repair and regeneration with improved function. Therefore, novel strategies are still needed to understand the effects of genetically modified transplanted stem cells on cardiac remodeling. The present study evaluates whether transplanted mouse ES cells overexpressing TIMP-1, an antiapoptotic and antifibrotic protein, can enhance cardiac myocyte differentiation, inhibit native cardiac myocyte apoptosis, reduce fibrosis, and improve cardiac function in the infarcted myocardium. MI was produced in C57BL/6 mice by coronary artery ligation. TIMP-1-ES cells, ES cells, or culture medium (control) were transplanted into the peri-infarct region of the heart. Immunofluorescence, TUNEL staining, caspase-3 activity, ELISAs, histology, and echocardiography were used to identify newly differentiated cardiac myocytes and assess apoptosis, fibrosis, and heart function. Two weeks post-MI, significantly (p < 0.05) enhanced engraftment and cardiac myocyte differentiation was observed in TIMP-1-ES cell-transplanted hearts compared with hearts transplanted with ES cells and control. Hearts transplanted with TIMP-1-ES cells demonstrated a reduction in apoptosis as well as an increase (p< 0.05) in p-Akt activity compared with ES cells or culture media controls. Infarct size and interstitial and vascular fibrosis were significantly (p< 0.05) decreased in the TIMP-1-ES cell group compared to controls. Furthermore, MMP-9, a key profibrotic protein, was significantly (p < 0.01) reduced following TIMP-1-ES cell transplantation. Echocardiography data showed fractional shortening and ejection fraction were significantly (p< 0.05) improved in the TIMP-1-ES cell group compared with respective controls. Our data suggest that transplanted ES cells overexpressing TIMP-1 attenuate adverse myocardial remodeling and improve cardiac function compared with ES cells that may have therapeutic

  6. Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: role of autophagy.

    PubMed

    Zhang, Yao-Jun; Yang, Shao-Hua; Li, Ming-Hui; Iqbal, Javaid; Bourantas, Christos V; Mi, Qiong-Yu; Yu, Yi-Hui; Li, Jing-Jing; Zhao, Shu-Li; Tian, Nai-Liang; Chen, Shao-Liang

    2014-12-01

    The present study aimed to test the hypothesis that berberine, a plant-derived anti-oxidant, attenuates adverse left ventricular remodelling and improves cardiac function in a rat model of myocardial infarction (MI). Furthermore, the potential mechanisms that mediated the cardioprotective actions of berberine, in particular the effect on autophagy, were also investigated. Acute MI was induced by ligating the left anterior descending coronary artery of Sprague-Dawley rats. Cardiac function was assessed by transthoracic echocardiography. The protein activity/levels of autophagy related to signalling pathways (e.g. LC-3B, Beclin-1) were measured in myocardial tissue by immunohistochemical staining and western blot. Four weeks after MI, berberine significantly prevented cardiac dysfunction and adverse cardiac remodelling. MI rats treated with low dose berberine (10 mg/kg per day) showed higher left ventricular ejection fraction and fractional shortening than those treated with high-dose berberine (50 mg/kg per day). Both doses reduced interstitial fibrosis and post-MI adverse cardiac remodelling. The cardioprotective action of berberine was associated with increased LC-3B II and Beclin-1 expressions. Furthermore, cardioprotection with berberine was potentially related to p38 MAPK inhibition and phospho-Akt activation. The present in vivo study showed that berberine is effective in promoting autophagy, and subsequently attenuating left ventricular remodelling and cardiac dysfunction after MI. The potential underlying mechanism is augmentation of autophagy through inhibition of p38 MAPK and activation of phospho-Akt signalling pathways.

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

    PubMed Central

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

    2012-01-01

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

  8. Prediction of Left Ventricular Remodeling after a Myocardial Infarction: Role of Myocardial Deformation: A Systematic Review and Meta-Analysis

    PubMed Central

    Huttin, Olivier; Coiro, Stefano; Selton-Suty, Christine; Juillière, Yves; Donal, Erwan; Magne, Julien; Sadoul, Nicolas; Zannad, Faiez; Rossignol, Patrick; Girerd, Nicolas

    2016-01-01

    Aims Left ventricular (LV) adverse or reverse remodeling after ST-segment elevation myocardial infarction (MI) is the best outcome to assess the benefit of revascularization. Speckle tracking echocardiography (STE) may accurately identify early deformation impairment, while also being predictive of LV remodeling during follow-up. This systematic analysis aimed to provide a comprehensive review of current findings on STE as a predictor of LV remodeling after MI. Methods PubMed databases were searched through December 2014 to identify studies in adults targeting the association between LV remodeling and STE. Meta-regression was performed for longitudinal analysis. Results A total of 23 prospective studies (3066 patients) were found eligible. Eleven studies reported an association between STE and adverse remodeling and twelve studies with reverse remodeling. Using peak systolic longitudinal strain, the most accurate cut-off to predict adverse remodeling and reverse remodeling ranged from -12.8% to -10.2% and from -13.7% to -9.5%, respectively. In smaller studies, assessment of circumferential strain and torsion showed additive value in predicting remodeling. Meta-regression analysis revealed that longitudinal STE was associated with adverse remodeling (pooled univariable OR = 1.27, 1.17–1.38, p<0.001; pooled multivariable OR = 1.38, 1.13–1.70, p = 0.002) while pooled ORs of longitudinal STE only tended to predict reverse remodeling (pooled OR = 0.75, 0.54–1.06, p = 0.09). Conclusions This systematic review suggests that STE is associated with changes in LV volume or function regardless of underlying mechanisms and deformation direction. Meta-regression demonstrates a strong association between peak longitudinal systolic strain and adverse remodeling. Added STE predictive value over other clinical, biological and imaging variables remains to be proven. PMID:28036335

  9. 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

  10. The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling.

    PubMed

    Janicki, Joseph S; Brower, Gregory L; Gardner, Jason D; Chancey, Amanda L; Stewart, James A

    2004-01-01

    The process of cardiac remodeling in response to cardiac injury and/or persistent elevations in wall stress generally relates to the progressive changes that occur in ventricular chamber dimensions and the various components of the myocardium, in particular the cardiomyocytes and the extracellular matrix. Volume overload, pressure overload or myocardial injury produces a sustained abnormal elevation in myocardial wall stress which initiates cardiac remodeling that frequently results in ventricular decompensation and heart failure. Regardless of the inciting cause, there appear to be three distinct phases to this process. In the initial phase, fibrillar collagen is partially degraded secondary to increased matrix metalloproteinase (MMP) activity. Following this, there is a chronic compensatory phase during which MMP activity and collagen concentration return to normal while cardiomyocyte size continues to progressively increase. The final phase is attained once the compensatory hypertrophic mechanisms are exhausted and is characterized by elevated MMP activity, marked ventricular dilatation and prominent fibrosis. Details of this progressive, dynamic remodeling process and its effect on ventricular function during chronic volume overload, chronic pressure overload and following myocardial infarction will be the focus of this article.

  11. Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1

    PubMed Central

    Bai, Bo; Man, Andy W.C.; Yang, Kangmin; Guo, Yumeng; Xu, Cheng; Tse, Hung-Fat; Han, Weiping; Bloksgaard, Maria; De Mey, Jo G.R.; Vanhoutte, Paul M.; Xu, Aimin; Wang, Yu

    2016-01-01

    Aims-SIRT1 exerts potent activity against cellular senescence and vascular ageing. By decreasing LKB1 protein levels, it promotes the survival and regeneration of endothelial cells. The present study aims to investigate the molecular mechanisms underlying SIRT1-mediated LKB1 degradation for the prevention of vascular ageing. Methods and Results-Co-immunoprecipitation assay demonstrated that SIRT1, via its amino-terminus, binds to the DOC domain of HERC2 [HECT and RLD domain containing E3 ubiquitin protein ligase 2], which then ubiquitinates LKB1 in the nuclear compartment of endothelial cells. Site-directed mutagenesis revealed that acetylation at lysine (K) 64 of LKB1 triggers the formation of SIRT1/HERC2/LKB1 protein complex and subsequent proteasomal degradation. In vitro cellular studies suggested that accumulation of acetylated LKB1 in the nucleus leads to endothelial activation, in turn stimulating the proliferation of vascular smooth muscle cells and the production of extracellular matrix proteins. Chromatin immunoprecipitation quantitative PCR confirmed that acetylated LKB1 interacts with and activates TGFβ1 promoter, which is inhibited by SIRT1. Knocking down either SIRT1 or HERC2 results in an increased association of LKB1 with the positive regulatory elements of TGFβ1 promoter. In mice without endothelial nitric oxide synthase, selective overexpression of human SIRT1 in endothelium prevents hypertension and age-related adverse arterial remodeling. Lentiviral-mediated knockdown of HERC2 abolishes the beneficial effects of endothelial SIRT1 on both arterial remodeling and arterial blood pressure control. Conclusion-By downregulating acetylated LKB1 protein via HERC2, SIRT1 fine-tunes the crosstalk between endothelial and vascular smooth muscle cells to prevent adverse arterial remodeling and maintain vascular homeostasis. PMID:27259994

  12. Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1.

    PubMed

    Bai, Bo; Man, Andy W C; Yang, Kangmin; Guo, Yumeng; Xu, Cheng; Tse, Hung-Fat; Han, Weiping; Bloksgaard, Maria; De Mey, Jo G R; Vanhoutte, Paul M; Xu, Aimin; Wang, Yu

    2016-06-28

    Aims-SIRT1 exerts potent activity against cellular senescence and vascular ageing. By decreasing LKB1 protein levels, it promotes the survival and regeneration of endothelial cells. The present study aims to investigate the molecular mechanisms underlying SIRT1-mediated LKB1 degradation for the prevention of vascular ageing.Methods and Results-Co-immunoprecipitation assay demonstrated that SIRT1, via its amino-terminus, binds to the DOC domain of HERC2 [HECT and RLD domain containing E3 ubiquitin protein ligase 2], which then ubiquitinates LKB1 in the nuclear compartment of endothelial cells. Site-directed mutagenesis revealed that acetylation at lysine (K) 64 of LKB1 triggers the formation of SIRT1/HERC2/LKB1 protein complex and subsequent proteasomal degradation. In vitro cellular studies suggested that accumulation of acetylated LKB1 in the nucleus leads to endothelial activation, in turn stimulating the proliferation of vascular smooth muscle cells and the production of extracellular matrix proteins. Chromatin immunoprecipitation quantitative PCR confirmed that acetylated LKB1 interacts with and activates TGFβ1 promoter, which is inhibited by SIRT1. Knocking down either SIRT1 or HERC2 results in an increased association of LKB1 with the positive regulatory elements of TGFβ1 promoter. In mice without endothelial nitric oxide synthase, selective overexpression of human SIRT1 in endothelium prevents hypertension and age-related adverse arterial remodeling. Lentiviral-mediated knockdown of HERC2 abolishes the beneficial effects of endothelial SIRT1 on both arterial remodeling and arterial blood pressure control.Conclusion-By downregulating acetylated LKB1 protein via HERC2, SIRT1 fine-tunes the crosstalk between endothelial and vascular smooth muscle cells to prevent adverse arterial remodeling and maintain vascular homeostasis.

  13. Targeted inhibition of Focal Adhesion Kinase Attenuates Cardiac Fibrosis and Preserves Heart Function in Adverse Cardiac Remodeling

    PubMed Central

    Zhang, Jie; Fan, Guangpu; Zhao, Hui; Wang, Zhiwei; Li, Fei; Zhang, Peide; Zhang, Jing; Wang, Xu; Wang, Wei

    2017-01-01

    Cardiac fibrosis in post-myocardial infarction (MI), seen in both infarcted and non-infarcted myocardium, is beneficial to the recovery of heart function. But progressively pathological fibrosis impairs ventricular function and leads to poor prognosis. FAK has recently received attention as a potential mediator of fibrosis, our previous study reported that pharmacological inhibition of FAK can attenuate cardiac fibrosis in post MI models. However, the long-term effects on cardiac function and adverse cardiac remodelling were not clearly investigated. In this study, we tried to determine the preliminary mechanisms in regulating CF transformation to myofibroblasts and ECM synthesis relevant to the development of adverse cardiac remolding in vivo and in vitro. Our study provides even more evidence that FAK is directly related to the activation of CF in hypoxia condition in a dose-dependent and time-dependent manner. Pharmacological inhibition of FAK significantly reduces myofibroblast differentiation; our in vivo data demonstrated that a FAK inhibitor significantly decreases fibrotic score, and preserves partial left ventricular function. Both PI3K/AKT signalling and ERK1/2 are necessary for hypoxia-induced CF differentiation and ECM synthesis; this process also involves lysyl oxidase (LOX). These findings suggest that pharmacological inhibition of FAK may become an effective therapeutic strategy against adverse fibrosis. PMID:28225063

  14. 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

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

    PubMed Central

    Louey, Samantha; Espinoza, Herbert; Chattergoon, Natasha; You, Fanglei; Thornburg, Kent L.; Giraud, George

    2015-01-01

    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

  16. Onset of hypertension during pregnancy is associated with long-term worse blood pressure control and adverse cardiac remodeling.

    PubMed

    Mesquita, Roberto F; Reis, Muriel; Beppler, Ana Paula; Bellinazzi, Vera Regina; Mattos, Sandra S; Lima-Filho, José L; Cipolli, José A; Coelho-Filho, Otavio R; Pio-Magalhães, José A; Sposito, Andrei C; Matos-Souza, José R; Nadruz, Wilson

    2014-11-01

    Up to 20% of women with hypertensive pregnancy disorders might persist with chronic hypertension. This study compared clinical and echocardiographic features between women whose hypertension began as hypertensive pregnancy disorders (PH group) and women whose diagnosis of hypertension did not occur during pregnancy (NPH group). Fifty PH and 100 NPH women were cross-sectionally evaluated by clinical, laboratory, and echocardiography analysis, and the groups were matched by duration of hypertension. PH exhibited lower age (46.6 ± 1.4 vs. 65.3 ± 1.1 years; P < .001), but higher systolic (159.8 ± 3.9 vs. 148.0 ± 2.5 mm Hg; P = .009) and diastolic (97.1 ± 2.4 vs. 80.9 ± 1.3 mm Hg; P < .001) blood pressure than NPH, although used more antihypertensive classes (3.4 ± 0.2 vs. 2.6 ± 0.1; P < .001). Furthermore, PH showed higher left ventricular wall thickness and increased prevalence of concentric hypertrophy than NPH after adjusting for age and blood pressure. In conclusion, this study showed that PH may exhibit worse blood pressure control and adverse left ventricular remodeling compared with NPH.

  17. Involvement of Inflammation and Adverse Vascular Remodelling in the Blood Pressure Raising Effect of Repeatedly Heated Palm Oil in Rats

    PubMed Central

    Ng, Chun-Yi; Kamisah, Yusof; Faizah, Othman; Jubri, Zakiah; Qodriyah, Hj Mohd Saad; Jaarin, Kamsiah

    2012-01-01

    Oil thermoxidation during deep frying generates harmful oxidative free radicals that induce inflammation and increase the risk of hypertension. This study aimed to investigate the effect of repeatedly heated palm oil on blood pressure, aortic morphometry, and vascular cell adhesion molecule-1 (VCAM-1) expression in rats. Male Sprague-Dawley rats were divided into five groups: control, fresh palm oil (FPO), one-time-heated palm oil (1HPO), five-time-heated palm oil (5HPO), or ten-time-heated palm oil (10HPO). Feeding duration was six months. Blood pressure was measured at baseline and monthly using tail-cuff method. After six months, the rats were sacrificed and the aortic arches were dissected for morphometric and immunohistochemical analyses. FPO group showed significantly lower blood pressure than all other groups. Blood pressure was increased significantly in 5HPO and 10HPO groups. The aortae of 5HPO and 10HPO groups showed significantly increased thickness and area of intima-media, circumferential wall tension, and VCAM-1 than other groups. Elastic lamellae were disorganised and fragmented in 5HPO- and 10HPO-treated rats. VCAM-1 expression showed a significant positive correlation with blood pressure. In conclusion, prolonged consumption of repeatedly heated palm oil causes blood pressure elevation, adverse remodelling, and increased VCAM-1, which suggests a possible involvement of inflammation. PMID:22778962

  18. Angiotensin converting enzyme 2 gene expression increased compensatory for left ventricular remodeling in patients with end-stage heart failure.

    PubMed

    Ohtsuki, Masatsugu; Morimoto, Shin-ichiro; Izawa, Hideo; Ismail, Tevfik F; Ishibashi-Ueda, Hatsue; Kato, Yasuchika; Horii, Taiko; Isomura, Tadashi; Suma, Hisayoshi; Nomura, Masanori; Hishida, Hitoshi; Kurahashi, Hiroki; Ozaki, Yukio

    2010-11-19

    It has been reported that angiotensin converting enzyme (ACE) 2, a homologue of ACE, has direct effects on cardiac function. However, the role of ACE2 in the development of human heart failure is not fully understood. We evaluated the expression of the ACE2 gene by means of real-time RT-PCR in myocardium from 14 patients with end-stage heart failure. The amount of ACE2 mRNA positively correlated with left ventricular (LV) end-diastolic diameter (r(2)=0.56, p<0.01) but did not significantly correlate with LV ejection fraction or plasma brain natriuretic peptide levels. In conclusion, our data show that the up-regulation of the ACE2 gene in the LV myocardium of patients with severe heart failure was associated with the degree of LV dilatation and may thereby constitute an important adaptive mechanism to retard the progression of adverse LV remodeling.

  19. 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

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

    PubMed

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

    2015-12-01

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

  1. Cardioprotective effects of lysyl oxidase inhibition against volume overload-induced extracellular matrix remodeling.

    PubMed

    El Hajj, Elia C; El Hajj, Milad C; Ninh, Van K; Gardner, Jason D

    2016-03-01

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

  2. 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

  3. Left Ventricular Remodeling and Function in Children with Biventricular Circulation After Fetal Aortic Valvuloplasty.

    PubMed

    Friedman, Kevin G; Freud, Lindsay; Escobar-Diaz, Maria; Banka, Puja; Emani, Sitaram; Tworetzky, Wayne

    2015-10-01

    Fetal aortic valvuloplasty (FAV) has shown promise in averting the progression of fetal aortic stenosis to hypoplastic left-heart syndrome. Altered loading conditions due to valvar disease, intrinsic endomyocardial abnormalities, and procedures that alter endomyocardial mechanics may place patients with biventricular circulation (BiV) after FAV at risk of abnormal LV remodeling and function. Using the most recent echo data on BiV patients after technically successful FAV (n = 34), we evaluated LV remodeling pattern, risk factors for pathologic LV remodeling, and the association between LV remodeling pattern and LV function. Median age at follow-up was 4.7 years (range 1.0-12.5). Cardiac interventions were common. At latest follow-up, no patient had hypoplastic LV. Nineteen patients (55 %) had dilated LV, and five (16 %) patients had severely dilated LV. LV remodeling patterns were as follows: 12 (35 %) normal ventricle, 11 (32 %) mixed hypertrophy, 8 (24 %) eccentric hypertrophy or remodeling, and 3 (9 %) concentric hypertrophy. Univariate factors associated with pathologic LV remodeling were long-standing AR, ≥2 cardiac interventions, EFE resection, and aortic or mitral regurgitation ≥ moderate at most recent follow-up. In multivariate analysis, only long-standing AR fraction remained associated with pathologic remodeling. Pathologic LV remodeling was associated with depressed ejection fraction, lower septal E´, and higher E/E´. Pathologic LV remodeling, primarily eccentric or mixed hypertrophy, is common in BiV patients after FAV and is related to LV loading conditions imposed by valvar disease. Pathologic remodeling is associated with both systolic and diastolic dysfunction in this population.

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

    PubMed

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

    2011-09-01

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

  5. Impact of family hypertension history on exercise-induced cardiac remodeling.

    PubMed

    Baggish, Aaron L; Weiner, Rory B; Yared, Kibar; Wang, Francis; Kupperman, Eli; Hutter, Adolph M; Picard, Michael H; Wood, Malissa J

    2009-07-01

    Left ventricular (LV) hypertrophy is a well-established, but highly variable, finding among exercise-trained persons. The causes for the variability in LV remodeling in response to exercise training remain incompletely understood. The present study sought to determine whether a family history of hypertension is a determinant of the cardiac response to exercise training. The cardiac parameters in 60 collegiate rowers (30 men/30 women; age 19.8 +/- 1.1 years) with (family history positive [FH+], n = 22) and without (family history negative [FH-], n = 38) a FH of hypertension were studied with echocardiography before and after 90 days of rowing training. The LV mass increased significantly in both groups. However, the LV mass increased significantly more in FH- persons (Delta 17 +/- 5 g/m(2)) than in FH+ persons (Delta 9 +/- 6 g/m(2), p <0.001) with distinctly differently patterns of LV hypertrophy between the 2 groups. FH- athletes experienced eccentric LV hypertrophy (relative wall thickness index 0.39 +/- 0.4) characterized by LV dilation. In contrast, FH+ athletes developed concentric LV hypertrophy (relative wall thickness index 0.44 +/- 0.3; p <0.001) characterized by LV wall thickening. Furthermore, the eccentric LV remodeling in FH- athletes was associated with a more robust enhancement of LV diastolic function than the concentric LV remodeling that occurred in FH+ athletes. In conclusion, these findings suggest that patterns of exercise-induced LV remodeling are strongly associated with FH history status.

  6. Effects of Obstructive Sleep Apnea and Obesity on Cardiac Remodeling: The Wisconsin Sleep Cohort Study

    PubMed Central

    Korcarz, Claudia E.; Peppard, Paul E.; Young, Terry B.; Chapman, Carrie B.; Hla, K. Mae; Barnet, Jodi H.; Hagen, Erika; Stein, James H.

    2016-01-01

    Study Objectives: To characterize the prospective associations of obstructive sleep apnea (OSA) with future echocardiographic measures of adverse cardiac remodeling Methods: This was a prospective long-term observational study. Participants had overnight polysomnography followed by transthoracic echocardiography a mean (standard deviation) of 18.0 (3.7) y later. OSA was characterized by the apnea-hypopnea index (AHI, events/hour). Echocardiography was used to assess left ventricular (LV) systolic and diastolic function and mass, left atrial volume and pressure, cardiac output, systemic vascular resistance, and right ventricular (RV) systolic function, size, and hemodynamics. Multivariate regression models estimated associations between log10(AHI+1) and future echocardiographic findings. A secondary analysis looked at oxygen desaturation indices and future echocardiographic findings. Results: At entry, the 601 participants were mean (standard deviation) 47 (8) y old (47% female). After adjustment for age, sex, and body mass index, baseline log10(AHI+1) was associated significantly with future reduced LV ejection fraction and tricuspid annular plane systolic excursion (TAPSE) ≤ 15 mm. After further adjustment for cardiovascular risk factors, participants with higher baseline log10(AHI+1) had lower future LV ejection fraction (β = −1.35 [standard error = 0.6]/log10(AHI+1), P = 0.03) and higher odds of TAPSE ≤ 15 mm (odds ratio = 6.3/log10(AHI+1), 95% confidence interval = 1.3–30.5, P = 0.02). SaO2 desaturation indices were associated independently with LV mass, LV wall thickness, and RV area (all P < 0.03) Conclusions: OSA is associated independently with decreasing LV systolic function and with reduced RV function. Echocardiographic measures of adverse cardiac remodeling are strongly associated with OSA but are confounded by obesity. Hypoxia may be a stimulus for hypertrophy in individuals with OSA. Citation: Korcarz CE, Peppard PE, Young TB, Chapman CB, Hla

  7. Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure

    PubMed Central

    Hutchinson, Kirk R.; Guggilam, Anuradha; Cismowski, Mary J.; Galantowicz, Maarten L.; West, Thomas A.; Stewart, James A.; Zhang, Xiaojin; Lord, Kevin C.

    2011-01-01

    Current surgical management of volume overload-induced heart failure (HF) leads to variable recovery of left ventricular (LV) function despite a return of LV geometry. The mechanisms that prevent restoration of function are unknown but may be related to the timing of intervention and the degree of LV contractile impairment. This study determined whether reduction of aortocaval fistula (ACF)-induced LV volume overload during the compensatory stage of HF results in beneficial LV structural remodeling and restoration of pump function. Rats were subjected to ACF for 4 wk; a subset then received a load-reversal procedure by closing the shunt using a custom-made stent graft approach. Echocardiography or in vivo pressure-volume analysis was used to assess LV morphology and function in sham rats; rats subjected to 4-, 8-, or 15-wk ACF; and rats subjected to 4-wk ACF followed by 4- or 11-wk reversal. Structural and functional changes were correlated to LV collagen content, extracellular matrix (ECM) proteins, and hypertrophic markers. ACF-induced volume overload led to progressive LV chamber dilation and contractile dysfunction. Rats subjected to short-term reversal (4-wk ACF + 4-wk reversal) exhibited improved chamber dimensions (LV diastolic dimension) and LV compliance that were associated with ECM remodeling and normalization of atrial and brain natriuretic peptides. Load-independent parameters indicated LV systolic (preload recruitable stroke work, Ees) and diastolic dysfunction (tau, arterial elastance). These changes were associated with an altered α/β-myosin heavy chain ratio. However, these changes were normalized to sham levels in long-term reversal rats (4-wk ACF + 11-wk reversal). Acute hemodynamic changes following ACF reversal improve LV geometry, but LV dysfunction persists. Gradual restoration of function was related to normalization of eccentric hypertrophy, LV wall stress, and ECM remodeling. These results suggest that mild to moderate LV systolic

  8. 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.

  9. 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.

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

    PubMed

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

    2014-06-01

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

  11. 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

    2014-05-07

    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.

  12. 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.

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

    PubMed

    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.

  14. Early intervention with a potent endothelin-A/endothelin-B receptor antagonist aggravates left ventricular remodeling after myocardial infarction in rats.

    PubMed

    Oie, Erik; Yndestad, Arne; Robins, Simon P; Børnerheim, Reidar; Asberg, Anders; Attramadal, Håvard

    2002-05-01

    Intervention with selective endothelin (ET)A receptor antagonists within 24h after myocardial infarction (MI) in rats has been reported to aggravate left ventricular (LV) remodeling. In contrast, beneficial effects are reported when initiation of treatment is delayed 7 days or more after MI. However, bosentan, a mixed ET(A)/ET(B) receptor antagonist with low affinity for the ET receptors, has been shown to exert beneficial effects independent of the time point of initiation of treatment after MI. The aim of the present study was to investigate to what extent early intervention with a mixed ET(A)/ET(B) receptor antagonist with higher affinity at the ET receptors (SB 209670) would also exert beneficial effects on postinfarction LV remodeling. After ligation of the left coronary artery, rats were randomized to treatment with SB 209670 (6.25 mg x kg(-1) SC b.i.d., n = 10) or vehicle (n = 12) for 26 days, starting 48h after MI. Treatment with SB 209670 adversely affected the postinfarction remodeling process causing further dilatation of the LV (LV end-diastolic diameter: 10.4+/-0.5 vs 9.1+/-0.2 mm; LV end-systolic diameter: 8.5+/-0.4 vs 7.2+/-0.2 mm, P < 0.05). However, SB 209670 did not significantly affect infarct size, compensatory cardiac hypertrophy, nor the myocardial mRNA levels of procollagen type I and III, and prolyl 4-hydroxylase and lysyl oxidase, 2 important enzymes affecting collagen secretion, stability and functionality. In addition, SB 209670 had no significant effects on LV collagen cross-linking or extent of fibrosis. Thus, our data demonstrate that early intervention with a potent, mixed ET(A)/ET(B) receptor antagonist after MI may promote dilatation of the LV without significant alterations of infarct size and extracellular matrix composition. Our data support the notion that the timing of initiation of ET receptor antagonism after MI is critical and that potent ET receptor antagonists may be harmful during the first few days after MI.

  15. Rheumatoid Arthritis is Associated with Left Ventricular Concentric Remodeling: Results of a Population-based Cross-sectional Study

    PubMed Central

    Myasoedova, Elena; Davis, John M.; Crowson, Cynthia S.; Roger, Véronique L.; Karon, Barry L.; Borgeson, Daniel D.; Therneau, Terry M.; Matteson, Eric L.; Rodeheffer, Richard J.; Gabriel, Sherine E.

    2014-01-01

    Objective To study left ventricular (LV) geometry in patients with rheumatoid arthritis (RA) who have no heart failure (HF) versus subjects without either RA or HF, and to determine the impact of RA on LV remodeling. Methods A cross-sectional, community-based study was conducted among adult (≥50 years) RA patients and age- and sex-matched non-RA subjects without a history of HF. All participants underwent a standard 2D/Doppler echocardiography. LV geometry was classified into four categories based on relative wall thickness and sex-specific cut-offs for LV mass index: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, or normal geometry. Results The study included 200 RA patients and 600 matched non-RA subjects (mean age 65; 74% female in both cohorts). RA patients were significantly more likely to have abnormal LV geometry than non-RA subjects (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.03, 2.00), adjusting for cardiovascular risk factors and comorbidities. Among those with abnormal LV geometry, RA patients had significantly increased odds of concentric LV remodeling (OR 4.73; 95% CI 2.85, 7.83). In linear regression analyses, LV mass index appeared to be lower in RA patients currently using corticosteroids (Beta +/− standard error: −0.082 +/− 0.027; p=0.002), adjusting for cardiovascular risk factors and comorbidities. Conclusion RA was strongly associated with abnormal LV remodeling, particularly, with concentric LV remodeling, among patients without HF. This association was significant beyond adjustment for cardiovascular risk factors and comorbidities. RA disease related factors may promote changes in LV geometry. The biological mechanisms underlying LV remodeling warrant further investigation. PMID:23553738

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

    PubMed Central

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

    2016-01-01

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

  17. 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

  18. 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.

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

    PubMed

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

    2016-01-01

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

  20. 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

  1. Reduced cardiac remodelling and prevention of glutathione deficiency after omega-3 supplementation in chronic heart failure.

    PubMed

    Fang, Yuehua; Favre, Julie; Vercauteren, Magalie; Laillet, Brigitte; Remy-Jouet, Isabelle; Skiba, Mohamed; Lallemand, Françoise; Dehaudt, Cathy; Monteil, Christelle; Thuillez, Christian; Mulder, Paul

    2011-06-01

    n-3 polyunsaturated fatty acids (omega-3) supplementation is associated with reduced cardiovascular mortality and post-infarction death. However, the impact of omega-3 supplementation in congestive heart failure (CHF) is still unknown. This study assesses the effects of omega-3 supplementation on left ventricular (LV) function and remodelling. We assessed, in rats with CHF induced by left coronary ligation, the effects of a 1-week and a 12-week supplementation with omega-3 (450 mg/kg per day) on LV hemodynamics, function and structure. Chronic omega-3 reduces total peripheral resistance due to an increase in cardiac output without modification of arterial pressure. Only chronic omega-3 reduces LV end-diastolic pressure and LV relaxation constant. Moreover, chronic omega-3 decreases LV systolic and diastolic diameters, LV weight and collagen density. Acute and chronic omega-3 increase LV γ-glutamyl-cysteine synthetase and oppose glutathione deficiency resulting in a reduction of myocardial oxidized glutathione. In experimental CHF, long-term omega-3 supplementation improves LV hemodynamics and function and prevents LV remodelling and glutathione deficiency. The latter might be one of the mechanisms involved, but whether other mechanism, independent of myocardial redox 'status', such as reduced inflammation, are implicated remains to be confirmed.

  2. Retinal remodeling.

    PubMed

    Jones, B W; Kondo, M; Terasaki, H; Lin, Y; McCall, M; Marc, R E

    2012-07-01

    Retinal photoreceptor degeneration takes many forms. Mutations in rhodopsin genes or disorders of the retinal pigment epithelium, defects in the adenosine triphosphate binding cassette transporter, ABCR gene defects, receptor tyrosine kinase defects, ciliopathies and transport defects, defects in both transducin and arrestin, defects in rod cyclic guanosine 3',5'-monophosphate phosphodiesterase, peripherin defects, defects in metabotropic glutamate receptors, synthetic enzymatic defects, defects in genes associated with signaling, and many more can all result in retinal degenerative disease like retinitis pigmentosa (RP) or RP-like disorders. Age-related macular degeneration (AMD) and AMD-like disorders are possibly due to a constellation of potential gene targets and gene/gene interactions, while other defects result in diabetic retinopathy or glaucoma. However, all of these insults as well as traumatic insults to the retina result in retinal remodeling. Retinal remodeling is a universal finding subsequent to retinal degenerative disease that results in deafferentation of the neural retina from photoreceptor input as downstream neuronal elements respond to loss of input with negative plasticity. This negative plasticity is not passive in the face of photoreceptor degeneration, with a phased revision of retinal structure and function found at the molecular, synaptic, cell, and tissue levels involving all cell classes in the retina, including neurons and glia. Retinal remodeling has direct implications for the rescue of vision loss through bionic or biological approaches, as circuit revision in the retina corrupts any potential surrogate photoreceptor input to a remnant neural retina. However, there are a number of potential opportunities for intervention that are revealed through the study of retinal remodeling, including therapies that are designed to slow down photoreceptor loss, interventions that are designed to limit or arrest remodeling events, and

  3. Role of reactive oxygen species in myocardial remodeling.

    PubMed

    Zhang, Min; Shah, Ajay M

    2007-03-01

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

  4. [FeLV infection in the cat: clinically relevant aspects].

    PubMed

    Boretti, F S; Lutz, H; Hofmann-Lehmann, R

    2011-11-01

    The feline leukemia virus (FeLV) is a retrovirus of the domestic cat that was described almost 50 years ago. The FeLV-infection may lead to fatal diseases in domestic and small wild cats. The use of efficacious diagnostics assays and vaccines led to a reduction of the FeLV prevalence; however, FeLV still poses a problem for the cat presented with the infection. This article aims to describe recent developments in diagnostics and findings in the infection pathogenesis that are clinically relevant.

  5. 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

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

    NASA Astrophysics Data System (ADS)

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

    2011-09-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2012-01-01

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

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

    PubMed

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

    2016-01-01

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

  9. 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

  10. Noninvasive LV pressure estimation using subharmonic emissions from microbubbles.

    PubMed

    Dave, Jaydev K; Halldorsdottir, Valgerdur G; Eisenbrey, John R; Raichlen, Joel S; Liu, Ji-Bin; McDonald, Maureen E; Dickie, Kris; Wang, Shumin; Leung, Corina; Forsberg, Flemming

    2012-01-01

    To develop a new noninvasive approach to quantify left ventricular (LV) pressures using subharmonic emissions from microbubbles, an ultrasound scanner was used in pulse inversion grayscale mode; unprocessed radiofrequency data were obtained with pulsed wave Doppler from the aorta and/or LV during Sonazoid infusion. Subharmonic data (in dB) were extracted and processed. Calibration factor (mm Hg/dB) from the aortic pressure was used to estimate LV pressures. Errors ranged from 0.19 to 2.50 mm Hg when estimating pressures using the aortic calibration factor, and were higher (0.64 to 8.98 mm Hg) using a mean aortic calibration factor. Subharmonic emissions from ultrasound contrast agents have the potential to noninvasively monitor LV pressures.

  11. Acute monoblastic leukemia in a FeLV-positive cat.

    PubMed

    Prihirunkit, Kreangsak; Narkkong, Nual Anong; Apibal, Suntaree

    2008-03-01

    A 1.6-year-old male domestic short hair cat was brought to the Veterinary Medical Teaching Hospital, Kasetsart University, with signs of severe anemia, depression, and general lymph node enlargement. Complete blood count revealed leukocytosis and massive undifferentiated blasts. Testing for antibodies specific to feline leukemia virus (FeLV) was positive, and FeLV nucleic acid was confirmed by nested polymerase chain reaction. Base on cytochemistry and ultrastructure, the cat was diagnosed with acute monoblastic leukemia.

  12. Classification and Prognostic Evaluation of Left Ventricular Remodeling in Patients With Asymptomatic Heart Failure.

    PubMed

    Pugliese, Nicola Riccardo; Fabiani, Iacopo; La Carrubba, Salvatore; Conte, Lorenzo; Antonini-Canterin, Francesco; Colonna, Paolo; Caso, Pio; Benedetto, Frank; Santini, Veronica; Carerj, Scipione; Romano, Maria Francesca; Citro, Rodolfo; Di Bello, Vitantonio

    2017-01-01

    Patients with asymptomatic heart failure (HF; stage A and B) are characterized by maladaptive left ventricular (LV) remodeling. Classic 4-group classification of remodeling considers only LV mass index and relative wall thickness as variables. Complex remodeling classification (CRC) includes also LV end-diastolic volume index. Main aim was to assess the prognostic impact of CRC in stage A and B HF. A total of 1,750 asymptomatic subjects underwent echocardiographic examination as a screening evaluation in the presence of cardiovascular risk factors. LV dysfunction, both systolic (ejection fraction) and diastolic (transmitral flow velocity pattern), was evaluated, together with LV remodeling. We considered a composite end point: all-cause death, myocardial infarction, coronary revascularizations, cerebrovascular events, and acute pulmonary edema. CRC was suitable for 1,729 patients (men 53.6%; age 58.3 ± 13 years). Two hundred thirty-eight patients presented systolic dysfunction (ejection fraction <50%) and 483 diastolic dysfunction. According to the CRC, 891 patients were normals or presented with physiologic hypertrophy, 273 concentric remodeling, 47 eccentric remodeling, 350 concentric hypertrophy, 29 mixed hypertrophy, 86 dilated hypertrophy, and 53 eccentric hypertrophy. Age and gender distribution was noticed (p <0.001). After a median follow-up of 21 months, Kaplan-Meier analysis showed different survival distribution (p <0.001) of the CRC patterns. In multivariate Cox regression (adjusted for age, gender, history of stable ischemic heart disease, classic remodeling classification, systolic, and diastolic dysfunction), CRC was independent predictor of primary end point (p = 0.044, hazard ratio 1.101, 95% CI 1.003 to 1.21), confirmed in a logistic regression (p <0.03). In conclusion, CRC could help physicians in prognostic stratification of patients in stage A and B HF.

  13. Effective RNA-silencing strategy of Lv-MSTN/GDF11 gene and its effects on the growth in shrimp, Litopenaeus vannamei.

    PubMed

    Lee, Ji-Hyun; Momani, Jalal; Kim, Young Mog; Kang, Chang-Keun; Choi, Jung-Hwa; Baek, Hae-Ja; Kim, Hyun-Woo

    2015-01-01

    Myostatin (MSTN), also known as GDF8, is a member of the transforming growth factor-β (TGF-β) superfamily and plays an important role in muscle growth, development, and differentiation. Recently, Lv-MSTN/GDF11, the primitive isoform of MSTN and GDF11, was identified from the shrimp Litopenaeus vannamei. The major production site for Lv-MSTN/GDF11 is in the heart, not the tail muscle, which differs from MSTNs in mammals. Among the three injected RNAs, long dsRNA was the most effective for Lv-MSTN/GDF11 knockdown and transcripts of Lv-MSTN/GDF11 decreased in both the heart (88.85%) and skeletal muscles (43.36%) 72h after injection of 10pmol of long dsRNA. We also found that higher doses of dsRNA did not lead to greater decreases in Lv-MSTN/GDF11 transcripts for amounts between 1pmol and 100pmol. Injection of Lv-MSTN/GDF11 dsRNA did not affect the upregulation of the skeletal actin gene (Lv-ACTINSK) in the tail muscle, but the expression of cytoplasmic and cardiac actins were upregulated in both the heart and tail muscle. Over the course of 8weeks of dsRNA injection, considerably higher mortality (~71%) was seen in the dsRNA-injected group compared to the control group (40%). Surviving shrimp in the dsRNA injected group had a lower growth rate due to the adverse effects of Lv-MSTN/GDF11 knockdown. Lv-MSTN/GDF11 appears to be involved in muscular or neuronal development, but not in doubling muscle fibers, as is the case with mammalian MSTN.

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

    NASA Astrophysics Data System (ADS)

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

    2012-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2011-09-01

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

  16. Relation of the ischaemic substrate to left ventricular remodelling by cardiac magnetic resonance at 1.5 T in rabbits

    PubMed Central

    Mansencal, Nicolas; Tissier, Renaud; Deux, Jean-François; Ghaleh, Bijan; Couvreur, Nicolas; Rienzo, Mario; Guéret, Pascal; Rahmouni, Alain; Berdeaux, Alain; Garot, Jérôme

    2010-01-01

    Objectives Contrast-enhanced cardiac magnetic resonance (CMR) for infarct sizing has been validated in large animals, but studies and follow-up are restricted. We sought to 1) validate CMR for assessment of myocardial area at risk (MAR) and infarct size (IS) in a rabbit model of reperfused myocardial infarction (MI); 2) analyse the relation between ischaemic substrates and subsequent left ventricular (LV) remodelling. Methods Experimental reperfused acute MI was induced in 16 rabbits. Ten animals underwent cross-registered cine and contrast-enhanced CMR and histopathology at day 3 for assessment of MAR and IS (group#1). The remaining 6 rabbits had serial CMR for the study of LV remodelling (group#2). Results In group#1, mean IS was 12.7±6.4% and 12.7±6.9% of total LV myocardial mass on CMR (late-enhancement technique) and histopathology (P=0.52; r=0.93). No significant difference occurred between CMR and histopathology for the calculation of MAR and IS/MAR ratio (P=0.18 and P=0.17), whereas correlations were strong (r=0.92 and r=0.95). In group#2, mean LV end-diastolic, end-systolic volumes and LV mass were significantly increased at 3 weeks compared with measurements at day 3 (P<0.01). Significant correlations between initial IS and the increase in LV end-diastolic volume (r=0.66) and the increase in LV mass (r=0.48) were observed, as well as correlations between initial MAR and the increase in LV end-diastolic volume (r=0.70) and the increase in LV mass (r=0.37). Conclusions Comprehensive CMR provides accurate assessment of IS and MAR in reperfused rabbit MI. Infarct size is closely related to LV remodelling. Through the infarct size/MAR ratio, this approach has great potential for assessing interventions aimed at cardioprotection. PMID:19936756

  17. Treatment of feline leukemia virus (FeLV) infection.

    PubMed

    Hartmann, K; Block, A; Ferk, G; Beer, B; Vollmar, A; Lutz, H

    1999-09-01

    FeLV infection is still considered to account for most disease-related deaths in pet cats. Different treatment attempts with various drugs were performed in the past but none resulted in healing or complete virus elimination. Therefore, it caused a sensation when Horber and Mayr [Horber, D., Mayr, B., 1991. Prax. 19, 311-314; Horber, D., Schnabl, W., Mayr, B., 1992. Tierarztl. Umschau 47, 556-560; Mayr, B., Horber, D., 1992. Kleintierprax. 37, 515-518] published that they were able to cure 80 to 100% FeLV-infected cats from viremia by using an immunomodulating compound. Articles in cat breeder and cat owner journals appeared assuming that obviously there is a rescue for FeLV-infected cats suffering from this deadly infection. The immunomodulator [Buttner, M., 1993. Comp. Immun. Microbiol. Infect. Dis. 18, 1-10] used in those studies was the so-called 'paramunity inducer' PIND-ORF (Baypamun, Bayer, Leverkusen, Germany) consisting of inactivated parapox ovis virus. Since that time, Baypamun is the most commonly used drug for treatment of FeLV infection in Germany and other European countries. Four placebo-controlled double-blind trials were performed to determine the therapeutic efficacy of Baypamun and other compounds in naturally FeLV-infected cats under controlled conditions.

  18. Predictors of Left Ventricle Remodeling: Combined Plasma B-type Natriuretic Peptide Decreasing Ratio and Peak Creatine Kinase-MB.

    PubMed

    Hsu, Jen-Te; Chung, Chang-Min; Chu, Chi-Ming; Lin, Yu-Shen; Pan, Kuo-Li; Chang, Jung-Jung; Wang, Po-Chang; Chang, Shih-Tai; Yang, Teng-Yao; Jang, Shih-Jung; Yang, Tsung-Han; Hsiao, Ju-Feng

    2017-01-01

    Background: Previous studies reported that patients who had an acute myocardial infarction (AMI) have found that measuring B-type natriuretic peptide (BNP) during the subacute phase of left ventricular (LV) remodeling can predict the possible course of LV remodeling. This study assessed the use of serial BNP serum levels combined with early creatine kinase-MB (CK-MB) to predict the development of significant LV remodeling in AMI patients. Methods: Nighty-seven patients with new onset AMI were assessed using serial echocardiographic studies and serial measurements of BNP levels, both performed on day-2 (BNP1), day-7 (BNP2), day-90 (BNP3), and day-180 (BNP4) after admission. LV remodeling was defined as >20% increase in biplane LV end-diastolic volume on day-180 compared to baseline (day-2). Results: Patients were divided into LV remodeling [LVR(+)] and non LV remodeling [LVR(-)] groups. No first-week BNP level was found to predict remodeling. However, the two groups had significantly different day-90 BNP level (208.1 ± 263.7 pg/ml vs. 82.4 ± 153.7 pg/ml, P = 0.039) and significantly different 3-month BNP decrease ratios ( R BNP13) (14.4 ± 92.2% vs. 69.4 ± 25.9%, P < 0.001). The appropriate cut-off value for R BNP13 was 53.2% (AUC = 0.764, P < 0.001). Early peak CK-MB (cut-off 48.2 ng/ml; AUC = 0.672; P = 0.014) was another independent predictor of remodeling. Additionally, combining peak CK-MB and R BNP13 offered an excellent discrimination for half-year remodeling when assessed by ROC curve (AUC = 0.818, P < 0.001). Conclusion: R BNP13 is a significant independent predictor of 6-month LV remodeling. The early peak CK-MB additionally offered an incremental power to the predictions derived from serial BNP examinations.

  19. Predictors of Left Ventricle Remodeling: Combined Plasma B-type Natriuretic Peptide Decreasing Ratio and Peak Creatine Kinase-MB

    PubMed Central

    Hsu, Jen-Te; Chung, Chang-Min; Chu, Chi-Ming; Lin, Yu-Shen; Pan, Kuo-Li; Chang, Jung-Jung; Wang, Po-Chang; Chang, Shih-Tai; Yang, Teng-Yao; Jang, Shih-Jung; Yang, Tsung-Han; Hsiao, Ju-Feng

    2017-01-01

    Background: Previous studies reported that patients who had an acute myocardial infarction (AMI) have found that measuring B-type natriuretic peptide (BNP) during the subacute phase of left ventricular (LV) remodeling can predict the possible course of LV remodeling. This study assessed the use of serial BNP serum levels combined with early creatine kinase-MB (CK-MB) to predict the development of significant LV remodeling in AMI patients. Methods: Nighty-seven patients with new onset AMI were assessed using serial echocardiographic studies and serial measurements of BNP levels, both performed on day-2 (BNP1), day-7 (BNP2), day-90 (BNP3), and day-180 (BNP4) after admission. LV remodeling was defined as >20% increase in biplane LV end-diastolic volume on day-180 compared to baseline (day-2). Results: Patients were divided into LV remodeling [LVR(+)] and non LV remodeling [LVR(-)] groups. No first-week BNP level was found to predict remodeling. However, the two groups had significantly different day-90 BNP level (208.1 ± 263.7 pg/ml vs. 82.4 ± 153.7 pg/ml, P = 0.039) and significantly different 3-month BNP decrease ratios (RBNP13) (14.4 ± 92.2% vs. 69.4 ± 25.9%, P < 0.001). The appropriate cut-off value for RBNP13 was 53.2% (AUC = 0.764, P < 0.001). Early peak CK-MB (cut-off 48.2 ng/ml; AUC = 0.672; P = 0.014) was another independent predictor of remodeling. Additionally, combining peak CK-MB and RBNP13 offered an excellent discrimination for half-year remodeling when assessed by ROC curve (AUC = 0.818, P < 0.001). Conclusion: RBNP13 is a significant independent predictor of 6-month LV remodeling. The early peak CK-MB additionally offered an incremental power to the predictions derived from serial BNP examinations. PMID:28138312

  20. Low Carbohydrate/High Fat Diet Attenuates Pressure Overload Induced Ventricular Remodeling and Dysfunction

    PubMed Central

    Duda, Monika K.; O’Shea, Karen M.; Lei, Biao; Barrows, Brian R.; Azimzadeh, Agnes M.; McElfresh, Tracy E.; Hoit, Brian D.; Kop, Willem J.; Stanley, William C.

    2009-01-01

    Background It is not known how carbohydrate and fat intake impact the development of left ventricular (LV) hypertrophy and contractile dysfunction in response to pressure overload. We hypothesized that a low carbohydrate/high fat diet prevents LV hypertrophy and dysfunction compared to high carbohydrate diets. Methods and Results Rats were fed high carbohydrate diets comprised of either starch or sucrose, or a low carbohydrate/high fat diet, and underwent abdominal aortic banding (AAB) for two months. AAB increased LV mass with all diets. LV end diastolic and systolic volumes, and the ratio of the mRNA for myosin heavy chainβ/α were increased with both high carbohydrate diets, but not with the low carbohydrate/high fat diet. Circulating levels of insulin and leptin, both stimulants for cardiac growth, were lower, and free fatty acids higher, with the low carbohydrate/high fat diet compared to high carbohydrate diets. Among AAB animals LV volumes were positively correlated with insulin, and LV mass correlated with leptin. Conclusion A low carbohydrate/high fat diet attenuated pressure overload-induced LV remodeling compared to high carbohydrate diets. This effect corresponded to lower insulin and leptin concentrations, suggesting they may contribute to the development of LV hypertrophy and dysfunction under conditions of pressure overload. PMID:18474346

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

    PubMed

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

    2015-01-01

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

  2. [The role of multispiral computed tomography in assessment of viability of the myocardium and prognostication of left ventricular remodeling in patients with ST-elevation myocardial infarction].

    PubMed

    Veselova, T N; Merkulova, I N; Iarovaia, E B; Ternovoĭ, S K; Ruda, M Ia

    2013-01-01

    Aim of the study was to assess perfusion defect and viability of the myocardium by the method of multispiral computed tomography (MSCT) in patients with ST-elevation acute myocardial infarction (AMI) and to assess their prognostic role in development of remodeling of the left ventricle (LV). We included into the study 117 patients with AMI. MSCT with intravenous contrast enhancement was carried out on days 3-4 and at 12 months after AMI. In the arterial phase we estimated volume of myocardial perfusion defect, LV end diastolic and end systolic volumes (LVEDV and LVESV), and LV ejection fraction (EF). Three types of myocardial opacification were distinguished on tomograms in delayed phase of MSCT: type I - subendocardial residual defect (RD), type II - transmural RD, type III - transmural delayed hyper enhancement (DE). Patients were divided in 3 groups: (1) with subendocardial RD (n=63), (2) with transmural RD (n=28), (3) with transmural DE (n=26). Development of LV remodeling was registered if at repeat MSCT LVEDV increased more or equal 20% from baseline. In patients with signs of viable myocardium (group 1) volume of perfusion defect was substantially smaller than in patients with nonviable myocardium (groups 2 and 3): 1cm3 (0.4-2.4) vs. 7.3 cm3 (5.3-10.0) and 6.3 cm3 (5.0-15.0), respectively, p<0.001. Compared with groups 2 and 3 patients of group 1 more often were female (p=0.04), had inferior MI (p<0.001), and spontaneous reperfusion (p<0.001). After 12 months LV remodeling was registered in 19.3% of patients, all had signs of nonviable myocardium in more or equal 3 LV segments. In patients with perfusion defect more or equal 10 cm3 probability of development of LV remodeling exceeded 50%. Disturbances of perfusion abnormalities and number of nonviable LV segments were main predictors of LV remodeling.

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

    PubMed

    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

    2006-04-24

    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 pound3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings pound1318), 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.

  4. Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling

    PubMed Central

    Pavo, Noemi; Lukovic, Dominika; Zlabinger, Katrin; Zimba, Abelina; Lorant, David; Goliasch, Georg; Winkler, Johannes; Pils, Dietmar; Auer, Katharina; Jan Ankersmit, Hendrik; Giricz, Zoltán; Baranyai, Tamas; Sárközy, Márta; Jakab, András; Garamvölgyi, Rita; Emmert, Maximilian Y.; Hoerstrup, Simon P.; Hausenloy, Derek J.; Ferdinandy, Péter; Maurer, Gerald; Gyöngyösi, Mariann

    2017-01-01

    We have analyzed the pathway networks of ischemia-affected and remote myocardial areas after repetitive ischemia/reperfusion (r-I/R) injury without ensuing myocardial infarction (MI) to elaborate a spatial- and chronologic model of cardioprotective gene networks to prevent left ventricular (LV) adverse remodeling. Domestic pigs underwent three cycles of 10/10 min r-I/R by percutaneous intracoronary balloon inflation/deflation in the mid left anterior descending artery, without consecutive MI. Sham interventions (n = 8) served as controls. Hearts were explanted at 5 h (n = 6) and 24 h (n = 6), and transcriptomic profiling of the distal (ischemia-affected) and proximal (non-affected) anterior myocardial regions were analyzed by next generation sequencing (NGS) and post-processing with signaling pathway impact and pathway network analyses. In ischemic region, r-I/R induced early activation of Ca-, adipocytokine and insulin signaling pathways with key regulator STAT3, which was also upregulated in the remote areas together with clusterin (CLU) and TNF-alpha. During the late phase of cardioprotection, antigen immunomodulatory pathways were activated with upregulation of STAT1 and CASP3 and downregulation of neprilysin in both zones, suggesting r-I/R induced intrinsic remote conditioning. The temporo-spatially differently activated pathways revealed a global myocardial response, and neprilysin and the STAT family as key regulators of intrinsic remote conditioning for prevention of adverse remodeling. PMID:28266659

  5. Teaching resources. Chromatin remodeling.

    PubMed

    Lue, Neal F

    2005-07-26

    This Teaching Resource provides lecture notes and slides for a class covering chromatin remodeling mechanisms and is part of the course "Cell Signaling Systems: a Course for Graduate Students." The lecture begins with a discussion of chromatin organization and then proceeds to describe the process of chromatin remodeling through a review of chromatin remodeling complexes and methods used to study their function.

  6. Contribution of ventricular remodeling to pathogenesis of heart failure in rats.

    PubMed

    Brower, G L; Janicki, J S

    2001-02-01

    We previously reported an approximately 50% incidence of rats with symptoms of congestive heart failure (CHF) at 8 wk postinfrarenal aorto-caval fistula. However, it was not clear whether compensatory ventricular remodeling could continue beyond 8 wk or whether the remaining animals would have developed CHF or died. Therefore, the intent of this study was to complete the characterization of this model of sustained volume overload by determining the morbidity and mortality and the temporal response of left ventricular (LV) remodeling and function beyond 8 wk. The findings demonstrate an upper limit to LV hypertrophy and substantial increases in LV volume and compliance, matrix metalloproteinase activity, and collagen volume fraction associated with the development of CHF. There was an 80% incidence of morbidity and mortality following 21 wk of chronic volume overload. These findings indicate that the development of CHF is triggered by marked ventricular dilatation and increased compliance occurring once the myocardial hypertrophic response is exhausted.

  7. 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.

  8. 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; 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

  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. Novel approach for automatic segmentation of LV endocardium via SPCNN

    NASA Astrophysics Data System (ADS)

    Ma, Yurun; Wang, Deyuan; Ma, Yide; Lei, Ruoming; Wang, Kemin

    2017-02-01

    Automatic segmentation of Left Ventricle (LV) is an essential task in the field of computer-aided analysis of cardiac function. In this paper, a simplified pulse coupled neural network (SPCNN) based approach is proposed to segment LV endocardium automatically. Different from the traditional image-driven methods, the SPCNN based approach is independent of the image gray distribution models, which makes it more stable. Firstly, the temporal and spatial characteristics of the cardiac magnetic resonance image are used to extract a region of interest and to locate LV cavity. Then, SPCNN model is iteratively applied with an increasing parameter to segment an optimal cavity. Finally, the endocardium is delineated via several post-processing operations. Quantitative evaluation is performed on the public database provided by MICCAI 2009. Over all studies, all slices, and two phases (end-diastole and end-systole), the average percentage of good contours is 91.02%, the average perpendicular distance is 2.24 mm and the overlapping dice metric is 0.86.These results indicate that the proposed approach possesses high precision and good competitiveness.

  11. Impact of thermodilution-derived coronary blood flow patterns after percutaneous coronary intervention on mid-term left ventricular remodeling in patients with ST elevation myocardial infarction.

    PubMed

    Sumiyoshi, Akinori; Fujii, Kenichi; Fukunaga, Masashi; Shibuya, Masahiko; Imanaka, Takahiro; Kawai, Kenji; Miki, Kojiro; Tamaru, Hiroto; Horimatsu, Tetsuo; Saita, Ten; Nishimura, Machiko; Masuyama, Tohru; Ishihara, Masaharu

    2017-01-01

    We recently reported the coronary thermodilution curve can be evaluated by analyzing the thermodilution curve obtained from a pressure sensor/thermistor-tipped guidewire, and presence of a bimodal-shaped thermodilution curve following primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction (STEMI) patients was associated with worse outcomes. This study evaluated whether the bimodal-shaped thermodilution curve predicts left ventricular (LV) remodeling after STEMI. The coronary thermodilution curve patterns were evaluated for 75 patients treated by pPCI for their first STEMI using a pressure sensor/thermistor-tipped guidewire, and classified into the three groups according to the thermodilution curve shape: narrow unimodal (n = 39), wide unimodal (n = 26), and bimodal pattern (n = 10). Echocardiography was performed at baseline and 6 months after STEMI. LV remodeling was defined as a >20 % increase in LV end-diastolic volumes (LVEDV). LVEDV at 6-month follow-up was greater in the bimodal group than in the other groups (p < 0.001). The prevalence of LV remodeling was highest in the bimodal group than in the narrow and wide unimodal groups (60, 12, and 15 %, respectively; p = 0.003). Multivariate analysis revealed a bimodal-shaped thermodilution curve as an independent predictor of the prevalence of LV remodeling. A bimodal-shaped thermodilution curve is associated with LV remodeling after STEMI. This easily assessable coronary thermodilution curve pattern is useful to predict mid-term LV remodeling for STEMI patients at the catheterization laboratory.

  12. 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

    ... 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 not... consist of the installation of Vossloh 101-LV concrete ties. FRA has received this request from the...

  13. Ethnicity-related variations of left ventricular remodeling in adolescent amateur football players.

    PubMed

    Pelà, G; Li Calzi, M; Crocamo, A; Pattoneri, P; Goldoni, M; Anedda, A; Musiari, L; Biggi, A; Bonetti, A; Montanari, A

    2015-06-01

    Adult and adolescent elite black athletes display - as compared with their white counterparts - excessively increased left ventricle (LV) wall thickness (LVWT), mass (LVM), and relative wall thickness (RWT). To investigate such ethnicity-related differences in non-professional adolescent athletes, 138 male, amateur football players [age 14.0 ± 1.7 years, 42 West-African blacks (BA) and 96 Italian whites (WA)] underwent an echocardiographic study of LV diameters, LVWT, maximal wall thickness (MWT), LVM, and RWT as remodeling index. BA vs WA exhibited greater thickness of septum and posterior wall, higher MWT (10.3 ± 1.7 vs 8.8 ± 1.1 mm), and higher LVM (117 ± 27 vs 101 ± 20 g/m(2)) and RWT (0.44 ± 0.07 vs 0.35 ± 0.04). Age, systolic blood pressure, body mass index, and ethnicity predicted MWT and LVM, whereas ethnicity was the sole strong predictor of RWT. The greater MWT, LVWT, and LVM of 14-year-old, amateur-level BA vs WA indicates that ethnicity substantially affects LV structure in adolescent, non-professional athletes. In contrast with MWT and LVM, elevated RWT was predicted by black ethnicity only. We suggest that concentric-type LV remodeling is a peculiar LV phenotype in adolescent African athletes.

  14. The Homeostatic Chemokine CCL21 Predicts Mortality in Aortic Stenosis Patients and Modulates Left Ventricular Remodeling

    PubMed Central

    Finsen, Alexandra Vanessa; Ueland, Thor; Sjaastad, Ivar; Ranheim, Trine; Ahmed, Mohammed S.; Dahl, Christen P.; Askevold, Erik T.; Aakhus, Svend; Husberg, Cathrine; Fiane, Arnt E.; Lipp, Martin; Gullestad, Lars; Christensen, Geir; Aukrust, Pål; Yndestad, Arne

    2014-01-01

    Background CCL21 acting through CCR7, is termed a homeostatic chemokine. Based on its role in concerting immunological responses and its proposed involvement in tissue remodeling, we hypothesized that this chemokine could play a role in myocardial remodeling during left ventricular (LV) pressure overload. Methods and Results Our main findings were: (i) Serum levels of CCL21 were markedly raised in patients with symptomatic aortic stenosis (AS, n = 136) as compared with healthy controls (n = 20). (ii) A CCL21 level in the highest tertile was independently associated with all-cause mortality in these patients. (iii) Immunostaining suggested the presence of CCR7 on macrophages, endothelial cells and fibroblasts within calcified human aortic valves. (iv). Mice exposed to LV pressure overload showed enhanced myocardial expression of CCL21 and CCR7 mRNA, and increased CCL21 protein levels. (v) CCR7−/− mice subjected to three weeks of LV pressure overload had similar heart weights compared to wild type mice, but increased LV dilatation and reduced wall thickness. Conclusions Our studies, combining experiments in clinical and experimental LV pressure overload, suggest that CCL21/CCR7 interactions might be involved in the response to pressure overload secondary to AS. PMID:25398010

  15. Timing effect of intramyocardial hydrogel injection for positively impacting left ventricular remodeling after myocardial infarction

    PubMed Central

    Yoshizumi, Tomo; Zhu, Yang; Jiang, Hongbin; D’Amore, Antonio; Sakaguchi, Hirokazu; Tchao, Jason; Tobita, Kimimasa; Wagner, William R.

    2016-01-01

    Intramyocardial injection of various injectable hydrogel materials has shown benefit in positively impacting the course of left ventricular (LV) remodeling after myocardial infarction (MI). However, since LV remodeling is a complex, time dependent process, the most efficacious time of hydrogel injection is not clear. In this study, we injected a relatively stiff, thermoresponsive and bioabsorbable hydrogel in rat hearts at 3 different time points - immediately after MI (IM), 3 d post-MI (3D), and 2 w post-MI (2W), corresponding to the beginnings of the necrotic, fibrotic and chronic remodeling phases. The employed left anterior descending coronary artery ligation model showed expected infarction responses including functional loss, inflammation and fibrosis with distinct time dependent patterns. Changes in LV geometry and contractile function were followed by longitudinal echocardiography for 10 w post-MI. While all injection times positively affected LV function and wall thickness, the 3D group gave better functional outcomes than the other injection times and also exhibited more local vascularization and less inflammatory markers than the earlier injection time. The results indicate an important role for injection timing in the increasingly explored concept of post-MI biomaterial injection therapy and suggest that for hydrogels with mechanical support as primary function, injection at the beginning of the fibrotic phase may provide improved outcomes. PMID:26774561

  16. Timing effect of intramyocardial hydrogel injection for positively impacting left ventricular remodeling after myocardial infarction.

    PubMed

    Yoshizumi, Tomo; Zhu, Yang; Jiang, Hongbin; D'Amore, Antonio; Sakaguchi, Hirokazu; Tchao, Jason; Tobita, Kimimasa; Wagner, William R

    2016-03-01

    Intramyocardial injection of various injectable hydrogel materials has shown benefit in positively impacting the course of left ventricular (LV) remodeling after myocardial infarction (MI). However, since LV remodeling is a complex, time dependent process, the most efficacious time of hydrogel injection is not clear. In this study, we injected a relatively stiff, thermoresponsive and bioabsorbable hydrogel in rat hearts at 3 different time points - immediately after MI (IM), 3 d post-MI (3D), and 2 w post-MI (2W), corresponding to the beginnings of the necrotic, fibrotic and chronic remodeling phases. The employed left anterior descending coronary artery ligation model showed expected infarction responses including functional loss, inflammation and fibrosis with distinct time dependent patterns. Changes in LV geometry and contractile function were followed by longitudinal echocardiography for 10 w post-MI. While all injection times positively affected LV function and wall thickness, the 3D group gave better functional outcomes than the other injection times and also exhibited more local vascularization and less inflammatory markers than the earlier injection time. The results indicate an important role for injection timing in the increasingly explored concept of post-MI biomaterial injection therapy and suggest that for hydrogels with mechanical support as primary function, injection at the beginning of the fibrotic phase may provide improved outcomes.

  17. Diacerein Improves Left Ventricular Remodeling and Cardiac Function by Reducing the Inflammatory Response after Myocardial Infarction

    PubMed Central

    Torina, Anali Galluce; Reichert, Karla; Lima, Fany; de Souza Vilarinho, Karlos Alexandre; de Oliveira, Pedro Paulo Martins; do Carmo, Helison Rafael Pereira; de Carvalho, Daniela Diógenes; Saad, Mário José Abdalla; Sposito, Andrei Carvalho; Petrucci, Orlando

    2015-01-01

    Background The inflammatory response has been implicated in the pathogenesis of left ventricular (LV) remodeling after myocardial infarction (MI). An anthraquinone compound with anti-inflammatory properties, diacerein inhibits the synthesis and activity of pro-inflammatory cytokines, such as tumor necrosis factor and interleukins 1 and 6. The purpose of this study was to investigate the effects of diacerein on ventricular remodeling in vivo. Methods and Results Ligation of the left anterior descending artery was used to induce MI in an experimental rat model. Rats were divided into two groups: a control group that received saline solution (n = 16) and a group that received diacerein (80 mg/kg) daily (n = 10). After 4 weeks, the LV volume, cellular signaling, caspase 3 activity, and nuclear factor kappa B (NF-κB) transcription were compared between the two groups. After 4 weeks, end-diastolic and end-systolic LV volumes were reduced in the treatment group compared to the control group (p < .01 and p < .01, respectively). Compared to control rats, diacerein-treated rats exhibited less fibrosis in the LV (14.65%± 7.27% vs. 22.57%± 8.94%; p < .01), lower levels of caspase-3 activity, and lower levels of NF-κB p65 transcription. Conclusions Treatment with diacerein once a day for 4 weeks after MI improved ventricular remodeling by promoting lower end-systolic and end-diastolic LV volumes. Diacerein also reduced fibrosis in the LV. These effects might be associated with partial blockage of the NF-κB pathway. PMID:25816098

  18. Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling

    PubMed Central

    Matsushima, Shouji; Kuroda, Junya; Zhai, Peiyong; Liu, Tong; Ikeda, Shohei; Nagarajan, Narayani; Yokota, Takashi; Kinugawa, Shintaro; Hsu, Chiao-Po; Li, Hong; Tsutsui, Hiroyuki

    2016-01-01

    NADPH oxidases (Noxes) produce ROS that regulate cell growth and death. NOX4 expression in cardiomyocytes (CMs) plays an important role in cardiac remodeling and injury, but the posttranslational mechanisms that modulate this enzyme are poorly understood. Here, we determined that FYN, a Src family tyrosine kinase, interacts with the C-terminal domain of NOX4. FYN and NOX4 colocalized in perinuclear mitochondria, ER, and nuclear fractions in CMs, and FYN expression negatively regulated NOX4-induced O2– production and apoptosis in CMs. Mechanistically, we found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. Transverse aortic constriction activated FYN in the left ventricle (LV), and FYN-deficient mice displayed exacerbated cardiac hypertrophy and dysfunction and increased ROS production and apoptosis. Deletion of Nox4 rescued the exaggerated LV remodeling in FYN-deficient mice. Furthermore, FYN expression was markedly decreased in failing human hearts, corroborating its role as a regulator of cardiac cell death and ROS production. In conclusion, FYN is activated by oxidative stress and serves as a negative feedback regulator of NOX4 in CMs during cardiac remodeling. PMID:27525436

  19. A targeted mutation within the feline leukemia virus (FeLV) envelope protein immunosuppressive domain to improve a canarypox virus-vectored FeLV vaccine.

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  1. 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

    2016-02-15

    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.

  2. 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

  3. Litopenaeus vannamei inhibitor of apoptosis protein 1 (LvIAP1) is essential for shrimp survival.

    PubMed

    Leu, Jiann-Horng; Chen, Yen-Chen; Chen, Li-Li; Chen, Kuan-Yu; Huang, Huai-Ting; Ho, Jan-Ming; Lo, Chu-Fang

    2012-09-01

    The members of the inhibitor of apoptosis protein (IAP) family are involved in the regulation of diverse cellular processes, including apoptosis, signal transduction and mitosis. Here, we report the cloning and characterization of three IAP genes from Pacific white shrimp Litopenaeus vannamei: LvIAP1, LvIAP2 and LvSurvivin. LvIAP1, the orthologue of Penaeus monodon IAP (PmIAP), consists of three BIR domains and one RING domain; LvIAP2 consists of two BIR domains and LvSurvivin has only one BIR domain. Expression profiling by absolute quantitative real-time RT-PCR revealed that of the three IAP genes, LvIAP1 had the highest expression levels in almost all examined tissues and LvSurvivin had the lowest expression levels. Furthermore, among the examined tissues, the lymphoid organs most strongly expressed all three genes. When LvIAP1 expression was silenced by injection of its corresponding dsRNA, the shrimp died within 48h after injection, whereas injection of the other two dsRNAs did not cause shrimp death. In LvIAP1-silenced shrimp, the number of circulating haemocytes decreased dramatically because of extensive apoptosis. This suggested that LvIAP1 is central to the regulation of shrimp haemocyte apoptosis.

  4. Temporal evaluation of left ventricular remodeling and function in rats with chronic volume overload.

    PubMed

    Brower, G L; Henegar, J R; Janicki, J S

    1996-11-01

    The left ventricle (LV) significantly dilates and hypertrophies in response to chronic volume overload. However, the temporal responses in LV mass, volume, and systolic/diastolic function secondary to chronic volume overload induced by an infrarenal arteriovenous (A-V) fistula in rats have not been well characterized. To this end, LV end-diastolic pressure, size, and function (i.e., isovolumetric pressure-volume relationships in the blood-perfused isolated heart) were assessed at 1, 2, 3, 5, and 8 wk post-A-V fistula and compared with age-matched control animals. Progressive hypertrophy (192% at 8 wk), ventricular dilatation (172% at 8 wk), and a decrease in ventricular stiffness (257% at 8 wk) occurred in the fistula groups. LV end-diastolic pressure increased from a control value of 4.2 +/- 3.1 mmHg to a peak value of 15.7 +/- 3.6 mmHg after 3 wk of volume overload. A subsequent decline in LVEDP to 11.0 +/- 6.0 mmHg together with further LV dilation (169%) corresponded to a significant decrease in LV stiffness (222%) at 5 wk post-A-V fistula. Myocardial contractility, as assessed by the isovolumetric pressure-volume relationship, was significantly reduced in all A-V fistula groups; however, the compensatory remodeling induced by 8 wk of chronic biventricular volume overload tended to preserve systolic function.

  5. Left Atrial Reverse Remodeling: Mechanisms, Evaluation, and Clinical Significance.

    PubMed

    Thomas, Liza; Abhayaratna, Walter P

    2017-01-01

    The left atrium is considered a biomarker for adverse cardiovascular outcomes, particularly in patients with left ventricular diastolic dysfunction and atrial fibrillation in whom left atrial (LA) enlargement is of prognostic importance. LA enlargement with a consequent decrease in LA function represents maladaptive structural and functional "remodeling" that in turn promotes electrical remodeling and a milieu conducive for incident atrial fibrillation. Medical and nonmedical interventions may arrest this pathophysiologic process to the extent that subsequent reverse remodeling results in a reduction in LA size and improvement in LA function. This review examines cellular and basic mechanisms involved in LA remodeling, evaluates the noninvasive techniques that can assess these changes, and examines potential mechanisms that may initiate reverse remodeling.

  6. Evaluation of Aortic Blood Flow and Wall Shear Stress in Aortic Stenosis and Its Association With Left Ventricular Remodeling

    PubMed Central

    von Knobelsdorff-Brenkenhoff, Florian; Karunaharamoorthy, Achudhan; Trauzeddel, Ralf Felix; Barker, Alex J; Blaszczyk, Edyta; Markl, Michael; Schulz-Menger, Jeanette

    2016-01-01

    Background Aortic stenosis (AS) leads to variable stress for the left ventricle (LV) and consequently a broad range of LV remodeling. Study aim was to describe blood flow patterns in the ascending aorta of AS patients and determine their association with remodeling. Methods and Results Thirty-seven patients with AS (14 mild, 8 moderate, 15 severe; age 63±13 years) and 37 healthy controls (age 60±10 years) underwent 4D-flow MRI. Helical and vortical flow formations and flow eccentricity were assessed in the ascending aorta. Normalized flow displacement from the vessel center and peak systolic wall shear stress (WSSpeak) in the ascending aorta were quantified. LV remodeling was assessed based on LV mass index (LVMI-I) and the ratio of LV mass to enddiastolic volume (relative wall mass; RWM). Marked helical and vortical flow formation and eccentricity were more prevalent in patients with AS than in healthy subjects, and AS patients exhibited an asymmetric and elevated distribution of WSSpeak. In AS, aortic orifice area was strongly negatively associated with vortical flow formation (p=0.0274), eccentricity (p=0.0070) and flow displacement (p=0.0021). Bicuspid aortic valve was associated with more intense helical (p=0.0098) and vortical flow formation (p=0.0536), higher flow displacement (p=0.11) and higher WSSpeak (p=0.0926). LVM-I and RWM were significantly associated with aortic orifice area (p=0.0611, p=0.0058) and flow displacement (p=0.0058, p=0.0283). Conclusions In this pilot study, AS leads to abnormal blood flow pattern and WSSpeak in the ascending aorta. In addition to aortic orifice area, normalized flow displacement was significantly associated with LV remodeling. PMID:26917824

  7. Low coronary driving pressure early in the course of myocardial infarction is associated with subendocardial remodelling and left ventricular dysfunction

    PubMed Central

    Koike, Marcia Kiyomi; De Carvalho Frimm, Clovis; Cúri, Mariana

    2007-01-01

    Subendocardial remodelling of the left ventricular (LV) non-infarcted myocardium has been poorly investigated. Previously, we have demonstrated that low coronary driving pressure (CDP) early postinfarction was associated with the subsequent development of remote subendocardial fibrosis. The present study aimed at examining the role of CDP in LV remodelling and function following infarction. Haemodynamics were performed in Wistar rats immediately after myocardial infarction (MI group) or sham surgery (SH group) and at days 1, 3, 7 and 28. Heart tissue sections were stained with HE, Sirius red and immunostained for α-actin. Two distinct LV regions remote to infarction were examined: subendocardium (SE) and interstitium (INT). Myocyte necrosis, leucocyte infiltration, myofibroblasts and collagen volume fraction were determined. Compared with SH, MI showed lower CDP and LV systolic and diastolic dysfunction. Necrosis was evident in SE at day 1. Inflammation and fibroplasia predominated in SE as far as day 7. Fibrosis was restricted to SE from day 3 on. Inflammation occurred in INT at days 1 and 3, but at a lower grade than in SE. CDP correlated inversely with SE necrosis (r = −0.65, P = 0.003, at day 1), inflammation (r = −0.76, P < 0.001, at day 1), fibroplasia (r = −0.47, P = 0.04, at day 7) and fibrosis (r = −0.83, P < 0.001, at day 28). Low CDP produced progressive LV expansion. Necrosis at day 1, inflammation at days 3 and 7, and fibroplasia at day 7 correlated inversely with LV function. CDP is a key factor to SE integrity and affects LV remodelling and function following infarction. PMID:17696909

  8. Cloning and characterization of a novel hemocyanin variant LvHMCV4 from shrimp Litopenaeus vannamei.

    PubMed

    Lu, Xin; Lu, Hui; Guo, Lingling; Zhang, Zehui; Zhao, Xianliang; Zhong, Mingqi; Li, Shengkang; Zhang, Yueling

    2015-10-01

    Recently, we found 3 variants of hemocyanin subunit with higher molecular weight in shrimp Litopenaeus vannamei (Named as LvHMCV1-3). In this study, a novel L. vannamei hemocyanin variant (Named as LvHMCV4) was further cloned and characterized. Bioinformatic analysis predicted that LvHMCV4 contains one open reading frame of 2137 bp and encodes a polypeptide of 678 amino acids. It shares 84-99% cDNA sequences identity to that of the classical form of L. vannamei hemocyanin (LvHMC, AJ250830.1) and LvHMCV1-3. LvHMCV4 possesses a conserved structure characteristic of the hemocyanin family and can be clustered into one branch along with other arthropod hemocyanins in a phylogenetic tree. Further, the full-length DNA of LvHMCV4 contains 2660 bp and two introns, which are located at the 80-538 bp and 2063-2227 bp regions, respectively. In addition, the mRNA transcript of LvHMCV4 was expressed highly in the hepatopancreas, lymphoid, brain and hemocytes, and weakly in the heart, intestine and gill, while no expression was found in the muscle, stomach and gut. Infection by Escherichia coli K12, Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio fluvialis, Streptococcus pyogenes or Staphylococcus aureus up-regulated significantly LvHMCV4 mRNA expression in the hepatopancreas. Furthermore, the recombinant protein of LvHMCV4 (rLvHMCV4) was prepared, which showed agglutination activities against six pathogenic bacteria at concentrations ranging from 15.6 to 125 μg/ml. When co-injected with V. parahaemolyticus in L.vannamei, rLvHMCV4 significantly increased the survival rate after 48 h injection. Together, these studies suggested that hemocyanin variant, LvHMCV4, might be involved in shrimp resistance to pathogenic infection.

  9. Remodeling A School Shop?

    ERIC Educational Resources Information Center

    Baker, G. E.

    1970-01-01

    Presents guidelines for remodeling a school shop combining major considerations of funds, program changes, class management, and flexibility, with the needs of wiring, painting, and placement of equipment. (Author)

  10. Endoventricular patch plasty improves results of LV aneurysmectomy.

    PubMed

    Jakob, H G; Zölch, B; Schuster, S; Iversen, S; Hake, U; Lippold, R; Erbel, R; Oelert, H

    1993-01-01

    From May 1985 to December 1991 52 patients were operated upon for postischemic left ventricular aneurysm (LV-A). Between May 1985 and July 1989 25 patients (group I) with a mean age of 59 (46-72) years underwent conventional aneurysmectomy with direct closure of the left ventricle (LV) and a mean of 1.9 (0-3) additional bypass grafts (54% triple-vessel disease). The hospital mortality was 8% (2/25) and the late mortality during a median follow-up time of 34 months was 28% (7/25) with a 4-year survival of 66%. Improvement in the quality of life (NYHA from 2.6 to 2.1, P = 0.078) and global left ventricular ejection fraction (EF) (from 35 to 38%) proved to be unsatisfactory in conjunction with the high late mortality rate. Between August 1989 and December 1991 a prospective series of 27 consecutive patients (group II) with a mean age of 61 (45-71) years underwent endoventricular patch plasty guided by two-dimensional transthoracic echocardiography (TTE) before and after surgery. The patch size and position were calculated preoperatively by measuring the distances from the mitral annulus to the infarct area which were reproduced during surgery with a simple ruler. A mean of 2.1 (0-4) bypass grafts were added with 62% of the patients having triple-vessel disease and 19% left main stenosis (P = 0.05, group I versus II). All patients have survived to date. One patient had to be excluded, giving a median follow-up time of 14 months for 26 patients. At the 6 months' control, the mean NYHA class was improved from 2.7 to 1.6, (P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Preventive Effect of Yuzu and Hesperidin on Left Ventricular Remodeling and Dysfunction in Rat Permanent Left Anterior Descending Coronary Artery Occlusion Model

    PubMed Central

    Yu, Hye Yon; Ahn, Ji Hun; Park, Se Won; Jung, Yi-Sook

    2015-01-01

    Left ventricular (LV) remodeling, which includes ventricular dilatation and increased interstitial fibrosis after myocardial infarction (MI), is the critical process underlying the progression to heart failure. Therefore, a novel approach for preventing LV remodeling after MI is highly desirable. Yuzu is a citrus plant originating in East Asia, and has a number of cardioprotective properties such as hesperidin. However, no study has proved whether yuzu can prevent LV remodeling. The aim of this study was to determine the effects of yuzu on heart failure (HF) and its potential impact on the LV remodeling process after MI. Our in vivo study using the permanent left anterior descending coronary artery (LAD) occlusion model demonstrate that one week pre-treatment with yuzu or its major metabolite hesperidin before LAD occlusion significantly attenuated cardiac dysfunction, myocyte apoptosis and inflammation. Not only yuzu but also hesperidin inhibited caspase-3 activity, myeloperoxidase expression, α-smooth muscle actin expression, and matrix metalloproteinase-2 activity in a permanent LAD occlusion rat model. To our knowledge, our findings provide the first evidence that yuzu and hesperidin prevent MI-induced ventricular dysfunction and structural remodeling of myocardium. PMID:25559243

  12. Preventive effect of yuzu and hesperidin on left ventricular remodeling and dysfunction in rat permanent left anterior descending coronary artery occlusion model.

    PubMed

    Yu, Hye Yon; Ahn, Ji Hun; Park, Se Won; Jung, Yi-Sook

    2015-01-01

    Left ventricular (LV) remodeling, which includes ventricular dilatation and increased interstitial fibrosis after myocardial infarction (MI), is the critical process underlying the progression to heart failure. Therefore, a novel approach for preventing LV remodeling after MI is highly desirable. Yuzu is a citrus plant originating in East Asia, and has a number of cardioprotective properties such as hesperidin. However, no study has proved whether yuzu can prevent LV remodeling. The aim of this study was to determine the effects of yuzu on heart failure (HF) and its potential impact on the LV remodeling process after MI. Our in vivo study using the permanent left anterior descending coronary artery (LAD) occlusion model demonstrate that one week pre-treatment with yuzu or its major metabolite hesperidin before LAD occlusion significantly attenuated cardiac dysfunction, myocyte apoptosis and inflammation. Not only yuzu but also hesperidin inhibited caspase-3 activity, myeloperoxidase expression, α-smooth muscle actin expression, and matrix metalloproteinase-2 activity in a permanent LAD occlusion rat model. To our knowledge, our findings provide the first evidence that yuzu and hesperidin prevent MI-induced ventricular dysfunction and structural remodeling of myocardium.

  13. Roles of HDAC2 and HDAC8 in Cardiac Remodeling in Renovascular Hypertensive Rats and the Effects of Valproic Acid Sodium.

    PubMed

    Li, Rui-Fang; Cao, Shan-Shan; Fang, Wei-Jin; Song, Ying; Luo, Xue-Ting; Wang, Hong-Yun; Wang, Jian-Gang

    2017-01-01

    Recent studies indicate that histone deacetylases (HDACs) activity is associated with the development and progression of cardiac hypertrophy. In this study, we investigated the effects of a HDACs inhibitor, valproic acid sodium (VPA), on cardiac remodeling and the differential expression of HDACs in left ventricles (LVs) of renovascular hypertensive rats. Renovascular hypertension was induced in rats by the two-kidney two-clip (2K2C) method. Cardiac remodeling, heart function and the differential expression of HDACs were examined at different weeks after 2K2C operation. The effects of VPA on cardiac remodeling, the expressions of HDACs, transforming growth factor-beta 1 (TGF-β1) and connective tissue growth factor (CTGF) in LV were investigated. The expressions of atrial natriuretic factor, β-myosin heavy chain, HDAC2 and HDAC8 increased in LV of 2K2C rats at 4, 8, 12 weeks after operation. Cardiac dysfunction, cardiac hypertrophy and fibrosis were markedly attenuated by VPA treatment in 2K2C rats. Further studies revealed that VPA inhibited the expressions of HDAC2, HDAC8, TGF-β1 and CTGF in LV of 2K2C rats. In summary, these data indicate that HDAC2 and HDAC8 play a key role in cardiac remodeling in renovascular hypertensive rats and that VPA attenuates hypertension and cardiac remodeling. The effect of VPA is possibly exerted via decreasing HDAC2, HDAC8, TGF-β1 and CTGF expressions in LV of 2K2C rats.

  14. Extracellular Matrix Remodeling During the Progression of Volume Overload-Induced Heart Failure

    PubMed Central

    Hutchinson, Kirk R.; Stewart, James A.; Lucchesi, Pamela A.

    2009-01-01

    Volume overload-induced heart failure results in progressive left ventricular remodeling characterized by chamber dilation, eccentric cardiac myocyte hypertrophy and changes in extracellular matrix (ECM) remodeling changes. The ECM matrix scaffold is an important determinant of the structural integrity of the myocardium and actively participates in force transmission across the LV wall. In response to this hemodynamic overload, the ECM undergoes a distinct pattern of remodeling that differs from pressure overload. Once thought to be a static entity, the ECM is now regarded to be a highly adaptive structure that is dynamically regulated by mechanical stress, neurohormonal activation, inflammation and oxidative stress, that result in alterations in collagen and other matrix components and a net change in matrix metalloproteinase (MMP) expression and activation. These changes dictate overall ECM turnover during volume overload hear failure progression. This review will discuss the cellular and molecular mechanisms that dictate the temporal patterns of ECM remodeling during heart disease progression. PMID:19524591

  15. Exposure to chronic alcohol accelerates development of wall stress and eccentric remodeling in rats with volume overload.

    PubMed

    Mouton, Alan J; Ninh, Van K; El Hajj, Elia C; El Hajj, Milad C; Gilpin, Nicholas W; Gardner, Jason D

    2016-08-01

    Chronic alcohol abuse is one of the leading causes of dilated cardiomyopathy (DCM) in the United States. Volume overload (VO) also produces DCM characterized by left ventricular (LV) dilatation and reduced systolic and diastolic function, eventually progressing to congestive heart failure. For this study, we hypothesized that chronic alcohol exposure would exacerbate cardiac dysfunction and remodeling due to VO. Aortocaval fistula surgery was used to induce VO, and compensatory cardiac remodeling was allowed to progress for either 3days (acute) or 8weeks (chronic). Alcohol was administered via chronic intermittent ethanol vapor (EtOH) for 2weeks before the acute study and for the duration of the 8week chronic study. Temporal alterations in LV function were assessed by echocardiography. At the 8week end point, pressure-volume loop analysis was performed by LV catheterization and cardiac tissue collected. EtOH did not exacerbate LV dilatation (end-systolic and diastolic diameter) or systolic dysfunction (fractional shortening, ejection fraction) due to VO. The combined stress of EtOH and VO decreased the eccentric index (posterior wall thickness to end-diastolic diameter ratio), increased end-diastolic pressure (EDP), and elevated diastolic wall stress. VO also led to increases in posterior wall thickness, which was not observed in the VO+EtOH group, and wall thickness significantly correlated with LV BNP expression. VO alone led to increases in interstitial collagen staining (picrosirius red), which while not statistically significant, tended to be decreased by EtOH. VO increased LV collagen I protein expression, whereas in rats with VO+EtOH, LV collagen I was not elevated relative to Sham. The combination of VO and EtOH also led to increases in LV collagen III expression relative to Sham. Rats with VO+EtOH had significantly lower collagen I/III ratio than rats with VO alone. During the acute remodeling phase of VO (3days), VO significantly increased collagen III

  16. Comparison of the usefulness of Doppler-derived deceleration time versus plasma brain natriuretic peptide to predict left ventricular remodeling after mechanical revascularization in patients with ST-elevation acute myocardial infarction and left ventricular systolic dysfunction.

    PubMed

    Cerisano, Giampaolo; Pucci, Paolo Domenico; Valenti, Renato; Boddi, Vieri; Migliorini, Angela; Tommasi, Maria Silvia; Raspanti, Silvia; Parodi, Guido; Antoniucci, David

    2005-04-15

    The correlation between Doppler deceleration time (DT) and brain natriuretic peptide (BNP) and their predictive value for detecting left ventricular (LV) remodeling in patients who are treated with primary percutaneous intervention for infarction and LV dysfunction are unknown. Fifty-six patients (64 +/- 12 years of age; 11 women) who had a first ST-segment elevation myocardial infarction and systolic dysfunction that was successfully treated with direct primary coronary intervention underwent 2-dimensional Doppler echocardiographic and plasma BNP evaluation at days 1 and 3 and 1 and 6 months after the index infarction. Repeat coronary angiograms were obtained at 1 and 6 months. Because of previous consistent evidence, 3 days after the index infarction was the time point of comparison between BNP and DT values. Echocardiographic LV remodeling was defined as an increase in end-diastolic volume index above baseline values of 2 x SD. Ventricular remodeling occurred in 20 patients (36%). Multivariate analyses that included BNP level, Doppler DT, echocardiographic measurements of systolic function, peak creatine kinase, and anterior infarct location showed Doppler DT to be the only predictor of LV remodeling (odds ratio 0.963, 95% confidence interval 0.936 to 0.990, p = 0.008). The optimal cutoff for DT in the prediction of 6-month LV remodeling was <136 ms (sensitivity 75%, specificity 97%, accuracy 81%, area under receiver-operating characteristic curve 0.90). Thus, in patients who have a first ST-segment elevation myocardial infarction and LV systolic dysfunction that is successfully treated with primary percutaneous coronary intervention, Doppler-derived DT 3 days after index infarction is more effective than BNP level in detecting patients who are at higher risk for 6-month LV remodeling.

  17. Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice

    PubMed Central

    Diwan, Abhinav; Krenz, Maike; Syed, Faisal M.; Wansapura, Janaka; Ren, Xiaoping; Koesters, Andrew G.; Li, Hairong; Kirshenbaum, Lorrie A.; Hahn, Harvey S.; Robbins, Jeffrey; Jones, W. Keith; Dorn, Gerald W.

    2007-01-01

    Following myocardial infarction, nonischemic myocyte death results in infarct expansion, myocardial loss, and ventricular dysfunction. Here, we demonstrate that a specific proapoptotic gene, Bnip3, minimizes ventricular remodeling in the mouse, despite having no effect on early or late infarct size. We evaluated the effects of ablating Bnip3 on cardiomyocyte death, infarct size, and ventricular remodeling after surgical ischemia/reperfusion (IR) injury in mice. Immediately following IR, no significant differences were observed between Bnip3–/– and WT mice. However, at 2 days after IR, apoptosis was diminished in Bnip3–/– periinfarct and remote myocardium, and at 3 weeks after IR, Bnip3–/– mice exhibited preserved LV systolic performance, diminished LV dilation, and decreased ventricular sphericalization. These results suggest myocardial salvage by inhibition of apoptosis. Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice, causing progressive LV dilation and diminished systolic function. Conditional Bnip3 overexpression prior to coronary ligation increased apoptosis and infarct size. These studies identify postischemic apoptosis by myocardial Bnip3 as a major determinant of ventricular remodeling in the infarcted heart, suggesting that Bnip3 may be an attractive therapeutic target. PMID:17909626

  18. Catestatin-A Novel Predictor of Left Ventricular Remodeling After Acute Myocardial Infarction

    PubMed Central

    Zhu, Dan; Xie, Hong; Wang, Xinyu; Liang, Ying; Yu, Haiyi; Gao, Wei

    2017-01-01

    Catestatin was discovered as a potent inhibitor of catecholamine secretion and plays important roles in the cardiovascular system. Our previous study demonstrates a close relationship between catestatin levels and prognosis of ST-elevation myocardial infarction (STEMI). Using the same population, the goal of this study is to investigate the ability of catestatin to predict left ventricular (LV) remodeling in STEMI patients. 72 patients and 30 controls were included. Catestatin was sampled after admission to the emergency room (ER), at day3 (D3), and day7 (D7) after STEMI. Echocardiography was performed at D3 and after 65 months for evaluation of LVEDD, EF, IVS, LVPW, E, A, E’, E/A, and E/E’. The changes of these parameters from D3 to 65 months were used to reflect the changes of ventricular structure and function. We found that plasma catestatin levels at D3 were highly correlated with the changes of LVEDD, EF, E, A, E’, E/A, as well as E/E’. Patients with higher catestatin levels developed worse ventricular function during the follow-up period. Single-point catestatin was effective to predict LVEDD change. And concurrently increasing catestatin and NT-proBNP levels predicted the highest risk of LV remodeling. This study suggests an important prognostic information of catestatin on LV remodeling.

  19. 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.

  20. LvDJ-1 plays an important role in resistance against Vibrio alginolyticus in Litopenaeus vannamei.

    PubMed

    Huang, Mingzhu; Liu, Yuan; Xie, Chenying; Wang, Wei-Na

    2015-05-01

    DJ-1 was first identified as an oncogene that transformed mouse NIH3T3 cells in cooperation with activated Ras. It has since exhibited a variety of functions in a range of organisms. In this study, the DJ-1 gene in Litopenaeus vannamei (LvDJ-1) was identified and characterized. A recombinant protein LvDJ-1 was produced in Pichia pastoris. LvDJ-1 expression in vivo was knocked down by dsRNA-mediated RNA interference (RNAi), which led to significantly decreased levels of LvDJ-1 mRNA and protein. When the L. vannamei were challenged with RNAi and Vibrio alginolyticus, the transcription and expression of copper zinc superoxide dismutase (LvCZSOD) in the hepatopancreas were dramatically lower in shrimp with knocked down LvDJ-1 than in controls. Transcription and expression of P53 (LvP53) were significantly higher in shrimp lacking LvDJ-1 than in controls. Hepatopancreas samples were analyzed using real time polymerase chain reaction and Western blot. Moreover, blood samples from the shrimp, assessed with flow cytometry, showed significant increases in respiratory burst and apoptosis in those lacking LvDJ-1 compared to the controls. Cumulative mortality in the shrimp lacking LvDJ-1 was significantly different from that in the control group after challenge with V. alginolyticus. Altogether, the results prove that LvDJ-1 regulates apoptosis and antioxidant activity, and that these functions play an important role in L. vannamei resistance against V. alginolyticus.

  1. Left ventricular remodeling after experimental myocardial cryoinjury in rats.

    PubMed

    Ciulla, Michele M; Paliotti, Roberta; Ferrero, Stefano; Braidotti, Paola; Esposito, Arturo; Gianelli, Umberto; Busca, Giuseppe; Cioffi, Ugo; Bulfamante, Gaetano; Magrini, Fabio

    2004-01-01

    The standard coronary ligation, the most studied model of experimental myocardial infarction in rats, is limited by high mortality and produces unpredictable areas of necrosis. To standardize the location and size of the infarct and to elucidate the mechanisms of myocardial remodeling and its progression to heart failure, we studied the functional, structural, and ultrastructural changes of myocardial infarction produced by experimental myocardial cryoinjury. The cryoinjury was successful in 24 (80%) of 30 male adult CD rats. A subepicardial infarct was documented on echocardiograms, with an average size of about 21%. Macroscopic examination reflected closely the stamp of the instrument used, without transition zones to viable myocardium. Histological examination, during the acute setting, revealed an extensive area of coagulation necrosis and hemorrhage in the subepicardium. An inflammatory infiltrate was evident since the 7th hour, whereas the reparative phase started within the first week, with proliferation of fibroblasts, endothelial cells, and myocytes. From the 7th day, deposition of collagen fibers was reported with a reparative scar completed at the 30th day. Ultrastructural study revealed vascular capillary damage and irreversible alterations of the myocytes in the acute setting and confirmed the histological findings of the later phases. The damage was associated with a progressive left ventricular (LV) remodeling, including thinning of the infarcted area, hypertrophy of the noninfarcted myocardium, and significant LV dilation. This process started from the 60th day and progressed over the subsequent 120 days period; at 180 days, a significant increase in LV filling pressure, indicative of heart failure, was found. In conclusion, myocardial cryodamage, although different in respect to ischemic damage, causes a standardized injury reproducing the cellular patterns of coagulation necrosis, early microvascular reperfusion, hemorrhage, inflammation

  2. Darbepoetin-α prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure

    PubMed Central

    Rastogi, Sharad; Imai, Makoto; Sharov, Victor G.; Mishra, Sudhish; Sabbah, Hani N.

    2008-01-01

    In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-α (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) ∼25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 μg/kg, n = 7) or to no therapy (HF, n = 7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1α, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1α and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia. PMID:18952719

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

    PubMed Central

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

    2016-01-01

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

  4. Effect of paroxetine on left ventricular remodeling in an in vivo rat model of myocardial infarction.

    PubMed

    Lassen, Thomas Ravn; Nielsen, Jan Møller; Johnsen, Jacob; Ringgaard, Steffen; Bøtker, Hans Erik; Kristiansen, Steen Buus

    2017-05-01

    Left ventricular (LV) remodeling following a myocardial infarction (MI) involves formation of reactive oxygen species (ROS). Paroxetine, a selective serotonin reuptake inhibitor, has an antioxidant effect in the vascular wall. We investigated whether paroxetine reduces myocardial ROS formation and LV remodeling following a MI. In a total of 32 Wistar rats, MI was induced by a 30-min ligation of the left anterior descending artery followed by 7- or 28-day reperfusion. During the 28 days of reperfusion, LV remodeling was evaluated by magnetic resonance imaging (MRI) and echocardiography (n = 20). After 28 days of reperfusion, the susceptibility to ventricular tachycardia was evaluated prior to sacrifice and histological assessment of myocyte cross-sectional area, fibrosis, and presence of myofibroblasts. Myocardial ROS formation was measured with dihydroethidium after 7 days of reperfusion in separate groups (n = 12). Diastolic LV volume, evaluated by MRI (417 ± 60 vs. 511 ± 64 µL, p < 0.05), and echocardiography (515 ± 80 vs. 596 ± 83 µL, p < 0.05) as well as diastolic LV internal diameter evaluated with echocardiography (7.2 ± 0.6 vs. 8.1 ± 0.7 mm, p < 0.05) were lower in the paroxetine group than in controls. Furthermore, myocyte cross-sectional area was reduced in the paroxetine group compared with controls (277 ± 26 vs. 354 ± 23 mm(3), p < 0.05) and ROS formation was reduced in the remote myocardium (0.415 ± 0.19 normalized to controls, p < 0.05). However, no differences in the presence of fibrosis or myofibroblasts were observed. Finally, paroxetine reduced the susceptibility to ventricular tachycardia (induced in 2/11 vs. 6/8 rats, p < 0.05). Paroxetine treatment following MI decreases LV remodeling and susceptibility to arrhythmias, probably by reducing ROS formation.

  5. 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

  6. Remodeling the Media Center.

    ERIC Educational Resources Information Center

    Baule, Steven M.

    1998-01-01

    Discusses items that need to be considered when remodeling a school media center. Highlights include space and location for various functions, including projections of print versus electronic media; electrical and data wiring needs; lighting; security and supervision; and reuse of existing furniture and equipment. (LRW)

  7. 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.

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

    PubMed

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

    2015-05-01

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

  9. Left and Right Ventricle Late Remodeling Following Myocardial Infarction in Rats

    PubMed Central

    Stefanon, Ivanita; Valero-Muñoz, María; Fernandes, Aurélia Araújo; Ribeiro, Rogério Faustino; Rodríguez, Cristina; Miana, Maria; Martínez-González, José; Spalenza, Jessica S.; Lahera, Vicente; Vassallo, Paula F.; Cachofeiro, Victoria

    2013-01-01

    Background The mechanisms involved in cardiac remodeling in left (LV) and right ventricles (RV) after myocardial infarction (MI) are still unclear. We assayed factors involved in collagen turnover in both ventricles following MI in rats either presenting signs of heart failure (pulmonary congestion and increased LVEDP) or not (INF-HF or INF, respectively). Methods MI was induced in male rats by ligation of the left coronary artery. Four weeks after MI gene expression of collagen I, connective tissue growth factor (CTGF), transforming growth factor β (TGF-β) and lysyl oxidase (LOX), metalloproteinase-2 (MMP2) and tissue inhibitor metalloproteinase-2 (TIMP2) as well as cardiac hemodynamic in both ventricles were evaluated. Results Ventricular dilatation, hypertrophy and an increase in interstitial fibrosis and myocyte size were observed in the RV and LV from INF-HF animals, whereas only LV dilatation and fibrosis in RV was present in INF. The LV fibrosis in INF-HF was associated with higher mRNA of collagen I, CTGF, TGF-β and LOX expressions than in INF and SHAM animals, while MMP2/TIMP2 mRNA ratio did not change. RV fibrosis in INF and INF-HF groups was associated with an increase in LOX mRNA and a reduction in MMP2/TIMP2 ratio. CTGF mRNA was increased only in the INF-HF group. Conclusions INF and INF-HF animals presented different patterns of remodeling in both ventricles. In the INF-HF group, fibrosis seems to be consequence of collagen production in LV, and by reductions in collagen degradation in RV of both INF and INF-HF animals. PMID:23741440

  10. 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

  11. Nucleosome Remodeling and Epigenetics

    PubMed Central

    Becker, Peter B.; Workman, Jerry L.

    2013-01-01

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

  12. Role of Arginase in Vessel Wall Remodeling

    PubMed Central

    Durante, William

    2013-01-01

    Arginase metabolizes the semi-essential amino acid l-arginine to l-ornithine and urea. There are two distinct isoforms of arginase, arginase I and II, which are encoded by separate genes and display differences in tissue distribution, subcellular localization, and molecular regulation. Blood vessels express both arginase I and II but their distribution appears to be cell-, vessel-, and species-specific. Both isoforms of arginase are induced by numerous pathologic stimuli and contribute to vascular cell dysfunction and vessel wall remodeling in several diseases. Clinical and experimental studies have documented increases in the expression and/or activity of arginase I or II in blood vessels following arterial injury and in pulmonary and arterial hypertension, aging, and atherosclerosis. Significantly, pharmacological inhibition or genetic ablation of arginase in animals ameliorates abnormalities in vascular cells and normalizes blood vessel architecture and function in all of these pathological states. The detrimental effect of arginase in vascular remodeling is attributable to its ability to stimulate vascular smooth muscle cell and endothelial cell proliferation, and collagen deposition by promoting the synthesis of polyamines and l-proline, respectively. In addition, arginase adversely impacts arterial remodeling by directing macrophages toward an inflammatory phenotype. Moreover, the proliferative, fibrotic, and inflammatory actions of arginase in the vasculature are further amplified by its capacity to inhibit nitric oxide (NO) synthesis by competing with NO synthase for substrate, l-arginine. Pharmacologic or molecular approaches targeting specific isoforms of arginase represent a promising strategy in treating obstructive fibroproliferative vascular disease. PMID:23717309

  13. Frequency of early remodeling of left ventricle and its comparison between patients with stroke volume ≥97 Ml versus patients with stroke volume <97 Ml after aortic valve replacement for severe aortic regurgitation

    PubMed Central

    Ali Rizvi, Hafiz Muhammad Farhan; Khalid, Zaigham Rasool; Baksh, Allah; Raza Baig, Mirza Ahmad

    2016-01-01

    Objectives: To evaluate the frequency of early remodeling in patients of severe aortic regurgitation after aortic valve replacement and to see the incidence of early remodeling in patients with stroke volume >97 ml versus < 97 ml before aortic valve replacement. Method: This was a prospective comparative study conducted from August 2013 to December 2014 in a tertiary care hospital. Fifty seven (57) patients of isolated chronic aortic regurgitation were included in this study. SPSS v23 was used for data analysis. Independent sample t-test was used for analysis of continuous variables and chi-square test for qualitative variables. Results: Out of fifty seven patients, early remodeling occurred in 34 (59.64%) patients after surgery. The mean pre-operative stroke volume of patient in whom remodeling occurred was 110.3+9.66 ml while mean pre-operative stroke volume of patients who did not undergo remodeling was 86.65+7.63 ml. There were 28 (82.4%) patients with stroke volume >97 ml in whom Remodeling occurred where as in patients with stroke volume <97 ml remodeling occurred only in 6 (17.6%) patients (p value 0.004). There was no in-hospital mortality. Conclusion: There is an association between stroke volume and early LV remodeling after Aortic valve replacement. Stroke volume >97 ml is a good predictor of early LV remodeling. PMID:28083026

  14. Recombinant feline leukemia virus (FeLV) variants establish a limited infection with altered cell tropism in specific-pathogen-free cats in the absence of FeLV subgroup A helper virus.

    PubMed

    Bechtel, M K; Hayes, K A; Mathes, L E; Pandey, R; Stromberg, P C; Roy-Burman, P

    1999-03-01

    Feline leukemia virus subgroup B (FeLV-B) is commonly associated with feline lymphosarcoma and arises through recombination between endogenous retroviral elements inherited in the cat genome and corresponding regions of the envelope (env) gene from FeLV subgroup A (FeLV-A). In vivo infectivity for FeLV-B is thought to be inefficient in the absence of FeLV-A. Proposed FeLV-A helper functions include enhanced replication efficiency, immune evasion, and replication rescue for defective FeLV-B virions. In vitro analysis of the recombinant FeLV-B-like viruses (rFeLVs) employed in this study confirmed these viruses were replication competent prior to their use in an in vivo study without FeLV-A helper virus. Eight specific-pathogen-free kittens were inoculated with the rFeLVs alone. Subsequent hematology and histology results were within normal limits, however, in the absence of detectable viremia, virus expression, or significant seroconversion, rFeLV proviral DNA was detected in bone marrow tissue of 4/4 (100%) cats at 45 weeks postinoculation (pi), indicating these rFeLVs established a limited but persistent infection in the absence of FeLV-A. Altered cell tropism was also noted. Focal infection was seen in T-cell areas of the splenic follicles in 3/4 (75%) rFeLV-infected cats analyzed, while an FeLV-A-infected cat showed focal infection in B-cell areas of the splenic follicles. Nucleotide sequence analysis of the surface glycoprotein portion of the rFeLV env gene amplified from bone marrow tissue collected at 45 weeks pi showed no sequence alterations from the original rFeLV inocula.

  15. Cardiac Resynchronization Therapy Restores Sympathovagal Balance in the Failing Heart by Differential Remodeling of Cholinergic Signaling

    PubMed Central

    DeMazumder, Deeptankar; Kass, David A.; O’Rourke, Brian; Tomaselli, Gordon F.

    2015-01-01

    Rationale Cardiac resynchronization therapy (CRT) is the only heart failure (HF) therapy documented to improve left ventricular (LV) function and reduce mortality. The underlying mechanisms are incompletely understood. While β-adrenergic signaling has been studied extensively, the effect of CRT on cholinergic signaling is unexplored. Objective We hypothesized that remodeling of cholinergic signaling plays an important role in the aberrant calcium signaling and depressed contractile and β-adrenergic responsiveness in dyssynchronous HF (DHF) that are restored by CRT. Methods and Results Canine tachypaced DHF and CRT models were generated to interrogate responses specific to dyssynchronous vs. resynchronized ventricular contraction during hemodynamic decompensation. Echocardiographic, electrocardiographic and invasive hemodynamic data were collected from normal controls, DHF and CRT models. LV tissue was used for biochemical analyses and functional measurements (calcium transient, sarcomere shortening) from isolated myocytes (N=42–104 myocytes/model; 6–9 hearts/model). Human LV myocardium was obtained for biochemical analyses from explanted failing (N=18) and non-failing (N=7) hearts. The M2 subtype of muscarinic acetylcholine receptors (M2-mAChR) was upregulated in human and canine HF compared to non-failing controls. CRT attenuated the increased M2-mAChR expression and Gαi-coupling, and enhanced M3-mAChR expression in association with enhanced calcium cycling, sarcomere shortening and β-adrenergic responsiveness. Despite model-dependent remodeling, cholinergic stimulation completely abolished isoproterenol-induced triggered activity in both DHF and CRT myocytes. Conclusions Remodeling of cholinergic signaling is a critical pathological component of human and canine HF. Differential remodeling of cholinergic signaling represents a novel mechanism for enhancing sympathovagal balance with CRT and may identify new targets for treatment of systolic HF. PMID

  16. Role of Circulating Angiotensin Converting Enzyme 2 in Left Ventricular Remodeling following Myocardial Infarction: A Prospective Controlled Study

    PubMed Central

    Ortiz-Pérez, José T.; Riera, Marta; Bosch, Xavier; De Caralt, Teresa M.; Perea, Rosario J.; Pascual, Julio; Soler, María José

    2013-01-01

    Angiotensin-converting enzyme 2 (ACE2) cleaves Angiotensin-II to Angiotensin-(1–7), a cardioprotective peptide. Serum soluble ACE2 (sACE2) activity is raised in chronic heart failure, suggesting a compensatory role in left ventricular dysfunction. Our aim was to study the relationship between sACE2 activity, infarct size, left ventricular systolic function and remodeling following ST-elevation myocardial infarction (STEMI). A contrast-enhanced cardiac magnetic resonance study was performed acutely in 95 patients with first STEMI and repeated at 6 months to measure LV end-diastolic volume index, ejection fraction and infarct size. Baseline sACE2 activities, measured by fluorescent enzymatic assay 24 to 48 hours and at 7 days from admission, were compared to that obtained in 22 matched controls. Patients showed higher sACE2 at baseline than controls (104.4 [87.4–134.8] vs 74.9 [62.8–87.5] RFU/µl/hr, p<0.001). At seven days, sACE2 activity significantly increased from baseline (115.5 [92.9–168.6] RFU/µl/hr, p<0.01). An inverse correlation between sACE2 activity with acute and follow-up ejection fraction was observed (r = −0.519, p<0.001; r = −0.453, p = 0.001, respectively). Additionally, sACE2 directly correlated with infarct size (r = 0.373, p<0.001). Both, infarct size (β = −0.470 [95%CI:−0.691:−0.248], p<0.001) and sACE2 at 7 days (β = −0.025 [95%CI:−0.048:−0.002], p = 0.030) were independent predictors of follow-up ejection fraction. Patients with sACE2 in the upper tertile had a 4.4 fold increase in the incidence of adverse left ventricular remodeling (95% confidence interval: 1.3 to 15.2, p = 0.027). In conclusion, serum sACE2 activity rises in relation to infarct size, left ventricular systolic dysfunction and is associated with the occurrence of left ventricular remodeling. PMID:23630610

  17. Value of three-dimensional strain parameters for predicting left ventricular remodeling after ST-elevation myocardial infarction.

    PubMed

    Xu, Lin; Huang, Xiaomin; Ma, Jun; Huang, Jiangming; Fan, Yongwang; Li, Huidi; Qiu, Jian; Zhang, Heye; Huang, Wenhua

    2017-02-01

    This study was to evaluate the value of multi-directional strain parameters derived from three-dimensional (3D) speckle tracking echocardiography (STE) for predicting left ventricular (LV) remodeling after ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) compared with that of two-dimensional (2D) global longitudinal strain (GLS). A total of 110 patients (mean age, 54 ± 9 years) after STEMI treated with primary PCI were enrolled in our study. At baseline (within 24 h after PCI), standard 2D echocardiography, 2D STE and 3D STE were performed to acquire the conventional echocardiographic parameters and strain parameters. At 3-month follow-up, standard 2D echocardiography was repeated to all the patients to determine LV remodeling, which was defined as a 20% increase in LV end-diastolic volume. At 3-month follow-up, LV remodeling occurred in 26 patients (24%). Compared with patients without LV remodeling, patients with remodeling had significantly reduced 2D GLS (-12.5 ± 3.2% vs -15.0 ± 3.1%, p < 0.001), 3D GLS (-9.9 ± 2.2% vs -13.1 ± 2.7%, p < 0.001), 3D global area strain (GAS) (-20.3 ± 3.9% vs -23.3 ± 4.8%, p = 0.005) and 3D global radial strain (GRS) (29.0 ± 7.4% vs 34.3 ± 8.5%, p = 0.007) at baseline, but there is no significant difference in 3D global circumferential strain (GCS) (-12.7 ± 2.9% vs -13.0 ± 3.2%, p = 0.822). Separated multivariate analysis shows that 2D GLS, 3D GLS, 3D GAS and 3D GRS all can be independent predictors of LV remodeling. However, receiver-operating characteristic curve analysis showed that the area under the curve of 3D GLS (0.82) for predicting LV remodeling was significantly higher than that of 2D GLS (0.72, p = 0.034), 3D GAS (0.68, p < 0.001) and 3D GRS (0.68, p < 0.001). In patients after STEMI, 2D GLS, 3D GLS, 3D GAS and 3D GRS but not 3D GCS measured after primary PCI are independent

  18. Beta-blockade improves adjacent regional sympathetic innervation during postinfarction remodeling.

    PubMed

    Kramer, C M; Nicol, P D; Rogers, W J; Seibel, P S; Park, C S; Reichek, N

    1999-10-01

    The effect of beta-blockade on left ventricular (LV) remodeling, when added to angiotensin-converting enzyme inhibition (ACEI) after anterior myocardial infarction (MI), is incompletely understood. On day 2 after coronary ligation-induced anteroapical infarction, 17 sheep were randomized to ramipril (ACEI, n = 8) or ramipril and metoprolol (ACEI-beta, n = 9). Magnetic resonance imaging was performed before and 8 wk after MI to measure changes in LV end-diastolic, end-systolic, and stroke volume indexes, LV mass index, ejection fraction (EF), and regional percent intramyocardial circumferential shortening. (123)I-labeled m-iodobenzylguanidine (MIBG) and fluorescent microspheres before and after adenosine were infused before death at 8 wk post-MI for quantitation of sympathetic innervation, blood flow, and blood flow reserve in adjacent and remote noninfarcted regions. Infarct size, regional blood flow, blood flow reserve, and the increase in LV mass and LV end-diastolic and end-systolic volume indexes were similar between groups. However, EF fell less over the 8-wk study period in the ACEI-beta group (-13 +/- 11 vs. -22 +/- 4% in ACEI, P < 0.05). The ratio of adjacent to remote region (123)I-MIBG uptake was greater in ACEI-beta animals than in the ACEI group (0.93 +/- 0.06 vs. 0.86 +/- 0.07, P < 0.04). When added to ACE inhibition after transmural anteroapical MI, beta-blockade improves EF and adjacent regional sympathetic innervation but does not alter LV size.

  19. Chromatin Remodeling and Plant Immunity.

    PubMed

    Chen, W; Zhu, Q; Liu, Y; Zhang, Q

    2017-01-01

    Chromatin remodeling, an important facet of the regulation of gene expression in eukaryotes, is performed by two major types of multisubunit complexes, covalent histone- or DNA-modifying complexes, and ATP-dependent chromosome remodeling complexes. Snf2 family DNA-dependent ATPases constitute the catalytic subunits of ATP-dependent chromosome remodeling complexes, which accounts for energy supply during chromatin remodeling. Increasing evidence indicates a critical role of chromatin remodeling in the establishment of long-lasting, even transgenerational immune memory in plants, which is supported by the findings that DNA methylation, histone deacetylation, and histone methylation can prime the promoters of immune-related genes required for disease defense. So what are the links between Snf2-mediated ATP-dependent chromosome remodeling and plant immunity, and what mechanisms might support its involvement in disease resistance?

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

    PubMed

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

    2015-11-01

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

  1. MRI Evaluation of Injectable Hyaluronic Acid-Based Hydrogel Therapy to Limit Ventricular Remodeling after Myocardial Infarction

    PubMed Central

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

    2015-01-01

    Injectable biomaterials are an attractive therapy to attenuate left ventricular (LV) remodeling after myocardial infarction (MI). Although studies have shown that injectable hydrogels improve cardiac structure and function in vivo, temporal changes in infarct material properties after treatment have not been assessed. Emerging imaging and modeling techniques now allow for serial, non-invasive estimation of infarct material properties. Specifically, cine MRI assesses global LV structure and function, late-gadolinium enhancement (LGE) MRI enables visualization of infarcted tissue to quantify infarct expansion, and spatial modulation of magnetization (SPAMM) tagging provides passive wall motion assessment as a measure of tissue strain, which can all be used to evaluate infarct properties when combined with finite element (FE) models. In this work, we investigated the temporal effects of degradable hyaluronic acid (HA) hydrogels on global LV remodeling, infarct thinning and expansion, and infarct stiffness in a porcine infarct model for 12 weeks post-MI using MRI and FE modeling. Hydrogel treatment led to decreased LV volumes, improved ejection fraction, and increased wall thickness when compared to controls. FE model simulations demonstrated that hydrogel therapy increased infarct stiffness for 12 weeks post-MI. Thus, evaluation of myocardial tissue properties through MRI and FE modeling provides insight into the influence of injectable hydrogel therapies on myocardial structure and function post-MI. PMID:26280951

  2. 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

  3. 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.

  4. Connective Tissue Growth Factor Regulates Cardiac Function and Tissue Remodeling in a Mouse Model of Dilated Cardiomyopathy

    PubMed Central

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

    2015-01-01

    Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective Tissue Growth Factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. Our aim was to test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase Cε (PKCε) mouse model of DCM. Transgenic mice expressing constitutively active PKCε in cardiomyocytes develop cardiac dysfunction that was evident by 3 months of age, and that progressed to cardiac fibrosis, heart failure, and increased mortality. Beginning at 3 months of age, PKCε mice were treated with a neutralizing monoclonal antibody to CTGF (FG-3149) for an additional 3 months. CTGF inhibition significantly improved left ventricular (LV) systolic and diastolic function in PKCε mice, and slowed the progression of LV dilatation. Using gene arrays and quantitative PCR, the expression of many genes associated with tissue remodeling were elevated in PKCε mice, but significantly decreased by CTGF inhibition. However total collagen deposition was not attenuated. The observation of significantly improved LV function by CTGF inhibition in PKCε mice suggests that CTGF inhibition may benefit patients with DCM. Additional studies to explore this potential are warranted. PMID:26549358

  5. Long-term intake of sesamin improves left ventricular remodelling in spontaneously hypertensive rats.

    PubMed

    Li, Wen-xing; Kong, Xiang; Zhang, Jun-xiu; Yang, Jie-ren

    2013-02-26

    This study was designed to evaluate the in vivo cardioprotective effects of food-derived sesamin in spontaneously hypertensive rats (SHR). The study was performed with 17-week-old male normotensive Wistar-Kyoto rats (WKY) and SHR which are untreated or treated with orally administered sesamin for 16 weeks before they were sacrificed. Long-term treatment with sesamin obviously improved left ventricular (LV) hypertrophy and fibrosis in SHR, as indicated by the decrease of LV weight/body weight, myocardial cell size, cardiac fibrosis and collagen type I expression as well as the amelioration of the LV ultrastructure. These effects were associated with reduced systolic blood pressure, enhanced cardiac total antioxidant capability and decreased malondialdehyde content, nitrotyrosine level and transforming growth factor β1 (TGF-β1) expression. All these results suggest that chronic treatment with sesamin improves LV remodeling in SHR through alleviation of oxidative and nitrative stress, reduction of blood pressure and downregulation of TGF-β1 expression.

  6. ET-receptor antagonism, myocardial gene expression, and ventricular remodeling during CHF in rats.

    PubMed

    Oie, E; Bjønerheim, R; Grogaard, H K; Kongshaug, H; Smiseth, O A; Attramadal, H

    1998-09-01

    Both myocardial and plasma endothelin-1 (ET-1) are elevated in congestive heart failure (CHF). However, the role played by endogenous ET-1 in the progression of CHF remains unknown. The aim of the present study was to investigate and correlate myocardial gene expression programs and left ventricular (LV) remodeling during chronic ET-receptor antagonism in CHF rats. After ligation of the left coronary artery, rats were randomized to oral treatment with a nonselective ET-receptor antagonist (bosentan, 100 mg . kg-1 . day-1, n = 11) or vehicle (saline, n = 13) for 15 days, starting 24 h after induction of myocardial infarction. Bosentan substantially attenuated LV dilatation during postinfarction failure as evaluated by echocardiography. Furthermore, bosentan decreased LV systolic and end-diastolic pressures and increased fractional shortening. Myocardial expression of preproET-1 mRNA and a fetal gene program characteristic of myocardial hypertrophy were increased in the CHF rats and were not affected by bosentan. Consistently, right ventricular-to-body weight ratios, diameters of cardiomyocytes, and echocardiographic analysis demonstrated a sustained hypertrophic response and a normalized relative wall thickness after intervention with bosentan. Thus the modest reduction of preload and afterload provided by bosentan substantially attenuates LV dilatation, causing improved pressure-volume relationships. However, the compensatory hypertrophic response was not altered by ET-receptor antagonism. Therefore, ET-1 does not appear to play a crucial role in the mechanisms of myocardial hypertrophy during the early phase of postinfarction failure.

  7. Diffuse myocardial fibrosis by T1-mapping in children with subclinical anthracycline cardiotoxicity: relationship to exercise capacity, cumulative dose and remodeling

    PubMed Central

    2013-01-01

    Background The late cardiotoxic effects of anthracycline chemotherapy influence morbidity and mortality in the growing population of childhood cancer survivors. Even with lower anthracycline doses, evidence of adverse cardiac remodeling and reduced exercise capacity exist. We aim to examine the relationship between cardiac structure, function and cardiovascular magnetic resonance (CMR) tissue characteristics with chemotherapy dose and exercise capacity in childhood cancer survivors. Methods Thirty patients (15 ± 3 years), at least 2 years following anthracycline treatment, underwent CMR, echocardiography, and cardiopulmonary exercise testing (peak VO2). CMR measured ventricular function, mass, T1 and T2 values, and myocardial extracellular volume fraction, ECV, a measure of diffuse fibrosis based on changes in myocardial T1 values pre- and post-gadolinium. Cardiac function was also assessed with conventional and speckle tracking echocardiography. Results Patients had normal LVEF (59 ± 7%) but peak VO2 was 17% lower than age-predicted normal values and were correlated with anthracycline dose (r = −0.49). Increased ECV correlated with decreased mass/volume ratio (r = −0.64), decreased LV wall thickness/height ratio (r = −0.72), lower peak VO2(r = −0.52), and higher cumulative dose (r = 0.40). Echocardiographic measures of systolic and diastolic function were reduced compared to normal values (p < 0.01), but had no relation to ECV, peak VO2 or cumulative dose. Conclusions Myocardial T1 and ECV were found to be early tissue markers of ventricular remodeling that may represent diffuse fibrosis in children with normal ejection fraction post anthracycline therapy, and are related to cumulative dose, exercise capacity and myocardial wall thinning. PMID:23758789

  8. Hypertension and cardiovascular remodelling in rats exposed to continuous light: protection by ACE-inhibition and melatonin.

    PubMed

    Simko, Fedor; Pechanova, Olga; Repova Bednarova, Kristina; Krajcirovicova, Kristina; Celec, Peter; Kamodyova, Natalia; Zorad, Stefan; Kucharska, Jarmila; Gvozdjakova, Anna; Adamcova, Michaela; Paulis, Ludovit

    2014-01-01

    Exposure of rats to continuous light attenuates melatonin production and results in hypertension development. This study investigated whether hypertension induced by continuous light (24 hours/day) exposure induces heart and aorta remodelling and if these alterations are prevented by melatonin or angiotensin converting enzyme inhibitor captopril. Four groups of 3-month-old male Wistar rats (10 per group) were treated as follows for six weeks: untreated controls, exposed to continuous light, light-exposed, and treated with either captopril (100 mg/kg/day) or melatonin (10 mg/kg/day). Exposure to continuous light led to hypertension, left ventricular (LV) hypertrophy and fibrosis, and enhancement of the oxidative load in the LV and aorta. Increase in systolic blood pressure by continuous light exposure was prevented completely by captopril and partially by melatonin. Both captopril and melatonin reduced the wall thickness and cross-sectional area of the aorta and reduced the level of oxidative stress. However, only captopril reduced LV hypertrophy development and only melatonin reduced LV hydroxyproline concentration in insoluble and total collagen in rats exposed to continuous light. In conclusion, captopril prevented LV hypertrophy development in the continuous light-induced hypertension model, while only melatonin significantly reduced fibrosis. This antifibrotic action of melatonin may be protective in hypertensive heart disease.

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

    PubMed

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

    2016-01-01

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

  10. 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.

  11. 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.

  12. Myocardial β2-adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure

    PubMed Central

    Rengo, G; Zincarelli, C; Femminella, GD; Liccardo, D; Pagano, G; de Lucia, C; Altobelli, GG; Cimini, V; Ruggiero, D; Perrone-Filardi, P; Gao, E; Ferrara, N; Lymperopoulos, A; Koch, WJ; Leosco, D

    2012-01-01

    BACKGROUND AND PURPOSE We investigated whether β2-adrenoceptor overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart. EXPERIMENTAL APPROACH We explored the angiogenic effects of β2-adrenoceptor overexpression in a rat model of post-myocardial infarction (MI) heart failure (HF). Cardiac adenoviral-mediated β2-adrenoceptor overexpression was obtained via direct intramyocardial injection 4-weeks post-MI. Adenovirus(Ad)-GFP and saline injected rats served as controls. Furthermore, we extended our observation to β2-adrenoceptor −/− mice undergoing MI. KEY RESULTS Transgenes were robustly expressed in the LV at 2 weeks post-gene therapy, whereas their expression was minimal at 4-weeks post-gene delivery. In HF rats, cardiac β2-adrenoceptor overexpression resulted in enhanced basal and isoprenaline-stimulated cardiac contractility at 2-weeks post-gene delivery. At 4 weeks post-gene transfer, Ad-β2-adrenoceptor HF rats showed improved LV remodeling and cardiac function. Importantly, β2-adrenoceptor overexpression was associated with a markedly increased capillary and arteriolar length density and enhanced in vivo myocardial blood flow and coronary reserve. At the molecular level, cardiac β2-adrenoceptor gene transfer induced the activation of the VEGF/PKB/eNOS pro-angiogenic pathway. In β2-adrenoceptor−/− mice, we found a ∼25% reduction in cardiac capillary density compared with β2-adrenoceptor+/+ mice. The lack of β2-adrenoceptors was associated with a higher mortality rate at 30 days and LV dilatation, and a worse global cardiac contractility compared with controls. CONCLUSIONS AND IMPLICATION β2-Adrenoceptors play an important role in the regulation of the angiogenic response in HF. The activation of VEGF/PKB/eNOS pathway seems to be strongly involved in this mechanism. PMID:22452704

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

    PubMed Central

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

    2016-01-01

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

  14. Low-level transcutaneous electrical stimulation of the auricular branch of vagus nerve ameliorates left ventricular remodeling and dysfunction by downregulation of matrix metalloproteinase 9 and transforming growth factor β1.

    PubMed

    Wang, Zhuo; Yu, Lilei; Huang, Bing; Wang, Songyun; Liao, Kai; Saren, Gaowa; Zhou, Xiaoya; Jiang, Hong

    2015-04-01

    Vagus nerve stimulation improves left ventricular (LV) remodeling by downregulation of matrix metalloproteinase 9 (MMP-9) and transforming growth factor β1 (TGF-β1). Our previous study found that low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve (LL-TS) could be substituted for vagus nerve stimulation to reverse cardiac remodeling. So, we hypothesize that LL-TS could ameliorate LV remodeling by regulation of MMP-9 and TGF-β1 after myocardial infarction (MI). Twenty-two beagle dogs were randomly divided into a control group (MI was induced by permanent ligation of the left coronary artery, n = 8), an LL-TS group (MI with long-term intermittent LL-TS, n = 8), and a normal group (sham ligation without stimulation, n = 6). At the end of 6 weeks follow-up, LL-TS significantly reduced LV end-systolic and end-diastolic dimensions, improved ejection fraction and ratio of early (E) to late (A) peak mitral inflow velocity. LL-TS attenuated interstitial fibrosis and collagen degradation in the noninfarcted myocardium compared with the control group. Elevated level of MMP-9 and TGF-β1 in LV tissue and peripheral plasma were diminished in the LL-TS treated dogs. LL-TS improves cardiac function and prevents cardiac remodeling in the late stages after MI by downregulation of MMP-9 and TGF-β1 expression.

  15. Experimental Myocardial Infarction Induces Altered Regulatory T Cell Hemostasis, and Adoptive Transfer Attenuates Subsequent Remodeling

    PubMed Central

    Sharir, Rinat; Semo, Jonathan; Shimoni, Sara; Ben-Mordechai, Tamar; Landa-Rouben, Natalie; Maysel-Auslender, Sofia; Shaish, Aviv; Entin–Meer, Michal; Keren, Gad; George, Jacob

    2014-01-01

    Background Ischemic cardiac damage is associated with upregulation of cardiac pro-inflammatory cytokines, as well as invasion of lymphocytes into the heart. Regulatory T cells (Tregs) are known to exert a suppressive effect on several immune cell types. We sought to determine whether the Treg pool is influenced by myocardial damage and whether Tregs transfer and deletion affect cardiac remodeling. Methods and Results The number and functional suppressive activity of Tregs were assayed in mice subjected to experimental myocardial infarction. The numbers of splenocyte-derived Tregs in the ischemic mice were significantly higher after the injury than in the controls, and their suppressive properties were significantly compromised. Compared with PBS, adoptive Treg transfer to mice with experimental infarction reduced infarct size and improved LV remodeling and functional performance by echocardiography. Treg deletion with blocking anti-CD25 antibodies did not influence infarct size or echocardiographic features of cardiac remodeling. Conclusion Treg numbers are increased whereas their function is compromised in mice with that underwent experimental infarction. Transfer of exogeneous Tregs results in attenuation of myocardial remodeling whereas their ablation has no effect. Thus, Tregs may serve as interesting potential interventional targets for attenuating left ventricular remodeling. PMID:25436994

  16. 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.

  17. Endothelial progenitor cells, microvascular obstruction, and left ventricular remodeling in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention.

    PubMed

    Porto, Italo; De Maria, Giovanni Luigi; Leone, Antonio Maria; Dato, Ilaria; D'Amario, Domenico; Burzotta, Francesco; Niccoli, Giampaolo; Trani, Carlo; Biasucci, Luigi Marzio; Bolognese, Leonardo; Crea, Filippo

    2013-09-15

    Endothelial progenitor cells (EPCs) are released from the bone marrow during cardiac ischemic events, potentially influencing vascular and myocardial repair. We assessed the clinical and angiographic correlates of EPC mobilization at the time of primary percutaneous coronary intervention in 78 patients with ST elevation myocardial infarction and the impact of both baseline and follow-up EPC levels on left ventricular (LV) remodeling. Blood samples were drawn from the aorta and the culprit coronary artery for cytofluorimetric EPC detection (CD34+CD45dimKDR+ cells, in percentage of cytofluorimetric counts). Area at risk was assessed by Bypass Angioplasty Revascularization Investigation myocardial jeopardy index, thrombotic burden as thrombus score and microvascular obstruction (MVO) as a combination of ST segment resolution and myocardial blush grade. Echocardiographic evaluation of LV remodeling was performed at 1-year follow-up in 54 patients, whereas peripheral EPC levels were reassessed in 40 patients. EPC levels during primary percutaneous coronary intervention were significantly higher in intracoronary than in aortic blood (0.043% vs 0.0006%, p <0.001). Both intracoronary and aortic EPC were related to area at risk extent, to intracoronary thrombus score (p <0.001), and inversely to MVO (p = 0.001). Peripheral EPC levels at 1-year follow-up were lower in patients with LV remodeling than in those without (0.001% [0.001 to 0.002] vs 0.003% [0.002 to 0.010]; p = 0.01) and independently predicted absence of remodeling at multivariate analysis. In conclusion, a rapid intracoronary EPC recruitment takes place in the early phases of ST elevation myocardial infarction, possibly reflecting an attempted reparative response. The extent of this mobilization seems to be correlated to the area at risk and to the amount of MVO. Persistently low levels of EPC are associated to LV remodeling.

  18. New Altered Non-Fibrillar Collagens in Human Dilated Cardiomyopathy: Role in the Remodeling Process

    PubMed Central

    Ortega, Ana; Tarazón, Estefanía; Triviño, Juan Carlos; Martínez-Dolz, Luis; González-Juanatey, José Ramón; Lago, Francisca; Portolés, Manuel; Rivera, Miguel

    2016-01-01

    Background In dilated cardiomyopathy (DCM), cardiac failure is accompanied by profound alterations of extracellular matrix associated with the progression of cardiac dilation and left ventricular (LV) dysfunction. Recently, we reported alterations of non-fibrillar collagen expression in ischemic cardiomyopathy linked to fibrosis and cardiac remodeling. We suspect that expression changes in genes coding for non-fibrillar collagens may have a potential role in DCM development. Objectives This study sought to analyze changes in the expression profile of non-fibrillar collagen genes in patients with DCM and to examine relationships between cardiac remodeling parameters and the expression levels of these genes. Methods and Results Twenty-three human left ventricle tissue samples were obtained from DCM patients (n = 13) undergoing heart transplantation and control donors (n = 10) for RNA sequencing analysis. We found increased mRNA levels of six non-fibrillar collagen genes, such as COL4A5, COL9A1, COL21A1, and COL23A1 (P < 0.05 for all), not previously described in DCM. Protein levels of COL8A1 and COL16A1 (P < 0.05 for both), were correspondingly increased. We also identified TGF-β1 significantly upregulated and related to both COL8A1 and COL16A1. Interestingly, we found a significant relationship between LV mass index and the gene expression level of COL8A1 (r = 0.653, P < 0.05). Conclusions In our research, we identified new non-fibrillar collagens with altered expression in DCM, being COL8A1 overexpression directly related to LV mass index, suggesting that they may be involved in the progression of cardiac dilation and remodeling. PMID:27936202

  19. Long-term cardiac remodeling and arrhythmias in nonelite marathon runners.

    PubMed

    Wilhelm, Matthias; Roten, Laurent; Tanner, Hildegard; Schmid, Jean-Paul; Wilhelm, Ilca; Saner, Hugo

    2012-07-01

    Long-term endurance sports are associated with atrial remodeling and atrial arrhythmias. More importantly, high-level endurance training may promote right ventricular (RV) dysfunction and complex ventricular arrhythmias. We investigated the long-term consequences of marathon running on cardiac remodeling as a potential substrate for arrhythmias with a focus on the right heart. We invited runners of the 2010 Grand Prix of Bern, a 10-mile race. Of 873 marathon and nonmarathon runners who applied, 122 (61 women) entered the final analysis. Subjects were stratified according to former marathon participations: control group (nonmarathon runners, n = 34), group 1 (1 marathon to 5 marathons, mean 2.7, n = 46), and group 2 (≥6 marathons, mean 12.8, n = 42). Mean age was 42 ± 7 years. Results were adjusted for gender, age, and lifetime training hours. Right and left atrial sizes increased with marathon participations. In group 2, right and left atrial enlargements were present in 60% and 74% of athletes, respectively. RV and left ventricular (LV) dimensions showed no differences among groups, and RV or LV dilatation was present in only 2.4% or 4.3% of marathon runners, respectively. In multiple linear regression analysis, marathon participation was an independent predictor of right and left atrial sizes but had no effect on RV and LV dimensions and function. Atrial and ventricular ectopic complexes during 24-hour Holter monitoring were low and equally distributed among groups. In conclusion, in nonelite athletes, marathon running was not associated with RV enlargement, dysfunction, or ventricular ectopy. Marathon running promoted biatrial remodeling.

  20. Study of the Reaction 48Ca + 248Cm → 296Lv* at RIKEN-GARIS

    NASA Astrophysics Data System (ADS)

    Kaji, Daiya; Morita, Kosuke; Morimoto, Kouji; Haba, Hiromitsu; Asai, Masato; Fujita, Kunihiro; Gan, Zaiguo; Geissel, Hans; Hasebe, Hiroo; Hofmann, Sigurd; Huang, MingHui; Komori, Yukiko; Ma, Long; Maurer, Joachim; Murakami, Masashi; Takeyama, Mirei; Tokanai, Fuyuki; Tanaka, Taiki; Wakabayashi, Yasuo; Yamaguchi, Takayuki; Yamaki, Sayaka; Yoshida, Atsushi

    2017-03-01

    The fusion reaction 48Ca + 248Cm → 296Lv* was investigated using the gas-filled recoil ion separator GARIS at RIKEN. The reaction was studied at excitation energies of 41.3 and 38.2 MeV. A total of seven decay chains were observed. Three of the chains were assigned to the decay of 292Lv and three to the decay of 293Lv. A possible observation of an α-decay branch of 284Cn populating the new spontaneously fissioning nucleus 280Ds is discussed. The assignment of one of the decay chains to the 3n evaporation channel, resulting in a spontaneous fission branch of 285Cn, or to the 2n channel, resulting in the population of the new fissioning nucleus 286Cn, is ambiguous. Measured cross sections are in agreement with previously published values.

  1. 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 ...

  2. Association of left atrial reservoir function with left atrial structural remodeling related to left ventricular dysfunction in asymptomatic patients with hypertension: evaluation by two-dimensional speckle-tracking echocardiography.

    PubMed

    Miyoshi, Hirokazu; Oishi, Yoshifumi; Mizuguchi, Yukio; Iuchi, Arata; Nagase, Norio; Ara, Nusrat; Oki, Takashi

    2015-01-01

    Left atrial (LA) structural and functional abnormalities are vital steps on the pathway toward heart failure with preserved ejection fraction in asymptomatic patients. The purpose of this study was to assess the relationship of LA function, particularly reservoir function, with LA structural remodeling related to the left ventricular (LV) dysfunction in asymptomatic patients with hypertension (HT) using conventional, tissue Doppler, and 2-D speckle-tracking echocardiography. Fifty age-matched healthy individuals and 140 patients with HT, including 75 with LA volume index (LAVI)<29 ml/m2 (normal LA group) and 65 with LAVI≥29 ml/m2 (large LA group), were enrolled. We defined peak early diastolic transmitral flow velocity/peak early diastolic mitral annular motion velocity (E/e')/peak systolic LA strain (S-LAs) as LA diastolic stiffness. The LV mass index, relative LV wall thickness, peak atrial systolic transmitral flow velocity, LA total, active, and passive emptying volume indexes, and E/e'/S-LAs were greatest, and S-LAs, peak early diastolic LA strain, peak systolic LV longitudinal strain and circumferential strain rate, and peak early diastolic LV radial strain rate were lower in the large LA group compared with control and/or normal LA group. Multivariate linear regression analysis revealed that aging, LA remodeling, and LV systolic and diastolic dysfunction are defined as strong predictors related to increased LA diastolic stiffness in the large LA group. HT alters LA dynamics significantly, with resultant increased LA volume and diastolic stiffness related to LV diastolic and systolic dysfunction, even in asymptomatic patients. Earlier treatment with renin–angiotensin system inhibitors may improve abnormal LA-LV interaction in this patient population.

  3. Building and Remodeling Synapses

    PubMed Central

    Benson, Deanna L.; Huntley, George W.

    2011-01-01

    Synaptic junctions are generated by adhesion proteins that bridge the synaptic cleft to firmly anchor pre- and postsynaptic membranes. Several cell adhesion molecule (CAM) families localize to synapses, but it is not yet completely understood how each synaptic CAM family contributes to synapse formation and/or structure, and whether or how smaller groups of CAMs serve as minimal, functionally cooperative adhesive units upon which structure is based. Synapse structure and function evolve over the course of development, and in mature animals, synapses are composed of a greater number of proteins, surrounded by a stabilizing extracellular matrix, and often contacted by astrocytic processes. Thus, in mature networks undergoing plasticity, persistent changes in synapse strength, morphology or number must be accompanied by selective and regulated remodeling of the neuropil. Recent work indicates that regulated, extracellular proteolysis may be essential for this, and rather than simply acting permissively to enable synapse plasticity, is more likely playing a proactive role in driving coordinated synaptic structural and functional modifications that underlie persistent changes in network activity. PMID:20882551

  4. Isolation and characterization of flat revertant cell lines from A-MuLV-transformed fibroblasts.

    PubMed

    Glass, D J; Rees-Jones, R W; Goff, S P

    1990-01-01

    Transformation of lymphoid and fibroblastic cells by Abelson murine leukemia virus (A-MuLV) is mediated by the viral tyrosine protein kinase. We do not yet know the important target proteins in the cell, the host proteins that modulate the kinase activity, or the host proteins involved in the signal-transduction pathway ultimately leading to altered patterns of cell growth. As a first step toward identifying these host proteins, we have isolated and characterized several flat revertant cell lines from transformed lines carrying v-abl. Clonal transformed cell lines used as parental strains were prepared by infecting Rat-2 fibroblasts with A-MuLV, using M-MuLV as helper. A rhodamine dye screening procedure was used to obtain three clones of morphologically flat revertant cells. Each of the three lines was non-refractile and contact inhibited. All the lines retained a transformation-competent copy of A-MuLV; all released high titers of virus capable of inducing foci on previously uninfected Rat-2 cells. Analyses of the revertant lines suggest that diverse mechanisms can lead to loss of transformed morphology.

  5. 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.

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

    PubMed

    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.

  7. A Meta-analysis of the effects of Exercise Training on Left Ventricular Remodeling Following Myocardial Infarction: Start early and go longer for greatest exercise benefits on remodeling

    PubMed Central

    2011-01-01

    Background The effects of variations in exercise training on Left ventricular (LV) remodeling in patients shortly after Myocardial Infarction (MI) are important but poorly understood. Methods Systematic review incorporating meta-analysis using meta-regression. Studies were identified via systematic searches of: OVID MEDLINE (1950 to 2009), Cochrane Central Register of Controlled Trials (1991 to 2009), AMED (1985 to 2009), EMBASE (1988 to 2009), PUBMED (1966 to 2009), SPORT DISCUS (1975 to 2009), SCOPUS (1950 to 2009) and WEB OF SCIENCE (1950 to 2009) using the medical subject headings: myocardial infarction, post myocardial infarction, post infarction, heart attack, ventricular remodeling, ventricular volumes, ejection fraction, left ventricular function, exercise, exercise therapy, kinesiotherapy, exercise training. Reference lists of all identified studies were also manually searched for further relevant studies. Studies selected were randomized controlled trials of exercise training interventions reporting ejection fraction (EF) and/or ventricular volumes in patients following recent MI (≤ 3 months) post-MI patients involving control groups. Studies were excluded if they were not randomized, did not have a 'usual-care' control (involving no exercise), evaluated a non-exercise intervention, or did not involve human subjects. Non-English studies were also excluded. Results After screening of 1029 trials, trials were identified that reported EF (12 trials, n = 647), End Systolic Volumes (ESV) (9 trials, n = 475) and End Diastolic Volumes (EDV) (10 trials, n = 512). Meta-regression identified that changes in EF effect size difference decreased as the time between MI and initiation of the exercise program lengthened, and increased as the duration of the program increased (Q = 25.48, df = 2, p < 0.01, R2 = 0.76). Greater reductions in ESV and EDV (as indicated by effect size decreases) occurred with earlier initiation of exercise training and with longer training

  8. 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.

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

    PubMed

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

    2015-08-14

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

  10. Comparison of three feline leukaemia virus (FeLV) point-of-care antigen test kits using blood and saliva.

    PubMed

    Westman, Mark E; Malik, Richard; Hall, Evelyn; Sheehy, Paul A; Norris, Jacqueline M

    2017-02-01

    Feline leukaemia virus (FeLV) can be a challenging infection to diagnose due to a complex feline host-pathogen relationship and occasionally unreliable test results. This study compared the accuracy of three point-of-care (PoC) FeLV p27 antigen test kits commonly used in Australia and available commercially worldwide (SNAP FIV/FeLV Combo, Witness FeLV/FIV and Anigen Rapid FIV/FeLV), using detection of FeLV provirus by an in-house real-time polymerase chain reaction (qPCR) assay as the diagnostic gold standard. Blood (n=563) and saliva (n=419) specimens were collected from a population of cats determined to include 491 FeLV-uninfected and 72 FeLV-infected individuals (45 progressive infections [p27 and qPCR positive], 27 regressive infections [p27 negative, qPCR positive]). Sensitivity and specificity using whole blood was 63% and 94% for SNAP Combo, 57% and 98% for Witness, and 57% and 98% for Anigen Rapid, respectively. SNAP Combo had a significantly lower specificity using blood compared to the other two kits (P=0.004 compared to Witness, P=0.007 compared to Anigen Rapid). False-positive test results occurred with all three kits using blood, and although using any two kits in parallel increased specificity, no combination of kits completely eliminated the occurrence of false-positive results. We therefore recommend FeLV proviral PCR testing for any cat that tests positive with a PoC FeLV antigen kit, as well as for any cat that has been potentially exposed to FeLV but tests negative with a FeLV antigen kit, before final assignment of FeLV status can be made with confidence. For saliva testing, sensitivity and specificity was 54% and 100%, respectively, for all three test kits. The reduced sensitivity of saliva testing compared to blood testing, although not statistically significant, suggests saliva testing with the current generation of PoC FeLV antigen kits is unsuitable for screening large populations of cats, such as in shelters.

  11. Circulating long-non coding RNAs as biomarkers of left ventricular diastolic function and remodelling in patients with well-controlled type 2 diabetes.

    PubMed

    de Gonzalo-Calvo, D; Kenneweg, F; Bang, C; Toro, R; van der Meer, R W; Rijzewijk, L J; Smit, J W; Lamb, H J; Llorente-Cortes, V; Thum, T

    2016-11-22

    Contractile dysfunction is underdiagnosed in early stages of diabetic cardiomyopathy. We evaluated the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers of subclinical cardiac abnormalities in type 2 diabetes. Forty-eight men with well-controlled type 2 diabetes and 12 healthy age-matched volunteers were enrolled in the study. Left ventricular (LV) parameters were measured by magnetic resonance imaging. A panel of lncRNAs was quantified in serum by RT-qPCR. No differences in expression levels of lncRNAs were observed between type 2 diabetes patients and healthy volunteers. In patients with type 2 diabetes, long intergenic non-coding RNA predicting cardiac remodeling (LIPCAR) was inversely associated with diastolic function, measured as E/A peak flow (P < 0.050 for all linear models). LIPCAR was positively associated with grade I diastolic dysfunction (P < 0.050 for all logistic models). Myocardial infarction-associated transcript (MIAT) and smooth muscle and endothelial cell-enriched migration/differentiation-associated long noncoding RNA (SENCR) were directly associated with LV mass to LV end-diastolic volume ratio, a marker of cardiac remodelling (P < 0.050 for all linear models). These findings were validated in a sample of 30 patients with well-controlled type 2 diabetes. LncRNAs are independent predictors of diastolic function and remodelling in patients with type 2 diabetes.

  12. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.

    PubMed

    Paulus, Walter J; Tschöpe, Carsten

    2013-07-23

    Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity.

  13. Circulating long-non coding RNAs as biomarkers of left ventricular diastolic function and remodelling in patients with well-controlled type 2 diabetes

    PubMed Central

    de Gonzalo-Calvo, D.; Kenneweg, F.; Bang, C.; Toro, R.; van der Meer, R. W.; Rijzewijk, L. J.; Smit, J. W.; Lamb, H. J.; Llorente-Cortes, V.; Thum, T.

    2016-01-01

    Contractile dysfunction is underdiagnosed in early stages of diabetic cardiomyopathy. We evaluated the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers of subclinical cardiac abnormalities in type 2 diabetes. Forty-eight men with well-controlled type 2 diabetes and 12 healthy age-matched volunteers were enrolled in the study. Left ventricular (LV) parameters were measured by magnetic resonance imaging. A panel of lncRNAs was quantified in serum by RT-qPCR. No differences in expression levels of lncRNAs were observed between type 2 diabetes patients and healthy volunteers. In patients with type 2 diabetes, long intergenic non-coding RNA predicting cardiac remodeling (LIPCAR) was inversely associated with diastolic function, measured as E/A peak flow (P < 0.050 for all linear models). LIPCAR was positively associated with grade I diastolic dysfunction (P < 0.050 for all logistic models). Myocardial infarction-associated transcript (MIAT) and smooth muscle and endothelial cell-enriched migration/differentiation-associated long noncoding RNA (SENCR) were directly associated with LV mass to LV end-diastolic volume ratio, a marker of cardiac remodelling (P < 0.050 for all linear models). These findings were validated in a sample of 30 patients with well-controlled type 2 diabetes. LncRNAs are independent predictors of diastolic function and remodelling in patients with type 2 diabetes. PMID:27874027

  14. Analysis of critical operating conditions for LV distribution networks with microgrids

    NASA Astrophysics Data System (ADS)

    Zehir, M. A.; Batman, A.; Sonmez, M. A.; Font, A.; Tsiamitros, D.; Stimoniaris, D.; Kollatou, T.; Bagriyanik, M.; Ozdemir, A.; Dialynas, E.

    2016-11-01

    Increase in the penetration of Distributed Generation (DG) in distribution networks, raises the risk of voltage limit violations while contributing to line losses. Especially in low voltage (LV) distribution networks (secondary distribution networks), impacts of active power flows on the bus voltages and on the network losses are more dominant. As network operators must meet regulatory limitations, they have to take into account the most critical operating conditions in their systems. In this study, it is aimed to present the impact of the worst operation cases of LV distribution networks comprising microgrids. Simulation studies are performed on a field data-based virtual test-bed. The simulations are repeated for several cases consisting different microgrid points of connection with different network loading and microgrid supply/demand conditions.

  15. Resistance to RadLV-induced leukemia: non-participation of splenic natural killer cells

    SciTech Connect

    St.-Pierre, Y.; Hugo, P.; Lemieux, S.; Lussier, G.; Potworowski, E.F.

    1988-08-01

    The phenotypic expression of genetically determined resistance to radiation leukemia virus (RadLV)-induced leukemia in mice has been shown to reside in the bone marrow. Because the bone marrow contains precursors of natural killer (NK) cells, known to play a role in retrovirally induced infections, and because these cells have been suggested as participating in resistance to radiation-induced leukemia, it was pertinent to establish whether their levels differed in strains of mice susceptible and resistant to leukemia. We therefore tested splenic NK cell levels in C57BL/Ka (susceptible) and B10.A(5R) (resistant) mice before viral inoculation, immediately after viral inoculation, and throughout the preleukemic period and showed that they were not different. This indicates that splenic NK cell levels have no bearing on the resistance to RadLV-induced leukemia and that other immune or non-immune mechanisms must be sought.

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

    PubMed Central

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

    2015-01-01

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

  17. Allogeneic Mesenchymal Precursor Cell Therapy to Limit Remodeling After Myocardial Infarction: The Effect of Cell Dosage

    PubMed Central

    Hamamoto, Hirotsugu; Gorman, Joseph H.; Ryan, Liam P.; Hinmon, Robin; Martens, Timothy P.; Schuster, Michael D.; Plappert, Theodore; Kiupel, Matti; St. John-Sutton, Martin G.; Itescu, Silviu; Gorman, Robert C.

    2011-01-01

    Background This experiment assessed the dose-dependent effect of a unique allogeneic STRO-3–positive mesenchymal precursor cell (MPC) on postinfarction left ventricular (LV) remodeling. The MPCs were administered in a manner that would simulate an off-the-self, early postinfarction, preventative approach to cardiac cell therapy in a sheep transmural myocardial infarct (MI) model. Methods Allogeneic MPCs were isolated from male crossbred sheep. Forty-six female sheep underwent coronary ligation to produce a transmural LV anteroapical infarction. One hour after infarction, the borderzone myocardium received an injection of 25, 75, 225, or 450 × 106 MPCs, or cell medium. Echocardiography was performed at 4 and 8 weeks after MI to quantify LV end-diastolic (LVEDV) and end-systolic volumes (LVESV), ejection fraction (EF), and infarct expansion. CD31 and smooth muscle actin (SMA) immunohistochemical staining was performed on infarct and borderzone specimens to quantify vascular density. Results Compared with controls, low-dose (25 and 75 × 106 cells) MPC treatment significantly attenuated infarct expansion and increases in LVEDV and LVESV. EF was improved at all cell doses. CD31 and SMA immunohistochemical staining demonstrated increased vascular density in the borderzone only at the lower cell doses. There was no evidence of myocardial regeneration within the infarct. Conclusion Allogeneic STRO-3 positive MPCs attenuate the remodeling response to transmural MI in a clinically relevant large-animal model. This effect is associated with vasculogenesis and arteriogenesis within the borderzone and infarct and is most pronounced at lower cell doses. PMID:19231391

  18. Ventricular remodeling in heart failure: the role of myocardial collagen.

    PubMed

    Janicki, J S; Brower, G L; Henegar, J R; Wang, L

    1995-01-01

    Collagen which is present in the myocardium in relatively small amounts is the most abundant structural protein of the connective tissue network. Its structural organization consists of a complex weave of collagen fibers that surrounds and interconnects myocytes, groups of myocytes, muscle fibers and muscle bundles. The conformation of interstitial fibrillar collagen makes it highly resistant to degradation by all proteinases other than specific collagenases. In hearts with myocardial damage secondary to myocardial infarction, chronic ischemia, inflammation, or cardiomyopathy, a complex sequence of compensatory events occur that eventually result in an adverse left ventricular remodeling. This continual state of remodeling is characterized by persistent collagenase activity, fibrillar collagen degradation, and progressive myocyte loss. The net effect is a shift in the balance between collagen synthesis and degradation which leads to an inadequate fibrillar collagen matrix, progressive ventricular dilatation and sphericalization with wall thinning and eventual congestive heart failure.

  19. Weight reduction via life-style modifications results in reverse remodelling and cardiac functional improvement in a patient with obesity.

    PubMed

    Hou, Chang; Zheng, Bo; Yang, Ying; Wang, Xin-Gang; Zhang, Bin; Shi, Qiu-Ping; Chen, Ming

    2017-03-09

    The prevalence of obesity has increased strikingly in recent years. Obesity is associated with increased left ventricular end-diastolic dimension (LVEDD), ventricular wall thickness, left ventricular (LV) mass, left atrial diameter, subtle myocardial systolic as well as diastolic dysfunction and has been identified as an independent predictor of these changes. It's convinced that weight reduction results in cardiac reverse remodelling, while the functional changes after weight reduction are variable. Here, we present a recent case of man with moderate obesity who acquires favourable regression in chamber size, wall thickness and significant improvement in cardiac function. Briefly, after life-style modifications and comprehensive secondary prevention, great amounts of weight loss was achieved simultaneously with decreased LVEDD and increased LV ejection fraction. As dietary intervention and regular physical activity are pivotal for these benefits, this non-invasive approach for weight loss should be advocated in selected patients.

  20. High prevalence of non-productive FeLV infection in necropsied cats and significant association with pathological findings.

    PubMed

    Suntz, M; Failing, K; Hecht, W; Schwartz, D; Reinacher, M

    2010-07-01

    Applying a combination of semi-nested PCR and immunohistology (IHC), the presence of exogenous feline leukemia virus infection was studied in 302 necropsied cats with various disorders. 9% showed the classical outcome of persistent productive FeLV infection which was represented by FeLV antigen expression in different organs. 152 cats (50%) harboured exogenous FeLV-specific proviral sequences in the bone marrow but did not express viral antigen. These cats were considered as horizontally but non-productively infected. Statistical evaluation showed a significant association of non-productive horizontal FeLV infection with a variety of parameters. Non-productively infected cats were statistically significantly older and more often originated from animal shelters than cats without exogenous FeLV infection. Furthermore, some pathological disorders like anemia, panleukopenia, and purulent inflammation showed significant association with non-productive FeLV infection. No significant association was found with lymphosarcoma, known for a long time to be induced by productive FeLV infection.

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

    PubMed

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

    2015-01-01

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

  2. 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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2015-11-01

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

  5. Small interfering RNA therapy against carbohydrate sulfotransferase 15 inhibits cardiac remodeling in rats with dilated cardiomyopathy.

    PubMed

    Watanabe, Kenichi; Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Nakamura, Takashi; Nakamura, Masahiko; Harima, Meilei; Yoneyama, Hiroyuki; Suzuki, Kenji

    2015-07-01

    Carbohydrate sulfotransferase 15 (CHST15) is a sulfotransferase responsible for biosynthesis of chondroitin sulfate E (CS-E), which plays important roles in numerous biological events such as biosynthesis of proinflammatory cytokines. However, the effects of CHST15 siRNA in rats with chronic heart failure (CHF) after experimental autoimmune myocarditis (EAM) have not yet been investigated. CHF was elicited in Lewis rats by immunization with cardiac myosin, and after immunization, the rats were divided into two groups and treated with either CHST15 siRNA (2μg/week) or vehicle. Age matched normal rats without immunizations were also included in this study. After 7weeks of treatment, we investigated the effects of CHST15 siRNA on cardiac function, proinflammatory cytokines, and cardiac remodeling in EAM rats. Myocardial functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by CHST15 siRNA treatment in rats with CHF compared with that of vehicle-treated CHF rats. CHST15 siRNA significantly reduced cardiac fibrosis, and hypertrophy and its marker molecules (left ventricular (LV) mRNA expressions of transforming growth factor beta1, collagens I and III, and atrial natriuretic peptide) compared with vehicle-treated CHF rats. CHF-induced increased myocardial mRNA expressions of proinflammatory cytokines [interleukin (IL)-6, IL-1β], monocyte chemoattractant protein-1, and matrix metalloproteinases (MMP-2 and -9), and CHST15 were also suppressed by the treatment with CHST15 siRNA. Western blotting study has confirmed the results obtained from mRNA analysis as CHST15 siRNA treated rats expressed reduced levels of inflammatory and cardiac remodeling marker proteins. Our results demonstrate for the first time, that CHST15 siRNA treatment significantly improved LV function and ameliorated the progression of cardiac remodeling in rats with CHF after EAM.

  6. 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.

  7. Mechanisms of ATP Dependent Chromatin Remodeling

    PubMed Central

    Gangaraju, Vamsi K.; Bartholomew, Blaine

    2007-01-01

    The inter-relationship between DNA repair and ATP dependent chromatin remodeling has begun to become very apparent with recent discoveries. ATP dependent remodeling complexes mobilize nucleosomes along DNA, promote the exchange of histones, or completely displace nucleosomes from DNA. These remodeling complexes are often categorized based on the domain organization of their catalytic subunit. The biochemical properties and structural information of several of these remodeling complexes are reviewed. The different models for how these complexes are able to mobilize nucleosomes and alter nucleosome structure are presented incorporating several recent findings. Finally the role of histone tails and their respective modifications in ATP-dependent remodeling are discussed. PMID:17306844

  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. Preclinical testing of the safety and tolerability of LV-mediated above normal alpha-L-iduronidase expression in murine and human hematopoietic cells using toxicology and biodistribution GLP studies.

    PubMed

    Visigalli, Ilaria; Delai, Stefania; Ferro, Francesca; Cecere, Francesca; Vezzoli, Michela; Sanvito, Francesca; Chanut, Franck; Benedicenti, Fabrizio; Spinozzi, Giulio; Wynn, Rob; Calabria, Andrea; Naldini, Luigi; Montini, Eugenio; Cristofori, Patrizia; Biffi, Alessandra

    2016-07-18

    In order to support the clinical application of hematopoietic stem cell (HSC) gene therapy for Mucopolysaccharidosis I (MPS I), we conducted biosafety studies to assess the toxicity and tumorigenic potential, as well as the biodistribution of HSCs and progenitor cells (HSPCs) transduced with lentiviral vectors (LV) encoding the cDNA of the alpha-iduronidase (IDUA) gene, which is mutated in MPS I patients. To this goal, toxicology and biodistribution studies were conducted employing Good Laboratory Practice (GLP) study practices. Vector integration sites studies were applied in order to predict adverse consequences of vector gene transfer and obtain HSC-related information. Overall, the results obtained in these studies provided robust evidence to support the safety and tolerability of high-efficiency LV-mediated gene transfer and above normal IDUA enzyme expression in both murine and human HSPCs and their in vivo progeny. Taken together these investigations provide essential safety data to support clinical testing of HSC gene therapy in MPS I patients. These studies have also underlined criticisms associated to the use of currently available models and highlighted the value of surrogate markers of tumorigenicity that may be further explored in the future. Notably, biological evidence supporting the efficacy of gene therapy on MPS I disease was also generated and the clonal contribution of LV-transduced HSPCs to hematopoiesis along serial transplantation was quantified in a minimum of 200-300 clones, with the different level of repopulating cells in primary recipients being reflected in the secondary.

  10. The immune responses triggered by CpG ODNs in shrimp Litopenaeus vannamei are associated with LvTolls.

    PubMed

    Sun, Rui; Wang, Mengqiang; Wang, Lingling; Yue, Feng; Yi, Qilin; Huang, Mengmeng; Liu, Rui; Qiu, Limei; Song, Linsheng

    2014-03-01

    CpG oligodeoxynucleotides (ODNs) represent a kind of pathogen-associated molecular patterns (PAMPs) as well as a novel adjuvant that activate the innate immune system through interaction with Toll-like receptor 9 (TLR9) in mammals. In the present study, the synthetic oligodeoxynucleotides, CpG ODN 2395, was employed to investigate the interactive mode of CpG ODNs with three known Tolls (LvToll1-3) from shrimp Litopenaeus vannamei. The mature peptides of extracellular domains of LvTolls (LvToll-ECDs) were recombinant expressed and their binding activities to CpG ODN 2395 were further examined by ELISA. rLvToll1-ECD and rLvToll3-ECD exhibited affinity to CpG ODN 2395 in a dose-dependent manner when their concentrations ranged from 0.25 to 2.00 μmol/L, while rLvToll2-ECD did not show any binding activities to CpG ODN 2395 in tested concentrations. Additionally, after the stimulation of CpG ODN 2395, the luciferase activities of HEK293T cells transfected with LvToll1-mosaic or LvToll3-mosaic were significantly increased to 2.38-fold (p<0.01) and 1.56-fold (p<0.01), while that in the HEK293T cells transfected with LvToll2-mosaic declined to 0.41-fold. The TNF-α activities were significantly enhanced (p<0.01), and a significant increase (p<0.05) of the NO production was observed at 12h post CpG ODN 2395 stimulation. Moreover, the induced TNF-α activities and increased NO production triggered by CpG ODN 2395 were abolished after the treatment of chloroquine (CQ). The uptake of CpG ODN 2395 by shrimp haemocytes was investigated using the laser scanning confocal microscope, and CpG ODN 2395 was observed to be internalized by the haemocytes and distributed in the cytoplasm with aggregated signals around the nucleuses. It suggested that the interactions of CpG ODNs with LvToll1 and LvToll3 as well as the mature of endosomes in the haemocytes of shrimp L. vannamei were indispensable for the triggering of immune responses by CpG ODNs, and the results provided a foundation

  11. 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.

  12. Neural remodeling in retinal degeneration.

    PubMed

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

    2003-09-01

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

  13. 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

  14. Vascular Remodeling in Pulmonary Hypertension

    PubMed Central

    Shimoda, Larissa A; Laurie, Steven S.

    2013-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2010-02-01

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

  16. Traditional Chinese Medication Qiliqiangxin attenuates cardiac remodeling after acute myocardial infarction in mice

    PubMed Central

    Tao, Lichan; Shen, Sutong; Fu, Siyi; Fang, Hongyi; Wang, Xiuzhi; Das, Saumya; Sluijter, Joost P. G.; Rosenzweig, Anthony; Zhou, Yonglan; Kong, Xiangqing; Xiao, Junjie; Li, Xinli

    2015-01-01

    In a multicenter randomized double-blind study we demonstrated that Qiliqiangxin (QLQX), a traditional Chinese medicine, had a protective effect in heart failure patients. However, whether and via which mechanism QLQX attenuates cardiac remodeling after acute myocardial infarction (AMI) is still unclear. AMI was created by ligating the left anterior descending coronary artery in mice. Treating the mice in the initial 3 days after AMI with QLQX did not change infarct size. However, QLQX treatment ameliorated adverse cardiac remodeling 3 weeks after AMI including better preservation of cardiac function, decreased apoptosis and reduced fibrosis. Peroxisome proliferator-activated receptor-γ (PPARγ) was down-regulated in control animals after AMI and up-regulated by QLQX administration. Interestingly, expression of AKT, SAPK/JNK, and ERK was not altered by QLQX treatment. Inhibition of PPARγ reduced the beneficial effects of QLQX in AMI remodeling, whereas activation of PPARγ failed to provide additional improvement in the presence of QLQX, suggesting a key role for PPARγ in the effects of QLQX during cardiac remodeling after AMI. This study indicates that QLQX attenuates cardiac remodeling after AMI by increasing PPARγ levels. Taken together, QLQX warrants further investigation as as a therapeutic intervention to mitigate remodeling and heart failure after AMI. PMID:25669146

  17. Increased Infarct Wall Thickness by a Bio-Inert Material Is Insufficient to Prevent Negative Left Ventricular Remodeling after Myocardial Infarction

    PubMed Central

    Rane, Aboli A.; Chuang, Joyce S.; Shah, Amul; Hu, Diane P.; Dalton, Nancy D.; Gu, Yusu; Peterson, Kirk L.; Omens, Jeffrey H.; Christman, Karen L.

    2011-01-01

    Background Several injectable materials have been shown to preserve or improve cardiac function as well as prevent or slow left ventricular (LV) remodeling post-myocardial infarction (MI). However, it is unclear as to whether it is the structural support or the bioactivity of these polymers that lead to beneficial effects. Herein, we examine how passive structural enhancement of the LV wall by an increase in wall thickness affects cardiac function post-MI using a bio-inert, non-degradable synthetic polymer in an effort to better understand the mechanisms by which injectable materials affect LV remodeling. Methods and Results Poly(ethylene glycol) (PEG) gels of storage modulus G′ = 0.5±0.1 kPa were injected and polymerized in situ one week after total occlusion of the left coronary artery in female Sprague Dawley rats. The animals were imaged using magnetic resonance imaging (MRI) at 7±1 day(s) post-MI as a baseline and again post-injection 49±4 days after MI. Infarct wall thickness was statistically increased in PEG gel injected vs. control animals (p<0.01). However, animals in the polymer and control groups showed decreases in cardiac function in terms of end diastolic volume, end systolic volume and ejection fraction compared to baseline (p<0.01). The cellular response to injection was also similar in both groups. Conclusion The results of this study demonstrate that passive structural reinforcement alone was insufficient to prevent post-MI remodeling, suggesting that bioactivity and/or cell infiltration due to degradation of injectable materials are likely playing a key role in the preservation of cardiac function, thus providing a deeper understanding of the influencing properties of biomaterials necessary to prevent post-MI negative remodeling. PMID:21731777

  18. 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

  19. 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.

  20. 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.

  1. 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

  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. 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

  4. 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…

  5. 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.

  6. Subdepressor dose of benidipine ameliorates diabetic cardiac remodeling accompanied by normalization of upregulated endothelin system in rats.

    PubMed

    Jesmin, Subrina; Hattori, Yuichi; Maeda, Seiji; Zaedi, Sohel; Sakuma, Ichiro; Miyauchi, Takashi

    2006-05-01

    We investigated whether benidipine, a long-acting calcium channel blocker (CCB), can normalize cardiac expression profiles of the endothelin (ET)-1 system in insulin-resistant diabetes. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of human Type 2 diabetes, were treated for 12 wk with vehicle or benidipine (3 mg.kg(-1).day(-1)). OLETF rats exhibited a significant increase in ET-1 in plasma and left ventricular (LV) tissues compared with nondiabetic controls. Expression of prepro-ET-1, ET-converting enzyme, and ET(A) and ET(B) receptors in LV tissues was also significantly higher in OLETF rats. The two MAPKs, JNK and p38MAPK, both of which are activated by ET-1, were more abundantly expressed in OLETF rat LV tissues. All these alterations were reversed to nondiabetic levels when OLETF rats were treated with the subdepressor dose of benidipine. Furthermore, benidipine therapy resulted in hindering cardiomyocyte hypertrophy and cardiac perivascular fibrosis in OLETF rats. The beneficial actions of benidipine at the subdepressor dose on cardiac remodeling in insulin-resistant diabetes may involve normalization of the upregulated ET-1 system.

  7. The frequency of occurrence and nature of recombinant feline leukemia viruses in the induction of multicentric lymphoma by infection of the domestic cat with FeLV-945.

    PubMed

    Ahmad, Shamim; Levy, Laura S

    2010-08-01

    During feline leukemia virus (FeLV) infection in the domestic cat, viruses with a novel envelope gene arise by recombination between endogenous FeLV-related elements and the exogenous infecting species. These recombinant viruses (FeLV-B) are of uncertain disease association, but have been linked to the induction of thymic lymphoma. To assess the role of FeLV-B in the induction of multicentric lymphoma and other non-T-cell disease, the frequency of occurrence and nature of FeLV-B were examined in diseased tissues from a large collection of FeLV-infected animals. Diseased tissues were examined by Southern blot and PCR amplification to detect the presence of FeLV-B. Further analysis was performed to establish the recombination junctions and infectivity of FeLV-B in diseased tissues. The results confirmed the frequent association of FeLV-B with thymic lymphoma but showed infrequent generation, low levels and lack of infectivity of FeLV-B in non-T-cell diseases including multicentric lymphoma.

  8. Adverse drug reactions.

    PubMed

    O'Reilly-Foley, Georgina

    2017-04-05

    What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article defined the different types of adverse drug reactions (ADRs) and explored when they can occur. It emphasised the importance of being knowledgeable about medications, considering patient safety when patients are taking medications, being alert to the possibility of ADRs, and recognising and responding to suspected ADRs.

  9. 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.

  10. Small artery remodelling in diabetes

    PubMed Central

    Rosei, Enrico Agabiti; Rizzoni, Damiano

    2010-01-01

    Abstract The aim of this article is to briefly review available data regarding changes in the structure of microvessels observed in patients with diabetes mellitus, and possible correction by effective treatment. The development of structural changes in the systemic vasculature is the end result of established hypertension. In essential hypertension, small arteries of smooth muscle cells are restructured around a smaller lumen and there is no net growth of the vascular wall, although in some secondary forms of hypertension, a hypertrophic remodelling may be detected. Moreover, in non-insulin-dependent diabetes mellitus a hypertrophic remodelling of subcutaneous small arteries is present. Indices of small resistance artery structure, such as the tunica media to internal lumen ratio, may have a strong prognostic significance in hypertensive and diabetic patients, over and above all other known cardiovascular risk factors. Therefore, regression of vascular alterations is an appealing goal of antihypertensive treatment. Different antihypertensive drugs seem to have different effect on vascular structure. In diabetic hypertensive patients, a significant regression of structural alterations of small resistance arteries with drugs blocking the renin–angiotensin system (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) was demonstrated. Alterations in the microcirculation represent a common pathological finding, and microangiopathy is one of the most important mechanisms involved in the development of organ damage as well as of clinical events in patients with diabetes mellitus. Renin–angiotensin system blockade seems to be effective in preventing/regressing alterations in microvascular structure. PMID:20646125

  11. Bone remodeling after renal transplantation.

    PubMed

    Bellorin-Font, Ezequiel; Rojas, Eudocia; Carlini, Raul G; Suniaga, Orlando; Weisinger, José R

    2003-06-01

    Several studies have indicated that bone alterations after transplantation are heterogeneous. Short-term studies after transplantation have shown that many patients exhibit a pattern consistent with adynamic bone disease. In contrast, patients with long-term renal transplantation show a more heterogeneous picture. Thus, while adynamic bone disease has also been described in these patients, most studies show decreased bone formation and prolonged mineralization lag-time faced with persisting bone resorption, and even clear evidence of generalized or focal osteomalacia in many patients. Thus, the main alterations in bone remodeling are a decrease in bone formation and mineralization up against persistent bone resorption, suggesting defective osteoblast function, decreased osteoblastogenesis, or increased osteoblast death rates. Indeed, recent studies from our laboratory have demonstrated that there is an early decrease in osteoblast number and surfaces, as well as in reduced bone formation rate and delayed mineralization after transplantation. These alterations are associated with an early increase in osteoblast apoptosis that correlates with low levels of serum phosphorus. These changes were more frequently observed in patients with low turnover bone disease. In contrast, PTH seemed to preserve osteoblast survival. The mechanisms of hypophosphatemia in these patients appear to be independent of PTH, suggesting that other phosphaturic factors may play a role. However, further studies are needed to determine the nature of a phosphaturic factor and its relationship to the alterations of bone remodeling after transplantation.

  12. Decoupled external forces in a predictor-corrector segmentation scheme for LV contours in Tagged MR images.

    PubMed

    Garcia-Barnes, Jaume; Andaluz, Albert; Carreras, Francesc; Gil, Debora

    2010-01-01

    Computation of functional regional scores requires proper identification of LV contours. On one hand, manual segmentation is robust, but it is time consuming and requires high expertise. On the other hand, the tag pattern in TMR sequences is a problem for automatic segmentation of LV boundaries. We propose a segmentation method based on a predictor-corrector (Active Contours - Shape Models) scheme. Special stress is put in the definition of the AC external forces. First, we introduce a semantic description of the LV that discriminates myocardial tissue by using texture and motion descriptors. Second, in order to ensure convergence regardless of the initial contour, the external energy is decoupled according to the orientation of the edges in the image potential. We have validated the model in terms of error in segmented contours and accuracy of regional clinical scores.

  13. Mesenchymal stem cells overexpressing CXCR4 attenuate remodeling of postmyocardial infarction by releasing matrix metalloproteinase-9.

    PubMed

    Huang, Wei; Wang, Tao; Zhang, Dongsheng; Zhao, Tiemin; Dai, Bo; Ashraf, Atif; Wang, Xiaohong; Xu, Meifeng; Millard, Ronald W; Fan, Guo-Chang; Ashraf, Muhammad; Yu, Xi-Yong; Wang, Yigang

    2012-03-20

    Myocardial infarction (MI) results in loss of myofibers in the ischemic zone of the heart, followed by scar formation. These factors increase barriers to mobilization of mesenchymal stem cells (MSC), thereby impeding their effectiveness in cardiac repair. This study examined MSC overexpressing CXCR4 (MSC(CX4)) to determine penetration into infarcted myocardium by releasing collagen degrading enzyme, matrix metalloproteinase-9 (MMP-9). In vitro, mouse MSC were utilized, including MSC using adenoviral transduction, to express CXCR4/green fluorescent protein (GFP) (MSC(CX4)), Null/GFP (MSC(Null)), MSC treated with siRNA targeting CXCR4 (MSC(siR)), MSC treated with control siRNA(MSC(Con-siR)), MSC(CX4) treated with siRNA targeting MMP-9 (MSC(CX4-siRMP9)) and MMP-14 (MSC(CX4-siRMP14)), MSC derived from MMP-9 knockout mouse with adenoviral transduction for GFP (MSC(MP9-)), or MSC(MP9-) plus overexpressing CXCR4 (MSC(MP9-CX4)). The ability to cross the basement membrane was evaluated in all MSC using a trans-collagen gel invasion assay. The CXCR4 and MMP expression were analyzed by Western blot. In vivo, MSC with various treatments were infused into mice via tail vein injections 7 days after MI. Echocardiography was performed before harvesting hearts for analysis at 4 weeks after MSC injection. Both in vitro and in vivo studies demonstrated upregulation of MMP-9 induced by MSC(CX4), promoting increased GFP(+) cell migration into the infarcted area in comparison to control group. This enhanced response was associated with reduced left ventricular (LV) fibrosis, increased LV free wall thickness, angiogenesis, and improved LV function. Under hypoxic conditions, MMP-9 is upregulated in MSC(CX4), thus facilitating cross of the basement membrane, resulting in an improved remodeling of post-MI tissue.

  14. 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

  15. 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.

  16. Characterizing the spectrum of right ventricular remodelling in response to chronic training.

    PubMed

    Sitges, Marta; Merino, Beatriz; Butakoff, Constatine; de la Garza, Maria Sanz; Paré, Carles; Montserrat, Silvia; Vidal, Barbara; Azqueta, Manel; Sarquella, Georgia; Gutierrez, Josep Antoni; Canal, Ramon; Brugada, Josep; Bijnens, Bart H

    2016-11-15

    The significance and spectrum of reduced right ventricular (RV) deformation, reported in endurance athletes, is unclear. To comprehensively analyze the cardiac performance at rest of athletes, especially focusing on integrating RV size and deformation to unravel the underlying triggers of this ventricular remodelling. Hundred professional male athletes and 50 sedentary healthy males of similar age were prospectively studied. Conventional echocardiographic parameters of all four chambers were obtained, as well as 2D echo-derived strain (2DSE) in the left (LV) and in the RV free wall with separate additional analysis of the RV basal and apical segments. Left and right-sided dimensions were larger in athletes than in controls, but with a disproportionate RA enlargement. RV global strain was lower in sportsmen (-26.8 ± 2.8% vs -28.5 ± 3.4%, p < 0.001) due to a decrease in the basal segment (-22.8 ± 3.5% vs -25.8 ± 4.0%, p < 0.001) resulting in a marked gradient of deformation from the RV inlet towards the apex. By integrating size, deformation and stroke volume, we observed that the LV working conditions were similar in all sportsmen while a wider variability existed in the RV. Cardiac remodelling in athletes is more pronounced in the right heart cavities with specific regional differences within the right ventricle, but with a wide variability among individuals. The large inter-individual differences, as well as its acute and chronic relevance warrant further investigation.

  17. Remodeling, Renovation, & Conversion of Educational Facilities.

    ERIC Educational Resources Information Center

    Association of Physical Plant Administrators of Universities and Colleges, Washington, DC.

    Based on a series of workshops, this collection of papers provides a framework for thought--emphasizing planning within time, flexibility, and maintenance constraints--as well as a practical guide for actual engineering of remodeling/renovation/conversion projects. Is remodeling always less expensive than new construction? Should high initial…

  18. Chromatin remodeling: nucleosomes bulging at the seams.

    PubMed

    Peterson, Craig L

    2002-04-02

    ATP-dependent chromatin remodeling enzymes, such as SWI/SNF, hydrolyze thousands of ATPs to regulate gene expression on chromatin fibers. Recent mechanistic studies suggest that these enzymes generate localized changes in DNA topology that drive formation of multiple, remodeled nucleosomal states.

  19. Adverse effects of cannabis.

    PubMed

    2011-01-01

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

  20. Adverse reactions to vaccines.

    PubMed

    Martin, Bryan L; Nelson, Michael R; Hershey, Joyce N; Engler, Renata J M

    2003-06-01

    (The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.) Immunization healthcare is becoming increasingly complex as the number and types of vaccines have continued to expand. Like all prescription drugs, vaccines may be associated with adverse events. The majority of these reactions are self-limited and not associated with prolonged disability. The media, Internet and public advocacy groups have focused on potentially serious vaccine-associated adverse events with questions raised about causal linkages to increasing frequencies of diseases such as autism and asthma. Despite a lack of evidence of a causal relationship to a variety of vaccine safety concerns, including extensive reviews by the Institute of Medicine, questions regarding vaccine safety continue to threaten the success of immunization programs. Risk communication arid individual risk assessment is further challenged by the public health success of vaccine programs creating the perception that certain vaccines are no longer necessary or justified because of the rare reaction risk. There is a need for improved understanding of true vaccine contraindications and precautions as well as host factors and disease threat in order to develop a patient specific balanced risk communication intervention. When they occur, vaccine related adverse events must be treated, documented and reported through the VAERS system. The increasing complexity of vaccination health care has led the Center of Disease Control and Prevention (CDC) to identify Vaccine Safety Assessment and Evaluation as a potential new specialty.

  1. 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.

  2. Role of thyroid hormones in ventricular remodeling.

    PubMed

    Rajagopalan, Viswanathan; Gerdes, A Martin

    2015-04-01

    Cardiac remodeling includes alterations in molecular, cellular, and interstitial systems contributing to changes in size, shape, and function of the heart. This may be the result of injury, alterations in hemodynamic load, neurohormonal effects, electrical abnormalities, metabolic changes, etc. Thyroid hormones (THs) serve as master regulators for diverse remodeling processes of the cardiovascular system-from the prenatal period to death. THs promote a beneficial cardiomyocyte shape and improve contractility, relaxation, and survival via reversal of molecular remodeling. THs reduce fibrosis by decreasing interstitial collagen and reduce the incidence and duration of arrhythmias via remodeling ion channel expression and function. THs restore metabolic function and also improve blood flow both by direct effects on the vessel architecture and decreasing atherosclerosis. Optimal levels of THs both in the circulation and in cardiac tissues are critical for normal homeostasis. This review highlights TH-based remodeling and clinically translatable strategies for diverse cardiovascular disorders.

  3. Adenosine A2A receptor agonist prevents cardiac remodeling and dysfunction in spontaneously hypertensive male rats after myocardial infarction

    PubMed Central

    da Silva, Jaqueline S; Gabriel-Costa, Daniele; Sudo, Roberto T; Wang, Hao; Groban, Leanne; Ferraz, Emanuele B; Nascimento, José Hamilton M; Fraga, Carlos Alberto M; Barreiro, Eliezer J; Zapata-Sudo, Gisele

    2017-01-01

    Background This work evaluated the hypothesis that 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), an agonist of adenosine A2A receptor, could be beneficial for preventing cardiac dysfunction due to hypertension associated with myocardial infarction (MI). Methods Male spontaneously hypertensive rats (SHR) were randomly divided into four groups (six animals per group): sham-operation (SHR-Sham), and myocardial infarction rats (SHR-MI) were treated orally either with vehicle or LASSBio-294 (10 and 20 mg.kg−1.d−1) for 4 weeks. Echocardiography and in vivo hemodynamic parameters measured left ventricle (LV) structure and function. Exercise tolerance was evaluated using a treadmill test. Cardiac remodeling was accessed by LV collagen deposition and tumor necrosis factor α expression. Results Early mitral inflow velocity was significantly reduced in the SHR-MI group, and there was significant recovery in a dose-dependent manner after treatment with LASSBio-294. Exercise intolerance observed in the SHR-MI group was prevented by 10 mg.kg−1.d−1 of LASS-Bio-294, and exercise tolerance exceeded that of the SHR-Sham group at 20 mg.kg−1.d−1. LV end-diastolic pressure increased after MI, and this was prevented by 10 and 20 mg.kg−1.d−1 of LASSBio-294. Sarcoplasmic reticulum Ca2+ ATPase levels were restored in a dose-dependent manner after treatment with LASSBio-294. Fibrosis and inflammatory processes were also counteracted by LASSBio-294, with reductions in LV collagen deposition and tumor necrosis factor α expression. Conclusion In summary, oral administration of LASSBio-294 after MI in a dose-dependent manner prevented the development of cardiac dysfunction, demonstrating this compound’s potential as an alternative treatment for heart failure in the setting of ischemic heart disease with superimposed chronic hypertension. PMID:28293100

  4. 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.

  5. Difficulties in demonstrating long term immunity in FeLV vaccinated cats due to increasing age-related resistance to infection

    PubMed Central

    2012-01-01

    Background Feline leukaemia virus (FeLV) is a pathogen causing fatal illness in cats worldwide, and as such there is a high demand for products to protect against disease. The duration of immunity provided by an inactivated FeLV vaccine, Versifel FeLV, when administered to cats of the target age was determined. Kittens received two vaccinations when aged 7 to 9 weeks old, and were subsequently challenged up to 36 months later with the FeLV-A Glasgow isolate. Results In all studies, all of the younger aged control kittens showed persistent FeLV p27 antigenaemia confirming that the challenge virus was severe and efficacious. In contrast, the control cats did not show the required level of persistent antigenaemia, with a maximum of 45% cats affected in the middle duration study and only 10% in the longer study. However, apart from one animal in the short duration study, all of the cats vaccinated with Versifel FeLV were negative for persistent antigenaemia and can be considered treatment successes. Conclusion In conclusion, we have shown that although age-related resistance to infection with a virulent FeLV challenge is evident from as early as 10 months of age, vaccination with Versifel FeLV may aid in the protection of cats from FeLV related disease up to three years after primary vaccination as kittens. PMID:22839692

  6. Molecular characterization of LvAV in response to white spot syndrome virus infection in the Pacific white shrimp (Litopenaeus vannamei).

    PubMed

    He, Shulin; Song, Lei; Qian, Zhaoying; Hou, Fujun; Liu, Yongjie; Wang, Xianzong; Peng, Zhangming; Sun, Chengbo; Liu, Xiaolin

    2015-07-01

    Litopenaeus vannamei is the most important farmed shrimp species globally, but its production is affected by several factors, including infectious disease. White spot syndrome virus (WSSV), in particular, causes significant shrimp losses. To understand the shrimp's immune response against WSSV, we cloned LvAV from L. vannamei and analyzed its expression pattern in different tissues, in addition to its expression following infection. We employed dsRNA and recombinant (r)LvAV to explore the potential role of LvAV in shrimp immunity when infected with WSSV. We find that LvAV is a C-type Lectin composed of 176 amino acids with a signal peptide and a specific C-type Lectin-type domain (CTLD). It shares 81% amino acid similarity with PmAV, an antiviral-like C-type Lectin from Penaeus monodom, and it is highly expressed in the hepatopancreas. Its expression is affected by infection with both WSSV and V. parahaemolyticus. Significantly, injection with rLvAV slowed WSSV replication, while injection with LvAV dsRNA initially led to enhanced virus propagation. Surprisingly, LvAV dsRNA subsequently led to a dramatic decrease in viral load in the later stages of infection, suggesting that LvAV may be subverted by WSSV to enhance viral replication or immune avoidance. Our results indicate that LvAV plays an important, but potentially complex role in the Pacific white shrimp's immune defense.

  7. The surface glycoprotein of a natural feline leukemia virus subgroup A variant, FeLV-945, as a determinant of disease outcome.

    PubMed

    Bolin, Lisa L; Ahmad, Shamim; Levy, Laura S

    2011-10-15

    Feline leukemia virus (FeLV) is a natural retrovirus of domestic cats associated with degenerative, proliferative and malignant diseases. Studies of FeLV infection in a cohort of naturally infected cats were undertaken to examine FeLV variation, the selective pressures operative in FeLV infection that lead to predominance of natural variants, and the consequences for infection and disease progression. A unique variant, designated FeLV-945, was identified as the predominant isolate in the cohort and was associated with non-T-cell diseases including multicentric lymphoma. FeLV-945 was assigned to the FeLV-A subgroup based on sequence analysis and receptor utilization, but was shown to differ in sequence from a prototype member of FeLV-A, designated FeLV-A/61E, in the long terminal repeat (LTR) and the surface glycoprotein gene (SU). A unique sequence motif in the FeLV-945 LTR was shown to function as a transcriptional enhancer and to confer a replicative advantage. The FeLV-945 SU protein was observed to differ in sequence as compared to FeLV-A/61E within functional domains known to determine receptor selection and binding. Experimental infection of newborn cats was performed using wild type FeLV-A/61E or recombinant FeLV-A/61E in which the LTR (61E/945L) or LTR and SU (61E/945SL) were exchanged for that of FeLV-945. Infection with either FeLV-A/61E or 61E/945L resulted in T-cell lymphoma of the thymus, although 61E/945L caused disease significantly more rapidly. In contrast, infection with 61E/945SL resulted in the rapid induction of a multicentric lymphoma of B-cell origin, thus recapitulating the outcome of natural infection and implicating FeLV-945 SU as a determinant of disease outcome. Recombinant FeLV-B was detected infrequently and at low levels in multicentric lymphomas, and was thereby not implicated in disease induction. Preliminary studies of receptor interaction indicated that virus particles bearing FeLV-945 SU bind to the FeLV-A receptor more

  8. [Ventricular "remodeling" after myocardial infarction].

    PubMed

    Cohen-Solal, A; Himbert, D; Guéret, P; Gourgon, R

    1991-06-01

    Cardiac failure is the principal medium-term complication of myocardial infarction. Changes in left ventricular geometry are observed after infarction, called ventricular remodeling, which, though compensatory initially, cause ventricular failure in the long-term. Experimental and clinical studies suggest that early treatment by coronary recanalisation, trinitrin and angiotensin converting enzyme inhibitors may prevent or limit the expansion and left ventricular dilatation after infarction, so improving ventricular function, and, at least in the animal, reduce mortality. Large scale trials with converting enzyme inhibitors are currently under way to determine the effects of this new therapeutic option. It would seem possible at present, independently of any reduction in the size of the infarction, to reduce or delay left ventricular dysfunction by interfering with the natural process of dilatation and ventricular modeling after infarction.

  9. Exercise-induced cardiac remodeling.

    PubMed

    Weiner, Rory B; Baggish, Aaron L

    2012-01-01

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

  10. 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.

  11. Zika Virus Induced Cellular Remodeling.

    PubMed

    Rossignol, Evan D; Peters, Kristen N; Connor, John H; Bullitt, Esther

    2017-03-20

    Zika virus (ZIKV) has been associated with morbidities such as Guillain-Barré, infant microcephaly, and ocular disease. The spread of this positive-sense, single-stranded RNA virus and its growing public health threat underscore gaps in our understanding of basic ZIKV virology. To advance knowledge of the virus replication cycle within mammalian cells, we use serial section three-dimensional electron tomography to demonstrate the widespread remodeling of intracellular membranes upon infection with ZIKV. We report extensive structural rearrangements of the endoplasmic reticulum and reveal stages of the ZIKV viral replication cycle. Structures associated with RNA genome replication and virus assembly are observed integrated within the endoplasmic reticulum, and we show viruses in transit through the Golgi apparatus for viral maturation, and subsequent cellular egress. This study characterizes in detail the three-dimensional ultrastructural organization of the ZIKV replication cycle stages. Our results show close adherence of the ZIKV replication cycle to the existing flavivirus replication paradigm.

  12. Tissue remodelling in pulmonary fibrosis.

    PubMed

    Knudsen, Lars; Ruppert, Clemens; Ochs, Matthias

    2017-03-01

    Many lung diseases result in fibrotic remodelling. Fibrotic lung disorders can be divided into diseases with known and unknown aetiology. Among those with unknown aetiology, idiopathic pulmonary fibrosis (IPF) is a common diagnosis. Because of its progressive character leading to a rapid decline in lung function, it is a fatal disease with poor prognosis and limited therapeutic options. Thus, IPF has motivated many studies in the last few decades in order to increase our mechanistic understanding of the pathogenesis of the disease. The current concept suggests an ongoing injury of the alveolar epithelium, an impaired regeneration capacity, alveolar collapse and, finally, a fibroproliferative response. The origin of lung injury remains elusive but a diversity of factors, which will be discussed in this article, has been shown to be associated with IPF. Alveolar epithelial type II (AE2) cells play a key role in lung fibrosis and their crucial role for epithelial regeneration, stabilisation of alveoli and interaction with fibroblasts, all known to be responsible for collagen deposition, will be illustrated. Whereas mechanisms of collagen deposition and fibroproliferation are the focus of many studies in the field, the awareness of other mechanisms in this disease is currently limited to biochemical and imaging studies including quantitative assessments of lung structure in IPF and animal models assigning alveolar collapse and collapse induration crucial roles for the degradation of the lung resulting in de-aeration and loss of surface area. Dysfunctional AE2 cells, instable alveoli and mechanical stress trigger remodelling that consists of collapsed alveoli absorbed by fibrotic tissue (i.e., collapse induration).

  13. 31P NMR 2D Mapping of Creatine Kinase Forward Flux Rate in Hearts with Postinfarction Left Ventricular Remodeling in Response to Cell Therapy

    PubMed Central

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

    2016-01-01

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

  14. A novel hydrodynamic approach of drag-reducing polymers to improve left ventricular hypertrophy and aortic remodeling in spontaneously hypertensive rats

    PubMed Central

    Zhang, Xinlu; Wang, Xu; Hu, Feng; Zhou, Boda; Chen, Hai-Bin; Zha, Daogang; Liu, Yili; Guo, Yansong; Zheng, Lemin; Xiu, Jiancheng

    2016-01-01

    Drag-reducing polymers (DRPs), when added in minute concentrations, have been shown to decrease peripheral vascular resistance. In this study, the effect of DRPs on the hypertension-induced left ventricular hypertrophy and aortic remodeling was evaluated in spontaneously hypertensive rats (SHR). Male SHR and age-matched Wistar rats were divided into four groups and received intravenous injection of normal saline (NS) or DRPs. Body weight (BW), heart rate (HR) and systolic blood pressure (SBP) were measured. Echocardiography was used to evaluate the changes in left ventricle (LV) function and global wall motion. The LV and aorta were stained by hematoxylin and eosin. Cell size of cardiomyocytes and aortic medial thickness were evaluated for each section. The expression of endothelin-1 (ET-1) of LV and aorta was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. There was no significant difference in the increase of SBP among SHR + NS, SHR + 10DRP and SHR + 20DRP groups. SHR + NS group had markedly smaller left ventricular end-systolic diameter and left ventricular end-diastolic diameter but bigger anterior and posterior systolic wall thicknesses, while there was no significant difference in fractional shortening and ejection fraction. The cross-sectional areas (CSAs) of cardiomyocytes and the medial thickness of the aorta in SHR + 10 (ppm) DRP and SHR + 20 (ppm) DRP groups were significantly reduced compared with SHR + NS group. The expression of ET-1 in SHR + 10DRP and SHR + 20DRP groups was significantly attenuated. These results suggest that chronic treatment with DRPs can protect against left ventricular hypertrophy and aortic remodeling. DRPs may offer a new approach to the treatment of left ventricular hypertrophy and aortic remodeling caused by hypertension. PMID:28008249

  15. A novel hydrodynamic approach of drag-reducing polymers to improve left ventricular hypertrophy and aortic remodeling in spontaneously hypertensive rats.

    PubMed

    Zhang, Xinlu; Wang, Xu; Hu, Feng; Zhou, Boda; Chen, Hai-Bin; Zha, Daogang; Liu, Yili; Guo, Yansong; Zheng, Lemin; Xiu, Jiancheng

    Drag-reducing polymers (DRPs), when added in minute concentrations, have been shown to decrease peripheral vascular resistance. In this study, the effect of DRPs on the hypertension-induced left ventricular hypertrophy and aortic remodeling was evaluated in spontaneously hypertensive rats (SHR). Male SHR and age-matched Wistar rats were divided into four groups and received intravenous injection of normal saline (NS) or DRPs. Body weight (BW), heart rate (HR) and systolic blood pressure (SBP) were measured. Echocardiography was used to evaluate the changes in left ventricle (LV) function and global wall motion. The LV and aorta were stained by hematoxylin and eosin. Cell size of cardiomyocytes and aortic medial thickness were evaluated for each section. The expression of endothelin-1 (ET-1) of LV and aorta was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. There was no significant difference in the increase of SBP among SHR + NS, SHR + 10DRP and SHR + 20DRP groups. SHR + NS group had markedly smaller left ventricular end-systolic diameter and left ventricular end-diastolic diameter but bigger anterior and posterior systolic wall thicknesses, while there was no significant difference in fractional shortening and ejection fraction. The cross-sectional areas (CSAs) of cardiomyocytes and the medial thickness of the aorta in SHR + 10 (ppm) DRP and SHR + 20 (ppm) DRP groups were significantly reduced compared with SHR + NS group. The expression of ET-1 in SHR + 10DRP and SHR + 20DRP groups was significantly attenuated. These results suggest that chronic treatment with DRPs can protect against left ventricular hypertrophy and aortic remodeling. DRPs may offer a new approach to the treatment of left ventricular hypertrophy and aortic remodeling caused by hypertension.

  16. Spacial and Temporal Patterns of Gene Expression After Cardiac MEK1 Gene Transfer Improve Post-Infarction Remodeling Without Inducing Global Hypertrophy.

    PubMed

    Fan, Yanying; Yang, Yi-Lin; Yeh, Che-Chung; Mann, Michael J

    2017-04-01

    Alteration of mitogen activated protein (MAP) kinase signaling in transgenic mice can ameliorate post-myocardial infarction (MI) remodeling. However, pre-existing changes in transgenic hearts and clinically unrealistic transgene expression likely affect the response to injury; it is unknown whether clinically relevant induction of transgene expression in an otherwise normal heart can yield similar benefits. Constitutively active MEK1 (aMEK1) or LacZ adeno-associated virus 9 (AAV9) vectors were injected into the left ventricular (LV) chambers of mice either just before or after coronary ligation. Hearts were evaluated via Western blot, quantitative polymerase chain reaction, histology, and echocardiography. AAV9-mediated aMEK1 delivery altered ERK1/2 expression/activation as in transgenic mice. Transgene expression was not immediately detectable but plateaued at 17 days, and therefore did not likely impact acute ischemia as it would in transgenics. With AAV9-aMEK1 injection just prior to MI, robust expression in the infarct border zone during post-MI remodeling increased border zone wall thickness and reduced infarct size versus controls at 4 weeks, but did not induce global hypertrophy. Significant improvements in local and global LV function were observed, as were trends toward a preservation of LV volume. Delivery after ligation significantly lowered transgene expression in the infarct border zone and did not yield structural or functional benefits. The primary benefits observed in transgenic mice, ameliorated remodeling, and reduced chronic infarct size, were achievable via clinically relevant gene transfer of aMEK1, supporting ongoing translational efforts. Important differences, however, were observed, and consideration must be given to the timing and distribution of transgene delivery and expression. J. Cell. Biochem. 118: 775-784, 2017. © 2016 Wiley Periodicals, Inc.

  17. 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...

  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. 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

  20. [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.

  1. Airway remodeling in asthma: what really matters.

    PubMed

    Fehrenbach, Heinz; Wagner, Christina; Wegmann, Michael

    2017-03-01

    Airway remodeling is generally quite broadly defined as any change in composition, distribution, thickness, mass or volume and/or number of structural components observed in the airway wall of patients relative to healthy individuals. However, two types of airway remodeling should be distinguished more clearly: (1) physiological airway remodeling, which encompasses structural changes that occur regularly during normal lung development and growth leading to a normal mature airway wall or as an acute and transient response to injury and/or inflammation, which ultimately results in restoration of a normal airway structures; and (2) pathological airway remodeling, which comprises those structural alterations that occur as a result of either disturbed lung development or as a response to chronic injury and/or inflammation leading to persistently altered airway wall structures and function. This review will address a few major aspects: (1) what are reliable quantitative approaches to assess airway remodeling? (2) Are there any indications supporting the notion that airway remodeling can occur as a primary event, i.e., before any inflammatory process was initiated? (3) What is known about airway remodeling being a secondary event to inflammation? And (4), what can we learn from the different animal models ranging from invertebrate to primate models in the study of airway remodeling? Future studies are required addressing particularly pheno-/endotype-specific aspects of airway remodeling using both endotype-specific animal models and "endotyped" human asthmatics. Hopefully, novel in vivo imaging techniques will be further advanced to allow monitoring development, growth and inflammation of the airways already at a very early stage in life.

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

    PubMed

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

    2016-12-01

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

  3. Maternal Uterine Vascular Remodeling During Pregnancy

    PubMed Central

    Osol, George; Mandala, Maurizio

    2009-01-01

    Sufficient uteroplacental blood flow is essential for normal pregnancy outcome and is accomplished by the coordinated growth and remodeling of the entire uterine circulation, as well as the creation of a new fetal vascular organ: the placenta. The process of remodeling involves a number of cellular processes, including hyperplasia and hypertrophy, rearrangement of existing elements, and changes in extracellular matrix. In this review, we provide information on uterine blood flow increases during pregnancy, the influence of placentation type on the distribution of uterine vascular resistance, consideration of the patterns, nature, and extent of maternal uterine vascular remodeling during pregnancy, and what is known about the underlying cellular mechanisms. PMID:19196652

  4. 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.

  5. Effects of a timely therapy with doxycycline on the left ventricular remodeling according to the pre-procedural TIMI flow grade in patients with ST-elevation acute myocardial infarction.

    PubMed

    Cerisano, Giampaolo; Buonamici, Piergiovanni; Valenti, Renato; Moschi, Guia; Taddeucci, Enrico; Giurlani, Letizia; Migliorini, Angela; Vergara, Ruben; Parodi, Guido; Sciagrà, Roberto; Romito, Roberta; Colonna, Paolo; Antoniucci, David

    2014-07-01

    Doxycycline has been demonstrated to reduced left ventricular (LV) remodeling, but its effect in patients with ST-elevation myocardial infarction (STEMI) and a baseline occluded [thrombolysis in myocardial infarction (TIMI) flow grade ≤1] infarct-related artery (IRA) is unknown. According to the baseline TIMI flow grade, 110 patients with a first STEMI were divided into 2 groups. Group 1: 77 patients with TIMI flow ≤1 (40 patients treated with doxycycline and 37 with standard therapy, respectively), and a Group 2: 33 patients with TIMI flow 2-3 (15 patients treated with doxycycline and 18 with standard therapy, respectively). The two randomized groups were well matched in baseline characteristics. A 2D-Echo was performed at baseline and at 6 months, together with a coronary angiography, for the remodeling and IRA patency assessment, respectively. The LV end-diastolic volume index (LVEDVi) decreased in Group 2 [-3 mL/m(2) (IQR: -12 to 4 mL/m(2))], and increased in Group 1 [6 mL/m(2) (IQR: -2 to 14 mL/m(2))], (p = 0.001). In Group 2, LVEDVi reduction was similar regardless of drug therapy, while in Group 1 the LVEDVi was smaller in patients treated with doxycycline as compared to control [3 mL/m(2) (IQR: -3 to 8 mL/m(2)) vs. 10 mL/m(2) (IQR: 1-27 mL/m(2)), p = 0.006]. A similar pattern was observed also for LV end-systolic volume and ejection fraction. In STEMI patients at higher risk, as those with a baseline TIMI flow grade ≤1, doxycycline reduces LV remodeling.

  6. 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.

  7. 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

  8. Simulations of trabecular remodeling and fatigue: is remodeling helpful or harmful?

    PubMed

    van Oers, René F M; van Rietbergen, Bert; Ito, Keita; Huiskes, Rik; Hilbers, Peter A J

    2011-05-01

    Microdamage-targeted resorption is paradoxal, because it entails the removal of bone from a region that was already overloaded. Under continued intense loading, resorption spaces could potentially cause more damage than they remove. To investigate this problem, we incorporated damage algorithms in a computer-simulation model for trabecular remodeling. We simulated damage accumulation and bone remodeling in a trabecular architecture, for two fatigue regimens, a 'moderate' regimen, and an 'intense' regimen with a higher number of loading cycles per day. Both simulations were also performed without bone remodeling to investigate if remodeling removed or exacerbated the damage. We found that remodeling tends to remove damage under the 'moderate' fatigue regimen, but it exacerbates damage under the 'intense' regimen. This harmful effect of remodeling may play a role in the development of stress fractures.

  9. Minireview: Nuclear Receptor Regulation of Osteoclast and Bone Remodeling

    PubMed Central

    Jin, Zixue; Li, Xiaoxiao

    2015-01-01

    Osteoclasts are bone-resorbing cells essential for skeletal remodeling and regeneration. However, excessive osteoclasts often contribute to prevalent bone degenerative diseases such as osteoporosis, arthritis, and cancer bone metastasis. Osteoclast dysregulation is also associated with rare disorders such as osteopetrosis, pycnodysostosis, Paget's disease, and Gorham-Stout syndrome. The nuclear receptor (NR) family of transcription factors functions as metabolic sensors that control a variety of physiological processes including skeletal homeostasis and serves as attractive therapeutic targets for many diseases. In this review, we highlight recent findings on the new players and the new mechanisms for how NRs regulate osteoclast differentiation and bone resorption. An enhanced understanding of NR functions in osteoclastogenesis will facilitate the development of not only novel osteoprotective medicine but also prudent strategies to minimize the adverse skeletal effects of certain NR-targeting drugs for a better treatment of cancer and metabolic diseases. PMID:25549044

  10. Myocardial tissue remodeling after orthotopic heart transplantation: a pilot cardiac magnetic resonance study.

    PubMed

    Coelho-Filho, Otavio Rizzi; Shah, Ravi; Lavagnoli, Carlos Fernando Ramos; Barros, Jose Carlos; Neilan, Tomas G; Murthy, Venkatesh L; de Oliveira, Pedro Paulo Martins; Souza, Jose Roberto Matos; de Oliveira Severino, Elaine Soraya Barbosa; de Souza Vilarinho, Karlos Alexandre; da Mota Silveira Filho, Lindemberg; Garcia, Jose; Semigran, Marc J; Coelho, Otavio Rizzi; Jerosch-Herold, Michael; Petrucci, Orlando

    2016-07-20

    After orthotopic heart transplantation (OHT), the allograft undergoes characteristic alterations in myocardial structure, including hypertrophy, increased ventricular stiffness, ischemia, and inflammation, all of which may decrease overall graft survival. Methods to quantify these phenotypes may clarify the pathophysiology of progressive graft dysfunction post-OHT. We performed cardiac magnetic resonance (CMR) with T1 mapping in 26 OHT recipients (mean age 47 ± 7 years, 30 % female, median follow-up post-OHT 6 months) and 30 age-matched healthy volunteers (mean age 50.5 ± 15 years; LVEF 63.5 ± 7 %). OHT recipients had a normal left ventricular ejection fraction (LVEF 65.3 ± 11 %) with higher LV mass relative to age-matched healthy volunteers (114 ± 27 vs. 85.8 ± 18 g; p < 0.001). There was no late gadolinium enhancement in either group. Both myocardial extracellular volume fraction (ECV) and intracellular lifetime of water (τic), a measure of cardiomyocyte hypertrophy, were higher in patients post-OHT (ECV: 0.39 ± 0.06 vs. 0.28 ± 0.03, p < 0.0001; τic: 0.12 ± 0.08 vs. 0.08 ± 0.03, p < 0.001). ECV was associated with LV mass (r = 0.74, p < 0.001). In follow-up, OHT recipients with normal biopsies by pathology (ISHLT grade 0R) in the first year post-OHT exhibited a lower ECV relative to patients with any rejection ≥2R (0.35 ± 0.02 for 0R vs. 0.45 ± 0, p < 0.001). Higher ECV but not LVEF was significantly associated with a reduced rejection-free survival. After OHT, markers of tissue remodeling by CMR (ECV and τic) are elevated and associated with myocardial hypertrophy. Interstitial myocardial remodeling (by ECV) is associated with cellular rejection. Further research on the impact of graft preservation and early immunosuppression on tissue-level remodeling of the allograft is necessary to delineate the clinical implications of these findings.

  11. Raise the Floor When Remodeling Science Labs

    ERIC Educational Resources Information Center

    Nation's Schools, 1972

    1972-01-01

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

  12. 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)

  13. B.B. Contracting & Remodeling Information Sheet

    EPA Pesticide Factsheets

    B.B. Contracting & Remodeling (the Company) is located in St. Louis, Missouri. The settlement involves renovation activities conducted at property constructed prior to 1978, located in St. Louis, Missouri.

  14. Adverse cutaneous drug reaction.

    PubMed

    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.

  15. Ventricular remodeling in global ischemia.

    PubMed

    Anversa, P; Zhang, X; Li, P; Olivetti, G; Cheng, W; Reiss, K; Sonnenblick, E H; Kajstura, J

    1995-06-01

    To determine the effects of chronic constriction of the left coronary artery on the function and structure of the heart, coronary artery narrowing was surgically induced in rats and ventricular pump performance, extent and distribution of myocardial damage, and the hypertrophic and hyperplastic response of myocytes were examined. Alterations in cardiac hemodynamics were found in all rats, but the characteristics of the physiological properties of the heart allowed a separation of the animals into two groups which exhibited left ventricular dysfunction and failure, respectively. Left ventricular hypertrophy occurred in both groups and was characterized by ventricular dilatation and wall thinning which were more severe in the failing animals. Multiple foci of myocardial damage across the wall were seen in all animals but tissue injury was more prominent in the endomyocardium and in failing rats. The anatomical and hemodynamic changes resulted in a significant increase in diastolic wall stress which paralleled the depression in ventricular performance. Myocyte cell loss and myocyte cellular hypertrophy were more severe with ventricular failure than with dysfunction. Finally, diastolic overload appeared to be coupled with activation of the DNA synthetic machinery of myocytes and nuclear mitotic division. In conclusion, a fixed lesion of the left coronary artery leads to abnormalities in cardiac dynamics with marked increases in diastolic wall stress and extensive ventricular remodeling in spite of compensatory myocyte cellular hypertrophy and hyperplasia in the remaining viable tissue.

  16. Impact of protein binding cavity volume (PCV) and ligand volume (LV) in rigid and flexible docking of protein-ligand complexes.

    PubMed

    Saranya, N; Jeyakanthan, J; Selvaraj, S

    2012-12-15

    The importance of protein binding cavity volume (PCV) and ligand volume (LV) in rigid and flexible docking has been studied in 48 protein-ligand complexes belonging to eight protein families. In continuation of our earlier study on protein flexibility in relationship to PCV and LV, this study analyzes the importance of PCV and LV in the scoring and ranking of ligands in docking experiments. Crystal structures of protein-ligand complexes with varied PCV were chosen for docking ligands of varied volume in each protein family. Docking and scoring accuracy have been evaluated by self and cross docking of ligands to the given protein conformation. Effect of PCV and LV in rigid and flexible docking has been studied both in apo and holo proteins. Rigid docking has performed well when appropriate protein conformation is used. Selecting the proteins with appropriate PCV based on the LV information is suggested for better results in ensemble docking.

  17. Mesenchymal stem cell therapy associated with endurance exercise training: Effects on the structural and functional remodeling of infarcted rat hearts.

    PubMed

    Lavorato, Victor Neiva; Del Carlo, Ricardo Junqueira; da Cunha, Daise Nunes Queiroz; Okano, Barbara Silva; Belfort, Felipe Gomes; de Freitas, Juliana Silveira; da Mota, Gloria de Fatima Alves; Quintão-Júnior, Judson Fonseca; Silame-Gomes, Luis Henrique Lobo; Drummond, Filipe Rios; Carneiro-Júnior, Miguel Araújo; de Oliveira, Edilamar Menezes; Monteiro, Betania Souza; Prímola-Gomes, Thales Nicolau; Natali, Antônio José

    2016-01-01

    We tested the effects of early mesenchymal stem cell (MSC) therapy associated with endurance exercise on the structural and functional cardiac remodeling of rats with myocardial infarctation (MI). Male Wistar rats (40 days old) were divided into 6 groups: control and exercise sham; control and exercise MI; and control and exercise MI MSC. MI was surgically induced and bone marrow-derived MSCs were immediately injected via caudal vein (concentration: 1 × 10(6 )cells). Twenty-four hours later ET groups exercised on a treadmill (5 days/week; 60 min/day; 60% of maximal running velocity) for 12 weeks. Structural and functional changes were determined by echocardiography. Contractility and intracellular global calcium ([Ca(2 +)]i) transient were measured in myocytes from the left ventricular (LV) non-infarcted area. Calcium regulatory proteins were measured by Western blot. MI increased (p < 0.05) heart, ventricular and LV weights and its ratios to body weight; LV internal dimension in diastole (LVID-D) and in systole (LVID-S) and LV free wall in diastole (LVFW-D), but reduced the thickness of interventricular septum in systole (IVS-S), ejection fraction (EF) and fractional shortening (FS). MI augmented (p < 0.05) the times to peak and to half relaxation of cell shortening as well as the amplitude of the [Ca(2 +)]i transient and the times to peak and to half decay. Early MSCs therapy restored LVFW-D, IVS-S and the amplitude and time to half decay of the [Ca(2 +)]i transient. Early endurance exercise intervention increased (p < 0.05) LVFW-S, IVS-S, EF and FS, and reduced the times to peak and to half relaxation of cell shortening, and the amplitude of the [Ca(2 +)]i transient. Exercise training also increased the expression of left ventricular SERCA2a and PLBser16. Nevertheless, the combination of these therapies did not cause additive effects. In conclusion, combining early MSCs therapy and endurance exercise does not potentiate the benefits of such treatments to

  18. Bone remodeling as a spatial evolutionary game.

    PubMed

    Ryser, Marc D; Murgas, Kevin A

    2017-04-07

    Bone remodeling is a complex process involving cell-cell interactions, biochemical signaling and mechanical stimuli. Early models of the biological aspects of remodeling were non-spatial and focused on the local dynamics at a fixed location in the bone. Several spatial extensions of these models have been proposed, but they generally suffer from two limitations: first, they are not amenable to analysis and are computationally expensive, and second, they neglect the role played by bone-embedded osteocytes. To address these issues, we developed a novel model of spatial remodeling based on the principles of evolutionary game theory. The analytically tractable framework describes the spatial interactions between zones of bone resorption, bone formation and quiescent bone, and explicitly accounts for regulation of remodeling by bone-embedded, mechanotransducing osteocytes. Using tools from the theory of interacting particle systems we systematically classified the different dynamic regimes of the spatial model and identified regions of parameter space that allow for global coexistence of resorption, formation and quiescence, as observed in physiological remodeling. In coexistence scenarios, three-dimensional simulations revealed the emergence of sponge-like bone clusters. Comparison between spatial and non-spatial dynamics revealed substantial differences and suggested a stabilizing role of space. Our findings emphasize the importance of accounting for spatial structure and bone-embedded osteocytes when modeling the process of bone remodeling. Thanks to the lattice-based framework, the proposed model can easily be coupled to a mechanical model of bone loading.

  19. The surface glycoprotein of feline leukemia virus isolate FeLV-945 is a determinant of altered pathogenesis in the presence or absence of the unique viral long terminal repeat.

    PubMed

    Bolin, Lisa L; Ahmad, Shamim; Lobelle-Rich, Patricia A; Ooms, Tara G; Alvarez-Hernandez, Xavier; Didier, Peter J; Levy, Laura S

    2013-10-01

    Feline leukemia virus (FeLV) is a naturally transmitted gammaretrovirus that infects domestic cats. FeLV-945, the predominant isolate associated with non-T-cell disease in a natural cohort, is a member of FeLV subgroup A but differs in sequence from the FeLV-A prototype, FeLV-A/61E, in the surface glycoprotein (SU) and long terminal repeat (LTR). Substitution of the FeLV-945 LTR into FeLV-A/61E resulted in pathogenesis indistinguishable from that of FeLV-A/61E, namely, thymic lymphoma of T-cell origin. In contrast, substitution of both FeLV-945 LTR and SU into FeLV-A/61E resulted in multicentric lymphoma of non-T-cell origin. These results implicated the FeLV-945 SU as a determinant of pathogenic spectrum. The present study was undertaken to test the hypothesis that FeLV-945 SU can act in the absence of other unique sequence elements of FeLV-945 to determine the disease spectrum. Substitution of FeLV-A/61E SU with that of FeLV-945 altered the clinical presentation and resulted in tumors that demonstrated expression of CD45R in the presence or absence of CD3. Despite the evident expression of CD45R, a typical B-cell marker, T-cell receptor beta (TCRβ) gene rearrangement indicated a T-cell origin. Tumor cells were detectable in bone marrow and blood at earlier times during the disease process, and the predominant SU genes from proviruses integrated in tumor DNA carried markers of genetic recombination. The findings demonstrate that FeLV-945 SU alters pathogenesis, although incompletely, in the absence of FeLV-945 LTR. Evidence demonstrates that FeLV-945 SU and LTR are required together to fully recapitulate the distinctive non-T-cell disease outcome seen in the natural cohort.

  20. 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.

  1. Biomass fuel smoke exposure was associated with adverse cardiac remodeling and left ventricular dysfunction in Peru.

    PubMed

    Burroughs Peña, M S; Velazquez, E J; Rivera, J D; Alenezi, F; Wong, C; Grigsby, M; Davila-Roman, V G; Gilman, R H; Miranda, J J; Checkley, W

    2016-12-19

    While household air pollution from biomass fuel combustion has been linked to cardiovascular disease, the effects on cardiac structure and function have not been well described. We sought to determine the association between biomass fuel smoke exposure and cardiac structure and function by transthoracic echocardiography. We identified a random sample of urban and rural residents living in the high-altitude region of Puno, Peru. Daily biomass fuel use was self-reported. Participants underwent transthoracic echocardiography. Multivariable linear regression was used to examine the relationship of biomass fuel use with echocardiographic measures of cardiac structure and function, adjusting for age, sex, height, body mass index, diabetes, physical activity, and tobacco use. One hundred and eighty-seven participants (80 biomass fuel users and 107 non-users) were included in this analysis (mean age 59 years, 58% women). After adjustment, daily exposure to biomass fuel smoke was associated with increased left ventricular internal diastolic diameter (P=.004), left atrial diameter (P=.03), left atrial area (four-chamber) (P=.004) and (two-chamber) (P=.03), septal E' (P=.006), and lateral E' (P=.04). Exposure to biomass fuel smoke was also associated with worse global longitudinal strain in the two-chamber view (P=.01). Daily biomass fuel use was associated with increased left ventricular size and decreased left ventricular systolic function by global longitudinal strain.

  2. Fibrinolysis inhibitors adversely affect remodeling of tissues sealed with fibrin glue.

    PubMed

    Krishnan, Lissy K; Vijayan Lal, Arthur; Uma Shankar, P R; Mohanty, Mira

    2003-01-01

    Experiments have been carried out to determine if aprotinin and epsilon -amino caproic acid increases the quality of Fibrin glue. A rat model was used for tissues such as liver and skin while rabbits were used for application of glue in dura mater. Apposition of all the tissues, glued with fibrin was found to be good and remnants of the polymerized fibrin were seen even on the seventh day of application, though inhibitors were not incorporated with the glue. In skin, excessive amounts of fibrin remained as a result of addition of aprotinin and epsilon -amino caproic acid, as compared to the glue applied without any inhibitor. After dural sealing, the wound repair and new bone formation at craniotomy site progressed well in the fibrin glue applied area as compared to the commercially available glue that contained aprotinin. The adhesive strength of the glue without or with fibrinolysis inhibitors was found to be similar, after 1h grafts on rat back. The observations from this study suggests that the use of aprotinin with fibrin glue may not be required because, even liver tissue that is known to have high fibrinolytic activity was sealed and repaired well in the absence of plasminogen inhibitors. On the other hand, it was found that if inhibitors were added, nondegraded matrix remained in the tissue even after 15 days and affected migration of repair cells. Thus, the inhibition of fibrinolysis after fibrin glue application is found detrimental to wound healing.

  3. 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.

  4. Telithromycin: review of adverse effects.

    PubMed

    2014-11-01

    Telithromycin is a macrolide antibiotic that has been marketed since the early 2000s. It has not been shown to be more effective against any bacteria than other macrolide antibiotics. Its antibacterial activity is in no way remarkable. In early 2014, we reviewed its adverse effect profile using data from periodic safety update reports, drug regulatory agencies, and detailed published case reports. In addition to the adverse effect profile telithromycin shares with the other macrolides, it provokes several specific adverse effects: visual disturbances due to impaired accommodation; taste and smell disorders; severe liver damage; worsening of myasthenia gravis; rhabdomyolysis; and loss of consciousness. Prolongation of the QT interval with standard oral doses is a worrisome adverse effect. In practice, it is better not to use telithromycin as it exposes patients to disproportionate, serious adverse effects. When treatment with a macrolide antibiotic appears necessary, it is prudent to choose a different macrolide, such as spiramycin or azithromycin, which have fewer adverse effects.

  5. Cardiac remodelling and RAS inhibition

    PubMed Central

    Ferrario, Carlos M.

    2016-01-01

    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

  6. Optimization of cDNA amplification of Apricot Latent Virus (ApLV) from various plant tissues sources.

    PubMed

    Gumus, M; Sipahioğlu, H M; Paylan, I C; Erkan, S

    2007-03-15

    Although the reverse transcriptase polymerase chain reaction (RT-PCR) procedure is basically simple operation, often it is not possible to achieve optimum results without optimizing the protocols. An RT-PCR method targeting a 200 bp sequence of the CP gene of Apricot Latent Virus (ApLV) was used as a model to improve the detection limit and to compare the behavior of three different plant tissues in a RT-PCR assay. A number of factors should be considered when selecting the optimal system for RT-PCR. Important considerations include the optimal concentrations of MgCl2, dNTP, Taq DNA polymerase enzyme, specific primer and the amount of cDNA for the downstream applications. This study therefore discusses a series of critical PCR parameters and feasible strategies for optimization of RT-PCR detection of ApLV.

  7. Periprosthetic Bone Remodelling in Total Knee Arthroplasty

    PubMed Central

    GEORGEANU, Vlad; ATASIEI, Tudor; GRUIONU, Lucian

    2014-01-01

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

  8. A Test in Context: E/A and E/e' to Assess Diastolic Dysfunction and LV Filling Pressure.

    PubMed

    Mitter, Sumeet S; Shah, Sanjiv J; Thomas, James D

    2017-03-21

    Diastolic dysfunction represents a combination of impaired left ventricular (LV) relaxation, restoration forces, myocyte lengthening load, and atrial function, culminating in increased LV filling pressures. Current Doppler echocardiography guidelines recommend using early to late diastolic transmitral flow velocity (E/A) to assess diastolic function, and E to early diastolic mitral annular tissue velocity (E/e') to estimate LV filling pressures. Although both parameters have important diagnostic and prognostic implications, they should be interpreted in the context of a patient's age and the rest of the echocardiogram to describe diastolic function and guide patient management. This review discusses: 1) the physiological basis for the E/A and E/e' ratios; 2) their roles in diagnosing diastolic dysfunction; 3) prognostic implications of abnormalities in E/A and E/e'; 4) special scenarios of the E/A and E/e' ratios that are either useful or challenging when evaluating diastolic function clinically; and 5) their usefulness in guiding therapeutic decision making.

  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. 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

  11. Regulation of the immediate-early genes of white spot syndrome virus by Litopenaeus vannamei kruppel-like factor (LvKLF).

    PubMed

    Huang, Ping-Han; Lu, Shao-Chia; Yang, Shu-Han; Cai, Pei-Si; Lo, Chu-Fang; Chang, Li-Kwan

    2014-10-01

    Kruppel-like factors (KLFs) belong to a subclass of Cys2/His2 zinc-finger DNA-binding proteins, and act as important regulators with diverse roles in cell growth, proliferation, differentiation, apoptosis and tumorigenesis. Our previous research showed that PmKLF from Penaeus monodon is crucial for white spot syndrome virus (WSSV) infection, yet the mechanisms by which PmKLF influences WSSV infection remain unclear. This study cloned KLF from Litopenaeus vannamei (LvKLF), which had 93% similarity with PmKLF. LvKLF formed a dimer via the C-terminal zinc-finger motif. Knockdown of LvKLF expression by dsRNA injection in WSSV-challenged shrimps was found to significantly inhibit the transcription of two important immediate-early (IE) genes, IE1 and WSSV304, and also reduced WSSV copy numbers. Moreover, reporter assays revealed that the promoter activities of these two WSSV IE genes were substantially enhanced by LvKLF. Mutations introduced in the promoter sequences of IE1 and WSSV304 were shown to abolish LvKLF activation of promoter activities; and an electrophoretic mobility shift assay demonstrated that LvKLF binds to putative KLF-response elements (KRE) in the promoters. Taken together, these results indicate that LvKLF transcriptional regulation of key IE genes is critical to WSSV replication.

  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. Transcriptional promoter and enhancer elements in the long terminal repeats (LTR) of endogenous murine leukemia virus (MuLV)-related proviral sequences

    SciTech Connect

    Ch'ang, L.Y.; Myer, F.E.; Yang, D.M.; Koh, C.K.; Yang, W.K.

    1987-05-01

    Mouse genome harbors 2 families of MuLV-related proviral sequences, which do not directly produce infectious virus, but may express RNA transcripts in a tissue-specific manner. The LTRS of MuLV-related sequences contain a mid-U3 inserted segment (IS) of approx. 200 bp not found in the LTR of infectious MuLVs. To test for the LTR promoter and enhancer activities, chloramphenicol acetyltransferase (CAT) gene, alone or carrying SV40 promoter, was linked to various LTR sequences of 2 MuLV and 6 representative MuLV-related DNA clones and the recombinant genes were examined for transient CAT expression in mouse NIH-3T3, mink CCL64 and human HT1080 cells by DNA transfection. While the CAT expression was high with the 2 ecotropic MuLV LTRs, very little to undetectable activities were obtained with all MuLV-related LTRs. To determine the basis for the very low activity of the MuLV-related LTRs, series of experiments were performed, which indicate that the TATA- and CCAAC-containing domain, downstream of the IS, is functionally intact as a promoter and that the IS sequences, while inactive as a promoter by itself, could provide a bi-directional enhancer-like activity to its own or MuLV LTR or SV40 promoter. Further studies suggest the presence of a cis-acting negative regulatory element in sequences upstream of the IS in both the 2 subfamilies of MuLV-related LTRs.

  14. Retinal remodeling in inherited photoreceptor degenerations.

    PubMed

    Marc, Robert E; Jones, Bryan W

    2003-10-01

    Photoreceptor degenerations initiated in rods or the retinal pigmented epithelium usually evoke secondary cone death and sensory deafferentation of the surviving neural retina. In the mature central nervous system, deafferentation evokes atrophy and connective re-patterning. It has been assumed that the neural retina does not remodel, and that it is a passive survivor. Screening of advanced stages of human and rodent retinal degenerations with computational molecular phenotyping has exposed a prolonged period of aggressive negative remodeling in which neurons migrate along aberrant glial columns and seals, restructuring the adult neural retina (1). Many neurons die, but survivors rewire the remnant inner plexiform layer (IPL), forming thousands of novel ectopic microneuromas in the remnant inner nuclear layer (INL). Bipolar and amacrine cells engage in new circuits that are most likely corruptive. Remodeling in human and rodent retinas emerges regardless of the molecular defects that initially trigger retinal degenerations. Although remodeling may constrain therapeutic intervals for molecular, cellular, or bionic rescue, the exposure of intrinsic retinal remodeling by the removal of sensory control in retinal degenerations suggests that neuronal organization in the normal retina may be more plastic than previously believed.

  15. Temperature-induced cardiac remodelling in fish

    PubMed Central

    Keen, Adam N.; Klaiman, Jordan M.; Shiels, Holly A.

    2017-01-01

    ABSTRACT Thermal acclimation causes the heart of some fish species to undergo significant remodelling. This includes changes in electrical activity, energy utilization and structural properties at the gross and molecular level of organization. The purpose of this Review is to summarize the current state of knowledge of temperature-induced structural remodelling in the fish ventricle across different levels of biological organization, and to examine how such changes result in the modification of the functional properties of the heart. The structural remodelling response is thought to be responsible for changes in cardiac stiffness, the Ca2+ sensitivity of force generation and the rate of force generation by the heart. Such changes to both active and passive properties help to compensate for the loss of cardiac function caused by a decrease in physiological temperature. Hence, temperature-induced cardiac remodelling is common in fish that remain active following seasonal decreases in temperature. This Review is organized around the ventricular phases of the cardiac cycle – specifically diastolic filling, isovolumic pressure generation and ejection – so that the consequences of remodelling can be fully described. We also compare the thermal acclimation-associated modifications of the fish ventricle with those seen in the mammalian ventricle in response to cardiac pathologies and exercise. Finally, we consider how the plasticity of the fish heart may be relevant to survival in a climate change context, where seasonal temperature changes could become more extreme and variable. PMID:27852752

  16. 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

  17. Late onset oral treatment with tranilast following large myocardial infarction has no beneficial effects on cardiac remodeling and mortality in rats

    PubMed Central

    BETGE, STEFAN; KUNZ, CHRISTIAN; FIGULLA, HANS; JUNG, CHRISTIAN

    2014-01-01

    Tranilast (Tra) reduces intracardiac interstitial fibrosis in the animal models of hypertensive heart failure and diabetic cardiomyopathy by inhibiting cardiac fibroblasts. The present study examined whether Tra has long-term effects on the cardiac remodeling in the remote area of the left ventricle (LV) following myocardial infarction (MI) in the rat. Treatment with Tra (n=40; 150 mg/kg twice daily) or placebo (Plac, n=36) was started at day 28 after induction of a large MI or sham-operation (ShO, n=18) in female Lewis rats. Collagen content was determined using high-performance liquid chromatography. Large MI led to a significant hypertrophy of the two ventricles, a severe dilatation of the LV and a shift of the chamber stiffness variables in the pressure volume curves. The six-month survival rates were Tra, 62.5%; Plac, 75%; and ShO, 100%. No significant difference was identified between Tra and Plac regarding survival rate and collagen content. Treatment with the anti-inflammatory and antifibrotic drug, Tra, started four weeks after the induction of a large MI in the rat, did not attenuate or positively influence remodeling in chronic ischemic heart failure and survival. Further studies are required to explore the effects of Tra on cardiac myocytes post-MI in more detail. PMID:25371734

  18. Molecular Aspects of Exercise-induced Cardiac Remodeling.

    PubMed

    Bernardo, Bianca C; McMullen, Julie R

    2016-11-01

    Exercise-induced cardiac remodeling is typically an adaptive response associated with cardiac myocyte hypertrophy and renewal, increased cardiac myocyte contractility, sarcomeric remodeling, cell survival, metabolic and mitochondrial adaptations, electrical remodeling, and angiogenesis. Initiating stimuli/triggers of cardiac remodeling include increased hemodynamic load, increased sympathetic activity, and the release of hormones and growth factors. Prolonged and strenuous exercise may lead to maladaptive exercise-induced cardiac remodeling including cardiac dysfunction and arrhythmia. In addition, this article describes novel therapeutic approaches for the treatment of heart failure that target mechanisms responsible for adaptive exercise-induced cardiac remodeling, which are being developed and tested in preclinical models.

  19. Two-dimensional speckle-tracking echocardiography assessment of left ventricular remodeling in patients after myocardial infarction and primary reperfusion

    PubMed Central

    Haberka, Maciej; Tabor, Zbigniew; Finik, Maciej; Gąsior, Zbigniew

    2014-01-01

    Introduction Left ventricular remodeling (LVR) is the most prognostically important consequence of acute myocardial infarction (AMI). The aim of the study was to assess the value of speckle tracking echocardiography in the prediction of left ventricular remodeling in patients after AMI and primary coronary angioplasty (PCI). Material and methods Eighty-eight patients (F/M = 31/57 patients; 63.6 ±11 years old) with coronary artery disease (CAD) and successful PCI were enrolled and divided into group I with ST-elevation myocardial infarction or non-ST elevation myocardial infarction and group II with stable angina pectoris. Conventional and speckle tracking echocardiography was performed 3 days (baseline), 30 days and 90 days after PCI. Patients were divided into 2 groups based on the presence of LVR (increase of LV end-diastolic and/or end-systolic volume > 20%) at 3 months follow-up. Results At initial presentation, 2-chamber longitudinal strain (9.4 ±3.5% vs. –11.6 ±3.6%, p < 0.04) and 4-chamber transverse strain (10.4 ±8.2% vs. 15.6 ±8%, p < 0.003) were lower in the LVR+ group compared to the LVR– group. LV wall motion score index did not differ between the two groups. After 30 days, circumferential apical and basal strain (–15.58 ±8.9% vs. –25.53 ±8.8%, p < 0.001; –15.02 ±5.6 vs. –19.78 ±6.3, p < 0.008), radial apical strain (9.96 ±8.4% vs. 14.15 ±5.5%, p < 0.03), 4-chamber longitudinal strain (–8.7 ±5.8% vs. –13.47 ±3.9%, p < 0.005), 4-chamber transverse strain (10.5 ±8.1% vs. 16.7 ±8.3%, p < 0.03), apical rotation (3.84 ±2.5° vs, 5.66 ±3.2°, p < 0.04) and torsion (6.15 ±4.1° vs. 8.98 ±4.6°, p < 0.03) were significantly decreased in the LVR+ group compared to the LVR– group. According to ROC analysis, circumferential apical strain > –15.92% (sensitivity 93%, specificity 59%, positive predictive value 90%) was the most powerful predictor of remodeling after primary PCI in AMI. Conclusions Our results suggest that

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

    PubMed

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

    2015-02-01

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

  1. High Dose β-Blocker Therapy Triggers Additional Reverse Remodeling in Patients With Idiopathic Non-Ischemic Cardiomyopathy.

    PubMed

    Nitta, Daisuke; Kinugawa, Koichiro; Imamura, Teruhiko; Kato, Naoko P; Komuro, Issei

    2016-12-02

    Carvedilol has established its evidence to improve prognosis and facilitate left ventricular reverse remodeling (LVRR) in heart failure patients with reduced left ventricular ejection fraction (LVEF), and many studies have supported its dose-dependency. However, there are few studies demonstrating the effect of high dose carvedilol in Japan. We enrolled 23 patients with idiopathic non-ischemic cardiomyopathy, in whom LVEF remained 45% or less despite 20 mg/ day of carvedilol therapy for > 3 months. After high dose (40 mg/day) carvedilol therapy for > 3 months, LVEF improved (+9.1%, P = 0.002), and LV end-diastolic diameter (LVDd) and LV end-systolic diameter (LVDs) reduced (-4.6 and -6.9 mm, respectively, P < 0.05) compared with the baseline data. Finally, 17 patients achieved LVRR after the high dose, when LVRR was defined as 1) those with final EF > 45%, and 2) those with final EF < 45% but who attained increases in LVEF > 10%, or LVEF > 5% with a decrease in LV end-diastolic dimension index (LVDDI) > 5%. Baseline predictors for LVRR after high dose carvedilol were the change rates of log B-type natriuretic peptide (BNP), LVDd, and LVDs from the time of pre-carvedilol introduction to enrollment (P < 0.05, respectively). In conclusion, high dose carvedilol triggered additional LVRR in patients with idiopathic non-ischemic cardiomyopathy and the change rates of log BNP, LVDd, and LVDs at 20 mg carvedilol may be predictors for the additional LVRR at high dose.

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

    PubMed

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

    2014-12-01

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

  3. The Chd Family of Chromatin Remodelers

    PubMed Central

    Marfella, Concetta G.A.; Imbalzano, Anthony N.

    2007-01-01

    Chromatin remodeling enzymes contribute to the dynamic changes that occur in chromatin structure during cellular processes such as transcription, recombination, repair, and replication. Members of the chromodomain helicase DNA-binding (Chd) family of enzymes belong to the SNF2 superfamily of ATP-dependent chromatin remodelers. The Chd proteins are distinguished by the presence of two N-terminal chromodomains that function as interaction surfaces for a variety of chromatin components. Genetic, biochemical, and structural studies demonstrate that Chd proteins are important regulators of transcription and play critical roles during developmental processes. Numerous Chd proteins are also implicated in human disease. PMID:17350655

  4. Serial magnetic resonance imaging of global and regional left ventricular remodeling during 1 year after acute myocardial infarction.

    PubMed

    Schroeder, A P; Houlind, K; Pedersen, E M; Nielsen, T T; Egeblad, H

    2001-01-01

    Biplane long-axis cine MRI was performed in 51 patients 1, 13, 26, and 52 weeks after their first AMI. LV mass index (LVMI) was significantly increased 1 week after AMI (84.3 +/- 16.9 vs. 68.1 +/- 11.4 g/m(2) controls, n = 48, p < 0.001), presumably owing to edema of the infarcted myocardium. Six months after AMI, LVMI decreased to 76.5 +/- 16.4 g/m(2), but had again augmented after 1 year (81.8 +/- 17.3 g/m(2), p < 0.05), suggesting late, compensatory left ventricular hypertrophy. In patients treated with primary percutaneous transluminal coronary angioplasty, LVMI decreased 5% over 1 year, while LVMI increased 10% in patients receiving thrombolysis (p < 0.05). In the entire population, the global increase in LVMI 1 year after AMI seemed to reflect global cavity dilatation with unchanged thickness of the vital myocardium. In conclusion, in patients receiving contemporary treatment, LV remodeling only partially complied with the classical patho-anatomical concept.

  5. Effect of Exercise Training on Left Ventricular Remodeling in Diabetic Patients with Diastolic Dysfunction: Rationale and Design

    PubMed Central

    Asrar ul Haq, Muhammad; Wong, Chiew; Levinger, Itamar; Srivastava, Piyush M.; Sbaraglia, Melissa; Toia, Deidre; Jerums, George; Selig, Steve; Hare, David L.

    2014-01-01

    INTRODUCTION This study will examine the effects of combined aerobic and resistance training on left ventricular remodeling in diabetic patients with diastolic dysfunction. This is the first randomized controlled trial to look for effects of combined strength training and aerobic exercise on myocardial function as well as other clinical, functional, or psychological parameters in diabetic patients with isolated diastolic dysfunction, and will provide important insights into the potential management strategies for heart failure with preserved ejection fraction. METHODS AND ANALYSIS This is a prospective, randomized controlled investigator initiated single center trial. Diabetic patients with LV diastolic dysfunction suitable for exercise training intervention will be randomized to three months of a supervised combination of aerobic and strength training exercises, or supervised light stretching (control arm). Pre and post intervention assessment will include stress echocardiography, peak aerobic power with 12-lead ECG, dual-energy X-ray absorptiometry, muscle strength, the capacity to perform activities of daily living (ADLs), and questionnaires to assess self-perceived quality of life and symptoms of depression. The primary endpoint is to compare any change in tissue Doppler-derived LV systolic and early diastolic velocities. ETHICS AND DISSEMINATION The current trial protocol has been approved by the Human Research Ethics Committee of Austin Health and the University of Melbourne, Melbourne. The study will be performed in accordance with the Declaration of Helsinki. The investigator, regardless of the outcome, will publish the results of the study. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry: ACTRN12610000943044. PMID:24653649

  6. 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

  7. 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

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

    PubMed

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

    2011-08-01

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

  9. Scar remodeling after strabismus surgery.

    PubMed Central

    Ludwig, I H

    1999-01-01

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

  10. 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.

  11. 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.

  12. Cutaneous adverse reactions to lenalidomide.

    PubMed

    Imbesi, S; Allegra, A; Calapai, G; Musolino, C; Gangemi, S

    2015-01-01

    Lenalidomide is an immunomodulatory drug (IMiD) used principally in the treatment of multiple myeloma (MM), myelodysplastic syndromes (MS) and amyloidosis. Adverse reactions related to lenalidomide include myelosuppression (mainly neutropenia but also thrombocytopenia), gastrointestinal problems, skin eruption, atrial fibrillation and asthenia, decreased peripheral blood stem cell yield during stem cell collection, venous thromboembolism, and secondary malignances. In this review we focused our attention on the cutaneous adverse reactions to lenalidomide.

  13. Lack of ABCG2 Leads to Biventricular Dysfunction and Remodeling in Response to Hypoxia

    PubMed Central

    Nagy, Bence M.; Nagaraj, Chandran; Egemnazarov, Bakytbek; Kwapiszewska, Grazyna; Stauber, Rudolf E.; Avian, Alexander; Olschewski, Horst; Olschewski, Andrea

    2017-01-01

    Aims: The ATP-binding cassette (ABC)G2 transporter protects the heart from pressure overload-induced ventricular dysfunction but also protects cancer cells from chemotherapeutic agents. It is upregulated in the myocardium of heart failure patients and clears hypoxia-induced intracellular metabolites. This study employs ABCG2 knockout (KO) mice to elucidate the relevance of ABCG2 for cardiac and pulmonary vascular structure and function in chronic hypoxia, and uses human primary cardiac fibroblasts to investigate the potential role of ABCG2 in cardiac fibrosis. Methods and results: ABCG2 KO and control mice (n = 10) were subjected to 4 weeks normoxia or hypoxia. This allowed for investigation of the interaction between genotype and hypoxia (GxH). In hypoxia, KO mice showed pronounced right (RV) and left (LV) ventricular diastolic dysfunction. Compared to normoxia, end-diastolic pressure (EDP) was increased in control vs. KO mice by +1.1 ± 0.3 mmHg vs. +4.8 ± 0.3 mmHg, p for GxH < 0.001 (RV) and +3.9 ± 0.5 mmHg vs. +11.5 ± 1.6 mmHg, p for GxH = 0.110 (LV). The same applied for myocardial fibrosis with +0.3 ± 0.1% vs. 1.3 ± 0.2%, p for GxH = 0.036 (RV) and +0.06 ± 0.03% vs. +0.36 ± 0.08%, p for GxH = 0.002 (LV), whereas systolic function and capillary density was unaffected. ABCG2 deficiency did not influence hypoxia-induced pulmonary hypertension or vascular remodeling. In line with these observations, human cardiac fibroblasts showed increased collagen production upon ABCG2 silencing in hypoxia (p for GxH = 0.04). Conclusion: Here we provide evidence for the first time that ABCG2 membrane transporter can play a crucial role in ventricular dysfunction and fibrosis in hypoxia-induced pulmonary hypertension. PMID:28270772

  14. Adipose-derived mesenchymal stem cells embedded in platelet-rich fibrin scaffolds promote angiogenesis, preserve heart function, and reduce left ventricular remodeling in rat acute myocardial infarction

    PubMed Central

    Chen, Yung-Lung; Sun, Cheuk-Kwan; Tsai, Tzu-Hsien; Chang, Li-Teh; Leu, Steve; Zhen, Yen-Yi; Sheu, Jiunn-Jye; Chua, Sarah; Yeh, Kuo-Ho; Lu, Hung-I; Chang, Hsueh-Wen; Lee, Fan-Yen; Yip, Hon-Kan

    2015-01-01

    Objective: This study tested the hypothesis that autologous adipose-derived mesenchymal stem cells (ADMSCs) embedded in platelet-rich fibrin (PRF) can significant promote myocardial regeneration and repair after acute myocardial infarction (AMI). Summary background: With avoiding the needle-related complications, PRF-embedded autologous ADMSCs graft provides a new effective stem cell-based therapeutic strategy for myocardial repair. Methods: Adult male Sprague-Dawley rats were equally divided (n = 8 per group) into group 1 (sham-operated), group 2 (AMI by ligating left coronary artery), group 3 (AMI+ PRF), and group 4 (AMI+PRF-embedded autologous ADMSCs). RPF with or without ADMSCs was patched on infarct area 1h after AMI induction. All animals were sacrificed on day 42 after echocardiography. Results: Left ventricular (LV) dimension and infarct/fibrotic areas were lowest in group 1, highest in group 2, in group 3 higher than in group 4, whereas LV performance and wall thickness exhibited a reversed pattern in all groups (all p < 0.001). Protein expressions of inflammatory (MMP-9, IL-1β), oxidative, apoptotic (Bax, cleaved PARP), fibrotic (Smad 3, TFG-β), hypertrophic (β-MHC), and heart failure (BNP) biomarkers displayed an identical pattern in infarct/fibrotic areas, whereas the protein expressions of anti-inflammatory (IL-10), anti-apoptotic (Bcl-2), anti-fibrotic (Smad1/5, BMP-2) biomarkers and α-MHC showed an opposite pattern (all p < 0.01). Angiogenic activities (c-Kit+, Sca-1+, CD31+, SDF-1α+, CXCR4+ cells; protein expressions of SDF-1α, CXCR4, VEGF) were highest in group 4 and lowest in group 1 (all p < 0.001). Conclusion: ADMSCs embedded in PRF offered significant benefit in preserving LV function and limiting LV remodeling after AMI. PMID:26175843

  15. 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

  16. Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction.

    PubMed

    Wang, Wei; Zhang, Fuyang; Xia, Yunlong; Zhao, Shihao; Yan, Wenjun; Wang, Helin; Lee, Yan; Li, Congye; Zhang, Ling; Lian, Kun; Gao, Erhe; Cheng, Hexiang; Tao, Ling

    2016-11-01

    Cardiac metabolic remodeling is a central event during heart failure (HF) development following myocardial infarction (MI). It is well known that myocardial glucose and fatty acid dysmetabolism contribute to post-MI cardiac dysfunction and remodeling. However, the role of amino acid metabolism in post-MI HF remains elusive. Branched chain amino acids (BCAAs) are an important group of essential amino acids and function as crucial nutrient signaling in mammalian animals. The present study aimed to determine the role of cardiac BCAA metabolism in post-MI HF progression. Utilizing coronary artery ligation-induced murine MI models, we found that myocardial BCAA catabolism was significantly impaired in response to permanent MI, therefore leading to an obvious elevation of myocardial BCAA abundance. In MI-operated mice, oral BCAA administration further increased cardiac BCAA levels, activated the mammalian target of rapamycin (mTOR) signaling, and exacerbated cardiac dysfunction and remodeling. These data demonstrate that BCAAs act as a direct contributor to post-MI cardiac pathologies. Furthermore, these BCAA-mediated deleterious effects were improved by rapamycin cotreatment, revealing an indispensable role of mTOR in BCAA-mediated adverse effects on cardiac function/structure post-MI. Of note, pharmacological inhibition of branched chain ketoacid dehydrogenase kinase (BDK), a negative regulator of myocardial BCAA catabolism, significantly improved cardiac BCAA catabolic disorders, reduced myocardial BCAA levels, and ameliorated post-MI cardiac dysfunction and remodeling. In conclusion, our data provide the evidence that impaired cardiac BCAA catabolism directly contributes to post-MI cardiac dysfunction and remodeling. Moreover, improving cardiac BCAA catabolic defects may be a promising therapeutic strategy against post-MI HF.

  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. Evaluation of a novel nested PCR for the routine diagnosis of feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV).

    PubMed

    Arjona, Alvaro; Barquero, Nuria; Doménech, Ana; Tejerizo, German; Collado, Victorio M; Toural, Cristina; Martín, Daniel; Gomez-Lucia, Esperanza

    2007-02-01

    Laboratory diagnosis of feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) usually involves both viruses, as the clinical signs are similar and coinfection may occur. Serological methods may not represent an accurate diagnosis: maternal antibodies or cross-reactions may give false positive results to FIV, and false negative results may occur in latent FeLV status, or in certain FIV infection stages. A nested polymerase chain reaction (PCR) technique was designed to detect FeLV, FIV and feline endogenous retrovirus simultaneously. The detection of endogenous sequences was considered indicative of successful DNA extraction. The technique was used to diagnose FIV and FeLV in the blood cells of 179 cats. The kappa value with the serological data was 0.69 for FeLV and 0.87 for FIV. The joint detection of FeLV and FIV by this novel nested PCR is sensitive, specific, fast and convenient, and its applicability for clinical diagnosis is promising, as the direct evidence of the presence of the virus is more realistic than the indirect data provided by the serological detection.

  19. 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.

  20. Continuous Fli-1 expression plays an essential role in the proliferation and survival of F-MuLV-induced erythroleukemia and human erythroleukemia.

    PubMed

    Cui, J-W; Vecchiarelli-Federico, L M; Li, Y-J; Wang, G-J; Ben-David, Y

    2009-07-01

    Erythroleukemia induced by Friend Murine Leukemia Virus (F-MuLV) serves as a powerful tool for the study of multistage carcinogenesis and hematological malignancies in mice. Fli-1, a proto-oncogene and member of the Ets family, is activated through viral integration in F-MuLV-induced erythroleukemia, and is the most critical event in the induction of this disease. Fli-1 aberrant regulation is also observed in human malignancies, including Ewing's sarcoma, which is often linked to expression of the EWS/Fli-1 fusion oncoprotein. Here we examined the effects of Fli-1 inhibition to further elucidate its role in these pathological occurrences. The constitutive suppression of Fli-1, through RNA interference (RNAi), inhibits growth and induces death in F-MuLV-induced erythroleukemia cells. Expression of a dominant negative protein Engrailed (En)/Fli-1 reduces proliferation of EWS/Fli-1-transformed NIH-3T3 cells, and both F-MuLV-induced and human erythroleukemia cells. F-MuLV-induced erythroleukemia cells also display increased apoptosis, associated with reduced expression of bcl-2, a known fli-1 target gene. Introduction of En/Fli-1 into an F-MuLV-infected erythroblastic cell line induces differentiation, as shown by increased alpha-globin expression. These results suggest, for the first time, an essential role for continuous Fli-1 overexpression in the maintenance and survival of the malignant phenotype in murine and human erythroleukemias.

  1. 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…

  2. 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…

  3. 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.

  4. Retinal remodeling in human retinitis pigmentosa.

    PubMed

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

    2016-09-01

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

  5. Immune modulation of resistance artery remodelling.

    PubMed

    Schiffrin, Ernesto L

    2012-01-01

    Low-grade inflammation plays a role in cardiovascular disease. The innate and the adaptive immune responses participate in mechanisms that contribute to inflammatory responses. It has been increasingly appreciated that different subsets of lymphocytes and the cytokines they produce modulate the vascular remodelling that occurs in cardiovascular disease. Effector T cells such as T-helper (Th) 1 (interferon-γ-producing) and Th2 lymphocytes (that produce interleukin-4), as well as Th17 (that produce interleukin-17), and T suppressor lymphocytes including regulatory T cells (Treg), which express the transcription factor forkhead box P3 (Foxp3), are involved in the remodelling of small arteries that occurs under the action of angiotensin II, deoxycorticosterone-salt and aldosterone-salt, as well as in models of hypertension such as the Dahl-salt-sensitive rat. The mechanism whereby the immune system is activated is unclear, but it has been suggested that neo-antigens may be generated by the elevation of blood pressure or other stimuli, leading to the activation of the immune response. Activated Th1 may contribute to vascular remodelling directly on blood vessels via effects of the cytokines produced or indirectly by actions on the kidney. The protective effect of Treg may be mediated similarly directly or via renal effects. These data offer promise for the discovery of new therapeutic targets to ameliorate vascular remodelling, which could lead to improved outcome in cardiovascular disease in humans.

  6. Endothelial cell dynamics in vascular remodelling.

    PubMed

    Barbacena, Pedro; Carvalho, Joana R; Franco, Claudio A

    2016-01-01

    In this ESCHM 2016 conference talk report, we summarise two recently published original articles Franco et al. PLoS Biology 2015 and Franco et al. eLIFE 2016. The vascular network undergoes extensive vessel remodelling to become fully functional. Is it well established that blood flow is a main driver for vascular remodelling. It has also been proposed that vessel pruning is a central process within physiological vessel remodelling. However, despite its central function, the cellular and molecular mechanisms regulating vessel regression, and their interaction with blood flow patterns, remain largely unexplained. We investigated the cellular process governing developmental vascular remodelling in mouse and zebrafish. We established that polarised reorganization of endothelial cells is at the core of vessel regression, representing vessel anastomosis in reverse. Moreover, we established for the first time an axial polarity map for all endothelial cells together with an in silico method for the computation of the haemodynamic forces in the murine retinal vasculature. Using network-level analysis and microfluidics, we showed that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/11 renders endothelial cells more sensitive to shear, resulting in axial polarisation at lower shear stress levels. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus.

  7. Pulmonary arterial strain- and remodeling-induced stiffening are differentiated in a chronic model of pulmonary hypertension.

    PubMed

    Golob, Mark J; Tabima, Diana M; Wolf, Gregory D; Johnston, James L; Forouzan, Omid; Mulchrone, Ashley M; Kellihan, Heidi B; Bates, Melissa L; Chesler, Naomi C

    2017-04-11

    Pulmonary hypertension (PH) is a debilitating vascular disease that leads to pulmonary artery (PA) stiffening, which is a predictor of patient mortality. During PH development, PA stiffening adversely affects right ventricular function. PA stiffening has been investigated through the arterial nonlinear elastic response during mechanical testing using a canine PH model. However, only circumferential properties were reported and in the absence of chronic PH-induced PA remodeling. Remodeling can alter arterial nonlinear elastic properties via chronic changes in extracellular matrix (ECM) content and geometry. Here, we used an established constitutive model to demonstrate and differentiate between strain-stiffening, which is due to nonlinear elasticity, and remodeling-induced stiffening, which is due to ECM and geometric changes, in a canine model of chronic thromboembolic PH (CTEPH). To do this, circumferential and axial tissue strips of large extralobar PAs from control and CTEPH tissues were tested in uniaxial tension, and data were fit to a phenomenological constitutive model. Strain-induced stiffening was evident from mechanical testing as nonlinear elasticity in both directions and computationally by a high correlation coefficient between the mechanical data and model (R(2)=0.89). Remodeling-induced stiffening was evident from a significant increase in the constitutive model stress parameter, which correlated with increased PA collagen content and decreased PA elastin content as measured histologically. The ability to differentiate between strain- and remodeling-induced stiffening in vivo may lead to tailored clinical treatments for PA stiffening in PH patients.

  8. Adaptive Redox Response of Mesenchymal Stromal Cells to Stimulation with Lipopolysaccharide Inflammagen: Mechanisms of Remodeling of Tissue Barriers in Sepsis

    DTIC Science & Technology

    2013-03-08

    Mechanisms of Remodeling of Tissue Barriers in Sepsis Nikolai V. Gorbunov1*, Bradley R. Garrison1, Dennis P. McDaniel2, Min Zhai1, Pei-Jyun Liao1... sepsis [2, 5]. This problem leads to the searching for other potential mechanisms that could produce adverse effects on host metabolome resulting...understanding of the basic cellular mechanisms implicated in redox adaptive responses in 16 tissue barriers. This particular area of the molecular

  9. Short-Term Left Ventricular Remodeling After Revascularization in Subacute Total and Subtotal Occlusion With the Infarct-Related Left Anterior Descending Artery

    PubMed Central

    Celik, Ahmet; Kalay, Nihat; Korkmaz, Hasan; Dogdu, Orhan; Sahin, Omer; Elcik, Deniz; Karacavus, Seyhan; Dogan, Ali; Inanc, Tugrul; Ozdogru, Ibrahim; Oguzhan, Abdurrahman; Topsakal, Ramazan

    2011-01-01

    Background Large randomized studies revealed that percutaneous coronary intervention has no clinical benefit in patients with total occlusion. The purpose of this study is to evaluate left ventricular remodelling after PCI for total and subtotal infarct-related left anterior desending artery in stable patients who have not received trombolytic theraphy. Methods Sixty stable patients with subacute anterior myocardial infarction who have total or subtotal occlusion in the infarct-related left anterior descending artery were enrolled the study (20 patient in the total-medical group, 20 patient in the total-PCI group and 20 patient in the subtotal-PCI group). All patients’ left ventricular diameters, volumes and ejection fractions measured at admission and after a month. Results The necrotic segment number in scintigraphy were similar in three groups. In the total-PCI group, there were significant increases in left ventricular diastolic diameter, left ventricular end-diastolic volume and left ventricular end-systolic volume at first month. A borderline significant increase was observed in LVEDV in the total-medical group at first month. No significant difference was seen in all echocardiographic parameters in the subtotal-PCI group at a month after discharge. The percentage of increase in LVEDV was significantly higher and the percentage of increase in LVESV was borderline significantly higher in the total-PCI group than the other groups. Conclusions In stable patients, PCI for total occlusion in the subacute phase of anterior MI causes an increase in LV remodeling. Nevertheless PCI for subtotal occlusion in the subacute phase of anterior MI may prevent LV remodeling.

  10. Heart remodeling induced by adjuvant trastuzumab-containing chemotherapy for breast cancer overexpressing human epidermal growth factor receptor type 2: a prospective study.

    PubMed

    Piotrowski, Grzegorz; Gawor, Rafał; Bourge, Robert C; Stasiak, Arkadiusz; Potemski, Piotr; Gawor, Zenon; Nanda, Navin C; Banach, Maciej

    2013-12-01

    We aimed to investigate the cardiac changes in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with trastuzumab in an adjuvant setting. Two hundred and fifty-three women with HER2-positive breast cancer were included. The assessment of cardiovascular system and echocardiography were performed and compared at baseline, at the termination of trastuzumab therapy and 6 months latter. Left heart remodeling was defined arbitrary as the change in at least one of the analyzed echocardiographic parameters of ≥standard deviation (SD) (in model I) or ≥2×SD (in model II) after 6-month follow-up. After 6-month follow-up 39 (31.7%), 27 (22%), 14 (11.4%), 10 (8.1%), 5 (4.1%) and 1 (0.8%), women had at least one parameter with a change exceeding mean difference ≥SD, respectively; and 30 (24.4%), 9 (7.5%), 3 (2.4%), 2 (1.6%) 1 (0.8%) exceeding mean difference ≥2SD. In stepwise multivariate regression analysis sedentary life style (OR16.7, p=0.003), positive cardiovascular family history (OR 6,9; p=0.013) and left ventricular ejection fraction change after 3 months (OR 1.2; p=0.007) were independent predictors of left heart remodeling in model I, whereas hypertension (OR 5.6; p=0.06) and positive cardiovascular family history (OR 3.9; p=0.032) were independent predictors of heart remodeling in model II. In conclusion, trastuzumab induces LV and left atrial cavity dilatation together with LV systolic function impairment.

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

    PubMed

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

    2012-07-01

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

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

    PubMed

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

    2015-02-01

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

  13. 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.

  14. Interaction between endoplasmic reticulum stress and caspase 8 activation in retrovirus MoMuLV-ts1-infected astrocytes.

    PubMed

    Liu, Na; Scofield, Virginia L; Qiang, Wenan; Yan, Mingshan; Kuang, Xianghong; Wong, Paul K Y

    2006-05-10

    The murine retrovirus, MoMuLV-ts1, induces progressive paralysis and immune deficiency in FVB/N mice. We have reported previously that ts1 infection causes apoptosis in astrocytes via endoplasmic reticulum (ER) and mitochondrial stress (Liu, N., Kuang, X., Kim, H.T., Stoica, G., Qiang, W., Scofield, V.L., Wong, P.K.Y. Wong. 2004. Possible involvement of both endoplasmic reticulum- and mitochondria-dependent pathways in MoMuLV-ts1-induced apoptosis in astrocytes. J. NeuroVirol. 10, 189-198). In the present study, we show that caspase 8 activation in these cells is mediated through ER stress-associated elevation of death receptor DR5 and the C/EBP homologous protein (GADD153/CHOP), an ER stress-initiated transcription factor, rather than through TNFalpha and TNF-R1 interactions on the cell surface. Treatment with Z-IETD-FMK, a specific inhibitor of caspase 8 enzymatic activity, reduced ER stress by two mechanisms: by inhibiting caspase 8 activation, and by preventing cleavage of the ER-associated membrane protein BAP31 into BAP20, which exacerbates the ER stress response. These findings suggest that caspase 8- and ER stress-associated apoptotic pathways are linked in ts1-infected astrocytes.

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

    PubMed

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

    2012-08-13

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

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

    PubMed Central

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

    1982-01-01

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

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

    PubMed Central

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

    2016-01-01

    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

  18. Intramyocardial Delivery of Mesenchymal Stem Cell-Seeded Hydrogel Preserves Cardiac Function and Attenuates Ventricular Remodeling after Myocardial Infarction

    PubMed Central

    Mathieu, Eva; Lamirault, Guillaume; Toquet, Claire; Lhommet, Pierre; Rederstorff, Emilie; Sourice, Sophie; Biteau, Kevin; Hulin, Philippe; Forest, Virginie; Weiss, Pierre

    2012-01-01

    Background To improve the efficacy of bone marrow-derived mesenchymal stem cell (MSC) therapy targeted to infarcted myocardium, we investigated whether a self-setting silanized hydroxypropyl methylcellulose (Si-HPMC) hydrogel seeded with MSC (MSC+hydrogel) could preserve cardiac function and attenuate left ventricular (LV) remodeling during an 8-week follow-up study in a rat model of myocardial infarction (MI). Methodology/Principal Finding Si-HPMC hydrogel alone, MSC alone or MSC+hydrogel were injected into the myocardium immediately after coronary artery ligation in female Lewis rats. Animals in the MSC+hydrogel group showed an increase in cardiac function up to 28 days after MI and a mid-term prevention of cardiac function alteration at day 56. Histological analyses indicated that the injection of MSC+hydrogel induced a decrease in MI size and an increase in scar thickness and ultimately limited the transmural extent of MI. These findings show that intramyocardial injection of MSC+hydrogel induced short-term recovery of ventricular function and mid-term attenuation of remodeling after MI. Conclusion/Significance These beneficial effects may be related to the specific scaffolding properties of the Si-HPMC hydrogel that may provide the ability to support MSC injection and engraftment within myocardium. PMID:23284842

  19. 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

  20. Ventricular remodeling: from bedside to molecule.

    PubMed

    Jaffe, R; Flugelman, M Y; Halon, D A; Lewis, B S

    1997-01-01

    The multiple mechanisms that bring about the decompensation of the hypertrophic remodeled myocardium are synergistic and not fully understood. Our current hypothesis is that the increased stress on the ventricle is initially offset by compensatory myocardial hypertrophy. In many instances, however, progressive ventricular dilatation and heart failure occur as a result of maladaptive hypertrophy (abnormal myosin-actin production), programmed cell death (apoptosis) and/or changes in the interstitial vasculature and collagen composition. The molecular and genetic background to these processes includes changes in myocardial gene expression, activation of the local tissue renin-angiotensin and other neurohormonal systems, increased matrix metalloproteinase activity (including collagenase), and expression of certain components of the immune system, such as TNF-alpha. Future research will hopefully provide better methods for limiting the remodeling-ventricular dilatation process by novel pharmacotherapies, gene therapy and, possibly, surgical therapy, and determine the impact of such interventions on survival.

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

    PubMed

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

    2016-01-01

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

  3. 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.

  4. 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…

  5. 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

  6. 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

  7. Reverse engineering adverse outcome pathways.

    PubMed

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

    2011-01-01

    The toxicological effects of many stressors are mediated through unknown, or incompletely characterized, mechanisms of action. The application of reverse engineering complex interaction networks from high dimensional omics data (gene, protein, metabolic, signaling) can be used to overcome these limitations. This approach was used to characterize adverse outcome pathways (AOPs) for chemicals that disrupt the hypothalamus-pituitary-gonadal endocrine axis in fathead minnows (FHM, Pimephales promelas). Gene expression changes in FHM ovaries in response to seven different chemicals, over different times, doses, and in vivo versus in vitro conditions, were captured in a large data set of 868 arrays. Potential AOPs of the antiandrogen flutamide were examined using two mutual information-based methods to infer gene regulatory networks and potential AOPs. Representative networks from these studies were used to predict network paths from stressor to adverse outcome as candidate AOPs. The relationship of individual chemicals to an adverse outcome can be determined by following perturbations through the network in response to chemical treatment, thus leading to the nodes associated with the adverse outcome. Identification of candidate pathways allows for formation of testable hypotheses about key biological processes, biomarkers, or alternative endpoints that can be used to monitor an AOP. Finally, the unique challenges facing the application of this approach in ecotoxicology were identified and a road map for the utilization of these tools presented.

  8. Mechanisms of epigenetic remodelling during preimplantation development.

    PubMed

    Ross, Pablo Juan; Canovas, Sebastian

    2016-01-01

    Epigenetics involves mechanisms independent of modifications in the DNA sequence that result in changes in gene expression and are maintained through cell divisions. Because all cells in the organism contain the same genetic blueprint, epigenetics allows for cells to assume different phenotypes and maintain them upon cell replication. As such, during the life cycle, there are moments in which the epigenetic information needs to be reset for the initiation of a new organism. In mammals, the resetting of epigenetic marks occurs at two different moments, which both happen to be during gestation, and include primordial germ cells (PGCs) and early preimplantation embryos. Because epigenetic information is reversible and sensitive to environmental changes, it is probably no coincidence that both these extensive periods of epigenetic remodelling happen in the female reproductive tract, under a finely controlled maternal environment. It is becoming evident that perturbations during the extensive epigenetic remodelling in PGCs and embryos can lead to permanent and inheritable changes to the epigenome that can result in long-term changes to the offspring derived from them, as indicated by the Developmental Origins of Health and Disease (DOHaD) hypothesis and recent demonstration of inter- and trans-generational epigenetic alterations. In this context, an understanding of the mechanisms of epigenetic remodelling during early embryo development is important to assess the potential for gametic epigenetic mutations to contribute to the offspring and for new epimutations to be established during embryo manipulations that could affect a large number of cells in the offspring. It is of particular interest to understand whether and how epigenetic information can be passed on from the gametes to the embryo or offspring, and whether abnormalities in this process could lead to transgenerationally inheritable phenotypes. The aim of this review is to highlight recent progress made in

  9. 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

  10. [Remodeling in asthma: review of the literature].

    PubMed

    Montero Mora, Patricia; González Espinosa, Alicia Ma; Guidos Foguelbach, Guillermo A; Tinajero Castañeda, Olga Adriana; Serrano Cuevas, Saúl

    2003-01-01

    Remodeling, understood as a new or different reconstruction, has been observed in every organ after a chronic inflammatory response. In allergy, it has very important clinical consequences. As an example, in asthma this process is responsible for functional deterioration. In this case, the myofibroblasts play a central role in the process, together with a succession of products that are involved. In this bibliographic review we analyze the most important factors.

  11. Right ventricular remodeling in pulmonary hypertension.

    PubMed

    Franco, Veronica

    2012-07-01

    The right ventricle (RV) is in charge of pumping blood to the lungs for oxygenation. Pulmonary arterial hypertension (PAH) is characterized by high pulmonary vascular resistance and vascular remodeling, which results in a striking increase in RV afterload and subsequent failure. There is still unexploited potential for therapies that directly target the RV with the aim of supporting and protecting the right side of the heart, striving to prolong survival in patients with PAH.

  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.

  13. Stepwise nucleosome translocation by RSC remodeling complexes.

    PubMed

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

    2016-02-19

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

  14. Retinal remodeling triggered by photoreceptor degenerations.

    PubMed

    Jones, Bryan W; Watt, Carl B; Frederick, Jeanne M; Baehr, Wolfgang; Chen, Ching-Kang; Levine, Edward M; Milam, Ann H; Lavail, Matthew M; Marc, Robert E

    2003-09-08

    Many photoreceptor degenerations initially affect rods, secondarily leading to cone death. It has long been assumed that the surviving neural retina is largely resistant to this sensory deafferentation. New evidence from fast retinal degenerations reveals that subtle plasticities in neuronal form and connectivity emerge early in disease. By screening mature natural, transgenic, and knockout retinal degeneration models with computational molecular phenotyping, we have found an extended late phase of negative remodeling that radically changes retinal structure. Three major transformations emerge: 1) Müller cell hypertrophy and elaboration of a distal glial seal between retina and the choroid/retinal pigmented epithelium; 2) apparent neuronal migration along glial surfaces to ectopic sites; and 3) rewiring through evolution of complex neurite fascicles, new synaptic foci in the remnant inner nuclear layer, and new connections throughout the retina. Although some neurons die, survivors express molecular signatures characteristic of normal bipolar, amacrine, and ganglion cells. Remodeling in human and rodent retinas is independent of the initial molecular targets of retinal degenerations, including defects in the retinal pigmented epithelium, rhodopsin, or downstream phototransduction elements. Although remodeling may constrain therapeutic intervals for molecular, cellular, or bionic rescue, it suggests that the neural retina may be more plastic than previously believed.

  15. Psoriatic architecture constructed by epidermal remodeling.

    PubMed

    Iizuka, Hajime; Takahashi, Hidetoshi; Ishida-Yamamoto, Akemi

    2004-08-01

    Epidermal remodeling is the concept that epidermal architecture is determined by a simple self-organizing mechanism; epidermal hyperproliferation constructs typical psoriatic architecture. This is based on the assumption that the enlargements in both the two-dimensional proliferative compartment (basal cell layer) and three-dimensional whole epidermal volume coexist. During this process, the dermal papillae become markedly, but passively, expanded by enlargement of the proliferative compartment. This creates a considerable shrinkage force against the crowded basal cell layer, which is forced to lose adherence to the dermal extracellular matrix (ECM). This results in anoikis, a type of apoptosis characterized by cell detachment, and, consequently, a markedly diminished epidermal turnover time in psoriasis. The papillary shrinkage force also explains the fact that dermal papillary height does not exceed a certain limit. At the cessation of hyperproliferation a normalisation remodeling takes place toward normal tissue architecture. Thus the concept of epidermal remodeling explains the self-organizing mechanism of the architectural change in psoriasis, which is essentially a reversible disorder depending on epidermal hyperproliferation.

  16. Application of Petri nets in bone remodeling.

    PubMed

    Li, Lingxi; Yokota, Hiroki

    2009-07-06

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

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

    PubMed Central

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

    2017-01-01

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

  18. A randomised phase II study of OSI-7904L versus 5-fluorouracil (FU)/leucovorin (LV) as first-line treatment in patients with advanced biliary cancers.

    PubMed

    Ciuleanu, T; Diculescu, M; Hoepffner, N M; Trojan, J; Sailer, V; Zalupski, M; Herrmann, T; Roth, A; Chick, J; Brock, K; Albert, D; Philip, P A

    2007-08-01

    The prognosis of advanced biliary tract carcinoma is poor with chemotherapy limited to a palliative role. This randomised study was designed to evaluate the effectiveness of a new liposomal thymidylate synthase inhibitor (TSI), OSI-7904L, in parallel with a modified de Gramont regimen of 5-FU/LV in patients with advanced biliary cancer. Patients with previously untreated advanced or metastatic carcinoma of the biliary tract were randomised to receive either OSI-7904L 12 mg/m2 intravenously every 21 days or a modified de Gramont schedule of 5-FU/LV (intravenous l-LV 200 mg/m2, bolus 5-FU 400 mg/m2 and a 46-h infusion of 5-FU 2,400 mg/m2) every 14 days. Twenty-two patients were randomised, 11 to each group. No patients responded in the OSI-7904L arm, while one patient achieved a partial response in the 5-FU/LV arm. The rates of disease stabilisation were 4/11 (OSI-7904L) and 10/11 (5-FU/LV). Both treatment arms were generally well tolerated. These results show that the activity of OSI-7904L is below a level of clinical relevance in advanced biliary tract cancer, providing only a small degree of disease stabilisation. A simplified de Gramont schedule appears to have marginally more activity. Both treatments were well tolerated.

  19. Androgens Contribute to Sex Differences in Myocardial Remodeling under Pressure Overload by a Mechanism Involving TGF-β

    PubMed Central

    Montalvo, Cecilia; Villar, Ana V.; Merino, David; García, Raquel; Ares, Miguel; Llano, Miguel; Cobo, Manuel; Hurlé, María A.; Nistal, J. Francisco

    2012-01-01

    Background In clinical studies, myocardial remodeling in aortic valve stenosis appears to be more favorable in women than in men, even after menopause. In the present study, we assessed whether circulating androgens contribute to a less favorable myocardial remodeling under pressure overload in males. We examined sex-related differences in one-year-old male and female mice. Whereas male mice at this age exhibited circulating androgen levels within the normal range for young adults, the circulating estrogens in females were reduced. The contribution of gonadal androgens to cardiac remodeling was analyzed in a group of same-age castrated mice. Methodology/Principal Findings Animals were subjected to transverse aortic constriction (TAC). Echocardiography was performed 2 weeks after TAC and myocardial mRNA levels of TGF-βs, Smads 2 and 3, collagens, fibronectin, β-myosin heavy chain and α-myosin heavy chain were determined by q-PCR. Protein detection of p-SMAD2/3 was performed by Western Blot. Histological staining of fibrosis was performed with picrosirius red and Masson's trichrome. Compared with females, males developed more severe tissue fibrosis, LV dilation and hemodynamic dysfunction. TAC-males showed higher myocardial expression levels of TGF-βs and the treatment with a neutralizing antibody to TGF-β prevented myocardial fibrosis development. Orchiectomy diminished TAC-induced up-regulation of TGF-βs and TGF-β target genes, and it also reduced fibrosis and hemodynamic dysfunction. The capability of androgens to induce TGF-β expression was confirmed in NIH-3T3 fibroblasts and H9C2 cardiomyocytes exposed to dihydrotestosterone. Conclusions/Significance Our results indicate that circulating androgens are responsible for the detrimental effects in the myocardium of older male mice subjected to pressure overload through a mechanism involving TGF-βs. PMID:22558184

  20. Crystallization and preliminary X-ray diffraction of the surfactant protein Lv-ranaspumin from the frog Leptodactylus vastus.

    PubMed

    Hissa, Denise Cavalcante; Bezerra, Gustavo Arruda; Obrist, Britta; Birner-Grünberger, Ruth; Melo, Vânia Maria Maciel; Gruber, Karl

    2012-03-01

    Lv-ranaspumin is a natural surfactant protein with a molecular mass of 23.5 kDa which was isolated from the foam nest of the frog Leptodactylus vastus. Only a partial amino-acid sequence is available for this protein and it shows it to be distinct from any protein sequence reported to date. The protein was purified from the natural source by ion-exchange and size-exclusion chromatography and was crystallized by sitting-drop vapour diffusion using the PEG/Ion screen at 293 K. A complete data set was collected to 3.5 Å resolution. The crystal belonged to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 51.96, b = 89.99, c = 106.00 Å. Assuming the presence of two molecules in the asymmetric unit, the solvent content was estimated to be 54%.

  1. Establishment of a novel feline leukemia virus (FeLV)-negative B-cell cell line from a cat with B-cell lymphoma.

    PubMed

    Mochizuki, Hiroyuki; Takahashi, Masashi; Nishigaki, Kazuo; Ide, Tetsuya; Goto-Koshino, Yuko; Watanabe, Shinya; Sato, Hirofumi; Sato, Masahiko; Kotera, Yukiko; Fujino, Yasuhito; Ohno, Koichi; Uchida, Kazuyuki; Tsujimoto, Hajime

    2011-04-15

    We established a novel feline B-cell line, MS4, from the neoplastic pleural effusion of a cat with cutaneous B-cell lymphoma. Immunophenotype staining of the MS4 cells was positive for CD20, CD79α, and IgA and negative for CD3, CD4, CD5, CD8α, CD18, CD21, CD22, IgM, IgG, Ig light chain, and MHC class II. PCR analysis for immunoglobulin heavy chain gene rearrangements revealed a monoclonal rearrangement, whereas no clonal rearrangement of the T-cell receptor γ gene was detected. Southern blotting with an exogenous feline leukemia virus (FeLV) U3 probe revealed no integration of exogenous FeLV provirus. The MS4 cell line is the first FeLV-negative feline B-cell lymphoma cell line, and may be used to investigate the pathogenesis of spontaneously occurring feline lymphoma and the development of new therapies.

  2. Adverse drug reactions: part II.

    PubMed

    Wooten, James M

    2010-11-01

    Pharmacovigilance is the process of identifying, monitoring, and effectively reducing adverse drug reactions. Adverse drug reactions (ADRs) are an important consideration when assessing a patient's health. The proliferation of new pharmaceuticals means that the incidence of ADRs is increasing. The goal for all health care providers must be to minimize the risk of ADRs as much as possible. Steps to achieve this include understanding the pharmacology for all drugs prescribed and proactively assessing and monitoring those patients at greatest risk for developing an ADR. Groups at greatest risk for developing ADRs include the elderly, children, and pregnant patients, as well as others. Pharmacovigilance must be effectively practiced by all health care providers in order to avoid ADRs.

  3. Adverse drug reactions: Part I.

    PubMed

    Wooten, James M

    2010-10-01

    Pharmacovigilance is the process of identifying, monitoring, and effectively reducing adverse drug reactions. Adverse drug reactions (ADRs) are an important consideration when assessing a patient's health. The proliferation of new pharmaceuticals means that the incidence of ADRs is increasing. The goal for all health care providers must be to minimize the risk of ADRs as much as possible. Steps to achieve this include understanding the pharmacology for all drugs prescribed and proactively assessing and monitoring those patients at greatest risk for developing an ADR. Groups at greatest risk for developing ADRs include the elderly, children, and pregnant patients, as well as others. Pharmacovigilance must effectively be practiced by all health providers in order to avoid ADRs.

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

    PubMed

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

    2010-02-01

    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.

  5. [Finasteride adverse effects: An update].

    PubMed

    Carreño-Orellana, Néstor; Moll-Manzur, Catherina; Carrasco-Zuber, Juan Eduardo; Álvarez-Véliz, Sergio; Berroeta-Mauriziano, Daniela; Porras-Kusmanic, Ninoska

    2016-12-01

    Finasteride is a 5-α reductase inhibitor that is widely used in the management of benign prostate hyperplasia and male pattern hair loss. It is well known that these agents improve the quality of life in men suffering from these conditions. However, they are associated with some transient and even permanent adverse effects. The aim of this article is to clarify the controversies about the safety of finasteride by analyzing the evidence available in the literature.

  6. [Pain as adverse drug reaction].

    PubMed

    Böhmdorfer, Birgit; Schaffarzick, Daniel; Nagano, Marietta; Janowitz, Susanne Melitta; Schweitzer, Ekkehard

    2012-09-01

    We present a multidisciplinary (anaesthesiology--clinical pharmacy--bioinformatics) analysis of pain as possible adverse drug reaction taking different manifestations of pain, indication groups, relevance to the Austrian drug market and possible mechanistic influence of drugs on development and apprehension of pain into consideration.We designed an overview that shows how transmitters that play a part in nociception and antinociception can be influenced by drugs. This allows conclusions to the dolorigene potential of therapeutics.

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

    PubMed

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

    2010-08-01

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

  8. Thiocolchicoside: review of adverse effects.

    PubMed

    2016-02-01

    Thiocolchicoside has long been used as a muscle relaxant, despite a lack of proven efficacy beyond the placebo effect. Its chemical structure consists of colchicine, a sugar (ose) and a sulphur-containing radical (thio), and its adverse effects are therefore likely to be similar to those of colchicine. Using the standard Prescrire methodology, we reviewed the available data on the adverse effects of thiocolchicoside. Liver injury, pancreatitis, seizures, blood cell disorders, severe cutaneous disorders, rhabdomyolysis and reproductive disorders have all been recorded in the French and European pharmacovigilance databases and in the periodic updates that the companies concerned submit to regulatory agencies. These data do not specify the frequency of the disorders nor do they identify the most susceptible patient populations. Thiocolchicoside is teratogenic in experimental animals and also damages chromosomes. Human data are limited to a follow-up of about 30 pregnant women (no major malformations) and reports of altered spermatogenesis, including cases of azoospermia. In practice, there is no justification for exposing patients to the adverse effects of thiocolchicoside. It is better to use an effective, well-known analgesic for patients complaining of muscle pain, starting with paracetamol.

  9. Adverse food-drug interactions.

    PubMed

    de Boer, Alie; van Hunsel, Florence; Bast, Aalt

    2015-12-01

    Food supplements and herbal products are increasingly popular amongst consumers. This leads to increased risks of interactions between prescribed drugs and these products containing bioactive ingredients. From 1991 up to 2014, 55 cases of suspected adverse drug reactions due to concomitant intake of health-enhancing products and drugs were reported to Lareb, the Netherlands Pharmacovigilance Centre. An overview of these suspected interactions is presented and their potential mechanisms of action are described. Mainly during the metabolism of xenobiotics and due to the pharmacodynamics effects interactions seem to occur, which may result in adverse drug reactions. Where legislation is seen to distinct food and medicine, legislation concerning these different bioactive products is less clear-cut. This can only be resolved by increasing the molecular knowledge on bioactive substances and their potential interactions. Thereby potential interactions can be better understood and prevented on an individual level. By considering the dietary pattern and use of bioactive substances with prescribed medication, both health professionals and consumers will be increasingly aware of interactions and these interactive adverse effects can be prevented.

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

    PubMed Central

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

    2014-01-01

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

  12. Nucleosome remodelers in double-strand break repair.

    PubMed

    Seeber, Andrew; Hauer, Michael; Gasser, Susan M

    2013-04-01

    ATP-dependent nucleosome remodelers use ATP hydrolysis to shift, evict and exchange histone dimers or octamers and have well-established roles in transcription. Earlier work has suggested a role for nucleosome remodelers such as INO80 in double-strand break (DSB) repair. This review will begin with an update on recent studies that explore how remodelers are recruited to DSBs. We then examine their impact on various steps of repair, focusing on resection and the formation of the Rad51-ssDNA nucleofilament. Finally, we will explore new studies that implicate remodelers in the physical movement of chromatin in response to damage.

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

    PubMed

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

    2006-06-01

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

  14. LRP1 regulates remodeling of the extracellular matrix by fibroblasts

    PubMed Central

    Gaultier, Alban; Hollister, Margaret; Reynolds, Irene; Hsieh, En-hui; Gonias, Steven L.

    2009-01-01

    Low density lipoprotein receptor-related protein (LRP1) is an endocytic receptor for diverse proteases, protease inhibitors, and other plasma membrane proteins, including the urokinase receptor (uPAR). LRP1 also functions in cell-signaling and regulates gene expression. The goal of this study was to determine whether LRP1 regulates remodeling of provisional extracellular matrix (ECM) by fibroblasts. To address this problem, we utilized an in vitro model in which type I collagen was reconstituted and overlaid with fibronectin. Either the collagen or fibronectin was fluorescently-labeled. ECM remodeling by fibroblasts deficient in LRP1, uPAR, or MT1-MMP was studied. MT1-MMP was required for efficient remodeling of the deep collagen layer but not involved in fibronectin remodeling. Instead, fibronectin was remodeled by a system that required urokinase-type plasminogen activator (uPA), uPAR, and exogenously-added plasminogen. LRP1 markedly inhibited fibronectin remodeling by regulating cell-surface uPAR and plasminogen activation. LRP1 also regulated remodeling of the deep collagen layer but not by controlling MT1-MMP. Instead, LRP1 deficiency or inhibition de-repressed a secondary pathway for collagen remodeling, which was active in MT1-MMP-deficient cells but not in uPAR-deficient cells. These results demonstrate that LRP1 regulates ECM remodeling principally by repressing pathways that require plasminogen activation by uPA in association with uPAR. PMID:19699300

  15. CHD chromatin remodelers and the transcription cycle.

    PubMed

    Murawska, Magdalena; Brehm, Alexander

    2011-01-01

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

  16. 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.

  17. miR-222 is Necessary for Exercise-induced Cardiac Growth and Protects Against Pathological Cardiac Remodeling

    PubMed Central

    Liu, Xiaojun; Xiao, Junjie; Zhu, Han; Wei, Xin; Platt, Colin; Damilano, Federico; Xiao, Chunyang; Bezzerides, Vassilios; Boström, Pontus; Che, Lin; Zhang, Chunxiang; Spiegelman, Bruce M; Rosenzweig, Anthony

    2015-01-01

    SUMMARY Exercise induces physiological cardiac growth and protects the heart against pathological remodeling. Recent work suggests exercise also enhances the heart’s capacity for repair, which could be important for regenerative therapies. While microRNAs are important in certain cardiac pathologies, less is known about their functional roles in exercise-induced cardiac phenotypes. We profiled cardiac microRNA expression in two distinct models of exercise and found microRNA-222 (miR-222) was upregulated in both. Downstream miR-222 targets modulating cardiomyocyte phenotype were identified, including HIPK1 and Homeobox-1. Inhibition of miR-222 in vivo completely blocked cardiac and cardiomyocyte growth in response to exercise, while reducing markers of cardiomyocyte proliferation. Importantly, mice with inducible cardiomyocyte miR-222 expression were resistant to adverse cardiac remodeling and dysfunction after ischemic injury. These studies implicate miR-222 as necessary for exercise-induced cardiomyocyte growth and proliferation in the adult mammalian heart and show that it is sufficient to protect the heart against adverse remodeling. PMID:25863248

  18. miR-222 is necessary for exercise-induced cardiac growth and protects against pathological cardiac remodeling.

    PubMed

    Liu, Xiaojun; Xiao, Junjie; Zhu, Han; Wei, Xin; Platt, Colin; Damilano, Federico; Xiao, Chunyang; Bezzerides, Vassilios; Boström, Pontus; Che, Lin; Zhang, Chunxiang; Spiegelman, Bruce M; Rosenzweig, Anthony

    2015-04-07

    Exercise induces physiological cardiac growth and protects the heart against pathological remodeling. Recent work suggests exercise also enhances the heart's capacity for repair, which could be important for regenerative therapies. While microRNAs are important in certain cardiac pathologies, less is known about their functional roles in exercise-induced cardiac phenotypes. We profiled cardiac microRNA expression in two distinct models of exercise and found microRNA-222 (miR-222) was upregulated in both. Downstream miR-222 targets modulating cardiomyocyte phenotypes were identified, including HIPK1 and HMBOX1. Inhibition of miR-222 in vivo completely blocked cardiac and cardiomyocyte growth in response to exercise while reducing markers of cardiomyocyte proliferation. Importantly, mice with inducible cardiomyocyte miR-222 expression were resistant to adverse cardiac remodeling and dysfunction after ischemic injury. These studies implicate miR-222 as necessary for exercise-induced cardiomyocyte growth and proliferation in the adult mammalian heart and show that it is sufficient to protect the heart against adverse remodeling.

  19. Adverse responses to local anaesthetics.

    PubMed

    Fisher, M M; Graham, R

    1984-11-01

    Progressive challenge was used to investigate twenty-seven patients with a history of an adverse response to local anaesthesia. True allergy was detected in only one patient. The method does not exclude reactions to additives and preservatives in local anaesthetics. If preservative-free local anaesthetics are used for subsequent exposure in patients with no response to progressive challenge, subsequent exposure is safe. The possibility that some of these patients may be reacting to preservatives in the solutions cannot be excluded by such testing. Where possible preservative-free local anaesthetic preparations should be used for subsequent anaesthesia.

  20. Adverse Outcomes in Group Psychotherapy

    PubMed Central

    Roback, Howard B.

    2000-01-01

    Group forms of therapy have been growing at a rapid rate, in part because of their documented effectiveness and economic considerations such as managed care. It is therefore becoming increasingly important to assess the psychological risks of these interventions. The author provides an overview of the published literature and conference presentations on negative effects in adult outpatient groups. Although much of the literature on adverse outcomes in group therapy focuses on single risk factors (e.g., negative leader, group process, or patient characteristics), the author argues that an interactional model should be encouraged. Means of reducing casualties are also discussed, as well as methodological issues and research directions. PMID:10896735

  1. Right ventricular relative wall thickness as a predictor of outcomes and of right ventricular reverse remodeling for patients with pulmonary hypertension.

    PubMed

    Sano, Hiroyuki; Tanaka, Hidekazu; Motoji, Yoshiki; Fukuda, Yuko; Mochizuki, Yasuhide; Hatani, Yutaka; Matsuzoe, Hiroki; Hatazawa, Keiko; Shimoura, Hiroyuki; Ooka, Junichi; Ryo-Koriyama, Keiko; Nakayama, Kazuhiko; Matsumoto, Kensuke; Emoto, Noriaki; Hirata, Ken-Ichi

    2017-03-01

    Mid-term right ventricular (RV) reverse remodeling after treatment in patients with pulmonary hypertension (PH) is associated with long-term outcome as well as baseline RV remodeling. However, baseline factors influencing mid-term RV reverse remodeling after treatment and its prognostic capability remain unclear. We studied 54 PH patients. Mid-term RV remodeling was assessed in terms of the RV area, which was traced planimetrically at the end-systole (RVESA). RV reverse remodeling was defined as a relative decrease in the RVESA of at least 15% at 10.2 ± 9.4 months after treatment. Long-term follow-up was 5 years. Adverse events occurred in ten patients (19%) and mid-term RV reverse remodeling after treatment was observed in 37 (69%). Patients with mid-term RV reverse remodeling had more favorable long-term outcomes than those without (log-rank: p = 0.01). Multivariate logistic regression analysis showed that RV relative wall thickness (RV-RWT), as calculated as RV free-wall thickness/RV basal linear dimension at end-diastole, was an independent predictor of mid-term RV reverse remodeling (OR 1.334; 95% CI, 1.039-1.713; p = 0.03). Moreover, patients with RV-RWT ≥0.21 showed better long-term outcomes than did those without (log-rank p = 0.03), while those with RV-RWT ≥0.21 and mid-term RV reverse remodeling had the best long-term outcomes. Patients with RV-RWT <0.21 and without mid-term RV reverse remodeling, on the other hand, had worse long-term outcomes than other sub-groups. In conclusions, RV-RWT could predict mid-term RV reverse remodeling after treatment in PH patients, and was associated with long-term outcomes. Our finding may have clinical implications for better management of PH patients.

  2. Vascular remodeling underlies rebleeding in hemophilic arthropathy.

    PubMed

    Bhat, Vikas; Olmer, Merissa; Joshi, Shweta; Durden, Donald L; Cramer, Thomas J; Barnes, Richard Fw; Ball, Scott T; Hughes, Tudor H; Silva, Mauricio; Luck, James V; Moore, Randy E; Mosnier, Laurent O; von Drygalski, Annette

    2015-11-01

    Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII-deficient mouse. We found soft-tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft-tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII-deficient mice involved pronounced remodeling with expression of α-Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of α-SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease.

  3. Specific remodeling of splenic architecture by cytomegalovirus.

    PubMed

    Benedict, Chris A; De Trez, Carl; Schneider, Kirsten; Ha, Sukwon; Patterson, Ginelle; Ware, Carl F

    2006-03-01

    Efficient immune defenses are facilitated by the organized microarchitecture of lymphoid organs, and this organization is regulated by the compartmentalized expression of lymphoid tissue chemokines. Mouse cytomegalovirus (MCMV) infection induces significant remodeling of splenic microarchitecture, including loss of marginal zone macrophage populations and dissolution of T and B cell compartmentalization. MCMV preferentially infected the splenic stroma, targeting endothelial cells (EC) as revealed using MCMV-expressing green fluorescent protein. MCMV infection caused a specific, but transient transcriptional suppression of secondary lymphoid chemokine (CCL21). The loss of CCL21 was associated with the failure of T lymphocytes to locate within the T cell zone, although trafficking to the spleen was unaltered. Expression of CCL21 in lymphotoxin (LT)-alpha-deficient mice is dramatically reduced, however MCMV infection further reduced CCL21 levels, suggesting that viral modulation of CCL21 was independent of LTalpha signaling. Activation of LTbeta-receptor signaling with an agonistic antibody partially restored CCL21 mRNA expression and redirected transferred T cells to the splenic T cell zone in MCMV-infected mice. These results indicate that virus-induced alterations in lymphoid tissues can occur through an LT-independent modulation of chemokine transcription, and targeting of the LT cytokine system can counteract lymphoid tissue remodeling by MCMV.

  4. 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

  5. Transspecies Transmission of Gammaretroviruses and the Origin of the Gibbon Ape Leukaemia Virus (GaLV) and the Koala Retrovirus (KoRV)

    PubMed Central

    Denner, Joachim

    2016-01-01

    Transspecies transmission of retroviruses is a frequent event, and the human immunodeficiency virus-1 (HIV-1) is a well-known example. The gibbon ape leukaemia virus (GaLV) and koala retrovirus (KoRV), two gammaretroviruses, are also the result of a transspecies transmission, however from a still unknown host. Related retroviruses have been found in Southeast Asian mice although the sequence similarity was limited. Viruses with a higher sequence homology were isolated from Melomys burtoni, the Australian and Indonesian grassland melomys. However, only the habitats of the koalas and the grassland melomys in Australia are overlapping, indicating that the melomys virus may not be the precursor of the GaLV. Viruses closely related to GaLV/KoRV were also detected in bats. Therefore, given the fact that the habitats of the gibbons in Thailand and the koalas in Australia are far away, and that bats are able to fly over long distances, the hypothesis that retroviruses of bats are the origin of GaLV and KoRV deserves consideration. Analysis of previous transspecies transmissions of retroviruses may help to evaluate the potential of transmission of related retroviruses in the future, e.g., that of porcine endogenous retroviruses (PERVs) during xenotransplantation using pig cells, tissues or organs. PMID:27999419

  6. 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 ...

  7. Transspecies Transmission of Gammaretroviruses and the Origin of the Gibbon Ape Leukaemia Virus (GaLV) and the Koala Retrovirus (KoRV).

    PubMed

    Denner, Joachim

    2016-12-20

    Transspecies transmission of retroviruses is a frequent event, and the human immunodeficiency virus-1 (HIV-1) is a well-known example. The gibbon ape leukaemia virus (GaLV) and koala retrovirus (KoRV), two gammaretroviruses, are also the result of a transspecies transmission, however from a still unknown host. Related retroviruses have been found in Southeast Asian mice although the sequence similarity was limited. Viruses with a higher sequence homology were isolated from Melomys burtoni, the Australian and Indonesian grassland melomys. However, only the habitats of the koalas and the grassland melomys in Australia are overlapping, indicating that the melomys virus may not be the precursor of the GaLV. Viruses closely related to GaLV/KoRV were also detected in bats. Therefore, given the fact that the habitats of the gibbons in Thailand and the koalas in Australia are far away, and that bats are able to fly over long distances, the hypothesis that retroviruses of bats are the origin of GaLV and KoRV deserves consideration. Analysis of previous transspecies transmissions of retroviruses may help to evaluate the potential of transmission of related retroviruses in the future, e.g., that of porcine endogenous retroviruses (PERVs) during xenotransplantation using pig cells, tissues or organs.

  8. Integrative network analysis reveals time-dependent molecular events underlying left ventricular remodeling in post-myocardial infarction patients.

    PubMed

    Pinet, Florence; Cuvelliez, Marie; Kelder, Thomas; Amouyel, Philippe; Radonjic, Marijana; Bauters, Christophe

    2017-02-03

    To elucidate the time-resolved molecular events underlying the LV remodeling (LVR) process, we developed a large-scale network model that integrates the 24 molecular variables (plasma proteins and non-coding RNAs) collected in the REVE-2 study at four time points (baseline, 1month, 3months and 1year) after MI. The REVE-2 network model was built by extending the set of REVE-2 variables with their mechanistic context based on known molecular interactions (1310 nodes and 8639 edges). Changes in the molecular variables between the group of patients with high LVR (>20%) and low LVR (<20%) were used to identify active network modules within the clusters associated with progression of LVR, enabling assessment of time-resolved molecular changes. Although the majority of molecular changes occur at the baseline, two network modules specifically show an increasing number of active molecules throughout the post-MI follow up: one involved in muscle filament sliding, containing the major troponin forms and tropomyosin proteins, and the other associated with extracellular matrix disassembly, including matrix metalloproteinases, tissue inhibitors of metalloproteinases and laminin proteins. For the first time, integrative network analysis of molecular variables collected in REVE-2 patients with known molecular interactions allows insight into time-dependent mechanisms associated with LVR following MI, linking specific processes with LV structure alteration. In addition, the REVE-2 network model provides a shortlist of prioritized putative novel biomarker candidates for detection of LVR after MI event associated with a high risk of heart failure and is a valuable resource for further hypothesis generation.

  9. Sex-specific differences in age-dependent progression of aortic dysfunction and related cardiac remodeling in spontaneously hypertensive rats.

    PubMed

    Al-Gburi, Suzan; Deussen, Andreas Johannes; Galli, Roberta; Muders, Michael H; Zatschler, Birgit; Neisser, Anja; Müller, Bianca; Kopaliani, Irakli

    2017-03-08

    Sex-specific differences in renin-angiotensin-system (RAS) and arterial pressure have been evidenced in many mammals including spontaneously hypertensive rats (SHRs). Although SHRs have been used extensively as a leading experimental model of hypertension, effects of sex-specific differences in RAS on aortic function and related cardiac remodeling during aging and hypertension have not been documented in detail. We examined structural and functional changes in aorta and heart of female and male SHRs at ages of 5, 14, 29 and 36-weeks. SHRs of both sexes were hypertensive from 14-weeks. Aortic endothelial dysfunction and fibrosis, left ventricular (LV) hypertrophy and cardiac fibrosis was evident at the age of 29-weeks in male SHRs, but first appeared only at the age of 36-weeks in female SHRs. There was a pronounced delay of matrix metalloproteinase-2 activity in aorta and heart of female SHRs, which was associated with preservation of 40 % more elastin and less extensive cardiac fibrosis than in males. At 5, 29 and 36-weeks of age female SHRs showed higher levels of aortic and myocardial AT2R and MasR mRNA and decreased ANGII-mediated aortic constriction. While female SHRs had increased relaxation to AT2R stimulation at 5 and 29-weeks compared to males, this difference disappeared at 36-weeks of age. This study documents sex-specific differences in the temporal progression of aortic dysfunction and LV hypertrophy in SHRs which are independent of arterial pressure and are apparently mediated by higher AT2R expression in the heart and aorta of female SHRs.

  10. "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)

  11. The international serious adverse events consortium.

    PubMed

    Holden, Arthur L; Contreras, Jorge L; John, Sally; Nelson, Matthew R

    2014-11-01

    The International Serious Adverse Events Consortium is generating novel insights into the genetics and biology of drug-induced serious adverse events, and thereby improving pharmaceutical product development and decision-making.

  12. Evaluation of the National Remodelling Team: Year 3. Final Report

    ERIC Educational Resources Information Center

    Easton, Claire; Eames, Anna; Wilson, Rebekah; Walker, Matthew; Sharp, Caroline

    2006-01-01

    The aim of the National Foundation for Educational Research (NFER) evaluation was to examine the effectiveness and impact of the work of the National Remodelling Team (NRT) in completing the third phase of the remodeling program and its effectiveness in applying its model, tools and techniques to the extended schools program. This evaluation has…

  13. CCR3 Blockade Attenuates Eosinophilic Ileitis and Associated Remodeling.

    PubMed

    Masterson, Joanne C; McNamee, Eóin N; Jedlicka, Paul; Fillon, Sophie; Ruybal, Joseph; Hosford, Lindsay; Rivera-Nieves, Jesús; Lee, James J; Furuta, Glenn T

    2011-11-01

    Intestinal remodeling and stricture formation is a complication of inflammatory bowel disease (IBD) that often requires surgical intervention. Although eosinophils are associated with mucosal remodeling in other organs and are increased in IBD tissues, their role in IBD-associated remodeling is unclear. Histological and molecular features of ileitis and remodeling were assessed using immunohistochemical, histomorphometric, flow cytometric, and molecular analysis (real-time RT-PCR) techniques in a murine model of chronic eosinophilic ileitis. Collagen protein was assessed by Sircol assay. Using a spontaneous eosinophilic Crohn's-like mouse model SAMP1/SkuSlc, we demonstrate an association between ileitis progression and remodeling over the course of 40 weeks. Mucosal and submucosal eosinophilia increased over the time course and correlated with increased histological inflammatory indices. Ileitis and remodeling increased over the 40 weeks, as did expression of fibronectin. CCR3-specific antibody-mediated reduction of eosinophils resulted in significant decrease in goblet cell hyperplasia, muscularis propria hypertrophy, villus blunting, and expression of inflammatory and remodeling genes, including fibronectin. Cellularity of local mesenteric lymph nodes, including T- and B-lymphocytes, was also significantly reduced. Thus, eosinophils participate in intestinal remodeling, supporting eosinophils as a novel therapeutic target.

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

    PubMed

    An, Wei; Yang, Jing

    2006-11-03

    Ping-Lv-Mixture (PLM) is a Chinese medicinal formula. The present study aimed to determine the effects of PLM on myocardial ischemia-reperfusion (MI/R) induced arrhythmias in rats. Arrhythmia model was established by occlusion of the left arterial descending coronary artery and thereafter reperfusion. A lead II electrocardiogram was monitored throughout the experiment. The results showed that pretreatment of PLM to MI/R rats significantly reduced the incidence and duration of ventricular tachycardia and ventricular fibrillation. On induction of MI/R, the activities of creatine kinase and lactate dehydrogenase were increased in vehicle group. PLM (0.04-1.00 g/kg) administration prevented the increase of these enzymes. Moreover, a significant increase of myocardium superoxide dismutase and decrease of malondialdehyde contents were observed in rats of PLM groups. On the other hand, the expressions of platelet activating factor (PAF) receptor mRNA was down-regulated in a dose-dependent manner in the PLM-treated groups by RT-PCR. Thus, it can be concluded that pretreatment with PLM inhibited lipid peroxidation in rats through suppressing the expression of PAF receptor, which may contribute to its preventive effect on myocardial ischemia-reperfusion induced arrhythmias.

  15. Crystallization and preliminary X-ray diffraction of the surfactant protein Lv-ranaspumin from the frog Leptodactylus vastus

    PubMed Central

    Hissa, Denise Cavalcante; Bezerra, Gustavo Arruda; Obrist, Britta; Birner-Grünberger, Ruth; Melo, Vânia Maria Maciel; Gruber, Karl

    2012-01-01

    Lv-ranaspumin is a natural surfactant protein with a molecular mass of 23.5 kDa which was isolated from the foam nest of the frog Leptodactylus vastus. Only a partial amino-acid sequence is available for this protein and it shows it to be distinct from any protein sequence reported to date. The protein was purified from the natural source by ion-exchange and size-exclusion chromatography and was crystallized by sitting-drop vapour diffusion using the PEG/Ion screen at 293 K. A complete data set was collected to 3.5 Å resolution. The crystal belonged to the orthorhombic space group P212121, with unit-cell parameters a = 51.96, b = 89.99, c = 106.00 Å. Assuming the presence of two molecules in the asymmetric unit, the solvent content was estimated to be 54%. PMID:22442233

  16. Mechanical Behaviors and Elastic Parameters of Laminated Fabric URETEK3216LV Subjected to Uniaxial and Biaxial Loading

    NASA Astrophysics Data System (ADS)

    Chen, Jianwen; Chen, Wujun; Wang, Mingyang; Ding, Yong; Zhou, Han; Zhao, Bing; Fan, Jin

    2017-01-01

    A comprehensive experimental study of the laminated fabric URETEK3216LV subjected to mono-uniaxial, uniaxial cyclic and biaxial cyclic loading was performed to expose the detailed mechanical behaviors and determine proper elastic parameters for the laminated fabrics under specific stress states. The elastic modulus-strain curves and elastic parameter response surfaces were used to reveal the mechanical behaviors, and a weighted average method of integrals was proposed to calculate the elastic parameters for different stress states. Results show that typical stress-strain curves consist of three distinct regions during loading: crimp region, nonlinear transition region and yarn extension region, which is consistent with those of the constitutive yarns. The elastic parameters and mechanical behaviors of the laminated fabric are stress-state specific, and they vary noticeably with the experimental protocols, stress ratios and stress levels. The proposed method is feasible to evaluate the elastic parameters no matter what stress states the materials are subjected to, and thus it may offer potential access to obtain accurate design and analysis of the airship structures under different loading conditions.

  17. Vessel remodelling, pregnancy hormones and extravillous trophoblast function.

    PubMed

    Chen, Jessie Z-J; Sheehan, Penelope M; Brennecke, Shaun P; Keogh, Rosemary J

    2012-02-26

    During early human pregnancy, extravillous trophoblast (EVT) cells from the placenta invade the uterine decidual spiral arterioles and mediate the remodelling of these vessels such that a low pressure, high blood flow can be supplied to the placenta. This is essential to facilitate normal growth and development of the foetus. Defects in remodelling can manifest as the serious pregnancy complication pre-eclampsia. During the period of vessel remodelling three key pregnancy-associated hormones, human chorionic gonadotrophin (hCG), progesterone (P(4)) and oestradiol (E(2)), are found in high concentrations at the maternal-foetal interface. Potentially these hormones may control EVT movement and thus act as regulators of vessel remodelling. This review will discuss what is known about how these hormones affect EVT proliferation, migration and invasion during vascular remodelling and the potential relationship between hCG, P(4), E(2) and the development of pre-eclampsia.

  18. Proliferation and tissue remodeling in cancer: the hallmarks revisited.

    PubMed

    Markert, E K; Levine, A J; Vazquez, A

    2012-10-04

    Although cancers are highly heterogeneous at the genomic level, they can manifest common patterns of gene expression. Here, we use gene expression signatures to interrogate two major processes in cancer, proliferation and tissue remodeling. We demonstrate that proliferation and remodeling signatures are partially independent and result in four distinctive cancer subtypes. Cancers with the proliferation signature are characterized by signatures of p53 and PTEN inactivation and concomitant Myc activation. In contrast, remodeling correlates with RAS, HIF-1α and NFκB activation. From the metabolic point of view, proliferation is associated with upregulation of glycolysis and serine/glycine metabolism, whereas remodeling is characterized by a downregulation of oxidative phosphorylation. Notably, the proliferation signature correlates with poor outcome in lung, prostate, breast and brain cancer, whereas remodeling increases mortality rates in colorectal and ovarian cancer.

  19. Chromatin remodeling in DNA double-strand break repair.

    PubMed

    Bao, Yunhe; Shen, Xuetong

    2007-04-01

    ATP-dependent chromatin remodeling complexes use ATP hydrolysis to remodel nucleosomes and have well-established functions in transcription. However, emerging lines of evidence suggest that chromatin remodeling complexes are important players in DNA double-strand break (DSB) repair as well. The INO80 and SWI2 subfamilies of chromatin remodeling complexes have been found to be recruited to the double-strand lesions and to function directly in both homologous recombination and non-homologous end-joining, the two major conserved DSB repair pathways. Improperly repaired DSBs are implicated in cancer development in higher organisms. Understanding how chromatin remodeling complexes contribute to DSB repair should provide new insights into the mechanisms of carcinogenesis and might suggest new targets for cancer treatment.

  20. Adverse reactions to drug additives.

    PubMed

    Simon, R A

    1984-10-01

    There is a long list of additives used by the pharmaceutical industry. Most of the agents used have not been implicated in hypersensitivity reactions. Among those that have, only reactions to parabens and sulfites have been well established. Parabens have been shown to be responsible for rare immunoglobulin E-mediated reactions that occur after the use of local anesthetics. Sulfites, which are present in many drugs, including agents commonly used to treat asthma, have been shown to provoke severe asthmatic attacks in sensitive individuals. Recent studies indicate that additives do not play a significant role in "hyperactivity." The role of additives in urticaria is not well established and therefore the incidence of adverse reactions in this patient population is simply not known. In double-blind, placebo-controlled studies, reactions to tartrazine or additives other than sulfites, if they occur at all, are indeed quite rare for the asthmatic population, even for the aspirin-sensitive subpopulation.

  1. Anti-remodeling effects of rapamycin in experimental heart failure: dose response and interaction with angiotensin receptor blockade.

    PubMed

    Bishu, Kalkidan; Ogut, Ozgur; Kushwaha, Sudhir; Mohammed, Selma F; Ohtani, Tomohito; Xu, Xiaolei; Brozovich, Frank V; Redfield, Margaret M

    2013-01-01

    While neurohumoral antagonists improve outcomes in heart failure (HF), cardiac remodeling and dysfunction progress and outcomes remain poor. Therapies superior or additive to standard HF therapy are needed. Pharmacologic mTOR inhibition by rapamycin attenuated adverse cardiac remodeling and dysfunction in experimental heart failure (HF). However, these studies used rapamycin doses that produced blood drug levels targeted for primary immunosuppression in human transplantation and therefore the immunosuppressive effects may limit clinical translation. Further, the relative or incremental effect of rapamycin combined with standard HF therapies targeting upstream regulators of cardiac remodeling (neurohumoral antagonists) has not been defined. Our objectives were to determine if anti-remodeling effects of rapamycin were preserved at lower doses and whether rapamycin effects were similar or additive to a standard HF therapy (angiotensin receptor blocker (losartan)). Experimental murine HF was produced by transverse aortic constriction (TAC). At three weeks post-TAC, male mice with established HF were treated with placebo, rapamycin at a dose producing immunosuppressive drug levels (target dose), low dose (50% target dose) rapamycin, losartan or rapamycin + losartan for six weeks. Cardiac structure and function (echocardiography, catheterization, pathology, hypertrophic and fibrotic gene expression profiles) were assessed. Downstream mTOR signaling pathways regulating protein synthesis (S6K1 and S6) and autophagy (LC3B-II) were characterized. TAC-HF mice displayed eccentric hypertrophy, systolic dysfunction and pulmonary congestion. These perturbations were attenuated to a similar degree by oral rapamycin doses achieving target (13.3±2.1 ng/dL) or low (6.7±2.5 ng/dL) blood levels. Rapamycin treatment decreased mTOR mediated regulators of protein synthesis and increased mTOR mediated regulators of autophagy. Losartan monotherapy did not attenuate remodeling, whereas

  2. Astakine LvAST binds to the β subunit of F1-ATP synthase and likely plays a role in white shrimp Litopeneaus vannamei defense against white spot syndrome virus.

    PubMed

    Liang, Gao-Feng; Liang, Yan; Xue, Qinggang; Lu, Jin-Feng; Cheng, Jun-Jun; Huang, Jie

    2015-03-01

    Cytokines play a critical role in innate and adaptive immunity. Astakines represent a group of invertebrate cytokines that are related to vertebrate prokineticin and function in promoting hematopoiesis in crustaceans. We have identified an astakine from the white shrimp Litopeneaus vannamei and named it LvAST in a previous research. In the present research, we investigated the interactions among LvAST, the envelope protein VP37 of white spot syndrome virus (i.e., WSSV), and the β subunit of F1-ATP synthase (ATPsyn-β) of the white shrimp (i.e., BP53) using binding assays and co-precipitations. We also examined the effects of LvAST on shrimp susceptibility to WSSV. We found that LvAST and VP37 competitively bound to BP53, but did not bind to each other. Shrimps that had been injected with recombinant LvAST exhibited significantly lower mortality and longer survival time in experimental infections by WSSV. In contrast, shrimps whose LvAST gene expression had been inhibited by RNA interference showed significantly higher WSSV infection intensity and shorter survival time following viral challenges. These results suggested that LvAST and WSSV both likely use ATPsyn-β as a receptor and LvAST plays a role in shrimp defense against WSSV infection. This represented the first research showing the involvement of astakines in host antiviral immunity.

  3. Chondromodulin I Is a Bone Remodeling Factor

    PubMed Central

    Nakamichi, Yuko; Shukunami, Chisa; Yamada, Takashi; Aihara, Ken-ichi; Kawano, Hirotaka; Sato, Takashi; Nishizaki, Yuriko; Yamamoto, Yoko; Shindo, Masayo; Yoshimura, Kimihiro; Nakamura, Takashi; Takahashi, Naoyuki; Kawaguchi, Hiroshi; Hiraki, Yuji; Kato, Shigeaki

    2003-01-01

    Chondromodulin I (ChM-I) was supposed from its limited expression in cartilage and its functions in cultured chondrocytes as a major regulator in cartilage development. Here, we generated mice deficient in ChM-I by targeted disruption of the ChM-I gene. No overt abnormality was detected in endochondral bone formation during embryogenesis and cartilage development during growth stages of ChM-I−/− mice. However, a significant increase in bone mineral density with lowered bone resorption with respect to formation was unexpectedly found in adult ChM-I−/− mice. Thus, the present study established that ChM-I is a bone remodeling factor. PMID:12509461

  4. Molecular mechanisms of synaptic remodeling in alcoholism.

    PubMed

    Kyzar, Evan J; Pandey, Subhash C

    2015-08-05

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

  5. 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.

  6. RNA helicase proteins as chaperones and remodelers

    PubMed Central

    Jarmoskaite, Inga; Russell, Rick

    2014-01-01

    Superfamily 2 helicase proteins are ubiquitous in RNA biology and have an extraordinarily broad set of functional roles. Central among these roles are to promote rearrangements of structured RNAs and to remodel RNA-protein complexes (RNPs), allowing formation of native RNA structure or progression through a functional cycle of structures. While all superfamily 2 helicases share a conserved helicase core, they are divided evolutionarily into several families, and it is principally proteins from three families, the DEAD-box, DEAH/RHA and Ski2-like families, that function to manipulate structured RNAs and RNPs. Strikingly, there are emerging differences in the mechanisms of these proteins, both between families and within the largest family (DEAD-box), and these differences appear to be tuned to their RNA or RNP substrates and their specific roles. This review outlines basic mechanistic features of the three families and surveys individual proteins and the current understanding of their biological substrates and mechanisms. PMID:24635478

  7. 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

  8. 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

  9. Chromatin remodeling: from transcription to cancer.

    PubMed

    Yaniv, Moshe

    2014-09-01

    In this short review article, I have tried to trace the path that led my laboratory from the early studies of the structure of papova minichromosomes and transcription control to the investigation of chromatin remodeling complexes of the SWI/SNF family. I discuss briefly the genetic and biochemical studies that lead to the discovery of the SWI/SNF complex in yeast and drosophila and summarize some of the studies on the developmental role of the murine complex. The discovery of the tumor suppressor function of the SNF5/INI1/SMARCB1 gene in humans and the identification of frequent mutations in other subunits of this complex in different human tumors opened a fascinating field of research on this epigenetic regulator. The hope is to better understand tumor development and to develop novel treatments.

  10. Remodeling of the fovea in Parkinson disease.

    PubMed

    Spund, B; Ding, Y; Liu, T; Selesnick, I; Glazman, S; Shrier, E M; Bodis-Wollner, I

    2013-05-01

    To quantify the thickness of the inner retinal layers in the foveal pit where the nerve fiber layer (NFL) is absent, and quantify changes in the ganglion cells and inner plexiform layer. Pixel-by-pixel volumetric measurements were obtained via Spectral-Domain optical coherence tomography (SD-OCT) from 50 eyes of Parkinson disease (PD) (n = 30) and 50 eyes of healthy control subjects (n = 27). Receiver operating characteristics (ROC) were used to classify individual subjects with respect to sensitivity and specificity calculations at each perifoveolar distance. Three-dimensional topographic maps of the healthy and PD foveal pit were created. The foveal pit is thinner and broader in PD. The difference becomes evident in an annular zone between 0.5 and 2 mm from the foveola and the optimal (ROC-defined) zone is from 0.75 to 1.5 mm. This zone is nearly devoid of NFL and partially overlaps the foveal avascular zone. About 78 % of PD eyes can be discriminated from HC eyes based on this zone. ROC applied to OCT pixel-by-pixel analysis helps to discriminate PD from HC retinae. Remodeling of the foveal architecture is significant because it may provide a visible and quantifiable signature of PD. The specific location of remodeling in the fovea raises a novel concept for exploring the mechanism of oxidative stress on retinal neurons in PD. OCT is a promising quantitative tool in PD research. However, larger scale studies are needed before the method can be applied to clinical follow-ups.

  11. Left Ventricular Remodeling and Myocardial Recovery on Mechanical Circulatory Support

    PubMed Central

    Simon, Marc A; Primack, Brian A.; Teuteberg, Jeffrey; Kormos, Robert L; Bermudez, Christian; Toyoda, Yoshiya; Shah, Hemal; Gorcsan, John; McNamara, Dennis M

    2009-01-01

    Background Myocardial recovery after VAD is rare but appears more common in non-ischemic cardiomyopathies (NICM). We sought to evaluate left ventricular (LV) end diastolic diameter (LVEDD) for predicting recovery after ventricular assist device (VAD). Methods and Results NICM patients receiving long-term mechanical support 1996–2008 were reviewed. Subjects were divided into 3 groups: mild, moderate and severe dilation (Group A: LVEDD <6.0 cm [n=22]; Group B: 6.0–7.0 cm [n=32]; Group C: >7.0 cm [n=48], respectively). Overall, recovery (successful explant without transplantation) occurred in 14 of 102 subjects (14%). Of these, 2 died and 2 required transplantation within one year. Recovery was more common in patients without LV dilation (Groups A/B/C = 32%/22%/0 %, P<0.001), as was sustained recovery (alive and transplant free one year after explant; A/B/C =27%/10%/0%, P=0.001). Of the recovery patients in Group A, 6/7 (86%) had sustained recovery versus 3/6 (50%) in Group B. Conclusions Recovery occurred in 32% of NICM patients without significant LV dilation at time of VAD, the majority of whom experienced significant sustained recovery. Recovery was not evident in those with severe LV dilation. Routine echocardiography at the time of implant may assist in targeting patients for recovery after VAD. PMID:20142020

  12. 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.

  13. [Effect of berberine on left ventricular remodeling in renovascular hypertensive rats].

    PubMed

    Zhao, Hai-Ping; Hong, Ying; Xie, Jun-Da; Xie, Xin-Ran; Wang, Jing; Fan, Jiang-Bo

    2007-03-01

    The purpose of this study is to evaluate the effects and the underline mechanisms of berberine on the cardiac function and left ventricular remodeling in rats with renovascular hypertension. The renovascular hypertensive model was established by the two-kidney, two-clip (2K2C) method in Sprague-Dawley (SD) rats. Two weeks after surgery, all the operated SD rats were randomly assigned into four groups: (1) renovascular hypertensive model group; (2) berberine 5 mg x kg(-1) group; (3) berberine 10 mg x kg(-1) group; (4) captopril 45 mg x kg(-1) group; and the sham operated rats were used as control. Four weeks after the drugs were administered, the cardiac function was assessed. The ratios of heart weight to body weight (HW/BW), left ventricular weight to body weight (LVW/BW) and right ventricular weight to body weight (RVW/BW) were compared between groups. Coronal sections of the left ventricular tissue (LV) were prepared for paraffin sections, picrosirius red and HE staining was performed. The left ventricular wall thickness (LVWT), interventricular septal thickness (IVST), the parameters of myocardial fibrosis indicated by interstitial collagen volume fraction (ICVF) and perivascular collagen area (PVCA) were assessed. Nitric oxide (NO), adenosine cyclophosphate (cAMP) and guanosine cyclophosphate (cGMP) concentrations of left ventricular tissue were measured. Berberine 5 mg x kg(-1) and 10 mg x kg(-1) increased the left ventricular +/- dp/dt(max) and HR. Berberine 10 mg x kg(-1) decreased HW/BW and LVW/BW. The image analysis showed that both 5 and 10 mg x kg(-1) of berberine decreased LVWT, ICVF and PVCA, while increased the NO and cAMP contents in left ventricular tissue. Berberine could improve cardiac contractility of 2K2C model rats, and inhibit left ventricular remodeling especially myocardial fibrosis in renovascular hypertension rats. And such effects may partially associate with the increased NO and cAMP content in left ventricular tissue.

  14. Nonenzymatic biomimetic remodeling of phospholipids in synthetic liposomes.

    PubMed

    Brea, Roberto J; Rudd, Andrew K; Devaraj, Neal K

    2016-08-02

    Cell membranes have a vast repertoire of phospholipid species whose structures can be dynamically modified by enzymatic remodeling of acyl chains and polar head groups. Lipid remodeling plays important roles in membrane biology and dysregulation can lead to disease. Although there have been tremendous advances in creating artificial membranes to model the properties of native membranes, a major obstacle has been developing straightforward methods to mimic lipid membrane remodeling. Stable liposomes are typically kinetically trapped and are not prone to exchanging diacylphospholipids. Here, we show that reversible chemoselective reactions can be harnessed to achieve nonenzymatic spontaneous remodeling of phospholipids in synthetic membranes. Our approach relies on transthioesterification/acyl shift reactions that occur spontaneously and reversibly between tertiary amides and thioesters. We demonstrate exchange and remodeling of both lipid acyl chains and head groups. Using our synthetic model system we demonstrate the ability of spontaneous phospholipid remodeling to trigger changes in vesicle spatial organization, composition, and morphology as well as recruit proteins that can affect vesicle curvature. Membranes capable of chemically exchanging lipid fragments could be used to help further understand the specific roles of lipid structure remodeling in biological membranes.

  15. PECAM-1 is necessary for flow-induced vascular remodeling

    PubMed Central

    Chen, Zhongming; Tzima, Ellie

    2009-01-01

    OBJECTIVE Vascular remodeling is a physiological process that occurs in response to long-term changes in hemodynamic conditions, but may also contribute to the pathophysiology of intima-media thickening (IMT) and vascular disease. Shear stress detection by the endothelium is thought to be an important determinant of vascular remodeling. Previous work showed that Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a component of a mechanosensory complex that mediates endothelial cell (EC) responses to shear stress. METHODS AND RESULTS We tested the hypothesis that PECAM-1 contributes to vascular remodeling by analyzing the response to partial carotid artery ligation in PECAM-1 knockout mice and wild-type littermates. PECAM-1 deficiency resulted in impaired vascular remodeling and significantly reduced IMT in areas of low flow. Inward remodeling was associated with PECAM-1-dependent NFκB activation, surface adhesion molecule expression and leukocyte infiltration as well as Akt activation and vascular cell proliferation. CONCLUSIONS PECAM-1 plays a crucial role in the activation of the NFκB and Akt pathways and inflammatory cell accumulation during vascular remodeling and IMT. Elucidation of some of the signals that drive vascular remodeling represent pharmacologically tractable targets for the treatment of restenosis after balloon angioplasty or stent placement. PMID:19390054

  16. Adverse effects of antihypertensive drugs.

    PubMed

    Husserl, F E; Messerli, F H

    1981-09-01

    Early essential hypertension is asymptomatic and should remain so throughout treatment. In view of the increasing number of available antihypertensive agents, clinicians need to become familiar with the potential side effects of these drugs. By placing more emphasis on non-pharmacological treatment (sodium restriction, weight loss, exercise) and thoroughly evaluating each case in particular, the pharmacological regimen can be optimally tailored to the patient's needs. Potential side effects should be predicted and can often be avoided; if they become clinically significant they should be rapidly recognised and corrected. These side effects can be easily remembered in most instances, as they fall into 3 broad categories: (a) those caused by an exaggerated therapeutic effect; (b) those due to a non-therapeutic pharmacological effect; and (c) those caused by a non-therapeutic, non-pharmacological effect probably representing idiosyncratic reactions. This review focuses mainly on adverse effects of the second and third kind. Each group of drugs in general shares the common side effects of the first two categories, while each individual drug has its own idiosyncratic side effects.

  17. Rethinking the Measurement of Adversity.

    PubMed

    Mersky, Joshua P; Janczewski, Colleen E; Topitzes, James

    2017-02-01

    Research on adverse childhood experiences (ACEs) has unified the study of interrelated risks and generated insights into the origins of disorder and disease. Ten indicators of child maltreatment and household dysfunction are widely accepted as ACEs, but further progress requires a more systematic approach to conceptualizing and measuring ACEs. Using data from a diverse, low-income sample of women who received home visiting services in Wisconsin ( N = 1,241), this study assessed the prevalence of and interrelations among 10 conventional ACEs and 7 potential ACEs: family financial problems, food insecurity, homelessness, parental absence, parent/sibling death, bullying, and violent crime. Associations between ACEs and two outcomes, perceived stress and smoking, were examined. The factor structure and test-retest reliability of ACEs was also explored. As expected, prevalence rates were high compared to studies of more representative samples. Except for parent/sibling death, all ACEs were intercorrelated and associated at the bivariate level with perceived stress and smoking. Exploratory factor analysis confirmed that conventional ACEs loaded on two factors, child maltreatment and household dysfunction, though a more complex four-factor solution emerged once new ACEs were introduced. All ACEs demonstrated acceptable test-retest reliability. Implications and future directions toward a second generation of ACE research are discussed.

  18. 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.

  19. Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension.

    PubMed

    Behringer, Arnica; Trappiel, Manuela; Berghausen, Eva Maria; Ten Freyhaus, Henrik; Wellnhofer, Ernst; Odenthal, Margarete; Blaschke, Florian; Er, Fikret; Gassanov, Natig; Rosenkranz, Stephan; Baldus, Stephan; Kappert, Kai; Caglayan, Evren

    2016-04-01

    Pulmonary arterial hypertension (PAH) is a fatal disease with limited therapeutic options. Pathophysiological changes comprise obliterative vascular remodelling of small pulmonary arteries, elevated mean pulmonary arterial systolic pressure (PASP) due to elevated resistance of pulmonary vasculature, adverse right ventricular remodelling, and heart failure. Recent findings also indicate a role of increased inflammation and insulin resistance underlying the development of PAH. We hypothesized that treatment of this condition with the peroxisome proliferator-activated receptor-γ (PPARγ) activator pioglitazone, known to regulate the expression of different genes addressing insulin resistance, inflammatory changes, and vascular remodelling, could be a beneficial approach. PAH was induced in adult rats by a single subcutaneous injection of monocrotaline (MCT). Pioglitazone was administered for 2 weeks starting 3 weeks after MCT-injection. At day 35, hemodynamics, organ weights, and -indices were measured. We performed morphological and molecular characterization of the pulmonary vasculature, including analysis of the degree of muscularization, proliferation rates, and medial wall thickness of the small pulmonary arteries. Furthermore, markers of cardiac injury, collagen content, and cardiomyocyte size were analyzed. Survival rates were monitored throughout the experimental period. Pioglitazone treatment improved survival, reduced PASP, muscularization of small pulmonary arteries, and medial wall thickness. Further, MCT-induced right ventricular hypertrophy and fibrosis were attenuated. This was accompanied with reduced cardiac expression of brain natriuretic peptide, as well as decreased cardiomyocyte size. Finally, pulmonary macrophage content and osteopontin gene expression were attenuated. Based on the beneficial impact of pioglitazone, activation of PPARγ might be a promising treatment option in PAH.

  20. Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

    PubMed Central

    Fu, Xuebin; Segiser, Adrian; Carrel, Thierry P.; Tevaearai Stahel, Hendrik T.; Most, Henriette

    2016-01-01

    Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation (hHTX) in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery. We herein review the current knowledge on the effects of volume unloading the left ventricle via different methods of hHTX in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under “reloaded” conditions. While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced changes in the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further improve our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients. PMID:27807535

  1. Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma

    PubMed Central

    Klingbeil, E. C.; Hew, K. M.; Nygaard, U. C.; Nadeau, K. C.

    2014-01-01

    Environmental determinants including aerosolized pollutants such as polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke have been associated with exacerbation and increased incidence of asthma. The influence of aerosolized pollutants on the development of immune dysfunction in asthmatics has been suggested to be mediated through epigenetic remodeling. Genome accessibility and transcription are regulated primarily through DNA methylation, histone modification, and microRNA transcript silencing. Epigenetic remodeling has been shown in studies to be associated with Th2 polarization and associated cytokine and chemokine regulation in the development of asthma. This review will present evidence for the contribution of the aerosolized pollutants PAH and environmental tobacco smoke to epigenetic remodeling in asthma. PMID:24760221

  2. 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

  3. 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

  4. 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

  5. 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.

  6. Arabidopsis FORGETTER1 mediates stress-induced chromatin memory through nucleosome remodeling

    PubMed Central

    Brzezinka, Krzysztof; Altmann, Simone; Czesnick, Hjördis; Nicolas, Philippe; Gorka, Michal; Benke, Eileen; Kabelitz, Tina; Jähne, Felix; Graf, Alexander; Kappel, Christian; Bäurle, Isabel

    2016-01-01

    Plants as sessile organisms can adapt to environmental stress to mitigate its adverse effects. As part of such adaptation they maintain an active memory of heat stress for several days that promotes a more efficient response to recurring stress. We show that this heat stress memory requires the activity of the FORGETTER1 (FGT1) locus, with fgt1 mutants displaying reduced maintenance of heat-induced gene expression. FGT1 encodes the Arabidopsis thaliana orthologue of Strawberry notch (Sno), and the protein globally associates with the promoter regions of actively expressed genes in a heat-dependent fashion. FGT1 interacts with chromatin remodelers of the SWI/SNF and ISWI families, which also display reduced heat stress memory. Genomic targets of the BRM remodeler overlap significantly with FGT1 targets. Accordingly, nucleosome dynamics at loci with altered maintenance of heat-induced expression are affected in fgt1. Together, our results suggest that by modulating nucleosome occupancy, FGT1 mediates stress-induced chromatin memory. DOI: http://dx.doi.org/10.7554/eLife.17061.001 PMID:27680998

  7. Landslide risk assessment in the Göta Älv river valley to limit consequences of climate change on society

    NASA Astrophysics Data System (ADS)

    Hedlund, Jonas; Lind, Bo; Tremblay, Marius; Zackrisson, Peter; Cederbom, Charlotte

    2010-05-01

    Higher temperatures, higher average precipitation and increased occurrence of extreme rainfall events are some expected climate changes in Sweden during the coming 70-100 years. Due to the changing climate the risk for floods, erosion and landslides are expected to increase. in large parts of the country. To prevent extensive floodings and damages of cities and infrastructure around Lake Vänern, it is necessary to allow controlled overflow from Lake Vänern through the river Göta Älv. An overflow in the river, in turn, leads to increased risk for erosion and landslides along the Göta Älv valley. In order to meet the upcoming climate changes and to handle the increasing flows through the river, we need to improve the knowledge of the stability of the entire river bank. The Swedish Government has commissioned the Swedish Geotechnical Institute (SGI) to investigate the landslide potential of the Göta Älv valley, taking the predicted climate changes into consideration. The investigated area includes the parts of Göta Älv that could be affected by the increased flows from Lake Vänern; areas where the increased flow will affect stability and where landslides could cause serious damages or damming of the river. The investigation area includes c. 90 km of the Göta Älv river plus tributaries in connection to Göta Älv. In the landslide risk analyses developed for Göta Älv, the likelihood of landslides and estimation of the subsequent consequences are included. The methodology involves mapping of landslide hazards and a judgement of the risk area on the basis of a risk matrix. The landslide risk analysis allows for an assessment of where geotechnical reinforcements would be necessary. A cost estimation for the required reinforcement measures is also provided. In areas where the estimated risk for a landslide is low (e.g. limited consequences), stability mapping in accordance with the model used by the Swedish Civil Contingencies Agency (MSB) is developed

  8. Biodistribution of LV-TSTA transduced rat bone marrow cells used for "ex-vivo" regional gene therapy for bone repair.

    PubMed

    Alaee, Farhang; Bartholomae, Cynthia; Sugiyama, Osamu; Virk, Mandeep S; Drissi, Hicham; Wu, Qian; Schmidt, Manfred; Lieberman, Jay R

    2015-01-01

    "Ex vivo" regional gene therapy using lentiviral (LV) vectors to over-express bone morphogenetic protein 2 (BMP-2) is an effective way to enhance bone healing in animal models. Here, we evaluated two different "ex vivo" approaches using either "same day" rat bone marrow cells (SDRBMCs) or cultured rat bone marrow cells (C-RBMCs), both transduced with a LV based two-step transcriptional activation system overexpressing GFP (LV-TSTA-EGFP), to assess the fate of the transduced cells and the safety of this approach. The transduced cells were implanted in femoral defects of syngeneic rats. Animals were sacrificed at 4, 14, 28 and 56 days after surgery (n=5 per group). Viral copies were detectable in the defect site of SD-RBMC group and gradually declined at 8w (5 log decrease compared to 4d). In the C-RBMC animals, there was a 2-4 log decline in the viral copy numbers at 2w and 4w, but at 8w there was a relative rise (about 100 fold) in the number of the viral vectors in the defect site of 4 (out of 5) animals compared to the previous time points. For both gene transfer approaches, the pattern of tissue distribution was non-specific and no histological abnormalities were noted in either group. In summary, we demonstrated that the LV-TSTA transduced cells remain in the defect site for at least 56 days, though the numbers decreased over time. There were no consistent findings of viral copies in internal organs which is encouraging with respect to the development of this strategy for use in humans.

  9. Hospital deaths and adverse events in Brazil

    PubMed Central

    2011-01-01

    Background Adverse events are considered a major international problem related to the performance of health systems. Evaluating the occurrence of adverse events involves, as any other outcome measure, determining the extent to which the observed differences can be attributed to the patient's risk factors or to variations in the treatment process, and this in turn highlights the importance of measuring differences in the severity of the cases. The current study aims to evaluate the association between deaths and adverse events, adjusted according to patient risk factors. Methods The study is based on a random sample of 1103 patient charts from hospitalizations in the year 2003 in 3 teaching hospitals in the state of Rio de Janeiro, Brazil. The methodology involved a retrospective review of patient charts in two stages - screening phase and evaluation phase. Logistic regression was used to evaluate the relationship between hospital deaths and adverse events. Results The overall mortality rate was 8.5%, while the rate related to the occurrence of an adverse event was 2.9% (32/1103) and that related to preventable adverse events was 2.3% (25/1103). Among the 94 deaths analyzed, 34% were related to cases involving adverse events, and 26.6% of deaths occurred in cases whose adverse events were considered preventable. The models tested showed good discriminatory capacity. The unadjusted odds ratio (OR 11.43) and the odds ratio adjusted for patient risk factors (OR 8.23) between death and preventable adverse event were high. Conclusions Despite discussions in the literature regarding the limitations of evaluating preventable adverse events based on peer review, the results presented here emphasize that adverse events are not only prevalent, but are associated with serious harm and even death. These results also highlight the importance of risk adjustment and multivariate models in the study of adverse events. PMID:21929810

  10. An investigation into the seroprevalence of Toxoplasma gondii, Bartonella spp., feline immunodeficiency virus (FIV), and feline leukaemia virus (FeLV) in cats in Addis Ababa, Ethiopia.

    PubMed

    Tiao, N; Darrington, C; Molla, B; Saville, W J A; Tilahun, G; Kwok, O C H; Gebreyes, W A; Lappin, M R; Jones, J L; Dubey, J P

    2013-05-01

    Toxoplasma gondii and Bartonella spp. are zoonotic pathogens of cats. Feline immunodeficiency virus (FIV), and feline leukaemia virus (FeLV) are immunosuppressive viruses of cats that can affect T. gondii oocyst shedding. In this study, the prevalence of antibodies to T. gondii, Bartonella spp., FIV, as well as FeLV antigens were determined in sera from feral cats (Felis catus) from Addis Ababa, Ethiopia. Using the modified agglutination test, IgG antibodies to T. gondii were found in 41 (85.4%) of the 48 cats with titres of 1:25 in one, 1:50 in one, 1:200 in six, 1:400 in six, 1:800 in six, 1:1600 in eight, and 1:3200 in 13 cats. Toxoplasma gondii IgM antibodies were found in 11/46 cats tested by ELISA, suggesting recent infection. Antibodies to Bartonella spp. were found in five (11%) of 46 cats tested. Antibodies to FIV or FeLV antigen were not detected in any of the 41 cats tested. The results indicate a high prevalence of T. gondii and a low prevalence of Bartonella spp. infection in cats in Ethiopia.

  11. Assessment of Longitudinal Reproducibility of Mice LV Function Parameters at 11.7 T Derived from Self-Gated CINE MRI

    PubMed Central

    Zuo, Zhi; Subgang, Anne; Abaei, Alireza; Rottbauer, Wolfgang; Stiller, Detlef; Ma, Genshan

    2017-01-01

    The objective of this work was the assessment of the reproducibility of self-gated cardiac MRI in mice at ultra-high-field strength. A group of adult mice (n = 5) was followed over 360 days with a standardized MR protocol including reproducible animal position and standardized planning of the scan planes. From the resulting CINE MRI data, global left ventricular (LV) function parameters including end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), and left ventricular mass (LVM) were quantified. The reproducibility of the self-gated technique as well as the intragroup variability and longitudinal changes of the investigated parameters was assessed. Self-gated cardiac MRI proved excellent reproducibility of the global LV function parameters, which was in the order of the intragroup variability. Longitudinal assessment did not reveal any significant variations for EDV, ESV, SV, and EF but an expected increase of the LVM with increasing age. In summary, self-gated MRI in combination with a standardized protocol for animal positioning and scan plane planning ensures reproducible assessment of global LV function parameters. PMID:28321415

  12. Characterizing "Adversity" of Pathology Findings in ...

    EPA Pesticide Factsheets

    The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment in the toxicologic pathology community regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop in June 2015 to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports. The international group of expert pathologists and toxicologists emphasized that a holistic, weight-of-evidence, case-specific approach should be followed for each adversity assessment. It was recommended that nonclinical adversity should typically be determined at a morphological level (most often the organ) in the pathology report and should refer specifically to the test species. Final adversity calls, integration of target pharmacology/pathway information, and consideration of human translation should generally be made in toxicology overview reports. Differences in interpretation and implications of adversity calls between (agro)chemical and pharmaceutical industries and among world regions were highlighted. The results of this workshop should serve a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP. This

  13. Structural remodeling, trafficking and functions of glycosylphosphatidylinositol-anchored proteins.

    PubMed

    Maeda, Yusuke; Kinoshita, Taroh

    2011-10-01

    Glycosylphosphatidylinositol (GPI) is a glycolipid that is covalently attached to proteins as a post-translational modification. Such modification leads to the anchoring of the protein to the outer leaflet of the plasma membrane. Proteins that are decorated with GPIs have unique properties in terms of their physical nature. In particular, these proteins tend to accumulate in lipid rafts, which are critical for the functions and trafficking of GPI-anchored proteins (GPI-APs). Recent studies mainly using mutant cells revealed that various structural remodeling reactions occur to GPIs present in GPI-APs as they are transported from the endoplasmic reticulum to the cell surface. This review examines the recent progress describing the mechanisms of structural remodeling of mammalian GPI-anchors, such as inositol deacylation, glycan remodeling and fatty acid remodeling, with particular focus on their trafficking and functions, as well as the pathogenesis involving GPI-APs and their deficiency.

  14. 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

  15. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling.

    PubMed

    Hoshikawa, Y; Voelkel, N F; Gesell, T L; Moore, M D; Morris, K G; Alger, L A; Narumiya, S; Geraci, M W

    2001-07-15

    Prostacyclin (PGI(2)) reduces pulmonary vascular resistance and attenuates vascular smooth muscle cell proliferation through signal transduction following ligand binding to its receptor. Because patients with severe pulmonary hypertension have a reduced PGI(2) receptor (PGI-R) expression in the remodeled pulmonary arterial smooth muscle, we hypothesized that pulmonary vascular remodeling may be modified PGI-R dependently. To test this hypothesis, PGI-R knockout (KO) and wild-type (WT) mice were subjected to a simulated altitude of 17,000 ft or Denver altitude for 3 wk, and right ventricular pressure and lung histology were assessed. The PGI-R KO mice developed more severe pulmonary hypertension and vascular remodeling after chronic hypoxic exposure when compared to the WT mice. Our results indicate that PGI(2) and its receptor play an important role in the regulation of hypoxia-induced pulmonary vascular remodeling, and that the absence of a functional receptor worsens pulmonary hypertension.

  16. Roles of chromatin remodellers in DNA double strand break repair.

    PubMed

    Jeggo, Penny A; Downs, Jessica A

    2014-11-15

    Now that we have a good understanding of the DNA double strand break (DSB) repair mechanisms and DSB-induced damage signalling, attention is focusing on the changes to the chromatin environment needed for efficient DSB repair. Mutations in chromatin remodelling complexes have been identified in cancers, making it important to evaluate how they impact upon genomic stability. Our current understanding of the DSB repair pathways suggests that each one has distinct requirements for chromatin remodelling. Moreover, restricting the extent of chromatin modifications could be a significant factor regulating the decision of pathway usage. In this review, we evaluate the distinct DSB repair pathways for their potential need for chromatin remodelling and review the roles of ATP-driven chromatin remodellers in the pathways.

  17. Determining School District Renovation/Remodeling/Repair Needs.

    ERIC Educational Resources Information Center

    MacKenzie, Donald G.; Phillips, Paul

    1991-01-01

    Bond issue funds were earmarked for remodeling 10 schools in a Florida school district. Describes a physical plant survey instrument used to examine each district school building to determine the district needs and the method that prioritizes those needs. (MLF)

  18. Balancing chromatin remodeling and histone modifications in transcription

    PubMed Central

    Petty, Emily; Pillus, Lorraine

    2013-01-01

    Chromatin remodelers use the energy of ATP hydrolysis to reposition or evict nucleosomes or to replace canonical histones with histone variants. By regulating nucleosome dynamics, remodelers gate access to the underlying DNA for replication, repair, and transcription. Nucleosomes are subject to extensive post-translational modifications that can recruit regulatory proteins or alter the local chromatin structure. Just as extensive cross-talk has been observed between different histone post-translational modifications, there is growing evidence for both coordinated and antagonistic functional relationships between nucleosome remodeling and modifying machineries. Defining the combined functions of the complexes that alter nucleosome interactions, position, and stability is key to understanding processes that require access to DNA, particularly with growing appreciation of their contributions to human health and disease. Here, we highlight recent advances in the interactions between histone modifications and the ISWI and CHD1 chromatin remodelers from studies in budding yeast, fission yeast, flies, and mammalian cells, with a focus on yeast. PMID:23870137

  19. 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

  20. Roles and activities of chromatin remodeling ATPases in plants.

    PubMed

    Han, Soon-Ki; Wu, Miin-Feng; Cui, Sujuan; Wagner, Doris

    2015-07-01

    Chromatin remodeling ATPases and their associated complexes can alter the accessibility of the genome in the context of chromatin by using energy derived from the hydrolysis of ATP to change the positioning, occupancy and composition of nucleosomes. In animals and plants, these remodelers have been implicated in diverse processes ranging from stem cell maintenance and differentiation to developmental phase transitions and stress responses. Detailed investigation of their roles in individual processes has suggested a higher level of selectivity of chromatin remodeling ATPase activity than previously anticipated, and diverse mechanisms have been uncovered that can contribute to the selectivity. This review summarizes recent advances in understanding the roles and activities of chromatin remodeling ATPases in plants.

  1. The effect of exercise training on transverse tubules in normal, remodeled, and reverse remodeled hearts.

    PubMed

    Kemi, Ole J; Hoydal, Morten A; Macquaide, Niall; Haram, Per M; Koch, Lauren G; Britton, Steven L; Ellingsen, Oyvind; Smith, Godfrey L; Wisloff, Ulrik

    2011-09-01

    The response of transverse (T)-tubules to exercise training in health and disease remains unclear. Therefore, we studied the effect of exercise training on the density and spacing of left ventricle cardiomyocyte T-tubules in normal and remodeled hearts that associate with detubulation, by confocal laser scanning microscopy. First, exercise training in normal rats increased cardiomyocyte volume by 16% (P < 0.01), with preserved T-tubule density. Thus, the T-tubules adapted to the physiologic hypertrophy. Next, we studied T-tubules in a rat model of metabolic syndrome with pressure overload-induced concentric left ventricle hypertrophy, evidenced by 15% (P < 0.01) increased cardiomyocyte size. These rats had only 85% (P < 0.01) of the T-tubule density of control rats. Exercise training further increased cardiomyocyte volume by 8% (P < 0.01); half to that in control rats, but the T-tubule density remained unchanged. Finally, post-myocardial infarction heart failure induced severe cardiac pathology, with a 70% (P < 0.01) increased cardiomyocyte volume that included both eccentric and concentric hypertrophy and 55% (P < 0.01) reduced T-tubule density. Exercise training reversed 50% (P < 0.01) of the pathologic hypertrophy, whereas the T-tubule density increased by 40% (P < 0.05) compared to sedentary heart failure, but remained at 60% of normal hearts (P < 0.01). Physiologic hypertrophy associated with conserved T-tubule spacing (~1.8-1.9 µm), whereas in pathologic hypertrophy, T-tubules appeared disorganized without regular spacing. In conclusion, cardiomyocytes maintain the relative T-tubule density during physiologic hypertrophy and after mild concentric pathologic hypertrophy, whereas after severe pathologic remodeling with a substantial loss of T-tubules; exercise training reverses the remodeling and partly corrects the T-tubule density.

  2. Cardiovascular remodeling and the peripheral serotonergic system.

    PubMed

    Ayme-Dietrich, Estelle; Aubertin-Kirch, Gaëlle; Maroteaux, Luc; Monassier, Laurent

    2017-01-01

    Plasma 5-hydroxytryptamine (5-HT; serotonin), released from blood platelets, plays a major role in the human cardiovascular system. Besides the effect of endogenous serotonin, many drugs targeting serotonergic receptors are widely used in the general population (antiobesity agents, antidepressants, antipsychotics, antimigraine agents), and may enhance the cardiovascular risk. Depending on the type of serotonin receptor activated and its location, the use of these compounds triggers acute and chronic effects. The acute cardiovascular response to 5-HT, named the Bezold-Jarish reflex, leads to intense bradycardia associated with atrioventricular block, and involves 5-HT3, 5-HT1B/1D, 5-HT7 and 5-HT2A/2B receptors. The chronic contribution of 5-HT and its receptors (5-HT4 and 5-HT2A/2B) in cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis and valve degeneration, will be explored in this review. Finally, through the analysis of the effects of sarpogrelate, some new aspects of 5-HT2A receptor pharmacology in vasomotor tone regulation and the interaction between endothelial and smooth muscle cells will also be discussed. The aim of this review is to emphasize the cardiac side effects caused by serotonin receptor activation, and to highlight their possible prevention by the development of new drugs targeting this system.

  3. Tissue remodeling investigation in varicose veins

    PubMed Central

    Ghaderian, Sayyed Mohammad Hossein; Khodaii, Zohreh

    2012-01-01

    Although the etiology of varicose veins remains unknown, recent studies have focused on endothelial cell integrity and function because the endothelium regulates vessel tone and synthesizes many pro- and anti-inflammatory factors. The aim of this study was to investigate the evidence involving the endothelium in the development of varicose vein disease. In addition, tissue remodeling was investigated in varicose veins to determine the expression of different types of collagen. Tissue specimens of superficial varicose veins and control saphenous vein were used for immunohistochemical and transmission electron microscope (TEM). α-smooth muscle actin, and collagen I, III, IV antibodies were applied for immunohistochemical investigation. Findings of this study showed alterations of the intima, such as focal intimal discontinuity and denudation of endothelium; and the media, such as irregular arrangements of smooth muscle cells and collagen fibres in varicose veins. Our findings showed some changes in terms of distribution of types I, III and IV collagen in the intima and media of varicose vein walls compared with controls. These alterations to the media suggest that the pathological abnormality in varicose veins may be due to the loss of muscle tone as a result of the breakup of its regular structure by the collagen fibres. These findings only described some changes in terms of distribution of these types of collagen in the intima and media of varicose vein walls which may result in venous wall dysfunction in varicosis. PMID:24551759

  4. Crosstalk between obesity and MMP-9 in cardiac remodelling -a cross-sectional study in apparent treatment-resistant hypertension.

    PubMed

    Ritter, Alessandra Mileni Versuti; de Faria, Ana Paula; Barbaro, Natália; Sabbatini, Andréa Rodrigues; Corrêa, Nathália Batista; Brunelli, Veridiana; Amorim, Rivadavio; Modolo, Rodrigo; Moreno, Heitor

    2017-04-01

    The balance between matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) plays a key role in the development of hypertension and obesity. We aimed to evaluate the levels of MMP-2 and 9 and TIMP-2 and -1 in obese and non-obese apparent treatment-resistant hypertensive subjects (aTRH) and its association with cardiac hypertrophy. This cross-sectional study enrolled 122 subjects and divided into obese aTRH (n = 67) and non-obese (n = 55) group. Clinical and biochemical data were compared between both groups, including office BP, ambulatory BP, plasma MMP-2 and 9, TIMP-2 and 1 and left ventricular mass index (LVMI). We found higher MMP-9 levels and MMP-9/TIMP-1 ratio in obese aTRH subjects but no difference in MMP-2 and TIMP-1 levels. Obesity influenced MMP-9 levels [β = 20.8 SE =8.6, p = 0.02) independently of potential confounders. In addition, we found a positive correlation between MMP-9 and anthropomorphic parameters. Finally, obese aTRH subjects with left ventricular hypertrophy (LVH) had greater MMP-9 levels compared with non-obese with LVH. Our study suggests that MMP-9 levels are influenced by obesity and may directly participate in the progressive LV remodelling process, suggesting a possible role for a higher cardiovascular risk in apparent resistant hypertensive subjects.

  5. KyoT2 downregulates airway remodeling in asthma.

    PubMed

    Hu, Mei; Ou-Yang, Hai-Feng; Han, Xing-Peng; Ti, Xin-Yu; Wu, Chang-Gui

    2015-01-01

    The typical pathological features of asthma are airway remodeling and airway hyperresponsiveness (AHR). KyoT2, a negative modulator of Notch signaling, has been linked to asthma in several previous studies. However, whether KyoT2 is involved in the regulation of airway remodeling or the modulation of airway resistance in asthma is unclear. In this study, we aimed to evaluate the therapeutic potential of KyoT2 in preventing asthma-associated airway remodeling and AHR. BALB/c mice were used to generate a mouse model of asthma. Additionally, the expression of Hes1 and Notch1 in airway was analyzed using Immunofluorescence examination. The asthmatic mice were intranasally administered adenovirus expressing KyoT2 and were compared to control groups. Furthermore, subepithelial fibrosis and other airway remodeling features were analyzed using hematoxylin and eosin staining, Van Gieson's staining and Masson's trichrome staining. AHR was also evaluated. This study revealed that KyoT2 downregulated the expression of Hes1, repressed airway remodeling, and alleviated AHR in asthmatic mice. It is reasonable to assume that KyoT2 downregulates airway remodeling and resistance in asthmatic mice through a Hes1-dependent mechanism. Therefore, KyoT2 is a potential clinical treatment strategy for asthma.

  6. FSTL1 PROMOTES ASTHMATIC AIRWAY REMODELING BY INDUCING ONCOSTATIN M

    PubMed Central

    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.

    2016-01-01

    Chronic asthma is associated with airway remodeling and decline in lung function. Here we show that follistatin like 1 (Fstl1), a mediator not previously associated with asthma is highly expressed by macrophages in the lungs of severe human asthmatics. Chronic allergen challenged Lys-Cretg/Fstl1Δ/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, while administration of an anti-OSM antibody 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/oncostatin M pathway may be a novel pathway to inhibit airway remodeling in severe human asthma. PMID:26355153

  7. 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.

  8. 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

  9. 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

  10. 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...

  11. 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

  12. 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

  13. Remodeling of alveolar septa after murine pneumonectomy

    PubMed Central

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

    2015-01-01

    In most mammals, removing one lung (pneumonectomy) results in the compensatory growth of the remaining lung. In mice, stereological observations have demonstrated an increase in the number of mature alveoli; however, anatomic evidence of the early phases of alveolar growth has remained elusive. To identify changes in the lung microstructure associated with neoalveolarization, we used tissue histology, electron microscopy, and synchrotron imaging to examine the configuration of the alveolar duct after murine pneumonectomy. Systematic histological examination of the cardiac lobe demonstrated no change in the relative frequency of dihedral angle components (Ends, Bends, and Junctions) (P > 0.05), but a significant decrease in the length of a subset of septal ends (“E”). Septal retraction, observed in 20–30% of the alveolar ducts, was maximal on day 3 after pneumonectomy (P < 0.01) and returned to baseline levels within 3 wk. Consistent with septal retraction, the postpneumonectomy alveolar duct diameter ratio (Dout:Din) was significantly lower 3 days after pneumonectomy compared to all controls except for the detergent-treated lung (P < 0.001). To identify clumped capillaries predicted by septal retraction, vascular casting, analyzed by both scanning electron microscopy and synchrotron imaging, demonstrated matted capillaries that were most prominent 3 days after pneumonectomy. Numerical simulations suggested that septal retraction could reflect increased surface tension within the alveolar duct, resulting in a new equilibrium at a higher total energy and lower surface area. The spatial and temporal association of these microstructural changes with postpneumonectomy lung growth suggests that these changes represent an early phase of alveolar duct remodeling. PMID:26078396

  14. Soluble Endoglin Modulates Aberrant Cerebral Vascular Remodeling

    PubMed Central

    Chen, Yongmei; Hao, Qi; Kim, Helen; Su, Hua; Letarte, Michelle; Karumanchi, S. Ananth; Lawton, Michael T.; Barbaro, Nicholas M.; Yang, Guo-Yuan; Young, William L.

    2009-01-01

    Objective Brain arteriovenous malformations (AVMs) are an important cause of neurological morbidity in young adults. The pathophysiology of these lesions is poorly understood. A soluble form of endoglin (sEng) has been shown to cause endothelial dysfunction and induce preeclampsia. We tested if sEng would be elevated in brain AVM tissues relative to epilepsy brain tissues, and also investigated whether sEng overexpression via gene transfer in the mouse brain would induce vascular dysplasia and associated changes in downstream signaling pathways. Methods Expression levels of sEng in surgical specimens were determined by Western blot assay and ELISA. Vascular dysplasia, levels of MMP and oxidative stress were determined by immunohistochemistry and gelatin zymography. Results Brain AVMs (n=33) had higher mean sEng levels (245 ± 175 vs 100 ± 60, % of control, P=0.04) compared with controls (n=8), as determined by Western blot. In contrast, membrane-bound Eng was not significantly different (108 ± 79 vs 100 ± 63, % of control, P=0.95). sEng gene transduction in the mouse brain induced abnormal vascular structures. It also increased matrix metalloproteinase (MMP) activity by 490 ± 30% (MMP-9), 220 ± 30% (MMP-2), and oxidants by 260 ± 20% (4-hydroxy-2-nonenal) at 2 weeks after injection, suggesting that MMPs and oxidative radicals may mediate sEng-induced pathological vascular remodeling. Interpretation The results suggest that elevated sEng may play a role in the generation of sporadic brain AVMs. Our findings may provide new targets for therapeutic intervention for patients with brain AVMs. PMID:19670444

  15. Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

    PubMed Central

    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.

    2015-01-01

    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

  16. Low levels of natural IgM antibodies against phosphorylcholine are independently associated with vascular remodeling in patients with coronary artery disease.

    PubMed

    Gleissner, Christian A; Erbel, Christian; Haeussler, Julia; Akhavanpoor, Mohammadreza; Domschke, Gabriele; Linden, Fabian; Doesch, Andreas O; Conradson, Göran; Buss, Sebastian J; Hofmann, Nina P; Gitsioudis, Gitsios; Katus, Hugo A; Korosoglou, Grigorios

    2015-01-01

    Low anti-phosphorylcholine (PC) IgM plasma levels have been associated with increased incidence of adverse events in coronary artery disease (CAD). The underlying mechanisms are unclear. We hypothesized that atheroprotection mediated by anti-PC IgM antibodies is associated with reduced vascular remodeling and therefore tested whether anti-PC IgM plasma levels independently predict vascular remodeling. In a prospective cross-sectional study, anti-PC IgM plasma levels were measured in 175 consecutive patients with suspected CAD undergoing cardiac computed tomography angiography. Plaque morphology was thoroughly analyzed. Vascular remodeling was defined by a change in the vessel diameter at the plaque site in comparison to the reference segment proximal to the lesion (reference diameter) of ≥10%. Mean age of the patients was 64.8 ± 10.7 years, 48.6% were female. In 98 patients CAD was diagnosed, 57 (58.2%) of which displayed non-obstructive CAD (stenosis <50%), whereas 41 (41.8%) exhibited obstructive CAD (stenosis ≥50%). In 34 of 98 (34.7%) CAD patients vascular remodeling was present. Mean anti-PC IgM levels did not differ between patients with and without CAD (70.8 ± 52.7 vs. 69.1 ± 55.1 U/mL). However, anti-PC IgM levels were significantly lower in CAD patients compared to those without vascular remodeling (46.6 ± 31.6 vs. 73.3 ± 58.5 U/mL, P = 0.024). Using multivariate logistic regression, anti-PC IgM plasma levels independently predicted coronary vascular remodeling (HR 0.322, 95% confidence interval 0.121-0.856, P = 0.023). In conclusion, low anti-PC IgM levels are independently associated with coronary vascular remodeling. These findings may represent the link between in vitro studies demonstrating atheroprotective effects of anti-PC IgM and clinical data demonstrating that low anti-PC IgM levels are associated with adverse outcome in CAD patients.

  17. Synergistic childhood adversities and complex adult psychopathology.

    PubMed

    Putnam, Karen T; Harris, William W; Putnam, Frank W

    2013-08-01

    Numerous studies find a cumulative effect of different types of childhood adversities on increasing risk for serious adult mental and medical outcomes. This study uses the National Comorbidity Survey-Replication sample to investigate the cumulative impact of 8 childhood adversities on complex adult psychopathology as indexed by (a) number of lifetime diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., DSM-IV; American Psychiatric Association, 1994); (b) number of 4 DSM-IV disorder categories (mood, anxiety, impulse control, and substance abuse disorders); and (c) coexistence of internalizing and externalizing disorders. Seven of the 8 childhood adversities were significantly associated with complex adult psychopathology. Individuals with 4 or more childhood adversities had an odds ratio of 7.3, 95% confidence interval [4.7, 11.7] for 4 disorder categories. Additive and multiplicative synergistic effects increasing adult psychopathology were found for specific pairwise combinations of childhood adversities. Synergistic patterns differed by gender suggesting that women are more impacted by sexual abuse and men by economic hardship. The absence of childhood adversities was protective, in that it significantly decreased an individual's risk for subsequent adult mental illness. The results support the clinical impression that increased childhood adversity is associated with more complex adult psychopathology.

  18. Patterns and Implications of Intracranial Arterial Remodeling in Stroke Patients

    PubMed Central

    Qiao, Ye; Anwar, Zeeshan; Intrapiromkul, Jarunee; liu, Li; Zeiler, Steven R.; Leigh, Richard; Zhang, Yiyi; Guallar, Eliseo; Wasserman, Bruce A.

    2015-01-01

    Background and Purpose Preliminary studies suggest ntracranial arteries are capable of accommodating plaque formation by remodeling. We sought to study the ability and extent of intracranial arteries to remodel using 3D high-resolution black blood MRI (BBMRI) and investigate its relation to ischemic events. Methods 42 patients with cerebrovascular ischemic events underwent 3D time-of-flight MRA and contrast-enhanced BBMRI examinations at 3T for intracranial atherosclerotic disease. Each plaque was classified by location (e.g., posterior vs. anterior circulation) and its likelihood to have caused a stroke identified on MRI (culprit, indeterminate, or non-culprit). Lumen area (LA), outer wall area (OWA), and wall area (WA) were measured at the lesion and reference sites. Plaque burden was calculated as WA divided by OWA. The arterial remodeling ratio (RR) was calculated as OWA at the lesion site divided by OWA at the reference site, after adjusting for vessel tapering. Arterial remodeling was categorized as positive if RR >1.05, intermediate if 0.95≤RR ≤ 1.05, and negative if RR <0.95. Results 137 plaques were identified in 42 patients (37% [50] posterior, 63% [87] anterior). Compared with anterior circulation plaques, posterior circulation plaques had a larger plaque burden (77.7±15.7 vs. 69.0±14.0, p=0.008), higher RR (1.14±0.38 vs. 0.95±0.32, p=0.002), and more often exhibited positive remodeling (54.0% vs.29.9%, p=0.011). Positive remodeling was marginally associated with downstream stroke presence when adjusted for plaque burden (OR 1.34, 95% CI: 0.99–1.81). Conclusions Intracranial arteries remodel in response to plaque formation, and posterior circulation arteries have a greater capacity for positive remodeling and, consequently, may more likely elude angiographic detection. Arterial remodeling may provide insight into stroke risk. PMID:26742795

  19. [Early left ventricular remodelling following acute coronary accident].

    PubMed

    Gaertner, Roger; Logeart, Damien; Michel, Jean-Baptiste; Mercadier, Jean-Jacques

    2004-01-01

    Ventricular remodelling following acute coronary syndromes is both complex and multiform. It is due to the response of the myocardium to the different agressions associated with these syndromes, in particular the ischemia and necrosis downstream of the occluded artery. We must not however neglect the role of the remodelling of the lesions resulting from spontaneous reperfusion or provoked by the cells and tissues associated with coronary microcirculation embolisms and the no-reflow phenomenon. Acute post-infarct remodelling is dominated by early ventricular dilatation which largely affects late prognosis, necrosis elimination and its replacement by a fibrotic scar in parallel with a compensatory hypertrophy of the non-infarcted myocardium. The diverse cellular and molecular components of this remodelling are increasingly well-known, allowing us to better explain the beneficial effects of the currently available medications and providing us with new potential therapeutic targets. A grading of this knowledge associated with the identification of new risk factors and early therapeutic interventions should help us to further limit the deleterious aspects of this remodelling in the goal of preventing, or at least delaying, the devolution towards heart failure.

  20. Subtype-specific neuronal remodeling during Drosophila metamorphosis.

    PubMed

    Veverytsa, Lyubov; Allan, Douglas W

    2013-01-01

    During metamorphosis in holometabolous insects, the nervous system undergoes dramatic remodeling as it transitions from its larval to its adult form. Many neurons are generated through post-embryonic neurogenesis to have adult-specific roles, but perhaps more striking is the dramatic remodeling that occurs to transition neurons from functioning in the larval to the adult nervous system. These neurons exhibit a remarkable degree of plasticity during this transition; many subsets undergo programmed cell death, others remodel their axonal and dendritic arbors extensively, whereas others undergo trans-differentiation to alter their terminal differentiation gene expression profiles. Yet other neurons appear to be developmentally frozen in an immature state throughout larval life, to be awakened at metamorphosis by a process we term temporally-tuned differentiation. These multiple forms of remodeling arise from subtype-specific responses to a single metamorphic trigger, ecdysone. Here, we discuss recent progress in Drosophila melanogaster that is shedding light on how subtype-specific programs of neuronal remodeling are generated during metamorphosis.

  1. Wall tissue remodeling regulates longitudinal tension in arteries.

    PubMed

    Jackson, Zane S; Gotlieb, Avrum I; Langille, B Lowell

    2002-05-03

    Changes in blood pressure or flow induce arterial remodeling that normalizes mechanical loads that are imposed on arterial tissue. Arteries are also under substantial longitudinal stretch (axial strain) that may be altered by growth or atrophy of tissues to which they are attached. We therefore tested whether axial strain is also regulated in a negative feedback manner through arterial remodeling. Axial strain in rabbit carotid arteries was increased from 62+/-2% to 97+/-2% without altering other mechanical loads on wall tissues. Strain was reduced within 3 days and completely normalized by 7 days. Remodeling involved tissue elaboration, endothelial cell replication rates were increased by >50-fold and smooth muscle cell replication rates were increased by >15-fold, and substantially elevated DNA, elastin, and collagen contents were recorded. Also, increased rates of apoptosis were indicated by degradation of DNA into oligonucleosomes, and matrix remodeling was reflected in enlarged fenestrae in the internal elastic lamina and increased expression and activation of gelatinases, especially matrix metalloproteinase-2. Intriguingly, reduced axial strain was not normalized, presumably because remodeling processes, apart from cell contraction, are ineffective in decreasing strain, and arterial smooth muscle orientation precludes large effects of contraction on axial strain.

  2. 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.

  3. 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

  4. Biological remodelling: Stationary energy, configurational change, internal variables and dissipation

    NASA Astrophysics Data System (ADS)

    Garikipati, K.; Olberding, J. E.; Narayanan, H.; Arruda, E. M.; Grosh, K.; Calve, S.

    2006-07-01

    Remodelling is defined as an evolution of microstructure or variations in the configuration of the underlying manifold. The manner in which a biological tissue and its subsystems remodel their structure is treated in a continuum mechanical setting. While some examples of remodelling are conveniently modelled as evolution of the reference configuration—Case I—others are more suited to an internal variable description—Case II. In this paper, we explore the applicability of stationary energy states to remodelled systems. A variational treatment is introduced by assuming that stationary energy states are attained by changes in microstructure via one of the two mechanisms—Cases I and II. The configurational change of a long-chain molecule is presented as an example of Case I, and collagen fibre reorientation in in vitro tissue constructs as an example of Case II. The second example is further studied for its thermodynamic dissipation characteristics. This leads to an important finding on the limitation of purely mechanical treatments of some types of remodelling phenomena.

  5. Cortical remodeling during menopause, rheumatoid arthritis, glucocorticoid and bisphosphonate therapy.

    PubMed

    Aeberli, Daniel; Schett, Georg

    2013-03