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Sample records for attenuates cardiac allograft

  1. Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys.

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    Kelishadi, Shahrooz S; Azimzadeh, Agnes M; Zhang, Tianshu; Stoddard, Tiffany; Welty, Emily; Avon, Christopher; Higuchi, Mitch; Laaris, Amal; Cheng, Xiang-Fei; McMahon, Christine; Pierson, Richard N

    2010-04-01

    Chronic rejection currently limits the long-term efficacy of clinical transplantation. Although B cells have recently been shown to play a pivotal role in the induction of alloimmunity and are being targeted in other transplant contexts, the efficacy of preemptive B cell depletion to modulate alloimmunity or attenuate cardiac allograft vasculopathy (CAV) (classic chronic rejection lesions found in transplanted hearts) in a translational model has not previously been described. We report here that the CD20-specific antibody (alphaCD20) rituximab depleted CD20+ B cells in peripheral blood, secondary lymphoid organs, and the graft in cynomolgus monkey recipients of heterotopic cardiac allografts. Furthermore, CD20+ B cell depletion therapy combined with the calcineurin inhibitor cyclosporine A (CsA) prolonged median primary graft survival relative to treatment with alphaCD20 or CsA alone. In animals treated with both alphaCD20 and CsA that achieved efficient B cell depletion, alloantibody production was substantially inhibited and the CAV severity score was markedly reduced. We conclude therefore that efficient preemptive depletion of CD20+ B cells is effective in a preclinical model to modulate pathogenic alloimmunity and to attenuate chronic rejection when used in conjunction with a conventional clinical immunosuppressant. This study suggests that use of this treatment combination may improve the efficacy of transplantation in the clinic.

  2. Risk factors of cardiac allograft vasculopathy.

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    Szyguła-Jurkiewicz, Bożena; Szczurek, Wioletta; Gąsior, Mariusz; Zembala, Marian

    2015-12-01

    Despite advances in prevention and treatment of heart transplant rejection, development of cardiac allograft vasculopathy (CAV) remains the leading factor limiting long-term survival of the graft. Cardiac allograft vasculopathy etiopathogenesis is not fully understood, but a significant role is attributed to endothelial cell damage, caused by immunological and non-immunological mechanisms. Immunological factors include the differences between the recipient's and the donor's HLA systems, the presence of alloreactive antibodies and episodes of acute rejection. Among the non-immunological factors the most important are the age of the donor, ischemia-reperfusion injury and cytomegalovirus infection. The classical cardiovascular risk factors (diabetes, hypertension, obesity and hyperlipidemia) are also important. This study presents an up-to-date overview of current knowledge on the vasculopathy etiopathogenesis and the role played by endothelium and inflammatory processes in CAV, and it also investigates the factors which may serve as risk markers of cardiac allograft vasculopathy.

  3. Cardiac allograft immune activation: current perspectives

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    Chang D

    2014-12-01

    Full Text Available David Chang, Jon Kobashigawa Cedars-Sinai Heart Institute, Los Angeles, CA, USA Abstract: Heart transplant remains the most durable option for end-stage heart disease. Cardiac allograft immune activation and heart transplant rejection remain among the main complications limiting graft and recipient survival. Mediators of the immune system can cause different forms of rejection post-heart transplant. Types of heart transplant rejection include hyperacute rejection, cellular rejection, antibody-mediated rejection, and chronic rejection. In this review, we will summarize the innate and adaptive immune responses which influence the post-heart transplant recipient. Different forms of rejection and their clinical presentation, detection, and immune monitoring will be discussed. Treatment of heart transplant rejection will be examined. We will discuss potential treatment strategies for preventing rejection post-transplant in immunologically high-risk patients with antibody sensitization. Keywords: heart transplant, innate immunity, adaptive immunity, rejection, immunosuppression

  4. Cardiac Allograft Vasculopathy : Molecular pathology of the transplanted heart

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    Huibers, M.M.H.

    2015-01-01

    Cardiac Allograft Vasculopathy (CAV) is a disease which has a high prevalence in Heart transplant (HTx) patients. It is characterized by concentric thickening of the wall of the coronary artery of the transplanted heart. The pathogenesis of CAV is complex; various cell types from both the host and

  5. Morpho-functional evaluation of enzymatic and detergent decellularization methods of cardiac allografts

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    М. Б. Васильева

    2015-10-01

    Full Text Available In this study we conducted a comparative analysis of enzyme and detergent methods of decellurizing cardiac allografts. It was shown that by using the detergent method, the highest degree of purification of the valve from the cells could be achieved, while preserving its original mechanical strength and the spatial structure of its matrix. Based on these data, the detergent method can be recommended as a preferred choice during preparation of allografts for use in cardiac surgery practice.

  6. Host-Based Th2 Cell Therapy for Prolongation of Cardiac Allograft Viability

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    Foley, Jason E.; Costanzo, Carliann M.; Sennesh, Joel D.; Solomon, Michael A.; Fowler, Daniel H.

    2011-01-01

    Donor T cell transfusion, which is a long-standing approach to prevent allograft rejection, operates indirectly by alteration of host T cell immunity. We therefore hypothesized that adoptive transfer of immune regulatory host Th2 cells would represent a novel intervention to enhance cardiac allograft survival. Using a well-described rat cardiac transplant model, we first developed a method for ex vivo manufacture of rat host-type Th2 cells in rapamycin, with subsequent injection of such Th2.R cells prior to class I and class II disparate cardiac allografting. Second, we determined whether Th2.R cell transfer polarized host immunity towards a Th2 phenotype. And third, we evaluated whether Th2.R cell therapy prolonged allograft viability when used alone or in combination with a short-course of cyclosporine (CSA) therapy. We found that host-type Th2.R cell therapy prior to cardiac allografting: (1) reduced the frequency of activated T cells in secondary lymphoid organs; (2) shifted post-transplant cytokines towards a Th2 phenotype; and (3) prolonged allograft viability when used in combination with short-course CSA therapy. These results provide further support for the rationale to use “direct” host T cell therapy for prolongation of allograft viability as an alternative to “indirect” therapy mediated by donor T cell infusion. PMID:21559526

  7. Host-based Th2 cell therapy for prolongation of cardiac allograft viability.

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    Shoba Amarnath

    Full Text Available Donor T cell transfusion, which is a long-standing approach to prevent allograft rejection, operates indirectly by alteration of host T cell immunity. We therefore hypothesized that adoptive transfer of immune regulatory host Th2 cells would represent a novel intervention to enhance cardiac allograft survival. Using a well-described rat cardiac transplant model, we first developed a method for ex vivo manufacture of rat host-type Th2 cells in rapamycin, with subsequent injection of such Th2.R cells prior to class I and class II disparate cardiac allografting. Second, we determined whether Th2.R cell transfer polarized host immunity towards a Th2 phenotype. And third, we evaluated whether Th2.R cell therapy prolonged allograft viability when used alone or in combination with a short-course of cyclosporine (CSA therapy. We found that host-type Th2.R cell therapy prior to cardiac allografting: (1 reduced the frequency of activated T cells in secondary lymphoid organs; (2 shifted post-transplant cytokines towards a Th2 phenotype; and (3 prolonged allograft viability when used in combination with short-course CSA therapy. These results provide further support for the rationale to use "direct" host T cell therapy for prolongation of allograft viability as an alternative to "indirect" therapy mediated by donor T cell infusion.

  8. Cardiac allograft vasculopathy after heart transplantation: risk factors and management.

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    Valantine, Hannah

    2004-05-01

    Cardiovascular disease post-transplant, particularly ischemic heart disease, is a significant problem for all transplant recipients. The major risk factors-smoking, obesity, diabetes, dyslipidemia and hypertension-are often more prevalent in heart transplant populations than in the general population. One of the main risk factors influencing graft loss and patient survival is cardiac allograft vasculopathy (CAV). Because CAV affects between 30% and 60% of cardiac transplant recipients within 5 years of surgery, prevention is a key focus for cardiac transplant teams today. CAV is caused by both immunologic mechanisms (e.g., acute rejection and anti-HLA antibodies) and non-immunologic mechanisms relating to the transplant itself or the recipient (e.g., donor age, hypertension, hyperlipidemia and pre-existing diabetes) or to the side effects often associated with immunosuppression with calcineurin inhibitors or corticosteroids (e.g., cytomegalovirus infection, nephrotoxicity and new-onset diabetes after transplantation). The calcineurin inhibitors, cyclosporine and tacrolimus, effectively prevent acute rejection, but do not prevent the development of CAV. CAV prevention will require a combined approach of new adjunct immunosuppressant agents (e.g., the proliferation signal inhibitors) and reduction in cardiovascular risk. Hypertension, hyperlipidemia and diabetes are also associated with the immunosuppression required to prevent organ rejection. Some studies have shown that hypertension is present more frequently in cyclosporine-treated patients than in tacrolimus-treated patients and that tacrolimus may be associated with a more favorable lipid profile. On the other hand, tacrolimus may be more diabetogenic than cyclosporine with current data suggesting a trend but no statistically significant supporting evidence. New-onset diabetes after transplantation is at times difficult to manage and may be an important determinant along with hypertension and hyperlipidemia of

  9. Early Cardiac Allograft Vasculopathy: Are the Viruses to Blame?

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    Ashim Aggarwal

    2012-01-01

    Full Text Available This paper describes a case of early (7 months after transplant cardiac allograft vasculopathy. This-43-year-old (CMV positive, EBV negative female patient underwent an orthotopic heart transplant with a (CMV negative, EBV positive donor heart. She had a history of herpes zoster infection and postherpetic neuralgia in the past. The patient’s panel reactive antibodies had been almost undetectable on routine surveillance testing, and her surveillance endomyocardial biopsies apart from a few episodes of mild-to-moderate acute cellular rejection (treated adequately with steroids never showed any evidence of humoral rejection. The postoperative course was complicated by multiple admissions for upper respiratory symptoms, and the patient tested positive for entero, rhino, and coronaviruses serologies. During her last admission (seven months postoperatively the patient developed mild left ventricular dysfunction with an ejection fraction of 40%. The patient’s endomyocardial biopsy done at that time revealed concentric intimal proliferation and inflammation resulting in near-total luminal occlusion in the epicardial and the intramyocardial coronary vessels, suggestive of graft vasculopathy with no evidence of rejection, and the patient had a fatal ventricular arrhythmia.

  10. Permanent rat cardiac allograft survival induced by ultraviolet B-irradiated donor lymphocytes and peritransplant cyclosporine

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    Oluwole, S.F.; Fawwaz, R.A.; Reemtsma, K.; Hardy, M.A.

    1988-08-01

    This study examines the effect of pretreatment with 10(8) ultraviolet B-irradiated donor leukocytes (UV-DL) with or without peritransplant cyclosporine (CyA) treatment (20 mg/kg on days 0, +1, and +2 relative to transplantation) on rat cardiac allograft survival across major histocompatibility loci. A single UV-DL pretreatment on day -3 or -7 (before transplantation) significantly prolonged survival of heart allografts from Wistar-Furth rats (W/F) in Lewis recipients from 6.8 +/- 0.8 days to 18.4 +/- 2.1 and 17.6 +/- 1.5 days (p less than 0.001), respectively. Multiple UV-DL infusions on days -14 and -7 increased the mean survival time to 20.0 +/- 0.9 days (p less than 0.001). Similarly, UV-DL infusion on day -3 or -7 significantly prolonged the mean survival time of heart allografts from ACI rats in Lewis rats. A single or multiple UV-DL infusions combined with peritransplant CyA led specifically to permanent W/F cardiac allograft survival (more than 200 days) in all recipients. Similarly, UV-DL infusion combined with peritransplant CyA led to indefinite survival of ACI cardiac allografts in two thirds of Lewis recipients. Adoptive transfer of splenocytes from long-term recipients of cardiac allografts, which specifically prolonged donor test grafts in syngeneic hosts, suggests that unresponsiveness to cardiac allografts is, in part, dependent on suppressor cells. This study emphasizes the importance of UV irradiation of DLs in the modulation of alloreactivity and the induction of donor-specific unresponsiveness in adult animals.

  11. Distinct phenotypes of cardiac allograft vasculopathy after heart transplantation : A histopathological study

    NARCIS (Netherlands)

    Huibers, Manon M H; Vink, Aryan; Kaldeway, Johannes; Huisman, André; Timmermans, Kim; Leenders, Max; Schipper, Marguèrite E I; Lahpor, Jaap R.; Kirkels, Hans J H; Klöpping, Corinne; de Jonge, Nicolaas; de Weger, Roel A.

    2014-01-01

    Introduction: Long-term survival after heart transplantation (HTx) is hampered by cardiac allograft vasculopathy (CAV). Better understanding of the pathophysiological mechanisms of CAV might have considerable consequences for therapeutic approaches in the future. The aim of the present study was to

  12. Donor-Specific Antibodies Are Produced Locally in Ectopic Lymphoid Structures in Cardiac Allografts

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    Huibers, M. M H; Gareau, A. J.; Beerthuijzen, J. M T; Siera-de Koning, E.; van Kuik, J.; Kamburova, E. G.; Vink, A.; de Jonge, N.; Lee, T. D G; Otten, H. G.; de Weger, R. A.

    Cardiac allograft vasculopathy (CAV) is a transplant pathology, limiting graft survival after heart transplantation. CAV arteries are surrounded by ectopic lymphoid structures (ELS) containing B cells and plasma cells. The aim of this study was to characterize the antigenic targets of antibodies

  13. Rosiglitazone suppresses cyclosporin-induced chronic transplant dysfunction and prolongs survival of rat cardiac allografts.

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    Chen, Yan; Liu, Yan; Yuan, Zhengwei; Tian, Lina; Dallman, Margaret J; Thompson, Paul W; Tam, Paul K H; Lamb, Jonathan R

    2007-06-27

    The lack of effective treatment for chronic transplant dysfunction restricts the long-term survival of solid organ allografts. Peroxisome proliferator-activated receptor ligands can suppress vascular inflammation. The aim of this study was to analyze the effects of rosiglitazone on chronic transplant dysfunction in a rat cardiac transplant model. Inbred male Fisher 344 (F344, RT1lvl) and Lewis (LEW, RT1(1)) rats were subjected to heterotopic abdominal heart transplantation according to standard procedures. Cyclosporine A was administered intraperitoneally to cover acute rejection, and rosiglitazone was administered orally by gavage daily from 3 days before the operation to the end of experiments. Rosiglitazone significantly prolonged the survival of cardiac allografts in rats (F344 to LEW) that had received a 10-day course of cyclosporin A compared to treatment with immunosuppressant alone. Analysis of allografts at 120 days posttransplantation showed that rosiglitazone reduced the inflammatory cell infiltrate in both the vessels and graft parenchyma as were neointimal formation, vascular occlusion, and fibrosis. Expression of transforming growth factor-beta and related proteins was less abundant after cyclosporin A/rosiglitazone treatment. The findings reported here demonstrate that rosiglitazone given under the cover of short-term treatment with cyclosporin A prolongs cardiac allograft survival and reduces the severity of chronic transplant dysfunction. This may be mediated in part through the downregulation of transforming growth factor-beta and related proteins. The combined effects of rosiglitazone and immunosuppressive drugs are potentially beneficial to patients receiving organ transplants.

  14. Xenon treatment attenuates early renal allograft injury associated with prolonged hypothermic storage in rats.

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    Zhao, Hailin; Yoshida, Akira; Xiao, Wei; Ologunde, Rele; O'Dea, Kieran P; Takata, Masao; Tralau-Stewart, Catherine; George, Andrew J T; Ma, Daqing

    2013-10-01

    Prolonged hypothermic storage elicits severe ischemia-reperfusion injury (IRI) to renal grafts, contributing to delayed graft function (DGF) and episodes of acute immune rejection and shortened graft survival. Organoprotective strategies are therefore needed for improving long-term transplant outcome. The aim of this study is to investigate the renoprotective effect of xenon on early allograft injury associated with prolonged hypothermic storage. Xenon exposure enhanced the expression of heat-shock protein 70 (HSP-70) and heme oxygenase 1 (HO-1) and promoted cell survival after hypothermia-hypoxia insult in human proximal tubular (HK-2) cells, which was abolished by HSP-70 or HO-1 siRNA. In the brown Norway to Lewis rat renal transplantation, xenon administered to donor or recipient decreased the renal tubular cell death, inflammation, and MHC II expression, while delayed graft function (DGF) was therefore reduced. Pathological changes associated with acute rejection, including T-cell, macrophage, and fibroblast infiltration, were also decreased with xenon treatment. Donors or recipients treated with xenon in combination with cyclosporin A had prolonged renal allograft survival. Xenon protects allografts against delayed graft function, attenuates acute immune rejection, and enhances graft survival after prolonged hypothermic storage. Furthermore, xenon works additively with cyclosporin A to preserve post-transplant renal function.

  15. Donors with a prior history of cardiac surgery are a viable source of lung allografts.

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    Costa, Joseph; Sreekanth, Sowmyashree; Kossar, Alex; Raza, Kashif; Robbins, Hilary; Shah, Lori; Sonett, Joshua R; Arcasoy, Selim; D'Ovidio, Frank

    2016-11-01

    End-stage lung disease continues to rise despite the lack of suitable lung donors, limiting the numbers of lung transplants performed each year. Expanded donor criteria, use of donation after cardiac death donors and the advent of ex vivo lung perfusion have resulted only in a slight increase in donor lung utilization. Organ donors with prior cardiac surgery (DPCS) present risks and technical challenges; however, they may be a potential source of suitable lung allografts with an experienced procurement surgeon. We present our experience having evaluated potential lung donors with a prior history of cardiac surgery, resulting in successful transplant outcomes. This is a single-institution retrospective review of brain-dead organ donors that were evaluated for lung donation in the period 2012-15. Donor and recipient characteristics were collected. Post-lung transplant survival was recorded. From 2012 to 2015, 259 donors were evaluated, 12 with a prior history of cardiac surgery of which 4 had coronary artery bypass, 3 had aortic root replacement, 2 had aortic valve replacement, 1 pulmonary embolectomy, 1 two-time reoperative valve replacement and 1 paediatric congenital ventricular septal defect repair. DPCS, 6/12 (50% dry run) provided suitable allografts generating six single-lung transplants (three right and three left, 1 donor provided twin single-lung transplants) and one double-lung transplant. Interval between cardiac surgery and procurement for those rejected was median 5840 (IQR 2350-8640) days and interval for the donors that provided allografts was median 438 (IQR 336-1095) days (Mann-Whitney, P = 0.07). Recipient 1-year survival from DPCS is 100%. Recipient 1-year survival was 92% in allografts explanted from donors with no prior cardiac surgery (2012-13). To date, this is the largest single-centre experience using lung allografts from brain-dead DPCS. Our experience shows despite predicted technical difficulties, with good communication between thoracic

  16. Omentin functions to attenuate cardiac hypertrophic response.

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    Matsuo, Kazuhiro; Shibata, Rei; Ohashi, Koji; Kambara, Takahiro; Uemura, Yusuke; Hiramatsu-Ito, Mizuho; Enomoto, Takashi; Yuasa, Daisuke; Joki, Yusuke; Ito, Masanori; Hayakawa, Satoko; Ogawa, Hayato; Kihara, Shinji; Murohara, Toyoaki; Ouchi, Noriyuki

    2015-02-01

    Cardiac hypertrophy occurs in many obesity-related conditions. Omentin is an adipose-derived plasma protein that is downregulated under obese conditions. Here, we investigated whether omentin modulates cardiac hypertrophic responses in vivo and in vitro. Systemic administration of an adenoviral vector expressing human omentin (Ad-OMT) to wild-type (WT) mice led to the attenuation of cardiac hypertrophy, fibrosis and ERK phosphorylation induced by transverse aortic constriction (TAC) or angiotensin II infusion. In cultured cardiomyocytes, stimulation with phenylephrine (PE) led to an increase in myocyte size, which was prevented by pretreatment with human omentin protein. Pretreatment of cardiomyocytes with omentin protein also reduced ERK phosphorylation in response to PE stimulation. Ad-OMT enhanced phosphorylation of AMP-activated protein kinase (AMPK) in the heart of WT mice after TAC operation. Blockade of AMPK activation by transduction with dominant-negative mutant forms of AMPK reversed the inhibitory effect of omentin on myocyte hypertrophy and ERK phosphorylation following PE stimulation. Moreover, fat-specific transgenic mice expressing human omentin showed reduced cardiac hypertrophy and ERK phosphorylation following TAC surgery compared to littermate controls. These data suggest that omentin functions to attenuate the pathological process of myocardial hypertrophy via the activation of AMPK in the heart, suggesting that omentin may represent a target molecule for the treatment of cardiac hypertrophy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Somatostatin receptor scintigraphy predicts impending cardiac allograft rejection before endomyocardial biopsy

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    Aparici, C.M.; Martin, J.C.; Tembl, A.; Flotats, A.; Estorch, M.; Catafau, A.M.; Berna, L.; Carrio, I. [Nuclear Medicine Department, Hospital Sant Pau, Barcelona (Spain); Narula, J.; Puig, M.; Camprecios, M.; Ballester, M. [Cardiology Department, Sant Pau Hospital, Barcelona (Spain)

    2000-12-01

    The invasive nature of endomyocardial biopsy has led to a search for alternative diagnostic modalities for the detection of cardiac allograft rejection. To date, no non-invasive test meets all the requirements for the detection of acute and chronic rejection. The rejection process usually presents with lymphocyte infiltration with or without myocyte necrosis, which indicates the severity of cardiac allograft rejection and the necessity of treatment. Activated lymphocytes express somatostatin receptors; thus somatostatin receptor imaging could be used to target them. The aim of this study was to assess the feasibility of using somatostatin receptor imaging to target activated lymphocytes in the process of cardiac allograft rejection. Thirteen somatostatin receptor imaging studies were performed on ten cardiac allograft recipients 12-4745 days after transplantation, simultaneously with endomyocardial biopsy, to assess the imaging of activated lymphocytes in comparison with histological findings. Somatostatin receptor imaging was performed 4 h after the injection of 110 MBq of the somatostatin analogue indium-111 pentetreotide. {sup 111}In-pentetreotide uptake was visually scored and semi-quantitatively estimated by the calculation of a heart-to-lung ratio (HLR). The visual score correlated with the HLR. Intense/moderate uptake on visual assessment and an HLR >1.6 was observed in eight studies. In three of these studies there was significant rejection in the simultaneous endomyocardial biopsy [International Society of Heart and Lung Transplantation (ISHLT) rejection grade 3A/4]. Intense/moderate uptake was associated with mild or no rejection in the remaining five patients, and in four of them the next endomyocardial biopsy performed 1 week later demonstrated significant rejection requiring treatment. Two patients with low uptake and an HLR <1.6 had no evidence of rejection either in the simultaneous endomyocardial biopsy or in the endomyocardial biopsy performed the

  18. Somatostatin receptor scintigraphy predicts impending cardiac allograft rejection before endomyocardial biopsy.

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    Aparici, C M; Narula, J; Puig, M; Camprecios, M; Martín, J C; Tembl, A; Flotats, A; Estorch, M; Catafau, A M; Bernà, L; Ballester, M; Carrió, I

    2000-12-01

    The invasive nature of endomyocardial biopsy has led to a search for alternative diagnostic modalities for the detection of cardiac allograft rejection. To date, no non-invasive test meets all the requirements for the detection of acute and chronic rejection. The rejection process usually presents with lymphocyte infiltration with or without myocyte necrosis, which indicates the severity of cardiac allograft rejection and the necessity of treatment. Activated lymphocytes express somatostatin receptors; thus somatostatin receptor imaging could be used to target them. The aim of this study was to assess the feasibility of using somatostatin receptor imaging to target activated lymphocytes in the process of cardiac allograft rejection. Thirteen somatostatin receptor imaging studies were performed on ten cardiac allograft recipients 12-4,745 days after transplantation, simultaneously with endomyocardial biopsy, to assess the imaging of activated lymphocytes in comparison with histological findings. Somatostatin receptor imaging was performed 4 h after the injection of 110 MBq of the somatostatin analogue indium-111 pentetreotide. 111In-pentetreotide uptake was visually scored and semi-quantitatively estimated by the calculation of a heart-to-lung ratio (HLR). The visual score correlated with the HLR. Intense/moderate uptake on visual assessment and an HLR >1.6 was observed in eight studies. In three of these studies there was significant rejection in the simultaneous endomyocardial biopsy [International Society of Heart and Lung Transplantation (ISHLT) rejection grade 3A/4]. Intense/moderate uptake was associated with mild or no rejection in the remaining five patients, and in four of them the next endomyocardial biopsy performed 1 week later demonstrated significant rejection requiring treatment. Two patients with low uptake and an HLR <1.6 had no evidence of rejection either in the simultaneous endomyocardial biopsy or in the endomyocardial biopsy performed the

  19. Detection of rejection of canine orthotopic cardiac allografts with indium-111 lymphocytes and gamma scintigraphy

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    Eisen, H.J.; Rosenbloom, M.; Laschinger, J.C.; Saffitz, J.E.; Cox, J.L.; Sobel, B.E.; Bolman, R.M. III; Bergmann, S.R.

    1988-07-01

    Previous studies have demonstrated the feasibility of detecting canine heterotopic cardiac allograft rejection scintigraphically after administration of 111In lymphocytes. To determine whether the approach is capable of detecting rejection in orthotopic cardiac transplants in which labeled lymphocytes circulating in the blood pool may reduce sensitivity, the present study was performed in which canine orthotopic cardiac transplants were evaluated in vivo. Immunosuppression was maintained with cyclosporine A (10-20 mg/kg/day) and prednisone (1 mg/kg/day) for 2 wk after transplantation. Subsequently, therapy was tapered. Five successful allografts were evaluated scintigraphically every 3 days after administration of 100-350 microCi 111In autologous lymphocytes. Correction for labeled lymphocytes circulating in the blood pool, but not actively sequestered in the allografts was accomplished by administering 3-6 mCi 99mTc autologous erythrocytes and employing a previously validated blood-pool activity correction technique. Cardiac infiltration of labeled lymphocytes was quantified as percent indium excess (%IE), scintigraphically detectable 111In in the transplant compared with that in blood, and results were compared with those of concomitantly performed endomyocardial biopsy. Scintigraphic %IE for hearts not undergoing rejection manifest histologically was 0.7 +/- 0.4. Percent IE for rejecting hearts was 6.8 +/- 4.0 (p less than 0.05). Scintigraphy detected each episode of rejection detected by biopsy. Scintigraphic criteria for rejection (%IE greater than 2 s.d. above normal) were not manifest in any study in which biopsies did not show rejection. Since scintigraphic results with 111In-labeled lymphocytes were concordant with biopsy results in orthotopic cardiac transplants, noninvasive detection of graft rejection in patients should be attainable with the approach developed.

  20. Immunological aspects of clinical and experimental cardiac valve allograft implantation

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    F.B.S. Oei (Frank)

    2001-01-01

    textabstractThe documented history of allogeneic cardiac valve implantation began in 1952. In that year, the first successful implantation of an canine aortic valve in the descendlng aorta of another dog, was carried out by Conrad Lam etal. Driven by the succes seen in this animal model Murray et

  1. The composition of ectopic lymphoid structures suggests involvement of a local immune response in cardiac allograft vasculopathy

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    Huibers, Manon M. H.; Gareau, Alison J.; Vink, Aryan; Kruit, Rianne; Feringa, Hannah; Beerthuijzen, Johanna M. T.; Siera-de Koning, Erica; Peeters, Ton; de Jonge, Nicolaas; de Weger, Roel A.; Lee, Timothy D. G.

    BACKGROUND: Cardiac allograft vasculopathy (CAV) is a multifactorial pathology limiting the survival of cardiac transplants. The etiology of CAV is unclear, but antibody-mediated and cellular-mediated responses have been implicated. We, and others, have observed ectopic lymphoid structures (ELS)

  2. Administration of the selective cyclooxygenase (COX)-2 inhibitor etodolac prolongs cardiac allograft survival in a mouse model.

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    Matsuyama, Masahide; Yoshimura, Rikio; Hase, Taro; Chargui, Jamel; Yoshimura, Norio; Touraine, Jean-Louis

    2010-01-01

    Etodolac, a selective cyclooxygenase-2 (COX-2) inhibitor, is a non-steroidal anti-inflammatory drug. COX-2 is a key factor in the progression of inflammation. Although inflammation is an essential pathologic feature of cardiac allograft rejection, the role of COX-2 in this process remains unclear. The aim of this study was to investigate the expression of COX and the effects of etodolac in a mouse cardiac allograft model. Balb/c mice (H-2d) were used as recipients and C57BL/6 (H-2b) mice as heart donors. Heart function was evaluated daily after transplantation by regular abdominal palpation of the heart and by laparotomy in cases where the beating became weak. Rejection was defined as total cessation of cardiac muscle contraction. COX-2 expression was analyzed by immunohistochemistry. Cardiac isograft was well tolerated (>150 days, n=5), while non-treated cardiac allograft was rapidly rejected (mean 10.9±2.4, n=7). In the etodolac-treated cardiac allograft (10 mg/kg/day by hypodermic injection), survival was extended to 18.53±2.1 days (n=7). The necrotic area and the grade of COX-2 immunostaining were more significantly reduced in the etodolac-treated cardiac allograft than in the non-treated cardiac allograft at day 14. These results indicate that etodolac contributes to protection against rejection after heart transplantation. Etodolac could therefore be used to suppress graft rejection by means of its anti-inflammatory properties.

  3. Loss of Myeloid Related Protein-8/14 Exacerbates Cardiac Allograft Rejection

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    Shimizu, Koichi; Libby, Peter; Rocha, Viviane Z.; Folco, Eduardo J.; Shubiki, Rica; Grabie, Nir; Jang, Sunyoung; Lichtman, Andrew H.; Shimizu, Ayako; Hogg, Nancy; Simon, Daniel I.; Mitchell, Richard N.; Croce, Kevin

    2011-01-01

    Background The calcium-binding proteins myeloid-related protein (MRP)-8 (S100A8) and MRP-14 (S100A9) form MRP-8/14 heterodimers (S100A8/A9, calprotectin) that regulate myeloid cell function and inflammatory responses, and serve as early serum markers for monitoring acute allograft rejection. Despite functioning as a pro-inflammatory mediator, the pathophysiological role of MRP-8/14 complexes in cardiovascular disease is incompletely defined. This study investigated the role of MRP-8/14 in cardiac allograft rejection using MRP-14-deficient mice (MRP14-/-) that lack MRP-8/14 complexes. Methods and Results We examined parenchymal rejection (PR) after major histocompatibility complex (MHC) class II allomismatched cardiac transplantation (bm12 donor heart and B6 recipients) in wild-type (WT) and MRP14-/- recipients. Allograft survival averaged 5.9 ± 2.9 weeks (n=10) in MRP14-/- recipients, compared to > 12 weeks (n = 15, p MRP14-/- recipients had significantly higher PR scores (2.8 ± 0.8, n=8) than did WT recipients (0.8 ± 0.8, n=12, pMRP14-/- recipients had significantly increased T-cell and macrophage infiltration, as well as increased mRNA levels of IFN-γ and IFN-γ–associated chemokines (CXCL9, CXCL10, and CXCL11), IL-6, and IL-17, with significantly higher levels of Th17 cells. MRP14-/- recipients also had significantly more lymphocytes in the adjacent paraaortic lymph nodes than did WT recipients (cell number per lymph node: 23.7 ± 0.7 × 105 for MRP14-/- vs. 6.0 ± 0.2 × 105 for WT, p MRP14-/- recipients of bm12 hearts expressed significantly higher levels of the co-stimulatory molecules CD80 and CD86 than did those of WT recipients 2 weeks after transplantation. Mixed leukocyte reactions using allo-EC-primed MRP14-/- DCs resulted in significantly higher antigen-presenting function than reactions using WT DCs. Ovalbumin-primed MRP14-/- DCs augmented proliferation of OT-II CD4+ T cells with increased IL-2 and IFN-γ production. Cardiac allografts of B6 MHC

  4. Methotrexate associated to lipid core nanoparticles improves cardiac allograft vasculopathy and the inflammatory profile in a rabbit heart graft model

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    A.I. Fiorelli

    2017-08-01

    Full Text Available Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and has no effective treatment. A lipid nanoemulsion (LDE can carry chemotherapeutic agents in the circulation and concentrates them in the heart graft. The aim of the study was to investigate the effects of methotrexate (MTX associated to LDE. Rabbits fed a 0.5% cholesterol diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10 mg·kg–1·day–1 orally and allocated to treatment with intravenous LDE-MTX (4 mg/kg, weekly, n=10 or with weekly intravenous saline solution (control group, n=10, beginning on the day of surgery. Animals were euthanized 6 weeks later. Compared to controls, grafts of LDE-MTX treated rabbits showed 20% reduction of coronary stenosis, with a four-fold increase in vessel lumen and 80% reduction of macrophage staining in grafts. Necrosis was attenuated by LDE-MTX. Native hearts of both LDE-MTX and Control groups were apparently normal. Gene expression of lipoprotein receptors was significantly greater in grafts compared to native hearts. In LDE-MTX group, gene expression of the pro-inflammatory factors tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-18, vascular cell adhesion molecule-1, and matrix metalloproteinase-12 was strongly diminished whereas expression of anti-inflammatory interleukin-10 increased. LDE-MTX promoted improvement of the cardiac allograft vasculopathy and diminished inflammation in heart grafts.

  5. Noninvasive assessment of treatment of cardiac allograft rejection with indium-111-labeled lymphocytes

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    Rosenbloom, M.; Eisen, H.J.; Laschinger, J.; Saffitz, J.E.; Sobel, B.E.; Bergmann, S.R.; Bolman, R.M. III

    1988-09-01

    We have shown previously that cardiac allograft rejection can be detected noninvasively with gamma scintigraphy after administration of indium-111 (111In)-labeled lymphocytes. To determine whether this technique could be used to monitor salvage immunosuppressive therapy in reversing rejection, 5 dogs were studied after thoracic heterotopic cardiac transplantation. Initial postoperative immunosuppression was maintained with cyclosporine (10-20 mg/kg/day) and prednisone (1 mg/kg/day) for 7 days after transplantation and then discontinued. Scintigraphy after administration of labeled lymphocytes was performed during initial immunosuppression and every 3 days after its termination. Endomyocardial biopsies were obtained on each day scintigraphy was performed. Once scintigraphic criteria for rejection were met (111In-lymphocyte uptake greater than mean +/- 2SD of normal myocardium), animals were treated with high dose methylprednisolone and cyclosporine. Myocardial 111In-lymphocyte activity compared with that in blood was 0.7 +/- 0.8 during initial immunosuppression, increased to 5.7 +/- 3.5 after termination of therapy (P less than 0.01), and diminished with salvage immunosuppressive therapy to 0.5 +/- 0.8 (P = NS compared with native hearts or allografts during initial immunosuppression). Scintigraphy accurately predicted all but one episode of biopsy-documented rejection and accurately detected reversal of rejection during salvage. Thus, scintigraphy with 111In-labeled lymphocytes should facilitate noninvasive monitoring of antirejection therapy in patients.

  6. Cyclosporine inhibits long-term survival in cardiac allografts treated with monoclonal antibody against CD45RB

    NARCIS (Netherlands)

    Parry, N; Lazarovits, AI; Wang, JJ; Garcia, B; Luke, P; Poppema, S; Zhong, R

    Background: We have previously reported that a monoclonal antibody to CD45RB is a novel immunosuppressive agent; however, the optimal regimen in cardiac allografts remains unknown. The present study was undertaken to determine the optimal protocol of this therapy and its interaction with

  7. Gene Transfer of Heme Oxygenase-1 Using an Adeno-Associated Virus Serotype 6 Vector Prolongs Cardiac Allograft Survival

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    Jacqueline M. Evans

    2012-01-01

    Full Text Available Introduction. Allograft survival can be prolonged by overexpression of cytoprotective genes such as heme oxygenase-1 (HO-1. Modifications in vector design and delivery have provided new opportunities to safely and effectively administer HO-1 into the heart prior to transplantation to improve long-term graft outcome. Methods. HO-1 was delivered to the donor heart using an adeno-associated virus vector (AAV with a pseudotype 6 capsid and vascular endothelial growth factor (VEGF to enhance myocardial tropism and microvascular permeability. Survival of mouse cardiac allografts, fully or partially mismatched at the MHC, was determined with and without cyclosporine A. Intragraft cytokine gene expression was examined by PCR. Results. The use of AAV6 to deliver HO-1 to the donor heart, combined with immunosuppression, prolonged allograft survival by 55.3% when donor and recipient were completely mismatched at the MHC and by 94.6% if partially mismatched. The combination of gene therapy and immunosuppression was more beneficial than treatment with either AAV6-HO-1 or CsA alone. IL-17a, b, e and f were induced in the heart at rejection. Conclusions. Pretreatment of cardiac allografts with AAV6-HO-1 plus cyclosporine A prolonged graft survival. HO-1 gene therapy represents a beneficial adjunct to immunosuppressive therapy in cardiac transplantation.

  8. Melatonin synergized with cyclosporine A improves cardiac allograft survival by suppressing inflammation and apoptosis.

    Science.gov (United States)

    Liu, Chen; Hong, Tao; Shao, Mengping; Chen, Zhenghang; Wang, Chunsheng

    2014-09-01

    Melatonin, a widespread physiological mediator, has been demonstrated to exhibit a dose‑dependent immunoregulatory effect in vitro and in vivo, including mediating physiological circadian rhythms, neutralizing free radicals and exerting antisenescence actions. In the present study, the efficacy and mechanism of melatonin alone or in combination with cyclosporine (CsA) in prolonging heart transplantation survival was examined. Daily treatment with melatonin (200 mg/kg/day) through a gavage, significantly prolonged the survival of cardiac grafts (mean survival time, 13.4±2.4 days; n=7; Pcardiac allograft by inhibiting inflammation‑induced apoptosis. These results provide evidence for a novel therapeutic approach for future immunosuppressive agents in organ transplantation.

  9. Effect of high-intensity interval training on progression of cardiac allograft vasculopathy.

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    Nytrøen, Kari; Rustad, Lene Annette; Erikstad, Ingrid; Aukrust, Pål; Ueland, Thor; Lekva, Tove; Gude, Einar; Wilhelmsen, Nils; Hervold, Anders; Aakhus, Svend; Gullestad, Lars; Arora, Satish

    2013-11-01

    Cardiac allograft vasculopathy (CAV) is a progressive form of atherosclerosis occurring in heart transplant (HTx) recipients, leading to increased morbidity and mortality. Given the atheroprotective effect of exercise on traditional atherosclerosis, we hypothesized that high-intensity interval training (HIIT) would reduce the progression of CAV among HTx recipients. Forty-three cardiac allograft recipients (mean ± SD age 51 ± 16 years; 67% men; time post-HTx 4.0 ± 2.2 years), all clinically stable and >18 years old, were randomized to either a HIIT group or control group (standard care) for 1 year. The effect of training on CAV progression was assessed by intravascular ultrasound (IVUS). IVUS analysis revealed a significantly smaller mean increase [95% CI] in atheroma volume (PAV) of 0.9% [95% CI -;0.3% to 1.9%] in the HIIT group as compared with the control group, 2.5% [1.6% to 3.5%] (p = 0.021). Similarly, the mean increase in total atheroma volume (TAV) was 0.3 [0.0 to 0.6] mm(3)/mm in the HIT group vs 1.1 [0.6 to 1.7] mm(3)/mm in the control group (p = 0.020), and mean increase in maximal intimal thickness (MIT) was 0.02-0.01 to 0.04] mm in the HIIT group vs 0.05 [0.03 to 0.08] mm in the control group (p = 0.054). Qualitative plaque progression (virtual histology parameters) and inflammatory activity (biomarkers) were similar between the 2 groups during the study period. HIIT among maintenance HTx recipients resulted in a significantly impaired rate of CAV progression. Future larger studies should address whether exercise rehabilitation strategies should be included in CAV management protocols. © 2013 International Society for Heart and Lung Transplantation. All rights reserved.

  10. Characteristics of cardiac allograft vasculopathy induced by immunomodulation in the miniature Swine.

    Science.gov (United States)

    Amano, Jun; Akashima, Tomohiro; Terasaki, Takamitsu; Wada, Yuko; Ito-Amano, Midori; Suzuki, Jun-Ichi; Isobe, Mitsuaki

    2015-01-01

    We aimed to develop swine cardiac transplantation model for study of cardiac allograft vasculopathy (CAV) and to characterize the mechanisms of its formation. Heterotropic cardiac transplantation was performed in swine leukocyte antigen mismatched miniature swine, and CAV was induced by immunomodulation by cyclosporine A (CyA). Histology and immunohistochemistry were performed to identify cellular components of CAV. Fluorescence in situ hybridization (FISH) was developed for detection of 1 and Y-chromosome for identification of cell origin in the female donor to the male recipient heart transplantation model. CAV was successfully developed by immunomodulation of CyA. Severity of CAV revealed more prominent in the distal epicardial coronary arteries than proximal coronary arteries. Phenotype of the SMCs proliferated in the intimal thickening of CAV were mostly embryonal/secretory type. Our new chromosome specific probes for FISH method were useful for discrimination of sex of each cell, and proliferated SMCs were revealed to be mainly donor origin. CAV mimicking human heart transplantation can be developed by appropriate immunomodulation in the swine. In swine CAV, proliferated SMCs seen in the intimal thickening were demonstrated to be from the donor origin.

  11. Serum exosomal protein profiling for the non-invasive detection of cardiac allograft rejection.

    Science.gov (United States)

    Kennel, Peter J; Saha, Amit; Maldonado, Dawn A; Givens, Raymond; Brunjes, Danielle L; Castillero, Estibaliz; Zhang, Xiaokan; Ji, Ruiping; Yahi, Alexandre; George, Isaac; Mancini, Donna M; Koller, Antonius; Fine, Barry; Zorn, Emmanuel; Colombo, Paolo C; Tatonetti, Nicholas; Chen, Emily I; Schulze, P Christian

    2017-07-19

    Exosomes are cell-derived circulating vesicles that play an important role in cell-cell communication. Exosomes are actively assembled and carry messenger RNAs, microRNAs and proteins. The "gold standard" for cardiac allograft surveillance is endomyocardial biopsy (EMB), an invasive technique with a distinct complication profile. The development of novel, non-invasive methods for the early diagnosis of allograft rejection is warranted. We hypothesized that the exosomal proteome is altered in acute rejection, allowing for a distinction between non-rejection and rejection episodes. Serum samples were collected from heart transplant (HTx) recipients with no rejection, acute cellular rejection (ACR) and antibody-mediated rejection (AMR). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of serum exosome was performed using a mass spectrometer (Orbitrap Fusion Tribrid). Principal component analysis (PCA) revealed a clustering of 3 groups: (1) control and heart failure (HF); (2) HTx without rejection; and (3) ACR and AMR. A total of 45 proteins were identified that could distinguish between groups (q < 0.05). Comparison of serum exosomal proteins from control, HF and non-rejection HTx revealed 17 differentially expressed proteins in at least 1 group (q < 0.05). Finally, comparisons of non-rejection HTx, ACR and AMR serum exosomes revealed 15 differentially expressed proteins in at least 1 group (q < 0.05). Of these 15 proteins, 8 proteins are known to play a role in the immune response. Of note, the majority of proteins identified were associated with complement activation, adaptive immunity such as immunoglobulin components and coagulation. Characterizing of circulating exosomal proteome in different cardiac disease states reveals unique protein expression patterns indicative of the respective pathologies. Our data suggest that HTx and allograft rejection alter the circulating exosomal protein content. Exosomal protein analysis could be a novel approach

  12. A novel therapy to attenuate acute kidney injury and ischemic allograft damage after allogenic kidney transplantation in mice.

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    Faikah Gueler

    Full Text Available Ischemia followed by reperfusion contributes to the initial damage to allografts after kidney transplantation (ktx. In this study we tested the hypothesis that a tetrapeptide EA-230 (AQGV, might improve survival and attenuate loss of kidney function in a mouse model of renal ischemia/reperfusion injury (IRI and ischemia-induced delayed graft function after allogenic kidney transplantation. IRI was induced in male C57Bl/6N mice by transient bilateral renal pedicle clamping for 35 min. Treatment with EA-230 (20-50mg/kg twice daily i.p. for four consecutive days was initiated 24 hours after IRI when acute kidney injury (AKI was already established. The treatment resulted in markedly improved survival in a dose dependent manner. Acute tubular injury two days after IRI was diminished and tubular epithelial cell proliferation was significantly enhanced by EA-230 treatment. Furthermore, CTGF up-regulation, a marker of post-ischemic fibrosis, at four weeks after IRI was significantly less in EA-230 treated renal tissue. To learn more about these effects, we measured renal blood flow (RBF and glomerular filtration rate (GFR at 28 hours after IRI. EA-230 improved both GFR and RBF significantly. Next, EA-230 treatment was tested in a model of ischemia-induced delayed graft function after allogenic kidney transplantation. The recipients were treated with EA-230 (50 mg/kg twice daily i.p. which improved renal function and allograft survival by attenuating ischemic allograft damage. In conclusion, EA-230 is a novel and promising therapeutic agent for treating acute kidney injury and preventing IRI-induced post-transplant ischemic allograft injury. Its beneficial effect is associated with improved renal perfusion after IRI and enhanced regeneration of tubular epithelial cells.

  13. Pentoxifylline Attenuates Cardiac Remodeling Induced by Tobacco Smoke Exposure

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    Minicucci, Marcos; Oliveira, Fernando; Santos, Priscila; Polegato, Bertha; Roscani, Meliza; Fernandes, Ana Angelica; Lustosa, Beatriz; Paiva, Sergio; Zornoff, Leonardo; Azevedo, Paula, E-mail: paulasa@fmb.unesp.br [Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, São Paulo, SP (Brazil)

    2016-05-15

    Tobacco smoke exposure is an important risk factor for cardiac remodeling. Under this condition, inflammation, oxidative stress, energy metabolism abnormalities, apoptosis, and hypertrophy are present. Pentoxifylline has anti‑inflammatory, anti-apoptotic, anti-thrombotic and anti-proliferative properties. The present study tested the hypothesis that pentoxifylline would attenuate cardiac remodeling induced by smoking. Wistar rats were distributed in four groups: Control (C), Pentoxifylline (PX), Tobacco Smoke (TS), and PX-TS. After two months, echocardiography, invasive blood pressure measurement, biochemical, and histological studies were performed. The groups were compared by two-way ANOVA with a significance level of 5%. TS increased left atrium diameter and area, which was attenuated by PX. In the isolated heart study, TS lowered the positive derivate (+dp/dt), and this was attenuated by PX. The antioxidants enzyme superoxide dismutase and glutathione peroxidase were decreased in the TS group; PX recovered these activities. TS increased lactate dehydrogenase (LDH) and decreased 3-hydroxyacyl Coenzyme A dehydrogenases (OH-DHA) and citrate synthase (CS). PX attenuated LDH, 3-OH-DHA and CS alterations in TS-PX group. TS increased IL-10, ICAM-1, and caspase-3. PX did not influence these variables. TS induced cardiac remodeling, associated with increased inflammation, oxidative stress, apoptosis, and changed energy metabolism. PX attenuated cardiac remodeling by reducing oxidative stress and improving cardiac bioenergetics, but did not act upon cardiac cytokines and apoptosis.

  14. Cyclosporine decreases vascular progenitor cell numbers after cardiac transplantation and attenuates progenitor cell growth in vitro.

    Science.gov (United States)

    Davies, William R; Wang, Shaohua; Oi, Keiji; Bailey, Kent R; Tazelaar, Henry D; Caplice, Noel M; McGregor, Christopher G A

    2005-11-01

    Recent experimental evidence suggests that the neointimal proliferation seen in cardiac allograft vasculopathy may in part derive from recipient progenitor cells. The effect of cyclosporine on these circulating progenitors in the setting of cardiac transplantation is currently unknown. Three surgical series were performed: sham operation alone, sham operation with immunosuppression, and heterotopic porcine cardiac transplantation with immunosuppression. The sham operation involved laparotomy and consecutive clamping of the abdominal aorta and inferior vena cava. Post-operative immunosuppression consisted of cyclosporine at therapeutic levels (100-300 ng/ml) and 0.5 mg/kg methylprednisolone. Endothelial outgrowth colony numbers (EOC(CFU)) and smooth muscle outgrowth colony numbers (SOC(CFU)) were quantified weekly for 4 weeks post-operatively. A series of in vitro experiments were performed to determine the effect of cyclosporine on the differentiation, migration, and proliferation of EOCs and SOCs. In the sham alone series there were no changes to either EOC(CFU) or SOC(CFU). In the sham with immunosuppression and the transplant series, both EOC(CFU) and SOC(CFU) fell in the first 2 weeks (p Cyclosporine, even at a low dose, prevented differentiation, inhibited proliferation, and attenuated migration of both EOCs and SOCs. Immunosuppression in the setting of cardiac transplantation causes a profound reduction in circulating progenitor cells capable of differentiating into endothelial and smooth muscle cells. This effect can in part be explained by the inhibitory effects of cyclosporine on progenitor growth and differentiation seen in this study.

  15. Host-derived smooth muscle cells accumulate in cardiac allografts: role of inflammation and monocyte chemoattractant protein 1.

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    Piotr Religa

    Full Text Available Transplant arteriosclerosis is characterized by inflammation and intimal thickening caused by accumulation of smooth muscle cells (SMCs both from donor and recipient. We assessed the relationship between clinical factors and the presence of host-derived SMCs in 124 myocardial biopsies from 26 consecutive patients who received hearts from opposite-sex donors. Clinical and demographic information was obtained from the patients' medical records. Host-derived SMCs accounted for 3.35+/-2.3% of cells in arterioles (range, 0.08-12.51%. As shown by linear regression analysis, an increased number of SMCs was associated with rejection grade (mean, 1.41+/-1.03, p = 0.034 and the number of leukocytes (19.1+/-12.7 per 20 high-power fields, p = 0.01. The accumulation of host-derived SMCs was associated with an increased number of leukocytes in the allografts. In vitro, monocyte chemoattractant protein 1 (MCP-1 released from leukocytes was crucial for SMC migration. After heart allotransplantation, mice treated with MCP-1-specific antibodies had significantly fewer host-derived SMCs in the grafts than mice treated with isotypic antibody controls. We conclude that the number of host-derived SMCs in human cardiac allografts is associated with the rejection grade and that MCP-1 may play pivotal role in recruiting host-derived SMCs into cardiac allografts.

  16. Cine CT for Attenuation Correction in Cardiac PET/CT

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    Alessio, Adam M.; Kohlmyer, Steve; Branch, Kelley; Chen, Grace; Caldwell, James; Kinahan, Paul

    2008-01-01

    In dual-modality PET/CT systems, the CT scan provides the attenuation map for PET attenuation correction. The current clinical practice of obtaining a single helical CT scan provides only a snapshot of the respiratory cycle, whereas PET occurs over multiple respiratory cycles. Misalignment of the attenuation map and emission image because of respiratory motion causes errors in the attenuation correction factors and artifacts in the attenuation-corrected PET image. To rectify this problem, we evaluated the use of cine CT, which acquires multiple low-dose CT images during a respiratory cycle. We evaluated the average and the intensity-maximum image of cine CT for cardiac PET attenuation correction. Methods Cine CT data and cardiac PET data were acquired from a cardiac phantom and from multiple patient studies. The conventional helical CT, cine CT, and PET data of an axially translating phantom were evaluated with and without respiratory motion. For the patient studies, we acquired 2 cine CT studies for each PET acquisition in a rest–stress 13N-ammonia protocol. Three readers visually evaluated the alignment of 74 attenuation image sets versus the corresponding emission image and determined whether the alignment provided acceptable or unacceptable attenuation-corrected PET images. Results In the phantom study, the attenuation correction from helical CT caused a major artifactual defect in the lateral wall on the PET image. The attenuation correction from the average and from the intensity-maximum cine CT images reduced the defect by 20% and 60%, respectively. In the patient studies, 77% of the cases using the average of the cine CT images had acceptable alignment and 88% of the cases using the intensity maximum of the cine CT images had acceptable alignment. Conclusion Cine CT offers an alternative to helical CT for compensating for respiratory motion in the attenuation correction of cardiac PET studies. Phantom studies suggest that the average and the intensity

  17. Reduced Progression of Cardiac Allograft Vasculopathy with Routine Use of Induction Therapy with Basiliximab

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    Ricardo Wang

    2015-01-01

    Full Text Available Abstract Introduction: Cardiac allograft vasculopathy (CAV is a major limitation for long-term survival of patients undergoing heart transplantation (HT. Some immunosuppressants can reduce the risk of CAV. Objectives: The primary objective was to evaluate the variation in the volumetric growth of the intimal layer measured by intracoronary ultrasound (IVUS after 1 year in patients who received basiliximab compared with that in a control group. Methods: Thirteen patients treated at a single center between 2007 and 2009 were analyzed retrospectively. Evaluations were performed with IVUS, measuring the volume of a coronary segment within the first 30 days and 1 year after HT. Vasculopathy was characterized by the volume of the intima of the vessel. Results: Thirteen patients included (7 in the basiliximab group and 6 in the control group. On IVUS assessment, the control group was found to have greater vessel volume (120–185.43 mm3 vs. 127.77–131.32 mm3; p = 0.051. Intimal layer growth (i.e., CAV was also higher in the control group (27.30–49.15 mm3 [∆80%] vs. 20.23–26.69 mm3 [∆33%]; p = 0.015. Univariate regression analysis revealed that plaque volume and prior atherosclerosis of the donor were not related to intima growth (r = 0.15, p = 0.96, whereas positive remodeling was directly proportional to the volumetric growth of the intima (r = 0.85, p < 0.001. Conclusion: Routine induction therapy with basiliximab was associated with reduced growth of the intima of the vessel during the first year after HT.

  18. Perioperative Risk Factors of Cardiac Allograft Vasculopathy in the Long-Term Follow-up.

    Science.gov (United States)

    Szyguła-Jurkiewicz, B; Zakliczyński, M; Szczurek, W; Skrzypek, M; Gąsior, M; Zembala, M

    2016-06-01

    Cardiac allograft vasculopathy (CAV) still remains to be one of the most important limiting factors for heart transplant recipients' long-term survival. The aim of our study was to identify the perioperative risk factors impacting the occurrence of CAV during the long-term follow-up. We retrospectively analysed the data from 198 consecutive adult patients, who underwent heart transplantation between 2007 and 2012, in whom at least one routine coronarography (CAG) was performed. CAV onset was defined as any lesion seen at least at one routine CAG. The average follow-up was 63.6 ± 14.7 months. The frequency of CAV in the analysed population was 36 (18.1%). Multivariate stepwise logistic regression analysis confirmed that NT-proBNP plasma concentration directly before heart transplant [logNT-proBNP OR = 16.455 (4.587-31.036), P < .0001], fibrinogen plasma concentration a month after heart transplant [OR = 1.022 (1.009-1.035), P < .001] and occurrence of diabetes [OR = 12.355 (1.417-35.750), P < .001], were independent predictors of CAV. Area under the ROC curves (AUC) indicated a well discriminatory power of plasma fibrinogen [AUC 0.9278, P < .001] and plasma NTproBNP concentration [AUC 0.9514, P < .001] in CAV prediction. The optimal cut-off value of fibrinogen was 509 mg/dL, and of NT-proBNP was 10080 pg/mL. Our data show that NT-proBNP and fibrinogen plasma concentrations as well as occurence of diabetes, both preexisting and new onset after heart transplant can be used to identify patients at risk of developing CAV. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. PG490-88, a derivative of triptolide, attenuates obliterative airway disease in a mouse heterotopic tracheal allograft model.

    Science.gov (United States)

    Leonard, Colm T; Soccal, Paola M; Berry, Gerald J; Doyle, Ramona L; Theodore, James; Duncan, Steven R; Rosen, Glenn D

    2002-12-01

    The current treatment of obliterative bronchiolitis in lung transplant recipients is sub-optimal. Triptolide is a novel immunosuppressant that has a mechanism of action distinct from currently available immunosuppressants, including induction of T-cell apoptosis, blockade of fibroblast proliferation/maturation and inhibition of transforming growth factor-beta (TGF-beta) mRNA production. We hypothesized that triptolide may be helpful in blocking obliterative airway disease in lung transplant recipients. We investigated the effect of PG490-88, a water-soluble derivative of triptolide, in a mouse heterotopic tracheal allograft model of obliterative airway disease. We show that PG490-88 attenuates airway obliteration in this model and inhibits accumulation of inflammatory cells, and therefore may have preventive or therapeutic benefits for patients with obliterative airway disease (OAD) following lung transplantation.

  20. Music exposure induced prolongation of cardiac allograft survival and generated regulatory CD4⁺ cells in mice.

    Science.gov (United States)

    Uchiyama, M; Jin, X; Zhang, Q; Amano, A; Watanabe, T; Niimi, M

    2012-05-01

    In clinical practice, music has been used to decrease stress, heart rate, and blood pressure and to provide a distraction from disease symptoms. We investigated sound effects on alloimmune responses in murine heart transplantation. Naïve and eardrum-ruptured CBA/N (CBA, H2(K)) underwent transplantation of a C57BL/6 (B6, H2(b)) heart and were exposed to 1 of 3 types of music-opera (La Traviata), classical (Mozart), and New Age (Enya)-or 1 of 6 different single sound frequencies for 7 days. An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Cell-proliferation, cytokine, and flow cytometry assessments were also performed. CBA recipients of a B6 graft exposed to opera and classical music had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively), whereas those exposed to 6 single sound frequencies and New Age did not (MSTs, 7, 8, 9, 8, 8, 8, and 11 days, respectively). Untreated and eardrum-ruptured CBA rejected B6 grafts acutely (MSTs, 7 and 8.5 days, respectively). Adoptive transfer of whole splenocytes, CD4(+) cells, and CD4(+)CD25(+) cells from opera-exposed primary recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and >50 days, respectively). Cell-proliferation, interleukin (IL)-2 and interferon-γ were suppressed in opera-exposed mice, whereas IL-4 and IL-10 from opera-exposed recipients were up-regulated. Flow cytometry studies showed an increased CD4(+)CD25(+)Foxp3(+) cell population in splenocytes from opera-exposed mice. In conclusion, exposure to some types of music may induce prolonged survival of fully allogeneic cardiac allografts and generate CD4(+)CD25(+)Foxp3(+) regulatory cells. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. A comparison of the effects of fish oil and flaxseed oil on cardiac allograft chronic rejection in rats.

    Science.gov (United States)

    Othman, Rgia A; Suh, Miyoung; Fischer, Gabor; Azordegan, Nazila; Riediger, Natalie; Le, Khuong; Jassal, Davinder S; Moghadasian, Mohammed H

    2008-03-01

    Both fish and flaxseed oils are major sources of different n-3 fatty acids. Beneficial effects of fish oil on posttransplantation complications have been reported. The current study aimed to compare the effects of flaxseed and fish oils in a rat cardiac allograft model. Male Fischer and Lewis rats were used as donors and recipients, respectively, to generate a heterotopic cardiac allograft model. Animals were randomly assigned into three groups and fed a diet supplemented with 1) 5% (wt/wt) safflower oil (control, n = 7), 2) 5% (wt/wt) flaxseed oil (n = 8), or 3) 2% (wt/wt) fish oil (n = 7), and an intraperitoneal injection of cyclosporine A (CsA; 1.5 mg.kg(-1).day(-1)) over 12 wk. Body weight, blood pressure, plasma levels of lipids, CsA, select cytokines, as well as graft function and chronic rejection features were assessed. Body weight and blood CsA levels were similar among the groups. Relative to controls, both treated groups had lower systolic and diastolic blood pressure and plasma levels of macrophage chemotactic protein-1. Treatment with fish oil significantly (P transplantation; however, neither of the oils was able to statistically significantly impact chronic rejection or histological evidence of apparent cyclosporine-induced nephrotoxicity in this model.

  2. Early inflammatory markers are independent predictors of cardiac allograft vasculopathy in heart-transplant recipients.

    Science.gov (United States)

    Labarrere, Carlos A; Woods, John R; Hardin, James W; Jaeger, Beate R; Zembala, Marian; Deng, Mario C; Kassab, Ghassan S

    2014-01-01

    Identification of risk is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure due to CAV (GFDCAV) in heart transplant patients, which account for 30% of all deaths. Early CAV detection involves invasive, risky, and expensive monitoring approaches. We determined whether prediction of CAV and GFDCAV improves by adding inflammatory markers to a previously validated atherothrombotic (AT) model. AT and inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) were measured in heart biopsies and sera of 172 patients followed prospectively for 8.9±5.0 years. Models were estimated for 5- and 10-year risk using (1) the first post-transplant biopsy only, or (2) all biopsies obtained within 3 months. Multivariate models were adjusted for other covariates and cross-validated by bootstrapping. After adding IL-6 and CRP to the AT models, we evaluated the significance of odds ratios (ORs) associated with the additional inflammatory variables and the degree of improvement in the area under the receiver operating characteristic curve (AUROC). When inflammatory markers were tested alone in prediction models, CRP (not IL-6) was a significant predictor of CAV and GFDCAV at 5 (CAV: p<0.0001; GFDCAV: p = 0.005) and 10 years (CAV: p<0.0001; GFDCAV: p = 0.003). Adding CRP (not IL-6) to the best AT models improved discriminatory power to identify patients destined to develop CAV (using 1st biopsy: p<0.001 and p = 0.001; using all 3-month biopsies: p<0.04 and p = 0.008 at 5- and 10-years, respectively) and GFDCAV (using 1st biopsy: 0.92 vs. 0.95 and 0.86 vs. 0.89; using all 3-month biopsies: 0.94 vs. 0.96 and 0.88 vs. 0.89 at 5- and 10-years, respectively), as indicated by an increase in AUROC. Early inflammatory status, measured by a patient's CRP level (a non-invasive, safe and inexpensive test), independently predicts CAV and GFDCAV. Adding CRP to a previously established AT model improves its predictive power.

  3. Early inflammatory markers are independent predictors of cardiac allograft vasculopathy in heart-transplant recipients.

    Directory of Open Access Journals (Sweden)

    Carlos A Labarrere

    Full Text Available BACKGROUND: Identification of risk is essential to prevent cardiac allograft vasculopathy (CAV and graft failure due to CAV (GFDCAV in heart transplant patients, which account for 30% of all deaths. Early CAV detection involves invasive, risky, and expensive monitoring approaches. We determined whether prediction of CAV and GFDCAV improves by adding inflammatory markers to a previously validated atherothrombotic (AT model. METHODS AND FINDINGS: AT and inflammatory markers interleukin-6 (IL-6 and C-reactive protein (CRP were measured in heart biopsies and sera of 172 patients followed prospectively for 8.9±5.0 years. Models were estimated for 5- and 10-year risk using (1 the first post-transplant biopsy only, or (2 all biopsies obtained within 3 months. Multivariate models were adjusted for other covariates and cross-validated by bootstrapping. After adding IL-6 and CRP to the AT models, we evaluated the significance of odds ratios (ORs associated with the additional inflammatory variables and the degree of improvement in the area under the receiver operating characteristic curve (AUROC. When inflammatory markers were tested alone in prediction models, CRP (not IL-6 was a significant predictor of CAV and GFDCAV at 5 (CAV: p<0.0001; GFDCAV: p = 0.005 and 10 years (CAV: p<0.0001; GFDCAV: p = 0.003. Adding CRP (not IL-6 to the best AT models improved discriminatory power to identify patients destined to develop CAV (using 1st biopsy: p<0.001 and p = 0.001; using all 3-month biopsies: p<0.04 and p = 0.008 at 5- and 10-years, respectively and GFDCAV (using 1st biopsy: 0.92 vs. 0.95 and 0.86 vs. 0.89; using all 3-month biopsies: 0.94 vs. 0.96 and 0.88 vs. 0.89 at 5- and 10-years, respectively, as indicated by an increase in AUROC. CONCLUSIONS: Early inflammatory status, measured by a patient's CRP level (a non-invasive, safe and inexpensive test, independently predicts CAV and GFDCAV. Adding CRP to a previously established AT model

  4. Overexpression of microRNA-99a Attenuates Cardiac Hypertrophy

    Science.gov (United States)

    Li, Ran; Bai, Jian; Ding, Liang; Gu, Rong; Wang, Lian; Xu, Biao

    2016-01-01

    Pathological cardiomyocyte hypertrophy is associated with significantly increased risk of heart failure, one of the leading medical causes of mortality worldwide. MicroRNAs are known to be involved in pathological cardiac remodeling. However, whether miR-99a participates in the signaling cascade leading to cardiac hypertrophy is unknown. To evaluate the role of miR-99a in cardiac hypertrophy, we assessed the expression of miR-99a in hypertrophic cardiomyocytes induced by isoprenaline (ISO)/angiotensin-II (Ang II) and in mice model of cardiac hypertrophy induced by transverse aortic constriction (TAC). Expression of miR-99a was evaluated in these hypertrophic cells and hearts. We also found that miR-99a expression was highly correlated with cardiac function of mice with heart failure (8 weeks after TAC surgery). Overexpression of miR-99a attenuated cardiac hypertrophy in TAC mice and cellular hypertrophy in stimuli treated cardiomyocytes through down-regulation of expression of mammalian target of rapamycin (mTOR). These results indicate that miR-99a negatively regulates physiological hypertrophy through mTOR signaling pathway, which may provide a new therapeutic approach for pressure-overload heart failure. PMID:26914935

  5. Overexpression of microRNA-99a Attenuates Cardiac Hypertrophy.

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    Li, Qiaoling; Xie, Jun; Wang, Bingjian; Li, Ran; Bai, Jian; Ding, Liang; Gu, Rong; Wang, Lian; Xu, Biao

    2016-01-01

    Pathological cardiomyocyte hypertrophy is associated with significantly increased risk of heart failure, one of the leading medical causes of mortality worldwide. MicroRNAs are known to be involved in pathological cardiac remodeling. However, whether miR-99a participates in the signaling cascade leading to cardiac hypertrophy is unknown. To evaluate the role of miR-99a in cardiac hypertrophy, we assessed the expression of miR-99a in hypertrophic cardiomyocytes induced by isoprenaline (ISO)/angiotensin-II (Ang II) and in mice model of cardiac hypertrophy induced by transverse aortic constriction (TAC). Expression of miR-99a was evaluated in these hypertrophic cells and hearts. We also found that miR-99a expression was highly correlated with cardiac function of mice with heart failure (8 weeks after TAC surgery). Overexpression of miR-99a attenuated cardiac hypertrophy in TAC mice and cellular hypertrophy in stimuli treated cardiomyocytes through down-regulation of expression of mammalian target of rapamycin (mTOR). These results indicate that miR-99a negatively regulates physiological hypertrophy through mTOR signaling pathway, which may provide a new therapeutic approach for pressure-overload heart failure.

  6. AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress.

    Science.gov (United States)

    Ma, Yuedong; Huang, Huiling; Jiang, Jingzhou; Wu, Lingling; Lin, Chunxi; Tang, Anli; Dai, Gang; He, Jiangui; Chen, Yili

    2016-06-10

    AVE 0991, the nonpeptide angiotensin-(1-7) (Ang-(1-7)) analog, is recognized as having beneficial cardiovascular effects. However, the mechanisms have not been fully elucidated. This study was designed to investigate the effects of AVE 0991 on cardiac hypertrophy and the mechanisms involved. Mice were underwent aortic banding to induce cardiac hypertrophy followed by the administration of AVE 0991 (20 mg kg·day (-1)) for 4 weeks. It was shown that AVE 0991 reduced left ventricular hypertrophy and improved heart function, characterized by decreases in left ventricular weight and left ventricular end-diastolic diameter, and increases in ejection fraction. Moreover, AVE 0991 significantly down-regulated mean myocyte diameter and attenuate the gene expression of the hypertrophic markers. Furthermore, AVE 0991 inhibited the expression of NOX 2 and NOX 4, meaning that AVE 0991 reduced oxidative stress of cardiac hypertrophy mice. Our data showed that AVE 0991 treatment could attenuate cardiac hypertrophy and improve heart function, which may be due to reduce oxidative stress. Copyright © 2016. Published by Elsevier Inc.

  7. Anti-MHC Class I Antibody Activation of Proliferation and Survival Signaling in Murine Cardiac Allografts1

    Science.gov (United States)

    Jindra, Peter T.; Hsueh, Aileen; Hong, Longshen; Gjertson, David; Shen, Xiu-Da; Gao, Feng; Dang, Julie; Mischel, Paul S.; Baldwin, William M.; Fishbein, Michael C.; Kupiec-Weglinski, Jerzy W.; Reed, Elaine F.

    2013-01-01

    Anti-MHC class I alloantibodies have been implicated in the process of acute and chronic rejection because these Abs can bind to endothelial cells and transduce signals leading to the activation of cell survival and proliferation pathways. To characterize the role of the MHC class I-signaling pathway in the pathogenesis of Ab-mediated rejection, we developed a mouse vascularized heterotopic cardiac allograft model in which B6.RAG1 KO hosts (H-2Kb/Db) received a fully MHC-incompatible BALB/c (H-2Kd/Dd) heart transplant and were passively transfused with anti-donor MHC class I Ab. We demonstrate that cardiac allografts of mice treated with anti-MHC class I Abs show characteristic features of Ab-mediated rejection including microvascular changes accompanied by C4d deposition. Phosphoproteomic analysis of signaling molecules involved in the MHC class I cell proliferation and survival pathways were elevated in anti-class I-treated mice compared with the isotype control-treated group. Pairwise correlations, hierarchical clustering, and multidimensional scaling algorithms were used to dissect the class I-signaling pathway in vivo. Treatment with anti-H-2Kd Ab was highly correlated with the activation of Akt and p70S6Kinase (S6K). When measuring distance as a marker of interrelatedness, multidimensional scaling analysis revealed a close association between members of the mammalian target of rapamycin pathway including mammalian target of rapamycin, S6K, and S6 ribosomal protein. These results provide the first analysis of the interrelationships between these signaling molecules in vivo that reflects our knowledge of the signaling pathway derived from in vitro experiments. PMID:18250428

  8. CXCR4 Antagonism Attenuates the Development of Diabetic Cardiac Fibrosis.

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    Po-Yin Chu

    Full Text Available Heart failure (HF is an increasingly recognized complication of diabetes. Cardiac fibrosis is an important causative mechanism of HF associated with diabetes. Recent data indicate that inflammation may be particularly important in the pathogenesis of cardiovascular fibrosis. We sought to determine the mechanism by which cardiac fibrosis develops and to specifically investigate the role of the CXCR4 axis in this process. Animals with type I diabetes (streptozotocin treated mice or type II diabetes (Israeli Sand-rats and controls were randomized to treatment with a CXCR4 antagonist, candesartan or vehicle control. Additional groups of mice also underwent bone marrow transplantation (GFP+ donor marrow to investigate the potential role of bone marrow derived cell mobilization in the pathogenesis of cardiac fibrosis. Both type I and II models of diabetes were accompanied by the development of significant cardiac fibrosis. CXCR4 antagonism markedly reduced cardiac fibrosis in both models of diabetes, similar in magnitude to that seen with candesartan. In contrast to candesartan, the anti-fibrotic actions of CXCR4 antagonism occurred in a blood pressure independent manner. Whilst the induction of diabetes did not increase the overall myocardial burden of GFP+ cells, it was accompanied by an increase in GFP+ cells expressing the fibroblast marker alpha-smooth muscle actin and this was attenuated by CXCR4 antagonism. CXCR4 antagonism was also accompanied by increased levels of circulating regulatory T cells. Taken together the current data indicate that pharmacological inhibition of CXCR4 significantly reduces diabetes induced cardiac fibrosis, providing a potentially important therapeutic approach.

  9. Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure.

    Science.gov (United States)

    Wang, Han-Jun; Wang, Wei; Cornish, Kurtis G; Rozanski, George J; Zucker, Irving H

    2014-10-01

    The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympathoexcitation in chronic heart failure (CHF). Increased sympathoexcitation is positively related to mortality in patients with CHF. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here, we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. To delete the transient receptor potential vanilloid 1 receptor-expressing CSAR afferents selectively, epicardial application of resiniferatoxin (50 μg/mL), an ultrapotent analog of capsaicin, was performed during myocardium infarction surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of resiniferatoxin largely prevented the elevated left ventricle end-diastolic pressure, lung edema, and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart, and increased cardiac contractile reserve in response to β-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that resiniferatoxin attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and transforming growth factor-β receptor I in CHF rats. Pressure-volume loop analysis showed that resiniferatoxin reduced the end-diastolic pressure volume relationships in CHF rats, indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF. © 2014 American Heart Association, Inc.

  10. Biliverdin, a natural product of heme catabolism, induces tolerance to cardiac allografts.

    Science.gov (United States)

    Yamashita, Kenichiro; McDaid, James; Ollinger, Robert; Tsui, Tung-Yu; Berberat, Pascal O; Usheva, Anny; Csizmadia, Eva; Smith, R Neal; Soares, Miguel P; Bach, Fritz H

    2004-04-01

    Biliverdin, a product of heme oxygenase-1 (HO-1) enzymatic action, is converted into bilirubin, which has been considered a waste product in the past. We now show that administration of biliverdin has a salutary effect in organ transplantation. A brief course of treatment with biliverdin leads to long-term survival of H-2 incompatible heart allografts. Furthermore, those recipients harboring long-surviving (>100 days) allografts were tolerant to donor antigens indicated by the acceptance of second donor strain hearts but not third-party grafts. Treatment with biliverdin decreased intragraft leukocyte infiltration and inhibited T cell proliferation. Likely related to tolerance induction, biliverdin interferes with T cell signaling by inhibiting activation of nuclear factor of activated T cells (NFAT) and nuclear factor kappaB (NF-kappaB), two transcription factors involved in interleukin-2 (IL-2) transcription and T cell proliferation, as well as suppressing Th1 interferon-gamma (IFN-gamma) production in vitro. These findings support the potential use of biliverdin, a natural product, in transplantation and other T cell mediated immune disorders.

  11. Morphological observations in the epicardial coronary arteries and their surroundings late after cardiac transplantation (allograft vascular disease)

    Science.gov (United States)

    Arbustini, E; Roberts, W C

    1996-10-01

    Conclusions from this review, based primarily on study of 39 cardiac allografts in place for >2 months, but also on a study of 37 grafts in place for epicardial coronary arteries and usually the intramural coronary arteries in the outer one-half of the left ventricular wall; (2) the resulting intimal lesion is relatively uniform, consisting mainly of cellular and acellular fibrous tissue; it is diffuse, affecting all segments of the major and minor epicardial coronary arteries; (3) the degree of resulting luminal narrowing is similar in most 5-mm coronary segments, making coronary angiography hazardous in reliably predicting accurately the degree of luminal narrowing; (4) the extensive adventitial fibrosis and the extensive fibrous tissue infiltration of the subepicardial tissues probably inhibit dilation and remodeling of the epicardial coronary arteries and indeed may constrict them; (5) luminal narrowing of the epicardial coronary arteries after transplantation may be the consequence of both intraluminal lesions and exterior compression from the surrounding fibrous tissue; (6) intraluminal and intralesion thrombus is commonly observed as are multiluminal channels in coronary plaques, suggesting that organization of thrombi plays some role in the progression of post-transplant epicardial coronary disease; (7) the coronary lesions developing after cardiac transplantation are morphologically quite different in composition than those occurring in natural (nontransplantation) atherosclerosis; and (8) inflammatory cellular infiltrates are often extensive in the subepicardial tissues and the infiltrates in this area may be extensive even when interstitial myocardial inflammatory infiltrates are minimal or absent.

  12. Retransplant and Medical Therapy for Cardiac Allograft Vasculopathy: International Society for Heart and Lung Transplantation Registry Analysis.

    Science.gov (United States)

    Goldraich, L A; Stehlik, J; Kucheryavaya, A Y; Edwards, L B; Ross, H J

    2016-01-01

    Cardiac retransplantation for heart transplant recipients with advanced cardiac allograft vasculopathy (CAV) remains controversial. The International Society for Heart and Lung Transplantation Registry was used to examine survival in adult heart recipients with CAV who were retransplanted (ReTx) or managed medically (MM). Recipients transplanted between 1995 and 2010 who developed CAV and were either retransplanted within 2 years of CAV diagnosis (ReTx) or alive at ≥2 years after CAV diagnosis, managed medically (MM), without retransplant, constituted the study groups. Donor, recipient, transplant characteristics and long-term survival were compared. The population included 65 patients in ReTx and 4530 in MM. During a median follow-up of 4 years, there were 24 deaths in ReTx, and 1466 in MM. Survival was comparable at 9 years (55% in ReTx and 51% in MM; p = 0.88). Subgroup comparison suggested survival benefit for retransplant versus MM in patients who developed systolic graft dysfunction. Adjusted predictors for 2-year mortality were diagnosis of CAV in the early era and longer time since CAV diagnosis following primary transplant. Retransplant was not an independent predictor in the model. Challenges associated with retransplantation as well as improved CAV treatment options support the current consensus recommendation limiting retransplant to highly selected patients with CAV. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  13. Cyclosporine mitigates graft coronary artery disease in murine cardiac allografts: description and validation of a novel fully allogeneic model.

    Science.gov (United States)

    Tanaka, Masashi; Mokhtari, Golnaz K; Balsam, Leora B; Cooke, David T; Kofidis, Theo; Zwierzchonievska, Monika; Robbins, Robert C

    2005-04-01

    The effect of cyclosporine (CsA) on the development of graft coronary artery disease (GCAD) is controversial. We developed a novel allogeneic mouse model of heart transplantation and investigated the effect of CsA on acute rejection and GCAD. Hearts of FVB mice (H-2(q)) were heterotopically transplanted into 60 C57BL/6 mice (H-2(b)). CsA was administered to recipients at 10, 20 or 30 mg/kg/day for 10 or 30 days after transplantation. Untreated recipients as well as isograft recipients served as controls. Viability of the grafts was assessed daily by palpation. Parenchymal rejection was scored in grafts surviving 30 days in the 30-day treatment groups. GCAD was evaluated by the percentage of luminal narrowing, intima/media ratio and percentage of diseased vessels. Blood CsA and creatinine levels were also evaluated. Results were evaluated statistically. All groups except the untreated control group and the allograft groups treated with 10 or 20 mg for 10 days showed significant graft survival (>/=33% survival for 30 days). An inverse correlation was observed between CsA treatment dose, parenchymal rejection score and degree of GCAD in the 30-day treatment groups. However, graft survival in the 20-mg/kg/day group was significantly better than that in the 30-mg/kg/day group. Serum creatine levels showed no nephrotoxicity. Relatively high-dose CsA mitigated parenchymal rejection and GCAD of the mouse cardiac allografts. In addition, a valuable mouse model mimicking the clinical course of GCAD was achieved with CsA treatment of 20 mg/kg/day for 30 days.

  14. LF 15-0195, a novel immunosuppressive agent prevents rejection and induces operational tolerance in a mouse cardiac allograft model.

    Science.gov (United States)

    Zhou, Dejun; O'Brien, Catherine; Shum, Jeffrey; Garcia, Bertha; Min, Weiping; Jevnikar, Anthony M; Dutartre, Patrick; Zhong, Robert

    2003-08-27

    LF 15-0195 (LF) is a new analogue of 15-deoxyspergualin (DSG) that is less toxic and more potent than DSG. The present study was undertaken to determine (1). the dose response of LF monotherapy, (2). its ability to induce tolerance, and (3) its interaction with cyclosporine (CsA), FK 506 (FK), and rapamycin (RAPA). Varying doses of LF were administered to determine dose-dependent effects on graft survival in a C57BL/6 to BALB/c heterotopic heart allograft mouse model. Transplanting-donor and third-party skin grafts into long-term survivors were used to assess the tolerance status. CsA, FK, and RAPA were combined with LF to determine their interactive effects on graft survival. The efficacy and toxicity of LF was dose dependent. High-dose LF monotherapy (>2 mg/kg) induced donor-specific operational tolerance, but it was associated with high mortality. Simultaneous administration of high-dose calcineurin inhibitors (CsA FK) prevented tolerance induced by LF. In contrast, a short course of LF combined with a subtherapeutic dose of CsA FK achieved indefinite survival of C57/BL6 cardiac allografts. RAPA and LF had a synergistic effect in induction of tolerance. The efficacy and toxicity of LF were dose dependent. A short course of LF significantly reduced the requirement of CsA or FK to prevent rejection. RAPA and LF had synergy in induction of tolerance. These data indicate that LF may be a promising agent that warrants further studies in nonhuman primate models of transplantation.

  15. Evolution in functional complexity of heart rate dynamics: a measure of cardiac allograft adaptability.

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    Kresh, J Y; Izrailtyan, I

    1998-09-01

    The capacity of self-organized systems to adapt is embodied in the functional organization of intrinsic control mechanisms. Evolution in functional complexity of heart rate variability (HRV) was used as measure of the capacity of the transplanted heart to express newly emergent regulatory order. In a cross-sectional study of 100 patients after (0-10 yr) heart transplantation (HTX), heart rate dynamics were assessed using pointwise correlation dimension (PD2) analysis. A new observation is that, commencing with the acute event of allograft transplantation, the dynamics of rhythm formation proceed through complex phase transitions. At implantation, the donor heart manifested metronome-like chronotropic behavior (PD2 approximately 1.0). At 11-100 days, dimensional complexity of HRV reached a peak (PD2 approximately 2.0) associated with resurgence in the high-frequency component (0.15-0.5 Hz) of the power spectral density. Subsequent dimensional loss to PD2 approximately 1.0 at 20-30 mo after HTX was followed by a progressive near-linear gain in system complexity, reaching PD2 approximately 3.0 7-10 yr after HTX. The "dynamic reorganization" in the allograft rhythm-generating system, seen in the first 100 days, is a manifestation of the adaptive capacity of intrinsic control mechanisms. The loss of HRV 2 yr after HTX implies a withdrawal of intrinsic autonomic control and/or development of an entrained dynamic pattern characteristic of extrinsic sympathetic input. The subsequent long-term progressive rise in dimensional complexity of HRV can be attributed to the restoration of a functional order patterning parasympathetic control. The recognition that the decentralized heart can restitute the multidimensional state space of HR generator dynamics independent of external autonomic signaling may provide a new perspective on principles that constitute homeodynamic regulation.

  16. Analysis of transforming growth factor-beta and profibrogenic molecules in a rat cardiac allograft model treated with cyclosporine.

    Science.gov (United States)

    Khanna, Ashwani K; Hosenpud, Jessica S; Plummer, Matthew S; Hosenpud, Jeffrey D

    2002-05-27

    Long-term treatment of heart transplantation recipients with cyclosporine (CsA) results in chronic nephrotoxic effects, which frequently lead to progressive renal failure. Transforming growth factor (TGF)-beta and other fibrogenic molecules are leading candidates for these effects, because CsA is known to induce TGF-beta. In this study we compared the expression of TGF-beta, collagen, fibronectin, metalloproteinases, and tissue inhibitors of metalloproteinases in kidneys from recipients of heterotopic heart transplants treated with CsA for 30 and 180 days. Using a clinically relevant experimental rodent model (strain combination Wistar Furth [RT1u] into Lewis [RT1l]), heterotopic heart transplantation was performed, creating disparate cardiac allografts. The transplant study population was divided into three groups: controls and those receiving CsA immunosuppression therapy to maintain graft survival for 30-day and 180-day periods. Comparisons were made of intrarenal expression of TGF-beta, collagen, fibronectin, metalloproteinase-2 (MMP-2), MMP-9, and tissue inhibitor of MMP-2, using reverse transcriptase-polymerase chain reaction. Intrarenal expression of TGF-beta protein was also compared using immunochemical staining technique, and circulating levels of TGF-beta protein were quantified by ELISA. Intrarenal expression of TGF-beta, collagen, fibronectin, MMP-2, MMP-9, and tissue inhibitor of MMP-2 was significantly increased in rats treated with CsA for 180 days compared with untreated rats and those treated for 30 days. Circulating levels and intrarenal expression of TGF-beta were also significantly increased in rats treated for 180 days. Posttransplantation nephrotoxicity in cardiac transplant recipients treated with CsA for a long term is related to increased expression of TGF-beta and other fibrogenic genes. Therapies designed to inhibit expression of TGF-beta could ameliorate CsA-associated nephrotoxicity in cardiac transplant recipients.

  17. Auditory stimulation of opera music induced prolongation of murine cardiac allograft survival and maintained generation of regulatory CD4+CD25+ cells

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    Uchiyama Masateru

    2012-03-01

    Full Text Available Abstract Background Interactions between the immune response and brain functions such as olfactory, auditory, and visual sensations are likely. This study investigated the effect of sounds on alloimmune responses in a murine model of cardiac allograft transplantation. Methods Naïve CBA mice (H2k underwent transplantation of a C57BL/6 (B6, H2b heart and were exposed to one of three types of music--opera (La Traviata, classical (Mozart, and New Age (Enya--or one of six different single sound frequencies, for 7 days. Additionally, we prepared two groups of CBA recipients with tympanic membrane perforation exposed to opera for 7 days and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment. An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Immunohistochemical, cell-proliferation, cytokine, and flow cytometry assessments were also performed. Results CBA recipients of a B6 cardiac graft that were exposed to opera music and Mozart had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively, whereas those exposed to a single sound frequency (100, 500, 1000, 5000, 10,000, or 20,000 Hz or Enya did not (MSTs, 7.5, 8, 9, 8, 7.5, 8.5 and 11 days, respectively. Untreated, CBA mice with tympanic membrane perforations and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment rejected B6 cardiac grafts acutely (MSTs, 7, 8 and 8 days, respectively. Adoptive transfer of whole splenocytes, CD4+ cells, or CD4+CD25+ cells from opera-exposed primary allograft recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and > 100 days, respectively. Proliferation of splenocytes, interleukin (IL-2 and interferon (IFN-γ production was suppressed in opera-exposed mice, and production of IL-4 and IL-10 from opera-exposed transplant recipients increased

  18. Auditory stimulation of opera music induced prolongation of murine cardiac allograft survival and maintained generation of regulatory CD4+CD25+ cells

    Science.gov (United States)

    2012-01-01

    Background Interactions between the immune response and brain functions such as olfactory, auditory, and visual sensations are likely. This study investigated the effect of sounds on alloimmune responses in a murine model of cardiac allograft transplantation. Methods Naïve CBA mice (H2k) underwent transplantation of a C57BL/6 (B6, H2b) heart and were exposed to one of three types of music--opera (La Traviata), classical (Mozart), and New Age (Enya)--or one of six different single sound frequencies, for 7 days. Additionally, we prepared two groups of CBA recipients with tympanic membrane perforation exposed to opera for 7 days and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment). An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Immunohistochemical, cell-proliferation, cytokine, and flow cytometry assessments were also performed. Results CBA recipients of a B6 cardiac graft that were exposed to opera music and Mozart had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively), whereas those exposed to a single sound frequency (100, 500, 1000, 5000, 10,000, or 20,000 Hz) or Enya did not (MSTs, 7.5, 8, 9, 8, 7.5, 8.5 and 11 days, respectively). Untreated, CBA mice with tympanic membrane perforations and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment) rejected B6 cardiac grafts acutely (MSTs, 7, 8 and 8 days, respectively). Adoptive transfer of whole splenocytes, CD4+ cells, or CD4+CD25+ cells from opera-exposed primary allograft recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and > 100 days, respectively). Proliferation of splenocytes, interleukin (IL)-2 and interferon (IFN)-γ production was suppressed in opera-exposed mice, and production of IL-4 and IL-10 from opera-exposed transplant recipients increased compared to

  19. Auditory stimulation of opera music induced prolongation of murine cardiac allograft survival and maintained generation of regulatory CD4+CD25+ cells.

    Science.gov (United States)

    Uchiyama, Masateru; Jin, Xiangyuan; Zhang, Qi; Hirai, Toshihito; Amano, Atsushi; Bashuda, Hisashi; Niimi, Masanori

    2012-03-23

    Interactions between the immune response and brain functions such as olfactory, auditory, and visual sensations are likely. This study investigated the effect of sounds on alloimmune responses in a murine model of cardiac allograft transplantation. Naïve CBA mice (H2k) underwent transplantation of a C57BL/6 (B6, H2b) heart and were exposed to one of three types of music--opera (La Traviata), classical (Mozart), and New Age (Enya)--or one of six different single sound frequencies, for 7 days. Additionally, we prepared two groups of CBA recipients with tympanic membrane perforation exposed to opera for 7 days and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment). An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Immunohistochemical, cell-proliferation, cytokine, and flow cytometry assessments were also performed. CBA recipients of a B6 cardiac graft that were exposed to opera music and Mozart had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively), whereas those exposed to a single sound frequency (100, 500, 1000, 5000, 10,000, or 20,000 Hz) or Enya did not (MSTs, 7.5, 8, 9, 8, 7.5, 8.5 and 11 days, respectively). Untreated, CBA mice with tympanic membrane perforations and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment) rejected B6 cardiac grafts acutely (MSTs, 7, 8 and 8 days, respectively). Adoptive transfer of whole splenocytes, CD4+ cells, or CD4+CD25+ cells from opera-exposed primary allograft recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and > 100 days, respectively). Proliferation of splenocytes, interleukin (IL)-2 and interferon (IFN)-γ production was suppressed in opera-exposed mice, and production of IL-4 and IL-10 from opera-exposed transplant recipients increased compared to that from splenocytes of

  20. Cardiac allograft vasculopathy by intravascular ultrasound in heart transplant patients: substudy from the Everolimus versus mycophenolate mofetil randomized, multicenter trial.

    Science.gov (United States)

    Kobashigawa, Jon A; Pauly, Daniel F; Starling, Randall C; Eisen, Howard; Ross, Heather; Wang, Shoei-Shen; Cantin, Bernard; Hill, James A; Lopez, Patricia; Dong, Gaohong; Nicholls, Stephen J

    2013-10-01

    A pre-planned substudy of a larger multicenter randomized trial was undertaken to compare the efficacy of everolimus with reduced-dose cyclosporine in the prevention of cardiac allograft vasculopathy (CAV) after heart transplantation to that of mycophenolate mofetil (MMF) with standard-dose cyclosporine. CAV is a major cause of long-term mortality following heart transplantation. Everolimus has been shown to reduce the severity and incidence of CAV as measured by first year intravascular ultrasound (IVUS). MMF, in combination with cyclosporine, has also been shown to have a beneficial effect in slowing the progression of CAV. Study patients were a pre-specified subgroup of the 553-patient Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial who underwent heart transplantation and were randomized to everolimus 1.5 mg or MMF 3 g/day. IVUS was performed at baseline and at 12 months. Evaluable IVUS data were available in 189 patients (34.6%). Increase in average maximal intimal thickness (MIT) from baseline to month 12 was significantly smaller in the everolimus 1.5 mg group compared with the MMF group (0.03 mm vs. 0.07 mm, p transplant recipients after 1 year, a finding, which was maintained in a range of patient subpopulations. CV surgery: transplantation, ventricular assistance, cardiomyopathy. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  1. Effect of ultraviolet-B-irradiated donor-specific blood transfusions and peritransplant immunosuppression with cyclosporine on rat cardiac allograft survival

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    Oluwole, S.F.; Lau, H.T.; Reemtsma, K.; Hardy, M.A.

    1988-02-01

    We have previously demonstrated that pretreatment of ACI recipients with ultraviolet-irradiated donor-specific blood transfusion (UV-DST) leads to permanent cardiac allograft survival without further host immunosuppression (ACI rats are weak responders to Lewis lymphocytes in mixed-lymphocyte reaction). This study examines the effect of UV-DST and the timing of transfusions on ACI cardiac allograft survival in Lewis recipients with and without the addition of peritransplant cyclosporine (CsA) (20 mg/kg i.m.) given on days 0, +1, and +2 in relation to the time of transplantation. The mean survival time (MST) of ACI cardiac allografts in Lewis recipients was significantly increased to 33.6 +/- 5.7 days (P less than 0.001) by CsA treatment alone as compared to 6.5 +/- 0.5 days survival in control. When DST was given on day -3 combined with CsA, graft survival was increased to 42.0 +/- 9.3 days (P less than 0.01), as compared to 5.8 +/- 1.3 days when DST alone was used. When DST was irradiated with ultraviolet B (UV-DST) and administered on day -3 combined with peritransplant CsA, the MST was increased to 68.83 +/- 16.1 days as compared to an MST of 10.0 +/- 1.0 days in controls treated with UV-DST alone. When UV-DST was given on day -7 and combined with peritransplant CsA immunosuppression, the results were similar. However, when UV-DST was peritransplant CsA course, 4 of 6 recipients maintained their ACI heart allografts indefinitely (greater than 300 days) in contrast to the effect of UV-DST alone (MST of 13.5 days). Third-party (W/F) UV-irradiated blood transfusions were ineffective in prolonging ACI cardiac allografts in Lewis rats, regardless of whether the transfusions were given alone or in combination with peritransplant immunosuppression with CsA.

  2. Adenovirus-mediated overexpression of glutathione-s-transferase mitigates transplant arteriosclerosis in rabbit carotid allografts.

    Science.gov (United States)

    Xu, Ya; Gong, Bin; Yang, Yongzhen; Awasthi, Yogesh C; Boor, Paul J

    2010-02-27

    Cardiac transplant arteriosclerosis or cardiac allograft vasculopathy remains the leading cause of graft failure and patient death in heart transplant recipients. Endothelial cell injury is crucial in the development of human atherosclerosis and may play a role in allograft vasculopathy. Glutathione-S-transferase (GST) is known to protect endothelial cells from damage by oxidants and toxins. However, the contribution of human GST A4-4 (hGSTA4-4) to vascular cell injury and consequent transplant arteriosclerosis is unknown. A recombinant adenoviral vector containing hGSTA4-4 gene was constructed and delivered to vascular endothelial cells in an in vivo rabbit carotid artery transplant model. Forty-five days after transplantation, allografts were harvested (n=28). Blood flow was measured by ultrasonography. In addition, grafts were analyzed by histology, morphometry, immunostaining, and western blot. The severity of arteriosclerosis in hGSTA4-4 transduced allografts was compared with control by measuring degree of stenosis by neointima. Decrease in blood flow in hGSTA4-4 transduced allografts was significantly less than control allografts, which also developed greater intimal thickening and stenosis than hGSTA4-4 transduced allografts in the proximal and distal regions of the graft. Leukocyte and macrophage infiltration was reduced in hGSTA4-4 transduced carotid arteries. Our data indicate that hGSTA4-4 overexpression protects the integrity of vessel wall from oxidative injury, and attenuates transplant arteriosclerosis.

  3. Suppression of acute and chronic cardiac allograft rejection in mice by inhibition of chemokine receptor 5 in combination with cyclosporine A.

    Science.gov (United States)

    Li, Jun; Xia, Jiahong; Zhang, Kailun; Xu, Lei

    2009-11-01

    Inhibition of chemokine receptor 5 (CCR5), a chemokine receptor expressed on activated T cells, is an effective antiviral therapy in patients with HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this study we examined the inhibition of CCR5 in combination with the treatment with cyclosporine A in acute and chronic rejection in cardiac transplantation. Eighty fully MHC-mismatched murine cardiac allograft models were randomized to four groups. Recipients in group A were treated with anti-CCR5 mAb and CsA, mice in group B were given anti-CCR5 mAb alone, animals in group C were administered only CsA, and group D were the control group with PBS. Acute and chronic rejection was investigated on day 7 and day 45 post-transplant, respectively. Allografts treated with anti-CCR5 mAb plus CsA showed significantly prolonged survival (44.73 +/- 0.258 d, P cardiac graft failure that has not been obviated by conventional immunosuppressive agents.

  4. Noninvasive PET quantitative myocardial blood flow with regadenoson for assessing cardiac allograft vasculopathy in orthotopic heart transplantation patients.

    Science.gov (United States)

    Pampaloni, Miguel Hernandez; Shrestha, Uttam M; Sciammarella, Maria; Seo, Youngho; Gullberg, Grant T; Botvinick, Elias H

    2017-08-01

    Risk stratification and early detection of cardiac allograft vasculopathy (CAV) is essential in orthotopic heart transplantation (OHT) patients. This study assesses the changes in myocardial blood flow (MBF) noninvasively in OHT patients using quantitative cardiac PET with regadenoson. Twelve patients (Group 1) (8 males, 4 females, mean age 55 ± 7 years) with no history of post OHT myocardial ischemia were enrolled 5.4 ± 2.0 years after OHT. Fifteen patients (Group 2) (9 males, 6 females, mean age 71 ± 9 years) with intermediate pretest probability but not documented evidence for coronary artery disease (CAD) were also included to serve as control. Global and regional MBFs were assessed using dynamic 13 N-NH 3 PET at rest and during regadenoson-induced hyperemia. The coronary flow reserve (CFR) was also calculated as the ratio of hyperemic to resting MBF. Mean regadenoson-induced rate-pressure products were similar in both groups, while there was an increase in resting rate-pressure product in Group 1 patients. Both mean and median values of resting MBF were higher in Group 1 than Group 2 patients (1.33 ± 0.31 and 1.01 ± 0.21 mL/min/g for Groups 1 and 2, respectively, P < .001), while mean hyperemic MBF values were similar in both Groups (2.68 ± 0.84 and 2.64 ± 0.94 mL/min/g, P = NS) but median hyperemic MBF values were lower in Group 1 than Group 2 patients (2.0 vs. 2.60 mL/min/g, P = .018). Both mean and median CFR values demonstrated a significant reduction for Group 1 compared to Group 2 patients (2.07 ± 0.74 vs 2.63 ± 0.48, P = .025). This study suggests that the MBF in OHT patients may be abnormal at resting state with diminished CFR. This hints that the epicardial and microvascular coronary subsystem may be exacerbated after OHT leading to the gradual progression of CAV.

  5. Cardiac expression of microsomal triglyceride transfer protein is increased in obesity and serves to attenuate cardiac triglyceride accumulation.

    Directory of Open Access Journals (Sweden)

    Emil D Bartels

    Full Text Available Obesity causes lipid accumulation in the heart and may lead to lipotoxic heart disease. Traditionally, the size of the cardiac triglyceride pool is thought to reflect the balance between uptake and beta-oxidation of fatty acids. However, triglycerides can also be exported from cardiomyocytes via secretion of apolipoproteinB-containing (apoB lipoproteins. Lipoprotein formation depends on expression of microsomal triglyceride transfer protein (MTP; the mouse expresses two isoforms of MTP, A and B. Since many aspects of the link between obesity-induced cardiac disease and cardiac lipid metabolism remain unknown, we investigated how cardiac lipoprotein synthesis affects cardiac expression of triglyceride metabolism-controlling genes, insulin sensitivity, and function in obese mice. Heart-specific ablation of MTP-A in mice using Cre-loxP technology impaired upregulation of MTP expression in response to increased fatty acid availability during fasting and fat feeding. This resulted in cardiac triglyceride accumulation but unaffected cardiac insulin-stimulated glucose uptake. Long-term fat-feeding of male C57Bl/6 mice increased cardiac triglycerides, induced cardiac expression of triglyceride metabolism-controlling genes and attenuated heart function. Abolishing cardiac triglyceride accumulation in fat-fed mice by overexpression of an apoB transgene in the heart prevented the induction of triglyceride metabolism-controlling genes and improved heart function. The results suggest that in obesity, the physiological increase of cardiac MTP expression serves to attenuate cardiac triglyceride accumulation albeit without major effects on cardiac insulin sensitivity. Nevertheless, the data suggest that genetically increased lipoprotein secretion prevents development of obesity-induced lipotoxic heart disease.

  6. Cardiac Ankyrin Repeat Protein Attenuates Cardiac Hypertrophy by Inhibition of ERK1/2 and TGF-β Signaling Pathways

    Science.gov (United States)

    Jia, Chunshi; Ma, Xiaowei; Zhang, Lei; Xie, Xiaojie; Zhang, Yong; Gao, Xiang; Zhang, Youyi; Zhu, Dahai

    2012-01-01

    Aims It has been reported that cardiac ankyrin repeat protein is associated with heart development and diseases. This study is aimed to investigate the role of CARP in heart hypertrophy in vivo. Methods and Results We generated a cardiac-specific CARP-overexpressing transgenic mouse. Although such animals did not display any overt physiological abnormality, they developed less cardiac hypertrophy in response to pressure overload than did wildtype mice, as indicated by heart weight/body weight ratios, echocardiographic and histological analyses, and expression of hypertrophic markers. These mice also exhibited less cardiac hypertrophy after infusion of isoproterenol. To gain a molecular insight into how CARP attenuated heart hypertrophy, we examined expression of the mitogen-activated protein kinase cascade and found that the concentrations of phosphorylated ERK1/2 and MEK were markedly reduced in the hearts of transgenic mice subjected to pressure overload. In addition, the expressions of TGF-β and phosphorylated Smad3 were significantly downregulated in the hearts of CARP Tg mice in response to pressure overload. Furthermore, addition of human TGF-β1 could reverse the inhibitory effect of CARP on the hypertrophic response induced by phenylephrine in cardiomyocytes. It was also evidenced that the inhibitory effect of CARP on cardiac hypertrophy was not attributed to apoptosis. Conclusion CARP attenuates cardiac hypertrophy, in which the ERK and TGF-β pathways may be involved. Our findings highlight the significance of CARP as an anti-hypertrophic factor in therapy of cardiac hypertrophy. PMID:23227174

  7. Herbal supplement attenuation of cardiac fibrosis in rats with CCl₄-induced liver cirrhosis.

    Science.gov (United States)

    Chang, Hsiao-Chuan; Chiu, Yung-Wei; Lin, Yueh-Min; Chen, Ray-Jade; Lin, James A; Tsai, Fuu-Jen; Tsai, Chang-Hai; Kuo, Yu-Chun; Liu, Jer-Yuh; Huang, Chih-Yang

    2014-02-28

    Previously we found carbon tetrachloride (CCl₄) induced cirrhosis associated cardiac hypertrophy and apoptosis. The purpose of this study is to determine whether further CCl₄ treatment would induce cardiac cell fibrosis. The cardiac tissues were analyzed by H&E. histological staining, Trichrome Masson staining and Western blotting. The results showed that the CCl₄-treated-only group exhibits more trichrome staining, meaning that more fibrosis is present. Moreover, CCl₄ could further induce cardiac-fibrosis via TGF-β-p-Smad2/3-CTGF pathway. However, our data showed that the CCl₄- indcued cardiac abnormalities were attenuated by Ocimum gratissimum extract (OGE) and silymarin co- treatments. In conclusion, our results indicated that the OGE and silymarin may be a potential traditional herb for the protection of cardiac tissues from the CCl4 induced cirrhosis associated cardiac fibrosis through modulating the TGF-β signaling pathway.

  8. Apocynin Attenuates Cardiac Injury in Type 4 Cardiorenal Syndrome via Suppressing Cardiac Fibroblast Growth Factor-2 With Oxidative Stress Inhibition.

    Science.gov (United States)

    Liu, Yang; Liu, Yu; Liu, Xun; Chen, Jie; Zhang, Kun; Huang, Feifei; Wang, Jing-Feng; Tang, Wanchun; Huang, Hui

    2015-06-24

    Type 4 cardiorenal syndrome (CRS) refers to the cardiac injury induced by chronic kidney disease. We aimed to assess oxidative stress and cardiac injury in patients with type 4 CRS, determine whether the antioxidant apocynin attenuated cardiac injury in rats with type 4 CRS, and explore potential mechanisms. A cross-sectional study was conducted among patients with type 4 CRS (n=17) and controls (n=16). Compared with controls, patients with type 4 CRS showed elevated oxidative stress, which was significantly correlated with cardiac hypertrophy and decreased ejection fraction. In vivo study, male Sprague-Dawley rats underwent 5/6 subtotal nephrectomy and sham surgery, followed with apocynin or vehicle treatment for 8 weeks. Eight weeks after surgery, the 5/6 subtotal nephrectomy rats mimicked type 4 CRS, showing increased serum creatinine, cardiac hypertrophy and fibrosis, and decreased ejection fraction compared with sham-operated animals. Cardiac malondialdehyde, NADPH oxidase activity, fibroblast growth factor-2, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation increased significantly in the 5/6 subtotal nephrectomy rats. These changes were significantly attenuated by apocynin. In vitro study showed that apocynin reduced angiotensin II-induced NADPH oxidase-dependent oxidative stress, upregulation of fibroblast growth factor-2 and fibrosis biomarkers, and ERK1/2 phosphorylation in cardiac fibroblasts. Importantly, the ERK1/2 inhibitor U0126 reduced the upregulation of fibroblast growth factor-2 and fibrosis biomarkers in angiotensin II-treated fibroblasts. Oxidative stress is a candidate mediator for type 4 CRS. Apocynin attenuated cardiac injury in type 4 CRS rats via inhibiting NADPH oxidase-dependent oxidative stress-activated ERK1/2 pathway and subsequent fibroblast growth factor-2 upregulation. Our study added evidence to the beneficial effect of apocynin in type 4 CRS. © 2015 The Authors. Published on behalf of the American Heart

  9. Short-term Pharmacological Inhibition of MyD88 Homodimerization by a Novel Inhibitor Promotes Robust Allograft Tolerance in Mouse Cardiac and Skin Transplantation.

    Science.gov (United States)

    Li, Chao; Zhang, Li-Min; Zhang, Xue; Huang, Xia; Liu, Yong; Li, Ming-Qiang; Xing, Shuai; Yang, Tao; Xie, Lin; Jiang, Feng-Chao; Jiang, Han-Ying; He, Wen-Tao; Zhou, Ping

    2017-02-01

    Most strategies for antirejection and tolerance induction in clinical transplantation have focused on modifying adaptive immunity, it is unclear whether pharmacological suppressing the innate immune system can promote transplant tolerance. We inhibited innate immunity by using our self-generated inhibitor of myeloid differentiation factor 88 (MyD88), TJ-M2010-5, and investigated its therapeutic effects and mechanisms in cardiac and skin transplant models. TJ-M2010-5 directly and indirectly interacted with the Toll/IL-1R domain of MyD88, inhibiting MyD88 homodimerization. In vitro, TJ-M2010-5 inhibited maturation of dendritic cells, which suppressed nuclear translocation of NF-κB and T cell activation. In vivo, short-term (10 days) monotherapy of TJ-M2010-5 resulted in long time survival of 50% of the cardiac allografts, and longer-term (14 days) combination treatment of TJ-M2010-5 with CD154 mAb resulted in survival of 29% of skin allografts, which outperformed far more than CsA did and stimulated the proliferation of CD4CD25FoxP3 Regulatory T cells in recipient mice. Pharmacological inhibition of MyD88 signaling by this novel inhibitor TJ-M2010-5 shows a powerful anti-rejection effect, which may have therapeutic potential in clinical transplantation. The inhibition of both innate and adaptive immunity may be necessary for tolerance induction in nonsolid organs.

  10. Minocycline attenuates cardiac dysfunction in tumor-burdened mice.

    Science.gov (United States)

    Devine, Raymond D; Eichenseer, Clayton M; Wold, Loren E

    2016-11-01

    Cardiovascular dysfunction as a result of tumor burden is becoming a recognized complication; however, the mechanisms remain unknown. A murine model of cancer cachexia has shown marked increases of matrix metalloproteinases (MMPs), known mediators of cardiac remodeling, in the left ventricle. The extent to which MMPs are involved in remodeling remains obscured. To this end a common antibiotic, minocycline, with MMP inhibitory properties was used to elucidate MMP involvement in tumor induced cardiovascular dysfunction. Tumor-bearing mice showed decreased cardiac function with reduced posterior wall thickness (PWTs) during systole, increased MMP and collagen expression consistent with fibrotic remodeling. Administration of minocycline preserved cardiac function in tumor bearing mice and decreased collagen RNA expression in the left ventricle. MMP protein levels were unaffected by minocycline administration, with the exception of MMP-9, indicating minocycline inhibition mechanisms are directly affecting MMP activity. Cancer induced cardiovascular dysfunction is an increasing concern; novel therapeutics are needed to prevent cardiac complications. Minocycline is a well-known antibiotic and recently has been shown to possess MMP inhibitory properties. Our findings presented here show that minocycline could represent a novel use for a long established drug in the prevention and treatment of cancer induced cardiovascular dysfunction. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Cinnamaldehyde attenuates pressure overload-induced cardiac hypertrophy.

    Science.gov (United States)

    Yang, Liu; Wu, Qing-Qing; Liu, Yuan; Hu, Zhe-Fu; Bian, Zhou-Yan; Tang, Qi-Zhu

    2015-01-01

    Cinnamaldehyde is a major bioactive compound isolated from the leaves of Cinnamomum osmophloeum. Studies have demonstrated that cinnamaldehyde has anti-bacterial activity, anti-tumorigenic effect, immunomodulatory effect, anti-fungal activity, anti-oxidative effect, anti-inflammatory and anti-diabetic effect. It has been proven that Cinnamaldehyde improves ischemia/reperfusion injury of pre-treatment. However, little is known about the effect of cinnamaldehyde on cardiac hypertrophy. Aortic banding (AB) was performed to induce cardiac hypertrophy in mice. Cinnamaldehyde premixed in diets was administered to mice after one week of AB. Echocardiography and catheter-based measurements of hemodynamic parameters were performed at week 7 after starting cinnamaldehyde (8 weeks after surgery). The extent of cardiac hypertrophy was evaluated by pathological and molecular analyses of heart samples. Meanwhile, the effect of cinnamaldehyde on myocardial hypertrophy, fibrosis and dysfunction induced by AB was investigated, as was assessed by heart weigh/body weight, lung weight/body weight, heart weight/tibia length, echocardiographic and haemodynamic parameters, histological analysis, and gene expression of hypertrophic and fibrotic markers. Our data demonstrated that echocardiography and catheter-based measurements of hemodynamic parameters at week 7 revealed the amelioration of systolic and diastolic abnormalities by cinnamaldehyde intervention. Cardiac fibrosis in AB mice was also decreased by cinnamaldehyde. Moreover, the beneficial effect of cinnamaldehyde was associated with the normalization in gene expression of hypertrophic and fibrotic markers. Further studies showed that pressure overload significantly induced the activation of extracellular signal-regulated kinase (ERK) signaling pathway, which was blocked by cinnamaldehyde. Cinnamaldehyde may be able to retard the progression of cardiac hypertrophy and fibrosis, probably via blocking ERK signaling pathway.

  12. PEG-coated gold nanoparticles attenuate β-adrenergic receptor-mediated cardiac hypertrophy.

    Science.gov (United States)

    Qiao, Yuhui; Zhu, Baoling; Tian, Aiju; Li, Zijian

    2017-01-01

    Gold nanoparticles (AuNPs) are widely used as a drug delivery vehicle, which can accumulate in the heart through blood circulation. Therefore, it is very important to understand the effect of AuNPs on the heart, especially under pathological conditions. In this study, we found that PEG-coated AuNPs attenuate β-adrenergic receptor (β-AR)-mediated acute cardiac hypertrophy and inflammation. However, both isoproterenol, a non-selective β-AR agonist, and AuNPs did not induce cardiac function change or cardiac fibrosis. AuNPs exerted an anti-cardiac hypertrophy effect by decreasing β 1 -AR expression and its downstream ERK1/2 hypertrophic pathway. Our results indicated that AuNPs might be safe and have the potential to be used as multi-functional materials (drug carrier systems and anti-cardiac hypertrophy agents).

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

    NARCIS (Netherlands)

    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

  14. Ablation of biglycan attenuates cardiac hypertrophy and fibrosis after left ventricular pressure overload.

    Science.gov (United States)

    Beetz, Nadine; Rommel, Carolin; Schnick, Tilman; Neumann, Elena; Lother, Achim; Monroy-Ordonez, Elsa Beatriz; Zeeb, Martin; Preissl, Sebastian; Gilsbach, Ralf; Melchior-Becker, Ariane; Rylski, Bartosz; Stoll, Monika; Schaefer, Liliana; Beyersdorf, Friedhelm; Stiller, Brigitte; Hein, Lutz

    2016-12-01

    Biglycan, a small leucine-rich proteoglycan, has been shown to play an important role in stabilizing fibrotic scars after experimental myocardial infarction. However, the role of biglycan in the development and regression of cardiomyocyte hypertrophy and fibrosis during cardiac pressure overload and unloading remains elusive. Thus, the aim of the present study was to assess the effect of biglycan on cardiac remodeling in a mouse model of left ventricular pressure overload and unloading. Left ventricular pressure overload induced by transverse aortic constriction (TAC) in mice resulted in left ventricular dysfunction, fibrosis and increased biglycan expression. Fluorescence- and magnetic-assisted sorting of cardiac cell types revealed upregulation of biglycan in the fibroblast population, but not in cardiomyocytes, endothelial cells or leukocytes after TAC. Removal of the aortic constriction (rTAC) after short-term pressure overload (3weeks) improved cardiac contractility and reversed ventricular hypertrophy but not fibrosis in wild-type (WT) mice. Biglycan ablation (KO) enhanced functional recovery but did not resolve cardiac fibrosis. After long-term TAC for 9weeks, ablation of biglycan attenuated the development of cardiac hypertrophy and fibrosis. In vitro, biglycan induced hypertrophy of neonatal rat cardiomyocytes and led to activation of a hypertrophic gene program. Putative downstream mediators of biglycan signaling include Rcan1, Abra and Tnfrsf12a. These genes were concordantly induced by TAC in WT but not in biglycan KO mice. Left ventricular pressure overload induces biglycan expression in cardiac fibroblasts. Ablation of biglycan improves cardiac function and attenuates left ventricular hypertrophy and fibrosis after long-term pressure overload. In vitro biglycan induces hypertrophy of cardiomyocytes, suggesting that biglycan may act as a signaling molecule between cell types to modulate cardiac remodeling. Copyright © 2016 Elsevier Ltd. All rights

  15. Piperine Attenuates Pathological Cardiac Fibrosis Via PPAR-γ/AKT Pathways

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    Zhen-Guo Ma

    2017-04-01

    Full Text Available Mitogen-activated protein kinases (MAPKs and AMP­activated protein kinase α (AMPKα play critical roles in the process of cardiac hypertrophy. Previous studies have demonstrated that piperine activates AMPKα and reduces the phosphorylation of extracellular signal-regulated kinase (ERK. However, the effect of piperine on cardiac hypertrophy remains completely unknown. Here, we show that piperine-treated mice had similar hypertrophic responses as mice treated with vehicle but exhibited significantly attenuated cardiac fibrosis after pressure overload or isoprenaline (ISO injection. Piperine inhibited the transformation of cardiac fibroblasts to myofibroblasts induced by transforming growth factor-β (TGF-β or angiotensin II (Ang II in vitro. This anti-fibrotic effect was independent of the AMPKα and MAPK pathway. Piperine blocked activation of protein kinase B (AKT and, downstream, glycogen synthase kinase 3β (GSK3β. The overexpression of constitutively active AKT or the knockdown of GSK3β completely abolished the piperine-mediated protection of cardiac fibroblasts. The cardioprotective effects of piperine were blocked in mice with constitutively active AKT. Pretreatment with GW9662, a specific inhibitor of peroxisome proliferator activated receptor-γ (PPAR-γ, reversed the effect elicited by piperine in vitro. In conclusion, piperine attenuated cardiac fibrosis via the activation of PPAR-γ and the resultant inhibition of AKT/GSK3β.

  16. Piperine Attenuates Pathological Cardiac Fibrosis Via PPAR-γ/AKT Pathways.

    Science.gov (United States)

    Ma, Zhen-Guo; Yuan, Yu-Pei; Zhang, Xin; Xu, Si-Chi; Wang, Sha-Sha; Tang, Qi-Zhu

    2017-04-01

    Mitogen-activated protein kinases (MAPKs) and AMP-activated protein kinase α (AMPKα) play critical roles in the process of cardiac hypertrophy. Previous studies have demonstrated that piperine activates AMPKα and reduces the phosphorylation of extracellular signal-regulated kinase (ERK). However, the effect of piperine on cardiac hypertrophy remains completely unknown. Here, we show that piperine-treated mice had similar hypertrophic responses as mice treated with vehicle but exhibited significantly attenuated cardiac fibrosis after pressure overload or isoprenaline (ISO) injection. Piperine inhibited the transformation of cardiac fibroblasts to myofibroblasts induced by transforming growth factor-β (TGF-β) or angiotensin II (Ang II) in vitro. This anti-fibrotic effect was independent of the AMPKα and MAPK pathway. Piperine blocked activation of protein kinase B (AKT) and, downstream, glycogen synthase kinase 3β (GSK3β). The overexpression of constitutively active AKT or the knockdown of GSK3β completely abolished the piperine-mediated protection of cardiac fibroblasts. The cardioprotective effects of piperine were blocked in mice with constitutively active AKT. Pretreatment with GW9662, a specific inhibitor of peroxisome proliferator activated receptor-γ (PPAR-γ), reversed the effect elicited by piperine in vitro. In conclusion, piperine attenuated cardiac fibrosis via the activation of PPAR-γ and the resultant inhibition of AKT/GSK3β. Copyright © 2017 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Published by Elsevier B.V. All rights reserved.

  17. Anti-transforming growth factor antibody at low but not high doses limits cyclosporine-mediated nephrotoxicity without altering rat cardiac allograft survival: potential of therapeutic applications.

    Science.gov (United States)

    Khanna, Ashwani K; Plummer, Matthew S; Hilton, Gail; Pieper, Galen M; Ledbetter, Steven

    2004-12-21

    Long-term treatment of cardiac transplant recipients with cyclosporine results in a progressive decline in kidney function in a large number of patients. This complication is one of the most important prognostic parameters that determine the outcome of cardiac transplantation. Transforming growth factor-beta (TGF-beta) is one of the most potent mediators of the fibrogenic effects of cyclosporine. With the use of an experimental rodent model, heterotopic heart transplantation was performed, creating histocompatibility-disparate allografts. Because TGF-beta in part mediates both the immunosuppressive and nephrotoxic effects of cyclosporine, recipients were treated with cyclosporine with and without anti-TGF-beta antibody to determine whether anti-TGF-beta antibody could reduce the nephrotoxic effects of cyclosporine. Intrarenal expression of TGF-beta, collagen, fibronectin, matrix metalloproteinase-2, and tissue inhibitor of metalloproteinase-2 was studied with the use of reverse transcription-polymerase chain reaction. Intrarenal expression of TGF-beta protein was studied by immunohistochemistry and with the use of ELISA to quantify circulating levels of TGF-beta protein in plasma. Cyclosporine-induced graft survival (immunosuppressive effect) was abrogated with a higher concentration (2.5 mg/kg) of anti-TGF-beta antibody, whereas a lower concentration (1 mg/kg) inhibited both cyclosporine-induced expression of fibrogenic molecules and renal toxicity. These results provide credence to the pivotal role of TGF-beta in immunosuppression-associated renal toxicity in recipients of cardiac transplantation. Furthermore, these findings support a potentially significant therapeutic use of optimal concentration of anti-TGF-beta antibody to ameliorate cyclosporine-associated nephrotoxicity in cardiac transplant recipients.

  18. Candesartan cilexetil attenuated cardiac remodeling by improving expression and function of mitofusin 2 in SHR.

    Science.gov (United States)

    Wang, Zuoguang; Niu, Qiuli; Peng, Xiaoyun; Li, Mei; Liu, Kuo; Liu, Ya; Liu, Jielin; Jin, Fei; Li, Xiao; Wei, Yongxiang

    2016-07-01

    Left ventricular hypotrophy (LVH) is very common in hypertensives even after antihypertensive treatment. Mitofusin 2 (Mfn2) is a critical negative regulator of vascular smooth muscle cell (VSMC) hypertrophy by regulating mitochondrial fusion, ras/raf/MEK signal pathway, et al. The purpose of this study was to investigate whether candesartan attenuated cardiac remodeling by improving expression and function of mitofusin 2 in SHR. Nine weeks old spontaneously hypertensive rats (SHR) were selected and treated with candesartan for eight weeks. Then, heart tissues were investigated for signs of cardiac remodeling, mitochondrial structure and membrane potential, mitochondrial enzyme activities, hydrogen peroxide, mRNA and protein expression of Mfn2/ras/raf/MEK signaling pathway in heart tissues. The results showed that cardiac remodeling was obviously in SHR group: cardiac cell alignment was irregular; cardiac fibers became thick, irregular and enlarged; cell density was reduced in SHR compared to WKY. After candesartan treatment, histopathological structure improved significantly which were consistent with mitochondrial morphology, mitochondrial membrane potential, mitochondrial enzyme activities, hydrogen peroxide, Mfn2/ras/raf/MEK gene and protein expression in cardiac tissues. What's more, although blood pressure was well controlled in a normal range, cardiac remodeling wasn't avoided. In general, candesartan obviously repressed cardiac hypertrophy and cardiac remodeling significantly compared to SHR untreated group, but didn't reverse it. Mfn2 is negatively associated with cardiac remodeling. Candesartan treatment can improve mitochondrial structure and function and regulate Mfn2/ras/raf/MEK signaling pathway. Mfn2 may be used a potential marker for cardiac remodeling and a novel therapeutic target for target organ damage protection. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  19. Cardiac Effects of Attenuating Gsα - Dependent Signaling.

    Directory of Open Access Journals (Sweden)

    Marcus R Streit

    Full Text Available Inhibition of β-adrenergic signalling plays a key role in treatment of heart failure. Gsα is essential for β-adrenergic signal transduction. In order to reduce side-effects of beta-adrenergic inhibition diminishing β-adrenergic signalling in the heart at the level of Gsα is a promising option.We analyzed the influence of Gsα on regulation of myocardial function and development of cardiac hypertrophy, using a transgenic mouse model (C57BL6/J mice overexpressing a dominant negative Gsα-mutant under control of the α-MHC-promotor. Cardiac phenotype was characterized in vivo and in vitro and under acute and chronic β-adrenergic stimulation. At rest, Gsα-DN-mice showed bradycardia (602 ± 13 vs. 660 ± 17 bpm, p<0.05 and decreased dp/dtmax (5037 ± 546- vs. 6835 ± 505 mmHg/s, p = 0.02. No significant differences were found regarding ejection fraction, heart weight and cardiomyocyte size. β-blockade by propranolol revealed no baseline differences of hemodynamic parameters between wildtype and Gsα-DN-mice. Acute adrenergic stimulation resulted in decreased β-adrenergic responsiveness in Gsα-DN-mice. Under chronic adrenergic stimulation, wildtype mice developed myocardial hypertrophy associated with increase of LV/BW-ratio by 23% (4.4 ± 0.2 vs. 3.5 ± 0.1 mg/g, p<0.01 and cardiac myocyte size by 24% (14927 ± 442 px vs. 12013 ± 583 px, p<0.001. In contrast, both parameters were unchanged in Gsα-DN-mice after chronic isoproterenol stimulation.Overexpression of a dominant negative mutant of Gsα leads to decreased β-adrenergic responsiveness and is protective against isoproterenol-induced hypertrophy. Thus, Gsα-DN-mice provide novel insights into β-adrenergic signal transduction and its modulation in myocardial overload and failure.

  20. Blueberry Anthocyanins-Enriched Extracts Attenuate Cyclophosphamide-Induced Cardiac Injury.

    Directory of Open Access Journals (Sweden)

    Yunen Liu

    Full Text Available We sought to explore the effect of blueberry anthocyanins-enriched extracts (BAE on cyclophosphamide (CTX-induced cardiac injury. The rats were divided randomly into five groups including normal control, CTX 100 mg/kg, BAE 80mg/kg, CTX+BAE 20mg/kg and CTX+BAE 80mg/kg groups. The rats in the three BAE-treated groups were administered BAE for four weeks. Seven days after BAE administration, rats in CTX group and two BAE-treated groups were intraperitoneally injected with a single dose of 100 mg/kg CTX. Cardiac injury was assessed using physiological parameters, Echo, morphological staining, real-time PCR and western blot. In addition, cardiotoxicity indices, inflammatory cytokines expression and oxidative stress markers were also detected. Four weeks 20mg/kg and 80mg/kg dose of BAE treatment following CTX exposure attenuated mean arterial blood pressure, heart rate and activities of heart enzymes, improved cardiac dysfunction, left ventricular hypertrophy and fibrosis. Importantly, BAE also attenuated CTX-induced LV leukocyte infiltration and inflammatory cytokines expression, ameliorated oxidative stress as well as cardiomyocyte apoptosis. In conclusion, BAE attenuated the CTX-induced cardiac injury and the protective mechanisms were related closely to the anti-inflammatory, antioxidant and anti-inflammatory characteristics of BAE.

  1. Blueberry Anthocyanins-Enriched Extracts Attenuate Cyclophosphamide-Induced Cardiac Injury.

    Science.gov (United States)

    Liu, Yunen; Tan, Dehong; Shi, Lin; Liu, Xinwei; Zhang, Yubiao; Tong, Changci; Song, Dequn; Hou, Mingxiao

    2015-01-01

    We sought to explore the effect of blueberry anthocyanins-enriched extracts (BAE) on cyclophosphamide (CTX)-induced cardiac injury. The rats were divided randomly into five groups including normal control, CTX 100 mg/kg, BAE 80mg/kg, CTX+BAE 20mg/kg and CTX+BAE 80mg/kg groups. The rats in the three BAE-treated groups were administered BAE for four weeks. Seven days after BAE administration, rats in CTX group and two BAE-treated groups were intraperitoneally injected with a single dose of 100 mg/kg CTX. Cardiac injury was assessed using physiological parameters, Echo, morphological staining, real-time PCR and western blot. In addition, cardiotoxicity indices, inflammatory cytokines expression and oxidative stress markers were also detected. Four weeks 20mg/kg and 80mg/kg dose of BAE treatment following CTX exposure attenuated mean arterial blood pressure, heart rate and activities of heart enzymes, improved cardiac dysfunction, left ventricular hypertrophy and fibrosis. Importantly, BAE also attenuated CTX-induced LV leukocyte infiltration and inflammatory cytokines expression, ameliorated oxidative stress as well as cardiomyocyte apoptosis. In conclusion, BAE attenuated the CTX-induced cardiac injury and the protective mechanisms were related closely to the anti-inflammatory, antioxidant and anti-inflammatory characteristics of BAE.

  2. MicroRNA-208a Silencing Attenuates Doxorubicin Induced Myocyte Apoptosis and Cardiac Dysfunction

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    Hasahya Tony

    2015-01-01

    Full Text Available Aims. GATA4 depletion is a distinct mechanism by which doxorubicin leads to cardiomyocyte apoptosis, and preservation of GATA4 mitigates doxorubicin induced myocyte apoptosis and cardiac dysfunction. We investigated a novel approach of attenuating doxorubicin induced cardiac toxicity by silencing miR-208a, a heart specific microRNA known to target GATA4. Methods and Results. Eight-week-old female Balb/C mice were randomly assigned to sham, antagomir, and control groups. Antagomir group were pretreated with miR-208a antagomir 4 days before doxorubicin administration. At day 0, control and antagomir groups received 20 mg/kg of doxorubicin, while sham mice received phosphate buffered solution. Echocardiography was done at day 7, after which animals were sacrificed and hearts harvested and assessed for apoptosis and expression of miR-208a, GATA4, and BCL-2. Doxorubicin significantly upregulated miR-208a, downregulated GATA4, and increased myocyte apoptosis, with resulting decrease in cardiac function. In contrast, therapeutic silencing of miR-208a salvaged GATA4 and BCL-2 and decreased apoptosis, with improvement in cardiac function. Conclusion. Doxorubicin upregulates miR-208a and promotes cardiomyocyte apoptosis, while therapeutic silencing of miR-208a attenuates doxorubicin induced myocyte apoptosis with subsequent improvement in cardiac function. These novel results highlight the therapeutic potential of targeting miR-208a to prevent doxorubicin cardiotoxicity.

  3. Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling.

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    Gitau, Samuel Chege; Li, Xuelian; Zhao, Dandan; Guo, Zhenfeng; Liang, Haihai; Qian, Ming; Lv, Lifang; Li, Tianshi; Xu, Bozhi; Wang, Zhiguo; Zhang, Yong; Xu, Chaoqian; Lu, Yanjie; Du, Zhiming; Shan, Hongli; Yang, Baofeng

    2015-12-01

    Ventricular hypertrophy is a powerful and independent predictor of cardiovascular morbid events. The vascular properties of low-dose acetyl salicylic acid (aspirin) provide cardiovascular benefits through the irreversible inhibition of platelet cyclooxygenase 1; however, the possible anti-hypertrophic properties and potential mechanism of aspirin have not been investigated in detail. In this study, healthy wild-type male mice were randomly divided into three groups and subjected to transverse aortic constriction (TAC) or sham operation. The TAC-operated mice were treated with the human equivalent of low-dose aspirin (10 mg·kg(-1)·d(-1)); the remaining mice received an equal amount of phosphate buffered saline with 0.65% ethanol, which was used as a vehicle. A cardiomyocyte hypertrophy model induced by angiotensin II (10 nmol·L(-1)) was treated with the human equivalent of low (10 or 100 μmol·L(-1)) and high (1000 μmol·L(-1)) aspirin concentrations in plasma. Changes in the cardiac structure and function were assessed through echocardiography and transmission electron microscopy. Gene expression was determined through RT-PCR and western blot analysis. Results indicated that aspirin treatment abrogated the increased thickness of the left ventricular anterior and posterior walls, the swelling of mitochondria, and the increased surface area in in vivo and in vitro hypertrophy models. Aspirin also normalized the upregulated hypertrophic biomarkers, β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), and b-type natriuretic peptide (BNP). Aspirin efficiently reversed the upregulation of β-catenin and P-Akt expression and the TAC- or ANG II-induced downregulation of GSK-3β. Therefore, low-dose aspirin possesses significant anti-hypertrophic properties at clinically relevant concentrations for anti-thrombotic therapy. The downregulation of β-catenin and Akt may be the underlying signaling mechanism of the effects of aspirin.

  4. Paradoxical Sleep Deprivation Causes Cardiac Dysfunction and the Impairment Is Attenuated by Resistance Training.

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    Giampá, Sara Quaglia de Campos; Mônico-Neto, Marcos; de Mello, Marco Tulio; Souza, Helton de Sá; Tufik, Sergio; Lee, Kil Sun; Koike, Marcia Kiyomi; Dos Santos, Alexandra Alberta; Antonio, Ednei Luiz; Serra, Andrey Jorge; Tucci, Paulo José Ferreira; Antunes, Hanna Karen Moreira

    2016-01-01

    Paradoxical sleep deprivation activates the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis, subsequently interfering with the cardiovascular system. The beneficial effects of resistance training are related to hemodynamic, metabolic and hormonal homeostasis. We hypothesized that resistance training can prevent the cardiac remodeling and dysfunction caused by paradoxical sleep deprivation. Male Wistar rats were distributed into four groups: control (C), resistance training (RT), paradoxical sleep deprivation for 96 hours (PSD96) and both resistance training and sleep deprivation (RT/PSD96). Doppler echocardiograms, hemodynamics measurements, cardiac histomorphometry, hormonal profile and molecular analysis were evaluated. Compared to the C group, PSD96 group had a higher left ventricular systolic pressure, heart rate and left atrium index. In contrast, the left ventricle systolic area and the left ventricle cavity diameter were reduced in the PSD96 group. Hypertrophy and fibrosis were also observed. Along with these alterations, reduced levels of serum testosterone and insulin-like growth factor-1 (IGF-1), as well as increased corticosterone and angiotensin II, were observed in the PSD96 group. Prophylactic resistance training attenuated most of these changes, except angiotensin II, fibrosis, heart rate and concentric remodeling of left ventricle, confirmed by the increased of NFATc3 and GATA-4, proteins involved in the pathologic cardiac hypertrophy pathway. Resistance training effectively attenuates cardiac dysfunction and hormonal imbalance induced by paradoxical sleep deprivation.

  5. Transplantation of mesenchymal stem cells overexpressing IL10 attenuates cardiac impairments in rats with myocardial infarction.

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    Meng, Xin; Li, Jianping; Yu, Ming; Yang, Jian; Zheng, Minjuan; Zhang, Jinzhou; Sun, Chao; Liang, Hongliang; Liu, Liwen

    2018-01-01

    Mesenchymal stem cell (MSC) has been well known to exert therapeutic potential for patients with myocardial infarction (MI). In addition, interleukin-10 (IL10) could attenuate MI through suppressing inflammation. Thus, the combination of MSC implantation with IL10 delivery may extend health benefits to ameliorate cardiac injury after MI. Here we established overexpression of IL10 in bone marrow-derived MSC through adenoviral transduction. Cell viability, apoptosis, and IL10 secretion under ischemic challenge in vitro were examined. In addition, MSC was transplanted into the injured hearts in a rat model of MI. Four weeks after the MI induction, MI, cardiac functions, apoptotic cells, and inflammation cytokines were assessed. In response to in vitro oxygen-glucose deprivation (OGD), IL10 overexpression in MSC (Ad.IL10-MSC) enhanced cell viability, decreased apoptosis, and increased IL10 secretion. Consistently, the implantation of Ad.IL10-MSCs into MI animals resulted in more reductions in myocardial infarct size, cardiac impairment, and cell apoptosis, compared to the individual treatments of either MSC or IL10 administration. Moreover, the attenuation of both systemic and local inflammations was most prominent for Ad.IL10-MSC treatment. IL10 overexpression and MSC may exert a synergistic anti-inflammatory effect to alleviate cardiac injury after MI. © 2017 Wiley Periodicals, Inc.

  6. Pharmacodynamics of cyclosporine in heart and heart-lung transplant recipients. I: Blood cyclosporine concentrations and other risk factors for cardiac allograft rejection.

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    Best, N G; Trull, A K; Tan, K K; Spiegelhalter, D J; Cary, N; Wallwork, J

    1996-11-27

    We have attempted to determine the optimal clinical use of cyclosporine during the first 3 months after heart transplantation. We used multiple logistic regression to quantify how blood cyclosporine concentrations and other potential risk factors influence the risk of histologically confirmed acute rejection in 111 heart transplant recipients. A 50% increase in cyclosporine concentration was associated with a 15% reduction in risk of rejection in the subsequent 5 days (P=0.002). Increasing oral corticosteroid dose also protected against rejection (P=0.01). Rejection was over 2.5 times more likely during the first 20 postoperative days, and patients with 2 HLA-DR mismatches who were transplanted for cardiomyopathy or who had multiple previous rejection episodes were predisposed to further rejection (Pcyclosporine concentrations was weakly associated with risk of rejection (P=0.1). Investigation of threshold levels for the cyclosporine concentration-effect relationship suggested that concentrations above 375 microgram L(-1) provide optimal protection against acute cardiac allograft rejection. This result yields an objectively defined therapeutic threshold for targeting early cyclosporine concentrations following heart transplantation, although the upper end of the range will depend on the individual's susceptibility to nephrotoxicity and infection.

  7. Exercise training prior to myocardial infarction attenuates cardiac deterioration and cardiomyocyte dysfunction in rats.

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    Bozi, Luiz Henrique Marchesi; Maldonado, Izabel Regina dos Santos Costa; Baldo, Marcelo Perim; Silva, Márcia Ferreira da; Moreira, José Bianco Nascimento; Novaes, Rômulo Dias; Ramos, Regiane Maria Soares; Mill, José Geraldo; Brum, Patricia Chakur; Felix, Leonardo Bonato; Gomes, Thales Nicolau Prímola; Natali, Antônio José

    2013-04-01

    The present study was performed to investigate 1) whether aerobic exercise training prior to myocardial infarction would prevent cardiac dysfunction and structural deterioration and 2) whether the potential cardiac benefits of aerobic exercise training would be associated with preserved morphological and contractile properties of cardiomyocytes in post-infarct remodeled myocardium. Male Wistar rats underwent an aerobic exercise training protocol for eight weeks. The rats were then assigned to sham surgery (SHAM), sedentary lifestyle and myocardial infarction or exercise training and myocardial infarction groups and were evaluated 15 days after the surgery. Left ventricular tissue was analyzed histologically, and the contractile function of isolated myocytes was measured. Student's t-test was used to analyze infarct size and ventricular wall thickness, and the other parameters were analyzed by the Kruskal-Wallis test followed by Dunn's test or a one-way analysis of variance followed by Tukey's test (pmyocardial infarction extension, a thicker infarcted wall and less collagen accumulation as compared to myocardial infarctions in sedentary animals. Myocardial infarction-induced left ventricular dilation and cardiac dysfunction, as evaluated by +dP/dt and -dP/dt, were both prevented by previous aerobic exercise training. Moreover, aerobic exercise training preserved cardiac myocyte shortening, improved the maximum shortening and relengthening velocities in infarcted hearts and enhanced responsiveness to calcium. Previous aerobic exercise training attenuated the cardiac dysfunction and structural deterioration promoted by myocardial infarction, and such benefits were associated with preserved cardiomyocyte morphological and contractile properties.

  8. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin induced cardiac injury in mice

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    Yousif Nasser

    2011-10-01

    Full Text Available Abstract Background Cardiac inflammation and generation of oxidative stress are known to contribute to trastuzumab (herceptin induced cardiac toxicity. Toll-like receptors (TLRs are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signaling, we investigated whether or not TLR4 is involved in trastuzumab induced cardiotoxicity. Methods Seven days after a single injection of herceptin (2 mg/kg; i.p., left ventricular pressure volume loops were measured in HeN compotent (TLR4+/+ and HeJ mutant (TLR4-/- treated with trastuzumab and control mice. Immunofluorescent staining for monocyte infiltration and analyses of plasma by (ELISAs for different chemokines including: MCP-1and tumor necrosis factor-α (TNF-α, Western immunoblotting assay for ICAM-1, and used troponin I for cardiac injury marker. Results Trastuzumab injection resulted in an impairment of left ventricular function in TLR-4 competent (HeN, in contrast TLR4-/- trastuzumab mice showed improved left ventricular function EF%, CO; p -/-; p -/-, marked reduction of myocardial troponin-I levels in TLR4-deficient mice. Data are presented as means ± SE; n = 8 in each group p Conclusions Treatment with trastuzumab induces an inflammatory response that contributes to myocardial tissue TLR4 mediates chemokine expression (TNF-α, MCP-1and ICAM-1, so in experimental animals TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in trastuzumab induced cardiomyopathy.

  9. SUCCESSFUL APPLICATION OF PERIPHERAL VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION FOR CARDIAC ALLOGRAFT ANTIBODY-MEDIATED REJECTION WITH SEVERE HEMODYNAMIC COMPROMISE

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    V. N. Poptsov

    2015-01-01

    Full Text Available Introduction. Acute antibody-mediated rejection (AMR is one of the severe complications of early and late period after heart transplantation (HT. Only few case reports and studies presented of mechanical circulatory support (MCS application for refractory acute rejection causing hemodynamic compromise. Aim. We report the case of a woman with cardiogenic shock caused by severe AMR that was successfully treatment by peripheral venoarterial extracorporeal membrane oxygenation (VA ECMO. Material and methods. In december 2014, a 60-year-old woman with dilated cardiomyopathy was operated for HT. The patient had a good initial cardiac allograft function and no and was discharged from ICU on the 4th day after HT. 1st endomyocardial biopsy (EMB (the 7th day after HT showed absence of acute cellular and antibody-mediated rejection. On the 11th day after HT patient aggravated and presented clinical signs of life-threatening acute cardiac allograft dysfunction: arterial blood pressure 78/49/38 mm Hg, HR 111 in min, CVP 20 mm Hg, PAP 47/34/25 mm Hg, PCWP 25 mm Hg, CI 1.5 l/min/m2, adrenalin 110 ng/kg/min, dopamine 15 mcg/kg/min. ECG showed impairment of systolic left (LVEF 25% and right (RVEF 15% ventricle function, left and right ventricle diffuse hypokinesis, thickness of IVS, LV and RV wall 1.7, 1.4 and 0.8 cm, tricuspid and mitral valve regurgitation 2–3 degrees. EMB presented AMR. In conscience peripheral VA ECMO was installed. We used peripheral transcutaneous cannulation technique via femoral vessels – arterial cannula 15 F, venous cannula – 23 F, vascular catheter 14 G for anterograde leg’s perfusion. ACT 130–150 sec. AMR therapy included: methylprednisolon pulse-therapy (10 mg/kg for 5 day, IgG, plasmapheresis (No 7, rituximab. Results. Under MCS by VA ECMO we noted quick improvement of hemodynamic, metabolic homeostasis and organ functions. On the 6th day of VA ECMO (blood flow 1.8 l/min: arterial blood pressure 133/81/54 mm Hg, CVP 5 mm

  10. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice.

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    Yousif, Nasser Ghaly; Al-Amran, Fadhil G

    2011-10-14

    Cardiac inflammation and generation of oxidative stress are known to contribute to trastuzumab (herceptin) induced cardiac toxicity. Toll-like receptors (TLRs) are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signaling, we investigated whether or not TLR4 is involved in trastuzumab induced cardiotoxicity. Seven days after a single injection of herceptin (2 mg/kg; i.p.), left ventricular pressure volume loops were measured in HeN compotent (TLR4+/+) and HeJ mutant (TLR4-/-) treated with trastuzumab and control mice. Immunofluorescent staining for monocyte infiltration and analyses of plasma by (ELISAs) for different chemokines including: MCP-1and tumor necrosis factor-α (TNF-α), Western immunoblotting assay for ICAM-1, and used troponin I for cardiac injury marker. Trastuzumab injection resulted in an impairment of left ventricular function in TLR-4 competent (HeN), in contrast TLR4-/- trastuzumab mice showed improved left ventricular function EF%, CO; p < 0.05, attenuation of mononuclear cell infiltration in TLR4 -/-; p < 0.05 vs.TLR-4 competent (HeN), reduced level of cytokines TNF-α, MCP-1 and ICAM-1 expression in TLR4-/-, marked reduction of myocardial troponin-I levels in TLR4-deficient mice. Data are presented as means ± SE; n = 8 in each group p < 0.05 vs.TLR-4 competent (HeN). Treatment with trastuzumab induces an inflammatory response that contributes to myocardial tissue TLR4 mediates chemokine expression (TNF-α, MCP-1and ICAM-1), so in experimental animals TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in trastuzumab induced cardiomyopathy.

  11. Inhibition of Uncoupling Protein 2 Attenuates Cardiac Hypertrophy Induced by Transverse Aortic Constriction in Mice

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    Xiao-Bing Ji

    2015-07-01

    Full Text Available Background: Uncoupling protein 2 (UCP2 is critical in regulating energy metabolism. Due to the significant change in energy metabolism of myocardium upon pressure overload, we hypothesize that UCP2 could contribute to the etiology of cardiac hypertrophy. Methods: Adult male C57BL/6J mice were subjected to pressure overload by using transverse aortic constriction (TAC, and then received genipin (a UCP2 selective inhibitor; 25 mg/kg/d, ip or vehicle for three weeks prior to histologic assessment of myocardial hypertrophy. ATP concentration, ROS level, and myocardial apoptosis were also examined. A parallel set of experiments was also conducted in UCP2-/- mice. Results: TAC induced left ventricular hypertrophy, as reflected by increased ventricular weight/thickness and increased size of myocardial cell (vs. sham controls. ATP concentration was decreased; ROS level was increased. Apoptosis and fibrosis markers were increased. TAC increased mitochondrial UCP2 expression in the myocardium at both mRNA and protein levels. Genipin treatment attenuated cardiac hypertrophy and the histologic/biochemical changes described above. Hypertrophy and associated changes induced by TAC in UCP2-/- mice were much less pronounced than in WT mice. Conclusions: Blocking UCP2 expression attenuates cardiac hypertrophy induced by pressure overload.

  12. Adenovirus-Mediated Overexpression of Glutathione-S-Transferase Mitigates Transplant Arteriosclerosis in Rabbit Carotid Allografts1

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    Xu, Ya; Gong, Bin; Yang, Yongzhen; Awasthi, Yogesh C.; Boor, Paul J.

    2010-01-01

    Background Cardiac transplant arteriosclerosis, or cardiac allograft vasculopathy, remains the leading cause of graft failure and patient death in heart transplant recipients. Endothelial cell injury is crucial in the development of human atherosclerosis and may play a role in allograft vasculopathy. Glutathione-S-Transferase (GST) is known to protect endothelial cells from damage by oxidants and toxins. However, the contribution of human glutathione-S-transferase A4-4 (hGSTA4-4) to vascular cell injury and consequent transplant arteriosclerosis is unknown. Methods A recombinant adenoviral vector containing hGSTA4-4 gene was constructed and delivered to vascular endothelial cells in an in vivo rabbit carotid artery transplant model. Forty five days after transplantation, allografts were harvested (n = 28). Blood flow was measured by ultrasonography. In addition, grafts were analyzed by histology, morphometry, immunostaining and western blot. Results The severity of arteriosclerosis in hGSTA4-4 transduced allografts was compared with control by measuring degree of stenosis by neointima. Decrease in blood flow in hGSTA4-4 transduced allografts was significantly less than control allografts, which also developed greater intimal thickening and stenosis than hGSTA4-4 transduced allografts in the proximal and distal regions of the graft. Leukocyte and macrophage infiltration was reduced in hGSTA4-4 transduced carotid arteries. Conclusion Our data indicates that hGSTA4-4 overexpression protects the integrity of vessel wall from oxidative injury, and attenuates transplant arteriosclerosis. PMID:20177342

  13. Inhibition of NF-κB activity in the hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by modulating cytokines and attenuating oxidative stress

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    Yu, Xiao-Jing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Jia, Lin-Lin; Qi, Jie; Song, Xin-Ai; Tan, Hong [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Cui, Wei [Department of Endocrinology and Metabolism, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Chen, Wensheng [Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China)

    2015-05-01

    We hypothesized that chronic inhibition of NF-κB activity in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), attenuating nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in the PVN of young spontaneously hypertensive rats (SHR). Young normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusions with NF–κB inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle for 4 weeks. SHR rats had higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, cardiomyocyte diameters of the left cardiac ventricle, and mRNA expressions of cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC). These SHR rats had higher PVN levels of proinflammatory cytokines (PICs), reactive oxygen species (ROS), the chemokine monocyte chemoattractant protein-1 (MCP-1), NAD(P)H oxidase activity, mRNA expression of NOX-2 and NOX-4, and lower PVN IL-10, and higher plasma levels of PICs and NE, and lower plasma IL-10. PVN infusion of NF-κB inhibitor PDTC attenuated all these changes. These findings suggest that NF-κB activation in the PVN increases sympathoexcitation and hypertensive response, which are associated with the increases of PICs and oxidative stress in the PVN; PVN inhibition of NF-κB activity attenuates PICs and oxidative stress in the PVN, thereby attenuates hypertension and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of NF-κB attenuates hypertension-induced cardiac hypertrophy. • PVN inhibition of NF-κB attenuates hypertension-induced neurohormonal excitation. • PVN inhibition of NF-κB attenuates hypertension-induced imbalance of cytokines

  14. Melatonin attenuated brain death tissue extract-induced cardiac damage by suppressing DAMP signaling.

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    Sung, Pei-Hsun; Lee, Fan-Yen; Lin, Ling-Chun; Chen, Kuan-Hung; Lin, Hung-Sheng; Shao, Pei-Lin; Li, Yi-Chen; Chen, Yi-Ling; Lin, Kun-Chen; Yuen, Chun-Man; Chang, Hsueh-Wen; Lee, Mel S; Yip, Hon-Kan

    2018-01-09

    We tested the hypothesis that melatonin prevents brain death (BD) tissue extract (BDEX)-induced cardiac damage by suppressing inflammatory damage-associated molecular pattern (DAMP) signaling in rats. Six hours after BD induction, levels of a DAMP component (HMGB1) and inflammatory markers (TLR-2, TLR-4, MYD88, IκB, NF-κB, IL-1β, IFN-γ, TNF-α and IL-6) were higher in brain tissue from BD animals than controls. Levels of HMGB1 and inflammatory markers were higher in BDEX-treated H9C2 cardiac myoblasts than in cells treated with healthy brain tissue extract. These increases were attenuated by melatonin but re-induced with luzindole (all P DAMP inflammatory axis.

  15. Nobiletin attenuates adverse cardiac remodeling after acute myocardial infarction in rats via restoring autophagy flux.

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    Wu, Xiaoqian; Zheng, Dechong; Qin, Yuyan; Liu, Zumei; Zhang, Guiping; Zhu, Xiaoyan; Zeng, Lihuan; Liang, Zhenye

    2017-10-14

    Our previous study showed that autophagy flux was impaired with sustained heart ischemia, which exacerbated adverse cardiac remodeling after acute myocardial infarction (AMI). Here we investigated whether Nobiletin, a citrus polymethoxylated flavonoids, could restore the autophagy flux and improve cardiac prognosis after AMI. AMI was induced by ligating left anterior descending (LAD) coronary artery in rats. Nobiletin improved the post-infarct cardiac dysfunction significantly and attenuated adverse cardiac remodeling. Meanwhile, Nobiletin protected H9C2 cells against oxygen glucose deprivation (OGD) in vitro. The impaired autophagy flux due to ischemia was ameliorated after Nobiletin treatment by testing the autophagy substrate, LC3BⅡ and P62 protein level both in vivo and in vitro. GFP-mRFP-LC3 adenovirus transfection also supported that Nobiletin restored the impaired autophagy flux. Specifically, the autophagy flux inhibitor, chloroquine, but not 3 MA, alleviated Nobiletin-mediated protection against OGD. Notably, Nobiletin does not affect the activation of classical upstream autophagy signaling pathways. However, Nobiletin increased the lysosome acidation which also supported that Nobiletin accelerated autophagy flux. Taken together, our findings suggested that Nobiletin restored impaired autophagy flux and protected against acute myocardial infarction, suggesting a potential role of autophagy flux in Nobiletin-mediated myocardial protection. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Exercise training attenuates hypertension and cardiac hypertrophy by modulating neurotransmitters and cytokines in hypothalamic paraventricular nucleus.

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    Lin-Lin Jia

    Full Text Available AIMS: Regular exercise as an effective non-pharmacological antihypertensive therapy is beneficial for prevention and control of hypertension, but the central mechanisms are unclear. In this study, we hypothesized that chronic exercise training (ExT delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs and restoring the neurotransmitters balance in the hypothalamic paraventricular nucleus (PVN in young spontaneously hypertensive rats (SHR. In addition, we also investigated the involvement of nuclear factor-κB (NF-κB p65 and NAD(PH oxidase in exercise-induced effects. METHODS AND RESULTS: Moderate-intensity ExT was administrated to young normotensive Wistar-Kyoto (WKY and SHR rats for 16 weeks. SHR rats had a significant increase in mean arterial pressure and cardiac hypertrophy. SHR rats also had higher levels of glutamate, norepinephrine (NE, phosphorylated IKKβ, NF-κB p65 activity, NAD(PH oxidase subunit gp91(phox, PICs and the monocyte chemokine protein-1 (MCP-1, and lower levels of gamma-aminobutyric acid (GABA and interleukin-10 (IL-10 in the PVN. These SHR rats also exhibited higher renal sympathetic nerve activity (RSNA, and higher plasma levels of PICs, and lower plasma IL-10. However, ExT ameliorates all these changes in SHR rats. CONCLUSION: These findings suggest that there are the imbalances between excitatory and inhibitory neurotransmitters and between pro- and anti-inflammatory cytokines in the PVN of SHR rats, which at least partly contributing to sympathoexcitation, hypertension and cardiac hypertrophy; chronic exercise training attenuates hypertension and cardiac hypertrophy by restoring the balances between excitatory and inhibitory neurotransmitters and between pro- and anti-inflammatory cytokines in the PVN; NF-κB and oxidative stress in the PVN may be involved in these exercise-induced effects.

  17. Multiparametric cardiovascular magnetic resonance surveillance of acute cardiac allograft rejection and characterisation of transplantation-associated myocardial injury: a pilot study.

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    Miller, Christopher A; Naish, Josephine H; Shaw, Steven M; Yonan, Nizar; Williams, Simon G; Clark, David; Bishop, Paul W; Ainslie, Mark P; Borg, Alex; Coutts, Glyn; Parker, Geoffrey J M; Ray, Simon G; Schmitt, Matthias

    2014-07-20

    Serial surveillance endomyocardial biopsies are performed in patients who have recently undergone heart transplantation in order to detect acute cardiac allograft rejection (ACAR) before symptoms occur, however the biopsy process is associated with a number of limitations. This study aimed to prospectively and longitudinally evaluate the performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting and monitoring ACAR in the early phase post-transplant, and characterize graft recovery following transplantation. All patients receiving a heart transplant at a single UK centre over a period of 25 months were approached within one month of transplantation. Multiparametric CMR was prospectively performed on the same day as biopsy on four separate occasions (6 weeks, 10 weeks, 15 weeks and 20 weeks post-transplant). CMR included assessment of global and regional ventricular function, myocardial tissue characterization (T1 mapping, T2 mapping, extracellular volume, LGE) and pixel-wise absolute myocardial blood flow quantification. CMR parameters were compared with biopsy findings. As is standard, grade 2R or higher ACAR was considered significant. 88 CMR-matched biopsies were performed in 22 patients. Eight (9%) biopsies in 5 patients demonstrated significant ACAR. Significant ACAR was associated with a reduction in circumferential strain (-12.7±2.5% vs. -13.7±3.6%, p=0.047) but there was considerable overlap between groups. Whilst trends were observed between ACAR and proposed CMR markers of oedema, particularly after adjusting for primary graft dysfunction, differences were not significant. Significant improvements were seen in markers of graft structure and contractility, oedema and microvascular function over the period studied, although few parameters normalised. This study provides novel insight into the myocardial injury associated with transplantation, and its recovery, however multiparametric CMR was not able to accurately detect ACAR

  18. The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One-Year Results of a Scandinavian Randomized Trial.

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    Arora, S; Andreassen, A K; Andersson, B; Gustafsson, F; Eiskjaer, H; Bøtker, H E; Rådegran, G; Gude, E; Ioanes, D; Solbu, D; Sigurdardottir, V; Dellgren, G; Erikstad, I; Solberg, O G; Ueland, T; Aukrust, P; Gullestad, L

    2015-07-01

    Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12-month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7-11 weeks after HTx or standard cyclosporine immunosuppression. Ninety-five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm(3) and 13.8 ± 28.0 mm(3) [all p-values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor-1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus-based CNI-free can potentially be considered in suitable de novo HTx recipients. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  19. Preliminary results of a prospective randomized study of cyclosporine versus tacrolimus in the development of cardiac allograft vasculopathy at 1 year after heart transplantation.

    Science.gov (United States)

    Sánchez-Lázaro, I J; Almenar-Bonet, L; Martínez-Dolz, L; Buendía-Fuentes, F; Navarro-Manchón, J; Raso-Raso, R; Agüero, J; Salvador-Sanz, A

    2010-10-01

    Cardiac allograft vasculopathy (CAV) is the leading cause of death after the first year post-heart transplantation (HT). Numerous factors have been implicated in the development of CAV. The aim of this prospective randomized study was to assess the impact of cyclosporine (CsA) and tacrolimus (Tac) on the development of CAV. From November 2006 to October 2008, 49 HT patients in our center were randomized to receive CsA or Tac. The additional treatment for all patients consisted of daclizumab induction and maintenance treatment with mycophenolate mofetil (1 g/12 hours) and steroids (withdrawal was not attempted). Thirteen patients died before coronary arteriography plus intravascular ultrasound of the left anterior descending artery was performed at 1 year after HT. Hence, the final number of patients included was 36 (18 per group). We considered significant CAV to be the presence of intimal proliferation>1 mm and/or>0.5 mm in 180°. The statistical methods were Student t and chi-square tests. There were no differences in baseline characteristics between the two groups. Nor were there significant differences in maximum intimal proliferation between the groups (CsA 0.65±0.29 vs Tac 0.82±0.51 mm; P=.292) or in the development of significant CAV when both criteria were combined (CsA 31.6% vs Tac 38.9%; P=.642). One year after HT, no differences were detected in the development of significant CAV according to the type of calcineurin inhibitor used when combined with daclizumab induction and maintenance treatment with mycophenolate mofetil and steroids. Copyright © 2010 Elsevier Inc. All rights reserved.

  20. A novel urotensin II receptor antagonist, KR-36996, improved cardiac function and attenuated cardiac hypertrophy in experimental heart failure.

    Science.gov (United States)

    Oh, Kwang-Seok; Lee, Jeong Hyun; Yi, Kyu Yang; Lim, Chae Jo; Park, Byung Kil; Seo, Ho Won; Lee, Byung Ho

    2017-03-15

    Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)benzo[b]thiophene-3-carboxamide (KR-36996), in experimental models of heart failure. KR-36996 displayed a high binding affinity (Ki=4.44±0.67nM) and selectivity for urotensin II receptor. In cell-based study, KR-36996 significantly inhibited urotensin II-induced stress fiber formation and cellular hypertrophy in H9c2 UT cells. In transverse aortic constriction-induced cardiac hypertrophy model in mice, the daily oral administration of KR-36996 (30mg/kg) for 14 days significantly decreased left ventricular weight by 40% (Pheart failure model in rats, repeated echocardiography and hemodynamic measurements demonstrated remarkable improvement of the cardiac performance by KR-36996 treatment (25 and 50mg/kg/day, p.o.) for 12 weeks. Moreover, KR-36996 decreased interstitial fibrosis and cardiomyocyte hypertrophy in the infarct border zone. These results suggest that potent and selective urotensin II receptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR-36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Reproducibility of the acute rejection diagnosis in human cardiac allografts. The Stanford Classification and the International Grading System

    DEFF Research Database (Denmark)

    Nielsen, H; Sørensen, Flemming Brandt; Nielsen, B

    1993-01-01

    Transplantation has become an accepted treatment of many cardiac end-stage diseases. Acute cellular rejection accounts for 15% to 20% of all graft failures. The first grading system of acute cellular rejection, the Stanford Classification, was introduced in 1979, and since then many other grading...... systems have evolved. Most recently, the International Grading System was introduced in The Journal of Heart and Lung Transplantation. In this study the interobserver reproducibility of both the Stanford Classification and the International Grading System is evaluated using Kappa statistics. Three...... observers evaluated 168 endomyocardial biopsy specimens according to the Stanford Classification and 100 endomyocardial biopsy specimens according to the International Grading System. The evaluation was carried out blindly. Kappa values of 54.1% and 51.5%, respectively, were obtained, both significantly...

  2. Exercise training prior to myocardial infarction attenuates cardiac deterioration and cardiomyocyte dysfunction in rats

    Directory of Open Access Journals (Sweden)

    Luiz Henrique Marchesi Bozi

    2013-04-01

    Full Text Available OBJECTIVES: The present study was performed to investigate 1 whether aerobic exercise training prior to myocardial infarction would prevent cardiac dysfunction and structural deterioration and 2 whether the potential cardiac benefits of aerobic exercise training would be associated with preserved morphological and contractile properties of cardiomyocytes in post-infarct remodeled myocardium. METHODS: Male Wistar rats underwent an aerobic exercise training protocol for eight weeks. The rats were then assigned to sham surgery (SHAM, sedentary lifestyle and myocardial infarction or exercise training and myocardial infarction groups and were evaluated 15 days after the surgery. Left ventricular tissue was analyzed histologically, and the contractile function of isolated myocytes was measured. Student's t-test was used to analyze infarct size and ventricular wall thickness, and the other parameters were analyzed by the Kruskal-Wallis test followed by Dunn's test or a one-way analysis of variance followed by Tukey's test (p<0.05. RESULTS: Myocardial infarctions in exercise-trained animals resulted in a smaller myocardial infarction extension, a thicker infarcted wall and less collagen accumulation as compared to myocardial infarctions in sedentary animals. Myocardial infarction-induced left ventricular dilation and cardiac dysfunction, as evaluated by +dP/dt and -dP/dt, were both prevented by previous aerobic exercise training. Moreover, aerobic exercise training preserved cardiac myocyte shortening, improved the maximum shortening and relengthening velocities in infarcted hearts and enhanced responsiveness to calcium. CONCLUSION: Previous aerobic exercise training attenuated the cardiac dysfunction and structural deterioration promoted by myocardial infarction, and such benefits were associated with preserved cardiomyocyte morphological and contractile properties.

  3. Cardiac-Specific Overexpression of Catalase Attenuates Lipopolysaccharide-Induced Myocardial Contractile Dysfunction: Role of Autophagy

    Science.gov (United States)

    Turdi, Subat; Han, Xuefeng; Huff, Anna F.; Roe, Nathan D.; Hu, Nan; Gao, Feng; Ren, Jun

    2012-01-01

    Lipopolysaccharide (LPS) from Gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complication in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity and carbonyl formation. Kaplan-Meier curve was constructed for survival following LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice following LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O2−, and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury following LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by antioxidant NAC and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. PMID:22902401

  4. Minocycline suppresses oxidative stress and attenuates fetal cardiac myocyte apoptosis triggered by in utero cocaine exposure

    Science.gov (United States)

    Sinha-Hikim, Indrani; Shen, Ruoqing; Nzenwa, Ify; Gelfand, Robert; Mahata, Sushil K.

    2015-01-01

    This study investigates the molecular mechanisms by which minocycline, a second generation tetracycline, prevents cardiac myocyte death induced by in utero cocaine exposure. Timed mated pregnant Sprague-Dawley (SD) rats received one of the following treatments twice daily from embryonic (E) day 15–21 (E15–E21): (i) intraperitoneal (IP) injections of saline (control); (ii) IP injections of cocaine (15 mg/kg BW); and (iii) IP injections of cocaine + oral administration of 25 mg/kg BW of minocycline. Pups were killed on postnatal day 15 (P15). Additional pregnant dams received twice daily IP injections of cocaine (from E15–E21) + oral administration of a relatively higher (37.5 mg/kg BW) dose of minocycline. Minocycline treatment continued from E15 until the pups were sacrificed on P15. In utero cocaine exposure resulted in an increase in oxidative stress and fetal cardiac myocyte apoptosis through activation of c-Jun-NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK)-mediated mitochondria-dependent apoptotic pathway. Continued minocycline treatment from E15 through P15 significantly prevented oxidative stress, kinase activation, perturbation of BAX/BCL-2 ratio, cytochrome c release, caspase activation, and attenuated fetal cardiac myocyte apoptosis after prenatal cocaine exposure. These results demonstrate in vivo cardioprotective effects of minocycline in preventing fetal cardiac myocyte death after prenatal cocaine exposure. Given its proven clinical safety and ability to cross the placental barrier and enter into the fetal circulation, minocycline may be an effective therapy for preventing cardiac consequences of in utero cocaine exposure. PMID:21424555

  5. Feasibility of using respiration-averaged MR images for attenuation correction of cardiac PET/MR imaging.

    Science.gov (United States)

    Ai, Hua; Pan, Tinsu

    2015-07-08

    Cardiac imaging is a promising application for combined PET/MR imaging. However, current MR imaging protocols for whole-body attenuation correction can produce spatial mismatch between PET and MR-derived attenuation data owing to a disparity between the two modalities' imaging speeds. We assessed the feasibility of using a respiration-averaged MR (AMR) method for attenuation correction of cardiac PET data in PET/MR images. First, to demonstrate the feasibility of motion imaging with MR, we used a 3T MR system and a two-dimensional fast spoiled gradient-recalled echo (SPGR) sequence to obtain AMR images ofa moving phantom. Then, we used the same sequence to obtain AMR images of a patient's thorax under free-breathing conditions. MR images were converted into PET attenuation maps using a three-class tissue segmentation method with two sets of predetermined CT numbers, one calculated from the patient-specific (PS) CT images and the other from a reference group (RG) containing 54 patient CT datasets. The MR-derived attenuation images were then used for attenuation correction of the cardiac PET data, which were compared to the PET data corrected with average CT (ACT) images. In the myocardium, the voxel-by-voxel differences and the differences in mean slice activity between the AMR-corrected PET data and the ACT-corrected PET data were found to be small (less than 7%). The use of AMR-derived attenuation images in place of ACT images for attenuation correction did not affect the summed stress score. These results demonstrate the feasibility of using the proposed SPGR-based MR imaging protocol to obtain patient AMR images and using those images for cardiac PET attenuation correction. Additional studies with more clinical data are warranted to further evaluate the method.

  6. Cyclosporine reduction in the presence of everolimus: 3-month data from a Canadian pilot study of maintenance cardiac allograft recipients.

    Science.gov (United States)

    Ross, Heather; Pflugfelder, Peter; Haddad, Haissam; Cantarovich, Marcelo; White, Michael; Ignaszewski, Andrew; Howlett, Jonathan; Vaillancourt, Marc; Dorent, Richard; Burton, Jeffrey R

    2008-02-01

    Concentration-controlled everolimus with concomitant cyclosporine (CsA) dose reduction in renal transplantation permits preservation of kidney function without loss of efficacy. Data are lacking regarding everolimus with reduced-dose CsA in maintenance cardiac transplant patients. In a multicenter, open-label, single-arm pilot study, concentration-controlled everolimus was initiated in patients receiving CsA microemulsion (Neoral) with/without mycophenolate mofetil (MMF) or azathioprine, and with/without corticosteroids. On the day of everolimus initiation, MMF/azathioprine was discontinued and CsA dose was reduced by 25% with further reductions as required in response to decreasing calculated glomerular filtration rate (cGFR). Of the 36 patients enrolled (intent-to-treat [ITT]), 27 underwent CsA dose reduction as planned (per protocol [PP]). During Week 1, the CsA dose was reduced by 23.3 +/- 7.3% in the ITT population (p or=3A occurred (2.7%). There was no graft loss or death. Hemoglobin and hematocrit levels decreased significantly, whereas cholesterol and triglyceride levels increased (all p transplant patients is associated with no significant decline in renal function, and no indication of increased rejection to Month 3 post-conversion. Evaluation of more substantial CsA dose reductions is required.

  7. Myocardial uptake of In-111 lymphocytes and I-125 antimyosin antibody in early detection of cardiac allograft rejection in rats

    Energy Technology Data Exchange (ETDEWEB)

    Ohta, Yoshiko (Tokyo Women' s Medical Coll. (Japan))

    1994-01-01

    We investigated whether In-111 lymphocytes (Lym) or I-125 antimyosin antibody (AM) was a more sensitive radiopharmaceutical for detecting cardiac rejection in comparison with histopathologic findings. Wistar-King rats received abdominal heart grafts from Lewis rats by means of Ono-Lindsey's technique and were sacrificed on days 7-14 after transplantation on oral administration of cyclosporine A (5 mg/kg body ratio/day). The transplanted and native hearts were removed 24 hr after simultaneous injection of both radiotracers, weighed, and counted by gamma counter with dual energy windows. Uptake ratios of transplanted/native heart uptake were calculated. The severity of histologic rejection was graded according to Billingham's classification. Uptake ratios were 3.5[+-]0.3 of In-111 Lym and 2.2[+-]0.4 of I-125 AM (p<0.01) in moderate rejected group (n:10), 8.6[+-]2.9, 4.3[+-]0.7 (p<0.001) in severe rejected group (n:6), respectively. These results suggest that In-111 Lym is a more reliable and sensitive radiotracer for detecting early rejection of the transplanted heart in this rat model. (author).

  8. Ultra-low Dose CT for Attenuation Correction of 82Rb Cardiac PET

    DEFF Research Database (Denmark)

    Sørensen, Maria Balshøj; Bouchelouche, Kirsten; Tolbod, Lars Poulsen

    Aim: Myocardial perfusion imaging (MPI) using cardiac PET with tracers like 82Rb and 15O-water is substantially lower in radiation dose than classic MIBI-based SPECT. However, for cardiac PET, the dose contribution of CT for attenuation correction (CTAC) is typically 20-30% of the total dose....... To reduce the total radiation dose of cardiac PET further, we set out to examine if the use of ultra-low dose CTAC (UL-CTAC) would affect the accuracy of the quantitative parameters related to MPI. Furthermore, we examined whether the low quality of the UL-CTAC would affect the technologist’s ability...... to perform manual adjustment for misalignment between PET and CTAC. The CT reconstruction algorithm Q.AC was used to improve quality and consistency of the CTAC. Method: 23 consecutive clinical patients (BMI: 26.9 [range: 15.4-38.8]) referred for 82Rb PET rest and stress imaging were included in the study...

  9. Hydrogen-rich saline attenuates hippocampus endoplasmic reticulum stress after cardiac arrest in rats.

    Science.gov (United States)

    Gao, Yu; Gui, Qinfang; Jin, Li; Yu, Pan; Wu, Lin; Cao, Liangbin; Wang, Qiang; Duan, Manlin

    2017-02-15

    Hydrogen-rich saline can selectively scavenge reactive oxygen species (ROS) and protect brain against ischemia reperfusion (I/R) injury. Endoplasmic reticulum stress (ERS) has been implicated in the pathological process of cerebral ischemia. However, very little is known about the role of hydrogen-rich saline in mediating pathophysiological reactions to ERS after I/R injury caused by cardiac arrest. The rats were randomly divided into three groups, sham group (n=30), ischemia/reperfusion group (n=40) and hydrogen-rich saline group (n=40). The rats in experimental groups were subjected to 4min of cardiac arrest and followed by resuscitation. Then they were randomized to receive 5ml/kg of either hydrogen-rich saline or normal saline. Hydrogen-rich saline significantly improves survival rate and neurological function. The beneficial effects of hydrogen-rich saline were associated with decreased levels of oxidative products, as well as the increased levels of antioxidant enzymes. Furthermore, the protective effects of hydrogen-rich saline were accompanied by the increased activity of glucose-regulated protein 78 (GRP78), the decreased activity of cysteinyl aspartate specific proteinase-12 (caspase-12) and C/EBP homologous protein (CHOP). Hydrogen-rich saline attenuates brain I/R injury may through inhibiting hippocampus ERS after cardiac arrest in rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Rosemary supplementation (Rosmarinus oficinallis L. attenuates cardiac remodeling after myocardial infarction in rats.

    Directory of Open Access Journals (Sweden)

    Bruna Paola Murino Rafacho

    Full Text Available Myocardial infarction (MI is one of the leading causes of morbidity and mortality worldwide. Dietary intervention on adverse cardiac remodeling after MI has significant clinical relevance. Rosemary leaves are a natural product with antioxidant/anti-inflammatory properties, but its effect on morphology and ventricular function after MI is unknown.To determine the effect of the dietary supplementation of rosemary leaves on cardiac remodeling after MI, male Wistar rats were divided into 6 groups after sham procedure or experimental induced MI: 1 Sham group fed standard chow (SR0, n = 23; 2 Sham group fed standard chow supplemented with 0.02% rosemary (R002 (SR002, n = 23; 3 Sham group fed standard chow supplemented with 0.2% rosemary (R02 (SR02, n = 22; 4 group submitted to MI and fed standard chow (IR0, n = 13; 5 group submitted to MI and fed standard chow supplemented with R002 (IR002, n = 8; and 6 group submitted to MI and fed standard chow supplemented with R02 (IR02, n = 9. After 3 months of the treatment, systolic pressure evaluation, echocardiography and euthanasia were performed. Left ventricular samples were evaluated for: fibrosis, cytokine levels, apoptosis, energy metabolism enzymes, and oxidative stress. Rosemary dietary supplementation attenuated cardiac remodeling by improving energy metabolism and decreasing oxidative stress. Rosemary supplementation of 0.02% improved diastolic function and reduced hypertrophy after MI. Regarding rosemary dose, 0.02% and 0.2% for rats are equivalent to 11 mg and 110 mg for humans, respectively.Our findings support further investigations of the rosemary use as adjuvant therapy in adverse cardiac remodeling.

  11. Effects of the novel protein kinase C inhibitor AEB071 (Sotrastaurin) on rat cardiac allograft survival using single agent treatment or combination therapy with cyclosporine, everolimus or FTY720.

    Science.gov (United States)

    Weckbecker, Gisbert; Pally, Charles; Beerli, Christian; Burkhart, Christoph; Wieczorek, Grazyna; Metzler, Barbara; Morris, Randall E; Wagner, Juergen; Bruns, Christian

    2010-05-01

    NVP-AEB071 (AEB, sotrastaurin), an oral inhibitor of protein kinase C (PKC), effectively blocks T-cell activation. The immunosuppressive effects of oral AEB were demonstrated in a rat local graft versus host (GvH) reaction and rat cardiac transplantation models. T-cell activation was suppressed by 95% in blood from AEB-treated rats, with a positive correlation between T-cell inhibition and AEB blood concentration. In GvH studies, AEB inhibited lymph node swelling dose-dependently (3-30 mg/kg). BN and DA cardiac allografts were acutely rejected within 6-10 days post-transplantation in untreated LEW rats. AEB at 10 and 30 mg/kg b.i.d. prolonged BN graft survival to a mean survival time of 15 and >28 days, and DA grafts to 6.5 and 17.5 days, respectively. In the DA to LEW model, combining a nonefficacious dose of AEB (10 mg/kg b.i.d.) with a nonefficacious dose of cyclosporine, everolimus or FTY720 led to prolonged median survival times (26 days, >68 days and >68 days, respectively). Pharmacokinetic monitoring excluded drug-drug interactions, suggesting synergy. In conclusion, these studies are the first to demonstrate that AEB prolongs rat heart allograft survival safely as monotherapy and in combination with nonefficacious doses of cyclosporine, everolimus or FTY720. Thus, AEB may have the potential to offer an alternative to calcineurin inhibitor-based therapies.

  12. Aristoyunnolin H attenuates extracellular matrix secretion in cardiac fibroblasts by inhibiting calcium influx.

    Science.gov (United States)

    Chen, Shao-Rui; Zhang, Wen-Ping; Bao, Jing-Mei; Cheng, Zhong-Bin; Yin, Sheng

    2017-01-01

    Aristoyunnolin H is a novel aristophyllene sesquiterpenoid isolated from the traditional Chinese medicine Aristolochia yunnanensis Franch. The present research was designed to explore the anti-fibrotic effects of aristoyunnolin H in adult rat cardiac fibroblasts (CFs) stimulated with angiotensin II (Ang II). Western blot analysis data showed that aristoyunnolin H reduced the upregulation of fibronectin (FN), connective tissue growth factor and collagen I(Col I) production induced by Ang II in CFs. By studying the dynamic intracellular changes of Ca(2+), we further found that while aristoyunnolin H relieved the calcium influx, it has no effect on intracellular calcium store release. Meanwhile, aristoyunnolin H also inhibited the Ang II-stimulated phosphorylation of Ca(2+)/calmodulin-dependent protein kinase II. In conclusion, aristoyunnolin H may attenuate extracellular matrix secretion in vitro by inhibiting Ang II-induced calcium signaling.

  13. Cardiac-specific overexpression of thioredoxin 1 attenuates mitochondrial and myocardial dysfunction in septic mice.

    Science.gov (United States)

    Sánchez-Villamil, Juana P; D'Annunzio, Verónica; Finocchietto, Paola; Holod, Silvia; Rebagliati, Inés; Pérez, Hernán; Peralta, Jorge G; Gelpi, Ricardo J; Poderoso, Juan J; Carreras, María C

    2016-12-01

    Sepsis-induced myocardial dysfunction is associated with increased oxidative stress and mitochondrial dysfunction. Current evidence suggests a protective role of thioredoxin-1 (Trx1) in the pathogenesis of cardiovascular diseases. However, it is unknown yet a putative role of Trx1 in sepsis-induced myocardial dysfunction, in which oxidative stress is an underlying cause. Transgenic male mice with Trx1 cardiac-specific overexpression (Trx1-Tg) and its wild-type control (wt) were subjected to cecal ligation and puncture or sham surgery. After 6, 18, and 24h, cardiac contractility, antioxidant enzymes, protein oxidation, and mitochondrial function were evaluated. Trx1 overexpression improved the average life expectancy (Trx1-Tg: 36, wt: 28h; p=0.0204). Sepsis induced a decrease in left ventricular developed pressure in both groups, while the contractile reserve, estimated as the response to β-adrenergic stimulus, was higher in Trx1-Tg in relation to wt, after 6h of the procedure. Trx1 overexpression attenuated complex I inhibition, protein carbonylation, and loss of membrane potential, and preserved Mn superoxide dismutase activity at 24h. Ultrastructural alterations in mitochondrial cristae were accompanied by reduced optic atrophy 1 (OPA1) fusion protein, and activation of dynamin-related protein 1 (Drp1) (fission protein) in wt mice at 24h, suggesting mitochondrial fusion/fission imbalance. PGC-1α gene expression showed a 2.5-fold increase in Trx1-Tg at 24h, suggesting mitochondrial biogenesis induction. Autophagy, demonstrated by electron microscopy and increased LC3-II/LC3-I ratio, was observed earlier in Trx1-Tg. In conclusion, Trx1 overexpression extends antioxidant protection, attenuates mitochondrial damage, and activates mitochondrial turnover (mitophagy and biogenesis), preserves contractile reserve and prolongs survival during sepsis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Induced Pluripotent Stem Cells-Derived Mesenchymal Stem Cells Attenuate Cigarette Smoke-Induced Cardiac Remodeling and Dysfunction

    Directory of Open Access Journals (Sweden)

    Yingmin Liang

    2017-07-01

    Full Text Available The strong relationship between cigarette smoking and cardiovascular disease (CVD has been well-documented, but the mechanisms by which smoking increases CVD risk appear to be multifactorial and incompletely understood. Mesenchymal stem cells (MSCs are regarded as an important candidate for cell-based therapy in CVD. We hypothesized that MSCs derived from induced pluripotent stem cell (iPSC-MSCs or bone marrow (BM-MSCs might alleviate cigarette smoke (CS-induced cardiac injury. This study aimed to investigate the effects of BM-MSCs or iPSC-MSCs on CS-induced changes in serum and cardiac lipid profiles, oxidative stress and inflammation as well as cardiac function in a rat model of passive smoking. Male Sprague-Dawley rats were randomly selected for exposure to either sham air (SA as control or 4% CS for 1 h per day for 56 days. On day 29 and 43, human adult BM-MSCs, iPSC-MSCs or PBS were administered intravenously to CS-exposed rats. Results from echocardiography, serum and cardiac lipid profiles, cardiac antioxidant capacity, cardiac pro- and anti-inflammatory cytokines and cardiac morphological changes were evaluated at the end of treatment. iPSC-MSC-treated group showed a greater effect in the improvement of CS-induced cardiac dysfunction over BM-MSCs-treated group as shown by increased percentage left ventricular ejection fraction and percentage fractional shortening, in line with the greater reversal of cardiac lipid abnormality. In addition, iPSC-MSCs administration attenuated CS-induced elevation of cardiac pro-inflammatory cytokines as well as restoration of anti-inflammatory cytokines and anti-oxidative markers, leading to ameliorate cardiac morphological abnormalities. These data suggest that iPSC-MSCs on one hand may restore CS-induced cardiac lipid abnormality and on the other hand may attenuate cardiac oxidative stress and inflammation via inhibition of CS-induced NF-κB activation, leading to improvement of cardiac remodeling and

  15. Uptake of donor lymphocytes treated with 8-methoxypsoralen and ultraviolet A light by recipient dendritic cells induces CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells and down-regulates cardiac allograft rejection

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, De-Hua [Organ Transplant Center, Chinese PLA 309th Hospital, No. 17A Hei-Shan-Hu Road, Beijing 100091 (China); Dou, Li-Ping [Department of Hematology, Chinese PLA General Hospital, No. 28 Fu-Xing Road, Beijing 100853 (China); Wei, Yu-Xiang; Du, Guo-Sheng; Zou, Yi-Ping; Song, Ji-Yong; Zhu, Zhi-Dong; Cai, Ming; Qian, Ye-Yong [Organ Transplant Center, Chinese PLA 309th Hospital, No. 17A Hei-Shan-Hu Road, Beijing 100091 (China); Shi, Bing-Yi, E-mail: shibingyi@medmail.com.cn [Organ Transplant Center, Chinese PLA 309th Hospital, No. 17A Hei-Shan-Hu Road, Beijing 100091 (China)

    2010-05-14

    Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy and has been demonstrated to be beneficial for graft-vs-host disease and solid-organ allograft rejection. ECP involves reinfusion of a patient's autologous peripheral blood leukocytes treated ex vivo with 8-methoxypsoralen and UVA light radiation (PUVA). Previous studies focused only on ECP treatment of recipient immune cells. Our study is the first to extend the target of ECP treatment to donor immune cells. The results of in vitro co-culture experiments demonstrate uptake of donor PUVA-treated splenic lymphocytes (PUVA-SPs) by recipient immature dendritic cells (DCs). Phagocytosis of donor PUVA-SPs does not stimulate phenotype maturation of recipient DCs. In the same co-culture system, donor PUVA-SPs enhanced production of interleukin-10 and interferon-{gamma} by recipient DCs and impaired the subsequent capability of recipient DCs to stimulate recipient naive T cells. Phagocytosis of donor PUVA-SP (PUVA-SP DCs) by recipient DCs shifted T-cell responses in favor of T helper 2 cells. Infusion of PUVA-SP DCs inhibited cardiac allograft rejection in an antigen-specific manner and induced CD4{sup +}CD25{sup high}Foxp3{sup +} regulatory T cells. In conclusion, PUVA-SP DCs simultaneously deliver the donor antigen and the regulatory signal to the transplant recipient, and thus can be used to develop a novel DC vaccine for negative immune regulation and immune tolerance induction.

  16. Evaluation of attenuation correction in cardiac PET using PET/MR.

    Science.gov (United States)

    Lau, Jeffrey M C; Laforest, R; Sotoudeh, H; Nie, X; Sharma, S; McConathy, J; Novak, E; Priatna, A; Gropler, R J; Woodard, P K

    2017-06-01

    Simultaneous acquisition Positron emission tomography/magnetic resonance (PET/MR) is a new technology that has potential as a tool both in research and clinical diagnosis. However, cardiac PET acquisition has not yet been validated using MR imaging for attenuation correction (AC). The goal of this study is to evaluate the feasibility of PET imaging using a standard 2-point Dixon volume interpolated breathhold examination (VIBE) MR sequence for AC. Evaluation was performed in both phantom and patient data. A chest phantom containing heart, lungs, and a lesion insert was scanned by both PET/MR and PET/CT. In addition, 30 patients underwent whole-body 18F-fluorodeoxyglucose PET/CT followed by simultaneous cardiac PET/MR. Phantom study showed 3% reduction of activity values in the myocardium due to the non-inclusion of the phased array coil in the AC. In patient scans, average standardized uptake values (SUVs) obtained by PET/CT and PET/MR showed no significant difference (n = 30, 4.6 ± 3.5 vs 4.7 ± 2.8, P = 0.47). There was excellent per patient correlation between the values acquired by PET/CT and PET/MR (R 2 = 0.97). Myocardial SUVs PET imaging using MR for AC shows excellent correlation with myocardial SUVs obtained by standard PET/CT imaging. The 2-point Dixon VIBE MR technique can be used for AC in simultaneous PET/MR data acquisition.

  17. Secoisolariciresinol diglucoside attenuates cardiac hypertrophy and oxidative stress in monocrotaline-induced right heart dysfunction.

    Science.gov (United States)

    Puukila, Stephanie; Fernandes, Rafael Oliveira; Türck, Patrick; Carraro, Cristina Campos; Bonetto, Jéssica Hellen Poletto; de Lima-Seolin, Bruna Gazzi; da Rosa Araujo, Alex Sander; Belló-Klein, Adriane; Boreham, Douglas; Khaper, Neelam

    2017-08-01

    Pulmonary arterial hypertension (PAH) occurs when remodeling of pulmonary vessels leads to increased pulmonary vascular resistance resulting in increased pulmonary arterial pressure. Increased pulmonary arterial pressure results in right ventricle hypertrophy and eventually heart failure. Oxidative stress has been implicated in the pathogenesis of PAH and may play a role in the regulation of cellular signaling involved in cardiac response to pressure overload. Secoisolariciresinol diglucoside (SDG), a component from flaxseed, has been shown to reduce cardiac oxidative stress in various pathophysiological conditions. We investigated the potential protective effects of SDG in a monocrotaline-induced model of PAH. Five- to six-week-old male Wistar rats were given a single intraperitoneal injection of monocrotaline (60 mg/kg) and sacrificed 21 days later where heart, lung, and plasma were collected. SDG (25 mg/kg) was given via gavage as either a 21-day co-treatment or pre-treatment of 14 days before monocrotaline administration and continued for 21 days. Monocrotaline led to right ventricle hypertrophy, increased lipid peroxidation, and elevated plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST). Co-treatment with SDG did not attenuate hypertrophy or ALT and AST levels but decreased reactive oxygen species (ROS) levels and catalase and superoxide dismutase activity compared to the monocrotaline-treated group. Pre-treatment with SDG decreased right ventricle hypertrophy, ROS levels, lipid peroxidation, catalase, superoxide dismutase, and glutathione peroxidase activity and plasma levels of ALT and AST when compared to the monocrotaline group. These findings indicate that pre-treatment with SDG provided better protection than co-treatment in this model of right heart dysfunction, suggesting an important role for SDG in PAH and right ventricular remodeling.

  18. Allogeneic pASC transplantation in humanized pigs attenuates cardiac remodeling post-myocardial infarction.

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    Rafael Dariolli

    Full Text Available Cell therapy repair strategies using adult mesenchymal stromal cells have shown promising evidence to prevent cardiac deterioration in rodents even in the absence of robust differentiation of the cells into cardiomyocytes. We tested whether increasing doses of porcine adipose-tissue derived mesenchymal stem cells (pASCs increase cardiac tissue perfusion in pigs post-myocardial infarction (MI receiving angiotensin-converting-enzyme inhibitor (ACE inhibitors and Beta-blockers similarly to patients. Female pigs were subjected to MI induction by sponge permanent occlusion of left circumflex coronary artery (LCx generating approximately 10% of injured LV area with minimum hemodynamic impact. We assessed tissue perfusion by real time myocardial perfusion echocardiography (RTMPE using commercial microbubbles before and following pASCs treatment. Four weeks after the occlusion of the left circumflex artery, we transplanted placebo or pASCs (1, 2 and 4x106 cells/Kg BW into the myocardium. The highest dose of pASCs increased myocardial vessel number and blood flow in the border (56% and 3.7-fold, respectively and in the remote area (54% and 3.9-fold, respectively while the non-perfused scar area decreased (up to 38%. We also found an increase of immature collagen fibers, although the increase in total tissue collagen and types I and III was similar in all groups. Our results provide evidence that pASCs-induced stimulation of tissue perfusion and accumulation of immature collagen fibers attenuates adverse remodeling post-MI beyond the normal beneficial effects associated with ACE inhibition and beta-blockade.

  19. Celastrol-Induced Suppression of the MiR-21/ERK Signalling Pathway Attenuates Cardiac Fibrosis and Dysfunction

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    Mian Cheng

    2016-05-01

    Full Text Available Backgroud: Myocardial fibrosis results in myocardial remodelling and dysfunction. Celastrol, a traditional oriental medicine, has been suggested to have cardioprotective effects. However, its underlying mechanism is unknown. This study investigated the ability of celastrol to prevent cardiac fibrosis and dysfunction and explored the underlying mechanisms. Methods: Animal and cell models of cardiac fibrosis were used in this study. Myocardial fibrosis was induced by transverse aortic constriction (TAC in mice. Cardiac hypertrophy and fibrosis were evaluated based on histological and biochemical measurements. Cardiac function was evaluated by echocardiography. The levels of transforming growth factor beta 1 (TGF-β1, extracellular signal regulated kinases 1/2 (ERK1/2 signalling were measured using Western blotting, while the expression of miR-21was analyzed by real-time qRT-PCR in vitro and in vivo. In vitro studies, cultured cardiac fibroblasts (CFs were treated with TGF-β1 and transfected with microRNA-21(miR21. Results: Celastrol treatment reduced the increased collagen deposition and down-regulated α-smooth muscle actin (α-SMA, atrial natriuretic peptide (ANP, brain natriuretic peptides (BNP, beta-myosin heavy chain (β-MHC, miR-21 and p-ERK/ERK. Cardiac dysfunction was significantly attenuated by celastrol treatment in the TAC mice model. Celastrol treatment reduced myocardial fibroblast viability and collagen content and down-regulated α-SMA in cultured CFs in vitro. Celastrol also inhibited the miR-21/ERK signalling pathway. Celastrol attenuated miR-21 up-regulation by TGF-β1 and decreased elevated p-ERK/ERK levels in CFs transfected with miR-21. Conclusion: MiR-21/ERK signalling could be a potential therapeutic pathway for the prevention of myocardial fibrosis. Celastrol ameliorates myocardial fibrosis and cardiac dysfunction, these probably related to miR-21/ERK signaling pathways in vitro and in vivo.

  20. Valsartan attenuates cardiac and renal hypertrophy in rats with experimental cardiorenal syndrome possibly through down-regulating galectin-3 signaling.

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    Zhang, M-J; Gu, Y; Wang, H; Zhu, P-F; Liu, X-Y; Wu, J

    2016-01-01

    Aortocaval fistula (AV) induced chronic volume overload in rats with preexisting mild renal dysfunction (right kidney remove: UNX) could mimic the type 4 cardiorenal syndrome (CRS): chronic renocardiac syndrome. Galectin-3, a β-galactoside binding lectin, is an emerging biomarker in cardiovascular as well as renal diseases. We observed the impact of valsartan on cardiac and renal hypertrophy and galectin-3 changes in this model. Adult male Sprague-Dawley (SD) rats (200-250 g) were divided into S (Sham, n = 7), M (UNX+AV, n = 7) and M+V (UNX+AV+valsartan, n = 7) groups. Eight weeks later, cardiac function was measured by echocardiography. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, renal blood flow and 24 hours albuminuria. Immunohistochemistry and real-time PCR were used to evaluate the expressions of galectin-3 in heart and renal. Cardiac hypertrophy and renal hypertrophy as well as cardiac enlargement were evidenced in this AV shunt induced chronic volume overload rat model with preexisting mild renal dysfunction. Cardiac and renal hypertrophy were significantly attenuated but cardiac enlargement was unaffected by valsartan independent of its blood pressure lowering effect. 24 hours urine albumin was significantly increased, which was significantly reduced by valsartan in this model. Immunohistochemistry and real-time PCR evidenced significantly up-regulated galectin-3 expression in heart and kidney and borderline increased myocardial collagen I expression, which tended to be lower post valsartan treatment. Up-regulated galectin-3 signaling might also be involved in the pathogenesis in this CRS model. The beneficial effects of valsartan in terms of attenuating cardiac and renal hypertrophy and reducing 24 hours albumin in this model might partly be mediated through down-regulating galectin-3 signal pathway.

  1. Cardiac computed tomography-derived epicardial fat volume and attenuation independently distinguish patients with and without myocardial infarction.

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    Amir Abbas Mahabadi

    Full Text Available Epicardial adipose tissue (EAT volume is associated with coronary plaque burden and adverse events. We aimed to determine, whether CT-derived EAT attenuation in addition to EAT volume distinguishes patients with and without myocardial infarction.In 94 patients with confirmed or suspected coronary artery disease (aged 66.9±14.7years, 61%male undergoing cardiac CT imaging as part of clinical workup, EAT volume was retrospectively quantified from non-contrast cardiac CT by delineation of the pericardium in axial images. Mean attenuation of all pixels from EAT volume was calculated. Patients with type-I myocardial infarction (n = 28 had higher EAT volume (132.9 ± 111.9ml vs. 109.7 ± 94.6ml, p = 0.07 and CT-attenuation (-86.8 ± 5.8HU vs. -89.0 ± 3.7HU, p = 0.03 than patients without type-I myocardial infarction, while EAT volume and attenuation were only modestly inversely correlated (r = -0.24, p = 0.02. EAT volume increased per standard deviation of age (18.2 [6.2-30.2] ml, p = 0.003, BMI (29.3 [18.4-40.2] ml, p<0.0001, and with presence of diabetes (44.5 [16.7-72.3] ml, p = 0.0002, while attenuation was higher in patients with lipid-lowering therapy (2.34 [0.08-4.61] HU, p = 0.04. In a model containing volume and attenuation, both measures of EAT were independently associated with the occurrence of type-I myocardial infarction (OR [95% CI]: 1.79 [1.10-2.94], p = 0.02 for volume, 2.04 [1.18-3.53], p = 0.01 for attenuation. Effect sizes remained stable for EAT attenuation after adjustment for risk factors (1.44 [0.77-2.68], p = 0.26 for volume; 1.93 [1.11-3.39], p = 0.02 for attenuation.CT-derived EAT attenuation, in addition to volume, distinguishes patients with vs. without myocardial infarction and is increased in patients with lipid-lowering therapy. Our results suggest that assessment of EAT attenuation could render complementary information to EAT volume regarding coronary risk burden.

  2. MR-based attenuation correction for cardiac FDG PET on a hybrid PET/MRI scanner: comparison with standard CT attenuation correction

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    Vontobel, Jan; Liga, Riccardo; Possner, Mathias; Clerc, Olivier F.; Mikulicic, Fran; Veit-Haibach, Patrick; Voert, Edwin E.G.W. ter; Fuchs, Tobias A.; Stehli, Julia; Pazhenkottil, Aju P.; Benz, Dominik C.; Graeni, Christoph; Gaemperli, Oliver; Herzog, Bernhard; Buechel, Ronny R.; Kaufmann, Philipp A. [University Hospital Zurich, Department of Nuclear Medicine, Zurich (Switzerland)

    2015-09-15

    The aim of this study was to evaluate the feasibility of attenuation correction (AC) for cardiac {sup 18}F-labelled fluorodeoxyglucose (FDG) positron emission tomography (PET) using MR-based attenuation maps. We included 23 patients with no known cardiac history undergoing whole-body FDG PET/CT imaging for oncological indications on a PET/CT scanner using time-of-flight (TOF) and subsequent whole-body PET/MR imaging on an investigational hybrid PET/MRI scanner. Data sets from PET/MRI (with and without TOF) were reconstructed using MR AC and semi-quantitative segmental (20-segment model) myocardial tracer uptake (per cent of maximum) and compared to PET/CT which was reconstructed using CT AC and served as standard of reference. Excellent correlations were found for regional uptake values between PET/CT and PET/MRI with TOF (n = 460 segments in 23 patients; r = 0.913; p < 0.0001) with narrow Bland-Altman limits of agreement (-8.5 to +12.6 %). Correlation coefficients were slightly lower between PET/CT and PET/MRI without TOF (n = 460 segments in 23 patients; r = 0.851; p < 0.0001) with broader Bland-Altman limits of agreement (-12.5 to +15.0 %). PET/MRI with and without TOF showed minimal underestimation of tracer uptake (-2.08 and -1.29 %, respectively), compared to PET/CT. Relative myocardial FDG uptake obtained from MR-based attenuation corrected FDG PET is highly comparable to standard CT-based attenuation corrected FDG PET, suggesting interchangeability of both AC techniques. (orig.)

  3. Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure.

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    Gesmundo, Iacopo; Miragoli, Michele; Carullo, Pierluigi; Trovato, Letizia; Larcher, Veronica; Di Pasquale, Elisa; Brancaccio, Mara; Mazzola, Marta; Villanova, Tania; Sorge, Matteo; Taliano, Marina; Gallo, Maria Pia; Alloatti, Giuseppe; Penna, Claudia; Hare, Joshua M; Ghigo, Ezio; Schally, Andrew V; Condorelli, Gianluigi; Granata, Riccarda

    2017-11-07

    It has been shown that growth hormone-releasing hormone (GHRH) reduces cardiomyocyte (CM) apoptosis, prevents ischemia/reperfusion injury, and improves cardiac function in ischemic rat hearts. However, it is still not known whether GHRH would be beneficial for life-threatening pathological conditions, like cardiac hypertrophy and heart failure (HF). Thus, we tested the myocardial therapeutic potential of GHRH stimulation in vitro and in vivo, using GHRH or its agonistic analog MR-409. We show that in vitro, GHRH(1-44)NH 2 attenuates phenylephrine-induced hypertrophy in H9c2 cardiac cells, adult rat ventricular myocytes, and human induced pluripotent stem cell-derived CMs, decreasing expression of hypertrophic genes and regulating hypertrophic pathways. Underlying mechanisms included blockade of Gq signaling and its downstream components phospholipase Cβ, protein kinase Cε, calcineurin, and phospholamban. The receptor-dependent effects of GHRH also involved activation of Gα s and cAMP/PKA, and inhibition of increase in exchange protein directly activated by cAMP1 (Epac1). In vivo, MR-409 mitigated cardiac hypertrophy in mice subjected to transverse aortic constriction and improved cardiac function. Moreover, CMs isolated from transverse aortic constriction mice treated with MR-409 showed improved contractility and reversal of sarcolemmal structure. Overall, these results identify GHRH as an antihypertrophic regulator, underlying its therapeutic potential for HF, and suggest possible beneficial use of its analogs for treatment of pathological cardiac hypertrophy. Copyright © 2017 the Author(s). Published by PNAS.

  4. Andrographolide Attenuates LPS-Induced Cardiac Malfunctions Through Inhibition of IκB Phosphorylation and Apoptosis in Mice

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    Jinlong Zhang

    2015-11-01

    Full Text Available Background/Aims: Cardiac malfunction is a common complication in sepsis and significantly increases the mortality of patients in septic shock. However, no studies have examined whether andrographolide (And reduces LPS-induced myocardial malfunction. Methods: Left ventricular systolic and diastolic functions were examined using echocardiography. TNF-a and IL-1ß protein levels were detected by an enzyme-linked immunosorbent assay (ELISA. NO oxidation products were determined using Griess reagent. Protein expression levels of inhibitors of NF-κBa (IκB and phospho-IκB were determined via Western blot. Oxidative injury was determined by measuring myocardial lipid peroxidation and superoxide dismutase activity. Cardiac apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nickend-labeling (TUNEL and cardiac caspase 3/7 activity. Results: And blunted LPS-induced myocardial malfunctions in mice. LPS induced TNF-a, IL-1ß, and NO production as well as I-κB phosphorylation. Cardiac apoptosis was attenuated via incubation with And, but the extent of oxidative injury remained unaffected. Conclusion: And prevents LPS-induced cardiac malfunctions in mice by inhibiting TNF-a, IL-1ß, and NO production, IκB phosphorylation, and cardiac apoptosis, indicating that And may be a potential agent for preventing myocardial malfunction during sepsis.

  5. Rapamycin Attenuated Cardiac Hypertrophy Induced by Isoproterenol and Maintained Energy Homeostasis via Inhibiting NF-κB Activation

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    Xi Chen

    2014-01-01

    Full Text Available Rapamycin, also known as sirolimus, is an immunosuppressant drug used to prevent rejection organ (especially kidney transplantation. However, little is known about the role of Rapa in cardiac hypertrophy induced by isoproterenol and its underlying mechanism. In this study, Rapa was administrated intraperitoneally for one week after the rat model of cardiac hypertrophy induced by isoproterenol established. Rapa was demonstrated to attenuate isoproterenol-induced cardiac hypertrophy, maintain the structure integrity and functional performance of mitochondria, and upregulate genes related to fatty acid metabolism in hypertrophied hearts. To further study the implication of NF-κB in the protective role of Rapa, cardiomyocytes were pretreated with TNF-α or transfected with siRNA against NF-κB/p65 subunit. It was revealed that the upregulation of extracellular circulating proinflammatory cytokines induced by isoproterenol was able to be reversed by Rapa, which was dependent on NF-κB pathway. Furthermore, the regression of cardiac hypertrophy and maintaining energy homeostasis by Rapa in cardiomyocytes may be attributed to the inactivation of NF-κB. Our results shed new light on mechanisms underlying the protective role of Rapa against cardiac hypertrophy induced by isoproterenol, suggesting that blocking proinflammatory response by Rapa might contribute to the maintenance of energy homeostasis during the progression of cardiac hypertrophy.

  6. AVE 3085, a novel endothelial nitric oxide synthase enhancer, attenuates cardiac remodeling in mice through the Smad signaling pathway.

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    Chen, Yili; Chen, Cong; Feng, Cong; Tang, Anli; Ma, Yuedong; He, Xin; Li, Yanhui; He, Jiangui; Dong, Yugang

    2015-03-15

    AVE 3085 is a novel endothelial nitric oxide synthase enhancer. Although AVE 3085 treatment has been shown to be effective in spontaneously restoring endothelial function in hypertensive rats, little is known about the effects and mechanisms of AVE 3085 with respect to cardiac remodeling. The present study was designed to examine the effects of AVE 3085 on cardiac remodeling and the mechanisms underlying the effects of this compound. Mice were subjected to aortic banding to induce cardiac remodeling and were then administered AVE 3085 (10 mg kg day(-1), orally) for 4 weeks. At the end of the treatment, the aortic banding-treated mice exhibited significant elevations in cardiac remodeling, characterized by an increase in left ventricular weight relative to body weight, an increase in the area of collagen deposition, an increase in the mean myocyte diameter, and increases in the gene expressions of the hypertrophic markers atrial natriuretic peptide (ANP) and β-MHC. These indexes were significantly decreased in the AVE 3085-treated mice. Furthermore, AVE 3085 treatment reduced the expression and activation of the Smad signaling pathway in the aortic banding-treated mice. Our data showed that AVE 3085 attenuated cardiac remodeling, and this effect was possibly mediated through the inhibition of Smad signaling. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Cardiomyocyte specific expression of Acyl-coA thioesterase 1 attenuates sepsis induced cardiac dysfunction and mortality

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    Xia, Congying [Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Dong, Ruolan [Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (China); Chen, Chen [Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Wang, Hong, E-mail: hong.wang1988@yahoo.com [Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Wang, Dao Wen, E-mail: dwwang@tjh.tjmu.edu.cn [Departments of Internal Medicine and Institute of Hypertension, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China)

    2015-12-25

    Compromised cardiac fatty acid oxidation (FAO) induced energy deprivation is a critical cause of cardiac dysfunction in sepsis. Acyl-CoA thioesterase 1 (ACOT1) is involved in regulating cardiac energy production via altering substrate metabolism. This study aims to clarify whether ACOT1 has a potency to ameliorate septic myocardial dysfunction via enhancing cardiac FAO. Transgenic mice with cardiomyocyte specific expression of ACOT1 (αMHC-ACOT1) and their wild type (WT) littermates were challenged with Escherichia coli lipopolysaccharide (LPS; 5 mg/kg i.p.) and myocardial function was assessed 6 h later using echocardiography and hemodynamics. Deteriorated cardiac function evidenced by reduction of the percentage of left ventricular ejection fraction and fractional shortening after LPS administration was significantly attenuated by cardiomyocyte specific expression of ACOT1. αMHC-ACOT1 mice exhibited a markedly increase in glucose utilization and cardiac FAO compared with LPS-treated WT mice. Suppression of cardiac peroxisome proliferator activated receptor alpha (PPARa) and PPARγ-coactivator-1α (PGC1a) signaling observed in LPS-challenged WT mice was activated by the presence of ACOT1. These results suggest that ACOT1 has potential therapeutic values to protect heart from sepsis mediated dysfunction, possibly through activating PPARa/PGC1a signaling. - Highlights: • ACOT1 has potential therapeutic values to protect heart from sepsis mediated dysfunction. • ACOT1 can regulate PPARa/PGC1a signaling pathway. • We first generate the transgenic mice with cardiomyocyte specific expression of ACOT1.

  8. Chronic Testosterone Replacement Exerts Cardioprotection against Cardiac Ischemia-Reperfusion Injury by Attenuating Mitochondrial Dysfunction in Testosterone-Deprived Rats

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    Pongkan, Wanpitak; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

    2015-01-01

    Background Although testosterone deficiency is associated with increased risks of heart disease, the benefits of testosterone therapy are controversial. Moreover, current understanding on the cardiac effect of testosterone during cardiac ischemia-reperfusion (I/R) periods is unclear. We tested the hypothesis that testosterone replacement attenuates the impairment of left ventricular (LV) function and heart rate variability (HRV), and reduces the infarct size and arrhythmias caused by I/R injury in orchiectomized (ORX) rats. Methodology ORX or sham-operated male Wistar rats (n = 24) were randomly divided and received either testosterone (2 mg/kg, subcutaneously administered) or the vehicle for 8 weeks. The ejection fraction (EF) and HRV were determined at baseline and the 4th and 8th week. I/R was performed by left anterior descending coronary artery ligation for 30 minutes, followed by a 120-minute reperfusion. LV pressure, arrhythmia scores, infarct size and cardiac mitochondrial function were determined. Results Prior to I/R, EF and HRV were impaired in the ORX group, but were restored in the testosterone-treated group. During I/R, arrhythmia scores and the infarct size were greater, and cardiac mitochondrial function was impaired, whereas the time to 1st VT/VF onset and the LV end-systolic pressure were decreased in the ORX group when compared to the sham group. Testosterone replacement attenuated the impairment of these parameters in ORX rats during I/R injury, but did not show any benefit or adverse effect in non-ORX rats. Conclusions Testosterone replacement restores cardiac function and autonomic regulation, and exerts cardioprotective effects during the I/R period via mitochondrial protection in ORX rats. PMID:25822979

  9. Selumetinib, an Oral Anti-Neoplastic Drug, May Attenuate Cardiac Hypertrophy via Targeting the ERK Pathway.

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    Li, Chen; Chen, Zhongxiu; Yang, Hao; Luo, Fangbo; Chen, Lihong; Cai, Huawei; Li, Yajiao; You, Guiying; Long, Dan; Li, Shengfu; Zhang, Qiuping; Rao, Li

    2016-01-01

    Although extracellular-regulated kinases (ERK) are a well-known central mediator in cardiac hypertrophy, no clinically available ERK antagonist has been tested for preventing cardiac hypertrophy. Selumetinib is a novel oral MEK inhibitor that is currently under Phase II and Phase III clinical investigation for advanced solid tumors. In this study, we investigated whether Selumetinib could inhibit the aberrant ERK activation of the heart in response to stress as well as prevent cardiac hypertrophy. In an in vitro model of PE-induced cardiac hypertrophy, Selumetinib significantly inhibited the ERK activation and prevented enlargement of cardiomyocytes or reactivation of certain fetal genes. In the pathologic cardiac hypertrophy model of ascending aortic constriction, Selumetinib provided significant ERK inhibition in the stressed heart but not in the other organs. This selective ERK inhibition prevented left ventricular (LV) wall thickening, LV mass increase, fetal gene reactivation and cardiac fibrosis. In another distinct physiologic cardiac hypertrophy model of a swimming rat, Selumetinib provided a similar anti-hypertrophy effect, except that no significant fetal gene reactivation or cardiac fibrosis was observed. Selumetinib, a novel oral anti-cancer drug with good safety records in a number of Phase II clinical trials, can inhibit ERK activity in the heart and prevent cardiac hypertrophy. These promising results indicate that Selumetinib could potentially be used to treat cardiac hypertrophy. However, this hypothesis needs to be validated in human clinical trials.

  10. An N-(alkylcarbonyl)anthranilic acid derivative prolongs cardiac allograft survival synergistically with cyclosporine A in a high-responder rat model.

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    Chen, Jibing; Xia, Junjie; Axelsson, Bengt; Fritzson, Ingela; Ekberg, Henrik; Törngren, Marie; Qi, Zhongquan

    2010-08-01

    We investigated the immunosuppressive effects of the dihydroortate dehydrogenase (DHODH) inhibitor compounds ABR-222417 and ABR-224050 from Active Biotech (Sweden). We verified the inhibitory effects of these compounds on the proliferation of CD4(+) and CD8(+) T-cells in vivo by using superantigen staphylococcus enterotoxin A (SEA)-mediated proliferation test. To evaluate their efficacy, the compounds were screened in a low-responder heart allograft transplantation model in rats [heart from Piebald Virol Glaxo (PVG) transplanted to Dark Agouti (DA)]. The immunosuppressive effects of the compounds were then investigated in a high-responder model (DA to PVG). Treatment with ABR-222417 (30 mg/kg) was more efficient than that with ABR-224050 (10 mg/kg), and the former provided a longer graft median survival time (MST, 29.5 days) than the latter (MST, 18.5 days). Furthermore, there was a marked increase in graft survival time (53 days) when low doses of ABR-222417 and cyclosporine A (CsA) were used in combination. No sign of tolerability problems was detected using this combination or when ABR-222417 was used singly at a higher dose. Furthermore, T-cell proliferation studies in vitro support that the anti proliferative effect of ABR-222417 is caused by inhibition of de novo pyrimidine synthesis, which is the consequence of DHODH inhibition. These results show that ABR-222417 had marked immunosuppressive effects on the heart allograft transplantation and that it exerts an even more powerful inhibitory effect on graft rejection when used in combination with CsA, with good tolerability. Copyright © 2010 Elsevier B.V. All rights reserved.

  11. Carotid body denervation improves autonomic and cardiac function and attenuates disordered breathing in congestive heart failure.

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    Marcus, Noah J; Del Rio, Rodrigo; Schultz, Evan P; Xia, Xiao-Hong; Schultz, Harold D

    2014-01-15

    In congestive heart failure (CHF), carotid body (CB) chemoreceptor activity is enhanced and is associated with oscillatory (Cheyne-Stokes) breathing patterns, increased sympathetic nerve activity (SNA) and increased arrhythmia incidence. We hypothesized that denervation of the CB (CBD) chemoreceptors would reduce SNA, reduce apnoea and arrhythmia incidence and improve ventricular function in pacing-induced CHF rabbits. Resting breathing, renal SNA (RSNA) and arrhythmia incidence were measured in three groups of animals: (1) sham CHF/sham-CBD (sham-sham); (2) CHF/sham-CBD (CHF-sham); and (3) CHF/CBD (CHF-CBD). Chemoreflex sensitivity was measured as the RSNA and minute ventilatory (VE) responses to hypoxia and hypercapnia. Respiratory pattern was measured by plethysmography and quantified by an apnoea-hypopnoea index, respiratory rate variability index and the coefficient of variation of tidal volume. Sympatho-respiratory coupling (SRC) was assessed using power spectral analysis and the magnitude of the peak coherence function between tidal volume and RSNA frequency spectra. Arrhythmia incidence and low frequency/high frequency ratio of heart rate variability were assessed using ECG and blood pressure waveforms, respectively. RSNA and VE responses to hypoxia were augmented in CHF-sham and abolished in CHF-CBD animals. Resting RSNA was greater in CHF-sham compared to sham-sham animals (43 ± 5% max vs. 23 ± 2% max, P CHF-CBD animals (25 ± 1% max, P CHF-sham). Low frequency/high frequency heart rate variability ratio was similarly increased in CHF and reduced by CBD (P CHF-sham animals and reduced in CHF-CBD animals (P CHF-sham animals (sham-sham 0.49 ± 0.05; CHF-sham 0.79 ± 0.06), and was attenuated in CHF-CBD animals (0.59 ± 0.05) (P CHF-sham and reduced in CHF-CBD animals (213 ± 58 events h(-1) CHF, 108 ± 48 events h(-1) CHF-CBD, P CHF-CBD compared to CHF-sham rabbits. Similar patterns of changes were observed longitudinally within the

  12. Rat adipose tissue-derived stem cells transplantation attenuates cardiac dysfunction post infarction and biopolymers enhance cell retention.

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    Maria E Danoviz

    Full Text Available BACKGROUND: Cardiac cell transplantation is compromised by low cell retention and poor graft viability. Here, the effects of co-injecting adipose tissue-derived stem cells (ASCs with biopolymers on cell cardiac retention, ventricular morphometry and performance were evaluated in a rat model of myocardial infarction (MI. METHODOLOGY/PRINCIPAL FINDINGS: 99mTc-labeled ASCs (1x10(6 cells isolated from isogenic Lewis rats were injected 24 hours post-MI using fibrin a, collagen (ASC/C, or culture medium (ASC/M as vehicle, and cell body distribution was assessed 24 hours later by gamma-emission counting of harvested organs. ASC/F and ASC/C groups retained significantly more cells in the myocardium than ASC/M (13.8+/-2.0 and 26.8+/-2.4% vs. 4.8+/-0.7%, respectively. Then, morphometric and direct cardiac functional parameters were evaluated 4 weeks post-MI cell injection. Left ventricle (LV perimeter and percentage of interstitial collagen in the spare myocardium were significantly attenuated in all ASC-treated groups compared to the non-treated (NT and control groups (culture medium, fibrin, or collagen alone. Direct hemodynamic assessment under pharmacological stress showed that stroke volume (SV and left ventricle end-diastolic pressure were preserved in ASC-treated groups regardless of the vehicle used to deliver ASCs. Stroke work (SW, a global index of cardiac function, improved in ASC/M while it normalized when biopolymers were co-injected with ASCs. A positive correlation was observed between cardiac ASCs retention and preservation of SV and improvement in SW post-MI under hemodynamic stress. CONCLUSIONS: We provided direct evidence that intramyocardial injection of ASCs mitigates the negative cardiac remodeling and preserves ventricular function post-MI in rats and these beneficial effects can be further enhanced by administering co-injection of ASCs with biopolymers.

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

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    Zhipeng Zeng

    2016-01-01

    Full Text Available 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. Daily sesame oil supplementation attenuates local renin-angiotensin system via inhibiting MAPK activation and oxidative stress in cardiac hypertrophy.

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    Liu, Chuan-Teng; Liu, Ming-Yie

    2017-04-01

    The renin-angiotensin system (RAS) is involved in the development of left ventricular hypertrophy (LVH) by which increases cardiac morbidity and mortality. Activation of mitogen-activated protein kinases (MAPKs) and oxidative stress are important in RAS-mediated cardiac hypertrophy. Sesame oil, a potent antioxidant, attenuates hypertension-dependent LVH. We examined the protective role of sesame oil on RAS-mediated MAPK activation and oxidative stress in rats. We induced LVH using a hypertensive model by subcutaneously injecting deoxycorticosterone acetate (DOCA; 15 mg/ml/kg in mineral oil; twice weekly for 5 weeks) and supplementing with 1% sodium chloride drinking water (DOCA/salt) to uninephrectomized rats. Sesame oil was gavaged (0.5 or 1 ml/kg/day for 7 days) after 4 weeks of DOCA/salt treatment. Cardiac histopathology, RAS parameters, expression of MAPKs, reactive oxygen species and lipid peroxidation were assessed 24 h after the last dose of sesame oil. Sesame oil significantly decreased the size of cardiomyocytes and the levels of cardiac renin, angiotensin-converting enzyme and angiotensin II. In addition, sesame oil down-regulated the expression of angiotensin type 1 receptor, JNK and p38 MAPK and apoptosis signal regulating kinase 1, c-Fos and c-Jun in rats receiving DOCA/salt. Furthermore, the induction of nicotinamide adenine dinucleotide phosphate oxidase, superoxide anion and hydroxyl radical and lipid peroxidation by DOCA/salt were inhibited by sesame oil. Sesame oil modulates cardiac RAS to ameliorate LVH by inhibiting MAPK activation and lowering oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Piperine Attenuates Pathological Cardiac Fibrosis Via PPAR-γ/AKT Pathways

    OpenAIRE

    Ma, Zhen-Guo; Yuan, Yu-Pei; Zhang, Xin; Xu, Si-Chi; Wang, Sha-Sha; Tang, Qi-Zhu

    2017-01-01

    Mitogen-activated protein kinases (MAPKs) and AMP?activated protein kinase ? (AMPK?) play critical roles in the process of cardiac hypertrophy. Previous studies have demonstrated that piperine activates AMPK? and reduces the phosphorylation of extracellular signal-regulated kinase (ERK). However, the effect of piperine on cardiac hypertrophy remains completely unknown. Here, we show that piperine-treated mice had similar hypertrophic responses as mice treated with vehicle but exhibited signif...

  16. Antiandrogenic therapy with finasteride attenuates cardiac hypertrophy and left ventricular dysfunction.

    Science.gov (United States)

    Zwadlo, Carolin; Schmidtmann, Elisa; Szaroszyk, Malgorzata; Kattih, Badder; Froese, Natali; Hinz, Hebke; Schmitto, Jan Dieter; Widder, Julian; Batkai, Sandor; Bähre, Heike; Kaever, Volkhard; Thum, Thomas; Bauersachs, Johann; Heineke, Joerg

    2015-03-24

    In comparison with men, women have a better prognosis when experiencing aortic valve stenosis, hypertrophic cardiomyopathy, or heart failure. Recent data suggest that androgens like testosterone or the more potent dihydrotestosterone contribute to the development of cardiac hypertrophy and failure. Therefore, we analyzed whether antiandrogenic therapy with finasteride, which inhibits the generation of dihydrotestosterone by the enzyme 5-α-reductase, improves pathological ventricular remodeling and heart failure. We found a strongly induced expression of all 3 isoforms of the 5-α-reductase (Srd5a1 to Srd5a3) in human and mouse hearts with pathological hypertrophy, which was associated with increased myocardial accumulation of dihydrotestosterone. Starting 1 week after the induction of pressure overload by transaortic constriction, mice were treated with finasteride for 2 weeks. Cardiac function, hypertrophy, dilation, and fibrosis were markedly improved in response to finasteride treatment in not only male, but also in female mice. In addition, finasteride also very effectively improved cardiac function and mortality after long-term pressure overload and prevented disease progression in cardiomyopathic mice with myocardial Gαq overexpression. Mechanistically, finasteride, by decreasing dihydrotestosterone, potently inhibited hypertrophy and Akt-dependent prohypertrophic signaling in isolated cardiac myocytes, whereas the introduction of constitutively active Akt blunted these effects of finasteride. Finasteride, which is currently used in patients to treat prostate disease, potently reverses pathological cardiac hypertrophy and dysfunction in mice and might be a therapeutic option for heart failure. © 2015 American Heart Association, Inc.

  17. Interleukin-6 deficiency attenuates angiotensin II-induced cardiac pathogenesis with increased myocyte hypertrophy.

    Science.gov (United States)

    Chen, Fan; Chen, Dandan; Zhang, Yubin; Jin, Liang; Zhang, Han; Wan, Miyang; Pan, Tianshu; Wang, Xiaochuan; Su, Yuheng; Xu, Yitao; Ye, Junmei

    2017-12-16

    Interleukin-6 (IL-6) signaling is critical for cardiomyocyte hypertrophy, while the role of IL-6 in the pathogenesis of myocardium hypertrophy remains controversial. To determine the essential role of IL-6 signaling for the cardiac development during AngII-induced hypertension, and to elucidate the mechanisms, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were infused subcutaneously with either vehicle or AngII (1.5 μg/h/mouse) for 1 week. Immunohistological and serum studies revealed that the extents of cardiac fibrosis, inflammation and apoptosis were reduced in IL-6 KO heart during AngII-stimulation, while cardiac hypertrophy was obviously induced. To investigate the underlying mechanisms, by using myocardial tissue and neonatal cardiomyocytes, we observed that IL-6/STAT3 signaling was activated under the stimulation of AngII both in vivo and in vitro. Further investigation suggested that STAT3 activation enhances the inhibitory effect of EndoG on MEF2A and hampers cardiomyocyte hypertrophy. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardiac hypertrophy during AngII stimulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Prevention of chronic renal allograft rejection by soluble CD83.

    Science.gov (United States)

    Lan, Zhu; Lian, Dameng; Liu, Weihua; Arp, Jacqueline; Charlton, Brayden; Ge, Wei; Brand, Stephen; Healey, Don; DeBenedette, Mark; Nicolette, Charles; Garcia, Bertha; Wang, Hao

    2010-12-27

    Recombinant human soluble CD83 had previously exhibited significant immunosuppressive properties that involved interference with dendritic cell maturation in both mouse and humans, inhibition of autoimmunity in mice, and induction of antigen-specific mouse cardiac allograft tolerance when used in combination with other immunosuppressive drugs. Our current research focus turned to examining the effects of peritransplant soluble CD83 (sCD83) administration on prevention of chronic renal allograft rejection. Fisher344-to-Lewis orthotopic rat renal transplants were performed with sequential recipient killing on postoperative days (PODs) 2, 14, and 140 to examine both the acute and chronic effects of peritransplant sCD83 treatment in rat recipients. Recipients treated with sCD83 exhibited a marked decrease in IgM and IgG deposition in the graft and antidonor antibody levels in the circulation, as early as POD14 and persisting until POD140. sCD83 treatment also reduced the infiltration of T cells and monocytes into the graft tissue and inhibited intragraft expression of MyD88 and inflammatory cytokine levels during the observation period. sCD83-treated grafts demonstrated normal histology beyond POD140, including dramatic reductions in tubular atrophy and interstitial fibrosis compared with untreated recipients. We have demonstrated that peritransplant treatment with recombinant sCD83 attenuates both innate and adaptive immune responses and leads to prevention of chronic rejection in a rat renal transplant model. Because sCD83 is of human origin, the therapeutic approach used in our rodent transplant model holds significant promise for clinical transplantation.

  19. Garlic oil attenuates the cardiac apoptosis in hamster-fed with hypercholesterol diet.

    Science.gov (United States)

    Cheng, Yi-Chang; Chang, Mu-Hsin; Tsai, Cheng-Chih; Chen, Tung-Sheng; Fan, Chung-Chen; Lin, Chien-Chung; Lai, Chao-Hung; Tsai, Fuu-Jen; Lin, James A; Huang, Chih-Yang

    2013-02-15

    Hypercholesterolemia is a well established risk factor for cardiac cell apoptosis. The purpose of this study is to evaluate the effects of garlic oil on cardiac apoptosis induced by a hypercholesterol diet. Twenty-four male Golden-Syrian hamsters at 3 months of age were randomly divided into three groups, control, cholesterol and garlic oil groups received a chow diet, chow diet with 2% cholesterol, and chow diet with 2% cholesterol and 1% garlic oil for 8 weeks, respectively. The TUNEL-positive apoptotic cells, and several apoptotic proteins were significantly induced in the excised left ventricle in cholesterol group, whereas significant reduction was observed in cholesterol plus garlic oil group. The IGFI receptor dependent survival pathway was inhibited in cholesterol group whereas it was obviously reversed in cholesterol plus garlic oil group. Our results suggest that administration of garlic oil shows protective effects on cardiac apoptosis in rats with high cholesterol intake. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Silencing nox4 in the paraventricular nucleus improves myocardial infarction-induced cardiac dysfunction by attenuating sympathoexcitation and periinfarct apoptosis.

    Science.gov (United States)

    Infanger, David W; Cao, Xian; Butler, Scott D; Burmeister, Melissa A; Zhou, Yi; Stupinski, John A; Sharma, Ram V; Davisson, Robin L

    2010-06-11

    Myocardial infarction (MI)-induced heart failure is characterized by central nervous system-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in heart failure. Redox signaling in the PVN and other central nervous system sites is a primary mechanism of neuro-cardiovascular regulation, and excessive oxidant production by activation of NADPH oxidases (Noxs) is implicated in some neuro-cardiovascular diseases. We tested the hypothesis that Nox-mediated redox signaling in the PVN contributes to MI-induced sympathoexcitation and cardiac dysfunction in mice. Real-time PCR revealed that Nox4 was the most abundantly expressed Nox in PVN under basal conditions. Coronary arterial ligation (MI) caused a selective upregulation of this homolog compared to Nox1 and Nox2. Adenoviral gene transfer of Nox4 (AdsiNox4) to PVN (bilateral) attenuated MI-induced superoxide formation in this brain region (day 14) to the same level as that produced by PVN-targeted gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD). MI mice treated with AdsiNox4 or AdCu/ZnSOD in the PVN showed marked improvement in cardiac function as assessed by echocardiography and left ventricular hemodynamic analysis. This was accompanied by significantly diminished sympathetic outflow and apoptosis in the periinfarct region of the heart. These results suggest that MI causes dysregulation of Nox4-mediated redox signaling in the PVN, which leads to sympathetic overactivation and a decline in cardiac function. Targeted inhibition of oxidant signaling in the PVN could provide a novel treatment for MI-induced heart failure.

  1. Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy following pressure overload

    NARCIS (Netherlands)

    Shimano, Masayuki; Ouchi, Noriyuki; Nakamura, Kazuto; van Wijk, Bram; Ohashi, Koji; Asaumi, Yasuhide; Higuchi, Akiko; Pimentel, David R.; Sam, Flora; Murohara, Toyoaki; van den Hoff, Maurice J. B.; Walsh, Kenneth

    2011-01-01

    Factors secreted by the heart, referred to as "cardiokines," have diverse actions in the maintenance of cardiac homeostasis and remodeling. Follistatin-like 1 (Fstl1) is a secreted glycoprotein expressed in the adult heart and is induced in response to injurious conditions that promote myocardial

  2. Activation of liver X receptors with T0901317 attenuates cardiac hypertrophy in vivo

    NARCIS (Netherlands)

    Kuipers, Irma; Li, Jiang; Vreeswijk-Baudoin, Inge; Koster, Johan; van der Harst, Pim; Sillje, Herman H. W.; Kuipers, Folkert; van Veldhuisen, Dirk J.; van Gilst, Wiek H.; de Boer, Rudolf A.

    2010-01-01

    Liver X receptor (LXR) is a nuclear receptor regulating cholesterol metabolism. Liver X receptor has also been shown to exert anti-proliferative and anti-inflammatory properties. In this study, we evaluated the effect of LXR activation on cardiac hypertrophy in vitro and in vivo. Treatment with the

  3. Preservation of CGRP in myocardium attenuates development of cardiac dysfunction in diabetic rats.

    Science.gov (United States)

    Sun, Tao; Guo, Zheng; Liu, Chao-Jie; Li, Mu-Rong; Li, Tu-Ping; Wang, Xin; Yuan, Da-Jiang

    2016-10-01

    Calcitonin gene-related peptide (CGRP) plays an important role in cardiovascular regulation, which was found reduced in serum of diabetic patients. To test the hypothesis that lack of CGRP in myocardium is associated with diabetic cardiac dysfunction, which may be improved by preservation of CGRP in diabetic rats. Diabetes was induced in male Sprague-Dawley rats by streptozotocin (50mg/kg). Two groups of the diabetic rats, one fed with standard laboratory chew and another with the laboratory food plus hot pepper (containing 0.0174% of capsaicin), to stimulate production and release of CGRP. Cardiac functions were evaluated by measurements of intraventricular pressures after 8weeks of development of diabetes. Transient receptor potential vanilloid type 1 (TRPV1), CGRP, β1-adreneregic receptor and norepinephrine were analyzed. Significantly lower levels of TRPV1 and CGRP were detected in the thoracic dorsal root ganglia (DRG) and myocardium of the diabetic animals, along with significant decline in left ventricular systolic pressure (by 24%) and heart rate (by 25%) and increase of the end-diastolic pressure (by 83%) with obvious reduction of CGRP in the DRG, by 41%, the myocardium (by 30%) and the serum (by 20%). The cardiac performance, the TRPV1 and the CGRP in the diabetic animals fed with hot pepper were well preserved. No any significant change in β1-adreneregic receptor and norepinephrine was detected. The findings may suggest a novel mechanism underlying diabetic cardiac dysfunctions via impairing TRPV1-CGRP pathway in myocardium. Preservation of the TRPV1-CGRP mechanism may prevent the development of cardiac dysfunction in diabetes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Treatment with Fenofibrate plus a low dose of Benznidazole attenuates cardiac dysfunction in experimental Chagas disease

    Directory of Open Access Journals (Sweden)

    Ágata C. Cevey

    2017-12-01

    Full Text Available Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory response observed from the beginning of infection, is critical for the control of parasite proliferation and evolution of Chagas disease. Peroxisome proliferator-activated receptors (PPAR-α, are known to modulate inflammation.In this study we investigated whether a PPAR-α agonist, Fenofibrate, improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricular end-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-α and NOS2 and heart remodeling mediators (MMP-9 and CTGF, and reduced serum creatine kinase activity. The fact that Fenofibrate partially inhibited NOS2 expression and NO release in the presence of a PPAR-α non-competitive inhibitor, suggested it also acted through PPAR-α-independent pathways. Since IκBα cytosolic degradation was inhibited by Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate that Fenofibrate acts through PPAR-α-dependent and -independent pathways.Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease. Keywords: Trypanosoma cruzi, Heart dysfunction, PPAR-α, Fenofibrate treatment, Inflammatory

  5. Alpha-lipoic acid attenuates cardiac fibrosis in Otsuka Long-Evans Tokushima Fatty rats

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    Lee Jung Eun

    2012-09-01

    Full Text Available Abstract Background Hyperglycemia leads to cardiac oxidative stress and an imbalance in glucose homeostasis. Diabetic cardiomyopathy is characterised by cardiac hypertrophy and fibrosis. However, the underlying mechanisms of diabetic cardiomyopathy are not fully understood. This study aimed to investigate the effects of alpha-lipoic acid (ALA on cardiac energy metabolism, antioxidant effect, and fibrosis in the hearts of Otsuka Long-Evans Tokushima fatty (OLETF rats. Methods Animals were separated into non-diabetic Long-Evans Tokushima Otsuka (LETO rats and diabetes-prone OLETF rats with or without ALA (200 mg/kg/day administration for 16 weeks. Diabetic cardiomyopathy was assessed by staining with Sirius Red. The effect of ALA on AMPK signalling, antioxidant enzymes, and fibrosis-related genes in the heart of OLETF rats were performed by Western blot analysis or immunohistochemistry. Results Western blot analysis showed that cardiac adenosine monophosphate-activated kinase (AMPK signalling was lower in OLETF rats than in LETO rats, and that ALA treatment increased the signalling in OLETF rats. Furthermore, the low antioxidant activity in OLETF rats was increased by ALA treatment. In addition to increased Sirius red staining of collagen deposits, transforming growth factor-β1 (TGF-β1 and connective tissue growth factor (CTGF were expressed at higher levels in OLETF rat hearts than in LETO rat hearts, and the levels of these factors were decreased by ALA. Conclusions ALA enhances AMPK signalling, antioxidant, and antifibrogenic effect. Theses findings suggest that ALA may have beneficial effects in the treatment of diabetic cardiomyopathy.

  6. Inhibition of PKR protects against H2O2-induced injury on neonatal cardiac myocytes by attenuating apoptosis and inflammation.

    Science.gov (United States)

    Wang, Yongyi; Men, Min; Xie, Bo; Shan, Jianggui; Wang, Chengxi; Liu, Jidong; Zheng, Hui; Yang, Wengang; Xue, Song; Guo, Changfa

    2016-12-08

    Reactive oxygenation species (ROS) generated from reperfusion results in cardiac injury through apoptosis and inflammation, while PKR has the ability to promote apoptosis and inflammation. The aim of the study was to investigate whether PKR is involved in hydrogen peroxide (H2O2) induced neonatal cardiac myocytes (NCM) injury. In our study, NCM, when exposed to H2O2, resulted in persistent activation of PKR due to NCM endogenous RNA. Inhibition of PKR by 2-aminopurine (2-AP) or siRNA protected against H2O2 induced apoptosis and injury. To elucidate the mechanism, we revealed that inhibition of PKR alleviated H2O2 induced apoptosis companied by decreased caspase3/7 activity, BAX and caspase-3 expression. We also revealed that inhibition of PKR suppressed H2O2 induced NFκB pathway and NLRP3 activation. Finally, we found ADAR1 mRNA and protein expression were both induced after H2O2 treatment through STAT-2 dependent pathway. By gain and loss of ADAR1 expression, we confirmed ADAR1 modulated PKR activity. Therefore, we concluded inhibition of PKR protected against H2O2-induced injury by attenuating apoptosis and inflammation. A self-preservation mechanism existed in NCM that ADAR1 expression is induced by H2O2 to limit PKR activation simultaneously. These findings identify a novel role for PKR/ADAR1 in myocardial reperfusion injury.

  7. L-carnitine attenuates cardiac remodelling rather than vascular remodelling in deoxycorticosterone acetate-salt hypertensive rats.

    Science.gov (United States)

    O'Brien, Daniel; Chunduri, Prasad; Iyer, Abishek; Brown, Lindsay

    2010-04-01

    L-carnitine is an important co-factor in fatty acid metabolism by mitochondria. This study has determined whether oral administration of L-carnitine prevents remodelling and the development of impaired cardiovascular function in deoxycorticosterone acetate (DOCA)-salt hypertensive rats (n = 6-12; #p carnitine (1.2% in food; 0.9 mg/g/day in DOCA-salt rats) decreased blood pressure (DOCA-salt 169 +/- 2; + L-carnitine 148 +/- 6# mmHg), decreased left ventricular wet weights (DOCA-salt 3.02 +/- 0.07; + L-carnitine 2.72 +/- 0.06# mg/g body-wt), decreased inflammatory cells in the replacement fibrotic areas, reduced left ventricular interstitial collagen content (DOCA-salt 14.4 +/- 0.2; + L-carnitine 8.7 +/- 0.5# % area), reduced diastolic stiffness constant (DOCA-salt 26.9 +/- 0.5; + L-carnitine 23.8 +/- 0.5# dimensionless) and decreased plasma malondialdehyde concentrations (DOCA-salt 26.9 +/- 0.8; + L-carnitine 21.2 +/- 0.4# micromol/l) without preventing endothelial dysfunction. L-carnitine attenuated the cardiac remodelling and improved cardiac function in DOCA-salt hypertension but produced minimal changes in aortic wall thickness and vascular function. This study suggests that the mitochondrial respiratory chain is a significant source of reactive oxygen species in the heart but less so in the vasculature in DOCA-salt rats, underlying the relatively selective cardiac responses to L-carnitine treatment.

  8. A knowledge-based method for reducing attenuation artefacts caused by cardiac appliances in myocardial PET/CT

    Science.gov (United States)

    Hamill, James J.; Brunken, Richard C.; Bybel, Bohdan; Di Filippo, Frank P.; Faul, David D.

    2006-06-01

    Attenuation artefacts due to implanted cardiac defibrillator leads have previously been shown to adversely impact cardiac PET/CT imaging. In this study, the severity of the problem is characterized, and an image-based method is described which reduces the resulting artefact in PET. Automatic implantable cardioverter defibrillator (AICD) leads cause a moving-metal artefact in the CT sections from which the PET attenuation correction factors (ACFs) are derived. Fluoroscopic cine images were measured to demonstrate that the defibrillator's highly attenuating distal shocking coil moves rhythmically across distances on the order of 1 cm. Rhythmic motion of this magnitude was created in a phantom with a moving defibrillator lead. A CT study of the phantom showed that the artefact contained regions of incorrect, very high CT values and adjacent regions of incorrect, very low CT values. The study also showed that motion made the artefact more severe. A knowledge-based metal artefact reduction method (MAR) is described that reduces the magnitude of the error in the CT images, without use of the corrupted sinograms. The method modifies the corrupted image through a sequence of artefact detection procedures, morphological operations, adjustments of CT values and three-dimensional filtering. The method treats bone the same as metal. The artefact reduction method is shown to run in a few seconds, and is validated by applying it to a series of phantom studies in which reconstructed PET tracer distribution values are wrong by as much as 60% in regions near the CT artefact when MAR is not applied, but the errors are reduced to about 10% of expected values when MAR is applied. MAR changes PET image values by a few per cent in regions not close to the artefact. The changes can be larger in the vicinity of bone. In patient studies, the PET reconstruction without MAR sometimes results in anomalously high values in the infero-septal wall. Clinical performance of MAR is assessed by two

  9. Severe Hypoglycemia-Induced Fatal Cardiac Arrhythmias Are Augmented by Diabetes and Attenuated by Recurrent Hypoglycemia.

    Science.gov (United States)

    Reno, Candace M; VanderWeele, Jennifer; Bayles, Justin; Litvin, Marina; Skinner, Allie; Jordan, Andrew; Daphna-Iken, Dorit; Fisher, Simon J

    2017-12-01

    We previously demonstrated that insulin-mediated severe hypoglycemia induces lethal cardiac arrhythmias. However, whether chronic diabetes and insulin deficiency exacerbates, and whether recurrent antecedent hypoglycemia ameliorates, susceptibility to arrhythmias remains unknown. Thus, adult Sprague-Dawley rats were randomized into four groups: 1) nondiabetic (NONDIAB), 2) streptozotocin-induced insulin deficiency (STZ), 3) STZ with antecedent recurrent (3 days) hypoglycemia (∼40-45 mg/dL, 90 min) (STZ+RH), and 4) insulin-treated STZ (STZ+Ins). Following treatment protocols, all rats underwent hyperinsulinemic (0.2 units ⋅ kg-1 ⋅ min-1), severe hypoglycemic (10-15 mg/dL) clamps for 3 h with continuous electrocardiographic recordings. During matched nadirs of severe hypoglycemia, rats in the STZ+RH group required a 1.7-fold higher glucose infusion rate than those in the STZ group, consistent with the blunted epinephrine response. Second-degree heart block was increased 12- and 6.8-fold in the STZ and STZ+Ins groups, respectively, compared with the NONDIAB group, yet this decreased 5.4-fold in the STZ+RH group compared with the STZ group. Incidence of third-degree heart block in the STZ+RH group was 5.6%, 7.8-fold less than the incidence in the STZ group (44%). Mortality due to severe hypoglycemia was 5% in the STZ+RH group, 6.2-fold less than that in the STZ group (31%). In summary, severe hypoglycemia-induced cardiac arrhythmias were increased by insulin deficiency and diabetes and reduced by antecedent recurrent hypoglycemia. In this model, recurrent moderate hypoglycemia reduced fatal severe hypoglycemia-induced cardiac arrhythmias. © 2017 by the American Diabetes Association.

  10. Dasatinib Attenuates Pressure Overload Induced Cardiac Fibrosis in a Murine Transverse Aortic Constriction Model.

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    Sundaravadivel Balasubramanian

    Full Text Available Reactive cardiac fibrosis resulting from chronic pressure overload (PO compromises ventricular function and contributes to congestive heart failure. We explored whether nonreceptor tyrosine kinases (NTKs play a key role in fibrosis by activating cardiac fibroblasts (CFb, and could potentially serve as a target to reduce PO-induced cardiac fibrosis. Our studies were carried out in PO mouse myocardium induced by transverse aortic constriction (TAC. Administration of a tyrosine kinase inhibitor, dasatinib, via an intraperitoneally implanted mini-osmotic pump at 0.44 mg/kg/day reduced PO-induced accumulation of extracellular matrix (ECM proteins and improved left ventricular geometry and function. Furthermore, dasatinib treatment inhibited NTK activation (primarily Pyk2 and Fak and reduced the level of FSP1 positive cells in the PO myocardium. In vitro studies using cultured mouse CFb showed that dasatinib treatment at 50 nM reduced: (i extracellular accumulation of both collagen and fibronectin, (ii both basal and PDGF-stimulated activation of Pyk2, (iii nuclear accumulation of Ki67, SKP2 and histone-H2B and (iv PDGF-stimulated CFb proliferation and migration. However, dasatinib did not affect cardiomyocyte morphologies in either the ventricular tissue after in vivo administration or in isolated cells after in vitro treatment. Mass spectrometric quantification of dasatinib in cultured cells indicated that the uptake of dasatinib by CFb was greater that that taken up by cardiomyocytes. Dasatinib treatment primarily suppressed PDGF but not insulin-stimulated signaling (Erk versus Akt activation in both CFb and cardiomyocytes. These data indicate that dasatinib treatment at lower doses than that used in chemotherapy has the capacity to reduce hypertrophy-associated fibrosis and improve ventricular function.

  11. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

    Science.gov (United States)

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S.; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J.; Lipskaia, Larissa; Chemaly, Elie R.

    2015-01-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy. PMID:26260012

  12. RORγt-expressing cells attenuate cardiac remodeling after myocardial infarction.

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    Daichi Enomoto

    Full Text Available Retinoic acid receptor-related orphan nuclear receptor γt (RORγt is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that RORγt plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of RORγt in cardiac remodeling after myocardial infarction (MI remains to be fully elucidated.MI was generated by ligating coronary artery. The expression of RORγt and IL-17A transcripts increased in murine hearts after MI. Additionally, immunohistochemical staining revealed that RORγt-expressing cells infiltrated in the border zone after MI. Flow cytometric analysis showed that RORγt-expressing cells were released from the spleen at day 1 after MI. Though RORγt-expressing cells in spleen expressed γδTCR or CD4, γδTCR+ cells were major population of RORγt-expressing cells that infiltrated into post-infarct myocardium. To address the biological functions of RORγt-expressing cells in infarcted hearts, we used mice with enhanced GFP gene heterozygously knocked-in at RORγt locus (RORγt+/- mice, which physiologically showed reduced expression of RORγt mRNA in thymus. Kaplan-Meier analysis showed that MI-induced mortality was higher in RORγt+/- mice than wild-type (WT mice. Masson's trichrome staining demonstrated that cardiac injury was exacerbated in RORγt+/- mice 7 days after MI (Injured area: RORγt+/-; 42.1±6.5%, WT; 34.0±3.7%, circumference of injured myocardium: RORγt+/-; 61.8±4.8%, WT; 49.6±5.1%, accompanied by exacerbation of cardiac function (fractional shortening: RORγt+/-; 32.9±2.9%, WT; 38.3±3.6%. Moreover, immunohistochemical analyses revealed that capillary density in border zone was significantly reduced in RORγt+/- mice after MI, compared with WT mice, associated with the reduced expression of angiopoietin 2. Finally, the mRNA expression of RORγt, IL-17A, IL-17F and IL-23 receptor (IL-23R mRNA and protein expression of IL-10

  13. Attenuation of human carotid-cardiac vagal baroreflex responses after physical detraining

    Science.gov (United States)

    Convertino, Victor A.; Fritsch, Janice M.

    1992-01-01

    Astronauts who are occupied with prelaunch schedules may have to limit their regular physical exercise routines. To assess a potential effect on blood pressure control, carotid baroreceptor-cardiac reflex responses of 16 men were evaluated before and after two weeks of exercise detraining that followed ten weeks of regular scheduled exercise (30 min/d, 4 d/week at 75 percent V(O2) max). After detraining, the baroreflex stimulus-response relationship had a reduced slope 0.4 msec/mmHg and range of response. In addition, there was a resetting of the relationship on the R-R interval axis. Both the minimum and maximum R-R interval responses to the stimulus were significantly reduced after detraining. Baseline systolic pressure did not change with detraining, and the carotid baroreceptor-cardiac response relationship did not shift on the pressure axis. These results suggest that detraining from regular exercise can compromise vagally-mediated mechanisms of blood pressure regulation.

  14. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhang, Dong-Mei [Department of Physiology, Dalian Medical University, Dalian 116044 (China); Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Suo, Yu-Ping [Department of Obstetrics and Gynecology, Shanxi Provincial People' s Hospital, Taiyuan 030012 (China); Yue, Li-Ying [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China)

    2014-02-01

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  15. Inhibition of TNF-α in hypothalamic paraventricular nucleus attenuates hypertension and cardiac hypertrophy by inhibiting neurohormonal excitation in spontaneously hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Song, Xin-Ai; Jia, Lin-Lin [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Cui, Wei [Department of Endocrinology and Metabolism, First Affiliated Hospital of Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhang, Meng [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Chen, Wensheng [Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Yuan, Zu-Yi [Department of Cardiovascular Medicine, First Affiliated Hospital of Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Guo, Jing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Li, Hui-Hua [Key Laboratory of Remodeling-related Cardiovascular Diseases, Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Liu, Hao, E-mail: haoliu75@163.com [Department of Neurosurgery, First Affiliated Hospital of Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China)

    2014-11-15

    We hypothesized that chronic inhibition of tumor necrosis factor-alpha (TNF-α) in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs), decreasing nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase activities, as well as restoring the neurotransmitters balance in the PVN of spontaneously hypertensive rats (SHR). Adult normotensive Wistar–Kyoto (WKY) and SHR rats received bilateral PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle for 4 weeks. SHR rats showed higher mean arterial pressure and cardiac hypertrophy compared with WKY rats, as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and cardiac atrial natriuretic peptide (ANP) and beta-myosin heavy chain (β-MHC) mRNA expressions. Compared with WKY rats, SHR rats had higher PVN levels of tyrosine hydroxylase, PICs, the chemokine monocyte chemoattractant protein-1 (MCP-1), NF-κB p65 activity, mRNA expressions of NOX-2 and NOX-4, and lower PVN levels of IL-10 and 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma norepinephrine. PVN infusion of pentoxifylline or etanercept attenuated all these changes in SHR rats. These findings suggest that SHR rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between pro- and anti-inflammatory cytokines in the PVN; and chronic inhibition of TNF-α in the PVN delays the progression of hypertension by restoring the balances of neurotransmitters and cytokines in the PVN, and attenuating PVN NF-κB p65 activity and oxidative stress, thereby attenuating hypertension-induced sympathetic hyperactivity and cardiac hypertrophy. - Highlights: • Spontaneously hypertensive rats exhibit neurohormonal excitation in the PVN. • PVN inhibition of

  16. Oral Contraceptives Attenuate Cardiac Autonomic Responses to Musical Auditory Stimulation: Pilot Study.

    Science.gov (United States)

    Milan, Réveni Carmem; Plassa, Bruna Oliveira; Guida, Heraldo Lorena; de Abreu, Luiz Carlos; Gomes, Rayana L; Garner, David M; Valenti, Vitor E

    2015-01-01

    The literature presents contradictory results regarding the effects of contraceptives on cardiac autonomic regulation. The research team aimed to evaluate the effects of musical auditory stimulation on cardiac autonomic regulation in women who use oral contraceptives. The research team designed a transversal observational pilot study. The setting was the Centro de Estudos do Sistema Nervoso Autônomo (CESNA) in the Departamento de Fonoaudiologia at the Universidade Estadual Paulista (UNESP) in Marília, SP, Brazil. Participants were 22 healthy nonathletic and nonsedentary females, all nonsmokers and aged between 18 and 27 y. Participants were divided into 2 groups: (1) 12 women who were not taking oral contraceptives, the control group; and (2) 10 women who were taking oral contraceptives, the oral contraceptive group. In the first stage, a rest control, the women sat with their earphones turned off for 20 min. After that period, the participants were exposed to 20 min of classical baroque music (ie, "Canon in D Major," Johann Pachelbel), at 63-84 dB. Measurements of the equivalent sound levels were conducted in a soundproof room, and the intervals between consecutive heartbeats (R-R intervals) were recorded, with a sampling rate of 1000 Hz. For calculation of the linear indices, the research team used software to perform an analysis of heart rate variability (HRV). Linear indices of HRV were analyzed in the time domain: (1) the standard deviation of normal-to-normal R-R intervals (SDNN), (2) the root-mean square of differences between adjacent normal R-R intervals in a time interval (RMSSD), and (3) the percentage of adjacent R-R intervals with a difference of duration greater than 50 ms (pNN50). The study also analyzed the frequency domain-low frequency (LF), high frequency (HF), and LF/HF ratio. For the control group, the musical auditory stimulation reduced (1) the SDNN from 52.2 ± 10 ms to 48.4 ± 16 ms (P = .0034); (2) the RMSSD from 45.8 ± 22 ms to 41.2

  17. Dietary nitrite supplementation attenuates cardiac remodeling in l-NAME-induced hypertensive rats.

    Science.gov (United States)

    Sonoda, Kunihiro; Ohtake, Kazuo; Uchida, Hiroyuki; Ito, Junta; Uchida, Masaki; Natsume, Hideshi; Tamada, Hazuki; Kobayashi, Jun

    2017-07-01

    Loss of nitric oxide (NO) bioavailability underlies the development of hypertensive heart disease. We investigated the effects of dietary nitrite on N(G)-nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Sprague-Dawley rats were divided into five groups: an untreated control group, an l-NAME-treated group, and three other l-NAME-treated groups supplemented with 10 mg/L or 100 mg/L of nitrite or 100 mg/L of captopril in drinking water. After the 8-week experimental period, mean arterial blood pressure was measured, followed by sampling of blood and heart tissue for assessment of nitrite/nitrate levels in the plasma and heart, the plasma level of angiotensin II (AT II), and the heart transcriptional levels of AT II type 1 receptor (AT1R), transforming growth factor-β1 (TGF-β1), and connective tissue proteins such as type 1 collagen and fibronectin. Heart tissue was analyzed by histopathological morphometry, including assessments of ventricular and coronary vascular hypertrophy and fibrosis, as well as immunohistochemistry analyses of myocardial expression of AT1R. l-NAME treatment reduced the plasma nitrate level and led to the development of hypertension, with increased plasma levels of AT II and increased heart transcriptional levels of AT1R and TGF-β1-mediated connective tissue proteins, showing myocardial and coronary arteriolar hypertrophy and fibrosis. However, dietary nitrite supplementation inhibited TGF-β1-mediated cardiac remodeling by suppressing AT II and AT1R. These results suggest that dietary nitrite levels achievable via a daily high-vegetable diet could improve hypertensive heart disease by inhibiting AT II-AT1R-mediated cardiac remodeling. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Long-Lived αMUPA Mice Show Attenuation of Cardiac Aging and Leptin-Dependent Cardioprotection.

    Directory of Open Access Journals (Sweden)

    Esther Levy

    Full Text Available αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT ancestors due to endogenously increased levels of the satiety hormone leptin. αMUPA mice share many benefits with mice under caloric restriction (CR including an extended life span. To understand mechanisms linked to cardiac aging, we explored the response of αMUPA hearts to ischemic conditions at the age of 6, 18, or 24 months. Mice were subjected to myocardial infarction (MI in vivo and to ischemia/reperfusion ex vivo. Compared to WT mice, αMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while αMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in αMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in αMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin abrogated the αMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the αMUPA myocardium. αMUPA mice did not show elevation in adiponectin, an adipokine previously implicated in CR-induced cardioprotection. WT mice treated for short-term CR exhibited cardioprotection similar to that of αMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in αMUPA mice, indicating the attenuation of cardiac aging. αMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR.

  19. Long-Lived αMUPA Mice Show Attenuation of Cardiac Aging and Leptin-Dependent Cardioprotection.

    Science.gov (United States)

    Levy, Esther; Kornowski, Ran; Gavrieli, Reut; Fratty, Ilana; Greenberg, Gabriel; Waldman, Maayan; Birk, Einat; Shainberg, Asher; Akirov, Amit; Miskin, Ruth; Hochhauser, Edith

    2015-01-01

    αMUPA transgenic mice spontaneously consume less food compared with their wild type (WT) ancestors due to endogenously increased levels of the satiety hormone leptin. αMUPA mice share many benefits with mice under caloric restriction (CR) including an extended life span. To understand mechanisms linked to cardiac aging, we explored the response of αMUPA hearts to ischemic conditions at the age of 6, 18, or 24 months. Mice were subjected to myocardial infarction (MI) in vivo and to ischemia/reperfusion ex vivo. Compared to WT mice, αMUPA showed functional and histological advantages under all experimental conditions. At 24 months, none of the WT mice survived the first ischemic day while αMUPA mice demonstrated 50% survival after 7 ischemic days. Leptin, an adipokine decreasing under CR, was consistently ~60% higher in αMUPA sera at baseline. Leptin levels gradually increased in both genotypes 24h post MI but were doubled in αMUPA. Pretreatment with leptin neutralizing antibodies or with inhibitors of leptin signaling (AG-490 and Wortmannin) abrogated the αMUPA benefits. The antibodies also reduced phosphorylation of the leptin signaling components STAT3 and AKT specifically in the αMUPA myocardium. αMUPA mice did not show elevation in adiponectin, an adipokine previously implicated in CR-induced cardioprotection. WT mice treated for short-term CR exhibited cardioprotection similar to that of αMUPA, however, along with increased adiponectin at baseline. Collectively, the results demonstrate a life-long increased ischemic tolerance in αMUPA mice, indicating the attenuation of cardiac aging. αMUPA cardioprotection is mediated through endogenous leptin, suggesting a protective pathway distinct from that elicited under CR.

  20. Bone allografting in children

    Science.gov (United States)

    Sadovoy, M. A.; Kirilova, I. A.; Podorognaya, V. T.; Matsuk, S. A.; Novoselov, V. P.; Moskalev, A. V.; Bondarenko, A. V.; Afanasev, L. M.; Gubina, E. V.

    2017-09-01

    A total of 522 patients with benign and intermediate bone tumors of various locations, aged 1 to 15 years, were operated in the period from 1996 to 2016. To diagnose skeleton tumors, we used clinical observation, X-ray, and, if indicated, tomography and tumor site biopsy. In the extensive bone resection, we performed bone reconstruction with the replacement of a defect with an allograft (bone strips, deproteinized and spongy grafts), sometimes in the combination with bone autografting. After segmental resection, the defects were filled with bone strips in the form of matchstick grafts; the allografts were received from the Laboratory for Tissue Preparation and Preservation of the Novosibirsk Research Institute of Traumatology and Orthopedics. According to the X-ray data, a complete reorganization of bone grafts occurred within 1.5 to 3 years. The long-term result was assessed as good.

  1. Heart selenoproteins status of metabolic syndrome-exposed pups: A potential target for attenuating cardiac damage.

    Science.gov (United States)

    Serrano, Alejandra; Nogales, Fátima; Sobrino, Paula; Murillo, María Luisa; Carreras, Olimpia; Ojeda, María Luisa

    2016-12-01

    Cardiac hypertrophy is the greatest complication in metabolic syndrome (MS), in dams and in offspring. The most effective therapies to avoid the evolution of MS are anti-oxidants, anti-inflammatories, and insulin sensitizers. Among anti-oxidant elements, Selenium (Se) exerts its functions through selenoproteins, which are essential for the correct functioning of the cardiovascular system. The aim of the study is analyze selenoproteins' implication in the transmission of future cardiovascular problems to MS progeny. Heart Se deposits, antioxidant enzymes' activities, biomolecular oxidation, and the expression of selenoproteins, AMPK, and NF-kB were measured in the offspring of dams exposed to a fructose-rich diet (65%) during gestation and lactation, with a normal Se content (0.1 ppm). Thyroid hormones and MCP-1 serum levels, as well as blood pressure and heart rate were also measured. Fructose-exposed pups have cardiomegaly, oxidation, and depletion in Se heart deposits, a decrease in selenoproteins' expression and in the p-AMPK/AMPKt energy ratio; an increase in NF-kB p65 expression, and a decrease of thyroid hormones and MCP-1. Heart rate and blood pressure were altered. These data indicate that dietary Se supplementation could be an inexpensive therapy for avoiding future cardiovascular complication in the progeny of MS dams. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. The Cardiac Sympathetic Nerve Activity in the Elderly Is Attenuated in the Right Lateral Decubitus Position

    Science.gov (United States)

    Sasaki, Konosuke; Haga, Mayu; Bao, Sarina; Sato, Haruka; Saiki, Yoshikatsu; Maruyama, Ryoko

    2017-01-01

    Objectives: The aim of this study was to evaluate the effect of the supine, left lateral decubitus, and right lateral decubitus positions on autonomic nervous activity in elderly adults by using spectral analysis of heart rate variability (HRV). Method: Forty-five adults aged 73.6 ± 5.7 years were enrolled. After lying in the supine position, all participants moved to the lateral decubitus positions in a random order and maintained the positions for 10 min, while electrocardiographic data were recorded to measure HRV. Results: The lowest heart rate continued for 10 min when participants were in the left lateral decubitus position compared with the other two positions (p < .001), while the HRV indexes remained unchanged. The low-frequency HRV to high-frequency HRV ratio (LF/HF) for the right lateral decubitus position was significantly lower than that for the other positions. Discussion: The right lateral decubitus position may attenuate sympathetic nerve activity in elderly adults. PMID:28516131

  3. Sulforaphane improves oxidative status without attenuating the inflammatory response or cardiac impairment induced by ischemia-reperfusion in rats.

    Science.gov (United States)

    Bonetto, Jéssica Hellen Poletto; Fernandes, Rafael Oliveira; Seolin, Bruna Gazzi de Lima; Müller, Dalvana Daneliza; Teixeira, Rayane Brinck; Araujo, Alex Sander; Vassallo, Dalton; Schenkel, Paulo Cavalheiro; Belló-Klein, Adriane

    2016-05-01

    Sulforaphane, a natural isothiocyanate, demonstrates cardioprotection associated with its capacity to stimulate endogenous antioxidants and to inhibit inflammation. The aim of this study was to investigate whether sulforaphane is capable of attenuating oxidative stress and inflammatory responses through the TLR4/MyD88/NFκB pathway, and thereby could modulate post-ischemic ventricular function in isolated rat hearts submitted to ischemia and reperfusion. Male Wistar rats received sulforaphane (10 mg·kg(-1)·day(-1)) or vehicle i.p. for 3 days. Global ischemia was performed using isolated hearts, 24 h after the last injection, by interruption of the perfusion flow. The protocol included a 20 min pre-ischemic period followed by 20 min of ischemia and a 20 min reperfusion. Although no changes in mechanical function were observed, sulforaphane induced a significant increase in superoxide dismutase and heme oxygenase-1 expression (both 66%) and significantly reduced reactive oxygen species levels (7%). No differences were observed for catalase and glutathione peroxidase expression or their activities, nor for thioredoxin reductase, glutaredoxin reductase and glutathione-S-transferase. No differences were found in lipid peroxidation or TLR4, MyD88, and NF-κB expression. In conclusion, although sulforaphane was able to stimulate endogenous antioxidants modestly, this result did not impact inflammatory signaling or cardiac function of hearts submitted to ischemia and reperfusion.

  4. Desmodium gangeticum root extract attenuates isoproterenol-induced cardiac hypertrophic growth in rats.

    Directory of Open Access Journals (Sweden)

    Divya Hitler

    2014-10-01

    Full Text Available Context: Desmodium gangeticum (L DC (Fabaceae; DG, a medicinal plant that grows in tropical habitats, is widely used to treat various ailments including digestive and inflammatory disorders. Aims: To investigate the possible cardioprotective activity of a DG root extract against isoproterenol (ISO-induced left ventricular cardiac hypertrophy (LVH in adult Wistar rats. Methods: Daily intraperitoneal administration of ISO (10 mg/kg body weight, single injection for 7 days induced LVH in rats. The LVH rats were post-treated orally with DG (100 mg/kg body weight for a period of 30 days. Thereafter, changes in heart weight (HW and body weight (BW, HW/BW ratio, percent of hypertrophy, collagen accumulation, activities of matrix metalloproteinase (MMP -2 and -9, superoxide dismutase (SOD and catalase (CAT enzymes, and the level of an oxidative stress marker, lipid peroxide (LPO, were determined. Results: HW/BW ratio, an indicator of hypertrophic growth, was significantly reduced in DG root post-treated LVH rats as compared with that for the non-treated LVH rats. The altered levels of ventricular LPO, collagen, MMPs-2 and -9, and antioxidant enzymes in the ISO-treated animals reverted back to near normal upon DG treatment. Further, the anti-hypertrophic activity of DG was comparable to that of the standard drug losartan (10 mg/kg. Conclusions: The results of the present study suggest that the aqueous root extract of DG exhibited anti-hypertrophic activity in-vivo by inhibiting ISO-induced ROS generation and MMP activities.

  5. Normovolaemic haemodilution attenuates cardiac depression induced by sodium bicarbonate in canine metabolic acidosis.

    Science.gov (United States)

    Tanaka, M; Nishikawa, T; Mizutani, T

    1996-09-01

    This study was designed to determine if coexisting metabolic acidosis or normovolaemic haemodilution, or both, modifies the acute cardiodepressant effect of i.v. sodium bicarbonate. Thirty-one mongrel dogs were anaesthetized with halothane, and the lungs ventilated mechanically; dogs were allocated randomly to one of four groups: control group (pHa 7.39 (SD 0.03), base excess -1.0 (1.6) mmol litre-1, haemoglobin 13.9 (2.5) g dl-1 (n = 8)), metabolic acidosis group (pHa 7.21 (0.05), base excess -11.2 (2.1) mmol litre1, haemoglobin 13.4 (2.6) g dl-1 (n = 8)), anaemia group (pHa 7.40 (0.04), base excess 0.1 (2.0) mmol litre-1, haemoglobin 7.2 (1.1) g dl-1 (n = 8)) or anaemia acidosis group (pHa 7.22 (0.04), base excess -11.0 (2.2) mmol litre-1, haemoglobin 7.4 (0.3) g dl-1 (n = 7)). Metabolic acidosis was induced by continuous i.v. infusion of hydrochloric acid 2 mol litre-1. Normovolaemic haemodilution was undertaken by phlebotomy and simultaneous exchange with lactated Ringer's solution at 37 degrees C. Mean arterial pressure (MAP), pulmonary artery pressure, right atrial pressure (RAP), maximum rate of change of pressure in the right ventricle (RV dP/dtmax) and pulmonary blood flow (PBF) were measured at 30 s, 1 and 3 min after administration of 7% sodium bicarbonate solution 1 mmol kg-1 given into the right atrium over 5 s. Sodium bicarbonate produced significant decreases in MAP and RV dP/dtmax at 30 s in all groups except for the anaemia acidosis group (P sodium bicarbonate 1 mmol kg-1 i.v. during metabolic acidosis was more pronounced than without acidosis, but was attenuated in the presence of normovolaemic haemodilution.

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

    Science.gov (United States)

    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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Trimetazidine attenuates pressure overload-induced early cardiac energy dysfunction via regulation of neuropeptide Y system in a rat model of abdominal aortic constriction.

    Science.gov (United States)

    Chen, Ailan; Li, Wanglin; Chen, Xinyu; Shen, Yuechun; Dai, Wenjun; Dong, Qi; Li, Xinchun; Ou, Caiwen; Chen, Minsheng

    2016-11-17

    Metabolism remodeling has been recognized as an early event following cardiac pressure overload. However, its temporal association with ventricular hypertrophy has not been confirmed. Moreover, whether trimetazidine could favorably affect this process also needs to be determined. The aim of the study was to explore the temporal changes of myocardial metabolism remodeling following pressure-overload induced ventricular hypertrophy and the potential favorable effect of trimetazidine on myocardial metabolism remodeling. A rat model of abdominal aortic constriction (AAC)-induced cardiac pressure overload was induced. These rats were grouped as the AAC (no treatment) or TMZ group according to whether oral trimetazidine (TMZ, 40 mg/kg/d, for 5 days) was administered. Changes in cardiac structures were sequentially evaluated via echocardiography. The myocardial ADP/ATP ratio was determined to reflect the metabolic status, and changes in serum neuropeptide Y systems were evaluated. Myocardial metabolic disorder was acutely induced as evidenced by an increased ADP/ATP ratio within 7 days of AAC before the morphological changes in the myocardium, accompanied by up-regulation of serum oxidative stress markers and expression of fetal genes related to hypertrophy. Moreover, the serum NPY and myocardial NPY-1R, 2R, and 5R levels were increased within the acute phase of AAC-induced cardiac pressure overload. Pretreatment with TMZ could partly attenuate myocardial energy metabolic homeostasis, decrease serum levels of oxidative stress markers, attenuate the induction of hypertrophy-related myocardial fetal genes, inhibit the up-regulation of serum NPY levels, and further increase the myocardial expression of NPY receptors. Cardiac metabolic remodeling is an early change in the myocardium before the presence of typical morphological ventricular remodeling following cardiac pressure overload, and pretreatment with TMZ may at least partly reverse the acute metabolic disturbance

  8. Cardiac Shock Wave Therapy Attenuates H9c2 Myoblast Apoptosis by Activating the AKT Signal Pathway

    Directory of Open Access Journals (Sweden)

    Weiwei Yu

    2014-04-01

    Full Text Available Background: Previous studies have demonstrated that Cardiac Shock Wave Therapy (CSWT improves myocardial perfusion and cardiac function in a porcine model of chronic myocardial ischemia and also ameliorates myocardial ischemia in patients with severe coronary artery disease (CAD. Apoptosis plays a key role in ischemic myocardial pathogenesis. However, it remains unclear whether CSWT is beneficial for ischemia/hypoxia (I/H-induced myocardial cell apoptosis and by which mechanism CSWT could improve heart function. We put forward the hypothesis that CSWT might protect heart function during ischemia/hypoxia by decreasing apoptosis. Methods: We generated ischemia/hypoxia (I/H-induced apoptosis in the H9c2 myoblast cell line to examine the CSWT function and possible mechanisms. H9c2 cells were treated under hypoxic serum-starved conditions for 24 h and then treated with or without CSWT (500 shots, 0.06, 0.09, 0.12mJ/mm2. The apoptotic cell rate was determined by flow cytometry assay, cell viability was examined by the MTT assay, nuclear fragmentation was detected by Hoechst 33342 staining, and the mitochondrial-mediated intrinsic pathway of apoptosis was assessed by the expression of Bax and Bcl-2 protein and Caspase3 activation. Results: First, apoptosis could be induced by ischemia/hypoxia in H9c2 cells. Second, CSWT attenuates the cell death and decreases the H9c2 cell apoptosis rate induced by ischemia and hypoxia. Third, CSWT suppresses the expression of apoptosis molecules that regulate the intrinsic pathway of apoptosis in H9c2 cells. Fourth, CSWT increases the phosphorylation of AKT, which indicates the activation of the PI3K-AKT pathway. Conclusions: These results indicate that CSWT exerts a protective effect against I/H-induced cell death, potentially by preventing the activation of components of the mitochondrial-dependent intrinsic apoptotic pathway. We also demonstrate that the PI3K-Akt pathway may be involved in the CSWT effects on

  9. Mechanical ventilation with high tidal volumes attenuates myocardial dysfunction by decreasing cardiac edema in a rat model of LPS-induced peritonitis

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    Smeding Lonneke

    2012-03-01

    Full Text Available Abstract Background Injurious mechanical ventilation (MV may augment organ injury remote from the lungs. During sepsis, myocardial dysfunction is common and increased endothelial activation and permeability can cause myocardial edema, which may, among other factors, hamper myocardial function. We investigated the effects of MV with injuriously high tidal volumes on the myocardium in an animal model of sepsis. Methods Normal rats and intraperitoneal (i.p. lipopolysaccharide (LPS-treated rats were ventilated with low (6 ml/kg and high (19 ml/kg tidal volumes (Vt under general anesthesia. Non-ventilated animals served as controls. Mean arterial pressure (MAP, central venous pressure (CVP, cardiac output (CO and pulmonary plateau pressure (Pplat were measured. Ex vivo myocardial function was measured in isolated Langendorff-perfused hearts. Cardiac expression of endothelial vascular cell adhesion molecule (VCAM-1 and edema were measured to evaluate endothelial inflammation and leakage. Results MAP decreased after LPS-treatment and Vt-dependently, both independent of each other and with interaction. MV Vt-dependently increased CVP and Pplat and decreased CO. LPS-induced peritonitis decreased myocardial function ex vivo but MV attenuated systolic dysfunction Vt-dependently. Cardiac endothelial VCAM-1 expression was increased by LPS treatment independent of MV. Cardiac edema was lowered Vt-dependently by MV, particularly after LPS, and correlated inversely with systolic myocardial function parameters ex vivo. Conclusion MV attenuated LPS-induced systolic myocardial dysfunction in a Vt-dependent manner. This was associated with a reduction in cardiac edema following a lower transmural coronary venous outflow pressure during LPS-induced coronary inflammation.

  10. Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Kristine Yee

    Full Text Available Epicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI, but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy.We studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22 post-MI. Next, a dose-ranging, blinded, randomized, placebo-controlled ("dose optimization" study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16. Finally, the superior product and dose (150 million cardiospheres were tested in a blinded, randomized, placebo-controlled ("pivotal" study (n = 22. Contrast-enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo.Dose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration.

  11. Physical phantom evaluation of EM-IntraSPECT (EMIS) algorithm for nonuniform attenuation correction in cardiac imaging

    Science.gov (United States)

    Krol, Andrzej; Bowsher, James E.; Feiglin, David H.; Gagne, George M.; Hellwig, Bradford J.; Tornai, Martin P.; Thomas, Frank D.

    2001-07-01

    The purpose of this study was to evaluate performance of the EM-IntraSPECT (EMIS) algorithm for non-uniform attenuation correction in the chest. EMIS is a maximum-likelihood expectation maximization (MLEM) algorithm for simultaneously estimating SPECT emission and attenuation parameters from emission data alone. EMIS uses the activity within the patient as transmission tomography sources, with which attenuation coefficients can be estimated. A thorax phantom with a normal heart was used. The activity images reconstructed by EMIS were compared to images reconstructed using a conventional MLEM with a fixed uniform attenuation map. Uniformity of normal heart was improved with EMIS as compared to a conventional MLEM.

  12. Impairment of cardiac function and remodeling induced by myocardial infarction in rats are attenuated by the nonpeptide angiotensin-(1-7) analog AVE 0991.

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    Zeng, Wu-tao; Chen, Wei-yan; Leng, Xiu-yu; Tang, Li-long; Sun, Xiu-ting; Li, Cui-ling; Dai, Gang

    2012-06-01

    We evaluated effects of the nonpeptide angiotensin (ANG)-(1-7) analog AVE 0991 (AVE) on cardiac function and remodeling as well as transforming growth factor-beta1 (TGF-β1)/tumor necrosis factor-alpha (TNF-α) expression in myocardial infarction rat models. Sprague-Dawley rats underwent either sham surgery or coronary ligation. They were divided into four groups: sham, control, AVE, and AVE+A-779 [[D-Ala(7) ]-ANG-(1-7), a selective antagonist for the ANG-(1-7)] group. After 4 weeks of treatment, the AVE group displayed a significant elevation in left ventricular fractional shorting (LVFS) (25.5 ± 7.3% vs. 18.4 ± 3.3%, P AVE group when compared to the control group. There were no differences in LVFS, LVEF, myocyte diameter, and infarct size between the control and AVE+A-779 groups. AVE also markedly attenuated the increased mRNA expression of collagen I (P AVE could improve cardiac function and attenuate ventricular remodeling in MI rat models. It may involve the inhibition of inflammatory factors TGF-β1/TNF-α overexpression and the action on the specific receptor Mas of ANG-(1-7). © 2010 Blackwell Publishing Ltd.

  13. Restoration of Circulating MFGE8 (Milk Fat Globule-EGF Factor 8) Attenuates Cardiac Hypertrophy Through Inhibition of Akt Pathway.

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    Deng, Ke-Qiong; Li, Jing; She, Zhi-Gang; Gong, Jun; Cheng, Wen-Lin; Gong, Fu-Han; Zhu, Xue-Yong; Zhang, Yan; Wang, Zhihua; Li, Hongliang

    2017-10-01

    Cardiac hypertrophy occurs in response to numerous stimuli like neurohumoral stress, pressure overload, infection, and injury, and leads to heart failure. Mfge8 (milk fat globule-EGF factor 8) is a secreted protein involved in various human diseases, but its regulation and function during cardiac hypertrophy remain unexplored. Here, we found that circulating MFGE8 levels declined significantly in failing hearts from patients with dilated cardiomyopathy. Correlation analyses revealed that circulating MFGE8 levels were negatively correlated with the severity of cardiac dysfunction and remodeling in affected patients. Deleting Mfge8 in mice maintained normal heart function at basal level but substantially exacerbated the hypertrophic enlargement of cardiomyocytes, reprogramming of pathological genes, contractile dysfunction, and myocardial fibrosis after aortic banding surgery. In contrast, cardiac-specific Mfge8 overexpression in transgenic mice significantly blunted aortic banding-induced cardiac hypertrophy. Whereas MAPK (mitogen-activated protein kinase) pathways were unaffected in either Mfge8 -knockout or Mfge8 -overexpressing mice, the activated Akt/PKB (protein kinase B)-Gsk-3β (glycogen synthase kinase-3β)/mTOR (mammalian target of rapamycin) pathway after aortic banding was significantly potentiated by Mfge8 deficiency but suppressed by Mfge8 overexpression. Inhibition of Akt with MK-2206 blocked the prohypertrophic effects of Mfge8 deficiency in angiotensin II-treated neonatal rat cardiomyocytes. Finally, administering a recombinant human MFGE8 in mice in vivo alleviated cardiac hypertrophy induced by aortic banding. Our findings indicate that Mfge8 is an endogenous negative regulator of pathological cardiac hypertrophy and may, thus, have potential both as a novel biomarker and as a therapeutic target for treatment of cardiac hypertrophy. © 2017 American Heart Association, Inc.

  14. Stimulation of ganglionated plexus attenuates cardiac neural remodeling and heart failure progression in a canine model of acute heart failure post-myocardial infarction.

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    Luo, Da; Hu, Huihui; Qin, Zhiliang; Liu, Shan; Yu, Xiaomei; Ma, Ruisong; He, Wenbo; Xie, Jing; Lu, Zhibing; He, Bo; Jiang, Hong

    2017-12-01

    Heart failure (HF) is associated with autonomic dysfunction. Vagus nerve stimulation has been shown to improve cardiac function both in HF patients and animal models of HF. The purpose of this present study is to investigate the effects of ganglionated plexus stimulation (GPS) on HF progression and autonomic remodeling in a canine model of acute HF post-myocardial infarction. Eighteen adult mongrel male dogs were randomized into the control (n=8) and GPS (n=10) groups. All dogs underwent left anterior descending artery ligation followed by 6-hour high-rate (180-220bpm) ventricular pacing to induce acute HF. Transthoracic 2-dimensional echocardiography was performed at different time points. The plasma levels of norepinephrine, B-type natriuretic peptide (BNP) and Ang-II were measured using ELISA kits. C-fos and nerve growth factor (NGF) proteins expressed in the left stellate ganglion as well as GAP43 and TH proteins expressed in the peri-infarct zone were measured using western blot. After 6h of GPS, the left ventricular end-diastolic volume, end-systolic volume and ejection fraction showed no significant differences between the 2 groups, but the interventricular septal thickness at end-systole in the GPS group was significantly higher than that in the control group. The plasma levels of norepinephrine, BNP, Ang-II were increased 1h after myocardial infarction while the increase was attenuated by GPS. The expression of c-fos and NGF proteins in the left stellate ganglion as well as GAP43 and TH proteins in cardiac peri-infarct zone in GPS group were significantly lower than that in control group. GPS inhibits cardiac sympathetic remodeling and attenuates HF progression in canines with acute HF induced by myocardial infarction and ventricular pacing. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Fruit vinegars attenuate cardiac injury via anti-inflammatory and anti-adiposity actions in high-fat diet-induced obese rats.

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    Bounihi, Abdenour; Bitam, Arezki; Bouazza, Asma; Yargui, Lyece; Koceir, Elhadj Ahmed

    2017-12-01

    Fruit vinegars (FVs) are used in Mediterranean folk medicine for their hypolipidemic and weight-reducing properties. To investigate the preventive effects of three types of FV, commonly available in Algeria, namely prickly pear [Opuntia ficus-indica (L.) Mill (Cectaceae)], pomegranate [Punica granatum L. (Punicaceae)], and apple [Malus domestica Borkh. (Rosaceae)], against obesity-induced cardiomyopathy and its underlying mechanisms. Seventy-two male Wistar rats were equally divided into 12 groups. The first group served as normal control (distilled water, 7 mL/kg bw), and the remaining groups were respectively treated with distilled water (7 mL/kg bw), acetic acid (0.5% w/v, 7 mL/kg bw) and vinegars of pomegranate, apple or prickly pear (at doses of 3.5, 7 and 14 mL/kg bw, acetic acid content as mentioned above) along with a high-fat diet (HFD). The effects of the oral administration of FV for 18 weeks on the body and visceral adipose tissue (VAT) weights, plasma inflammatory and cardiac enzymes biomarkers, and in heart tissue were evaluated. Vinegars treatments significantly (p < .05) attenuated the HFD-induced increase in bw (0.2-0.5-fold) and VAT mass (0.7-1.8-fold), as well as increase in plasma levels of CRP (0.1-0.3-fold), fibrinogen (0.2-0.3-fold), leptin (1.7-3.7-fold), TNF-α (0.1-0.6-fold), AST (0.9-1.4-fold), CK-MB (0.3-1.4-fold) and LDH (2.7-6.7-fold). Moreover, vinegar treatments preserved myocardial architecture and attenuated cardiac fibrosis. These findings suggest that pomegranate, apple and prickly pear vinegars may prevent HFD-induced obesity and obesity-related cardiac complications, and that this prevention may result from the potent anti-inflammatory and anti-adiposity properties of these vinegars.

  16. Activation of angiotensin-(1-7)/Mas axis in the brain lowers blood pressure and attenuates cardiac remodeling in hypertensive transgenic (mRen2)27 rats.

    Science.gov (United States)

    Kangussu, Lucas M; Guimaraes, Priscila S; Nadu, Ana Paula; Melo, Marcos B; Santos, Robson A S; Campagnole-Santos, Maria Jose

    2015-10-01

    Activation of the peripheral angiotensin-(1-7)/Mas axis of the renin-angiotensin system produces important cardioprotective actions, counterbalancing the deleterious actions of an overactivity of Ang II/AT1 axis. In the present study we evaluated whether the chronic increase in Ang-(1-7) levels in the brain could ameliorate cardiac disorders observed in transgenic (mRen2)27 hypertensive rats through actions on Mas receptor. Sprague Dawley (SD) and transgenic (mRen2)27 hypertensive rats, instrumented with telemetry probe for arterial pressure (AP) measurement were subjected to 14 days of ICV infusion of Ang-(1-7) (200 ng/h) or Ang-(1-7) associated with Mas receptor antagonist (A779, 1 μg/h) or 0.9% sterile saline (0.5 μl/h) through osmotic mini-pumps. Ang-(1-7) infusion in (mRen2)27 rats reduced blood pressure, normalized the baroreflex control of HR, restored cardiac autonomic balance, reduced cardiac hypertrophy and pre-fibrotic alterations and decreased the altered imbalance of Ang II/Ang-(1-7) in the heart. In addition, there was an attenuation of the increased levels of atrial natriuretic peptide, brain natriuretic peptide, collagen I, fibronectin and TGF-β in the heart of (mRen2)27 rats. Furthermore, most of these effects were mediated in the brain by Mas receptor, since were blocked by its selective antagonist, A779. These data indicate that increasing Ang-(1-7) levels in the brain can attenuate cardiovascular disorders observed in (mRen2)27 hypertensive rats, probably by improving the autonomic balance to the heart due to centrally-mediated actions on Mas receptor. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling

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    Allyson eKranstuber

    2012-07-01

    Full Text Available Diabetic heart disease is a distinct clinical entity that can progress to heart failure and sudden death. However, the mechanisms responsible for the alterations in excitation-contraction coupling leading to cardiac dysfunction during diabetes are not well known. Hyperglycemia, the landmark of diabetes, leads to the formation of advanced glycation end products (AGE on long-lived proteins, including SR Ca2+ regulatory proteins. However, their pathogenic role on SR Ca2+ handling in cardiac myocytes is unknown. Therefore, we investigated whether an AGE cross-link breaker could prevent the alterations in SR Ca2+ cycling that lead to in vivo cardiac dysfunction during diabetes. Streptozotocin-induced diabetic rats were treated with Alagebrium Chloride (ALT-711 for 8 weeks and compared to age-matched placebo-treated diabetic rats and healthy rats. Cardiac function was assessed by echocardiographic examination. Ventricular myocytes were isolated to assess SR Ca2+ cycling by confocal imaging and quantitative Western blots. Diabetes resulted in in vivo cardiac dysfunction and ALT-711 therapy partially alleviated diastolic dysfunction by decreasing isovolumetric relaxation time and myocardial performance index (by 27 and 41% vs. untreated diabetic rats, respectively, P<0.05. In cardiac myocytes, diabetes induced prolongation of cytosolic Ca2+ transient clearance by 43% and decreased SR Ca2+ load by 25% (P<0.05; these parameters were partially improved after ALT-711 therapy. SERCA2a and RyR2 protein expression was significantly decreased in the myocardium of untreated diabetic rats (by 64 and 36% vs. controls, respectively, P<0.05, but preserved in the treated diabetic group compared to controls. Collectively, our result suggest that, in a model of type 1 diabetes, AGE accumulation primarily impairs SR Ca2+ reuptake in cardiac myocytes and that long term treatment with an AGE cross-link breaker partially normalized SR Ca2+ handling and improved diabetic

  18. RU28318, an Aldosterone Antagonist, in Combination with an ACE Inhibitor and Angiotensin Receptor Blocker Attenuates Cardiac Dysfunction in Diabetes

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    Ibrahim F. Benter

    2013-01-01

    Full Text Available Aims. We evaluated the effects of RU28318 (RU, a selective mineralocorticoid receptor (MR antagonist, Captopril (Capt, an angiotensin converting enzyme inhibitor, and Losartan (Los, an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R- induced cardiac dysfunction in hearts obtained from normal and diabetic rats. Methods. Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I followed by a period of 30 min of reperfusion (R. Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple. Recovery of cardiac hemodynamics was evaluated. Results. Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment. Conclusions. RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving -dP/dt (a measure of diastolic function when administered to diabetic hearts after ischemia.

  19. Platelet-derived or soluble CD154 induces vascularized allograft rejection independent of cell-bound CD154

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    Xu, He; Zhang, Xiaojie; Mannon, Roslyn B.; Kirk, Allan D.

    2006-01-01

    CD154 is a cell surface molecule expressed on activated T cells that binds to CD40, an activating molecule on APCs. Its blockade has been shown to prevent allograft rejection, presumably by interrupting interactions between T cells and APCs. It is known that activated human platelets express and shed CD154 and can induce APC activation and other immune processes in vitro. Here we show that platelet-derived CD154 is sufficient to initiate cardiac allograft rejection independent of any cellular...

  20. Neutrophil mediated smooth muscle cell loss precedes allograft vasculopathy

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    Lee Timothy DG

    2010-06-01

    Full Text Available Abstract Background Cardiac allograft vasculopathy (AV is a pathological process of vascular remodeling leading to late graft loss following cardiac transplantation. While there is consensus that AV is alloimmune mediated, and evidence that the most important alloimmune target is medial smooth muscle cells (SMC, the role of the innate immune response in the initiation of this disease is still being elucidated. As ischemia reperfusion (IR injury plays a pivotal role in the initiation of AV, we hypothesize that IR enhances the early innate response to cardiac allografts. Methods Aortic transplants were performed between fully disparate mouse strains (C3H/HeJ and C57BL/6, in the presence of therapeutic levels of Cyclosporine A, as a model for cardiac AV. Neutrophils were depleted from some recipients using anti-PMN serum. Grafts were harvested at 1,2,3,5d and 1,2wk post-transplant. Ultrastructural integrity was examined by transmission electron microscopy. SMC and neutrophils were quantified from histological sections in a blinded manner. Results Grafts exposed to cold ischemia, but not transplanted, showed no medial SMC loss and normal ultrastructural integrity. In comparison, allografts harvested 1d post-transplant exhibited > 90% loss of SMC (p Conclusions These novel data show that there is extensive damage to medial SMC at 1d post-transplant. By depleting neutrophils from recipients it was demonstrated that a portion of the SMC loss was mediated by neutrophils. These results provide evidence that IR activation of early innate events contributes to the etiology of AV.

  1. Silencing Nox4 in the Paraventricular Nucleus Improves Myocardial Infarction-Induced Cardiac Dysfunction by Attenuating Sympathoexcitation and Peri-infarct Apoptosis

    Science.gov (United States)

    Infanger, David W.; Cao, Xian; Butler, Scott D.; Burmeister, Melissa A.; Zhou, Yi; Stupinski, John A.; Sharma, Ram V.; Davisson, Robin L.

    2010-01-01

    Rationale: Myocardial infarction (MI)-induced heart failure (HF) is characterized by central nervous system (CNS)-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in HF. Redox signaling in the PVN and other CNS sites is a primary mechanism of neuro-cardiovascular regulation, and excessive oxidant production by activation of NADPH oxidases (Nox) is implicated in some neuro-cardiovascular diseases. Objective: We tested the hypothesis that Nox-mediated redox signaling in the PVN contributes to MI-induced sympathoexcitation and cardiac dysfunction in mice. Methods and Results: Real-time PCR revealed that Nox4 was the most abundantly expressed Nox in PVN under basal conditions. Coronary arterial ligation (MI) caused a selective upregulation of this homologue compared to Nox1 and Nox2. Adenoviral gene transfer of Nox4 siRNA (AdsiNox4) to PVN (bilateral) attenuated MI-induced superoxide formation in this brain region (day 14) to the same level as that produced by PVN-targeted gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD). MI mice treated with AdsiNox4 or AdCu/ZnSOD in the PVN showed marked improvement in cardiac function as assessed by echocardiography and left ventricular hemodynamic analysis. This was accompanied by significantly diminished sympathetic outflow and apoptosis in the peri-infarct region of the heart. Conclusions: These results suggest that MI causes dysregulation of Nox4-mediated redox signaling in the PVN, which leads to sympathetic overactivation and a decline in cardiac function. Targeted inhibition of oxidant signaling in the PVN could provide a novel treatment for MI-induced HF. PMID:20413786

  2. What do we really know about allografts?

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    Amendola, Annunziato; Stolley, Mary P

    2009-04-01

    The use of allografts in sports medicine is becoming increasingly popular, and, therefore, this issue of Clinics in Sports Medicine is dedicated to the use of allografts in sports medicine. The majority of indications are related to the use of soft tissue grafts for ligament reconstruction, osteochondral (OC) allografts for articular surface reconstruction, and meniscal allografts for meniscal transplantation. There is an increasing amount of science and literature dealing with healing and outcomes, but many questions still remain. There are a number of issues, controversies, and lack of long-term outcomes to make definitive statements on what is really known about allograft use in sports medicine.

  3. Attenuated Cardiac Mitochondrial-Dependent Apoptotic Effects by Li-Fu Formula in Hamsters Fed with a Hypercholesterol Diet

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    Wei-Wen Kuo

    2011-01-01

    Full Text Available Apoptosis involves in the pathogenesis of various cardiac abnormalities. This study intends to evaluate the effects of Li-Fu formula on cardiac apoptosis induced by hyper-cholesterol diet. Twenty-four male Golden Syrian hamsters were randomly divided into Control, Cholesterol and Li-Fu formula groups. Histopathological analysis, western blotting and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL assays were performed to measure the effects of Li-Fu formula on left ventricle. Significantly reduced TUNEL-positive cells and mitochondria- dependent apoptosis were observed in the left ventricle of hamsters from Li-Fu formula group compared to the Cholesterol group. Additionally, induced cardiac insulin like growth factor I receptor (IGFIR-dependent survival pathway was detected in the Li-Fu formula group compared to the Cholesterol group. Besides, minor fibrosis, increased collagen deposition, and myofibril disarray was detected in the Cholesterol group, whereas the reductions of collagen deposition and myofibril disarray were observed in the Li-Fu formula group. This study demonstrated that Li-Fu formula not only reduced the mitochondria-dependent apoptosis and fibrosis, but also enhanced the IGF-I survival pathway in the left ventricle from high cholesterol-fed hamsters. We suggest the protective effects of Li-Fu formula on cardiac apoptosis and therapeutic potentials against cardiovascular disease.

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

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

    2017-02-05

    We investigated the role of tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) on pressure overload-induced cardiac hypertrophy and the underlying molecular mechanisms by using a TRADD deficiency mice model. 6-8 weeks wild-type and TRADD knockout mice were performed to transverse aorta constriction (TAC) or sham operation (6-8 mice for each group). 14 days after TAC, cardiac function was measured by echocardiography, as well as by pathological and molecular analyses of heart samples. The expressions of cardiac hypertrophic and fibrotic markers were detected by qPCR. Phosphorylated and total TAK1, Akt, and p38 MAPK levels were examined by Western blotting. The ratios of lung or heart/body weight, wall thickness/chamber diameter of left ventricular and cross area of cardiomyocyte were significantly reduced in TRADD knockout (KO) mice than those of wild-type mice after TAC. Moreover, cardiac hypertrophic and fibrotic markers were downregulated in TRADD knockout mice than those of wild-type mice following TAC. Protein expression analysis showed phosphorylated TAK1, p38 MAPK and AKT were upregulated after TAC in both wild-type and TRADD KO mice, phosphorylation of TAK1 and p38 MAPK was reduced more remarkably after TRADD deficiency, while phosphorylated AKT expression was similar between TRADD KO and wild-type mice following TAC. Our data suggest that TRADD KO blunts pressure overload-induced cardiac hypertrophy through mediating TAK1/p38 MAPK but not AKT phosphorylation in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Inhibition of histone methyltransferase EZH2 ameliorates early acute renal allograft rejection in rats.

    Science.gov (United States)

    Li, Long; Zhang, Yi; Xu, Ming; Rong, Ruiming; Wang, Jina; Zhu, Tongyu

    2016-10-26

    Although histone methyltransferases EZH2 has been proved to have significant regulatory effect on the immune rejection after hematopoietic stem cell transplantation, its role in solid-organ transplantation remains uncovered. In this study, we investigate whether histone methylation regulation can impact renal allograft rejection in rat models. Allogeneic rat renal transplantation model (Wistar to Lewis) was established, and the recipients were administrated with EZH2 inhibitor DZNep after transplantation. Renal allografts and peripheral blood were collected on day 5 after transplantation for histological examination and mechanism investigation. We found that inhibition of EZH2 by DZNep after transplantation significantly ameliorated acute rejection (AR), with decreased histological injury and reduced inflammatory infiltration in renal allografts. Attenuation of AR was due to the prohibited activation of alloreactive T cells, the subsequent impaired production of inflammatory cytokines, and also the elevated apoptosis of alloreactive T cells in both renal allografts and periphery. However, inhibition of EZH2 did not increase the regulatory T cells during the AR. Disruption of EZH2 by DZNep suppressed the immune responses of alloreactive T cells and ameliorated AR of renal allografts. This suggests a therapeutic potential of targeting histone methyltransferases EZH2 in treating allograft rejection after solid organ transplantation.

  6. Probucol Attenuates Cyclophosphamide-induced Oxidative Apoptosis, p53 and Bax Signal Expression in Rat Cardiac Tissues

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    Yousif A. Asiri

    2010-01-01

    Full Text Available Cyclophosphamide (CP is a widely used drug in cancer chemotherapy and immunosuppression, which could cause toxicity of the normal cells due to its toxic metabolites. Probucol, a cholesterol-lowering drug, acts as potential inhibitor of DNA damage and shows to protect against doxorubicin-induced cardiomyopathy by enhancing the endogenous antioxidant system including glutathione peroxidase, catalase and superoxide dismutase. This study examined the possible protective effects of probucol, a lipid-lowering compound with strong antioxidant properties, against CPinduced cardiotoxicity. This objective could be achieved through studying the gene expression-based on the possible protective effects of probucol against CP-induced cardiac failure in rats. Adult male Wistar albino rats were assigned into four treatment groups: Animals in the first (control and second (probucol groups were injected intraperitoneally with corn oil and probucol (61 mg/kg/day, respectively, for two weeks. Animals in the third (CP and fourth (probucol plus CP groups were injected with the same doses of corn oil and probucol (61 mg/kg/day, respectively, for one week before and one week after a single dose of CP (200 mg/kg, I.P.. The p53, Bax, Bcl2 and oxidative genes signal expression were measured by real time PCR. CP-induced cardiotoxicity was clearly observed by a significant increase in serum creatine phosphokinase isoenzyme (CK-MB (117%, lactate dehydrogenase (LDH (64%, free (69% and esterified cholesterol (42% and triglyceride (69% compared to control group. In cardiac tissues, CP significantly increases the mRNA expression levels of apoptotic genes, p53 with two-fold and Bax with 1.6-fold, and decreases the anti-apoptotic gene Bcl2 with 0.5-fold. Moreover, CP caused downregulation of antioxidant genes, glutathione peroxidase, catalase, and superoxide dismutase and increased the lipid peroxidation and decreased adenosine triphosphate (ATP (40% and ATP/ADP (44% in cardiac

  7. Therapeutic hypothermia attenuates global cerebral reperfusion-induced mitochondrial damage by suppressing dynamin-related protein 1 activation and mitochondria-mediated apoptosis in a cardiac arrest rat model.

    Science.gov (United States)

    Fan, Jingjing; Cai, Shenquan; Zhong, Hao; Cao, Liangbin; Hui, Kangli; Xu, Miaomiao; Duan, Manlin; Xu, Jianguo

    2017-04-24

    Therapeutic hypothermia is effective to attenuate brain ischemia/reperfusion (I/R) injury after cardiac arrest, and multiple mechanisms have been proposed. Dynamin-related protein 1 (Drp1), a large GTPases of dynamin superfamily, predominantly controls mitochondrial fission and is related to IR-induced Cyt C release and apoptosis. However, the effect of therapeutic hypothermia on Drp1 and mitochondrial fission after cardiac arrest remains still unclear. In this study, non-cardiac arrest and post-cardiac arrest rats received 6-h normothermia (37-38°C) or therapeutic hypothermia (32-34°C), and the hippocampus was harvested at 6h and 72h after cardiac arrest. Results showed the expression of Drp1 and Cyt C increased after cardiac arrest, but therapeutic hypothermia partially reversed this increase at 6h after cardiac arrest. Transmission electron microscopy (TEM) also showed a change in morphology following therapeutic hypothermia after cardiac arrest. Moreover, therapeutic hypothermia could decrease the histopathological damage, inhibit the apoptosis of CA1 neurons and improve the survival and neurological outcomes at 72h after cardiac arrest. Taken together, our study demonstrates that therapeutic hypothermia is neuroprotective against global cerebral I/R injury, which is, at least partially, ascribed to the inhibition Drp1 and Cyt C expression and the protection of mitochondrial structure. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. CXCR4 Antagonist TG-0054 Mobilizes Mesenchymal Stem Cells, Attenuates Inflammation, and Preserves Cardiac Systolic Function in a Porcine Model of Myocardial Infarction.

    Science.gov (United States)

    Hsu, Wan-Tseng; Jui, Hsiang-Yiang; Huang, Ying-Huey; Su, Mao-Yuan M; Wu, Yen-Wen; Tseng, Wen-Yih I; Hsu, Ming-Chu; Chiang, Bor-Luen; Wu, Kenneth K; Lee, Chii-Ming

    2015-01-01

    Interaction between chemokine stromal cell-derived factor 1 and the CXC chemokine receptor 4 (CXCR4) governs the sequestration and mobilization of bone marrow stem cells. We investigated the therapeutic potential of TG-0054, a novel CXCR4 antagonist, in attenuating cardiac dysfunction after myocardial infarction (MI). In miniature pigs (minipigs), TG-0054 mobilized CD34(+)CXCR4(+), CD133(+)CXCR4(+), and CD271(+)CXCR4(+) cells into peripheral circulation. After isolation and expansion, TG-0054-mobilized CD271(+) cells were proved to be mesenchymal stem cells (designated CD271-MSCs) since they had trilineage differentiation potential, surface markers of MSCs, and immunosuppressive effects on allogeneic lymphocyte proliferation. MI was induced in 22 minipigs using balloon occlusion of the left anterior descending coronary artery, followed by intravenous injections of 2.85 mg/kg of TG-0054 or saline at 3 days and 7 days post-MI. Serial MRI analyses revealed that TG-0054 treatment prevented left ventricular (LV) dysfunction at 12 weeks after MI (change of LV ejection fraction from baseline, -1.0 ± 6.2% in the TG-0054 group versus -7.9 ± 5.8% in the controls). The preserved cardiac function was accompanied by a significant decrease in the myocardial expression of TNF-α, IL-1β, and IL-6 at 7 days post-MI. Moreover, the plasma levels of TNF-α, IL-1β, and IL-6 were persistently suppressed by the TG-0054 treatment. Infusion of TG-0054-mobilized CD271-MSCs reduced both myocardial and plasma cytokine levels in a pattern, which is temporally correlated with TG-0054 treatment. This study demonstrated that TG-0054 improves the impaired LV contractility following MI, at least in part, by mobilizing MSCs to attenuate the postinfarction inflammation. This insight may facilitate exploring novel stem cell-based therapy for treating post-MI heart failure.

  9. Resveratrol Co-Treatment Attenuates the Effects of HIV Protease Inhibitors on Rat Body Weight and Enhances Cardiac Mitochondrial Respiration.

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    Burger Symington

    Full Text Available Since the early 1990s human immunodeficiency virus (HIV/acquired immunodeficiency syndrome (AIDS emerged as a global health pandemic, with sub-Saharan Africa the hardest hit. While the successful roll-out of antiretroviral (ARV therapy provided significant relief to HIV-positive individuals, such treatment can also elicit damaging side-effects. Here especially HIV protease inhibitors (PIs are implicated in the onset of cardio-metabolic complications such as type-2 diabetes and coronary heart disease. As there is a paucity of data regarding suitable co-treatments within this context, this preclinical study investigated whether resveratrol (RSV, aspirin (ASP or vitamin C (VitC co-treatment is able to blunt side-effects in a rat model of chronic PI exposure (Lopinavir/Ritonavir treatment for 4 months. Body weights and weight gain, blood metabolite levels (total cholesterol, HDL, LDL, triglycerides, echocardiography and cardiac mitochondrial respiration were assessed in PI-treated rats ± various co-treatments. Our data reveal that PI treatment significantly lowered body weight and cardiac respiratory function while no significant changes were found for heart function and blood metabolite levels. Moreover, all co-treatments ameliorated the PI-induced decrease in body weight after 4 months of PI treatment, while RSV co-treatment enhanced cardiac mitochondrial respiratory capacity in PI-treated rats. This pilot study therefore provides novel hypotheses regarding RSV co-treatment that should be further assessed in greater detail.

  10. Pre-Conditioning with CDP-Choline Attenuates Oxidative Stress-Induced Cardiac Myocyte Death in a Hypoxia/Reperfusion Model

    Science.gov (United States)

    González-Pacheco, Héctor; Méndez-Domínguez, Aurelio; Hernández, Salomón; López-Marure, Rebeca; Vazquez-Mellado, Maria J.; Aguilar, Cecilia; Rocha-Zavaleta, Leticia

    2014-01-01

    Background. CDP-choline is a key intermediate in the biosynthesis of phosphatidylcholine, which is an essential component of cellular membranes, and a cell signalling mediator. CDP-choline has been used for the treatment of cerebral ischaemia, showing beneficial effects. However, its potential benefit for the treatment of myocardial ischaemia has not been explored yet. Aim. In the present work, we aimed to evaluate the potential use of CDP-choline as a cardioprotector in an in vitro model of ischaemia/reperfusion injury. Methods. Neonatal rat cardiac myocytes were isolated and subjected to hypoxia/reperfusion using the coverslip hypoxia model. To evaluate the effect of CDP-choline on oxidative stress-induced reperfusion injury, the cells were incubated with H2O2 during reperfusion. The effect of CDP-choline pre- and postconditioning was evaluated using the cell viability MTT assay, and the proportion of apoptotic and necrotic cells was analyzed using the Annexin V determination by flow cytometry. Results. Pre- and postconditioning with 50 mg/mL of CDP-choline induced a significant reduction of cells undergoing apoptosis after hypoxia/reperfusion. Preconditioning with CDP-choline attenuated postreperfusion cell death induced by oxidative stress. Conclusion. CDP-choline administration reduces cell apoptosis induced by oxidative stress after hypoxia/reperfusion of cardiac myocytes. Thus, it has a potential as cardioprotector in ischaemia/reperfusion-injured cardiomyocytes. PMID:24578622

  11. Diazoxide Attenuates Postresuscitation Brain Injury in a Rat Model of Asphyxial Cardiac Arrest by Opening Mitochondrial ATP-Sensitive Potassium Channels

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    Haidong Wu

    2016-01-01

    Full Text Available Objective. We investigated whether and how diazoxide can attenuate brain injury after cardiopulmonary resuscitation (CPR by selective opening of mitochondrial ATP-sensitive potassium (mitoKATP channels. Methods. Adult male Sprague-Dawley rats with induced cerebral ischemia (n=10 per group received an intraperitoneal injection of 0.1% dimethyl sulfoxide (1 mL; vehicle group, diazoxide (10 mg/kg; DZ group, or diazoxide (10 mg/kg plus 5-hydroxydecanoate (5 mg/kg; DZ + 5-HD group 30 min after CPR. The control group (sham group, n=5 underwent sham operation, without cardiac arrest. Mitochondrial respiratory control rate (RCR was determined. Brain cell apoptosis was assessed using TUNEL staining. Expression of Bcl-2, Bax, and protein kinase C epsilon (PKCε in the cerebral cortex was determined by Western blotting and immunohistochemistry. Results. The neurological deficit scores (NDS in the vehicle group decreased significantly at 24 h and 48 h after CPR. Diazoxide significantly improved NDS and mitochondrial RCR after CPR at both time points; 5-HD cotreatment abolished these effects. Diazoxide decreased TUNEL-positive cells following CPR, upregulated Bcl-2 and PKCε, downregulated Bax, and increased the Bcl-2/Bax ratio; 5-HD cotreatment reversed these effects. Conclusions. Diazoxide attenuates postresuscitation brain injury, protects mitochondrial function, inhibits brain cell apoptosis, and activates the PKC pathway by opening mitoKATP channels.

  12. Validation of attenuation correction using transmission truncation compensation with a small field of view dedicated cardiac SPECT camera system.

    Science.gov (United States)

    Noble, Gavin L; Ahlberg, Alan W; Kokkirala, Aravind Rao; Cullom, S James; Bateman, Timothy M; Cyr, Giselle M; Katten, Deborah M; Tadeo, Glenn D; Case, James A; O'Sullivan, David M; Heller, Gary V

    2009-01-01

    Although attenuation correction (AC) has been successfully applied to large field of view (LFOV) cameras, applicability to small field of view (SFOV) cameras is a concern due to truncation. This study compared perfusion images between a LFOV and SFOV camera with truncation compensation, using the same AC solution. Seventy-eight clinically referred patients underwent rest-stress single-photon emission computed tomography (SPECT) using both a SFOV and LFOV camera in a randomized sequence. Blinded images were interpreted by a consensus of three experienced readers. The percentage of normal images for SFOV and LFOV was significantly higher with than without AC (72% vs 44% and 72% vs 49%, both P cameras was better with than without AC (kappa = 0.736 to 0.847 vs 0.545 to 0.774). Correlation for the summed stress score was higher with than without AC (r (2) = 0.892 vs 0.851, both P camera yields similar results to a LFOV camera. The higher interpretive agreement between cameras after attenuation correction suggests that such images are preferable to non-attenuation-corrected images.

  13. Targeted P2X7 R shRNA delivery attenuates sympathetic nerve sprouting and ameliorates cardiac dysfunction in rats with myocardial infarction.

    Science.gov (United States)

    Gao, Hongmei; Yin, Jie; Shi, Yugen; Hu, Hesheng; Li, Xiaolu; Xue, Mei; Cheng, Wenjuan; Wang, Ye; Li, Xinran; Li, Yongkang; Wang, Yu; Yan, Suhua

    2017-04-01

    Inflammation-dominated sympathetic sprouting adjacent to the necrotic region following myocardial infarction (MI) has been implicated in the etiology of arrhythmias resulting in sudden cardiac death; however, the mechanisms responsible remain to be elucidated. Although P2X7 R is a key immune mediator, its role has yet to be explored. We investigated whether P2X7 R regulates NF-κB and affects cardiac sympathetic reinnervation in rats undergoing MI. An adenoviral vector with a short hairpin RNA (shRNA) sequence inserted was adopted for the inhibition of P2X7 R in vivo. Myocardial infarction was induced by left coronary artery ligation, and immediately after that, recombinant P2X7 R-shRNA adenovirus, negative adenovirus (control), or normal saline solution (vehicle) was injected intramyocardially around the MI region and border areas. A high level of P2X7 R was activated in the infarcted tissue at an early stage. The administration of P2X7 R RNAi resulted in the inhibition of Akt and Erk1/2 phosphorylation and decreased the activation of NF-κB and macrophage infiltration, as well as attenuated the expression of nerve growth factor (NGF). Eventually, the NGF-induced sympathetic hyperinnervation was blunted, as assessed by the immunofluorescence of tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP 43). At 7 days post-MI, the arrhythmia score of programmed electrical stimulation in the vehicle-treated infarcted rats was higher than the MI-shRNA group. Further amelioration of cardiac dysfunction was also detected. The administration of P2X7 R RNAi during the acute inflammatory response phase prevented the process of sympathetic hyperinnervation after MI, which was associated in part with inhibiting the Akt and ERK1/2 pathways and NF-κB activation. © 2016 John Wiley & Sons Ltd.

  14. Netrin-1 abrogates ischemia/reperfusion-induced cardiac mitochondrial dysfunction via nitric oxide-dependent attenuation of NOX4 activation and recoupling of NOS.

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    Siu, Kin Lung; Lotz, Christopher; Ping, Peipei; Cai, Hua

    2015-01-01

    Despite an established role of mitochondrial dysfunction in cardiac ischemia/reperfusion (I/R) injury, the upstream activators have remained incompletely defined. We have recently identified an innovative role of exogenously applied netrin-1 in cardioprotection, which is mediated by increased nitric oxide (NO) bioavailability. Here, we tested the hypothesis that this "pharmacological" treatment of netrin-1 preserves mitochondrial function via novel mechanisms that are NO dependent. Freshly isolated C57BL6 mouse hearts were perfused using a Langendorff system, and subjected to a 20min global ischemia/60min reperfusion, in the presence or absence of netrin-1. I/R induced marked increases in infarct size, total superoxide and hydrogen peroxide production, activity and protein abundance of NADPH oxidase (NOX) isoform 4 (NOX4), as well as impaired mitochondrial integrity and function, all of which were attenuated by netrin-1. This protective effect of netrin-1 is attributed to cGMP, a downstream effector of NO. The protein levels of NOX1 and NOX2 were however unaffected, and infarct size from NOX1 and NOX2 knockouts was not different from wild type animals. Scavenging of NO with PTIO reversed inhibitory effects of netrin-1 on NOX4, while NO donor attenuated NOX4 protein abundance. In vivo NOX4 RNAi, or sepiapterin perfusion, resulted in recoupling of NOS, decreased infarct size, and blockade of dysfunctional mitochondrial swelling and mitochondrial superoxide production. These data demonstrate that netrin-1 induces cardioprotection through inhibition of NOX4 activity, which leads to recoupling of NOS, augmented NO bioavailability, reduction in oxidative stress, and ultimately preservation of mitochondrial function. The NO-dependent NOX4 inhibition connects with our previously established pathway of DCC/ERK1/2/eNOS/NO/DCC feed-forward mechanism, to maintain NOS in the coupling state to attenuate oxidative stress to preserve mitochondrial function. These findings may

  15. Bone Allografts: What Is the Risk of Disease Transmission with Bone Allografts?

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    ... Selected References and Additional Resources American Academy of Periodontology Position Paper: Tissue banking of bone allografts used ... HIV virus in freeze-dried bone allografts. Pract Periodontics Aesthet Dent 1995;7:13–22. Mellonig JT, ...

  16. Cardiac autonomic dysfunction in chronic stroke women is attenuated after submaximal exercise test, as evaluated by linear and nonlinear analysis.

    Science.gov (United States)

    Francica, Juliana Valente; Bigongiari, Aline; Mochizuki, Luís; Scapini, Kátia Bilhar; Moraes, Oscar Albuquerque; Mostarda, Cristiano; Caperuto, Erico Chagas; Irigoyen, Maria Cláudia; De Angelis, Katia; Rodrigues, Bruno

    2015-09-29

    We evaluated cardiac autonomic modulation in women with chronic ischemic stroke (at least 4 years post-stroke) at rest and in response to submaximal exercise test. Fourteen post-stroke women (S group) and 10 healthy women (C group) participated in this study. Autonomic modulation (using linear and nonlinear analysis), blood pressure and metabolic variables at rest were evaluated immediately after the exercise test and during the recovery period (20 min). All participants underwent submaximal exercise test on cycle ergometer with gas analysis. At rest, the S group displayed higher lactate concentration, systolic (SBP) and diastolic blood pressure (DBP) values when compared to C group. Furthermore, the S group had lower heart rate variability (HRV) in time domain (SDNN: S = 30 ± 5 vs. 40 ± 8 ms; rMSSD: S = 14 ± 2 vs. C = 34 ± 3 ms), decreased high frequency band of pulse interval (S = 8.4 ± 2 vs. 33.1 ± 9 %) and 2V pattern of symbolic analysis (S = 17.3 ± 1 vs. 30 ± 3 %) (both indicators of cardiac vagal modulation) when compared to C group. Immediately after exercise, S group presented higher values of lactate, SBP, DBP and double product when compared to C group, as well as decreased heart rate recovery (HRR) measured at the first, second and third minutes. At recovery time, all HRV parameters in time and frequency domains improved in the S group; however, HF band remained lower when compared to C group. After the exercise test, women with chronic stroke presented reduced heart rate variability, reduced cardiac vagal modulation, as well as reduced HRR, while displayed an improvement of heart rate variability and cardiac vagal modulation when compared to their baseline. These results reinforce the importance of a physically active lifestyle for cardiovascular autonomic disorders observed in chronic stroke women.

  17. Qiliqiangxin Attenuates Phenylephrine-Induced Cardiac Hypertrophy through Downregulation of MiR-199a-5p

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    Haifeng Zhang

    2016-05-01

    Full Text Available Background/Aims: Qiliqiangxin (QL, a traditional Chinese medicine, has long been used to treat chronic heart failure. Previous studies demonstrated that QL could prevent cardiac remodeling and hypertrophy in response to hypertensive or ischemic stress. However, little is known about whether QL could modulate cardiac hypertrophy in vitro, and (if so whether it is through modulation of specific hypertrophy-related microRNA. Methods: The primary neonatal rat ventricular cardiomyocytes were isolated, cultured, and treated with phenylephrine (PE, 50 µmol/L, 48 h to induce hypertrophy in vitro, in the presence or absence of pretreatment with QL (0.5 µg/ml, 48 h. The cell surface area was determined by immunofluorescent staining for α-actinin. The mRNA levels of hypertrophic markers including atrial natriuretic peptide (ANP, brain natriuretic peptide (BNP, and β-myosin heavy chain (MYH7 were assayed by qRT-PCRs. The protein synthesis of cardiomyocytes was determined by the protein/DNA ratio. The miR-199a-5p expression level was quantified in PE-treated cardiomyocytes and heart samples from acute myocardial infarction (AMI mouse model. MiR-199a-5p overexpression was used to determine its role in the anti-hypertrophic effect of QL on cardiomyocytes. Results: PE induced obvious enlargement of cell surface in cardiomyocytes, paralleling with increased ANP, BNP, and MYH7 mRNA levels and elevated protein/DNA ratio. All these changes were reversed by the treatment with QL. Meanwhile, miR-199a-5p was increased in AMI mouse heart tissues. Of note, the increase of miR-199a-5p in PE-treated cardiomyocytes was reversed by the treatment with QL. Moreover, overexpression of miR-199a-5p abolished the anti-hypertrophic effect of QL on cardiomyocytes. Conclusion: QL prevents PE-induced cardiac hypertrophy. MiR-199a-5p is increased in cardiac hypertrophy, while reduced by treatment with QL. miR-199a-5p suppression is essential for the anti-hypertrophic effect of QL

  18. Radiation sterilization of tissue allografts: A review

    OpenAIRE

    Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

    2016-01-01

    Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be ste...

  19. Leiomyoma in a Renal Allograft

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    Yan Jun Li

    2016-01-01

    Full Text Available Leiomyomas are smooth muscle tumours that are rarely found in the kidney. There is one report of a leiomyoma in a kidney transplant in a paediatric recipient. Here, we report an adult renal transplant recipient who developed an Epstein-Barr virus-positive leiomyoma in his allograft 15 years after transplantation. The patient was converted to everolimus for posttransplant immunosuppression management and there was no sign of progression over a year.

  20. A novel, biodegradable, thermoresponsive hydrogel attenuates ventricular remodeling and improves cardiac function following myocardial infarction - a review.

    Science.gov (United States)

    Yi, Xin; Li, Xiaoyan; Ren, Shan; He, Yiyu; Wan, Weiguo; Wen, Ying; Jiang, Xuejun

    2014-01-01

    Myocardial infarction (MI) and the subsequent heart failure remain among of the leading causes of morbidity and mortality in world wide. A number of studies have demonstrated that intramyocardial biomaterials injections improve cardiac function after implantation because of their angiogenic potential. Thermoresponsive hydrogels, one member of the hydrogels family, are a kind of biomaterial whose structure is similar to that of extracellular matrix. These hydrogels have been interesting for biomedical uses as they can swell in situ under physiological conditions and provide the advantage of convenient administration. The hydrogel that our team is interested in is a novel biodegradable injectable thermoresponsive hydrogel-the copolymer dextran-poly (ε-caprolactone) -2-hydroxylethyl methacrylatepoly (N-isopropylacrylaminde) (Dex-PCL-HEMA/PNIPAAm). Thus, this review will focus on requirements and challenges of injectable synthetic material, and possible mechanism of thermoresponsive hydrogel in treating MI. The main emphases are on the work done and future interesting studies in our laboratory.

  1. The nonpeptide ANG-(1-7) mimic AVE 0991 attenuates cardiac remodeling and improves baroreflex sensitivity in renovascular hypertensive rats.

    Science.gov (United States)

    Cunha, Thelma Maria Bedeti; Lima, Wanderson Geraldo; Silva, Marcelo Eustáquio; Souza Santos, Robson Augusto; Campagnole-Santos, Maria José; Alzamora, Andréia Carvalho

    2013-03-12

    The nonpeptide Ang-(1-7) analog, AVE 0991, is recognized as having beneficial cardiovascular effects similar to those induced by Ang-(1-7). In this study, we evaluated the effects of AVE 0991 on cardiovascular functions and on cardiac and renal remodeling in rats with 2K1C renovascular hypertension. Fisher rats underwent surgery to induce 2K1C renovascular hypertension and were then treated with AVE 0991 (1 or 3mg/kg) for 28days. At the end of treatment, the blood pressure (BP), heart rate (HR), and baroreflex sensitivity were evaluated, in conscious animals. The rats were then euthanized and the heart and kidneys removed for subsequent histological analysis. Treatment with AVE 0991 in 2K1C rats restored the baroreflex sensitivity of both bradycardic and tachycardic components to levels comparable to those of normotensive SHAM rats. At a higher dose (3mg/kg), AVE 0991 was also anti-hypertensive in 2K1C rats. Furthermore, AVE 0991 reduced the heart weight, thickness of myocardial fibers, number of inflammatory cells, and area of collagen deposition in the hearts of 2K1C rats compared to SHAM rats. The inflammatory process and tissue area of collagen deposition were decreased in the clipped kidney of AVE 0091-treated 2K1C rats. Our data showed that oral treatment with AVE 0991 reduces blood-pressure cardiac remodeling and improves baroreflex sensitivity in 2K1C renovascular hypertensive rats. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Assessment of myocardial bridge by cardiac CT: Intracoronary transluminal attenuation gradient derived from diastolic phase predicts systolic compression

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    Yu, Meng Meng; Zhang, Yang; Li, Yue Hua; Li, Wen Bin; Li, Ming Hua; Zhang, Jiayin [Institute of Diagnostic and Interventional Radiology, Shanghai Jiao Tong University Affiliated Sixth People' s Hospital, Shangha (China)

    2017-08-01

    To study the predictive value of transluminal attenuation gradient (TAG) derived from diastolic phase of coronary computed tomography angiography (CCTA) for identifying systolic compression of myocardial bridge (MB). Consecutive patients diagnosed with MB based on CCTA findings and without obstructive coronary artery disease were retrospectively enrolled. In total, 143 patients with 144 MBs were included in the study. Patients were classified into three groups: without systolic compression, with systolic compression < 50%, and with systolic compression ≥ 50%. TAG was defined as the linear regression coefficient between intraluminal attenuation in Hounsfield units (HU) and length from the vessel ostium. Other indices such as the length and depth of the MB were also recorded. TAG was the lowest in MB patients with systolic compression ≥ 50% (-19.9 ± 8.7 HU/10 mm). Receiver operating characteristic curve analysis was performed to determine the optimal cutoff values for identifying systolic compression ≥ 50%. The result indicated an optimal cutoff value of TAG as -18.8 HU/10 mm (area under curve = 0.778, p < 0.001), which yielded higher sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy (54.1, 80.5, 72.8, and 75.0%, respectively). In addition, the TAG of MB with diastolic compression was significantly lower than the TAG of MB without diastolic compression (-21.4 ± 4.8 HU/10 mm vs. -12.7 ± 8 HU/10 mm, p < 0.001). TAG was a better predictor of MB with systolic compression ≥ 50%, compared to the length or depth of the MB. The TAG of MB with persistent diastolic compression was significantly lower than the TAG without diastolic compression.

  3. Total lymphoid irradiation assessed for possible enhancement of immunosuppression in hyperimmunized dogs receiving renal allografts

    Energy Technology Data Exchange (ETDEWEB)

    Sonoda, Kazuhiko (Yamato Seiwa Hospital, Kanagawa (Japan)); Rapaport, F.T.

    1992-12-01

    With performed antibodies to human leukocyte antigens (HLA) appearing in an increasing number of patients today, hyperimmunization constitutes a major problem in clinical transplantation. In adult beagle dogs hyperimmunized with skin allografts and buffy coat injection, we performed renal allograft transplantation to assess the efficacy of total lymphoid irradiation (TLI) employed as a preoperative measure in combination with cyclosporine (CyA) and methyl-prednisolone (MPL) in effecting immunosuppression. The mean survival period were 6.5 days in dogs withheld preliminary treatment, 9.0 days in the dogs receiving CyA and MPL, 26.7 days in those administered one-stage TLI, and 68 days (terminated by euthanasia) of the dogs given two-stage TLI. TLI administered two stages is considered an effective method of enhancing immunosuppression sufficiently to enable the attenuation of adverse reaction to renal allograft in hyperimmunized recipients. (author).

  4. The effect of CT-based attenuation correction on the automatic perfusion score of myocardial perfusion imaging using a dedicated cardiac solid-state CZT SPECT/CT.

    Science.gov (United States)

    Kennedy, John A; Brodov, Yafim; Weinstein, Adam L; Israel, Ora; Frenkel, Alex

    2017-05-01

    Data regarding cardiac cadmium-zinc-telluride (CZT)-specific augmented databases and their impact on CT-based attenuation correction (AC) perfusion scores in myocardial perfusion imaging (MPI) were obtained on a multiple-pinhole CZT SPECT/CT. Summed stress (SSS) and rest scores (SRS) were measured using automated software in three independent patient groups: group 1 (n = 80) underwent MPI on both CZT and conventional sodium iodide (NaI) devices, group 2 (n = 80) with low coronary artery disease likelihood and normal MPI provided reference CZT databases; and group 3 (n = 152) served to compare AC and non-AC (NAC) scores on CZT. Group 1 CZT and NaI scores gave a significant 1:1 linear correlation for CZT scores referenced to the custom database vs NaI scores referenced to the default database, but these were not concordant when CZT scores were referenced to the default database. AC significantly decreased average SSS and SRS in men vs NAC, 4.29 ± 6.30 vs 5.37 ± 7.26 (P < 0.001) and 2.37 ± 4.72 vs 3.13 ± 5.85 (P < 0.001), but not in women, 2.28 ± 3.42 vs 2.28 ± 3.08 (p NS) and 0.46 ± 1.51 vs 0.61 ± 1.86, (p NS), respectively. Specifically designed databases for solid-state CZT cardiac SPECT provide accurate quantitation of perfusion scores concordant with those previously validated for conventional SPECT. AC and NAC CZT scores differed significantly, especially in men.

  5. Early and transient sodium-hydrogen exchanger isoform 1 inhibition attenuates subsequent cardiac hypertrophy and heart failure following coronary artery ligation.

    Science.gov (United States)

    Kilić, Ana; Huang, Cathy X; Rajapurohitam, Venkatesh; Madwed, Jeffrey B; Karmazyn, Morris

    2014-12-01

    Na(+)/H(+) exchanger 1 (NHE-1) inhibition attenuates the hypertrophic response and heart failure in various experimental models. As the hypertrophic program is rapidly initiated following insult, we investigated whether early and transient administration of a NHE-1 inhibitor will exert salutary effects on cardiomyocyte hypertrophy or heart failure using both in vitro and in vivo approaches. Neonatal cardiomyocytes were treated with the novel, potent, and highly specific NHE-1 inhibitor BIX (N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine; 100 nM) for 1 hour in the presence of 10 µM phenylephrine, after which the cells were maintained for a further 23 hours in the absence of NHE-1 inhibition. One-hour treatment with the NHE-1 inhibitor prevented phenylephrine-induced hypertrophy, which was associated with prevention of activation of calcineurin, a key component of the hypertrophic process. Experiments were then performed in rats subjected to coronary artery ligation, in which the NHE-1 inhibitor was administered immediately after infarction for a 1-week period followed by a further 5 weeks of sustained coronary artery occlusion in the absence of drug treatment. This approach significantly attenuated left ventricular hypertrophy and improved both left ventricular systolic and diastolic dysfunction, which was also associated with inhibition of calcineurin activation. Our findings indicate that early and transient administration of an NHE-1 inhibitor bestows subsequent inhibition of cardiomyocyte hypertrophy in culture as well as cardiac hypertrophy and heart failure in vivo, suggesting a critical early NHE-1-dependent initiation of the hypertrophic program. The study also suggests a preconditioning-like phenomenon in preventing hypertrophy and heart failure by early and transient NHE-1 inhibition. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

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

    Science.gov (United States)

    Hu, Nan; Zhang, Yingmei

    2017-08-01

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

  7. DISTURBANCE OF THE CARDIOMYOCYTE’S MACROMOLECULAR STRUCTURE IN HEART ALLOGRAFTS AS A SIGN OF CHRONIC REJECTION

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    A. G. Kupriyanova

    2012-01-01

    Full Text Available Chronic rejection, especially cardiac allograft vasculopathy, is a major limiting factor for long-term transplant survival. This process affects not only the blood vessels, but also cardiomyocytes. However, there are extremely few reports on the evaluation of their macromolecular structure state. The aim of the study was to evaluate the structural proteins of cardiomyocytes (actin, myosin, troponin I, titin, desmin, vinculin of heart allografts in different periods after the operation (from 6 days to 15 years. Major changes of macromolecular structure were revealed in late period after transplantation (6 months – 15 years. The contribution of humoral immune response in the process of chronic cardiac allograft rejection was observed: in eight of twelve recipients episodes of acute humoral rejection had been repeatedly registered; disorders of the expression of 5 proteins out of 6 characterized were found in recipients with recurrent and persistent antibody-mediated rejection. 

  8. Extracts of Crataegus oxyacantha and Rosmarinus officinalis Attenuate Ischemic Myocardial Damage by Decreasing Oxidative Stress and Regulating the Production of Cardiac Vasoactive Agents

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    Raúl Enrique Cuevas-Durán

    2017-11-01

    Full Text Available Numerous studies have supported a role for oxidative stress in the development of ischemic damage and endothelial dysfunction. Crataegus oxyacantha (Co and Rosmarinus officinalis (Ro extracts are polyphenolic-rich compounds that have proven to be efficient in the treatment of cardiovascular diseases. We studied the effect of extracts from Co and Ro on the myocardial damage associated with the oxidative status and to the production of different vasoactive agents. Rats were assigned to the following groups: (a sham; (b vehicle-treated myocardial infarction (MI (MI-V; (c Ro extract-treated myocardial infarction (MI-Ro; (d Co extract-treated myocardial infarction (MI-Co; or (e Ro+Co-treated myocardial infarction (MI-Ro+Co. Ro and Co treatments increased total antioxidant capacity, the expression of superoxide dismutase (SOD-Cu2+/Zn2+, SOD-Mn2+, and catalase, with the subsequent decline of malondialdehyde and 8-hydroxy-2′-deoxyguanosine levels. The extracts diminished vasoconstrictor peptide levels (angiotensin II and endothelin-1, increased vasodilators agents (angiotensin 1–7 and bradikinin and improved nitric oxide metabolism. Polyphenol treatment restored the left intraventricular pressure and cardiac mechanical work. We conclude that Ro and Co treatment attenuate morphological and functional ischemic-related changes by both an oxidant load reduction and improvement of the balance between vasoconstrictors and vasodilators.

  9. Thaliporphine preserves cardiac function of endotoxemic rabbits by both directly and indirectly attenuating NFκB signaling pathway.

    Directory of Open Access Journals (Sweden)

    A S Lee

    Full Text Available Cardiac depression in sepsis is associated with the increased morbidity and mortality. Although myofilaments damage, autonomic dysfunction, and apoptosis play roles in sepsis-induced myocardial dysfunction, the underlying mechanism is not clear. All of these possible factors are related to NFκB signaling, which plays the main role in sepsis signaling. Thaliporphine was determined to possess anti-inflammatory and cardioprotective activity by suppressing NFκB signaling in rodents. The purpose of this study is to further prove this protective effect in larger septic animals, and try to find the underlying mechanisms. The systolic and diastolic functions were evaluated in vivo by pressure-volume analysis at different preloads. Both preload-dependent and -independent hemodynamic parameters were performed. Inflammatory factors of whole blood and serum samples were analyzed. Several sepsis-related signaling pathways were also determined at protein level. Changes detected by conductance catheter showed Thaliporphine could recover impaired left ventricular systolic function after 4 hours LPS injection. It could also reverse the LPS induced steeper EDPVR and gentler ESPVR, thus improve Ees, Ea, and PRSW. Thaliporphine may exert this protective effect by decreasing TNFα and caspase3 dependent cell apoptosis, which was consistent with the decreased serum cTnI and LDH concentration. Thaliporphine could protect sepsis-associated myocardial dysfunction in both preload-dependent and -independent ways. It may exert these protective effects by both increase of "good"-PI3K/Akt/mTOR and decrease of "bad"-p38/NFκB pathways, which followed by diminishing TNFα and caspase3 dependent cell apoptosis.

  10. Cardiac catheterization

    Science.gov (United States)

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

  11. Alternatives to allograft corneal transplantation.

    Science.gov (United States)

    Jhanji, Vishal; Sharma, Namrata; Agarwal, Tushar; Vajpayee, Rasik B

    2010-07-01

    Corneal transplantation is the most commonly performed solid organ transplantation in the world. Despite a glorious history of more than a 100 years, the success of conventional corneal transplantation surgery is marred by problems like graft rejection,graft infection and associated glaucoma due to long-term use of topical corticosteroids.In addition there is a dearth of donor corneal tissue in some parts of the world which subsequently adds on to the existing burden on the eye banks every year. We propose alternatives to the conventional corneal transplantation surgery for the management of corneal scarring. The potential use of alternatives to allograft corneal transplantation surgery has been described by corneal surgeons around the world. These techniques consist of nonsurgical interventions like contact lens fitting. Surgical alternatives include excimer laser phototherapeutic keratectomy, optical iridectomy, rotational autokeratoplasty and contralateral autokeratoplasty. Although these techniques are not practiced routinely, however, their appropriate utilization would clearly help the corneal surgeons to get rid of certain problems associated with allograft corneal transplantation. Careful selection of patients can yield encouraging results with the use of these alternative techniques. Visual outcomes may not be as good as after a routine keratoplasty; nevertheless, this setback is outweighed by advantages such as absence of corneal graft rejection. We also believe that the use of these techniques would at least partially resolve the issue of scarcity of donor corneal tissue in the developing world.

  12. Radiation sterilization of skin allograft

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    Kairiyama, E. [Comision Nacional de Energia Atomica, Centro Atomico Ezeiza, Presbitero Juan Gonzalez y Aragon No. 15, (B1802AYA) Ezeiza, Buenos Aires (Argentina)], E-mail: kairiyam@cae.cnea.gov.ar; Horak, C.; Spinosa, M.; Pachado, J. [Comision Nacional de Energia Atomica, Centro Atomico Ezeiza, Presbitero Juan Gonzalez y Aragon No. 15, (B1802AYA) Ezeiza, Buenos Aires (Argentina); Schwint, O. [J.P. Garrahan Hospital, Buenos Aires (Argentina)

    2009-07-15

    In the treatment of burns or accidental loss of skin, cadaveric skin allografts provide an alternative to temporarily cover a wounded area. The skin bank facility is indispensable for burn care. The first human skin bank was established in Argentina in 1989; later, 3 more banks were established. A careful donor selection is carried out according to the national regulation in order to prevent transmissible diseases. As cadaveric human skin is naturally highly contaminated, a final sterilization is necessary to reach a sterility assurance level (SAL) of 10{sup -6}. The sterilization dose for 106 batches of processed human skin was determined on the basis of the Code of Practice for the Radiation Sterilization of Tissue Allografts: Requirements for Validation and Routine Control (2004) and ISO 11137-2 (2006). They ranged from 17.6 to 33.4 kGy for bioburdens of >10-162.700 CFU/100 cm{sup 2}. The presence of Gram negative bacteria was checked for each produced batch. From the analysis of the experimental results, it was observed that the bioburden range was very wide and consequently the estimated sterilization doses too. If this is the case, the determination of a tissue-specific dose per production batch is necessary to achieve a specified requirement of SAL. Otherwise if the dose of 25 kGy is preselected, a standardized method for substantiation of this dose should be done to confirm the radiation sterilization process.

  13. Radiation sterilization of skin allograft

    Science.gov (United States)

    Kairiyama, E.; Horak, C.; Spinosa, M.; Pachado, J.; Schwint, O.

    2009-07-01

    In the treatment of burns or accidental loss of skin, cadaveric skin allografts provide an alternative to temporarily cover a wounded area. The skin bank facility is indispensable for burn care. The first human skin bank was established in Argentina in 1989; later, 3 more banks were established. A careful donor selection is carried out according to the national regulation in order to prevent transmissible diseases. As cadaveric human skin is naturally highly contaminated, a final sterilization is necessary to reach a sterility assurance level (SAL) of 10 -6. The sterilization dose for 106 batches of processed human skin was determined on the basis of the Code of Practice for the Radiation Sterilization of Tissue Allografts: Requirements for Validation and Routine Control (2004) and ISO 11137-2 (2006). They ranged from 17.6 to 33.4 kGy for bioburdens of >10-162.700 CFU/100 cm 2. The presence of Gram negative bacteria was checked for each produced batch. From the analysis of the experimental results, it was observed that the bioburden range was very wide and consequently the estimated sterilization doses too. If this is the case, the determination of a tissue-specific dose per production batch is necessary to achieve a specified requirement of SAL. Otherwise if the dose of 25 kGy is preselected, a standardized method for substantiation of this dose should be done to confirm the radiation sterilization process.

  14. MORPHOLOGY OF ISCHEMIC INJURY OF LIVER ALLOGRAFT

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    L. V. Shkalova

    2010-01-01

    Full Text Available The literature data in modern transplantology concerning morphology of ischemic injury of liver allograft are analyzed in the article. Questions of pathogenesis of liver allograft ischemic injury, histological features that indicate the possibility of donor liver transplantation are discussed in detail, as well as the role of steatosis and its reverse is highlighted. We tried to systematize the morphological changes depending on severity of ischemic injury; also we focused on the questions of persistency of the ischemic injury in the liver allograft

  15. Vancomycin iontophoresis of allograft bone.

    Science.gov (United States)

    Edmondson, M C; Day, R; Wood, D

    2014-01-01

    The most concerning infection of allografts and operative procedures is methicillin resistant Staphylococcus aureus (MRSA) and no current iontophoresed antibiotics effectively combat this microbe. It was initially hypothesised that iontophoresis of vancomycin through bone would not be effective due to its large molecular size and lack of charge. The aim of this study was to determine whether this was a viable procedure and to find the optimum conditions for its use. An iontophoresis cell was set up with varying concentrations of Vancomycin within the medulla of a section of sheep tibia, sealed from an external saline solution. The cell was run for varying times, Vancomycin concentrations and voltages, to gain information on optimisation of conditions for impregnating the graft. Each graft was then sectioned and dust ground from the exposed surface. The dust was serially washed to extract the Vancomycin and concentrations measured and plotted for all variables tested. Vancomycin was successfully delivered and impregnated to the graft using the iontophoresis technique. The first order fit to the whole data set gave a significant result (p = 0.0233), with a significant concentration (p = 0.02774) component. The time component was the next most significant (p = 0.0597), but did not exceed the 95% confidence level. Iontophoresis is an effective method for delivering Vancomycin to allograft bone. The concentrations of the vancomycin solution affected the bone concentration, but results were highly variable. Further study should be done on the effectiveness of delivering different antibiotics using this method. Cite this article: Bone Joint Res 2014;3:101-7.

  16. The composition of the microbiota modulates allograft rejection.

    Science.gov (United States)

    Lei, Yuk Man; Chen, Luqiu; Wang, Ying; Stefka, Andrew T; Molinero, Luciana L; Theriault, Betty; Aquino-Michaels, Keston; Sivan, Ayelet S; Nagler, Cathryn R; Gajewski, Thomas F; Chong, Anita S; Bartman, Caroline; Alegre, Maria-Luisa

    2016-07-01

    Transplantation is the only cure for end-stage organ failure, but without immunosuppression, T cells rapidly reject allografts. While genetic disparities between donor and recipient are major determinants of the kinetics of transplant rejection, little is known about the contribution of environmental factors. Because colonized organs have worse transplant outcome than sterile organs, we tested the influence of host and donor microbiota on skin transplant rejection. Compared with untreated conventional mice, pretreatment of donors and recipients with broad-spectrum antibiotics (Abx) or use of germ-free (GF) donors and recipients resulted in prolonged survival of minor antigen-mismatched skin grafts. Increased graft survival correlated with reduced type I IFN signaling in antigen-presenting cells (APCs) and decreased priming of alloreactive T cells. Colonization of GF mice with fecal material from untreated conventional mice, but not from Abx-pretreated mice, enhanced the ability of APCs to prime alloreactive T cells and accelerated graft rejection, suggesting that alloimmunity is modulated by the composition of microbiota rather than the quantity of bacteria. Abx pretreatment of conventional mice also delayed rejection of major antigen-mismatched skin and MHC class II-mismatched cardiac allografts. This study demonstrates that Abx pretreatment prolongs graft survival, suggesting that targeting microbial constituents is a potential therapeutic strategy for enhancing graft acceptance.

  17. Porphyrin-adsorbed Allograft Bone: A Photoactive, Antibiofilm Surface.

    Science.gov (United States)

    Dastgheyb, Sana S; Toorkey, Cyrus B; Shapiro, Irving M; Hickok, Noreen J

    2015-09-01

    Allograft bone is commonly used to augment bone stock. Unfortunately, allograft is prone to bacterial contamination and current antimicrobial therapies are inadequate. Photoactivated porphyrins combat bacterial growth by production of reactive oxygen species (ROS); however, to our knowledge, they have not been tested in the setting of allograft bone. We asked: (1) Does 5,10,15,20-tetrakis-(4-aminophenyl)-porphyrin (TAPP) stably adsorb to morselized, mineralized allograft? (2) Does Staphylococcus aureus acquire TAPP from TAPP-allograft? (3) Is TAPP-allograft antibacterial to S. aureus? (4) Is ROS production critical for antimicrobial activity? (5) Does illuminated TAPP-allograft dislodge biofilm? (6) Could other photoactive dyes (TAPP, TMPyP, TSP, THP, and methylene blue) confer antimicrobial properties to allograft? TAPP adsorption to allograft (TAPP-allograft), its localization in S. aureus, and TAPP-allograft long-term stability were determined spectrophotometrically. Antimicrobial activity was measured while activated with light or in the dark during incubation with S. aureus or after allograft biofilm formation. Glutathione was added to illuminated TAPP-allograft to quench ROS and antimicrobial activity was determined. Light-dependent antimicrobial activity of other photoactive dyes (TMPyP, TSP, THP, and methylene blue) adsorbed to allograft was also tested. We found (1) porphyrins strongly adhere to bone allograft; and (2) the bacteria are not able to sequester TAPP from the TAPP-allograft; (3) when illuminated, TAPP-allograft is resistant to bacterial adherence; (4) the effects of TAPP are inhibited by the radical scavenger glutathione, indicating ROS-dependent antimicrobial activity; (5) illumination of TAPP-allograft disrupts biofilms; and, (6) other photoactive dyes impede biofilm formation on allograft bone in the presence of light. Porphyrins stably associate with allograft and are inactive until illuminated. Illuminated TAPP-allograft markedly reduces

  18. High-mobility group box 1 accelerates early acute allograft rejection via enhancing IL-17+ γδ T-cell response.

    Science.gov (United States)

    Xia, Quansong; Duan, Lihua; Shi, Lifeng; Zheng, Fang; Gong, Feili; Fang, Min

    2014-04-01

    Th17 and γδ T cells are the dominant IL-17-producing cell. We previously reported that high-mobility group box 1 (HMGB1) is critical in inducing IL-17-producing alloreactive T cells during early stage of acute allograft rejection. However, the role of γδ T cells during this process and its implication in HMGB1-mediated allograft rejection are not fully understood. Here, we use a murine model of cardiac allograft transplantation to further study the role of HMGB1 and IL-17-producing γδ T cells in acute allograft rejection. It was found that the expression of HMGB1 was increased in allograft, while blockade of HMGB1 suppressed IL-17(+) γδ T-cell response and inhibited the gene transcription of IL-23 and IL-1β. Furthermore, in vitro HMGB1 indirectly promoted the development of IL-17(+) γδ T cells by stimulating dendritic cells to produce IL-23 and IL-1β, meanwhile depletion of γδ T cells in vivo prolonged allograft survival and reduced the level of IL-17 in serum. In conclusion, our findings inferred that increased HMGB1 expression could enhance IL-17(+) γδ T-cell response by promoting the secretion of IL-23 and IL-1β, while IL-17(+) γδ T cells contribute to the early stage of acute allograft rejection. © 2014 Steunstichting ESOT.

  19. [Attitude towards organ and tissue donation in Europe : Prerequisite for osteochondral allograft treatment].

    Science.gov (United States)

    Schmidt, S; Schulte, A; Schwarz, S; Hofmann, N; Tietz, S; Boergel, M; Sixt, S U

    2017-09-27

    The biggest obstacle to overcome for routine treatment of various pathologies with fresh osteochondral allograft is the availability of tissue for transplantation. Large fresh osteochondral allografts are usually harvested from organ donors, but in contrast to organs, tissues can be procured after cardiac arrest. Medical staff as well the general public are much less aware of the possibilities and requirements of tissue donation compared to organ donation. This review aims to highlight the current situation of organ and tissue donation in Europe and to raise this much needed awareness. For this research, PubMed database was scanned using the terms "tissue/organ donation", "bone donation/transplantation", "cartilage transplantation/allografts" and "osteochrondral allografts". Relatives of potential donors are often not approached because physicians and nurses do not feel sufficiently prepared for this task and, thus, are reluctant to address this topic. Different options could alleviate the pressure medical staff is feeling. Furthermore, there are different factors influencing consent that can be addressed to increase donation rates. Currently, a lot of potential concerning musculoskeletal tissue grafts remains unused. Most importantly, families should be encouraged to speak about their potenzial will to donate and educational programs should be established to increase trust in organ and tissue donation and the allocation system and to increase knowledge about the importance of transplantation medicine. But joined efforts of different parts of the medical systems and different organizations involved in tissue transplantation should improve the situation for patients waiting for much needed transplants.

  20. C. sinensis ablates allograft vasculopathy when used as an adjuvant therapy with cyclosporin A.

    Science.gov (United States)

    Jordan, J L; Hirsch, G M; Lee, T D G

    2008-07-01

    Immunosuppressive treatments are available to suppress acute cardiac rejection; however, no viable treatment exists for long-term cardiac graft failure. Moreover, extended use of calcineurin inhibitor immunosuppressants, the mainstay of the current therapeutic for cardiac transplantation, leads to significant associated pathologies such as nephrotoxicity and increased risk of cardiac disease. For the last ten years alternatives to calcineurin inhibitors, or adjuvant therapies designed to complement their activities, have been explored. In tandem with this development, there has been considerable interest in Traditional Chinese Medicines (TCM) as sources for novel therapeutics. Our study examines the ability of the TCM Cordyceps sinensis to reduce acute and chronic rejection associated with cardiac transplantation. The objectives of this study were to first determine if oral delivery of the extract could reduce acute rejection in a rat heterotopic heart model of transplantation. The second objective was to determine, in vitro, if a sterile, aqueous extract of C. sinensis could decrease CD8+ T cell activity. The third objective was to determine if oral delivery of the extract could ablate allograft vasculopathy in a mouse abdominal aortic transplant model. We found that oral delivery of the extract demonstrated a reduction in acute rejection when used in conjunction with a sub-therapeutic dose of Cyclosporine. Further, we found, using a mixed lymphocyte reaction, that the extract was able to significantly reduce CD8+ T cell activity. Finally, we demonstrate that oral delivery of the extract, used with a therapeutic dose of Cyclosporine to suppress acute rejection, ablates allograft vasculopathy.

  1. Cardiorespiratory fitness attenuates risk for major adverse cardiac events in hyperlipidemic men and women independent of statin therapy: The Henry Ford ExercIse Testing Project.

    Science.gov (United States)

    Hung, Rupert K; Al-Mallah, Mouaz H; Qadi, Mohamud A; Shaya, Gabriel E; Blumenthal, Roger S; Nasir, Khurram; Brawner, Clinton A; Keteyian, Steven J; Blaha, Michael J

    2015-08-01

    We sought to evaluate the effect of cardiorespiratory fitness (CRF) in predicting mortality, myocardial infarction (MI), and revascularization in patients with hyperlipidemia after stratification by gender and statin therapy. This retrospective cohort study included 33,204 patients with hyperlipidemia (57 ± 12 years old, 56% men, 25% black) who underwent physician-referred treadmill stress testing at the Henry Ford Health System from 1991 to 2009. Patients were stratified by gender, baseline statin therapy, and estimated metabolic equivalents from stress testing. We computed hazard ratios using Cox regression models after adjusting for demographics, cardiac risk factors, comorbidities, pertinent medications, interaction terms, and indication for stress testing. There were 4,851 deaths, 1,962 MIs, and 2,686 revascularizations over a median follow-up of 10.3 years. In men and women not on statin therapy and men and women on statin therapy, each 1-metabolic equivalent increment in CRF was associated with hazard ratios of 0.86 (95% CI 0.85-0.88), 0.83 (95% CI 0.81-0.85), 0.85 (95% CI 0.83-0.87), and 0.84 (95% CI 0.81-0.87) for mortality; 0.93 (95% CI 0.90-0.96), 0.87 (95% CI 0.83-0.91), 0.89 (95% CI 0.86-0.92), and 0.90 (95% CI 0.86-0.95) for MI; and 0.91 (95% CI 0.88-0.93), 0.87 (95% CI 0.83-0.91), 0.89 (95% CI 0.87-0.92), and 0.90 (95% CI 0.86-0.94) for revascularization, respectively. No significant interactions were observed between CRF and statin therapy (P > .23). Higher CRF attenuated risk for mortality, MI, and revascularization independent of gender and statin therapy in patients with hyperlipidemia. These results reinforce the prognostic value of CRF and support greater promotion of CRF in this patient population. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. An experimental phantom study of the effect of gadolinium-based MR contrast agents on PET attenuation coefficients and PET quantification in PET-MR imaging: application to cardiac studies.

    Science.gov (United States)

    O' Doherty, Jim; Schleyer, Paul

    2017-12-01

    Simultaneous cardiac perfusion studies are an increasing trend in PET-MR imaging. During dynamic PET imaging, the introduction of gadolinium-based MR contrast agents (GBCA) at high concentrations during a dual injection of GBCA and PET radiotracer may cause increased attenuation effects of the PET signal, and thus errors in quantification of PET images. We thus aimed to calculate the change in linear attenuation coefficient (LAC) of a mixture of PET radiotracer and increasing concentrations of GBCA in solution and furthermore, to investigate if this change in LAC produced a measurable effect on the image-based PET activity concentration when attenuation corrected by three different AC strategies. We performed simultaneous PET-MR imaging of a phantom in a static scenario using a fixed activity of 40 MBq [18 F]-NaF, water, and an increasing GBCA concentration from 0 to 66 mM (based on an assumed maximum possible concentration of GBCA in the left ventricle in a clinical study). This simulated a range of clinical concentrations of GBCA. We investigated two methods to calculate the LAC of the solution mixture at 511 keV: (1) a mathematical mixture rule and (2) CT imaging of each concentration step and subsequent conversion to LAC at 511 keV. This comparison showed that the ranges of LAC produced by both methods are equivalent with an increase in LAC of the mixed solution of approximately 2% over the range of 0-66 mM. We then employed three different attenuation correction methods to the PET data: (1) each PET scan at a specific millimolar concentration of GBCA corrected by its corresponding CT scan, (2) each PET scan corrected by a CT scan with no GBCA present (i.e., at 0 mM GBCA), and (3) a manually generated attenuation map, whereby all CT voxels in the phantom at 0 mM were replaced by LAC = 0.1 cm-1. All attenuation correction methods (1-3) were accurate to the true measured activity concentration within 5%, and there were no trends in image

  3. Attenuation of cardiac dysfunction and remodeling of myocardial infarction by microRNA-130a are mediated by suppression of PTEN and activation of PI3K dependent signaling.

    Science.gov (United States)

    Lu, Chen; Wang, Xiaohui; Ha, Tuanzhu; Hu, Yuanping; Liu, Li; Zhang, Xia; Yu, Honghui; Miao, Jonathan; Kao, Race; Kalbfleisch, John; Williams, David; Li, Chuanfu

    2015-12-01

    Activation of PI3K/Akt signaling protects the myocardium from ischemia/reperfusion injury. MicroRNAs have been demonstrated to play an important role in the regulation of gene expression at the post-transcriptional level. In this study, we examined whether miR-130a will attenuate cardiac dysfunction and remodeling after myocardial infarction (MI) via PI3K/Akt dependent mechanism. To determine the role of miR-130a in the proliferation and migration of endothelial cells, HUVECs were transfected with miR-130a mimics before the cells were subjected to scratch-induced wound injury. Transfection of miR-130a mimics stimulated the migration of endothelial cells into the wound area and increased phospho-Akt levels. To examine the effect of miR-130a on cardiac dysfunction and remodeling after MI, Lentivirus expressing miR-130a (LmiR-130a) was delivered into mouse hearts seven days before the mice were subjected to MI. Cardiac function was assessed by echocardiography before and for up to 21 days after MI. Ejection fraction (EF%) and fractional shortening (FS%) in the LmiR-130a transfected MI hearts were significantly greater than in LmiR-control and untransfected control MI groups. LmiR-130a transfection increased capillary number and VEGF expression, and decreased collagen deposition in the infarcted myocardium. Importantly, LmiR-130a transfection significantly suppressed PTEN expression and increased the levels of phosphorylated Akt in the myocardium. However, treatment of LmiR-130a-transfected mice with LY294002, a PI3K inhibitor, completely abolished miR-130a-induced attenuation of cardiac dysfunction after MI. miR-130a plays a critical role in attenuation of cardiac dysfunction and remodeling after MI. The mechanisms involve activation of PI3K/Akt signaling via suppression of PTEN expression. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Attenuation of cardiac dysfunction and remodeling of myocardial infarction by microRNA-130a is mediated by suppression of PTEN and activation of PI3K dependent signaling

    Science.gov (United States)

    Lu, Chen; Wang, Xiaohui; Ha, Tuanzhu; Hu, Yuanping; Liu, Li; Zhang, Xia; Yu, Honghui; Miao, Jonathan; Kao, Race; Kalbfleisch, John; Williams, David; Li, Chuanfu

    2015-01-01

    Objective Activation of PI3K/Akt signaling protects the myocardium from ischemia/reperfusion injury. MicroRNAs have been demonstrated to play an important role in the regulation of gene expression at the post-transcriptional level. In this study, we examined whether miR-130a will attenuate cardiac dysfunction and remodeling after myocardial infarction (MI) via PI3K/Akt dependent mechanism. Approaches and Results To determine the role of miR-130a in the proliferation and migration of endothelial cells, HUVECs were transfected with miR-130a mimics before the cells were subjected to scratch-induced wound injury. Transfection of miR-130a mimics stimulated the migration of endothelial cells into the wound area and increased phosphor-Akt levels. To examine the effect of miR-130a on cardiac dysfunction and remodeling after MI, Lentivirus expressing miR-130a (LmiR-130a) was delivered into mouse hearts seven days before the mice were subjected to MI. Cardiac function was assessed by echocardiography before and for up to 21 days after MI. Ejection fraction (EF%) and fractional shortening (FS%) in the LmiR-130a transfected MI hearts were significantly greater than in LmiR-control and untransfected control MI groups. LmiR-130a transfection increased capillary number and VEGF expression, and decreased collagen deposition in the infarcted myocardium. Importantly, LmiR-130a transfection significantly suppressed PTEN expression and increased the levels of phosphorylated Akt in the myocardium. However, treatment of LmiR-130a-transfected mice with LY294002, a PI3K inhibitor, completely abolished miR-130a-induced attenuation of cardiac dysfunction after MI. Conclusions miR-130a plays a critical role in attenuation of cardiac dysfunction and remodeling after MI. The mechanisms involve activation of PI3K/Akt signaling via suppression of PTEN expression. PMID:26458524

  5. Magnetic resonance imaging of massive bone allografts with histologic correlation

    Energy Technology Data Exchange (ETDEWEB)

    Hoeffner, E.G. [Dept. of Radiology, Wayne State Univ. School of Medicine, Detroit, MI (United States); Soulen, R.L. [Dept. of Radiology, Wayne State Univ. School of Medicine, Detroit, MI (United States); Ryan, J.R. [Dept. of Orthopaedic Surgery, Wayne State Univ. School of Medicine, Detroit, MI (United States); Qureshi, F. [Dept. of Pathology, Wayne State Univ. School of Medicine, Detroit, MI (United States)

    1996-02-01

    The objective of this study was to better understand the MRI appearance of massive bone allografts. The MRI findings of three massive bone allografts imaged in vivo were correlated with the histologic findings following removal of the allografts. A fourth allograft, never implanted, was imaged and evaluated histologically. Allografts were placed for the treatment of primary or recurrent osteosarcoma. The in-vivo allografts have a heterogeneous appearance on MRI which we attribute to the revascularization process. Fibrovascular connective tissue grows into the graft in a patchy, focal fashion, down the medullary canal from the graft-host junction and adjacent to the periosteum. The marrow spaces are initially devoid of normal cellular elements and occupied by fat and gelatinous material. This normal postoperative appearance of massive bone allografts must not be interpreted as recurrent neoplasm or infection in the allograft. Recognition of these complications rests on features outside the marrow. (orig./MG)

  6. Magnetic Resonance for Noninvasive Detection of Microcirculatory Disease Associated With Allograft Vasculopathy: Intracoronary Measurement Validation.

    Science.gov (United States)

    Mirelis, Jesús G; García-Pavía, Pablo; Cavero, Miguel A; González-López, Esther; Echavarria-Pinto, Mauro; Pastrana, Miguel; Segovia, Javier; Oteo, Juan F; Alonso-Pulpón, Luis; Escaned, Javier

    2015-07-01

    Cardiac allograft vasculopathy affects both epicardial and microcirculatory coronary compartments. Magnetic resonance perfusion imaging has been proposed as a useful tool to assess microcirculation mostly outside the heart transplantation setting. Instantaneous hyperemic diastolic flow velocity-pressure slope, an intracoronary physiology index, has demonstrated a better correlation with microcirculatory remodelling in cardiac allograft vasculopathy than other indices such as coronary flow velocity reserve. To investigate the potential of magnetic resonance perfusion imaging to detect the presence of microcirculatory remodeling in cardiac allograft vasculopathy, we compared magnetic resonance perfusion data with invasive intracoronary physiological indices to study microcirculation in a population of heart transplantation recipients with macrovascular nonobstructive disease demonstrated with intravascular ultrasound. We studied 8 heart transplantation recipients (mean age, 61 [12] years, 100% male) with epicardial allograft vasculopathy defined by intravascular ultrasound, nonsignificant coronary stenoses and negative visually-assessed wall-motion/perfusion dobutamine stress magnetic resonance. Quantitative stress and rest magnetic resonance perfusion data to build myocardial perfusion reserve index, noninvasively, and 4 invasive intracoronary physiological indices were determined. Postprocessed data showed a mean (standard deviation) myocardial perfusion reserve index of 1.22 (0.27), while fractional flow reserve, coronary flow velocity reserve, hyperemic microvascular resistance and instantaneous hyperemic diastolic flow velocity-pressure slope were 0.98 (0.02), cm/s/mmHg, 2.34 (0.55) cm/s/mmHg, 2.00 (0.69) cm/s/mmHg and 0.91 (0.65) cm/s/mmHg, respectively. The myocardial perfusion reserve index correlated strongly only with the instantaneous hyperemic diastolic flow velocity-pressure slope (r=0.75; P=.033). Myocardial perfusion reserve index derived from a

  7. Never in mitosis gene A related kinase-6 attenuates pressure overload-induced activation of the protein kinase B pathway and cardiac hypertrophy.

    Directory of Open Access Journals (Sweden)

    Zhouyan Bian

    Full Text Available Cardiac hypertrophy appears to be a specialized form of cellular growth that involves the proliferation control and cell cycle regulation. NIMA (never in mitosis, gene A-related kinase-6 (Nek6 is a cell cycle regulatory gene that could induce centriole duplication, and control cell proliferation and survival. However, the exact effect of Nek6 on cardiac hypertrophy has not yet been reported. In the present study, the loss- and gain-of-function experiments were performed in Nek6 gene-deficient (Nek6-/- mice and Nek6 overexpressing H9c2 cells to clarify whether Nek6 which promotes the cell cycle also mediates cardiac hypertrophy. Cardiac hypertrophy was induced by transthoracic aorta constriction (TAC and then evaluated by echocardiography, pathological and molecular analyses in vivo. We got novel findings that the absence of Nek6 promoted cardiac hypertrophy, fibrosis and cardiac dysfunction, which were accompanied by a significant activation of the protein kinase B (Akt signaling in an experimental model of TAC. Consistent with this, the overexpression of Nek6 prevented hypertrophy in H9c2 cells induced by angiotonin II and inhibited Akt signaling in vitro. In conclusion, our results demonstrate that the cell cycle regulatory gene Nek6 is also a critical signaling molecule that helps prevent cardiac hypertrophy and inhibits the Akt signaling pathway.

  8. Mineralocorticoid Receptor Deficiency in T Cells Attenuates Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction Through Modulating T-Cell Activation.

    Science.gov (United States)

    Li, Chao; Sun, Xue-Nan; Zeng, Meng-Ru; Zheng, Xiao-Jun; Zhang, Yu-Yao; Wan, Qiangyou; Zhang, Wu-Chang; Shi, Chaoji; Du, Lin-Juan; Ai, Tang-Jun; Liu, Yuan; Liu, Yan; Du, Li-Li; Yi, Yi; Yu, Ying; Duan, Sheng-Zhong

    2017-07-01

    Although antagonists of mineralocorticoid receptor (MR) have been widely used to treat heart failure, the underlying mechanisms are incompletely understood. Recent reports show that T cells play important roles in pathologic cardiac hypertrophy and heart failure. However, it is unclear whether and how MR functions in T cells under these pathologic conditions. We found that MR antagonist suppressed abdominal aortic constriction-induced cardiac hypertrophy and decreased the accumulation and activation of CD4 + and CD8 + T cells in mouse heart. T-cell MR knockout mice manifested suppressed cardiac hypertrophy, fibrosis, and dysfunction compared with littermate control mice after abdominal aortic constriction. T-cell MR knockout mice had less cardiac inflammatory response, which was illustrated by decreased accumulation of myeloid cells and reduced expression of inflammatory cytokines. Less amounts and activation of T cells were observed in the heart of T-cell MR knockout mice after abdominal aortic constriction. In vitro studies showed that both MR antagonism and deficiency repressed activation of T cells, whereas MR overexpression elevated activation of T cells. These results demonstrated that MR blockade in T cells protected against abdominal aortic constriction-induced cardiac hypertrophy and dysfunction. Mechanistically, MR directly regulated T-cell activation and modulated cardiac inflammation. Targeting MR in T cells specifically may be a feasible strategy for more effective treatment of pathologic cardiac hypertrophy and heart failure. © 2017 American Heart Association, Inc.

  9. Calprotectin - A novel noninvasive marker for intestinal allograft monitoring

    NARCIS (Netherlands)

    Sudan, Debra; Vargas, Luciano; Sun, Yimin; Bok, Lisette; Dijkstra, Gerard; Langnas, Alan

    Objective: To identify a noninvasive screening test for intestinal allograft monitoring. Summary Background Data: Intestinal allograft rejection is difficult to distinguish from other causes of diarrhea and can rapidly lead to severe exfoliation or death. Protocol biopsies are standard for allograft

  10. Urinary calprotectin and posttransplant renal allograft injury

    DEFF Research Database (Denmark)

    Tepel, Martin; Borst, Christoffer; Bistrup, Claus

    2014-01-01

    OBJECTIVE: Current methods do not predict the acute renal allograft injury immediately after kidney transplantation. We evaluated the diagnostic performance of urinary calprotectin for predicting immediate posttransplant allograft injury. METHODS: In a multicenter, prospective-cohort study of 144...... regression showed that higher urinary calprotectin concentrations and older donor age predicted lower eGFR four weeks, 6 months, and 12 months after transplantation. CONCLUSIONS: Urinary calprotectin is an early, noninvasive predictor of immediate renal allograft injury after kidney transplantation......., 0.92; 95% CI, 0.77 to 0.98; specificity, 0.48; 95% CI, 0.31 to 0.66). Higher urinary calprotectin concentrations predicted impaired kidney function 4 weeks after transplantation, as well as 6 months and 12 months after transplantation. When data were analyzed using the urinary calprotectin...

  11. Omega-3 Fatty Acid Supplementation Appears to Attenuate Particulate Air Pollution-induced Cardiac Effects and Lipid Changes in Healthy Middle-aged Adults.

    Science.gov (United States)

    Context: Air pollution exposure has been associated with adverse cardiovascular effects. A recent epidemiologic study reported that omega-3 fatty acid (fish oil) supplementation blunted the cardiac responses to air pollution exposure. Objective: To evaluate in a randomized contro...

  12. Caveolin-3 Overexpression Attenuates Cardiac Hypertrophy via Inhibition of T-type Ca2+ Current Modulated by Protein Kinase Cα in Cardiomyocytes*

    Science.gov (United States)

    Markandeya, Yogananda S.; Phelan, Laura J.; Woon, Marites T.; Keefe, Alexis M.; Reynolds, Courtney R.; August, Benjamin K.; Hacker, Timothy A.; Roth, David M.; Patel, Hemal H.; Balijepalli, Ravi C.

    2015-01-01

    Pathological cardiac hypertrophy is characterized by subcellular remodeling of the ventricular myocyte with a reduction in the scaffolding protein caveolin-3 (Cav-3), altered Ca2+ cycling, increased protein kinase C expression, and hyperactivation of calcineurin/nuclear factor of activated T cell (NFAT) signaling. However, the precise role of Cav-3 in the regulation of local Ca2+ signaling in pathological cardiac hypertrophy is unclear. We used cardiac-specific Cav-3-overexpressing mice and in vivo and in vitro cardiac hypertrophy models to determine the essential requirement for Cav-3 expression in protection against pharmacologically and pressure overload-induced cardiac hypertrophy. Transverse aortic constriction and angiotensin-II (Ang-II) infusion in wild type (WT) mice resulted in cardiac hypertrophy characterized by significant reduction in fractional shortening, ejection fraction, and a reduced expression of Cav-3. In addition, association of PKCα and angiotensin-II receptor, type 1, with Cav-3 was disrupted in the hypertrophic ventricular myocytes. Whole cell patch clamp analysis demonstrated increased expression of T-type Ca2+ current (ICa, T) in hypertrophic ventricular myocytes. In contrast, the Cav-3-overexpressing mice demonstrated protection from transverse aortic constriction or Ang-II-induced pathological hypertrophy with inhibition of ICa, T and intact Cav-3-associated macromolecular signaling complexes. siRNA-mediated knockdown of Cav-3 in the neonatal cardiomyocytes resulted in enhanced Ang-II stimulation of ICa, T mediated by PKCα, which caused nuclear translocation of NFAT. Overexpression of Cav-3 in neonatal myocytes prevented a PKCα-mediated increase in ICa, T and nuclear translocation of NFAT. In conclusion, we show that stable Cav-3 expression is essential for protecting the signaling mechanisms in pharmacologically and pressure overload-induced cardiac hypertrophy. PMID:26170457

  13. CYP2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPKα2 and enhancing nuclear translocation of Akt1.

    Science.gov (United States)

    Wang, Bei; Zeng, Hesong; Wen, Zheng; Chen, Chen; Wang, Dao Wen

    2016-10-01

    Cytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5'-AMP-activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1. Moreover, we tested whether EETs enhanced cross talk between AMPKα2 and phosphorylated Akt1 (p-Akt1), and stimulated nuclear translocation of p-Akt1, to exert their antihypertrophic effects. AMPKα2(-/-) mice that overexpressed CYP2J2 in heart were treated with Ang II for 2 weeks. Interestingly, overexpression of CYP2J2 suppressed cardiac hypertrophy and increased levels of atrial natriuretic peptide (ANP) in the heart tissue and plasma of wild-type mice but not AMPKα2(-/-) mice. The CYP2J2 metabolites, 11,12-EET, activated AMPKα2 to induce nuclear translocation of p-Akt1 selectively, which increased the production of ANP and therefore inhibited the development of cardiac hypertrophy. Furthermore, by co-immunoprecipitation analysis, we found that AMPKα2β2γ1 and p-Akt1 interact through the direct binding of the AMPKγ1 subunit to the Akt1 protein kinase domain. This interaction was enhanced by 11,12-EET. Our studies reveal a novel mechanism in which CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPKα2β2γ1 and protect against cardiac hypertrophy and suggest that overexpression of CYP2J2 might have clinical potential to suppress cardiac hypertrophy and heart failure. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  14. Garlic attenuates cardiac oxidative stress via activation of PI3K/AKT/Nrf2-Keap1 pathway in fructose-fed diabetic rat.

    Directory of Open Access Journals (Sweden)

    Raju Padiya

    Full Text Available Cardiovascular complication due to diabetes has remained a major cause of death. There is an urgent need to intervene the cardiac complications in diabetes by nutritional or pharmacological agents. Thus the present study was designed to find out the effectiveness of garlic on cardiac complications in insulin-resistant diabetic rats.SD rats were fed high fructose (65% diet alone or along with raw garlic homogenate (250 mg/kg/day or nutrient-matched (65% corn starch control diet for 8 weeks. Fructose-fed diabetic rats showed cardiac hypertrophy, increased NFkB activity and increased oxidative stress. Administration of garlic significantly decreased (p<0.05 cardiac hypertrophy, NFkB activity and oxidative stress. Although we did not observe any changes in myocardial catalase, GSH and GPx in diabetic heart, garlic administration showed significant (p<0.05 increase in all three antioxidant/enzymes levels. Increased endogenous antioxidant enzymes and gene expression in garlic treated diabetic heart are associated with higher protein expression of Nrf2. Increased myocardial H2S levels, activation of PI3K/Akt pathway and decreased Keap levels in fructose-fed heart after garlic administration might be responsible for higher Nrf2 levels.Our study demonstrates that raw garlic homogenate is effective in reducing cardiac hypertrophy and fructose-induced myocardial oxidative stress through PI3K/AKT/Nrf2-Keap1 dependent pathway.

  15. Ultrastructural basis of acute renal allograft rejection

    NARCIS (Netherlands)

    V.D. Vuzevski (Vojislav)

    1976-01-01

    textabstractAn attempt was made: I. to demonstrate the evolution and the time of onset of the ultrastructural morphological changes in the renal parenchyma and blood vessels, as well as the ultrastructural feature of the interstitial cellular infiltration in acute rejection of kidney allografts; 2.

  16. Meniscal Allograft Transplantation: Factors Predicting Failure

    Science.gov (United States)

    Parkinson, Ben; Smith, Nicholas; Thompson, Peter; Spalding, Tim

    2017-01-01

    Background: Meniscal allograft transplantation (MAT) has been shown to provide a significant improvement in patient reported outcomes for individuals with post-menisectomy syndrome. The typical patients undergoing MAT often have multiple other pathologies that require treatment at the time of surgery and it is difficult to ascertain which factors influence the outcome. Hypothesis / Purpose: The aim of this study was to determine the predictors of meniscal allograft transplantation failure in a large series in order to refine the indications for surgery and better inform future patients. Study Design: Prospective case series. Methods: All patients undergoing MAT at a single institution between May 2005 and May 2014, with a minimum of one year follow up were prospectively evaluated and included in this study. Failure was defined as removal of the allograft, revision transplantation or conversion to a joint replacement. Patients were grouped according to the articular cartilage status at the time of surgery; Group 1 – intact or partial thickness chondral loss; Group 2 - full thickness chondral loss one condyle; Group 3 - full thickness chondral loss both condyles. The Cox proportional hazards model was used to determine significant predictors of failure (cartilage grade at the time of MAT, IKDC score, lateral or medial allografts, gender, additional procedures and tissue bank source), independently of other factors. Kaplan-Meier survival curves were produced for overall survival and significant predictors of failure in the Cox proportional hazards model. Results: There were 125 consecutive MATs performed, with one patient lost to follow up. The median follow up was 3 years (range 1 – 10 years). The 5 year graft survival for the entire cohort was 82% (97% group 1, 82% group 2, 62% group 3). The probability of failure in group 1 was 85% lower (95% confidence interval 13 – 97%) than in group 3 at any time. The probability of failure with lateral allografts was 76

  17. Comparison of fresh osteochondral autografts and allografts: a canine model.

    Science.gov (United States)

    Glenn, R Edward; McCarty, Eric C; Potter, Hollis G; Juliao, Saul F; Gordon, Jeffrey D; Spindler, Kurt P

    2006-07-01

    Osteochondral autografts and allografts have been widely used in the treatment of isolated grade IV articular cartilage lesions of the knee. However, the authors are not aware of any study that has prospectively compared fresh osteochondral autografts to fresh allografts with regard to imaging, biomechanical testing, and histology. The imaging, biomechanical properties, and histologic appearance of fresh osteochondral autograft and fresh allograft are similar with respect to bony incorporation into host bone, articular cartilage composition, and biomechanical properties. Controlled laboratory study. Eighteen adult dogs underwent bilateral knee osteochondral graft implantation after creation of an Outerbridge grade IV cartilage defect. One knee received an autograft, and the contralateral knee received a fresh allograft. Nine dogs were sacrificed at 3 months, and 9 dogs were sacrificed at 6 months. Graft analysis included gross examination, radiographs, magnetic resonance imaging, biomechanical testing, and histology. Magnetic resonance imaging demonstrated excellent bony incorporation of both autografts and allografts. Biomechanical testing demonstrated no significant difference between autografts versus allografts versus control at 3 or 6 months (P = .36-.91). A post hoc calculation showed 80% power to detect a 30% difference between allograft and control. Histologic examination showed normal cartilage structure for both autografts and allografts. Fresh osteochondral autograft and fresh allograft tissues are not statistically different with respect to bony incorporation, articular cartilage composition, or biomechanical properties up to 6 months after implantation. The use of fresh allograft tissue to treat osteochondral defects eliminates morbidity associated with harvesting autograft tissue without compromising the results of the surgical procedure.

  18. Performance of CryoValve SG decellularized pulmonary allografts compared with standard cryopreserved allografts.

    Science.gov (United States)

    Konuma, Takeshi; Devaney, Eric J; Bove, Edward L; Gelehrter, Sarah; Hirsch, Jennifer C; Tavakkol, Zarry; Ohye, Richard G

    2009-09-01

    There is no ideal option for pulmonary valve replacement in children. Cryopreserved pulmonary allografts frequently demonstrate early valve regurgitation and may elicit an immune response. To improve these shortcomings, the SynerGraft process (CryoLife, Kennesaw, GA) decellularizes an allograft, leaving only connective tissue, which then becomes repopulated with host cells. A previous study at our institution demonstrated superior short-term durability of the SynerGraft-processed CryoValve SG compared with standard allografts. Longer-term impact of the technology remains unknown. A single institution review was performed of all CryoValve SGs implanted between 2001 and 2004. Forty-one CryoValve SG patients and 41 age and diagnosis-matched standard allograft controls were evaluated. Demographics, survival, reintervention, and echocardiographic findings were analyzed. There were no significant differences between groups in demographics, valve diameter, orthotopic-heterotopic allograft position, or follow-up. For the entire cohort, there was no difference in early or late insufficiency or stenosis at a mean follow-up of 46 +/- 14 months. However, freedom from moderate to severe insufficiency (>3+) was significantly better for CryoValve SG patients (p = 0.05). In addition, for patients greater than 2 years of age, CryoValve SGs were significantly less regurgitant (p = 0.045) and stenotic (p = 0.041). Long-term survival was identical at 85% (35 of 41). When compared with standard allografts, CryoValve SGs demonstrate superior freedom from significant insufficiency at intermediate follow-up. In older children, CryoValve SGs display less insufficiency and stenosis. For infants, patient age, valve diameter, previous conduit, and rapid somatic growth would likely be the predominant factors leading to allograft failure.

  19. Factors Predicting Meniscal Allograft Transplantation Failure.

    Science.gov (United States)

    Parkinson, Ben; Smith, Nicholas; Asplin, Laura; Thompson, Peter; Spalding, Tim

    2016-08-01

    Meniscal allograft transplantation (MAT) is performed to improve symptoms and function in patients with a meniscal-deficient compartment of the knee. Numerous studies have shown a consistent improvement in patient-reported outcomes, but high failure rates have been reported by some studies. The typical patients undergoing MAT often have multiple other pathologies that require treatment at the time of surgery. The factors that predict failure of a meniscal allograft within this complex patient group are not clearly defined. To determine predictors of MAT failure in a large series to refine the indications for surgery and better inform future patients. Cohort study; Level of evidence, 3. All patients undergoing MAT at a single institution between May 2005 and May 2014 with a minimum of 1-year follow-up were prospectively evaluated and included in this study. Failure was defined as removal of the allograft, revision transplantation, or conversion to a joint replacement. Patients were grouped according to the articular cartilage status at the time of the index surgery: group 1, intact or partial-thickness chondral loss; group 2, full-thickness chondral loss 1 condyle; and group 3, full-thickness chondral loss both condyles. The Cox proportional hazards model was used to determine significant predictors of failure, independently of other factors. Kaplan-Meier survival curves were produced for overall survival and significant predictors of failure in the Cox proportional hazards model. There were 125 consecutive MATs performed, with 1 patient lost to follow-up. The median follow-up was 3 years (range, 1-10 years). The 5-year graft survival for the entire cohort was 82% (group 1, 97%; group 2, 82%; group 3, 62%). The probability of failure in group 1 was 85% lower (95% CI, 13%-97%) than in group 3 at any time. The probability of failure with lateral allografts was 76% lower (95% CI, 16%-89%) than medial allografts at any time. This study showed that the presence of severe

  20. Factors Predicting Meniscal Allograft Transplantation Failure

    Science.gov (United States)

    Parkinson, Ben; Smith, Nicholas; Asplin, Laura; Thompson, Peter; Spalding, Tim

    2016-01-01

    Background: Meniscal allograft transplantation (MAT) is performed to improve symptoms and function in patients with a meniscal-deficient compartment of the knee. Numerous studies have shown a consistent improvement in patient-reported outcomes, but high failure rates have been reported by some studies. The typical patients undergoing MAT often have multiple other pathologies that require treatment at the time of surgery. The factors that predict failure of a meniscal allograft within this complex patient group are not clearly defined. Purpose: To determine predictors of MAT failure in a large series to refine the indications for surgery and better inform future patients. Study Design: Cohort study; Level of evidence, 3. Methods: All patients undergoing MAT at a single institution between May 2005 and May 2014 with a minimum of 1-year follow-up were prospectively evaluated and included in this study. Failure was defined as removal of the allograft, revision transplantation, or conversion to a joint replacement. Patients were grouped according to the articular cartilage status at the time of the index surgery: group 1, intact or partial-thickness chondral loss; group 2, full-thickness chondral loss 1 condyle; and group 3, full-thickness chondral loss both condyles. The Cox proportional hazards model was used to determine significant predictors of failure, independently of other factors. Kaplan-Meier survival curves were produced for overall survival and significant predictors of failure in the Cox proportional hazards model. Results: There were 125 consecutive MATs performed, with 1 patient lost to follow-up. The median follow-up was 3 years (range, 1-10 years). The 5-year graft survival for the entire cohort was 82% (group 1, 97%; group 2, 82%; group 3, 62%). The probability of failure in group 1 was 85% lower (95% CI, 13%-97%) than in group 3 at any time. The probability of failure with lateral allografts was 76% lower (95% CI, 16%-89%) than medial allografts at

  1. Early treatment with xenon protects against the cold ischemia associated with chronic allograft nephropathy in rats.

    Science.gov (United States)

    Zhao, Hailin; Luo, Xianghong; Zhou, Zhaowei; Liu, Juying; Tralau-Stewart, Catherine; George, Andrew J T; Ma, Daqing

    2014-01-01

    Chronic allograft nephropathy (CAN) is a common finding in kidney grafts with functional impairment. Prolonged hypothermic storage-induced ischemia-reperfusion injury is associated with the early onset of CAN. As the noble gas xenon is clinically used as an anesthetic and has renoprotective properties in a rodent model of ischemia-reperfusion injury, we studied whether early treatment with xenon could attenuate CAN associated with prolonged hypothermic storage. Exposure to xenon enhanced the expression of insulin growth factor-1 (IGF-1) and its receptor in human proximal tubular (HK-2) cells, which, in turn, increased cell proliferation. Xenon treatment before or after hypothermia-hypoxia decreased cell apoptosis and cell inflammation after reoxygenation. The xenon-induced HK-2 cell proliferation was abolished by blocking the IGF-1 receptor, mTOR, and HIF-1α individually. In the Fischer-to-Lewis rat allogeneic renal transplantation model, xenon exposure of donors before graft retrieval or recipients after engraftment enhanced tubular cell proliferation and decreased tubular cell death and cell inflammation associated with ischemia-reperfusion injury. Compared with control allografts, xenon treatment significantly suppressed T-cell infiltration and fibrosis, prevented the development of CAN, and improved renal function. Thus, xenon treatment promoted recovery from ischemia-reperfusion injury and reduced susceptibility to the subsequent development of CAN in allografts.

  2. HSF1 and NF-κB p65 participate in the process of exercise preconditioning attenuating pressure overload-induced pathological cardiac hypertrophy

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Tongyi [Department of Cardiothoracic Surgery, No. 401 Hospital of PLA, Qingdao (China); Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Zhang, Ben [Centre of Cardiovascular Surgery, Guangzhou General Hospital of Guangzhou Military Region, Guangzhou (China); Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Yang, Fan; Cai, Chengliang; Wang, Guokun [Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Han, Qingqi, E-mail: handoctor@gmail.com [Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China); Zou, Liangjian, E-mail: zouliangjiansh@gmail.com [Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai (China)

    2015-05-08

    Pathological cardiac hypertrophy, often accompanied by hypertension, aortic stenosis and valvular defects, is typically associated with myocyte remodeling and cardiac dysfunction. Exercise preconditioning (EP) has been proven to enhance the tolerance of the myocardium to cardiac ischemia-reperfusion injury. However, the effects of EP in pathological cardiac hypertrophy are rarely reported. 10-wk-old male Sprague–Dawley rats (n = 80) were randomly divided into four groups: sham, TAC, EP + sham and EP + TAC. Two EP groups were subjected to 4 weeks of treadmill training, and the EP + TAC and TAC groups were followed by TAC operations. The sham and EP + sham groups underwent the same operation without aortic constriction. Eight weeks after the surgery, we evaluated the effects of EP by echocardiography, morphology, and histology and observed the expressions of the associated proteins. Compared with the respective control groups, hypertrophy-related indicators were significantly increased in the TAC and EP + TAC groups (p < 0.05). However, between the TAC and EP + TAC groups, all of these changes were effectively inhibited by EP treatment (p < 0.05). Furthermore, EP treatment upregulated the expression of HSF1 and HSP70, increased the HSF1 levels in the nuclear fraction, inhibited the expression of the NF-κB p65 subunit, decreased the NF-κB p65 subunit levels in the nuclear fraction, and reduced the IL2 levels in the myocardia of rats. EP could effectively reduce the cardiac hypertrophic responses induced by TAC and may play a protective role by upregulating the expressions of HSF1 and HSP70, activating HSF1 and then inhibiting the expression of NF-κB p65 and nuclear translocation. - Highlights: • EP could effectively reduce the cardiac hypertrophic responses induced by TAC. • EP may play a protective role by upregulating the expressions of HSF1 and HSP70 and then activating HSF1. • EP may play a protective role by inhibiting the expression

  3. Trimetazidine attenuates pressure overload-induced early cardiac energy dysfunction via regulation of neuropeptide Y system in a rat model of abdominal aortic constriction

    OpenAIRE

    Chen, Ailan; Li, Wanglin; Chen, Xinyu; Shen, Yuechun; Dai, Wenjun; Dong, Qi; Li, Xinchun; Ou, Caiwen; Chen, Minsheng

    2016-01-01

    Background Metabolism remodeling has been recognized as an early event following cardiac pressure overload. However, its temporal association with ventricular hypertrophy has not been confirmed. Moreover, whether trimetazidine could favorably affect this process also needs to be determined. The aim of the study was to explore the temporal changes of myocardial metabolism remodeling following pressure-overload induced ventricular hypertrophy and the potential favorable effect of trimetazidine ...

  4. Apoptosis signal-regulating kinase 1 inhibition attenuates cardiac hypertrophy and cardiorenal fibrosis induced by uremic toxins: Implications for cardiorenal syndrome.

    Science.gov (United States)

    Savira, Feby; Cao, Longxing; Wang, Ian; Yang, Wendi; Huang, Kevin; Hua, Yue; Jucker, Beat M; Willette, Robert N; Huang, Li; Krum, Henry; Li, Zhiliang; Fu, Qiang; Wang, Bing Hui

    2017-01-01

    Intracellular accumulation of protein-bound uremic toxins in the setting of cardiorenal syndrome leads to adverse effects on cardiorenal cellular functions, where cardiac hypertrophy and cardiorenal fibrosis are the hallmarks. In this study, we sought to determine if Apoptosis Signal-Regulated Kinase 1 (ASK1), an upstream regulator of cellular stress response, mediates cardiac hypertrophy and cardiorenal fibrosis induced by indoxyl sulfate (IS) and p-cresol sulfate (PCS) in vitro, and whether ASK1 inhibition is beneficial to ameliorate these cellular effects. PCS augmented cardiac myocyte hypertrophy and fibroblast collagen synthesis (as determined by 3H-leucine and 3H-proline incorporation, respectively), similar to our previous finding with IS. IS and PCS also increased collagen synthesis of proximal tubular cells and renal mesangial cells. Pro-hypertrophic (α-skeletal muscle actin and β-MHC) and pro-fibrotic genes (TGF-β1 and ctgf) were induced by both IS and PCS. Western blot analyses revealed the activation of ASK1 and downstream mitogen activated protein kinases (MAPKs) (p38MAPK and ERK1/2) as well as nuclear factor-kappa B (NF-κB) by IS and PCS. ASK1, OAT1/3, ERK1/2 and p38MAPK inhibitors suppressed all these effects. In summary, IS and PCS exhibit pro-hypertrophic and pro-fibrotic properties, at least in part, via the activation of ASK1 and its downstream pathways. ASK1 inhibitor is an effective therapeutic agent to alleviate protein-bound uremic toxin-induced cardiac hypertrophy and cardiorenal fibrosis in vitro, and may be translated further for cardiorenal syndrome therapy.

  5. Osseous metaplasia in a kidney allograft.

    Science.gov (United States)

    Bataille, Stanislas; Daniel, Laurent; Legris, Tristan; Vacher-Coponat, Henri; Purgus, Raj; Berland, Yvon; Moal, Valerie

    2010-11-01

    Osseous metaplasia is defined by the presence of heterotopic normal bone tissue in a soft tissue. The bone matrix is associated with osteoblasts, osteoclasts, adipocytes and haematopoietic stem cells. Osseous metaplasia pathophysiology is not well known, but many factors have been incriminated including chronic inflammation and chronic ischaemia. We describe the second case of osseous metaplasia in a kidney allograft. Numerous factors might favour its development including factors linked to transplantation failure environment.

  6. Should fractures in massive intercalary bone allografts of the lower limb be treated with ORIF or with a new allograft?

    Science.gov (United States)

    Aponte-Tinao, Luis A; Ayerza, Miguel A; Muscolo, D Luis; Farfalli, Germán L

    2015-03-01

    Massive bone allografts have been used for limb salvage of bone tumor resections as an alternative to endoprostheses, although they have different outcomes and risks. There is no general consensus about when to use these alternatives, but when it is possible to save the native joints after the resection of a long bone tumor, intercalary allografts offer some advantages despite complications, such as fracture. The management and outcomes of this complication deserve more study. The purposes of this study were to (1) analyze the fracture frequency in a group of patients treated with massive intercalary bone allografts of the femur and tibia; (2) compare the results of allografts treated with open reduction and internal fixation (ORIF) with those treated with resection and repeat allograft reconstruction; and (3) determine the likelihood that treatment of a fracture resulted in a healed intercalary reconstruction. We reviewed patients treated with intercalary bone allografts between 1991 and 2011. During this period, patients were generally treated with intercalary allografts when after tumor resection at least 1 cm of residual epiphysis remained to allow fixation of the osteotomy junction. To obtain a homogeneous group of patients, we excluded allograft-prosthesis composites and osteoarticular and hemicylindrical intercalary allografts from this study. We analyzed the fracture rate of 135 patients reconstructed with segmental intercalary bone allografts of the lower extremities (98 femurs and 37 tibias). In patients whose grafts fractured were treated either by internal fixation or a second allograft, ORIF generally was attempted but after early failures in femur fractures, these fractures were treated with a second allograft. Using a chart review, we ascertained the frequency of osseous union, complications, and reoperations after the treatment of fractured intercalary allografts. Followup was at a mean of 101 months (range, 24-260 months); of the original 135

  7. Morning surge of ventricular arrhythmias in a new arrhythmogenic canine model of chronic heart failure is associated with attenuation of time-of-day dependence of heart rate and autonomic adaptation, and reduced cardiac chaos.

    Directory of Open Access Journals (Sweden)

    Yujie Zhu

    Full Text Available Patients with chronic heart failure (CHF exhibit a morning surge in ventricular arrhythmias, but the underlying cause remains unknown. The aim of this study was to determine if heart rate dynamics, autonomic input (assessed by heart rate variability (HRV and nonlinear dynamics as well as their abnormal time-of-day-dependent oscillations in a newly developed arrhythmogenic canine heart failure model are associated with a morning surge in ventricular arrhythmias. CHF was induced in dogs by aortic insufficiency & aortic constriction, and assessed by echocardiography. Holter monitoring was performed to study time-of-day-dependent variation in ventricular arrhythmias (PVCs, VT, traditional HRV measures, and nonlinear dynamics (including detrended fluctuations analysis α1 and α2 (DFAα1 & DFAα2, correlation dimension (CD, and Shannon entropy (SE at baseline, as well as 240 days (240 d and 720 days (720 d following CHF induction. LV fractional shortening was decreased at both 240 d and 720 d. Both PVCs and VT increased with CHF duration and showed a morning rise (2.5-fold & 1.8-fold increase at 6 AM-noon vs midnight-6 AM during CHF. The morning rise in HR at baseline was significantly attenuated by 52% with development of CHF (at both 240 d & 720 d. Morning rise in the ratio of low frequency to high frequency (LF/HF HRV at baseline was markedly attenuated with CHF. DFAα1, DFAα2, CD and SE all decreased with CHF by 31, 17, 34 and 7%, respectively. Time-of-day-dependent variations in LF/HF, CD, DFA α1 and SE, observed at baseline, were lost during CHF. Thus in this new arrhythmogenic canine CHF model, attenuated morning HR rise, blunted autonomic oscillation, decreased cardiac chaos and complexity of heart rate, as well as aberrant time-of-day-dependent variations in many of these parameters were associated with a morning surge of ventricular arrhythmias.

  8. [Effect of cyclosporine and simulect mono and combination therapy on cardiac allo-transplantation in rats].

    Science.gov (United States)

    Xiong, Hai-Bo; Xia, Sui-Sheng; Huang, Zu-Fal; Ye, Qi-Fa; Wen, Hao

    2005-10-01

    To observe the effect of cyclosporine and simulect mono or combination therapy on cardiac allo-transplantation in rats. Recipients with allografts were treated with different doses of cyclosporine and/or simulect after cardiac allo-transplantation. Graft survival time was observed; the histopathological examination of graft tissues was performed; and levels of serum IL-2 and IL-4 were determined. Mono or combination therapy with cyclosporine and/or simulect increased the survival of cardiac allografts. With the prolongation of survival time of the grafts, the rejection of grafts was moderated. The serum IL-2 level increased in acute rejected grafts; the serum IL-4 level increased evidently in long survival grafts. Cyclosporine and simulect have an effect in the prolongation of cardiac allograft survival in rats, and the combination therapy shows an evident synergistic effect.

  9. Ação do soro de cabra anti-soro de coelho imunizado ou não com células linfóides do doador sobre o alotransplante cardíaco em ratos: immunosupression of goat antiserum against rabbit serum immunized or not with donor lymphoid cells Cardiac allograft in rats

    Directory of Open Access Journals (Sweden)

    Haylton Jorge Suaid

    2002-01-01

    rejeição aguda dos corações transplantados não apresentaram anticorpos citotóxicos circulantes. O fator causador do bloqueio parace n��o estar vinculado aos bloqueios de citotoxicidade "in vitro" e do teor de precepitinas do SAL.OBJECTIVE: To study the immunosupression efficacy an specific anti-antilymphocytic serum prepared in goats in a model of cardiac allografts in rats. METHODS: Three rabbits were immunized with lymphoid cells obtained from mesenteric lymphatic nodes of Wistar rats. Each one received subcutaneously 3x10(9 cells mixed with Freund's adjuvant. After 2 weeks, they were injected with the same amount of cells at weekly intervals for 4 additional times. In the 5th week they were bled and their serum were mixed. This serum, which had a cytotoxic titer of 1:1024, was used to immunize 2 goats that gave rise to the anti-antilymphocytic serum (AAS-1 and AAS-2. As control we immunized 1 additional goat with normal rabbit serum (ANS. The gel diffusion technique (AAS x rabbit serum showed precipitation bands against till the following dilution: AAS-1 - 1/64, AAS-2 - 1/128 and ANS 1/124. Both AAS were able to block the in vitro lymphocytotoxity of goat antilymphocytic serum till dilution of 1:2 while ANS did not. The hearts from Wistar rats (donors were transplanted in Holtzman rats. The transplanted rats were divide in groups: C1 - 11 animals (control that received no serum; C2 - 5 animals (control that received 1ml of goat normal serum; A- 19 animals - A1 with 5 rats injected intravenously in the day of surgery with 0.5ml of AAS-1, A2 with 7 rats injected with 1ml of AAS-1 only in the of surgery, and A3 with 7 rats that received 1ml of AAS-1 in days 0, 1 and 2 postoperatively; and group B with 19 rats (B1, B2 and B3 treated as group A except with the AAS-2 serum. RESULTS: Mean heart survival in groups C1 and C2 was respectively 11.9 and 14.6 days Survival range in the subgroups A1 and A2 were respectively 9 to 230 days and 23 to 230 days. In subgroup A

  10. Limbal autograft and allograft transplantations in patients with corneal burns.

    Science.gov (United States)

    Ozdemir, O; Tekeli, O; Ornek, K; Arslanpençe, A; Yalçindağ, N F

    2004-03-01

    To investigate and compare the surgical outcomes of limbal autograft and limbal allograft transplantations in patients with corneal burns. In total, 20 patients (n=22 eyes) with chemical burn and two patients (n=2 eyes) with thermal burn were included in this study. Limbal autograft or limbal allograft transplantation surgery was performed in all patients. HLA-typing was tested before allograft surgeries. Limbal allografting was performed in all eyes using donor tissue from live relatives. Systemic cyclosporine A was administered for immunosuppression. The corneal surface was successfully reconstructed in all eyes (100%) after limbal autografting, two eyes required additional amniotic membrane transplantation and one eye required allografting. The mean follow-up period for limbal autografts was 13.9 +/- 7.0 months. Limbal allografting failed to reduce corneal vascularity and opacification in five (55.6%) eyes and was successful only in four (44.4%) eyes (mean follow-up 16.2 +/- 11.2 months) (P=0.002). In all, 15 eyes undergoing limbal autografting completed re-epithelialization of the cornea at a mean of 35.6 +/- 60.2 days. The mean epithelial healing time in nine eyes undergoing limbal allografting was 13.0 +/- 7.3 days (P=0.525). After limbal autografting, functional vision (> or =1/10) was attained in 12 (80%) eyes. Only one eye (11.1%) achieved functional vision after limbal allografting (P=0.036). Penetrating keratoplasty was performed in three patients following limbal allografting. No cyclosporine-associated side effects were observed. Limbal autograft transplantation is an effective and safe procedure for unilateral corneal burns. It seems that limbal allograft transplantation is better combined with penetrating keratoplasty for a better visual outcome and higher graft survival rate. Systemic immunosuppression seems to be necessary for limbal allografts even in the presence of HLA-matched donor tissues.

  11. Decreased cardiac SERCA2 expression, SR Ca uptake, and contractile function in hypothyroidism are attenuated in SERCA2 overexpressing transgenic rats.

    Science.gov (United States)

    Vetter, Roland; Rehfeld, Uwe; Reissfelder, Christoph; Fechner, Henry; Seppet, Enn; Kreutz, Reinhold

    2011-03-01

    The sarco/endoplasmic reticulum (SR) Ca(2+)-ATPase SERCA2a has a key role in controlling cardiac contraction and relaxation. In hypothyroidism, decreased expression of the thyroid hormone (TH)-responsive SERCA2 gene contributes to slowed SR Ca(2+) reuptake and relaxation. We investigated whether cardiac expression of a TH-insensitive SERCA2a cDNA minigene can rescue SR Ca(2+) handling and contractile function in female SERCA2a-transgenic rats (TG) with experimental hypothyroidism. Wild-type rats (WT) and TG were rendered hypothyroid by 6-N-propyl-2-thiouracil treatment for 6 wk; control rats received no treatment. In vivo measured left ventricular (LV) hemodynamic parameters were compared with SERCA2a expression and function in LV tissue. Hypothyroidism decreased LV peak systolic pressure, dP/dt(max), and dP/dt(min) in both WT and TG. However, loss of function was less in TG. Thus slowed relaxation in hypothyroidism was found to be 1.5-fold faster in TG compared with WT (P hypothyroid TG (P hypothyroid WT), and the hypothyroidism-caused decline of LV SERCA2a mRNA expression in TG by -24% was markedly less than the decrease of -49% in WT (P hypothyroid rat heart. However, SR Ca(2+) uptake and in vivo heart function were only partially rescued.

  12. Soaking morselized allograft in bisphosphonate can impair implant fixation

    DEFF Research Database (Denmark)

    Jakobsen, Thomas; Baas, Jørgen; Bechtold, Joan E

    2007-01-01

    The use of impacted, morselized allograft is a well-established way to provide initial stability of revision joint replacements. We investigated whether rinsing morselized allograft in bisphosphonate and subsequently impacting it around experimental titanium-coated implants would further facilita...

  13. Combining bisphosphonates with allograft bone for implant fixation

    NARCIS (Netherlands)

    Mathijssen, N.M.C.; Buma, P.; Hannink, G.J.

    2014-01-01

    The aim of this review was to discuss the current state of research of combining bisphosphonates with allograft bone for implant fixation. The allograft bone can only be reached by the bisphosphonate once it has been revascularized. However, this can be circumvented by local administration of

  14. Allograft Arthrodesis of the Knee in High-grade Osteosarcoma

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    Teng-Le Huang

    2005-09-01

    Conclusion: Due to the high rate of complications in this study, we conclude that allograft arthrodesis should be left as a salvage or “back-up” reconstructive procedure after resection of osteosarcoma around the knee, unless there are special indications for this procedure. We found allograft fracture to be the most common complication.

  15. Patient And Allograft Survival After Transplantation With A Living ...

    African Journals Online (AJOL)

    (Tacrolimus, Mycophenolate Mofetil, Sirolimus,. Monoclonal antibodies against interleukin-2 receptor) have reduced the incidence of acute rejection among recipients of renal allografts to as low as 10-30O/0~~ and it is anticipated that this lowered frequency will translate into decreased incidence of allograft loss. It has been ...

  16. Butanolic fraction of Moringa oleifera Lam. (Moringaceae) attenuates isoprotrenol-induced cardiac necrosis and oxidative stress in rats: an EPR study.

    Science.gov (United States)

    Panda, Sunanda

    2015-01-01

    The preventive effect of Moringa oleifera polyphenolic fraction (MOPF) on cardiac damage was evaluated in isoproterenol (ISO) induced cardiotoxicity model of Wistar rats. Male rats in different groups were treated with MOPF orally at the dose of 50, 100 and 150 mg/kg/day for 28 days and were subsequently administered (s.c.) with ISO (85 mg/kg body weight) for the last two days. At the end of the experiment levels of serum troponin-T, creatine kinase-MB, lactate dehydrogenase, content of malondialdehyde (MDA), activities/levels of different cellular antioxidants were estimated in control and experimental groups. Additionally, scavenging potential to the hydroxyl radical of the fraction was measured by electron paramagnetic resonance (EPR). ISO administered rats showed significant increase in the levels of serum troponin-I, creatine kinase, lactate dehydrogenase, and heart tissue MDA content. Furthermore, marked reduction in the activities of antioxidants such as superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione levels were observed. EPR study showed an increase in signal intensity in ISO-induced rats. Triphenyl tetrazolium chloride (TTC) staining of heart section revealed a marked increase in infarcted area in ISO-induced rats. Histological features of the heart also indicated a disruption in the structure of cardiac myofibrils in these animals. MOPF (100 mg/kg body weight) pretreatment prevented all these adverse effects of ISO. Present results show that the rich polyphenolic content of Moringa oleifera significantly reduced the myocardial damage and decreased the oxidative stress, possibly through hydroxyl radical scavenging activity as evidenced from the EPR spectra.

  17. Osteochondral Allograft Transplantation for Femoral Trochlear Dysplasia

    Science.gov (United States)

    Vansadia, Dharmpal V.; Heltsley, James R.; Montgomery, Scott; Suri, Misty; Jones, Deryk G.

    2016-01-01

    Background: The risk factors for patellofemoral joint instability include laxity of medial patellar restraints, abnormal limb geometry, femoral and tibial malrotation, patella alta, and trochlear dysplasia. Femoral trochlear dysplasia is characterized by a hypoplastic or shallow trochlear groove. Case Report: We report the case of a 31-year-old female with trochlear dysplasia and recurrent patella dislocations, laxity of the medial patellofemoral ligament (MPFL), and high-grade chondromalacia of the trochlea and the patella. Surgical treatment goals were to re-create a trochlear groove, restore bony restraint, and realign and offload the patella. First, a triplane tibial tubercle osteotomy (TTO) was performed, and the patella was everted 360° with a subvastus approach. The MPFL was reconstructed using a gracilis allograft. A fresh osteochondral allograft transplant trochlea was sized, and a 35-mm diameter graft was transplanted to re-create the groove. The TTO was secured in a new anterior, medial, and distal position. The patient was braced for 6 weeks and completed a rehabilitation protocol. At 9-month follow-up, she had made significant gains in range of motion (0°-140°) and activity compared to her preoperative status. She reported no pain or recurrent dislocations. Conclusion: This case demonstrates a viable surgical option for treatment of instability resulting from trochlear dysplasia with patellofemoral chondromalacia. The osteochondral allograft transplantation surgery technique allows patients to have a stable, pain-free knee joint and participate in activities compared to nonoperative management. However, the long-term outcomes of this procedure are unknown. PMID:27999505

  18. Chemical sterilization of allograft dermal tissues.

    Science.gov (United States)

    Phipps, Abigail; Vaynshteyn, Edward; Kowalski, John B; Ngo, Manh-Dan; Merritt, Karen; Osborne, Joel; Chnari, Evangelia

    2017-12-01

    Common terminal sterilization methods are known to alter the natural structure and properties of soft tissues. One approach to providing safe grafts with preserved biological properties is the combination of a validated chemical sterilization process followed by an aseptic packaging process. This combination of processes is an accepted method for production of sterile healthcare products as described in ANSI/AAMI ST67:2011. This article describes the validation of the peracetic acid and ethanol-based (PAAE) chemical sterilization process for allograft dermal tissues at the Musculoskeletal Transplant Foundation (MTF, Edison, NJ). The sterilization capability of the PAAE solution used during routine production of aseptically processed dermal tissue forms was determined based on requirements of relevant ISO standards, ISO 14161:2009 and ISO 14937:2009. The resistance of spores of Bacillus subtilis, Clostridium sporogenes, Mycobacterium terrae, Pseudomonas aeruginosa, Enterococcus faecium, and Staphylococcus aureus to the chemical sterilization process employed by MTF was determined. Using a worst-case scenario testing strategy, the D value was calculated for the most resistant microorganism, Bacillus. The 12D time parameter determined the minimum time required to achieve a SAL of 10 -6 . Microbiological performance qualification demonstrated a complete kill of 10 6 spores at just a quarter of the full cycle time. The validation demonstrated that the PAAE sterilization process is robust, achieves sterilization of allograft dermal tissue to a SAL 10 -6 , and that in combination with aseptic processing secures the microbiological safety of allograft dermal tissue while avoiding structural and biochemical tissue damage previously observed with other sterilization methods such as ionizing irradiation.

  19. Resistance of Foxp3+ regulatory T cells to Nur77-induced apoptosis promotes allograft survival.

    Directory of Open Access Journals (Sweden)

    Ran Tao

    Full Text Available The NR4A nuclear receptor family member Nur77 (NR4A1 promotes thymocyte apoptosis during negative selection of autoreactive thymocytes, but may also function in mature extrathymic T cells. We studied the effects of over-expression of Nur77 on the apoptosis of murine peripheral T cells, including thymic-derived Foxp3+ regulatory (Treg cells. Overexpression of Nur77 in the T cell lineage decreased numbers of peripheral CD4 and CD8 T cells by approximately 80% compared to wild-type (WT mice. However, the proportions of Treg cells were markedly increased in the thymus (61% of CD4+Foxp3+ singly positive thymocytes vs. 8% in WT and secondary lymphoid organs (40-50% of CD4+Foxp3+ T cells vs. 7-8% in WT of Nur77 transgenic (Nur77Tg mice, and immunoprecipitation studies showed Nur77 was associated with a recently identified HDAC7/Foxp3 transcriptional complex. Upon activation through the T cell receptor in vitro or in vivo, Nur77Tg T cells showed only marginally decreased proliferation but significantly increased apoptosis. Fully allogeneic cardiac grafts transplanted to Nur77Tg mice survived long-term with well-preserved structure, and recipient splenocytes showed markedly enhanced apoptosis and greatly reduced anti-donor recall responses. Allografts in Nur77Tg recipients had significantly increased expression of multiple Treg-associated genes, including Foxp3, Foxp1, Tip60 and HDAC9. Allograft rejection was restored by CD25 monoclonal antibody therapy, indicating that allograft acceptance was dependent upon Treg function in Nur77Tg recipients. These data show that compared to conventional CD4 and CD8 T cells, Foxp3+ Tregs are relatively resistant to Nur77-mediated apoptosis, and that tipping the balance between the numbers of Tregs and responder T cells in the early period post-transplantation can determine the fate of the allograft. Hence, induced expression of Nur77 might be a novel means to achieve long-term allograft survival.

  20. Meniscal allograft transplantation: a meta-analysis

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    De Bruycker Manolito

    2017-01-01

    Full Text Available Purpose: This meta-analysis evaluates the mid- to long-term survival outcome of MAT (meniscal allograft transplantation. Potential prognosticators, with particular focus on chondral status and age of the patient at the time of transplantation, were also analysed. Study design: Meta-analysis. Methods: An online database search was performed using following search string: “meniscal allograft transplantation” and “outcome”. A total of 65 articles were analysed for a total of 3157 performed MAT with a mean follow-up of 5.4 years. Subjective and clinical data was analysed. Results: The subjective and objective results of 2977 patients (3157 allografts were analysed; 70% were male, 30% were female. Thirty-eight percent received an isolated MAT. All other patients underwent at least one concomitant procedure. Lysholm, Knee injury and Osteoarthritis Outcome (KOOS, International Knee Documentation Committee (IKDC and Visual Analogue Scale (VAS scores were analysed. All scores showed a good patient satisfaction at long-term follow-up. The mean overall survival rate was 80.9%. Complication rates were comparable to standard meniscal repair surgery. There was a degenerative evolution in osteoarthritis with at least one grade in 1760 radiographically analysed patients. Concomitant procedures seem to have no effect on the outcome. Age at transplantation is a negative prognosticator. The body mass index (BMI of the patient shows a slightly negative correlation with the outcome of MAT. Conclusions: MAT is a viable solution for the younger patient with chronic pain in the meniscectomised knee joint. The complications are not severe and comparable to meniscal repair. The overall failure rate at final follow-up is acceptable and the allograft heals well in most cases, but MAT cannot be seen as a definitive solution for post-meniscectomy pain. The correct approach to the chronic painful total meniscectomised knee joint thus requires consideration of all

  1. Complications of massive allograft reconstruction for bone tumors

    Directory of Open Access Journals (Sweden)

    Abolhasan Borjian

    2006-11-01

    Full Text Available BACKGROUND: Since the evolution of multi-drug chemotherapy and radiotherapy and new sophisticated surgical techniques, limb salvage and reconstruction, rather than amputation, has become the preferred treatment for patients with bone tumors. One option is allograft replacement. Although allograft has several advantages, it is not without complications. This study was performed to observe these complications in a group of patients treated with allograft replacement for bone tumor resection. The purpose was to gain an overview of the factors predisposing to these complications to minimize their occurrence. METHODS: This retrospective study was performed on patients with benign aggressive and malignant bone tumors undergoing limb reconstruction with allograft between 1997 and 2005 in Al-Zahra and Kashani Hospitals in Isfahan, Iran. Data was collected from patient files, clinical notes, radiographs and a recent physical examination. Complications including local recurrence, fracture of allograft, fixation failure, nonunion, infection, skin necrosis and neurological damage were recorded. RESULTS: Sixty patients including 39 males and 21 females were studied. The mean age of patients was 23 ± 11.7 years. The mean follow-up interval was 28.1 ± 12.4 months (mean ± SD. Complications were allograft fracture in 20%, local recurrence in 16%, fixation failure in 11%, nonunion in 6%, infection in 6%, skin necrosis in 6%, and peroneal nerve palsy in 1% of cases. Most local recurrences (60% were those with a mal-performed biopsy. Most allograft fractures occurred when a short plate was used. CONCLUSIONS: Allograft replacement for bone tumors remains a valid option. To avoid complications, biopsy should be done by a trained surgeon in bone oncology. A long plate is recommended for fixation. Sterility and graft processing must be optimal. Autogenous bone graft must be added at host-allograft junction. KEY WORDS: Bone tumors, bone allograft, limb

  2. OSTEOARTICULAR ALLOGRAFTS IN PAEDIATRIC BONE TUMOR RECONSTRUCTION OF THE KNEE.

    Science.gov (United States)

    Campanacci, D A; Dursky, S; Totti, F; Frenos, F; Scoccianti, G; Beltrami, G; Capanna, R

    2015-01-01

    Osteoarticular allografts represent a reconstructive option after bone tumor resection around the knee in growing children. The major advantage is the chance to preserve the growth plate of the remaining bone, but the disadvantage is the high failure rate eventually requiring definitive prosthetic replacement at skeletal maturity. We retrospectively reviewed 22 patients who underwent osteoarticular allograft reconstructions of the distal femur (16) or proximal tibia (6). There were 12 females and 10 males with an average age at surgery of 11 years (7-15). The diagnosis was osteosarcoma in 19 cases and Ewing sarcoma in 3. All patients underwent pre- and post-operative chemotherapy. At an average follow-up of 103 months (12-167), 18 patients (82%) were alive and 4 had died (18%). We observed 10 allograft failures requiring prosthetic replacement, 6 in distal femur and 4 in proximal tibia reconstructions. At last follow-up 8 allografts (36%) were still in place. Overall allograft survival was 79.6% at five and 45.8% at ten years. In distal femur, allograft survival was 86.2% at five and 59.1% at ten years. In proximal tibia, allograft survival was 62.5% at 5 years and 31.2% at 67 months. Average limb shortening was 3 cm (0- 5) in 8 patients with the allograft still in situ and 2 cm (0-4) in 10 patients after prosthetic replacement. Average MSTS functional score of the whole series was 25 (83.7%). The MSTS score of patients after revision with prosthetic replacement was 24 (80%) while patients who still had the allograft retained had an average MSTS scores of 26.8 (89.3%). In conclusion, osteoarticular allograft reconstruction of the knee after bone tumor resection in pediatric age can be considered a temporary solution with the aim to limit limb length discrepancy before definitive prosthetic replacement after skeletal maturity.

  3. Sterilization of skin allografts by ionizing radiation.

    Science.gov (United States)

    Bourroul, Selma Cecília; Herson, Marisa Roma; Pino, Eddy; Matho, Monica Beatriz

    2002-11-01

    The skin has a fundamental role in the viability of human body. In the case of extensive wounds, skin allografts provide an alternative to cover temporarily the damaged areas. After donor screening and preservation in glycerol 85%, the skin can be stored in a Skin Bank. Glycerol at this concentration has a bacteriostatic effect after certain time of preservation. On the other hand, skin sterilization by ionizing radiation may reduce the quarentine period for transplantation in patients. The objective of this work was to evaluate allograft sterilization using two sources of ionizing radiation. Through the analysis of stress-strain, it was intended to verify possible effects of the radiation on the structure of preserved grafts. Three groups of skin samples were selected. The first group was maintained in the initial conditions, not irradiated. The second was exposed to cobalt-60, while the third one was irradiated using an Dynamitron Accelerator JOB188 electron beam. The irradiation dose was 25 kGy for both tests. Both irradiation sources, and the Instron Universal Machine used for biomechanical experiments, are installed at the Centro de Tecnologia das Radiações/Instituto de Pesquisas Energéticas e Nucleares (São Paulo, Brazil). According to the preliminary results, biomechanical characteristics of the samples irradiated seem to be maintained with regard to the non irradiated group.

  4. Adefovir nephrotoxicity in a renal allograft recipient

    Directory of Open Access Journals (Sweden)

    N George

    2015-01-01

    Full Text Available Adefovir dipivoxil, an oral prodrug of adefovir, is used in the treatment of lamivudine-resistant hepatitis B virus (HBV infection. Nephrotoxicity manifesting as proximal renal tubular dysfunction and acute tubular necrosis (ATN were commonly reported in the past, when higher doses were used for the treatment of human immunodeficiency virus infection. However, nephrotoxicity is rare at lower doses that are currently recommended for the treatment of HBV infection. A 31-year-old female was detected to be hepatitis B surface antigen positive months after a kidney transplant. The patient was initiated on lamivudine, but developed resistance after 1 year of treatment, at which time low-dose adefovir was added. The patient developed renal allograft dysfunction after 10 months of starting adefovir. Serum creatinine increased from 1.1 mg/dl to 1.9 mg/dl, along with progressively increasing sub-nephrotic proteinuria. Renal allograft biopsy revealed features of ATN. After discontinuation of adefovir, proteinuria resolved and renal dysfunction improved slowly over the next 2 years. Adefovir-induced nephrotoxicity, although uncommon at lower doses, needs to be considered in the differential diagnosis of renal dysfunction and sub-nephrotic proteinuria occurring in patients receiving adefovir for prolonged periods.

  5. Opportunistic infections in renal allograft recipients.

    Science.gov (United States)

    Gupta, R K

    2007-04-01

    Two major factors for successful organ transplantation are better control of rejection and better prevention and treatment of infections. In renal allograft recipients, immunosuppressive drug therapy is the major cause of immunocompromised status and occurrence of infections, which arise most commonly as a result of invasion by endogenous opportunists. It may also follow colonization by exogenous environmental organisms and via transfer of cytomegalovirus along with the transplanted kidney. The overall incidence of opportunistic infections varies from center to center; up to 15% of renal transplant recipients die of these infections. Clinical signs and symptoms of infection in immunocompromised patients may be concealed or imitated by the underlying disease, and a high index of clinical suspicion is vital. The unusual pathogens encountered in these patients demand thorough investigation. A total of 84 opportunistic infections encountered in renal allograft recipients during histopathologic and cytopathological evaluation of various specimens during the last 15 years is presented in this report. Invasive fungal infections were the most common pathogens, amounting to 55% of all infections. The dramatic increase in the diversity and number of opportunistic infections detected in these patients is not only due to an increasing population of susceptible individuals but also due to an improved recognition by advanced laboratory diagnostic techniques. The success of management of opportunistic infections depends on strong clinical suspicion, early diagnosis, and prompt treatment. The challenges of early diagnosis of opportunistic infections and prompt treatment are great; the rewards are even greater.

  6. [Hand allograft in agenesic newborn: feasibility study].

    Science.gov (United States)

    Gazarian, A; Abrahamyan, D O

    2007-10-01

    Would a newborn with a single hand benefit from hand allograft? Transantebrachial aplasia is the chosen clinical form of agenesia in our interrogation. The feasibility study presents several aspects: 1) ethical and psychological aspects. Is this a desired surgery for agenesic population? Which are the functional, psychological and social situations of agenesic patient? Is the hand transplantation in newborn ethically acceptable? What is the parents' attitude toward agenesia? Can we envisage organ donation in neonatal period? 2) immunological aspects. The non-vital character of this condition and its' good functional tolerance cannot make accepting the risk of adverse effects of hand allotransplantation. Hence, one may consider this surgery only without immunosuppression. Can the peculiarities of the neonate "immature" immune system represent an opportunity of easier tolerance obtaining, avoiding immunosuppression? 3) anatomical and technical aspects. The proximal tissues at the level of amputation are all hypoplastic in agenesic patients. Can we efficaciously suture those structures with donor eutrophic tissues? 4) cognitive aspects. Is a neonate born with only one hand is able to use two? A feasibility study on such a subject needs to take into account all these aspects. This research is useful because, even if hand allograft in agenesic newborn will never be done, the provided information will allow to progress in the vaster domain of composite tissue allotransplantation in perinatology.

  7. Exogenous heat shock cognate protein 70 pretreatment attenuates cardiac and hepatic dysfunction with associated anti-inflammatory responses in experimental septic shock.

    Science.gov (United States)

    Hsu, Jong-Hau; Yang, Rei-Cheng; Lin, Shih-Jen; Liou, Shu-Fen; Dai, Zen-Kong; Yeh, Jwu-Lai; Wu, Jiunn-Ren

    2014-12-01

    It has been recently demonstrated that intracellular heat shock cognate protein 70 (HSC70) can be released into extracellular space with physiologic effects. However, its extracellular function in sepsis is not clear. In this study, we hypothesize that extracellular HSC70 can protect against lipopolysaccharide (LPS)-induced myocardial and hepatic dysfunction because of its anti-inflammatory actions. In Wistar rats, septic shock developed with hypotension, tachycardia, and myocardial and hepatic dysfunction at 4 h following LPS administration (10 mg/kg, i.v.). Pretreatment with recombinant bovine HSC70 (20 μg/kg, i.v.) attenuated LPS-induced hypotension and tachycardia by 21% and 23%, respectively (P shock cognate protein 70 also prevented LPS-induced hypoglycemia (217 vs. 59 mg/dL, P shock, extracellular HSC70 conveys pleiotropic protection on myocardial, hepatic, and systemic derangements, with associated inhibition of proinflammatory mediators including tumor necrosis factor α, nitric oxide, cyclooxygenase 2, and matrix metalloproteinase 9, through mitogen-activated protein kinase/nuclear factor κB signaling pathways. Therefore, extracellular HSC70 may have a promising role in the prophylactic treatment of sepsis.

  8. [The clinical use of cryopreserved human skin allografts for transplantation].

    Science.gov (United States)

    Martínez-Flores, Francisco; Chacón-Gómez, María; Madinaveitia-Villanueva, Juan Antonio; Barrera-Lopez, Araceli; Aguirre-Cruz, Lucinda; Querevalu-Murillo, Walter

    2015-01-01

    The biological recovery of human skin allografts is the gold standard for preservation in Skin Banks. However, there is no worldwide consensus about specific allocation criteria for preserved human skin allografts with living cells. A report is presented on the results of 5 years of experience of using human skin allografts in burned patient in the Skin and Tissue Bank at the "Instituto Nacional de Rehabilitacion" The human skin allografts were obtained from multi-organ donors. processed and preserved at -80 °C for 12 months. Allocation criteria were performed according to blood type match, clinical history, and burned body surface. Up to now, the Skin and Tissue Bank at 'Instituto Nacional de Rehabilitacion" has processed and recovered 125,000 cm(2) of human skin allografts. It has performed 34 surgical implants on 21 burned patients. The average of burn body surface was 59.2%. More than two-thirds (67.7%) of recipients of skin allografts were matched of the same to type blood of the donor, and 66.6% survived after 126 days hospital stay. It is proposed to consider recipient's blood group as allocation criteria to assign tissue; and use human skin allografts on patiens affected with burns over 30% of body surface (according the "rule of the 9"). Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

  9. Cobalt Protoporphyrin Improves Heart Function by Attenuating Cardiac Beta-oxidation and Restoring Redox Balance in an Animal Model of Experimental Diabetes

    Directory of Open Access Journals (Sweden)

    Jian eCao

    2012-06-01

    Full Text Available Myocardial dysfunction and coronary macro/microvascular alterations are the hallmarks of diabetic cardiomyopathy and are ascribed to increased oxidative stress and altered nitric oxide synthase (NOS activity. We hypothesize that pretreatment by cobalt-protoporphyrin IX (CoPP ameliorates both myocardial function and coronary circulation in streptozotocin(STZ-induced diabetic rats. Isolated hearts from diabetic rats in Langendorff configuration displayed lower left ventricular (LV function and higher coronary resistance (CR compared to hearts from control animals. CoPP treatment of diabetic animals (0.3mg/100g body weight i.p., once a week for three weeks significantly increased all the contractile/relaxation indexes (p<0.01, while decreasing CR (p<0.01. CoPP enhanced HO-1 protein levels and reduced oxidative/nitrosative stress in diabetic animals, as indicated by the significant (p<0.05 decrease in heart GSSG/GSHtotal, O2-, malondialdehyde (MDA, and 3-nitrotyrosine levels. CoPP increased adiponectin levels and phosphorylation of AKT and AMPK and reversed the eNOS/iNOS expression imbalance observed in the untreated diabetic heart. Furthermore, after CoPP treatment, a rise in malonylCoA as well as a decrease in acetylCoA was observed in diabetic hearts. In this experimental model of diabetic cardiomyopathy, CoPP treatment improved both cardiac function and coronary flow by blunting oxidative/nitrosative stress, restoring eNOS/ iNOS expression balance and increasing HO-1 levels, thereby favoring improvement in both endothelial function and insulin sensitivity.

  10. Scintiphotos in the diagnosis of renal allograft malfunction

    Energy Technology Data Exchange (ETDEWEB)

    Payne, J.; Telfer, N.; Barbour, B.H.; Berne, T.V.

    1972-01-01

    Scintigraphy and other radioisotope techniques using hippuran have become a useful adjunct in the monitoring of renal allograft function. Technetium has been used in the evaluation of renal blood flow, rejection, and post-transplant anuria. Combined assessment provides a good compromise and enables various complications following transplantation to be differentiated. This review was undertaken in order to correlate the visual interpretation of 158 scintiphoto studies with the clinical course of 89 renal allografts. The accuracy and reproducibility of the techniques have been evaluated to determine practical indications for the use of gamma camera studies in the diagnosis of renal allograft malfunction.

  11. Percutaneous fusion of lumbar facet with bone allograft

    Directory of Open Access Journals (Sweden)

    Félix Dolorit Verdecia

    2015-03-01

    Full Text Available OBJECTIVE: To assess the evolution of the cases treated with percutaneous facet fusion with bone allograft in lumbar facet disease. METHOD: Between 2010 and 2014, 100 patients (59 women and 41 men diagnosed with lumbar facet disease underwent surgery. RESULTS: The lumbar facet fusion with bone allograft shows good clinical results, is performed on an outpatient basis, and presents minimal complications and rapid incorporation of the patient to the activities of daily living. CONCLUSIONS: The lumbar facet fusion with bone allograft appears to be an effective treatment for lumbar facet disease.

  12. Innovations in cardiac transplantation.

    Science.gov (United States)

    Hasan, Reema; Ela, Ashraf Abou El; Goldstein, Daniel

    2017-03-16

    As the number of people living with heart failure continues to grow, future treatments will focus on efficient donor organ donation and ensuring safe and durable outcomes. This review will focus on organ procurement, graft surveillance and emerging therapies. Preliminary studies into donation after cardiac death have indicated that this may be an effective means to increase the donor pool. Novel preservation techniques that include ex-vivo perfusion to improve donor metabolic stabilization prior to implantation may also expand the donor pool. Biomarkers, including circulating-free DNA, are emerging that could replace the endomyocardial biopsy for acute graft rejection, but we lack a risk predictive biomarker in heart transplantation. Novel immune suppressants are being investigated. Emerging therapeutics to reduce the development of chronic allograft vasculopathy are yet to be found. This review highlights the most recent studies and future possible therapies that will improve outcomes in cardiac transplantation. Larger clinical trials are currently taking place and will be needed in the future to develop and sustain current trends toward better survival rates with cardiac transplantation.

  13. Surgical revascularization induces angiogenesis in orthotopic bone allograft

    NARCIS (Netherlands)

    Willems, Wouter F.; Kremer, Thomas; Friedrich, Patricia; Bishop, Allen T.

    2012-01-01

    Remodeling of structural bone allografts relies on adequate revascularization, which can theoretically be induced by surgical revascularization. We developed a new orthotopic animal model to determine the technical feasibility of axial arteriovenous bundle implantation and resultant angiogenesis. We

  14. Renalase Gene Polymorphism in Patients After Renal Allograft Transplantation

    Directory of Open Access Journals (Sweden)

    Andrzej Pawlik

    2014-06-01

    Full Text Available Background/Aims: Renalase is a recently discovered protein, which is likely involved in regulation of blood pressure in humans and animals. Previous studies suggest that renalase reflects kidney functioning. A common missense polymorphism in the flavin-adenine dinucleotide-binding domain of human renalase (Glu37Asp has been described. In this study we examined the association between (Glu37Asp polymorphism (rs2296545 in renalase gene and kidney allograft function. Methods: The study enrolled 270 Caucasian kidney allograft recipients. SNP within the renalase was genotyped using TaqMan genotyping assays. Results: There were no statistically significant associations between renalase gene rs2296545 polymorphism and delayed graft function, acute rejection, chronic allograft dysfunction as well as creatinine serum concentrations and blood pressure values after transplantation. Conclusions: The results of this study suggest, that renalase gene rs2296545 polymorphism is not important factor determining renal allograft function.

  15. Deceased donor skin allograft banking: Response and utilization

    Directory of Open Access Journals (Sweden)

    Gore Madhuri

    2010-10-01

    Full Text Available Background: In the absence of xenograft and biosynthetic skin substitutes, deceased donor skin allografts is a feasible option for saving life of patient with extensive burn injury in our country. Aims: The first deceased donor skin allograft bank in India became functional at Lokmanya Tilak Municipal (LTM medical college and hospital on 24 th April 2000. The response of Indian society to this new concept of skin donation after death and the pattern of utilization of banked allografts from 2000 to 2010 has been presented in this study. Settings and Design: This allograft skin bank was established by the department of surgery. The departments of surgery and microbiology share the responsibility of smooth functioning of the bank. Materials and Methods: The response in terms of number of donations and the profile of donors was analyzed from records. Pattern and outcome of allograft utilization was studied from specially designed forms. Results: During these ten years, 262 deceased donor skin allograft donations were received. The response showed significant improvement after counselling was extended to the community. Majority of the donors were above 70 years of age and procurement was done at home for most. Skin allografts from 249 donors were used for 165 patients in ten years. The outcome was encouraging with seven deaths in 151 recipients with burn injuries. Conclusions: Our experience shows that the Indian society is ready to accept the concept of skin donation after death. Use of skin allografts is life saving for large burns. We need to prepare guidelines for the establishment of more skin banks in the country.

  16. THE DIAGNOSIS OF LIVER ALLOGRAFT ACUTE REJECTION IN LIVER BIOPSIES

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    L. V. Shkalova

    2011-01-01

    Full Text Available We performed histological examination of 80 liver allograft biopsies, the diagnosis of acute rejection was proved in 34 cases. Histological changes in liver biopsies in different grades of acute rejection were estimated according to Banff classification 1995, 1997 and were compared with current literature data. The article deals with the question of morphological value of grading acute rejection on early and late, also we analyze changes in treat- ment tactics after morphological verification of liver allograft acute rejection. 

  17. Incidental Eosinophilic Chromophobe Renal Cell Carcinoma in Renal Allograft

    Directory of Open Access Journals (Sweden)

    Abdullah Alharbi

    2017-01-01

    Full Text Available The incidence of renal cell carcinoma (RCC in renal allograft in transplant recipients is 0.22–0.25%. De novo clear cell, papillary, and chromophobe RCCs and RCCs with sarcomatoid differentiation originating in renal allograft have been reported. Routine surveillance for graft tumours is not routinely practiced and these tumours are commonly asymptomatic and incidentally discovered. We describe a case of incidental, eosinophilic chromophobe RCC in a 31-year-old, long-term renal transplant male recipient, who presented with acute gastroenteritis 11 years after transplantation. The graft was nonfunctional at the time of presentation. Abdominal ultrasound and computed tomography scan demonstrated 1.8 cm well-defined, round enhancing lesion, confined to the renal allograft and suspicious for malignancy. Pathological examination of graft nephrectomy specimen showed gross, histopathological, and immunohistochemical features of eosinophilic chromophobe RCC. Fifty-five months after surgery, the patient was alive and free of malignancy. To the best of our knowledge, only five chromophobe RCCs originating in a renal allograft were previously described in English literature. We suggest that chromophobe RCC should be considered in the differential diagnosis of renal allograft mass, including eosinophilic tumours, and emphasise the importance of periodic screening of renal allograft in all renal transplant recipients.

  18. Incidental Eosinophilic Chromophobe Renal Cell Carcinoma in Renal Allograft.

    Science.gov (United States)

    Alharbi, Abdullah; Al Turki, Maram S; Aloudah, Noura; Alsaad, Khaled O

    2017-01-01

    The incidence of renal cell carcinoma (RCC) in renal allograft in transplant recipients is 0.22-0.25%. De novo clear cell, papillary, and chromophobe RCCs and RCCs with sarcomatoid differentiation originating in renal allograft have been reported. Routine surveillance for graft tumours is not routinely practiced and these tumours are commonly asymptomatic and incidentally discovered. We describe a case of incidental, eosinophilic chromophobe RCC in a 31-year-old, long-term renal transplant male recipient, who presented with acute gastroenteritis 11 years after transplantation. The graft was nonfunctional at the time of presentation. Abdominal ultrasound and computed tomography scan demonstrated 1.8 cm well-defined, round enhancing lesion, confined to the renal allograft and suspicious for malignancy. Pathological examination of graft nephrectomy specimen showed gross, histopathological, and immunohistochemical features of eosinophilic chromophobe RCC. Fifty-five months after surgery, the patient was alive and free of malignancy. To the best of our knowledge, only five chromophobe RCCs originating in a renal allograft were previously described in English literature. We suggest that chromophobe RCC should be considered in the differential diagnosis of renal allograft mass, including eosinophilic tumours, and emphasise the importance of periodic screening of renal allograft in all renal transplant recipients.

  19. Clinical and functional outcomes of tibial intercalary allograft reconstructions

    Directory of Open Access Journals (Sweden)

    Lucas López Millán

    2012-12-01

    Full Text Available Background The purpose of this study was to evaluate the survival, the complications and the functional outcome of intercalary tibial allografts reconstructions following tumor resections. Methods Intercalary tibia segmental allografts were implanted in 26 consecutive patients after segmental resections. Average follow-up was 6 years. Allograft survival was determined with the Kaplan-Meier method. Function was evaluated with the Musculoskeletal Tumor Society scoring system (MSTS. Results The rate of survival was 84% (CI 95%: 90%- 70% at 5 years and 79% at 10 years (CI 95%: 95%-63%. Allografts were removed in 5 patients (3 due to infections and 2 due to local recurrences. Two patients showed diaphyseal nonunion and 3 had an incomplete fracture, but it was not necessary to remove the allografts. Average MSTS functional score was 29 points (range 27 to 30. Conclusions Despite the incidence of complications, this analysis showed an acceptable survival with excellent functional scores. The use of intercalary allograft clearly has a place in the reconstruction of a segmental defect created by the resection of a tumor in the diaphyseal and/or metaphyseal portion of the tibia.

  20. Successful reversal of acute vascular rejection and cyclosporine-associated nephrotoxicity in renal allograft with combined sirolimus and mycophenolate mofetil as immunotherapy.

    Science.gov (United States)

    Ołdakowska-Jedynak, U; Paczek, L; Mucha, K; Foroncewicz, B; Perkowska-Ptasińska, A

    2006-01-01

    Cyclosporine (CsA) has substantially improved patient and graft survival rates in solid organ transplantation. In clinical studies, sirolimus has been shown to be as effective as CsA to maintain survival of renal and cardiac allografts without causing nephrotoxicity. Herein we describe a patient with biopsy-proven CsA-associated nephrotoxicity and refractory renal allograft rejection who was converted from steroids, CsA, and azathioprine to steroids, sirolimus (RAPA), and low-dose mycophenolate mofetil (MMF). The follow-up period was 60 months. We observed substantial improvement, even normalization in renal function. Our patient did not give consent to repeat biopsy after conversion. We also observed a beneficial effect of CsA withdrawal on blood pressure control. The spectrum of adverse events induced by sirolimus seemed to be mild relative to the potency of the immunosuppressive effect. The excellent response to combined RAPA and MMF in this patient was probably due to "concerted actions" of these agents on both B- and T-cell functions. The combination enhanced therapeutic efficacy while minimizing the toxicity of individual drugs used in the regimen. These findings suggest that sirolimus, when used as a base therapy in combination with low-dose MMF in a renal allograft recipient, may be an alternative to CsA-based therapy, providing potent immunosuppression of a renal allograft. Sirolimus administration facilitated steroids dose reduction.

  1. Kidney allograft offers: Predictors of turndown and the impact of late organ acceptance on allograft survival.

    Science.gov (United States)

    Cohen, J B; Shults, J; Goldberg, D S; Abt, P L; Sawinski, D L; Reese, P P

    2017-07-31

    There is growing interest in understanding patterns of organ acceptance and reducing discard. Little is known about how donor factors, timing of procurement, and geographic location affect organ offer decisions. We performed a retrospective cohort study of 47 563 deceased donor kidney match-runs from 2007 to 2013. Several characteristics unrelated to allograft quality were independently associated with later acceptance in the match-run: Public Health Service increased-risk donor status (adjusted odds ratio [aOR] 2.49, 95% confidence interval [CI] 2.29-2.69), holiday or weekend procurement (aOR 1.11, 95% CI 1.07-1.16), shorter donor stature (aOR 1.53 for 180 cm, 95% CI 1.28-1.94), and procurement in an area with higher intensity of market competition (aOR 1.71, 95% CI 1.62-1.78) and with the longest waiting times (aOR 1.41, 95% CI 1.34-1.49). Later acceptance in the match-run was associated with delayed graft function but not all-cause allograft failure (adjusted hazard ratio 1.01, 95% CI 0.96-1.07). Study limitations include a lack of match-run data for discarded organs and the possibility of sequence inaccuracies for some nonlocal matches. Interventions are needed to reduce turndowns of viable organs, especially when decisions are driven by infectious risk, weekend or holiday procurement, geography, or other donor characteristics unrelated to allograft quality. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

  2. Quadriceps tendon allografts as an alternative to Achilles tendon allografts: a biomechanical comparison.

    Science.gov (United States)

    Mabe, Isaac; Hunter, Shawn

    2014-12-01

    Quadriceps tendon with a patellar bone block may be a viable alternative to Achilles tendon for anterior cruciate ligament reconstruction (ACL-R) if it is, at a minimum, a biomechanically equivalent graft. The objective of this study was to directly compare the biomechanical properties of quadriceps tendon and Achilles tendon allografts. Quadriceps and Achilles tendon pairs from nine research-consented donors were tested. All specimens were processed to reduce bioburden and terminally sterilized by gamma irradiation. Specimens were subjected to a three phase uniaxial tension test performed in a custom environmental chamber to maintain the specimens at a physiologic temperature (37 ± 2 °C) and misted with a 0.9 % NaCl solution. There were no statistical differences in seven of eight structural and mechanical between the two tendon types. Quadriceps tendons exhibited a significantly higher displacement at maximum load and significantly lower stiffness than Achilles tendons. The results of this study indicated a biomechanical equivalence of aseptically processed, terminally sterilized quadriceps tendon grafts with bone block to Achilles tendon grafts with bone block. The significantly higher displacement at maximum load, and lower stiffness observed for quadriceps tendons may be related to the failure mode. Achilles tendons had a higher bone avulsion rate than quadriceps tendons (86 % compared to 12 %, respectively). This was likely due to observed differences in bone block density between the two tendon types. This research supports the use of quadriceps tendon allografts in lieu of Achilles tendon allografts for ACL-R.

  3. Splenectomy increases the survival time of heart allograft via developing immune tolerance

    Science.gov (United States)

    2013-01-01

    Background The spleen is an active lymphoid organ. The effect of splenectomy on the immune response remains unclear. This study investigated whether splenectomy can induce immune tolerance and has a beneficial role in cardiac allograft. Methods Wistar rats were used for heart donors. The Sprague–Dawley (SD) rats designated as the recipients of heart transplantation (HT) were randomly assigned into four groups: sham, splenectomy, HT, splenectomy + HT. The survival of transplanted hearts was assessed by daily checking of abdominal palpation. At various time points after transplantation, the transplanted hearts were collected and histologically examined; the level of CD4+CD25+ T regulatory lymphocytes (Tregs) and rate of lymphocyte apoptosis (annexin-v+ PI+ cells) in the blood were analyzed by using flow cytometric method. Results 1) Splenectomy significantly prolonged the mean survival time of heart allografts (7 ± 1.1 days and 27 ± 1.5 days for HT and splenectomy + HT, respectively; n = 12-14/group, HT vs. splenectomy + HT, p Splenectomy delayed pathological changes (inflammatory cell infiltration, myocardial damage) of the transplanted hearts in splenectomy + HT rats; 3) The level of CD4+CD25+ Tregs in the blood of splenectomized rats was significantly increased within 7 days (2.4 ± 0.5%, 4.9 ± 1.3% and 5.3 ± 1.0% for sham, splenectomy and splenectomy + HT, respectively; n = 15/group, sham vs. splenectomy or splenectomy + HT, p splenectomy surgery and gradually decreased to baseline level; 4) Splenectomy increased the rate of lymphocyte apoptosis (day 7: 0.3 ± 0.05%, 3.9 ± 0.9% and 4.1 ± 0.9% for sham, splenectomy and splenectomy + HT, respectively; n = 15/group, sham vs. splenectomy or splenectomy + HT, p Splenectomy inhibits the development of pathology and prolongs the survival time of cardiac allograft. The responsible mechanism is associated with induction of immune

  4. Uncemented allograft-prosthetic composite reconstruction of the proximal femur

    Directory of Open Access Journals (Sweden)

    Li Min

    2014-01-01

    Full Text Available Background: Allograft-prosthetic composite can be divided into three groups names cemented, uncemented, and partially cemented. Previous studies have mainly reported outcomes in cemented and partially cemented allograft-prosthetic composites, but have rarely focused on the uncemented allograft-prosthetic composites. The objectives of our study were to describe a surgical technique for using proximal femoral uncemented allograft-prosthetic composite and to present the radiographic and clinical results. Materials and Methods: Twelve patients who underwent uncemented allograft-prosthetic composite reconstruction of the proximal femur after bone tumor resection were retrospectively evaluated at an average followup of 24.0 months. Clinical records and radiographs were evaluated. Results: In our series, union occurred in all the patients (100%; range 5-9 months. Until the most recent followup, there were no cases with infection, nonunion of the greater trochanter, junctional bone resorption, dislocation, allergic reaction, wear of acetabulum socket, recurrence, and metastasis. But there were three periprosthetic fractures which were fixed using cerclage wire during surgery. Five cases had bone resorption in and around the greater trochanter. The average Musculoskeletal Tumor Society (MSTS score and Harris hip score (HHS were 26.2 points (range 24-29 points and 80.6 points (range 66.2-92.7 points, respectively. Conclusions: These results showed that uncemented allograft-prosthetic composite could promote bone union through compression at the host-allograft junction and is a good choice for proximal femoral resection. Although this technology has its own merits, long term outcomes are yet not validated.

  5. Mannan binding lectin : a two-faced regulator of renal allograft injury?

    NARCIS (Netherlands)

    Damman, Jeffrey; Seelen, Marc A.

    Complement activation plays an important role in the pathogenesis of renal allograft injury after kidney transplantation. There are three known pathways of complement activation, namely, classical, alternative, and lectin pathways. In renal allograft injury, contradictory results were reported about

  6. Cardiac catheterization - discharge

    Science.gov (United States)

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

  7. Salvage of humeral nonunions with onlay bone plate allograft augmentation.

    Science.gov (United States)

    Hornicek, F J; Zych, G A; Hutson, J J; Malinin, T I

    2001-05-01

    Eight women and one man were treated for 10 established diaphyseal humeral nonunions. Six patients sustained fractures in motor vehicle accidents and two patients sustained fractures in a fall. Two of the fractures were open. One patient with multiple myeloma originally was treated conservatively and received local radiation, followed by open reduction and internal plate fixation. The other patients previously were treated with fracture braces, intramedullary nails, dynamic compression plates, or a combination of these techniques. After removal of the surgical hardware and fibrous tissue at the nonunion site, stable fixation was accomplished using a cortical long bone plate allograft (femoral and tibial) or fibular shaft allograft and a dynamic compression plate. All humeral nonunions had united at an average of 2.9 months. Radiographic incorporation of the allograft cortical bone plate and fibular shaft into the host cortex occurred in all but one patient by 3 months. Graft to host junction healing was accomplished by incorporation of the cortical allograft plate into the host cortex, resulting in an increased diameter of the bone. Cortical allograft bone plates and fibular grafts provide structural and probably osteoinductive support to enhance healing of these nonunions.

  8. Significant prolongation of segmental pancreatic allograft survival in two species

    Energy Technology Data Exchange (ETDEWEB)

    Du Toit, D.F.; Heydenrych, J.J.

    1988-06-01

    A study was conducted to assess the suppression of segmental pancreatic allograft rejection by cyclosporine (CSA) alone in baboons and dogs, and subtotal marrow irradiation (TL1) alone and TL 1 in combination with CSA in baboons. Total pancreatectomy in the dog and primate provided a reliable diabetic model, induced an absolute deficiency of insulin and was uniformly lethal if not treated. Continuous administration of CSA in baboons resulted in modest allograft survival. As in baboons, dogs receiving CSA 25 mg/kg/d rendered moderate graft prolongation but a dose of 40 mg/kg/d resulted in significant graft survival (greater than 100 days) in 5 of 8 allograft recipients. Irradiation alone resulted in minimal baboon pancreatic allograft survival of 20 baboons receiving TL1 1,000 rad and CSA, 3 had graft survival greater than of 100 days. Of 15 baboons receiving TL1 800 rad and CSA, 6 had graft survival of greater than 100 days. In conclusion, CSA administration in dogs and TL1 in combination with CSA in baboons resulted in highly significant segmental pancreatic allograft survival.

  9. Evaluation of full cortical allografts in 25 dogs.

    Science.gov (United States)

    Sinibaldi, K R

    1989-06-01

    Twenty-five dogs received 26 cortical allografts from Apr 9, 1976 through Jan 31, 1982. Cortical allografts were used to reconstruct fractures of the femur, humerus, tibia, radius, and ulna. These grafts were used to replace comminuted fragments; to lengthen bones; to correct malunions, delayed unions, and nonunions; and in one case, to replace bone lost to sequestrum formation in an infected fracture site. All fractures were stabilized by use of standard ASIF techniques and dynamic compression plates. Frozen bone allografts were used in all cases. These were harvested aseptically and stored in a household freezer for 3 days to one year before use. Clinically normal function was achieved in 96% of the dogs.

  10. Nephron-Sparing Surgery for Adenocarcinoma in a Renal Allograft

    Directory of Open Access Journals (Sweden)

    Fernando Vázquez Alonso

    2012-01-01

    Full Text Available The incidence of malignant tumors in recipients of renal allografts is higher than in the general population. Renal cell carcinoma (RCC accounts for 4.6% of the tumors in transplanted patients; of them, only 10% are found in transplanted kidneys. Transplantectomy has always been the usual treatment. However, during the last years, nephron-sparing surgery of the allograft is more frequently done in well-selected cases, and therefore dialysis can be avoided. We report the case of a 37-year-old female patient with renal transplant, diagnosed with a 4.5 cm tumor in the lower pole of the renal allograft. The patient underwent partial nephrectomy successfully. Six years after surgery, there is no evidence of recurrence of the disease and the patient maintains an adequate renal function.

  11. In vitro elution of moxifloxacin from cancellous bone allografts.

    Science.gov (United States)

    Kanellakopoulou, Kyriaki; Sahinides, Theophilos; Tsaganos, Thomas; Galanakis, Nearchos; Giamarellou, Helen; Giamarellos-Bourboulis, Evangelos J

    2010-01-01

    The characteristics of cancellous bone allografts as carriers of moxifloxacin are described. Particles of cancellous bone were compressed into a wire-mesh cylinder and impregnated into a solution of moxifloxacin for different time periods. Five replicas were impregnated for 1 h; another five for 24 h; and another five for 48 h. Impregnated allografts were then transferred into vials containing 5 ml of Mueller-Hinton broth and incubated at 37 degrees C. Broth was replaced daily. Concentrations of moxifloxacin in broth were determined after analysis by an high performance liquid chromatography system. Moxifloxacin was eluted at very high concentrations within the first days. Concentrations remained above 100 microg/ml until day 8 and above 40 microg/ml until day 20. It is concluded that cancellous bone allografts may allow the adequate in vitro elution of moxifloxacin. The latter results support their application in experimental models of osteomyelitis.

  12. Porous Allograft Bone Scaffolds: Doping with Strontium

    Science.gov (United States)

    Zhao, Yantao; Guo, Dagang; Hou, Shuxun; Zhong, Hongbin; Yan, Jun; Zhang, Chunli; Zhou, Ying

    2013-01-01

    Strontium (Sr) can promote the process of bone formation. To improve bioactivity, porous allograft bone scaffolds (ABS) were doped with Sr and the mechanical strength and bioactivity of the scaffolds were evaluated. Sr-doped ABS were prepared using the ion exchange method. The density and distribution of Sr in bone scaffolds were investigated by inductively coupled plasma optical emission spectrometry (ICP-OES), X-ray photoelectron spectroscopy (XPS), and energy-dispersive X-ray spectroscopy (EDS). Controlled release of strontium ions was measured and mechanical strength was evaluated by a compressive strength test. The bioactivity of Sr-doped ABS was investigated by a simulated body fluid (SBF) assay, cytotoxicity testing, and an in vivo implantation experiment. The Sr molar concentration [Sr/(Sr+Ca)] in ABS surpassed 5% and Sr was distributed nearly evenly. XPS analyses suggest that Sr combined with oxygen and carbonate radicals. Released Sr ions were detected in the immersion solution at higher concentration than calcium ions until day 30. The compressive strength of the Sr-doped ABS did not change significantly. The bioactivity of Sr-doped material, as measured by the in vitro SBF immersion method, was superior to that of the Sr-free freeze-dried bone and the Sr-doped material did not show cytotoxicity compared with Sr-free culture medium. The rate of bone mineral deposition for Sr-doped ABS was faster than that of the control at 4 weeks (3.28±0.23 µm/day vs. 2.60±0.20 µm/day; p<0.05). Sr can be evenly doped into porous ABS at relevant concentrations to create highly active bone substitutes. PMID:23922703

  13. Porous allograft bone scaffolds: doping with strontium.

    Directory of Open Access Journals (Sweden)

    Yantao Zhao

    Full Text Available Strontium (Sr can promote the process of bone formation. To improve bioactivity, porous allograft bone scaffolds (ABS were doped with Sr and the mechanical strength and bioactivity of the scaffolds were evaluated. Sr-doped ABS were prepared using the ion exchange method. The density and distribution of Sr in bone scaffolds were investigated by inductively coupled plasma optical emission spectrometry (ICP-OES, X-ray photoelectron spectroscopy (XPS, and energy-dispersive X-ray spectroscopy (EDS. Controlled release of strontium ions was measured and mechanical strength was evaluated by a compressive strength test. The bioactivity of Sr-doped ABS was investigated by a simulated body fluid (SBF assay, cytotoxicity testing, and an in vivo implantation experiment. The Sr molar concentration [Sr/(Sr+Ca] in ABS surpassed 5% and Sr was distributed nearly evenly. XPS analyses suggest that Sr combined with oxygen and carbonate radicals. Released Sr ions were detected in the immersion solution at higher concentration than calcium ions until day 30. The compressive strength of the Sr-doped ABS did not change significantly. The bioactivity of Sr-doped material, as measured by the in vitro SBF immersion method, was superior to that of the Sr-free freeze-dried bone and the Sr-doped material did not show cytotoxicity compared with Sr-free culture medium. The rate of bone mineral deposition for Sr-doped ABS was faster than that of the control at 4 weeks (3.28 ± 0.23 µm/day vs. 2.60 ± 0.20 µm/day; p<0.05. Sr can be evenly doped into porous ABS at relevant concentrations to create highly active bone substitutes.

  14. A novel system improves preservation of osteochondral allografts.

    Science.gov (United States)

    Cook, James L; Stoker, Aaron M; Stannard, James P; Kuroki, Keiichi; Cook, Cristi R; Pfeiffer, Ferris M; Bozynski, Chantelle; Hung, Clark T

    2014-11-01

    Osteochondral allografting is an option for successful treatment of large articular cartilage defects. Use of osteochondral allografting is limited by graft availability, often because of loss of chondrocyte viability during storage. The purpose of this study was to compare osteochondral allografts implanted in canine knees after 28 days or 60 days of storage for (1) initial (1 week) safety and feasibility; (2) integrity and positioning with time (12 weeks and 6 months); and (3) gross, cell viability, histologic, biochemical, and biomechanical characteristics at an endpoint of 6 months. With Institutional Animal Care and Use Committee approval, adult dogs (n=16) were implanted with 8-mm cylindrical osteochondral allografts in the lateral and medial femoral condyles of one knee. Osteochondral allografts preserved for 28 or 60 days using either the current tissue bank standard-of-care (SOC) or a novel system (The Missouri Osteochondral Allograft Preservation System, or MOPS) were used, creating four treatment groups: SOC 28-day, MOPS 28-day, SOC 60-day, and MOPS 60-day. Bacteriologic analysis of tissue culture and media were performed. Dogs were assessed by radiographs and arthroscopy at interim times and by gross, cell viability, histology, biochemistry, and biomechanical testing at the 6-month endpoint. With the numbers available, there was no difference in infection frequency during storage (5% for SOC and 3% for MOPS; p=0.5). No infected graft was implanted and no infections occurred in vivo. MOPS grafts had greater chondrocyte viability at Day 60 (90% versus 53%; p=0.002). For 60-day storage, MOPS grafts were as good as or better than SOC grafts with respect to all outcome measures assessed 6 months after implantation. Donor chondrocyte viability is important for osteochondral allograft success. MOPS allows preservation of chondrocyte viability for up to 60 days at sufficient levels to result in successful outcomes in a canine model of large femoral condylar

  15. Autonomic cardiac innervation

    Science.gov (United States)

    Hasan, Wohaib

    2013-01-01

    function, including in possible neurotransmitter changes. Certainly, neurotrophins and cytokines regulate transcriptional factors in adult autonomic neurons that have vital differentiation roles in development. Particularly for parasympathetic cardiac ganglion neurons, additional examinations of developmental regulatory mechanisms will potentially aid in understanding attenuated parasympathetic function in a number of conditions, including heart failure. PMID:23872607

  16. Cardiac Overexpression of Insulin-Like Growth Factor I (IGF-1) Attenuates Chronic Alcohol Intake-Induced Myocardial Contractile Dysfunction But Not Hypertrophy: Role of Akt, mTOR, GSK3β and PTEN

    Science.gov (United States)

    Zhang, Bingfang; Turdi, Subat; Li, Quan; Lopez, Faye L.; Eason, Anna R.; Anversa, Piero; Ren, Jun

    2010-01-01

    Chronic alcohol intake leads to the development of alcoholic cardiomyopathy manifested by cardiac hypertrophy and contractile dysfunction. This study was designed to examine the effect of transgenic overexpression of insulin-like growth factor I (IGF-1) on alcohol-induced cardiac contractile dysfunction. Wild-type FVB and cardiac-specific IGF-1 mice were placed on a 4% alcohol or control diet for 16 weeks. Cardiac geometry and mechanical function were evaluated by echocardiography, cardiomyocyte and intracellular Ca2+ properties. Histological analyses for cardiac fibrosis and apoptosis were evaluated by Masson trichrome staining and TUNEL assay, respectively. Expression and/or phosphorylation of Cu/Zn superoxide dismutase (SOD1), Ca2+ handling proteins, key signaling molecules for survival including Akt, mTOR, GSK3β, Foxo3a and the negative regulator of Akt phosphatase and tensin homolog on chromosome ten (PTEN) as well as mitochondrial proteins UCP-2 and PGC1α were evaluated by western blot analysis. Chronic alcohol intake led to cardiac hypertrophy, interstitial fibrosis, reduced mitochondrial number, compromised cardiac contractile function and intracellular Ca2+ handling, decreased SOD1 expression, elevated superoxide production and overt apoptosis, all of which with the exception of cardiac hypertrophy were abrogated by the IGF-1 transgene. Immunoblotting data showed reduced phosphorylation of Akt, mTOR, GSK3β and Foxo3a, upregulated Foxo3a and PTEN, as well as dampened SERCA2a, PGC1α and UCP-2 following alcohol intake. All these alcohol-induced changes in survival and mitochondrial proteins were alleviated by IGF-1. Taken together, these data favor a beneficial role of IGF-1 in alcohol-induced myocardial contractile dysfunction independent of cardiac hypertrophy. PMID:20678571

  17. Osteoinductive and Osteopromotive Variability among Different Demineralized Bone Allografts.

    Science.gov (United States)

    Wei, Lingfei; Miron, Richard J; Shi, Bin; Zhang, Yufeng

    2015-06-01

    The purpose of this investigation was to compare the osteoinductive and osteopromotive potential of two widely used demineralized freeze-dried bone allografts (DFDBA) (Osteotech® DFDBA and LifeNet® DFDBA). Twenty-seven male Wistar rats (mean body weight 200 g) were treated with either DFDBA from Osteotech and LifeNet or control for femoral and intramuscular defects and assigned to histological analysis at 2, 4, and 8 weeks postimplantation. Hematoxylin and eosin (H&E), Safranin-O, tartrate-resistant acid phosphatase (TRAP), and osteopontin (OPN) staining were performed. Quantitative analysis of mineralized new bone to total volume (BV/TV) was assessed by micro-computed tomography. Both allografts demonstrated osteoinductive potential at 2 weeks as assessed by intramuscular bone formation. LifeNet DFDBA displayed continual new bone formation at 4 and 8 weeks, whereas Osteotech particles were fully resorbed by 4 weeks postimplantation. Femur defects demonstrated significantly greater BV/TV at 4 and 8 weeks with higher expression of OPN staining around LifeNet DFDBA particles. TRAP-positive cells were visible in and around both allograft materials. The results from the present study indicate that variability among allografts exists. In the present, LifeNet DFDBA supported more new bone formation. Further larger animal models or clinical trials are required to validate these findings. © 2013 Wiley Periodicals, Inc.

  18. Could Uric acid have a Pathogenic Role in Chronic Allograft ...

    African Journals Online (AJOL)

    Introduction: Chronic allograft dysfunction (CAD) is the primary cause of chronic graft failure after kidney transplantation. The pathogenesis of CAD involves both antigen-dependent and antigen-independent mechanisms. Serum uric acid could have a role in both mechanisms. Review: Hyperuricemia in subjects with renal ...

  19. Cytokine mRNA expression during experimental corneal allograft rejection

    NARCIS (Netherlands)

    Torres, P. F.; de Vos, A. F.; van der Gaag, R.; Martins, B.; Kijlstra, A.

    1996-01-01

    Allograft rejection is the main cause of corneal graft failure. T lymphocytes and macrophages have been implied to be involved in corneal rejection, but little is known about the molecular mechanism in this process. In this study, cytokine mRNA expression in the cornea was analysed during

  20. Pelvic massive allograft reconstruction after bone tumour resection.

    Science.gov (United States)

    Campanacci, Domenico; Chacon, Sara; Mondanelli, Nicola; Beltrami, Giovanni; Scoccianti, Guido; Caff, Giuseppe; Frenos, Filippo; Capanna, Rodolfo

    2012-12-01

    The purpose of this report was to retrospectively review a series treated with pelvic tumour resection and massive allograft reconstruction, and determine survival of patients and implants, functional results and morbidity of surgical technique. From 1999, 33 patients underwent pelvic tumour resection and massive allograft reconstruction. The mean age was 40 years (range, 14-72) and 29 patients had a primary malignant tumour. The resection involved the acetabular area in all but three patients. At a median follow-up of 33 months (range, two-143) four patients had local recurrence. The morbidity was high: five deep infections (15 %), requiring two allograft removal, six hip dislocations (18 %), eight sciatic nerve palsy (24 %), persistent in six cases, and two loosening of the acetabular component. Implant survival was 87.3 % at last follow up. The cumulative overall patient's survival was 41.5 % at five and ten years. The average MSTS functional score was 70 % (range, 54-100 %) when the acetabulum was preserved while it was 61 % (30-100 %) in patients with acetabular resection. In conclusion, pelvic allografts represent a valid option for reconstruction after resection of pelvic tumours but due to the associated morbidity, patients should be carefully selected.

  1. Left versus right deceased donor renal allograft outcome.

    LENUS (Irish Health Repository)

    Phelan, Paul J

    2009-12-01

    It has been suggested that the left kidney is easier to transplant than the right kidney because of the longer length of the left renal vein, facilitating the formation of the venous anastomosis. There are conflicting reports of differing renal allograft outcomes based on the side of donor kidney transplanted (left or right).We sought to determine the effect of side of donor kidney on early and late allograft outcome in our renal transplant population. We performed a retrospective analysis of transplanted left-right deceased donor kidney pairs in Ireland between January 1, 1998 and December 31, 2008. We used a time to death-censored graft failure approach for long-term allograft survival and also examined serum creatinine at different time points post-transplantation. All outcomes were included from day of transplant onwards. A total of 646 transplants were performed from 323 donors. The incidence of delayed graft function was 16.1% in both groups and there was no significant difference in acute rejection episodes or serum creatinine from 1 month to 8 years post-transplantation.There were 47 death-censored allograft failures in the left-sided group compared to 57 in the right-sided group (P = 0.24). These observations show no difference in renal transplant outcome between the recipients of left- and right-sided deceased donor kidneys.

  2. Veto cell suppression mechanisms in the prevention of allograft rejection

    DEFF Research Database (Denmark)

    Jacobsen, I M; Claesson, Mogens Helweg

    1998-01-01

    on the surface of the veto-active cell. Data from a large number of experimental and clinical studies strongly indicate that veto-active cells function in vivo and are capable of preventing allograft rejection. Thus, donor-cell-mediated veto activity is the most likely explanation for the well-known graft...

  3. Live Skin Allograft in the Management of Severe Burns | Saidi ...

    African Journals Online (AJOL)

    Skin allograft is the use of skin from a genetically non-identical member of the same species as the recipient. ... Disadvantages of its use include the limited abundance and availability of donors, possible transmission of disease, the eventual rejection by the host and its handling, storing, transporting and associated costs of ...

  4. Primary Nonfunction of Renal Allograft Secondary to Acute Oxalate Nephropathy

    Directory of Open Access Journals (Sweden)

    Ravi Parasuraman

    2011-01-01

    Full Text Available Primary nonfunction (PNF accounts for 0.6 to 8% of renal allograft failure, and the focus on causes of PNF has changed from rejection to other causes. Calcium oxalate (CaOx deposition is common in early allograft biopsies, and it contributes in moderate intensity to higher incidence of acute tubular necrosis and poor graft survival. A-49-year old male with ESRD secondary to polycystic kidney disease underwent extended criteria donor kidney transplantation. Posttransplant, patient developed delayed graft function (DGF, and the biopsy showed moderately intense CaOx deposition that persisted on subsequent biopsies for 16 weeks, eventually resulting in PNF. The serum oxalate level was 3 times more than normal at 85 μmol/L (normal <27 μmol/L. Allograft nephrectomy showed massive aggregates of CaOx crystal deposition in renal collecting system. In conclusion, acute oxalate nephropathy should be considered in the differential diagnosis of DGF since optimal management could change the outcome of the allograft.

  5. Apoptosis of acinar cells in pancreas allograft rejection

    NARCIS (Netherlands)

    Boonstra, J. G.; Wever, P. C.; Laterveer, J. C.; Bruijn, J. A.; van der Woude, F. J.; ten Berge, I. J.; Daha, M. R.

    1997-01-01

    BACKGROUND: Recently it has been recognized that apoptosis of target cells may occur during liver and kidney allograft rejection and is probably induced by infiltrating cells. Pancreas rejection is also characterized by a cellular infiltrate, however, the occurrence of apoptosis has not been

  6. Second line options for hyperlipidemia management after cardiac transplantation.

    Science.gov (United States)

    Shah, M K H; Critchley, W R; Yonan, N; Williams, S G; Shaw, S M

    2013-06-01

    Despite widespread statin therapy, 91% of cardiac transplant patients have hyperlipidemia within 5 years from cardiac transplantation. The implications of this are profound, particularly given that coronary allograft vasculopathy is a leading cause of death. Unfortunately the solution is not easy, with problems of toleration at higher statin doses and a lack of good quality evidence for second line agents. We review the literature and discuss some of the key issues transplant physicians are faced with when considering alternatives to statin therapy. © 2012 Blackwell Publishing Ltd.

  7. Assessment of Kidney Function After Allograft Transplantation by Texture Analysis.

    Science.gov (United States)

    Abbasian Ardakani, Ali; Mohammadi, Afshin; Khalili Najafabad, Bahareh; Abolghasemi, Jamileh

    2017-03-01

    Ultrasonography is the preferable imaging technique for monitoring and assessing complications in kidney allograft transplants. Computer-aided diagnostic system based on texture analysis in ultrasonographic imaging is recommended to identify changes in kidney function after allograft transplantation. A total of 61 biopsy-proven kidney allograft recipients (11 rejected and 50 unrejected) were assessed by a computer-aided diagnostic system. Up to 270 statistical texture features were extracted as descriptors for each region of interest in each recipient. Correlations of texture features with serum creatinine level and differences between rejected and unrejected allografts were analyzed. An area under the receiver operating characteristic curve was calculated for each significant texture feature. Linear discriminant analysis was employed to analyze significant features and increase discriminative power. Recipients were classified by the first nearest neighbor classifier. Fourteen texture features had a significant correlation with serum creatinine level and 16 were significantly different between the rejected and unrejected allografts, for which an area under the curve values were in the range of 0.575 for difference entropy S(4,0) to 0.676 for kurtosis. Using all 16 features, linear discriminant analysis indicated higher performance for classification of the two groups with an area under the curve of 0.975, which corresponded to a sensitivity of 90.9%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 98.0%. Texture analysis was a reliable method, with the potential for characterization, and can help physicians to diagnose kidney failure after transplantation on ultrasonographic imaging.

  8. Local mechanical anisotropy in human cranial dura mater allografts.

    Science.gov (United States)

    Sacks, M S; Jimenez Hamann, M C; Otaño-Lata, S E; Malinin, T I

    1998-08-01

    Human cranial dura mater (CDM) allograft's success as a repair biomaterial is partly due to its high mechanical strength, which facilitates its ability to form water-tight barriers and resist high in-vivo mechanical loads. Previous studies on CDM allograft mechanical behavior used large test specimens and concluded that the allograft was mechanically isotropic. However, we have quantified CDM microstructure using small angle light scattering (SALS) and found regions of well-aligned fibers displaying structural symmetry between the right and left halves (Jimenez et al., 1998). The high degree of fiber alignment in these regions suggests that they are mechanically anisotropic. However, identification of these regions using SALS requires irreversible tissue dehydration, which may affect mechanical properties. Instead, we utilized CDM structural symmetry to estimate the fiber architecture of one half of the CDM using computer graphics to flip the SALS fiber architecture map of the corresponding half about the plane of symmetry. Test specimens (20 mm x 4 mm) were selected parallel and perpendicular to the preferred fiber directions and subjected to uniaxial mechanical failure testing. CDM allografts were found to be locally anisotropic, having an ultimate tensile strength (UTS) parallel to the fibers of 12.76 +/- 1.65 MPa, and perpendicular to the fibers of 5.21 +/- 1.01 MPa (mean +/- sem). These results indicate that uniaxial mechanical tests on large samples used in previous studies tended to mask the local anisotropic nature of the smaller constituent sections. The testing methods established in this study can be used in the evaluation of new CDM processing methods and post-implant allograft mechanical integrity.

  9. Metabolomic Profiling in Individuals with a Failing Kidney Allograft.

    Directory of Open Access Journals (Sweden)

    Roberto Bassi

    Full Text Available Alteration of certain metabolites may play a role in the pathophysiology of renal allograft disease.To explore metabolomic abnormalities in individuals with a failing kidney allograft, we analyzed by liquid chromatography-mass spectrometry (LC-MS/MS; for ex vivo profiling of serum and urine and two dimensional correlated spectroscopy (2D COSY; for in vivo study of the kidney graft 40 subjects with varying degrees of chronic allograft dysfunction stratified by tertiles of glomerular filtration rate (GFR; T1, T2, T3. Ten healthy non-allograft individuals were chosen as controls.LC-MS/MS analysis revealed a dose-response association between GFR and serum concentration of tryptophan, glutamine, dimethylarginine isomers (asymmetric [A]DMA and symmetric [S]DMA and short-chain acylcarnitines (C4 and C12, (test for trend: T1-T3 = p<0.05; p = 0.01; p<0.001; p = 0.01; p = 0.01; p<0.05, respectively. The same association was found between GFR and urinary levels of histidine, DOPA, dopamine, carnosine, SDMA and ADMA (test for trend: T1-T3 = p<0.05; p<0.01; p = 0.001; p<0.05; p = 0.001; p<0.001; p<0.01, respectively. In vivo 2D COSY of the kidney allograft revealed significant reduction in the parenchymal content of choline, creatine, taurine and threonine (all: p<0.05 in individuals with lower GFR levels.We report an association between renal function and altered metabolomic profile in renal transplant individuals with different degrees of kidney graft function.

  10. Decellularized Allografts for Right Ventricular Outflow Tract Reconstruction in Children.

    Science.gov (United States)

    da Costa, Francisco Diniz Affonso; Etnel, Jonathan R G; Torres, Renato; Balbi Filho, Eduardo M; Torres, Rafael; Calixto, Allyson; Mulinari, Leonardo A

    2017-09-01

    Determine the midterm outcomes of decellularized allografts for right ventricular outflow tract (RVOT) reconstruction in children less than 12 years of age. The study included all consecutive patients submitted to RVOT reconstruction with decellularized allografts between June 2006 and June 2016. Besides clinical and echocardiographic control, 20 patients with more than five years of follow-up were evaluated with computed tomography (CT) scans to determine allograft diameters and calcium scores. Structural valve deterioration was defined as any peak gradient above 40 mm Hg and/or insufficiency of moderate or severe degree. Conduit failure was defined as the need for allograft reintervention. There were 59 patients with a median age of six years (range = 0.01-12 years). The most common operation was the Ross procedure (34%). Mean clinical follow-up was 5.4 (2.8) years and was 94% complete. At eight years, only two patients needed a reintervention, with a 90.9% freedom from this event. Structural valve deterioration occurred in 13 patients, 5 due to stenosis and 8 due to insufficiency, with a freedom from structural valve deterioration due to any cause of 64.9% at eight years. Late CT scans demonstrated the absence or minimal calcification of the conduits. Decellularized allografts for RVOT reconstruction in children were associated with a low incidence of structural valve deterioration and conduit failure. Although these results still need to be confirmed in larger series and with longer follow-up, our data suggest favorable outcomes, at least in the first decade after the operation.

  11. Intraoperative High-Dose Dexamethasone in Cardiac Surgery and the Risk of Rethoracotomy

    NARCIS (Netherlands)

    van Osch, Dirk; Dieleman, Jan M.; Nathoe, Hendrik M.; Boasson, Marc P.; Kluin, Jolanda; Bunge, Jeroen J. H.; Nierich, Arno P.; Rosseel, Peter M.; Maaten, van der Joost; Hofland, Jan; Diephuis, Jan C.; de Lange, Fellery; Boer, Christa; van Dijk, Diederik

    2015-01-01

    Background. Cardiac surgery with the use of cardiopulmonary bypass is associated with a systemic inflammatory response. Intraoperative corticosteroids are administered to attenuate this inflammatory response. The recent Dexamethasone for Cardiac Surgery (DECS) trial could not demonstrate a

  12. Radioprotection provides functional mechanics but delays healing of irradiated tendon allografts after ACL reconstruction in sheep.

    Science.gov (United States)

    Seto, Aaron U; Culp, Brian M; Gatt, Charles J; Dunn, Michael

    2013-12-01

    Successful protection of tissue properties against ionizing radiation effects could allow its use for terminal sterilization of musculoskeletal allografts. In this study we functionally evaluate Achilles tendon allografts processed with a previously developed radioprotective treatment based on (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) crosslinking and free radical scavenging using ascorbate and riboflavin, for ovine anterior cruciate ligament reconstruction. Arthroscopic anterior cruciate ligament (ACL) reconstruction was performed using double looped allografts, while comparing radioprotected irradiated and fresh frozen allografts after 12 and 24 weeks post-implantation, and to control irradiated grafts after 12 weeks. Radioprotection was successful at preserving early subfailure mechanical properties comparable to fresh frozen allografts. Twelve week graft stiffness and anterior-tibial (A-T) translation for radioprotected and fresh frozen allografts were comparable at 30 % of native stiffness, and 4.6 and 5 times native A-T translation, respectively. Fresh frozen allograft possessed the greatest 24 week peak load at 840 N and stiffness at 177 N/mm. Histological evidence suggested a delay in tendon to bone healing for radioprotected allografts, which was reflected in mechanical properties. There was no evidence that radioprotective treatment inhibited intra-articular graft healing. This specific radioprotective method cannot be recommended for ACL reconstruction allografts, and data suggest that future efforts to improve allograft sterilization procedures should focus on modifying or eliminating the pre-crosslinking procedure.

  13. Adeno-associated viral vector 2.9 thymosin ß4 application attenuates rejection after heart transplantation: results of a preclinical study in the pig.

    Science.gov (United States)

    Postrach, Johannes; Schmidt, Maximilian; Thormann, Michael; Thein, Eckart; Burdorf, Lars; Reichart, Bruno; Sotlar, Karl; Walz, Christoph; Faber, Claudius; Bauer, Andreas; Schmoeckel, Michael; Kupatt, Christian; Hinkel, Rabea

    2014-10-27

    Graft survival is the most important factor for morbidity and mortality in cardiac transplantation. Improved immunosuppression significantly reduced early graft rejection. However, acute rejection may predispose to chronic rejection. Targeting both phases of the recipient's immune-reactivity by means of long-acting recombinant adeno-associated viral vectors (AAVs) encoding anti-inflammatory and cardioprotective factors appears to be a promising therapeutic approach. We investigate thymosin ß4 (Tß4) possessing anti-inflammatory and prosurvival abilities, as a means for pretransplant gene therapy. Heterotopic, abdominal transplantation of cardiac allografts into landrace or into Munich mini pigs (n=5 per group) was performed. Transplants were transduced with AAV2.9 before transplantation by means of in situ perfusion of the donor organ. Vascuar endothelial growth factor and AAV2.9.Tß4 or AAV2.9.LacZ were added to the autologous blood used for perfusing the grafts for a period of 45 min. Immunosuppression was applied for 10 days after the operation. Transgene expression, capillary density, graft function, survival, and rejection were assessed. The AAV2.9 transduction induced robust overexpression of the transgene. In addition, Tß4 ameliorated inflammation, necrosis, vascular reaction (acute rejection) and in parallel improved capillary density. In addition, graft survival was significantly prolonged (10±3 days AAV2.9.LacZ vs. 31±4 days AAV2.9.Tß4). In the mini pig model, regional myocardial function of the grafts was improved by Tß4 transduction compared to LacZ (9.1%±0.9% subendocardial segment shortening in AAV2.9.LacZ vs. 15.8%±2.3% in AAV2.9.Tß4). In situ AAV2.9-mediated gene transfer of thymosin β4 attenuated graft rejection in a heterotopic heart transplantation model. Perioperative cardioprotection by means of gene therapy might improve graft survival in cardiac allotransplantation.

  14. Involvement of the Fas system in liver allograft rejection.

    Science.gov (United States)

    Rivero, M; Crespo, J; Mayorga, M; Fábrega, E; Casafont, F; Pons-Romero, F

    2002-06-01

    Recent studies suggest that apoptosis is an important mechanism of cell death in the rejection of liver allografts and that this process is mediated via Fas. The aim of this study was to analyze the expression of the Fas system during the liver allograft rejection and its evolution after treatment. We evaluated 14 patients with liver allograft rejection before and after treatment. Fas immunostaining was performed by the labeled streptavidin-biotin peroxidase method using a 200-fold dilution of a monoclonal antibody. Assessment of apoptosis was determined by the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) technique on deparaffined liver samples. Serum levels of soluble Fas antigen (sFas) were detected by an enzyme immunoassay procedure. Twelve liver transplant patients without allograft rejection were analyzed as a control group. The number of hepatocytes expressing Fas antigen, the percentage of apoptotic hepatocytes, and the sFas levels were higher in patients with liver allograft rejection than in controls (27.9+/-23.1% vs 1.4+/-1.2%, p < 0.001; 2.2+/-0.9% vs 1.0+/-0.1%, p = 0.02; 24.2+/-39.6 vs 2.8+/-4.0 IU/ml, p = 0.03, respectively). There was a correlation between the levels of sFas, AST (r = 0.86, p < 0.001), ALT (r = 0.78, p = 0.02), and gamma-globulin levels (r = 0.86, p < 0.001). After the rejection treatment we found a significant decrease in the Fas antigen expression (18.6+/-13.3%, p < 0.05), TUNEL index (0.2+/-0.4, p < 0.05), and levels of sFas (9.9+/-30.25 IU/ml, p = 0.005). 1) The demonstration of hepatocytes with Fas antigen expression and the labeling of the nuclei by the TUNEL assay suggest that apoptosis mediated by the Fas system plays a role in the pathogenesis of liver allograft rejection. 2) The Fas expression and the sFas levels decreased in patients with treatment response.

  15. Donation after cardiac death in abdominal organ transplantation.

    Science.gov (United States)

    Reich, David J; Guy, Stephen R

    2012-01-01

    This article reviews the field of donation after cardiac death, focusing on the history, ethicolegal issues, clinical outcomes, best practices, operative techniques, and emerging strategies to optimize utilization of this resource. Donation after cardiac death is one effective way to decrease the organ shortage and has contributed the largest recent increase in abdominal organ allografts. Currently, donation after cardiac death organs confer an increased risk of ischemic cholangiopathy after liver transplant and of delayed graft function after kidney transplant. As this field matures, risk factors for donation after cardiac death organ transplant will be further identified and clinical outcomes will improve as a result of protocol standardization and ongoing research. © 2012 Mount Sinai School of Medicine.

  16. Pilot Study of Renal Diffusion Tensor Imaging as a Correlate to Histopathology in Pediatric Renal Allografts.

    Science.gov (United States)

    Li, Yi; Lee, Marsha M; Worters, Pauline W; MacKenzie, John D; Laszik, Zoltan; Courtier, Jesse L

    2017-06-01

    Fractional anisotropy (FA) is a measure of molecular motion obtained from diffusion tensor imaging (DTI). The objective of this study was to assess the use of FA as a noninvasive correlate of renal allograft histopathology. Sixteen pediatric renal allograft recipients were imaged using DTI in a prospective study, between October 2014 and January 2016, before a same-day renal allograft biopsy. The Kendall tau correlation coefficient was used to assess the relationship between cortical and medullary FA values and several clinically important Banff renal allograft histopathology scores. The Mann-Whitney U test was also used to compare cortical and medullary FA values in the region of biopsy in patients whose biopsy results did and in those whose biopsy results did not change clinical management. Medullary FA values had direct inverse correlation with several histopathology scores: tubulitis (designated "t" score in Banff pathologic classification, p histopathology scores and a potential noninvasive method of assessing renal allograft health in pediatric allograft recipients.

  17. Micro-organisms isolated from cadaveric samples of allograft musculoskeletal tissue.

    Science.gov (United States)

    Varettas, Kerry

    2013-12-01

    Allograft musculoskeletal tissue is commonly used in orthopaedic surgical procedures. Cadaveric donors of musculoskeletal tissue supply multiple allografts such as tendons, ligaments and bone. The microbiology laboratory of the South Eastern Area Laboratory Services (SEALS, Australia) has cultured cadaveric allograft musculoskeletal tissue samples for bacterial and fungal isolates since 2006. This study will retrospectively review the micro-organisms isolated over a 6-year period, 2006-2011. Swab and tissue samples were received for bioburden testing and were inoculated onto agar and/or broth culture media. Growth was obtained from 25.1 % of cadaveric allograft musculoskeletal tissue samples received. The predominant organisms isolated were coagulase-negative staphylococci and coliforms, with the heaviest bioburden recovered from the hemipelvis. The rate of bacterial and fungal isolates from cadaveric allograft musculoskeletal tissue samples is higher than that from living donors. The type of organism isolated may influence the suitability of the allograft for transplant.

  18. Biological effects of rAAV-caAlk2 coating on structural allograft healing

    DEFF Research Database (Denmark)

    Koefoed, Mette; Ito, Hiromu; Gromov, Kirill

    2005-01-01

    Structural bone allografts often fracture due to their lack of osteogenic and remodeling potential. To overcome these limitations, we utilized allografts coated with recombinant adeno-associated virus (rAAV) that mediate in vivo gene transfer. Using beta-galactosidase as a reporter gene, we show...... that 4-mm murine femoral allografts coated with rAAV-LacZ are capable of transducing adjacent inflammatory cells and osteoblasts in the fracture callus following transplantation. While this LacZ vector had no effect on allograft healing, bone morphogenetic protein signals delivered via rAAV-caAlk2...... coating induced endochondral bone formation directly on the cortical surface of the allograft by day 14. By day 28 there was evidence of remodeling of the new woven bone and massive osteoclastic resorption of the cortical surface of the rAAV-caAlk2-coated allografts only. Micro-CT analysis of r...

  19. Fresh Osteochondral Allograft Versus Autograft: Twelve-Month Results in Isolated Canine Knee Defects.

    Science.gov (United States)

    McCarty, Eric C; Fader, Ryan R; Mitchell, Justin J; Glenn, R Edward; Potter, Hollis G; Spindler, Kurt P

    2016-09-01

    Osteochondral autografts and allografts have been widely used in the treatment of isolated grade 4 articular cartilage lesions of the knee. However, there is a paucity of literature regarding the basic science investigating the direct comparison between fresh osteochondral allografts to autografts. At 12 months, fresh osteochondral allografts are equal to autografts with respect to function, bony incorporation into host bone, and chondrocyte viability. Controlled laboratory study. Eight adult mongrel dogs underwent bilateral hindlimb osteochondral graft implantation in the knee after creation of an acute Outerbridge grade 4 cartilage defect. One hindlimb of each dog knee received an autograft, and the contralateral knee received an allograft. All dogs were sacrificed at 12 months. Graft analysis included gross examination, radiographs, magnetic resonance imaging (MRI), biomechanical testing, and histology. MRI demonstrated excellent bony incorporation of both autografts and allografts, except for 1 allograft that revealed partial incorporation. Histologic examination of cartilage showed intact hyaline appearance for both autografts and allografts, with fibrocartilage at the host-graft interface of both. Biomechanical testing demonstrated no significant difference between allografts and autografts (P = .76). Furthermore, no significant difference was observed between allografts and the native cartilage with biomechanical testing (P = .84). After 12 months from time of implantation, fresh osteochondral allograft tissue and autograft tissue in this study were not statistically different with respect to biomechanical properties, gross morphology, bony incorporation, or overall histologic characteristics. When compared with the previously reported 6-month incorporation rates, there was improved allograft and autograft incorporation at 12 months. With no significant differences in gross examination, radiographs, MRI, biomechanical testing, or histology in the canine

  20. Modulating Wnt Signaling Pathway to Enhance Allograft Integration in Orthopedic Trauma Treatment

    Science.gov (United States)

    2014-04-01

    formation at the allograft site using µCT scans and partially completed mechanical testing. Data presented in report reveals statistically that use...of anti-Sost or anti-Dkk-1 antibodies enhances new bone formation around the allograft over all time points. Anti-Dkk-1 antibody treatment also seems...outcomes. Total Volume (TV) – this indicates the overall hard callus volume around the allograft and is suggestive of earlier healing events. Bone

  1. Use of Cortical Strut Allograft After Extended Trochanteric Osteotomy in Revision Total Hip Arthroplasty.

    Science.gov (United States)

    Lim, Chin Tat; Amanatullah, Derek F; Huddleston, James I; Hwang, Katherine L; Maloney, William J; Goodman, Stuart B

    2017-05-01

    Cortical strut allografts restore bone stock and improve postoperative clinical scores after revision total hip arthroplasty (THA). However, use of a cortical strut allograft is implicated in delayed healing of an extended trochanteric osteotomy (ETO). To date, there are no reports directly comparing ETO with or without cortical strut allografts. We reviewed prospectively gathered data on 50 revision THAs performed from 2004-2014 using an ETO. We compared the demographic, radiological, and clinical outcome of patients with (16 hips) and without (34 hips) cortical strut allograft after an ETO. There were no significant differences in Western Ontario McMaster Universities Osteoarthritis Index or Harris Hip Score between the ETOs with and without a cortical strut allograft. Fifteen of the ETOs (94%) with a cortical strut allograft and 31 of the ETOs (91%) without a cortical strut allograft were in situ at final follow-up (P = 1.000). A higher proportion hips with cortical strut allograft (100%, 16 patients) had preoperative Paprosky grade bone loss more than IIIA compared to those without allograft (29%, 10 patients) (P < .001). There were no differences in femoral stem subsidence (P = .207), alignment (P = .934), or migration of the osteotomized fragment (P = .171). Fourteen of the ETOs (88%) in patients with cortical strut allograft united compared to 34 ETOs (100%) in patients without allograft (P = .095). Our study shows that the use of cortical strut allograft during revision THA with ETO does not reduce the rate of union, radiological or clinical outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. The reduction of allograft arteriosclerosis in intestinal transplant is associated with sphingosine kinase 1/sphingosine-1-phosphate signaling after fish oil treatment.

    Science.gov (United States)

    Li, Qiurong; Wang, Chenyang; Zhang, Qiang; Tang, Chun; Li, Ning; Li, Jieshou

    2012-05-27

    Transplant arteriosclerosis is a major cause of late intestinal allograft dysfunction. However, little is known about the immunologic and molecular mechanisms underlying it, and no effective treatment is available. This study aimed to investigate the role of sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) in transplant arteriosclerosis and find out whether fish oil (FO) attenuates allograft arteriosclerosis through S1P signaling. A rat model with orthotopic intestinal transplantation was conducted in this study. Animals received daily FO supplementation after intestinal transplant. The allogeneic recipients by phosphate-buffered saline or corn oil treatment served as controls. The allograft arteriosclerosis was characterized, and the expression of SPHK1 and S1P receptors (S1P₁, S1P₂, and S1P₃) was determined on day 190 posttransplant. The allogeneic controls presented transplant vasculopathy in mesenteric vessels, including intimal thickening, fibrosis, and leukocyte infiltration. The transplant arteriosclerosis was markedly reduced in FO-fed animals. The pression of SPHK1 and its activity were significantly augmented, and the expression of S1P₁ and S1P₃ messenger RNA was up-regulated in the allogeneic controls. FO supplementation suppressed the activation of SPHK1 and led to a decrease in the expression of S1P₁ and S1P₃ in these tissues in transplant arteriosclerosis. These results demonstrate that the activation of SPHK1/S1P signaling plays a possible role in the pathogenesis of transplant arteriosclerosis. The reduction of allograft arteriosclerosis by FO may be associated with down-regulation of SPHK1/S1P signaling. Understanding the role of FO for SPHK1/S1P may help us to identify considerable therapeutic targets for transplant arteriosclerosis.

  3. Late Acute Rejection Occuring in Liver Allograft Recipients

    Directory of Open Access Journals (Sweden)

    Eric M Yoshida

    1996-01-01

    Full Text Available To study the effect of immunosuppressive reduction on the incidence and consequence of late acute rejection (LAR in liver allograft recipients, mean daily prednisone dose, mean cyclosporine A (CsA trough and nadir levels were retrospectively reviewed for the nearest 12-week period preceding six episodes of LAR in five liver allograft recipients (group 1. Results were compared with those from a cohort of 12 liver allograft recipients who did not develop LAR (group 2. LAR was defined as acute rejection occurring more than 365 days post-transplantation. Median follow-up for both groups was similar (504 days, range 367 to 1050, versus 511 days, range 365 to 666, not significant. Mean trough CsA levels were lower in patients with LAR compared with those without (224±66 ng/mL versus 233±49 ng/mL but the difference was not statistically significant. In contrast, mean daily prednisone dose (2.5±1.6 mg/ day versus 6.5±2.9 mg/day, P=0.007 and CsA nadir values (129±60 ng/mL versus 186±40 ng/mL, P=0.03 were significantly lower in patients who developed LAR compared with those who did not. Five of six episodes (83% of LAR occurred in patients receiving less than 5 mg/day of prednisone, versus a single LAR episode in only one of 12 patients (8% receiving prednisone 5 mg/day or more (P=0.004. In all but one instance, LAR responded to pulse methylprednisolone without discernible affect on long term graft function. The authors conclude that liver allograft recipients remain vulnerable to acute rejection beyond the first post-transplant year; and reduction of immunosuppressive therapy, particularly prednisone, below a critical, albeit low dose, threshold increases the risk of LAR.

  4. Efficacy of Acellular Nerve Allografts in Trigeminal Nerve Reconstruction.

    Science.gov (United States)

    Yampolsky, Andrew; Ziccardi, Vincent; Chuang, Sung-Kiang

    2017-10-01

    During trigeminal nerve repair, a gap is sometimes encountered that prevents the tension-free apposition of nerve endings. The use of a processed acellular nerve allograft is a novel technique that shows promise in overcoming this problem. The goal of the present study was to support the slowly evolving body of evidence that acellular processed nerve allografts (Avance; Axogen, Alachua, FL) are a viable alternative to autogenous nerve grafting and the use of conduits for reconstructing defects of the trigeminal nerve. The study design consisted of a retrospective review of the medical records of patients referred to Rutgers School of Dental Medicine for management of trigeminal nerve injuries from July 2008 to August 2014. Sixteen patients met the inclusion criteria for the present study. All patients underwent nerve grafting using a processed nerve allograft. All operations were performed by the same surgeon (V.Z.). Serial neurosensory testing was performed by 1 clinician (V.Z.) in a standardized fashion. The primary outcome variable was the interval to functional sensory recovery as defined by the Medical Research Council Scale. The participants ranged in age from 16 to 62 years (mean 32). Of the 16 patients, 12 were female (75%) and 4 were male (25%), and 3 were smokers (18.75%) and 13 were nonsmokers (81.25%). One half of the patients (n = 8; 50%) underwent surgery on the inferior alveolar nerve, and 8 (50%) underwent surgery on the lingual nerve. The most common mechanism of injury was impacted third molar removal (n = 9; 56.25%) Of the 16 patients, 15 (93.75%) achieved functional sensory recovery during the study period. The results of the present study support the hypothesis that processed nerve allografts are effective in reconstructing small (<2-cm) trigeminal nerve defects. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  5. Proteinuria after kidney transplantation, relationship to allograft histology and survival.

    Science.gov (United States)

    Amer, H; Fidler, M E; Myslak, M; Morales, P; Kremers, W K; Larson, T S; Stegall, M D; Cosio, F G

    2007-12-01

    Proteinuria is associated with reduced kidney allograft survival. Herein we assessed the association between proteinuria, graft histology and survival. The cohort included 613 kidney allograft recipients who had proteinuria (measured) and surveillance biopsies at 1-year posttransplant. Proteinuria >150 mg/day was detected in 276 patients (45%) and in 182 of these, proteinuria was below 500. In >84% of patients even low levels of proteinuria were associated with albuminuria. Proteinuria was associated with the presence of graft glomerular pathology and the use of sirolimus. Eighty percent of patients with proteinuria >1500 mg/day had glomerular pathology on biopsy. However, lower levels of proteinuria were not associated with specific pathologies at 1 year. Compared to no sirolimus, sirolimus use was associated with higher prevalence of proteinuria (40% vs. 76%, p Proteinuria was associated with reduced graft survival (HR = 1.40, p = 0.001) independent of other risk factors including, glomerular pathology, graft function, recipient age and acute rejection. The predominant pathology in lost allografts (n = 57) was glomerular, particularly in patients with 1-year proteinuria >500. Thus, proteinuria, usually at low levels (proteinuria relate to poor graft survival. Proteinuria and glomerular pathology relate independently to survival.

  6. INFLUENCE OF VARIOUS FACTORS UPON DECISION ON PANCREAS ALLOGRAFT SUITABILITY

    Directory of Open Access Journals (Sweden)

    S. V. Arzumanov

    2015-01-01

    Full Text Available AAim. To identify factors influencing upon decision on pancreas allograft suitability for transplant and their clinical significance. Materials and methods. We reviewed 95 multiorgan donors under the age of 45, who were considered as pancreas donor between January 2010 and December 2013. 28 pancreata were procured (Group I, 67 pancreata were refused (Group II. Demographic, clinical and laboratory data, anatomical hepatopancreatoduodenal varieties were taken into account. Results. We found that only three factors have an effect on pancreas allograft refusal probability. According to our data, non-transplantation of the liver from the same donor increases the pancreas graft refusal in 4 times. Elevated donor’s sodium and urea blood levels also increase the probability of donor pancreas denial for transplantation. For example, the probability of pancreas graft refusal from the donor with sodium level 145 mmol/l and urea level 6.0 mol/l is only 32%. As compared to the donor with sodium level 160 mmol/l and urea 12.0 mol/l where probability reaches 85%. Other factors: demographic, laboratory, clinical indicators, gepatopancreatoduodenal blood supply variations were not predictive for the procurement decision. Conclusion. Main predictors of pancreas allograft refusal to be taken into account, appropriate correction of donor metabolic disturbances and sufficient experience of the surgeon performing the procurement can increase the availability of pancreas transplantation.  

  7. Multidetector computed tomography findings of spontaneous renal allograft ruptures

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    Basaran, C. [Department of Radiology, Baskent University Faculty of Medicine, Ankara (Turkey)], E-mail: ceylab@baskent-ank.edu.tr; Donmez, F.Y.; Tarhan, N.C.; Coskun, M. [Department of Radiology, Baskent University Faculty of Medicine, Ankara (Turkey); Haberal, M. [Department of General Surgery, Baskent University Faculty of Medicine, Ankara (Turkey)

    2009-05-15

    Aim: To describe the characteristics of spontaneous renal allograft rupture using multidetector computed tomography (MDCT). Method: Five patients with spontaneous renal allograft rupture, as confirmed by pathologic examination, were referred to our institution between 1985 and 2008. The clinical records and preoperative MDCT findings of the patients were studied retrospectively. Results: Clinical and/or histological findings were consistent with acute rejection in all cases. Using MDCT, disruption of the capsular integrity and parenchymal rupture was seen in four patients. Four of the five patients showed decreased enhancement and swollen grafts. Perirenal (n = 4), subcapsular (n = 1), and intraparenchymal (n = 1) haematomas were also seen. In the patient with an intraparenchymal haematoma there was no disruption of capsular integrity, but capsular irregularities were seen near the haematoma. Conclusion: MDCT is a useful investigative tool for the evaluation of suspected spontaneous renal allograft rupture. As well as a swollen graft, disruption of the capsule, parenchyma, and/or haematoma should prompt the radiologist to consider this diagnosis.

  8. Experimental rat models of chronic allograft nephropathy: a review

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    Shrestha B

    2014-07-01

    Full Text Available Badri Shrestha, John HaylorSheffield Kidney Institute, Sheffield Teaching Hospitals NHS Trust, Sheffield, UKAbstract: Chronic allograft nephropathy (CAN is the leading cause of late allograft loss after renal transplantation (RT, which continues to remain an unresolved problem. A rat model of CAN was first described in 1969 by White et al. Although the rat model of RT can be technically challenging, it is attractive because the pathogenesis of CAN is similar to that following human RT and the pathological features of CAN develop within months as compared with years in human RT. The rat model of RT is considered as a useful investigational tool in the field of experimental transplantation research. We have reviewed the literature on studies of rat RT reporting the donor and recipient strain combinations that have investigated resultant survival and histological outcomes. Several different combinations of inbred and outbred rat combinations have been reported to investigate the multiple aspects of transplantation, including acute rejection, cellular and humoral rejection mechanisms and their treatments, CAN, and potential targets for its prevention.Keywords: interventions, therapy, late allograft loss, renal transplantation

  9. PREGNANCY AND CHILDBIRTH IN PATIENTS WITH RENAL ALLOGRAFT (CASE REPORT

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    R. R. Temirbulatov

    2017-01-01

    Full Text Available Relevance. Kidney transplantation is the method of choice for women of reproductive age with late stage of chronic kidney disease, who want to realize their  childbearing function. Pregnancy and childbirth in patients with renal  allografts are classified as an increased risk due to the more frequent complications compared to the general population. Progressive pregnancy is observed in 5–12 % of patients with renal  allograft, the frequency of favorable outcomes in such  cases  is 65–92 %.Objective. To identify the most common complications in pregnancy in women with a transplanted kidney, to review the algorithms for maintaining this category of patientsMaterial and methods. In the  clinic  of obstetrics and  gynecology two patients with a renal  allograft were examined and  delivered, observed in common with specialists from the Research Institute of Surgery and Urgent Medicine.Results. Both patients were delivered by a cesarean section, the postoperative period proceeded without complications in both cases.Conclusions. This  category of patients needs to be  closely monitored throughout the  pregnancy by a multidisciplinary team  of specialists. This article describes the clinical cases  of pregnancy in patients with a transplanted kidney.

  10. Incorporation of perforated and demineralized cortical bone allografts. Part I: radiographic and histologic evaluation.

    Science.gov (United States)

    Lewandrowski, K U; Schollmeier, G; Ekkemkamp, A; Uhthoff, H K; Tomford, W W

    2001-01-01

    Massive cortical bone allografts have been found to incorporate slowly into host bone. They are subject to complications such as nonunion, fatigue fracture and infection. In an attempt to improve osteoinduction in cortical bone allografts, laser perforated and partially demineralized cortical bone allografts were orthotopically transplanted into the sheep tibia. In this model, mid-shaft tibial bone allografts from out-bred sheep donor animals were prepared by partial demineralization and drilling of 0.33-mm diameter holes with a pulsed, 2.94-microm wavelength Erbium:Yttrium-Aluminum-Garnet laser. Recipient animals of the same out-bred strain were divided into three groups of eight according to the type of cortical allograft used: group 1, fresh-frozen, no treatment; group 2, laser hole grid; and group 3, laser hole grid and partial demineralization. Plain films were taken in two standard views at monthly intervals. Incorporation was evaluated at nine months postoperatively. Longitudinal radiographic data was correlated to a histologic and morphometric evaluation of each bone graft. Computer tomography was used for the latter analysis. Results showed that untreated allografts, although surrounded by a periosteal bone cuff, were poorly incorporated. Partial demineralization lead to excessive resorption of allografts, but little new bone formation. Laser perforation and partial demineralization induced complete incorporation of allografts into the host bone. Based on the results of the radiographic, histologic and morphometric evaluation, the development of laser-perforated and partially demineralized bone allografts was proposed for clinical use.

  11. Impaired renal allograft function is associated with increased arterial stiffness in renal transplant recipients

    DEFF Research Database (Denmark)

    Kneifel, M; Scholze, A; Burkert, A

    2006-01-01

    It is important whether impairment of renal allograft function may deteriorate arterial stiffness in renal transplant recipients. In a cross-sectional study, arterial vascular characteristics were non-invasively determined in 48 patients with renal allograft using applanation tonometry and digital...... of large arteries S1 and small arteries S2 in renal transplant recipients (each p renal allograft (p ...-Wallis test between groups). It is concluded that impairment of renal allograft function is associated with an increased arterial stiffness in renal transplant recipients....

  12. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy

    DEFF Research Database (Denmark)

    Ito, Hiromu; Koefoed, Mette; Tiyapatanaputi, Prarop

    2005-01-01

    Structural allograft healing is limited because of a lack of vascularization and remodeling. To study this we developed a mouse model that recapitulates the clinical aspects of live autograft and processed allograft healing. Gene expression analyses showed that there is a substantial decrease...... in the genes encoding RANKL and VEGF during allograft healing. Loss-of-function studies showed that both factors are required for autograft healing. To determine whether addition of these signals could stimulate allograft vascularization and remodeling, we developed a new approach in which rAAV can be freeze...

  13. Prolongation of segmental and pancreaticoduodenal allografts in the primate with total-lymphoid irradiation and cyclosporine

    Energy Technology Data Exchange (ETDEWEB)

    Du Toit, D.F.; Heydenrych, J.J.; Smit, B.; Louw, G.; Zuurmond, T.; Els, D.; Du Toit, L.B.; Weideman, A.; Davids, H.; van der Merwe, E.

    1987-09-01

    The prolongation of segmental and pancreaticoduodenal allografts (PDA) by total lymphoid irradiation (TLI) and in combination with cyclosporine (CsA) was assessed in a well established total pancreatectomy, diabetic, primate transplantation model. Pancreatic transplantation was performed in 119 pancreatectomized baboons (Papio ursinus). Of a total of 109 allografts performed, 71 were segmental allografts (open duct drainage) and 38 PDA. Of 119 graft recipients, 10 received segmental pancreatic autografts. TLI and CsA administered separately to segmental allograft recipients resulted in modest allograft survival and indefinite graft survival was not observed. 8 of 17 (47%) segmental allograft recipients that received TLI and CsA had graft survival beyond 100 days, indicating highly significant pancreatic allograft survival. All long-term segmental allograft recipients were rendered normoglycemic (plasma glucose less than 8 mmol/L) by this immunosuppressive regimen. In contrast, poor results were observed in PDA recipients treated with TLI and CsA. Mean survival in 18 treated PDA recipients was 23.8 days, 8 survived longer than 20 days (44.4%), and 1 greater than 100 days (5.5%). Despite treatment, early rejection of the duodenum in PDA recipients frequently resulted in necrosis and perforation and contributed to a high morbidity and mortality. This study indicates that, in contrast to the significant prolongation of segmental allografts by TLI and CsA, poor immunosuppression was achieved by this regimen in PDA recipients and was associated with a high morbidity and mortality caused by early rejection of the duodenum.

  14. Quantification of renal allograft perfusion using arterial spin labeling MRI: initial results

    Energy Technology Data Exchange (ETDEWEB)

    Lanzman, Rotem S.; Wittsack, Hans-Joerg; Bilk, Philip; Kroepil, Patric; Blondin, Dirk [University Hospital Duesseldorf, Department of Radiology, Duesseldorf (Germany); Martirosian, Petros; Schick, Fritz [University Hospital Tuebingen, Section for Experimental Radiology, Department of Diagnostic Radiology, Tuebingen (Germany); Zgoura, Panagiota; Voiculescu, Adina [University Hospital Duesseldorf, Department of Nephrology, Duesseldorf (Germany)

    2010-06-15

    To quantify renal allograft perfusion in recipients with stable allograft function and acute decrease in allograft function using nonenhanced flow-sensitive alternating inversion recovery (FAIR)-TrueFISP arterial spin labeling (ASL) MR imaging. Following approval of the local ethics committee, 20 renal allograft recipients were included in this study. ASL perfusion measurement and an anatomical T2-weighted single-shot fast spin-echo (HASTE) sequence were performed on a 1.5-T scanner (Magnetom Avanto, Siemens, Erlangen, Germany). T2-weighted MR urography was performed in patients with suspected ureteral obstruction. Patients were assigned to three groups: group a, 6 patients with stable allograft function over the previous 4 months; group b, 7 patients with good allograft function who underwent transplantation during the previous 3 weeks; group c, 7 allograft recipients with an acute deterioration of renal function. Mean cortical perfusion values were 304.8 {+-} 34.4, 296.5 {+-} 44.1, and 181.9 {+-} 53.4 mg/100 ml/min for groups a, b and c, respectively. Reduction in cortical perfusion in group c was statistically significant. Our results indicate that ASL is a promising technique for nonenhanced quantification of cortical perfusion of renal allografts. Further studies are required to determine the clinical value of ASL for monitoring renal allograft recipients. (orig.)

  15. A rat model of pulmonary infection after cardiac transplant.

    Science.gov (United States)

    Chen, Hao; Yu, Weiyong; Lu, Chen; Zhan, Yanxia; Cheng, Yunfeng; Mei, Yunqing

    2015-04-01

    Cardiac allograft rejection and infection are leading causes of morbidity and mortality after transplant. The lack of an animal model has hindered related research. We have developed a rat model of pulmonary infection after cardiac transplant to address this issue. Lewis rats received Wistar rat heart allografts, cardiac rejection was induced by cessation of cyclosporine injection, and pulmonary infection was induced by Pseudomonas aeruginosa intrabronchial inoculation. Development of pulmonary infection and/or heart rejection was assessed by histopathology. Histopathologic findings showed that a dose of 2 × 108 colony forming units of Pseudomonas aeruginosa intrabronchial inoculation is sufficient to cause severe pneumonia without being lethal to transplanted animals. Daily administration of 10 mg/kg of cyclosporine reliably suppressed rejection, and withdrawal for 7 days can obtain a consistent International Society for Heart and Lung Transplantation 3R rejection. The current study represents a simple and effective rat model of pulmonary infection along, or in combination, with rejection after heart transplant, which can be used for research of infection-rejection in cardiac transplant settings.

  16. Use of autoperfusion for distant procurement of heart-lung allografts.

    Science.gov (United States)

    Ladowski, J S; Kapelanski, D P; Teodori, M F; Stevenson, W C; Hardesty, R L; Griffith, B P

    1985-05-01

    Heart-lung transplantation has been limited to on-site organ procurement because current methods of lung preservation are unreliable for periods in excess of one hour. A method of dynamic heart-lung preservation has been evaluated as a possible means for distant procurement for human transplantation. Canine and bovine heart-lung blocks were removed and preserved by autoperfusion for periods of two to nine hours. The key features of the method included normothermic coronary autoperfusion with donor blood by an autoregulating beating heart, and a stabilizing reservoir bag interposed between the donor aorta and the right atrium. The reservoir is positioned one meter above the aortic valve, and determines the pressure in the aorta. Flow from the bag to the right heart dictates venous return, pulmonary blood flow, and ventricular stroke volume. The lungs are ventilated with room air and 5% to 10% of CO2, at 4 liters/minute. Normothermia is ensured by immersion of the heart-lungs block in a temperature controlled crystalloid bath. Eleven canine and eight bovine heart-lung blocks were evaluated for two to nine hours. Lung function was excellent during this period, and cardiac output did not decline from pre-harvest levels. Five heart-lung allografts were transplanted after an average of four hours of autoperfusion and all functioned satisfactorily. All animals could be weaned from the extracorporeal circulation support. Two to three hours later, cardiac outputs and arterial pO2 were normal. The peak airway pressures averaged 29 cm H2O.(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Elevated urine heparanase levels are associated with proteinuria and decreased renal allograft function.

    Directory of Open Access Journals (Sweden)

    Itay Shafat

    Full Text Available Heparanase is an endo-β-glucuronidase that cleaves heparan sulfate side chains, leading to structural modifications that loosen the extracellular matrix barrier and associated with tumor metastasis, inflammation and angiogenesis. In addition, the highly sulfated heparan sulfate proteoglycans are important constituents of the glomerular basement membrane and its permselective properties. Recent studies suggest a role for heparanase in several experimental and human glomerular diseases associated with proteinuria such as diabetes, minimal change disease, and membranous nephropathy. Here, we quantified blood and urine heparanase levels in renal transplant recipients and patients with chronic kidney disease (CKD, and assessed whether alterations in heparanase levels correlate with proteinuria and renal function. We report that in transplanted patients, urinary heparanase was markedly elevated, inversely associated with estimated glomerular filtration rate (eGFR, suggesting a relationship between heparanase and graft function. In CKD patients, urinary heparanase was markedly elevated and associated with proteinuria, but not with eGFR. In addition, urinary heparanase correlated significantly with plasma heparanase in transplanted patients. Such a systemic spread of heparanase may lead to damage of cells and tissues alongside the kidney.The newly described association between heparanase, proteinuria and decreased renal function is expected to pave the way for new therapeutic options aimed at attenuating chronic renal allograft nephropathy, leading to improved graft survival and patient outcome.

  18. Infiltrating inflammatory cell phenotypes and apoptosis in rejected human corneal allografts.

    Science.gov (United States)

    Larkin, D F; Alexander, R A; Cree, I A

    1997-01-01

    The aim of this study was to survey the histopathological and immunohistochemical features of rejected human corneal allografts. Following graft failure in each case due to rejection, paraffin-embedded specimens of 17 corneal transplants which had been replaced were examined by light microscopy and immunohistochemistry. Specimens were either first (n = 9), second (n = 4) or third (n = 4) grafts and were removed at varying intervals from 4 weeks following documented rejection. Those grafts which were removed earliest following onset of rejection had the most intense graft inflammatory infiltrates. Immunohistochemical staining showed a high proportion of graft stroma-infiltrating cells expressing leucocyte common antigen, and many of these cells also bore T cell or macrophage markers. Leucocyte-keratocyte apposition and regional loss of keratocytes were observed in all rejection specimens, but not in non-rejected control grafts. In situ end-labelling of DNA double-strand breaks and morphological features identified keratocyte apoptosis in 5 of 12 specimens examined for this phenomenon. Corneal endothelial cells were absent in 7 specimens and present in reduced numbers in the remaining 10 specimens. Endothelial cell monolayer attenuation and keratocyte loss are consistent findings in grafts removed subsequent to clinically observed endothelial rejection. Death of donor corneal cells is mediated, at least in part, by apoptosis. The stromal inflammatory infiltrate consists mainly of T lymphocytes and macrophages, which may be responsible for induction of keratocyte apoptosis.

  19. Allografts with autogenous platelet-rich plasma for tibial defect reconstruction: a rabbit study.

    Science.gov (United States)

    Nather, Aziz; Wong, Keng Lin; David, Vikram; Pereira, Barry P

    2012-12-01

    To evaluate the effect of autogenous platelet-rich plasma (PRP) for fresh-frozen allografts in tibial defect reconstruction in rabbits. 40 adult New Zealand white rabbits underwent tibial defect reconstruction with autografts (n=12), allografts without PRP (n=12), or allografts with PRP (n=12) and were observed for 12, 16, and 24 weeks (4 for each period). Tibias of the remaining 4 rabbits were used as donor allografts, and the remaining allografts were procured from recipient rabbits. A 1.5- cm cortical segment of the tibia was osteotomised, and then fixed with a 9-hole mini-compression plate and 2 cerclage wires. Allografts were stripped off the periosteum and soft tissues and medullary contents, and then stored in a freezer at -80 ºC. All allografts were deep frozen for at least 4 weeks before transplantation. 7 ml of whole blood was drawn to prepare 1 ml of PRP. The PRP was then mixed with 1.0 ml of human thrombin to form a platelet gel. The PRP gel was then packed into the medullary canal of the allograft and applied on the cortical surface before tibial defect reconstruction. Rabbits were sacrificed at 12, 16, and 24 weeks. The specimens were assessed for bone union at host-graft junctions and for bone resorption, new bone formation, callus encasement, and viable osteocyte counts. There were 4 specimens in each group at each observation period. Osteoid bridging the gap at host-graft junctions was noted in all specimens in the autograft and allograft-with-PRP groups at week 12 and in the allograft-without-PRP group at week 24. Bone union in allografts without PRP was delayed. All indices for biological incorporation (resorption index, new bone formation index, callus encasement index, and viable osteocyte count) were significantly greater in the autograft than allograft-without-PRP groups, except for the resorption index at week 24, whereas the differences were not significant between the autograft and allograft-with-PRP groups. The differences between the 2

  20. Cardiac Malpositions

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, Shi Joon; Im, Chung Gie; Yeon, Kyung Mo; Hasn, Man Chung [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1979-06-15

    Cardiac Malposition refers to any position of the heart other than a left-sided heart in a situs solitus individual. Associated cardiac malformations are so complex that even angiocardiographic and autopsy studies may not afford an accurate information. Although the terms and classifications used to describe the internal cardiac anatomy and their arterial connections in cardiac malpositions differ and tend to be confusing, common agreement exists on the need for a segmental approach to diagnosis. Authors present 18 cases of cardiac malpositions in which cardiac catheterization and angiocardiography were done at the Department of Radiology, Seoul National University Hospital between 1971 and 1979. Authors analyzed the clinical, radiographic, operative and autopsy findings with the emphasis on the angiocardiographic findings. The results are as follows: 1. Among 18 cases with cardiac malpositions, 6 cases had dextrocardia with situs inversus, 9 cases had dextrocardia with situs solitus and 3 cases had levocardia with situs inversus. 2. There was no genuine exception to visceroatrial concordance rule. 3. Associated cardiac malpositions were variable and complex with a tendency of high association of transposition and double outlet varieties with dextrocardia in situs solitus and levocardia in situs inversus. Only one in 6 cases of dextrocardia with situs inversus had pure transposition. 4. In two cases associated pulmonary atresia was found at surgery which was not predicted by angiocardiography. 5. Because many of the associated complex lesions can be corrected surgically provided the diagnosis is accurate, the selective biplane angiocardiography with or without cineradiography is essential.

  1. Cardiac sarcoidosis

    Directory of Open Access Journals (Sweden)

    Costello BT

    2016-04-01

    Full Text Available Benedict T Costello,1,2 James Nadel,3 Andrew J Taylor,1,21Department of Cardiovascular Medicine, The Alfred Hospital, 2Baker IDI Heart and Diabetes Research Institute, Melbourne, VIC, 3School of Medicine, University of Notre Dame, Sydney, NSW, Australia Abstract: Cardiac sarcoidosis is a rare but life-threatening condition, requiring a high degree of clinical suspicion and low threshold for investigation to make the diagnosis. The cardiac manifestations include heart failure, conducting system disease, and arrhythmias predisposing to sudden cardiac death. A number of investigations are available to assist in making the diagnosis. The diagnosis may be made from the clinical history and evidence of inflammation on imaging modalities in the active phase and evidence of myocardial scarring in the chronic phase. Keywords: cardiac magnetic resonance, positron emission tomography, sarcoidosis, sudden cardiac death

  2. Combined treatment with chemokine receptor 5 blocker and cyclosporine induces prolonged graft survival in a mouse model of cardiac transplantation.

    Science.gov (United States)

    Jun, Li; Kailun, Zhang; Aini, Xie; Lei, Xu; Guohua, Wang; Sihua, Wang; Ping, Ye; Tucheng, Sun; Xionggang, Jiang; Wenwei, Chen; Jiahong, Xia

    2010-04-01

    Inhibition of chemokine receptor 5 (CCR5), a chemokine receptor expressed on activated T cells, is efficacious in modulating inflammation and immunity as well as in patients with human immunodeficiency virus infection. This study examined the effect and mechanism of CCR5 blockade in combination with cyclosporine in prolonging cardiac allograft survival in mice. Hearts from BALB/c mice were transplanted into C57BL/10 recipients. They were administrated with anti-CCR5 antibody (Ab) or control Ab and cyclosporine or phosphate-buffered (PBS) saline, respectively. To investigate the role of regulatory cells, naïve mice (secondary recipients) underwent adoptive transfer of splenocytes from anti-CCR5 Ab plus cyclosporine-treated recipients and cardiac allograft transplantation. Compared with recipients treated with control Ab plus PBS, allografts treated with anti-CCR5 Ab and cyclosporine showed significantly prolonged survival (p cyclosporine-treated recipients induced significantly prolonged survival in secondary recipients (p cyclosporine is effective in protecting the cardiac allograft in a robust murine model. This effect is partly mediated by regulatory cell recruitment and control of effector cell infiltration.

  3. Cardiac ablation procedures

    Science.gov (United States)

    Catheter ablation; Radiofrequency catheter ablation; Cryoablation - cardiac ablation; AV nodal reentrant tachycardia - cardiac ablation; AVNRT - cardiac ablation; Wolff-Parkinson-White Syndrome - cardiac ablation; Atrial fibrillation - cardiac ablation; Atrial flutter - ...

  4. The renal arterial resistive index and stage of chronic kidney disease in patients with renal allograft

    DEFF Research Database (Denmark)

    Winther, Stine O; Thiesson, Helle C; Poulsen, Lene N

    2012-01-01

    The study investigated the optimal threshold value of renal arterial resistive index as assessed by Doppler ultrasonography determining chronic kidney disease stage 4 or higher in patients with renal allograft.......The study investigated the optimal threshold value of renal arterial resistive index as assessed by Doppler ultrasonography determining chronic kidney disease stage 4 or higher in patients with renal allograft....

  5. Scapular allograft reconstruction after total scapulectomy: surgical technique and functional results

    NARCIS (Netherlands)

    Capanna, R.; Totti, F.; Geest, I.C.M. van der; Muller, D.A.

    2015-01-01

    HYPOTHESIS: Scapular allograft reconstruction after total scapulectomy preserving the rotator cuff muscles is an oncologically safe procedure and results in good functional outcome with a low complication rate. METHODS: The data of 6 patients who underwent scapular allograft reconstruction after a

  6. No effect of platelet-rich plasma with frozen or processed bone allograft around noncemented implants

    DEFF Research Database (Denmark)

    Jensen, T B; Rahbek, O; Overgaard, S

    2005-01-01

    We compared processed morselized bone allograft with fresh-frozen bone graft around noncemented titanium implants. Also, the influence of platelet-rich plasma (PRP) in combination with bone allograft was evaluated. Analysis was based on implant fixation and histomorphometry. PRP was prepared...

  7. Intestinal Graft Failure: Should We Perform the Allograft Enterectomy Before or With Retransplantation?

    Science.gov (United States)

    Nagai, Shunji; Mangus, Richard S; Anderson, Eve; Ekser, Burcin; Kubal, Chandrashekhar A; Fridell, Jonathan A; Tector, A Joseph

    2017-02-01

    Intestinal graft dysfunction is sometimes irreversible and requires allograft enterectomy with or without retransplantation. There is no comprehensive assessment of allograft enterectomy regarding indications and outcomes. The aim of this study was to evaluate management of patients with intestinal graft failure with special reference to indications and outcomes of allograft enterectomy and the procedure's validity as a bridge to retransplantation. Graft and patient survivals, reason for graft failure, and rejection episodes were evaluated in 221 intestinal recipients (primary transplantation [n = 201], retransplantation [n = 20]). Indications, surgical factors, and outcomes of allograft enterectomy were investigated. Reasons for isolated enterectomy included systemic infection in 11, gastrointestinal bleeding in 1, and severe electrolyte imbalance in 1, all of which were associated with rejection. One isolated intestinal transplantation patient underwent isolated enterectomy due to cytomegalovirus enteritis. One multivisceral transplantation patient underwent isolated allograft enterectomy due to bowel necrosis. Of these 15 patients, 3 died from persistent infection postoperatively, whereas 8 underwent retransplantation with median interval of 74 days (42-252 days). Allosensitization occurred between isolated enterectomy and retransplantation in 2, one of whom lost the second graft due to rejection. Simultaneous allograft enterectomy and retransplantation was performed in 3 isolated intestinal transplantation and 9 multivisceral transplantation patients. Patient survival after retransplantation was similar between patients who underwent isolated allograft enterectomy and those who did simultaneous enterectomy with retransplantation (P = 0.82). In cases of irreversible intestinal graft dysfunction, isolated allograft enterectomy successfully provides recovery from comorbidities as a lifesaving procedure and does not compromise outcomes of retransplantation.

  8. DEFECTIVE BRONCHUS-ASSOCIATED LYMPHOID-TISSUE IN LONG-TERM SURVIVING RAT LUNG ALLOGRAFTS

    NARCIS (Netherlands)

    WINTER, JB; PROP, J; GROEN, M; PETERSEN, AH; UYAMA, T; MEEDENDORP, B; WILDEVUUR, CRH

    1995-01-01

    In a previous study we found that a local immune response did not develop in the bronchus-associated lymphoid tissue (BALT) of infected rat allografts. We hypothesized that the BALT in rat lung allografts was damaged after allotransplantation. Therefore, we investigated three prerequisites for a

  9. Pubovaginal sling using cadaveric allograft fascia for the treatment of intrinsic sphincter deficiency.

    Science.gov (United States)

    Wright, E J; Iselin, C E; Carr, L K; Webster, G D

    1998-09-01

    Pubovaginal sling is the definitive management of female stress urinary incontinence due to intrinsic sphincter deficiency. Customarily, autologous fascia has been used, although synthetic material has its proponents. Harvesting autologous fascia at surgery is associated with postoperative discomfort, and synthetic material has a history of infection and erosion. To assess whether allograft fascia is free from these drawbacks, we retrospectively compared the outcome of women undergoing pubovaginal sling using either autologous or cadaveric allograft fascia. We reviewed our experience during the last 28 months with patients treated with the pubovaginal sling for intrinsic sphincter deficiency. All patients underwent preoperative video urodynamics. The outcome was assessed using the SEAPI scoring system. Special attention was devoted to local sling tolerance. Operative time and length of hospital stay were compared between patients with allograft and autograft pubovaginal sling. A total of 92 women (mean age 60 years) underwent allograft (59) or autograft (33) pubovaginal sling. Preoperative parameters, such as percent of patients who had had previous incontinence surgery, mean leak point pressure and SEAPI incontinence score, were similar in both populations. Mean followup was 11.5 months (range 1 to 28) for the overall population. The SEAPI scoring system showed that patients were markedly improved, with no significant difference between the allograft and autograft groups. Allograft and autograft pubovaginal slings were equally well tolerated, and no infection or erosion was encountered. Mean operative time and hospital stay were significantly shorter when using allograft compared to autograft fascia. The success rates of allograft and autograft pubovaginal sling were equally high, and no complications related to the cadaveric origin of the allograft fascia were observed. Allograft pubovaginal sling was well tolerated, and its use significantly shortened operative

  10. [Reconstruction of periprosthetic fractures of hip with cortical bone plates allografts].

    Science.gov (United States)

    Zhou, Zong-ke; Pei, Fu-xing; Tu, Chong-qi; Yang, Jing; Shen, Bin; Liu, Lei; Fatou, Camara-yagouba

    2004-12-22

    To observe clinical results for reconstruction of periprosthetic fractures of hip with cortical bone plates allografts by deep-freezing and ethylene oxide treatment. Seven patients with periprosthetic fractures of hip underwent cortical bone plates allografts by deep-freezing at -70 degrees C after being treatment of 48 degrees C ethylene oxide. And evaluate clinical outcome by examining T lymphocytes, Harris scores, X-rays photograph, and bone scintigraphy. There were not activity of immune rejection and infection in all patients. Harris scores of patients increased 21, 32, 40, 40 scores at 3, 6, 12, 24 months after surgery. T-lymphocytes, antibody and immunocomplex in blood was normal postoperation. X-ray film indicated that fracture was healed at 3 months and there was partially bone conjunction between allograft strut and host bone. There was incorporation of 85% allograft strut to host bone, and 15% allograft strut was partially absorbed at 12 months after surgery. The size of femur of host was added 3 mm to 5 mm, averaged 4.3 mm at 12 months postoperation. Density of 80% allograft plates was as same as host bone after remodeling and the absorbtion of 10% allograft plates stopped at 24 months after surgery. There was thick of nuclein in the area of allograft cortical bone plates by bone scintigraphy examination at 3 months postoperation, and the thick of nuclein was stronger at 6, and 12 months after surgery. Allograft cortical bone plates by deep frozen at -70 degrees C after being treatment of 48 degrees C ethylene oxide is suitable for mechanical fixation and biological bone transplantation, and it can increase bone reservation, augment strength of femur once the allograft strut incorporates to host bone, and avoid removing metal implant in second operation when being applied into reconstruction femoral fracture in joint replacement.

  11. Cardiac Rehabilitation

    Science.gov (United States)

    Cardiac rehabilitation (rehab) is a medically supervised program to help people who have A heart attack Angioplasty or coronary artery bypass grafting for coronary heart disease A heart valve repair or replacement A ...

  12. Cardiac rehabilitation

    Science.gov (United States)

    ... ncbi.nlm.nih.gov/pubmed/25503364 . Balady GJ, Williams MA, Ades PA, et al. Core components of ... ncbi.nlm.nih.gov/pubmed/22070836 . Thompson PD. Exercise-based, comprehensive cardiac rehabilitation. In: Mann DL, Zipes ...

  13. Cardiac arrest

    Science.gov (United States)

    ... also run other tests, depending on your health history and the results of these tests. Treatment Cardiac arrest needs emergency treatment right away to get the heart started again. Cardiopulmonary resuscitation (CPR) . This is often the first type of ...

  14. Cardiac Angiosarcoma

    Directory of Open Access Journals (Sweden)

    Monique Esteves Cardoso

    2011-01-01

    Full Text Available Despite cardiac metastases are found in about 20% of cancer deaths, the presence of primary cardiac tumors is rare. Most primary tumors are benign, and malignant tumors comprise about 15%. We report a 21-year-old man with fever, dyspnea, and hemoptysis that was diagnosed with angiosarcoma of the right atrium and pulmonary metastasis. Patient was submitted to surgical tumor resection without adjuvant therapy and died four months after diagnosis.

  15. Cardiac Angiosarcoma

    OpenAIRE

    Cardoso, Monique Esteves; Canale, Leonardo Secchin; Ramos, Rosana Grandelle; Salvador Junior, Edson da Silva; Lachtermacher, Stephan

    2011-01-01

    Despite cardiac metastases are found in about 20% of cancer deaths, the presence of primary cardiac tumors is rare. Most primary tumors are benign, and malignant tumors comprise about 15%. We report a 21-year-old man with fever, dyspnea, and hemoptysis that was diagnosed with angiosarcoma of the right atrium and pulmonary metastasis. Patient was submitted to surgical tumor resection without adjuvant therapy and died four months after diagnosis.

  16. Cardiac Angiosarcoma

    Science.gov (United States)

    Cardoso, Monique Esteves; Canale, Leonardo Secchin; Ramos, Rosana Grandelle; Salvador Junior, Edson da Silva; Lachtermacher, Stephan

    2011-01-01

    Despite cardiac metastases are found in about 20% of cancer deaths, the presence of primary cardiac tumors is rare. Most primary tumors are benign, and malignant tumors comprise about 15%. We report a 21-year-old man with fever, dyspnea, and hemoptysis that was diagnosed with angiosarcoma of the right atrium and pulmonary metastasis. Patient was submitted to surgical tumor resection without adjuvant therapy and died four months after diagnosis. PMID:24826214

  17. Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts.

    Science.gov (United States)

    Streblow, D N; Hwee, Y K; Kreklywich, C N; Andoh, T; Denton, M; Smith, P; Hart, E; Broekel, R; Pallett, C; Rogers, K; Streblow, A D; Chuop, M; Perry, A; Slifka, M; Messaoudi, I; Orloff, S L

    2015-07-01

    Cytomegalovirus accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants; however, the mechanisms involved are unclear. We determined the efficacy of a CMV vaccine in preventing CMV-accelerated rat cardiac allograft rejection in naïve recipients of CMV+ donor hearts. F344 donor rats were infected with RCMV 5 days prior to heterotopic cardiac transplantation into CMV-naïve or H2 O2 -inactivated RCMV-vaccinated Lewis recipients. Recipients of RCMV-infected donor hearts rejected at POD59, whereas vaccinated recipients exhibited a significantly prolonged time to rejection-POD97, similar to recipients of uninfected donor hearts (POD108). Although all of the donor hearts were preinfected, the vaccinated recipients had lower graft and PBMC viral loads at POD 7 compared to unvaccinated controls. Adoptive T cell and passive antibody transfers from vaccinated Lewis rats into naïve recipients demonstrate that both T-cell and B-cell arms of the adaptive immune response provide protection against CMV-accelerated rejection. Similar findings were obtained when testing three different adjuvants in passive transfer experiments. We have determined that the timing of the vaccine prior to transplantation and the specific adjuvant play critical roles in mediating anti-viral responses and promoting graft survival. CMV vaccination prior to transplantation may effectively increase graft survival. © Copyright 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals Inc.

  18. Fresh osteochondral allografts-procurement and tissue donation in Europe.

    Science.gov (United States)

    Schmidt, S; Schulte, A; Schwarz, S; Hofmann, N; Tietz, S; Boergel, M; Sixt, S U

    2017-07-01

    Fresh osteochondral allografts are a well-established treatment for large, full-thickness cartilage defects. The clinical outcome for carefully selected patients is very favorable, especially for the young and active and graft survival up to 25 years has been described in the literature. Furthermore, a high patient satisfaction rate has been reported, but the biggest obstacle to overcome is the availability of tissue for transplantation. Large fresh bone allografts for cartilage damage repair only can be harvested from organ donors following organ removal or cadaveric donors, preferably in the setting of an operation room to minimize possible contamination of the tissue. Apart from the logistic challenges this entails, an experienced recovery team is needed. Furthermore, the public as well as medical staff is much less aware of the possibility and requirements of tissue donation than organ donation and families of deceased are rarely approached for bone and cartilage donation. This review aims to highlight the current situation of organ and tissue donation in Europe with special focus on the processing of bones and possible safety and quality concerns. We analyze what may prevent consent and what might be done to improve the situation of tissue donation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. T-cell exhaustion in allograft rejection and tolerance.

    Science.gov (United States)

    Thorp, Edward B; Stehlik, Christian; Ansari, M Javeed

    2015-02-01

    The role of T-cell exhaustion in the failure of clearance of viral infections and tumors is well established. There are several ongoing trials to reverse T-cell exhaustion for treatment of chronic viral infections and tumors. The mechanisms leading to T-cell exhaustion and its role in transplantation, however, are only beginning to be appreciated and are the focus of the present review. Exhausted T cells exhibit a distinct molecular profile reflecting combinatorial mechanisms involving the interaction of multiple transcription factors important in control of cell metabolism, acquisition of effector function and memory capacity. Change of microenvironmental cues and limiting leukocyte recruitment can modulate T-cell exhaustion. Impaired leukocyte recruitment induces T-cell exhaustion and prevents allograft rejection. Preventing or reversing T-cell exhaustion may lead to prevention of transplant tolerance or triggering of rejection; therefore, caution should be exercised in the use of agents blocking inhibitory receptors for the treatment of chronic viral infections or tumors in transplant recipients. Further definition of the role of T-cell exhaustion in clinical transplantation and an understanding of the mechanisms of induction of T-cell exhaustion are needed to develop strategies for preventing allograft rejection and induction of tolerance.

  20. [Skin manifestations in adults with a liver allograft].

    Science.gov (United States)

    Daza, Francisca; Poniachik, Jaime; Zemelman, Viviana; Ibarra, José; Espinoza, Miguel; Castillo, Jaime; Cardemil, Gonzalo; Díaz, Juan Carlos; Saure, Alexandre; Lembach, Hans; Calderón, Perla

    2015-05-01

    Skin manifestations after liver transplantation are increasing due to long term immunosuppressive therapy along with an increase in patient survival. Several studies have reported dermatologic complications following renal transplant, but few have studied dermatologic problems after liver transplantation. To describe the different types of cutaneous lesions encountered in adults receiving a liver allograft. To evaluate the frequency of cutaneous manifestations of patients in the liver transplant waiting list. Eighty patients submitted to a liver transplant and 70 patients in the liver transplant waiting list were evaluated with a complete dermatological physical examination. Sixty one percent of patients with a liver allograft had at least one skin manifestation. Of these, 34% had superficial fungal infections, 31% had viral infections, 20% had cutaneous side effects due to immunosuppressive treatment, 10% had malignant lesions, 2% had bacterial infections and one patient had a graft versus host disease. Only 28% of patients in the liver transplant waiting list had dermatologic problems, and the vast majority were lesions linked to liver cirrhosis. Cutaneous infections were the most common skin problems in liver transplant patients. Although neoplastic lesions are the most commonly mentioned lesions in the literature, only a 10% of our liver transplant patients presented these type of lesions.

  1. Prostate Cancer Metastatic to the Renal Allograft: A Case Report.

    Science.gov (United States)

    Alaini, A; Singh, P; Shah, R; Fischer, E; Ganta, K; Barrett, T; Servilla, K

    Malignancy is a leading cause of morbidity and mortality in organ transplant recipients who receive immunosuppression. Cancers associated with viruses such as nonmelanotic skin cancer and Kaposi sarcoma occur in allograft recipients at rates that far exceed that in the general population. The increased risk and tumor type may depend not only on degree of immune system modulation but also on the type of organ transplanted. In kidney transplant recipients, the risk of cancers such as prostate and breast does not seem to be increased. However, these cancers tend to be advanced and aggressive. The management of these cancers is similar to the general population with the additional consideration for reduction in immunosuppression and conversion to sirolimus. Given the increased survival of both transplanted organs as well as organ recipients along with the increased number of older recipients, the diagnosis of prostate cancer in the older male organ recipient is increasing. The long-term outcomes using current treatment guidelines for prostate cancer in these individuals are not clear. We report a case of known localized prostate cancer in a renal transplant recipient presenting with metastasis diagnosed as tumor infiltration of the allograft. Our patient, upon initial diagnosis of cancer, opted for radiation with eventual androgen-deprivation therapy. This unusual site of prostate cancer spread heightens the need for awareness among providers as well as the need for further studies of the outcomes in these patients undergoing treatments designed using guidelines developed for those with normally functioning immunity. Copyright © 2016. Published by Elsevier Inc.

  2. Presumed serum sickness following thymoglobulin treatment of acute cellular rejection of a cardiac allograft.

    Science.gov (United States)

    Ratushny, Vladimir; Capell, Brian C; Rosenbach, Misha

    2017-09-01

    Serum sickness is a hypersensitivity reaction to proteins in antiserum derived from nonhuman animal sources and can be seen in patients being treated with antiserum to prevent transplant rejection. Serum sickness may display variable clinical presentations. Because cutaneous findings may be the initial symptom in some cases, it is important for dermatologists to be able to recognize this condition given its potentially life-threatening symptoms. We present a case of a 35-year-old man with presumed serum sickness after receiving thymoglobulin for the treatment of acute cellular rejection of a heart transplant. The clinical presentation, laboratory findings, and treatment options are reviewed.

  3. Recipient origin of neointimal vascular smooth muscle cells in cardiac allografts with transplant arteriosclerosis

    NARCIS (Netherlands)

    Hillebrands, JL; van den Hurk, BMH; Klatter, FA; Popa, ER; Nieuwenhuis, P; Rozing, J

    2000-01-01

    Background: Coronary artery disease is today's most important post-heart transplantation problem after the first perioperative year. Histologically, coronary artery disease is characterized by transplant arteriosclerosis. The current view on this vasculopathy is that vascular smooth muscle (VSM)

  4. The Impact of Ventricular Assist Device Prior to Transplantation on Morphological Parameters in Cardiac Allografts

    DEFF Research Database (Denmark)

    Wassilew, Katharina

    2017-01-01

    by eyeballing irrespective of the presence of ACR. The EMBs were also evaluated for level of IF on a collagen stain (Sirius red) and further quantified using NIKON software (NIS elements AR 4.10.02). Fisher’s exact test was performed to analyze the relationship between C4d and C3d in both patient groups...

  5. Application of Ultrasound Elastography for Chronic Allograft Dysfunction in Kidney Transplantation.

    Science.gov (United States)

    Wang, Zijie; Yang, Haiwei; Suo, Chuanjian; Wei, Jifu; Tan, Ruoyun; Gu, Min

    2017-09-01

    Interstitial fibrosis is the main characteristic of chronic allograft dysfunction, which remains the key factor affecting long-term allograft survival after kidney transplantation. Ultrasound elastography (UE), including real-time elastography, transient elastography, and acoustic radiation force impulse, has been applied widely in breast, thyroid, and liver diseases, especially in the assessment of liver fibrosis. Recently, numerous studies have reported the efficacy of UE methods in evaluating renal allograft fibrosis. This review aims to investigate the clinical applications, limitations, and future roles of UE in current clinical practice in light of changing management paradigms. In current clinical practice, UE methods, especially transient elastographic measurement, appear to be useful for ruling out fibrosis but do not have sufficient accuracy to distinguish between various stages of allograft fibrosis. Moreover, there remain considerable issues to be solved for the application of UE in kidney transplantation. Thus, UE methods cannot replace the crucial role of renal allograft biopsy in the diagnosis and evaluation of allograft fibrosis in kidney transplantation. Perhaps UE methods could be of more importance in the long-term observation and evaluation of allograft fibrosis during follow-up. © 2017 by the American Institute of Ultrasound in Medicine.

  6. Anterior cruciate ligament allograft surgery: underreporting of graft source, graft processing, and donor age.

    Science.gov (United States)

    Sikka, Robby S; Narvy, Steven J; Vangsness, C Thomas

    2011-03-01

    There has been much controversy regarding the effects of sterilization techniques and graft history on the structural integrity of allograft ligaments used in reconstruction of the anterior cruciate ligament. The purpose of this review was to comprehensively examine anterior cruciate ligament allograft studies published in the last decade to evaluate the extent to which tissue source, tissue processing techniques, and donor age are reported. The authors reviewed 202 articles published from 1999 through November 2009, of which 68 retrospective, prospective, biomechanical, and histology studies evaluating 4689 allografts were included. The majority of studies do not accurately report key elements of graft history including tissue bank, processing or sterilization technique, or donor age. Underreporting was particularly prominent in clinical studies as compared with basic science studies. Limited reporting of allograft processing, allograft source, and donor age raises serious questions regarding the generalizability of published studies of allograft tissue for anterior cruciate ligament reconstruction. Conclusion/ Orthopaedic surgeons who use allograft tissue must understand the tissue treatments being used (ie, preservation methods, chemical and sterilization processes) to best inform their patients regarding the risks, benefits, and long-term outcomes when such tissues are used. A complete understanding of the implanted tissue, as well as surgeon and recipient demographics, is necessary to ensure appropriate and predictable long-term outcomes.

  7. Long-Term Results of Reconstruction with Pelvic Allografts after Wide Resection of Pelvic Sarcomas

    Directory of Open Access Journals (Sweden)

    Mehmet Ayvaz

    2014-01-01

    Full Text Available Reconstruction after the resection of a pelvic tumor is a challenging procedure in orthopedic oncology. The main advantage of allograft reconstruction is restoration of the bony architecture of the complex pelvic region. However, high complication rates such as infection and allograft resorption had been reported in the literature. In this study, we aimed to retrospectively review nine patients treated with pelvic resection and structural pelvic allograft reconstruction. Functional results, complications, and survival of the patients and the allografts were evaluated. At a mean follow-up of 79 months, three patients were dead. Major complications were detected in eight of the nine patients. Infection (four of the nine patients and allograft resorption (three of the nine patients were the most common causes of failure. The cumulative survival of the patients was 66.7 percent at 70 months. However, allograft survival was only 26.7 percent at 60 months. Mean MSTS score was 69. In conclusion, we suggest that other reconstruction options should be preferred after pelvic resections because of the high complication rates associated with massive allograft reconstruction.

  8. Renal allograft loss in the first post-operative month: causes and consequences.

    LENUS (Irish Health Repository)

    Phelan, Paul J

    2013-01-15

    Early transplant failure is a devastating outcome after kidney transplantation. We report the causes and consequences of deceased donor renal transplant failure in the first 30 d at our center between January 1990 and December 2009. Controls were adult deceased donor transplant patients in the same period with an allograft that functioned >30 d. The incidence of early graft failure in our series of 2381 consecutive deceased donor transplants was 4.6% (n = 109). The causes of failure were allograft thrombosis (n = 48; 44%), acute rejection (n = 19; 17.4%), death with a functioning allograft (n = 17; 15.6%), primary non-function (n = 14;12.8%), and other causes (n = 11; 10.1%). Mean time to allograft failure was 7.3 d. There has been a decreased incidence of all-cause early failure from 7% in 1990 to <1% in 2009. Patients who developed early failure had longer cold ischemia times when compared with patients with allografts lasting >30 d (p < 0.001). Early allograft failure was strongly associated with reduced patient survival (p < 0.001). In conclusion, early renal allograft failure is associated with a survival disadvantage, but has thankfully become less common in recent years.

  9. Pressure surge attenuator

    Science.gov (United States)

    Christie, Alan M.; Snyder, Kurt I.

    1985-01-01

    A pressure surge attenuation system for pipes having a fluted region opposite crushable metal foam. As adapted for nuclear reactor vessels and heads, crushable metal foam is disposed to attenuate pressure surges.

  10. Successful retransplantation of a kidney allograft affected by thrombotic microangiopathy into a second transplant recipient.

    Science.gov (United States)

    Kamar, Nassim; Rischmann, Pascal; Guilbeau-Frugier, Céline; Sallusto, Federico; Khedis, Mehdi; Delisle, Marie-Bernadette; Noury, Didier; Fort, Marylise; Rostaing, Lionel

    2008-09-01

    The donor organ shortage has compelled transplant centers to use organs from nontraditional sources. One example is the reuse of a previously transplanted organ, such as a kidney or liver retrieved from a brain-dead allograft recipient. For the first time, we reused a previously transplanted kidney that experienced intractable recurrent thrombotic microangiopathy (TMA) from a living allograft recipient. Within a few weeks posttransplantation, a deceased kidney allograft recipient developed intractable severe recurrent idiopathic TMA in the allograft despite intensive plasma exchanges and steroid and rituximab therapy. This required nephrectomy to cure TMA. The index recipient was believed to have a well-functioning allograft despite TMA (serum creatinine, 1.36 mg/dL [120 micromol/L]) and microalbuminuria with albumin of 1.2 g/dL [12 g/L]), and it appeared mildly damaged on biopsy examination. After donor and recipient informed consents were obtained and after approval of the French Agency of Biomedicine, the TMA allograft was reused and transplanted into a recipient whose original kidney disease was polycystic kidney disease. The retransplantation was uneventful, and at 6 months posttransplantation, the ultimate recipient's serum creatinine level was 1.06 mg/L (97 micromol/L) and albuminuria was 0.5 g/dL (5 g/L). A routine kidney biopsy showed mild glomerular lesions. After allograft nephrectomy, the donor's hematologic TMA symptoms dissipated within 10 days. We conclude that a kidney allograft with TMA recurrence can be successfully retransplanted into another recipient with excellent kidney function while still curing the first recipient of recurrent TMA. This might increase the number of kidney allografts from extended criteria donors.

  11. Cyclosporine-associated end-stage nephropathy after cardiac transplantation: incidence and progression.

    Science.gov (United States)

    Goldstein, D J; Zuech, N; Sehgal, V; Weinberg, A D; Drusin, R; Cohen, D

    1997-03-15

    The salutary immunosuppressive effects of cyclosporine in extending cardiac allograft survival may be curtailed by its nephrotoxic effects. We reviewed our first 9 years of experience with cyclosporine after cardiac transplantation, to evaluate the incidence and progression of cyclosporine-associated end-stage renal failure necessitating chronic hemodialysis. Retrospective computer-based file review and personal interview when possible. The population at risk was comprised of all adult cardiac recipients surviving at least 3 years (n=293). Of these, 19 (6.5%) developed end-stage renal failure requiring chronic hemodialysis. There were 17 men and 2 women (mean age of 45 +/- 11 years). The mean creatinine clearance for the study group decreased by 38% (Ptransplant) by 6 months after transplantation and by 48% by 3 years postoperatively (Ptransplant). The mean serum creatinine rose by 80% (Ptransplant) by 6 months after transplantation and by 125% by 3 years postoperatively (Ptransplant). Time elapsed from transplantation to hemodialysis ranged from 3.7 to 9.5 years (mean 6.4 +/- 2). Actuarial 1- year survival after onset of hemodialysis was 75%. Although cyclosporine remains the central immunosuppressive agent for cardiac allograft recipients, its use leads to a greater than one-third decrease in creatinine clearance by 6 months after transplantation and progression to end-stage renal failure, requiring hemodialysis in 6.5% of cardiac transplant recipients. Moreover, these patients are at increased risk of death compared with other cardiac allograft recipients. This data warrants the search of alternative or adjunctive agents that would allow decreased dosing or reduced nephrotoxicity of cyclosporine, while maintaining equivalent survival.

  12. Autoimmune Response Confers Decreased Cardiac Function in ...

    African Journals Online (AJOL)

    Conclusion: Valve replacement in patients with rheumatic heart disease (RHD) does not attenuate ... valve replacement. Clinically, two-dimensional echocardiography is widely used as an effective approach to evaluate cardiac function heart function of patients with ... neurologic disorders, renal or liver disease, acute.

  13. Cardiac echinococcosis

    Directory of Open Access Journals (Sweden)

    Ivanović-Krstić Branislava A.

    2002-01-01

    Full Text Available Cardiac hydatid disease is rare. We report on an uncommon hydatid cyst localized in the right ventricular wall, right atrial wall tricuspid valve left atrium and pericard. A 33-year-old woman was treated for cough, fever and chest pain. Cardiac echocardiograpic examination revealed a round tumor (5.8 x 4 cm in the right ventricular free wall and two smaller cysts behind that tumor. There were cysts in right atrial wall and tricuspidal valve as well. Serologic tests for hydatidosis were positive. Computed tomography finding was consistent with diagnosis of hydatid cyst in lungs and right hylar part. Surgical treatment was rejected due to great risk of cardiac perforation. Medical treatment with albendazole was unsuccessful and the patient died due to systemic hydatid involvement of the lungs, liver and central nervous system.

  14. [Cardiac amyloidosis].

    Science.gov (United States)

    Boussabah, Elhem; Zakhama, Lilia; Ksontini, Iméne; Ibn Elhadj, Zied; Boukhris, Besma; Naffeti, Sana; Thameur, Moez; Ben Youssef, Soraya

    2008-09-01

    PREREQUIS: Amyloidosis is a rare infiltrative disease characterized by multiple clinical features. Various organs are involved and the cardiovascular system is a common target of amyloidosis. Cardiac involvement may occur with or without clinical manifestations and is considered as a major prognostic factor. To analyze the clinical features of cardiac involvement, to review actual knowledgement concerning echocardiographic diagnostic and to evaluate recent advances in treatment of the disease. An electronic search of the relevant literature was carried out using Medline and Pubmed. Keys words used for the final search were amyloidosis, cardiopathy and echocardiography. We considered for analysis reviews, studies and articles between 1990 and 2007. Amyloidosis represents 5 to 10% of non ischemic cardiomyoparhies. Cardiac involvement is the first cause of restrictive cardiomyopathy witch must be evoked in front of every inexplained cardiopathy after the age of forty. The amyloid nature of cardiopathy is suggered if some manifestations were associated as a peripheric neuropathy, a carpal tunnel sydrome and proteinuria > 3g/day. Echocardiography shows dilated atria, a granular sparkling appearance of myocardium, diastolic dysfunction and thickened left ventricle contrasting with a low electric voltage. The proof of amyloidosis is brought by an extra-cardiac biopsy, the indications of endomyocardial biopsy are very limited. The identification of the amyloid nature of cardiopathy has an direct therapeutic implication: it indicates the use of digitalis, calcium channel blockers and beta-blockers. Today the treatment of amyloidosis remains very unsatisfactory especially in the cardiac involvement. An early diagnosis before the cardiac damage may facilitate therapy and improve prognosis.

  15. Inhaled nitric oxide improves lung allograft function after prolonged storage.

    Science.gov (United States)

    Okabayashi, K; Triantafillou, A N; Yamashita, M; Aoe, M; DeMeester, S R; Cooper, J D; Patterson, G A

    1996-08-01

    Morbidity caused by early allograft dysfunction, manifested by a progressive increase in pulmonary vascular resistance and a decrease in oxygenation, remains a serious problem in lung transplantation. Inhalation of nitric oxide, an essential homeostatic molecule, has been shown to have beneficial effects on a variety of acute lung injuries. The purpose of the present study was to investigate the effect of inhaled nitric oxide on posttransplant function of canine left lung allografts. Fourteen dogs underwent left lung allotransplantation. Donors received systemic heparin and prostaglandin E1 followed by pulmonary artery flush with modified Euro-Collins solution. Donor left lungs were stored for 18 hours at 1 degree C and subsequently implanted. Immediately after reperfusion, the contralateral right main pulmonary artery and bronchus were ligated. The chest was closed and recipients turned to the supine position for the 6-hour assessment period. Hemodynamic and arterial and venous blood gas analyses were made at 15-minute intervals at an inspired oxygen fraction of 1.0 and 5 cm of water positive end-expiratory pressure. Animals were killed at the end of the assessment. Allograft myeloperoxidase activity assays and wet/dry weight ratios were done. In group I (n = 5), nitric oxide gas was administered continuously at concentrations of 60 to 70 ppm before reperfusion and throughout the 6-hour assessment period. In group II (n = 5), nitric oxide administration was initiated at the same concentration after reperfusion injury had developed. Group III animals (n = 4) received no nitric oxide. Significant improvement in gas exchange was apparent in group I. At the end of the 6-hour assessment period, mean arterial oxygen tension was 253.8 +/- 44.7 mm Hg and 114.9 +/- 25.5 mm Hg in groups I and III, respectively (p < 0.05). Group II animals had no improvement in oxygenation with nitric oxide. Systemic hemodynamics were unaffected by nitric oxide. However, an immediate

  16. The beginning of clinical tolerance in solid organ allografts.

    Science.gov (United States)

    Monaco, Anthony P

    2004-06-01

    Development of effective multidrug immunosuppressive regimens and improvements in the management of chronically immunosuppressed patients have produced extraordinary patient and allograft survival in clinical organ transplantation. Unfortunately, significant problems of morbidity and mortality related to chronic immunosuppression remain. Thus, there is an enormous motivation and interest in inducing specific unresponsiveness (tolerance) to clinical solid organ allografts. Operational clinical tolerance may be defined as stable, normal graft function in the total absence of a requirement for maintenance immunosuppression. Alternatively, the concept of employing tolerogenic strategies to permit graft acceptance with dramatically reduced immunosuppression requirements is referred to as prope' or minimal immunosuppression tolerance. There have been isolated examples of clinical tolerance, usually in the context of spontaneous or induced donor chimerism, excellent HLA matching, and/or drug weaning or patient noncompliance. The various attempts that are currently being employed to induce some type of clinical tolerance are reviewed in this manuscript. Strategies in which all immunosuppression was to be withdrawn from the recipient (donor-specific unresponsiveness) are first discussed. These include strategies that utilize initial immunoablation with varying doses of irradiation and/or lymphocytic antibodies with or without donor-specific bone marrow infusion and short-term standard immunosuppressive therapy. Strategies to induce prope' or minimal immunosuppression tolerance that utilize induction lymphoablation with polyclonal or monoclonal antilymphocyte antibodies, with or without donor bone marrow infusion, followed by limited low-dose immunosuppressive therapy are also discussed. The ethical considerations in testing clinical tolerance strategies and protocols are discussed in detail. The limited number of clinical tolerance studies already available affirms that

  17. Frequency and characteristics of coronary thrombosis in the epicardial coronary arteries after cardiac transplantation.

    Science.gov (United States)

    Arbustini, E; Dal Bello, B; Morbini, P; Grasso, M; Diegoli, M; Fasani, R; Pilotto, A; Bellini, O; Pellegrini, C; Martinelli, L; Campagna, C; Gavazzi, A; Specchia, G; Viganò, M; Roberts, W C

    1996-10-01

    We investigated at autopsy or at retransplantation the frequency and characteristics of coronary thrombosis in 76 cardiac allografts: 37 in place for 2 to 99 months (late). The 76 allografts were inserted in 69 patients: a single 1 in 56 patients and 2 allografts in 13 patients, 7 of whom subsequently died and had an autopsy. An average of 140 sections from 70 5-mm-long segments of 8 epicardial coronary arteries were examined from each of the 76 allografts with both hematoxylin-eosin and Movat pentachrome stains. Thrombus was found in only 1 coronary artery (3%) (the right one) of the 37 early allografts, and in 24 of 39 late allografts (61%). Of the latter 39 grafts, 29 (79%) had allograft vascular disease (AVD) and 24 (83%) of them had coronary thrombosis. Of the 312 epicardial coronary arteries (4 major and 4 minor) examined in the 39 late cases, 66 arteries (21%) contained thrombus. Of the 24 late cases with thrombus in at least 1 artery, thrombus was present in 66 (34%) of the 192 epicardial coronary arteries examined: in 6 of the 8 arteries in 3 patients; in 5 arteries in 2 patients; in 4 arteries in 1 patient; in 3 arteries in 5 patients; in 2 arteries in 6 patients, and in a single artery in 7 patients. In all 66 arteries with thrombus (24 patients) the thrombus was longer than 5 mm. The thrombus in the late cases was entirely nonocclusive (mural) in 51 (77%) of the 66 epicardial coronary arteries containing thrombus and entirely occlusive in 10 arteries (15%). It consisted exclusively of multiluminal channels in 6 arteries (9%) and combinations in 1 artery (2%). Acute myocardial infarcts were present in 3 patients, all of whom had occlusive thrombi. In all 10 arteries with occlusive thrombi, the thrombus was larger than the underlying plaque and no occlusive thrombi were located over ulcerated plaques. These observations demonstrate that thrombus is common in epicardial coronary arteries >2 months after cardiac transplantation.

  18. Amniotic membrane allografts: development and clinical utility in ophthalmology

    Directory of Open Access Journals (Sweden)

    Rizzuti A

    2014-12-01

    Full Text Available Allison Rizzuti,1,2 Adam Goldenberg,1 Douglas R Lazzaro1,2 1SUNY Downstate Medical Center, 2Kings County Hospital Center, Brooklyn, NY, USA Abstract: Amniotic membrane, the innermost layer of the placenta, is a tissue that promotes epithelialization, while decreasing inflammation, neovascularization, and scarring. It is used in the surgical management of a wide variety of ophthalmic conditions where it functions as a graft or patch in ocular surface reconstruction. The development of new preservation techniques, as well as a sutureless amniotic membrane, has allowed for easier, in-office placement, without the disadvantages of an operating room procedure. The purpose of this review is to describe the historical development of amniotic membrane in ophthalmology and to describe its current clinical applications, particularly focusing on recent advances. Keywords: ocular surface, cornea, stem cells, prokera, allograft, patch, transplantation

  19. The outcomes of simultaneous liver and kidney transplantation using donation after cardiac death organs.

    Science.gov (United States)

    Alhamad, Tarek; Spatz, Christin; Uemura, Tadahiro; Lehman, Eric; Farooq, Umar

    2014-12-15

    There has been a remarkable increase in simultaneous liver and kidney transplantations (SLK). As organ demand has increased, so has the use of donation after cardiac death (DCD). However, little is known about the outcomes of DCD in SLK. We performed a retrospective analysis using the United Network for Organ Sharing database to compare the outcomes of DCD SLK to donation after brain death (DBD) and determine the impact of donor and recipient factors on allograft and patient survival. Between 2002 and 2011, a total of 3,026 subjects received SLK from DBD and 98 from DCD. Kidney, liver, and patient survival from DCD donors were inferior to DBD at 1, 3, and 5 years (P=0.0056, P=0.0035, and P=0.0205, respectively). With the use of the Cox model, DCD was a significant risk factor for kidney and liver allograft failure and patient mortality. Recipient factors that were associated with worse allograft and patient outcomes included black race, diabetes, being on a ventilator, hospitalization, delayed graft function, hepatocellular carcinoma, and intensive care unit stay. Older age of the donor was also associated with worse outcomes. Despite the decreased allograft and patient survival compared with DBD, DCD SLK provides an acceptable option for SLK, with a survival probability of more than 50% at 5 years.

  20. Ultrasound molecular imaging of acute cardiac transplantation rejection using nanobubbles targeted to T lymphocytes.

    Science.gov (United States)

    Liu, Jinfeng; Chen, Yihan; Wang, Guohua; Lv, Qing; Yang, Yali; Wang, Jing; Zhang, Pingyu; Liu, Jie; Xie, Yu; Zhang, Li; Xie, Mingxing

    2018-02-08

    Clinical surveillance of acute heart transplantation rejection requires repeated invasive endomyocardial biopsies and noninvasive diagnostic techniques are desperately needed. It is acknowledged that T lymphocyte infiltration is the central process of acute rejection. We hypothesized that ultrasound molecular imaging with T lymphocyte-targeted nanobubbles could be used to detect acute rejection in heart transplantation. In this study, nanobubbles bearing anti-CD3 antibody (NB CD3 ) or isotype antibody (NB con ) were prepared and characterized. There was significant adhesion of NB CD3 to T lymphocytes compared with NB con in vitro. The signal intensity of the adherent NB CD3 was significantly higher than that of the NB con in allograft rats, but not significantly different in isograft rats. Furthermore, the signal intensity of NB CD3 in allograft rats was significantly higher than that in isograft rats, indicating more T lymphocyte infiltration in allograft rats compared with isograft rats. These results were further confirmed by immunohistochemistry examination, and the signal intensity of NB CD3 was positively correlated with the number of T lymphocytes in allograft rats. In summary, ultrasound molecular imaging with T lymphocyte-targeted nanobubbles can detect T lymphocyte infiltration in acute rejection and could be used as a noninvasive method in acute rejection detection after cardiac transplantation. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Cardiac transplant experience with cyclosporine.

    Science.gov (United States)

    Patel, J K; Kobashigawa, J A

    2004-03-01

    The advent of cyclosporine 20 years ago was a major advance in the field of solid organ transplantation. Its use enabled directed immunosuppression with a consequent decrease in the incidence of graft failure, acute rejection, and systemic infection. The early oil-based preparation, however, was difficult to administer and had limited bioavailability and unpredictable pharmacokinetics. The drug also has a fairly narrow therapeutic window with major long-term side effects, which include nephrotoxicity, malignancy, hyperlipidemia, and hypertension. The introduction of a microemulsion preparation (Neoral) with improved bioavailability has been associated with lower rates of rejection and comparable tolerability, therefore allowing the use of lower doses. Traditionally cyclosporine toxicity has been minimized by monitoring trough levels. Monitoring of levels 2 hours after dosing may provide a more accurate determination of cyclosporine exposure. The next phase in cardiac transplantation immunosuppression will most likely see a significantly diminished role for cyclosporine with the introduction of newer, more potent immunosuppressive agents with more favorable side-effect profiles. These agents, which include mycophenolate mofetil, sirolimus, and everolimus, also hold the promise of having a major impact on the development of transplant vasculopathy, which up to now has been an important determinant of limiting long-term allograft survival.

  2. Optimising femoral-head osteochondral allograft transplantation in a preclinical model

    Directory of Open Access Journals (Sweden)

    Brett D. Crist

    2016-04-01

    Conclusion: These data provide initial translational and clinical evidence for large osteochondral allografts as a potential option for functional resurfacing of full-thickness cartilage defects of the femoral head.

  3. The Relationship of Anti-MICA Antibodies and MICA Expression with Heart Allograft Rejection

    National Research Council Canada - National Science Library

    Suarez-Alvarez, B; Lopez-Vazquez, A; Gonzalez, M. Zapico; Fdez-Morera, J. L; Diaz-Molina, B; Blanco-Gelaz, M. A; Pascual, D; Martinez-Borra, J; Muro, M; Alvarez-Lopez, M. R; Lopez-Larrea, C

    2007-01-01

    The role of MICA antibodies in acute heart allograft rejection was examined utilizing 190 pre- and post-transplant serum samples from 44 patients collected during the first year after transplantation...

  4. Identification of β2-microglobulin as a urinary biomarker for chronic allograft nephropathy using proteomic methods.

    LENUS (Irish Health Repository)

    Johnston, Olwyn

    2011-08-01

    Chronic allograft nephropathy (CAN) remains the leading cause of renal graft loss after the first year following renal transplantation. This study aimed to identify novel urinary proteomic profiles, which could distinguish and predict CAN in susceptible individuals.

  5. Combined Massive Allograft and Intramedullary Vascularized Fibula Transfer: The Capanna Technique for Lower-Limb Reconstruction

    National Research Council Canada - National Science Library

    Bakri, Karim; Stans, Anthony; Mardini, Samir; Moran, Steven

    2008-01-01

    .... Recently, a novel approach to limb salvage has been described by Capanna and colleagues whereby a massive bone allograft and intramedullary vascularized fibula are combined to reconstruct large, segmental bone defects...

  6. Chemokines in Chronic Liver Allograft Dysfunction Pathogenesis and Potential Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Bin Liu

    2013-01-01

    Full Text Available Despite advances in immunosuppressive drugs, long-term success of liver transplantation is still limited by the development of chronic liver allograft dysfunction. Although the exact pathogenesis of chronic liver allograft dysfunction remains to be established, there is strong evidence that chemokines are involved in organ damage induced by inflammatory and immune responses after liver surgery. Chemokines are a group of low-molecular-weight molecules whose function includes angiogenesis, haematopoiesis, mitogenesis, organ fibrogenesis, tumour growth and metastasis, and participating in the development of the immune system and in inflammatory and immune responses. The purpose of this review is to collect all the research that has been done so far concerning chemokines and the pathogenesis of chronic liver allograft dysfunction and helpfully, to pave the way for designing therapeutic strategies and pharmaceutical agents to ameliorate chronic allograft dysfunction after liver transplantation.

  7. Banff 07 Classification of Renal Allograft Pathology: Updates and Future Directions

    National Research Council Canada - National Science Library

    Solez, K; Colvin, R. B; Racusen, L. C; Haas, M; Sis, B; Mengel, M; Halloran, P. F; Baldwin, W; Banfi, G; Collins, A. B; Cosio, F; David, D. S. R; Drachenberg, C; Einecke, G; Fogo, A. B; Gibson, I. W; Glotz, D; Iskandar, S. S; Kraus, E; Lerut, E; Mannon, R. B; Mihatsch, M; Nankivell, B. J; Nickeleit, V; Papadimitriou, J. C; Randhawa, P; Regele, H; Renaudin, K; Roberts, I; Seron, D; Smith, R. N; Valente, M

    2008-01-01

    .... A total of 235 pathologists, clinicians and scientists met to address unsolved issues in transplantation and adapt the Banff schema for renal allograft rejection in response to emerging data and technologies...

  8. Targeted inhibition of renal Rho kinase reduces macrophage infiltration and lymphangiogenesis in acute renal allograft rejection

    NARCIS (Netherlands)

    Poosti, Fariba; Yazdani, Saleh; Dolman, M. Emmy M.; Kok, Robbert Jan; Chen, Cheng; Ding, Guohua; Lacombe, Marie; Prakash, Jai; van den Born, Jacob; Hillebrands, Jan-Luuk; van Goor, Harry; de Borst, Martin H.

    2012-01-01

    The Rho kinase pathway plays an important role in epithelial dedifferentiation and inflammatory cell infiltration. Recent studies suggest that inflammation promotes lymphangiogenesis, which has been associated with renal allograft rejection. We investigated whether targeted inhibition of the Rho

  9. Eyelid reconstruction with acellular human dermal allograft after chemical and thermal burns.

    Science.gov (United States)

    Jiaqi, Chen; Zheng, Wang; Jianjun, Gu

    2006-03-01

    To evaluate the efficacy of eyelid reconstruction with acellular dermal allograft in patients with eyelid defect after chemical and thermal burns. Eyelid reconstruction was performed in 15 eyelids of 13 patients during the period of June 2001-October 2004 by a single senior surgeon (Chen). Among them five patients had thermal burns, and eight patients had chemical burns. The acellular dermal allograft was used as a tarsus substitute that was sutured into the place between the levator aponeurosis in upper lid or retractor in lower eyelid and the remaining tarsus. After a mean follow-up of 9 months, satisfactory function and cosmesis were obtained. No implant rejection or severe complications were observed. Acellular dermal allograft may be used safely as a posterior lamellar spacer graft after chemical and thermal burns; the allograft appears to be biocompatible and does not aggravate the inflammation in the injured eyelid.

  10. Effects of cryopreservation on the immunogenicity of porcine arterial allografts in early stages of transplant vasculopathy.

    Science.gov (United States)

    Solanes, Núria; Rigol, Montserrat; Khabiri, Ebrahim; Castellà, Manuel; Ramírez, José; Roqué, Mercè; Agustí, Elba; Roig, Eulàlia; Pérez-Villa, Fèlix; Segalés, Joaquim; Pomar, José Luís; Engel, Pablo; Massaguer, Anna; Martorell, Jaume; Rodríguez, Jose Antonio; Sanz, Ginés; Heras, Magda

    2005-10-01

    The number of revascularization procedures including coronary and lower extremity bypass, have increased greatly in the last decade. It suggests a growing need for vascular grafts. Cryopreserved allografts could represent a viable alternative but their immunologic reactivity remains controversial. 71 pigs (40 recipients and 31 donors) were used. Two femoral grafts per recipient animal were implanted for 3, 7, and 30 days. Types of grafts: fresh autograft as a control graft (n=19), fresh allograft (n=31) and cryopreserved allograft (n=30). Histological and immunohistochemical studies were performed. Fresh allografts compared to autografts showed intimal inflammatory infiltration at 3 days (328 vs. 0 macrophages/mm2; P<0.05) and 7 days (962 vs. 139 T lymphocytes/mm2; P<0.05) post-transplantation. At 30 days, there was a loss of endothelial cells, presence of luminal thrombus and aneurismal lesions (total area=15.8 vs. 8.4 mm2; P<0.05). Cryopreservation did not reduce these lesions nor modify endothelial nitric oxide synthase (eNOS) expression nor modify the number of animals that developed anti-SLA antibodies. Moreover, at 7 days, cryopreserved allografts compared to fresh allografts showed a higher expression of P-selectin (5 out of 5 vs. 1 out of 5; P<0.05) and, at 30 days, a greater inflammatory reactivity (2692 vs. 1107 T lymphocytes/mm2 in media; P<0.05) with a trend towards a higher presence of multinucleated giant cells than in the fresh ones. The cryopreservation method used maintained immunogenicity of allografts and increased the inflammatory reactivity found in fresh allografts up to 30 days of vascular transplantation.

  11. The effect of medial meniscectomy and meniscal allograft transplantation on knee and anterior cruciate ligament biomechanics.

    Science.gov (United States)

    Spang, Jeffrey T; Dang, Alan B C; Mazzocca, Augustus; Rincon, Lina; Obopilwe, Elifho; Beynnon, Bruce; Arciero, Robert A

    2010-02-01

    Our purpose was to evaluate the effect of meniscectomy and meniscal allograft transplant on anterior cruciate ligament (ACL) and knee biomechanics. A differential variable reluctance transducer was placed in the ACL of 10 human cadaveric knees to record strain. Tibial displacement from a neutral reference was recorded relative to the position of the femur. Testing was performed at 30 degrees, 60 degrees, and 90 degrees of knee flexion. Six cycles of anterior-posterior loads were applied to the limit of 150 N. After a testing cycle, a medial meniscectomy was performed and the testing cycle was repeated. A meniscal allograft transplant was performed, and a final testing cycle was conducted. ACL strain and tibial displacement in the meniscectomy and meniscal allograft states were compared with the intact-knee state. Tibial displacement after meniscectomy significantly increased at all angles. The meniscal allograft transplant restored tibial displacement to normal values at 30 degrees and 90 degrees. ACL strain increased significantly after meniscectomy at 60 degrees and 90 degrees of flexion, and meniscal allograft transplant returned the strain values to normal at 60 degrees and 90 degrees. In most cases medial meniscectomy produced a significant increase in tibial displacement relative to the femur, and meniscal allograft transplantation restored displacement values to normal. Meniscectomy increased ACL strain and meniscal allograft transplant restored strain values to normal in 2 of 3 tested flexion angles. The absence of the medial meniscus exposes the ACL to increased strain, whereas meniscal allograft lowered the strain on the native ACL. This could have implications for those patients undergoing ACL reconstruction who have concomitant removal of the medial meniscus. (c) 2010 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

  12. High-Throughput Proteomic Approaches to the Elucidation of Potential Biomarkers of Chronic Allograft Injury (CAI

    Directory of Open Access Journals (Sweden)

    Hilary Cassidy

    2013-09-01

    Full Text Available This review focuses on the role of OMICs technologies, concentrating in particular on proteomics, in biomarker discovery in chronic allograft injury (CAI. CAI is the second most prevalent cause of allograft dysfunction and loss in the first decade post-transplantation, after death with functioning graft (DWFG. The term CAI, sometimes referred to as chronic allograft nephropathy (CAN, describes the deterioration of renal allograft function and structure as a result of immunological processes (chronic antibody-mediated rejection, and other non-immunological factors such as calcineurin inhibitor (CNI induced nephrotoxicity, hypertension and infection. Current methods for assessing allograft function are costly, insensitive and invasive; traditional kidney function measurements such as serum creatinine and glomerular filtration rate (GFR display poor predictive abilities, while the current “gold-standard” involving histological diagnosis with a renal biopsy presents its own inherent risks to the overall health of the allograft. As early as two years post-transplantation, protocol biopsies have shown more than 50% of allograft recipients have mild CAN; ten years post-transplantation more than 50% of the allograft recipients have progressed to severe CAN which is associated with diminishing graft function. Thus, there is a growing medical requirement for minimally invasive biomarkers capable of identifying the early stages of the disease which would allow for timely intervention. Proteomics involves the study of the expression, localization, function and interaction of the proteome. Proteomic technologies may be powerful tools used to identify novel biomarkers which would predict CAI in susceptible individuals. In this paper we will review the use of proteomics in the elucidation of novel predictive biomarkers of CAI in clinical, animal and in vitro studies.

  13. Respiratory metapneumoviral infection without co-infection in association with acute and chronic lung allograft dysfunction

    Directory of Open Access Journals (Sweden)

    Dosanjh A

    2015-03-01

    Full Text Available Amrita DosanjhDepartment of Pediatrics, Rady Children’s Hospital, San Diego, CA, USABackground: Metapneumoviral respiratory infection is a community-acquired respiratory viral (CARV infection. Lung transplantation recipients exposed to CARV are at risk for development of allograft rejection. The cellular and molecular pathways initiated by viral infection leading to allograft dysfunction are not completely understood. The aim of this study was to identify human metapneumoviral (hMPV cases in association with allograft rejection.Methods: A literature search was conducted to identify cases of both hMPV and allograft rejection within 6 months of the initial infection. This resulted in 1,007 lung transplantation recipients, with a total of 2,883 samples identified. Of these, 57 demonstrated isolated hMPV without co-infection with other agents.Results: The results of the study indicate that 35% of acute hMPV infections without co-infection, at the time of detection by molecular diagnostic platforms, were associated with acute cellular rejection within 3 months. There were 9.4% of the cases subsequently associated with chronic allograft dysfunction/bronchiolitis obliterans syndrome, which was collectively termed chronic rejection for purposes of analysis. In conclusion, the prompt identification of isolated hMPV from lung transplantation patients is an important treatable risk factor for subsequent allograft dysfunction. The cellular and molecular pathogenesis of viral-induced allograft rejection remains a topic of future study.Keywords: viral infection, bronchiolitis obliterans, acute cellular rejection, allograft, lung, metapneumovirus

  14. Age-related changes in CT attenuation of the thymus in children

    Energy Technology Data Exchange (ETDEWEB)

    Sklair-Levy, M.; Agid, R.; Sella, T.; Strauss-Liviatan, N.; Bar-Ziv, J. [Department of Radiology, Hadassah University Hospital, Jerusalem (Israel)

    2000-08-01

    Background. The CT appearance of the normal and abnormal thymus and its age-related changes have been described. However, there is no information regarding the change in thymus CT attenuation values in children. Objective. The aim of the present study was to evaluate the normal CT attenuation of the thymus in infants and children and discover when the decline begins. Materials and methods. CT attenuation values of the thymus were retrospectively evaluated in 152 children between ages of 1 day and up to 14 years. For each patient the mean value of the CT thymus attenuation was calculated and compared to CT attenuation of the chest wall and cardiac muscles. We also examined the correlation between thymic attenuation, gender, and disease. The statistical analysis used was multivariate linear regression. Results. CT attenuation of the thymus declines with age, beginning only after the 1st year of life. The thymus is more hyperdense than the chest wall and cardiac muscles in infants less than 1 year. The thymus is denser in males than females. In malignant conditions, in infants less than 1 year, thymus CT attenuation is decreased. In older children thymus attenuation was similar to that for the chest wall and cardiac muscles. Conclusion. The decline in thymic CT attenuation with age is consistent with fatty infiltration of the gland. The measurements given in this report can serve as a basis for comparison to determine whether the thymus of a young child is normal or pathological. (orig.)

  15. Nanoparticle Enhanced MRI Scanning to Detect Cellular Inflammation in Experimental Chronic Renal Allograft Rejection

    Directory of Open Access Journals (Sweden)

    S. R. Alam

    2015-01-01

    Full Text Available Objectives. We investigated whether ultrasmall paramagnetic particles of iron oxide- (USPIO- enhanced magnetic resonance imaging (MRI can detect experimental chronic allograft damage in a murine renal allograft model. Materials and Methods. Two cohorts of mice underwent renal transplantation with either a syngeneic isograft or allograft kidney. MRI scanning was performed prior to and 48 hours after USPIO infusion using T2∗-weighted protocols. R2∗ values were calculated to indicate the degree of USPIO uptake. Native kidneys and skeletal muscle were imaged as reference tissues and renal explants analysed by histology and electron microscopy. Results. R2∗ values in the allograft group were higher compared to the isograft group when indexed to native kidney (median 1.24 (interquartile range: 1.12 to 1.36 versus 0.96 (0.92 to 1.04, P<0.01. R2∗ values were also higher in the allograft transplant when indexed to skeletal muscle (6.24 (5.63 to 13.51 compared to native kidney (2.91 (1.11 to 6.46 P<0.05. Increased R2∗ signal in kidney allograft was associated with macrophage and iron staining on histology. USPIO were identified within tissue resident macrophages on electron microscopy. Conclusion. USPIO-enhanced MRI identifies macrophage.

  16. Lyophilized allografts without pre-treatment with glutaraldehyde are more suitable than cryopreserved allografts for pulmonary artery reconstruction

    Directory of Open Access Journals (Sweden)

    J.R. Olmos-Zúãiga

    2016-01-01

    Full Text Available Various methods are available for preservation of vascular grafts for pulmonary artery (PA replacement. Lyophilization and cryopreservation reduce antigenicity and prevent thrombosis and calcification in vascular grafts, so both methods can be used to obtain vascular bioprostheses. We evaluated the hemodynamic, gasometric, imaging, and macroscopic and microscopic findings produced by PA reconstruction with lyophilized (LyoPA grafts and cryopreserved (CryoPA grafts in dogs. Eighteen healthy crossbred adult dogs of both sexes weighing between 18 and 20 kg were used and divided into three groups of six: group I, PA section and reanastomosis; group II, PA resection and reconstruction with LyoPA allograft; group III, PA resection and reconstruction with CryoPA allograft. Dogs were evaluated 4 weeks after surgery, and the status of the graft and vascular anastomosis were examined macroscopically and microscopically. No clinical, radiologic, or blood-gas abnormalities were observed during the study. The mean pulmonary artery pressure (MPAP in group III increased significantly at the end of the study compared with baseline (P=0.02 and final [P=0.007, two-way repeat-measures analysis of variance (RM ANOVA] values. Pulmonary vascular resistance of groups II and III increased immediately after reperfusion and also at the end of the study compared to baseline. The increase shown by group III vs group I was significant only if compared with after surgery and study end (P=0.016 and P=0.005, respectively, two-way RM ANOVA. Microscopically, permeability was reduced by ≤75% in group III. In conclusion, substitution of PAs with LyoPA grafts is technically feasible and clinically promising.

  17. Lyophilized allografts without pre-treatment with glutaraldehyde are more suitable than cryopreserved allografts for pulmonary artery reconstruction

    Energy Technology Data Exchange (ETDEWEB)

    Olmos-Zúãiga, J.R.; Jasso-Victoria, R. [Department of Experimental Surgery, National Institute of Respiratory Diseases ' Ismael Cosío Villegas' , Mexico City (Mexico); Díaz-Martínez, N.E. [Medical and Pharmaceutical Biotechnology, Center for Research and Assistance in Technology and Design of the State of Jalisco, Guadalajara, Jalisco (Mexico); Gaxiola-Gaxiola, M.O. [Laboratory of Morphology, National Institute of Respiratory Diseases ' Ismael Cosío Villegas' , Mexico City (Mexico); Sotres-Vega, A.; Heras-Romero, Y.; Baltazares-Lipp, M. [Department of Experimental Surgery, National Institute of Respiratory Diseases ' Ismael Cosío Villegas' , Mexico City (Mexico); Baltazares-Lipp, M.E. [Hemodynamics and Echocardiography Service, National Institute of Respiratory Diseases ' Ismael Cosío Villegas' , Mexico City (Mexico); Santillán-Doherty, P. [Medical Administration, National Institute of Respiratory Diseases ' Ismael Cosío Villegas' , Mexico City (Mexico); Hernández-Jiménez, C. [Department of Experimental Surgery, National Institute of Respiratory Diseases ' Ismael Cosío Villegas' , Mexico City (Mexico)

    2015-12-04

    Various methods are available for preservation of vascular grafts for pulmonary artery (PA) replacement. Lyophilization and cryopreservation reduce antigenicity and prevent thrombosis and calcification in vascular grafts, so both methods can be used to obtain vascular bioprostheses. We evaluated the hemodynamic, gasometric, imaging, and macroscopic and microscopic findings produced by PA reconstruction with lyophilized (LyoPA) grafts and cryopreserved (CryoPA) grafts in dogs. Eighteen healthy crossbred adult dogs of both sexes weighing between 18 and 20 kg were used and divided into three groups of six: group I, PA section and reanastomosis; group II, PA resection and reconstruction with LyoPA allograft; group III, PA resection and reconstruction with CryoPA allograft. Dogs were evaluated 4 weeks after surgery, and the status of the graft and vascular anastomosis were examined macroscopically and microscopically. No clinical, radiologic, or blood-gas abnormalities were observed during the study. The mean pulmonary artery pressure (MPAP) in group III increased significantly at the end of the study compared with baseline (P=0.02) and final [P=0.007, two-way repeat-measures analysis of variance (RM ANOVA)] values. Pulmonary vascular resistance of groups II and III increased immediately after reperfusion and also at the end of the study compared to baseline. The increase shown by group III vs group I was significant only if compared with after surgery and study end (P=0.016 and P=0.005, respectively, two-way RM ANOVA). Microscopically, permeability was reduced by ≤75% in group III. In conclusion, substitution of PAs with LyoPA grafts is technically feasible and clinically promising.

  18. Inhibition of chemokine-glycosaminoglycan interactions in donor tissue reduces mouse allograft vasculopathy and transplant rejection.

    Directory of Open Access Journals (Sweden)

    Erbin Dai

    2010-05-01

    Full Text Available Binding of chemokines to glycosaminoglycans (GAGs is classically described as initiating inflammatory cell migration and creating tissue chemokine gradients that direct local leukocyte chemotaxis into damaged or transplanted tissues. While chemokine-receptor binding has been extensively studied during allograft transplantation, effects of glycosaminoglycan (GAG interactions with chemokines on transplant longevity are less well known. Here we examine the impact of interrupting chemokine-GAG interactions and chemokine-receptor interactions, both locally and systemically, on vascular disease in allografts.Analysis of GAG or CC chemokine receptor 2 (CCR2 deficiency were coupled with the infusion of viral chemokine modulating proteins (CMPs in mouse aortic allograft transplants (n = 239 mice. Inflammatory cell invasion and neointimal hyperplasia were significantly reduced in N-deacetylase-N-sulfotransferase-1 (Ndst1(f/fTekCre(+ heparan sulfate (GAG-deficient (Ndst1(-/-, p<0.044 and CCR2-deficient (Ccr2(-/-, p<0.04 donor transplants. Donor tissue GAG or CCR2 deficiency markedly reduced inflammation and vasculopathy, whereas recipient deficiencies did not. Treatment with three CMPs was also investigated; Poxviral M-T1 blocks CC chemokine receptor binding, M-T7 blocks C, CC, and CXC GAG binding, and herpesviral M3 binds receptor and GAG binding for all classes. M-T7 reduced intimal hyperplasia in wild type (WT (Ccr2(+/+, p< or =0.003 and Ccr2(-/-, pallografts, but not in Ndst1(-/- aortic allografts (p = 0.933. M-T1 and M3 inhibited WT (Ccr2(+/+ and Ndst1(+/+, p< or =0.006 allograft vasculopathy, but did not block vasculopathy in Ccr2(-/- (p = 0.61. M-T7 treatment alone, even without immunosuppressive drugs, also significantly prolonged survival of renal allograft transplants (p< or =0.001.Interruption of chemokine-GAG interactions, even in the absence of chemokine-receptor blockade, is a highly effective approach to reduction of

  19. Comparative study and histomorphometric analysis of bone allografts lyophilized and sterilized by autoclaving, gamma irradiation and ethylene oxide in rats.

    Science.gov (United States)

    Almeida, Otavio Machado de; Jorgetti, Wanda; Oksman, Denis; Jorgetti, Camilo; Rocha, Diógenes Laércio; Gemperli, Rolf

    2013-01-01

    To compare three sterilization methods (autoclave, gamma irradiation and ethylene oxide) over non demineralized lyophilized bone allografts. Bone allografts were implanted on paravertebral muscles of 21 rats. After 30 days animals were sacrificed and grafts underwent comparative analysis regarding histomorphometric and macroscopic parameters. Allografts that underwent the three sterilization methods presents similar weight gain, cortical thickness similar to control group, and less fibrosis than the control group. Grafts that underwent sterilization in autoclave presented less presence of multinucleated giant cells, although not statistically significant. There was also no statistically significant difference regarding mineralization on the three groups. The three sterilization methods cause similar effects on bone allografts regarding macroscopic and histomorphometric parameters.

  20. Cost-utility of osteoarticular allograft versus endoprosthetic reconstruction for primary bone sarcoma of the knee: A markov analysis.

    Science.gov (United States)

    Wilson, Robert J; Sulieman, Lina M; VanHouten, Jacob P; Halpern, Jennifer L; Schwartz, Herbert S; Devin, Clinton J; Holt, Ginger E

    2017-03-01

    The most cost-effective reconstruction after resection of bone sarcoma is unknown. The goal of this study was to compare the cost effectiveness of osteoarticular allograft to endoprosthetic reconstruction of the proximal tibia or distal femur. A Markov model was used. Revision and complication rates were taken from existing studies. Costs were based on Medicare reimbursement rates and implant prices. Health-state utilities were derived from the Health Utilities Index 3 survey with additional assumptions. Incremental cost-effectiveness ratios (ICER) were used with less than $100 000 per quality-adjusted life year (QALY) considered cost-effective. Sensitivity analyses were performed for comparison over a range of costs, utilities, complication rates, and revisions rates. Osteoarticular allografts, and a 30% price-discounted endoprosthesis were cost-effective with ICERs of $92.59 and $6 114.77. One-way sensitivity analysis revealed discounted endoprostheses were favored if allografts cost over $21 900 or endoprostheses cost less than $51 900. Allograft reconstruction was favored over discounted endoprosthetic reconstruction if the allograft complication rate was less than 1.3%. Allografts were more cost-effective than full-price endoprostheses. Osteoarticular allografts and price-discounted endoprosthetic reconstructions are cost-effective. Sensitivity analysis, using plausible complication and revision rates, favored the use of discounted endoprostheses over allografts. Allografts are more cost-effective than full-price endoprostheses. © 2017 Wiley Periodicals, Inc.

  1. Importance of Donor Chondrocyte Viability for Osteochondral Allografts.

    Science.gov (United States)

    Cook, James L; Stannard, James P; Stoker, Aaron M; Bozynski, Chantelle C; Kuroki, Keiichi; Cook, Cristi R; Pfeiffer, Ferris M

    2016-05-01

    Osteochondral allograft (OCA) transplantation provides a biological treatment option for functional restoration of large articular cartilage defects in multiple joints. While successful outcomes after OCA transplantation have been linked to viable donor chondrocytes, the importance of donor cell viability has not been comprehensively validated. To use a canine model to determine the importance of donor chondrocyte viability at the time of implantation with respect to functional success of femoral condylar OCAs based on radiographic, gross, cell viability, histologic, biochemical, and biomechanical outcome measures. Controlled laboratory study. After approval was obtained from the institutional animal care and use committee, adult female dogs (N = 16) were implanted with 8-mm cylindrical OCAs from male dogs in the lateral and medial femoral condyles of 1 knee. OCAs were preserved for 28 or 60 days after procurement, and chondrocyte viability was quantified before implantation. Two different storage media, temperatures, and time points were used to obtain a spectrum of percentage chondrocyte viability at the time of implantation. A successful outcome was defined as an OCA that was associated with graft integration, maintenance of hyaline cartilage, lack of associated cartilage disorder, and lack of fibrillation, fissuring, or fibrous tissue infiltration of the allograft based on subjective radiographic, gross, and histologic assessments at 6 months after implantation. Chondrocyte viability ranged from 23% to 99% at the time of implantation. All successful grafts had >70% chondrocyte viability at the time of implantation, and no graft with chondrocyte viability <70% was associated with a successful outcome. Live-dead stained sections and histologic findings with respect to cell morphological features suggested that successful grafts were consistently composed of viable chondrocytes in lacunae, while grafts that were not successful were composed of nonviable

  2. Toll-like receptor 9 mediated responses in cardiac fibroblasts.

    Directory of Open Access Journals (Sweden)

    Ingrid Kristine Ohm

    Full Text Available Altered cardiac Toll-like receptor 9 (TLR9 signaling is important in several experimental cardiovascular disorders. These studies have predominantly focused on cardiac myocytes or the heart as a whole. Cardiac fibroblasts have recently been attributed increasing significance in mediating inflammatory signaling. However, putative TLR9-signaling through cardiac fibroblasts remains non-investigated. Thus, our aim was to explore TLR9-signaling in cardiac fibroblasts and investigate the consequence of such receptor activity on classical cardiac fibroblast cellular functions. Cultivated murine cardiac fibroblasts were stimulated with different TLR9 agonists (CpG A, B and C and assayed for the secretion of inflammatory cytokines (tumor necrosis factor α [TNFα], CXCL2 and interferon α/β. Expression of functional cardiac fibroblast TLR9 was proven as stimulation with CpG B and -C caused significant CXCL2 and TNFα-release. These responses were TLR9-specific as complete inhibition of receptor-stimulated responses was achieved by co-treatment with a TLR9-antagonist (ODN 2088 or chloroquine diphosphate. TLR9-stimulated responses were also found more potent in cardiac fibroblasts when compared with classical innate immune cells. Stimulation of cardiac fibroblasts TLR9 was also found to attenuate migration and proliferation, but did not influence myofibroblast differentiation in vitro. Finally, results from in vivo TLR9-stimulation with subsequent fractionation of specific cardiac cell-types (cardiac myocytes, CD45+ cells, CD31+ cells and cardiac fibroblast-enriched cell-fractions corroborated our in vitro data and provided evidence of differentiated cell-specific cardiac responses. Thus, we conclude that cardiac fibroblast may constitute a significant TLR9 responder cell within the myocardium and, further, that such receptor activity may impact important cardiac fibroblast cellular functions.

  3. Cardiac-generated prostanoids mediate cardiac myocyte apoptosis after myocardial ischaemia

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    Qiu, Hong; Liu, Jun-Yan; Wei, Dongguang; Li, Ning; Yamoah, Ebenezer N.; Hammock, Bruce D.; Chiamvimonvat, Nipavan

    2012-01-01

    Aims The objective of the present study is to elucidate the pathogenic role of eicosanoids in myocardial infarction (MI). The accumulation of eicosanoid metabolites in ischaemic myocardium has been demonstrated in animal models and patients with MI, and it occurs in parallel with the development of irreversible cardiac damage. However, the key question that remains unanswered is whether cardiac-generated eicosanoids are the cause or the consequence of cardiac cell damage in MI. Methods and results We used a clinically relevant animal model of MI and metabolic profiling to monitor the eicosanoid profile in ischaemic myocardium. We demonstrate that ischaemia induces the generation of prostanoids mainly through the cyclooxygenase (COX)-1 pathway in the myocardium. Cardiac-generated prostanoids, particularly prostaglandin D2 (PGD2), can directly induce apoptosis in cardiac myocytes. This effect involves the up-regulation of the pro-apoptotic gene, Fas ligand (FasL), in a D-type prostanoid receptor-independent manner. The treatment of the MI mice with low-dose aspirin effectively inhibits the ischaemia-induced prostanoid generation and FasL expression in the myocardium, leading to the reduction in cardiac apoptosis following cardiac ischaemia. Conclusions Cardiac ischaemia results in COX-1-mediated generation of prostanoids, which by inducing cardiac myocyte apoptosis, contribute to the cardiac cell loss following MI. The benefits of low-dose aspirin treatment in MI may be attributable, in part, to the inhibition of cardiac prostanoid generation and attenuation of apoptosis. Further understanding of the mechanisms underlying prostanoid-induced cardiac apoptosis may be of significant value in designing new therapeutic strategies to prevent aberrant cell loss following MI and subsequent progression to heart failure. PMID:22707158

  4. Quantifying massive allograft healing of the canine femur in vivo and ex vivo: a pilot study.

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    Santoni, Brandon G; Ehrhart, Nicole; Betancourt-Benitez, Ricardo; Beck, Christopher A; Schwarz, Edward M

    2012-09-01

    Allograft integration in segmental osseous defects is unpredictable. Imaging techniques have not been applied to investigate angiogenesis and bone formation during allograft healing in a large-animal model. We used dynamic contrast-enhanced (DCE)-MRI and cone beam (CB)-CT to quantify vascularity and bone volume in a canine femoral allograft model and determined their relationship with biomechanical testing and histomorphometry. Femoral ostectomy was performed in three dogs and reconstructed with a 5-cm allograft and compression plate. At 0.5, 3, and 6 months, we performed DCE-MRI to quantify vascular permeability (Ktrans) and perfused fraction and CB-CT to quantify bone volume. We also performed posteuthanasia torsional testing and dynamic histomorphometry of the grafted and nonoperated femurs. DCE-MRI confirmed the avascular nature of allograft healing (perfused fraction, 2.08%-3.25%). CB-CT demonstrated new bone formation at 3 months (26.2, 3.7, and 2.2 cm(3)) at the graft-host junctions, which remodeled down at 6 months (14.0, 2.2, and 2.0 cm(3)). The increased bone volume in one subject was confirmed with elevated Ktrans (0.22) at 3 months. CB-CT-identified remodeled bone at 6 months was corroborated by histomorphometry. Allografted femurs recovered only 40% of their strength at 6 months. CB-CT and DCE-MRI can discriminate differences in angiogenesis and bone formation in the canine allograft model, which has potential to detect a small (32%) drug or device effect on biomechanical healing with only five animals per group.

  5. Neurotoxin from Naja naja atra venom inhibits skin allograft rejection in rats.

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    Xu, Yin-Li; Kou, Jian-Qun; Wang, Shu-Zhi; Chen, Cao-Xin; Qin, Zheng-Hong

    2015-09-01

    Recent studies reported that Naja naja atra venom (NNAV) regulated immune function and had a therapeutic effect on adjunctive arthritis and nephropathy. We hypothesized that NNAV and its active component, neurotoxin (NTX), might inhibit skin allograft rejection. Skin allografts were used to induce immune rejection in rats. In addition, mixed lymphocyte culture (MLC) was used to mimic immune rejection reaction in vitro. Both NNAV and NTX were orally given starting from 5days prior to skin allograft surgery. The results showed that oral administration of NNAV or NTX prolonged the survival of skin allografts and inhibited inflammatory response. The production of Th1 cytokines (IFN-γ, IL-2) was also suppressed. NTX inhibited T-cell proliferation and CD4(+) T cell division induced by skin allografts. NTX also showed immunosuppressive activity in mixed lymphocyte culture. Atropine alone inhibited Con A-induced proliferation of T cells and potentiated NTX' s inhibitory effects on T cells, while pilocarpine only slightly enhanced Con A-induced T cell proliferation and partially reversed the inhibitory effect of NTX. On the other hand, neither nicotine nor mecamylamine had an influence on NTX's inhibitory effects on Con A-induced T cell proliferation in vitro. NTX inhibited T cell proliferation by arresting the cell cycle at the G0/G1 phase. The present study revealed that NNAV and NTX suppressed skin allograft rejection by inhibiting T cell-mediated immune responses. These findings suggest both NNAV and NTX as potential immunosuppressants for preventing the immune response to skin allografts. Copyright © 2015. Published by Elsevier B.V.

  6. Scapular allograft reconstruction after total scapulectomy: surgical technique and functional results.

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    Capanna, Rodolfo; Totti, Francesca; Van der Geest, Ingrid C M; Müller, Daniel A

    2015-08-01

    Scapular allograft reconstruction after total scapulectomy preserving the rotator cuff muscles is an oncologically safe procedure and results in good functional outcome with a low complication rate. The data of 6 patients who underwent scapular allograft reconstruction after a total scapulectomy for tumor resection were retrospectively reviewed. At least 1 of the rotator cuff muscles was preserved and the size-matched scapular allograft fixed to the residual host acromion with a plate and screws. The periscapular muscles and the residual joint capsule were sutured to the corresponding insertions of the allograft. The mean follow-up was 5.5 years (range, 24-175 months). In all patients, a wide surgical margin was achieved. The average functional scores were 20 points for the International Society of Limb Salvage score and 60 points for the American Shoulder and Elbow Surgeons score. Mean active shoulder flexion of 60° (range, 30°-90°) and mean active abduction of 62° (range, 30°-90°) were achieved. During the follow-up, 1 patient (16.6%) had a local recurrence and lung metastasis, whereas the remaining 5 patients (83.3%) were disease free. Two breakages of the osteosynthesis and 2 allograft fractures were observed, necessitating a revision surgery in 2 cases (33.3%). In this series, no infection, allograft resorption, or shoulder instability occurred. Allograft substitution of a completely removed scapula is an oncologically safe procedure, with good functional results, avoiding common complications in prosthetic replacements such as infection and dislocation of the shoulder joint. Copyright © 2015 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

  7. Ganciclovir prophylaxis improves late murine cytomegalovirus-induced renal allograft damage.

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    Shimamura, Masako; Seleme, Maria C; Guo, Lingling; Saunders, Ute; Schoeb, Trenton R; George, James F; Britt, William J

    2013-01-15

    Human cytomegalovirus (CMV) infection is associated with inferior survival in renal transplant patients, and ganciclovir (GCV) prophylaxis is associated with improved survival. In a murine CMV (MCMV) renal transplantation model, ganciclovir prophylaxis improved innate infiltrates and allograft damage during the period of prophylaxis. In this study, late effects were examined after the discontinuation of prophylaxis. MCMV D+/R- and D-/R- allogeneic transplants were performed with cyclosporine immunosuppression. One D+/R- cohort received ganciclovir prophylaxis for 14 days after transplantation followed by 28 days without ganciclovir. At 42 days after transplantation, grafts were analyzed for histologic tissue damage and immune infiltrates. Another D+/R- cohort was treated with anti-NK1.1 antibodies for 14 days after transplantation and compared with animals without natural killer (NK) cell depletion. At day 42, MCMV-infected transplants had higher damage scores (15.6±0.6) compared with uninfected transplants (8.3±0.9; Pganciclovir-treated allografts (9.5±1.4). MCMV-infected grafts contained greater frequencies of NK cell and myeloid infiltrates compared with uninfected grafts (Pganciclovir-treated grafts. NK cell depletion improved allograft histology of MCMV-infected grafts. MCMV infection exacerbates late renal allograft damage and is associated with NK and myeloid cell infiltrates. Ganciclovir prophylaxis reduces allograft injury and NK cell and myeloid infiltrates even after the cessation of prophylaxis. NK cell depletion in MCMV-infected transplants also improves histology. These results suggest that ganciclovir prophylaxis may have a long-term beneficial effect on CMV-infected renal allografts and suggest a potential role for NK cells in the pathogenesis of CMV-associated allograft injury.

  8. A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation.

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    Moll, Herwig P; Lee, Andy; Peterson, Clayton R; Revuelta Cervantes, Jesus; Wojcik, Brandon M; Parulkar, Anshul; Mele, Alessandra; LoGerfo, Philip J; Siracuse, Jeffrey J; Csizmadia, Eva; da Silva, Cleide G; Ferran, Christiane

    2016-11-01

    Inflammation is central to the pathogenesis of transplant arteriosclerosis (TA). We questioned whether physiologic levels of anti-inflammatory A20 influence TA severity. We performed major histocompatibility complex mismatched aorta to carotid artery interposition grafts, using wild type (WT) or A20 heterozygote (HET) C57BL/6 (H-2) donors and BALB/c (H-2) recipients, and conversely BALB/c donors and WT/HET recipients. We analyzed aortic allografts by histology, immunohistochemistry, immunofluorescence, and gene profiling (quantitative real-time reverse-transcriptase polymerase chain reaction). We validated select in vivo A20 targets in human and mouse smooth muscle cell (SMC) cultures. We noted significantly greater intimal hyperplasia in HET versus WT allografts, indicating aggravated TA. Inadequate upregulation of A20 in HET allografts after transplantation was associated with excessive NF-кB activation, gauged by higher levels of IkBα, p65, VCAM-1, ICAM-1, CXCL10, CCL2, TNF, and IL-6 (mostly localized to SMC). Correspondingly, cytokine-induced upregulation of TNF and IL-6 in human and mouse SMC cultures inversely correlated with A20 expression. Aggravated TA in HET versus WT allografts correlated with increased intimal SMC proliferation, and a higher number of infiltrating IFNγ and Granzyme B CD4 T cells and natural killer cells, and lower number of FoxP3 regulatory T cells. A20 haploinsufficiency in allograft recipients did not influence TA. A20 haploinsufficiency in vascular allografts aggravates lesions of TA by exacerbating inflammation, SMC proliferation, and infiltration of pathogenic T cells. A20 single nucleotide polymorphisms associating with lower A20 expression or function in donors of vascularized allografts may inform risk and severity of TA, highlighting the clinical implications of our findings.

  9. Processed allografts and type I collagen conduits for repair of peripheral nerve gaps.

    Science.gov (United States)

    Whitlock, Elizabeth L; Tuffaha, Sami H; Luciano, Janina P; Yan, Ying; Hunter, Daniel A; Magill, Christina K; Moore, Amy M; Tong, Alice Y; Mackinnon, Susan E; Borschel, Gregory H

    2009-06-01

    Autografting is the gold standard in the repair of peripheral nerve injuries that are not amenable to end-to-end coaptation. However, because autografts result in donor-site defects and are a limited resource, an effective substitute would be valuable. In a rat model, we compared isografts with Integra NeuraGen (NG) nerve guides, which are a commercially available type I collagen conduit, with processed rat allografts comparable to AxoGen's Avance human decellularized allograft product. In a 14-mm sciatic nerve gap model, isograft was superior to processed allograft, which was in turn superior to NG conduit at 6 weeks postoperatively (P < 0.05 for number of myelinated fibers both at midgraft and distal to the graft). At 12 weeks, these differences were no longer apparent. In a 28-mm graft model, isografts again performed better than processed allografts at both 6 and 22 weeks; regeneration through the NG conduit was often insufficient for analysis in this long graft model. Functional tests confirmed the superiority of isografts, although processed allografts permitted successful reinnervation of distal targets not seen in the NG conduit groups. Processed allografts were inherently non-immunogenic and maintained some internal laminin structure. We conclude that, particularly in a long gap model, nerve graft alternatives fail to confer the regenerative advantages of an isograft. However, AxoGen processed allografts are superior to a currently available conduit-style nerve guide, the Integra NeuraGen. They provide an alternative for reconstruction of short nerve gaps where a conduit might otherwise be used.

  10. Therapeutic Potential of Polyphenols in Cardiac Fibrosis

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    Ning Zhang

    2018-02-01

    Full Text Available Cardiac fibrosis, in response to injury and stress, is central to a broad constellation of cardiovascular diseases. Fibrosis decreases myocardial wall compliance due to extracellular matrix (ECM accumulation, leading to impaired systolic and diastolic function and causing arrhythmogenesis. Although some conventional drugs, such as β-blockers and renin-angiotensin-aldosterone system (RAAS inhibitors, have been shown to alleviate cardiac fibrosis in clinical trials, these traditional therapies do not tend to target all the fibrosis-associated mechanisms, and do not hamper the progression of cardiac fibrosis in patients with heart failure. Polyphenols are present in vegetables, fruits, and beverages and had been proposed as attenuators of cardiac fibrosis in different models of cardiovascular diseases. Together with results found in the literature, we can show that some polyphenols exert anti-fibrotic and myocardial protective effects by mediating inflammation, oxidative stress, and fibrotic molecular signals. This review considers an overview of the mechanisms of cardiac fibrosis, illustrates their involvement in different animal models of cardiac fibrosis treated with some polyphenols and projects the future direction and therapeutic potential of polyphenols on cardiac fibrosis.

  11. iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by Generating Alloantigen-Specific Regulatory T Cells

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    Songjie Cai

    2017-05-01

    Full Text Available Regulatory dendritic cell (DCregs-based immunotherapy is a potential therapeutic tool for transplant rejection. We generated DCregs from murine induced pluripotent stem cells (iPSCs, which could remain in a “stable immature stage” even under strong stimulation. Harnessing this characteristic, we hypothesized that iPS-DCregs worked as a negative vaccine to generate regulatory T cells (Tregs, and induced donor-specific allograft acceptance. We immunized naive CBA (H-2Kk mice with B6 (H-2Kb iPS-DCregs and found that Tregs (CD4+CD25+FOXP3+ significantly increased in CBA splenocytes. Moreover, immunized CBA recipients permanently accepted B6 cardiac grafts in a donor-specific pattern. We demonstrated mechanistically that donor-type iPS-DCregs triggered transforming growth factor β1 secretion, under which the donor-antigen peptides directed naive CD4+ T cells to differentiate into donor-specific FOXP3+ Tregs instead of into effector T cells in vivo. These findings highlight the potential of iPS-DCregs as a key cell therapy resource in clinical transplantation.

  12. Cardiac conduction system

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    The cardiac conduction system is a group of specialized cardiac muscle cells in the walls of the heart that send signals to the ... contract. The main components of the cardiac conduction system are the SA node, AV node, bundle of ...

  13. Sudden Cardiac Arrest (SCA)

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    ... Arrest (SCA) Back to Heart Diseases & Disorders Sudden Cardiac Arrest (SCA) Sudden Cardiac Arrest ( SCA ) occurs when the heart stops beating, abruptly ... to saving someone who is having a sudden cardiac arrest , it is important to understand the difference. The ...

  14. Cryopreserved cancellous bone allograft in periodontal intraosseous defects.

    Science.gov (United States)

    Borghetti, A; Novakovitch, G; Louise, F; Simeone, D; Fourel, J

    1993-02-01

    The purpose of this study was to evaluate the potential of cryopreserved cancellous bone allograft (CCBA) in the treatment of intraosseous periodontal defects compared to surgical debridement alone (DEBR). Cancellous bone was procured from femur heads that had been extracted for hip prosthesis procedures and cryopreserved in liquid nitrogen (-196 degrees C) in a tissue bank. Ten patients without systemic disorders and advanced periodontal disease (at least 2 intraosseous defects) participated in this investigation. Measurements from the cemento-enamel junction were made after initial therapy for clinical attachment level; also gingival recession, probing pocket depth, plaque index, and gingival index and, at the time of surgery, alveolar crest height and osseous defect depth were measured. All measurements were repeated at 1 year-reentry. Sixteen defects were debrided and grafted (test sites) and 13 defects were debrided only (control sites). Soft tissue measurements showed no statistical differences between the 2 groups. Defect fill was significantly greater with CCBA (1.75 mm) than with DEBR (0.56 mm). Defect depth reduction was 2.06 mm for CCBA and 0.78 mm for DEBR. These values correspond to a percent-defect resolution of 60% for CCBA and 29% for DEBR. Hard tissue measurements showed significant differences between the 2 groups. CCBA seems to be effective in the short-term treatment of intraosseous periodontal defects.

  15. Restrictive allograft syndrome after lung transplantation: new radiological insights

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    Dubbeldam, Adriana; Barthels, Caroline; Coolen, Johan; Verschakelen, Johny A.; Wever, Walter de [University Hospitals Leuven, Department of Radiology, Leuven (Belgium); Verleden, Stijn E.; Vos, Robin; Verleden, Geert M. [University Hospitals Leuven, Department of Pneumology, Leuven (Belgium)

    2017-07-15

    To describe the CT changes in patients with restrictive allograft syndrome (RAS) after lung transplantation, before and after clinical diagnosis. This retrospective study included 22 patients with clinical diagnosis of RAS. Diagnosis was based on a combination of forced expiratory volume (FEV1) decline (≥20 %) and total lung capacity (TLC) decline (≥10 %). All available CT scans after transplantation were analyzed for the appearance and evolution of lung abnormalities. In 14 patients, non-regressing nodules and reticulations predominantly affecting the upper lobes developed an average of 13.9 months prior to the diagnosis of RAS. Median graft survival after onset of non-regressing abnormalities was 33.5 months, with most patients in follow-up (9/14). In eight patients, a sudden appearance of diffuse consolidations mainly affecting both upper and lower lobes was seen an average of 2.8 months prior to the diagnosis of RAS. Median graft survival was 6.4 months after first onset of non-regressing abnormalities, with graft loss in most patients (6/8). RAS has been previously described as a homogenous group. However, our study shows two different groups of RAS-patients: one with slow progression and one with fast progression. The two groups show different onset and progression patterns of CT abnormalities. (orig.)

  16. Nontubercular mycobacterial infection in a renal allograft recipient

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    U Anandh

    2017-01-01

    Full Text Available A 71-year-old male, a renal allograft recipient, presented to us with a history of fever and right palm swelling. He had a history of fever 7 years back when he was treated with antitubercular treatment (ATT. Three years back, he was diagnosed to have gout and he was started on allopurinol. He developed severe bone marrow toxicity and allopurinol was changed to febuxostat. On admission, routine investigations did not reveal any focus of infection. The fluid aspirate from the palm revealed acid-fast bacilli (AFB. He was started on ATT; however, he did not show significant improvement. Two months later, he developed multiple subcutaneous lesions, and the pus again came positive for AFB. Due to lack of improvement, the aspirate was sent for molecular diagnostic identification. The mycobacteria was identified as Mycobacterium haemophilum. His treatment was changed to rifampicin, clarithromycin, and ciprofloxacin. As he showed slow improvement, his immunosuppression was tapered slowly. At 7 months of therapy, he is clinically better and his lesions are healing. His renal functions stayed stable despite tapering of cyclosporine in a patient who is on rifampicin. This case, the first report of M. haemophilum infection in a kidney transplant recipient in India, illustrates the difficulty in diagnosing nontubercular mycobacterial infection in transplant recipients. It also emphasizes the dilemma in tapering immunosuppressive drugs in disseminated nontubercular mycobacterial infections where there are considerable interactions between ATT and immunosuppressives.

  17. Alveolar Ridge Preservation Using Xenogeneic Collagen Matrix and Bone Allograft

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    Andreas O. Parashis

    2014-01-01

    Full Text Available Alveolar ridge preservation (ARP has been shown to prevent postextraction bone loss. The aim of this report is to highlight the clinical, radiographic, and histological outcomes following use of a bilayer xenogeneic collagen matrix (XCM in combination with freeze-dried bone allograft (FDBA for ARP. Nine patients were treated after extraction of 18 teeth. Following minimal flap elevation and atraumatic extraction, sockets were filled with FDBA. The XCM was adapted to cover the defect and 2-3 mm of adjacent bone and flaps were repositioned. Healing was uneventful in all cases, the XCM remained in place, and any matrix exposure was devoid of further complications. Exposed matrix portions were slowly vascularized and replaced by mature keratinized tissue within 2-3 months. Radiographic and clinical assessment indicated adequate volume of bone for implant placement, with all planned implants placed in acceptable positions. When fixed partial dentures were placed, restorations fulfilled aesthetic demands without requiring further augmentation procedures. Histological and immunohistochemical analysis from 9 sites (4 patients indicated normal mucosa with complete incorporation of the matrix and absence of inflammatory response. The XCM + FDBA combination resulted in minimal complications and desirable soft and hard tissue therapeutic outcomes, suggesting the feasibility of this approach for ARP.

  18. Structural Allograft versus Autograft for Instrumented Atlantoaxial Fusions in Pediatric Patients: Radiologic and Clinical Outcomes in Series of 32 Patients.

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    Zhang, Yue-Hui; Shen, Lei; Shao, Jiang; Chou, Dean; Song, Jia; Zhang, Jing

    2017-09-01

    Allograft with wire techniques showed a low fusion rate in pediatric atlantoaxial fusions (AAFs) in early studies. Using allograft in pediatric AAFs with screw/rod constructs has not been reported. Thus we compared the fusion rate and clinical outcomes in pediatric patients who underwent AAFs with screw/rod constructs using either a structural autograft or allograft. Pediatric patients (aged ≤12 years) who underwent AAFs between 2007 and 2015 were retrospectively evaluated. Patients were divided into 2 groups (allograft or autograft). Clinical and radiographic results were collected from hospital records and compared. A total of 32 patients were included (18 allograft, 14 autograft). There were no significant group differences in age, sex, weight, diagnosis, or duration of follow-up. A similar fusion rate was achieved (allograft: 94%, 17/18; autograft: 100%, 14/14); however, the average fusion time was 3 months longer in the allograft group. Blood loss was significantly lower in the allograft group (68 ± 8.5 mL) than the autograft group (116 ± 12.5 mL). Operating time and length of hospitalization were slightly (nonsignificantly) shorter for the allograft group. A significantly higher overall incidence of surgery-related complications was seen in the autograft group, including a 16.7% (2/14) rate of donor-site-related complications. The use of allograft for AAF was safe and efficacious when combined with rigid screw/rod constructs in pediatric patients, with a similar fusion rate to autografts and an acceptable complication rate. Furthermore, blood loss was less when using allograft and donor-site morbidity was eliminated; however, the fusion time was increased. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Assessment of early renal allograft dysfunction with blood oxygenation level-dependent MRI and diffusion-weighted imaging

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    Park, Sung Yoon [Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of); Kim, Chan Kyo, E-mail: chankyokim@skku.edu [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Park, Byung Kwan [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Kim, Sung Ju; Lee, Sanghoon [Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Huh, Wooseong [Department of Nephrology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2014-12-15

    Highlights: • R2* and ADC in renal allografts are moderately correlated with eGFR. • R2* and ADC are lower in early allograft dysfunction than normal allograft function. • No significant difference between AR and ATN was found in both R2* and ADC. - Abstract: Purpose: To investigate blood oxygenation level-dependent (BOLD) MRI and diffusion-weighted imaging (DWI) at 3 T for assessment of early renal allograft dysfunction. Materials and methods: 34 patients with a renal allograft (early dysfunction, 24; normal, 10) were prospectively enrolled. BOLD MRI and DWI were performed at 3 T. R2* and apparent diffusion coefficient (ADC) values were measured in cortex and medulla of the allografts. Correlation between R2* or ADC values and estimated glomerular filtration rate (eGFR) was investigated. R2* or ADC values were compared among acute rejection (AR), acute tubular necrosis (ATN) and normal function. Results: In all renal allografts, cortical or medullary R2* and ADC values were moderately correlated with eGFR (P < 0.05). Early dysfunction group showed lower R2* and ADC values than normal function group (P < 0.05). AR or ATN had lower R2* values than normal allografts (P < 0.05), and ARs had lower cortical ADC values than normal allografts (P < 0.05). No significant difference of R2* or ADC values was found between AR and ATN (P > 0.05). Conclusion: BOLD MRI and DWI at 3 T may demonstrate early functional state of renal allografts, but may be limited in characterizing a cause of early renal allograft dysfunction. Further studies are needed.

  20. Stromal stem cells and platelet-rich plasma improve bone allograft integration.

    Science.gov (United States)

    Lucarelli, Enrico; Fini, Milena; Beccheroni, Amira; Giavaresi, Gianluca; Di Bella, Claudia; Aldini, Nicolò Nicoli; Guzzardella, Gaetano; Martini, Lucia; Cenacchi, Annarita; Di Maggio, Nunzia; Sangiorgi, Luca; Fornasari, Pier Maria; Mercuri, Mario; Giardino, Roberto; Donati, Davide

    2005-06-01

    Early vascular invasion is a key factor in bone allograft incorporation. It may reduce the complications related to slow and incomplete bone integration. Bone-marrow-derived stromal stem cells associated with platelet-rich plasma are potent angiogenic inducers proven to release vascular endothelial growth factor. Our goal was to test whether the combination of stromal stem cells and platelet-rich plasma is able to increase massive allograft integration in a large animal model with sacrifice at 4 months. A critical defect was made in the mid-diaphysis of the metatarsal bone of 10 sheep; the study group received an allograft plus stromal stem cells, platelet-rich plasma, and collagen (six animals) and the control group received only the allograft (four animals). Investigation was done with radiographs, mechanical tests and histomorphometric analysis, including new vascularization. Results showed substantial new bone formation in the allograft of the study group. Bone formation is correlated with better vascular invasion and remodeling of the graft in the study group. These results confirm the key role played by stromal stem cells and platelet-rich plasma in bone repair. Further studies are needed to better define the role stromal stem cells play when implanted alone.

  1. Proteinuria as a Noninvasive Marker for Renal Allograft Histology and Failure: An Observational Cohort Study.

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    Naesens, Maarten; Lerut, Evelyne; Emonds, Marie-Paule; Herelixka, Albert; Evenepoel, Pieter; Claes, Kathleen; Bammens, Bert; Sprangers, Ben; Meijers, Björn; Jochmans, Ina; Monbaliu, Diethard; Pirenne, Jacques; Kuypers, Dirk R J

    2016-01-01

    Proteinuria is routinely measured to assess renal allograft status, but the diagnostic and prognostic values of this measurement for renal transplant pathology and outcome remain unclear. We included 1518 renal allograft recipients in this prospective, observational cohort study. All renal allograft biopsy samples with concomitant data on 24-hour proteinuria were included in the analyses (n=2274). Patients were followed for ≥7 years post-transplantation. Compared with proteinuria proteinuria 0.3-1.0 g/24 h, 2.17 (95% CI, 1.49 to 3.18; Pproteinuria 1.0-3.0 g/24 h, and 3.01 (95% CI, 1.75 to 5.18; Pproteinuria >3.0 g/24 h, independent of GFR and allograft histology. The predictive performance of proteinuria for graft failure was lower at 3 months after transplant (area under the receiver-operating characteristic curve [AUC] 0.64, Pproteinuria were repeat transplantation, mean arterial pressure, transplant glomerulopathy, microcirculation inflammation, and de novo/recurrent glomerular disease. The discriminatory power of proteinuria for these intragraft injury processes was better in biopsy samples obtained >3 months after transplant (AUC 0.73, Pproteinuria >1.0 g/24 h. These data support current clinical guidelines to routinely measure proteinuria after transplant, but illustrate the need for more sensitive biomarkers of allograft injury and prognosis. Copyright © 2016 by the American Society of Nephrology.

  2. The effect of gamma irradiation on the osteoinductivity of demineralized human bone allograft.

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    Babak Arjmand

    2014-03-01

    Full Text Available The gamma irradiation has been used for end sterilization of allograft bones and its effects with a 25 kGy dosage on the osteoinductive properties of demineralized bone allograft powder was studied. This work carried out using an experimental method in an animal model. In this study the demineralized bone allograft powder which had been sterilized and prepared with gamma irradiation in a 25 kGy dosage in 18 hours, was used as a study group and the demineralized bone allograft powder which had been prepared aseptically was used as the reference group. 30 mg of bone powder from each group were implanted into right and left paravertebral muscles of eighteen rats, separately. After four weeks, the implanted samples were harvested with a 0.5 cm border and then the osteoinductivity of implants in two groups were compared with histopathologic studies. In 94.4% of the reference samples a new bone formation was observed. In the study group, this difference was observed only in 27.7% of samples (P<0.002. It appears that using gamma irradiation may lead to a reduction in osteoinduction properties of demineralized bone allograft powder.

  3. Proteinuria as a Noninvasive Marker for Renal Allograft Histology and Failure: An Observational Cohort Study

    Science.gov (United States)

    Lerut, Evelyne; Emonds, Marie-Paule; Herelixka, Albert; Evenepoel, Pieter; Claes, Kathleen; Bammens, Bert; Sprangers, Ben; Meijers, Björn; Jochmans, Ina; Monbaliu, Diethard; Pirenne, Jacques; Kuypers, Dirk R.J.

    2016-01-01

    Proteinuria is routinely measured to assess renal allograft status, but the diagnostic and prognostic values of this measurement for renal transplant pathology and outcome remain unclear. We included 1518 renal allograft recipients in this prospective, observational cohort study. All renal allograft biopsy samples with concomitant data on 24-hour proteinuria were included in the analyses (n=2274). Patients were followed for ≥7 years post-transplantation. Compared with proteinuria failure were 1.14 (95% confidence interval [95% CI], 0.81 to 1.60; P=0.50), for proteinuria 0.3–1.0 g/24 h, 2.17 (95% CI, 1.49 to 3.18; P3.0 g/24 h, independent of GFR and allograft histology. The predictive performance of proteinuria for graft failure was lower at 3 months after transplant (area under the receiver-operating characteristic curve [AUC] 0.64, P3 months after transplant (AUC 0.73, P1.0 g/24 h. These data support current clinical guidelines to routinely measure proteinuria after transplant, but illustrate the need for more sensitive biomarkers of allograft injury and prognosis. PMID:26152270

  4. Vertebrectomy, bone allograft fusion, and antitumor vaccination for the treatment of vertebral fibrosarcoma in a dog.

    Science.gov (United States)

    Chauvet, A E; Hogge, G S; Sandin, J A; Lipsitz, D

    1999-01-01

    To describe the surgical technique of vertebrectomy with bone allograft fusion and the use of antitumor vaccine for the treatment of a primary vertebral neoplasm in a dog. Case Report. A 3 year old 32 kg female spayed mixed breed dog with progressive paraplegia. Myelography was performed to identify an L5 lytic lesion with spinal cord compression. A dorsal laminectomy was performed to decompress the spinal cord and obtain biopsies. Pathologic fracture of the vertebral body two days later was treated with L5 vertebrectomy, cortical allograft implantation, and bilateral plating from L4 to L6. Tumor samples were used to create an autologous cytokine-gene-engineered tumor cell vaccine. Recheck radiographs and neurologic examinations were obtained 1, 2, 7, and 13 months after surgery. The histopathologic diagnosis was fibrosarcoma. Although slight osteopenia of the allograft was noted thirteen months after surgery, the allograft and plate fixation remained stable. The patient tolerated the antitumor vaccination protocol well. Two years after the procedures the dog was able to ambulate normally but remained urinary and fecal incontinent. Vertebrectomy and cortical allograft implantation with plating permitted this patient to return to a functional lifestyle with its owners.

  5. Rescue Arterial Revascularization Using Cryopreserved Iliac Artery Allograft in Liver Transplant Patients.

    Science.gov (United States)

    Mohkam, Kayvan; Darnis, Benjamin; Rode, Agnès; Hetsch, Nathalie; Balbo, Gregorio; Bourgeot, Jean-Paul; Mezoughi, Salim; Demian, Hassan; Ducerf, Christian; Mabrut, Jean-Yves

    2017-08-01

    Management of hepatic arterial complications after liver transplant remains challenging. The aim of our study was to assess the efficacy of rescue arterial revascularization using cryopreserved iliac artery allografts in this setting. Medical records of patients with liver transplants who underwent rescue arterial revascularization using cryopreserved iliac artery allografts at a single institution were reviewed. From 1992 to 2015, 7 patients underwent rescue arterial revascularization using cryopreserved iliac artery allografts for hepatic artery pseudoaneurysm (3 patients), thrombosis (2 patients), aneurysm (1 patient), or stenosis (1 patient). Two patients developed severe complications, comprising one biliary leakage treated percutaneously, and one acute necrotizing pancreatitis causing death on postoperative day 29. After a median follow-up of 75 months (range, 1-269 mo), 2 patients had an uneventful long-term course, whereas 4 patients developed graft thrombosis after a median period of 120 days (range, 2-488 d). Among the 4 patients who developed graft thrombosis, 1 patient developed ischemic cholangitis, 1 developed acute ischemic hepatic necrosis and was retransplanted, and 2 patients did not develop any further complications. Despite a high rate of allograft thrombosis, rescue arterial revascularization using cryopreserved iliac artery allografts after liver transplant is an effective and readily available approach, with a limited risk of infection and satisfactory long-term graft and patient survival.

  6. Broth versus solid agar culture of swab samples of cadaveric allograft musculoskeletal tissue.

    Science.gov (United States)

    Varettas, Kerry

    2013-12-01

    As part of the donor assessment protocol, bioburden assessment must be performed on allograft musculoskeletal tissue samples collected at the time of tissue retrieval. Swab samples of musculoskeletal tissue allografts from cadaveric donors are received at the microbiology department of the South Eastern Area Laboratory Services (Australia) to determine the presence of bacteria and fungi. This study will review the isolation rate of organisms from solid agar and broth culture of swab samples of cadaveric allograft musculoskeletal tissue over a 6-year period, 2006-2011. Swabs were inoculated onto horse blood agar (anaerobic, 35 °C) and chocolate agar (CO2, 35 °C) and then placed into a cooked meat broth (aerobic, 35 °C). A total of 1,912 swabs from 389 donors were received during the study period. 557 (29.1 %) swabs were culture positive with the isolation of 713 organisms, 249 (34.9 %) from solid agar culture and an additional 464 (65.1 %) from broth culture only. This study has shown that the broth culture of cadaveric allograft musculoskeletal swab samples recovered a greater amount of organisms than solid agar culture. Isolates such as Clostridium species and Staphylococcus aureus would not have been isolated from solid agar culture alone. Broth culture is an essential part of the bioburden assessment protocol of swab samples of cadaveric allograft musculoskeletal tissue in this laboratory.

  7. Effect of a novel sterilization method on biomechanical properties of soft tissue allografts.

    Science.gov (United States)

    Baldini, T; Caperton, K; Hawkins, M; McCarty, E

    2016-12-01

    Evaluate allograft tissue commonly used in soft tissue reconstruction to determine whether stiffness and strength were significantly altered after grafts were treated with different sterilization methods. Unprocessed, irradiated, and grafts treated with supercritical CO2 were compared. Thirty-eight anterior or posterior tibialis tendons were obtained from a tissue bank (Allograft Innovations, Gainesville, FL). Group I was unprocessed, group II was sterilized with gamma irradiation (20-28 kGy), and group III was sterilized with supercritical CO2. The grafts were pretensioned to 89 N for 300 s. Specimens were then loaded from 50 to 300 N at 0.5 Hz for 250 cycles before being loaded to failure at 50 mm/min. Dependent variables were compared between sterilization groups with one-way ANOVA (P sterilization methods tested in this study do not affect allograft strength. The supercritical CO2 sterilization method resulted in significantly lower stiffness than unprocessed and irradiated allografts. However, the stiffness and strength of all groups tested were greater than that of published values of the native intact anterior cruciate ligament (ACL). This study provides previously unpublished mechanical test data on a new sterilization technique that will assist surgeons to decide which allograft to use in ACL reconstruction surgery. III.

  8. Imaging of CD47 Expression in Xenograft and Allograft Tumor Models

    Directory of Open Access Journals (Sweden)

    Alexander Zheleznyak

    2013-11-01

    Full Text Available CD47 functions as a marker of “self” by inhibiting phagocytosis of autologous cells. CD47 has been shown to be overexpressed by various tumor types as a means of escaping the antitumor immune response. The goal of this research was to investigate the utility of CD47 imaging using positron emission tomography (PET in both human xenograft and murine allograft tumor models. Anti-CD47 antibodies were conjugated with p-isothiocyanatobenzyldesferrioxamine (Df-Bz-NCS and labeled with 89Zr. We employed xenograft and allograft small-animal models of cancer in biodistribution and PET imaging studies to investigate the specificity and PET imaging robustness of CD47. Ab-Df-Bz-NCS conjugates were labeled with 89Zr with specific activity of 0.9 to 1.6 μCi/μg. Biodistribution studies in the xenograft and allograft model showed similar specific tumor uptake of the antihuman and antimouse CD47 antibodies. However, the tracer retention in the liver, spleen, and kidneys was significantly higher in the allograft-bearing animals, suggesting uptake mediated by the CD47 normally expressed throughout the reticular endothelial system. CD47, a marker of “self,” was evaluated as a diagnostic PET biomarker in xenograft and allograft cancer animal models. CD47 imaging is feasible, warranting further studies and immunoPET tracer development.

  9. Reconstruction of the medial patellofemoral ligament: Evaluation of the clinical results of autografts versus allografts.

    Science.gov (United States)

    Calvo Rodríguez, R; Figueroa Poblete, D; Anastasiadis Le Roy, Z; Etchegaray Bascur, F; Vaisman Burucker, A; Calvo Mena, R

    2015-01-01

    The purpose of the study was to evaluate the functional results after medial patellofemoral ligament (MPFL) reconstruction in patients using auto- and allograft. A retrospective study was conducted on 28 patients with recurrent patellar dislocation, with 13 patients (13 knees) undergoing MPFL reconstruction with hamstring autograft, and 15 patients (16 knees) with reconstruction surgery with allograft. The total group included 13 males and 15 females, with an age range of 15 to 38 years. The graft-related morbidity was studied and a clinical assessment was performed using the pre- and postoperative Kujala score. Associated complications were reported for each group. All the patients had more than 12 months of follow up. No recurrent dislocations or graft related complications were reported in either group. The post-operative Kujala subjective knee score was 89.2 in the autograft group, and 92.6 in the allograft group (p >.05). One patient in the allograft group received a revision surgery due to poor positioning of anchors. Another patient in the allograft group had non-displaced patella fracture related to the bone tunnels and another patient had flexion deficit and needed mobilization under anesthesia. There were no significant differences between both groups, and the results were comparable. Copyright © 2014 SECOT. Published by Elsevier Espana. All rights reserved.

  10. Hair Follicle Dermal Sheath Derived Cells Improve Islet Allograft Survival without Systemic Immunosuppression

    Directory of Open Access Journals (Sweden)

    Xiaojie Wang

    2015-01-01

    Full Text Available Immunosuppressive drugs successfully prevent rejection of islet allografts in the treatment of type I diabetes. However, the drugs also suppress systemic immunity increasing the risk of opportunistic infection and cancer development in allograft recipients. In this study, we investigated a new treatment for autoimmune diabetes using naturally immune privileged, hair follicle derived, autologous cells to provide localized immune protection of islet allotransplants. Islets from Balb/c mouse donors were cotransplanted with syngeneic hair follicle dermal sheath cup cells (DSCC, group 1 or fibroblasts (FB, group 2 under the kidney capsule of immune-competent, streptozotocin induced, diabetic C57BL/6 recipients. Group 1 allografts survived significantly longer than group 2 (32.2 ± 12.2 versus 14.1 ± 3.3 days, P<0.001 without administration of any systemic immunosuppressive agents. DSCC reduced T cell activation in the renal lymph node, prevented graft infiltrates, modulated inflammatory chemokine and cytokine profiles, and preserved better beta cell function in the islet allografts, but no systemic immunosuppression was observed. In summary, DSCC prolong islet allograft survival without systemic immunosuppression by local modulation of alloimmune responses, enhancing of beta cell survival, and promoting of graft revascularization. This novel finding demonstrates the capacity of easily accessible hair follicle cells to be used as local immunosuppression agents in islet transplantation.

  11. Landing gear noise attenuation

    Science.gov (United States)

    Moe, Jeffrey W. (Inventor); Whitmire, Julia (Inventor); Kwan, Hwa-Wan (Inventor); Abeysinghe, Amal (Inventor)

    2011-01-01

    A landing gear noise attenuator mitigates noise generated by airframe deployable landing gear. The noise attenuator can have a first position when the landing gear is in its deployed or down position, and a second position when the landing gear is in its up or stowed position. The noise attenuator may be an inflatable fairing that does not compromise limited space constraints associated with landing gear retraction and stowage. A truck fairing mounted under a truck beam can have a compliant edge to allow for non-destructive impingement of a deflected fire during certain conditions.

  12. O bloqueio do sistema renina-angiotensina atenua a remodelação cardíaca de ratos submetidos a estenose aórtica Blockade of renin-angiotensin system attenuates cardiac remodeling in rats undergoing aortic stenosis

    Directory of Open Access Journals (Sweden)

    Giancarlo Gonçalves

    2005-04-01

    Full Text Available OBJETIVO: Avaliar o papel do bloqueador dos receptores AT1 e do inibidor da enzima conversora da angiotensina na remodelação cardíaca induzida por estenose aórtica em ratos. MÉTODOS: Ratos Wistar foram divididos em 4 grupos: controle (C, n=13, estenose aórtica (EAo, n=11, EAo com lisinopril, 20 mg/kg/dia (LIS, n=11 e EAo com losartan, 40 mg/kg/dia (LOS, n=9. Os tratamentos foram iniciados 3 dias antes da cirurgia. Após 6 semanas, os animais foram submetidos ao estudo ecocardiográfico, quantificação da concentração de hidroxiprolina e da área seccional (CSA miocitária do ventrículo esquerdo (VE. RESULTADOS: A EAo induziu aumento da espessura da parede do VE. Os animais LIS e LOS não apresentaram diferença em relação aos animais controles. Os ratos EAo e LIS apresentaram maiores diâmetros do átrio esquerdo que os ratos controles, enquanto nos animais LOS não houve diferença. Os animais com EAo apresentaram maiores valores da porcentagem de encurtamento que os controle. Esse fato não foi modificado com LIS ou LOS. A CSA dos animais do grupo EAo foi maior que a dos controle. Entretanto, o tratamento com LOS e com LIS atenuou o aumento da área induzida pela EAo. A EAo resultou em aumento na concentração de HOP, enquanto o grupo LOS não apresentou diferença em relação ao grupo controle. CONCLUSÃO: O bloqueio do sistema renina-angiotensina, com bloqueador AT1 e com IECA, pode atenuar o desenvolvimento de hipertrofia cardíaca, porém só o bloqueio dos receptores AT1 atenua a fibrose intersticial do VE.OBJECTIVE: To assess the role of the AT1 receptor blocker and the angiotensin-converting enzyme inhibitor in cardiac remodeling induced by aortic stenosis in rats. METHODS: Wistar rats were divided into the following 4 groups: 1 C - control (n=13; 2 AoS - aortic stenosis (n=11; 3 LIS - AoS treated with lisinopril, 20 mg/kg/day (n=11; and 4 LOS - AoS treated with losartan, 40 mg/kg/day (n=9. The treatments were initiated 3

  13. What Causes Sudden Cardiac Arrest?

    Science.gov (United States)

    ... Back To Health Topics / Sudden Cardiac Arrest Sudden Cardiac Arrest Also known as Cardiac Arrest , Sudden Cardiac Death ... the condition For People Who Have Survived Sudden Cardiac Arrest If you've already had SCA, you're ...

  14. What Is Sudden Cardiac Arrest?

    Science.gov (United States)

    ... Back To Health Topics / Sudden Cardiac Arrest Sudden Cardiac Arrest Also known as Cardiac Arrest , Sudden Cardiac Death ... the condition For People Who Have Survived Sudden Cardiac Arrest If you've already had SCA, you're ...

  15. Osteogenic protein-1 increases the fixation of implants grafted with morcellised bone allograft and ProOsteon bone substitute: an experimental study in dogs

    DEFF Research Database (Denmark)

    Jensen, T B; Overgaard, S; Lind, M

    2007-01-01

    Impacted bone allograft is often used in revision joint replacement. Hydroxyapatite granules have been suggested as a substitute or to enhance morcellised bone allograft. We hypothesised that adding osteogenic protein-1 to a composite of bone allograft and non-resorbable hydroxyapatite granules (...

  16. The use of allograft as a bone graft substitute in patients with congenital spine deformities.

    Science.gov (United States)

    Hedequist, Daniel; Yeon, Howard; Emans, John

    2007-09-01

    The purpose of this study was to determine the safety and efficacy of using allograft bone as a substitute for iliac crest bone graft when treating pediatric patients with congenital spine deformities. We performed a retrospective review of 107 pediatric patients who underwent instrumentation and arthrodesis using allograft for congenital spine deformity between 1995 and 2002. Pseudoarthrosis was defined as implant failure, a clear radiographic pseudoarthrosis, or any loss of correction more than 10 degrees from the immediate postoperative radiographs to the final follow-up radiographs. The pseudoarthrosis rate in this series was 2.8%, and the infection rate was 0.9%. We conclude that freeze-dried corticocancellous allograft is a safe and effective alternative to iliac crest bone graft in this patient population.

  17. Evaluation of an Osseous Allograft Membrane for Guided Tissue Regeneration in the Dog.

    Science.gov (United States)

    Stepaniuk, Kevin S; Gingerich, Wade

    2015-01-01

    Clinical application of a demineralized freeze-dried cortical bone membrane allograft (DFBMA) for treatment of intra(infra)bony periodontal pockets in dogs was evaluated. The mean pre-treatment periodontal probing depth equaled 7.2-mm. Post-treatment probing depths in all 11 cases were normal, with a mean periodontal probing gain of 5.4-mm. Guided tissue regeneration using a commercially available veterinary canine DFBMA and canine demineralized freeze-dried bone allograft (DFDBA) resulted in clinically significant periodontal attachment gains. The gain of new periodontal tissue attachment was statistically significant (P < 0.0001). The commercially available veterinary allograft products predictably increased new periodontal attachment without any identified membrane sequelae in these 11 cases.

  18. Antibody-engineered nanoparticles selectively inhibit mesenchymal cells isolated from patients with chronic lung allograft dysfunction.

    Science.gov (United States)

    Cova, Emanuela; Colombo, Miriam; Inghilleri, Simona; Morosini, Monica; Miserere, Simona; Peñaranda-Avila, Jesus; Santini, Benedetta; Piloni, Davide; Magni, Sara; Gramatica, Furio; Prosperi, Davide; Meloni, Federica

    2015-01-01

    Chronic lung allograft dysfunction represents the main cause of death after lung transplantation, and so far there is no effective therapy. Mesenchymal cells (MCs) are primarily responsible for fibrous obliteration of small airways typical of chronic lung allograft dysfunction. Here, we engineered gold nanoparticles containing a drug in the hydrophobic section to inhibit MCs, and exposing on the outer hydrophilic surface a monoclonal antibody targeting a MC-specific marker (half-chain gold nanoparticles with everolimus). Half-chain gold nanoparticles with everolimus have been synthesized and incubated with MCs to evaluate the effect on proliferation and apoptosis. Drug-loaded gold nanoparticles coated with the specific antibody were able to inhibit proliferation and induce apoptosis without stimulating an inflammatory response, as assessed by in vitro experiments. These findings demonstrate the effectiveness of our nanoparticles in inhibiting MCs and open new perspectives for a local treatment of chronic lung allograft dysfunction.

  19. Joint degeneration following meniscal allograft transplantation in a canine model: mechanical properties and semiquantitative histology of articular cartilage.

    Science.gov (United States)

    Elliott, Dawn M; Jones, Relief; Setton, Lori A; Scully, Sean P; Vail, T Parker; Guilak, Farshid

    2002-03-01

    This study examined the hypothesis that meniscal allograft transplantation serves a "chondroprotective" role and prevents the histological and biomechanical changes of the articular cartilage following meniscectomy. Skeletally mature mongrel dogs underwent total medial meniscectomy and received either a fresh meniscal allograft ( n=10) or no further treatment ( n=10). Semiquantitative histology and biomechanical analysis of the femoral articular cartilage was used to assess cartilage pathology 12 weeks following surgery. Histological analysis showed significant changes in cartilage structure that did not differ between the meniscectomy and allograft transplantation groups. Similarly, the tensile modulus of the surface zone cartilage was significantly lower than that in unoperated controls following either meniscectomy or allograft transplantation. A significant correlation was observed between the biomechanical and histological changes, suggesting that degenerative changes in cartilage structure and mechanical function are interrelated. Our findings do not support the hypothesis that meniscal allograft transplantation provides chondroprotection of the femoral condyle and also suggest that it does not lead to increased degenerative changes.

  20. Intrapancreatic Splenule in a Pancreas Allograft: Case Report.

    Science.gov (United States)

    Yadav, K; Serrano, O K; Kandaswamy, R

    2016-11-01

    A 16-year-old white man was involved in a motor vehicle collision and suffered head, chest, and abdominal trauma. Despite initial resuscitative efforts, he progressed to brain death and was designated to be an organ donor by his family. He had no earlier medical or surgical history and no high-risk behaviors. Blood work revealed normal creatinine, liver function tests, lipase, and amylase. Viral serologies were negative except for cytomegalovirus IgG and Epstein-Barr virus nucleic acid. Imaging revealed a right kidney contusion, a manubrial fracture, and fractures of right first rib and bilateral scapulae. No other abdominal trauma was identified, specifically to the pancreas, duodenum, or spleen. Our transplant center accepted the pancreas from this donor. During back-table inspection of the pancreas, a 1.5 × 1.5 cm dark purple rubbery mass was identified within the parenchyma of the pancreas in the tail. An incisional biopsy of the lesion was sent for frozen section, which yielded a mixed inflammatory infiltrate consisting of neutrophils and lymphocytes and an overlying fibrous capsule. The diagnosis of lymphoma or another neoplasm could not be definitely ruled out. Owing to uncertainty in diagnosis, the entire lesion was excised along with the distal pancreas with the use of a linear stapler. The staple line was oversewn with running 4-0 polypropylene suture, and the pancreas was transplanted. After surgery, the pancreas allograft functioned well with a small pancreatic leak, which had resolved by the first postoperative outpatient visit. Published by Elsevier Inc.

  1. Comparison of allograft and polyetheretherketone (PEEK) cage subsidence rates in anterior cervical discectomy and fusion (ACDF).

    Science.gov (United States)

    Yson, Sharon C; Sembrano, Jonathan N; Santos, Edward Rainier G

    2017-04-01

    Structural allografts and PEEK cages are commonly used interbody fusion devices in ACDF. The subsidence rates of these two spacers have not yet been directly compared. The primary aim of this study was to compare the subsidence rate of allograft and PEEK cage in ACDF. The secondary aim was to determine if the presence of subsidence affects the clinical outcome. We reviewed 67 cases (117 levels) of ACDF with either structural allograft or PEEK cages. There were 85 levels (48 cases) with PEEK and 32 levels (19 cases) with allograft spacers. Anterior and posterior disc heights at each operative level were measured at immediate and 6months post-op. Subsidence was defined as a decrease in anterior or posterior disc heights >2mm. NDI of the subsidence (SG) and non-subsidence group (NSG) were recorded. Chi-square test was used to analyze subsidence rates. T-test was used to analyze clinical outcomes (α=0.05). There was no statistically significant difference between subsidence rates of the PEEK (29%; 25/85) and allograft group (28%; 9/32) (p=0.69). Overall mean subsidence was 2.3±1.7mm anteriorly and 2.6±1.2mm posteriorly. Mean NDI improvement was 11.7 (from 47.1 to 35.4; average follow-up: 12mos) for the SG and 14.0 (from 45.8 to 31.8; average follow-up: 13mos) for the NSG (p=0.74). Subsidence rate does not seem to be affected by the use of either PEEK or allograft as spacers in ACDF. Furthermore, subsidence alone does not seem to be predictive of clinical outcomes of ACDF. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Aortic allografts in treatment of aortic valve and ascending aorta prosthetic endocarditis

    Directory of Open Access Journals (Sweden)

    S.V. Spiridonov

    2017-03-01

    Full Text Available The aim – to assess short- and long-term results of aortic root replacement using aortic allografts in patients with prosthetic endocarditis. Materials and methods. Since February 2009 until June 2016 aortic valve and ascending aorta replacement using aortic allografts was performed in 26 patients with prosthetic endocarditis. In 50 % of cases at initial operation aortic valve replacement was performed, in another 50 % of cases – aortic valve and ascending aorta replacement. Echocardiography was performed 10 days, 3, 6 and 12 months, 2, 3 and 5 years after surgery. Analysis of long-term results included all cases of deaths, prosthesis-related complications and recurrence of endocarditis. Results. 30-day mortality was 23.1 %. Extracorporeal membranous oxygenation (ECMO was used only in 5 patients (19.2 %. Four patients were weaned from ECMO. We did not observe any allograft-related complications. During follow-up period there were no cases of reoperation due to structural allograft failure. Relapse of infection occurred in 1 patient (3.8 % four years after the operation and led to lethal outcome. Conclusion. Reoperations using allografts are an effective surgical treatment of prosthetic endocarditis. In majority of cases prosthetic endocarditis was caused by gram-positive cocci (Staphylococcus. In 84.6 % of cases it was associated with destruction of paravalvular structures and abscesses formation. Heart failure was a causative factor of different complications in these patients, which required ECMO in 19.2 % of patients. In 80 % of cases patients were weaned from ECMO. Allografts using for the treatment of prosthetic endocarditis is associated with high resistance to infection and with a significant rate of freedom from recurrence of endocarditis within 3 years after surgery.

  3. Anatomical Glenoid Reconstruction Using Fresh Osteochondral Distal Tibia Allograft After Failed Latarjet Procedure.

    Science.gov (United States)

    Sanchez, Anthony; Ferrari, Marcio B; Akamefula, Ramesses A; Frank, Rachel M; Sanchez, George; Provencher, Matthew T

    2017-04-01

    In the treatment of recurrent anterior glenohumeral instability, the Latarjet procedure has been shown to fail. This results in a need for viable revisional procedures for patients who present with this challenging pathology. We report our preferred technique for anatomical glenoid reconstruction using a fresh osteochondral distal tibia allograft after a failed Latarjet procedure. This bony augmentation technique employs a readily available dense, weight-bearing osseous tissue source that has excellent conformity, as well as the added benefit of a cartilaginous surface to correct chondral deficiencies. Given its effectiveness in the Latarjet revision setting and low complication rate, the distal tibia allograft is a reasonable treatment option.

  4. Does allograft failure impact school attendance in children? A NAPRTCS study.

    Science.gov (United States)

    Chen, Ashton; Martz, Karen; Rao, Panduranga

    2012-04-0