Science.gov

Sample records for acute cardiac rejection

  1. Expression of Tumor Necrosis Factor in Human Acute Cardiac Rejection

    PubMed Central

    Arbustini, Eloisa; Grasso, Maurizia; Diegoli, Marta; Bramerio, Manuela; Foglieni, Andrea Scotti; Albertario, Marco; Martinelli, Luigi; Gavazzi, Antonello; Goggi, Claudio; Campana, Carlo; Vigano, Mario

    1991-01-01

    The authors performed an immunohistochemical study on expression of tumor necrosis factor alpha (TNFα) in endomyocardial biopsies from human cardiac allografts. TNFα immunoreactivity was found in 45% biopsies with mild acute rejection, in 83% biopsies with focal moderate rejection, in 80% biopsies with diffuse moderate rejection. Biopsies with absent rejection did not show immunoreactive cells. In mild rejection, positive cells were few and scanty monocytes and macrophages (MAC-387 and LN5 positive cells) and T lymphocytes (UCHL-1/CD45 RO positive cells) (up to 20% of all infiltrating cells). Expression of major histocompatibility complex (MHC) class II antigens on infiltrating and endothelial cells occurred earlier and independent of TNFα reactivity. Number of immunoreactive cells increased in moderate rejection (up to 50%). Immunoreactivity was also present in nonpigmented macrophages in part of the biopsies with resolving rejection (45%). The authors conclude that TNFα is expressed in acute cardiac rejection by immunologically activated inflammatory cells. Immunoreactive cells increase in number with increasing severity of the reaction. ImagesFigure 1Figure 2Figure 3Figure 4 PMID:1928295

  2. The Complex Role of iNOS in Acutely-Rejecting Cardiac Transplants

    PubMed Central

    Pieper, Galen M.; Roza, Allan M.

    2008-01-01

    This review summarizes the evidence for a detrimental role of nitric oxide (NO) derived from inducible NO synthase (iNOS) and/or reactive nitrogen species such as peroxynitrite in acutely-rejecting cardiac transplants. In chronic cardiac transplant rejection, iNOS may have an opposing beneficial component. The purpose of this review is primarily to address issues related to acute rejection which is a recognized risk factor for chronic rejection. The evidence for a detrimental role is based upon strategies involving non-selective NOS inhibitors, NO neutralizers, selective iNOS inhibitors and iNOS gene deletion in rodent models of cardiac rejection. The review is discussed in the context of the impact on various components including graft survival, histological rejection and cardiac function which may contribute in toto to the process of graft rejection. Possible limitations of each strategy are discussed in order to understand better the variance in published findings including issues related to the potential importance of cell localization of iNOS expression. Finally, the concept of a dual role of NO and its down-stream product, peroxynitrite, in rejection vs. immune regulation is discussed. PMID:18291116

  3. Alteration in systemic vascular resistance and cardiac output during acute cellular rejection and recovery in heart transplant recipients.

    PubMed

    Garan, Arthur R; Uriel, Nir; Sayer, Gabriel; Sims, Daniel; Zahner, Doris; Farr, Maryjane; Mancini, Donna; Jorde, Ulrich P

    2010-03-01

    Coronary vascular reserve is impaired during acute cellular rejection of the orthotopically transplanted heart, but changes in the peripheral vasculature during rejection have not been well described. To investigate whether peripheral vascular compensatory mechanisms are preserved after orthotopic heart transplantation (OHT), we longitudinally observed systemic vascular resistance (SVR) and cardiac output (CO) during acute cellular rejection. CO decreased during high-grade acute cellular rejection, and maintenance of mean arterial pressure was achieved by increases in SVR, and these changes did not return to baseline until several months after histologic resolution of rejection. PMID:19875310

  4. Nitric oxide formation in acutely rejecting cardiac allografts correlates with GTP cyclohydrolase I activity

    PubMed Central

    2005-01-01

    Inducible nitric oxide synthase (iNOS) is a prominent component of the complex array of mediators in acute graft rejection. While NO production is determined by iNOS expression, BH4 (tetrahydrobiopterin), a cofactor of iNOS synthesized by GTP cyclohydrolase I, has been considered critical in sustaining NO production. In the present study, we examined time-dependent changes in iNOS and GTP cyclohydrolase I in rat cardiac allografts. The increase in iNOS protein and mRNA in allografts was similar at POD4 (post-operative day 4) and POD6. However, the peak increase in intragraft NO level at POD4 was not sustained at POD6. This disparity could not be explained by any decrease in iNOS enzyme activity measured ex vivo with optimal amounts of substrate and cofactors. Lower iNOS activity could be explained by changes in total biopterin levels in allografts at POD4 that was decreased to baseline at POD6. Changes in biopterin production correlated with lower GTP cyclohydrolase I protein levels but not by any change in GTP cyclohydrolase I mRNA. Functionally, allografts displayed bradycardia and distended diastolic and systolic dimensions at POD6 but not at POD4. Likewise, histological rejection scores were increased at POD4 but with a secondary increased stage at POD6. It is hypothesized that the dissimilar amounts of NO at early and later stages of rejection is due to uncoupling of iNOS arising from disproportionate synthesis of BH4. These findings provide insight into a potential pathway regulating NO bioactivity in graft rejection. Such knowledge may potentially assist in the design of newer strategies to prevent acute graft rejection. PMID:16000090

  5. Sirt1-Positive Lymphocytes in Acute Cellular Cardiac Allograft Rejection: Contributor to Pathogenesis and a Therapeutic Target.

    PubMed

    Welsh, Kerry J; Zhao, Bihong; Buja, L Maximilian; Brown, Robert E

    2016-01-01

    Cardiac allograft rejection remains a problem, despite advances with immunosuppressants. Understanding the mechanisms behind rejection is essential for developing targeted therapies. The goal of this investigation is to explore Sirtuin 1 (Sirt1) as a therapeutic target for cardiac allograft rejection. Thirteen endomyocardial biopsy specimens with acute cellular rejection (grade 2R or 3R) were selected. CD3, CD4, CD8, CD20, CD68, T-cell intracytoplasmic antigen (TIA-1), and Sirt1 expressions were determined by immunohistochemical stains. Comparison of Sirt1 expression was made with 10 cases of grade 0R and grade 1R. Quantitative image analysis was performed. There were 2 cases of grade 3R and 11 cases of grade 2R acute cellular rejection. Sirtuin 1 expression was present in the majority of mononuclear cells (median percentage, 73.5; interquartile range, 51.2-100%); staining was also observed in cardiomyocytes. Twelve of the 13 cases (92.3%) had an elevated CD8/FoxP3 ratio, coinciding with acute cellular rejection. Sirtuin 1 expression in the nuclei of FoxP3+ cells can lead to deacetylation and inactivation of FoxP3 rendering the T-suppressor cells inactive and promoting acute cellular rejection. The use of a Sirt1 inhibitor may be a therapeutic option in expanding the functionality of the FoxP3+ T-suppressor cells and moderating the severity of such rejection. PMID:26771391

  6. Prediction of acute cardiac rejection by changes in left ventricular volumes

    SciTech Connect

    Novitzky, D.; Cooper, D.K.; Boniaszczuk, J.

    1988-11-01

    Sixteen patients underwent heart transplantation (11 orthotopic, five heterotopic). Monitoring for acute rejection was by both endomyocardial biopsy (EMB) and multigated equilibrium blood pool scanning with technetium 99m-labelled red blood cells. From the scans information was obtained on left ventricular volumes (stroke, end-diastolic, and end-systolic), ejection fraction, and heart rate. Studies (208) were made in the 16 patients. There was a highly significant correlation between the reduction in stroke volume and end-diastolic volume (and a less significant correlation in end-systolic volume) and increasing acute rejection seen on EMB. Heart rate and ejection fraction did not correlate with the development of acute rejection. Correlation of a combination of changes in stroke volume and end-diastolic volume with EMB showed a sensitivity of 85% and a specificity of 96%. Radionuclide scanning is therefore a useful noninvasive tool for monitoring acute rejection.

  7. Effect of graft preservation and acute rejection on hypoxia-inducible factor-1 in rat cardiac allografts.

    PubMed

    Keränen, M A I; Nykänen, A I; Krebs, R; Tuuminen, R; Sandelin, H; Koskinen, P K; Lemström, K B

    2006-12-01

    Hypoxia plays an integral part in cardiac transplantation as prolonged graft preservation is an individual risk factor for the development of cardiac allograft vasculopathy (CAV). In this study we characterized the role of hypoxia-inducible factor-1 (HIF-1) during prolonged graft preservation, ischemia-reperfusion (I/R), acute rejection, and chronic rejection. Heart transplantations were performed from Dark Agouti (DA) to Wister-Furth (allo) or DA to DA (syn) rats, without immunosuppression (acute rejection model, harvested at day 5) or with cyclosporine (chronic rejection model, harvested at day 60). To study the effect of preservation on HIF-1 regulation, normal DA hearts were subjected to different cold ischemia times with or without 45 minutes of additional warm ischemia. The role of I/R was studied by harvesting syngrafts at different time points after reperfusion. Real-time reverse-transcriptase polymerase chain reaction quantified total HIF-1 mRNA, while enzyme-linked immunosorbent assay and immunohistochemistry quantified and localized HIF-1 protein. Our results show that HIF-1 nuclear immunoreactivity is increased during graft preservation and I/R leads to loss of nuclear HIF-1 immunoreactivity. Acute rejection induced HIF-1 in mRNA level. Our findings thus indicated that HIF-1 is activated during transplantation and suggested that manipulation of the HIF-1 pathway might reveal new therapeutic options to manage CAV. PMID:17175275

  8. Haptoglobin Enhances Cardiac Transplant Rejection

    PubMed Central

    Shen, Hua; Heuzey, Elizabeth; Mori, Daniel; Wong, Christine; Colangelo, Christopher; Chung, Lisa M.; Bruce, Can; Slizovskiy, Ilya B.; Booth, Carmen J.; Kreisel, Daniel; Goldstein, Daniel R.

    2015-01-01

    Rationale Early graft inflammation enhances both acute and chronic rejection of heart transplants, but it is unclear how this inflammation is initiated. Objective To identify specific inflammatory modulators and determine their underlying molecular mechanisms after cardiac transplantation. Methods and Results We used a murine heterotopic cardiac transplant model to identify inflammatory modulators of early graft inflammation. Unbiased mass spectrometric analysis of cardiac tissue before and up to 72 hours after transplantation revealed that 22 proteins including haptoglobin, a known anti-oxidant, are significantly upregulated in our grafts. Through the use of haptoglobin deficient mice, we show that 80% of haptoglobin deficient recipients treated with peri-operative administration of the costimulatory blocking agent CTLA4 immunoglobulin exhibited > 100 days survival of full major histocompatibility complex mismatched allografts, whereas all similarly treated wild type recipients rejected their transplants by 21 days post transplantation. We found that haptoglobin modifies the intra-allograft inflammatory milieu by enhancing levels of the inflammatory cytokine IL-6 and the chemokine MIP-2 but impair levels of the immunosuppressive cytokine IL-10. Haptoglobin also enhances dendritic cell graft recruitment and augments anti-donor T cell responses. Moreover, we confirmed that the protein is present in human cardiac allograft specimens undergoing acute graft rejection. Conclusions Our findings provide new insights into the mechanisms of inflammation after cardiac transplantation and suggest that, in contrast to its prior reported anti-oxidant function in vascular inflammation, haptoglobin is an enhancer of inflammation after cardiac transplantation. Haptoglobin may also be a key component in other sterile inflammatory conditions. PMID:25801896

  9. Renal and Cardiac Endothelial Heterogeneity Impact Acute Vascular Rejection in Pig-to-Baboon Xenotransplantation

    PubMed Central

    Knosalla, C.; Yazawa, K.; Behdad, A.; Bodyak, N.; Shang, H.; Bühler, L.; Houser, S.; Gollackner, B.; Griesemer, A.; Schmitt-Knosalla, I.; Schuurman, H.-J.; Awwad, M.; Sachs, D. H.; Cooper, D. K. C.; Yamada, K.; Usheva, A.; Robson, S. C.

    2010-01-01

    Xenograft outcomes are dictated by xenoantigen expression, for example, Gal α 1, 3Gal (Gal), but might also depend on differing vascular responses. We investigated whether differential vascular gene expression in kidney and cardiac xenografts correlate with development of thrombotic microangiopathy (TM) and consumptive coagulation (CC). Immunosuppressed baboons underwent miniswine or hDAF pig kidney (n = 6) or heart (n = 7), or Gal-transferase gene-knockout (GalT-KO) (thymo)kidney transplantation (n = 14). Porcine cDNA miniarrays determined donor proinflammatory, apoptosis-related and vascular coagulant/fibrinolytic gene expression at defined time points; validated by mRNA, protein levels and immunopathology. hDAF-transgenic and GalT-KO xenografts, (particularly thymokidneys) exhibited prolonged survival. CC was seen with Gal-expressing porcine kidneys (3 of 6), only 1 of 7 baboons post-cardiac xenotransplantation and was infrequent following GalT-KO grafts (1 of 14). Protective-type genes (heme oxygenase-I, superoxide dismutases and CD39) together with von Willebrand factor and P-selectin were upregulated in all renal grafts. Transcriptional responses in Gal-expressing xenografts were comparable to those seen in the infrequent GalT-KO rejection. In cardiac xenografts, fibrin deposition was associated with increased plasminogen activator inhibitor-1 expression establishing that gene expression profiles in renal and cardiac xenografts differ in a quantitative manner. These findings suggest that therapeutic targets may differ for renal and cardiac xenotransplants. PMID:19422330

  10. Treating humoral rejection after cardiac transplantation.

    PubMed

    Verheyen, Jef; Vermeulen, Tom; Janssen Van Doorn, Karin; Vrints, Christiaan; Conraads, Viviane

    2011-04-01

    Whereas effective strategies are available to treat acute cellular cardiac rejection, humoral rejection, also called vascular or antibody-mediated rejection, is more difficult to manage. Antibody-mediated (non-cellular) rejections (AMR) are rare and few successfully treated cases have been described in the literature. We report on a female patient, diagnosed with humoral rejection, leading to severe ventricular dysfunction and haemodynamic compromise, two months after transplantation. The patient received a combination therapy, consisting of plasmapheresis and immunoglobulins, which resulted in complete resolution of immunohistochemical signs of AMR. In this report, we will overview AMR and discuss several treatment modalities. PMID:21591590

  11. Diagnostic Performance of Echocardiography for the Detection of Acute Cardiac Allograft Rejection: A Systematic Review and Meta-Analysis

    PubMed Central

    Pan, Xudong; Sun, Lizhong

    2015-01-01

    Objective Many studies have addressed the diagnostic performance of echocardiography to evaluate acute cardiac allograft rejection compared with endomyocardial biopsy. But the existence of heterogeneity limited its clinical application. Thus, we conducted a comprehensive, systematic literature review and meta-analysis for the purpose. Methods Studies prior to September 1, 2014 identified by Medline/PubMed, EMBASE and Cochrance were examined by two independent reviews. We conducted meta-analysis by using Meta-DiSc 1.4 software. An assessment tool of QUADAS-2 was applied to evaluate the risk of bias and applicability of the studies. Results Thirty studies met the inclusion criteria of meta-analysis. The four parameters of pressure half time, isovolumic relaxation time, index of myocardial performance and late diastolic mitral annular motion velocity were included in the meta-analysis, with a pooled diagnostic odds ratio of 10.43, 6.89, 15.95 and 5.68 respectively, and the area under the summary receiver operating characteristic curves value of 0.829, 0.599, 0.871 and 0.685 respectively. Conclusion The meta-analysis and systematic review demonstrate that no single parameter of echocardiography showed a reliable diagnostic performance for acute cardiac allograft rejection. A result of echocardiography for ACAR should be comprehensively considered by physicians in the context of clinical presentations and imaging feature. PMID:25822627

  12. Thallium kinetics in rat cardiac transplant rejection

    SciTech Connect

    Barak, J.H.; LaRaia, P.J.; Boucher, C.A.; Fallon, J.T.; Buckley, M.J.

    1988-04-01

    Cardiac transplant rejection is a very complex process involving both cellular and vascular injury. Recently, thallium imaging has been used to assess acute transplant rejection. It has been suggested that changes in thallium kinetics might be a sensitive indicator of transplant rejection. Accordingly, thallium kinetics were assessed in vivo in acute untreated rat heterotopic (cervical) transplant rejection. Male Lewis rats weighing 225-250 g received heterotopic heart transplants from syngeneic Lewis rats (group A; n = 13), or allogeneic Brown Norway rats (group B; n = 11). Rats were imaged serially on the 2nd and the 7th postoperative days. Serial cardiac thallium content was determined utilizing data collected every 150 sec for 2 hr. The data were fit to a monoexponential curve and the decay rate constant (/sec) derived. By day 7 all group B hearts had histological evidence of severe acute rejection, and demonstrated decreased global contraction. Group A hearts showed normal histology and contractility. However, thallium uptakes and washout of the two groups were the same. Peak thallium uptake of group B was +/- 3758 1166 counts compared with 3553 +/- 950 counts in the control group A (P = 0.6395); The 2-hr percentage of washout was 12.1 +/- 1.04 compared with 12.1 +/- 9.3 (P = 1.0000); and the decay constant was -0.00002065 +/- 0.00001799 compared with -0.00002202 +/- 0.00001508 (P = 0.8409). These data indicate that in vivo global thallium kinetics are preserved during mild-to-severe acute transplant rejection. These findings suggest that the complex cellular and extracellular processes of acute rejection limit the usefulness of thallium kinetics in the detection of acute transplant rejection.

  13. Successful use of the TandemHeart percutaneous ventricular assist device as a bridge to recovery for acute cellular rejection in a cardiac transplant patient.

    PubMed

    Velez-Martinez, M; Rao, K; Warner, J; Dimaio, J; Ewing, G; Mishkin, J D; Mammen, P P A; Drazner, M H; Markham, D W; Patel, P C

    2011-12-01

    In this report, we presented a patient who benefited from hemodynamic support with the TandemHeart percutaneous ventricular assist device (pVAD; Cardiac Assist, Inc) implantation in the setting of early acute graft rejection 2 months after orthotopic heart transplant. The TandemHeart initially had been used for temporary hemodynamic assistance during postcardiotomy heart failure and high-risk coronary interventions. More recently, its use in patients with cardiogenic shock from acute myocardial infarction, fulminant myocarditis, and critical aortic stenosis has been reported. To our knowledge, this is one of the first reported cases in which the TandemHeart pVAD served as a successful device for support during acute cardiac transplant rejection. PMID:22172864

  14. Cellular and Functional Imaging of Cardiac Transplant Rejection

    PubMed Central

    Wu, Yijen L.; Ye, Qing

    2011-01-01

    Heart transplantation is now an established treatment for patients suffering from end-stage heart diseases. With the advances in immunosuppressive treatment, the survival rate for transplant patients has improved greatly. However, allograft rejection, both acute and chronic, after heart transplantation is still a limitation leading to morbidity and mortality. The current clinical gold standard for screening rejection is endomyocardial biopsy (EMB), which is not only invasive, but also error-prone, due to the limited sample size and the site location of sampling. It would be highly desirable to have reliable and noninvasive alternatives for EMB in monitoring cardiac allograft rejection. The objective of this review is to highlight how cardiovascular imaging can contribute to noninvasively detecting and to evaluating both acute and chronic allograft rejection after heart transplantation, in particular, cardiovascular MRI (CMRI); and how CMRI can assess both immune cell infiltration at the rejecting organ, and the cardiac dysfunctions resulting from allograft rejection. PMID:21359095

  15. Smooth muscle cells of the coronary arterial tunica media express tumor necrosis factor-alpha and proliferate during acute rejection of rabbit cardiac allografts.

    PubMed Central

    Tanaka, H.; Swanson, S. J.; Sukhova, G.; Schoen, F. J.; Libby, P.

    1995-01-01

    Graft coronary arteriosclerosis (GCA) frequently limits the long-term success of cardiac transplantation. The pathogenic mechanisms of and stimuli that provoke GCA remain uncertain. Whatever the initiating factors, deranged control of smooth muscle cells (SMC) proliferation likely contributes to the intimal hyperplasia that produces obstructive lesions. To identify mediators that may contribute to ongoing modulation of SMC functions during acute rejection and to explore the mechanisms of the pathogenesis of graft coronary arteriosclerosis, we studied the kinetics of proliferation and the expression of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory and SMC growth-promoting cytokine, in coronary arterial SMCs in rabbit hearts transplanted heterotopically without immunosuppression. Hearts were harvested at 2 (n = 5), 5 (n = 5), and 8.2 +/- 0.4 (mean +/- SD, n = 5) days after transplantation, just before graft failure as judged clinically. SMC proliferation was assessed by continuous bromodeoxyuridine labeling (BrdU 10 mg/kg/d. s.q.). Whole heart cross sections were stained immunohistochemically with monoclonal antibodies that recognize TNF-alpha, BrdU, and SMCs (muscle alpha-actin). Major epicardial coronary arteries (five to nine profiles in each animal) were evaluated. Histological rejection grades by the International Society for Heart and Lung Transplantation scale at 2, 5, and 10 days were 1.6 +/- 0.9, 2.8 +/- 1.1, and 4.0 +/- 0.0, respectively. Medial SMCs in normal hearts and 2 days after transplant expressed little or no TNF-alpha and displayed negligible BrdU incorporation. At 5 days after transplantation, some medial SMCs stained for TNF-alpha and had a low BrdU labeling index (0.5 +/- 0.8%). At 8.2 days after transplant, almost all medial SMCs expressed TNF-alpha intensely and had a high labeling index (29.8 +/- 8.0%). These results demonstrate that acute rejection activates medial SMCs in coronary arteries to express TNF-alpha and that SMC

  16. Antimyosin imaging in cardiac transplant rejection

    SciTech Connect

    Johnson, L.L.; Cannon, P.J. )

    1991-09-01

    Fab fragments of antibodies specific for cardiac myosin have been labeled with indium-111 and injected intravenously into animals and into patients with heart transplants. The antibodies, developed by Khaw, Haber, and co-workers, localize in cardiac myocytes that have been damaged irreversibly by ischemia, myocarditis, or the rejection process. After clearance of the labeled antibody from the cardiac blood pool, planar imaging or single photon emission computed tomography is performed. Scintigrams reveal the uptake of the labeled antimyosin in areas of myocardium undergoing transplant rejection. In animal studies, the degree of antimyosin uptake appears to correlate significantly with the degree of rejection assessed at necropsy. In patients, the correlation between scans and pathologic findings from endomyocardial biopsy is not as good, possibly because of sampling error in the endomyocardial biopsy technique. The scan results at 1 year correlate with either late complications (positive) or benign course (negative). Current limitations of the method include slow blood clearance, long half-life of indium-111, and hepatic uptake. Overcoming these limitations represents a direction for current research. It is possible that from these efforts a noninvasive approach to the diagnosis and evaluation of cardiac transplantation may evolve that will decrease the number of endomyocardial biopsies required to evaluate rejection. This would be particularly useful in infants and children. 31 references.

  17. Renal graft irradiation in acute rejection

    SciTech Connect

    Pilepich, M.V.; Sicard, G.A.; Breaux, S.R.; Etheredge, E.E.; Blum, J.; Anderson, C.B.

    1983-03-01

    To evaluate the effect of graft irradiation in the treatment of acute rejection of renal transplants, a randomized study was conducted from 1978 to 1981. Patients with acute rejection were given standard medical management in the form of intravenous methylprednisolone, and were chosen randomly to receive either graft irradiation (175 rads every other day, to a total of 525 rads) or simulated (sham) irradiation. Eighty-three rejections occurring in 64 grafts were randomized to the protocol. Rejection reversal was recorded in 84.5% of control grafts and 75% of the irradiated grafts. Recurrent rejections were more frequent and graft survival was significantly lower in the irradiated group (22%) than in the control group (54%). Graft irradiation does not appear to be beneficial in the treatment of acute rejection of renal transplants when used in conjunction with high-dose steroids.

  18. The biology of acute transplant rejection.

    PubMed Central

    Tilney, N L; Kupiec-Weglinski, J W

    1991-01-01

    An intriguing and increasingly understood facet of immune responses is the ability of a recipient to destroy a foreign tissue or organ graft. The phenomenon of acute rejection of an allograft involves a series of complex and inter-related cellular and humoral events, culminating in graft death. Some of the current thinking surrounding this phenomenon is reviewed. PMID:1867525

  19. Imaging of cardiac allograft rejection in dogs using indium-111 monoclonal antimyosin Fab

    SciTech Connect

    Addonizio, L.J.; Michler, R.E.; Marboe, C.; Esser, P.E.; Johnson, L.L.; Seldin, D.W.; Gersony, W.M.; Alderson, P.O.; Rose, E.A.; Cannon, P.J.

    1987-03-01

    The acute rejection of cardiac allografts is currently diagnosed by the presence of myocyte necrosis on endomyocardial biopsy. We evaluated the efficacy of noninvasive scintigraphic imaging with indium-111-labeled anticardiac myosin Fab fragments (indium-111 antimyosin) to detect and quantify cardiac allograft rejection. Six dogs that had intrathoracic heterotopic cardiac allograft transplantation were injected with indium-111 antimyosin and planar and single photon emission computed tomographic (SPECT) images were obtained in various stages of acute and subacute rejection. Four dogs had an allograft older than 8 months and had been on long-term immunosuppressive therapy; two dogs had an allograft less than 2 weeks old and were not on immunosuppressive therapy. Count ratios comparing heterotopic with native hearts were calculated from both SPECT images and in vitro scans of excised and sectioned hearts and were compared with the degree of rejection scored by an independent histopathologic review. Indium-111 antimyosin uptake was not visible in planar or SPECT images of native hearts. Faint diffuse uptake was apparent in cardiac allografts during long-term immunosuppression and intense radioactivity was present in hearts with electrocardiographic evidence of rejection. The heterotopic to native heart count ratios in SPECT images correlated significantly with the count ratios in the excised hearts (r = 0.93) and with the histopathologic rejection score (r = 0.97). The distribution of indium-111 antimyosin activity in right and left ventricles corresponded to areas of histopathologic abnormalities.

  20. Total lymphoid irradiation for treatment of intractable cardiac allograft rejection

    SciTech Connect

    Hunt, S.A.; Strober, S.; Hoppe, R.T.; Stinson, E.B. )

    1991-03-01

    The ability of postoperative total lymphoid irradiation to reverse otherwise intractable cardiac allograft rejection was examined in a group of 10 patients in whom conventional rejection therapy (including pulsed steroids and monoclonal or polyclonal anti-T-cell antibody therapy) had failed to provide sustained freedom from rejection. Follow-up periods range from 73 to 1119 days since the start of total lymphoid irradiation. No patient died or sustained serious morbidity because of the irradiation. Three patients have had no further rejection (follow-up periods, 105 to 365 days). Two patients died--one in cardiogenic shock during the course of total lymphoid irradiation, the other with recurrent rejection caused by noncompliance with his medical regimen. Total lymphoid irradiation appears to be a safe and a moderately effective immunosuppressive modality for 'salvage' therapy of cardiac allograft rejection unresponsive to conventional therapy.

  1. Cardiac function and rejection following transplantation of the heart

    SciTech Connect

    Schober, O.; Schuler, S.; Gratz, K.; Warnecke, H.; Lang, W.; Hetzer, R.; Creutzig, H.

    1985-05-01

    It was the purpose of the study to evaluate the noninvasive detection of rejection following cardiac transplantation. Multigated cardiac blood pool imaging (MUGA) at rest with assessment of ejection fraction (EF) and regional wall motion was determined prospectively in 14 patients with 180 studies (follow up 5.1 +- 3.2 months) following orthotopic cardiac transplantation. The results were compared with histological examination of a percutaneous endocardial biopsy specimen (EMB) from the right ventricle. Diagnosis of rejection by EF measurement was defined by a decrease of 10% if EF < 70%, and 15% if EF > 70%. In 152 studies a normal MUGA study correlated with none rejection as defined by EMB. In 14 of 22 studies with moderate or severe rejection decrease of EF followed the rejection with a delay of 5 days. Septal wall motion abnormalities were typical. In 6 studies an abnormal temporal course of EF was not related to a similar finding in EMB. A sensitivity of 69% and a specifity of 96% can be estimated in the investigated group, in which all patients survived during the period of the study. It is concluded that rejection can be excluded by noninvasive MUGA (specifity 96%) and that MUGA is predictive of rejection (sensitivity 67%) mostly with a delay of 5 days.

  2. Detection of cardiac transplant rejection with radiolabeled lymphocytes. [Rats

    SciTech Connect

    Bergmann, S.R.; Lerch, R.A.; Carlson, E.M.; Saffitz, J.E.; Sobel, B.E.

    1982-03-01

    To determine whether rejections of cardiac transplants could be detected specifically and non-invasively by lymphocytes labeled with indium-111 (111In), we studied 36 allogeneic and 14 isogeneic heterotopic cardiac transplants in rats. Allogeneic grafts accumulated autologous 111In-lymphocytes, detectable scintigraphically 24 hours after i.v. injection of the labeled cells. At the time of peak histologic rejection, the allogeneic grafts accumulated 92. +/- 4.8 times more activity than the native hearts (determined by well counting). The tissue-to-blood ratio in the rejecting transplants was 3.7 +/- 2.2; total uptake by the graft was 2.9 +/- 2.1% of the injected dose. Autoradiography confirmed that graft radioactivity was associated with labeled lymphocytes. In contrast, isogeneic grafts showed no signs of rejection and did not accumulate radioactivity. Because conventionally isolated and labeled lymphocytes are often contaminated with platelets, we prepared both 111In-platelets and purified 111In-lymphocytes for use in additional experiments. Allogeneic grafts accumulated platelets and purified lymphocytes independently. Thus, deposition of immunologically active cells in the rejecting graft representing specific pathophysiologic events can be detected. The results suggest that rejection of cardiac transplants can be detected noninvasively, potentially facilitating objective early clinical detection of rejection and titration of antirejection therapy.

  3. LATE ACUTE REJECTION IN LIVER TRANSPLANT: A SYSTEMATIC REVIEW

    PubMed Central

    NACIF, Lucas Souto; PINHEIRO, Rafael Soares; PÉCORA, Rafael Antônio de Arruda; DUCATTI, Liliana; ROCHA-SANTOS, Vinicius; ANDRAUS, Wellington; D'ALBUQUERQUE, Luiz Carneiro

    2015-01-01

    Introduction: Late acute rejection leads to worse patient and graft survival after liver transplantation. Aim: To analyze the reported results published in recent years by leading transplant centers in evaluating late acute rejection and update the clinical manifestations, diagnosis and treatment of liver transplantation. Method: Systematic literature review through Medline-PubMed database with headings related to late acute rejection in articles published until November 2013 was done. Were analyzed demographics, immunosuppression, rejection, infection and graft and patient survival rates. Results: Late acute rejection in liver transplantation showed poor results mainly regarding patient and graft survival. Almost all of these cohort studies were retrospective and descriptive. The incidence of late acute rejection varied from 7-40% in these studies. Late acute rejection was one cause for graft loss and resulted in different outcomes with worse patient and graft survival after liver transplant. Late acute rejection has been variably defined and may be a cause of chronic rejection with worse prognosis. Late acute rejection occurs during a period in which the goal is to maintain lower immunosuppression after liver transplantation. Conclusion: The current articles show the importance of late acute rejection. The real benefit is based on early diagnosis and adequate treatment at the onset until late follow up after liver transplantation. PMID:26537150

  4. Imaging-based diagnosis of acute renal allograft rejection

    PubMed Central

    Thölking, Gerold; Schuette-Nuetgen, Katharina; Kentrup, Dominik; Pawelski, Helga; Reuter, Stefan

    2016-01-01

    Kidney transplantation is the best available treatment for patients with end stage renal disease. Despite the introduction of effective immunosuppressant drugs, episodes of acute allograft rejection still endanger graft survival. Since efficient treatment of acute rejection is available, rapid diagnosis of this reversible graft injury is essential. For diagnosis of rejection, invasive core needle biopsy of the graft is the “gold-standard”. However, biopsy carries the risk of significant graft injury and is not immediately feasible in patients taking anticoagulants. Therefore, a non-invasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review current imaging-based state of the art approaches for non-invasive diagnostics of acute renal transplant rejection. We especially focus on new positron emission tomography-based as well as targeted ultrasound-based methods. PMID:27011915

  5. Ischemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts.

    PubMed

    Dashkevich, A; Raissadati, A; Syrjälä, S O; Zarkada, G; Keränen, M A I; Tuuminen, R; Krebs, R; Anisimov, A; Jeltsch, M; Leppänen, V-M; Alitalo, K; Nykänen, A I; Lemström, K B

    2016-04-01

    Organ damage and innate immunity during heart transplantation may evoke adaptive immunity with serious consequences. Because lymphatic vessels bridge innate and adaptive immunity, they are critical in immune surveillance; however, their role in ischemia-reperfusion injury (IRI) in allotransplantation remains unknown. We investigated whether the lymphangiogenic VEGF-C/VEGFR3 pathway during cardiac allograft IRI regulates organ damage and subsequent interplay between innate and adaptive immunity. We found that cardiac allograft IRI, within hours, increased graft VEGF-C expression and lymphatic vessel activation in the form of increased lymphatic VEGFR3 and adhesion protein expression. Pharmacological VEGF-C/VEGFR3 stimulation resulted in early lymphatic activation and later increase in allograft inflammation. In contrast, pharmacological VEGF-C/VEGFR3 inhibition during cardiac allograft IRI decreased early lymphatic vessel activation with subsequent dampening of acute and chronic rejection. Genetic deletion of VEGFR3 specifically in the lymphatics of the transplanted heart recapitulated the survival effect achieved by pharmacological VEGF-C/VEGFR3 inhibition. Our results suggest that tissue damage rapidly changes lymphatic vessel phenotype, which, in turn, may shape the interplay of innate and adaptive immunity. Importantly, VEGF-C/VEGFR3 inhibition during solid organ transplant IRI could be used as lymphatic-targeted immunomodulatory therapy to prevent acute and chronic rejection. PMID:26689983

  6. IL-15 is decreased upon CsA and FK506 treatment of acute rejection following heart transplantation in mice

    PubMed Central

    YU, ZHIYONG; ZHOU, XIAOPING; YU, SONGFENG; XIE, HAIYANG; ZHENG, SHUSEN

    2015-01-01

    The aim of this study was to investigate the effect of cyclosporine A (CsA) and tacrolimus (FK506) on interleukin-15 (IL-15) production during acute rejection following heart transplantation in mice. Inbred male Balb/c (H-2d) and C57BL/6 (H-2b) mice were used to establish a heterotopic intra-abdominal cardiac transplantation model. The mice were divided in four groups: syngeneic control, allogeneic acute rejection, allogeneic rejection treated with CsA, and allogeneic rejection treated with FK506. The expression of IL-15, IL-2, and tumor necrosis factor-α (TNF-α) was measured using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. A low level of IL-15 was detected in transplanted hearts of the control group, with a significant increase observed in the allogeneic acute rejection group. Compared to the allogeneic acute rejection group, IL-15 expression was significantly decreased in the CsA-and FK506-treated allogeneic rejection groups. The TNF-α expression pattern was similar to that of IL-15 in all groups. IL-2 expression was increased in the allogeneic acute rejection group and was inhibited in mice treated with CsA and FK506. In conclusion, increased IL-15 expression in rejected murine heart grafts may be reduced by CsA and FK506 in vivo. PMID:25333459

  7. 19F MRI detection of acute allograft rejection with in vivo perfluorocarbon labeling of immune cells.

    PubMed

    Hitchens, T Kevin; Ye, Qing; Eytan, Danielle F; Janjic, Jelena M; Ahrens, Eric T; Ho, Chien

    2011-04-01

    Current diagnosis of organ rejection following transplantation relies on tissue biopsy, which is not ideal due to sampling limitations and risks associated with the invasive procedure.We have previously shown that cellular magnetic resonance imaging (MRI) of iron-oxide labeled immune-cell infiltration can provide a noninvasive measure of rejection status by detecting areas of hypointensity on T 2*-weighted images. In this study, we tested the feasibility of using a fluorine-based cellular tracer agent to detect macrophage accumulation in rodent models of acute allograft rejection by fluorine-19 ((19) F) MRI and magnetic resonance spectroscopy. This study used two rat models of acute rejection, including abdominal heterotopic cardiac transplant and orthotopic kidney transplant models. Following in vivo labeling of monocytes and macrophages with a commercially available agent containing perfluoro-15-crown-5-ether, we observed (19) F-signal intensity in the organs experiencing rejection by (19) F MRI, and conventional (1) H MRI was used for anatomical context. Immunofluorescence and histology confirmed macrophage labeling. These results are consistent with our previous studies and show the complementary nature of the two cellular imaging techniques. With no background signal, (19) F MRI/magnetic resonance spectroscopy can provide unambiguous detection of fluorine labeled cells, and may be a useful technique for detecting and quantifying rejection grade in patients. PMID:21305593

  8. Acute kidney injury after pediatric cardiac surgery

    PubMed Central

    Singh, Sarvesh Pal

    2016-01-01

    Acute kidney injury is a common complication after pediatric cardiac surgery. The definition, staging, risk factors, biomarkers and management of acute kidney injury in children is detailed in the following review article. PMID:27052074

  9. Early diagnosis of acute postoperative renal transplant rejection

    SciTech Connect

    Tisdale, P.L.; Collier, B.D.; Kauffman, H.M.; Adams, M.B.; Isitman, A.T.; Hellman, R.S.; Rao, S.A.; Joestgen, T.; Krohn, L.

    1985-05-01

    A prospective evaluation of In-111 labeled autologous platelet scintigraphy for the early diagnosis of acute postoperative renal transplant rejection was undertaken. To date, 28 consecutive patients between 7 and 14 days post-op have been injected with 500..mu..Ci of In-111 platelets followed by imaging at 24 and 48 hours. Activity within the renal transplant exceeding activity in the adjacent iliac vessels was considered to be evidence of rejection, and both chemical evidence and clinical impression of rejection at 5 days after completion of imaging was accepted as proof of ongoing or incipient rejection at the time of scintigraphy. In addition, to visual inspection, independent quantitative analysis compared the area-normalized activity over the transplant with the adjacent iliac vessels (normal <1.0). For 5 patients, positive In-111 scintigraphy was present before convincing clinical evidence of rejection. In-111 platelet scintigraphy is useful not only to confirm the clinical diagnosis of rejection but also to establish the early, pre-clinical diagnosis of incipient acute postoperative renal transplant rejection.

  10. Noninvasive detection of human cardiac transplant rejection with indium-111 antimyosin (Fab) imaging

    SciTech Connect

    Frist, W.; Yasuda, T.; Segall, G.; Khaw, B.A.; Strauss, H.W.; Gold, H.; Stinson, E.; Oyer, P.; Baldwin, J.; Billingham, M.

    1987-11-01

    Diagnosis of rejection after cardiac transplantation is currently made by right ventricular endomyocardial biopsy. To evaluate antimyosin imaging as a noninvasive means of detecting human cardiac rejection, the Fab fragment of murine monoclonal antimyosin antibodies was labeled with indium-111 and given intravenously to 18 patients (age 45 +/- 12 years) in 20 studies 7 days to 9 years after transplantation. Endomyocardial biopsy specimens were obtained at the time of each imaging study. Eight patients had positive scans confirmed by biopsy as rejection, and eight patients had negative scans and no evidence of rejection on biopsy. Discordance was observed in four studies, two with positive scans and no rejection on biopsy and two with negative scans and positive biopsy. The sensitivity, specificity, and overall accuracy of the technique were each 80%. Imaging with radiolabeled antimyosin antibody Fab fragments may be of value in the noninvasive identification of rejection in the cardiac transplant recipient.

  11. Acute allograft rejection and immunosuppression: influence on endogenous melatonin secretion.

    PubMed

    Cardell, Markus; Jung, Florian Johannes; Zhai, Wei; Hillinger, Sven; Welp, Andre; Manz, Bernhard; Weder, Walter; Korom, Stephan

    2008-04-01

    Melatonin displays a dose-dependent immunoregulatory effect in vitro and in vivo. Exogenous high-dose melatonin therapy exerted an immunosuppressive effect, abrogating acute rejection (AR), significantly prolonging transplant survival. Endogenous melatonin secretion, in response to heterotopic rat cardiac allograft transplantation (Tx), was investigated during the AR response and under standardized immunosuppressive maintenance therapy with cyclosporin A (CsA) and rapamycin (RPM). Recipients of syngeneic transplants, and recipients of allogeneic grafts, either untreated or receiving immunosuppressive therapy constituted the experimental groups. Endogenous circadian melatonin levels were measured at 07:00, 19:00, and 24:00 hr, using a novel radioimmunoassay (RIA) procedure, under standardized 12-hr-light/dark-conditions (light off: 19:00 hr; light on: 07:00 hr), before and after Tx. Neither the operative trauma, nor the challenge with a perfused allograft or the AR response influenced endogenous melatonin peak secretion. Immunosuppressive therapy with CsA led to a significant increase in peak secretion, measured for days 7 (212 +/- 40.7 pg/mL; P < 0.05), 14 (255 +/- 13.9 pg/mL; P < 0.001), and 21 (219 +/- 34 pg/mL; P < 0.01) after Tx, as compared with naïve animals (155 +/- 25.8 pg/mL). In contrast, treatment with RPM significantly decreased the melatonin peak post-Tx up to day 7 (87 +/- 25.2 pg/mL; P < 0.001), compared with naïve animals (155 +/- 25.8 pg/mL). These findings imply a robust nature of the endogenous circadian melatonin secretion kinetics, even against the background of profound allogeneic stimuli. Immunosuppressive maintenance therapy with CsA and RPM modulated early melatonin secretion, indicating a specific secondary action of these drugs. Further studies are necessary to disclose the long-term effect of immunosuppressive therapy on circadian melatonin secretion in transplant recipients. PMID:18339121

  12. Failure to diagnose cardiac treatment rejection with Tc99m-PYP images

    SciTech Connect

    McKillop, J.H.; McDougall, I.R.; Goris, M.L.; Mason, J.W.; Reitz, B.A.

    1981-08-01

    The possibility of diagnosing transplant rejection using Tc-99m-PYP imaging was examined in 12 cardiac transplant recipients. Two patients were studied on two occasions. The presence or absence of active rejection was established by endomyocardial biopsy. The intensity and pattern of myocardial uptake of the tracer did not differ significantly in the two patients studied at the time of rejection compared to the remainder. It is concluded that a single Tc-99m-PYP study cannot be used to diagnose cardiac transplant rejection.

  13. Rejection of cardiac allografts by T cells expressing a restricted repertoire of T-cell receptor V beta genes.

    PubMed Central

    Shirwan, H; Barwari, L; Cramer, D V

    1997-01-01

    We have recently shown that T cells infiltrating cardiac allografts early in graft rejection use a limited T-cell receptor (TCR) V beta repertoire. In this study we tested whether this limited repertoire of V beta genes is important for graft rejection. A cell line, AL2-L3, was established from LEW lymphocytes infiltrating ACI heart allografts 2 days after transplantation. This cell line is composed of CD4+ T cells that primarily recognize the class II RTI.B major histocompatibility complex (MHC) molecule expressed by the donor graft. This cell line precipitated acute rejection of donor hearts with a median survival time (MST) of 10.5 days following adoptive transfer to sublethally irradiated LEW recipients. This rate of graft rejection was significantly (P < 0.0007) accelerated when compared with a MST of 60 days for allografts in irradiated control recipients. The AL2-L3-mediated acceleration of graft rejection was donor specific as WF third-party heart allografts were rejected with a delayed tempo (MST = 28.5 days). The V beta repertoire of this cell line was primarily restricted to the expression of V beta 4, 15 and 19 genes. The nucleotide sequence analysis of the beta-chain cDNAs from this cell line demonstrated that the restricted use of the V gene repertoire was not shared with the N, D and J regions. A wide variety of CDR3 loops and J beta genes were used in association with selected V beta genes. These data provide evidence for the role a restricted repertoire of V beta genes plays in cardiac allograft rejection in this model. The restricted usage of the V beta repertoire in an early T-cell response to allografts may provide the opportunity to therapeutically disrupt the rejection reaction by targeting selected T-cell populations for elimination at the time of organ transplantation. Images Figure 2 PMID:9176111

  14. Acute myocarditis presenting as cardiac tamponade.

    PubMed Central

    Nwizu, Chidi; Onwuanyi, Anekwe E.

    2004-01-01

    We report a case of acute fulminant myocarditis presenting with cardiac tamponade and shock. The patient was managed in the coronary care unit with emergency pericardiotomy, invasive hemodynamic monitoring, and supportive therapy for cardiac failure. Pleural effusion and pneumonia complicated her clinical course. She responded well to therapy with normalization of left ventricular systolic function. This case demonstrates the potential for complete recovery with appropriate management in acute myocarditis even with a fulminant course. Images Figure 1 PMID:15586655

  15. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection.

    PubMed

    Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E; Padera, Robert F; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D'Agostino, Emmanuel; Goldberg, Hilary J; Perrella, Mark A; Forteza, Rosanna Malbran; Rosas, Ivan O; Visner, Gary; El-Chemaly, Souheil

    2015-11-01

    Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

  16. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

    PubMed Central

    Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E.; Padera, Robert F.; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D’Agostino, Emmanuel; Goldberg, Hilary J.; Perrella, Mark A.; Forteza, Rosanna Malbran; Rosas, Ivan O.; Visner, Gary; El-Chemaly, Souheil

    2015-01-01

    Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

  17. Blocking MHC class II on human endothelium mitigates acute rejection

    PubMed Central

    Abrahimi, Parwiz; Qin, Lingfeng; Chang, William G.; Bothwell, Alfred L.M.; Tellides, George; Saltzman, W. Mark; Pober, Jordan S.

    2016-01-01

    Acute allograft rejection is mediated by host CD8+ cytotoxic T lymphocytes (CTL) targeting graft class I major histocompatibility complex (MHC) molecules. In experimental rodent models, rejection requires differentiation of naive CD8+ T cells into alloreactive CTL within secondary lymphoid organs, whereas in humans, CTL may alternatively develop within the graft from circulating CD8+ effector memory T cells (TEM) that recognize class I MHC molecules on graft endothelial cells (EC). This latter pathway is poorly understood. Here, we show that host CD4+ TEM, activated by EC class II MHC molecules, provide critical help for this process. First, blocking HLA-DR on EC lining human artery grafts in immunodeficient mice reduces CD8+ CTL development within and acute rejection of the artery by adoptively transferred allogeneic human lymphocytes. Second, siRNA knockdown or CRISPR/Cas9 ablation of class II MHC molecules on EC prevents CD4+ TEM from helping CD8+ TEM to develop into CTL in vitro. Finally, implanted synthetic microvessels, formed from CRISPR/Cas9-modified EC lacking class II MHC molecules, are significantly protected from CD8+ T cell–mediated destruction in vivo. We conclude that human CD8+ TEM–mediated rejection targeting graft EC class I MHC molecules requires help from CD4+ TEM cells activated by recognition of class II MHC molecules. PMID:26900601

  18. A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation

    PubMed Central

    Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A.; Gong, Yongquan; Fischbein, Michael P.; Robbins, Robert C.; Naesens, Maarten

    2013-01-01

    Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design. PMID:24127489

  19. Sensitivity of scintigraphy with /sup 111/In-lymphocytes for detection of cardiac allograft rejection

    SciTech Connect

    Eisenberg, S.B.; Eisen, H.J.; Sobel, B.E.; Bergmann, S.R.; Bolman, R.M. 3d.

    1988-12-01

    We recently demonstrated the feasibility of noninvasive detection of cardiac allograft rejection after administration of indium-111-labeled lymphocytes. To determine the sensitivity and specificity of the technique, as well as its value for delineating the severity of rejection, we studied 16 dogs with heterotopic thoracic cardiac allografts. Five animals were evaluated while exposed to immunosuppressive agents. Animals were scanned sequentially after administration of 100-400 microCi of indium-111-labeled autologous lymphocytes. Myocardial lymphocyte infiltration was expressed as the indium excess (IE), defined as the ratio of indium activity of the transplant or native heart compared with that in blood. Scintigraphic results were compared with characteristics of simultaneously obtained endomyocardial biopsies. Among 17 biopsy documented episodes of rejection, 16 were detected scintigraphically. Among 18 biopsies with no evidence of rejection, scintigraphy was uniformly negative. Thus, the sensitivity and specificity of scintigraphy were 94 and 100%, respectively. Biopsies graded as showing no rejection were associated with an IE of 0.3 +/- 0.5 (+/- SD); those graded as mild, 2.8 +/- 1.7; those as moderate, 10.7 +/- 7.2; and those graded as indicative of severe rejection, 14.2 +/- 4.5. Thus, scintigraphy with indium-111-labeled lymphocytes sensitively and specifically detects cardiac allograft rejection and delineates the intensity of the rejection process. It should be useful clinically for assessing potential allograft rejection noninvasively.

  20. Rejection of Cardiac Xenografts Transplanted from α 1,3-Galactosyltransferase Gene-Knockout (GalT-KO) Pigs to Baboons

    PubMed Central

    Hisashi, Y.; Yamada, K.; Kuwaki, K.; Tseng, Y.-L; Dor, F. J. M. F.; Houser, S. L; Robson, S. C.; Schuurman, H.-J.; Cooper, D. K. C.; Sachs, D. H.; Colvin, R. B.; Shimizu, A.

    2010-01-01

    The use of α 1,3-galactosyltransferase gene-knockout (GalT-KO) swine donors in discordant xenotransplantation has extended the survival of cardiac xenografts in baboons following transplantation. Eight baboons received heterotopic cardiac xenografts from GalT-KO swine and were treated with a chronic immunosuppressive regimen. The pathologic features of acute humoral xenograft rejection (AHXR), acute cellular xenograft rejection (ACXR) and chronic rejection were assessed in the grafts. No hyperacute rejection developed and one graft survived up to 6 months after transplantation. However, all GalT-KO heart grafts underwent graft failure with AHXR, ACXR and/or chronic rejection. AHXR was characterized by interstitial hemorrhage and multiple thrombi in vessels of various sizes. ACXR was characterized by TUNEL+ graft cell injury with the infiltration of T cells (including CD3 and TIA-1+ cytotoxic T cells), CD4+ cells, CD8+ cells, macrophages and a small number of B and NK cells. Chronic xenograft vasculopathy, a manifestation of chronic rejection, was characterized by arterial intimal thickening with TUNEL+ dead cells, antibody and complement deposition, and/or cytotoxic T-cell infiltration. In conclusion, despite the absence of the Gal epitope, acute and chronic antibody and cell-mediated rejection developed in grafts, maintained by chronic immunosupression, presumably due to de novo responses to non-Gal antigens. PMID:19032222

  1. Simkania negevensis and acute cellular rejection in lung transplant recipients.

    PubMed

    Jamal, Alainna J; Resende, Mariangela R; Prochnow, Taisa; McGilvray, Ian; Pilewski, Joseph M; Crespo, Maria M; Singer, Lianne G; McCurry, Kenneth R; Kolls, Jay K; Keshavjee, Shaf; Liles, W Conrad; Husain, Shahid

    2015-08-01

    Simkania negevensis infection has been hypothesized to play a role in lung transplant rejection. The incidence of S. negevensis infection and its association with acute cellular rejection (ACR) were determined in a prospective cohort study of 78 lung transplant recipients (LTRs) in Toronto, Canada, and Pittsburgh, USA, from July 2007 to January 2010. Simkania negevensis testing was detected by quantitative polymerase chain reaction (PCR) on bronchoalveolar lavage fluid. The relationship between S. negevensis and ACR was examined using Cox proportional hazards models and generalized linear and latent mixed models. Cumulative incidence estimates for time-to-ACR in S. negevensis PCR-positive vs. PCR-negative LTRs were 52.7% vs. 31.1% at six months and 68.9% vs. 44.6% at one yr, respectively. Although not statistically significant, there was a trend toward a higher risk of ACR among S. negevensis PCR-positive vs. PCR-negative LTRs in all statistical models. PMID:26009941

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

    SciTech Connect

    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.

  3. Cardiac papillary fibroelastoma presenting as acute stroke

    PubMed Central

    Abbasi, Atif Saleem; Da Costa, Mark; Hennessy, Terry; Kiernan, Thomas John

    2013-01-01

    We present a case of a young woman who was initially diagnosed with acute stroke with no obvious risk factors. Preliminary investigation with transthoracic echocardiography and subsequent advanced imaging with transoesophageal echocardiography suggested the diagnosis of a benign cardiac tumour on the anterior leaflet of mitral valve. The patient underwent urgent surgical resection. Histology confirmed the diagnosis of cardiac papillary fibroelastoma. She made complete clinical recovery with no recurrence of symptoms. PMID:23761612

  4. Acute Cardiac Tamponade: An Unusual Cause of Acute Renal Failure

    PubMed Central

    Phadke, Gautam; Whaley-Connell, Adam; Dalal, Pranavkumar; Markley, John; Rich, Andrew

    2012-01-01

    We are reporting a case of acute renal failure after cardiac surgery due to acute pericardial effusion. The patient had normal baseline renal function but developed acute oliguric renal failure with a significant increase in serum creatinine postoperatively. Pericardiotomy led to an improvement in blood pressure, immediate diuresis and quick recovery of renal function back to baseline. Pericardial tamponade should be included in the consideration of causes of the cardiorenal syndrome. PMID:22619656

  5. Cardiac Manifestation of Acute Lymphoblastic Leukemia.

    PubMed

    Werner, Rudolf A; Rudelius, Martina; Thurner, Annette; Higuchi, Takahiro; Lapa, Constantin

    2016-07-01

    Here, we report on a 38-year-old man with unclear right heart failure. Imaging with cardiac MRI and combined PET/CT with F-FDG revealed a hypermetabolic mass extending from the right ventricle to the atrium. In addition, intense glucose utilization throughout the bone marrow was noted. Biopsies of both bone marrow and cardiac mass were performed and revealed precursor B-cell acute lymphoblastic leukemia with gross leukemic infiltration of the myopericardium, a rare manifestation of acute lymphoblastic leukemia at initial diagnosis. PMID:27088389

  6. Peer Rejection Cues Induce Cardiac Slowing after Transition into Adolescence

    ERIC Educational Resources Information Center

    Gunther Moor, Bregtje; Bos, Marieke G. N.; Crone, Eveline A.; van der Molen, Maurits W.

    2014-01-01

    The present study examined developmental and gender differences in sensitivity to peer rejection across the transition into adolescence by examining beat-by-beat heart rate responses. Children between the ages of 8 and 14 years were presented with unfamiliar faces of age-matched peers and were asked to predict whether they would be liked by the…

  7. Shotgun Proteomics Identifies Proteins Specific for Acute Renal Transplant Rejection

    SciTech Connect

    Sigdel, Tara K.; Kaushal, Amit; Gritsenko, Marina A.; Norbeck, Angela D.; Qian, Weijun; Xiao, Wenzhong; Camp, David G.; Smith, Richard D.; Sarwal, Minnie M.

    2010-01-04

    Acute rejection (AR) remains the primary risk factor for renal transplant outcome; development of non-invasive diagnostic biomarkers for AR is an unmet need. We used shotgun proteomics using LC-MS/MS and ELISA to analyze a set of 92 urine samples, from patients with AR, stable grafts (STA), proteinuria (NS), and healthy controls (HC). A total of 1446 urinary proteins were identified along with a number of NS specific, renal transplantation specific and AR specific proteins. Relative abundance of identified urinary proteins was measured by protein-level spectral counts adopting a weighted fold-change statistic, assigning increased weight for more frequently observed proteins. We have identified alterations in a number of specific urinary proteins in AR, primarily relating to MHC antigens, the complement cascade and extra-cellular matrix proteins. A subset of proteins (UMOD, SERPINF1 and CD44), have been further cross-validated by ELISA in an independent set of urine samples, for significant differences in the abundance of these urinary proteins in AR. This label-free, semi-quantitative approach for sampling the urinary proteome in normal and disease states provides a robust and sensitive method for detection of urinary proteins for serial, non-invasive clinical monitoring for graft rejection after

  8. Serum metabolomics study of the acute graft rejection in human renal transplantation based on liquid chromatography-mass spectrometry.

    PubMed

    Zhao, Xinjie; Chen, Jihong; Ye, Lei; Xu, Guowang

    2014-05-01

    Acute graft rejection is one of the most common and serious postcomplications in renal transplantation. A noninvasive method is needed to specifically monitor acute graft rejection. We investigated metabolic alterations of acute graft rejection in human renal transplantation by applying a metabolomics approach. Sera from 11 acute graft rejection subjects and 16 nonacute graft rejection subjects were analyzed by a nontargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach including both hydrophilic interaction chromatography and reversed-phase liquid chromatography separations. Discriminative metabolites of acute graft rejection after transplantation were detected, including creatinine, kynurenine, uric acid, polyunsaturated fatty acid, phosphatidylcholines, sphingomyelins, lysophosphatidylcholines, etc. The lower level of serum dehydroepiandrosterone sulfate was found in the acute graft rejection group before transplantation. The results revealed comprehensive metabolic abnormalities in acute graft rejection. The findings are valuable for the clinic noninvasive diagnosis or therapy of acute graft rejection. PMID:24641727

  9. Monocytic Tissue Transglutaminase in a Rat Model for Reversible Acute Rejection and Chronic Renal Allograft Injury

    PubMed Central

    Zakrzewicz, Anna; Atanasova, Srebrena; Padberg, Winfried

    2015-01-01

    Acute rejection is a major risk factor for chronic allograft injury (CAI). Blood leukocytes interacting with allograft endothelial cells during acute rejection were suggested to contribute to the still enigmatic pathogenesis of CAI. We hypothesize that tissue transglutaminase (Tgm2), a multifunctional protein and established marker of M2 macrophages, is involved in acute and chronic graft rejection. We focus on leukocytes accumulating in blood vessels of rat renal allografts (Fischer-344 to Lewis), an established model for reversible acute rejection and CAI. Monocytes in graft blood vessels overexpress Tgm2 when acute rejection peaks on day 9 after transplantation. Concomitantly, caspase-3 is activated, suggesting that Tgm2 expression is linked to apoptosis. After resolution of acute rejection on day 42, leukocytic Tgm2 levels are lower and activated caspase-3 does not differ among isografts and allografts. Cystamine was applied for 4 weeks after transplantation to inhibit extracellular transglutaminase activity, which did, however, not reduce CAI in the long run. In conclusion, this is the first report on Tgm2 expression by monocytes in vivo. Tgm2 may be involved in leukocytic apoptosis and thus in reversion of acute rejection. However, our data do not support a role of extracellular transglutaminase activity as a factor triggering CAI during self-limiting acute rejection. PMID:26063971

  10. Histopathologic insights into the mechanism of anti-non-Gal antibody-mediated pig cardiac xenograft rejection

    PubMed Central

    Byrne, Guerard W; Azimzadeh, Agnes M; Ezzelarab, Mohamed; Tazelaar, Henry D; Ekser, Burcin; Pierson, Richard N; Robson, Simon C; Cooper, David K C; McGregor, Christopher G A

    2013-01-01

    The histopathology of cardiac xenograft rejection has evolved over the last 20 yr with the development of new modalities for limiting antibody-mediated injury, advancing regimens for immune suppression, and an ever-widening variety of new donor genetics. These new technologies have helped us progress from what was once an overwhelming anti-Gal-mediated hyperacute rejection to a more protracted anti-Gal-mediated vascular rejection to what is now a more complex manifestation of non-Gal humoral rejection and coagulation dysregulation. This review summarizes the changing histopathology of Gal- and non-Gal-mediated cardiac xenograft rejection and discusses the contributions of immune-mediated injury, species-specific immune-independent factors, transplant and therapeutic procedures, and donor genetics to the overall mechanism(s) of cardiac xenograft rejection. PMID:25098626

  11. SPECT- and PET-Based Approaches for Noninvasive Diagnosis of Acute Renal Allograft Rejection

    PubMed Central

    Pawelski, Helga; Schnöckel, Uta; Kentrup, Dominik; Grabner, Alexander; Schäfers, Michael; Reuter, Stefan

    2014-01-01

    Molecular imaging techniques such as single photon emission computed tomography (SPECT) or positron emission tomography are promising tools for noninvasive diagnosis of acute allograft rejection (AR). Given the importance of renal transplantation and the limitation of available donors, detailed analysis of factors that affect transplant survival is important. Episodes of acute allograft rejection are a negative prognostic factor for long-term graft survival. Invasive core needle biopsies are still the “goldstandard” in rejection diagnostics. Nevertheless, they are cumbersome to the patient and carry the risk of significant graft injury. Notably, they cannot be performed on patients taking anticoagulant drugs. Therefore, a noninvasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review SPECT- and PET-based approaches for noninvasive molecular imaging-based diagnostics of acute transplant rejection. PMID:24804257

  12. Diagnosis of acute cardiac ischemia.

    PubMed

    Pope, J Hector; Selker, Harry P

    2003-02-01

    A better understanding of coronary syndromes allow physicians to appreciate UAP and AMI as part of a continuum of ACI. ACI is a life-threatening condition whose identification can have major economic and therapeutic importance as far as threatening dysrhythmias and preventing or limiting myocardial infarction size. The identification of ACI continues to challenge the skill of even experienced clinicians, yet physicians continue (appropriately) to admit the overwhelming majority of patients with ACI; in the process, they admit many patients without acute ischemia [2], overestimating the likelihood of ischemia in low-risk patients because of magnified concern for this diagnosis for prognostic and therapeutic reasons. Studies of admitting practices from a decade ago have yielded useful clinical information but have shown that neither clinical symptoms nor the ECG could reliably distinguish most patients with ACI from those with other conditions. Most studies have evaluated the accuracy of various technologies for diagnosing ACI, yet only a few have evaluated the clinical impact of routine use. The prehospital 12-lead ECG has moderate sensitivity and specificity for the diagnosis of ACI. It has demonstrated a reduction of the mean time to thrombolysis by 33 minutes and short-term overall mortality in randomized trials. In the general ED setting, only the ACI-TIPI has demonstrated, in a large-scale multicenter clinical trial, a reduction in unnecessary hospitalizations without decreasing the rate of appropriate admission for patients with ACI. The Goldman chest pain protocol has good sensitivity for AMI but was not shown to result in any differences in hospitalization rate, length of stay, or estimated costs in the single clinical impact study performed. The protocol's applicability to patients with UAP has not been evaluated. Single measurement of biomarkers at presentation to the ED has poor sensitivity for AMI, although most biomarkers have high specificity. Serial

  13. Cardiac Surgery-Associated Acute Kidney Injury

    PubMed Central

    Mao, Huijuan; Katz, Nevin; Ariyanon, Wassawon; Blanca-Martos, Lourdes; Adýbelli, Zelal; Giuliani, Anna; Danesi, Tommaso Hinna; Kim, Jeong Chul; Nayak, Akash; Neri, Mauro; Virzi, Grazia Maria; Brocca, Alessandra; Scalzotto, Elisa; Salvador, Loris; Ronco, Claudio

    2013-01-01

    Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious postoperative complication of cardiac surgery requiring cardiopulmonary bypass (CPB), and it is the second most common cause of AKI in the intensive care unit. Although the complication has been associated with the use of CPB, the etiology is likely multifactorial and related to intraoperative and early postoperative management including pharmacologic therapy. To date, very little evidence from randomized trials supporting specific interventions to protect from or prevent AKI in broad cardiac surgery populations has been found. The definition of AKI employed by investigators influences not only the incidence of CSA-AKI, but also the identification of risk variables. The advent of novel biomarkers of kidney injury has the potential to facilitate the subclinical diagnosis of CSA-AKI, the assessment of its severity and prognosis, and the early institution of interventions to prevent or reduce kidney damage. Further studies are needed to determine how to optimize cardiac surgical procedures, CPB parameters, and intraoperative and early postoperative blood pressure and renal blood flow to reduce the risk of CSA-AKI. No pharmacologic strategy has demonstrated clear efficacy in the prevention of CSA-AKI; however, some agents, such as the natriuretic peptide nesiritide and the dopamine agonist fenoldopam, have shown promising results in renoprotection. It remains unclear whether CSA-AKI patients can benefit from the early institution of such pharmacologic agents or the early initiation of renal replacement therapy. PMID:24454314

  14. Cardiac surgery-associated acute kidney injury.

    PubMed

    Mao, Huijuan; Katz, Nevin; Ariyanon, Wassawon; Blanca-Martos, Lourdes; Adýbelli, Zelal; Giuliani, Anna; Danesi, Tommaso Hinna; Kim, Jeong Chul; Nayak, Akash; Neri, Mauro; Virzi, Grazia Maria; Brocca, Alessandra; Scalzotto, Elisa; Salvador, Loris; Ronco, Claudio

    2013-10-01

    Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious postoperative complication of cardiac surgery requiring cardiopulmonary bypass (CPB), and it is the second most common cause of AKI in the intensive care unit. Although the complication has been associated with the use of CPB, the etiology is likely multifactorial and related to intraoperative and early postoperative management including pharmacologic therapy. To date, very little evidence from randomized trials supporting specific interventions to protect from or prevent AKI in broad cardiac surgery populations has been found. The definition of AKI employed by investigators influences not only the incidence of CSA-AKI, but also the identification of risk variables. The advent of novel biomarkers of kidney injury has the potential to facilitate the subclinical diagnosis of CSA-AKI, the assessment of its severity and prognosis, and the early institution of interventions to prevent or reduce kidney damage. Further studies are needed to determine how to optimize cardiac surgical procedures, CPB parameters, and intraoperative and early postoperative blood pressure and renal blood flow to reduce the risk of CSA-AKI. No pharmacologic strategy has demonstrated clear efficacy in the prevention of CSA-AKI; however, some agents, such as the natriuretic peptide nesiritide and the dopamine agonist fenoldopam, have shown promising results in renoprotection. It remains unclear whether CSA-AKI patients can benefit from the early institution of such pharmacologic agents or the early initiation of renal replacement therapy. PMID:24454314

  15. Indium-111 antimyosin scintigraphy to assess myocardial damage in patients with suspected myocarditis and cardiac rejection

    SciTech Connect

    Carrio, I.; Berna, L.; Ballester, M.; Estorch, M.; Obrador, D.; Cladellas, M.; Abadal, L.; Ginjaume, M.

    1988-12-01

    Indium-111 antimyosin scans were used to assess myocardial damage in patients with suspected myocarditis and cardiac transplant rejection. The calculation of a myocardium to lung ratio (AM index) to quantify antimyosin uptake was performed. AM index in normal subjects (n = 8) at 48 hr postinjection was 1.46 +/- 0.04. In patients with suspected myocarditis (16 studies in 13 patients), AM index was 2.0 +/- 0.5 (p less than 0.001); suggesting a considerable incidence of ongoing cell damage in this group, despite the small proportion of positive right ventricular endomyocardial biopsy (RVbx) (4/13). In patients studied after cardiac transplantation (37 studies in 17 patients), AM indexes correlated with RVbx. In patients with RVbx proven rejection (n = 14), AM index was 1.87 +/- 0.19 (p less than 0.001). In patients with RVbx showing infiltrates but not myocyte damage (n = 13), AM index was 1.80 +/- 0.27 (p = 0.02). In patients with normal RVbx (n = 10), AM index was 1.56 +/- 0.17 (p = NS versus controls; p = 0.001 versus those with positive RVbx). Calculated AM indexes correlated with graded visual analysis of the scans (r = 0.823; p = 0.001). Antimyosin scans are an appropriate method to assess myocardial damage in patients with suspected myocarditis and cardiac rejection.

  16. Gene-based bio-signature patterns and cardiac allograft rejection.

    PubMed

    Mehra, Mandeep R; Uber, Patricia A; Benitez, Roberto M

    2010-01-01

    Clinicians have long awaited an alternative to invasive endomyocardial biopsy for surveillance of cardiac transplant rejection. Transcriptional signals in peripheral blood mononuclear cells allow for the development of multigene-based panels that can inform on the presence or absence of immunologic quiescence. The informative genes represent several biologic pathways, including T-cell activation (PDCD1), T-cell migration (ITGA4), and mobilization of hematopoietic precursors (WDR40A and microRNA gene family cMIR), and steroid-responsive genes such as IL1R2, the decoy receptor for interleukin 2. The greatest value may include the ability to inform on the potential of future proclivity for rejection, allowing patients to be stratified into low, intermediate, or high risk subsets for future rejection. In these individuals, this knowledge may allow clinicians to use tailored approaches to immunosuppression, thereby avoiding adverse pharmacologic effects in low-risk patients while improving rejection outcomes in those at high risk for future allograft compromise. Despite these advances, clinical entrenchment of gene-based pharmacotherapy in cardiac transplantation will require independent replication and validation of investigational findings. PMID:19945064

  17. Computational Chemical Imaging for Cardiovascular Pathology: Chemical Microscopic Imaging Accurately Determines Cardiac Transplant Rejection

    PubMed Central

    Tiwari, Saumya; Reddy, Vijaya B.; Bhargava, Rohit; Raman, Jaishankar

    2015-01-01

    Rejection is a common problem after cardiac transplants leading to significant number of adverse events and deaths, particularly in the first year of transplantation. The gold standard to identify rejection is endomyocardial biopsy. This technique is complex, cumbersome and requires a lot of expertise in the correct interpretation of stained biopsy sections. Traditional histopathology cannot be used actively or quickly during cardiac interventions or surgery. Our objective was to develop a stain-less approach using an emerging technology, Fourier transform infrared (FT-IR) spectroscopic imaging to identify different components of cardiac tissue by their chemical and molecular basis aided by computer recognition, rather than by visual examination using optical microscopy. We studied this technique in assessment of cardiac transplant rejection to evaluate efficacy in an example of complex cardiovascular pathology. We recorded data from human cardiac transplant patients’ biopsies, used a Bayesian classification protocol and developed a visualization scheme to observe chemical differences without the need of stains or human supervision. Using receiver operating characteristic curves, we observed probabilities of detection greater than 95% for four out of five histological classes at 10% probability of false alarm at the cellular level while correctly identifying samples with the hallmarks of the immune response in all cases. The efficacy of manual examination can be significantly increased by observing the inherent biochemical changes in tissues, which enables us to achieve greater diagnostic confidence in an automated, label-free manner. We developed a computational pathology system that gives high contrast images and seems superior to traditional staining procedures. This study is a prelude to the development of real time in situ imaging systems, which can assist interventionists and surgeons actively during procedures. PMID:25932912

  18. Cardiac MRI of acute coronary syndrome.

    PubMed

    Akerem Khan, Shamruz; Khan, Shamruz Akarem; Williamson, Eric E; Foley, Thomas A; Cullen, Ethany L; Young, Phillip M; Araoz, Philip A

    2013-05-01

    Acute coronary syndrome (ACS) is a major cause of morbidity and mortality worldwide. New serological biomarkers, such as troponins, have improved the diagnosis of ACS; however, the diagnosis of ACS can still be difficult as there is marked heterogeneity in its presentation and significant overlap with other disorders presenting with chest pain. Evidence is accumulating that cardiac MRI provides information that can aid the detection and differential diagnosis of ACS, guide clinical decision-making and improve risk-stratification after an event. In this review, we present the relevant cardiac MRI techniques that can be used to detect ACS accurately, provide differential diagnosis, identify the sequelae of ACS, and determine prognostication after ACS. PMID:23668741

  19. Acute Kidney Injury Subsequent to Cardiac Surgery.

    PubMed

    Kramer, Robert S; Herron, Crystal R; Groom, Robert C; Brown, Jeremiah R

    2015-03-01

    Acute kidney injury (AKI) after cardiac surgery is a common and underappreciated syndrome that is associated with poor shortand long-term outcomes. AKI after cardiac surgery may be epiphenomenon, a signal for adverse outcomes by virtue of other affected organ systems, and a consequence of multiple factors. Subtle increases in serum creatinine (SCr) postoperatively, once considered inconsequential, have been shown to reflect a kidney injury that likely occurred in the operating room during cardiopulmonary bypass (CPB) and more often in susceptible individuals. The postoperative elevation in SCr is a delayed signal reflecting the intraoperative injury. Preoperative checklists and the conduct of CPB represent opportunities for prevention of AKI. Newer definitions of AKI provide us with an opportunity to scrutinize perioperative processes of care and determine strategies to decrease the incidence of AKI subsequent to cardiac surgery. Recognizing and mitigating risk factors preoperatively and optimizing intraoperative practices may, in the aggregate, decrease the incidence of AKI. This review explores the pathophysiology of AKI and addresses the features of patients who are the most vulnerable to AKI. Preoperative strategies are discussed with particular attention to a readiness for surgery checklist. Intraoperative strategies include minimizing hemodilution and maximizing oxygen delivery with specific suggestions regarding fluid management and plasma preservation. PMID:26390675

  20. Acute Kidney Injury Subsequent to Cardiac Surgery

    PubMed Central

    Kramer, Robert S.; Herron, Crystal R.; Groom, Robert C.; Brown, Jeremiah R.

    2015-01-01

    Abstract: Acute kidney injury (AKI) after cardiac surgery is a common and underappreciated syndrome that is associated with poor short- and long-term outcomes. AKI after cardiac surgery may be epiphenomenon, a signal for adverse outcomes by virtue of other affected organ systems, and a consequence of multiple factors. Subtle increases in serum creatinine (SCr) postoperatively, once considered inconsequential, have been shown to reflect a kidney injury that likely occurred in the operating room during cardiopulmonary bypass (CPB) and more often in susceptible individuals. The postoperative elevation in SCr is a delayed signal reflecting the intraoperative injury. Preoperative checklists and the conduct of CPB represent opportunities for prevention of AKI. Newer definitions of AKI provide us with an opportunity to scrutinize perioperative processes of care and determine strategies to decrease the incidence of AKI subsequent to cardiac surgery. Recognizing and mitigating risk factors preoperatively and optimizing intraoperative practices may, in the aggregate, decrease the incidence of AKI. This review explores the pathophysiology of AKI and addresses the features of patients who are the most vulnerable to AKI. Preoperative strategies are discussed with particular attention to a readiness for surgery checklist. Intraoperative strategies include minimizing hemodilution and maximizing oxygen delivery with specific suggestions regarding fluid management and plasma preservation. PMID:26390675

  1. Pretransplant thymic function predicts acute rejection in antithymocyte globulin-treated renal transplant recipients.

    PubMed

    Bamoulid, Jamal; Courivaud, Cécile; Crepin, Thomas; Carron, Clémence; Gaiffe, Emilie; Roubiou, Caroline; Laheurte, Caroline; Moulin, Bruno; Frimat, Luc; Rieu, Philippe; Mousson, Christiane; Durrbach, Antoine; Heng, Anne-Elisabeth; Rebibou, Jean-Michel; Saas, Philippe; Ducloux, Didier

    2016-05-01

    Lack of clear identification of patients at high risk of acute rejection hampers the ability to individualize immunosuppressive therapy. Here we studied whether thymic function may predict acute rejection in antithymocyte globulin (ATG)-treated renal transplant recipients in 482 patients prospectively studied during the first year post-transplant of which 86 patients experienced acute rejection. Only CD45RA(+)CD31(+)CD4(+) T cell (recent thymic emigrant [RTE]) frequency (RTE%) was marginally associated with acute rejection in the whole population. This T-cell subset accounts for 26% of CD4(+) T cells. Pretransplant RTE% was significantly associated with acute rejection in ATG-treated patients (hazard ratio, 1.04; 95% confidence interval, 1.01-1.08) for each increased percent in RTE/CD4(+) T cells), but not in anti-CD25 monoclonal (αCD25 mAb)-treated patients. Acute rejection was significantly more frequent in ATG-treated patients with high pretransplant RTE% (31.2% vs. 16.4%) or absolute number of RTE/mm(3) (31.7 vs. 16.1). This difference was not found in αCD25 monclonal antibody-treated patients. Highest values of both RTE% (>31%, hazard ratio, 2.50; 95% confidence interval, 1.09-5.74) and RTE/mm(3) (>200/mm(3), hazard ratio, 3.71; 95% confidence interval, 1.59-8.70) were predictive of acute rejection in ATG-treated patients but not in patients having received αCD25 monoclonal antibody). Results were confirmed in a retrospective cohort using T-cell receptor excision circle levels as a marker of thymic function. Thus, pretransplant thymic function predicts acute rejection in ATG-treated patients. PMID:27083287

  2. Cardiac Arrhythmias and Abnormal Electrocardiograms After Acute Stroke.

    PubMed

    Ruthirago, Doungporn; Julayanont, Parunyou; Tantrachoti, Pakpoom; Kim, Jongyeol; Nugent, Kenneth

    2016-01-01

    Cardiac arrhythmias and electrocardiogram (ECG) abnormalities occur frequently but are often underrecognized after strokes. Acute ischemic and hemorrhagic strokes in some particular area of brain can disrupt central autonomic control of the heart, precipitating cardiac arrhythmias, ECG abnormalities, myocardial injury and sometimes sudden death. Identification of high-risk patients after acute stroke is important to arrange appropriate cardiac monitoring and effective management of arrhythmias, and to prevent cardiac morbidity and mortality. More studies are needed to better clarify pathogenesis, localization of areas associated with arrhythmias and practical management of arrhythmias and abnormal ECGs after acute stroke. PMID:26802767

  3. Donor Heart Treatment With COMP-Ang1 Limits Ischemia-Reperfusion Injury and Rejection of Cardiac Allografts.

    PubMed

    Syrjälä, S O; Nykänen, A I; Tuuminen, R; Raissadati, A; Keränen, M A I; Arnaudova, R; Krebs, R; Koh, G Y; Alitalo, K; Lemström, K B

    2015-08-01

    The major cause of death during the first year after heart transplantation is primary graft dysfunction due to preservation and ischemia-reperfusion injury (IRI). Angiopoietin-1 is a Tie2 receptor-binding paracrine growth factor with anti-inflammatory properties and indispensable roles in vascular development and stability. We used a stable variant of angiopoietin-1 (COMP-Ang1) to test whether ex vivo intracoronary treatment with a single dose of COMP-Ang1 in donor Dark Agouti rat heart subjected to 4-h cold ischemia would prevent microvascular dysfunction and inflammatory responses in the fully allogeneic recipient Wistar Furth rat. COMP-Ang1 reduced endothelial cell-cell junction disruption of the donor heart in transmission electron microscopy during 4-h cold ischemia, improved myocardial reflow, and reduced microvascular leakage and cardiomyocyte injury of transplanted allografts during IRI. Concurrently, the treatment reduced expression of danger signals, dendritic cell maturation markers, endothelial cell adhesion molecule VCAM-1 and RhoA/Rho-associated protein kinase activation and the influx of macrophages and neutrophils. Furthermore, COMP-Ang1 treatment provided sustained anti-inflammatory effects during acute rejection and prevented the development of cardiac fibrosis and allograft vasculopathy. These results suggest donor heart treatment with COMP-Ang1 having important clinical implications in the prevention of primary and subsequent long-term injury and dysfunction in cardiac allografts. PMID:25932532

  4. Immunosuppression in cardiac graft rejection: A human in vitro model to study the potential use of new immunomodulatory drugs

    SciTech Connect

    Crescioli, Clara Squecco, Roberta; Cosmi, Lorenzo; Sottili, Mariangela; Gelmini, Stefania; Borgogni, Elisa; Sarchielli, Erica; Scolletta, Sabino; Francini, Fabio; Annunziato, Francesco; Vannelli, Gabriella Barbara; Serio, Mario

    2008-04-01

    CXCL10-CXCR3 axis plays a pivotal role in cardiac allograft rejection, so that targeting CXCL10 without inducing generalized immunosuppression may be of therapeutic significance in allotransplantation. Since the role of resident cells in cardiac rejection is still unclear, we aimed to establish reliable human cardiomyocyte cultures to investigate Th1 cytokine-mediated response in allograft rejection. We used human fetal cardiomyocytes (Hfcm) isolated from fetal hearts, obtained after legal abortions. Hfcm expressed specific cardiac lineage markers, specific cardiac structural proteins, typical cardiac currents and generated ventricular action potentials. Thus, Hfcm represent a reliable in vitro tool for allograft rejection research, since they resemble the features of mature cells. Hfcm secreted CXCL10 in response to IFN{gamma} and TNF{alpha}{alpha}; this effect was magnified by cytokine combination. Cytokine synergy was associated to a significant TNF{alpha}-induced up-regulation of IFN{gamma}R. The response of Hfcm to some currently used immunosuppressive drugs compared to rosiglitazone, a peroxisome proliferator-activated receptor {gamma} agonist and Th1-mediated response inhibitor, was also evaluated. Only micophenolic acid and rosiglitazone halved CXCL10 secretion by Hfcm. Given the pivotal role of IFN{gamma}-induced chemokines in Th1-mediated allograft rejection, these preliminary results suggest that the combined effects of immunosuppressive agents and rosiglitazone could be potentially beneficial to patients receiving heart transplants.

  5. Successful therapy with rituximab of refractory acute humoral renal transplant rejection: a case report.

    PubMed

    Celik, A; Saglam, F; Cavdar, C; Sifil, A; Atila, K; Sarioglu, S; Bora, S; Gulay, H; Camsari, T

    2008-01-01

    Acute humoral rejection (AHR) is generally less responsive to conventional anti-rejection treatment with consequent allograft losses. Therapeutic options include antilymphocyte antibody (ATG), intravenous immunglobulin (IVIG), plasmapheresis, or immunoadsorption with protein A together with intensification of immunsuppression with a tacrolimus/mycophenolate mofetil combination. This report describes a transplant recipient who responded to rituximab therapy as treatment for steroid-, ATG-, IVIG-, and plasmapheresis-resistant AHR. PMID:18261611

  6. Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma.

    PubMed

    Spain, L; Higgins, R; Gopalakrishnan, K; Turajlic, S; Gore, M; Larkin, J

    2016-06-01

    Immune checkpoint inhibitors such as ipilimumab and nivolumab improve survival in patients with advanced melanoma and are increasingly available to clinicians for use in the clinic. Their safety in organ transplant recipients is not well defined but published case reports describing treatment with ipilimumab have not been complicated by graft rejection. No cases of anti-programmed cell death protein 1 administration are reported in this group. We describe a case of acute graft rejection in a kidney transplant recipient after treatment with nivolumab, after progression on ipilimumab. Potential factors increasing the risk of graft rejection in this case are discussed, in particular the contribution of nivolumab. PMID:26951628

  7. The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients

    PubMed Central

    Hasanzamani, Boshra; Hami, Maryam; Zolfaghari, Vajihe; Torkamani, Mahtab; Ghorban Sabagh, Mahin; Ahmadi Simab, Saiideh

    2016-01-01

    Introduction: It is known that cytomegalovirus (CMV) infection is a common problem among kidney transplant patients. This infection can be increased morbidity and decreased graft survival. This problem has been associated with acute rejection too. Patients and Methods: One hundred and thirty renal transplant patients were included in a prospective, case-control study. The renal transplant patients were divided into two groups; patients group with CMV infection and control group without CMV infection. Serum CMV-IgG in all patients was positive (donor and recipients). None of patients had received anti-thymocyte-globulin and thymoglobulin. CMV infection was diagnosed by quantitative CMV-PCR (polymerase chain reaction) test (more than 500 copies/μg). Rejection episode was defined by kidney isotope scan or biopsy. Results: In the group of 66 CMV infection patients (41 male [62.1%] and 25 female [37.9%]) the incidence of graft rejection was 36%, however in the group of 64 control patients the incidence of graft rejection was 9.4 % (P < 0.005). Conclusion: CMV infection is important predisposing factor for acute allograft rejection after kidney transplantation. The results of this study suggests that the control of CMV infection could decrease episodes of acute kidney rejection. PMID:27471740

  8. Outcome of Acute Graft Rejection Associated with Hemodynamic Compromise in Pediatric Heart Transplant Recipients

    PubMed Central

    Tissot, Cecile; Buckvold, Shannon; Gralla, Jane; Ivy, D. Dunbar; Pietra, Biagio A.; Miyamoto, Shelley D.

    2011-01-01

    We sought to analyze the outcome of hemodynamically significant acute graft rejection in pediatric heart transplant recipients from a single-center experience. Acute graft rejection remains a major cause of morbidity and mortality for patients who undergo orthotopic heart transplantation and has been associated with the severity of the rejection episode. A retrospective review of all children experiencing a hemodynamically significant rejection episode after orthotopic heart transplantation was performed. Fifty-three patients with 54 grafts had 70 rejection episodes requiring intravenous inotropic support. Forty-one percent of these patients required high-dose inotropic support, with the remaining 59% of patients requiring less inotropic support. Overall graft survival to hospital discharge was 41% for patients in the high-dose group compared to 94% in the low-dose group. Six-month graft survival in patients who required high-dose inotropes remained at 41% compared to 44% in the low-dose group. Hemodynamically significant acute graft rejection in pediatric heart transplant recipients is a devastating problem with poor short- and long-term outcomes. Survival to hospital discharge is dismal in patients who require high-dose inotropic support. In contrast, survival to discharge is quite good in patients who require only low-dose inotropic support; however, six-month graft survival in this group is low secondary to a high incidence of graft failure related to worsening or aggressive transplant coronary artery disease. PMID:20963408

  9. Acute renal transplant rejection in children: assessment by Duplex Doppler sonography.

    PubMed

    Vergesslich, K A; Khoss, A E; Balzar, E; Schwaighofer, B; Ponhold, W

    1988-01-01

    Over a two year period 74 consecutive Duplex Doppler scans were performed in 23 children with renal allografts and were compared to the Doppler sonographic findings in orthotopic kidneys of 25 age matched healthy controls. The Doppler waveforms of renal arterial flow were analyzed qualitatively assessing systolic and diastolic flow amplitudes, for quantitation the Pourcelot index (PI) was used. There was no variation between the Doppler waveforms in recipients with normal allograft function and healthy controls. In 12 patients with biopsy proven acute rejection a decrease or absence of the diastolic flow amplitude was noted, resulting in increased pulsatility of the Doppler waveform. The mean PI in acute rejection differed significantly from the mean PI in normal allograft function. Duplex Doppler sonography is a useful imaging modality in the differentiation between acute rejection and normal allograft function and should therefore be integrated in the screening of children after renal transplantation. PMID:3054768

  10. Use of [18F]FDG PET to Monitor The Development of Cardiac Allograft Rejection

    PubMed Central

    Daly, Kevin P.; Dearling, Jason L. J.; Seto, Tatsuichiro; Dunning, Patricia; Fahey, Frederic; Packard, Alan B.; Briscoe, David M.

    2014-01-01

    Background Positron Emission Tomography (PET) has the potential to be a specific, sensitive and quantitative diagnostic test for transplant rejection. To test this hypothesis, we evaluated 18F-labeled fluorodeoxyglucose ([18F]FDG) and 13N-labeled ammonia ([13N]NH3) small animal PET imaging in a well-established murine cardiac rejection model. Methods Heterotopic transplants were performed using minor MHC mismatched B6.C-H2bm12 donor hearts in C57BL/6(H-2b) recipients. C57BL/6 donor hearts into C57BL/6 recipients served as isograft controls. [18F]FDG PET imaging was performed weekly between post-transplant days 7 and 42 and the percent injected dose was computed for each graft. [13N]NH3 imaging was performed to evaluate myocardial perfusion. Results There was a significant increase in [18F]FDG uptake in allografts from day 14 to day 21 (1.6% to 5.2%; P<0.001) and uptake in allografts was significantly increased on post-transplant days 21 (5.2% vs. 0.9%; P=0.005) and 28 (4.8% vs. 0.9%; P=0.006) compared to isograft controls. Furthermore, [18F]FDG uptake correlated with an increase in rejection within allografts between days 14 and 28 post-transplant. Finally, the uptake of [13N]NH3 was significantly lower relative to the native heart in allografts with chronic vasculopathy compared to isograft controls on day 28 (P=0.01). Conclusions PET imaging with [18F]FDG can be used following transplantation to monitor the evolution of rejection. In addition, decreased uptake of [13N]NH3 in rejecting allografts may be reflective of decreased myocardial blood flow. These data suggest that combined [18F]FDG and [13N]NH3 PET imaging could be used as a non-invasive, quantitative technique for serial monitoring of allograft rejection and has potential application in human transplant recipients. PMID:25675207

  11. CXCL9 and CXCL10 accelerate acute transplant rejection mediated by alloreactive memory T cells in a mouse retransplantation model

    PubMed Central

    ZHUANG, JIAWEI; SHAN, ZHONGGUI; MA, TENG; LI, CHUN; QIU, SHUIWEI; ZHOU, XIAOBIAO; LIN, LIANFENG; QI, ZHONGQUAN

    2014-01-01

    C-X-C motif chemokine ligand (CXCL) 9 and CXCL10 play key roles in the initiation and development of acute transplant rejection. Previously, higher levels of RANTES expression and secretion were demonstrated in retransplantation or T-cell memory-transfer models. In the present study, the effect of the chemokines, CXCL9 and CXCL10, were investigated in a mouse retransplantation model. BALB/c mice were used as donors, while C57BL/6 mice were used as recipients. In the experimental groups, a heterotopic heart transplantation was performed six weeks following skin grafting. In the control groups, a heterotopic heart transplantation was performed without skin grafting. Untreated mice served as blank controls. The mean graft survival time of the heterotopic heart transplantations was 7.7 days in the experimental group (n=6), as compared with 3.25 days in the control group (n=6; P<0.001). On day three following cardiac transplantation, histological evaluation of the grafts revealed a higher International Society for Heart & Lung Transplantation grade in the experimental group as compared with the control group. In addition, gene expression and serum concentrations of CXCL9, CXCL10, interferon-γ, and interleukin-2 were markedly higher in the experimental group when compared with the control group. Differences between the levels of CXCL9 and CXCL10 in the pre- and post-transplant mice indicated that the chemokines may serve as possible biomarkers to predict acute rejection. The results of the present study demonstrated that CXCL9 and CXCL10 play a critical role in transplantation and retransplantation. High levels of these cytokines during the pre-transplant period may lead to extensive acute rejection. Thus, the observations enhance the understanding of the mechanism underlying the increased expression and secretion of CXCL9 and CXCL10 by alloreactive memory T cells. PMID:24944628

  12. Insights from computational modeling in inflammation and acute rejection in limb transplantation.

    PubMed

    Wolfram, Dolores; Starzl, Ravi; Hackl, Hubert; Barclay, Derek; Hautz, Theresa; Zelger, Bettina; Brandacher, Gerald; Lee, W P Andrew; Eberhart, Nadine; Vodovotz, Yoram; Pratschke, Johann; Pierer, Gerhard; Schneeberger, Stefan

    2014-01-01

    Acute skin rejection in vascularized composite allotransplantation (VCA) is the major obstacle for wider adoption in clinical practice. This study utilized computational modeling to identify biomarkers for diagnosis and targets for treatment of skin rejection. Protein levels of 14 inflammatory mediators in skin and muscle biopsies from syngeneic grafts [n = 10], allogeneic transplants without immunosuppression [n = 10] and allografts treated with tacrolimus [n = 10] were assessed by multiplexed analysis technology. Hierarchical Clustering Analysis, Principal Component Analysis, Random Forest Classification and Multinomial Logistic Regression models were used to segregate experimental groups. Based on Random Forest Classification, Multinomial Logistic Regression and Hierarchical Clustering Analysis models, IL-4, TNF-α and IL-12p70 were the best predictors of skin rejection and identified rejection well in advance of histopathological alterations. TNF-α and IL-12p70 were the best predictors of muscle rejection and also preceded histopathological alterations. Principal Component Analysis identified IL-1α, IL-18, IL-1β, and IL-4 as principal drivers of transplant rejection. Thus, inflammatory patterns associated with rejection are specific for the individual tissue and may be superior for early detection and targeted treatment of rejection. PMID:24926998

  13. T cell immunohistochemistry refines lung transplant acute rejection diagnosis and grading

    PubMed Central

    2013-01-01

    Objective Lung transplant volume has been increasing. However, inaccurate and uncertain diagnosis for lung transplant rejection hurdles long-term outcome due to, in part, interobserver variability in rejection grading. Therefore, a more reliable method to facilitate diagnosing and grading rejection is warranted. Method Rat lung grafts were harvested on day 3, 7, 14 and 28 post transplant for histological and immunohistochemical assessment. No immunosuppressive treatment was administered. We explored the value of interstitial T lymphocytes quantification by immunohistochemistry and compared the role of T cell immunohistochemistry with H&E staining in diagnosing and grading lung transplant rejection. Results Typical acute rejection from grade A1 to A4 was found. Rejection severity was heterogeneously distributed in one-third transplanted lungs (14/40): lesions in apex and center were more augmented than in the base and periphery of the grafts, respectively. Immunohistochemistry showed profound difference in T lymphocyte infiltration among grade A1 to A4 rejections. The coincidence rate of H&E and immunohistochemistry was 77.5%. The amount of interstitial T lymphocyte infiltration increased gradually with the upgrading of rejection. The statistical analysis demonstrated that the difference in the amount of interstitial T lymphocytes between grade A2 and A3 was not obvious. However, T lymphocytes in lung tissue of grade A4 were significantly more abundant than in other grades. Conclusions Rejection severity was heterogeneously distributed within lung grafts. Immunohistochemistry improves the sensitivity and specificity of rejection diagnosis, and interstitial T lymphocyte quantitation has potential value in diagnosing and monitoring lung allograft rejection. Virtual slides The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1536075282108217. PMID:24330571

  14. Expanding the antibody-mediated component of plasma cell-rich acute rejection: A case series

    PubMed Central

    Uppin, M. S.; Gudithi, S.; Taduri, G.; Prayaga, A. K.; Raju, S. B.

    2016-01-01

    Renal allograft rejection is mediated by T-cells (T-cell mediated rejection) or by donor-specific antibodies (DSAs) (antibody mediated rejection, ABMR). Plasma cell-rich acute rejection (PCAR) is a unique entity due to its peculiar morphology and poor prognostic behavior. All allograft biopsies done at our center from January 2013 to October 2014 were reviewed, and seven were identified with a diagnosis of PCAR with antibody mediated rejection (ABMR). The allograft biopsies were classified as per the Banff 2007 schema. Immunohistochemistry with C4d, SV 40, CD3, CD20, CD138, kappa and lambda light chain was performed. Total 210 allograft biopsies were performed in the study period of which seven biopsies (3.3%) were diagnosed as PCAR with ABMR. All these were late ABMRs (more than 6 months) with median posttransplant duration of 17 months. The allograft biopsy showed features of PCAR along with glomerulitis, peritubular capillaritis, and positive C4d. DSA was positive in six patients. All the patients were treated with standard therapeutic measures of acute cellular rejection (ACR) and ABMR including steroids, plasma exchange, rituximab and intravenous immunoglobulins. All the patients had persistent graft dysfunction or graft loss on follow-up. PMID:27194831

  15. HLA-G Polymorphism (rs16375) and Acute Rejection in Liver Transplant Recipients

    PubMed Central

    Azarpira, Negar; Aghdaie, Mahdokht H.; Kazemi, Kurosh; Darai, Masumeh

    2014-01-01

    Background. HLA-G molecules exhibit immunomodulatory properties that can delay graft rejection. The 14 bp insertion/deletion polymorphism (INDEL) (rs16375) influences the stability of final HLA-G mRNA and its soluble isoforms. Objective. The present study aimed to investigate the possible association between this polymorphism and the incidence of acute rejection in Iranian liver transplant recipients. Methods. Different genotypes were evaluated by PCR. The patients who had acute rejection within 6 months after transplantation were classified as acute rejection (AR) group, while others were considered as nonacute rejection (NAR) group. Results. Among the recipients, 21 patients (21%) had at least one episode of AR, while the other 79 patients (79%) had normal liver function. No significant differences were found between the two groups regarding sex, MELD score, and primary liver disease. Also, no difference was observed concerning rs16375 genotype and allele frequency (P = 0.44, OR: 0.69; CI: 0.21–2.10). Conclusion. The study results revealed no significant difference between the AR and the NAR groups regarding the 14 bp INDEL genotypes and alleles. Further studies are recommended to be conducted on other polymorphic sites as well as monitoring of serum HLA-G concentration in order to ascertain the potential implications of this marker in our population. PMID:24591768

  16. Usefulness of liver stiffness measurement during acute cellular rejection in liver transplantation.

    PubMed

    Crespo, Gonzalo; Castro-Narro, Graciela; García-Juárez, Ignacio; Benítez, Carlos; Ruiz, Pablo; Sastre, Lydia; Colmenero, Jordi; Miquel, Rosa; Sánchez-Fueyo, Alberto; Forns, Xavier; Navasa, Miquel

    2016-03-01

    Liver stiffness measurement (LSM) is a useful method to estimate liver fibrosis and portal hypertension. The inflammatory process that takes place in post-liver transplant acute cellular rejection (ACR) may also increase liver stiffness. We aimed to explore the association between liver stiffness and the severity of ACR, as well as to assess the relationship between liver stiffness and response to rejection treatment in a prospective study that included 27 liver recipients with biopsy-proven ACR, 30 stable recipients with normal liver tests, and 30 hepatitis C virus (HCV)-infected LT recipients with histologically diagnosed HCV recurrence. Patients with rejection were stratified into 2 groups (mild and moderate/severe) according to the severity of rejection evaluated with the Banff score. Routine biomarkers and LSM with FibroScan were performed at the time of liver biopsy (baseline) and at 7, 30, and 90 days in patients with rejection and at baseline in control patients. Median baseline liver stiffness was 5.9 kPa in the mild rejection group, 11 kPa in the moderate/severe group (P = 0.001), 4.2 kPa in stable recipients (P = 0.02 versus mild rejection), and 13.6 kPa in patients with recurrent HCV (P = 0.17 versus moderate/severe rejection). The area under the receiver operator characteristic curve of LSM to discriminate mild versus moderate/severe ACR was 0.924, and a LSM value of 8.5 kPa yielded a positive predictive value of 100% to diagnose moderate/severe rejection. Liver stiffness improved in 7%, 21%, and 64% of patients with moderate/severe rejection at 7, 30, and 90 days. In conclusion, according to the results of this exploratory study, LSM is associated with the severity of ACR in liver transplantation and thus may be of help in its assessment. PMID:26609794

  17. Management of Acute Regurgitation in Left-Sided Cardiac Valves

    PubMed Central

    Mokadam, Nahush A.; Stout, Karen K.; Verrier, Edward D.

    2011-01-01

    The management of acute, severe cardiac valvular regurgitation requires expeditious multidisciplinary care. Although acute, severe valvular regurgitation can be a true surgical emergency, accurate diagnosis and subsequent treatment decisions require clinical acumen, appropriate imaging, and sound judgment. An accurate and timely diagnosis is essential for successful outcomes and requires appropriate expertise and a sufficiently high degree of suspicion in a variety of settings. Whereas cardiovascular collapse is the most obvious and common presentation of acute cardiac valvular regurgitation, findings may be subtle, and the clinical presentation can often be nonspecific. Consequently, other acute conditions such as sepsis, pneumonia, or nonvalvular heart failure may be mistaken for acute valvular regurgitation. In comparison with that of the right-sided valves, regurgitation of the left-sided valves is more common and has greater clinical impact. Therefore, this review focuses on acute regurgitation of the aortic and mitral valves. PMID:21423463

  18. Lactate and lactate clearance in acute cardiac care patients

    PubMed Central

    Lazzeri, Chiara; Picariello, Claudio; Dini, Carlotta Sorini; Gensini, Gian Franco; Valente, Serafina

    2012-01-01

    Hyperlactataemia is commonly used as a diagnostic and prognostic tool in intensive care settings. Recent studies documented that serial lactate measurements over time (or lactate clearance), may be clinically more reliable than lactate absolute value for risk stratification in different pathological conditions. While the negative prognostic role of hyperlactataemia in several critical ill diseases (such as sepsis and trauma) is well established, data in patients with acute cardiac conditions (i.e. acute coronary syndromes) are scarce and controversial. The present paper provides an overview of the current available evidence on the clinical role of lactic acid levels and lactate clearance in acute cardiac settings (acute coronary syndromes, cardiogenic shock, cardiac surgery), focusing on its prognostic role. PMID:24062898

  19. Use of surface-enhanced Raman scattering as a prognostic indicator of acute kidney transplant rejection

    PubMed Central

    Chi, Jingmao; Zaw, Thet; Cardona, Iliana; Hosnain, Mujtaba; Garg, Neha; Lefkowitz, Heather R.; Tolias, Peter; Du, Henry

    2015-01-01

    We report an early, noninvasive and rapid prognostic method of predicting potential acute kidney dysfunction using surface-enhanced Raman scattering (SERS). Our analysis was performed on urine samples collected prospectively from 58 kidney transplant patients using a He-Ne laser (632.8 nm) as the excitation source. All abnormal kidney function episodes (three acute rejections and two acute kidney failures that were eventually diagnosed independently by clinical biopsy) consistently exhibited unique SERS spectral features in just one day following the transplant surgery. These results suggested that SERS analysis provides an early and more specific indication to kidney function than the clinically used biomarker, serum creatinine (sCr). PMID:25798301

  20. Haptoglobin activates innate immunity to enhance acute transplant rejection in mice

    PubMed Central

    Shen, Hua; Song, Yang; Colangelo, Christopher M.; Wu, Terence; Bruce, Can; Scabia, Gaia; Galan, Anjela; Maffei, Margherita; Goldstein, Daniel R.

    2011-01-01

    Immune tolerance to transplanted organs is impaired when the innate immune system is activated in response to the tissue necrosis that occurs during harvesting and implantation procedures. A key molecule in this immune pathway is the intracellular TLR signal adaptor known as myeloid differentiation primary response gene 88 (MyD88). After transplantation, MyD88 induces DC maturation as well as the production of inflammatory mediators, such as IL-6 and TNF-α. However, upstream activators of MyD88 function in response to transplantation have not been identified. Here, we show that haptoglobin, an acute phase protein, is an initiator of this MyD88-dependent inflammatory process in a mouse model of skin transplantation. Necrotic lysates from transplanted skin elicited higher inflammatory responses in DCs than did nontransplanted lysates, suggesting DC-mediated responses are triggered by factors released during transplantation. Analysis of transplanted lysates identified haptoglobin as one of the proteins upregulated during transplantation. Expression of donor haptoglobin enhanced the onset of acute skin transplant rejection, whereas haptoglobin-deficient skin grafts showed delayed acute rejection and antidonor T cell priming in a MyD88-dependent graft rejection model. Thus, our results show that haptoglobin release following skin necrosis contributes to accelerated transplant rejection, with potential implications for the development of localized immunosuppressive therapies. PMID:22156194

  1. Clinical significance of lactate in acute cardiac patients

    PubMed Central

    Lazzeri, Chiara; Valente, Serafina; Chiostri, Marco; Gensini, Gian Franco

    2015-01-01

    Lactate, as a metabolite of easy and quick assessment, has been studied over time in critically ill patients in order to evaluate its prognostic ability. The present review is focused on the prognostic role of lactate levels in acute cardiac patients (that is with acute coronary syndrome, cardiogenic shock, cardiac arrest, non including post cardiac surgery patients). In patients with ST-elevation myocardial infarction treated with mechanical revascularization, hyperlactatemia identified a subset of patients at higher risk for early death and in-hospital complications, being strictly related mainly to hemodynamic derangement. The prognostic impact of hyperlactatemia on mortality has been documented in patients with cardiogenic shock and in those with cardiac arrest even if there is no cut-off value of lactate to be associated with worse outcome or to guide resuscitation or hemodynamic management. Therapeutic hypothermia seems to affect per se lactate values which have been shown to progressively decrease during hypothermia. The mechanism(s) accounting for lactate levels during hypothemia seem to be multiple ranging from the metabolic effects of reduced temperatures to the hemodynamic effects of hypothermia (i.e., reduced need of vasopressor agents). Serial lactate measurements over time, or lactate clearance, have been reported to be clinically more reliable than lactate absolute value also in acute cardiac patients. Despite differences in study design, timing of lactate measurements and type of acute cardiac conditions (i.e., cardiogenic shock, cardiac arrest, refractory cardiac arrest), available evidence strongly suggests that higher lactate levels can be observed on admission in non-survivors and that higher lactate clearance is associated with better outcome. PMID:26322188

  2. Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection.

    PubMed

    Shi, Guanfang; Field, David J; Ko, Kyung-ae; Ture, Sara; Srivastava, Kalyan; Levy, Scott; Kowalska, M Anna; Poncz, Mortimer; Fowell, Deborah J; Morrell, Craig N

    2014-02-01

    Th cells are the major effector cells in transplant rejection and can be divided into Th1, Th2, Th17, and Treg subsets. Th differentiation is controlled by transcription factor expression, which is driven by positive and negative cytokine and chemokine stimuli at the time of T cell activation. Here we discovered that chemokine platelet factor 4 (PF4) is a negative regulator of Th17 differentiation. PF4-deficient and platelet-deficient mice had exaggerated immune responses to cardiac transplantation, including increased numbers of infiltrating Th17 cells and increased plasma IL-17. Although PF4 has been described as a platelet-specific molecule, we found that activated T cells also express PF4. Furthermore, bone marrow transplantation experiments revealed that T cell-derived PF4 contributes to a restriction in Th17 differentiation. Taken together, the results of this study demonstrate that PF4 is a key regulator of Th cell development that is necessary to limit Th17 differentiation. These data likely will impact our understanding of platelet-dependent regulation of T cell development, which is important in many diseases, in addition to transplantation. PMID:24463452

  3. Combined Detection of Serum IL-10, IL-17, and CXCL10 Predicts Acute Rejection Following Adult Liver Transplantation

    PubMed Central

    Kim, Nayoung; Yoon, Young-In; Yoo, Hyun Ju; Tak, Eunyoung; Ahn, Chul-Soo; Song, Gi-Won; Lee, Sung-Gyu; Hwang, Shin

    2016-01-01

    Discovery of non-invasive diagnostic and predictive biomarkers for acute rejection in liver transplant patients would help to ensure the preservation of liver function in the graft, eventually contributing to improved graft and patient survival. We evaluated selected cytokines and chemokines in the sera from liver transplant patients as potential biomarkers for acute rejection, and found that the combined detection of IL-10, IL-17, and CXCL10 at 1-2 weeks post-operation could predict acute rejection following adult liver transplantation with 97% specificity and 94% sensitivity. PMID:27498551

  4. Tumor Necrosis Factor Receptor 2: Its Contribution to Acute Cellular Rejection and Clear Cell Renal Carcinoma

    PubMed Central

    Wang, Jun; Al-Lamki, Rafia S.

    2013-01-01

    Tumor necrosis factor receptor 2 (TNFR2) is a type I transmembrane glycoprotein and one of the two receptors that orchestrate the complex biological functions of tumor necrosis factor (TNF, also designed TNF-α). Accumulating experimental evidence suggests that TNFR2 plays an important role in renal disorders associated with acute cellular rejection and clear cell renal carcinoma but its exact role in these settings is still not completely understood. This papers reviews the factors that may mediate TNFR2 induction in acute cellular rejection and clear cell renal carcinoma and its contribution to these conditions and discusses its therapeutic implications. A greater understanding of the function of TNFR2 may lead to the development of new anti-TNF drugs. PMID:24350291

  5. Vascularized composite allotransplantation: current standards and novel approaches to prevent acute rejection and chronic allograft deterioration.

    PubMed

    Kueckelhaus, Maximilian; Fischer, Sebastian; Seyda, Midas; Bueno, Ericka M; Aycart, Mario A; Alhefzi, Muayyad; ElKhal, Abdallah; Pomahac, Bohdan; Tullius, Stefan G

    2016-06-01

    The advent of more potent immunosuppressants led to the first successful human upper extremity transplantation in 1998. At this time, >100 upper extremity transplants, 30 face transplants, and a variety of other vascularized composite allotransplantation (VCA) procedures have been performed around the world. VCA recipients present unique challenges for transplantation. The incidence of acute rejection exceeds 80% in hand and face transplantation and is well documented, whereas reports about antibody-mediated rejection and chronic rejection remain scarce. Immunosuppression protocols commonly used at US centers are derived from solid organ transplantation protocols. Novel approaches to minimize rejections in VCA may include improved HLA matching and considerations toward cytomegalovirus infection status. New graft preservation techniques may decrease immunogenicity prior to transplant. Novel monitoring methods such as valid biomarkers, ultrasound biomicroscopy, and sentinel flaps may enable earlier diagnosis of rejection. Cell-based therapies are being explored to achieve immunosuppressive regimen minimization or even tolerance induction. The efficacy of local immunosuppression in clinical VCA remains controversial. In conclusion, although immunosuppressive strategies adapted from SOT have demonstrated good midterm results, focusing on the unique features of VCA grafts may enable additional, more specific treatment strategies in the future and improved long-term graft outcomes. PMID:26265179

  6. The effect of pravastatin on acute rejection after kidney transplantation--a pilot study.

    PubMed

    Katznelson, S; Wilkinson, A H; Kobashigawa, J A; Wang, X M; Chia, D; Ozawa, M; Zhong, H P; Hirata, M; Cohen, A H; Teraski, P I

    1996-05-27

    Hyperlipidemia is an important complication of kidney transplantation affecting up to 74% of recipients. HMG-CoA reductase inhibitors are reported to provide safe and effective treatment for this problem. A recent study suggests that pravastatin, an HMG-CoA reductase inhibitor, also decreases the incidence of both clinically severe acute rejection episodes and natural killer cell cytotoxicity after orthotopic heart transplantation. We have performed a prospective randomized pilot study of the effect of pravastatin on these same parameters after cadaveric kidney transplantation. Graft recipients were randomized to receive pravastatin after transplantation or no pravastatin (24 patients in each group) in addition to routine cyclosporine and prednisone immunosuppression. Lipid levels, acute rejection episodes and serial natural killer cell cytotoxicities were followed for 4 months after the transplant. At the end of the study period, pravastatin had successfully controlled mean total cholesterol levels (202.6 +/- 9.3 vs. 236.5 +/- 11.9 mg/dl, P < 0.02), LDL levels (107.9 +/- 6.6 vs.149.6 +/- 10.7 mg/dl, P < 0.002), and triglyceride levels (118.8 +/- 14.2 vs. 157.2 +/- 13.8 mg/dl, P < 0.05). In addition, the pravastatin-treated group experienced a reduction in the incidence of biopsy-proven acute rejection episodes (25% vs. 58%, P = 0.01), the incidence of multiple rejections episodes (P < 0.05), and the use of both pulse methylprednisolone (P = 0.01) and OKT3 (P = 0.02). Mean natural killer cell cytotoxicity was similarly reduced (11.3 +/- 1.6 vs. 20.0 +/- 2.0% lysis of K562 target cells, P < 0.002). These data suggest that pravastatin exerts an additional immunosuppressive effect in kidney transplant recipients treated with cyclosporine-based immunosuppression. PMID:8633373

  7. Arsenic trioxide attenuated the rejection of major histocompatibility complex fully-mismatched cardiac allografts in mice.

    PubMed

    Yan, S; Zhang, Q Y; Zhou, B; Xue, L; Chen, H; Wang, Y; Zheng, S S

    2009-06-01

    We investigated the effects of arsenic trioxide (As(2)O(3)) on allogeneic immune response using a mouse heart transplantation model. Mice were randomly divided into 4 groups of 6 animals each. The control group received phosphate-buffered saline (PBS); the As(2)O(3)-treated group, intraperitoneal (IP) injection of As(2)O(3) (1 mg/kg) from days -3 to 10 after heart transplantation. The cyclosporine (CsA)-treated group was given a subtherapeutic dose of CsA (10 mg/kg) IP, and the As(2)O(3) plus CsA-treated group, a combined protocol of As(2)O(3) and CsA. Six days after transplantation, cardiac allografts were harvested for immunohistology and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The survival of the allografts was significantly improved among the As(2)O(3)-treated group compared with the control group (17.2 +/- 1.9 vs 8.0 +/- 0.9 days; P < .05). A marked prolongation (28.6 +/- 6.0 days) of graft survival was achieved by the combined protocol compared with the CsA-treated group (9.6 +/- 3.0 days; P < .05) or the As(2)O(3)-treated group. Allografts of As(2)O(3)-treated and As(2)O(3) plus CsA-treated mice showed a changing pattern of Th1/Th2 cytokine mRNA expression. Allograft rejection was apparently alleviated by low-dose As(2)O(3), and particularly when combined with a subtherapeutic CsA dose. PMID:19545743

  8. Clinical significance of automatic warning function of cardiac remote monitoring systems in preventing acute cardiac episodes

    PubMed Central

    Chen, Shou-Qiang; Xing, Shan-Shan; Gao, Hai-Qing

    2014-01-01

    Objective: In addition to ambulatory Holter electrocardiographic recording and transtelephonic electrocardiographic monitoring (TTM), a cardiac remote monitoring system can provide an automatic warning function through the general packet radio service (GPRS) network, enabling earlier diagnosis, treatment and improved outcome of cardiac diseases. The purpose of this study was to estimate its clinical significance in preventing acute cardiac episodes. Methods: Using 2 leads (V1 and V5 leads) and the automatic warning mode, 7160 patients were tested with a cardiac remote monitoring system from October 2004 to September 2007. If malignant arrhythmias or obvious ST-T changes appeared in the electrocardiogram records was automatically transferred to the monitoring center, the patient and his family members were informed, and the corresponding precautionary or therapeutic measures were implemented immediately. Results: In our study, 274 cases of malignant arrhythmia, including sinus standstill and ventricular tachycardia, and 43 cases of obvious ST-segment elevation were detected and treated. Because of early detection, there was no death or deformity. Conclusions: A cardiac remote monitoring system providing an automatic warning function can play an important role in preventing acute cardiac episodes. PMID:25674124

  9. Urinary proteomic shotgun approach for identification of potential acute rejection biomarkers in renal transplant recipients

    PubMed Central

    2012-01-01

    Background Acute rejection (AR) episodes in renal transplant recipients are suspected when plasma creatinine is elevated and other potential causes out ruled. Graft biopsies are however needed for definite diagnosis. Non-invasive AR-biomarkers is an unmet clinical need. The urinary proteome is an interesting source in the search for such a biomarker in this population. Methods In this proof of principle study, serial urine samples in the early post transplant phase from 6 patients with biopsy verified acute rejections and 6 age-matched controls without clinical signs of rejection were analyzed by shotgun proteomics. Results Eleven proteins fulfilled predefined criteria for regulation in association with AR. They presented detectable regulation already several days before clinical suspicion of AR (increased plasma creatinine). The regulated proteins could be grouped by their biological function; proteins related to growth and proteins related to immune response. Growth-related proteins (IGFBP7, Vasorin, EGF and Galectin-3-binding protein) were significantly up-regulated in association with AR (P = 0.03) while proteins related to immune response (MASP2, C3, CD59, Ceruloplasmin, PiGR and CD74) tended to be up-regulated ( P = 0.13). Conclusion The use of shotgun proteomics provides a robust and sensitive method for identification of potentially predictive urinary biomarkers of AR. Further validation of the current findings is needed to establish their potential clinical role with regards to clinical AR diagnosis. Trial registration ClinicalTrials.gov number NCT00139009 PMID:23369437

  10. Perspectives on the value of biomarkers in acute cardiac care and implications for strategic management.

    PubMed

    Kossaify, Antoine; Garcia, Annie; Succar, Sami; Ibrahim, Antoine; Moussallem, Nicolas; Kossaify, Mikhael; Grollier, Gilles

    2013-01-01

    Biomarkers in acute cardiac care are gaining increasing interest given their clinical benefits. This study is a review of the major conditions in acute cardiac care, with a focus on biomarkers for diagnostic and prognostic assessment. Through a PubMed search, 110 relevant articles were selected. The most commonly used cardiac biomarkers (cardiac troponin, natriuretic peptides, and C-reactive protein) are presented first, followed by a description of variable acute cardiac conditions with their relevant biomarkers. In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care. Point-of-care testing and multi-markers use are essential for prompt diagnostic approach and tailored strategic management. PMID:24046510

  11. Effect of adopting a new histological grading system of acute rejection after heart transplantation

    PubMed Central

    Balk, A.; Zondervan, P.; van der Meer, P.; van Gelder, T.; Mochtar, B.; Simoons, M.; Weimar, W.

    1997-01-01

    Background—Treatment policy of acute rejection after heart transplantation has been changed after adopting the ISHLT endomyocardial biopsy grading system in 1991.
Objective—To determine the effect of this policy change on clinical outcome after transplantation.
Methods—The outcome of 147 patients who had a transplant before (early group, median follow up 96 months) and 114 patients who had a transplant after (late group, median follow up 41 months) the introduction of the ISHLT biopsy grading system was studied retrospectively. Initially "moderate rejection" according to Billingham's conventional criteria was treated. From January 1991 grade 3A and higher was considered to require intensification of immunosuppression.
Results—There were some differences between the two groups: recipients (50 v 44 years) as well as donors (28 v 24 years) were older in the "late group" and more patients of this group received early anti-T cell prophylaxis (92% v 56%). Despite more extensive use of early prophylaxis more rejection episodes were diagnosed (2.4 v 1.4) and considerably more courses of rejection treatment were instituted in the late compared with the early group (3.2 v 1.5). There were no deaths because of rejection in the late group, however, more infections occurred within the first year (mean 1.8 v 1.4) and more non-skin malignancies within the first 41 months were diagnosed (8 of 57 v 6 of 147, 95% CIs of difference includes 0). The incidence of graft vascular disease in the late group has been comparable to the early group until now. 
Conclusion—The interpretation of the ISHLT grading system resulted in lowering of the threshold for the diagnosis of rejection thereby increasing the number of rejections and subsequently the immunosuppressive load and its complications.

 Keywords: transplantation;  biopsy grading system;  rejection PMID:9470880

  12. Molecular Classifiers for Acute Kidney Transplant Rejection in Peripheral Blood by Whole Genome Gene Expression Profiling

    PubMed Central

    Kurian, S. M.; Williams, A. N.; Gelbart, T.; Campbell, D.; Mondala, T. S.; Head, S. R.; Horvath, S.; Gaber, L.; Thompson, R.; Whisenant, T.; Lin, W.; Langfelder, P.; Robison, E. H.; Schaffer, R. L.; Fisher, J. S.; Friedewald, J.; Flechner, S. M.; Chan, L. K.; Wiseman, A. C.; Shidban, H.; Mendez, R.; Heilman, R.; Abecassis, M. M.; Marsh, C. L.; Salomon, D. R.

    2015-01-01

    There are no minimally invasive diagnostic metrics for acute kidney transplant rejection (AR), especially in the setting of the common confounding diagnosis, acute dysfunction with no rejection (ADNR). Thus, though kidney transplant biopsies remain the gold standard, they are invasive, have substantial risks, sampling error issues and significant costs and are not suitable for serial monitoring. Global gene expression profiles of 148 peripheral blood samples from transplant patients with excellent function and normal histology (TX; n = 46), AR (n = 63) and ADNR (n = 39), from two independent cohorts were analyzed with DNA microarrays. We applied a new normalization tool, frozen robust multi-array analysis, particularly suitable for clinical diagnostics, multiple prediction tools to discover, refine and validate robust molecular classifiers and we tested a novel one-by-one analysis strategy to model the real clinical application of this test. Multiple three-way classifier tools identified 200 highest value probesets with sensitivity, specificity, positive predictive value, negative predictive value and area under the curve for the validation cohort ranging from 82% to 100%, 76% to 95%, 76% to 95%, 79% to 100%, 84% to 100% and 0.817 to 0.968, respectively. We conclude that peripheral blood gene expression profiling can be used as a minimally invasive tool to accurately reveal TX, AR and ADNR in the setting of acute kidney transplant dysfunction. PMID:24725967

  13. Cardiac Arrest in a Heart Transplant Patient Receiving Dexmedetomidine During Cardiac Catheterization.

    PubMed

    Schwartz, Lawrence Israel; Miyamoto, Shelley D; Stenquist, Scott; Twite, Mark David

    2016-06-01

    Dexmedetomidine is an α-2 agonist with a sedative and cardiopulmonary profile that makes it an attractive anesthetic in pediatric cardiac patients. Cardiac transplant patients may suffer from acute cellular rejection of the cardiac conduction system and, therefore, are at an increased risk of the electrophysiological effect of dexmedetomidine. We present such a patient who had a cardiac arrest while receiving dexmedetomidine during cardiac catheterization. Because acute cellular rejection of the cardiac conduction system is difficult to diagnose, dexmedetomidine should be used with caution in pediatric heart transplant patients. PMID:26721807

  14. Cortical perfusion index: A predictor of acute rejection in transplanted kidneys

    SciTech Connect

    Atkins, H.L.; Oster, Z.H.; Anaise, D.; Wein, S.; Waltzer, W.; Gonder, A.; Cooch, E.; Rapaport, F.T.

    1985-05-01

    The presently available non-invasive methods for the diagnosis of acute rejection crisis (ARC) of renal transplants are not satisfactory. However, the need for such a test is of paramount clinical importance. A prospective study of 74 post-transplantation events in renal allograft recipients was performed. Clinical, surgical exploration and biopsy data were correlated with TC-99m DTPA scintigraphy using the following indices: Global perfusion index (GPI), cortical perfusion index (CPI), medullary perfusion index (MPI), the peak-to-plateau ratio (P/P), iliac artery peak to renal peak time (delta-P) and washout half-time (T1/2). Of the 74 events, 24 were proven to be due to acute rejection crisis (ARC), 13 were of ureteral obstruction, 18 various nephropathies and 19 in stable renal transplant function. The P/P, delta-P and T1/2 were not good predictors of ARC; the sensitivity was 79%, 79% and 80% respectively. The sensitivity of the GPI was 58% and the specificity was 87%. The cortical perfusion index rated better: specificity=84% and sensitivity=87%. However, the best indicator of ARC seemed to be the percent increase in cortical perfusion index over previous values obtained during stable graft function. Thus the sensitivity was found to be 91% and specificity was 96%. The difference between global and cortical perfusion indices reflects shunting of blood for cortex to medulla. This study suggest that the cortical perfusion index (CPI) and the percent increase in CPI can be used to non-invasively diagnose acute renal allograft rejection.

  15. Early diagnosis of acute postoperative renal transplant rejection by indium-111-labeled platelet scintigraphy

    SciTech Connect

    Tisdale, P.L.; Collier, B.D.; Kauffman, H.M.; Adams, M.B.; Isitman, A.T.; Hellman, R.S.; Hoffmann, R.G.; Rao, S.A.; Joestgen, T.; Krohn, L.

    1986-08-01

    A prospective evaluation of /sup 111/In-labeled platelet scintigraphy (IPS) for the early diagnosis of acute postoperative renal transplant rejection (TR) was undertaken. The results of IPS were compared with in vitro biochemical tests, the clinical finding of graft tenderness, and combined (/sup 99m/Tc)DTPA and (/sup 131/I)orthoiodohippurate scintigraphy. With a sensitivity of 0.93 and a specificity of 0.95, IPS provided otherwise unavailable diagnostic information. Furthermore, postoperative IPS was a good predictor of long-term allograft survival.

  16. MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11

    SciTech Connect

    Liu, Xiaoyou; Dong, Changgui; Jiang, Zhengyao; Wu, William K.K.; Chan, Matthew T.V.; Zhang, Jie; Li, Haibin; Qin, Ke; Sun, Xuyong

    2015-04-10

    Kidney transplantation is the major therapeutic option for end-stage kidney diseases. However, acute rejection could cause allograft loss in some of these patients. Emerging evidence supports that microRNA (miRNA) dysregulation is implicated in acute allograft rejection. In this study, we used next-generation sequencing to profile miRNA expression in normal and acutely rejected kidney allografts. Among 75 identified dysregulated miRNAs, miR-10b was the most significantly downregulated miRNAs in rejected allografts. Transfecting miR-10b inhibitor into human renal glomerular endothelial cells recapitulated key features of acute allograft rejection, including endothelial cell apoptosis, release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor α, interferon-γ, and chemokine (C–C motif) ligand 2) and chemotaxis of macrophages whereas transfection of miR-10b mimics had opposite effects. Downregulation of miR-10b directly derepressed the expression of BCL2L11 (an apoptosis inducer) as revealed by luciferase reporter assay. Taken together, miR-10b downregulation mediates many aspects of disease pathogenicity of acute kidney allograft rejection. Restoring miR-10b expression in glomerular endothelial cells could be a novel therapeutic approach to reduce acute renal allograft loss. - Highlights: • miR-10b was the most downregulated microRNAs in acutely rejected renal allografts. • miR-10b downregulation triggered glomerular endothelial cell apoptosis. • miR-10b downregulation induced release of pro-inflammatory cytokines. • miR-10b downregulation derepressed its pro-apoptotic target BCL2L11.

  17. Difficulties, guidelines and review of developing an acute rejection model after rat intestinal transplantation.

    PubMed

    Andres, Ane Miren; Santamaria, Monica; Hernandez-Oliveros, Francisco; Guerra, Laura; Lopez, Sergio; Stringa, Pablo; Vallejo, Maria Teresa; Largo, Carlota; Encinas, Jose Luis; Garcia de Las Heras, Maria Soledad; Lopez-Santamaria, Manuel; Tovar, Juan Antonio

    2016-05-01

    Experimental small bowel transplantation (SBT) in rats has been proven to be a useful tool for the study of ischemia-reperfusion and immunological aspects related to solid organ transplantation. However, the model is not completely refined, specialized literature is scarce and complex technical details are typically omitted or confusing. Most studies related to acute rejection (AR) use the orthotopic standard, with small sample sizes due to its high mortality, whereas those studying chronic rejection (CR) use the heterotopic standard, which allows longer term survival but does not exactly reflect the human clinical scenario. Various animal strains have been used, and the type of rejection and the timing of its analysis differ among authors. The double purpose of this study was to develop an improved unusual AR model of SBT using the heterotopic technique, and to elaborate a guide useful to implement experimental models for studying AR. We analyzed the model's technical details and expected difficulties in overcoming the learning curve for such a complex microsurgical model, identifying the potential problem areas and providing a step-by-step protocol and reference guide for future surgeons interested in the topic. We also discuss the historic and more recent options in the literature. PMID:27102447

  18. Teratocarcinomas Arising from Allogeneic Induced Pluripotent Stem Cell-Derived Cardiac Tissue Constructs Provoked Host Immune Rejection in Mice

    PubMed Central

    Kawamura, Ai; Miyagawa, Shigeru; Fukushima, Satsuki; Kawamura, Takuji; Kashiyama, Noriyuki; Ito, Emiko; Watabe, Tadashi; Masuda, Shigeo; Toda, Koichi; Hatazawa, Jun; Morii, Eiichi; Sawa, Yoshiki

    2016-01-01

    Transplantation of induced pluripotent stem cell-derived cardiac tissue constructs is a promising regenerative treatment for cardiac failure: however, its tumourigenic potential is concerning. We hypothesised that the tumourigenic potential may be eliminated by the host immune response after allogeneic cell transplantation. Scaffold-free iPSC-derived cardaic tissue sheets of C57BL/6 mouse origin were transplanted into the cardiac surface of syngeneic C57BL/6 mice and allogeneic BALB/c mice with or without tacrolimus injection. Syngeneic mice and tacrolimus-injected immunosuppressed allogeneic mice formed teratocarcinomas with identical phenotypes, characteristic, and time courses, as assessed by imaging tools including 18F-fluorodeoxyglucose-positron emission tomography. In contrast, temporarily immunosuppressed allogeneic mice, following cessation of tacrolimus injection displayed diminished progression of the teratocarcinoma, accompanied by an accumulation of CD4/CD8-positive T cells, and finally achieved complete elimination of the teratocarcinoma. Our results indicated that malignant teratocarcinomas arising from induced pluripotent stem cell-derived cardiac tissue constructs provoked T cell-related host immune rejection to arrest tumour growth in murine allogeneic transplantation models. PMID:26763872

  19. Endothelial RAGE exacerbates acute postischaemic cardiac inflammation.

    PubMed

    Ziegler, Tilman; Horstkotte, Melanie; Lange, Philipp; Ng, Judy; Bongiovanni, Dario; Hinkel, Rabea; Laugwitz, Karl-Ludwig; Sperandio, Markus; Horstkotte, Jan; Kupatt, Christian

    2016-08-01

    Advanced glycation end-products (AGEs) interact with their receptor RAGE, leading to an inflammatory state. We investigated the role of RAGE in postischaemic leukocyte adhesion after myocardial infarction and its effect on postischaemic myocardial function. Wildtype (WT), ICAM-1-/-, RAGE-/- or ICAM-1/RAGE-/- mice underwent 20 minutes (min) of LAD-occlusion followed by 15 min of reperfusion. We applied in vivo fluorescence microscopy visualising Rhodamine-6G labelled leukocytes. To differentiate between endothelial and leukocyte RAGE, we generated bone marrow chimeric mice. Invasive hemodynamic measurements were performed in mice undergoing 45 min of myocardial ischaemia (via LAD-occlusion) followed by 24 hours of reperfusion. Left-ventricular developed pressure (LVDP) was assessed by insertion of a millar-tip catheter into the left ventricle. In the acute model of myocardial ischaemia, leukocyte retention (WT 68 ± 4 cells/hpf) was significantly reduced in ICAM-1-/- (40 ± 3 cells/hpf) and RAGE-/- mice (38 ± 4 cells/hpf). ICAM-1/RAGE-/- mice displayed an additive reduction of leukocyte retention (ICAM-1/RAGE-/- 15 ± 3 cells/hpf). Ly-6G+ neutrophil were predominantly reduced in ICAM-1/RAGE-/- hearts (28 %), whereas Ly-6C+ proinflammatory monocytes decreased to a lesser extent (55 %). Interestingly, PMN recruitment was not affected in chimeric mice with RAGE deficiency in BM cells (WT mice reconstituted with ICAM-1/RAGE-/- BM: 55 ± 4 cells/hpf) while in mice with global RAGE deficiency (ICAM-1/RAGE-/- mice reconstituted with ICAM-1/RAGE-/- BM) leucocyte retention was significantly reduced (13 ± 1 cells/hpf), similar to non-transplanted ICAM/RAGE-/- mice. Furthermore, postischaemic LVDP increased in ICAM-1/RAGE-/- animals (98 ± 4 mmHg vs 86 ± 4 mmHg in WT mice). In conclusion, combined deficiency of ICAM-1 and RAGE reduces leukocyte influx into infarcted myocardium and improves LV function during the acute phase after myocardial ischaemia and reperfusion

  20. Acute Liver Allograft Antibody-Mediated Rejection: an inter-institutional study of routine histopathological features

    PubMed Central

    O'Leary, Jacqueline G.; Shiller, S. Michelle; Bellamy, Christopher; Nalesnik, Michael A.; Kaneku, Hugo; Terasaki, Paul I.; Klintmalm, Göran B.; Demetris, Anthony J.

    2015-01-01

    Acute antibody-mediated rejection (AMR) occurs in a minority of sensitized liver transplant recipients. Although histopathologic characteristics have been described, a generalizable scoring system used to trigger a more in-depth analysis is needed to screen for this rare but important finding. Toward this goal, we created a training and validation cohort from 3 high volume liver transplant programs of putative acute AMR and control cases that were evaluated blindly by 4 independent transplant pathologists. The evaluations were performed on H&E sections alone without knowledge of serum DSA results nor C4d stains. Characteristics strongly correlated with acute AMR included portal eosinophilia (OR=4.37, p<0.001), portal vein endothelial cell hypertrophy (OR=2.88, p<0.001), and eosinophilic central venulitis (OR=2.48, p=0.003). These and other characteristics were incorporated into models created from the training cohort alone. The final Acute-AMR (aAMR) score exhibited a strong correlation with acute AMR in the training (OR=2.86, p<0.001) and validation cohort (OR=2.49, p<0.001). SPSS tree classification was used to select 2 cutoffs, one that optimized specificity at a score >1.75 (sensitivity = 34%, specificity = 87%) and a second that optimized sensitivity at a score >1.0 (sensitivity = 81%, specificity = 71%). In conclusion, routine histopathological features of the aAMR score can be used to screen for acute AMR on routine H&E in liver transplant biopsies, a diagnosis that requires substantiation by donor-specific HLA alloantibody testing, C4d staining, and exclusion of other insults. PMID:25045154

  1. Early detection of acute kidney injury after pediatric cardiac surgery

    PubMed Central

    Jefferies, John Lynn; Devarajan, Prasad

    2016-01-01

    Acute kidney injury (AKI) is increasingly recognized as a common problem in children undergoing cardiac surgery, with well documented increases in morbidity and mortality in both the short and the long term. Traditional approaches to the identification of AKI such as changes in serum creatinine have revealed a large incidence in this population with significant negative impact on clinical outcomes. However, the traditional diagnostic approaches to AKI diagnosis have inherent limitations that may lead to under-diagnosis of this pathologic process. There is a dearth of randomized controlled trials for the prevention and treatment of AKI associated with cardiac surgery, at least in part due to the paucity of early predictive biomarkers. Novel non-invasive biomarkers have ushered in a new era that allows for earlier detection of AKI. With these new diagnostic tools, a more consistent approach can be employed across centers that may facilitate a more accurate representation of the actual prevalence of AKI and more importantly, clinical investigation that may minimize the occurrence of AKI following pediatric cardiac surgery. A thoughtful management approach is necessary to mitigate the effects of AKI after cardiac surgery, which is best accomplished in close collaboration with pediatric nephrologists. Long-term surveillance for improvement in kidney function and potential development of chronic kidney disease should also be a part of the comprehensive management strategy. PMID:27429538

  2. Efficacy of rabbit anti-thymocyte globulin for steroid-resistant acute rejection after liver transplantation

    PubMed Central

    Lee, Jae Geun; Lee, Juhan; Lee, Jung Jun; Song, Seung Hwan; Ju, Man Ki; Choi, Gi Hong; Kim, Myoung Soo; Choi, Jin Sub; Kim, Soon Il; Joo, Dong Jin

    2016-01-01

    Abstract Acute cellular rejection after liver transplantation (LT) can be treated with steroid pulse therapy, but there is no ideal treatment for steroid-resistant acute rejection (SRAR). We aimed to determine the feasibility and potential complications of rabbit anti-thymocyte globulin (rATG) application to treat SRAR in liver transplant recipients. We retrospectively reviewed medical records of 429 recipients who underwent LT at Severance Hospital between January 2010 and March 2015. We compared clinical features and graft survival between patients with steroid-sensitive acute rejection (SSAR; n = 23) and SRAR (n = 11). We also analyzed complications and changes in laboratory findings after 2.5 mg/kg rATG treatment in patients with SRAR for 6 to 10 days. There were no significant differences in gender, age, model for end-stage liver disease score, Child–Turcotte–Pugh score, or original liver diseases between patients with SSAR and SRAR, although deceased donors were more frequently associated with the SRAR group (P = 0.004). All SRAR patients responded positively to rATG treatment; after treatment, the patients’ median AST levels decreased from 138 to 63 IU/L, and their median ALT levels dropped from 327 to 70 IU/L 1 day after rATG treatment (P = 0.022 and 0.017, respectively). Median aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin levels significantly decreased 1 month post-treatment (P = 0.038, 0.004, and 0.041, respectively). Median survival after LT was 23 months, and median survival after rATG was 22 months in patients with SRAR. Adverse effects included hepatitis C virus (HCV) reactivation, fungemia, and cytomegalovirus (CMV) infection. Nine SRAR patients survived with healthy liver function, 1 died from a traffic accident during follow-up, and 1 died from graft-versus-host disease and fungemia. Administration of rATG is an effective therapeutic option for SRAR with acceptable complications in liver

  3. Efficacy of rabbit anti-thymocyte globulin for steroid-resistant acute rejection after liver transplantation.

    PubMed

    Lee, Jae Geun; Lee, Juhan; Lee, Jung Jun; Song, Seung Hwan; Ju, Man Ki; Choi, Gi Hong; Kim, Myoung Soo; Choi, Jin Sub; Kim, Soon Il; Joo, Dong Jin

    2016-06-01

    Acute cellular rejection after liver transplantation (LT) can be treated with steroid pulse therapy, but there is no ideal treatment for steroid-resistant acute rejection (SRAR). We aimed to determine the feasibility and potential complications of rabbit anti-thymocyte globulin (rATG) application to treat SRAR in liver transplant recipients. We retrospectively reviewed medical records of 429 recipients who underwent LT at Severance Hospital between January 2010 and March 2015. We compared clinical features and graft survival between patients with steroid-sensitive acute rejection (SSAR; n = 23) and SRAR (n = 11). We also analyzed complications and changes in laboratory findings after 2.5 mg/kg rATG treatment in patients with SRAR for 6 to 10 days. There were no significant differences in gender, age, model for end-stage liver disease score, Child-Turcotte-Pugh score, or original liver diseases between patients with SSAR and SRAR, although deceased donors were more frequently associated with the SRAR group (P = 0.004). All SRAR patients responded positively to rATG treatment; after treatment, the patients' median AST levels decreased from 138 to 63 IU/L, and their median ALT levels dropped from 327 to 70 IU/L 1 day after rATG treatment (P = 0.022 and 0.017, respectively). Median aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin levels significantly decreased 1 month post-treatment (P = 0.038, 0.004, and 0.041, respectively). Median survival after LT was 23 months, and median survival after rATG was 22 months in patients with SRAR. Adverse effects included hepatitis C virus (HCV) reactivation, fungemia, and cytomegalovirus (CMV) infection. Nine SRAR patients survived with healthy liver function, 1 died from a traffic accident during follow-up, and 1 died from graft-versus-host disease and fungemia. Administration of rATG is an effective therapeutic option for SRAR with acceptable complications in liver transplant recipients

  4. Analysis of NAD(P)H fluorescence components in cardiac myocytes from human biopsies: a new tool to improve diagnostics of rejection of transplanted patients

    NASA Astrophysics Data System (ADS)

    Cheng, Y.; Mateasik, A.; Poirier, N.; Miró, J.; Dahdah, N.; Chorvat, D., Jr.; Chorvatova, A.

    2009-02-01

    Tissue autofluorescence is one of the most versatile non-invasive tools for mapping the metabolic state in living tissues. Increasing interest in the imaging and diagnosis of living cells and tissues, based on their intrinsic fluorescence rather than fluorescence labeling, is closely connected to the latest developments in high-performance spectroscopic and microscopic techniques. We investigate metabolic state of cardiac cells isolated from one additional human biopsy from transplanted pediatric patients presenting either no rejection (R0) or mild rejection (R1). Two different approaches for isolation of human cardiac myocytes are also compared. Spectrally-resolved fluorescence lifetime detection of NAD(P)H fluorescence (excitation by pulsed 375 nm picosecond laser) is tested as a promising new tool for quantitative analysis of intrinsic cellular autofluorescence signals in living cardiomyocytes. This work opens new horizons in the evaluation of cardiac transplant rejection using latest fluorescence imaging approaches.

  5. Cardiac computed tomography in patients with acute chest pain.

    PubMed

    Nieman, Koen; Hoffmann, Udo

    2015-04-14

    The efficient and reliable evaluation of patients with acute chest pain is one of the most challenging tasks in the emergency department. Coronary computed tomography (CT) angiography may play a major role, since it permits ruling out coronary artery disease with high accuracy if performed with expertise in properly selected and prepared patients. Several randomized trials have established early cardiac CT as a viable safe and potentially more efficient alternative to functional testing in the evaluation of acute chest pain. Ongoing investigations explore whether advanced anatomic and functional assessments such as high-risk coronary plaque, resting myocardial perfusion, and left ventricular function, or the simulation of the fractional coronary flow reserve will add information to the anatomic assessment for stenosis, which would allow expanding the benefits of cardiac CT from triage to treatment decisions. Especially, the combination of high-sensitive troponins and coronary computed tomography angiography may play a valuable role in future strategies for the management of patients presenting with acute chest pain. PMID:25687351

  6. Successful Salvage Treatment of Resistant Acute Antibody-Mediated Kidney Transplant Rejection with Eculizumab.

    PubMed

    Khan, Saif A; Al-Riyami, Dawood; Al-Mula Abed, Yasser W; Mohammed, Saja; Al-Riyami, Marwa; Al-Lawati, Nabil M

    2016-08-01

    Antibody-mediated rejection (ABMR) jeopardises short- and long-term transplant survival and remains a challenge in the field of organ transplantation. We report the first use of the anticomplement agent eculizumab in Oman in the treatment of a 61-year-old female patient with ABMR following a living unrelated kidney transplant. The patient was admitted to the Sultan Qaboos University Hospital in Muscat, Oman, in 2013 on the eighth day post-transplantation with serum creatinine (Cr) levels of 400 µmol/L which continued to rise, necessitating haemodialysis. A biopsy indicated ABMR with acute cellular rejection. No improvement was observed following standard ABMR treatment and she continued to require dialysis. Five doses of eculizumab were administered over six weeks with a subsequent dramatic improvement in renal function. The patient became dialysis-free with serum Cr levels of 119 µmol/L within four months. This case report indicates that eculizumab is a promising agent in the treatment of ABMR. PMID:27606122

  7. Successful Salvage Treatment of Resistant Acute Antibody-Mediated Kidney Transplant Rejection with Eculizumab

    PubMed Central

    Khan, Saif A.; Al-Riyami, Dawood; Al-Mula Abed, Yasser W.; Mohammed, Saja; Al-Riyami, Marwa; Al-Lawati, Nabil M.

    2016-01-01

    Antibody-mediated rejection (ABMR) jeopardises short- and long-term transplant survival and remains a challenge in the field of organ transplantation. We report the first use of the anticomplement agent eculizumab in Oman in the treatment of a 61-year-old female patient with ABMR following a living unrelated kidney transplant. The patient was admitted to the Sultan Qaboos University Hospital in Muscat, Oman, in 2013 on the eighth day post-transplantation with serum creatinine (Cr) levels of 400 µmol/L which continued to rise, necessitating haemodialysis. A biopsy indicated ABMR with acute cellular rejection. No improvement was observed following standard ABMR treatment and she continued to require dialysis. Five doses of eculizumab were administered over six weeks with a subsequent dramatic improvement in renal function. The patient became dialysis-free with serum Cr levels of 119 µmol/L within four months. This case report indicates that eculizumab is a promising agent in the treatment of ABMR. PMID:27606122

  8. Acute Rejection Associated with Donor-Specific Anti-MICA Antibody in a Highly Sensitized Pediatric Renal Transplant Recipient

    PubMed Central

    Narayan, Shoba; Tsai, Eileen W.; Zhang, Qiuheng; Wallace, William D.; Reed, Elaine F.; Ettenger, Robert B.

    2013-01-01

    Allograft rejection in HLA identical transplant recipients and in patients without detectable donor specific anti-HLA antibodies has lead to the identification of non-HLA antigens as targets of the alloimmune response. Major Histocompatibility Complex class I-related chain A (MICA) antigen has been recognized as an important non-HLA target in renal transplantation. Recent studies have shown that anti-MICA antibodies are associated with acute renal allograft rejection and failure. Current cross match procedures using donor lymphocytes fail to detect MICA antibodies. Transplant candidates are not routinely tested for pre-sensitization to MICA antigens nor are transplant donors typed for MICA alleles. Optimal classification and treatment of acute rejection associated with MICA antibody remains unknown. In this case report, we are the first to describe the clinical course and treatment of donor specific MICA antibody associated with both Banff type II A acute cellular rejection (ACR) and antibody mediated rejection (AMR) in a highly sensitized pediatric renal re-transplant recipient. This case also emphasizes the importance of pre-transplant screening for donor specific MICA antibody especially in highly sensitized renal transplant patients.. PMID:21199204

  9. Derivation and Validation of a Cytokine-Based Assay to Screen for Acute Rejection in Renal Transplant Recipients

    PubMed Central

    De Serres, Sacha A.; Mfarrej, Bechara G.; Grafals, Monica; Riella, Leonardo V.; Magee, Ciara N.; Yeung, Melissa Y.; Dyer, Christine; Ahmad, Usaila; Chandraker, Anil

    2012-01-01

    Summary Background and objectives Acute rejection remains a problem in renal transplantation. This study sought to determine the utility of a noninvasive cytokine assay in screening of acute rejection. Design, setting, participants, & measurements In this observational cross-sectional study, 64 patients from two centers were recruited upon admission for allograft biopsy to investigate acute graft dysfunction. Blood was collected before biopsy and assayed for a panel of 21 cytokines secreted by PBMCs. Patients were classified as acute rejectors or nonrejectors according to a classification rule derived from an initial set of 32 patients (training cohort) and subsequently validated in the remaining patients (validation cohort). Results Although six cytokines (IL-1β, IL-6, TNF-α, IL-4, GM-CSF, and monocyte chemoattractant protein-1) distinguished acute rejectors in the training cohort, logistic regression modeling identified a single cytokine, IL-6, as the best predictor. In the validation cohort, IL-6 was consistently the most accurate cytokine (area under the receiver-operating characteristic curve, 0.85; P=0.006), whereas the application of a prespecified cutoff level, as determined from the training cohort, resulted in a sensitivity and specificity of 92% and 63%, respectively. Secondary analyses revealed a strong association between IL-6 levels and acute rejection after multivariate adjustment for clinical characteristics (P<0.001). Conclusions In this pilot study, the measurement of a single cytokine can exclude acute rejection with a sensitivity of 92% in renal transplant recipients presenting with acute graft dysfunction. Prospective studies are needed to determine the utility of this simple assay, particularly for low-risk or remote patients. PMID:22498498

  10. Alloreactive T Cells to Identify Risk HLA Alleles for Retransplantation After Acute Accelerated Steroid-Resistant Rejection.

    PubMed

    Leyking, S; Wolf, M; Mihm, J; Schaefer, M; Bohle, R M; Fliser, D; Sester, M; Sester, U

    2015-10-01

    The risk of rejection by cellular alloreactivity to the transplant donor is not routinely assessed. Here we analyzed alloreactive T cells in kidney transplant recipients and report how their detection may have helped to prevent rejection of a second kidney graft in a patient with a history of acute accelerated steroid-resistant nonhumoral rejection. Alloreactive CD4 and CD8 T cells were quantified using a flow-cytometric mixed lymphocyte reaction assay based on interferon-γ induction. A group of 16 nonrejecting transplant recipients did not show any alloreactive T-cell immunity to their respective donors, whereas alloreactivity to third-party controls was detectable. In the patient with rejection, HLA-specific antibodies were not detectable before and shortly after rejection, but after transplantation the patient showed exceptionally high frequencies of alloreactive T cells against 2 of 11 HLA-typed controls (0.604% and 0.791% alloreactive CD4 T cells and 0.792% and 0.978% alloreactive CD8 T cells) who shared HLA alleles (HLA-A*24, -B*44, -C*02, -DQB1*5) with the kidney donor. These HLA alleles were subsequently excluded for allocation of a second graft. No alloreactive T cells were observed toward the second kidney donor, and this transplantation was performed successfully. Thus, shared HLA alleles between the donor and third-party controls may suggest that alloreactive T cells had contributed to rejection of the first graft. The rejecting patient highlights that determination of cellular alloreactivity before transplantation may be applied to identify unacceptable mismatches and to reduce the risk for acute cellular rejection episodes. PMID:26518945

  11. Acute effects of carbon monoxide on cardiac electrical stability

    SciTech Connect

    Verrier, R.L.; Mills, A.K.; Skornik, W.A. )

    1990-10-01

    The objective of this project was to determine the effects of acute carbon monoxide exposure on cardiac electrical stability. To obtain a comprehensive assessment, diverse biological models were employed. These involved cardiac electrical testing in the normal and ischemic heart in anesthetized and conscious dogs. The experimental plan was designed both to examine the direct effects of carbon monoxide exposure on the myocardium and to evaluate possible indirect influences through alterations in platelet aggregability or changes in central nervous system activity in the conscious animal. Our results indicate that exposure to relatively high levels of carbon monoxide, leading to carboxyhemoglobin concentrations of up to 20 percent, is without significant effect on ventricular electrical stability. This appears to be the case in the acutely ischemic heart as well as in the normal heart. It is important to note that the total exposure period was in the range of 90 to 124 minutes. The possibility that longer periods of exposure or exacerbation from nicotine in cigarette smoke could have a deleterious effect cannot be excluded. We also examined whether or not alterations in platelet aggregability due to carbon monoxide exposure could be a predisposing factor for cardiac arrhythmias. A model involving partial coronary artery stenosis was used to simulate the conditions under which platelet plugs could lead to myocardial ischemia and life-threatening arrhythmias. We found no changes either in the cycle frequency of coronary blood flow oscillations or in platelet aggregability during carbon monoxide exposure. Thus, carbon monoxide exposure does not appear to alter platelet aggregability or its effect on coronary blood flow during stenosis. In the final series of experiments, we examined the effects of carbon monoxide exposure in the conscious state.

  12. Busulfan depletes neutrophils and delays accelerated acute rejection of discordant xenografts in the guinea pig-to-rat model.

    PubMed

    Brauer, Robert B; Beck, Tino; Stehle, Ingo; Kremer, Marcus; Heidecke, Claus-Dieter

    2003-01-01

    Complement factor C6 plays a critical role in mediating hyperacute rejection of discordant xenografts. In order to explore the mechanism of discordant xenograft rejection, we investigated kinetics and phenotypes of the cellular infiltrate in xenografts in untreated and leukocyte-depleted recipients, in relation to graft survival. Guinea pig cardiac xenografts were heterotopically transplanted to totally C6-deficient PVG (C-) rats. Grafts were removed after 0, 6, 12, and 24 h ( n = 6). Histological evaluation was performed with hematoxylin and eosin (H & E) and immunoperoxidase staining. The agents fucoidin and busulfan were applied to delay xenograft rejection further. Within 6 h, minimal perivascular edema with isolated infiltrating CD11b/c- and ED1-positive cells were found. An intense infiltration of CD11b/c- and ED1-positive cells with interstitial hemorrhage was present after 24 h, though with little CD161 and CD3 cell infiltration. Inhibition of cell adhesion by fucoidin did not prolong xenograft survival (34 +/- 15 h, n = 4, P<0.47), but the depletion of granulocytes by injection of busulfan did prolong survival of the discordant xenografts, to 62 +/- 22 h ( n = 7, P < or = 0.0039). These results demonstrate a significant effect of specific depletion of granulocytes and macrophages by busulfan therapy on guinea pig cardiac xenograft survival in PVG (C-) rats, suggesting the participation of these infiltrating cells in the xenoreactive rejection process. PMID:12545340

  13. Use of indium-111-labeled cells in measurement of cellular dynamics of experimental cardiac allograft rejection

    SciTech Connect

    Oluwole, S.; Wang, T.; Fawwaz, R.; Satake, K.; Nowygrod, R.; Reemtsma, K.; Hardy, M.A.

    1981-01-01

    This study evaluates the kinetics and utility of infused indium-111-labeled cells in detecting rejection in ACI to Lewis rat heart allografts. Syngeneic leukocytes, lymph node lymphocytes, and platelets were isolated and labeled with indium-111 (/sup 111/In) oxine, respectively, and were infused i.v. into Lewis rats carrying beating ACI or syngeneic hearts from post-transplant days 0 to 6. Recipients were imaged serially at 24 hr after infusion of labeled cells followed by excision of both native and transplanted hearts for direct isotope count. Labeled leukocytes accumulative progressively in the allograft with the scan becoming positive by post-transplant day 4. The ratio of allograft to native heart isotope counts rose from 1.25 on day 1 to 10.07 (P less than 0.0001) on day 7. The Lewis recipients infused with labeled lymphocytes showed a positive scan on days 6 and 7 whereas the allograft to native heart isotope count ratio rose from 0.97 on day 1 to 5.33 (P less than 0.001) on day 7. Recipients infused with /sup 111/In-labeled platelets showed a positive scan on days 5 to 7 and the allograft to native heart isotope count ratio rose sharply from 2.56 on day 4 to 16.98 (P less than 0.005) on day 7. Syngeneic heart grafts failed to demonstrate significant accumulation of any of the labeled cell population. These studies confirm the importance of nonlymphocytic cells in cellular rejection, evaluate the kinetics of graft invasion by the various cell types, and suggest that the techniques used afford a method for a safe and an early detection of allograft rejection.

  14. Association of IL-6 promoter and IFN-γ gene polymorphisms with acute rejection of liver transplantation.

    PubMed

    Karimi, Mohammad Hossein; Daneshmandi, Saeed; Pourfathollah, Ali Akbar; Geramizadeh, Bita; Malekhosseini, Seyed Ali; Nikeghbalian, Saman; Yaghobi, Ramin; Bolandparvaz, Shahram

    2011-10-01

    Liver transplantation is one of the most important therapies for end-stage liver diseases and is associated with major problems including infections and acute rejection. The outcome of transplantation can be determined by immune responses as a key role in response to the graft. Inflammatory and anti-inflammatory mediators especially cytokines influence the graft microenvironment. Th1 and Th2 immune responses in contrast to regulatory responses cause acute rejection or help graft survival. In this study, we evaluated the gene polymorphisms of IL-6 G-174C, TGF-β T + 869C, IL-4 C-590T, and IFN-γ T + 874A cytokines in liver transplant patients. ARMS-PCR method was used to characterize IL-6 G-174C, TGF-β T + 869C and IFN-γ T + 874A polymorphisms and PCR-RFLP using AvaII restriction enzyme was done for IL-4 C-590T characterization in 70 liver transplant patients. Acute rejection episodes were diagnosed according to standard criteria. The analysis of the results showed that IL-6-174 GG genotype ( P = 0.009, OR = 4.333, 95% CI = 1.043-18.000), IL-6-174G allele (P = 0.011, OR = 5.273, 95% CI = 1.454-19.127) was more frequent and IFN-γ +874 TT genotype was less frequent (P = 0.043, OR = 0.143, 95% CI = 0.0118-1.190) in acute rejection than in non-rejection patients. TGF-β T + 869C and IL-4 C-590T frequencies were not significantly different (P > 0.05). According to the results, it can be conclude that IL-6 G-174C and IFN-γ T + 874A gene polymorphisms have predictive values for acute rejection after liver transplantation. High producer genotype of IL-6 is a genetic risk factor and IFN-γ is a protective factor for acute rejection development. PMID:21132384

  15. Belatacept for prevention of acute rejection in adult patients who have had a kidney transplant: an update

    PubMed Central

    Wojciechowski, David; Vincenti, Flavio

    2012-01-01

    In June 2011, the US Food and Drug Administration approved belatacept for the prophylaxis of organ rejection in adult kidney transplant recipients. This review discusses the use of belatacept for the prevention of acute rejection as part of a maintenance immunosuppression regimen. Belatacept is a selective costimulation blocker designed to provide effective immunosuppression while avoiding the toxicities associated with calcineurin inhibitors. Phase III trial data have demonstrated that belatacept is noninferior to cyclosporine in 1-year patient and allograft survival. Three-year data demonstrate an ongoing improvement in mean measured glomerular filtration rate in belatacept-treated versus cyclosporine-treated patients. However, the rate of acute rejection was higher in belatacept-treated patients compared with cyclosporine. Specifically, there was a higher incidence of Banff type II rejections in patients treated with belatacept. Despite the higher Banff grade, rejections on belatacept were not associated with other factors associated with poor outcomes, such as the development of donor-specific antibodies or reduced estimated glomerular filtration rate. One safety issue that must be considered when using belatacept is the potential for increased risk of post-transplant lymphoproliferative disease. There were more cases of post-transplant lymphoproliferative disease in belatacept-treated patients, especially in recipients seronegative for Epstein–Barr virus or patients treated with lymphocyte-depleting agents. Therefore, belatacept can be recommended for use in Epstein–Barr virus antibody-positive recipients. PMID:23152668

  16. Gastroesophageal Reflux Disease Is Associated With an Increased Rate of Acute Rejection in Lung Transplant Allografts

    PubMed Central

    Shah, N.S.; Force, S.D.; Mitchell, P.O.; Lin, E.; Lawrence, E.C.; Easley, K.; Qian, J.; Ramirez, A.; Neujahr, D.C.; Gal, A.; Leeper, K.; Pelaez, A.

    2012-01-01

    Purpose Gastric fundoplication (GF) for gastroesophageal reflux disease (GERD) may protect against the progression of chronic rejection in lung transplant (LT) recipients. However, the association of GERD with acute rejection episodes (ARE) is uncertain. This study sought to identify if ARE were linked to GERD in LT patients. Methods This single-center retrospective observational study, of patients transplanted from January 1, 2000, to January 31, 2009, correlated results of pH probe testing for GERD with ARE (≥International Society for Heart and Lung Transplantation A1 or B1). We compared the rates of ARE among patients with GERD (DeMeester Score > 14.7) versus without GERD as number of ARE per 1,000 patient-days after LT. Patients undergoing GF prior to LT were excluded. Results The analysis included 60 LT subjects and 9,249 patient-days: 33 with GERD versus 27 without GERD. We observed 51 ARE among 60 LT recipients. The rate of ARE was highest among patients with GERD: 8.49 versus 2.58, an incidence density ratio (IDR) of 3.29 (P = .00016). Upon multivariate negative binomial regression modeling, only GERD was associated with ARE (IDR 2.15; P = .009). Furthermore, GERD was associated with multiple ARE (36.4% vs 0%; P < .0001) and earlier onset compared with patients without GERD: ARE proportion at 2 months was 0.55 versus 0.26 P = .004). Conclusion In LT recipients, GERD was associated with a higher rate, multiple events, and earlier onset of ARE. The efficacy of GF to reduce ARE among patients with GERD needs further evaluation. PMID:20832573

  17. Prevention of Allogeneic Cardiac Graft Rejection by Transfer of Ex Vivo Expanded Antigen-Specific Regulatory T-Cells

    PubMed Central

    Takasato, Fumika; Morita, Rimpei; Schichita, Takashi; Sekiya, Takashi; Morikawa, Yasuhide; Kuroda, Tatsuo; Niimi, Masanori; Yoshimura, Akihiko

    2014-01-01

    The rate of graft survival has dramatically increased using calcineurin inhibitors, however chronic graft rejection and risk of infection are difficult to manage. Induction of allograft-specific regulatory T-cells (Tregs) is considered an ideal way to achieve long-term tolerance for allografts. However, efficient in vitro methods for developing allograft-specific Tregs which is applicable to MHC full-mismatched cardiac transplant models have not been established. We compared antigen-nonspecific polyclonal-induced Tregs (iTregs) as well as antigen-specific iTregs and thymus-derived Tregs (nTregs) that were expanded via direct and indirect pathways. We found that iTregs induced via the indirect pathway had the greatest ability to prolong graft survival and suppress angiitis. Antigen-specific iTregs generated ex vivo via both direct and indirect pathways using dendritic cells from F1 mice also induced long-term engraftment without using MHC peptides. In antigen-specific Treg transferred models, activation of dendritic cells and allograft-specific CTL generation were suppressed. The present study demonstrated the potential of ex vivo antigen-specific Treg expansion for clinical cell-based therapeutic approaches to induce lifelong immunological tolerance for allogeneic cardiac transplants. PMID:24498362

  18. Cardiac troponins as indicators of acute myocardial damage in dogs.

    PubMed

    Burgener, Iwan A; Kovacevic, Alan; Mauldin, G Neal; Lombard, Christophe W

    2006-01-01

    Cardiac troponin I (cTnI) and T (cTnT) have a high sequence homology across phyla and are sensitive and specific markers of myocardial damage. The purpose of this study was to evaluate the Cardiac Reader, a human point-of-care system for the determination of cTnT and myoglobin, and the Abbott Axsym System for the determination of cTnI and creatine kinase isoenzyme MB (CK-MB) in healthy dogs and in dogs at risk for acute myocardial damage because of gastric dilatation-volvulus (GDV) and blunt chest trauma (BCT). In healthy dogs (n = 56), cTnI was below detection limits (<0.1 microg/L) in 35 of 56 dogs (reference range 0-0.7 microg/L), and cTnT was not measurable (<0.05 ng/mL) in all but 1 dog. At presentation, cTnI, CK-MB, myoglobin, and lactic acid were all significantly higher in dogs with GDV (n = 28) and BCT (n = 8) than in control dogs (P < .001), but cTnT was significantly higher only in dogs with BCT (P = .033). Increased cTnI or cTnT values were found in 26 of 28 (highest values 1.1-369 microg/L) and 16 of 28 dogs (0.1-1.7 ng/mL) with GDV, and in 6 of 8 (2.3-82.4 microg/L) and 3 of 8 dogs (0.1-0.29 ng/mL) with BCT, respectively. In dogs suffering from GDV, cTnI and cTnT increased further within the first 48 hours (P < .001). Increased cardiac troponins suggestive of myocardial damage occurred in 93% of dogs with GDV and 75% with BCT. cTnI appeared more sensitive, but cTnT may be a negative prognostic indicator in GDV. Both systems tested seemed applicable for the measurement of canine cardiac troponins, with the Cardiac Reader particularly suitable for use in emergency settings. PMID:16594583

  19. Bronchogenic Carcinoma with Cardiac Invasion Simulating Acute Myocardial Infarction

    PubMed Central

    Das, Anirban; Das, Sibes K.; Pandit, Sudipta; Karmakar, Rathindra Nath

    2016-01-01

    Cardiac metastases in bronchogenic carcinoma may occur due to retrograde lymphatic spread or by hematogenous dissemination of tumour cells, but direct invasion of heart by adjacent malignant lung mass is very uncommon. Pericardium is frequently involved in direct cardiac invasion by adjacent lung cancer. Pericardial effusion, pericarditis, and tamponade are common and life threatening presentation in such cases. But direct invasion of myocardium and endocardium is very uncommon. Left atrial endocardium is most commonly involved in such cases due to anatomical contiguity with pulmonary hilum through pulmonary veins, and in most cases left atrial involvement is asymptomatic. But myocardial compression and invasion by adjacent lung mass may result in myocardial ischemia and may present with retrosternal, oppressive chest pain which clinically may simulate with the acute myocardial infarction (AMI). As a result, it leads to misdiagnosis and delayed diagnosis of lung cancer. Here we report a case of non-small-cell carcinoma of right lung which was presented with asymptomatic invasion in left atrium and retrosternal chest pain simulating AMI due to myocardial compression by adjacent lung mass, in a seventy-four-year-old male smoker. PMID:27042370

  20. Acute exercise modifies titin phosphorylation and increases cardiac myofilament stiffness.

    PubMed

    Müller, Anna E; Kreiner, Matthias; Kötter, Sebastian; Lassak, Philipp; Bloch, Wilhelm; Suhr, Frank; Krüger, Martina

    2014-01-01

    Titin-based myofilament stiffness is largely modulated by phosphorylation of its elastic I-band regions N2-Bus (decreases passive stiffness, PT) and PEVK (increases PT). Here, we tested the hypothesis that acute exercise changes titin phosphorylation and modifies myofilament stiffness. Adult rats were exercised on a treadmill for 15 min, untrained animals served as controls. Titin phosphorylation was determined by Western blot analysis using phosphospecific antibodies to Ser4099 and Ser4010 in the N2-Bus region (PKG and PKA-dependent. respectively), and to Ser11878 and Ser 12022 in the PEVK region (PKCα and CaMKIIδ-dependent, respectively). Passive tension was determined by step-wise stretching of isolated skinned cardiomyocytes to sarcomere length (SL) ranging from 1.9 to 2.4 μm and showed a significantly increased PT from exercised samples, compared to controls. In cardiac samples titin N2-Bus phosphorylation was significantly decreased by 40% at Ser4099, however, no significant changes were observed at Ser4010. PEVK phosphorylation at Ser11878 was significantly increased, which is probably mediated by the observed exercise-induced increase in PKCα activity. Interestingly, relative phosphorylation of Ser12022 was substantially decreased in the exercised samples. Surprisingly, in skeletal samples from acutely exercised animals we detected a significant decrease in PEVK phosphorylation at Ser11878 and an increase in Ser12022 phosphorylation; however, PKCα activity remained unchanged. In summary, our data show that a single exercise bout of 15 min affects titin domain phosphorylation and titin-based myocyte stiffness with obviously divergent effects in cardiac and skeletal muscle tissues. The observed changes in titin stiffness could play an important role in adapting the passive and active properties of the myocardium and the skeletal muscle to increased physical activity. PMID:25477822

  1. Acute exercise modifies titin phosphorylation and increases cardiac myofilament stiffness

    PubMed Central

    Müller, Anna E.; Kreiner, Matthias; Kötter, Sebastian; Lassak, Philipp; Bloch, Wilhelm; Suhr, Frank; Krüger, Martina

    2014-01-01

    Titin-based myofilament stiffness is largely modulated by phosphorylation of its elastic I-band regions N2-Bus (decreases passive stiffness, PT) and PEVK (increases PT). Here, we tested the hypothesis that acute exercise changes titin phosphorylation and modifies myofilament stiffness. Adult rats were exercised on a treadmill for 15 min, untrained animals served as controls. Titin phosphorylation was determined by Western blot analysis using phosphospecific antibodies to Ser4099 and Ser4010 in the N2-Bus region (PKG and PKA-dependent. respectively), and to Ser11878 and Ser 12022 in the PEVK region (PKCα and CaMKIIδ-dependent, respectively). Passive tension was determined by step-wise stretching of isolated skinned cardiomyocytes to sarcomere length (SL) ranging from 1.9 to 2.4 μm and showed a significantly increased PT from exercised samples, compared to controls. In cardiac samples titin N2-Bus phosphorylation was significantly decreased by 40% at Ser4099, however, no significant changes were observed at Ser4010. PEVK phosphorylation at Ser11878 was significantly increased, which is probably mediated by the observed exercise-induced increase in PKCα activity. Interestingly, relative phosphorylation of Ser12022 was substantially decreased in the exercised samples. Surprisingly, in skeletal samples from acutely exercised animals we detected a significant decrease in PEVK phosphorylation at Ser11878 and an increase in Ser12022 phosphorylation; however, PKCα activity remained unchanged. In summary, our data show that a single exercise bout of 15 min affects titin domain phosphorylation and titin-based myocyte stiffness with obviously divergent effects in cardiac and skeletal muscle tissues. The observed changes in titin stiffness could play an important role in adapting the passive and active properties of the myocardium and the skeletal muscle to increased physical activity. PMID:25477822

  2. Rapamycin Treatment of Healthy Pigs Subjected to Acute Myocardial Ischemia-Reperfusion Injury Attenuates Cardiac Functions and Increases Myocardial Necrosis

    PubMed Central

    Lassaletta, Antonio D; Elmadhun, Nassrene Y; Zanetti, Arthus V D; Feng, Jun; Anduaga, Javier; Gohh, Reginald Y.; Sellke, Frank W; Bianchi, Cesario

    2013-01-01

    Background The Mechanistic Target of Rapamycin (mTOR) pathway is a major regulator of cell immunity and metabolism. mTOR is a well-known suppressor of tissue rejection in organ transplants, however, it has other non-immune functions including in the cardiovascular system, where it is a regulator of heart hypertrophy and locally, in coated vascular stents, inhibits vascular wall cell growth and hence neointimal formation/restenosis. Because the mTOR pathway plays major roles in normal cell growth, metabolism and survival, we hypothesized that inhibiting it with rapamycin, prior to an acute myocardial ischemia-reperfusion injury (IRI), would confer cardioprotection by virtue of slowing down cardiac function and metabolism. Methods Yorkshire pigs received orally either placebo or 4 mg/day rapamycin for 7 days before the IRI. All animals underwent median sternotomy and the mid-left anterior descending coronary artery was occluded for 60 min followed by 120 min of reperfusion. Left ventricular pressure-volume data was collected throughout the operation. The ischemic and infarcted areas were determined by monastral blue and triphenyltetrazolium chloride staining, respectively and plasma cardiac troponin I concentration. mTOR kinase activities were monitored in remote cardiac tissue by western blotting with specific antibodies against specific substrates phosphorylating sites. Results Rapamycin pre-treatement impaired endothelial-dependent vasorelaxation, attenuated cardiac function during IRI, and increased myocardial necrosis. Western blotting confirmed effective inhibition of myocardial mTOR kinase activities. Conclusions Pre-treatment of healthy pigs with rapamycin prior to acute myocardial IRI is associated with decreased cardiac function and higher myocardial necrosis. PMID:24266948

  3. Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation

    PubMed Central

    Ashraf, M. I.; Schwelberger, H. G.; Brendel, K. A.; Feurle, J.; Andrassy, J.; Kotsch, K.; Regele, H.; Pratschke, J.; Maier, H. T.

    2016-01-01

    Abstract Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor–recipient combinations (C57Bl/6 wild‐type and Lcn2−/−, Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation. PMID:26595644

  4. Higher Risk of Acute Cellular Rejection in Lung Transplant Recipients with Cystic Fibrosis.

    PubMed

    Calabrese, Fiorella; Lunardi, Francesca; Nannini, Nazarena; Balestro, Elisabetta; Loy, Monica; Marulli, Giuseppe; Calabrese, Francesca; Vuljan, Stefania Edith; Schiavon, Marco; Perissinotto, Egle; Rea, Federico

    2015-01-01

    BACKGROUND Acute cellular rejection (ACR) affects up to 40% of recipients within the first year after lung transplant (LTx). The aim of this study was to determine the frequency of ACR and associated major risk factors in cystic fibrosis (CF) recipients. Bronchiolitis obliterans syndrome (BOS) and 1-year/long-term survival were also evaluated. MATERIAL AND METHODS ACR was reviewed in 643 scheduled biopsies from 44 CF (Group 1) versus 89 other recipients (Group 2). We performed univariate/multivariate analyses of risk factors for ACR and BOS, and survival analysis. RESULTS Group 1 showed higher ACR frequency, especially for ACR ≥ A2. Multivariable generalized linear models considering both native lung disease and age showed that higher values of ACR index were significantly related to the pretransplant diagnosis of CF. BOS and long-term survival were not influenced by the increased incidence of ACR. Poorer long-term survival was observed in Group 2. CONCLUSIONS CF recipients have a higher ACR risk, which may be due to enhanced immune activation related to a genetic disorder, and younger age. PMID:26718747

  5. Colchicine Acutely Suppresses Local Cardiac Production of Inflammatory Cytokines in Patients With an Acute Coronary Syndrome

    PubMed Central

    Martínez, Gonzalo J; Robertson, Stacy; Barraclough, Jennifer; Xia, Qiong; Mallat, Ziad; Bursill, Christina; Celermajer, David S; Patel, Sanjay

    2015-01-01

    Background Interleukin (IL)-1β, IL-18, and downstream IL-6 are key inflammatory cytokines in the pathogenesis of coronary artery disease. Colchicine is believed to block the NLRP3 inflammasome, a cytosolic complex responsible for the production of IL-1β and IL-18. In vivo effects of colchicine on cardiac cytokine release have not been previously studied. This study aimed to (1) assess the local cardiac production of inflammatory cytokines in patients with acute coronary syndromes (ACS), stable coronary artery disease and in controls; and (2) determine whether acute administration of colchicine inhibits their production. Methods and Results Forty ACS patients, 33 with stable coronary artery disease, and 10 controls, were included. ACS and stable coronary artery disease patients were randomized to oral colchicine treatment (1 mg followed by 0.5 mg 1 hour later) or no colchicine, 6 to 24 hours prior to cardiac catheterization. Blood samples from the coronary sinus, aortic root (arterial), and lower right atrium (venous) were collected and tested for IL-1β, IL-18, and IL-6 using ELISA. In ACS patients, coronary sinus levels of IL-1β, IL-18, and IL-6 were significantly higher than arterial and venous levels (P=0.017, <0.001 and <0.001, respectively). Transcoronary (coronary sinus-arterial) gradients for IL-1β, IL-18, and IL-6 were highest in ACS patients and lowest in controls (P=0.077, 0.033, and 0.014, respectively). Colchicine administration significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% (P=0.028, 0.032, and 0.032, for IL-1β, IL-18, and IL-6, respectively). Conclusions ACS patients exhibit increased local cardiac production of inflammatory cytokines. Short-term colchicine administration rapidly and significantly reduces levels of these cytokines. PMID:26304941

  6. Control of breathing during acute change in cardiac preload in a patient with partial cardiopulmonary bypass.

    PubMed

    Bekteshi, Edgar; Bell, Harold J; Haouzi, Annick; El-Banayosy, Aly; Haouzi, Philippe

    2010-01-31

    We recently had the opportunity to investigate the ventilatory effects of changing the rate of venous return to the heart (and thus pulmonary gas exchange) in a patient equipped with a venous-arterial oxygenated shunt (extracorporeal membrane oxygenation (ECMO) support). The presence of the ECMO support provided a condition wherein venous return to the right heart could be increased or decreased while maintaining total aortic blood flow and arterial blood pressure (ABP) constant. The patient, who had received a heart transplant 12 years ago, was admitted for acute cardiac failure related to graft rejection. The clinical symptomatology was that of right heart failure. We studied the patient on the 4th day of ECMO support, while she was breathing spontaneously. The blood flow diverted through the ECMO system represented 2/3 of the total aortic flow (4 l min(-1)). With these ECMO settings, the baseline level of ventilation was low (3.89+/-0.99 l min(-1)), but PET(CO2) was not elevated (37+/-2 mmHg). When Pa(CO2) in the blood coming from the ECMO was increased, no stimulatory effect on ventilation was observed. However, when the diversion of the venous return to the ECMO was stopped then restored, minute ventilation respectively increased then decreased by more than twofold with opposite changes in PET(CO2). These maneuvers were associated with large changes in the size of the right atrium and ventricle and of the left atrium. This observation suggests that the change in venous return affects breathing by encoding some of the consequences of the changes in cardiac preload. The possible sites of mediation are discussed. PMID:19837189

  7. Existence of circulating anti-endothelial cell antibodies after heart transplantation is associated with post-transplant acute allograft rejection.

    PubMed

    Lehle, Karla; Kroher, Johannes; Kolat, Philipp; von Süßkind-Schwendi, Marietta; Schmid, Christof; Haneya, Assad; Rupprecht, Leopold; Hirt, Stephan

    2016-05-01

    Anti-endothelial cell antibodies (AECA) may be involved in the development of heart allograft rejection. Its detection might be a cheap and noninvasive method to identify high-risk patients. An indirect immunofluorescence method on human umbilical vein endothelial cells was used to investigate the presence of AECAs in 260 pre- and post-transplant serum samples sequentially collected from 34 patients within the first year after heart transplantation (HTX). The presence of AECAs before (23.5 %) and early after HTX (14.7 %) was associated with a significantly increased risk of early acute rejection (75 and 60 %, respectively) compared to 33 % in AECA-negative patients (p = 0.049). Moreover, rejections from AECA-positive patients were more severe (p = 0.057) with a significantly increased incidence of multiple (p = 0.025). The mean number of the sum of rejection episodes was significantly higher in AECA-positive patients (p ≤ 0.05). Patients free of AECAs mainly received mycophenolate mofetil as primary immunosuppression (p = 0.067). Nevertheless, the presence of AECAs did not affect long-term outcome and mortality of HTX patients. Despite a low number of patient samples, the detection of AECAs before and early after HTX could be used as a biomarker for an increased risk of early acute rejection in high-risk patients. This easy method might be a valuable tool to support screening procedures to improve individualized immunosuppressive therapy. PMID:25820657

  8. Increased Numbers of Circulating CD8 Effector Memory T Cells before Transplantation Enhance the Risk of Acute Rejection in Lung Transplant Recipients

    PubMed Central

    San Segundo, David; Ballesteros, María Ángeles; Naranjo, Sara; Zurbano, Felipe; Miñambres, Eduardo; López-Hoyos, Marcos

    2013-01-01

    The effector and regulatory T cell subpopulations involved in the development of acute rejection episodes in lung transplantation remain to be elucidated. Twenty-seven lung transplant candidates were prospectively monitored before transplantation and within the first year post-transplantation. Regulatory, Th17, memory and naïve T cells were measured in peripheral blood of lung transplant recipients by flow cytometry. No association of acute rejection with number of peripheral regulatory T cells and Th17 cells was found. However, effector memory subsets in acute rejection patients were increased during the first two months post-transplant. Interestingly, patients waiting for lung transplant with levels of CD8+ effector memory T cells over 185 cells/mm3 had a significant increased risk of rejection [OR: 5.62 (95% CI: 1.08-29.37), p=0.04]. In multivariate analysis adjusted for age and gender the odds ratio for rejection was: OR: 5.89 (95% CI: 1.08-32.24), p=0.04. These data suggest a correlation between acute rejection and effector memory T cells in lung transplant recipients. The measurement of peripheral blood CD8+ effector memory T cells prior to lung transplant may define patients at high risk of acute lung rejection. PMID:24236187

  9. INHALATION OF OZONE AND DIESEL EXHAUST PARTICLES (DEP) INDUCES ACUTE AND REVERSIBLE CARDIAC GENE EXPRESSION CHANGES

    EPA Science Inventory

    We have recently shown that episodic but not acute exposure to ozone or DEP induces vascular effects that are associated with the loss of cardiac mitochondrial phospholipid fatty acids (DEP 2.0 mg/m3 > ozone, 0.4 ppm). In this study we determined ozone and DEP-induced cardiac gen...

  10. MOEMS-based cardiac enzymes detector for acute myocardial infarction

    NASA Astrophysics Data System (ADS)

    Amritsar, Jeetender; Stiharu, Ion G.; Packirisamy, Muthukumaran; Balagopal, Ganesharam; Li, Xing

    2004-10-01

    Biomedical applications of MOEMS are limited only by the mankind imagination. Precision measurements on minute amounts of biological material could be performed by optical means with a remarkable accuracy. Although available in medical laboratories for general purposes, such analyzers are making their way directly to the users in the form of dedicated equipment. Such an example is a test kit to detect the existence of cardiac enzymes in the blood stream. Apart from the direct users, the medical personnel will make use of such tools given the practicality of the kit. In a large proportion of patients admitted to the hospital suspected of Acute Myocardial Infarction (AMI), the symptoms and electrocardiographic changes are inconclusive. This necessitates the use of biochemical markers of myocardial damage for correct exclusion or conformation of AMI. In this study the concept of MOEMS is applied for the detection of enzyme reaction, in which glass spectrums are scanned optically when enzyme molecules adsorb on their surface. This paper presents the optical behavior of glass spectrums under Horseradish Peroxide (HRP) enzyme reaction. The reported experimental results provide valuable information that will be useful in the development of biosensors for enzymatic detection. This paper also reports the dynamic behavior of different glass spectrums.

  11. Prediction and Prevention of Acute Kidney Injury after Cardiac Surgery

    PubMed Central

    Shin, Su Rin; Kim, Won Ho; Kim, Dong Joon; Shin, Il-Woo; Sohn, Ju-Tae

    2016-01-01

    The incidence of acute kidney injury after cardiac surgery (CS-AKI) ranges from 33% to 94% and is associated with a high incidence of morbidity and mortality. The etiology is suggested to be multifactorial and related to almost all aspects of perioperative management. Numerous studies have reported the risk factors and risk scores and novel biomarkers of AKI have been investigated to facilitate the subclinical diagnosis of AKI. Based on the known independent risk factors, many preventive interventions to reduce the risk of CS-AKI have been tested. However, any single preventive intervention did not show a definite and persistent benefit to reduce the incidence of CS-AKI. Goal-directed therapy has been considered to be a preventive strategy with a substantial level of efficacy. Many pharmacologic agents were tested for any benefit to treat or prevent CS-AKI but the results were conflicting and evidences are still lacking. The present review will summarize the current updated evidences about the risk factors and preventive strategies for CS-AKI. PMID:27419130

  12. Spontaneous resolution of acute rejection and tolerance induction with IL-2 fusion protein in vascularized composite allotransplantation.

    PubMed

    Jindal, R; Unadkat, J; Zhang, W; Zhang, D; Ng, T W; Wang, Y; Jiang, J; Lakkis, F; Rubin, P; Lee, W P A; Gorantla, V S; Zheng, X X

    2015-05-01

    Vascularized composite allotransplantation (VCA) has emerged as a treatment option for treating nonlife-threatening conditions. Therefore, in order to make VCA a safe reconstruction option, there is a need to minimize immunosuppression, develop tolerance-inducing strategies and elucidate the mechanisms of VCA rejection and tolerance. In this study we explored the effects of hIL-2/Fc (a long-lasting human IL-2 fusion protein), in combination with antilymphocyte serum (ALS) and short-term cyclosporine A (CsA), on graft survival, regulatory T cell (Treg) proliferation and tolerance induction in a rat hind-limb transplant model. We demonstrate that hIL-2/Fc therapy tips the immune balance, increasing Treg proliferation and suppressing effector T cells, and permits VCA tolerance as demonstrated by long-term allograft survival and donor-antigen acceptance. Moreover, we observe two distinct types of acute rejection (AR), progressive and reversible, within hIL-2/Fc plus ALS and CsA treated recipients. Our study shows differential gene expression profiles of FoxP3 versus GzmB, Prf1 or interferon-γ in these two types of AR, with reversible rejection demonstrating higher Treg to Teff gene expression. This correlation of gene expression profile at the first clinical sign of AR with VCA outcomes can provide the basis for further inquiry into the mechanistic aspects of VCA rejection and future drug targets. PMID:25676865

  13. Combined use of myeloid-related protein 8/14 and procalcitonin as diagnostic markers for acute allograft rejection in kidney transplantation recipients.

    PubMed

    Jung, Da-Yeon; Park, Jae Berm; Lee, Eun-Na; Lee, Hyun-Ah; Joh, Jae-Won; Kwon, Choon Hyuck; Ki, Chang-Seok; Lee, Soo-Youn; Kim, Sung-Joo

    2008-02-01

    The myeloid-related proteins 8 and 14 exist as a dimeric complex (MRP 8/14) and serve as early and highly specific markers for inflammatory processes, such as allograft rejection and non-viral (bacterial or fungal) infections. An elevated procalcitonin (PCT) concentration in serum also serves as a diagnostic indicator of non-viral infection. Therefore, by measuring both MRP 8/14 and PCT serum concentrations, one may be able to distinguish between acute allograft rejection and non-viral infections in non-rejection transplant recipients. Here, we investigated whether MRP 8/14 and PCT can function as prognostic (Study I) or diagnostic (Study II) markers for allograft rejection in renal transplant recipients. In Study I, the serum concentrations of MRP 8/14 and PCT during the first 2 weeks after transplantation did not differ between patients who did and did not suffer organ rejection within 1 year post-transplantation; these findings suggest that the MRP 8/14 and PCT parameters are not valid prognostic markers. However, in Study II, patients with acute rejection or non-rejection/non-viral infection groups displayed a significant increase in serum MRP 8/14 concentration, and non-rejection patients with non-viral infections only had elevation in the PCT serum concentrations. These results indicate that the combined use of MRP 8/14 and PCT serum concentrations can allow one to distinguish between allograft rejection and other inflammatory processes, such as infection. PMID:18158120

  14. ELISA-based detection of C4d after liver transplantation--a helpful tool for differential diagnosis between acute rejection and HCV-recurrence?

    PubMed

    Schmeding, Maximilian; Kienlein, Stefan; Röcken, Christoph; Neuhaus, Ruth; Neuhaus, Peter; Heidenhain, Christoph; Neumann, Ulf P

    2010-08-01

    Hepatitis-C is the most common indication for liver transplantation. Recurrence of HCV is universal leading to graft failure in up to 40% of all patients. The differentiation between acute rejection and recurrent hepatitis-C is crucial as rejection treatments are likely to aggravate HCV-recurrence. Histological examination of liver biopsy remains the gold standard for diagnosis of acute rejection but has failed in the past to distinguish between acute rejection and recurrent hepatitis-C. In a retrospective study we have recently reported that C4d as a marker of the activated complement cascade is detectable in a hepatic specimen in acute rejection after liver transplantation and may serve as a valuable tool in differential diagnosis between ACR and HCV-recurrence. We performed a prospective analysis by ELISA measurement of C4d concentration in cryo-preserved liver biopsies of LTX patients who had either experienced acute rejection, hepatitis-C recurrence or displayed no pathological alterations (controls). Opposed to our immunohistologically based findings in paraffinized tissue we were unable to detect significant differences of C4d concentration in ELISA of cryo-preserved liver tissue. Consequently the role and potential value of C4d as a diagnostic marker may not be determined using ELISA-based tissue evaluation. PMID:20558292

  15. Clinical validation of an artificial neural network trained to identify acute allograft rejection in liver transplant recipients.

    PubMed

    Hughes, V F; Melvin, D G; Niranjan, M; Alexander, G A; Trull, A K

    2001-06-01

    Artificial neural networks (ANNs) are techniques of nonlinear data modeling that have been studied in a wide variety of medical applications. An ANN was developed to assist in the diagnosis of acute rejection in liver transplant recipients. We investigated the diagnostic accuracy of this ANN on a new data set of patients from the same hospital. In addition, we compared the diagnostic accuracy of the ANN with that of the individual input variables (alanine aminotransferase [ALT] and bilirubin levels and day posttransplantation). Clinical and biochemical data were collected retrospectively for 124 consecutive liver transplantations (117 patients) over the first 3 months after transplantation. Diagnostic accuracy was calculated using receiver operating characteristic (ROC) curve analysis. The ANN differentiated rejection from rejection-free episodes in the new data set over the first 3 months posttransplantation with an area under the ROC curve of 0.902 and sensitivity and specificity of 80.0% and 90.1% at the optimum decision threshold, respectively. The ANN was significantly more specific than ALT or bilirubin level or day posttransplantation at their corresponding optimum decision thresholds (P <.0001). Peak ANN output occurred 1 day earlier than peak values for either ALT or bilirubin (P <.005). The diagnostic accuracy of the ANN was greater than that of any of the individual variables that had been used as inputs. It would be a useful adjunct to conventional liver function tests for monitoring liver transplant recipients in the early postoperative period. PMID:11443576

  16. African-American Race Modifies the Influence of Tacrolimus Concentrations on Acute Rejection and Toxicity in Kidney Transplant Recipients

    PubMed Central

    Taber, David J.; Gebregziabher, Mulugeta G.; Srinivas, Titte R.; Chavin, Kenneth D.; Baliga, Prabhakar K.; Egede, Leonard E.

    2015-01-01

    STUDY OBJECTIVE To determine the effect of tacrolimus trough concentrations on clinical outcomes in kidney transplantation, while assessing if African-American (AA) race modifies these associations. DESIGN Retrospective longitudinal cohort study of solitary adult kidney transplants. SETTING Large tertiary care transplant center. PATIENTS Adult solitary kidney transplant recipients (n=1078) who were AA (n=567) or non-AA (n =511). EXPOSURE Mean and regressed slope of tacrolimus trough concentrations. Subtherapeutic concentrations were lower than 8 ng/ml. MEASUREMENTS AND MAIN RESULTS AA patients were 1.7 times less likely than non-AA patients to achieve therapeutic tacrolimus concentrations (8 ng/ml or higher) during the first year after kidney transplant (35% vs 21%, respectively, p<0.001). AAs not achieving therapeutic concentrations were 2.4 times more likely to have acute cellular rejection (ACR) as compared with AAs achieving therapeutic concentrations (20.8% vs 8.5%, respectively, p<0.01) and 2.5 times more likely to have antibody-mediated rejection (AMR; 8.9% vs 3.6%, respectively, p<0.01). Rates of ACR (8.3% vs 6.7%) and AMR (2.0% vs 0.9% p=0.131) were similar in non-AAs compared across tacrolimus concentration groups. Multivariate modeling confirmed these findings and demonstrated that AAs with low tacrolimus exposure experienced a mild protective effect for the development of interstitial fibrosis/ tubular atrophy (IF/TA; hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.47–1.32) with the opposite demonstrated in non-AAs (HR 2.2, 95% CI 0.90–5.1). CONCLUSION In contradistinction to non-AAs, AAs who achieve therapeutic tacrolimus concentrations have substantially lower acute rejection rates but are at risk of developing IF/TA. These findings may reflect modifiable time-dependent racial differences in the concentration-effect relationship of tacrolimus. Achievement of therapeutic tacrolimus trough concentrations, potentially through genotyping and

  17. Gene Silencing of 4-1BB by RNA Interference Inhibits Acute Rejection in Rats with Liver Transplantation

    PubMed Central

    Shi, Yang; Hu, Shuqun; Song, Qingwei; Yu, Shengcai; Zhou, Xiaojun; Yin, Jun; Qin, Lei; Qian, Haixin

    2013-01-01

    The 4-1BB signal pathway plays a key role in organ transplantation tolerance. In this study, we have investigated the effect of gene silencing of 4-1BB by RNA interference (RNAi) on the acute rejection in rats with liver transplantation. The recombination vector of lentivirus that contains shRNA targeting the 4-1BB gene (LV-sh4-1BB) was constructed. The liver transplantation was performed using the two-cuff technique. Brown-Norway (BN) recipient rats were infected by the recombinant LVs. The results showed that gene silencing of 4-1BB by RNAi downregulated the 4-1BB gene expression of the splenic lymphocytes in vitro, and the splenic lymphocytes isolated from the rats with liver transplantation. LV-sh4-1BB decreased the plasma levels of liver injury markers including AST, ALT, and BIL and also decreased the level of plasma IL-2 and IFN-γ in recipient rats with liver transplantation. Lentivirus-mediated delivery of shRNA targeting 4-1BB gene prolonged the survival time of recipient and alleviated the injury of liver morphology in recipient rats with liver transplantation. In conclusion, our results demonstrate that gene silencing of 4-1BB by RNA interference inhibits the acute rejection in rats with liver transplantation. PMID:23484089

  18. A suspected case of plasma cell-rich acute renal transplant rejection associated with de novo donor-specific antibody.

    PubMed

    Yoshikawa, Mikiko; Kitamura, Ken; Ishimura, Takeshi; Hara, Shigeo; Fujisawa, Masato; Nishi, Shinichi

    2015-07-01

    A kidney transplant case with de novo donor-specific antibody showed monoclonal plasma cell infiltration into the graft with ABO incompatibility. Three years after transplantation, the patient's graft function suddenly deteriorated. Interstitial edema and the predominant infiltration of inflammatory plasma cells with kappa chain monoclonality were observed in biopsy specimens. The in situ hybridization of Epstein-Barr virus was negative and post-transplant lymphoproliferative disorder was not evident from radiological examinations. On laboratory examination, the patient had de novo donor-specific antibody for HLA-DQ. We suspected plasma cell-rich acute rejection for which methylprednisolone pulse therapy, plasma exchange, rituximab, and 15-deoxyspergualin were given. In the ensuing biopsy, the degree of plasma cell infiltration was similar to the first biopsy; however, kappa chain monoclonality relatively weakened. Owing to resistance to these treatments, intravenous immunoglobulin (IVIG) (0.5 g/kg/day) was added. The serum creatinine level gradually declined to 3.1 mg/dL; however, it increased up to 3.6 mg/dL again. In the final biopsy, the infiltrated plasma cells disappeared but severe interstitial fibrosis developed. This case showed difficulty in the diagnosis and treatment of plasma cell-rich acute rejection. A detailed consideration of this case may be helpful in understanding the clinical features and pathogenesis of this condition. PMID:26031590

  19. Elevated Cardiac Troponin in Acute Stroke without Acute Coronary Syndrome Predicts Long-Term Adverse Cardiovascular Outcomes

    PubMed Central

    Bhatt, Reema; Bove, Alfred A.

    2014-01-01

    Background. Elevated cardiac troponin in acute stroke in absence of acute coronary syndrome (ACS) has unclear long-term outcomes. Methods. Retrospective analysis of 566 patients admitted to Temple University Hospital from 2008 to 2010 for acute stroke was performed. Patients were included if cardiac troponin I was measured and had no evidence of ACS and an echocardiogram was performed. Of 200 patients who met the criteria, baseline characteristics, electrocardiograms, and major adverse cardiovascular events (MACE) were reviewed. Patients were characterized into two groups with normal and elevated troponins. Primary end point was nonfatal myocardial infarction during follow-up period after discharge. The secondary end points were MACE and death from any cause. Results. For 200 patients, 17 patients had positive troponins. Baseline characteristics were as follows: age 63.1 ± 13.8, 64% African Americans, 78% with hypertension, and 22% with previous CVA. During mean follow-up of 20.1 months, 7 patients (41.2%) in elevated troponin and 6 (3.3%) patients in normal troponin group had nonfatal myocardial infarction (P = 0.0001). MACE (41.2% versus 14.2%, P = 0.01) and death from any cause (41.2% versus 14.5%, P = 0.017) were significant in the positive troponin group. Conclusions. Elevated cardiac troponin in patients with acute stroke and no evidence of ACS is strong predictor of long-term cardiac outcomes. PMID:25530906

  20. TLR Signals Promote IL-6/IL-17-Dependent Transplant Rejection1

    PubMed Central

    Chen, Luqiu; Ahmed, Emily; Wang, Tongmin; Wang, Ying; Ochando, Jordi; Chong, Anita S.; Alegre, Maria-Luisa

    2010-01-01

    Acute allograft rejection has often been correlated with Th1 differentiation, whereas transplantation tolerance is frequently associated with induction of regulation. The discovery of the Th17 phenotype has prompted its scrutiny in transplant rejection. Although IL-17 has recently been observed in settings of acute allograft rejection and drives rejection in T-bet-deficient mice that have impaired type 1 T cell responses, there is little evidence of its requirement during acute rejection in wild-type animals. We and others have previously shown that TLR9 signaling by exogenous CpG at the time of transplantation is sufficient to abrogate anti-CD154-mediated acceptance of fully mismatched cardiac allografts. In this study, we investigated the mechanism by which acute rejection occurs in this inflammatory context. Our results indicate that CpG targets recipient hematopoietic cells and that its pro-rejection effects correlate both with prevention of anti-CD154-mediated conversion of conventional CD4+ T cells into induced regulatory T cells (iTregs) and with the expression of IFN-γ and IL-17 by intra-graft CD4+ T cells. Moreover, the combined elimination of IL-6 and IL-17 signaling abrogated the ability of CpG to promote acute cardiac allograft rejection. Thus, pro-inflammatory signals at the time of transplantation can change the quality of the effector immune response and reveal a pathogenic function for IL-6 and IL-17 in wild-type recipients. PMID:19414775

  1. SPR detection of cardiac troponin T for acute myocardial infarction.

    PubMed

    Pawula, Maria; Altintas, Zeynep; Tothill, Ibtisam E

    2016-01-01

    A surface plasmon resonance (SPR) sensor developed for the rapid, sensitive and specific detection of cardiac troponin T (cTnT) in serum samples is reported in this work. An extensive optimisation of assay parameters was conducted to achieve optimal detection strategy. Both direct and sandwich immunoassay formats were investigated and optimised. The response obtained was enhanced further by the use of gold nanoparticles (AuNPs) conjugated to the anti-cTnT detection antibody. A regeneration method was developed to enable the reuse of the SPR sensor for multiple sample application. The SPR immunosensor showed good reproducibility for cTnT detection in the concentration range of 25-1000 ng mL(-1) and 5-400 ng mL(-1) for the direct and sandwich assays in buffer, respectively. The linear regression analysis was performed and R(2) value was found as 0.99 for both assays. In order to optimise the sensor for serum analysis, nonspecific binding of serum proteins was reduced through the use of additives in the dilution buffer. To achieve greater sensitivity, the performance of the cTnT immunosensor sandwich assay in human serum was evaluated using non-modified and AuNP modified detector antibodies. A detection limit (LOD) for the immunosensor in 50% serum was assessed as 5 ng mL(-1) cTnT for the standard sandwich assay and 0.5 ng mL(-1) cTnT when using AuNP conjugated detector antibodies with a linear dynamic range of 0.5-40 ng mL(-1). The dissociation constant was found as 3.28 × 10(-9) M using Langmuir binding model which indicates high affinity between cTnT and its antibody. The proposed SPR immunosensor has a promising potential to be developed for point-of-care testing for the early diagnosis of acute myocardial infarction (AMI). This method can also be used for the rapid detection of biomarkers in central nervous system diseases. PMID:26695335

  2. Functional engineered human cardiac patches prepared from nature's platform improve heart function after acute myocardial infarction.

    PubMed

    Wang, Qingjie; Yang, Hui; Bai, Aobing; Jiang, Wei; Li, Xiuya; Wang, Xinhong; Mao, Yishen; Lu, Chao; Qian, Ruizhe; Guo, Feng; Ding, Tianling; Chen, Haiyan; Chen, Sifeng; Zhang, Jianyi; Liu, Chen; Sun, Ning

    2016-10-01

    With the advent of induced pluripotent stem cells and directed differentiation techniques, it is now feasible to derive individual-specific cardiac cells for human heart tissue engineering. Here we report the generation of functional engineered human cardiac patches using human induced pluripotent stem cells-derived cardiac cells and decellularized natural heart ECM as scaffolds. The engineered human cardiac patches can be tailored to any desired size and shape and exhibited normal contractile and electrical physiology in vitro. Further, when patching on the infarct area, these patches improved heart function of rats with acute myocardial infarction in vivo. These engineered human cardiac patches can be of great value for normal and disease-specific heart tissue engineering, drug screening, and meet the demands for individual-specific heart tissues for personalized regenerative therapy of myocardial damages in the future. PMID:27509303

  3. Acute response and chronic stimulus for cardiac structural and functional adaptation in a professional boxer.

    PubMed

    Oxborough, David; George, Keith; Utomi, Victor; Lord, Rachel; Morton, James; Jones, Nigel; Somauroo, John

    2014-06-01

    The individual response to acute and chronic changes in cardiac structure and function to intense exercise training is not fully understood and therefore evidence in this setting may help to improve the timing and interpretation of pre-participation cardiac screening. The following case report highlights an acute increase in right ventricular (RV) size and a reduction in left ventricular (LV) basal radial function with concomitant increase at the mid-level in response to a week's increase in training volume in a professional boxer. These adaptations settle by the second week; however, chronic physiological adaptation occurs over a 12-week period. Electrocardiographic findings demonstrate an acute lateral T-wave inversion at 1 week, which revert to baseline for the duration of training. It appears that a change in training intensity and volume generates an acute response within the RV that acts as a stimulus for chronic adaptation in this professional boxer. PMID:25988031

  4. Clinical investigation: thyroid function test abnormalities in cardiac arrest associated with acute coronary syndrome

    PubMed Central

    Iltumur, Kenan; Olmez, Gonul; Arıturk, Zuhal; Taskesen, Tuncay; Toprak, Nizamettin

    2005-01-01

    Introduction It is known that thyroid homeostasis is altered during the acute phase of cardiac arrest. However, it is not clear under what conditions, how and for how long these alterations occur. In the present study we examined thyroid function tests (TFTs) in the acute phase of cardiac arrest caused by acute coronary syndrome (ACS) and at the end of the first 2 months after the event. Method Fifty patients with cardiac arrest induced by ACS and 31 patients with acute myocardial infarction (AMI) who did not require cardioversion or cardiopulmonary resuscitation were enrolled in the study, as were 40 healthy volunteers. The patients were divided into three groups based on duration of cardiac arrest (<5 min, 5–10 min and >10 min). Blood samples were collected for thyroid-stimulating hormone (TSH), tri-iodothyronine (T3), free T3, thyroxine (T4), free T4, troponin-I and creatine kinase-MB measurements. The blood samples for TFTs were taken at 72 hours and at 2 months after the acute event in the cardiac arrest and AMI groups, but only once in the control group. Results The T3 and free T3 levels at 72 hours in the cardiac arrest group were significantly lower than in both the AMI and control groups (P < 0.0001). On the other hand, there were no significant differences between T4, free T4 and TSH levels between the three groups (P > 0.05). At the 2-month evaluation, a dramatic improvement was observed in T3 and free T3 levels in the cardiac arrest group (P < 0.0001). In those patients whose cardiac arrest duration was in excess of 10 min, levels of T3, free T3, T4 and TSH were significantly lower than those in patients whose cardiac arrest duration was under 5 min (P < 0.001, P < 0.001, P < 0.005 and P < 0.05, respectively). Conclusion TFTs are significantly altered in cardiac arrest induced by ACS. Changes in TFTs are even more pronounced in patients with longer periods of resuscitation. The changes in the surviving patients were characterized by euthyroid sick

  5. CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection

    PubMed Central

    Harper, Simon J. F.; Ali, Jason M.; Wlodek, Elizabeth; Negus, Marg C.; Harper, Ines G.; Chhabra, Manu; Qureshi, M. Saeed; Mallik, Mekhola; Bolton, Eleanor; Bradley, J. Andrew; Pettigrew, Gavin J.

    2015-01-01

    Adaptive CD8 T-cell immunity is the principal arm of the cellular alloimmune response, but its development requires help. This can be provided by CD4 T cells that recognize alloantigen “indirectly,” as self-restricted allopeptide, but this process remains unexplained, because the target epitopes for CD4 and CD8 T-cell recognition are “unlinked” on different cells (recipient and donor antigen presenting cells (APCs), respectively). Here, we test the hypothesis that the presentation of intact and processed MHC class I alloantigen by recipient dendritic cells (DCs) (the “semidirect” pathway) allows linked help to be delivered by indirect-pathway CD4 T cells for generating destructive cytotoxic CD8 T-cell alloresponses. We show that CD8 T-cell–mediated rejection of murine heart allografts that lack hematopoietic APCs requires host secondary lymphoid tissue (SLT). SLT is necessary because within it, recipient dendritic cells can acquire MHC from graft parenchymal cells and simultaneously present it as intact protein to alloreactive CD8 T cells and as processed peptide alloantigen for recognition by indirect-pathway CD4 T cells. This enables delivery of essential help for generating cytotoxic CD8 T-cell responses that cause rapid allograft rejection. In demonstrating the functional relevance of the semidirect pathway to transplant rejection, our findings provide a solution to a long-standing conundrum as to why SLT is required for CD8 T-cell allorecognition of graft parenchymal cells and suggest a mechanism by which indirect-pathway CD4 T cells provide help for generating effector cytotoxic CD8 T-cell alloresponses at late time points after transplantation. PMID:26420874

  6. [The influence of selected cytokine gene polymorphisms on the occurrence of acute and chronic rejection and on kidney graft survival].

    PubMed

    Kocierz, Magdalena; Kujawa-Szewieczek, Agata; Kolonko, Aureliusz; Chudek, Jerzy; Wiecek, Andrzej

    2009-01-01

    Genetically determined interindividual differences in the production of mediators of immune response may influence the outcomes of kidney transplantation. Of the cytokine gene polymorphisms that determine the level of gene expression, TNF-a -08G/A, IFN-g +874T/A and microsatellite (CA)n, TGF-b1 +869T/C and +915G/C, IL-6 -174G/C, and IL-10 -592C/A, -819C/T, and -1082G/A seem to have the strongest impact on graft survival. Increased risk of acute rejection (AR) was demonstrated for high-producing genotypes of pro-inflammatory cytokines such as TNF-a and IFN-g, while the association with polymorphisms of TGF-b1 and IL-10 remains unclear. A high production of profibrotic TGF-b1 is associated with interstitial fibrosis and tubular atrophy (IF/TA). In contrast, high genetically determined IL-6 gene expression played a protective role in the development of chronic rejection (CR). The risk of graft loss was greater among high TNF-a and low TGF-b1 or IL-6 producers. The results of kidney transplantation are also influenced by the donor's cytokine expression profile. Low IL-6 production donor genotype was associated with a higher prevalence of AR, CR, and IF/TA. Low donor transcriptional TGF-b1 gene activity predisposed the recipient to AR episodes and high IFN-g expression to IF/TA development. To date, study results are highly inconsistent, so the applicability of cytokine polymorphism genotyping remains questionable. In summary, it is difficult to conclude whether or not cytokine polymorphism genotyping is useful in the risk assessment of rejection and kidney graft survival and in applying optimal immunosuppressive medication. PMID:20097948

  7. Characteristics of Circulating Donor-Specific Anti-HLA Antibodies and Acute Rejection in the Kidney Allograft

    PubMed Central

    Kannabhiran, Dinesh; Lee, John; Schwartz, Joseph E.; Friedlander, Rex; Aull, Meredith; Muthukumar, Thangamani; Campbell, Sean; Epstein, David; Seshan, Surya V.; Kapur, Sandip; Sharma, Vijay K.; Suthanthiran, Manikkam; Dadhania, Darshana

    2016-01-01

    Background Characteristics of pretransplant antibodies directed at donor HLA (DSA) associated with adverse outcomes in kidney transplant recipients are being elucidated but uncertainties exist. Methods Prospectively screening of pretransplant sera from 543 kidney recipients using single antigen bead assays identified 154 recipients with DSA and 389 without. We investigated the association of DSA features to acute rejection (AR) and graft failure. Results One-year AR incidence was higher in DSA positive group (P<0.001), primarily due to antibody mediated rejection (AMR, 13% vs. 1.8%, P<0.001) and not T-cell mediated rejection (ACR, 5% vs.6%, P=0.65). Risk of AMR increased progressively with a rise in DSA MFI-Sum (P<0.0001). Both DSA MFI-Sum ≥6000 (OR=18; 95%CI, 7.0 to 47; P<0.001) and DSA specificity, presence of DSA against both HLA class I and II (OR=39; 95%CI, 14 to 106; P<0.0001), predicted one-year AMR, independent of other covariates. In a combined model, DSA specificity predicted AMR, independent of DSA MFI-Sum. In multivariable Cox proportional hazards models, the covariate-adjusted hazard ratio for graft failure was 2.03 (95%CI, 1.05 to 3.92; P=0.04) for DSA MFI-Sum≥6000 and 2.23 (95% CI, 1.04 to 4.80; P=0.04) for class I and II DSA. Prediction of graft loss was not independent of AMR. Conclusions Our study supports the hypothesis that characterization of pretransplant DSA, specifically presence of DSA against both HLA class I and II and the strength, as quantified by DSA MFI-Sum, is useful to estimate AMR and graft failure risk in kidney graft recipients. Elevated risk of graft failure is attributable to increased risk of AMR. PMID:25629531

  8. Delayed Cytotoxic T Lymphocyte-Associated Protein 4-Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection.

    PubMed

    Young, J S; Chen, J; Miller, M L; Vu, V; Tian, C; Moon, J J; Alegre, M-L; Sciammas, R; Chong, A S

    2016-08-01

    Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein cytotoxic T lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) blocks T cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective with naïve T cells and less so with activated or memory T cells. In this study, we used a mouse model of allosensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days after sensitization, for inhibiting ongoing allospecific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allospecific germinal center B cell response and inhibited alloantibody production. Using adoptively transferred T cell receptor transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4(+) and T follicular helper responses. Remarkably, delaying CTLA4-Ig until day 6 after transplantation in a fully mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, whereas transferred hyperimmune sera reversed the effects of delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig for inhibiting ongoing B cell responses even when the graft-specific T cell response was robustly established. PMID:26928966

  9. Methylprednisolone-hemisuccinate and its metabolites in serum, urine and bile from two patients with acute graft rejection.

    PubMed Central

    Lawson, G J; Chakraborty, J; Tredger, J M; Baylis, E M

    1995-01-01

    Methylprednisolone-hemisuccinate (MPHS), methylprednisolone (MP), 20-alpha-hydroxy- (20 alpha HMP) and 20-beta-hydroxymethyl-prednisolone (20 beta HMP) concentrations were measured in serum, urine and bile from two liver transplant recipients who had received 1 g MPHS by a 1 h intravenous infusion for treatment of an acute rejection episode. These patients excreted similar total amounts of the dose in urine as patients with rheumatoid arthritis (historical controls) who had normal liver function. The transplant patients showed a ratio in urine of 'total metabolites'/MPHS that was one third that of patients with rheumatoid arthritis. Less than 0.2% of the administered MPHS appeared in bile as MPHS, MP, 20 alpha HMP and 20 beta HMP during the 24 h following infusion. Liver transplantation did not affect the overall elimination of drug in urine. However, the impaired liver function following transplantation resulted in reduced conversion of MPHS to its active form (MP). PMID:7742157

  10. Fiber optic probe enabled by surface-enhanced Raman scattering for early diagnosis of potential acute rejection of kidney transplant

    NASA Astrophysics Data System (ADS)

    Chi, Jingmao; Chen, Hui; Tolias, Peter; Du, Henry

    2014-06-01

    We have explored the use of a fiber-optic probe with surface-enhanced Raman scattering (SERS) sensing modality for early, noninvasive and, rapid diagnosis of potential renal acute rejection (AR) and other renal graft dysfunction of kidney transplant patients. Multimode silica optical fiber immobilized with colloidal Ag nanoparticles at the distal end was used for SERS measurements of as-collected urine samples at 632.8 nm excitation wavelength. All patients with abnormal renal graft function (3 AR episodes and 2 graft failure episodes) who were clinically diagnosed independently show common unique SERS spectral features in the urines collected just one day after transplant. SERS-based fiber-optic probe has excellent potential to be a bedside tool for early diagnosis of kidney transplant patients for timely medical intervention of patients at high risk of transplant dysfunction.

  11. Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation

    PubMed Central

    Dedeoglu, Burç; Meijers, Ruud W. J.; Klepper, Mariska; Hesselink, Dennis A.; Baan, Carla C.; Litjens, Nicolle H. R.; Betjes, Michiel G. H.

    2016-01-01

    Background End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR). Methods 222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31+ naive T cells were determined as T-cell ageing parameters. Results Of the 222 patients analyzed, 30 (14%) developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively) and the number of related donor kidney transplantation was significantly lower (p = 0.018) in the EAR group. EAR-patients showed lower CD4+CD28null T-cell numbers (p<0.01) and the same trend was observed for CD8+CD28null T-cell numbers (p = 0.08). No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4+CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028). In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001). Conclusion Immunological ageing-related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR. PMID:26950734

  12. Inducible expression of indoleamine 2,3-dioxygenase attenuates acute rejection of tissue-engineered lung allografts in rats.

    PubMed

    Ebrahimi, Ammar; Kardar, Gholam Ali; Teimoori-Toolabi, Ladan; Toolabi, LadanTeimoori; Ghanbari, Hossein; Sadroddiny, Esmaeil

    2016-01-15

    Lung disease remains one of the principal causes of death worldwide and the incidence of pulmonary diseases is increasing. Complexity in treatments and shortage of donors leads us to develop new ways for lung disease treatment. One promising strategy is preparing engineered lung for transplantation. In this context, employing new immunosuppression strategies which suppresses immune system locally rather than systemic improves transplant survival. This tends to reduce the difficulties in transplant rejection and the systemic impact of the use of immunosuppressive drugs which causes side effects such as serious infections and malignancies. In our study examining the immunosuppressive effects of IDO expression, we produced rat lung tissues with the help of decellularized tissue, differentiating medium and rat mesenchymal stem cells. Transduction of these cells by IDO expressing lentiviruses provided inducible and local expression of this gene. To examine immunosuppressive properties of IDO expression by these tissues, we transplanted these allografts into rats and, subsequently, evaluated cytokine expression and histopathological properties. Expression of inflammatory cytokines IFNγ and TNFα were significantly downregulated in IDO expressing allograft. Moreover, acute rejection score of this experimental group was also lower comparing other two groups and mRNA levels of FOXP3, a regulatory T cell marker, upregulated in IDO expressing group. However, infiltrating lymphocyte counting did not show significant difference between groups. This study demonstrates that IDO gene transfer into engineered lung allograft tissues significantly attenuates acute allograft damage suggesting local therapy with IDO as a strategy to reduce the need for systemic immunosuppression and, thereby, its side effects. PMID:26506443

  13. PULMONARY AND CARDIAC GENE EXPRESSION FOLLOWING ACUTE ULTRAFINE CARBON PARTICLE INHALATION IN HYPERTENSIVE RATS

    EPA Science Inventory

    Inhalation of ultrafine carbon particles (ufCP) causes cardiac physiological changes without marked pulmonary injury or inflammation. We hypothesized that acute ufCP exposure of 13 months old Spontaneously Hypertensive (SH) rats will cause differential effects on the lung and hea...

  14. C1 Inhibitor in Acute Antibody-Mediated Rejection Nonresponsive to Conventional Therapy in Kidney Transplant Recipients: A Pilot Study.

    PubMed

    Viglietti, D; Gosset, C; Loupy, A; Deville, L; Verine, J; Zeevi, A; Glotz, D; Lefaucheur, C

    2016-05-01

    Complement inhibitors have not been thoroughly evaluated in the treatment of acute antibody-mediated rejection (ABMR). We performed a prospective, single-arm pilot study to investigate the potential effects and safety of C1 inhibitor (C1-INH) Berinert added to high-dose intravenous immunoglobulin (IVIG) for the treatment of acute ABMR that is nonresponsive to conventional therapy. Kidney recipients with nonresponsive active ABMR and acute allograft dysfunction were enrolled between April 2013 and July 2014 and received C1-INH and IVIG for 6 months (six patients). The primary end point was the change in eGFR at 6 months after inclusion (M+6). Secondary end points included the changes in histology and DSA characteristics and adverse events as evaluated at M+6. All patients showed an improvement in eGFR between inclusion and M+6: from 38.7 ± 17.9 to 45.2 ± 21.3 mL/min/1.73 m(2) (p = 0.0277). There was no change in histological features, except a decrease in the C4d deposition rate from 5/6 to 1/6 (p = 0.0455). There was a change in DSA C1q status from 6/6 to 1/6 positive (p = 0.0253). One deep venous thrombosis was observed. In a secondary analysis, C1-INH patients were compared with a similar historical control group (21 patients). C1-INH added to IVIG is safe and may improve allograft function in kidney recipients with nonresponsive acute ABMR. PMID:26693703

  15. Human Cardiac-Derived Adherent Proliferating Cells Reduce Murine Acute Coxsackievirus B3-Induced Myocarditis

    PubMed Central

    Miteva, Kapka; Haag, Marion; Peng, Jun; Savvatis, Kostas; Becher, Peter Moritz; Seifert, Martina; Warstat, Katrin; Westermann, Dirk; Ringe, Jochen; Sittinger, Michael; Schultheiss, Heinz-Peter

    2011-01-01

    Background Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. We recently isolated and identified novel cardiac-derived cells from human cardiac biopsies: cardiac-derived adherent proliferating cells (CAPs). They have similarities with mesenchymal stromal cells, which are known for their anti-apoptotic and immunomodulatory properties. We explored whether CAPs application could be a novel strategy to improve acute Coxsackievirus B3 (CVB3)-induced myocarditis. Methodology/Principal Findings To evaluate the safety of our approach, we first analyzed the expression of the coxsackie- and adenovirus receptor (CAR) and the co-receptor CD55 on CAPs, which are both required for effective CVB3 infectivity. We could demonstrate that CAPs only minimally express both receptors, which translates to minimal CVB3 copy numbers, and without viral particle release after CVB3 infection. Co-culture of CAPs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis and viral progeny release. In addition, CAPs reduced CD4 and CD8 T cell proliferation. All CAPs-mediated protective effects were nitric oxide- and interleukin-10-dependent and required interferon-γ. In an acute murine model of CVB3-induced myocarditis, application of CAPs led to a decrease of cardiac apoptosis, cardiac CVB3 viral load and improved left ventricular contractility parameters. This was associated with a decline in cardiac mononuclear cell activity, an increase in T regulatory cells and T cell apoptosis, and an increase in left ventricular interleukin-10 and interferon-γ mRNA expression. Conclusions We conclude that CAPs are a unique type of cardiac-derived cells and promising tools to improve acute CVB3-induced myocarditis. PMID:22174827

  16. Immune biomarker panel monitoring utilizing IDO enzyme activity and CD4 ATP levels: prediction of acute rejection versus viral replication events

    PubMed Central

    Dharnidharka, Vikas R.; Gupta, Sushil; Khasawneh, Eihab Al; Haafiz, Allah; Shuster, Jonathan J.; Theriaque, Douglas W.; Shahlaee, Amir H.; Garrett, Timothy J.

    2011-01-01

    Infections have become as important an event as acute rejection post-transplant for long-term allograft survival. Less invasive biomarkers tested so far predict risk for one event or the other, not both. We prospectively tested blood and urine monthly for twelve months post-transplant from children receiving a kidney transplant. The indoleamine 2,3 dioxygenase (IDO) enzyme pathway was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (trp). Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with acute rejection or major infection events or stable group (no events) in the next 30 days. The 25 subjects experienced 6 discrete episodes of acute rejection in 5 subjects and 16 discrete events of major infection in 14 subjects (7 BK viruria, 6 cytomegaloviremia, 1 Epstein-Barr and cytomegaloviremia, 2 transplant pyelonephritis). Mean serum kyn/trp ratios were significantly elevated in the group that experienced acute rejection (p = 0.02).Within-subject analyses revealed that over time, urine kyn/trp ratios showed an increase (p = 0.01) and blood CD4-ATP levels showed a decrease (p = 0.007) prior to a major infection event. These pilot results suggest that a panel of biomarkers together can predict over- or under-immunosuppression, but need independent validation. PMID:21492353

  17. Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis.

    PubMed

    Booth, Adam J; Wood, Sherri C; Cornett, Ashley M; Dreffs, Alyssa A; Lu, Guanyi; Muro, Andrés F; White, Eric S; Bishop, D Keith

    2012-03-01

    Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA(-/-)) and wild-type (WT) mice. While EDA(-/-) mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA(-/-) mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which enhance

  18. Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection.

    PubMed

    Jiang, X; Nguyen, T T; Tian, W; Sung, Y K; Yuan, K; Qian, J; Rajadas, J; Sallenave, J-M; Nickel, N P; de Jesus Perez, V; Rabinovitch, M; Nicolls, M R

    2015-07-01

    The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal-regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling. PMID:25727073

  19. Cyclosporine does not prevent microvascular loss in transplantation but can synergize with a neutrophil elastase inhibitor, elafin, to maintain graft perfusion during acute rejection

    PubMed Central

    Jiang, Xinguo; Nguyen, Tom T.; Tian, Wen; Sung, Yon K.; Yuan, Ke; Qian, Jin; Rajadas, Jayakumar; Sallenave, Jean-Michel; Nickel, Nils P.; de Jesus Perez, Vinicio; Rabinovitch, Marlene; Nicolls, Mark R.

    2015-01-01

    The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal-regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling. PMID:25727073

  20. A 3’-UTR Polymorphism in Soluble Epoxide Hydrolase Gene Is Associated with Acute Rejection in Renal Transplant Recipients

    PubMed Central

    Gervasini, Guillermo; García-Cerrada, Montserrat; Coto, Eliecer; Vergara, Esther; García-Pino, Guadalupe; Alvarado, Raul; Fernández-Cavada, Maria Jesús; Suárez-Álvarez, Beatriz; Barroso, Sergio; Doblaré, Emilio; Díaz-Corte, Carmen; López-Larrea, Carlos; Cubero, Juan Jose

    2015-01-01

    Background and Purpose Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites that play a protective role against damaging processes that may occur after re-oxygenation of the graft. We aimed to investigate whether the presence of functional polymorphisms in the gene encoding soluble epoxy hydrolase (EPHX2), which metabolizes EETs to less active compounds, may play a role in the outcome of renal transplantation. Methods In a group of 259 Caucasian renal transplant recipients and 183 deceased donors, we determined the presence of three common EPHX2 SNPs, namely rs41507953 (K55R), rs751141 (R287Q) and rs1042032 A/G. Associations with parameters of graft function and the incidence of acute rejection were retrospectively investigated throughout the first year after grafting by logistic regression adjusting for clinical and demographic variables. Results Carriers of the rs1042032 GG genotype displayed significantly lower estimated glomerular filtration rate (eGFR) (38.15 ± 15.57 vs. 45.99 ± 16.05; p = 0.04) and higher serum creatinine values (1.57 ± 0.58 vs. 1.30 ± 0.47 g/dL; p=0.02) one year after grafting, compared to patients carrying the wildtype A-allele. The same GG genotype was also associated to increased risk of acute rejection. Interestingly, this association was observed for the genotype of both recipients [OR =6.34 (1.35-29.90); p = 0.015] and donors [OR = 5.53 (1.10-27.80); p=0.042]. A statistical model including both genotypes along with other meaningful demographic and clinical variables resulted in an increased significance for the association with the recipients’ genotype [OR=8.28 (1.21-74.27); p=0.031]. Conclusions Our results suggest that genetic variability in the EETs-metabolizing gene, EPHX2, may have a significant impact on the outcome of deceased-donor renal transplantation. PMID:26230946

  1. mir-155 regulates cardiac allograft rejection by targing the expression of suppressor of cytokine signaling-1 (DOCS1) in dendritic cells

    PubMed Central

    Gao, Yi; Liu, Fang; Zhou, Qiwei; Guo, Meng; Zhang, Mingjian; Guo, Wenyuan; Wang, Liming; Hu, Liping; Hu, Chaozhou; Shi, Yongzhao; Liu, Yushan; Wang, Quanxing

    2014-01-01

    Previously, we observed that mir-155 is induced during dendritic cell (DC) differentiation. We now demon-strated convincing evidence indicating that mir-155 promotes DC maturation and regulates its capacity for antigen presentation and induction of alloreactive T cell activation. Interestingly, the induction of miR-155 expression in DCs is dependent on the TLR4/Myd88/NF-κB signaling. Our mechanistic studies further revealed that SOCS1 is a direct target for mir-155, and by binding to its 3’UTR, mir-155 is likely to affect SOCS1 translation. Suppression of mir-155 expression in DCs significantly attenuated LPS-induced DC maturation along with reduced capability to stimulate allogeneic T cell proliferation. As a result, administration of antagomiR-155 provided protection for cardiac allografts from rejection. Together, our data support that suppression of miR-155 in DCs could be a viable therapeutic strategy for prevention and treatment of allograft rejection in clinical setting of transplantation. PMID:25550988

  2. Useful laboratory tests for studying thrombogenesis in acute cardiac syndromes.

    PubMed

    Fareed, J; Hoppensteadt, D A; Leya, F; Iqbal, O; Wolf, H; Bick, R

    1998-08-01

    We review laboratory tests that evaluate thrombogenesis during acute coronary syndromes. These tests have been found to be valuable research tools in more clearly understanding the pathophysiology of acute coronary syndromes. In particular, we describe tissue factor, tissue factor pathway inhibitor, prothrombin fragment 1.2, thrombin-antithrombin complex, fibrinopeptide A, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), t-PA-PAI complex, Bbeta 15-42-related peptides, fibrinogen degradation products, fibrin degradation products, D-dimer, platelet factor 4, beta-thromboglobulin, 5-hydroxytryptamine, thromboxane B2, prostacyclin, endothelin, angiotensin-converting enzyme, soluble thrombomodulin, C1-esterase inhibitor, anaphylotoxins C3a, C4a, and C5a, bradykinin, tumor necrosis factor, leukotriene C4, platelet activating factor, anti-phospholipid antibody, and von Willebrand factor. Some of these tests may prove to be useful in clinical diagnosis and management of acute coronary syndromes. Clinical outcome studies are needed to determine which tests may be cost effective and medically useful. PMID:9702994

  3. Effects of acute stress on cardiac endocannabinoids, lipogenesis, and inflammation in rats

    PubMed Central

    Lim, James; Piomelli, Daniele

    2014-01-01

    Objective Trauma exposure can precipitate acute/post-traumatic stress responses (AS/PTSD) and disabling cardiovascular disorders (CVD). Identifying acute stress-related physiologic changes that may increase CVD risk could inform development of early CVD-prevention strategies. The endocannabinoid system (ECS) regulates hypothalamic-pituitary-adrenal (HPA) axis response and stress-related cardiovascular function. We examine stress-related endocannabinoid system (ECS) activity and its association with cardiovascular biochemistry/function following acute stress. Methods Rodents (n=8-16/group) were exposed to predator odor or saline; elevated plus maze (EPM), blood pressure (BP), serum and cardiac tissue ECS markers, and lipid metabolism were assessed at 24h and 2wks post-exposure. Results At 24h the predator odor group demonstrated anxiety-like behavior and had (a) elevated serum markers of cardiac failure/damage (brain natriuretic peptide [BNP]: 275.1 vs. 234.6, p=0.007; troponin-I: 1.50 vs. 0.78, p=0.076), lipogenesis (triacylglycerols [TAG]: 123.5 vs. 85.93, p=0.018), and inflammation (stearoyl delta-9 desaturase activity [SCD-16]: 0.21 vs. 0.07, p<0.001); (b) significant decrease in cardiac endocannabinoid (2-arachidonoyl-sn-glycerol, 2-AG: 29.90 vs. 65.95, p<0.001) and fatty acid ethanolamides (FAE: oleoylethanolamide, OEA: 114.3 vs. 125.4, p=0.047; palmitoylethanolamide, PEA: 72.96 vs. 82.87, p=0.008); and (c) increased cardiac inflammation (IL-1β/IL-6 ratio: 19.79 vs.13.57, p=0.038; TNF-α/IL-6 ratio: 1.73 vs. 1.03, p=0.019) and oxidative stress (thiobarbituric acid reactive substances [TBARS]: 7.81 vs. 7.05, p=0.022), that were associated with cardiac steatosis (higher TAG: 1.09 vs. 0.72, p<0.001). Cardiac lipogenesis persisted, and elevated BP emerged two weeks after exposure. Conclusions Acute psychological stress elicits ECS-related cardiac responses associated with persistent, potentially-pathological changes in rat cardiovascular biochemistry

  4. National Heart Attack Alert Program position paper: chest pain centers and programs for the evaluation of acute cardiac ischemia.

    PubMed

    Zalenski, R J; Selker, H P; Cannon, C P; Farin, H M; Gibler, W B; Goldberg, R J; Lambrew, C T; Ornato, J P; Rydman, R J; Steele, P

    2000-05-01

    The National Heart Attack Alert Program (NHAAP), which is coordinated by the National Heart, Lung, and Blood Institute (NHLBI), promotes the early detection and optimal treatment of patients with acute myocardial infarction and other acute coronary ischemic syndromes. The NHAAP, having observed the development and growth of chest pain centers in emergency departments with special interest, created a task force to evaluate such centers and make recommendations pertaining to the management of patients with acute cardiac ischemia. This position paper offers recommendations to assist emergency physicians in EDs, including those with chest pain centers, in providing comprehensive care for patients with acute cardiac ischemia. PMID:10783408

  5. A partial defect in technetium-99m pyrophosphate image suggesting cardiac rupture following acute myocardial infarction.

    PubMed

    Tsujino, M; Hiroe, M; Sugimoto, K; Miyahara, Y; Ishii, Z; Taniguchi, K; Marumo, F

    1992-01-01

    We present the case of a 70-year-old woman with acute myocardial infarction who died of cardiac rupture on the 2nd hospital day. Dual isotope single photon emission computed tomography (SPECT) using thallium-201 chloride and technetium-99m pyrophosphate (PYP) performed on the 2nd hospital day showed a large perfusion defect in the anteroseptal wall on 201Tl image and a increased accumulation on 99mTc-PYP image in the anterior area consistent with a partial defect. Autopsy performed 1 h after death revealed a tear in the left ventricular anterior wall consistent with the defect on the 99mTc-PYP image. We propose that the finding of a partial defect in 99mTc-PYP is an interesting finding which may be associated with cardiac rupture following acute myocardial infarction. PMID:1533369

  6. Acute effects of carbon monoxide on cardiac electrical stability. Research report, Sep 85-Jul 88

    SciTech Connect

    Verrier, R.L.; Mills, A.K.; Skornik, W.A.

    1990-01-01

    The objective of the project was to determine the effects of acute carbon monoxide exposure on cardiac electrical stability in the normal and ischemic heart of anesthetized and conscious dogs. Exposure (90 to 120 minutes) to relatively high levels of carbon monoxide, leading to carboxyhemoglobin concentrations of up to 20 percent, was without significant effect on ventricular electrical stability in laboratory dogs. This appears to be the case in the acutely ischemic heart as well as in the normal heart. Using a model involving partial coronary artery stenosis, no changes were found in either the cycle frequency of coronary blood flow oscillations or in platelet aggregability during carbon monoxide exposure. Also examined were the effects of carbon monoxide exposure in the conscious state in order to take into consideration possible adverse consequences mediated by the central nervous system. The study found no adverse effects on the cardiac-excitable properties in response to either a 2-hour- or 24-hour-exposure paradigm.

  7. Novel biomarkers for early diagnosis of acute kidney injury after cardiac surgery in adults

    PubMed Central

    Kališnik, Jurij Matija

    2016-01-01

    Acute kidney injury after cardiac surgery with cardiopulmonary bypass is a common and serious complication and it is associated with increased morbidity and mortality. Diagnosis of acute kidney injury is based on the serum creatinine levels which rise several hours to days after the initial injury. Thus, novel biomarkers that will enable faster diagnosis are needed in clinical practice. There are numerous urine and serum proteins that indicate kidney injury and are under extensive research. Despite promising basic research results and assembled data, which indicate superiority of some biomarkers to creatinine, we are still awaiting clinical application. PMID:27212976

  8. MicroRNA signature of intestinal acute cellular rejection in formalin-fixed paraffin-embedded mucosal biopsies.

    PubMed

    Asaoka, T; Sotolongo, B; Island, E R; Tryphonopoulos, P; Selvaggi, G; Moon, J; Tekin, A; Amador, A; Levi, D M; Garcia, J; Smith, L; Nishida, S; Weppler, D; Tzakis, A G; Ruiz, P

    2012-02-01

    Despite continuous improvement of immunosuppression, small bowel transplantation (SBT) is plagued by a high incidence of acute cellular rejection (ACR) that is frequently intractable. Therefore, there is a need to uncover novel insights that will lead to strategies to achieve better control of ACR. We hypothesized that particular miRNAs provide critical regulation of the intragraft immune response. The aim of our study was to identify miRNAs involved in intestinal ACR. We examined 26 small intestinal mucosal biopsies (AR/NR group; 15/11) obtained from recipients after SBT or multivisceral transplantation. We investigated the expression of 384 mature human miRNAs and 280 mRNAs associated with immune, inflammation and apoptosis processes. We identified differentially expressed 28 miRNAs and 58 mRNAs that characterized intestinal ACR. We found a strong positive correlation between the intragraft expression levels of three miRNAs (miR-142-3p, miR-886-3p and miR-132) and 17 mRNAs including CTLA4 and GZMB. We visualized these miRNAs within cells expressing CD3 and CD14 proteins in explanted intestinal allografts with severe ACR. Our data suggested that miRNAs have a critical role in the activation of infiltrating cells during intestinal ACR. These differences in miRNA expression patterns can be used to identify novel biomarkers and therapeutic targets for immunosuppressive agents. PMID:22026534

  9. Prediction of Renal Allograft Acute Rejection Using a Novel Non-Invasive Model Based on Acoustic Radiation Force Impulse.

    PubMed

    Yang, Cheng; Jin, Yunjie; Wu, Shengdi; Li, Long; Hu, Mushuang; Xu, Ming; Rong, Ruiming; Zhu, Tongyu; He, Wanyuan

    2016-09-01

    Point shear wave elastography based on acoustic radiation force impulse is a novel technology used to quantify tissue stiffness by measuring shear wave speed. A total of 115 kidney transplantation recipients were consecutively enrolled in this prospective study. The patients were subdivided into two groups using 1 mo post-transplantation as the cutoff time for determining the development of acute rejection (AR). Shear wave speed was significantly higher in the AR group than in the non-AR group. We created a model called SEV, comprising shear wave speed, estimated glomerular filtration rate and kidney volume change, that could successfully discriminate patients with or without AR. The area under the receiver operating characteristic curve of SEV was 0.89, which was higher than values for other variables; it was even better in patients within 1 mo post-transplantation (0.954), but was lower than the estimated glomerular filtration rate in patients after 1 mo post-transplantation. Therefore, the SEV model may predict AR after renal transplantation with a high degree of accuracy, and it may be more useful in the early post-operative stage after renal transplantation. PMID:27267289

  10. Modulation of lymphocyte subpopulations by extracorporeal photopheresis in patients with acute graft-versus-host disease or graft rejection.

    PubMed

    Lorenz, Katrin; Rommel, Katharina; Mani, Jiju; Jin, Nan; Hilgendorf, Inken; Ho, Anthony D; Freund, Mathias; Schmitt, Michael; Schmitt, Anita

    2015-03-01

    Extracorporeal photopheresis (ECP) constitutes a promising treatment for patients with steroid-refractory acute graft-versus-host disease (aGvHD) after allogeneic stem cell transplantation and for patients with graft rejection after solid organ transplantation (SOT). There is an increasing body of evidence that modulation of lymphocyte subsets might play a crucial role in the mechanism of action in ECP. We therefore analyzed immunological effects concomitantly with clinical findings in patients under ECP therapy using multicolor flow cytometry. In a patient with steroid-refractory aGvHD and a patient with progressive bronchiolitis obliterans syndrome (BOS) after double-lung transplantation, clinical responses to ECP therapy were paralleled by an increase of CD4 + CD25hiFoxP3 + regulatory T cells and a decrease of T(EMRA) (CD3 + CD8+ CD45RA+ CD62L+ effector memory T) cells as well as of natural killer (NK)T cells. In summary, immunomonitoring of T cell subsets can elucidate the mechanism of action in ECP. PMID:24913503

  11. Low incidence of acute rejection in hepatitis B virus positive liver transplant recipients and the impact of hepatitis B immunoglobulin.

    PubMed

    Veerappan, Annapoorani; VanWagner, Lisa B; Mathew, James M; Huang, Xuemei; Miller, Joshua; Lapin, Brittany; Levitsky, Josh

    2016-04-01

    Historically, hepatitis B virus (HBV) liver transplantation (LT) recipients have less acute cellular rejection (ACR) than those without HBV. We questioned whether this has persisted in an era of decreased Hepatitis B immunoglobulin use (HBIG) given its in vitro immunoregulatory effects. We compared the incidence, risk factors and outcomes of ACR among 40,593 primary LT recipients with HBV, hepatitis C, steatohepatitis, and immune liver disease (OPTN 2000-2011). We also assessed the in vitro effect of HBIG on alloimmune lymphoproliferation and regulatory T cell generation using mixed lymphocyte reactions. In multivariate analysis, HBV status remained a strong independent predictor of freedom from ACR (OR 0.58, 95% CI: 1.5-2.1). Patient (67.7% vs 72.3%) and graft (60.8% vs 69.1%) survival were significantly lower in patients with ACR versus no ACR for all causes except HBV. HBIG use had no statistical association with ACR. In vitro, HBIG at concentrations equivalent to clinical dosing did not inhibit lymphoproliferation or promote regulatory T cell development. In summary, the incidence and impact of ACR is lower now for HBV LT and does not appear to be secondary to HBIG by our in vitro and in vivo analyses. Rather, it may be due to the innate immunosuppressive properties of chronic HBV infection. PMID:26924082

  12. Impact of ABO Incompatibility on the Development of Acute Antibody-Mediated Rejection in Kidney Transplant Recipients Presensitized to HLA

    PubMed Central

    Chung, Byung Ha; Joo, Yu Young; Lee, Jaesin; Kim, Hyung Duk; Kim, Ji-Il; Moon, In Sung; Choi, Bum Soon; Oh, Eun-Jee; Park, Cheol Whee; Kim, Yong-Soo; Yang, Chul Woo

    2015-01-01

    Whether the coexistence of anti-A/B antibody and donor specific anti-HLA antibody (HLA-DSA) has a synergistic impact on the development of acute antibody-mediated rejection (AAMR) in kidney transplant recipients (KTRs) is unclear. This study includes 92 KTRs who received a kidney from an ABO-incompatible (ABOi) donor or were presensitized to donor HLA (HLAs) and 292 controls (CONT). HLAs was defined as a crossmatch positivity or the presence of HLA-DSA. We compared the incidence of AAMR among ABOi (n = 58), ABOi+HLAs (n = 12), HLAs (n = 22), and CONT (n = 292) groups and evaluated the risk factors and antibody type (anti-A/B vs. HLA-DSA) responsible for AAMR. AAMR developed less frequently in ABOi and CONT than in the ABOi+HLAs or HLAs (P < 0.05 for all); however, there was no difference between the ABOi+HLAs and HLAs groups. AAMR developed more frequently with strong HLA-DSA at baseline; however, high baseline anti-A/B titer did not affect AAMR development. Strong baseline HLA-DSA was an independent predictor for AAMR, however the baseline anti-A/B titer was not. All four AAMR episodes in ABOi+HLAs were positive to HLA-DSA but not to anti-A/B. In conclusion, ABO incompatibility does not increase the risk for AAMR in HLAs KTRs. PMID:25897756

  13. Update on management of cardiac arrhythmias in acute coronary syndromes.

    PubMed

    Willich, T; Goette, A

    2015-04-01

    This review summarizes different types of arrhythmias in patients with acute coronary syndromes and provides an overview of the available therapeutic options for acute care and management of critical arrhythmias. The different therapeutic options are depending on the origin and type of arrhythmia. The main common dominant mechanisms are intramural re-entry in ischemia and triggered activity in reperfusion. The different forms of arrhythmia were explained in detail. Atrial arrhythmias are mainly atrial fibrillation; other forms are rare and usually self-limited. As therapeutic options antiarrhythmic drug therapy with beta-blockers or amiodarone and direct current cardioversion are suitable. Ventricular arrhythmias can be divided in premature ventricular complexes, accelerated idioventricular rhythm, non-sustained ventricular tachycardia, sustained ventricular tachycardia (VT), ventricular fibrillation (VF) and electrical storm. As therapeutic options antiarrhythmic drug therapy, implantable cardioverter defibrillator therapy (ICD), radiofrequency catheter ablation (RFA) and stellate ganglion blockade are available. The treatment with antiarrhythmic drug is rather cautious recommended, with the exception of beta-blockers. An additional drug therapy with ranolazine may be considered. The advantage of ICD therapy for long-term primary or secondary prophylactic therapy has been well documented. ICD therapy is associated with significant reduction in mortality compared with antiarrhythmic drug therapy (mainly amiodarone), with the exception of beta-blockers. RFA and stellate ganglion blockade are rather intended as therapeutically options for incessant VT/VF or electrical storm. PMID:25612305

  14. Acute kidney injury after using contrast during cardiac catheterization in children with heart disease.

    PubMed

    Hwang, Young Ju; Hyun, Myung Chul; Choi, Bong Seok; Chun, So Young; Cho, Min Hyun

    2014-08-01

    Acute kidney injury (AKI) is closely associated with the mortality of hospitalized patients and long-term development of chronic kidney disease, especially in children. The purpose of our study was to assess the evidence of contrast-induced AKI after cardiac catheterization in children with heart disease and evaluate the clinical usefulness of candidate biomarkers in AKI. A total of 26 children undergoing cardiac catheterization due to various heart diseases were selected and urine and blood samples were taken at 0 hr, 6 hr, 24 hr, and 48 hr after cardiac catheterization. Until 48 hr after cardiac catheterization, there was no significant increase in serum creatinine level in all patients. Unlike urine kidney injury molecule-1, IL-18 and neutrophil gelatinase-associated lipocalin, urine liver-type fatty acid-binding protein (L-FABP) level showed biphasic pattern and the significant difference in the levels of urine L-FABP between 24 and 48 hr. We suggest that urine L-FABP can be one of the useful biomarkers to detect subclinical AKI developed by the contrast before cardiac surgery. PMID:25120320

  15. [Acute mediastinitis except in a context of cardiac surgery].

    PubMed

    Doddoli, C; Trousse, D; Avaro, J-P; Djourno, X-B; Giudicelli, R; Fuentes, P; Thomas, P

    2010-02-01

    Acute mediastinitis is a life-threatening complication (20 to 40 % of mortality) secondary to oropharyngeal abscesses, neck infections or oesophageal leak spreading into the mediastium. Early diagnosis and optimal therapeutic approach are crucial for patient survival. CT scanning of the cervical and thoracic area is a useful tool for diagnosis and follow-up. Treatment is based on broad-spectrum antibiotherapy, adequate surgery, mediastinal drainage, and treatment of possible organ failure. There is no surgical standardized attitude. Mini-invasive approach could be satisfactory when prompt diagnosis is established and the thoracic drainage is effective. Repeated postoperative CT scanning and close clinical and laboratory monitoring could make an additional thoracotomy a second-line procedure. PMID:20207299

  16. Elevated urinary sVCAM-1, IL6, sIL6R and TNFR1 concentrations indicate acute kidney transplant rejection in the first 2 weeks after transplantation.

    PubMed

    Reinhold, Stephan W; Straub, Rainer H; Krüger, Bernd; Kaess, Bernhard; Bergler, Tobias; Weingart, Christian; Banas, Miriam C; Krämer, Bernhard K; Banas, Bernhard

    2012-03-01

    We tested the hypothesis that increased urinary cytokine concentrations may indicate an acute kidney transplant rejection. Eight patients with an early rejection in their protocol biopsy about 14days after transplantation (group A), 9 patients with a biopsy proven rejection 2-3months after transplantation (group B) and 18 patients without acute rejection in their protocol biopsies both at 14days and 3months (group C, represents the control group) were chosen for this study. At the time of biopsy, the mean urinary concentration of interleukin 6 (IL6), soluble IL6 receptor (sIL6R), tumor necrosis factor receptor 1 (TNFR1), and soluble vascular cell adhesion molecule -1 (sVCAM-1) were significantly higher in patients with an early acute transplant rejection, i.e. in group A compared to patients in the control group (p<0.01). Additionally we found already 14days after transplantation significantly higher concentrations of urinary sIL6R and sVCAM-1 in group B patients who suffered of late acute rejection compared to patients with no acute rejection (group C, p<0.05). No significant correlation could be shown for interleukin 1 receptor antagonist (IL1ra), TNF, and TNFR2. In conclusion, elevated urinary concentrations of IL6, sIL6R, TNFR1 and sVCAM-1 clearly indicate an early acute transplant rejection. Especially sVCAM-1 may also serve as an early marker of an upcoming late rejection. However, further studies are warranted to verify the value of individual cytokine profiles to predict acute rejection episodes. PMID:22209080

  17. Cardiac function in an endothermic fish: cellular mechanisms for overcoming acute thermal challenges during diving.

    PubMed

    Shiels, H A; Galli, G L J; Block, B A

    2015-02-01

    Understanding the physiology of vertebrate thermal tolerance is critical for predicting how animals respond to climate change. Pacific bluefin tuna experience a wide range of ambient sea temperatures and occupy the largest geographical niche of all tunas. Their capacity to endure thermal challenge is due in part to enhanced expression and activity of key proteins involved in cardiac excitation-contraction coupling, which improve cardiomyocyte function and whole animal performance during temperature change. To define the cellular mechanisms that enable bluefin tuna hearts to function during acute temperature change, we investigated the performance of freshly isolated ventricular myocytes using confocal microscopy and electrophysiology. We demonstrate that acute cooling and warming (between 8 and 28°C) modulates the excitability of the cardiomyocyte by altering the action potential (AP) duration and the amplitude and kinetics of the cellular Ca(2+) transient. We then explored the interactions between temperature, adrenergic stimulation and contraction frequency, and show that when these stressors are combined in a physiologically relevant way, they alter AP characteristics to stabilize excitation-contraction coupling across an acute 20°C temperature range. This allows the tuna heart to maintain consistent contraction and relaxation cycles during acute thermal challenges. We hypothesize that this cardiac capacity plays a key role in the bluefin tunas' niche expansion across a broad thermal and geographical range. PMID:25540278

  18. Cardiac function in an endothermic fish: cellular mechanisms for overcoming acute thermal challenges during diving

    PubMed Central

    Shiels, H. A.; Galli, G. L. J.; Block, B. A.

    2015-01-01

    Understanding the physiology of vertebrate thermal tolerance is critical for predicting how animals respond to climate change. Pacific bluefin tuna experience a wide range of ambient sea temperatures and occupy the largest geographical niche of all tunas. Their capacity to endure thermal challenge is due in part to enhanced expression and activity of key proteins involved in cardiac excitation–contraction coupling, which improve cardiomyocyte function and whole animal performance during temperature change. To define the cellular mechanisms that enable bluefin tuna hearts to function during acute temperature change, we investigated the performance of freshly isolated ventricular myocytes using confocal microscopy and electrophysiology. We demonstrate that acute cooling and warming (between 8 and 28°C) modulates the excitability of the cardiomyocyte by altering the action potential (AP) duration and the amplitude and kinetics of the cellular Ca2+ transient. We then explored the interactions between temperature, adrenergic stimulation and contraction frequency, and show that when these stressors are combined in a physiologically relevant way, they alter AP characteristics to stabilize excitation–contraction coupling across an acute 20°C temperature range. This allows the tuna heart to maintain consistent contraction and relaxation cycles during acute thermal challenges. We hypothesize that this cardiac capacity plays a key role in the bluefin tunas' niche expansion across a broad thermal and geographical range. PMID:25540278

  19. Preoperative Low Serum Bicarbonate Levels Predict Acute Kidney Injury After Cardiac Surgery.

    PubMed

    Jung, Su-Young; Park, Jung Tak; Kwon, Young Eun; Kim, Hyung Woo; Ryu, Geun Woo; Lee, Sul A; Park, Seohyun; Jhee, Jong Hyun; Oh, Hyung Jung; Han, Seung Hyeok; Yoo, Tae-Hyun; Kang, Shin-Wook

    2016-03-01

    Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Although lower than normal serum bicarbonate levels are known to be associated with consecutive renal function deterioration in patients with chronic kidney injury, it is not well-known whether preoperative low serum bicarbonate levels are associated with the development of AKI in patients who undergo cardiac surgery. Therefore, the clinical implication of preoperative serum bicarbonate levels on AKI occurrence after cardiac surgery was investigated. Patients who underwent coronary artery bypass or valve surgery at Yonsei University Health System from January 2013 to December 2014 were enrolled. The patients were divided into 3 groups based on preoperative serum bicarbonate levels, which represented group 1 (below normal levels) <23 mEq/L; group 2 (normal levels) 23 to 24 mEq/L; and group 3 (elevated levels) >24 mEq/L. The primary outcome was the predicated incidence of AKI 48 hours after cardiac surgery. AKI was defined according to Acute Kidney Injury Network criteria. Among 875 patients, 228 (26.1%) developed AKI within 48 hours after cardiac surgery. The incidence of AKI was higher in group 1 (40.9%) than in group 2 (26.5%) and group 3 (19.5%) (P < 0.001). In addition, the duration of postoperative stay in a hospital intensive care unit (ICU) was longer for AKI patients and for those in the low-preoperative-serum-bicarbonate-level groups. A multivariate logistic regression analysis showed that low preoperative serum bicarbonate levels were significantly associated with AKI even after adjustment for age, sex, hypertension, diabetes mellitus, operation type, preoperative hemoglobin, and estimated glomerular filtration rate. In conclusion, low serum bicarbonate levels were associated with higher incidence of AKI and prolonged ICU stay. Further studies are needed to clarify whether strict correction of bicarbonate levels close to normal limits may have a protective

  20. [Time costs cardiac muscle tissue--prehospital therapy of acute myocardial infarct--a case report].

    PubMed

    Eschenburg, G; Pappert, D; Ohlmeier, H

    2003-01-01

    Symptoms of an acute myocardial infarction are a common reason for calling the emergency physician. Pre-hospital mortality caused by cardiac infarction is constantly high. The main potential for decreasing infarction mortality lies in the pre-hospital period. The problems and prospects of treatment in the early period are described in the case of a 73-year-old patient with an acute anterior infarction. The diagnostic and therapeutic approach is shown and discussed in this concrete case, taking into consideration the guidelines for diagnostics and therapy of acute myocardial infarction in the pre-hospital period of the German Society for Cardiology. A particular focus is the management of pre-hospital thrombolysis, the preconditions, realization and risks of which are described. In this context, the experience and competence of the emergency physician is prerequisite for the exact diagnosis and therapy. Furthermore, the importance of a smooth transition from pre-hospital therapy to intensive care is emphasized. PMID:12666508

  1. Non-invasive Diagnosis of Acute Cellular Rejection in Liver Transplant Recipients: A Proteomic Signature Validated by ELISA

    PubMed Central

    Massoud, Omar; Heimbach, Julie; Viker, Kimberly; Krishnan, Anuradha; Poterucha, John; Sanchez, William; Watt, Kymberly; Wiesner, Russell; Charlton, Michael

    2011-01-01

    Diagnosis of acute cellular rejection (ACR) requires a liver biopsy with attendant expense, and risk. The first aim was to prospectively determine, in an exploratory analysis, whether there is a serum proteome signature associated with histologically confirmed ACR. The second aim was to use simpler and faster ELISA-based assays for proteins identified as differentially abundant in the proteomic analysis to identify patients with ACR in a separate validation cohort. We used sequential high abundance protein depletion and iTRAQ LC/MS/MS mass spectrometry to characterize the serum proteome in serum samples of patients with ACR and without ACR. Of the 41 proteins identified as differentially abundant, 7 (serum amyloid A (SAA), complement 4 (C4), fibrinogen, complement 1q (C1q), complement 3 (C3), Heat Shock Protein 60 (HSP60), and Heat Shock Protein 70 (HSP70)) could be measured using ELISA-based assays in a validation cohort of patients with ACR (n=25) and without ACR (n=21). Mean ALT levels in patients with and without ACR were (mean +/− SD) 198+/−27 and 153+/−34 U/L respectively. Among the seven proteins for which ELISA assays were available, C4 and C1q were both independent predictors for ACR. C4 had the greatest predictivity in differentiating patients with/without ACR. C4 of ≤0.31gm/L had a 97% sensitivity, 62% specificity, 74% positive predictive value and 94% negative predictive value. The combination C4 ≤0.31 gm/L and ALT ≥70 IU/ml had 96% sensitivity, 81% specificity, 86% positive predictive value and 94% negative predictive value. In summary, in this exploratory analysis, serum complement C4 and ALT levels are highly predictive of ACR in liver transplant recipients. Confirmation in a prospective, larger, diverse population is needed. PMID:21618694

  2. Bone marrow transplantation modulates tissue macrophage phenotype and enhances cardiac recovery after subsequent acute myocardial infarction

    PubMed Central

    Protti, Andrea; Mongue-Din, Heloise; Mylonas, Katie J.; Sirker, Alexander; Sag, Can Martin; Swim, Megan M.; Maier, Lars; Sawyer, Greta; Dong, Xuebin; Botnar, Rene; Salisbury, Jon; Gray, Gillian A.; Shah, Ajay M.

    2016-01-01

    Background Bone marrow transplantation (BMT) is commonly used in experimental studies to investigate the contribution of BM-derived circulating cells to different disease processes. During studies investigating the cardiac response to acute myocardial infarction (MI) induced by permanent coronary ligation in mice that had previously undergone BMT, we found that BMT itself affects the remodelling response. Methods and results Compared to matched naive mice, animals that had previously undergone BMT developed significantly less post-MI adverse remodelling, infarct thinning and contractile dysfunction as assessed by serial magnetic resonance imaging. Cardiac rupture in male mice was prevented. Histological analysis showed that the infarcts of mice that had undergone BMT had a significantly higher number of inflammatory cells, surviving cardiomyocytes and neovessels than control mice, as well as evidence of significant haemosiderin deposition. Flow cytometric and histological analyses demonstrated a higher number of alternatively activated (M2) macrophages in myocardium of the BMT group compared to control animals even before MI, and this increased further in the infarcts of the BMT mice after MI. Conclusions The process of BMT itself substantially alters tissue macrophage phenotype and the subsequent response to acute MI. An increase in alternatively activated macrophages in this setting appears to enhance cardiac recovery after MI. PMID:26688473

  3. Evaluation of the acute cardiac and central nervous system effects of the fluorocarbon trifluoromethane in baboons

    SciTech Connect

    Branch, C.A.; Goldberg, D.A.; Ewing, J.R.; Butt, S.S.; Gayner, J.; Fagan, S.C.

    1994-12-31

    The gaseous fluorocarbon trifluoromethane has recently been investigated for its potential as an in vivo gaseous indicator for nuclear magnetic resonance studies of brain perfusion. Trifluoromethane may also have significant value as a replacement for chlorofluorocarbon fire retardants. Because of possible species-specific cardiotoxic and anesthetic properties, the toxicological evaluation of trifluoromethane in primates (Papio anubis) is necessary prior to its evaluation in humans. We report the acute cardiac and central nervous system effects of trifluoromethane in eight anesthetized baboons. A dose-response effect was established for respiratory rate, electroencephalogram, and cardiac sinus rate, which exhibited a stepwise decrease from 10% trifluoromethane. No spontaneous arrhythmias were noted, and arterial blood pressure remained unchanged at any inspired level. Intravenous epinephrine infusions (1 {mu}g/kg) induced transient cardiac arrhythmia in 1 animal only at 70% FC-23 (v/v) trifluoromethane. Trifluoromethane appears to induce mild dose-related physiological changes at inspired levels of 30% or more, indicative of an anesthetic effect. These data suggest that trifluoromethane may be safe to use in humans, without significant adverse acute effects, at an inspired level of 30%. 23 refs., 3 figs., 3 tabs.

  4. Upper gastrointestinal haemorrhage in the acute cardiac care setting: antiplatelets and endoscopy.

    PubMed

    Musa, S A; Brecker, S J; Rahman, T M; Kang, J Y

    2012-05-01

    Upper gastrointestinal haemorrhage (UGIH) in cardiac patients receiving antiplatelets presents a difficult management problem. The aim of this study was to describe a series of cardiac inpatients receiving antiplatelets who underwent endoscopy for an acute UGIH. Cardiac inpatients receiving antiplatelets and requiring endoscopy for UGIH over an 18-month period were followed up. Forty-one patients were studied. Most patients (25 [61%]) presented with melaena. Antiplatelets were withheld in 34 (83%) patients; predominantly in those with higher pre-endoscopy Rockall scores (median, 4; interquartile range [IQR], 3-5 versus median, 3; IQR, 2-4; P < 0.05). Positive findings were identified at endoscopy in 80%. Duodenal ulcers were the most common lesion and adrenaline the most common method of haemostasis. Median time to first endoscopy was 0 (IQR, 0-1) days. Seven (17%) patients re-bled, median Rockall score was six (IQR, 4-8). Three (7%) patients experienced procedural complications, two patients became hypoxic and one patient died. Following endoscopy, antiplatelets were restarted after a median of three (IQR, 3-5) days. On discharge, 27/28 (96%) patients continued with antiplatelet and proton-pump inhibitor therapy. Thirty-day inpatient mortality was 7% (3 patients). One patient re-bled within six months of discharge. Endoscopy helped assess the risk of re-bleeding and timing of antiplatelet re-introduction in cardiac inpatients experiencing UGIH. PMID:22555229

  5. Acute kidney injury following cardiac surgery: current understanding and future directions.

    PubMed

    O'Neal, Jason B; Shaw, Andrew D; Billings, Frederic T

    2016-01-01

    Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2-5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI. PMID:27373799

  6. Study of the association between the donors and recipients angiotensin-converting enzyme insertion/deletion gene polymorphism and the acute renal allograft rejection

    PubMed Central

    Azmandian, Jalal; Mohamadifar, Mohamadamir; Rahmanian-Koshkaki, Sara; Mehdipoor, Mohammad; Nematollahi, Mohamad-Hadi; Saburi, Amin; Mandegary, Ali

    2015-01-01

    Background: Angiotensin converting enzyme (ACE) is involved in various pathophysiological conditions including renal function. ACE levels are under genetic control. Objectives: This study was designed to investigate the association between the donors and recipients ACE-I/D gene polymorphism and risk of acute rejection outcome in renal allograft recipients. Patients and Methods: ACE-I/D polymorphism was determined in 200 donor-recipient pairs who had been referred to Afzalipour hospital in Kerman. ACE-I/D polymorphism was detected using polymerase chain reaction (PCR). Acute rejection (AR) during at least six months post-transplantation was defined as a 20% increase in creatinine level from the postoperative baseline in the absence of other causes of graft dysfunction which responded to antirejection therapy. Results: The observed allele frequencies were II 9.8%, ID 35.6% and DD 44.4% in donors and II 9.8%, ID 35.1% and DD 52.7% in recipients. There were no significant association between ACE genotypes and AR episodes (ORID=0.96 [0.18-5.00] and ORDD: 1.24 [0.25-6.07] for the donors) and (ORID: 0.29 [0.06-1.45] and ORDD: 0.75 [0.19-2.90] for the recipients). Conclusions: It seems that donor and recipient ACE-I/D genotype might not be a risk factor for acute renal allograft rejection. However, due to conflicting results from this and other studies, multicenter collaborative studies with more participants and concomitant evaluation of ACE polymorphism with other polymorphisms in renin–angiotensin system (RAS) are suggested to determine whether ACE genotypes are significant predictors of renal allograft rejection. PMID:26311652

  7. Cardiac Physiologic and Genetic Predictors of Hyperoxia-Induced Acute Lung Injury in Mice

    PubMed Central

    Cho, Hye-Youn; Miller-DeGraff, Laura; Walker, Christopher; Clark, James A.; Myers, Page H.; Rouse, D. Clay; Kleeberger, Steven R.

    2012-01-01

    Exposure of mice to hyperoxia produces pulmonary toxicity similar to acute lung injury/acute respiratory distress syndrome, but little is known about the interactions within the cardiopulmonary system. This study was designed to characterize the cardiopulmonary response to hyperoxia, and to identify candidate susceptibility genes in mice. Electrocardiogram and ventilatory data were recorded continuously from 4 inbred and 29 recombinant inbred strains during 96 hours of hyperoxia (100% oxygen). Genome-wide linkage analysis was performed in 27 recombinant inbred strains against response time indices (TIs) calculated from each cardiac phenotype. Reductions in minute ventilation, heart rate (HR), low-frequency (LF) HR variability (HRV), high-frequency HRV, and total power HRV were found in all mice during hyperoxia exposure, but the lag time before these changes began was strain dependent. Significant (chromosome 9) or suggestive (chromosomes 3 and 5) quantitative trait loci were identified for the HRTI and LFTI. Functional polymorphisms in several candidate susceptibility genes were identified within the quantitative trait loci and were associated with hyperoxia susceptibility. This is the first study to report highly significant interstrain variation in hyperoxia-induced changes in minute ventilation, HR, and HRV, and to identify polymorphisms in candidate susceptibility genes that associate with cardiac responses. Results indicate that changes in HR and LF HRV could be important predictors of subsequent adverse outcome during hyperoxia exposure, specifically the pathogenesis of acute lung injury. Understanding the genetic mechanisms of these responses may have significant diagnostic clinical value. PMID:22052878

  8. Risk scoring for prediction of acute cardiac complications from imbalanced clinical data.

    PubMed

    Liu, Nan; Koh, Zhi Xiong; Chua, Eric Chern-Pin; Tan, Licia Mei-Ling; Lin, Zhiping; Mirza, Bilal; Ong, Marcus Eng Hock

    2014-11-01

    Fast and accurate risk stratification is essential in the emergency department (ED) as it allows clinicians to identify chest pain patients who are at high risk of cardiac complications and require intensive monitoring and early intervention. In this paper, we present a novel intelligent scoring system using heart rate variability, 12-lead electrocardiogram (ECG), and vital signs where a hybrid sampling-based ensemble learning strategy is proposed to handle data imbalance. The experiments were conducted on a dataset consisting of 564 chest pain patients recruited at the ED of a tertiary hospital. The proposed ensemble-based scoring system was compared with established scoring methods such as the modified early warning score and the thrombolysis in myocardial infarction score, and showed its effectiveness in predicting acute cardiac complications within 72 h in terms of the receiver operation characteristic analysis. PMID:25375686

  9. Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction.

    PubMed

    Taniyama, Yoshiaki; Katsuragi, Naruto; Sanada, Fumihiro; Azuma, Junya; Iekushi, Kazuma; Koibuchi, Nobutaka; Okayama, Keita; Ikeda-Iwabu, Yuka; Muratsu, Jun; Otsu, Rei; Rakugi, Hiromi; Morishita, Ryuichi

    2016-02-01

    We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model. Administration of Pn neutralizing antibody resulted in a significant decrease in the infarcted and fibrotic areas of the myocardium, which prevented ventricular wall thinning and dilatation. The inhibition of fibrosis by Pn neutralizing antibody was associated with a significant decrease in gene expression of fibrotic markers, including collagen I, collagen III, and transforming growth factor-β1. Importantly, the number of α-smooth muscle actin-positive myofibroblasts was significantly reduced in the hearts of animals treated with Pn neutralizing antibody, whereas cardiomyocyte proliferation and angiogenesis were comparable in the IgG and neutralizing antibody groups. Moreover, the level of Pn-1 expression was significantly correlated with the severity of myocardial infarction. In addition, Pn-1, but not Pn-2 or Pn-4, inhibited fibroblast and myocyte attachment, which might account for the cell slippage observed during cardiac remodeling. Collectively, these results indicate that therapeutics that specifically inhibit Pn exon-17, via a neutralizing antibody or drug, without suppressing other periostin variants might offer a new class of medication for the treatment of acute myocardial infarction patients. PMID:26644236

  10. Approaches to Improving Cardiac Structure and Function During and After an Acute Myocardial Infarction: Acute and Chronic Phases.

    PubMed

    Kloner, Robert A; Dai, Wangde; Hale, Sharon L; Shi, Jianru

    2016-07-01

    While progress has been made in improving survival following myocardial infarction, this injury remains a major source of mortality and morbidity despite modern reperfusion therapy. While one approach has been to develop therapies to reduce lethal myocardial cell reperfusion injury, this concept has not translated to the clinics, and several recent negative clinical trials raise the question of whether reperfusion injury is important in humans undergoing reperfusion for acute ST segment elevation myocardial infarction. Therapy aimed at reducing myocardial cell death while the myocytes are still ischemic is more likely to further reduce myocardial infarct size. Developing new therapies to further reduce left ventricular remodeling after the acute event is another approach to preserving structure and function of the heart after infarction. Such therapy may include chronic administration of pharmacologic agents and/or therapies developed from the field of regenerative cardiology, including cellular or non-cellular materials such as extracellular matrix. The optimal therapy will be to administer agents that both reduce myocardial infarct size in the acute phase of infarction as well as reduce adverse left ventricular remodeling during the chronic or healing phase of myocardial infarction. Such a dual approach will help optimize the preservation of both cardiac structure and function. PMID:26612091

  11. Cardiac Failure 30 Years after Treatment Containing Anthracycline for Childhood Acute Lymphoblastic Leukemia

    PubMed Central

    Goldberg, John M.; Scully, Rebecca E.; Sallan, Stephen E.; Lipshultz, Steven E.

    2012-01-01

    In 1977, a 5-year-old girl diagnosed with acute lymphoblastic leukemia (ALL) was treated on DFCI Childhood ALL Protocol 77-01, receiving a cumulative doxorubicin dose of 465 mg/m2, cranial radiation, and other drugs. After being in continuous complete remission for 34 months, she developed heart failure (HF) and was treated with digoxin and furosemide. At 16, she was diagnosed and treated for dilated cardiomyopathy. Over the years she continued to have bouts of HF, which became less responsive to treatment. At 36, she received a heart transplant. Six months later, she stopped taking her medications and suffered a sudden cardiac death. PMID:22584777

  12. Serum and salivary cardiac analytes in acute myocardial infarction related to oral health status

    NASA Astrophysics Data System (ADS)

    Ebersole, Jeffrey L.; Kryscio, Richard J.; Campbell, Charles; Kinane, Denis F.; McDevitt, John T.; Christodoulides, Nicolaos; Floriano, Pierre N.; Miller, Craig S.

    2014-06-01

    With the advent of an increased emphasis on the potential to utilize biomarkers in saliva for systemic diseases, the issue of existing oral disease is an important consideration that could adversely affect the interpretation of diagnostic results obtained from saliva. We addressed the question does a patient's oral inflammation status confound biomarker levels used in diagnosis of acute myocardial infarction (AMI). The results demonstrated that multiple serum biomarkers and a few salivary biomarkers reflected the cardiac event. Importantly, oral health of the individual had minimal impact on the validity of the serum or salivary biomarker effectiveness.

  13. Predictors of Acute Renal Failure During Extracorporeal Membrane Oxygenation in Pediatric Patients After Cardiac Surgery.

    PubMed

    Lv, Lin; Long, Cun; Liu, Jinping; Hei, Feilong; Ji, Bingyang; Yu, Kun; Hu, Qiang; Hu, Jinxiao; Yuan, Yuan; Gao, Guodong

    2016-05-01

    Acute renal failure (ARF) is associated with increased mortality in pediatric extracorporeal membrane oxygenation (ECMO). The aim of this study was to identify predictors of ARF during ECMO in pediatric patients after cardiac surgery. A retrospective study analyzed 42 children (≤15 years) after cardiac surgery requiring venous-arterial ECMO between December 2008 and December 2014 at Fuwai Hospital. ARF was defined as ≥300% rise in serum creatinine (SCr) concentration from baseline or application of dialysis. Multivariate logistic regression was performed to identify the predictors of ARF during ECMO. A total of 42 children (age, interquartile range [IQR], 13.0 [7.2-29.8] months; weight, IQR, 8.5 [6.7-11.0] kg) after cardiac surgery requiring ECMO were included in this study. The total survival rate was 52.4%, and the incidence of ARF was 40.5%. As the result of univariate analysis, ECMO duration, cardiopulmonary resuscitation, maximum free hemoglobin (FHB) during ECMO, lactate level, and mean blood pressure before initiation of ECMO were entered in multiple logistic regression analysis. In multiple logistic regression analysis, FHB during ECMO (OR 1.136, 95% CI 1.023-1.261) and lactate level before initiation of ECMO (OR 1.602, 95% CI 1.025-2.502) were risk factors for ARF during ECMO after pediatric cardiac surgery. There was a linear correlation between maximum SCr and maximum FHB (Pearson's r = 0.535, P = 0.001). Maximum SCr during ECMO has also a linear correlation with lactate level before initiation of ECMO (Pearson's r = 0.342, P = 0.044). Increased FHB during ECMO and high lactate level before initiation of ECMO were risk factors for ARF during ECMO in pediatric patients after cardiac surgery. PMID:26636965

  14. Prognostic implications of cardiac scintigraphic parameters obtained in the early phase of acute myocardial infarction

    SciTech Connect

    Suzuki, A.; Matsushima, H.; Satoh, A.; Hayashi, H.; Sotobata, I.

    1988-06-01

    A cohort of 76 patients with acute myocardial infarction was studied with infarct-avid scan, radionuclide ventriculography, and thallium-201 myocardial perfusion scintigraphy. Infarct area, left ventricular ejection fraction, and defect score were calculated as radionuclide indices of the extent of myocardial infarction. The correlation was studied between these indices and cardiac events (death, congestive heart failure, postinfarction angina, and recurrence of myocardial infarction) in the first postinfarction year. High-risk patients (nonsurvivors and patients who developed heart failure) had a larger infarct area, a lower left ventricular ejection fraction, and a larger defect score than the others. Univariate linear discriminant analysis was done to determine the optimal threshold of these parameters for distinguishing high-risk patients from others. Radionuclide parameters obtained in the early phase of acute myocardial infarction were useful for detecting both patients with grave complications and those with poor late prognosis during a mean follow-up period of 2.6 years.

  15. [Cardiac Angiosarcoma with Acute Myocardial Infarction due to Tumor Embolism;Report of a Case].

    PubMed

    Date, Yusuke; Miyazu, Katsuyuki; Ikeda, Masahiro

    2016-09-01

    We report the case of a 28-year-old man with a rare angiosarcoma complicated by acute myocardial infarction secondary to tumor embolism. He was transported to our emergency unit because of sudden onset of chest pain. The echocardiography showed a 42×60 mm mass in the left ventricle, and the coronary angiography showed embolic occlusion of the proximal left anterior descending and circumflex arteries. Emergent surgical removal of the mass was attempted under cardiopulmonary bypass, concomitant with double coronary artery bypass grafting and mitral valve replacement with a mechanical prosthesis. However, complete tumor excision was impossible. The postoperative pathological examination revealed undifferentiated angiosarcoma. Twenty days after the operation, the patient suffered acute cerebral hemorrhage from a metastatic tumor in the brain. He died at 37 days after the initial cardiac surgery. PMID:27586319

  16. Impact of cardiac magnet resonance imaging on management of ventricular septal rupture after acute myocardial infarction

    PubMed Central

    Gassenmaier, Tobias; Gorski, Armin; Aleksic, Ivan; Deubner, Nikolas; Weidemann, Frank; Beer, Meinrad

    2013-01-01

    A 74-year-old man was admitted to the cardiac catheterization laboratory with acute myocardial infarction. After successful angioplasty and stent implantation into the right coronary artery, he developed cardiogenic shock the following day. Echocardiography showed ventricular septal rupture. Cardiac magnet resonance imaging (MRI) was performed on the critically ill patient and provided detailed information on size and localization of the ruptured septum by the use of fast MRI sequences. Moreover, the MRI revealed that the ventricular septal rupture was within the myocardial infarction area, which was substantially larger than the rupture. As the patient’s condition worsened, he was intubated and had intra-aortic balloon pump implanted, and extracorporeal membrane oxygenation was initiated. During the following days, the patient’s situation improved, and surgical correction of the ventricular septal defect could successfully be performed. To the best of our knowledge, this case report is the first description of postinfarction ventricular septal rupture by the use of cardiac MRI in an intensive care patient with cardiogenic shock and subsequent successful surgical repair. PMID:23710303

  17. Preoperative Low Serum Bicarbonate Levels Predict Acute Kidney Injury After Cardiac Surgery

    PubMed Central

    Jung, Su-Young; Park, Jung Tak; Kwon, Young Eun; Kim, Hyung Woo; Ryu, Geun Woo; Lee, Sul A.; Park, Seohyun; Jhee, Jong Hyun; Oh, Hyung Jung; Han, Seung Hyeok; Yoo, Tae-Hyun; Kang, Shin-Wook

    2016-01-01

    Abstract Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Although lower than normal serum bicarbonate levels are known to be associated with consecutive renal function deterioration in patients with chronic kidney injury, it is not well-known whether preoperative low serum bicarbonate levels are associated with the development of AKI in patients who undergo cardiac surgery. Therefore, the clinical implication of preoperative serum bicarbonate levels on AKI occurrence after cardiac surgery was investigated. Patients who underwent coronary artery bypass or valve surgery at Yonsei University Health System from January 2013 to December 2014 were enrolled. The patients were divided into 3 groups based on preoperative serum bicarbonate levels, which represented group 1 (below normal levels) <23 mEq/L; group 2 (normal levels) 23 to 24 mEq/L; and group 3 (elevated levels) >24 mEq/L. The primary outcome was the predicated incidence of AKI 48 hours after cardiac surgery. AKI was defined according to Acute Kidney Injury Network criteria. Among 875 patients, 228 (26.1%) developed AKI within 48 hours after cardiac surgery. The incidence of AKI was higher in group 1 (40.9%) than in group 2 (26.5%) and group 3 (19.5%) (P < 0.001). In addition, the duration of postoperative stay in a hospital intensive care unit (ICU) was longer for AKI patients and for those in the low-preoperative-serum-bicarbonate-level groups. A multivariate logistic regression analysis showed that low preoperative serum bicarbonate levels were significantly associated with AKI even after adjustment for age, sex, hypertension, diabetes mellitus, operation type, preoperative hemoglobin, and estimated glomerular filtration rate. In conclusion, low serum bicarbonate levels were associated with higher incidence of AKI and prolonged ICU stay. Further studies are needed to clarify whether strict correction of bicarbonate levels close to normal limits may have a

  18. Cardiac Autonomic Effects of Acute Exposures to Airborne Particulates in Men and Women

    NASA Technical Reports Server (NTRS)

    Howarth, M. S.; Schlegel, T. T.; Knapp, C. F.; Patwardhan, A. R.; Jenkins, R. A.; Ilgner, R. H.; Evans, J. M.

    2007-01-01

    The aim of this research was to investigate cardiac autonomic changes associated with acute exposures to airborne particulates. Methods: High fidelity 12-lead ECG (CardioSoft, Houston, TX) was acquired from 19 (10 male / 9 female) non-smoking volunteers (age 33.6 +/- 6.6 yrs) during 10 minutes pre-exposure, exposure and post-exposure to environmental tobacco smoke (ETS), cooking oil fumes, wood smoke and sham (water vapor). To control exposure levels, noise, subject activity, and temperature, all studies were conducted inside an environmental chamber. Results: The short-term fractal scaling exponent (Alpha-1) and the ratio of low frequency to high frequency Heart Rate Variability (HRV) powers (LF/HF, a purported sympathetic index) were both higher in males (p<0.017 and p<0.05, respectively) whereas approximate entropy (ApEn) and HF/(LF+HF) (a purported parasympathetic index) were both lower in males (p<0.036, and p<0.044, respectively). Compared to pre-exposure (p<0.0002) and sham exposure (p<0.047), male heart rates were elevated during early ETS post-exposure. Our data suggest that, in addition to tonic HRV gender differences, cardiac responses to some acute airborne particulates are gender related.

  19. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury

    SciTech Connect

    Chen, Lijuan; Wang, Yingjie; Pan, Yaohua; Zhang, Lan; Shen, Chengxing; Qin, Gangjian; Ashraf, Muhammad; Weintraub, Neal; Ma, Genshan; Tang, Yaoliang

    2013-02-15

    Highlights: ► Cardiac progenitor-derived (CPC) Exosomes protect H9C2 from apoptosis in vitro. ► CPC-exosomes protect cardiomyoyctes from MI/R induced apoptosis in vivo. ► CPC-exosomes were taken up by H9C2 with high efficiency using PKH26 labeling. ► miR-451, one of GATA4-responsive miRNA cluster, is enriched in CPC-exosomes. -- Abstract: Background: Cardiac progenitors (CPC) mediate cardioprotection via paracrine effects. To date, most of studies focused on secreted paracrine proteins. Here we investigated the CPC-derived-exosomes on protecting myocardium from acute ischemia/reperfusion (MI/R) injury. Methods and results: CPC were isolated from mouse heart using two-step protocol. Exosomes were purified from conditional medium, and confirmed by electron micrograph and Western blot using CD63 as a marker. qRT-PCR shows that CPC-exosomes have high level expression of GATA4-responsive-miR-451. Exosomes were ex vivo labeled with PKH26, We observed exosomes can be uptaken by H9C2 cardiomyoblasts with high efficiency after 12 h incubation. CPC-exosomes protect H9C2 from oxidative stress by inhibiting caspase 3/7 activation invitro. In vivo delivery of CPC-exosomes in an acute mouse myocardial ischemia/reperfusion model inhibited cardiomyocyte apoptosis by about 53% in comparison with PBS control (p < 0.05). Conclusion: Our results suggest, for the first time, the CPC-exosomes can be used as a therapeutic vehicle for cardioprotection, and highlights a new perspective for using non-cell exosomes for cardiac disease.

  20. Acute effects of intravenous dronedarone on electrocardiograms, hemodynamics and cardiac functions in anesthetized dogs

    PubMed Central

    SAENGKLUB, Nakkawee; LIMPRASUTR, Vudhiporn; SAWANGKOON, Suwanakiet; BURANAKARL, Chollada; HAMLIN, Robert L.; KIJTAWORNRAT, Anusak

    2015-01-01

    Dronedarone is a class III antiarrhythmic that has been used for management of atrial fibrillation in humans, but limited information was found in dogs. The objective of this study was to determine the acute effects of escalating concentrations of dronedarone on electrocardiograms (ECG), hemodynamics and cardiac mechanics in healthy dogs. A total of 7 beagle dogs were anesthetized with isoflurane and instrumented to obtain lead II ECG, pressures at ascending aorta, right atrium, pulmonary artery and left ventricle, and left ventricular pressure-volume relationship. Five dogs were given vehicle and followed by escalating doses of dronedarone (0.5, 1.0 and 2.5 mg/kg, 15 min for each dose), and two dogs were used as a vehicle-treated control. All parameters were measured at 15 min after the end of each dose. The results showed that all parameters in vehicle-treated dogs were unaltered. Dronedarone at 2.5 mg/kg significantly lengthened PQ interval (P<0.01), reduced cardiac output (P<0.01) and increased systemic vascular resistance (P<0.01). Dronedarone produced negative inotropy assessed by significantly lowered end-systolic pressure-volume relationship, preload recruitable stroke work, contractility index and dP/dtmax. It also impaired diastolic function by significantly increased end-diastolic pressure-volume relationship, tau and dP/dtmin. These results suggested that acute effects of dronedarone produced negative dromotropy, inotropy and lusitropy in anesthetized dogs. Care should be taken when given dronedarone to dogs, especially when the patients have impaired cardiac function. PMID:26346474

  1. Acute effects of intravenous dronedarone on electrocardiograms, hemodynamics and cardiac functions in anesthetized dogs.

    PubMed

    Saengklub, Nakkawee; Limprasutr, Vudhiporn; Sawangkoon, Suwanakiet; Buranakarl, Chollada; Hamlin, Robert L; Kijtawornrat, Anusak

    2016-03-01

    Dronedarone is a class III antiarrhythmic that has been used for management of atrial fibrillation in humans, but limited information was found in dogs. The objective of this study was to determine the acute effects of escalating concentrations of dronedarone on electrocardiograms (ECG), hemodynamics and cardiac mechanics in healthy dogs. A total of 7 beagle dogs were anesthetized with isoflurane and instrumented to obtain lead II ECG, pressures at ascending aorta, right atrium, pulmonary artery and left ventricle, and left ventricular pressure-volume relationship. Five dogs were given vehicle and followed by escalating doses of dronedarone (0.5, 1.0 and 2.5 mg/kg, 15 min for each dose), and two dogs were used as a vehicle-treated control. All parameters were measured at 15 min after the end of each dose. The results showed that all parameters in vehicle-treated dogs were unaltered. Dronedarone at 2.5 mg/kg significantly lengthened PQ interval (P<0.01), reduced cardiac output (P<0.01) and increased systemic vascular resistance (P<0.01). Dronedarone produced negative inotropy assessed by significantly lowered end-systolic pressure-volume relationship, preload recruitable stroke work, contractility index and dP/dtmax. It also impaired diastolic function by significantly increased end-diastolic pressure-volume relationship, tau and dP/dtmin. These results suggested that acute effects of dronedarone produced negative dromotropy, inotropy and lusitropy in anesthetized dogs. Care should be taken when given dronedarone to dogs, especially when the patients have impaired cardiac function. PMID:26346474

  2. Vasopressin, renin, and cortisol responses to hemorrhage during acute blockade of cardiac nerves in conscious dogs

    NASA Technical Reports Server (NTRS)

    O'Donnell, C. P.; Keil, L. C.; Thrasher, T. N.

    1993-01-01

    The effect of acute cardiac nerve blockade (CNB) on the increases in plasma renin activity (PRA), arginine vasopressin (AVP), and cortisol in response to a 30 ml/kg hemorrhage was determined in conscious dogs (n = 9). Procaine was infused into the pericardial space to produce acute reversible CNB, or saline was infused in the control hemorrhage. Blood was removed from the inferior vena cava at a rate of 1 ml.kg-1.min-1. In the control hemorrhage, plasma AVP increased from 1.8 +/- 0.3 to 219 +/- 66 pg/ml, PRA increased from 0.63 +/- 0.20 to 3.08 +/- 0.91 ng angiotensin I (ANG I).ml-1.3 h-1, and cortisol increased from 1.4 +/- 0.2 to 4.0 +/- 0.7 micrograms/dl. When the hemorrhage was repeated during acute CNB, plasma AVP increased from 2.8 +/- 1.6 to 185 +/- 59 pg/ml, PRA increased from 0.44 +/- 0.14 to 2.24 +/- 0.27 ng ANG I.ml-1.3 h-1, and cortisol increased from 1.9 +/- 0.3 to 5.4 +/- 0.6 micrograms/dl, and none of the increases differed significantly from the responses during the control hemorrhage. Left atrial pressure fell significantly after removal of 6 ml/kg of blood, but mean arterial pressure was maintained at control levels until blood loss reached 20 ml/kg during pericardial infusion of either saline or procaine. The declines in MAP at the 30 ml/kg level of hemorrhage in both treatments were similar. These results demonstrate that acutely blocking input from cardiac receptors does not reduce the increases in plasma AVP, cortisol, and PRA in response to a 30 ml/kg hemorrhage. The results of this study do not support the hypothesis that input from cardiac receptors is required for a normal AVP response to hemorrhage and suggest that other receptors, presumably arterial baroreceptors, can stimulate AVP and cortisol secretion in the absence of signals from the heart.

  3. Greater Volume of Acute Normovolemic Hemodilution May Aid in Reducing Blood Transfusions After Cardiac Surgery

    PubMed Central

    Goldberg, Joshua; Paugh, Paugh; Dickinson, Timothy A.; Fuller, John; Paone, Gaetano; Theurer, Patty F.; Shann, Kenneth G.; Sundt, Thoralf M.; Prager, Richard L.; Likosky, Donald S.

    2016-01-01

    Background Perioperative red blood cell transfusions (RBC) are associated with increased morbidity and mortality after cardiac surgery. Acute normovolemic hemodilution (ANH) is recommended to reduce perioperative transfusions; however, supporting data are limited and conflicting. We describe the relationship between ANH and RBC transfusions after cardiac surgery using a multi-center registry. Methods We analyzed 13,534 patients undergoing cardiac surgery between 2010 and 2014 at any of the 26 hospitals participating in a prospective cardiovascular perfusion database. The volume of ANH (no ANH, <400mL, 400–799mL, ≥800mL) was recorded and linked to each center’s surgical data. We report adjusted relative risks reflecting the association between the use and amount of ANH and the risk of perioperative RBC transfusion. Results were adjusted for preoperative risk factors, procedure, BSA, preoperative HCT, and center. Results ANH was used in 17% of the patients. ANH was associated with a reduction in RBC transfusions (RRadj 0.74, p <0.001). Patients having ≥800mL of ANH had the most profound reduction in RBC transfusions (RRadj 0.57, p<0.001). Platelet and plasma transfusions were also significantly lower with ANH. The ANH population had superior postoperative morbidity and mortality compared to the no ANH population. Conclusions There is a significant association between ANH and reduced perioperative RBC transfusion in cardiac surgery. Transfusion reduction is most profound with larger volumes of ANH. Our findings suggest the volume of ANH, rather than just its use, may be an important feature of a center’s blood conservation strategy. PMID:26206721

  4. Normalizing Rejection.

    PubMed

    Conn, Vicki S; Zerwic, Julie; Jefferson, Urmeka; Anderson, Cindy M; Killion, Cheryl M; Smith, Carol E; Cohen, Marlene Z; Fahrenwald, Nancy L; Herrick, Linda; Topp, Robert; Benefield, Lazelle E; Loya, Julio

    2016-02-01

    Getting turned down for grant funding or having a manuscript rejected is an uncomfortable but not unusual occurrence during the course of a nurse researcher's professional life. Rejection can evoke an emotional response akin to the grieving process that can slow or even undermine productivity. Only by "normalizing" rejection, that is, by accepting it as an integral part of the scientific process, can researchers more quickly overcome negative emotions and instead use rejection to refine and advance their scientific programs. This article provides practical advice for coming to emotional terms with rejection and delineates methods for working constructively to address reviewer comments. PMID:26041785

  5. Monitoring Pharmacologically Induced Immunosuppression by Immune Repertoire Sequencing to Detect Acute Allograft Rejection in Heart Transplant Patients: A Proof-of-Concept Diagnostic Accuracy Study

    PubMed Central

    Valantine, Hannah A.; Penland, Lolita; Luikart, Helen; Strehl, Calvin; Cohen, Garrett; Khush, Kiran K.; Quake, Stephen R.

    2015-01-01

    Background It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation. Methods and Findings In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without). We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient’s net state of immunosuppression (correlation with tacrolimus level, r = −0.867, 95% CI −0.968 to −0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9%) and a specificity of 82.0% (95% CI 72.1% to 89.1%) (cell-free donor-derived DNA as noninvasive gold standard). To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several

  6. Cardiac MR enables diagnosis in 90% of patients with acute chest pain, elevated biomarkers and unobstructed coronary arteries

    PubMed Central

    Emrich, K; Abegunewardene, N; Oberholzer, K; Dueber, C; Muenzel, T; Kreitner, K-F

    2015-01-01

    Objective: To assess the diagnostic value of cardiac MRI (CMR) in patients with acute chest pain, elevated cardiac enzymes and a negative coronary angiogram. Methods: This study included a total of 125 patients treated in the chest pain unit during a 39-month period. Each included patient underwent MRI within a median of 3 days after cardiac catheterization. The MRI protocol comprised cine, oedema-sensitive and late gadolinium-enhancement imaging. The standard of reference was a consensus diagnosis based on clinical follow-up and the synopsis of all clinical, laboratory and imaging data. Results: MRI revealed a multitude of diagnoses, including ischaemic cardiomyopathy (CM), dilated CM, myocarditis, Takotsubo CM, hypertensive heart disease, hypertrophic CM, cardiac amyloidosis and non-compaction CM. MRI-based diagnoses were the same as the final reference diagnoses in 113/125 patients (90%), with the two diagnoses differing in only 12/125 patients. In two patients, no final diagnosis could be established. Conclusion: CMR performed early after the onset of symptoms revealed a broad spectrum of diseases. CMR delivered a correct final diagnosis in 90% of patients with acute chest pain, elevated cardiac enzymes and a negative coronary angiogram. Advances in knowledge: Diagnosing patients with acute coronary syndrome but unobstructed coronary arteries remains a challenge for cardiologists. CMR performed early after catheterization reveals a broad spectrum of diseases with only a simple and quick examination protocol, and there is a high concordance between MRI-based diagnoses and final reference diagnoses. PMID:25782462

  7. β-cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection

    PubMed Central

    El Khatib, Moustafa; Sakuma, Toshie; Tonne, Jason M.; Mohamed, Magid S.; Holditch, Sara J.; Lu, Brian; Kudva, Yogish C.; Ikeda, Yasuhiro

    2015-01-01

    Protection of beta cells from autoimmune destruction potentially cures type 1 diabetes mellitus (T1D). During antigen presentation, interactions between cytotoxic T-lymphocyte antigen-4 (CTLA4) and B7 molecules, or programmed death 1 (PD1) and its ligand PDL1, negatively regulate immune responses in a non-redundant manner. Here, we employed beta cell-targeted adeno-associated virus serotype 8 (AAV8)-based vectors to over-express an artificial PDL1-CTLA4Ig polyprotein or IL10. Beta cell-targeted expression of PDL1-CTLA4Ig or IL10 preserved beta cell mass and protected NOD mice from T1D development. When NOD mice were treated with vectors at early onset of hyperglycemia, PDL1-CTLA4Ig or IL10 alone failed to normalize the early onset of hyperglycemia. When drug-induced diabetic mice received MHC-matched allo-islets, with or without pretreatment of the PDL1-CTLA4Ig-expressing vector, PDL1-CTLA4Ig-expressing islets were protected from rejection for at least 120 days. Similarly, transplantation of PDL1-CTLA4Ig-expressing MHC-matched islets into mice with established T1D resulted in protection of allo-islets from acute rejection, although islet grafts were eventually rejected. Thus, the present study demonstrates the potent immuno-suppressive effects of beta cell-targeted PDL1-CTLA4Ig overexpression against T1D development and allo-islet rejection. The gene-based simultaneous inhibition of PD1 and CTLA4 pathways provides a unique strategy for immunosuppression-free tissue/organ transplantation, especially in the setting of no established autoimmunity. PMID:25786871

  8. Association between the presence of anti-HLA antibodies with acute rejection and chronic allograft nephropathy in the first year after kidney transplantation.

    PubMed

    Toresan, R; Manfro, R C; Proença, M C C; Veronese, F J V; Salim, P H; da Silva, D M; Ribeiro, A R; Edelweiss, M I A; Pegas, K L; Jobim, L F J

    2008-04-01

    The clinical relevance of anti-HLA antibodies following kidney transplantation has been a recent focus of research. Patients who present anti-HLA antibodies in the posttransplantation period have shown higher incidences of acute rejection episodes (ARE) and chronic allograft nephropathy (CAN). The objective of this study was to evaluate the presence of anti-HLA antibodies during the first year after kidney transplantation and their association with the occurrence of ARE and CAN. Eighty-eight kidney transplant recipients were evaluated for the presence of IgG anti-HLA antibodies using an enzyme-linked immunosorbent assay (LAT-M and LAT-1240, One Lambda Inc, Calif, United States). Protocol kidney biopsies were performed in consenting patients. ARE and CAN were diagnosed by clinical, laboratory, and histopathological criteria. Anti-HLA antibodies were observed in 20 (22.7%) patients. At 1 year follow-up, 26.1% presented ARE and 51.2% developed CAN. Nine patients (45%) with antibodies developed ARE as opposed to 20.6% without antibodies and 64.7% developed CAN as opposed to 47.8% of those without antibodies. In the histological analysis, the anti-HLA antibodies were associated with Banff IIA ARE (P = .001) and Banff grade II CAN (P = .012). Routine posttransplantation search for antibodies may identify cases at higher risk for acute and chronic rejection, and perhaps help to tailor the immunosuppressive regimen. PMID:18454996

  9. Acute renal failure after cardiac transplantation: a case report and review of the literature.

    PubMed Central

    Cruz, D. N.; Perazella, M. A.

    1996-01-01

    Acute renal failure (ARF) is a relatively frequent complication associated with heart transplantation. It develops in the first few days postoperatively and is characterized by oliguria with laboratory and urinary indices typical of pre-renal azotemia. Cyclosporine, especially with higher doses, is one of the many factors which play an integral part in the nephrotoxicity following cardiac transplant. Poor preoperative renal function and perioperative hemodynamic compromise may also contribute to ARF. The actual incidence of ARF now encountered by transplant centers may be lower than previously reported, the result of lower cyclosporine doses. Currently, management is entirely supportive, but novel therapeutic approaches with atrial natriuretic peptide-like substances are being explored. A case illustrating the typical clinical presentation of ARF after heart transplant will be presented and the clinical features will be reviewed. PMID:9381741

  10. Cost-effectiveness analysis of acute kidney injury biomarkers in pediatric cardiac surgery

    PubMed Central

    Petrovic, Stanislava; Lakic, Dragana; Peco-Antic, Amira; Vulicevic, Irena; Ivanisevic, Ivana; Kotur-Stevuljevic, Jelena; Jelic-Ivanovic, Zorana

    2015-01-01

    Introduction Acute kidney injury (AKI) is significant problem in children with congenital heart disease (CHD) who undergo cardiac surgery. The economic impact of a biomarker-based diagnostic strategy for AKI in pediatric populations undergoing CHD surgery is unknown. The aim of this study was to perform the cost effectiveness analysis of using serum cystatin C (sCysC), urine neutrophil gelatinase-associated lipocalin (uNGAL) and urine liver fatty acid-binding protein (uL-FABP) for the diagnosis of AKI in children after cardiac surgery compared with current diagnostic method (monitoring of serum creatinine (sCr) level). Materials and methods We developed a decision analytical model to estimate incremental cost-effectiveness of different biomarker-based diagnostic strategies compared to current diagnostic strategy. The Markov model was created to compare the lifetime cost associated with using of sCysC, uNGAL, uL-FABP with monitoring of sCr level for the diagnosis of AKI. The utility measurement included in the analysis was quality-adjusted life years (QALY). The results of the analysis are presented as the incremental cost-effectiveness ratio (ICER). Results Analysed biomarker-based diagnostic strategies for AKI were cost-effective compared to current diagnostic method. However, uNGAL and sCys C strategies yielded higher costs and lower effectiveness compared to uL-FABP strategy. uL-FABP added 1.43 QALY compared to current diagnostic method at an additional cost of $8521.87 per patient. Therefore, ICER for uL-FABP compared to sCr was $5959.35/QALY. Conclusions Our results suggest that the use of uL-FABP would represent cost effective strategy for early diagnosis of AKI in children after cardiac surgery. PMID:26110039

  11. Reduction of Leukocyte Counts by Hydroxyurea Improves Cardiac Function in Rats with Acute Myocardial Infarction

    PubMed Central

    Zhu, Guiyue; Yao, Yucai; Pan, Lingyun; Zhu, Wei; Yan, Suhua

    2015-01-01

    Background This study aimed to decrease leukocytes counts by hydroxyurea (Hu) in an acute myocardial infarction (AMI) rat model and examine its effect on the inflammatory response of myocardial infarction and cardiac functions. Material/Methods AMI was successfully caused in 36 rats, and 12 control rats received sham operation. Rats in the AMI group were then randomly divided into Hu and vehicle group with 18 rats each. Rats in the Hu AMI group received Hu (200 mg/kg) intragastrically while vehicle AMI group received saline. Leukocytes counts, cardiac functions, myocardial tissue morphology, and levels of soluble intercellular adhesion molecule-1 (sICAM), P-selectin and platelet activating factor (PAF) were measured and compared among the three groups four weeks after AMI induction. Results Leukocytes, neutrophils, and leukomonocyte counts in vehicle AMI rats were significantly higher than that of the normal control group (p<0.05). However, Hu treatment decreased their counts significantly (p<0.05). sICAM, P-selectin, and PAF level in vehicle AMI group were significantly higher than those of the normal group, and their level was also decreased by Hu treatment (p<0.05). Echocardiography analysis showed that Hu treatment increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) compared to that of vehicle AMI group (p<0.05). Histopathological examination showed that Hu significantly reduced the swelling of the heart muscle fiber in necrotic foci and the number of inflammatory cells infiltrated into myocardial interstitium compared to vehicle AMI group. Conclusions Decrease leukocytes counts by Hu significantly reduced inflammatory reaction and improved cardiac functions in AMI rats. PMID:26675565

  12. Effects of acute, intermittent exercise in hypoxic environments on the release of cardiac troponin.

    PubMed

    Li, F; Hu, Y; Nie, J; Fu, F H

    2016-04-01

    The purpose of this study was to examine the effects of acute, intermittent exercise performed in hypoxic environments on the release of cardiac troponin (cTn). Ten well-trained, male marathon runners (22.1 ± 2.6 years, 64.0 ± 4.9 kg and 177.3 ± 3.9 cm) completed three intermittent exercise protocols under normoxic (trial N) and hypoxic (trial AH and RH) conditions. In trial N, the fraction of inspiration oxygen (FIO2 ) was 21.0% and exercise intensity was 90% and 50% normoxic velocity of VO2max (vVO2max ). In trial AH, FIO2 was 14.4% (simulated altitude of 3000 m) and exercise intensity was 90% and 50% normoxic vVO2max . In trial RH, FIO2 was 14.4% and exercise intensity was 90% and 50% hypoxic vVO2max . High-sensitivity cardiac troponin T (hs-cTnT) and cardiac troponin I (cTnI) were measured pre- and 0, 2, 4, and 24 h post-exercise. Hs-cTnT was elevated in all three trials, peaking at 2 to 4 h and returning to the baseline 24 h post-exercise. CTnI increased in trial AH, peaking at 2 to 4 h and returning below the detection limit 24 h post-exercise. It is concluded that the stimulus of hypoxia did not in and of itself induce more cTn to be released, but exercise intensity could affect this response in hypoxic environments. PMID:25943765

  13. Cardiac-surgery associated acute kidney injury requiring renal replacement therapy. A Spanish retrospective case-cohort study

    PubMed Central

    2009-01-01

    Background Acute kidney injury is among the most serious complications after cardiac surgery and is associated with an impaired outcome. Multiple factors may concur in the development of this disease. Moreover, severe renal failure requiring renal replacement therapy (RRT) presents a high mortality rate. Consequently, we studied a Spanish cohort of patients to assess the risk factors for RRT in cardiac surgery-associated acute kidney injury (CSA-AKI). Methods A retrospective case-cohort study in 24 Spanish hospitals. All cases of RRT after cardiac surgery in 2007 were matched in a crude ratio of 1:4 consecutive patients based on age, sex, treated in the same year, at the same hospital and by the same group of surgeons. Results We analyzed the data from 864 patients enrolled in 2007. In multivariate analysis, severe acute kidney injury requiring postoperative RRT was significantly associated with the following variables: lower glomerular filtration rates, less basal haemoglobin, lower left ventricular ejection fraction, diabetes, prior diuretic treatment, urgent surgery, longer aortic cross clamp times, intraoperative administration of aprotinin, and increased number of packed red blood cells (PRBC) transfused. When we conducted a propensity analysis using best-matched of 137 available pairs of patients, prior diuretic treatment, longer aortic cross clamp times and number of PRBC transfused were significantly associated with CSA-AKI. Patients requiring RRT needed longer hospital stays, and suffered higher mortality rates. Conclusion Cardiac-surgery associated acute kidney injury requiring RRT is associated with worse outcomes. For this reason, modifiable risk factors should be optimised and higher risk patients for acute kidney injury should be identified before undertaking cardiac surgery. PMID:19772621

  14. In Emergency Department Patients with Acute Chest Pain, Stress Cardiac MRI Observation Unit Care Reduces 1- year Cardiac-Related Health Care Expenditures: A Randomized Trial

    PubMed Central

    Miller, Chadwick D.; Hwang, Wenke; Case, Doug; Hoekstra, James W.; Lefebvre, Cedric; Blumstein, Howard; Hamilton, Craig A.; Harper, Erin N.; Hundley, W. Gregory

    2013-01-01

    Objective To compare the direct cost of medical care and clinical events during the first year after patients with intermediate risk acute chest pain were randomized to stress cardiovascular magnetic resonance (CMR) observation unit (OU) testing, versus inpatient care. Background In a recent study, randomization to OU-CMR reduced median index hospitalization cost compared to inpatient care in patients presenting to the emergency department with intermediate risk acute chest pain. Methods Emergency department patients with intermediate risk chest pain were randomized to OU-CMR (OU care, cardiac markers, stress CMR) or inpatient care (admission, care per admitting provider). This analysis reports the direct cost of cardiac-related care and clinical outcomes (MI, revascularization, cardiovascular death) during the first year of follow-up subsequent to discharge. Consistent with health economics literature, provider cost was calculated from work-related relative value units using the Medicare conversion factor; facility charges were converted to cost using departmental specific cost-to-charge ratios. Linear models were used to compare cost accumulation among study groups. Results One-hundred nine (109) randomized subjects were included in this analysis (52 OU-CMR, 57 inpatient care). The median age was 56 years; baseline characteristics were similar in both groups. At 1 year, 6% of OU-CMR and 9% of inpatient care participants experienced a major cardiac event (p=0.72) with 1 patient in each group experiencing a cardiac event after discharge. First-year cardiac-related costs were significantly lower for participants randomized to OU-CMR compared to participants receiving inpatient care (geometric mean = $3101 vs $4742 including the index visit (p = .004) and $29 vs $152 following discharge (p = .012)). During the year following randomization, 6% of OU-CMR and 9% of inpatient care participants experienced a major cardiac event (p=0.72). Conclusions An OU-CMR strategy

  15. Anhedonia Predicts Major Adverse Cardiac Events and Mortality in Patients 1 Year After Acute Coronary Syndrome

    PubMed Central

    Davidson, Karina W.; Burg, Matthew M.; Kronish, Ian M.; Shimbo, Daichi; Dettenborn, Lucia; Mehran, Roxana; Vorchheimer, David; Clemow, Lynn; Schwartz, Joseph E.; Lespérance, Francois; Rieckmann, Nina

    2010-01-01

    Context Depression is a consistent predictor of recurrent events and mortality in ACS patients, but it has 2 core diagnostic criteria with distinct biological correlates—depressed mood and anhedonia. Objective To determine if depressed mood and/or anhedonia (loss of pleasure or interest) predict 1-year medical outcomes for patients with Acute Coronary Syndrome (ACS). Design Observational cohort study of post-ACS patients hospitalized between May 2003 and June 2005. Within one week of admission, patients underwent a structured psychiatric interview to assess clinically impairing depressed mood, anhedonia, and major depressive episode (MDE); also assessed were the Global Registry of Acute Coronary Events risk score, Charlson comorbidity index, left ventricular ejection fraction, antidepressant use, and depressive symptom severity. Setting Coronary care and cardiac care step-down units of 3 university hospitals in New York and Connecticut. Participants Consecutive sample of 453 ACS patients (aged 25–93 years; 42% women). Main Outcomes Measures All-cause mortality (ACM) and documented major adverse cardiac events (MACE; myocardial infarction, hospitalization for unstable angina, or urgent revascularization) were actively surveyed for 1 year after admission. Results There were 67 events (16 deaths and 51 MACE; 14.8%). 108 (24%) and 77 (17%) patients with anhedonia and depressed mood, respectively. After controlling for sex, age, and medical covariates, anhedonia (adjusted hazard ratio, 1.58; 95% confidence interval, 1.16–2.14; P<.01) and MDE (adjusted hazard ratio, 1.48; 95% confidence interval, 1.07–2.04; P=.02) were significant predictors of combined MACE/ACM, but depressed mood was not. Anhedonia continued to significantly predict outcomes controlling for MDE diagnosis and depressive symptom severity, each of which were no longer significant. Conclusions Anhedonia identifies risk for MACE/ACM beyond that of established medical prognostic indicators

  16. Increased C4d in post-reperfusion biopsies and increased donor specific antibodies at one-week post transplant are risk factors for acute rejection in mild to moderately sensitized kidney transplant recipients

    PubMed Central

    Djamali, Arjang; Muth, Brenda; Ellis, Thomas M.; Mohamed, Maha; Fernandez, Luis; Miller, Karen; Bellingham, Janet; Odorico, Jon; Mezrich, Joshua; Pirsch, John; D’Alessandro, Tony; Vidyasagar, Vijay; Hofmann, R. Michael; Torrealba, Jose; Kaufman, Dixon; Foley, David

    2013-01-01

    In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean calculated panel reactive antibody and MFImax ranged from 10.3% to 57.2%, and 262 to 1691, respectively, between low and high-risk protocols. Mean MFImax increased significantly from transplant to one-week and one-year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32% including 14% cellular, 12% antibody-mediated and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71 to 6.45) and increased donor specific antibodies at 1 week post-transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients. PMID:23447068

  17. Epicardial delivery of VEGF and cardiac stem cells guided by 3-dimensional PLLA mat enhancing cardiac regeneration and angiogenesis in acute myocardial infarction.

    PubMed

    Chung, Hye-Jin; Kim, Jong-Tae; Kim, Hee-Jung; Kyung, Hei-Won; Katila, Pramila; Lee, Jeong-Han; Yang, Tae-Hyun; Yang, Young-Il; Lee, Seung-Jin

    2015-05-10

    Congestive heart failure is mostly resulted in a consequence of the limited myocardial regeneration capacity after acute myocardial infarction. Targeted delivery of proangiogenic factors and/or stem cells to the ischemic myocardium is a promising strategy for enhancing their local and sustained therapeutic effects. Herein, we designed an epicardial delivery system of vascular endothelial growth factor (VEGF) and cardiac stem cells (CSCs) using poly(l-lactic acid) (PLLA) mat applied to the acutely infarcted myocardium. The fibrous VEGF-loaded PLLA mat was fabricated by an electrospinning method using PLLA solution emulsified VEGF. This mat not only allowed for sustained release of VEGF for 4weeks but boosted migration and proliferation of both endothelial cells and CSCs in vitro. Furthermore, sustained release of VEGF showed a positive effect on in vitro capillary-like network formation of endothelial cells compared with bolus treatment of VEGF. PLLA mat provided a permissive 3-dimensional (3D) substratum that led to spontaneous cardiomyogenic differentiation of CSCs in vitro. Notably, sustained stimulation by VEGF-loaded PLLA mat resulted in a substantial increase in the expression of proangiogenic mRNAs of CSCs in vitro. The epicardially implanted VEGF-loaded PLLA mat showed modest effects on angiogenesis and cardiomyogenesis in the acutely infarcted hearts. However, co-implantation of VEGF and CSCs using the PLLA mat showed meaningful therapeutic effects on angiogenesis and cardiomyogenesis compared with controls, leading to reduced cardiac remodeling and enhanced global cardiac function. Collectively, the PLLA mat allowed a smart cargo that enabled the sustained release of VEGF and the delivery of CSCs, thereby synergistically inducing angiogenesis and cardiomyogenesis in acute myocardial infarction. PMID:25681051

  18. Troponin Marker for Acute Coronary Occlusion and Patient Outcome Following Cardiac Arrest

    PubMed Central

    Pearson, David A.; Wares, Catherine M.; Mayer, Katherine A.; Runyon, Michael S.; Studnek, Jonathan R.; Ward, Shana L.; Kraft, Kathi M.; Heffner, Alan C.

    2015-01-01

    Introduction The utility of troponin as a marker for acute coronary occlusion and patient outcome after out-of-hospital cardiac arrest (OHCA) is unclear. We sought to determine whether initial or peak troponin was associated with percutaneous coronary intervention (PCI), OHCA survival or neurological outcome. Methods Single-center retrospective-cohort study of OHCA patients treated in a comprehensive clinical pathway from November 2007 to October 2012. Troponin I levels were acquired at presentation, four and eight hours after arrest, and then per physician discretion. Cardiac catheterization was at the cardiologist’s discretion. Survival and outcome were determined at hospital discharge, with cerebral performance category score 1–2 defined as a good neurological outcome. Results We enrolled 277 patients; 58% had a shockable rhythm, 44% survived, 41% good neurological outcome. Of the 107 (38%) patients who underwent cardiac catheterization, 30 (28%) had PCI. Initial ED troponin (median, ng/mL) was not different in patients requiring PCI vs no PCI (0.32 vs 0.09, p=0.06), although peak troponin was higher (4.19 versus 1.57, p=0.02). Of the 85 patients who underwent cardiac catheterization without STEMI (n=85), there was no difference in those who received PCI vs no PCI in initial troponin (0.22 vs 0.06, p=0.40) or peak troponin (2.58 vs 1.43, p=0.27). Regarding outcomes, there was no difference in initial troponin in survivors versus non-survivors (0.09 vs 0.22, p=0.11), or those with a good versus poor neurological outcome (0.09 vs 0.20, p=0.11). Likewise, there was no difference in peak troponin in survivors versus non-survivors (1.64 vs 1.23, p=0.07), or in those with a good versus poor neurological outcome (1.57 vs 1.26, p=0.14). Conclusion In our single-center patient cohort, peak troponin, but not initial troponin, was associated with higher likelihood of PCI, while neither initial nor peak troponin were associated with survival or neurological outcome in

  19. Post Cardiac Surgery Acute Kidney Injury: A Woebegone Status Rejuvenated by the Novel Biomarkers

    PubMed Central

    Jayaraman, Rajesh; Sunder, Sham; Sathi, Satyanand; Gupta, Vijay Kumar; Sharma, Neera; Kanchi, Prabhu; Gupta, Anurag; Daksh, Sunil Kumar; Ram, Pranith; Mohamed, Ashik

    2014-01-01

    Background: Acute kidney injury (AKI) is common after cardiac surgery, the incidence varying between 7.7% and 28.1%. It significantly increases morbidity and mortality. Creatinine considerably delays the diagnosis with its own attended demerits. Novel urinary biomarkers are emerging which help in rapid diagnosis thus reducing the morbidity and mortality. Biomarkers of our study were neutrophil gelatinase-associated lipocalin (NGAL) and Interleukin-18 (IL-18). Objectives: To find out the incidence of AKI in post-cardiac surgery patients in our hospital, the ability of the two biomarkers in early diagnosis in predicting the severity of AKI based on RIFLE’s criteria and their ability to discriminate pre-renal from intrinsic AKI. Patients and Methods: One-hundred patients who underwent cardiac surgery were selected. Midstream urine samples were collected at 3 time intervals (baseline before surgery, 24 hours and 7 days after surgery). Biomarkers were measured by ELISA using BIORAD processors. Fractional excretion of sodium and urea were used to discriminate pre-renal from intrinsic AKI. Results: Out of 100 patients, 31 had AKI, 11 being pre-renal and 20 intrinsic AKI. Four patients required renal replacement therapy (12.9% among AKI cases and 4% in the overall study cohort). Four among 31 expired in intensive care unit. Identifiable risk factors for AKI included insulin requiring diabetes mellitus, chronic obstructive pulmonary disease, increased cardio-pulmonary bypass time, combined valvular surgery and coronary artery bypass grafting, employment of intra-aortic balloon counter pulsation, left main coronary artery occlusion and an ejection fraction of < 40%. NGAL was extremely sensitive (area under curve-0.96) in detecting intrinsic AKI at 24 hours followed by IL-18 ratio with an area under curve of 0.89. Creatinine at 24 hours was able to detect only 31.6% of intrinsic AKI. None of the pre-renal cases showed rise in the urinary biomarker levels. Patients with

  20. Low renal oximetry correlates with acute kidney injury after infant cardiac surgery.

    PubMed

    Owens, Gabe E; King, Karen; Gurney, James G; Charpie, John R

    2011-02-01

    Acute kidney injury (AKI) is a frequent complication after cardiopulmonary bypass surgery during infancy. Standard methods for evaluating renal function are not particularly sensitive nor are proximate indicators of renal dysfunction that allow intervention in real time. Near-infrared spectroscopy (NIRS) is a newer noninvasive technology that continuously evaluates regional oximetry and may correlate with renal injury and adverse outcomes after cardiac surgery in infants. This prospective observational study enrolled 40 infants (age, <12 months) undergoing biventricular repair. Continuous renal oximetry data were collected for the first 48 postoperative hours and correlated with postoperative course, standard laboratory data, and the occurrence of acute renal injury. Subjects with low renal oximetry (below 50% for >2 h) had significantly higher postoperative peak creatinine levels by 48 h (0.8 ± 0.4 vs. 0.52 ± 0.2; p = 0.003) and a higher incidence of AKI (50 vs. 3.1%; p = 0.003) than those with normal renal oximetry. These subjects also required more ventilator days and greater vasoactive support, and they had elevated lactate levels. Prolonged low renal near-infrared oximetry appears to correlate with renal dysfunction, decreased systemic oxygen delivery, and the overall postoperative course in infants with congenital heart disease undergoing biventricular repair. PMID:21085945

  1. Role of cardiac volume receptors in the control of ADH release during acute simulated weightlessness in man

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Benjamin, B. A.; Keil, L. C.; Sandler, H.

    1984-01-01

    Hemodynamic responses and antidiuretic hormone (ADH) were measured during body position changes, designed to induce central blood volume shifts in ten cardiac and one heart-lung transplant recipients, to assess the contribution of cardiac volume receptors in the control of ADH release during the initial acute phase of exposure to weightlessness. Each subject underwent 15 min of a sitting-control period (C) followed by 30 min of 6 deg headdown tilt (T) and 30 min of resumed sitting (S). Venous blood samples and cardiac dimensions were taken at 0 and 15 min of C; 5, 15, and 30 min of T; and 5, 15, and 30 min of S. Blood samples were analyzed for hematocrit, plasma osmolality, plasma renin activity (PRA), and ADH. Heart rate and blood pressure were recorded every two min. Plasma osmolality was not altered by posture changes. Mean left ventricular end-diastolic volume increased (P less than 0.05) from 90 ml in C to 106 ml in T and returned to 87 ml in S. Plasma ADH was reduced by 20 percent (P less than 0.05) with T, and returned to control levels with S. These responses were similar in six normal cardiac-innervated control subjects. These data may suggest that cardiac volume receptors are not the primary mechanism for the control of ADH release during acute central volume shifts in man.

  2. Diagnostic and Prognostic Properties of Osteoprotegerin in Patients with Acute Dyspnoea: Observations from the Akershus Cardiac Examination (ACE) 2 Study

    PubMed Central

    Pervez, Mohammed Osman; Pedersen, Marit Holmefjord; Brynildsen, Jon; Høiseth, Arne Didrik; Hagve, Tor-Arne; Røsjø, Helge; Omland, Torbjørn

    2016-01-01

    Background Circulating osteoprotegerin (OPG) levels are increased in patients with chronic heart failure (HF). The diagnostic and prognostic merit of OPG measurement in patients admitted with acute dyspnoea is unknown. Objectives To evaluate the diagnostic and prognostic value of measuring OPG in patients admitted to hospital with acute dyspnoea. Methods OPG was analysed by ELISA in 308 patients admitted due to acute dyspnoea. Investigators blinded to OPG results adjudicated the diagnosis for the index hospitalization. Clinical outcomes were obtained from hospital records. Results In total, 139 patients (45%) were hospitalized with acute HF. OPG levels on hospital admission were higher in patients with acute HF vs. no acute HF, 7.8 (5.5–10.4) vs. 5.4 (3.8–7.2) pmol/L, p<0.001. The area under the receiver operator characteristic curve (ROC AUC) of OPG to discriminate between HF vs. non-HF was 0.695 [95% CI 0.636–0.754]. OPG did not provide incremental information to the ED physician’s prediction or N-terminal pro-B-type natriuretic peptide regarding the diagnosis of acute HF. OPG levels (log transformed) were associated with mortality in crude analysis (HR (95% CI) 1.87 (1.34 to 2.61), p<0.001), but this association was attenuated and no longer significant after including established cardiac biomarkers into the model. Conclusion In patients admitted to hospital with acute dyspnoea, OPG levels are higher in patients with acute HF than in those with dyspnoea from other causes. However, OPG does not provide incremental information beyond ED physician assessment for the diagnosis of acute HF or beyond clinical risk variables and established cardiac biomarkers concerning prognosis. PMID:27463973

  3. Cardiac oxygen limitation during an acute thermal challenge in the European perch: effects of chronic environmental warming and experimental hyperoxia.

    PubMed

    Ekström, Andreas; Brijs, Jeroen; Clark, Timothy D; Gräns, Albin; Jutfelt, Fredrik; Sandblom, Erik

    2016-08-01

    Oxygen supply to the heart has been hypothesized to limit cardiac performance and whole animal acute thermal tolerance (CTmax) in fish. We tested these hypotheses by continuously measuring venous oxygen tension (Pvo2) and cardiovascular variables in vivo during acute warming in European perch (Perca fluviatilis) from a reference area during summer (18°C) and a chronically heated area (Biotest enclosure) that receives warm effluent water from a nuclear power plant and is normally 5-10°C above ambient (24°C at the time of experiments). While CTmax was 2.2°C higher in Biotest compared with reference perch, the peaks in cardiac output and heart rate prior to CTmax occurred at statistically similar Pvo2 values (2.3-4.0 kPa), suggesting that cardiac failure occurred at a common critical Pvo2 threshold. Environmental hyperoxia (200% air saturation) increased Pvo2 across temperatures in reference fish, but heart rate still declined at a similar temperature. CTmax of reference fish increased slightly (by 0.9°C) in hyperoxia, but remained significantly lower than in Biotest fish despite an improved cardiac output due to an elevated stroke volume. Thus, while cardiac oxygen supply appears critical to elevate stroke volume at high temperatures, oxygen limitation may not explain the bradycardia and arrhythmia that occur prior to CTmax Acute thermal tolerance and its thermal plasticity can, therefore, only be partially attributed to cardiac failure from myocardial oxygen limitations, and likely involves limiting factors on multiple organizational levels. PMID:27280433

  4. Risk factors of cardiac allograft vasculopathy

    PubMed Central

    Szczurek, Wioletta; Gąsior, Mariusz; Zembala, Marian

    2015-01-01

    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. PMID:26855649

  5. Acute Auditory Stimulation with Different Styles of Music Influences Cardiac Autonomic Regulation in Men

    PubMed Central

    da Silva, Sheila Ap. F.; Guida, Heraldo L.; dos Santos Antonio, Ana Marcia; de Abreu, Luiz Carlos; Monteiro, Carlos B. M.; Ferreira, Celso; Ribeiro, Vivian F.; Barnabe, Viviani; Silva, Sidney B.; Fonseca, Fernando L. A.; Adami, Fernando; Petenusso, Marcio; Raimundo, Rodrigo D.; Valenti, Vitor E.

    2014-01-01

    Background: No clear evidence is available in the literature regarding the acute effect of different styles of music on cardiac autonomic control. Objectives: The present study aimed to evaluate the acute effects of classical baroque and heavy metal musical auditory stimulation on Heart Rate Variability (HRV) in healthy men. Patients and Methods: In this study, HRV was analyzed regarding time (SDNN, RMSSD, NN50, and pNN50) and frequency domain (LF, HF, and LF / HF) in 12 healthy men. HRV was recorded at seated rest for 10 minutes. Subsequently, the participants were exposed to classical baroque or heavy metal music for five minutes through an earphone at seated rest. After exposure to the first song, they remained at rest for five minutes and they were again exposed to classical baroque or heavy metal music. The music sequence was random for each individual. Standard statistical methods were used for calculation of means and standard deviations. Besides, ANOVA and Friedman test were used for parametric and non-parametric distributions, respectively. Results: While listening to heavy metal music, SDNN was reduced compared to the baseline (P = 0.023). In addition, the LF index (ms2 and nu) was reduced during exposure to both heavy metal and classical baroque musical auditory stimulation compared to the control condition (P = 0.010 and P = 0.048, respectively). However, the HF index (ms2) was reduced only during auditory stimulation with music heavy metal (P = 0.01). The LF/HF ratio on the other hand decreased during auditory stimulation with classical baroque music (P = 0.019). Conclusions: Acute auditory stimulation with the selected heavy metal musical auditory stimulation decreased the sympathetic and parasympathetic modulation on the heart, while exposure to a selected classical baroque music reduced sympathetic regulation on the heart. PMID:25177673

  6. Role of basiliximab in the prevention of acute cellular rejection in adult to adult living-related liver transplantation: a single center experience

    PubMed Central

    Gruttadauria, S; Mandalà, L; Biondo, D; Spampinato, M; Lamonaca, V; Volpes, R; Vizzini, G; Marsh, JW; Marcos, A; Gridelli, B

    2007-01-01

    We report our single center experience with the use of basiliximab, a chimeric monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor (CD25), in combination with a steroid- and tacrolimus-based regimen in adult to adult living-related liver transplantation (ALRLT). Sixty consecutive ALRLTs were analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after transplantation) followed by tacrolimus (0.15 mg/kg/day; 10–15 ng/mL target trough levels) and a dose regimen of steroids (starting with 20 mg iv, switched to po as soon as the patient was able to eat, and weaned off within 1–2 months). Follow-up ranged from 6 to 1699.4 days after transplantation (mean 517.5 days, SD ± 413.4; median 424 days). Of the recipients, 95% remained rejection-free during follow-up, with an actuarial rejection-free probability of 96.61% within 3 months. Three patients had episodes of biopsy-proven acute cellular rejection (ACR). Actuarial patient and graft survival rates at 3 years were 82.09% and 75.61%. Six patients (10%) experienced sepsis. There was no evidence of cytomegalovirus infections or side-effects related to the basiliximab. We found zero de novo malignancy, although we observed 5 patients with metastatic spread of their primary malignancy during the follow-up. Basiliximab in association with tacrolimus and steroids is effective in reducing episodes of ACR and increasing ACR-free survival after ALRLT. PMID:19707350

  7. Evaluation of cerebral-cardiac syndrome using echocardiography in a canine model of acute traumatic brain injury.

    PubMed

    Qian, Rong; Yang, Weizhong; Wang, Xiumei; Xu, Zhen; Liu, Xiaodong; Sun, Bing

    2015-01-01

    Previous studies have confirmed that traumatic brain injury (TBI) can induce general adaptation syndrome (GAS), which subsequently results in myocardial dysfunction and damage in some patients with acute TBI; this condition is also termed as cerebral-cardiac syndrome. However, most clinicians ignore the detection and treatment of myocardial dysfunction, and instead concentrate only on the serious neural damage that is observed in acute TBI, which is one of the most important fatal factors. Therefore, clarification is urgently needed regarding the relationship between TBI and myocardial dysfunction. In the present study, we evaluated 18 canine models of acute TBI, by using real-time myocardial contrast echocardiography and strain rate imaging to accurately evaluate myocardial function and regional microcirculation, including the strain rate of the different myocardial segments, time-amplitude curves, mean ascending slope of the curve, and local myocardial blood flow. Our results suggest that acute TBI often results in cerebral-cardiac syndrome, which rapidly progresses to the serious stage within 3 days. This study is the first to provide comprehensive ultrasonic characteristics of cerebral-cardiac syndrome in an animal model of TBI. PMID:26064794

  8. Recipient–derived EDA fibronectin promotes cardiac allograft fibrosis

    PubMed Central

    Booth, Adam J; Wood, Sherri C; Cornett, Ashley M; Dreffs, Alyssa A; Lu, Guanyi; Muro, Andrés F; White, Eric S; Bishop, D Keith

    2014-01-01

    Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA−/−) and wild-type (WT) mice. While EDA−/− mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA−/− mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which

  9. Endoplasmic reticulum stress in bone marrow-derived cells prevents acute cardiac inflammation and injury in response to angiotensin II.

    PubMed

    Li, T-T; Jia, L-X; Zhang, W-M; Li, X-Y; Zhang, J; Li, Y-L; Li, H-H; Qi, Y-F; Du, J

    2016-01-01

    Inflammation plays an important role in hypertensive cardiac injury. The endoplasmic reticulum (ER) stress pathway is involved in the inflammatory response. However, the role of ER stress in elevated angiotensin II (Ang II)-induced cardiac injury remains unclear. In this study, we investigated the role of ER stress in Ang II-induced hypertensive cardiac injury. Transcriptome analysis and quantitative real-time PCR showed that Ang II infusion in mice increased ER stress-related genes expression in the heart. C/EBP homologous protein (CHOP) deficiency, a key mediator of ER stress, increased infiltration of inflammatory cells, especially neutrophils, the production of inflammatory cytokines, chemokines in Ang II-infused mouse hearts. CHOP deficiency increased Ang II-induced cardiac fibrotic injury: (1) Masson trichrome staining showed increased fibrotic areas, (2) immunohistochemistry staining showed increased expression of α-smooth muscle actin, transforming growth factor β1 and (3) quantitative real-time PCR showed increased expression of collagen in CHOP-deficient mouse heart. Bone marrow transplantation experiments indicated that CHOP deficiency in bone marrow cells was responsible for Ang II-induced cardiac fibrotic injury. Moreover, TUNEL staining and flow cytometry revealed that CHOP deficiency decreased neutrophil apoptosis in response to Ang II. Taken together, our study demonstrated that hypertension induced ER stress after Ang II infusion. ER stress in bone marrow-derived cells protected acute cardiac inflammation and injury in response to Ang II. PMID:27277680

  10. Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes.

    PubMed

    Modena, B D; Kurian, S M; Gaber, L W; Waalen, J; Su, A I; Gelbart, T; Mondala, T S; Head, S R; Papp, S; Heilman, R; Friedewald, J J; Flechner, S M; Marsh, C L; Sung, R S; Shidban, H; Chan, L; Abecassis, M M; Salomon, D R

    2016-07-01

    Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation. PMID:26990570

  11. Pre-Transplant Donor-Specific T-Cell Alloreactivity Is Strongly Associated with Early Acute Cellular Rejection in Kidney Transplant Recipients Not Receiving T-Cell Depleting Induction Therapy

    PubMed Central

    Crespo, Elena; Lucia, Marc; Cruzado, Josep M.; Luque, Sergio; Melilli, Edoardo; Manonelles, Anna; Lloberas, Nuria; Torras, Joan; Grinyó, Josep M.; Bestard, Oriol

    2015-01-01

    Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rapidly recognize alloantigens and activate the effector immune response, which leads to allograft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by de novo activated naïve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell responses were evaluated using the IFN-γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90), to assess the main clinical variables associated with cellular sensitization and its predominant time-frame impact on allograft outcome, and was further validated in an independent new set of kidney transplant recipients (n = 67). We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year incidence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular rejection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosuppression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensitization before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction therapy. PMID:25689405

  12. Depression of Complement Regulatory Factors in Rat and Human Renal Grafts Is Associated with the Progress of Acute T-Cell Mediated Rejection

    PubMed Central

    Yamanaka, Kazuaki; Kakuta, Yoichi; Miyagawa, Shuji; Nakazawa, Shigeaki; Kato, Taigo; Abe, Toyofumi; Imamura, Ryoichi; Okumi, Masayoshi; Maeda, Akira; Okuyama, Hiroomi; Mizuno, Masashi; Nonomura, Norio

    2016-01-01

    Background The association of complement with the progression of acute T cell mediated rejection (ATCMR) is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs) in acute T-cell mediated rejection using rat and human renal allografts. Methods We prepared rat allograft and syngeneic graft models of renal transplantation. The expression of Complement components and Cregs was assessed in the rat grafts using quantitative real-time PCR (qRT-PCR) and immunofluorescent staining. We also administered anti-Crry and anti-CD59 antibodies to the rat allograft model. Further, we assessed the relationship between the expression of membrane cofactor protein (MCP) by immunohistochemical staining in human renal grafts and their clinical course. Results qRT-PCR results showed that the expression of Cregs, CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry), was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model. In contrast, the expression of complement components and receptors: C3, C3a receptor, C5a receptor, Factor B, C9, C1q, was increased, but not the expression of C4 and C5, indicating a possible activation of the alternative pathway. When anti-Crry and anti-CD59 mAbs were administered to the allograft, the survival period for each group was shortened. In the human ATCMR cases, the group with higher MCP expression in the grafts showed improved serum creatinine levels after the ATCMR treatment as well as a better 5-year graft survival rate. Conclusions We conclude that the expression of Cregs in allografts is connected with ATCMR. Our results suggest that controlling complement activation in renal grafts can be a new strategy for the treatment of ATCMR. PMID:26928779

  13. Immuno-histological assessment of sub-clinical acute and borderline rejection in renal allograft recipients: Data from a transplant center in India.

    PubMed

    Badwal, Sonia; Kumar, Arun; Hooda, A K; Varma, P P

    2015-11-01

    This single-center study was carried out on living related and unrelated renal transplant recipients (RTRs) to evaluate the usefulness of surveillance biopsies in monitoring stable renal allografts using immuno-histological markers for immune-activation. This is a prospective, longitudinal study. Protocol biopsies of 60 RTRs with stable graft function were evaluated at three, six and 12 months post-transplant. Immuno-histological evaluation was carried out using immune-activation markers (perforins, granzyme and interleukin-2R), phenotypic markers (CD-3 and CD-20), viral markers and C4d. The demographic and clinical profile was recorded for each patient. All cases of acute sub-clinical rejection (SCR) were treated and borderline SCR cases were followed-up without treatment. SCR at three and six months post-transplant was evident in 16.7% and 3.7% of RTRs, respectively. Positive statistical association of SCR was seen with HLA-DR mismatches, whereas patients receiving induction therapy and tacrolimus-based immunosuppression exhibited a lower incidence of SCR. T cell phenotype with persistent expression of immune-activation markers exhibited positive statistical association with interstitial fibrosis and tubular atrophy at 12-month follow-up biopsy. The mean creatinine levels were significantly lower in the protocol biopsy group than the non-protocol biopsy group. No significant difference was found between the mean creatinine levels of the SCR group after treatment and the non-SCR cases within the protocol biopsy group. Early treatment of sub-clinical acute rejection leads to better functional outcomes. However, persistent immune-activation is associated with chronicity and may have implications on long-term graft survival. PMID:26586064

  14. Sildenafil improves cardiac output and exercise performance during acute hypoxia, but not normoxia.

    PubMed

    Hsu, Andrew R; Barnholt, Kimberly E; Grundmann, Nicolas K; Lin, Joseph H; McCallum, Stewart W; Friedlander, Anne L

    2006-06-01

    Sildenafil causes pulmonary vasodilation, thus potentially reducing impairments of hypoxia-induced pulmonary hypertension on exercise performance at altitude. The purpose of this study was to determine the effects of sildenafil during normoxic and hypoxic exercise. We hypothesized that 1) sildenafil would have no significant effects on normoxic exercise, and 2) sildenafil would improve cardiac output, arterial oxygen saturation (SaO2), and performance during hypoxic exercise. Ten trained men performed one practice and three experimental trials at sea level (SL) and simulated high altitude (HA) of 3,874 m. Each cycling test consisted of a set-work-rate portion (55% work capacity: 1 h SL, 30 min HA) followed immediately by a time trial (10 km SL, 6 km HA). Double-blinded capsules (placebo, 50, or 100 mg) were taken 1 h before exercise in a randomly counterbalanced order. For HA, subjects also began breathing hypoxic gas (12.8% oxygen) 1 h before exercise. At SL, sildenafil had no effects on any cardiovascular or performance measures. At HA, sildenafil increased stroke volume (measured by impedance cardiography), cardiac output, and SaO2 during set-work-rate exercise. Sildenafil lowered 6-km time-trial time by 15% (P<0.05). SaO2 was also higher during the time trial (P<0.05) in response to sildenafil, despite higher work rates. Post hoc analyses revealed two subject groups, sildenafil responders and nonresponders, who improved time-trial performance by 39% (P<0.05) and 1.0%, respectively. No dose-response effects were observed. During cycling exercise in acute hypoxia, sildenafil can greatly improve cardiovascular function, SaO2, and performance for certain individuals. PMID:16455814

  15. Achieving better in-hospital and after-hospital care of patients with acute cardiac disease.

    PubMed

    Scott, Ian A; Denaro, Charles P; Bennett, Cameron J; Hickey, Annabel C; Mudge, Alison M; Flores, Judy L; Sanders, Daniela C J; Thiele, Justine M; Wenck, Beres; Bennett, John W; Jones, Mark A

    2004-05-17

    In patients hospitalised with acute coronary syndromes (ACS) and congestive heart failure (CHF), evidence suggests opportunities for improving in-hospital and after-hospital care, patient self-care, and hospital-community integration. A multidisciplinary quality improvement program was designed and instigated in Brisbane in October 2000 involving 250 clinicians at three teaching hospitals, 1080 general practitioners (GPs) from five Divisions of General Practice, 1594 patients with ACS and 904 patients with CHF. Quality improvement interventions were implemented over 17 months after a 6-month baseline period and included: clinical decision support (clinical practice guidelines, reminders, checklists, clinical pathways); educational interventions (seminars, academic detailing); regular performance feedback; patient self-management strategies; and hospital-community integration (discharge referral summaries; community pharmacist liaison; patient prompts to attend GPs). Using a before-after study design to assess program impact, significantly more program patients compared with historical controls received: ACS: Angiotensin-converting enzyme (ACE) inhibitors and lipid-lowering agents at discharge, aspirin and beta-blockers at 3 months after discharge, inpatient cardiac counselling, and referral to outpatient cardiac rehabilitation. CHF: Assessment for reversible precipitants, use of prophylaxis for deep-venous thrombosis, beta-blockers at discharge, ACE inhibitors at 6 months after discharge, imaging of left ventricular function, and optimal management of blood pressure levels. Risk-adjusted mortality rates at 6 and 12 months decreased, respectively, from 9.8% to 7.4% (P = 0.06) and from 13.4% to 10.1% (P = 0.06) for patients with ACS and from 22.8% to 15.2% (P < 0.001) and from 32.8% to 22.4% (P = 0.005) for patients with CHF. Quality improvement programs that feature multifaceted interventions across the continuum of care can change clinical culture, optimise care

  16. Electrochemical aptasensor of cardiac troponin I for the early diagnosis of acute myocardial infarction.

    PubMed

    Jo, Hunho; Gu, Hyunwoo; Jeon, Weejeong; Youn, Hyungjun; Her, Jin; Kim, Seong-Kyeong; Lee, Jeongbong; Shin, Jae Ho; Ban, Changill

    2015-10-01

    Cardiac troponin I (cTnI) is well-known as a promising biomarker for the early diagnosis of acute myocardial infarction (AMI). In this work, single-stranded DNA aptamers against cTnI were identified by the Systematic Evolution of Ligands by Exponential enrichment (SELEX) method. The aptamer candidates exhibited a high selectivity and sensitivity toward both cTnI and the cardiac Troponin complex. The binding affinities of each aptamer were evaluated based on their dissociation constants (Kd) by surface plasma resonance. The Tro4 aptamer that had the highest binding capacity to cTnI showed a very low Kd value (270 pM) compared with that of a cTnI antibody (20.8 nM). Furthermore, we designed a new electrochemical aptasensor based on square wave voltammetry using ferrocene-modified silica nanoparticles. The developed aptasensor demonstrated an excellent analytical performance for cTnI with a wide linear range of 1-10 000 pM in a buffer and a detection limit of 1.0 pM (24 pg/mL; S/N = 3), which was noticeably lower than the cutoff values (70-400 pg/mL). The specificity of the aptamers was also examined using nontarget proteins, demonstrating that the proposed sensor responded to only cTnI. In addition, cTnI was successfully detected in a human serum albumin solution. On the basis of the calibration curve that was constructed, the concentrations of cTnI in a solution supplemented with human serum were effectively measured. The calculated values correlated well with the actual concentrations of cTnI. It is anticipated that the highly sensitive and selective aptasensor for cTnI could be readily applicable for the accurate diagnosis of AMI. PMID:26352249

  17. Effect of Acute Xanthine Oxidase Inhibition on Myocardial Energetics During Basal and Very High Cardiac Workstates

    PubMed Central

    Lee, Joseph; Hu, Qingsong; Mansoor, Abdul; Kamdar, Forum

    2014-01-01

    Myocardial ischemia is associated with reduced myocardial adenosine triphosphate (ATP) and increased free adenosine diphosphate (ADP) similar to the normal heart at very high cardiac workstates (HCW). We examined whether acute xanthine oxidase inhibition (XOI) in vivo can decrease myocardial free ADP in normal hearts functioning at basal cardiac workstates (BCW) or very HCW (catecholamine-induced). Myocardial high-energy phosphate (31P magnetic resonance spectroscopy), blood flow (radioactive microspheres), and oxygen consumption (MVO2) were measured in an open-chest canine model before and after infusion of vehicle or an XO inhibitor (allopurinol or febuxostat; n= 10 in each group) during BCW and infusion of dobutamine + dopamine to induce a very HCW. During BCW, both allopurinol and febuxostat resulted in higher phosphocreatine (PCr)/ATP, corresponding to lower ADP levels. During vehicle infusion, HCW caused a decrease of PCr/ATP and an increase in myocardial free ADP. Although XOI did not prevent an increase in free ADP during catecholamine infusion, the values in the allopurinol or febuxostat groups (0.141±0.012 and 0.136±0.011 μmol/g dry wt, respectively) remained significantly less than in the vehicle group (0.180±0.017; P<0.05). Thus, at a given rate of ATP synthesis, XOI decreased the free ADP level needed to drive ATP synthesis, suggesting a more energy-efficient status. As contractile dysfunction in ischemia is characterized by increase of myocardial free ADP and energy deficiency, the data suggest that XOI might be a potential therapy for improving energy efficiency during myocardial ischemia. PMID:21584861

  18. Acute and long-term renal and metabolic effects of piretanide in congestive cardiac failure.

    PubMed Central

    McNabb, W R; Noormohamed, F H; Lant, A F

    1988-01-01

    1. The renal and metabolic effects of the sulphamoylbenzoic acid diuretic, piretanide, have been studied, under controlled dietary conditions, in 39 patients with congestive cardiac failure. 2. In acute studies, peak saluresis occurred within 4 h of oral piretanide administration; saluresis was complete within 6 h, after which a significant antidiuretic effect was observed. Addition of triamterene, 50 mg, blunted the 0-6 h kaliuretic effect of piretanide. Over 24 h, piretanide, alone, caused insignificant urinary losses of potassium when compared with control. 3. In comparative studies, the piretanide dose-response curve was found to be parallel to that of frusemide over the dose range studied. The 0-6 h saluretic responses of piretanide, 6, 12 and 18 mg, were found to be equivalent to frusemide, 40, 80 and 120 mg respectively. The collective mean ratios of all the saluretic responses to each dose of piretanide with the corresponding dose of frusemide was observed to be 0.99 +/- 0.12, over 0-6 h period, and 0.86 +/- 0.09 over the 24 h period. The relative potency of piretanide, when compared with frusemide was found to be 6.18 (95% confidence limits 4.87-8.33), over the 0-6 h period, and 4.73 (95% confidence limits 3.65-6.14), over 24 h period. 4. In 15 patients in severe cardiac failure, urinary recovery of piretanide, over first 6 h, at the start of treatment was 21.2 +/- 2.1% while efficiency of the diuretic (mmol Na/mg drug) was 47.3 +/- 4.1. Long-term piretanide therapy was continued in the same group for up to and in some cases over 3 years. No other diuretics or potassium supplements were given. Piretanide dosage ranged from 6 to 24 mg day-1 according to clinical need. Plasma potassium fell significantly at 12 and 24 months, though remaining within the normal range. At these same times, significant elevations in both plasma urate and total fasting cholesterol were observed. Two patients developed overt gout on high dose piretanide therapy (24 mg day-1

  19. The kSORT Assay to Detect Renal Transplant Patients at High Risk for Acute Rejection: Results of the Multicenter AART Study

    PubMed Central

    Hsieh, Sue; Dai, Hong; Bestard, Oriol; Metes, Diana; Zeevi, Andrea; Gritsch, Albin; Cheeseman, Jennifer; Macedo, Camila; Peddy, Ram; Medeiros, Mara; Vincenti, Flavio; Asher, Nancy; Salvatierra, Oscar; Shapiro, Ron; Kirk, Allan; Reed, Elaine; Sarwal, Minnie M.

    2014-01-01

    Background Development of noninvasive molecular assays to improve disease diagnosis and patient monitoring is a critical need. In renal transplantation, acute rejection (AR) increases the risk for chronic graft injury and failure. Noninvasive diagnostic assays to improve current late and nonspecific diagnosis of rejection are needed. We sought to develop a test using a simple blood gene expression assay to detect patients at high risk for AR. Methods and Findings We developed a novel correlation-based algorithm by step-wise analysis of gene expression data in 558 blood samples from 436 renal transplant patients collected across eight transplant centers in the US, Mexico, and Spain between 5 February 2005 and 15 December 2012 in the Assessment of Acute Rejection in Renal Transplantation (AART) study. Gene expression was assessed by quantitative real-time PCR (QPCR) in one center. A 17-gene set—the Kidney Solid Organ Response Test (kSORT)—was selected in 143 samples for AR classification using discriminant analysis (area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI 0.91–0.98), validated in 124 independent samples (AUC = 0.95; 95% CI 0.88–1.0) and evaluated for AR prediction in 191 serial samples, where it predicted AR up to 3 mo prior to detection by the current gold standard (biopsy). A novel reference-based algorithm (using 13 12-gene models) was developed in 100 independent samples to provide a numerical AR risk score, to classify patients as high risk versus low risk for AR. kSORT was able to detect AR in blood independent of age, time post-transplantation, and sample source without additional data normalization; AUC = 0.93 (95% CI 0.86–0.99). Further validation of kSORT is planned in prospective clinical observational and interventional trials. Conclusions The kSORT blood QPCR assay is a noninvasive tool to detect high risk of AR of renal transplants. Please see later in the article for the Editors' Summary PMID

  20. Cardiac Rhythm Monitoring After Acute Decompensation for Heart Failure: Results from the CARRYING ON for HF Pilot Study

    PubMed Central

    Mortara, Andrea; Diotallevi, Paolo; Gallone, Giuseppe; Mariconti, Barbara; Gronda, Edoardo; Gentili, Alessandra; Bisetti, Silvia; Botto, Giovanni Luca

    2016-01-01

    Background There’s scarce evidence about cardiovascular events (CV) in patients with hospitalization for acute heart failure (HF) and no indication for immediate device implant. Objective The CARdiac RhYthm monitorING after acute decompensatiON for Heart Failure study was designed to assess the incidence of prespecified clinical and arrhythmic events in this patient population. Methods In this pilot study, 18 patients (12 (67%) male; age 72±10; 16 (89%) NYHA II-III), who were hospitalized for HF with low left ventricular ejection fraction (LVEF) (<40%) and no immediate indication for device implant received an implantable loop recorder (ILR) before hospital discharge. Follow-up visits were scheduled at 3 and 6 months, and at every 6 months until study closure; device data were remotely reviewed monthly. CV mortality, unplanned CV hospitalization, and major arrhythmic events during follow-up were analyzed. Results During a median follow-up of 593 days, major CV occurred in 13 patients (72%); of those, 7 patients had at least 1 cardiac arrhythmic event, 2 had at least a clinical event (CV hospitalization or CV death), and 4 had both an arrhythmic and a CV event. Six (33%) patients experienced 10 major clinical events, 5 of them (50%) were HF related. During follow-up, 2 (11%) patients died due to a CV cause and 3 (16%) patients received a permanent cardiac device. Conclusions After an acute HF hospitalization, patients with LVEF<40% and who are not readily eligible for permanent cardiac device implant have a known high incidence of major CV event. In these patients, ILR allows early detection of major cardiac arrhythmias and the ability to react appropriately in a timely manner. Trial Registration ClinicalTrials.gov NCT01216670; https://clinicaltrials.gov/ct2/show/NCT01216670 PMID:27118481

  1. Peri-operative heart-type fatty acid binding protein is associated with acute kidney injury after cardiac surgery

    PubMed Central

    Schaub, Jennifer A.; Garg, Amit X.; Coca, Steven G.; Testani, Jeffrey M.; Shlipak, Michael G.; Eikelboom, John; Kavsak, Peter; McArthur, Eric; Shortt, Colleen; Whitlock, Richard; Parikh, Chirag R.

    2015-01-01

    Acute Kidney Injury (AKI) is a common complication after cardiac surgery and is associated with worse outcomes. Since heart fatty acid binding protein (H-FABP) is a myocardial protein that detects cardiac injury, we sought to determine if plasma H-FABP was associated with AKI in the TRIBE-AKI cohort; a multi-center cohort of 1219 patients at high risk for AKI who underwent cardiac surgery. The primary outcomes of interest were any AKI (Acute Kidney Injury Network (AKIN) stage 1 or higher) and severe AKI (AKIN stage 2 or higher). The secondary outcome was long-term mortality after discharge. Patients who developed AKI had higher levels of H-FABP pre- and post-operatively than patients who did not have AKI. In analyses adjusted for known AKI risk factors, first post-operative log(H-FABP) was associated with severe AKI (adjusted OR 5.39 [95% CI, 2.87-10.11] per unit increase), while pre-operative log(H-FABP) was associated with any AKI (2.07 [1.48-2.89]) and mortality (1.67 [1.17-2.37]). These relationships persisted after adjustment for change in serum creatinine (for first postoperative log(H-FABP)) and biomarkers of cardiac and kidney injury, including brain natriuretic peptide, cardiac troponin-I, interleukin-18, liver fatty acid binding protein, kidney injury molecule-1, and neutrophil gelatinase associated lipocalin. Thus, peri-operative plasma H-FABP levels may be used for risk-stratification of AKI and mortality following cardiac surgery. PMID:25830762

  2. SYSTEMIC IMBALANCE OF ESSENTIAL METALS AND CARDIAC GENE EXPRESSION IN RATS FOLLOWING ACUTE PULMONARY ZINC EXPOSURE

    EPA Science Inventory

    We have recently demonstrated that PM containing water-soluble zinc may cause cardiac injury following pulmonary exposure. To investigate if pulmonary zinc exposure causes systemic metal imbalance and direct cardiac effects, we intratracheally (IT) instilled male Wistar Kyoto (WK...

  3. Early Acute Antibody-Mediated Rejection of a Negative Flow Crossmatch 3rd Kidney Transplant with Exclusive Disparity at HLA-DP

    PubMed Central

    Mierzejewska, Beata; Schroder, Paul M.; Baum, Caitlin E.; Blair, Annette; Smith, Connie; Duquesnoy, Rene J.; Marrari, Marilyn; Gohara, Amira; Malhotra, Deepak; Kaw, Dinkar; Liwski, Robert; Rees, Michael A.; Stepkowski, Stanislaw

    2014-01-01

    Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA. PMID:24755353

  4. An autopsy case of cardiac tamponade caused by a ruptured ventricular aneurysm associated with acute myocarditis.

    PubMed

    Kondo, Takeshi; Nagasaki, Yasushi; Takahashi, Motonori; Nakagawa, Kanako; Kuse, Azumi; Morichika, Mai; Sakurada, Makoto; Asano, Migiwa; Ueno, Yasuhiro

    2016-01-01

    We report an autopsy case of hemopericardium caused by rupture of a ventricular aneurysm associated with acute myocarditis in an infant boy aged 2 years and 10 months. Three days before his death, the patient developed fever. On the day of death, he described an urge to defecate and attempted to do so in an upright position. While straining to defecate without success for a prolonged period, he stopped breathing and collapsed. On autopsy, his heart weighed 91.7 g and cardiac tamponade was evident, the pericardial cavity being filled with 140 mL of blood that had come from a 1.5-cm-long rupture in a 2.7×1.5 cm ventricular aneurysm in the posterior left ventricular wall. Patchy grayish-white discoloration was noted in the myocardium. Histologically, CD3-positive T lymphocytic infiltration accompanied by pronounced macrophage infiltration was observed in the myocardium. Hemorrhagic necrosis was detected in the area of the ventricular aneurysm. Staining for matrix metalloproteinase (MMP) expression revealed abundant MMP-2, MMP-7, and MMP-9. Polymerase chain reaction to detect viruses failed to identify any specific causative viruses in the myocardium. In this case of lymphocytic (viral) and histiocytic myocarditis with pronounced macrophage infiltration and upregulation of MMP expression, myocardial remodeling and associated wall weakening had resulted in formation and rupture of an aneurysm. PMID:26832375

  5. Acute myocardial infarction: the enduring challenge for cardiac protection and survival.

    PubMed

    Yasuda, Satoshi; Shimokawa, Hiroaki

    2009-11-01

    Although considerable advances have been made in the diagnosis and management of acute myocardial infarction (AMI), the disorder is still a major cause of morbidity and mortality worldwide and continues to pose significant therapeutic challenges. The use of biomarkers to aid the diagnosis of AMI is now increasing and has enabled better understanding of the pathophysiology of the disorder and identification of patients who require urgent reperfusion therapy. Early percutaneous coronary intervention (PCI) appears to be beneficial when performed in a timely manner with a door-to-balloon time <90 min. The goal of PCI is now shifting from simple revascularization of occluded coronary arteries to optimum reperfusion at the microvascular level. Effective strategies and pharmacological agents need to be developed for better cardiac protection during AMI. Most deaths resulting from AMI occur within 1 h of its onset, and half of them occur before hospital admission. Thus, an effective pre-hospital lifeline system should be an important priority, achieved through the chain of survival, including the immediate implementation of definitive resuscitative efforts and rapidly transporting the patients to the hospital. PMID:19809203

  6. Left Bundle Branch Block in Acute Cardiac Events: Insights From a 23-Year Registry.

    PubMed

    Alkindi, Fahad; El-Menyar, Ayman; Al-Suwaidi, Jassim; Patel, Ashfaq; Gehani, Abdurrazzak A; Singh, Rajvir; Albinali, Hajar; Arabi, Abdulrahman

    2015-10-01

    Between 1991 and 2013, we evaluated the demographics, presentations, and final diagnosis of patients hospitalized with acute cardiac events and left bundle branch block (LBBB). Of 50 992 patients, 768 (1.5%) had LBBB. Compared with non-LBBB patients, patients with LBBB were mostly older, female, diabetic, and had hypertension and chronic kidney failure (CKF; P < .001 for all). Dyspnea (P < .001) and dizziness (P = .037) were more frequent in patients with LBBB. The most frequent cause of admission with LBBB was congestive heart failure (CHF; 54.2%), followed by ST-elevation myocardial infarction (STEMI; 13.3%), valvular heart disease (9.4%), unstable angina (8.3%) and Non-STEMI (7.7%). On multivariate analysis, CKF (odds ratio [OR]: 2.02, 95% confidence interval [CI]: 1.09-3.70) and LBBB (OR: 2.96, 95% CI: 2.01-4.42) were predictors of in-hospital mortality in the entire study population. Further analysis of patients with LBBB showed that CKF (OR: 2.93, 95% CI: 1.40-6.12) was the only predictor of in-hospital mortality. Regardless the presenting symptoms, CHF was the final diagnosis in most cases with LBBB. PMID:25477500

  7. DJ-1 protects against cell death following acute cardiac ischemia–reperfusion injury

    PubMed Central

    Dongworth, R K; Mukherjee, U A; Hall, A R; Astin, R; Ong, S-B; Yao, Z; Dyson, A; Szabadkai, G; Davidson, S M; Yellon, D M; Hausenloy, D J

    2014-01-01

    Novel therapeutic targets are required to protect the heart against cell death from acute ischemia–reperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson's disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemia–reperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n=5, P<0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n=6, P<0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n=6 cells, P<0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1L166P and DJ-1Cys106A mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n≥7, P<0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection. PMID:24577080

  8. Prognostic Role of Multiple Cardiac Biomarkers in Newly Diagnosed Acute Coronary Syndrome Patients.

    PubMed

    Rahman, M M; Alam, M M; Jahan, N A; Shila, J S; Arslam, M I

    2016-04-01

    Acute coronary syndrome includes unstable angina and myocardial infarction with or without ST-segment elevation, is life-threatening disorders that remain a source of high morbidity and mortality despite advances in treatment. The aim of the study was to evaluate the prognostic role of serum cTnI, CK-MB, hsCRP, MPO and BNP in newly diagnosed acute coronary syndrome patients. This cohort study was carried out in the Department of Biochemistry, Bangabandhu Sheikh Mujib Medical University in cooperation with the Department of Cardiology, BSMMU and NICVD during the period of March 2013 to February 2014. A total 100 newly diagnosed acute coronary syndrome patients were purposively enrolled in this study within 24 hours of attacked, among them 30 were NSTEMI, 65 were STEMI and 5 were unstable angina. Serum cTnI, CK-MB, hsCRP, MPO and BNP concentrations were measured at enrollment and grouping of the study subjects were done on the basis of their empirical cut off values into two groups. In cTnI: Group I (n=20) having cTnI <4ng/ml and Group II (n=80) having cTnI ≥4ng/ml. In CK-MB: Group I (n=18) having CK-MB <10ng/ml and Group II (n= 82) having CK-MB ≥10ng/ml. In hsCRP: Group I (n=36) having hsCRP <5mg/L and Group II (n=64) having hsCRP ≥5mg/L. In MPO: Group I (n=30) having MPO <285.5pmol/L and Group II (n=70) having MPO ≥285.5pmol/L. In BNP: Group I (n=26) having BNP <135pg/ml and Group II (n=74) having BNP ≥135pg/ml. All the study subjects were treated and managed identically by standard management protocol and were followed up periodically up to three months from the onset of events during hospital stay and after discharge. Clinical outcomes of the study subjects such as good recovery, morbidity (recurrent ACS, heart failure, arrhythmia and revascularization) and mortality were evaluated with respect to their base line cTnI, CK-MB, hsCRP, MPO and BNP concentrations. Increased levels of base line cardiac biomarkers in Group II patients showed significantly

  9. Acute Kidney Injury in ICU Patients Following Non-Cardiac Surgery at Masih Daneshvari Hospital: Joint Modeling Application

    PubMed Central

    Khoundabi, Batoul; Mansourian, Marjan; Kazempoor Dizaji, Mehdi; Hashemian, Seyed Mohammadreza

    2015-01-01

    Background: Admission to the intensive care unit (ICU) is often complicated by early acute kidney injury (AKI). AKI is associated with high rates of mortality and morbidity. Risk factors and incidence of AKI have been notably high following non-cardiac surgery in the past decade. The aim of this study was to determine the hazard rate of AKI, the effect of risk factors of AKI and also to assess the changes in urine output (UO) as a predictor of AKI using joint modeling in patients undergoing non-cardiac surgery. Materials and Methods: In this retrospective cohort study, 400 non-cardiac-operated patients admitted during 3 years to the ICU of Masih Daneshvari Hospital were selected according to the consecutive sample selection method. Random mixed effect model and survival model were used to assess UO changes and the effect of UO and other risk factors on the hazard rate of AKI using joint analysis. Results: AKI occurred in 8.8% of the Iranian non-cardiac-operated patients. Survival model showed that the risk of AKI in lower diastolic blood pressure (DBP), higher Acute Physiology and Chronic Health Evaluation II score (APACHE II score), emergency surgery, longer hospitalization and male patients was higher (P=0.001). Using joint modeling, an association was found between the risk of AKI and UO (−0.19, P=0.002). Conclusion: Several predictors were found to be associated with AKI in the Iranian patients after non-cardiac surgery. A relationship between longitudinal and survival responses was found in this study and joint modeling caused considerable improvement in estimations compared to separate longitudinal and survival models. PMID:26221152

  10. Contribution of damage-associated molecular patterns to transfusion-related acute lung injury in cardiac surgery

    PubMed Central

    Müller, Marcella C.A.; Tuinman, Pieter R.; Vlaar, Alexander P.; Tuip, Anita M.; Maijoor, Kelly; Achouiti, Achmed; van t Veer, Cornelis; Vroom, Margreeth B.; Juffermans, Nicole P.

    2014-01-01

    Background The incidence of transfusion-related acute lung injury (TRALI) in cardiac surgery patients is high and this condition contributes to an adverse outcome. Damage-associated molecular pattern (DAMP) molecules, HMGB1 and S100A12, are thought to mediate inflammatory changes in acute respiratory distress syndrome. We aimed to determine whether DAMP are involved in the pathogenesis of TRALI in cardiac surgery patients. Materials and methods This was a secondary analysis of a prospective observational trial in cardiac surgery patients admitted to the Intensive Care Unit of a university hospital in the Netherlands. Fourteen TRALI cases were randomly matched with 32 transfused and non-transfused controls. Pulmonary levels of HMGB1, S100A12 and inflammatory cytokines (interleukins-1β, -6, and -8 and tumour necrosis factor-α) were determined when TRALI evolved. In addition, systemic and pulmonary levels of soluble receptor for advanced glycation end products (sRAGE) were determined. Results HMGB1 expression and levels of sRAGE in TRALI patients did not differ from those in controls. There was a trend towards higher S100A12 levels in TRALI patients compared to the controls. Furthermore, S100A12 levels were associated with increased levels of markers of pulmonary inflammation, prolonged cardiopulmonary bypass, hypoxemia and duration of mechanical ventilation. Conclusion No evidence was found that HMGB1 and sRAGE contribute to the development of TRALI. S100A12 is associated with duration of cardiopulmonary bypass, pulmonary inflammation, hypoxia and prolonged mechanical ventilation and may contribute to acute lung injury in cardiac surgery patients. PMID:24887223