Pre-transplantation specification of stem cells to cardiac lineage for regeneration of cardiac tissue.

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Mayorga, Maritza; Finan, Amanda; Penn, Marc

2009-03-01

Myocardial infarction (MI) is a lead cause of mortality in the Western world. Treatment of acute MI is focused on restoration of antegrade flow which inhibits further tissue loss, but does not restore function to damaged tissue. Chronic therapy for injured myocardial tissue involves medical therapy that attempts to minimize pathologic remodeling of the heart. End stage therapy for chronic heart failure (CHF) involves inotropic therapy to increase surviving cardiac myocyte function or mechanical augmentation of cardiac performance. Not until the point of heart transplantation, a limited resource at best, does therapy focus on the fundamental problem of needing to replace injured tissue with new contractile tissue. In this setting, the potential for stem cell therapy has garnered significant interest for its potential to regenerate or create new contractile cardiac tissue. While to date adult stem cell therapy in clinical trials has suggested potential benefit, there is waning belief that the approaches used to date lead to regeneration of cardiac tissue. As the literature has better defined the pathways involved in cardiac differentiation, preclinical studies have suggested that stem cell pretreatment to direct stem cell differentiation prior to stem cell transplantation may be a more efficacious strategy for inducing cardiac regeneration. Here we review the available literature on pre-transplantation conditioning of stem cells in an attempt to better understand stem cell behavior and their readiness in cell-based therapy for myocardial regeneration.

Mediastinitis after cardiac transplantation

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Noedir A. G. Stolf

2000-05-01

Full Text Available OBJECTIVE: Assessment of incidence and behavior of mediastinitis after cardiac transplantation. METHODS: From 1985 to 1999, 214 cardiac transplantations were performed, 12 (5.6% of the transplanted patients developed confirmed mediastinitis. Patient's ages ranged from 42 to 66 years (mean of 52.3±10.0 years and 10 (83.3% patients were males. Seven (58.3% patients showed sternal stability on palpation, 4 (33.3% patients had pleural empyema, and 2 (16.7% patients did not show purulent secretion draining through the wound. RESULTS: Staphylococcus aureus was the infectious agent identified in the wound secretion or in the mediastinum, or both, in 8 (66.7% patients. Staphylococcus epidermidis was identified in 2 (16.7% patients, Enterococcus faecalis in 1 (8.3% patient, and the cause of mediastinitis could not be determined in 1 (8.3% patient. Surgical treatment was performed on an emergency basis, and the extension of the débridement varied with local conditions. In 2 (16.7% patients, we chose to leave the surgical wound open and performed daily dressings with granulated sugar. Total sternal resection was performed in only 1 (8.3% patient. Out of this series, 5 (41.7% patients died, and the causes of death were related to the infection. Autopsy revealed persistence of mediastinitis in 1 (8.3% patient. CONCLUSION: Promptness in diagnosing mediastinitis and precocious surgical drainage have changed the natural evolution of this disease. Nevertheless, observance of the basic precepts of prophylaxis of infection is still the best way to treat mediastinitis.

Influence of preoperative propranolol on cardiac index during the anhepatic phase of liver transplantation

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Emerson Seiberlich

2015-06-01

Full Text Available INTRODUCTION: Liver transplantation is the best therapeutic option for end-stage liver disease. Non-selective beta-blocker medications such as propranolol act directly on the cardiovascular system and are often used in the prevention of gastrointestinal bleeding resulting from HP. The effects of propranolol on cardiovascular system of cirrhotic patients during liver transplantation are not known. OBJECTIVE: Evaluate the influence of propranolol used preoperatively on cardiac index during the anhepatic phase of liver transplantation. METHOD: 101 adult patients (73 male [72.2%] who underwent cadaveric donor orthotopic liver transplantation by piggyback technique with preservation of the retrohepatic inferior vena cava performed at Hospital das Clinicas, Federal University of Minas Gerais were evaluated. There was no difference in severity between groups by the MELD system, p = 0.70. The preoperative use of propranolol and the cardiac index outcome were compared during the anhepatic phase of liver transplantation in 5 groups (I: increased cardiac index, II: cardiac index reduction lower than 16%, III: cardiac index reduction equal to or greater than 16% and less than 31%, IV: cardiac index reduction equal to or greater than 31% and less than 46%, V: cardiac index reduction equal to or greater than 46%. RESULTS: Patients in group I (46.4% who received propranolol preoperatively were statistically similar to groups II (60%, III (72.7%, IV (50% and V (30.8%, p = 0.57. CONCLUSION: The use of propranolol before transplantation as prophylaxis for gastrointestinal bleeding may be considered safe, as it was not associated with worsening of cardiac index in anhepatic phase of liver transplantation.

Thallium kinetics in rat cardiac transplant rejection

International Nuclear Information System (INIS)

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

1988-01-01

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

Utility of proverb interpretation measures with cardiac transplant candidates.

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Dugbartey, A T

1998-12-01

To assess metaphorical understanding and proverb interpretation in cardiac transplant candidates, the neuropsychological assessment records of 22 adults with end-stage cardiac disease under consideration for transplantation were analyzed. Neuropsychological tests consisted of the Controlled Oral Word Association Test, Halstead Category Test, Rey-Osterrieth Complex Figure Test (Copy), Trial Making Test, and summed scores for the proverb items of the WAIS-R Comprehension subtest. Analysis showed that the group tended to interpret proverbs literally. Proverb scores were significantly associated with scores on the Similarities and Picture Arrangement subtests of the WAIS-R. There was a moderate negative association between number of reported heart attacks and Proverb scores. The need for brief yet robust assessments including measures of inferential thinking and conceptualization in transplant candidates are highlighted.

Heterotopic cardiac transplantation decreases the capacity for rat myocardial protein synthesis

International Nuclear Information System (INIS)

Klein, I.; Samarel, A.M.; Welikson, R.; Hong, C.

1991-01-01

Heterotopic cardiac isografts are vascularly perfused hearts that maintain structural and functional integrity for prolonged periods of time. When placed in an infrarenal location, the heart is hemodynamically unloaded and undergoes negative growth, leading to cardiac atrophy. At 7 and 14 days after transplantation, the transplanted heart was decreased in size compared with the in situ heart (p less than 0.001). To assess the possible mechanism(s) to account for this reduction in size we studied in vivo rates of total left ventricular (LV) protein synthesis, total LV RNA content, and 18S ribosomal RNA content by nucleic acid hybridization. The LV protein synthetic rate was 4.7 and 5.3 mg/day in the in situ heart and was significantly decreased to 2.9 and 2.7 mg/day in the transplanted hearts at 7 and 14 days, respectively. LV RNA content of the transplant declined to 53% and 48% of the in situ value at 7 and 14 days, respectively. Hybridization studies revealed that LV 18S ribosomal subunit content was reduced proportionately to total RNA in the heterotopic hearts. As a result of these changes, there was no significant difference in the efficiency of total LV protein synthesis between the in situ and transplanted hearts. The present studies demonstrate that the hemodynamic unloading and cardiac atrophy that is characteristic of heterotopic cardiac transplantation is accompanied by a decrease in LV total RNA content and 18S RNA, resulting in a decreased capacity for myocardial protein synthesis

Effect of total lymphoid irradiation on pancreatic islet xenograft survival in rats

International Nuclear Information System (INIS)

Nakajima, Y.; Lie, T.S.; Nakauo, H.; Nakagawa, K.; Segawa, M.

1984-01-01

Before transplantation of Syrian hamster pancreatic islet xenografts to diabetic rats the recipients received total lymphatic system irradiation and cyclosporin A treatment after transplantation for immunosuppression. The xenograft survival times were measured and the rat anti-hamster lymphocytotoxic titers were determined by 51 Cr release assay

Effect of total lymphoid irradiation on pancreatic islet xenograft survival in rats

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Nakajima, Y; Lie, T S [Bonn Univ. (Germany, F.R.). Chirurgische Klinik und Poliklinik; Nakauo, H; Nakagawa, K; Segawa, M [Nara Women' s Univ. (Japan). Dept. of Physics

1984-01-01

Before transplantation of Syrian hamster pancreatic islet xenografts to diabetic rats the recipients received total lymphatic system irradiation and cyclosporin A treatment after transplantation for immunosuppression. The xenograft survival times were measured and the rat anti-hamster lymphocytotoxic titers were determined by /sup 51/Cr release assay.

Pre-transplant reversible pulmonary hypertension predicts higher risk for mortality after cardiac transplantation.

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Butler, Javed; Stankewicz, Mark A; Wu, Jack; Chomsky, Don B; Howser, Renee L; Khadim, Ghazanfar; Davis, Stacy F; Pierson, Richard N; Wilson, John R

2005-02-01

Pre-transplant fixed pulmonary hypertension is associated with higher post-transplant mortality. In this study, we assessed the significance of pre-transplant reversible pulmonary hypertension in patients undergoing cardiac transplantation. Overall, we studied 182 patients with baseline normal pulmonary pressures or reversible pulmonary hypertension, defined as a decrease in pulmonary vascular resistance (PVR) to 50 mm Hg had a higher risk of death (odds ratio [OR] 5.96, 95% confidence interval [CI] 1.46 to 19.84 as compared with PAS 4.0 WU, but patients with TPG > or =16 had a higher risk of mortality (OR 4.93, 95% CI 1.84 to 13.17). PAS pressure was an independent predictor of mortality (OR 1.04, 95% CI 1.02 to 1.06). Recipient body mass index, history of sternotomy; and donor ischemic time were the other independent predictors of mortality. Pre-transplant pulmonary hypertension, even when reversible to a PVR of < or =2.5 WU, is associated with a higher mortality post-transplant.

Supplementary Administration of Everolimus Reduces Cardiac Systolic Function in Kidney Transplant Recipients.

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Tsujimura, Kazuma; Ota, Morihito; Chinen, Kiyoshi; Nagayama, Kiyomitsu; Oroku, Masato; Nishihira, Morikuni; Shiohira, Yoshiki; Abe, Masami; Iseki, Kunitoshi; Ishida, Hideki; Tanabe, Kazunari

2017-05-26

BACKGROUND The effect of everolimus, one of the mammalian targets of rapamycin inhibitors, on cardiac function was evaluated in kidney transplant recipients. MATERIAL AND METHODS Seventy-six participants who underwent kidney transplant between March 2009 and May 2016 were retrospectively reviewed. To standardize everolimus administration, the following criteria were used: (1) the recipient did not have a donor-specific antigen before kidney transplantation; (2) the recipient did not have proteinuria and uncontrollable hyperlipidemia after kidney transplantation; and (3) acute rejection was not observed on protocol biopsy 3 months after kidney transplantation. According to these criteria, everolimus administration for maintenance immunosuppression after kidney transplantation was included. Cardiac function was compared between the treatment group (n=30) and non-treatment group (n=46). RESULTS The mean observation periods of the treatment and non-treatment groups were 41.3±12.6 and 43.9±19.8 months, respectively (p=0.573). The mean ejection fraction and fractional shortening of the treatment and non-treatment groups after kidney transplant were 66.5±7.9% vs. 69.6±5.5% (p=0.024) and 37.1±6.2% vs. 39.3±4.7% (p=0.045), respectively. In the treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation did not differ significantly (p=0.604 and 0.606, respectively). In the non-treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation differed significantly (p=0.004 and 0.006, respectively). CONCLUSIONS Supplementary administration of everolimus after kidney transplantation can reduce cardiac systolic function.

Human tumour xenografts established and serially transplanted in mice immunologically deprived by thymectomy, cytosine arabinoside and whole-body irradiation

International Nuclear Information System (INIS)

Selby, P.J.; Thomas, J.M.; Peckham, M.J.

1980-01-01

Mice immunologically deprived by thymectomy, cytosine arabinoside treatment and whole-body irradiation were used to study the growth of human tumours as xenografts. 10/16 melanoma biopsies, 4/13 ovarian carcinoma biopsies and 3/6 uterine cancer biopsies grew as serially transplantable xenograft lines. The tumour lines were studied through serial passages by histology, histo-chemistry, electron microscopy, chromosome analysis, immune fluorescence, growth rate measurement and mitotic counts. They retained the characteristics of the tumours of origin, with the exception of loss of pigmentation in two melanomas, histological dedifferentiation in the uterine carcinomas, and increased mitotic frequency and growth rate in some melanomas. It was concluded that this type of animal preparation is as useful as alternative methods of immunological deprivation, or as athymic nude mice, for the growth of human tumour xenografts, at least for some experimental purposes. (author)

Tolerability of sirolimus: a decade of experience at a single cardiac transplant center.

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Thibodeau, Jennifer T; Mishkin, Joseph D; Patel, Parag C; Kaiser, Patricia A; Ayers, Colby R; Mammen, Pradeep P A; Markham, David W; Ring, William Steves; Peltz, Matthias; Drazner, Mark H

2013-01-01

Sirolimus is used in cardiac transplant recipients to prevent rejection, progression of cardiac allograft vasculopathy, and renal dysfunction. However, sirolimus has many potential side effects and its tolerability when used outside of clinical trials is not well established. We describe a decade of experience with sirolimus in cardiac transplant recipients at our institution. We retrospectively reviewed records of all adult cardiac transplant recipients living between September 1999 and February 2010 (n = 329) and identified 67 patients (20%) who received sirolimus. The indications for sirolimus were cardiac allograft vasculopathy (67%), renal dysfunction (25%), rejection (4%), and intolerability of tacrolimus (3%). One-third of patients discontinued sirolimus at a median (25th, 75th percentiles) of 0.9 (0.2, 1.6) yr of duration. Over 70% of subjects experienced an adverse event attributed to sirolimus. Adverse events were associated with higher average sirolimus levels (9.1 ng/mL vs. 7.1 ng/mL, p = 0.004). We conclude that sirolimus is frequently used in cardiac transplant recipients (20%) and commonly causes side effects, often necessitating discontinuation. Higher average sirolimus levels were associated with adverse events, suggesting that tolerability may improve if levels are maintained within the lower end of the current therapeutic range; however, the improvement in tolerability would need to be balanced with the potential for decreased efficacy. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tacrolimus-related hypertrophic cardiomyopathy in an adult cardiac transplant patient

Institute of Scientific and Technical Information of China (English)

LIU Tong; DONG Jian-zeng; GAO Yun; GAO Yu-long; CHENG Yu-tong; WANG Su; LI Zhi-zhong; ZHANG Hai-bo; MENG Xu; MA Chang-sheng

2012-01-01

Left ventricular hypertrophy associated with the use of tacrolimus is a rare complication of solid organ transplantation in adult recipients.We present a cardiac transplant recipient who developed severe concentric left ventricular hypertrophy with congestive heart failure related to myocardial hypertrophy on tacrolimus.Hypertrophy improved when the drug was discontinued and replaced with sirolimus.

Seronegative neuromyelitis optica after cardiac transplantation.

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Kim, Elecia; Van Vrancken, Michael; Shaji, Mohamed; Mir, Osman; Spak, Cedric W; Gupta, Manu; Shamim, Sadat A

2016-01-01

We report a case of a 42-year-old man who presented with progressive weakness and blindness over the course of several months and met criteria for seronegative neuromyelitis optica. This presentation was in the setting of immunosuppression following cardiac transplant. No infectious causes were found within the neuroaxis, and he ultimately died with complete blindness, quadriplegia, and respiratory failure attributed to panmyelitis and brain stem inflammation despite aggressive therapies.

Radiographic findings in the chest of patients following cardiac transplantation

International Nuclear Information System (INIS)

Shirazi, K.K.; Amendola, M.A.; Tisnado, J.; Cho, S.R.; Beachley, M.C.; Lower, R.R.

1983-01-01

The postoperative chest radiographic findings in 38 patients undergoing orthotopic (37 patients) and heterotopic (1 patient) cardiac transplantation were evaluated. Findings were correlated with those of echocardiograms, sputum and blood cultures, and lung and heart biopsies. The radiographic manifestations in the chest of these patients are classified in the following three main categories: 1) newly formed cardiac silhouette findings due to the transplanted heart itself, i.e., changes in size and shape of the new heart and pericardial effusion resulting from the placement of a smaller heart in a larger pericardial sac. 2) infectious complications due to bacteria, fungal, and other opportunistic agents secondary to immunosuppressive therapy, and 3) usual postoperatice complications following thoracomoty and open-heart surgery. (orig.)

Gelatin Hydrogel Enhances the Engraftment of Transplanted Cardiomyocytes and Angiogenesis to Ameliorate Cardiac Function after Myocardial Infarction.

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Kazuaki Nakajima

Full Text Available Cell transplantation therapy will mean a breakthrough in resolving the donor shortage in cardiac transplantation. Cardiomyocyte (CM transplantation, however, has been relatively inefficient in restoring cardiac function after myocardial infarction (MI due to low engraftment of transplanted CM. In order to ameliorate engraftment of CM, the novel transplantation strategy must be invented. Gelatin hydrogel (GH is a biodegradable water-soluble polymer gel. Gelatin is made of collagen. Although we observed that collagen strongly induced the aggregation of platelets to potentially cause coronary microembolization, GH did not enhance thrombogenicity. Therefore, GH is a suitable biomaterial in the cell therapy after heart failure. To assess the effect of GH on the improvement of cardiac function, fetal rat CM (5×10(6 or 1x10(6 cells were transplanted with GH (10 mg/ml to infarcted hearts. We compared this group with sham operated rats, CM in phosphate buffered saline (PBS, only PBS, and only GH-transplanted groups. Three weeks after transplantation, cardiac function was evaluated by echocardiography. The echocardiography confirmed that transplantation of 5×10(6 CM with GH significantly improved cardiac systolic function, compared with the CM+PBS group (fractional area change: 75.1±3.4% vs. 60.7±5.9%, p<0.05, only PBS, and only GH groups (60.1±6.5%, 65.0±2.8%, p<0.05. Pathological analyses demonstrated that in the CM+GH group, CM were efficiently engrafted in infarcted myocardium (p<0.01 and angiogenesis was significantly enhanced (p<0.05 in both central and peripheral areas of the scar. Moreover, quantitative RT-PCR revealed that angiogenic cytokines, such as basic fibroblast growth factor, vascular endothelial growth factor, and hepatocyte growth factor, were significantly enriched in the CM+GH group (p<0.05. Here, we report that GH confined the CM effectively in infarcted myocardium after transplantation, and that CM transplanted with GH

Cardiac toxoplasmosis after heart transplantation diagnosed by endomyocardial biopsy.

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Petty, L A; Qamar, S; Ananthanarayanan, V; Husain, A N; Murks, C; Potter, L; Kim, G; Pursell, K; Fedson, S

2015-10-01

We describe a case of cardiac toxoplasmosis diagnosed by routine endomyocardial biopsy in a patient with trimethoprim-sulfamethoxazole (TMP-SMX) intolerance on atovaquone prophylaxis. Data are not available on the efficacy of atovaquone as Toxoplasma gondii prophylaxis after heart transplantation. In heart transplant patients in whom TMP-SMX is not an option, other strategies may be considered, including the addition of pyrimethamine to atovaquone. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cardiac sarcoidosis and heart transplantation: a report of four consecutive patients

DEFF Research Database (Denmark)

Milman, N.; Andersen, Claus Bøgelund; Mortensen, Sven Aage

2008-01-01

Heart transplantation (HTx) is a well-established treatment for severe cardiac failure. However, HTx for cardiac sarcoidosis is rare; less than 80 patients have been reported worldwide. In many patients, the diagnosis was not made prior to HTx. The aim of this study was to describe the use of HTx...

Risk factors for biliary complications after liver transplantation from donation after cardiac death

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LYU Guoyue

2015-12-01

Full Text Available Liver transplantation has become the effective therapeutic method for end-stage liver disease, but the incidence of biliary complications after liver transplantation remains high. With an increasing number of liver transplantation procedures from donation after cardiac death (DCD, it is necessary to investigate the risk factors for biliary complications after liver transplantation from DCD and enhance our understanding of such risk factors in order to reduce biliary complications after liver transplantation from DCD.

Pregnancy after cardiac transplantation. Report of one case and review

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Solange Bordignon

2000-12-01

Full Text Available A 14-year-old female patient became pregnant 6 years after heart transplantation. The pregnancy evolved uneventfully, and the newborn infant was healthy. Five months after delivery, the mother was in good condition with preserved ventricular function, and the baby had normal neuro-psychomotor development. Even though the case reported here was a success, pregnancy following cardiac transplantation is considered a high-risk condition and remains contraindicated.

Interpretive conundrum on the exclusion criterion of "transplantation with xenografts" for tissue and cell donation.

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Cox, Michael A; Brubaker, Scott A

2012-06-01

In the context of the EU Directives for human tissues and cells (2004/23/EC, 2006/17/EC and 2006/86/EC) further interest has arisen on the practical application of a few clauses. One such aspect, for the evaluation phase of a potential donor, is the interpretation of the exclusion criterion "transplantation with xenografts." This article outlines the consensus viewpoints regarding the earlier evaluation of the risks related to xenotransplantation and describes the current status of the terminology and recommendations/laws in several healthcare sectors. The application of uniform terminology is encouraged within the healthcare sectors at the international level.

Simple, rapid 125I-labeled cyclosporine double antibody/polyethylene glycol radioimmunoassay used in a pediatric cardiac transplant program

International Nuclear Information System (INIS)

Berk, L.S.; Webb, G.; Imperio, N.C.; Nehlsen-Cannarella, S.L.; Eby, W.C.

1986-01-01

We modified the Sandoz cyclosporine radioimmunoassay because of our need for frequent clinical monitoring of cyclosporine drug levels in allo- and xenograft pediatric cardiac transplant patients. With application of a commercially available [ 125 I]cyclosporine label in place of [ 3 H]cyclosporine and a second antibody/polyethylene glycol (PEG) method of separation in place of charcoal separation, we simplified and enhanced the speed and precision of assay performance. Studies of 140 whole blood samples comparing this new method to the [ 3 H]cyclosporine radioimmunoassay (RIA) method of Berk and colleagues yielded a coefficient of correlation of 0.96 (p less than 0.00001) with means of 626 and 667 ng/ml for [ 3 H]RIA and [ 125 I]RIA, respectively, and a regression equation of y = 28 + 1.02x. The major advantages are that total assay time is reduced to approximately 1 h; [ 125 I]cyclosporine label is used, avoiding the problems associated with liquid scintillation counting; and precision is enhanced by separating bound and free fractions with second antibody/PEG. These modifications should provide for greater ease of assay performance and improved clinical utility of cyclosporine monitoring not only in the pediatric but also in the adult transplant patient

The price of donation after cardiac death in liver transplantation : a prospective cost-effectiveness study

NARCIS (Netherlands)

van der Hilst, Christian S.; IJtsma, Alexander J. C.; Bottema, Jan T.; van Hoek, Bart; Dubbeld, Jeroen; Metselaar, Herold J.; Kazemier, Geert; van den Berg, Aad P.; Porte, Robert J.; Slooff, Maarten J. H.

This study aims to perform a detailed prospective observational multicenter cost-effectiveness study by comparing liver transplantations with Donation after Brain Death (DBD) and Donation after Cardiac Death (DCD) grafts. All liver transplantations in the three Dutch liver transplant centers between

Cardiac risk stratification with myocardial perfusion imaging in potential renal-pancreas transplant recipients

International Nuclear Information System (INIS)

McCarthy, M.C.; Larcos, G.; Chapman, J.

1998-01-01

Full text: Combined renal/pancreas transplantation is used in patients with severe type-1 diabetes and renal failure. Many patients have asymptomatic coronary artery disease (CAD). Thus, myocardial perfusion imaging (MPI) is widely used for preoperative risk assessment, however, its value has recently been challenged. The purpose of this study was to determine the predictive value of MPI compared to coronary angiography and/or thirty day perioperative cardiac events (cardiac death, myocardial infarction and unstable angina). We reviewed the MPI in 132 patients that were referred for possible renal pancreas transplantation during the period between 1987 - June 1997. Fifty five patients were excluded because of: still awaiting transplantation (n=19) ongoing medical assessment (n=21), received kidney only transplant (n=6) or other factors (n=9). Thus, 77 patients form the basis of this report. Seventy one patients were transplanted, 5 had coronary angiography and one died before transplantation but with coronary anatomy defined at autopsy. All patients (39 male, 38 female; mean age 37 years) had Tl-201 or Tc-99m MIBI SPECT at Westmead (n=54) or elsewhere (n=23). Patients underwent MPI, a mean of 12.1 months before transplantation and a mean of 6 months before coronary angiography or autopsy. MPI was normal in 64 (83%) and abnormal in 13 (17%) patients. Of the abnormal MPI, 7 patients had CAD and one had unstable angina post-operatively (PPV = 8/13; 61%). One patient had a fixed defect post CABG but proceeded to transplant with-out event; the other 4 patients had normal coronary anatomy. Of the normal MPIs there were no transplant related cardiac events, but one patient required CABG >12 months post MPI and a further patient died >12 months post transplant and was shown to have CAD at autopsy (NPV=62/64;97%). In conclusion we have found an excellent NPV and an acceptable PPV for MPI in potential renal pancreas graft recipients

Cardiac risk stratification with myocardial perfusion imaging in potential renal-pancreas transplant recipients

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McCarthy, M.C.; Larcos, G.; Chapman, J. [Westmead Hospital, Westmead, Sydney, NSW (Australia). Departments of Nuclear Medicine and Ultrasound

1998-06-01

Full text: Combined renal/pancreas transplantation is used in patients with severe type-1 diabetes and renal failure. Many patients have asymptomatic coronary artery disease (CAD). Thus, myocardial perfusion imaging (MPI) is widely used for preoperative risk assessment, however, its value has recently been challenged. The purpose of this study was to determine the predictive value of MPI compared to coronary angiography and/or thirty day perioperative cardiac events (cardiac death, myocardial infarction and unstable angina). We reviewed the MPI in 132 patients that were referred for possible renal pancreas transplantation during the period between 1987 - June 1997. Fifty five patients were excluded because of: still awaiting transplantation (n=19) ongoing medical assessment (n=21), received kidney only transplant (n=6) or other factors (n=9). Thus, 77 patients form the basis of this report. Seventy one patients were transplanted, 5 had coronary angiography and one died before transplantation but with coronary anatomy defined at autopsy. All patients (39 male, 38 female; mean age 37 years) had Tl-201 or Tc-99m MIBI SPECT at Westmead (n=54) or elsewhere (n=23). Patients underwent MPI, a mean of 12.1 months before transplantation and a mean of 6 months before coronary angiography or autopsy. MPI was normal in 64 (83%) and abnormal in 13 (17%) patients. Of the abnormal MPI, 7 patients had CAD and one had unstable angina post-operatively (PPV = 8/13; 61%). One patient had a fixed defect post CABG but proceeded to transplant with-out event; the other 4 patients had normal coronary anatomy. Of the normal MPIs there were no transplant related cardiac events, but one patient required CABG >12 months post MPI and a further patient died >12 months post transplant and was shown to have CAD at autopsy (NPV=62/64;97%). In conclusion we have found an excellent NPV and an acceptable PPV for MPI in potential renal pancreas graft recipients

Stable xenon CT measurement of cerebral blood flow in cardiac transplantation candidates: Correlation with cognitive function

International Nuclear Information System (INIS)

Bello, J.A.; Fink, M.E.; Hilal, S.K.; Rose, E.A.; Reemtsma, K.

1987-01-01

Thirteen consecutive unselected patients with NYHA class 4 cardiac failure referred for cardiac transplantation underwent neurologic examination and cerebral blood flow measurement (rCBF) using the stable xenon enhanced CT method on a GE9800 system. Eleven men and two women were studied (mean age = 43.8 +- 6.1). On neurological examination, six of the patients demonstrated normal mental function; the remaining seven patients demonstrated memory, language, or learning impairment. There was no difference in mean cardiac output between the groups (4.9 L/min +- 1.68 vs. 4.2L/min +- 1.57). rCBF was significantly reduced in the impaired group. Cognitive impairment in patients with cardiac failure can be correlated with cerebral ischemia. Stable xenon CT measurement of rCBF in transplant candidates may help identify patients requiring more rapid transplantation to prevent permanent cerebral injury

Parental role in decision making about pediatric cardiac transplantation: familial and ethical considerations.

Science.gov (United States)

Higgins, S S

2001-10-01

Parents of children with complex or terminal heart conditions often face agonizing decisions about cardiac transplantation. There are differences in the level of involvement that parents prefer when making such decisions. The purpose of this study was to identify and describe parents' preferences for their roles in decisions related to cardiac transplantation. A prospective ethnographic method was used to study 24 parents of 15 children prior to their decision of accepting or rejecting the transplant option for their children. Findings revealed that the style of parent decision making ranged from a desire to make an independent, autonomous choice to a wish for an authoritarian, paternalistic choice. Nurses and physicians can best support families in this situation, showing sensitivity to the steps that parents use to make their decisions. An ethical model of decision making is proposed that includes respect for differences in beliefs and values of all persons involved in the transplantation discussion. Copyright 2001 by W.B. Saunders Company

Functional significance of cardiac reinnervation in heart transplant recipients.

Science.gov (United States)

Schwaiblmair, M; von Scheidt, W; Uberfuhr, P; Ziegler, S; Schwaiger, M; Reichart, B; Vogelmeier, C

1999-09-01

There is accumulating evidence of structural sympathetic reinnervation after human cardiac transplantation. However, the functional significance of reinnervation in terms of exercise capacity has not been established as yet; we therefore investigated the influence of reinnervation on cardiopulmonary exercise testing. After orthotopic heart transplantation 35 patients (mean age, 49.1 +/- 8.4 years) underwent positron emission tomography with scintigraphically measured uptake of C11-hydroxyephedrine (HED), lung function testing, and cardiopulmonary exercise testing. Two groups were defined based on scintigraphic findings, indicating a denervated group (n = 15) with a HED uptake of 5.45%/min and a reinnervated group (n = 20) with a HED uptake of 10.59%/min. The two study groups did not show significant differences with regard to anthropometric data, number of rejection episodes, preoperative hemodynamics, and postoperative lung function data. The reinnervated group had a significant longer time interval from transplantation (1625 +/- 1069 versus 800 +/- 1316 days, p exercise (137 +/- 15 versus 120 +/- 20 beats/min, p = .012), peak oxygen uptake (21.0 +/- 4 versus 16.1 +/- 5 mL/min/kg, p = .006), peak oxygen pulse (12.4 +/- 2.9 versus 10.2 +/- 2.7 mL/min/beat, p = .031), and anaerobic threshold (11.2 +/- 1.8 versus 9.5 +/- 2.1 mL/min, p = .046) were significantly increased in comparison to denervated transplant recipients. Additionally, a decreased functional dead space ventilation (0.24 +/- 0.05 versus 0.30 +/- 0.05, p = .004) was observed in the reinnervated group. Our study results support the hypothesis that partial sympathetic reinnervation after cardiac transplantation is of functional significance. Sympathetic reinnervation enables an increased peak oxygen uptake. This is most probably due to partial restoration of the chronotropic and inotropic competence of the heart as well as an improved oxygen delivery to the exercising muscles and a reduced ventilation

Perioperative period in cardiac transplantation from donors with brain death due to methanol poisoning

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V. N. Poptsov

2017-01-01

Full Text Available The successful use of donor hearts from people died of methanol poisoning helps reducing the deficit of donor organs for patients requiring urgent cardiac transplantation [3]. We present our experience of successful cardiac transplantations from 2 donors who died due to methanol poisoning. Given the possibility of performing a cardiac transplant from this group of donors a protocol has been developed at the V.I. Shumakov Federal Research Center of Transplantology and Artificial Organs of the Ministry of Healthcare of the Russian Federation which includes clinical, laboratory and instrumental criteria for the selection of heart donor and recipient. The possibility of delayed onset myocardial contractile dysfunction due to methanol poisoning means that a longer conditioningperiod is vital as well as compulsory clinical, laboratory and expert chocardiographic examinations of the potential donor heart.

Iodine-123 metaiodobenzylguanidine imaging of the heart in idiopathic congestive cardiomyopathy and cardiac transplants

International Nuclear Information System (INIS)

Glowniak, J.V.; Turner, F.E.; Gray, L.L.; Palac, R.T.; Lagunas-Solar, M.C.; Woodward, W.R.

1989-01-01

Iodine-123 metaiodobenzylguanidine ([ 123 I]MIBG) is a norepinephrine analog which can be used to image the sympathetic innervation of the heart. In this study, cardiac imaging with [ 123 I]MIBG was performed in patients with idiopathic congestive cardiomyopathy and compared to normal controls. Initial uptake, half-time of tracer within the heart, and heart to lung ratios were all significantly reduced in patients compared to normals. Uptake in lungs, liver, salivary glands, and spleen was similar in controls and patients with cardiomyopathy indicating that decreased MIBG uptake was not a generalized abnormality in these patients. Iodine-123 MIBG imaging was also performed in cardiac transplant patients to determine cardiac nonneuronal uptake. Uptake in transplants was less than 10% of normals in the first 2 hr and nearly undetectable after 16 hr. The decreased uptake of MIBG suggests cardiac sympathetic nerve dysfunction while the rapid washout of MIBG from the heart suggests increased cardiac sympathetic nerve activity in idiopathic congestive cardiomyopathy

Multidrug Resistant Pseudomonas Mycotic Pseudoaneurysm following Cardiac Transplant Bridged by Ventricular Assistant Device

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C. Aye

2017-01-01

Full Text Available Mycotic pseudoaneurysm of aorta following cardiac surgery is rare but is highly fatal if it is unrecognized and untreated. Here, we report a case of a 45-year-old male patient who presented with rapidly progressive multiple pseudoaneurysms of the ascending aorta infected with multidrug resistant (MDR Pseudomonas aeruginosa at 5 weeks after cardiac transplantation, on a background of prior bridging therapy with left ventricular assistant device (LVAD. The patient was successfully treated with the newer cephalosporin, Ceftolozane/Tazobactam, in combination with surgery. This is the first reported case of mycotic pseudoaneurysm infected with MDR Pseudomonas. This case also highlights the importance of high vigilance and timely multimodality treatment in the diagnosis and management of mycotic pseudoaneurysm following cardiac transplant, especially in patients who had LVAD.

Islet transplantation using donors after cardiac death: report of the Japan Islet Transplantation Registry.

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Saito, Takuro; Gotoh, Mitsukazu; Satomi, Susumu; Uemoto, Shinji; Kenmochi, Takashi; Itoh, Toshinori; Kuroda, Yoshikazu; Yasunami, Youichi; Matsumoto, Shnichi; Teraoka, Satoshi

2010-10-15

This report summarizes outcomes of islet transplantation employing donors after cardiac death (DCD) between 2004 and 2007 as reported to the Japan Islet Transplantation Registry. Sixty-five islet isolations were performed for 34 transplantations in 18 patients with insulin-dependent diabetes mellitus, including two patients who had prior kidney transplantation. All but one donor (64/65) was DCD at the time of harvesting. Factors influencing criteria for islet release included duration of low blood pressure of the donor, cold ischemic time, and usage of Kyoto solution for preservation. Multivariate analysis selected usage of Kyoto solution as most important. Of the 18 recipients, 8, 4, and 6 recipients received 1, 2, and 3 islet infusions, respectively. Overall graft survival defined as C-peptide level more than or equal to 0.3 ng/mL was 76.5%, 47.1%, and 33.6% at 1, 2, and 3 years, respectively, whereas corresponding graft survival after multiple transplantations was 100%, 80.0%, and 57.1%, respectively. All recipients remained free of severe hypoglycemia while three achieved insulin independence for 14, 79, and 215 days. HbA1c levels and requirement of exogenous insulin were significantly improved in all patients. Islet transplantation employing DCD can ameliorate severe hypoglycemic episodes, significantly improve HbA1c levels, sustain significant levels of C-peptide, and achieve insulin independence after multiple transplantations. Thus, DCD can be an important resource for islet transplantation if used under strict releasing criteria and in multiple transplantations, particularly in countries where heart-beating donors are not readily available.

Quantitative 1H MR spectroscopy of the brain in patients with congestive heart failure before and after cardiac transplantation

International Nuclear Information System (INIS)

Lim, Soo Mee; Lee, Ho Kyu; Choi, Choong Gon; Lim, Tae Hwan; Lee, Jung Hee

1999-01-01

To evaluate the effects of cardiac transplantation on the brain in patients with congestive heart failure (CHF), using quantitative 1 H MR spectroscopy ( 1 H-MRS). Ten patients with CHF underwent MRI and quantitative 1 H-MRS before and 1-2 and 4-9 months after cardiac transplantation. MR spectra were obtained from parietal white matter (PWM) and occipital gray matter (OGM) using PROBE (PROton Brain Exam). Changes in MR signal intensity were evaluated, and the cerebral metabolic concentrations in PWM and OGM were compared. For comparative purposes, 20 normal volunteers were included. No abnormal MR signal intensity was seen in the brain before or after cardiac transplantation. Changes in cerebral metabolic concentrations were observed on 1 H-MRS; concentrations of creatine (Cr) in PWM, and of N-acetylacepartate (NAA), Cr and myo-Inositol(mI) in OGM were significantly lower before transplantation. After successful transplantation, Cr levels returned to their normal range in PWM and OGM, while a slightly increase choline (Cho) level was observed in PWM. Cerebral hypoperfusion in CHF can be evaluated using 1 H-MRS. MRS may play a substantial role in monitoring the effect of cardiac transplantation

Cardiac transplant in young female patient diagnosed with diffuse systemic sclerosis.

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Bennasar, Guillermo; Carlevaris, Leandro; Secco, Anastasia; Romanini, Felix; Mamani, Marta

2016-01-01

Systemic sclerosis (SS) in a multifactorial and systemic, chronic, autoimmune disease that affects the connective tissue. We present this clinical case given the low prevalence of diffuse SS with early and progressive cardiac compromise in a young patient, and treatment with cardiac transplantation. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Computational chemical imaging for cardiovascular pathology: chemical microscopic imaging accurately determines cardiac transplant rejection.

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Saumya Tiwari

Full Text Available 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.

Transcriptome analysis of the immune reaction of the pearl oyster Pinctada fucata to xenograft from Pinctada maxima.

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Wei, Jinfen; Fan, Sigang; Liu, Baosuo; Zhang, Bo; Su, Jiaqi; Yu, Dahui

2017-08-01

The pearl oyster Pinctada maxima exhibits great difficulty to culture pearls through nuclear insertion with an allograft, but it is easy for P. fucata to culture pearls after allografting. If P. fucata could be used as a surrogate mother to culture P. maxima pearls, it would benefit the pearl culture industry of P. maxima. However, this is blocked by the immune rejection of P. fucata against P. maxima mantle grafts. In this study, the immune responses of P. fucata hemocyte to allograft and xenograft were investigated after transplantation by transcriptome analysis. In total, 107.93 Gb clean reads were produced and assembled using the reference genome of P. fucata. Gene Ontology Term enrichment and KEGG enrichment analyses indicated that apoptosis, hippo signaling pathway, oxidation-reduction, MAPK signaling pathway, ribosome, protein processing in endoplasmic reticulum, purine metabolism, NF-kappa B signaling pathway, oxidative phosphorylation, Ras signaling pathway, and ubiquitin mediated proteolysis were involved in response to transplantation. Many genes related to oxidation-reduction reactions, the MAPK signaling pathway, and apoptosis were identified by comparison of the allograft group and the xenograft group at 0 h, 6 h, 12 h, 24 h, 48 h, 72 h, and 96 h post-transplantation. Among them, the expression levels of NADH dehydrogenase, succinate dehydrogenase and other dehydrogenases were increased significantly in the xenograft groups compared with allograft groups at 0 h post transplantation, indicating that a respiratory burst of neutrophils occurred immediately after xenograft transplantation. Additionally, HSP70 was highly expressed from 0 h to 96 h in the xenograft groups, indicating an oyster immune response to the xenograft. The genes enriched in the ribosome and hippo-signaling pathways were also identified, and expression patterns of these DEGs were different as compared between transplantation and control groups. Finally, altered

Quantitative {sup 1}H MR spectroscopy of the brain in patients with congestive heart failure before and after cardiac transplantation

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Lim, Soo Mee; Lee, Ho Kyu; Choi, Choong Gon; Lim, Tae Hwan [Asan Medical Center, Ulsan Univ. College of Medicine, Ulsan (Korea, Republic of); Lee, Jung Hee [Asan Institute for Life Sciences, Seoul (Korea, Republic of)

1999-12-01

To evaluate the effects of cardiac transplantation on the brain in patients with congestive heart failure (CHF), using quantitative {sup 1}H MR spectroscopy ({sup 1}H-MRS). Ten patients with CHF underwent MRI and quantitative {sup 1}H-MRS before and 1-2 and 4-9 months after cardiac transplantation. MR spectra were obtained from parietal white matter (PWM) and occipital gray matter (OGM) using PROBE (PROton Brain Exam). Changes in MR signal intensity were evaluated, and the cerebral metabolic concentrations in PWM and OGM were compared. For comparative purposes, 20 normal volunteers were included. No abnormal MR signal intensity was seen in the brain before or after cardiac transplantation. Changes in cerebral metabolic concentrations were observed on {sup 1}H-MRS; concentrations of creatine (Cr) in PWM, and of N-acetylacepartate (NAA), Cr and myo-Inositol(mI) in OGM were significantly lower before transplantation. After successful transplantation, Cr levels returned to their normal range in PWM and OGM, while a slightly increase choline (Cho) level was observed in PWM. Cerebral hypoperfusion in CHF can be evaluated using {sup 1}H-MRS. MRS may play a substantial role in monitoring the effect of cardiac transplantation.

Eicosapentenoic Acid Attenuates Allograft Rejection in an HLA-B27/EGFP Transgenic Rat Cardiac Transplantation Model.

Science.gov (United States)

Liu, Zhong; Hatayama, Naoyuki; Xie, Lin; Kato, Ken; Zhu, Ping; Ochiya, Takahiro; Nagahara, Yukitoshi; Hu, Xiang; Li, Xiao-Kang

2012-01-01

The development of an animal model bearing definite antigens is important to facilitate the evaluation and modulation of specific allo-antigen responses after transplantation. In the present study, heterotopic cardiac transplantation was performed from F344/EGFPTg and F344/HLA-B27Tg rats to F344 rats. The F344 recipients accepted the F344/EGFPTg transplants, whereas they rejected the cardiac tissue from the F344/HLA-B27Tg rats by 39.4 ± 6.5 days, due to high production of anti-HLA-B27 IgM- and IgG-specific antibodies. In addition, immunization of F344 rats with skin grafts from F344/HLA-B27Tg rats resulted in robust production of anti- HLA-B27 IgM and IgG antibodies and accelerated the rejection of a secondary cardiac allograft (7.4 ± 1.9 days). Of interest, the F344 recipients rejected cardiac grafts from double transgenic F344/HLA-B27&EGFPTg rats within 9.0 ± 3.2 days, and this was associated with a significant increase in the infiltration of lymphocytes by day 7, suggesting a role for cellular immune rejection. Eicosapentenoic acid (EPA), one of the ω-3 polyunsaturated fatty acids in fish oil, could attenuate the production of anti-HLA IgG antibodies and B-cell proliferation, significantly prolonging double transgenic F344HLA-B27&EGFPTg to F344 rat cardiac allograft survival (36.1 ± 13.6 days). Moreover, the mRNA expression in the grafts was assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), revealing an increase in the expression of the HO-1, IL-10, TGF-β, IDO, and Foxp3 genes in the EPA-treated group. Hence, our data indicate that HLA-B27 and/or GFP transgenic proteins are useful for establishing a unique animal transplantation model to clarify the mechanism underlying the allogeneic cellular and humoral immune response, in which the transplant antigens are specifically presented. Furthermore, we also demonstrated that EPA was effective in the treatment of rat cardiac allograft rejection and may allow the development of

QUALITY OF LIFE ASSESSMENT IN CARDIAC TRANSPLANT RECIPIENTS

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A. O. Shevchenko

2014-01-01

Full Text Available Background. Quality of life (QoL is an important criterion for the treatment effi cacy that provides an important data regarding patient’s personal estimation of social adaptation and ability to perform daily duties.Methods. The study was aimed to evaluate QoL in cardiac transplant recipients. We have enrolled 42 stage D heart failure patients aged 29–61 (mean 39,23 ± 12,31 y/o, 38 males and 4 females, survived cardiac transplant surgery between Jan 2008 and Jan 2013. QoL was evaluated using the SF-36 survey prior to the heart surgery and during the follow-up period up to the 5 years.Results. Pre-operative assessment revealed low QoL indices of physical activity as well as general health status. Follow-up showed dramatic improvement in all QoL measures during 1 year after the surgery which was consistent through the whole observation period. There was an increase in physical functioning index by 2,8 times (p < 0,01, physical status dependent role functioning by 14 times (р < 0,0001, emotional status dependent role functioning by 3 times (р = 0,02, social functioning by 4,8 times (p = 0,002, pain threshold by 3 times (p = 0,02, psychic health by 3,6 times (p = 0,001, life activity by 2,6 times(p = 0,003, and total health by 1,6 times (p = 0,03. Physical activity was restored in 90% of patients during the fi rst year.Conclusion. The study shows signifi cant improvement in all QoL variables after heart transplantation in stage D heart failure patients. Main indices of physical, psychical, and social activities rise at the fi rst year and remain high during the 5-year period. These data support heart transplantation as a radical and effective method of terminal heart failure treatment.

Can tricuspid annuloplasty of the donor heart reduce valve insufficiency following cardiac transplantation with bicaval anastomosis?

Science.gov (United States)

Fiorelli, Alfredo I; Oliveira, José L; Santos, Ronaldo H B; Coelho, Guilherme B; Oliveira, Adriana S; Lourenço-Filho, Domingos D; Lapenna, Gisele; Dias, Ricardo R; Bacal, Fernando; Bocchi, Edimar A; Stolf, Noedir A G

2010-06-01

The aim of this study was to evaluate the degree of tricuspid valve insufficiency after orthotopic cardiac transplantation with bicaval anastomosis and prophylactic donor heart annuloplasty. At present, our cardiac transplantation experience includes 478 cases. After January 2002, we included 30 consecutive patients in this study who had undergone orthotopic cardiac transplantation and survived >6 months. The patients were divided into 2 groups: group I, 15 patients who underwent transplantation with prophylactic tricuspid annuloplasty on the donor heart with the De Vega technique; and group II, 15 patients who underwent transplantation without this procedure. Their preoperative clinical characteristics were the same. During the late postoperative follow-up, the degree of tricuspid insufficiency was evaluated by transthoracic Doppler echocardiography and assessed according to the Simpson scale: 0, absent; 1, mild; 2, moderate; and 3, severe. Hemodynamic parameters were evaluated invasively by means of a Swan-Ganz catheter during routine endomyocardial biopsies. The mean follow-up time was 26.9 +/- 5.4 months (range, 12-36 months). In group I, 1 patient (6.6%) died from infection in the 18th month after the operation; the death was not related to the annuloplasty. In group II, 1 death (6.6%) occurred after 10 months because of rejection (P > .05). After the 24-month follow-up, the mean degree of tricuspid insufficiency was 0.4 +/- 0.5 in group I and 1.7 +/- 0.9 in group II (P tricuspid annuloplasty on the donor heart was able to reduce significantly the degree of valvular insufficiency, even in cardiac transplantation with bicaval anastomosis; however, it did not modify significantly the hemodynamic performance of the allograft during the investigation period. It is very important to extend the observation period and casuistics to verify other benefits that this technique may offer.

Successful cardiac transplantation outcomes in patients with adult congenital heart disease.

Science.gov (United States)

Menachem, Jonathan N; Golbus, Jessica R; Molina, Maria; Mazurek, Jeremy A; Hornsby, Nicole; Atluri, Pavan; Fuller, Stephanie; Birati, Edo Y; Kim, Yuli Y; Goldberg, Lee R; Wald, Joyce W

2017-09-01

The purpose of our study is (1) to characterise patients with congenital heart disease undergoing heart transplantation by adult cardiac surgeons in a large academic medical centre and (2) to describe successful outcomes associated with our multidisciplinary approach to the evaluation and treatment of adults with congenital heart disease (ACHD) undergoing orthotopic heart transplantation (OHT). Heart failure is the leading cause of death in patients with ACHD leading to increasing referrals for OHT. The Penn Congenital Transplant Database comprises a cohort of patients with ACHD who underwent OHT between March 2010 and April 2016. We performed a retrospective cohort study of the 20 consecutive patients. Original cardiac diagnoses include single ventricle palliated with Fontan (n=8), dextro-transposition of the great arteries after atrial switch (n=4), tetralogy of Fallot (n=4), pulmonary atresia (n=1), Ebstein anomaly (n=1), unrepaired ventricular septal defect (n=1) and Noonan syndrome with coarctation of the aorta (n=1). Eight patients required pretransplant inotropes and two required pretransplant mechanical support. Nine patients underwent heart-liver transplant and three underwent heart-lung transplant. Three patients required postoperative mechanical circulatory support. Patients were followed for an average of 38 months as of April 2016, with 100% survival at 30 days and 1 year and 94% overall survival (19/20 patients). ACHD-OHT patients require highly specialised, complex and multidisciplinary healthcare. The success of our programme is attributed to using team-based, patient-centred care including our multidisciplinary staff and specialists across programmes and departments. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

CARDIAC TRANSPLANT REJECTION AND NON-INVASIVE COMON CAROTID ARTERY WALL FUNCTIONAL INDICES

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A. O. Shevchenko

2015-01-01

Full Text Available Allograft rejection would entail an increase in certain blood biomarkers and active substances derived from activated inflammatory cells which could influence entire vascular endothelial function and deteriorate arterial wall stiffness. We propose that carotid wall functional indices measured with non-invasive ultrasound could we valuable markers of the subclinical cardiac allograft rejection. Aim. Our goal was to analyze the clinical utility of functional common carotid wall (CCW variables measured with high-resolution Doppler ultrasound as a non-invasive screening tool for allograft rejection in cardiac transplant patients (pts. Methods. One hundred and seventy one pts included 93 cardiac recipients, 30 dilated cardiomyopathy waiting list pts, and 48 stable coronary artery disease (SCAD pts without decompensated heart failure were included. Along with resistive index (Ri, pulsative index (Pi, and CCW intima-media thickness (IMT, CCW rigidity index (iRIG was estimated using empirical equation. Non-invasive evaluation was performed in cardiac transplant recipients prior the endomyo- cardial biopsy. Results. Neither of Ri, Pi, or CCW IMT were different in studied subgroups. iRIG was signifi- cantly lower in SCAD pts when compared to the dilated cardiomyopathy subgroup. The later had similar values with cardiac transplant recipients without rejection. Antibody-mediated and cellular rejection were found in 22 (23.7% and 17 (18.3% cardiac recipients, respectively. Mean iRIG in pts without rejection was significantly lower in comparison to antibody-mediated rejection and cell-mediated (5514.7 ± 2404.0 vs 11856.1 ± 6643.5 and 16071.9 ± 10029.1 cm/sec2, respectively, p = 0.001. Area under ROC for iRIG was 0.90 ± 0.03 units2. Analysis showed that iRIG values above estimated treshold 7172 cm/sec2 suggested relative risk of any type of rejection 17.7 (95%CI = 6.3–49.9 sensitivity 80.5%, specificity – 81.1%, negative predictive value – 84

High-dose stabilized chlorite matrix WF10 prolongs cardiac xenograft survival in the hamster-to-rat model without inducing ultrastructural or biochemical signs of cardiotoxicity

DEFF Research Database (Denmark)

Hansen, A; Kemp, K; Kemp, E

2001-01-01

of high dose WF10 as a single drug regimen in the hamster-to-rat xenotransplantation model and searched for possible cardiotoxic side effects. WF10 prolonged cardiac xenograft survival, but did not induce tolerence or inhibit pathological signs of acute rejection. Hamsters from the donor population...

[Cardiac transplantation and neoplasms: experiences at Escola Paulista de Medicina of the Federal University of São Paulo].

Science.gov (United States)

Mello Junior, Walter Teixeira de; Branco, João Nelson R; Catani, Roberto; Aguiar, Luciano de Figueiredo; Paez, Rodrigo Pereira; Buffolo, Enio

2006-02-01

To study the occurrence and types of neoplasms developed by patients who underwent an orthotopic cardiac transplantation under the Program of Cardiac Transplantation of Escola Paulista de Medicina, Federal University of São Paulo. This is an observational study of 106 patients who underwent orthotopic cardiac transplantation from November 1986 to September 2002 and survived at least thirty days following the procedure. The triple immunosuppressive regimen given included cyclosporin A, azathioprine and a corticosteroid agent. Only two patients received OKT3 in addition to the regimen established. Mean follow-up was 61.4 months (ranging from two months to 192 months). Twenty-three patients (21.3%) developed neoplasms--56.5% of these were skin neoplasm, 30.1%, solid tumors, and 13.4% of post-transplant lymphoproliferative disease (PTLD). Mean interval between transplantation and diagnosis of neoplasm was: 54.9 months for skin neoplasm; 24.8 months for solid tumors and 70.3 months for PTLD. Malignant neoplasms are relatively common in the population studied. Skin cancer was the most common type compared to the other types of neoplasms. Solid tumors were more frequently diagnosed than the lymphoproliferative diseases in the population examined.

Avaliação da doença vascular do enxerto no transplante cardíaco: experiência de um centro brasileiro Assessment of cardiac allograft vasculopathy in cardiac transplantation: experience of a Brazilian center

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Elide Sbardellotto Mariano da Costa

2012-10-01

Full Text Available FUNDAMENTO: O transplante cardíaco continua sendo o tratamento de escolha para a insuficiência cardíaca refratária ao tratamento otimizado. Dois métodos diagnósticos apresentam elevada sensibilidade no diagnóstico de episódios de rejeição ao enxerto e Doença Vascular do Enxerto (DVE, causas importantes de mortalidade no pós-transplante. OBJETIVO: Avaliar a relação entre os resultados do ultrassom intracoronariano (USIV e os laudos das biópsias endomiocárdicas (BX no seguimento de pacientes submetidos a transplante cardíaco em um serviço de referência brasileiro. MÉTODOS: Foi realizado um ensaio epidemiológico retrospectivo observacional, com pacientes submetidos a transplante cardíaco ortotópico, no período de 2000 a 2009. Foram analisados os prontuários desses pacientes e os resultados dos USIV e BX realizados rotineiramente no seguimento clínico pós-transplante e terapêutica em uso. RESULTADOS: Dos 77 pacientes analisados, 63,63% são do sexo masculino, nas faixas etárias de 22 a 69 anos. Quanto aos resultados dos USIV, 33,96% foram classificados em Stanford classe I, e 32,08%, como Stanford IV. Dos 143 laudos das biópsias, 51,08% tiveram resultado 1R, 3R em 0,69% dos laudos, e 14,48% apresentaram a descrição de efeito Quilty. Todos usaram antiproliferativos, 80,51% usaram inibidores da calcineurina e 19,48% usaram inibidores do sinal de proliferação (ISP. CONCLUSÃO: A avaliação dos pacientes pós-transplante cardíaco por meio do USIV incorpora informações detalhadas para o diagnóstico precoce e sensível da DVE, que são complementadas pelas informações histológicas fornecidas pelas BX, estabelecendo uma possível relação causal entre a DVE e os episódios de rejeição humoral.BACKGROUND: Cardiac transplantation continues to be the treatment of choice for heart failure refractory to optimized treatment. Two methods have high sensitivity for diagnosing allograft rejection episodes and cardiac

High-sensitivity cardiac troponin I assay to screen for acute rejection in patients with heart transplant.

Science.gov (United States)

Patel, Parag C; Hill, Douglas A; Ayers, Colby R; Lavingia, Bhavna; Kaiser, Patricia; Dyer, Adrian K; Barnes, Aliessa P; Thibodeau, Jennifer T; Mishkin, Joseph D; Mammen, Pradeep P A; Markham, David W; Stastny, Peter; Ring, W Steves; de Lemos, James A; Drazner, Mark H

2014-05-01

A noninvasive biomarker that could accurately diagnose acute rejection (AR) in heart transplant recipients could obviate the need for surveillance endomyocardial biopsies. We assessed the performance metrics of a novel high-sensitivity cardiac troponin I (cTnI) assay for this purpose. Stored serum samples were retrospectively matched to endomyocardial biopsies in 98 cardiac transplant recipients, who survived ≥3 months after transplant. AR was defined as International Society for Heart and Lung Transplantation grade 2R or higher cellular rejection, acellular rejection, or allograft dysfunction of uncertain pathogenesis, leading to treatment for presumed rejection. cTnI was measured with a high-sensitivity assay (Abbott Diagnostics, Abbott Park, IL). Cross-sectional analyses determined the association of cTnI concentrations with rejection and International Society for Heart and Lung Transplantation grade and the performance metrics of cTnI for the detection of AR. Among 98 subjects, 37% had ≥1 rejection episode. cTnI was measured in 418 serum samples, including 35 paired to a rejection episode. cTnI concentrations were significantly higher in rejection versus nonrejection samples (median, 57.1 versus 10.2 ng/L; P<0.0001) and increased in a graded manner with higher biopsy scores (P(trend)<0.0001). The c-statistic to discriminate AR was 0.82 (95% confidence interval, 0.76-0.88). Using a cut point of 15 ng/L, sensitivity was 94%, specificity 60%, positive predictive value 18%, and negative predictive value 99%. A high-sensitivity cTnI assay seems useful to rule out AR in cardiac transplant recipients. If validated in prospective studies, a strategy of serial monitoring with a high-sensitivity cTnI assay may offer a low-cost noninvasive strategy for rejection surveillance. © 2014 American Heart Association, Inc.

Comparative analysis of diagnostic significance of biomarkers’ panels in cardiac recipients in the long term period after transplantation

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O. P. Shevchenko

2017-01-01

Full Text Available Aim. To perform comparative analysis of the diagnostic efficacy of sCD40L, PDGF-BB, VEGF-A and ST2 in recipients with cardiac rejection in different periods after transplantation. Materials and methods. The study included 144 cardiac recipients aged from 12 to 71 (mean age 44 ± 14 years old, among those 112 were men. Venous blood plasma taken on the same day with endomyocardial biopsy was used for the study. The concentrations of soluble CD40 ligand (sCD40L, vascular endothelial growth factor (VEGF-A, platelet-derived growth factor (PDGF-BB were measured using xMAP technology. The concentrations of ST2 were measured by ELISA. Results. Men had significantly higher levels of ST2 and VEGF-A compared to women (p = 0.03. No correlation was found between the levels of biomarkers (sCD40L, PDGF-BB, VEGF-A, ST2 and age, diagnosis before transplantation, presence of arterial hypertension and diabetes mellitus. Comparative analysis of the biomarkers’ levels didn’t show significant difference between patients with heart transplant rejection and without it in the first month and in the first year after transplantation. The ST2 level was significantly higher in patients with heart rejection (p = 0.01 in the long term period (1–5 years after transplantation compared to patients without rejection. Relative risk of cardiac transplant rejection was significantly higher in patients with high (>22.8 ng/ml ST2 level (RR = 2.59 ± 0.33; Se – 35%, Sp – 93%. However, its combination with other biomarkers improved their diagnostic value. Relative risk for panel including ST2, VEGF-A and PDGF-BB 3.47 ± 0.55, Se – 57%, Sp – 91%; relative risk for panel including ST2, sCD40L and PDGF-BB was 3.75 ± 0.59, Se – 50%, Sp – 92%. The highest diagnostic efficacy for the heart transplant rejection was reached by a panel of biomarkers that included ST2 and PDGF-BB (RR = 5.0 ± 0.56 [95% CI 1.68–14.92], Se – 63%, Sp – 94%. Conclusion. ST2 had the biggest

Effect of donor age on long-term survival following cardiac transplantation.

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Topkara, Veli K; Cheema, Faisal H; Kesavaramanujam, Satish; Mercando, Michelle L; Forster, Catherine S; Argenziano, Michael; Esrig, Barry C; Oz, Mehmet C; Naka, Yoshifumi

2006-01-01

The current shortage of donor hearts has forced the criteria of organ procurement to be extended, leading to increased use of older donor hearts to bridge the gap between demand and availability. Our objective was to analyze the effect of donor age on outcomes after cardiac transplantation. We retrospectively studied 864 patients who underwent cardiac transplantation at New York Presbyterian Hospital - Columbia University between 1992 and 2002. Patients were divided into two groups; donor age or =40 years (Group B, n = 264). Characteristics including gender, body mass index, and cytomegalovirus (CMV) status were significantly different between the two donor age groups. Race, CMV status, toxoplasmosis status, left ventricular assist device prior to transplant, diabetes mellitus, and retransplantation were similar in both the recipient groups, while age, gender, and BMI were different. Early mortality was lower in Group A, 5%, versus 9.5% in Group B. Multivariate analysis revealed recipient female gender (odd ratio (OR) = 1.71), retransplantation (OR = 1.63), and increased donor age (OR = 1.02) as significant predictors of poor survival in the recipient population. Actuarial survival at 1 year (86.7% vs 81%), 5 years (75% vs 65%), and 10 years (56% vs 42%) was significantly different as well with a log rank p = 0.002. These findings suggest that increased donor age is an independent predictor of long-term survival. However, the shortage of organs makes it difficult to follow strict guidelines when placing hearts; therefore, decisions need to be made on a relative basis.

Cardiac retransplantation is an efficacious therapy for primary cardiac allograft failure

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Acker Michael A

2008-05-01

Full Text Available Abstract Background Although orthotopic heart transplantation has been an effective treatment for end-stage heart failure, the incidence of allograft failure has increased, necessitating treatment options. Cardiac retransplantation remains the only viable long-term solution for end-stage cardiac allograft failure. Given the limited number of available donor hearts, the long term results of this treatment option need to be evaluated. Methods 709 heart transplants were performed over a 20 year period at our institution. Repeat cardiac transplantation was performed in 15 patients (2.1%. A retrospective analysis was performed to determine the efficacy of cardiac retransplantation. Variables investigated included: 1 yr and 5 yr survival, length of hospitalization, post-operative complications, allograft failure, recipient and donor demographics, renal function, allograft ischemic time, UNOS listing status, blood group, allograft rejection, and hemodynamic function. Results Etiology of primary graft failure included transplant arteriopathy (n = 10, acute rejection (n = 3, hyperacute rejection (n = 1, and a post-transplant diagnosis of metastatic melanoma in the donor (n = 1. Mean age at retransplantation was 45.5 ± 9.7 years. 1 and 5 year survival for retransplantation were 86.6% and 71.4% respectively, as compared to 90.9% and 79.1% for primary transplantation. Mean ejection fraction was 67.3 ± 12.2% at a mean follow-up of 32.6 ± 18.5 mos post-retransplant; follow-up biopsy demonstrated either ISHLT grade 1A or 0 rejection (77.5 ± 95.7 mos post-transplant. Conclusion Cardiac retransplantation is an efficacious treatment strategy for cardiac allograft failure.

Quantification of absolute myocardial perfusion at rest and during exercise with positron emission tomography after human cardiac transplantation

International Nuclear Information System (INIS)

Krivokapich, J.; Stevenson, L.W.; Kobashigawa, J.; Huang, S.C.; Schelbert, H.R.

1991-01-01

The maximal exercise capacity of cardiac transplant recipients is reduced compared with that of normal subjects. To determine if this reduced exercise capacity is related to inadequate myocardial perfusion during exercise, myocardial perfusion was measured noninvasively with use of positron emission tomography and nitrogen (N)-13 ammonia. Twelve transplant recipients with no angiographic evidence of accelerated coronary atherosclerosis were studied. Serial N-13 ammonia imaging was performed at rest and during supine bicycle exercise. The results were compared with those from 10 normal volunteers with a low probability of having cardiac disease. A two-compartment kinetic model for estimating myocardial perfusion was applied to the data. Transplant recipients achieved a significant lower exercise work load than did the volunteers (42 ± 16 vs. 128 ± 22 W), but a higher venous lactate concentration (31.3 ± 14.9 vs. 13.7 ± 4.1 mg/100 ml). Despite the difference in exercise work load, there was no significant difference in the cardiac work achieved by transplant recipients and normal subjects as evidenced by similar rate-pressure products of 24,000 ± 3,400 versus 21,300 ± 2,800 betas/min per mm Hg, respectively. In addition, myocardial blood flow during exercise was not significantly different between the two groups (1.70 ± 0.60 vs. 1.56 ± 0.71 ml/min per g, respectively). This study demonstrates that the myocardial flow response to the physiologic stress of exercise is appropriate in transplant recipients and does not appear to explain the decreased exercise capacity in these patients

Could Cells from Your Nose Fix Your Heart? Transplantation of Olfactory Stem Cells in a Rat Model of Cardiac Infarction

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Cameron McDonald

2010-01-01

Full Text Available This study examines the hypothesis that multipotent olfactory mucosal stem cells could provide a basis for the development of autologous cell transplant therapy for the treatment of heart attack. In humans, these cells are easily obtained by simple biopsy. Neural stem cells from the olfactory mucosa are multipotent, with the capacity to differentiate into developmental fates other than neurons and glia, with evidence of cardiomyocyte differentiation in vitro and after transplantation into the chick embryo. Olfactory stem cells were grown from rat olfactory mucosa. These cells are propagated as neurosphere cultures, similar to other neural stem cells. Olfactory neurospheres were grown in vitro, dissociated into single cell suspensions, and transplanted into the infarcted hearts of congeneic rats. Transplanted cells were genetically engineered to express green fluorescent protein (GFP in order to allow them to be identified after transplantation. Functional assessment was attempted using echocardiography in three groups of rats: control, unoperated; infarct only; infarcted and transplanted. Transplantation of neurosphere-derived cells from adult rat olfactory mucosa appeared to restore heart rate with other trends towards improvement in other measures of ventricular function indicated. Importantly, donor-derived cells engrafted in the transplanted cardiac ventricle and expressed cardiac contractile proteins.

The Impact of Ventricular Assist Device Prior to Transplantation on Morphological Parameters in Cardiac Allografts

DEFF Research Database (Denmark)

Wassilew, Katharina

2017-01-01

. The Cochran-Mantel-Haenzsel test was applied to assess significance of the differences in interactions between groups. To evaluate the impact of bridge- to- transplant mechanical circulatory support on development on transplant vasculopathy in cardiac allografts, the intramyocardial terminal arterial network...... allograft dysfunction, as MCS patients show a higher frequency of antibody-mediated rejection (AMR) episodes. We aimed to analyze the effects of MCS on cardiac AMR with regards to capillary C3d and C4d depositions. Regarding the functional parameters, both acute cellular rejection (ACR) and an increase...... of interstitial fibrosis (IF) often correlate with impaired ventricular function. The innate immune system, in particular macrophages, plays an important role in the resorptive process of ACR and is, on the other hand, known to promote IF. In this study we aimed to analyze the effect of ACR and specifically...

Effect of long-term calcitonin administration on steroid-induced osteoporosis after cardiac transplantation.

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Kapetanakis, Emmanouil I; Antonopoulos, Athanassios S; Antoniou, Theofani A; Theodoraki, Kassiani A; Zarkalis, Dimitrios A; Sfirakis, Peter D; Chilidou, Despina A; Alivizatos, Peter A

2005-05-01

Early, rapid bone loss and fractures after cardiac transplantation are well-documented complications of steroid administration; therefore, we undertook this study on the effects of long-term calcitonin on steroid-induced osteoporosis. Twenty-three heart transplant recipients on maintenance immunosuppression with cyclosporine, mycophenolate mofetil and prednisone were retrospectively studied. All patients received long-term prophylactic treatment with elemental calcium and vitamin D. Twelve (52.2%) patients also received long-term intranasal salmon calcitonin, whereas 11 (47.8%) received none. Bone mineral density and vertebral fractures were assessed at yearly intervals. Statistical comparisons between each group's bone loss during the first year and in the early (1 to 3 years), intermediate (4 to 6 years) and late (7+ years) post-transplantation periods were done. Lumbar spine bone loss was significant during the early follow-up period in the group not receiving calcitonin (0.744 +/- 0.114 g/cm(2) vs 0.978 +/- 0.094 g/cm(2) [p = 0.002]). The calcitonin group showed bone mineral density (BMD) levels within normal average values throughout the study period. BMD increased in the no-calcitonin group during the intermediate (4 to 6 years) and late (7+ years) follow-up periods, with values approaching normal average and no significant difference between the 2 groups (0.988 +/- 0.184 g/cm(2) vs 0.982 +/- 0.088 g/cm(2) [p = 0.944] and 0.89 +/- 0.09 g/cm(2) vs 1.048 +/- 0.239 g/cm(2) [p = 0.474], respectively). Prophylactic treatment with intranasal salmon calcitonin prevents rapid bone loss associated with high-dose steroids early after cardiac transplantation. Long-term administration does not seem warranted in re-establishing BMD.

The relative contribution of paracine effect versus direct differentiation on adipose-derived stem cell transplantation mediated cardiac repair.

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Dezhong Yang

Full Text Available BACKGROUND: Recent studies have demonstrated that transplantation of adipose-derived stem cell (ADSC can improve cardiac function in animal models of myocardial infarction (MI. However, the mechanisms underlying the beneficial effect are not fully understood. In this study, we characterized the paracrine effect of transplanted ADSC and investigated its relative importance versus direct differentiation in ADSC transplantation mediated cardiac repair. METHODOLOGY/PRINCIPAL FINDINGS: MI was experimentally induced in mice by ligation of the left anterior descending coronary artery. Either human ADSC, conditioned medium (CM collected from the same amount of ADSC or control medium was injected into the peri-infarct region immediately after MI. Compared with the control group, both ADSC and ADSC-CM significantly reduced myocardial infarct size and improved cardiac function. The therapeutic efficacy of ADSC was moderately superior to ADSC-CM. ADSC-CM significantly reduced cardiomyocyte apoptosis in the infarct border zone, to a similar degree with ADSC treatment. ADSC enhanced angiogenesis in the infarct border zone, but to a stronger degree than that seen in the ADSC-CM treatment. ADSC was able to differentiate to endothelial cell and smooth muscle cell in post-MI heart; these ADSC-derived vascular cells amount to about 9% of the enhanced angiogenesis. No cardiomyocyte differentiated from ADSC was found. CONCLUSIONS: ADSC-CM is sufficient to improve cardiac function of infarcted hearts. The therapeutic function of ADSC transplantation is mainly induced by paracrine-mediated cardioprotection and angiogenesis, while ADSC differentiation contributes a minor benefit by being involved in angiogenesis. Highlights 1 ADSC-CM is sufficient to exert a therapeutic potential. 2. ADSC was able to differentiate to vascular cells but not cardiomyocyte. 3. ADSC derived vascular cells amount to about 9% of the enhanced angiogenesis. 4. Paracrine effect is the major

Temporal morphologic changes in human colorectal carcinomas following xenografting.

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Barkla, D H; Tutton, P J

1983-03-01

The temporal morphologic changes of human colorectal carcinomas following xenografting into immunosuppressed mice were investigated by the use of light and transmission electron microscopy. The results show that colorectal carcinomas undergo a series of morphologic changes during the initial 30-day period following transplantation. During the initial 1-5-day period the majority of tumor cells die, and during the following 5-10-day period the necrotic debris created during the 1-5-day period is removed by host-supplied inflammatory cells. Only small groups of peripherally placed tumor cells survived at the end of the first 10 days. During the 10-20-day period the tumor cell populations of xenografts were reestablished by a morphologically heterogeneous population of tumor cells, and during the 20-30 day period consolidation of this process continued and some xenografts showed macroscopic evidence of growth. The authors hypothesize that human colorectal carcinomas, like the antecedent epithelium, contain subpopulations of undifferentiated cells that give rise to populations of more-differentiated cells.

Predicting acute cardiac rejection from donor heart and pre-transplant recipient blood gene expression.

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Hollander, Zsuzsanna; Chen, Virginia; Sidhu, Keerat; Lin, David; Ng, Raymond T; Balshaw, Robert; Cohen-Freue, Gabriela V; Ignaszewski, Andrew; Imai, Carol; Kaan, Annemarie; Tebbutt, Scott J; Wilson-McManus, Janet E; McMaster, Robert W; Keown, Paul A; McManus, Bruce M

2013-02-01

Acute rejection in cardiac transplant patients remains a contributory factor to limited survival of implanted hearts. Currently, there are no biomarkers in clinical use that can predict, at the time of transplantation, the likelihood of post-transplant acute cellular rejection. Such a development would be of great value in personalizing immunosuppressive treatment. Recipient age, donor age, cold ischemic time, warm ischemic time, panel-reactive antibody, gender mismatch, blood type mismatch and human leukocyte antigens (HLA-A, -B and -DR) mismatch between recipients and donors were tested in 53 heart transplant patients for their power to predict post-transplant acute cellular rejection. Donor transplant biopsy and recipient pre-transplant blood were also examined for the presence of genomic biomarkers in 7 rejection and 11 non-rejection patients, using non-targeted data mining techniques. The biomarker based on the 8 clinical variables had an area under the receiver operating characteristic curve (AUC) of 0.53. The pre-transplant recipient blood gene-based panel did not yield better performance, but the donor heart tissue gene-based panel had an AUC = 0.78. A combination of 25 probe sets from the transplant donor biopsy and 18 probe sets from the pre-transplant recipient whole blood had an AUC = 0.90. Biologic pathways implicated include VEGF- and EGFR-signaling, and MAPK. Based on this study, the best predictive biomarker panel contains genes from recipient whole blood and donor myocardial tissue. This panel provides clinically relevant prediction power and, if validated, may personalize immunosuppressive treatment and rejection monitoring. Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Targeting the Innate Immune Response to Improve Cardiac Graft Recovery after Heart Transplantation: Implications for the Donation after Cardiac Death

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Stefano Toldo

2016-06-01

Full Text Available Heart transplantation (HTx is the ultimate treatment for end-stage heart failure. The number of patients on waiting lists for heart transplants, however, is much higher than the number of available organs. The shortage of donor hearts is a serious concern since the population affected by heart failure is constantly increasing. Furthermore, the long-term success of HTx poses some challenges despite the improvement in the management of the short-term complications and in the methods to limit graft rejection. Myocardial injury occurs during transplantation. Injury initiated in the donor as result of brain or cardiac death is exacerbated by organ procurement and storage, and is ultimately amplified by reperfusion injury at the time of transplantation. The innate immune system is a mechanism of first-line defense against pathogens and cell injury. Innate immunity is activated during myocardial injury and produces deleterious effects on the heart structure and function. Here, we briefly discuss the role of the innate immunity in the initiation of myocardial injury, with particular focus on the Toll-like receptors and inflammasome, and how to potentially expand the donor population by targeting the innate immune response.

Hepatobiliary scanning in cardiac transplant patients maintained on cyclosporine

International Nuclear Information System (INIS)

Dhekne, R.D.; Long, S.E.; Moore, W.H.; Frazier, O.H.

1987-01-01

Many patients receiving cyclosporine (CSA) develop hepatic dysfunction or pancreatitis. The authors reviewed 106 records of cardiac transplant patients maintained on CSA. Eleven patients underwent 16 hepatobiliary scans (HBSs) for abdominal pain and/or abnormal liver function. Of 16 HBSs, ten demonstrated normal gallbladder visualization. Follow-up in all cases confirmed scan findings. Five patients had no gallbladder visualization; confirmation of acute cholecystitis was obtained by surgery in two and by autopsy in three. One patient had previous cholecystectomy. The authors found HPS useful for evaluating acute cholecystitis in patients receiving CSA with or without associated drug-related pancreatitis and hepatic insufficiency and suggest that HBS can assist in the selection of patients for CSA dose adjustment

Some quantitative studies on the transplantation of human tissues into nude mice

International Nuclear Information System (INIS)

Zietman, A.; Suit, H.D.; Sedlacek, R.

1987-01-01

Quantitative cell transplantation assays (TD/sub 50/) were performed for human tumors xenografted into athymic NCr(nμ/nμ) nude mice. Transplantation assays for FaDu when transplanted into brain and when transplanted into subcutaneous tissues are compared. Effects of immunization are discussed and results are given

Allogeneic unresponsiveness to orthotopic cardiac transplants in DL-A-identical radiation chimeras

International Nuclear Information System (INIS)

Boyd, A.D.; Spencer, F.C.; Hirose, H.; Engelman, R.M.; Cannon, F.D.; Ferrebee, J.W.; Rapaport, F.T.

1975-01-01

Nine Cooperstown beagles of known DL-A genotypes were exposed to supralethal total-body irradiation and received bone-marrow allografts from DL-A-identical donors. Four to 5 months later, the resulting chimeras received orthotopic cardiac allografts from their corresponding donors of marrow. Six chimeras died of operative complications in the immediate postoperative period. The other 3 chimeras survived from 173 to 547 days; 1 dog died at 173 days as a result of right-sided heart failure, secondary to stenosis at the site of the pulmonary artery anastomosis. The other two recipients continue to be active and healthy at 545 and 547 days. The results indicate that dogs can be rendered specifically tolerant to orthotopic cardiac allografts by supralethal total-body irradiation and the transplantation of marrow obtained from the prospective allograft donor

Cryopreservation of human colorectal carcinomas prior to xenografting

International Nuclear Information System (INIS)

Linnebacher, Michael; Maletzki, Claudia; Ostwald, Christiane; Klier, Ulrike; Krohn, Mathias; Klar, Ernst; Prall, Friedrich

2010-01-01

Molecular heterogeneity of colorectal carcinoma (CRC) is well recognized, forming the rationale for molecular tests required before administration of some of the novel targeted therapies that now are rapidly entering the clinics. For clinical research at least, but possibly even for future individualized tumor treatment on a routine basis, propagation of patients' CRC tissue may be highly desirable for detailed molecular, biochemical or functional analyses. However, complex logistics requiring close liaison between surgery, pathology, laboratory researchers and animal care facilities are a major drawback in this. We here describe and evaluate a very simple cryopreservation procedure for colorectal carcinoma tissue prior to xenografting that will considerably reduce this logistic complexity. Fourty-eight CRC collected ad hoc were xenografted subcutaneously into immunodeficient mice either fresh from surgery (N = 23) or after cryopreservation (N = 31; up to 643 days). Take rates after cryopreservation were satisfactory (71%) though somewhat lower than with tumor tissues fresh from surgery (74%), but this difference was not statistically significant. Re-transplantation of cryopreserved established xenografts (N = 11) was always successful. Of note, in this series, all of the major molecular types of CRC were xenografted successfully, even after cryopreservation. Our procedure facilitates collection, long-time storage and propagation of clinical CRC specimens (even from different centres) for (pre)clinical studies of novel therapies or for basic research

Heart transplantation from older donors

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V. N. Poptsov

2017-01-01

Full Text Available In the current situation of the shortage of suitable donor organs, heart transplantation from older donors is one of the ways to increase the performance of more heart transplants, particularly, in patients with urgent need of transplantation. While planning a heart transplantation from older donor one should consider increased risk of early cardiac allograft dysfunction, preexisting coronary artery disease, accelerated transplant vasculopathy which may adversely affect early and long-term survival of recipients. Subject to careful selection of donor–recipient pairs, effective prevention and treatment of early cardiac allograft dysfunction, pre-existing atherosclerosis and transplant vasculopathy the early and long-term survival of heart transplant recipients from older donors is comparable to heart transplantation from young donors.

Impact of long term left ventricular assist device therapy on donor allocation in cardiac transplantation.

Science.gov (United States)

Uriel, Nir; Jorde, Ulrich P; Woo Pak, Sang; Jiang, Jeff; Clerkin, Kevin; Takayama, Hiroo; Naka, Yoshifumi; Schulze, P Christian; Mancini, Donna M

2013-02-01

Left Ventricular Assist Devices (LVAD) are increasingly used as a bridge to transplant (BTT) for patients with advanced congestive heart failure (CHF) and are assigned United Network for Organ Sharing (UNOS) high priority status (1B or 1A). The purpose of our study was asses the effect of organ allocation in the era of continuous flow pumps. A retrospective chart review was performed of all patients transplanted between 1/2001-1/2011 at Columbia University Medical Center. Seven hundred twenty six adult heart transplantations were performed. Two hundred seventy four BTT patients were implanted with LVAD; of which 227 patients were transplanted. Sixty three patients were transplanted as UNOS-1B, while 164 were transplanted as UNOS-1A (72%). Of these 164 patients, 65 were transplanted during their 30-day 1A period (43%) and 96 after upgrading to UNOS-1A for device complication (56%). For 452 non-device patients 139 (31%) were transplanted as UNOS-1A, 233 as UNOS-1B (52%), and 80 as UNOS-2 (17%). The percentage of patients bridged with LVAD increased from 19% in 2001 to 64% in 2010 while the number transplanted during their 30 day 1A grace period declined from 57% in 2005 to 16% in 2011; i.e. 84% of BTT patients in 2011 needed more than 30 days 1A time to be transplanted. Most LVAD patients are now transplanted while suffering device complication. There was no difference in post transplant survival between LVAD patients transplanted as UNOS 1B, 1A grace period or for a device complication As wait time for cardiac transplantation increased the percentage of patients being bridged to transplant with an LVAD has increased with the majority of them transplanted in the setting of device complication. Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

HEart trAnsplantation Registry of piTie-Salpetriere University Hospital

Science.gov (United States)

2018-01-08

Cardiac Transplant Disorder; Cardiac Death; Heart Failure; Acute Cellular Graft Rejection; Antibody-Mediated Graft Rejection; Cardiac Allograft Vasculopathy; Heart Transplant Rejection; Immune Tolerance

Sildenafil vs. Nitroprussiato de Sódio durante Teste de Reatividade Pulmonar pré-transplante cardíaco Sildenafil vs. sodium before nitroprusside for the pulmonary hypertension reversibility test before cardiac transplantation

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Aguinaldo Figueiredo Freitas Jr

2012-09-01

Full Text Available FUNDAMENTO: A hipertensão pulmonar é associada ao pior prognóstico no pós-transplante cardíaco. O teste de reatividade pulmonar com Nitroprussiato de Sódio (NPS está associado a elevados índices de hipotensão arterial sistêmica, disfunção ventricular do enxerto transplantado e elevadas taxas de desqualificação para o transplante. OBJETIVO: Neste estudo, objetivou-se comparar os efeitos do Sildenafil (SIL e NPS sobre variáveis hemodinâmicas, neuro-hormonais e ecocardiográficas durante teste de reatividade pulmonar. MÉTODOS: Os pacientes foram submetidos, simultaneamente, ao cateterismo cardíaco direito, ao ecocardiograma e à dosagem de BNP e gasometria venosa, antes e após administração de NPS (1 - 2 µg/Kg/min ou SIL (100 mg, dose única. RESULTADOS: Ambos reduziram a hipertensão pulmonar, porém o nitrato promoveu hipotensão sistêmica significativa (Pressão Arterial Média - PAM: 85,2 vs. 69,8 mmHg, p BACKGROUND: Pulmonary hypertension is associated with a worse prognosis after cardiac transplantation. The pulmonary hypertension reversibility test with sodium nitroprusside (SNP is associated with a high rate of systemic arterial hypotension, ventricular dysfunction of the transplanted graft and high rates of disqualification from transplantation. OBJECTIVE: This study was aimed at comparing the effects of sildenafil (SIL and SNP on hemodynamic, neurohormonal and echocardiographic variables during the pulmonary reversibility test. METHODS: The patients underwent simultaneously right cardiac catheterization, echocardiography, BNP measurement, and venous blood gas analysis before and after receiving either SNP (1 - 2 µg/kg/min or SIL (100 mg, single dose. RESULTS: Both drugs reduced pulmonary hypertension, but SNP caused a significant systemic hypotension (mean blood pressure - MBP: 85.2 vs. 69.8 mm Hg; p < 0.001. Both drugs reduced cardiac dimensions and improved left cardiac function (SNP: 23.5 vs. 24.8%, p = 0

Prevalence of nursing diagnosis of decreased cardiac output and the predictive value of defining characteristics in patients under evaluation for heart transplant

OpenAIRE

Matos, Lígia Neres; Guimarães, Tereza Cristina Felippe; Brandão, Marcos Antônio Gomes; Santoro, Deyse Conceição

2012-01-01

The purposes of the study were to identify the prevalence of defining characteristics (DC) of decreased cardiac output (DCO) in patients with cardiac insufficiency under evaluation for heart transplantation, and to ascertain the likelihood of defining characteristics being predictive factors for the existence of reduction in cardiac output. Data was obtained by retrospective documental analysis of the clinical records of right-sided heart catheterizations in 38 patients between 2004 and 2009....

Cardiac regeneration therapy: connections to cardiac physiology.

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Takehara, Naofumi; Matsubara, Hiroaki

2011-12-01

Without heart transplantation, a large number of patients with failing hearts worldwide face poor outcomes. By means of cardiomyocyte regeneration, cardiac regeneration therapy is emerging with great promise as a means for restoring loss of cardiac function. However, the limited success of clinical trials using bone marrow-derived cells and myoblasts with heterogeneous constituents, transplanted at a wide range of cell doses, has led to disagreement on the efficacy of cell therapy. It is therefore essential to reevaluate the evidence for the efficacy of cell-based cardiac regeneration therapy, focusing on targets, materials, and methodologies. Meanwhile, the revolutionary innovation of cardiac regeneration therapy is sorely needed to help the millions of people who suffer heart failure from acquired loss of cardiomyocytes. Cardiac regeneration has been used only in limited species or as a developing process in the rodent heart; now, the possibility of cardiomyocyte turnover in the human heart is being revisited. In the pursuit of this concept, the use of cardiac stem/progenitor stem cells in the cardiac niche must be focused to usher in a second era of cardiac regeneration therapy for the severely injured heart. In addition, tissue engineering and cellular reprogramming will advance the next era of treatment that will enable current cell-based therapy to progress to "real" cardiac regeneration therapy. Although many barriers remain, the prevention of refractory heart failure through cardiac regeneration is now becoming a realistic possibility.

Hemodynamic exercise testing. A valuable tool in the selection of cardiac transplantation candidates.

Science.gov (United States)

Chomsky, D B; Lang, C C; Rayos, G H; Shyr, Y; Yeoh, T K; Pierson, R N; Davis, S F; Wilson, J R

1996-12-15

Peak exercise oxygen consumption (Vo2), a noninvasive index of peak exercise cardiac output (CO), is widely used to select candidates for heart transplantation. However, peak exercise Vo2 can be influenced by noncardiac factors such as deconditioning, motivation, or body composition and may yield misleading prognostic information. Direct measurement of the CO response to exercise may avoid this problem and more accurately predict prognosis. Hemodynamic and ventilatory responses to maximal treadmill exercise were measured in 185 ambulatory patients with chronic heart failure who had been referred for cardiac transplantation (mean left ventricular ejection fraction, 22 +/- 7%; mean peak Vo2, 12.9 +/- 3.0 mL. min-1.kg-1). CO response to exercise was normal in 83 patients and reduced in 102. By univariate analysis, patients with normal CO responses had a better 1-year survival rate (95%) than did those with reduced CO responses (72%) (P 14 mL.min-1.kg-1 (88%) was not different from that of patients with peak Vo2 of 10 mL.min-1.kg-1 (89%) (P < .0001). By Cox regression analysis, exercise CO response was the strongest independent predictor of survival (risk ratio, 4.3), with peak Vo2 dichotomized at 10 mL. min-1.kg-1 (risk ratio, 3.3) as the only other independent predictor. Patients with reduced CO responses and peak Vo2 of < or = 10 mL.min-1.kg-1 had an extremely poor 1-year survival rate (38%). Both CO response to exercise and peak exercise Vo2 provide valuable independent prognostic information in ambulatory patients with heart failure. These variables should be used in combination to select potential heart transplantation candidates.

Plasma NGAL and glomerular filtration rate in cardiac transplant recipients treated with standard or reduced calcineurin inhibitor levels

DEFF Research Database (Denmark)

Gustafsson, Finn; Gude, Einar; Sigurdardottir, Vilborg

2014-01-01

GFR) at baseline (R(2) = 0.21; p year (median [25-75 % percentiles]: ΔmGFR 5.5 [-0.5-11.5] vs -1 [-7-4] ml/min/1.73 m(2); p = 0.006). Baseline P-NGAL predicted mGFR after 1 year (R(2) = 0.18; p ...: P-NGAL was measured in 88 cardiac transplantation patients (median 5 years post-transplant) with renal dysfunction randomized to continuation of conventional calcineurin inhibitor-based immunosuppression or switching to an everolimus-based regimen. RESULTS: P-NGAL correlated with measured GFR (m...

Transplante cardíaco e infecção Cardiac transplantation and infection

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Wilson José COUTO

2001-06-01

the incidence of infection, the etiological agents, to present the clinical aspects and the surgical morbi-mortality in patients who underwent cardiac transplant at Federal University of São Paulo. Material and Methods: From November 1966 to June 1998, a total of 97 patients were operated by the UNIFESP Cardiovascular Surgery team and survived longer than 1 week after the transplantation and were studied retrospectively as far as infections. The age of the patients ranged from 3 to 63 years (average 44.4 ± 13 years. Most of the patients had dilated myocardiopathy (46, or Chagas (24 or ischemis (23. The follow up ranged from 0.33 to 119 months (36 ± 30.7 months Results: Of the 97 patients, 16 (16.4% had infection as the main cause of death, followed by rejection in 10 (10.3%. The causes of infection were: bacterial sepsis in 6 patients, pneumonia in 6, intra-abdominal infection in 2, toxoplasmosis in 1 and cytomegalovirus infection in 1. There were 142 infection episodes, bacterial 76 (52.5%, viral 34 (28.8%, fungi 20 (17.5% and protozoa 12 (12.4%. There were 8 episodes of the reactivation were treated successfully with alopurinol. Conclusions: Our data showed the predominance of bacterial infections as the cause of most mortality. In transplanted patients suffering from Chagas´disease, the reactivation of the disease may be adequately controlled by means of alopurinol. Such data serve as orientation in our community for our programs of transplants, since they show particular aspects of our enviroment.

Transplante experimental cardíaco heterotópico e cutâneo em camundongos Experimental heterotopic cardiac and cutaneous transplantation in mice

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Patrícia Sestrheim

2005-06-01

Full Text Available OBJETIVO: Estudo experimental com o objetivo de desenvolver e avaliar a viabilidade das técnicas de transplante experimental cardíaco heterotópico abdominal vascularizado e cutâneo em camundongos, criando um instrumento para investigação da eficácia de soluções de preservação, novas drogas imunossupressoras, agentes biológicos, terapia gênica e indução de tolerância imunológica. MÉTODO: Para este estudo, as técnicas utilizadas foram descritas previamente por Corry et al. e Billingham et al. RESULTADOS: O tempo cirúrgico total para a realização dos transplantes cardíacos (n=20 foi, em média, 60,3±6,3 minutos e para os transplantes cutâneos (n=20, 17,75±0,71 minutos. A média de sobrevida dos aloenxertos cutâneos (n=34 e cardíacos (n=24 foi, respectivamente, 7 e 11 dias, enquanto que os isoenxertos sobreviveram por mais de 100 dias. CONCLUSÕES: Ambas as técnicas se caracterizaram pela fácil reprodutibilidade dos modelos experimentais. As diferenças entre as técnicas não se limitaram às peculiaridades metodológicas ou ao tempo de sobrevida e vascularização, mas principalmente à sua imunogenicidade e suscetibilidade à rejeição.OBJECTIVE: This is an experimental study which aims at developing and evaluating the feasibility of experimental techniques of vascularized and cutaneous abdominal heterotopic heart transplant in mice, creating an instrument of investigation for the effectiveness of prservation solutions, new immunosuppressive drugs, biological agents, genetic therapy and induction of immunological tolerance. METHOD: The techniques used in this work were previously described by Corry et al. and Billingham et al. RESULTS: The total surgical time to perform the cardiac transplants (n=20 was on average 60.3+6.3 minutes and the time of cutaneous transplants (n= 20 17.75+0.71 minutes. The average survival of the cutaneous allografts (n=34 and cardiac (n=24 allografts was 7 and 11 days, respectively, while

Induction of transplantation tolerance to fully mismatched cardiac allografts by T cell mediated delivery of alloantigen

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Tian, Chaorui; Yuan, Xueli; Jindra, Peter T.; Bagley, Jessamyn; Sayegh, Mohamed H.; Iacomini, John

2010-01-01

Induction of transplantation tolerance has the potential to allow for allograft acceptance without the need for life-long immunosuppression. Here we describe a novel approach that uses delivery of alloantigen by mature T cells to induce tolerance to fully allogeneic cardiac grafts. Adoptive transfer of mature alloantigen-expressing T cells into myeloablatively conditioned mice results in long-term acceptance of fully allogeneic heart transplants without evidence of chronic rejection. Since myeloablative conditioning is clinically undesirable we further demonstrated that adoptive transfer of mature alloantigen-expressing T cells alone into mice receiving non-myeloablative conditioning resulted in long-term acceptance of fully allogeneic heart allografts with minimal evidence of chronic rejection. Mechanistically, tolerance induction involved both deletion of donor-reactive host T cells and the development of regulatory T cells. Thus, delivery of alloantigen by mature T cells induces tolerance to fully allogeneic organ allografts in non-myeloablatively conditioned recipients, representing a novel approach for tolerance induction in transplantation. PMID:20452826

Efficacy of pasireotide in controlling severe hypercortisolism until cardiac transplantation

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Roberto Attanasio

2017-03-01

Full Text Available Cushing’s syndrome is associated with increased morbidity and mortality. Although surgery is the first-line treatment, drugs can still play a role as an ancillary treatment to be employed while waiting for surgery, after unsuccessful operation or in patients unsuitable for surgery. We were asked to evaluate a 32-year-old male waiting for cardiac transplantation. Idiopathic hypokinetic cardiomyopathy had been diagnosed since 6 years. He was on treatment with multiple drugs, had a pacemaker, an implantable cardioverter and an external device for the support of systolic function. Physical examination showed severely impaired general status, signs of hypercortisolism and multiple vertebral compression fractures. We administered teriparatide, and the few evaluable parameters supported the diagnosis of ACTH-dependent hypercortisolism: serum cortisol was 24.2 μg/dL in the morning and 20.3 μg/dL after overnight 1 mg dexamethasone, urinary free cortisol (UFC was 258 μg/24 h and ACTH 125 pg/mL. Pituitary CT was negative. Pasireotide 300 μg bid was administered and uptitrated to 600 μg bid. Treatment was well tolerated, achieving dramatic improvement of clinical picture with progressive normalization of serum cortisol and ACTH levels as well as UFC. After 4 months, the patient underwent successful heart transplantation. Many complications ensued and were overcome. Pituitary MRI was negative. On pasireotide 300 μg bid and prednisone 2.5 mg/day (as part of immunosuppressive therapy, morning serum cortisol and ACTH were 15.6 μg/dL and 54 pg/mL respectively, UFC was 37 μg/24 h, fasting glucose: 107 mg/dL and HbA1c: 6.5%. In conclusion, primary treatment with pasireotide achieved remission of hypercortisolism, thus allowing the patient to undergo heart transplantation.

Pulmonary infection in patients with cyclosporine, azathioprine, and corticosteroids after cardiac transplantation

International Nuclear Information System (INIS)

Murayama, Sadayuki; Ikezoe, Junpei; Godwin, J.D.; Marglin, S.I.; Allen, M.D.

1991-01-01

Between November 1985 and November 1989, 54 patients have undergone 55 cardiac transplants, 5 of whom died during operation or one week after transplantation. The remaining 49 patients with a minimum follow-up of 5 months were studied to examine pulmonary infection clinically and radiologically while receiving triple drug immunosuppression consisting of cyclosporine, azathioprine, and prednisolone. Pulmonary infection occurred in 14 patients (29%) with a total of 21 occasions. Causative organisms were identified in 9 occasions, with the most common organism being Cytomegalovirus (CMV). One patient died of pulmonary infection with Aspergillus. Causative organisms occurring in the remaining 12 occasions of pulmonary infection were unknown, which did not lead to death. Because pulmonary infection of unknown organisms rapidly responded to convensional antibiotics, it seemed to have been caused by bacteria. Pulmonary infection of unknown organism occurred 13.2±3.2 months after transplantation, as compared with 3.3±1.0 months in pulmonary infection of known organisms. Chest plain radiographic features fell into four types: (1) interstitial shadow seen in pulmonary infection of CMV, Pneumocystis carinii, or Hemophilia influenza, (2) patchy, and basilar and lobular consolidation shadows in bacterial pneumonia, (3) localized nodular shadow in aspergillosis, and (4) multiple patchy and confluent opacity patterns occurring in herpes simplex viral infection. Pulmonary infection of influenza bacteria for one patient and pulmonary infection of unknown organisms for 4 patients were difficult to identify from pulmonary infection of CMV. (N.K.)

β-HPV Infection Correlates with Early Stages of Carcinogenesis in Skin Tumors and Patient-Derived Xenografts from a Kidney Transplant Recipient Cohort.

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Borgogna, Cinzia; Olivero, Carlotta; Lanfredini, Simone; Calati, Federica; De Andrea, Marco; Zavattaro, Elisa; Savoia, Paola; Trisolini, Elena; Boldorini, Renzo; Patel, Girish K; Gariglio, Marisa

2018-01-01

Many malignancies that occur in high excess in kidney transplant recipients (KTRs) are due to viruses that thrive in the setting of immunosuppression. Keratinocyte carcinoma (KC), the most frequently occurring cancer type in KTR, has been associated with skin infection by human papillomavirus (HPV) from the beta genus. In this report, we extend our previous investigation aimed at identifying the presence of active β-HPV infection in skin tumors from KTRs through detection of viral protein expression. Using a combination of antibodies raised against the E4 and L1 proteins of the β-genotypes, we were able to visualize infection in five tumors [one keratoacanthoma (KA), three actinic keratoses (AKs), and one seborrheic keratoses (SKs)] that were all removed from two patients who had been both transplanted twice, had developed multiple KCs, and presented with a long history of immunosuppression (>30 years). These infected tissues displayed intraepidermal hyperplasia and increased expression of the ΔNp63 protein, which extended into the upper epithelial layers. In addition, using a xenograft model system in nude mice displaying a humanized stromal bed in the site of grafting, we successfully engrafted three AKs, two of which were derived from the aforementioned KTRs and displayed β-HPV infection in the original tumor. Of note, one AK-derived xenograft, along with its ensuing lymph node metastasis, was diagnosed as squamous cell carcinoma (SCC). In the latter, both β-HPV infection and ΔNp63 expression were no longer detectable. Although the overall success rate of engrafting was very low, the results of this study show for the first time that β-HPV + and ΔNp63 + intraepidermal hyperplasia can indeed progress to an aggressive SCC able to metastasize. Consistent with a series of reports attributing a causative role of β-HPV at early stages of skin carcinogenesis through ΔNp63 induction and increased keratinocytes stemness, here we provide in vivo evidence that

Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants.

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Kaul, A M K; Goparaju, S; Dvorina, N; Iida, S; Keslar, K S; de la Motte, C A; Valujskikh, A; Fairchild, R L; Baldwin, W M

2015-02-01

Acute and chronic rejection impact distinct compartments of cardiac allografts. Intramyocardial mononuclear cell infiltrates define acute rejection, whereas chronic rejection affects large arteries. Hearts transplanted from male to female C57BL/6 mice undergo acute rejection with interstitial infiltrates at 2 weeks that resolve by 6 weeks when large arteries develop arteriopathy. These processes are dependent on T cells because no infiltrates developed in T cell-deficient mice and transfer of CD4 T cells restored T cell as well as macrophage infiltrates and ultimately neointima formation. Markers of inflammatory macrophages were up-regulated in the interstitium acutely and decreased as markers of wound healing macrophages increased chronically. Programmed cell death protein, a negative costimulator, and its ligand PDL1 were up-regulated in the interstitium during resolution of acute rejection. Blocking PDL1:PD1 interactions in the acute phase increased interstitial T cell infiltrates. Toll-like receptor (TLR) 4 and its endogenous ligand hyaluronan were increased in arteries with neointimal expansion. Injection of hyaluronan fragments increased intragraft production of chemokines. Our data indicate that negative costimulatory pathways are critical for the resolution of acute interstitial infiltrates. In the arterial compartment recognition of endogenous ligands including hyaluronan by the innate TLRs may support the progression of arteriopathy. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Establishment of human patient-derived endometrial cancer xenografts in NOD scid gamma mice for the study of invasion and metastasis.

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Kenji Unno

Full Text Available Most endometrial cancers are detected early and have a good prognosis, while some endometrial cancers are highly invasive, metastasize early, and respond suboptimally to therapy. Currently, appropriate model systems to study the aggressive nature of these tumors are lacking. The objective of this study was to establish a mouse xenograft model of endometrial tumors derived from patients in order to study the biological aggressive characteristics that underlie invasion and metastasis.Endometrial tumor tissue fragments (1.5 mm × 1.5 mm from patients undergoing surgery, were transplanted under the renal capsule of NOD scid gamma mice. After 6-8 weeks, tumors were excised and serially transplanted into additional mice for propagation. Immunohistochemical analysis of the tumors was done for various tumor markers.Four cases of different subtypes of endometrial cancer were grown and propagated in mice. Three of the four tumor cases invaded into the kidneys and to adjacent organs. While all tumors exhibited minimal to no staining for estrogen receptor α, progesterone receptor staining was observed for tumor grafts. In addition, levels and localization of E-cadherin, cytokeratin and vimentin varied depending on subtype. Finally, all tumor xenografts stained positively for urokinase plasminogen activator while 3 tumor xenografts, which showed invasive characteristics, stained positively for urokinase plasminogen activator receptor.Endometrial tumors transplanted under the renal capsule exhibit growth, invasion and local spread. These tumors can be propagated and used to study aggressive endometrial cancer.

Propionibacterium acnes as a cause of lung abscess in a cardiac transplant recipient.

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Veitch, David; Abioye, Abu; Morris-Jones, Stephen; McGregor, Alastair

2015-12-16

A 29-year-old man was admitted with fevers, cough, left-sided chest pain and lethargy for 1 week. He had a cardiac transplant 10 years prior and was on immunosuppressive drugs. He was found to have a pulmonary lesion and went on to develop a lung abscess. Propionibacterium acnes was identified on matrix-assisted laser desorption ionisation mass spectrometry-time of flight and 16s rRNA gene sequencing after drainage. He was curatively treated with co-trimoxazole and co-amoxiclav. He divulged a longstanding history of seborrhoeic dermatitis with frequent flares leading to large volumes of squames collecting on his bed sheets. We hypothesise this was a possible route of entry: inhalation of the Propionibacterium. This case highlights how a common commensal bacterium, P. acnes, was able to cause pathology in an immunosuppressed patient. This is the only case of a patient with transplantation developing a P. acnes pulmonary infection and the only case of P. acnes causing these clinical features to be reported in the literature. 2015 BMJ Publishing Group Ltd.

Development and Validation of Predictive Models of Cardiac Mortality and Transplantation in Resynchronization Therapy

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Eduardo Arrais Rocha

2015-01-01

Full Text Available Abstract Background: 30-40% of cardiac resynchronization therapy cases do not achieve favorable outcomes. Objective: This study aimed to develop predictive models for the combined endpoint of cardiac death and transplantation (Tx at different stages of cardiac resynchronization therapy (CRT. Methods: Prospective observational study of 116 patients aged 64.8 ± 11.1 years, 68.1% of whom had functional class (FC III and 31.9% had ambulatory class IV. Clinical, electrocardiographic and echocardiographic variables were assessed by using Cox regression and Kaplan-Meier curves. Results: The cardiac mortality/Tx rate was 16.3% during the follow-up period of 34.0 ± 17.9 months. Prior to implantation, right ventricular dysfunction (RVD, ejection fraction < 25% and use of high doses of diuretics (HDD increased the risk of cardiac death and Tx by 3.9-, 4.8-, and 5.9-fold, respectively. In the first year after CRT, RVD, HDD and hospitalization due to congestive heart failure increased the risk of death at hazard ratios of 3.5, 5.3, and 12.5, respectively. In the second year after CRT, RVD and FC III/IV were significant risk factors of mortality in the multivariate Cox model. The accuracy rates of the models were 84.6% at preimplantation, 93% in the first year after CRT, and 90.5% in the second year after CRT. The models were validated by bootstrapping. Conclusion: We developed predictive models of cardiac death and Tx at different stages of CRT based on the analysis of simple and easily obtainable clinical and echocardiographic variables. The models showed good accuracy and adjustment, were validated internally, and are useful in the selection, monitoring and counseling of patients indicated for CRT.

The Australian and New Zealand Cardiothoracic Organ Transplant Registry: first report 1984-1992.

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Keogh, A M; Kaan, A

1992-12-01

This initial report of the Australian and New Zealand Cardiothoracic Organ Transplant Registry summarises the results of all cardiothoracic transplants performed between February 1984 and April 1992. A total of 549 first cardiothoracic transplant procedures and six cardiac retransplant operations were performed in five transplant units throughout Australia and New Zealand. There were 466 orthotopic cardiac transplants and one heterotopic transplant with overall survival 86% at one year and 80% at five years. Two of six patients who underwent cardiac retransplantation are alive. Fifty-three heart-lung transplants were performed with 72% one year and 42% five year survival. Twenty-nine single lung transplant procedures were undertaken, with actuarial survival 72% at 12 months. Factors influencing waiting period and post-transplant survival for each type of procedure are detailed. The relative lack of donors compared with recipient demand has produced increased waiting times for every type of cardiothoracic organ transplant.

Assessment of human MAPCs for stem cell transplantation and cardiac regeneration after myocardial infarction in SCID mice.

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Dimomeletis, Ilias; Deindl, Elisabeth; Zaruba, Marc; Groebner, Michael; Zahler, Stefan; Laslo, Saskia M; David, Robert; Kostin, Sawa; Deutsch, Markus A; Assmann, Gerd; Mueller-Hoecker, Josef; Feuring-Buske, Michaela; Franz, Wolfgang M

2010-11-01

Clinical studies suggest that transplantation of total bone marrow (BM) after myocardial infarction (MI) is feasible and potentially effective. However, focusing on a defined BM-derived stem cell type may enable a more specific and optimized treatment. Multilineage differentiation potential makes BM-derived multipotent adult progenitor cells (MAPCs) a promising stem cell pool for regenerative purposes. We analyzed the cardioregenerative potential of human MAPCs in a murine model of myocardial infarction. Human MAPCs were selected by negative depletion of CD45(+)/glycophorin(+) BM cells and plated on fibronectin-coated dishes. In vitro, stem cells were analyzed by reverse transcription polymerase chain reaction. In vivo, we transplanted human MAPCs (5 × 10(5)) by intramyocardial injection after MI in severe combined immunodeficient (SCID) beige mice. Six and 30 days after the surgical procedure, pressure-volume relationships were investigated in vivo. Heart tissues were analyzed immunohistochemically. Reverse transcription polymerase chain reaction experiments on early human MAPC passages evidenced an expression of Oct-4, a stem cell marker indicating pluripotency. In later passages, cardiac markers (Nkx2.5, GATA4, MLC-2v, MLC-2a, ANP, cTnT, cTnI,) and smooth muscle cell markers (SMA, SM22α) were expressed. Transplantation of human MAPCs into the ischemic border zone after MI resulted in an improved cardiac function at day 6 (ejection fraction, 26% vs 20%) and day 30 (ejection fraction, 30% vs 23%). Confirmation of human MAPC marker vimentin in immunohistochemistry demonstrated that human MAPC integrated in the peri-infarct region. The proliferation marker Ki67 was absent in immunohistochemistry and teratoma formation was not found, indicating no tumorous potential of transplanted human MAPCs in the tumor-sensitive SCID model. Transplantation of human MAPCs after MI ameliorates myocardial function, which may be explained by trophic effects of human MAPCs. Lack of

Proteomic Identification of Non-Gal Antibody Targets After Pig-to-Primate Cardiac Xenotransplantation

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Byrne, Guerard W.; Stalboerger, Paul G.; Davila, Eduardo; Heppelmann, Carrie J.; Gazi, Mozammel H.; McGregor, Hugh C. J.; LaBreche, Peter T.; Davies, William R.; Rao, Vinay P.; Oi, Keiji; Tazelaar, Henry D.; Logan, John S.; McGregor, Christopher G. A.

2008-01-01

Background Experience with non-antigenic galactose α1,3 galactose (αGal) polymers and development of αGal deficient pigs has reduced or eliminated the significance of this antigen in xenograft rejection. Despite these advances, delayed xenograft rejection (DXR) continues to occur most likely due to antibody responses to non-Gal endothelial cell (EC) antigens. Methods To gauge the diversity of the non-Gal antibody response we used antibody derived from CD46 transgenic heterotopic cardiac xenografts performed without T-cell immunosuppression, Group A (n = 4) and Gal knockout (GT-KO) heart transplants under tacrolimus and sirolimus immunosuppression, Group B (n = 8). Non-Gal antibody was measured by flow cytometry and by Western blots using GT-KO EC membrane antigens. A nanoLC/MS/MS analysis of proteins recovered from 2D gels was used to identify target antigens. Results Group A recipients exhibited a mixed cellular and humoral rejection. Group B recipients mainly exhibited classical DXR. Western blot analysis showed a non-Gal antibody response induced by GT+ and GT-KO hearts to an overlapping set of pig aortic EC membrane antigens. Proteomic analysis identified 14 potential target antigens but failed to define several immunodominant targets. Conclusions These experiments indicate that the non-Gal antibody response is directed to a number of stress response and inflammation related pig EC antigens and a few undefined targets. Further analysis of these antibody specificities using alternative methods is required to more fully define the repertoire of non-Gal antibody responses. PMID:18957049

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

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

2018-01-01

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

Materializing Heart Regeneration: Biomimicry of Key Observations in Cell Transplantation Therapies and Natural Cardiac Regeneration

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Kong, Yen P.; Jongpaiboonkit, Leena

2016-07-01

New regenerative paradigms are needed to address the growing global problem of heart failure as existing interventions are unsatisfactory. Outcomes from the current paradigm of cell transplantation have not been stellar but the mechanistic knowledge learned from them is instructive in the development of future paradigms. An emerging biomaterial-based approach incorporating key mechanisms and additional ones scrutinized from the process of natural heart regeneration in zebrafish may become the next evolution in cardiac repair. We highlight, with examples, tested key concepts and pivotal ones that may be integrated into a successful therapy.

Impact of fixed pulmonary hypertension on post-heart transplant outcomes in bridge-to-transplant patients

DEFF Research Database (Denmark)

Alba, Ana Carolina; Rao, Vivek; Ross, Heather J

2010-01-01

Fixed pulmonary hypertension (FPH) is considered a contraindication to cardiac transplantation. Ventricular assist device (VAD) therapy through prolonged left ventricular unloading may reverse FPH. Our aim was to assess post-transplant outcomes and survival in patients with and without FPH...

Central nervous system infections in heart transplant recipients

NARCIS (Netherlands)

van de Beek, Diederik; Patel, Robin; Daly, Richard C.; McGregor, Christopher G. A.; Wijdicks, Eelco F. M.

2007-01-01

OBJECTIVE: To study central nervous system infections after heart transplantations. DESIGN: Retrospective cohort study. SETTING: Cardiac Transplant Program at Mayo Clinic, Rochester, Minnesota. Patients Three hundred fifteen consecutive patients who underwent heart transplantation from January 1988

Update on Islet Transplantation

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McCall, Michael; James Shapiro, A.M.

2012-01-01

Clinical islet transplantation has progressed considerably over the past 12 years, and >750 patients with type 1 diabetes have received islet transplants internationally over this time. Many countries are beginning to accept the transition from research to accepted and funded clinical care, especially for patients with brittle control that cannot be stabilized by more conventional means. Major challenges remain, including the need for more than one donor, and the requirement for potent, chronic immunosuppression. Combining immunological tolerance both to allo- and autoantigens, and a limitless expandable source of stem cell- or xenograft-derived insulin-secreting cells represent remaining hurdles in moving this effective treatment to a potential cure for all those with type 1 or 2 diabetes. PMID:22762022

Circulating endothelial progenitor cell numbers are not associated with donor organ age or allograft vasculopathy in cardiac transplant recipients.

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Thomas, H E; Parry, G; Dark, J H; Arthur, H M; Keavney, B D

2009-02-01

Increasing age is associated with reduced numbers of circulating endothelial progenitor cells (EPCs). It is unclear whether this relates to depletion or impairment of bone marrow progenitors, or to deficient mobilization signals from aging tissues. In cardiac transplant patients, one previous study has reported an association between circulating EPCs and the risk of cardiac allograft vasculopathy (CAV). We investigated whether increased donor heart age, a strong risk factor for CAV, was associated with reduced circulating EPC numbers in a group of cardiac transplant recipients matched for factors which influence EPC numbers, but with maximally discordant donor heart ages. We identified 32 patient pairs, matched for factors known to influence EPC numbers, but who had discordant donor heart ages by at least 20 years. EPCs were quantified using flow cytometry for absolute counts of cells expressing all the combinations of CD45, CD34, CD133 and the kinase domain receptor (KDR). There were no significant differences in the numbers of circulating EPCs between patients with old or young donor heart age. There was no association between the presence of CAV and circulating EPC numbers. We suggest that the increased susceptibility to CAV of older donor hearts is not mediated via circulating EPCs. Our results are consistent with the theory that the normal age-related decline in EPC numbers relates to bone marrow aging rather than failure of target tissues to induce EPC mobilization.

Selective lymphoid irradiation: III. Prolongation of cardiac xenografts and allografts in presensitized rats

International Nuclear Information System (INIS)

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

1982-01-01

Selective lymphoid irradiation (SLI) with palladium-109-hematoporphyrin (Pd-H) combined with antilymphocyte globulin (ALG) induces either donor-specific permanent rat heart allograft acceptance or significant allograft prolongation depending on the degree of donor-recipient matching. The purpose of this study was to determine if SLI combined with ALG can affect ACI heart allograft survival in Lewis recipients presensitized to ACI, and of hamster heart xenografts of Lewis rats. SLI combined with ALG delays allograft and xenograft rejection in the presence of induced or preformed antidonor antibodies, and converts primarily a humoral rejection into a cellular rejection by mechanisms as yet uncertain. Such peritransplant treatment had significant effect on the levels of antidonor complement-dependent cytotoxic antibody titers but did not correlate directly with graft survival. Histological analysis of rejected hearts in all groups demonstrated primarily a humoral hyperacute rejection in control animals and in recipients treated with ALG alone, while peritransplant treatment with Pd-H and ALG resulted not only in prolonged graft survival but histologically, primarily a cellular rejection of the graft

Electrocardiographic Characteristics of Potential Organ Donors and Associations with Cardiac Allograft Utilization

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Khush, Kiran K.; Menza, Rebecca; Nguyen, John; Goldstein, Benjamin A.; Zaroff, Jonathan G.; Drew, Barbara J.

2012-01-01

Background Current regulations require that all cardiac allograft offers for transplantation must include an interpreted 12-lead electrocardiogram (ECG). However, little is known about the expected ECG findings in potential organ donors, or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for transplantation. Methods and Results A single experienced reviewer interpreted the first ECG obtained after brainstem herniation in 980 potential organ donors managed by the California Transplant Donor Network from 2002-2007. ECG abnormalities were summarized, and associations between specific ECG findings and cardiac allograft utilization for transplantation were studied. ECG abnormalities were present in 51% of all cases reviewed. The most common abnormalities included voltage criteria for left ventricular hypertrophy (LVH), prolongation of the corrected QT interval (QTc), and repolarization changes (ST/T wave abnormalities). Fifty seven percent of potential cardiac allografts in this cohort were accepted for transplantation. LVH on ECG was a strong predictor of allograft non-utilization. No significant associations were seen between QTc prolongation, repolarization changes and allograft utilization for transplantation, after adjusting for donor clinical variables and echocardiographic findings. Conclusions We have performed the first comprehensive study of ECG findings in potential donors for cardiac transplantation. Many of the common ECG abnormalities seen in organ donors may result from the heightened state of sympathetic activation that occurs after brainstem herniation, and are not associated with allograft utilization for transplantation. PMID:22615333

Heart transplantation and arterial elasticity

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Colvin-Adams M

2013-12-01

Full Text Available Monica Colvin-Adams,1 Nonyelum Harcourt,1 Robert LeDuc,2 Ganesh Raveendran,1 Yassir Sonbol,3 Robert Wilson,1 Daniel Duprez11Cardiovascular Division, University of Minnesota, Minneapolis, MN, USA; 2Division of Biostatistics University of Minnesota, Minneapolis, MN, USA; 3Cardiovascular Division, St Luke's Hospital System, Sugar Land, TX, USAObjective: Arterial elasticity is a functional biomarker that has predictive value for cardiovascular morbidity and mortality in nontransplant populations. There is little information regarding arterial elasticity in heart transplant recipients. This study aimed to characterize small (SAE and large (LAE artery elasticity in heart transplant recipients in comparison with an asymptomatic population free of overt cardiovascular disease. A second goal was to identify demographic and clinical factors associated with arterial elasticity in this unique population.Methods: Arterial pulse waveform was registered noninvasively at the radial artery in 71 heart transplant recipients between 2008 and 2010. SAEs and LAEs were derived from diastolic pulse contour analysis. Comparisons were made to a healthy cohort of 1,808 participants selected from our prevention clinic database. Multiple regression analyses were performed to evaluate associations between risk factors and SAE and LAE within the heart transplant recipients.Results: LAE and SAE were significantly lower in heart transplant recipients than in the normal cohort (P <0.01 and P < 0.0001, respectively. Female sex and history of ischemic cardiomyopathy were significantly associated with reduced LAE and SAE. Older age and the presence of moderate cardiac allograft vasculopathy were also significantly associated with reduced SAE. Transplant duration was associated with increased SAE.Conclusion: Heart transplants are associated with peripheral endothelial dysfunction and arterial stiffness, as demonstrated by a significant reduction in SAE and LAE when compared with a

Prognostic value of intravenous dipyridamole thallium imaging in patients with diabetes mellitus considered for renal transplantation

International Nuclear Information System (INIS)

Camp, A.D.; Garvin, P.J.; Hoff, J.; Marsh, J.; Byers, S.L.; Chaitman, B.R.

1990-01-01

Patients with diabetes and end-stage renal failure are known to have a high risk for cardiac morbidity and mortality associated with renal transplantation. The most efficient method to determine preoperative cardiac risk has not been established. To determine the effectiveness of intravenous dipyridamole thallium imaging in predicting cardiac events, 40 diabetic renal transplant candidates were studied preoperatively in a prospective trial. The study group consisted of 40 patients whose average age was 42 years (range 27 to 64); 34 (85%) were hypertensive and 21 (53%) were cigarette smokers. Cardiac history included chest pain in 6 patients and prior myocardial infarction in 3 patients. Dipyridamole thallium imaging showed reversible defects in 9 patients, fixed defects in 8 patients and normal scans in 23 patients. Dipyridamole thallium imaging was performed using 0.56 mg/kg of dipyridamole infused intravenously over 4 minutes. Cardiac events occurred only in patients with reversible thallium defects, of which there were 6. Of these 6 patients, 3 had cardiac events before transplantation and 3 had them in the early postoperative phase (within 6 weeks of surgery). Of 21 patients who underwent renal transplantation, 3 had cardiac events within 6 weeks of transplantation. The average duration of follow-up was 11 months (range 1 to 21). Thus, dipyridamole thallium imaging is an effective method of identifying renal transplant candidates likely to develop cardiac complications. Routine coronary angiography may not be necessary to screen all renal transplant candidates for coronary artery disease before surgery

Transplante cardíaco humano: experiência inicial Human cardiac transplant: initial experience

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Noedir A. G Stolf

1986-12-01

Full Text Available No Instituto do Coração, de março de 1985 a fevereiro de 1986,11 pacientes foram submetidos a transplante cardíaco ortotópico. Eram todos do sexo masculino, com idade variando de 39 a 54 anos; 6 com cardiopatia isquémica, 4 com cardiomiopatia dilatada e um com cardiomiopatia chagásica. Foi realizado estudo hemodinâmico através de catéter de Swan-Ganz, no pré-operatório, no pós-operatório, após estabilização na unidade de recuperação, e trinta ou mais dias após o transplante. Os dados mostram melhora progressiva em relação ao índice cardíaco, pressão em artéria pulmonar, pressão de capilar pulmonar, resistência vascular pulmonar e resistência vascular sistêmica. Três dos 11 pacientes apresentaram disfunção renal transitória no pós-operatório imediato e que regrediram até o 15º dia, enquanto que 2 pacientes apresentaram aumento moderado da creatinina plasmática. Apenas 3 pacientes não apresentaram qualquer episódio de rejeição; nos demais, esses episódios foram um diagnóstico histológico sem repercussões clínicas. Complicações infecciosas ocorreram em 9 pacientes e foram de fácil controle clínico. No pós-operatório tardio, a hipertensão esteve presente em 8 pacientes, sendo mais acentuada em 2 deles. Não houve óbitos, nesta série de pacientes; todos estão assintomáticos e os 6 primeiros estão trabalhando.At the Instituto do Cora��ão, University of São Paulo Medical School, 11 patients were submitted to heart transplantation from march 1985 up to february 1986. All were male, with ages of 39-59 years, 6 with coronary heart disease, 4 with dilated cardiomyopathy and 1 with Chagas cardiomyopathy. The patients were studied hemodynamically with a Swan-Ganz catheter pre-operatively, at the arrival in the intensive care unit, in the first postoperative day and 30 or more days after the transplant. The data showed that there was a progressive increase of cardiac index and decreases of

Heart transplantation in adults with congenital heart disease.

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Houyel, Lucile; To-Dumortier, Ngoc-Tram; Lepers, Yannick; Petit, Jérôme; Roussin, Régine; Ly, Mohamed; Lebret, Emmanuel; Fadel, Elie; Hörer, Jürgen; Hascoët, Sébastien

2017-05-01

With the advances in congenital cardiac surgery and postoperative care, an increasing number of children with complex congenital heart disease now reach adulthood. There are already more adults than children living with a congenital heart defect, including patients with complex congenital heart defects. Among these adults with congenital heart disease, a significant number will develop ventricular dysfunction over time. Heart failure accounts for 26-42% of deaths in adults with congenital heart defects. Heart transplantation, or heart-lung transplantation in Eisenmenger syndrome, then becomes the ultimate therapeutic possibility for these patients. This population is deemed to be at high risk of mortality after heart transplantation, although their long-term survival is similar to that of patients transplanted for other reasons. Indeed, heart transplantation in adults with congenital heart disease is often challenging, because of several potential problems: complex cardiac and vascular anatomy, multiple previous palliative and corrective surgeries, and effects on other organs (kidney, liver, lungs) of long-standing cardiac dysfunction or cyanosis, with frequent elevation of pulmonary vascular resistance. In this review, we focus on the specific problems relating to heart and heart-lung transplantation in this population, revisit the indications/contraindications, and update the long-term outcomes. Copyright © 2017. Published by Elsevier Masson SAS.

pO2 Fluctuation Pattern and Cycling Hypoxia in Human Cervical Carcinoma and Melanoma Xenografts

International Nuclear Information System (INIS)

Ellingsen, Christine; Øvrebø, Kirsti Marie; Galappathi, Kanthi; Mathiesen, Berit; Rofstad, Einar K.

2012-01-01

Purpose: Blood perfusion in tumors is spatially and temporally heterogeneous, resulting in local fluctuations in tissue oxygen tension (pO 2 ) and tissue regions showing cycling hypoxia. In this study, we investigated whether the pO 2 fluctuation pattern and the extent of cycling hypoxia differ between tumor types showing high (e.g., cervical carcinoma xenograft) and low (e.g., melanoma xenograft) fractions of connective tissue-associated blood vessels. Methods and Materials: Two cervical carcinoma lines (CK-160 and TS-415) and two melanoma lines (A-07 and R-18) transplanted into BALB/c nu/nu mice were included in the study. Tissue pO 2 was measured simultaneously in two positions in each tumor by using a two-channel OxyLite fiber-optic oxygen-sensing device. The extent of acute and chronic hypoxia was assessed by combining a radiobiological and a pimonidazole-based immunohistochemical assay of tumor hypoxia. Results: The proportion of tumor regions showing pO 2 fluctuations, the pO 2 fluctuation frequency in these regions, and the relative amplitude of the pO 2 fluctuations were significantly higher in the melanoma xenografts than in the cervical carcinoma xenografts. Cervical carcinoma and melanoma xenografts did not differ significantly in the fraction of acutely hypoxic cells or the fraction of chronically hypoxic cells. However, the ratio between fraction of acutely hypoxic cells and fraction of chronically hypoxic cells was significantly higher in melanoma than in cervical carcinoma xenografts. Conclusions: Temporal heterogeneity in blood flow and tissue pO 2 in tumors may depend on tumor histology. Connective tissue surrounding microvessels may stabilize blood flow and pO 2 and, thus, protect tumor tissue from cycling hypoxia.

Long-term results after aortic valve replacement with the Biocor PSB stentless xenograft in the elderly.

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Luciani, G B; Santini, F; Auriemma, S; Barozzi, L; Bertolini, P; Mazzucco, A

2001-05-01

This study seeks to define the long-term results after Biocor PSB stentless aortic valve replacement (AVR) in elderly patients, including the effects of No-React treatment. We reviewed the outcomes of 106 consecutive patients, aged 70+/-6 years, having Biocor PSB (93 standard, 13 No-React) AVR between October 1992 and October 1996. There were three early deaths (3%) and 15 late deaths (15%), during a mean follow-up of 5.8+/-1.6 years. At 8 years, survival was 82%+/-4% and freedom from cardiac death was 94%+/-3%. Freedom from valve failure was 92%+/-4% at 8 years (No-React: 92%+/-8% at 4 years). Replacement of the xenograft was required in 5 patients. Freedom from reoperation was 91%+/-4% at 8 years (No-React: 92%+/-8% at 4 years). Four bleeding and two embolic events were recorded: overall valve-related event-free survival was 81%+/-7% at 8 years (No-React: 76%+/-12% at 4 years). Age of long-term survivors averaged 77+/-5 years and their New York Heart Association status was 1.3+/-0.6 (versus 2.9+/-0.6 preoperatively, p = 0.01). Satisfactory freedom from cardiac events and from valve deterioration added to uniform improvement in functional status despite advanced age and high prevalence of comorbid conditions make AVR with the Biocor PSB xenograft a valid long-term therapy for the elderly. No-React treatment does not influence xenograft durability.

Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome.

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Saida, Satoshi; Watanabe, Ken-ichiro; Sato-Otsubo, Aiko; Terui, Kiminori; Yoshida, Kenichi; Okuno, Yusuke; Toki, Tsutomu; Wang, RuNan; Shiraishi, Yuichi; Miyano, Satoru; Kato, Itaru; Morishima, Tatsuya; Fujino, Hisanori; Umeda, Katsutsugu; Hiramatsu, Hidefumi; Adachi, Souichi; Ito, Etsuro; Ogawa, Seishi; Ito, Mamoru; Nakahata, Tatsutoshi; Heike, Toshio

2013-05-23

Transient abnormal myelopoiesis (TAM) is a clonal preleukemic disorder that progresses to myeloid leukemia of Down syndrome (ML-DS) through the accumulation of genetic alterations. To investigate the mechanism of leukemogenesis in this disorder, a xenograft model of TAM was established using NOD/Shi-scid, interleukin (IL)-2Rγ(null) mice. Serial engraftment after transplantation of cells from a TAM patient who developed ML-DS a year later demonstrated their self-renewal capacity. A GATA1 mutation and no copy number alterations (CNAs) were detected in the primary patient sample by conventional genomic sequencing and CNA profiling. However, in serial transplantations, engrafted TAM-derived cells showed the emergence of divergent subclones with another GATA1 mutation and various CNAs, including a 16q deletion and 1q gain, which are clinically associated with ML-DS. Detailed genomic analysis identified minor subclones with a 16q deletion or this distinct GATA1 mutation in the primary patient sample. These results suggest that genetically heterogeneous subclones with varying leukemia-initiating potential already exist in the neonatal TAM phase, and ML-DS may develop from a pool of such minor clones through clonal selection. Our xenograft model of TAM may provide unique insight into the evolutionary process of leukemia.

Socioeconomic aspects of heart transplantation.

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Evans, R W

1995-03-01

Heart transplantation is an established treatment modality for end-stage cardiac disease. Unfortunately, relative to other health care priorities, heart transplantation has fallen into disrepute. Efforts to reform the health care system have focused on three fundamental issues--cost, quality, and access. On each count, heart transplantation is vulnerable to criticism. Managed care is an incremental approach to health care reform that imposes fiscal constraint on providers. This constraint is expressed in the form of capitation which, in turn, requires providers to assume risk and accept economic responsibility for clinical decisions. While the need for transplantation is considerable, there are both clinical and economic factors limiting the overall level of activity. In 1993, over 2200 heart transplants were performed in the United States on people who were dying of end-stage cardiac disease. The total demand for heart transplantation was estimated to be about 5900 persons, which was not met due to an insufficient supply of donor hearts. Absent donors, the fiscal consequences of heart transplantation are minimized. In 1993, actuaries estimated that the total charge per heart transplant was $209,100. By designating centers based on price and quality considerations, managed care plans have reduced this per procedure expense to less than $100,000. While the benefits of transplantation are noteworthy, there are still concerns. Sixty percent of patients report that they are able to work, but only 30% do so. Employers hope to improve upon this record by expanding the designated center approach. In conclusion, the future of heart transplantation is unclear. Opportunities for innovation are limited, although the management of heart failure is an area of increased interest.

Assessment of a novel VEGF targeted agent using patient-derived tumor tissue xenograft models of colon carcinoma with lymphatic and hepatic metastases.

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Ketao Jin

Full Text Available The lack of appropriate tumor models of primary tumors and corresponding metastases that can reliably predict for response to anticancer agents remains a major deficiency in the clinical practice of cancer therapy. It was the aim of our study to establish patient-derived tumor tissue (PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastases useful for testing of novel molecularly targeted agents. PDTT of primary colon carcinoma, lymphatic and hepatic metastases were used to create xenograft models. Hematoxylin and eosin staining, immunohistochemical staining, genome-wide gene expression analysis, pyrosequencing, qRT-PCR, and western blotting were used to determine the biological stability of the xenografts during serial transplantation compared with the original tumor tissues. Early passages of the PDTT xenograft models of primary colon carcinoma, lymphatic and hepatic metastases revealed a high degree of similarity with the original clinical tumor samples with regard to histology, immunohistochemistry, genes expression, and mutation status as well as mRNA expression. After we have ascertained that these xenografts models retained similar histopathological features and molecular signatures as the original tumors, drug sensitivities of the xenografts to a novel VEGF targeted agent, FP3 was evaluated. In this study, PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastasis have been successfully established. They provide appropriate models for testing of novel molecularly targeted agents.

Selective lymphoid irradiation. V. Synergism with pretransplant thymectomy or thymic irradiation in cardiac transplantation in rats

International Nuclear Information System (INIS)

Iga, C.; Fawwaz, R.; Nowygrod, R.; Reemtsma, K.; Hardy, M.A.

1985-01-01

Selective lymphoid irradiation (SLI) using palladium-109-hematoporphyrin (Pd-H), given four days prior to transplantation, combined with two doses of antilymphocyte globulin (ALG) (10 mg, days -2 and -1), was evaluated as a method of induction of permanent heterotopic cardiac allograft survival in the highly histoincompatible rat strain combination of ACI (RT1(1))-to-Lewis (RT1a). Both Pd-H and ALG localize poorly in the thymus, so this study evaluated whether thymic irradiation (TI) or thymectomy (TX) of the adult recipient results in indefinite allograft survival. Immunosuppression with Pd-H or ALG alone gave a mean survival time (MST) of 6.7 +/- 0.6 days, but the combination of the two agents led to an MST of 17.6 +/- 3.4 days. When TI was combined with Pd-H and ALG, cardiac allograft survival was prolonged to 50.2 +/- 13.9 days, but TI alone showed an MST of 10.3 +/- 1.8 days. Permanent cardiac allograft survival (greater than 250 days) was achieved in all thymectomized recipients treated with the combination of Pd-H and a brief course of ALG. These animals also accepted second-set skin grafts and rejected third-party skin grafts following more than 150 days of ACI cardiac allograft survival. Thymic irradiation, although effective in acting synergistically with SLI and ALG, led to prolonged, but limited allograft survival, although thymectomy with SLI and ALG is synergistic in prolonging allograft survival permanently without chronic immunosuppression

The impact of neurologic complications on outcome after heart transplantation

NARCIS (Netherlands)

van de Beek, Diederik; Kremers, Walter; Daly, Richard C.; Edwards, Brooks S.; Clavell, Alfredo L.; McGregor, Christopher G. A.; Wijdicks, Eelco F. M.

2008-01-01

OBJECTIVE: To study neurologic complications after heart transplant. DESIGN: Retrospective cohort study. SETTING: Cardiac transplant program at Mayo Clinic, Rochester, Minnesota. PATIENTS: We retrospectively studied 313 patients who underwent heart transplant at Mayo Clinic Rochester from January 1,

Clinical islet isolation and transplantation outcomes with deceased cardiac death donors are similar to neurological determination of death donors.

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Andres, Axel; Kin, Tatsuya; O'Gorman, Doug; Livingstone, Scott; Bigam, David; Kneteman, Norman; Senior, Peter; Shapiro, A M James

2016-01-01

In islet transplantation, deceased cardiac death (DCD) donation has been identified as a potential extended source. There are currently no studies comparing outcomes between these categories, and our goal was to compare islet isolation success rates and transplantation outcomes between DCD and neurological determination of death (NDD) donors. Islet isolations from 15 DCD and 418 NDD were performed in our centre between September 2008 and September 2014. Donor variables, islet yields, metabolic function of isolated isled and insulin requirements at 1-month post-transplant were compared. Compared to NDD, pancreata from DCD were more often procured locally and donors required less vasopressive support (P islet yields were similar between NDD and DCD (576 vs. 608 × 10(3) islet equivalent, P = 0.628 and 386 vs. 379, P = 0.881, respectively). The metabolic function was similar between NDD and DCD, as well as the mean decrease in insulin requirement at 1-month post-transplantation (NDD: 64.82%; DCD: 60.17% reduction, P = 0.517). These results support the broader use of DCD pancreata for islet isolation. A much larger DCD islet experience will be required to truly determine noninferiority of both short- and long-term outcomes. © 2015 Steunstichting ESOT.

[Investigation of follicular development and oocyte maturation after cryopreservation and xenograft of newborn mouse ovaries].

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Qin, Bo-Lin; Chen, Xue-Jin; Shi, Zhen-Dan; Li, Wan-Li; Tian, Yun-Bo

2006-02-25

In order to explore the feasibility of cryopreserving primordial follicles in attaining their developmental competence following freezing and thawing, ovaries from newborn mice were cryopreserved and the thawed ovaries were xenografted into kidney capsules of adult female mice. Ovaries were isolated from newborn B6C2F(1) female mice, infiltrated by Leibovitz 15 (L-15) medium containing 10% (V/V) fetal bovine serum (FBS) and 1.5 mol/L dimethylsulfoxide (DMSO), and then packed into 0.25 ml plastic straws. The ovaries contained in straws were frozen under nitrogen vapour at -40 degrees C in Cryocell 1200 programmable freezer, and stored in liquid nitrogen for periods ranging from 1 week to 6 months. Upon thawing, the straws were dipped into room temperature water for 10~20 s, after which the ovaries were collected and washed in L-15 buffer containing 10% (V/V) FBS without DMSO to remove cryoprotectant. The thawed ovaries were transplanted into kidney capsules of 8~12-week old adult B6C2F(1) female recipient mice by two protocols, with either 1 or 2 ovaries in each capsule. Upon withdrawal after at least 14 d of transplantation, only 45.00% (72/160) of the ovaries were recovered from 40 recipients transplanted with 2 ovaries in each capsule, compared to 82.50% (33/40) in 20 recipients with only 1 ovary in each capsule. The grafted ovaries exhibited similar follicular developmental progression to that of natural ovaries. There were antral follicles present in the transplanted ovaries on day 14, whose number increased more substantially on day 19 after transplantation. Following stimulation of the recipient mice with 10 IU PMSG on day 19 after xenografting, follicles further developed to preovulatory stage with appearance of cumulus oocytes and enlarged antrum. Oocytes from these fully grown antral follicles were collected and matured in vitro in modified essential medium-alpha (MEMalpha). After 16~17 h of culture, 40.90% of the oocytes exhibited germinal vesicle

Xenograft transplantation of human malignant astrocytoma cells into immunodeficient rats: an experimental model of glioblastoma.

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Miura, Flávio Key; Alves, Maria Jose Ferreira; Rocha, Mussya Cisotto; da Silva, Roseli; Oba-Shinjo, Sueli Mieko; Marie, Suely Kazue Nagahashi

2010-03-01

Astrocytic gliomas are the most common intracranial central nervous system neoplasias, accounting for about 60% of all primary central nervous system tumors. Despite advances in the treatment of gliomas, no effective therapeutic approach is yet available; hence, the search for a more realistic model to generate more effective therapies is essential. To develop an experimental malignant astrocytoma model with the characteristics of the human tumor. Primary cells from subcutaneous xenograft tumors produced with malignant astrocytoma U87MG cells were inoculated intracerebrally by stereotaxis into immunosuppressed (athymic) Rowett rats. All four injected animals developed non-infiltrative tumors, although other glioblastoma characteristics, such as necrosis, pseudopalisading cells and intense mitotic activity, were observed. A malignant astrocytoma intracerebral xenograft model with poorly invasive behavior was achieved in athymic Rowett rats. Tumor invasiveness in an experimental animal model may depend on a combination of several factors, including the cell line used to induce tumor formation, the rat strains and the status of the animal's immune system.

Establishment of canine hemangiosarcoma xenograft models expressing endothelial growth factors, their receptors, and angiogenesis-associated homeobox genes

International Nuclear Information System (INIS)

Kodama, Atsushi; Yanai, Tokuma; Sakai, Hiroki; Matsuura, Satoko; Murakami, Mami; Murai, Atsuko; Mori, Takashi; Maruo, Kouji; Kimura, Tohru; Masegi, Toshiaki

2009-01-01

Human hemangiosarcoma (HSA) tends to have a poor prognosis; its tumorigenesis has not been elucidated, as there is a dearth of HSA clinical specimens and no experimental model for HSA. However, the incidence of spontaneous HSA is relatively high in canines; therefore, canine HSA has been useful in the study of human HSA. Recently, the production of angiogenic growth factors and their receptors in human and canine HSA has been reported. Moreover, the growth-factor environment of HSA is very similar to that of pathophysiological angiogenesis, which some homeobox genes regulate in the transcription of angiogenic molecules. In the present study, we established 6 xenograft canine HSA tumors and detected the expression of growth factors, their receptors, and angiogenic homeobox genes. Six primary canine HSAs were xenografted to nude mice subcutaneously and serially transplanted. Subsequently, the expressions of vascular endothelial growth factor (VEGF)-A, basic fibroblast growth factors (bFGF), flt-1 and flk-1 (receptors of VEGF-A), FGFR-1, and angiogenic homeobox genes HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 were investigated in original and xenograft tumors by histopathology, immunostaining, and reverse transcription polymerase chain reaction (RT-PCR), using canine-specific primer sets. Histopathologically, xenograft tumors comprised a proliferation of neoplastic cells that were varied in shape, from spindle-shaped and polygonal to ovoid; some vascular-like structures and vascular clefts of channels were observed, similar to those in the original tumors. The expression of endothelial markers (CD31 and vWF) was detected in xenograft tumors by immunohistochemistry and RT-PCR. Moreover, the expression of VEGF-A, bFGF, flt-1, flk-1, FGFR-1, HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 was detected in xenograft tumors. Interestingly, expressions of bFGF tended to be higher in 3 of the xenograft HSA tumors than in the other tumors. We established 6 xenograft canine HSA

Evolução tardia do transplante cardíaco na doença de Chagas: long-term evolution in cardiac transplantation Chagas' Disease

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Alfredo I Fiorelli

1990-08-01

Full Text Available Nas formas cardíacas da doença de Chagas que evoluem com insuficiência cardíaca refratária ao tratamento clínico, o transplante é a única alternativa, ao lado da cardiomioplastia. Os autores apresentam a evolução tardia de seis pacientes com miocardiopatia chagásica terminal submetidos a transplante cardíaco ortotópico. O período médio de observação foi de 25,2 meses. O diagnóstico de reativação da doença de Chagas apoiou-se na observação clínica, na investigação laboratorial do parasita, nas biópsias endomiocárdicas e dos nódulos de subcutâneo. A análise dos resultados demonstra que: 1 os testes laboratoriais mostraram-se ineficazes no diagnóstico da reativação da doença, sendo que as biópsias mostraram maior índice de positividade; 2 a pulsoterapia com corticóide predispõe à reativação; 3 a doença linfoproliferativa apresenta alta incidência na doença de Chagas, sendo a principal complicação tardia. Possivelmente, o benzonidazol apresente seu efeito oncogênico potencializado. Tendo em vista o caráter endêmico da doença e a falta de alternativa terapêutica, tornou-se obrigatória a analise do esquema imunossupressor, do tratamento da reativação e a maior experiência clínica, para posições mais definidas.In the cardiac forms of Chagas' Disease that develop with refractory cardiac failure under clinical treatment, the transplant is the only alternative along with the cardiomyoplasty. The authors present the six patient late evolution with terminal chagasic myocardiopathy submitted under on orthopic heart transplantation. The average period of observation was of 25.2 months. The diagnosis of Chagas' Disease reativation relies on the clinical observation, laboratory investigation of parasito, endomyocardial biopsy and subcutaneous nodules. The analyses of the results show that: 1 the laboratory exams were useless in the diagnosis of the disease reativation, but the biopsy presented hight

Radiation responses of human bladder cancer assessed in vitro or as xenografts in immune-deprived mice

International Nuclear Information System (INIS)

Tannock, I.; Choo, B.; Buick, R.

1984-01-01

The response to radiation of cells derived from transitional cell carcinoma (TCC) of the human bladder has been studied. In vitro radiation survival curves for two established cell lines, RT-4 and MGH-U1, and for a cell line HB-10 derived recently from biopsy of a metastatic lymph node were characterized by values of D 0 and anti n in the range of 1.1-1.5 Gy and 2-7 respectively. The oxygen enhancement ratio of HB-10 cells was 2.8. Xenografts derived from the line HB-10 were irradiated in vivo under both aerobic and hypoxic conditions and cell survival was assessed in agar. Both aerobic and hypoxic survival curves were similar to that obtained for irradiation of hypoxic HB-10 cells in culture. Another tumor line, HB-15, derived from a cystoscopic biopsy of primary TCC, was maintained by transplantation of xenografts. Regrowth curves for HB-15 xenografts after radiation doses of 10 or 20 Gy were parallel to the growth curve for untreated controls but with volume reduced by factors of about 5 and 20 respectively. Cells derived from TCC of the human bladder exhibit parameters of radiation survival similar to those of other mammalian cells, and that xenografts derived from such cells contain a high proportion of hypoxic cells

Aortic valve replacement with the Biocor PSB stentless xenograft.

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Bertolini, P; Luciani, G B; Vecchi, B; Pugliese, P; Mazzucco, A

1998-08-01

The midterm clinical results after aortic valve replacement with the Biocor PSB stentless xenograft on all patients operated between October 1992 and October 1996 were reviewed. One hundred six patients, aged 70+/-6 years, had aortic valve replacement for aortic stenosis (67%), regurgitation (11%), or both (22%). Associated procedures were done in 49 patients (46%), including coronary artery bypass in 30 patients, mitral valve repair/replacement in 16, and ascending aorta replacement in 5 patients. Aortic cross-clamp and cardiopulmonary bypass times were 96+/-24 and 129+/-31 minutes, respectively. There were 3 (3%) early deaths due to low output (2 patients) and cerebrovascular accident (1 patient). Follow-up of survivors ranged from 6 to 66 months (mean, 39+/-14 months). Survival was 94%+/-2% and 90%+/-3% at 1 and 5 years. There were 5 late deaths due to cardiac cause (2), cancer (2), and pulmonary embolism (1 patient). No patient had structural valve deterioration, whereas 100% and 95%+/-3% were free from valve-related events at 1 and 5 years. There were two reoperations due to narrowing of the left coronary ostium and endocarditis, with an actuarial freedom from reoperation of 99%+/-1% and 98+/-1% at 1 and 5 years, respectively. Functional results demonstrated a mean peak transprosthetic gradient of 16+/-12 mm Hg, with only 1 patient (1%) with a 55 mm Hg gradient. No cases of valve regurgitation greater than mild were recorded at follow-up. Assessment of New York Heart Association functional class demonstrated a significant improvement (2.9+/-0.6 versus 1.4+/-0.7; p=0.01). All patients were free from anticoagulation. Aortic valve replacement using the Biocor PSB stentless xenograft offers excellent midterm survival, negligible valve deterioration, and a very low rate of valve-related events, which are comparable to estimates reported with other models of stentless xenografts and currently available stented xenografts. Hemodynamic performance is favorable and

pO{sub 2} Fluctuation Pattern and Cycling Hypoxia in Human Cervical Carcinoma and Melanoma Xenografts

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Ellingsen, Christine; Ovrebo, Kirsti Marie; Galappathi, Kanthi; Mathiesen, Berit [Radiation Biology and Tumor Physiology Group, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo (Norway); Rofstad, Einar K., E-mail: einar.k.rofstad@rr-research.no [Radiation Biology and Tumor Physiology Group, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo (Norway)

2012-07-15

Purpose: Blood perfusion in tumors is spatially and temporally heterogeneous, resulting in local fluctuations in tissue oxygen tension (pO{sub 2}) and tissue regions showing cycling hypoxia. In this study, we investigated whether the pO{sub 2} fluctuation pattern and the extent of cycling hypoxia differ between tumor types showing high (e.g., cervical carcinoma xenograft) and low (e.g., melanoma xenograft) fractions of connective tissue-associated blood vessels. Methods and Materials: Two cervical carcinoma lines (CK-160 and TS-415) and two melanoma lines (A-07 and R-18) transplanted into BALB/c nu/nu mice were included in the study. Tissue pO{sub 2} was measured simultaneously in two positions in each tumor by using a two-channel OxyLite fiber-optic oxygen-sensing device. The extent of acute and chronic hypoxia was assessed by combining a radiobiological and a pimonidazole-based immunohistochemical assay of tumor hypoxia. Results: The proportion of tumor regions showing pO{sub 2} fluctuations, the pO{sub 2} fluctuation frequency in these regions, and the relative amplitude of the pO{sub 2} fluctuations were significantly higher in the melanoma xenografts than in the cervical carcinoma xenografts. Cervical carcinoma and melanoma xenografts did not differ significantly in the fraction of acutely hypoxic cells or the fraction of chronically hypoxic cells. However, the ratio between fraction of acutely hypoxic cells and fraction of chronically hypoxic cells was significantly higher in melanoma than in cervical carcinoma xenografts. Conclusions: Temporal heterogeneity in blood flow and tissue pO{sub 2} in tumors may depend on tumor histology. Connective tissue surrounding microvessels may stabilize blood flow and pO{sub 2} and, thus, protect tumor tissue from cycling hypoxia.

Permanent and temporary pacemaker implantation after orthotopic heart transplantation

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Bacal Fernando

2000-01-01

Full Text Available PURPOSE:To determine the indication for and incidence and evolution of temporary and permanent pacemaker implantation in cardiac transplant recipients. METHODS: A retrospective review of 114 patients who underwent orthotopic heart transplantation InCor (Heart Institute USP BR between March 1985 and May 1993. We studied the incidence of and indication for temporary pacing, the relationship between pacing and rejection, the need for pemanent pacing and the clinical follow-up. RESULTS: Fourteen of 114 (12%heart transplant recipients required temporary pacing and 4 of 114 (3.5% patients required permanent pacing. The indication for temporary pacing was sinus node dysfunction in 11 patients (78.5% and atrioventricular (AV block in 3 patients (21.4%. The indication for permanent pacemaker implantation was sinus node dysfunction in 3 patients (75% and atrioventricular (AV block in 1 patient (25%. We observed rejection in 3 patients (21.4% who required temporary pacing and in 2 patients (50% who required permanent pacing. The previous use of amiodarone was observed in 10 patients (71.4% with temporary pacing. Seven of the 14 patients (50% died during follow-up. CONCLUSION: Sinus node dysfunction was the principal indication for temporary and permanent pacemaker implantation in cardiac transplant recipients. The need for pacing was related to worse prognosis after cardiac transplantation.

Cardiac glycosides induce cell death in human cells by inhibiting general protein synthesis.

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Andrea Perne

2009-12-01

Full Text Available Cardiac glycosides are Na(+/K(+-pump inhibitors widely used to treat heart failure. They are also highly cytotoxic, and studies have suggested specific anti-tumor activity leading to current clinical trials in cancer patients. However, a definitive demonstration of this putative anti-cancer activity and the underlying molecular mechanism has remained elusive.Using an unbiased transcriptomics approach, we found that cardiac glycosides inhibit general protein synthesis. Protein synthesis inhibition and cytotoxicity were not specific for cancer cells as they were observed in both primary and cancer cell lines. These effects were dependent on the Na(+/K(+-pump as they were rescued by expression of a cardiac glycoside-resistant Na(+/K(+-pump. Unlike human cells, rodent cells are largely resistant to cardiac glycosides in vitro and mice were found to tolerate extremely high levels.The physiological difference between human and mouse explains the previously observed sensitivity of human cancer cells in mouse xenograft experiments. Thus, published mouse xenograft models used to support anti-tumor activity for these drugs require reevaluation. Our finding that cardiac glycosides inhibit protein synthesis provides a mechanism for the cytotoxicity of CGs and raises concerns about ongoing clinical trials to test CGs as anti-cancer agents in humans.

An Update on Cardiac Transplantation in the United States.

Science.gov (United States)

Everly, Matthew J

2014-01-01

Heart transplantation in the United States remains an important option for those with heart failure. Survival rates over the last 25 years have improved with the advent of newer immunosuppressive agents, innovation, and a better understanding of managing risk. However, many patients continue to experience allograft failure after transplantation. Innovations in modalities to reduce acute and chronic rejection are needed to improve the long-term success of heart transplantation.

A pilot programme of organ donation after cardiac death in China.

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Huang, Jiefu; Millis, J Michael; Mao, Yilei; Millis, M Andrew; Sang, Xinting; Zhong, Shouxian

2012-03-03

China's aims are to develop an ethical and sustainable organ transplantation system for the Chinese people and to be accepted as a responsible member of the international transplantation community. In 2007, China implemented the Regulation on Human Organ Transplantation, which was the first step towards the establishment of a voluntary organ donation system. Although progress has been made, several ethical and legal issues associated with transplantation in China remain, including the use of organs from executed prisoners, organ scarcity, the illegal organ trade, and transplantation tourism. In this Health Policy article we outline the standards used to define cardiac death in China and a legal and procedural framework for an organ donation system based on voluntary donation after cardiac death that adheres to both China's social and cultural principles and international transplantation standards. Copyright © 2012 Elsevier Ltd. All rights reserved.

Long-term outcomes of clinical transplantation of pancreatic islets with uncontrolled donors after cardiac death: a multicenter experience in Japan.

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Anazawa, T; Saito, T; Goto, M; Kenmochi, T; Uemoto, S; Itoh, T; Yasunami, Y; Kenjo, A; Kimura, T; Ise, K; Tsuchiya, T; Gotoh, M

2014-01-01

Pancreatic islet transplantation has emerged as an effective treatment for type 1 diabetes mellitus, but its use is limited due to an insufficient supply of cadaveric pancreata. In Japan, uncontrolled donors after cardiac death (DCD) are not deemed to be suitable for whole-organ pancreatic transplantation, and can provide a source of pancreas for islet transplantation. However, the long-term outcomes and utility of uncontrolled DCD in the clinical setting remain controversial. Here, we summarize the long-term outcomes of islet transplantation employing uncontrolled DCD as reported to the Japan Islet Transplantation Registry. Sixty-four isolations and 34 transplantations of pancreatic islets were conducted in 18 subjects with type 1 diabetes mellitus under the cover of immunosuppression with basiliximab, sirolimus, and tacrolimus. All donors were uncontrolled DCD at the time of harvesting. The mean follow-up time was 76 months. Of the 18 recipients, 8, 4, and 6 recipients received 1, 2, and 3 islet infusions, respectively. Overall graft survivals (defined as a C-peptide level ≥0.3 ng/mL) were 72.2%, 44.4%, and 22.2% at 1, 2, and 5 years, respectively, whereas the corresponding graft survivals after multiple infusions were 90.0%, 70.0%, and 30.0%, respectively. Three of these recipients achieved insulin independence in 14, 79, and 215 days. HbA1c levels and the requirement of exogenous insulin were improved before loss of graft function. All recipients became free of severe hypoglycemia unawareness, however, at least 5 of 14 patients who had graft failure experienced recurrence of severe hypoglycemia after the loss of graft function. Islet transplantation from DCD can relieve glucose instability and problems with hypoglycemia when the graft is functioning. However, islets from uncontrolled DCD may be associated with reduced long-term graft survival. Further improvements in the clinical outcome by modification of islet isolation/transplantation protocols are

Molecular nuclear cardiac imaging

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Lee, Dong Soo; Paeng, Jin Chul [College of Medicine, Seoul National Univ., Seoul (Korea, Republic of)

2004-04-01

Molecular nuclear cardiac imaging has included Tc-99m Annexin imaging to visualize myocardial apoptosis, but is now usually associated with gene therapy and cell-based therapy. Cardiac gene therapy was not successful so far but cardiac reporter gene imaging was made possible using HSV-TK (herpes simplex virus thymidine kinase) and F-18 FHBG (fluoro-hydroxymethylbutyl guanine) or I-124 FIAU (fluoro-deoxyiodo-arabino-furanosyluracil). Gene delivery was performed by needle injection with or without catheter guidance. TK expression did not last longer than 2 weeks in myocardium. Cell-based therapy of ischemic heart or failing heart looks promising, but biodistribution and differentiation of transplanted cells are not known. Reporter genes can be transfected to the stem/progenitor cells and cells containing these genes can be transplanted to the recipients using catheter-based purging or injection. Repeated imaging should be available and if promoter are varied to let express reporter transgenes, cellular (trans)differentiation can be studied. NIS (sodium iodide symporter) or D2R receptor genes are promising in this aspect.

Molecular nuclear cardiac imaging

International Nuclear Information System (INIS)

Lee, Dong Soo; Paeng, Jin Chul

2004-01-01

Molecular nuclear cardiac imaging has included Tc-99m Annexin imaging to visualize myocardial apoptosis, but is now usually associated with gene therapy and cell-based therapy. Cardiac gene therapy was not successful so far but cardiac reporter gene imaging was made possible using HSV-TK (herpes simplex virus thymidine kinase) and F-18 FHBG (fluoro-hydroxymethylbutyl guanine) or I-124 FIAU (fluoro-deoxyiodo-arabino-furanosyluracil). Gene delivery was performed by needle injection with or without catheter guidance. TK expression did not last longer than 2 weeks in myocardium. Cell-based therapy of ischemic heart or failing heart looks promising, but biodistribution and differentiation of transplanted cells are not known. Reporter genes can be transfected to the stem/progenitor cells and cells containing these genes can be transplanted to the recipients using catheter-based purging or injection. Repeated imaging should be available and if promoter are varied to let express reporter transgenes, cellular (trans)differentiation can be studied. NIS (sodium iodide symporter) or D2R receptor genes are promising in this aspect

Orthotopic heart transplantation in the prince sultan cardiac center.

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Al Fagih, M R

1996-01-01

In this report we attempt to demonstrate the efforts involved in establishing and organizing the heart transplant program at the Armed Forces Hospital in Riyadh, Saudi Arabia. From 1986 to date, 25 orthotopic heart transplants were performed at this center. Patient age ranged from 22 months to 57 years; 4 patients were below 12 years of age and 4 aged 50 years and above. The incidations for transplantation were cardiomyopathy in 15 patients, ischemic heart disease in 6 patients, and valvular heart disease in 4 patients. Fourteen recipients have died. Three of them were classified as hospital deaths, occuring before the patient could be discharged after the procedure; the reminder died from rejection and associated problems. Eight patients of them died within the first year. The longest survival period was almost 8 years. The overall 8 years survival rate was 45%, which is comparable to the international figures. Shortage of donors may affect the future of the transplant programs. Increasing the awareness of the public about the importance of organ donation and transplantation is crucial in this regard.

Pulmonary infection in patients with cyclosporine, azathioprine, and corticosteroids after cardiac transplantation; Clinical and radiographic assessment

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Murayama, Sadayuki; Ikezoe, Junpei; Godwin, J.D.; Marglin, S.I.; Allen, M.D. (University of Washington Medical Center, Seattle, WA (United States))

1991-07-01

Between November 1985 and November 1989, 54 patients have undergone 55 cardiac transplants, 5 of whom died during operation or one week after transplantation. The remaining 49 patients with a minimum follow-up of 5 months were studied to examine pulmonary infection clinically and radiologically while receiving triple drug immunosuppression consisting of cyclosporine, azathioprine, and prednisolone. Pulmonary infection occurred in 14 patients (29%) with a total of 21 occasions. Causative organisms were identified in 9 occasions, with the most common organism being Cytomegalovirus (CMV). One patient died of pulmonary infection with Aspergillus. Causative organisms occurring in the remaining 12 occasions of pulmonary infection were unknown, which did not lead to death. Because pulmonary infection of unknown organisms rapidly responded to convensional antibiotics, it seemed to have been caused by bacteria. Pulmonary infection of unknown organism occurred 13.2{+-}3.2 months after transplantation, as compared with 3.3{+-}1.0 months in pulmonary infection of known organisms. Chest plain radiographic features fell into four types: (1) interstitial shadow seen in pulmonary infection of CMV, Pneumocystis carinii, or Hemophilia influenza, (2) patchy, and basilar and lobular consolidation shadows in bacterial pneumonia, (3) localized nodular shadow in aspergillosis, and (4) multiple patchy and confluent opacity patterns occurring in herpes simplex viral infection. Pulmonary infection of influenza bacteria for one patient and pulmonary infection of unknown organisms for 4 patients were difficult to identify from pulmonary infection of CMV. (N.K.).

Failure to diagnose cardiac treatment rejection with Tc99m-PYP images

International Nuclear Information System (INIS)

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

1981-01-01

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

South Asian Ethnicity as a Risk Factor for Major Adverse Cardiovascular Events after Renal Transplantation

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Vangala, Sai K.; Silver, Samuel A.; Wong, Steven C.W.; Huang, Michael; Rapi, Lindita; Nash, Michelle M.; Zaltzman, Jeffrey S.

2011-01-01

Summary Background and objectives South Asians (SAs) comprise 25% of all Canadian visible minorities. SAs constitute a group at high risk for cardiovascular disease in the general population, but the risk in SA kidney transplant recipients has never been studied. Design, setting, participants, & measurements In a cohort study of 864 kidney recipients transplanted from 1998 to 2007 and followed to June 2009, we identified risk factors including ethnicity associated with major cardiac events (MACEs, a composite of nonfatal myocardial infarction, coronary intervention, and cardiac death) within and beyond 3 months after transplant. Kaplan-Meier methodology and multivariate Cox regression analysis were used to determine risk factors for MACEs. Results There was no difference among SAs (n = 139), whites (n = 550), blacks (n = 65), or East Asians (n = 110) in baseline risk, including pre-existing cardiac disease. Post-transplant MACE rate in SAs was 4.4/100 patient-years compared with 1.31, 1.16, and 1.61/100 patient-years in whites, blacks, and East Asians, respectively (P diabetes, systolic BP, and prior cardiac disease. SAs also experienced more MACEs within 3 months after transplant compared with whites (P < 0.0001), blacks (P = 0.04), and East Asians (P = 0.006). However, graft and patient survival was similar to other groups. Conclusions SA ethnicity is an independent risk factor for post-transplant cardiac events. Further study of this high-risk group is warranted. PMID:20884776

Comparing Outcomes of Donation After Cardiac Death Versus Donation After Brain Death in Liver Transplant Recipients with Hepatitis C: A Systematic Review and Meta-Analysis

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Malcolm Wells

2014-01-01

Full Text Available BACKGROUND: Liver transplantation (LT using organs donated after cardiac death (DCD is increasing due, in large part, to a shortage of organs. The outcome of using DCD organs in recipients with hepatits C virus (HCV infection remains unclear due to the limited experience and number of publications addressing this issue.

Reduced size liver transplantation from a donor supported by a Berlin Heart.

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Misra, M V; Smithers, C J; Krawczuk, L E; Jenkins, R L; Linden, B C; Weldon, C B; Kim, H B

2009-11-01

Patients on cardiac assist devices are often considered to be high-risk solid organ donors. We report the first case of a reduced size liver transplant performed using the left lateral segment of a pediatric donor whose cardiac function was supported by a Berlin Heart. The recipient was a 22-day-old boy with neonatal hemochromatosis who developed fulminant liver failure shortly after birth. The transplant was complicated by mild delayed graft function, which required delayed biliary reconstruction and abdominal wall closure, as well as a bile leak. However, the graft function improved quickly over the first week and the patient was discharged home with normal liver function 8 weeks after transplant. The presence of a cardiac assist device should not be considered an absolute contraindication for abdominal organ donation. Normal organ procurement procedures may require alteration due to the unusual technical obstacles that are encountered when the donor has a cardiac assist device.

Survival of Free and Encapsulated Human and Rat Islet Xenografts Transplanted into the Mouse Bone Marrow

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Meier, Raphael P. H.; Seebach, Jörg D.; Morel, Philippe; Mahou, Redouan; Borot, Sophie; Giovannoni, Laurianne; Parnaud, Geraldine; Montanari, Elisa; Bosco, Domenico; Wandrey, Christine; Berney, Thierry; Bühler, Leo H.; Muller, Yannick D.

2014-01-01

Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow) and 10 days (kidney capsule). Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation. PMID:24625569

Survival of free and encapsulated human and rat islet xenografts transplanted into the mouse bone marrow.

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Raphael P H Meier

Full Text Available Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow and 10 days (kidney capsule. Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation.

A tale of two cases of pulmonary arteriovenous malformation: How they fared after cardiac transplantation.

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Wisotzkey, Bethany L; Magyar, Dari L; Jones, Thomas K; Boucek, Robert J; Permut, Lester C; Kemna, Mariska S; Law, Yuk M

2018-02-01

In single ventricle patients, aortopulmonary collaterals (APCs) and pulmonary arteriovenous malformations (PAVMs) following superior cavopulmonary shunt (CPS) can complicate orthotopic heart transplant (OHT) by cyanosis and hemoptysis. Although PAVMs can regress with the restoration of hepatic venous flow to the pulmonary circulation, the effects of hypoxemia on the "unconditioned" allograft are not known. Two patients with significant PAVMs after CPS were cyanotic following OHT. One patient with predominantly unilateral left PAVMs had arterial saturation levels less than 70% despite pulmonary vasodilators and ventilation. A custom flow restrictor-covered stent was deployed in the pulmonary artery of the affected side, redirecting the blood flow to the contralateral lung, immediately improving cyanosis. When the PAVMs regressed, the flow restrictor stent was dilated to eliminate the constriction. The second patient with PAVMs had cyanosis and severe hemoptysis from APCs post-OHT. The APCs required an extensive coil embolization, while the cyanosis responded to oxygen and pulmonary vasodilators. Both recipients did well with gradual resolution of PAVMs within 8 months. Despite cyanosis from right-to-left intrapulmonary shunting, allograft function recovered. Novel transcatheter interventions can play a role in patients with significant APCs or PAVM following cardiac transplantation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Protection of xenografts by a combination of immunoisolation and a single dose of anti-CD4 antibody.

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Mckenzie, A W; Georgiou, H M; Zhan, Y; Brady, J L; Lew, A M

2001-01-01

Immunoisolation is the separation of transplanted cells from cells of the immune system using a semipermeable membrane. Using one such immunoisolation capsule-the TheraCyte device-we have assessed the survival of encapsulated xenogeneic tissue in vivo as well as the contribution of CD4+ve T cells to encapsulated xenograft rejection. The foreign body reaction to the TheraCyte capsule in vivo was assessed by transplanting empty capsules into normal mice. These capsules elicit a foreign body response by the host animal. Encapsulated CHO, NIT-1, and PK-15 cells were placed in culture and in immunodeficient mice to investigate their growth characteristics in the TheraCyte device. These cell lines survive both in culture and in immunodeficient SCID mice. Xenogeneic PK cells were also transplanted into normal C57BL/6 mice. These cells do not survive in normal mice despite the absence of direct contact between infiltrating and encapsulated cells. In addition, the survival of encapsulated cells in mice treated with a single dose of anti-CD4 antibody was examined. This was assessed using two systems: 1) histological analysis of capsule sections; 2) a quantitative luciferase reporter system using PK cells transfected to express luciferase. In both cases, anti-CD4 antibody contributed to prolonged encapsulated xenogeneic cell survival. Encapsulated xenogeneic cells survive in immunodeficient mice but not normal mice. Treatment of normal mice with anti-CD4 antibody results in prolonged survival of xenogeneic cells that can be measured using a luciferase reporter system. These results highlight the contribution of CD4+ve T cells to encapsulated xenograft rejection.

Biological characterization of two xenografts derived from human CUPs (carcinomas of unknown primary

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Bernheim Alain

2007-12-01

Full Text Available Abstract Background Carcinomas of unknown primary site (CUP are epithelial malignancies revealed by metastatic lesions in the absence of any detectable primary tumor. Although they often adopt an aggressive clinical pattern, their basic biology remains poorly understood. Laboratory research on their biology have been hampered so far by the absence of cell lines representative of CUPs. Methods We attempted xenografts of CUP clinical specimens in immunodeficient mice and subsequent in vitro culture of transplanted malignant cells. Whenever possible, malignant xenografted or cultured cells were characterized by microsatellite genotyping, immunohistology, electron microscopy, multifish chromosome analysis and search of TP 53 gene mutations. Results Successful xenografts were achieved in 2 cases out of 4. One of them (Capi1 was lost after 3 passages whereas the other one (Capi3 has been adapted to in vitro culture and is currently available to the scientific community with reliable identification based on microsatellite genotyping. Both Capi1 and Capi3 have histological characteristics of adenocarcinomas and display intense expression of EMA, CEA and cytokeratin 7. Multifish chromosome analysis demonstrated a translocation involving chromosomes 4 and 21 in both specimens. Distinct rare missense mutations of the TP53 gene were detected in Capi1 (codon 312 and Capi3 (codon 181; the codon 181 mutation is consistent with a previously reported similar finding in a small series of CUP specimens. Finally, intense membrane expression of c-kit was recorded in Capi3. Conclusion Our data suggest that xenografted tumors can be obtained from a substantial fraction of CUP clinical specimens. The hypothesis of a preferential association of CUPs with TP 53 mutations of codon 181 deserves further investigations. The Capi3 cell line will be a useful tool for assessment of novel c-kit inhibitors.

Cardiac allograft immune activation: current perspectives

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Chang D

2014-12-01

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

Liver transplantation using organs from deceased organ donors: a single organ transplant center experience.

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Han, Ming; Guo, Zhi-Yong; Zhao, Qiang; Wang, Xiao-Ping; Yuan, Xiao-Peng; Jiao, Xing-Yuan; Yang, Chun-Hua; Wang, Dong-Ping; Ju, Wei-Qiang; Wu, Lin-Wei; Hu, An-Bin; Tai, Qiang; Ma, Yi; Zhu, Xiao-Feng; He, Xiao-Shun

2014-08-01

In 2011, a pilot program for deceased organ donation was initiated in China. We describe the first successful series of liver transplants in the pilot program. From July 2011 to August 2012, our center performed 26 liver transplants from a pool of 29 deceased donors. All organ donation and allograft procurement were conducted according to the national protocol. The clinical data of donors and recipients were collected and summarized retrospectively. Among the 29 donors, 24 were China Category II donors (organ donation after cardiac death), and five were China Category III donors (organ donation after brain death followed by cardiac death). The recipients were mainly the patients with hepatocellular carcinoma. The one-year patient survival rate was 80.8% with a median follow-up of 422 (2-696) days. Among the five mortalities during the follow-up, three died of tumor recurrence. In terms of post-transplant complications, 9 recipients (34.6%) experienced early allograft dysfunction, 1 (3.8%) had non-anastomotic biliary stricture, and 1 (3.8%) was complicated with hepatic arterial thrombosis. None of these complications resulted in patient death. Notably, primary non-function was not observed in any of the grafts. With careful donor selection, liver transplant from deceased donors can be performed safely and plays a critical role in overcoming the extreme organ shortage in China.

Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides

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José Manuel Calderón-Montaño

2014-01-01

Full Text Available Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na+/K+-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies.

Orthotopic Patient-Derived Glioblastoma Xenografts in Mice.

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Xu, Zhongye; Kader, Michael; Sen, Rajeev; Placantonakis, Dimitris G

2018-01-01

Patient-derived xenografts (PDX) provide in vivo glioblastoma (GBM) models that recapitulate actual tumors. Orthotopic tumor xenografts within the mouse brain are obtained by injection of GBM stem-like cells derived from fresh surgical specimens. These xenografts reproduce GBM's histologic complexity and hallmark biological behaviors, such as brain invasion, angiogenesis, and resistance to therapy. This method has become essential for analyzing mechanisms of tumorigenesis and testing the therapeutic effect of candidate agents in the preclinical setting. Here, we describe a protocol for establishing orthotopic tumor xenografts in the mouse brain with human GBM cells.

Comparison of intratumoral FDG and Cu-ATSM distributions in cancer tissue originated spheroid (CTOS) xenografts, a tumor model retaining the original tumor properties

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Furukawa, Takako; Yuan, Qinghua; Jin, Zhao-Hui; Aung, Winn; Yoshii, Yukie; Hasegawa, Sumitaka; Endo, Hiroko; Inoue, Masahiro; Zhang, Ming-Rong; Fujibayashi, Yasuhisa; Saga, Tsuneo

2014-01-01

Introduction: The intratumoral distributions of [ 18 F]FDG and [ 64 Cu]Cu-ATSM have been reported to be similar in adenocarcinomas but different in squamous cell carcinoma (SCC) in clinical studies. In the present study, we compared the intratumoral distributions of these two tracers in cancer tissue originated spheroid (CTOS) xenografts derived from adenocarcinoma and SCC, which retain the histological characteristics of the original tumors, and in cancer cell line xenografts of corresponding origin, to investigate the underlying mechanism of the distinct FDG and Cu-ATSM distribution patterns in adenocarcinoma and SCC. Methods: CTOSs derived from colon adenocarcinoma and lung SCC and cell lines established from colon adenocarcinoma and lung SCC, which were used for comparison, were subcutaneously transplanted into immunodeficient mice. One hour after administering [ 14 C]FDG and [ 64 Cu]Cu-ATSM, the intratumoral distributions were compared in the xenografts by using dual-tracer autoradiography. Adjacent sections were evaluated for necrosis, vasculature anatomy, Ki-67 antigen, and pimonidazole adducts using hematoxylin and eosin and immunohistochemical staining. Results: There was a higher regional overlap of high FDG and Cu-ATSM accumulations in the adenocarcinoma CTOS xenografts than in the SCC CTOS xenografts, while the overlap in the adenocarcinoma cell line xenograft was lower than that observed in the SCC cell line. High FDG accumulation occurred primarily in proximity to necrotic or pimonidazole adduct positive regions, while high Cu-ATSM accumulation occurred primarily in live cell regions separate from the necrotic regions. The adenocarcinoma CTOS xenograft had the stereotypical glandular structure, resulting in more intricately mixed regions of live and necrotic cells compared to those observed in the SCC CTOS or the cell line xenografts. Conclusion: Tumor morphological characteristics, specifically the spatial distribution of live and necrotic cell

Morphological features of the porcine lacrimal gland and its compatibility for human lacrimal gland xenografting.

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Henker, Robert; Scholz, Michael; Gaffling, Simone; Asano, Nagayoshi; Hampel, Ulrike; Garreis, Fabian; Hornegger, Joachim; Paulsen, Friedrich

2013-01-01

In this study, we present first data concerning the anatomical structure, blood supply and location of the lacrimal gland of the pig. Our data indicate that the porcine lacrimal gland may serve as a potential xenograft candidate in humans or as an animal model for engineering of a bioartificial lacrimal gland tissue construct for clinical application. For this purpose, we used different macroscopic preparation techniques and digital reconstruction of the histological gland morphology to gain new insights and important information concerning the feasibility of a lacrimal gland transplantation from pig to humans in general. Our results show that the lacrimal gland of the pig reveals a lot of morphological similarities to the analogous human lacrimal gland and thus might be regarded as a xenograft in the future. This is true for a similar anatomical location within the orbit as well as for the feeding artery supply to the organ. Functional differences concerning the composition of the tear fluid, due to a different secretory unit distribution within the gland tissue will, however, be a challenge in future investigations.

Morphological features of the porcine lacrimal gland and its compatibility for human lacrimal gland xenografting.

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Robert Henker

Full Text Available In this study, we present first data concerning the anatomical structure, blood supply and location of the lacrimal gland of the pig. Our data indicate that the porcine lacrimal gland may serve as a potential xenograft candidate in humans or as an animal model for engineering of a bioartificial lacrimal gland tissue construct for clinical application. For this purpose, we used different macroscopic preparation techniques and digital reconstruction of the histological gland morphology to gain new insights and important information concerning the feasibility of a lacrimal gland transplantation from pig to humans in general. Our results show that the lacrimal gland of the pig reveals a lot of morphological similarities to the analogous human lacrimal gland and thus might be regarded as a xenograft in the future. This is true for a similar anatomical location within the orbit as well as for the feeding artery supply to the organ. Functional differences concerning the composition of the tear fluid, due to a different secretory unit distribution within the gland tissue will, however, be a challenge in future investigations.

Breast Reconstruction After Solid Organ Transplant.

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Koonce, Stephanie L; Giles, Brian; McLaughlin, Sarah A; Perdikis, Galen; Waldorf, James; Lemaine, Valerie; TerKonda, Sarvam

2015-09-01

Solid organ transplant patients frequently develop posttransplant malignancies including breast cancer. They may desire breast reconstruction after mastectomy, which could potentially be complicated by their transplant status, immunosuppressive regimen, and previous operations. We review our experience with patients who have undergone solid organ transplant and subsequent breast reconstruction after mastectomy After institutional review board approval, we queried our prospective breast reconstruction and solid organ transplant databases for corresponding patients. Inclusion criteria comprised breast reconstruction after solid organ transplant. A chart review was conducted of identified patients. Seventeen patients were identified: 1 pulmonary transplant, 4 cardiac transplants, 2 liver transplants, 1 pancreas transplant, 2 combined kidney/pancreas transplants, and 7 kidney transplants. Indications for mastectomy included posttransplant malignancy and prophylaxis. Median time from transplant to completion of reconstruction was 186 months (range, 11-336 months). Median age at transplant was 34.5 years (range, 21-65 years) with the median age of the patients at reconstructive surgery 51.5 years (range, 34-71 years). Median body mass index was 25.3 (range, 21.3-46.5). No significant complications were noted after reconstructive surgery. All patients were on full immunosuppression at time of reconstruction. Breast reconstruction is a viable option for transplant patients after mastectomy and should not be refused based on their transplant status. Close coordination with the transplant team and careful preoperative planning is essential for optimal outcomes.

Analyzing the mechanisms of cell killing by ionizing radiation in monolayer, spheroids and xenografted tumours

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Horas, J.A.; Olguín, O.R.; Rizzotto, M.G.

2017-01-01

A relationship between oxygen enhancement ratio (OER) and parameters of Linear Quadratic (LQ) model in hypoxic and aerobic conditions in several cell lines grown as monolayer, spheroids and transplanted tumors (xenograft) is tested. By considering this relationship, the two mechanisms of cell death by radiation appear. Surviving Fraction (SF) fits are compared in both oxygenation conditions by using the LQ. The data are obtained from literature. The existence of such mechanisms and their implications in the different systems studied is shown. The validity of one or other mechanism in each case is determined and the OER dependence with dose. (authors) [es

Prognostic value of sympathetic innervation and cardiac asynchrony in dilated cardiomyopathy

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Manrique, Alain; Hitzel, Anne; Vera, Pierre; Bernard, Mathieu; Bauer, Fabrice; Menard, Jean-Francois; Sabatier, Remi; Jacobson, Arnold; Agostini, Denis

2008-01-01

The purpose of the study is to examine prognostic values of cardiac I-123 metaiodobenzylguanidine (MIBG) uptake and cardiac dyssynchrony in patients with dilated cardiomyopathy (DCM). Ninety-four patients with non-ischemic DCM underwent I-123 MIBG imaging for assessing cardiac sympathetic innervation and equilibrium radionuclide angiography. Mean phase angles and SD of the phase histogram were computed for both right ventricular (RV) and left ventricular (LV). Phase measures of interventricular (RV-LV) and intraventricular (SD-RV and SD-LV) asynchrony were computed. Most patients were receiving beta-blockers (89%) and angiotensin-converting enzyme inhibitors (88%). One patient (1%) was lost to follow-up, six had cardiac death (6.4%), eight had heart transplantation (8.6%), and seven had unplanned hospitalization for heart failure (7.5%; mean follow-up: 37 ± 16 months). Patients with poor clinical outcome were older, had higher The New York Heart Association functional class, impaired right ventricular ejection fraction and left ventricular ejection fraction, and impaired cardiac I-123 MIBG uptake. On multivariate analysis, I-123 MIBG heart-to-mediastinum (H/M) uptake ratio <1.6 was the only predictor of both primary (cardiac death or heart transplantation, RR = 7.02, p < 0.01) and secondary (cardiac death, heart transplantation, or recurrent heart failure, RR = 8.10, p = 0.0008) end points. In patients receiving modern medical therapy involving beta-blockers, I-123 MIBG uptake, but not intra-LV asynchrony, was predictive of clinical outcome. The impact of beta-blockers on the prognostic value of ventricular asynchrony remains to be clarified. (orig.)

Kupffer cell blockade prevents rejection of human insulinoma cell xenograft in rats

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Lazar, G. Jr.; Farkas, G.; Lazar, G.

1998-01-01

Alloantigens are recognized by T-cells in the context of both class I and class II antigen, but class II antigens predominate in the recognition of xenoantigens. Since class II molecules bind peptides derived from exogenous proteins that have been phagocytized and digested into small fragments by antigen presenting cells, in the present studies the effect of gadolinium chloride (GdCl 3 )-induced Kupffer cell blockade on the survival of discordant insulinoma cell xenografts was investigated. Insulinoma cells isolated by means of collagenase from human insulinoma and cultured were transplanted through the v. portae into the liver of streptozotocin-induced diabetic, male, CFY inbred rats. In the control, streptozotocin-treated rats, the decrease in blood glucose level was only transitory, in contrast with the GdCl 3 -pretreated diabetic rats, which remained normoglycaemic during the 2-week observation period. Histologically, in the liver and lung of rats pre-treated with GdCl 3 , large areas of extensively proliferating insulinoma cells were seen, whereas no insulinoma cells were seen in either the liver or the lung of diabetic-control rats, not-treated with GdCl 3 . These studies suggest that the Kupffer cells play significant roles in the recognition of xenoantigens and the induction of xenograft rejection. (orig.)

MicroRNAs in Heart Failure, Cardiac Transplantation, and Myocardial Recovery: Biomarkers with Therapeutic Potential.

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Shah, Palak; Bristow, Michael R; Port, J David

2017-12-01

Heart failure is increasing in prevalence with a lack of recently developed therapies that produce major beneficial effects on its associated mortality. MicroRNAs are small non-coding RNA molecules that regulate gene expression, are differentially regulated in heart failure, and are found in the circulation serving as a biomarker of heart failure. Data suggests that microRNAs may be used to detect allograft rejection in cardiac transplantation and may predict the degree of myocardial recovery in patients with a left ventricular assist device or treated with beta-blocker therapy. Given their role in regulating cellular function, microRNAs are an intriguing target for oligonucleotide therapeutics, designed to mimic or antagonize (antagomir) their biological effects. We review the current state of microRNAs as biomarkers of heart failure and associated conditions, the mechanisms by which microRNAs control cellular function, and how specific microRNAs may be targeted with novel therapeutics designed to treat heart failure.

Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts

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Shunqiang Li

2013-09-01

Full Text Available To characterize patient-derived xenografts (PDXs for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.

Risk stratification in patients with advanced heart failure requiring biventricular assist device support as a bridge to cardiac transplantation.

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Cheng, Richard K; Deng, Mario C; Tseng, Chi-hong; Shemin, Richard J; Kubak, Bernard M; MacLellan, W Robb

2012-08-01

Prior studies have identified risk factors for survival in patients with end-stage heart failure (HF) requiring left ventricular assist device (LVAD) support. However, patients with biventricular HF may represent a unique cohort. We retrospectively evaluated a consecutive cohort of 113 adult, end-stage HF patients at University of California Los Angeles Medical Center who required BIVAD support between 2000 and 2009. Survival to transplant was 66.4%, with 1-year actuarial survival of 62.8%. All patients were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Level 1 or 2 and received Thoratec (Pleasanton, CA) paracorporeal BIVAD as a bridge to transplant. Univariate analyses showed dialysis use, ventilator use, extracorporal membrane oxygenation use, low cardiac output, preserved LV ejection fraction (restrictive physiology), normal-to-high sodium, low platelet count, low total cholesterol, low high-density and high-density lipoprotein, low albumin, and elevated aspartate aminotransferase were associated with increased risk of death. We generated a scoring system for survival to transplant. Our final model, with age, sex, dialysis, cholesterol, ventilator, and albumin, gave a C-statistic of 0.870. A simplified system preserved a C-statistic of 0.844. Patients were divided into high-risk or highest-risk groups (median respective survival, 367 and 17 days), with strong discrimination between groups for death. We have generated a scoring system that offers high prognostic ability for patients requiring BIVAD support and hope that it may assist in clinical decision making. Further studies are needed to prospectively validate our scoring system. Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Diagnosis of cardiac allograft rejection with indium-111 labeled platelets in cyclosporin treated rats

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Fawwaz, R.A.; Iga, C.; Hardy, M.A.; Alderson, P.O.

1984-01-01

Rejection of heart transplants remains difficult to diagnose. Indium-111 (In-111) labeled lymphocytes accumulate in rat cardiac allografts when recipients are treated with Cyclosporin (Cy), even in the absence of clinical rejection. This presumably occurs because of the non-specific 'interstitial infiltration' caused by Cy. This study examines the usefulness of In-111 labeled platelets in differentiating experimental cardiac allograft rejection from Cy-induced tissue changes. The authors initially examined the migration patterns of syngeneic In-111 labeled platelets in groups of Lewis recipients of ACI cardiac allografts treated with IM Cy (10mg/kg) for 6-14 days. In addition, 10 control animals were not immunosuppressed, and 10 were treated with Cy but received Lewis cardiac isografts. Syngeneic In-111 platelets were injected IV into each animal 24 hours prior to sacrifice. Three to five rats from each group were killed at 3 ,7, 14, 21 and 28 days after transplantation and the % ID/gm in the transplanted hearts and native hearts were determined and correlated with histopathology. Untreated Lewis recipients rejected ACI hearts in 6.5 +- 0.4 days while Cy prolonged allograft survival in a variable fashion. In-111 platelet accumulation correlated well with the degree of rejection determined independently by histopathology. No significant In-111 platelet accumulation was detected in non-rejecting cardiac transplants or in native hearts in Cy treated or control animals. The results suggest that In-111 labeled platelets will be an effective agent for diagnosis of cardiac rejection, even in the presence of Cy treatment

Cardiac systolic function in cirrhotic patients’ candidate of liver trans-plantation compared with control group

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Roya Sattarzadeh-Badkoubeh

2017-02-01

Full Text Available Background: We assessed different systolic cardiac indices to describe left and right ventricular dysfunction in cirrhotic patients before liver transplantation. Methods: In this case-control study, eighty-one consecutive individuals with the confirmed hepatic cirrhosis and candidate for liver transplantation in the Imam Khomeini Hospital between March 2008 and March 2010 were selected. Thirty-two age and gender cross-matched healthy volunteers were also selected as the control group. A detailed two-dimensional and Doppler echocardiography was obtained in all patients and controls performed by the same operator on the day of admission. Results: Dimensions of both left and right atriums as well as left ventricular end-diastolic volume and basal right ventricular dimension in the cirrhotic group were significantly higher than control group. Left ventricular end-systolic dimensions as well as aortic annulus diameter were not different between the two study groups. Left ventricular outflow tract velocity time integral, isovolumic pre-ejection time, isovolumic relaxation time, stroke volume, left ventricular ejection fraction, IVCT+IVRT+ET, systolic velocity of tricuspid annulus, systolic velocity of basal segment of RV free wall, systolic velocity of basal segment of septal wall, peak strain of septal margin (base, peak strain of septal margin (midpoint, peak strain of lateral margin (midpoint, strain rate of septal margin (base, strain rate of septal margin (midpoint, strain rate of lateral margin (base, strain rate of lateral margin (midpoint, Tei index (left and right ventricles, systolic time interval and tricuspid annular plane systolic excursion were higher in cirrhotic group, significantly, (P< 0.05. Left ventricular ejection time and systolic velocity of mid segment of lateral wall were lower in cirrhotic group, significantly, (P< 0.05. Conclusion: In this study, the effects of liver on heart were volume overload, hyperdynamic state and

In Vitro Contracture Test Results and Anaesthetic Management of a Patient with Emery-Dreifuss Muscular Dystrophy for Cardiac Transplantation

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Frank Schuster

2012-01-01

Full Text Available Emery-Dreifuss muscular dystrophy (EDMD is a hereditary neuromuscular disorder characterized by slowly progressive muscle weakness, early contractures, and dilated cardiomyopathy. We reported an uneventful general anaesthesia using total intravenous anaesthesia (TIVA for cardiac transplantation in a 19-year-old woman suffering from EDMD. In vitro contracture test results of two pectoralis major muscle bundles of the patient suggest that exposition to triggering agents does not induce a pathological sarcoplasmic calcium release in the lamin A/C phenotype. However, due to the lack of evidence in the literature, we would recommend TIVA for patients with EDMD if general anaesthesia is required.

Total Artificial Heart Implantation as a Bridge to Heart Transplantation in an Active Duty Service Member With Amyloid Cardiomyopathy.

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Scully, Michael S; Wessman, Dylan E; McKee, James M; Francisco, Gregory M; Nayak, Keshav R; Kobashigawa, Jon A

2017-03-01

Cardiac involvement by light-chain (AL) amyloid occurs in up to 50% of patients with primary AL amyloidosis. The prognosis of amyloid heart disease is poor with 1-year survival rates of 35 to 40%. Historically, heart transplantation was considered controversial for patients with AL amyloid cardiomyopathy (CM) given the systemic nature of the disease and poor survival. We present a case report of an active duty service member diagnosed with advanced cardiac amyloid who underwent total artificial heart transplant as a bridge to heart transplant and eventual autologous stem cell transplant. A 47-year-old active duty male initially evaluated for atypical chest pain was found to have severe concentric left ventricular hypertrophy on echocardiogram but normal voltage on electrocardiogram. Cardiac magnetic resonance imaging, laboratory studies, and bone marrow biopsy established the diagnosis of cardiac amyloidosis. At the time of diagnosis, the patient's prognosis was very poor with a median survival of 5 months on the basis of the Mayo Clinic revised prognostic staging system for amyloidosis. The patient developed rapidly progressive left ventricular dysfunction and heart failure leading to cardiac arrest. The patient received a total artificial heart as a bridge to orthotopic heart and kidney transplantation and eventual stem cell transplant. He continues to be in remission and has a fair functional capacity without restriction in activities of daily living or moderate exercise. Amyloid CM is a rare and devastating disease. The natural course of the disease has made heart transplant in these patients controversial. Modern advancements in chemotherapies and advanced heart failure treatments have improved outcomes for select patients with AL amyloid CM undergoing heart transplantation. There is ongoing research seeking improvement in treatment options and outcomes for patients with this deadly disease. Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.

Correlation of an abnormal rest /sup 201/Tl myocardial image: Pathological findings in cardiac transplant recipients

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McKillop, J.H.; McDougall, I.R.; Billingham, M.; Schroeder, J.S.

1982-06-01

Rest myocardial /sup 201/Tl scintigraphy was undertaken in 15 males mean age 39 years (22-54) who had been accepted for cardiac transplantation. Complete pathological correlation was obtained in 14 after transplantation and in 1 who died before a suitable donor heart became available. The average time from scintigraphy to pathological evaluation was 42 days (9-103). All the /sup 201/Tl images were grossly abnormal and on the basis of these studies it was not possible to differentiate ischemic from idiopathic cardiomyopathy. Each of the three views of the /sup 201/Tl study was divided into three segments, therefore 135 areas were available for comparison (3 x 3 x 15). Eighty-eight of these were abnormal on scan and 78 of these were abnormal pathologically. The right ventricle was seen on all rest images but the degree of uptake bore no relationship to the measured thickness of the right ventricular wall. Structures such as the atrial wall and the enlarged papillary muscle were visualized in some patients. In two patients there was an improvement of the rest /sup 201/Tl image in delayed views and histologically these areas showed a mixture of muscle and fibrous tissue. The sensitivity of /sup 201/Tl imaging in this study was 89% and there was close correlation of the images with gross and microscopic pathological findings.

Retransplantation in 7,290 primary transplant patients: a 10-year multi-institutional study.

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Radovancevic, Branislav; McGiffin, David C; Kobashigawa, Jon A; Cintron, Guillermo B; Mullen, G Martin; Pitts, Douglas E; O'Donnell, Jacqueline; Thomas, Cindi; Bourge, Robert C; Naftel, David C

2003-08-01

Cardiac retransplantation is a controversial procedure due to the disparity between donor heart demand and supply. Of 7,290 patients undergoing primary cardiac transplantation between January 1990 and December 1999 at 42 institutions contributing to the Cardiac Transplant Research Database (CTRD), 106 patients later underwent a second and 1 patient a third cardiac transplant procedure. The actuarial freedom from retransplantation was 99.2% and 96.8% at 1 and 10 years, respectively. Reasons for retransplantation included early graft failure (n = 34), acute cardiac rejection (n = 15), coronary allograft vasculopathy (CAV, n = 39), non-specific graft failure (n = 7), and miscellaneous (n = 10). The only risk factor associated with retransplantation was younger age, reflecting the policy of preferential retransplantation of younger patients. Survival after retransplantation was inferior to that after primary transplantation (56% and 38% at 1 and 5 years, respectively). Risk factors associated with death after retransplantation included retransplantation for acute rejection (p = 0.0005), retransplantation for early graft failure (p = 0.03), and use of a female donor (p = 0.005). Survival after retransplantation for acute rejection was poorest (32% and 8% at 1 and 5 years, respectively) followed by retransplantation for early graft failure (50% and 39% at 1 and 5 years, respectively). Survival after retransplantation for CAV has steadily improved with successive eras. The results of retransplantation for acute rejection and early graft failure are poor enough to suggest that this option is not advisable. However, retransplantation for CAV is currently associated with satisfactory survival and should continue to be offered to selected patients.

Time-dependent changes in B-type natriuretic peptide after heart transplantation: correlation with allograft rejection and function.

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Bader, Feras M; Rogers, R Kevin; Kfoury, Abdallah G; Gilbert, Edward M; Horne, Ben D; Stehlik, Josef; Renlund, Dale G

2009-01-01

Endomyocardial biopsy is the gold standard to diagnose cardiac allograft rejection, although a noninvasive modality such as brain natriuretic peptide (BNP) is attractive. The authors examined the correlation of BNP levels with rejection patterns and allograft function in cardiac allograft recipients followed up to 8 years. One hundred forty-four consecutive patients underwent endomyocardial biopsy, right heart catheterization, and blood sampling. BNP levels decreased during the first 6 months after transplant but then reached a plateau. Time-dependent correlations were made between BNP levels and allograft rejection, left ventricular ejection fraction, pulmonary capillary wedge pressure, right atrial pressure, and serum creatinine. BNP levels were not different between patients with any rejection pattern and no rejection prior to or after 6 months following transplant. BNP levels did not correlate with ejection fraction, pulmonary capillary wedge pressure, right atrial pressure, or creatinine in the first 6 months after transplant. Statistically significant correlations existed between BNP and these parameters after 6 months following transplant. In cardiac transplant recipients, BNP levels decrease in the first 6 months following transplant and then reach a plateau regardless of the presence, type, or severity of allograft rejection. BNP levels do predict allograft rejection but correlate with allograft function after 6 months following transplant.

Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice.

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Noriyuki Kashiyama

rejection of the allogeneic iPSC-cardiac. This imaging tool may enable the understanding and monitoring host-immune response of the host, allogeneic cell transplantation therapy.

[Cardiac involvement in Churg-Strauss syndrome].

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Brucato, Antonio; Maestroni, Silvia; Masciocco, Gabriella; Ammirati, Enrico; Bonacina, Edgardo; Pedrotti, Patrizia

2015-09-01

agents, particularly cyclophosphamide in case of myocardial inflammation. Thus, early diagnosis of cardiac involvement and subsequent therapy may prevent progression of cardiac disease. At present, the role of troponin and brain natriuretic peptide in monitoring and therapy remains unclear. Orthotopic heart transplantation is feasible in case of severe disease, even if the experience is limited in -EGPA, and optimal post-transplantation immunosuppressive strategy has yet to be defined.

Intracoronary artery transplantation of cardiomyoblast-like cells from human adipose tissue-derived multi-lineage progenitor cells improve left ventricular dysfunction and survival in a swine model of chronic myocardial infarction

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Okura, Hanayuki [The Center for Medical Engineering and Informatics, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0879 (Japan); Department of Somatic Stem Cell Therapy and Health Policy, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Saga, Ayami; Soeda, Mayumi [Department of Somatic Stem Cell Therapy and Health Policy, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Miyagawa, Shigeru; Sawa, Yoshiki [Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0879 (Japan); Daimon, Takashi [Division of Biostatistics, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan); Ichinose, Akihiro [Department of Plastic Surgery, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo (Japan); Matsuyama, Akifumi, E-mail: akifumi-matsuyama@umin.ac.jp [The Center for Medical Engineering and Informatics, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0879 (Japan); Department of Plastic Surgery, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo (Japan); RIKEN Program for Drug Discovery and Medical Technology Platforms, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045 (Japan)

2012-09-07

Highlights: Black-Right-Pointing-Pointer We administered human CLCs in a swine model of MI via intracoronary artery. Black-Right-Pointing-Pointer Histological studies demonstrated engraftment of hCLCs into the scarred myocardium. Black-Right-Pointing-Pointer Echocardiography showed rescue of cardiac function in the hCLCs transplanted swine. Black-Right-Pointing-Pointer Transplantation of hCLCs is an effective therapeutics for cardiac regeneration. -- Abstract: Transplantation of human cardiomyoblast-like cells (hCLCs) from human adipose tissue-derived multi-lineage progenitor cells improved left ventricular function and survival of rats with myocardial infarction. Here we examined the effect of intracoronary artery transplantation of human CLCs in a swine model of chronic heart failure. Twenty-four pigs underwent balloon-occlusion of the first diagonal branch followed by reperfusion, with a second balloon-occlusion of the left ascending coronary artery 1 week later followed by reperfusion. Four weeks after the second occlusion/reperfusion, 17 of the 18 surviving animals with severe chronic MI (ejection fraction <35% by echocardiography) were immunosuppressed then randomly assigned to receive either intracoronary artery transplantation of hCLCs hADMPCs or placebo lactic Ringer's solution with heparin. Intracoronary artery transplantation was followed by the distribution of DiI-stained hCLCs into the scarred myocardial milieu. Echocardiography at post-transplant days 4 and 8 weeks showed rescue and maintenance of cardiac function in the hCLCs transplanted group, but not in the control animals, indicating myocardial functional recovery by hCLCs intracoronary transplantation. At 8 week post-transplantation, 7 of 8 hCLCs transplanted animals were still alive compared with only 1 of the 5 control (p = 0.0147). Histological studies at week 12 post-transplantation demonstrated engraftment of the pre DiI-stained hCLCs into the scarred myocardium and their expression of

Drug-Induced Rhabdomyolysis with Elevated Cardiac Troponin T

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Gro Egholm

2015-01-01

Full Text Available The essential role of cardiac troponin in the diagnosis of acute myocardial infarction has led to the development of high-sensitivity assays, which are able to detect very small amounts of myocardial necrosis. The high-sensitivity cardiac troponin T assay, however, is not entirely specific for myocardial injury. This case report describes a 48-year-old woman, who, two years after cardiac transplantation, presented with rhabdomyolysis. During the course of the disease, her troponin T level was elevated on repeated occasions, but other definitive evidence of myocardial injury was not found. Asymptomatic cardiac troponin T elevations during rhabdomyolysis may be due to either cardiac involvement or false positive results stemming from skeletal muscle injury.

Allogeneic amniotic membrane-derived mesenchymal stromal cell transplantation in a porcine model of chronic myocardial ischemia

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Kimura M

2012-01-01

Full Text Available Introduction. Amniotic membrane contains a multipotential stem cell population and is expected to possess the machinery to regulate immunological reactions. We investigated the safety and efficacy of allogeneic amniotic membrane-derived mesenchymal stromal cell (AMSC transplantation in a porcine model of chronic myocardial ischemia as a preclinical trial. Methods. Porcine AMSCs were isolated from amniotic membranes obtained by cesarean section just before delivery and were cultured to increase their numbers before transplantation. Chronic myocardial ischemia was induced by implantation of an ameroid constrictor around the left circumflex coronary artery. Four weeks after ischemia induction, nine swine were assigned to undergo either allogeneic AMSC transplantation or normal saline injection. Functional analysis was performed by echocardiography, and histological examinations were carried out by immunohistochemistry 4 weeks after AMSC transplantation. Results. Echocardiography demonstrated that left ventricular ejection fraction was significantly improved and left ventricular dilatation was well attenuated 4 weeks after AMSC transplantation. Histological assessment showed a significant reduction in percentage of fibrosis in the AMSC transplantation group. Injected allogeneic green fluorescent protein (GFP-expressing AMSCs were identified in the immunocompetent host heart without the use of any immunosuppressants 4 weeks after transplantation. Immunohistochemistry revealed that GFP colocalized with cardiac troponin T and cardiac troponin I. Conclusions. We have demonstrated that allogeneic AMSC transplantation produced histological and functional improvement in the impaired myocardium in a porcine model of chronic myocardial ischemia. The transplanted allogeneic AMSCs survived without the use of any immunosuppressants and gained cardiac phenotype through either their transdifferentiation or cell fusion.

Cardiopulmonary transplantation service establishment in the 1990s: Australia--a developing country?

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Esmore, D; Williams, T; Bergin, P; Rosenfeldt, F; Cochrane, A; Griffiths, A; Federman, J

1992-10-01

1. A National Transplantation Service has been established at the Alfred Hospital performing more than 50 transplants per year. 2. Increased access to transplantation technology has facilitated an improvement in national population servicing from 2.7 to 6.2 transplants per million population per year. National funding of A$4.062 million per year has been secured. 3. Basic research into organ preservation has facilitated transcontinental organ procurement. 4. An active lung transplantation program has been established synchronous with the cardiac transplant service activities. 5. MCS program establishment has paralleled clinical transplantation activities. 6. Budget management and cost containment has been achieved through rationalisation of management protocols.

ROLE OF PRE- AND POST-TRANSPLANT FACTORS IN THE DEVELOPMENT OF CORONARY DISEASE OF THE TRANSPLANT HEART

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E. K. Kurlianskaya

2015-01-01

Full Text Available Aim: to assess the relationship between preand post-transplantation factors and degree of coronary artery lesion, reported by intravascular ultrasound study (IVUS in patients who underwent orthotopic heart transplantation (OHT surgery. Materials and methods. The study comprised of 27 patients who underwent OHT more than 2 years before. The age of patients was 46,8 ± 10,4 years old. All of them were preoperatively classified by HLA system. All patients received transthoracic echocardiography at terms of 1, 6, 12 and 24 months after OHT. Coronary angiography (CAG and IVUS were performed at 24 ± 6 months. Results. In CAG none of the patients showed angiographic signs of CA stenosis, but changes of various degrees were detected by IVUS. Results obtained by IVUS were clustered to select two groups with different degree of coronary artery lesion. The donor’s age in Group 2 was evidently higher compared to Group 1 (34,77 ± 1,03 and 40,00 ± 2,04 years, respectively, p = 0,043. Donor-recipient coincidence frequency was lower in group with significant CA lesion (by 2,36, р = 0,003. The number of cardiac surgeries performed prior to OHT was higher in Group 2 (by 2,8, р = 0,008. Post-transplant factor analysis showed that the number of diabetes mellitus (DM cases revealed after transplantation was more frequent in Group 2 (by 3,2 vs Group 1, р = 0,021. Conclusion. The degree of CA lesion according to IVUS at 24-month period after OTH was associated with several post-transplant factors, which were the presence of cardiac surgical interventions before transplantation, low HLA donor-recipient coincidence frequency, and donor’s age. The more significant CA lesion is, the more cases of DM after OHT occur. 

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

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

1988-01-01

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

Suicidal hanging donors for lung transplantation

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Ananiadou, Olga; Schmack, Bastian; Zych, Bartlomiej; Sabashnikov, Anton; Garcia-Saez, Diana; Mohite, Prashant; Weymann, Alexander; Mansur, Ashham; Zeriouh, Mohamed; Marczin, Nandor; De Robertis, Fabio; Simon, Andre Rüdiger; Popov, Aron-Frederik

2018-01-01

Abstract In the context of limited donor pool in cardiothoracic transplantation, utilization of organs from high risk donors, such as suicidal hanging donors, while ensuring safety, is under consideration. We sought to evaluate the outcomes of lung transplantations (LTx) that use organs from this group. Between January 2011 and December 2015, 265 LTx were performed at our center. Twenty-two recipients received lungs from donors after suicidal hanging (group 1). The remaining 243 transplantations were used as a control (group 2). Analysis of recipient and donor characteristics as well as outcomes was performed. No statistically significant difference was found in the donor characteristics between analyzed groups, except for higher incidence of cardiac arrest, younger age and smoking history of hanging donors (P donor cause of death is not associated with poor mid-term survival or chronic lung allograft dysfunction following transplantation. These results encourage assessment of lungs from hanging donors, and their consideration for transplantation. PMID:29620623

NORMOTHERMIC EXTRACORPOREAL PERFUSION IN SITU IN DECEASED ORGAN DONORS WITH IRREVERSIBLE CARDIAC ARREST AND ONE HOUR OF ASYSTOLE. 5-YEAR OUTCOMES OF KIDNEY TRANSPLANTATION

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A. E. Skvortsov

2016-01-01

Full Text Available Aim. The global shortage of deceased organ donors caused increasing interest to the transplant program based on the use of organs from the donors with sudden irreversible cardiac arrest, or asystolic donors (DCD. Ischemia-reperfusion injury as a result of cardiac arrest remains a key problem that limits the use of organs from DCD. Our clinical study was intended to determine the acceptability of renal transplants derived from the DCD using extracorporeal perfusion in situ after 60 minutes of asystole. Materials and methods. In 2009–2014, St. Petersburg Organ Procurement Organization (OPO obtained kidneys from 29 DCD with critically expanded warm ischemic time (WIT. The design of this study was approved by the Scientifi c Board and Ethics Committee of the State Research Institute for Emergency Medicine (Decision 7/0615/09. Initially, no one of died patients was considered as potential organ donors. In case of failed advanced CPR the death of a patient was declared initiating the protocol of subnormothermic extracorporeal abdominal perfusion with ECMO, thrombolytics (strepokinase 1.5 mln U, and LD. The procedures were established by the authorized OPO team which arrived with perfusion equipment in 30–40 minutes after declaration of donors’ death. Mean WIT was 58.1 (19.39 minutes (Mean (SD. Resuscitated grafts were transplanted into 58 recipients. The outcomes of transplantation of resuscitated kidneys were compared to those of 112 KTx from 115 brain death donors (BDDs. Results. Immediate functioning of kidney grafts was observed in 28 (48.3% of 58 recipients. There were 4 cases of primary graft non-function. By the end of the fi rst post-transplant year there was an acute rejection rate of 12.1% (9 episodes of rejection in the DCD group vs. 23.2% (26 episodes of rejection in the BDD group (p < 0.05. The actuarial 5-year graft survival rate was 82.8% (n = 48 in DCD group, and 87.5% (n = 98 in BDD group (p > 0.05. Creatinine levels at the end

Endostar, a recombined humanized endostatin, enhances the radioresponse for human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts in mice

International Nuclear Information System (INIS)

Wen Qinglian; Meng Maobin; Tu Lingli; Jia Li; Zhou Lin; Xu Yong; Lu You; Yang Bo

2009-01-01

The purpose of this paper is to determine the efficacy of combining radiation therapy with endostar, a recombined humanized endostatin, in human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts. Tumor xenografts were established in the hind limb of male athymic nude mice (BALB/c-nu) by subcutaneous transplantation. The tumor-bearing mice were assigned into four treatment groups: sham therapy (control), endostar (20 mg/kg, once daily for 10 days), radiation therapy (6 Gray per day to 30 Gray, once a day for 1 week), and endostar plus radiation therapy (combination). The experiment was repeated and mice were killed at days 3, 6, and 10 after initiation therapy, and the tumor tissues and blood samples were collected to analyze the kinetics of antitumor, antiangiogenesis, and antivascularization responses of different therapies. In human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts, endostar significantly enhanced the effects of tumor growth inhibition, endothelial cell and tumor cell apoptosis induction, and improved tumor cell hypoxia of radiation therapy. Histological analyses demonstrated that endostar plus radiation also induced a significant reduction in microvascular density, microvascular area, and vascular endothelial growth factor and matrix metalloproteinase-2 expression compared with radiation and endostar alone respectively. We concluded that endostar significantly sensitized the function of radiation in antitumor and antiangiogenesis in human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts by increasing the apoptosis of the endothelial cell and tumor cell, improving the hypoxia of the tumor cell, and changing the proangiogenic factors. These data provided a rational basis for clinical practice of this multimodality therapy. (author)

The effect of total blood exchange with PHP solution on cardiac xenotransplantation.

Science.gov (United States)

Liu, H; Agishi, T; Suga, H; Hayasaka, Y; Teraoka, S; Ota, K

1995-04-01

Prevention of hyperacute rejection is a difficult and unsolved problem in xenotransplantation. Natural antibodies and complement activation have been known to play an important role in the xenotransplantation between discordant species pairs. In the present study, total blood exchange (TBE) was performed with pyridoxalated-hemoglobin-polyoxyethylene conjugate (PHP) solution (Ajinomoto Co., Inc., Kawasaki, Japan) before cardiac xenotransplantation in order to remove the immunoglobulins and prolong xenograft survival time. Guinea pigs and rats were used as the discordant species combination for donor and recipient. Two groups were established: Group 1, untreated control (n = 8) and Group 2, TBT with PHP solution (n = 8). The exchange blood transfusion was carried out at the rate of 15-20 ml/h utilizing PHP solution using a blood pump. After the blood exchange was processed, hematocrit (Ht) levels dropped to 4 or 5%, and a cardiac xenotransplantation was performed within 24 h. The levels of serum IgA, IgM, and IgG were decreased to less than 25, 25, and 10% of the base line, respectively, after blood exchange. A mean xenograft survival time in Group 2 was prolonged to 472 +/- 74 min and to 10.4 +/- 1.8 min in Group 1 (p < 0.01). A titer of the anti-guinea pig lymphocytotoxic antibody in rat serum was decreased to almost nil. The data from this study suggest that total blood exchange with PHP solution may be useful in preoperative removal of xenograft antibodies in xenotransplantation.

Aortic Valve Replacement for Infective Endocarditis in a Renal Transplant Recipient

Directory of Open Access Journals (Sweden)

Masmoudi Sayda

2000-01-01

Full Text Available Renal transplant recipients are more prone to developing infections. We report a 37-year old renal transplant recipient who developed infective endocarditis of the aortic valve, heart failure and renal allograft dysfunction. He underwent aortic valve replacement which was followed by improvement in cardiac as well as allograft function.

Advances in Cell Transplantation Therapy for Diseased Myocardium

Directory of Open Access Journals (Sweden)

Outi M. Villet

2011-01-01

Full Text Available The overall objective of cell transplantation is to repopulate postinfarction scar with contractile cells, thus improving systolic function, and to prevent or to regress the remodeling process. Direct implantation of isolated myoblasts, cardiomyocytes, and bone-marrow-derived cells has shown prospect for improved cardiac performance in several animal models and patients suffering from heart failure. However, direct implantation of cultured cells can lead to major cell loss by leakage and cell death, inappropriate integration and proliferation, and cardiac arrhythmia. To resolve these problems an approach using 3-dimensional tissue-engineered cell constructs has been investigated. Cell engineering technology has enabled scaffold-free sheet development including generation of communication between cell graft and host tissue, creation of organized microvascular network, and relatively long-term survival after in vivo transplantation.

Subnormothermic ex vivo liver perfusion reduces endothelial cell and bile duct injury after donation after cardiac death pig liver transplantation.

Science.gov (United States)

Knaak, Jan M; Spetzler, Vinzent N; Goldaracena, Nicolas; Boehnert, Markus U; Bazerbachi, Fateh; Louis, Kristine S; Adeyi, Oyedele A; Minkovich, Leonid; Yip, Paul M; Keshavjee, Shaf; Levy, Gary A; Grant, David R; Selzner, Nazia; Selzner, Markus

2014-11-01

An ischemic-type biliary stricture (ITBS) is a common feature after liver transplantation using donation after cardiac death (DCD) grafts. We compared sequential subnormothermic ex vivo liver perfusion (SNEVLP; 33°C) with cold storage (CS) for the prevention of ITBS in DCD liver grafts in pig liver transplantation (n = 5 for each group). Liver grafts were stored for 10 hours at 4°C (CS) or preserved with combined 7-hour CS and 3-hour SNEVLP. Parameters of hepatocyte [aspartate aminotransferase (AST), international normalized ratio (INR), factor V, and caspase 3 immunohistochemistry], endothelial cell (EC; CD31 immunohistochemistry and hyaluronic acid), and biliary injury and function [alkaline phosphatase (ALP), total bilirubin, and bile lactate dehydrogenase (LDH)] were determined. Long-term survival (7 days) after transplantation was similar between the SNEVLP and CS groups (60% versus 40%, P = 0.13). No difference was observed between SNEVLP- and CS-treated animals with respect to the peak of serum INR, factor V, or AST levels within 24 hours. CD31 staining 8 hours after transplantation demonstrated intact EC lining in SNEVLP-treated livers (7.3 × 10(-4) ± 2.6 × 10(-4) cells/μm(2)) but not in CS-treated livers (3.7 × 10(-4) ± 1.3 × 10(-4) cells/μm(2) , P = 0.03). Posttransplant SNEVLP animals had decreased serum ALP and serum bilirubin levels in comparison with CS animals. In addition, LDH in bile fluid was lower in SNEVLP pigs versus CS pigs (14 ± 10 versus 60 ± 18 μmol/L, P = 0.02). Bile duct histology revealed severe bile duct necrosis in 3 of 5 animals in the CS group but none in the SNEVLP group (P = 0.03). Sequential SNEVLP preservation of DCD grafts reduces bile duct and EC injury after liver transplantation. © 2014 American Association for the Study of Liver Diseases.

Immune function surveillance: association with rejection, infection and cardiac allograft vasculopathy.

Science.gov (United States)

Heikal, N M; Bader, F M; Martins, T B; Pavlov, I Y; Wilson, A R; Barakat, M; Stehlik, J; Kfoury, A G; Gilbert, E M; Delgado, J C; Hill, H R

2013-01-01

Rejection, cardiac allograft vasculopathy (CAV), and infection are significant causes of mortality in heart transplantation recipients. Assessing the immune status of a particular patient remains challenging. Although endomyocardial biopsy (EMB) and angiography are effective for the identification of rejection and CAV, respectively, these are expensive, invasive, and may have numerous complications. The aim of this study was to evaluate the immune function and assess its utility in predicting rejection, CAV, and infection in heart transplantation recipients. We prospectively obtained samples at the time of routine EMB and when clinically indicated for measurement of the ImmuKnow assay (IM), 12 cytokines and soluble CD30 (sCD30). EMB specimens were evaluated for acute cellular rejection, and antibody-mediated rejection (AMR). CAV was diagnosed by the development of angiographic coronary artery disease. Infectious episodes occurring during the next 30 days after testing were identified by the presence of positive bacterial or fungal cultures and/or viremia that prompted treatment with antimicrobials. We collected 162 samples from 56 cardiac transplant recipients. There were 31 infection episodes, 7 AMR, and 4 CAV cases. The average IM value was significantly lower during infection, (P = .04). Soluble CD30 concentrations showed significantly positive correlation with infection episodes, (P = .001). Significant positive correlation was observed between interleukin-5(IL-5) and AMR episodes (P = .008). Tumor necrosis factor-α and IL-8 showed significant positive correlation with CAV (P = .001). Immune function monitoring appears promising in predicting rejection, CAV, and infection in cardiac transplantation recipients. This approach may help in more individualized immunosuppression and it may also minimize unnecessary EMBs and cardiac angiographies. Published by Elsevier Inc.

Study on the effect of the survival time and the T cells in the discordant heart xenotransplantation produced by intrathymic inoculation with xenogeneic antigen using the model of pig to monkey

International Nuclear Information System (INIS)

Qu Jichen; Jiang Gening; Ding Jiaan

2005-01-01

Objective: This study was designed to investigate the effect of survival time and T cells on the delayed xenograft rejection caused by intrathymic injection of xenogeneic antigen in the discordant cardiac xenotransplantation, and to investigate the possibility of inducing the tolerance for cardiac xenografts. Methods: In this experiment, pig and monkey were, respectively, selected as donor and recipient. Donor and recipient were divided randomly into four groups. In the blank group (group A) recipients didn't accept any treatments but heart xenotransplantation; In the whole body irradiation (WBI) group (group B) 3 Gy ( 60 Co) was received on d30 before transplantation. In the intrathymic injection group (group C) monkeys were pretreated by the intrathymic injection of pig spleen cells (5 x 10 7 ) on d21 before transplantation, the other treatments were the same as that in group A. In the irradiation and intrathymic injection group (group D) monkeys were pretreated by WBI and the intrathymic injection of pig spleen cells at the time just as that in group B and group C. In every group, monkeys were performed heterotopic heart xenotransplantation in abdomen in order to observe the survival time of cardiac xenografts. Results: (1) Survival time of donor heart in group D (91.1 ± 22.8 h) was significantly longer than group B(42.56 ± 1.4 h) and group A (35.6 ± 2.2 h) (P 0.05). (3) The results of MLR showed that there is significant reduction in group D than in group A and B (P + and CD8+ T cells in peripheral blood, but pretreatment with IT and WBI can induce T cells immune 4 suppression or immune tolerance, that is similar to allotransplantation in the rodent. (2) Pretreatment with IT and WBI can induce T cells immune suppression or immune tolerance. (authors)

Post-transplant outcome in chronic myeloid leukemia

International Nuclear Information System (INIS)

Raza, S.; Ullah, K.; Ahmed, P.; Kamal, M.K.

2008-01-01

To determine post-transplant survival in chronic myeloid leukaemia patients undergoing allogeneic stem cell transplant. All patients of chronic myeloid leukaemia in chronic phase having HLA identical donor and age under 55 years, normal hepatic, renal and cardiac functions with good performance status were selected. Patients in accelerated phase or blast crisis, poor performance status, impaired hepatic, renal, cardiac functions or pregnancy were excluded. Survival was calculated from the date of transplant to death or last follow-up according to Kaplan-Meier and Cox (proportional hazard) regression analysis methods. Thirty seven patients with chronic myeloid leukaemia underwent allogeneic stem cell transplant from HLA identical sibling donors. Thirty two patients were male and five were females. Median age of patients was 28 years. All patients and donors were CMV positive. Post-transplant complications encountered were acute GvHD (Grade II-IV) (n=13, 35.1%), chronic GvHD in 18.9% (n=7), Veno Occlusive Disease (VOD) in 5.4% (n=2), acute renal failure in 2.7% (n=1), haemorrhagic cystitis in 2.7% (n=1), bacterial infections in 40.5% (n=15), fungal infections in 16.2% (n=6), CMV infection in 5.4% (n=2), tuberculosis in 5.4% (n=2), Herpes Zoster infection 2.7% (n=1) and relapse in 2.7% (n=1). Mortality was observed in 27% (n=10). Major causes of mortality were GvHD, VOD, septicemia, CMV infection and disseminated Aspergillosis. Overall Disease Free Survival (DFS) was 73% with a median duration of follow-up of 47.4 + 12 months. DFS was 81% in standard risk and 54.5% in high-risk group. Results of allogeneic stem cell transplant in standard risk group CML patients were good and comparable with other international centres, however, results in high-risk CML patients need further improvement, although, number of patients in this group is small. (author)

Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

Energy Technology Data Exchange (ETDEWEB)

Kim, Manbok, E-mail: manbok66@dankook.ac.kr [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Rahman, Masmudur M. [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Cogle, Christopher R. [Department of Hematology/Oncology, University of Florida, Gainesville, FL 32610 (United States); McFadden, Grant [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States)

2015-07-10

Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases.

Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

International Nuclear Information System (INIS)

Kim, Manbok; Rahman, Masmudur M.; Cogle, Christopher R.; McFadden, Grant

2015-01-01

Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases

Pretransplant cachexia and morbid obesity are predictors of increased mortality after heart transplantation.

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Lietz, K; John, R; Burke, E A; Ankersmit, J H; McCue, J D; Naka, Y; Oz, M C; Mancini, D M; Edwards, N M

2001-07-27

Extremes in body weight are a relative contraindication to cardiac transplantation. We retrospectively reviewed 474 consecutive adult patients (377 male, 97 female, mean age 50.3+/-12.2 years), who received 444 primary and 30 heart retransplants between January of 1992 and January of 1999. Of these, 68 cachectic (body mass index [BMI]27-30 kg/m2), and 55 morbidly obese (BMI>30 kg/m2) patients were compared with 238 normal-weight recipients (BMI=20-27 kg/m2). We evaluated the influence of pretransplant BMI on morbidity and mortality after cardiac transplantation. Kaplan-Meier survival distribution and Cox proportional hazards model were used for statistical analyses. Morbidly obese as well as cachectic recipients demonstrated nearly twice the 5-year mortality of normal-weight or overweight recipients (53% vs. 27%, respectively, P=0.001). An increase in mortality was seen at 30 days for morbidly obese and cachectic recipients (12.7% and 17.7%, respectively) versus a 30-day mortality rate of 7.6% in normal-weight recipients. Morbidly obese recipients experienced a shorter time to high-grade acute rejection (P=0.004) as well as an increased annual high-grade rejection frequency when compared with normal-weight recipients (P=0.001). By multivariable analysis, the incidence of transplant-related coronary artery disease (TCAD) was not increased in morbidly obese patients but cachectic patients had a significantly lower incidence of TCAD (P=0.05). Cachectic patients receiving oversized donor hearts had a significantly higher postoperative mortality (P=0.02). The risks of cardiac transplantation are increased in both morbidly obese and cachectic patients compared with normal-weight recipients. However, the results of cardiac transplantation in overweight patients is comparable to that in normal-weight patients. Recipient size should be kept in mind while selecting patients and the use of oversized donors in cachectic recipients should be avoided.

Human cardiomyocyte progenitor cell transplantation preserves long-term function of the infarcted mouse myocardium

NARCIS (Netherlands)

Smits, Anke M.; van Laake, Linda W.; den Ouden, Krista; Schreurs, Chantal; Szuhai, Karoly; van Echteld, Cees J.; Mummery, Christine L.; Doevendans, Pieter A.; Goumans, Marie-Jose

2009-01-01

Recent clinical studies revealed that positive results of cell transplantation on cardiac function are limited to the short- and mid-term restoration phase following myocardial infarction (MI), emphasizing the need for long-term follow-up. These transient effects may depend on the transplanted

Unilateral lung transplantation for pulmonary fibrosis.

Science.gov (United States)

1986-05-01

Improvements in immunosuppression and surgical techniques have made unilateral lung transplantation feasible in selected patients with end-stage interstitial lung disease. We report two cases of successful unilateral lung transplantation for end-stage respiratory failure due to pulmonary fibrosis. The patients, both oxygen-dependent, had progressive disease refractory to all treatment, with an anticipated life expectancy of less than one year on the basis of the rate of progression of the disease. Both patients were discharged six weeks after transplantation and returned to normal life. They are alive and well at 26 months and 14 months after the procedure. Pulmonary-function studies have shown substantial improvement in their lung volumes and diffusing capacities. For both patients, arterial oxygen tension is now normal and there is no arterial oxygen desaturation with exercise. This experience shows that unilateral lung transplantation, for selected patients with end-stage interstitial lung disease, provides a good functional result. Moreover, it avoids the necessity for cardiac transplantation, as required by the combined heart-lung procedure, and permits the use of the donor heart for another recipient.

Aspergillus Pericarditis with Tamponade in a Renal Transplant Patient

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Sylvia Biso

2017-01-01

Full Text Available Aspergillus pericarditis is a rare and life-threatening infection in immunosuppressed patients. It has nonspecific clinical manifestations that often mimic other disease entities especially in patients who have extensive comorbidities. Diagnosis is oftentimes delayed and rarely done antemortem. A high degree of suspicion in immunocompromised patients is necessary for evaluation and timely diagnosis. This is a case of Aspergillus pericarditis with cardiac tamponade in a renal transplant patient with liver cirrhosis. Two months after transplant, he developed decompensation of his cirrhosis from hepatitis C, acute cellular rejection, and Kluyvera bacteremia, followed by vancomycin-resistant Enterococcus faecium (VRE bacteremia. Four months after transplant, the patient presented with lethargy and fluid overload. He subsequently developed shock and ventilator-dependent respiratory failure. An echocardiogram showed pericardial effusion with cardiac tamponade. He had emergent pericardiocentesis that showed purulent drainage. He was started on broad-spectrum antibiotics. Amphotericin B was initiated when the pericardial fluid grew mold that was later identified as Aspergillus fumigatus. The patient quickly decompensated and expired.

Technetium myocardial perfusion scanning in prerenal transplant evaluation in the United kingdom.

LENUS (Irish Health Repository)

Wong, C F

2008-06-01

Because death with a functioning graft remains one of the most important causes of long-term renal transplant failure, cardiac risk stratification and screening for coronary artery disease are essential components of pretransplant assessment. Pretransplant screening for occult coronary artery disease in a subset of these patients may improve outcome. The UK follows the European Best practice guideline 1.5.5 E. Although echocardiography, thallium myocardial perfusion scanning (MPS), dobutamine stress echocardiography, and coronary angiography have been suggested as means of cardiovascular assessment, the best means of assessment remains undetermined. Therefore, we investigated the role of 99m technetium sestamibi myocardial perfusion scanning as an assessment tool for identifying those patients with end-stage renal failure at high risk of cardiovascular death after renal transplantation. Retrospectively, we studied 126 patients that had a MPS as part of their pretransplant assessment. Overall unadjusted survival was 65% at 3 years. Twelve deaths resulted from cardiovascular causes. A reversible defect on MPS was associated with a fatal cardiac event and all-cause mortality. The unadjusted hazard ratio of cardiac event with reversible defect on MPS was 3.1 (95% confidence interval, 1.1 to 18.2) and hazard ratio of death with reversible defect on MPS was 1.92 (95% confidence interval, 1.1 to 4.4). Thus, MPS may be a useful tool in cardiac risk stratification and in selecting patients with a favorable outcome after renal transplantation. Our patients with a reversible defect in particular have increased cardiac mortality. This group may benefit from coronary angiography.

One year of high-intensity interval training improves exercise capacity, but not left ventricular function in stable heart transplant recipients: a randomised controlled trial.

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Rustad, Lene A; Nytrøen, Kari; Amundsen, Brage H; Gullestad, Lars; Aakhus, Svend

2014-02-01

Heart transplant recipients have lower exercise capacity and impaired cardiac function compared with the normal population. High-intensity interval training (HIIT) improves exercise capacity and cardiac function in patients with heart failure and hypertension, but the effect on cardiac function in stable heart transplant recipients is not known. Thus, we investigated whether HIIT improved cardiac function and exercise capacity in stable heart transplant recipients by use of comprehensive rest- and exercise-echocardiography and cardiopulmonary exercise testing. Fifty-two clinically stable heart transplant recipients were randomised either to HIIT (4 × 4 minutes at 85-95% of peak heart rate three times per week for eight weeks) or to control. Three such eight-week periods were distributed throughout one year. Echocardiography (rest and submaximal exercise) and cardiopulmonary exercise testing were performed at baseline and follow-up. One year of HIIT increased VO 2peak from 27.7 ± 5.5 at baseline to 30.9 ± 5.0 ml/kg/min at follow-up, while the control group remained unchanged (28.5 ± 7.0 vs. 28.0 ± 6.7 ml/kg per min, p HIIT. Whereas HIIT is feasible in heart transplant recipients and effectively improves exercise capacity, it does not alter cardiac systolic and diastolic function significantly. Thus, the observed augmentation in exercise capacity is best explained by extra-cardiac adaptive mechanisms.

Celecoxib plays a multiple role to peripheral blood lymphocytes and allografts in acute rejection in rats after cardiac transplantation

Institute of Scientific and Technical Information of China (English)

ZHANG Xue-feng; ZHANG Fan; LIU Hong-yu; SUN Guo-dong; LIU Zong-hong; L(U) Hang; CHI Chao; LI Chun-yu

2009-01-01

Background Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is a non-steroidal anti-inflammatory drug used as an adjuvant to sensitize cancer cells to apoptosis. However, in rats suffering from acute rejection, celecoxib reduced apoptosis of myocardial cells. We hypothesize that celecoxib reduces myocardial apoptosis either by inducing apoptosis in peripheral blood lymphocytes (PBLs) or by altering the percentage of CD4+ and CD8+ lymphocytes. Methods After cardiac transplantation, rats were administered intragastrically with celecoxib (50 mg/kg per day) for 3, 5 or 7 days, at which time the graft was excised and evaluated for organ rejection. In addition, PBLs were isolated from the blood to determine PBLs apoptosis, and the percentage of CD4+ and CD8+ lymphocytes. Results Celecoxib induced PBLs apoptosis in 3 days, but protected the cells from apoptosis at 5 and 7 days. Also, the percentage of CD4+ lymphocytes decreased only at 3 days, but a reduction in the percentage of CD8+ lymphocytes was not seen until 7 days after the transplant surgery. Celecoxib only decreased acute rejection at 5 days, with no discernible difference in rejection after 3 and 7 days. Conclusions The results suggested that celecoxib displayed a multiple physiological function in a time-dependent manner.

[Cardiac sarcoidosis: diagnostics, treatment and follow-up].

Science.gov (United States)

Dudziak, Maria; Jankowska, Hanna; Dorniak, Karolina

2018-03-27

Sarcoidosis is a generalised granulomatous disorder of unknown aetiology. Cardiac involvement may affect conduction system, myocardium, valvular apparatus and pericardium. Clinical spectrum ranges from asymptomatic involvement to sudden cardiac death. Patients with biopsy-proven extracardiac sarcoidosis should be screened for cardiac involvement (standard ECG, 24-hour Holter ECG, echocardiography) and in case of any abnormalities found on these tests, more advanced diagnostic methods should be used. Steroid treatment is still the mainstay of therapy in cardiac sarcoidosis. Several immunosuppresive agents are also effective and used in different combinations with steroids, as well as heart failure treatment (including ACE inhibitors, angiotensin receptor blockers, beta-blockers and diuretics). Advanced heart block requires pacemaker implantation, and implantable cardioverterdefibrillator is an effective treatment in primary and secondary prophylaxis of sudden cardiac death. Heart transplantation is considered in advanced, drug-resistant heart failure or incessant ventricular arrhythmias unresponsive to other forms of therapy. © 2018 MEDPRESS.

Initial experience with xenograft bioconduit for the treatment of complex prosthetic valve endocarditis.

Science.gov (United States)

Roubelakis, Apostolos; Karangelis, Dimos; Sadeque, Syed; Yanagawa, Bobby; Modi, Amit; Barlow, Clifford W; Livesey, Steven A; Ohri, Sunil K

2017-07-01

The treatment of complex prosthetic valve endocarditis (PVE) with aortic root abscess remains a surgical challenge. Several studies support the use of biological tissues to minimize the risk of recurrent infection. We present our initial surgical experience with the use of an aortic xenograft conduit for aortic valve and root replacement. Between October 2013 and August 2015, 15 xenograft bioconduits were implanted for complex PVE with abscess (13.3% female). In 6 patients, concomitant procedures were performed: coronary bypass (n=1), mitral valve replacement (n=5) and tricuspid annuloplasty (n=1). The mean age at operation was 60.3±15.5 years. The mean Logistic European system for cardiac operating risk evaluation (EuroSCORE) was 46.6±23.6. The median follow-up time was 607±328 days (range: 172-1074 days). There were two in-hospital deaths (14.3% mortality), two strokes (14.3%) and seven patients required permanent pacemaker insertion for conduction abnormalities (46.7%). The mean length of hospital stay was 26 days. At pre-discharge echocardiography, the conduit mean gradient was 9.3±3.3mmHg and there was either none (n=6), trace (n=6) or mild aortic insufficiency (n=1). There was no incidence of mid-term death, prosthesis-related complications or recurrent endocarditis. Xenograft bioconduits may be safe and effective for aortic valve and root replacement for complex PVE with aortic root abscess. Although excess early mortality reflects the complexity of the patient population, there was good valve hemodynamics, with no incidence of recurrent endocarditis or prosthesis failure in the mid-term. Our data support the continued use and evaluation of this biological prosthesis in this high-risk patient cohort.

Chest radiographic findings and complications of the temporary implantation of the Jarvik-7 artificial heart while awaiting orthotopic heart transplantation: Experience with five cases

International Nuclear Information System (INIS)

Sadler, L.R.; Fuhrman, C.R.; Hardesty, R.A.; Griffith, B.P.

1986-01-01

The Jarvik-7 artificial heart was originally introduced as a therapeutic alternative to cardiac transplantation in patients with endstage refractory cardiac disease. Its use has been expanded to those patients awaiting cardiac transplantation in whom death is impending and for whom a suitable donor match is unavailable. At Presbyterian-University Hospital of Pittsburgh five patients have had Jarvik-7 hearts implanted as a temporary measure while awaiting compatible donors for cardiac transplantation. The authors believe this is the largest patient group to undergo this procedure at a single institution. They present a brief description of the Jarvik-7 heart, the clinical factors affecting patient selection, and the radiographic appearance of a normally functioning Jarvik-7 heart, and review the chest radiographic complications seen in the patient group, along with eventual patient outcome

Vitrification and xenografting of human ovarian tissue.

Science.gov (United States)

Amorim, Christiani Andrade; Dolmans, Marie-Madeleine; David, Anu; Jaeger, Jonathan; Vanacker, Julie; Camboni, Alessandra; Donnez, Jacques; Van Langendonckt, Anne

2012-11-01

To assess the efficiency of two vitrification protocols to cryopreserve human preantral follicles with the use of a xenografting model. Pilot study. Gynecology research unit in a university hospital. Ovarian biopsies were obtained from seven women aged 30-41 years. Ovarian tissue fragments were subjected to one of three cryopreservation protocols (slow freezing, vitrification protocol 1, and vitrification protocol 2) and xenografted for 1 week to nude mice. The number of morphologically normal follicles after cryopreservation and grafting and fibrotic surface area were determined by histologic analysis. Apoptosis was assessed by the TUNEL method. Morphometric analysis of TUNEL-positive surface area also was performed. Follicle proliferation was evaluated by immunohistochemistry. After xenografting, a difference was observed between the cryopreservation procedures applied. According to TUNEL analysis, both vitrification protocols showed better preservation of preantral follicles than the conventional freezing method. Moreover, histologic evaluation showed a significantly higher proportion of primordial follicles in vitrified (protocol 2)-warmed ovarian tissue than in frozen-thawed tissue. The proportion of growing follicles and fibrotic surface area was similar in all groups. Vitrification procedures appeared to preserve not only the morphology and survival of preantral follicles after 1 week of xenografting, but also their ability to resume folliculogenesis. In addition, vitrification protocol 2 had a positive impact on the quiescent state of primordial follicles after xenografting. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Transplantation of Hearts Donated after Circulatory Death

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Christopher W. White

2018-02-01

Full Text Available Cardiac transplantation has become limited by a critical shortage of suitable organs from brain-dead donors. Reports describing the successful clinical transplantation of hearts donated after circulatory death (DCD have recently emerged. Hearts from DCD donors suffer significant ischemic injury prior to organ procurement; therefore, the traditional approach to the transplantation of hearts from brain-dead donors is not applicable to the DCD context. Advances in our understanding of ischemic post-conditioning have facilitated the development of DCD heart resuscitation strategies that can be used to minimize ischemia-reperfusion injury at the time of organ procurement. The availability of a clinically approved ex situ heart perfusion device now allows DCD heart preservation in a normothermic beating state and minimizes exposure to incremental cold ischemia. This technology also facilitates assessments of organ viability to be undertaken prior to transplantation, thereby minimizing the risk of primary graft dysfunction. The application of a tailored approach to DCD heart transplantation that focuses on organ resuscitation at the time of procurement, ex situ preservation, and pre-transplant assessments of organ viability has facilitated the successful clinical application of DCD heart transplantation. The transplantation of hearts from DCD donors is now a clinical reality. Investigating ways to optimize the resuscitation, preservation, evaluation, and long-term outcomes is vital to ensure a broader application of DCD heart transplantation in the future.

In vivo bioluminescence imaging using orthotopic xenografts towards patient's derived-xenograft Medulloblastoma models.

Science.gov (United States)

Asadzadeh, Fatemeh; Ferrucci, Veronica; DE Antonellis, Pasqualino; Zollo, Massimo

2017-03-01

Medulloblastoma is a cerebellar neoplasia of the central nervous system. Four molecular subgrups have been identified (MBWNT, MBSHH, MBgroup3 and MBgroup4) with distinct genetics and clinical outcome. Among these, MBgroup3-4 are highly metastatic with the worst prognosis. The current standard therapy includes surgery, radiation and chemotherapy. Thus, specific treatments adapted to cure those different molecular subgroups are needed. The use of orthotopic xenograft models, together with the non-invasive in vivo biolumiscence imaging (BLI) technology, is emerging during preclinical studies to test novel therapeutics for medulloblastoma treatment. Orthotopic MB xenografts were performed by injection of Daoy-luc cells, that had been previously infected with lentiviral particles to stably express luciferase gene, into the fourth right ventricle of the cerebellum of ten nude mice. For the implantation, specific stereotactic coordinates were used. Seven days after the implantation the mice were imaged by acquisitions of bioluminescence imaging (BLI) using IVIS 3D Illumina Imaging System (Xenogen). Tumor growth was evaluated by quantifying the bioluminescence signals using the integrated fluxes of photons within each area of interest using the Living Images Software Package 3.2 (Xenogen-Perkin Elmer). Finally, histological analysis using hematoxylin-eosin staining was performed to confirm the presence of tumorigenic cells into the cerebellum of the mice. We describe a method to use the in vivo bioluminescent imaging (BLI) showing the potential to be used to investigate the potential antitumorigenic effects of a drug for in vivo medulloblastoma treatment. We also discuss other studies in which this technology has been applied to obtain a more comprehensive knowledge of medulloblastoma using orthotopic xenograft mouse models. There is a need to develop patient's derived-xenograft (PDX) model systems to test novel drugs for medulloblastoma treatment within each molecular sub

[Kidney transplantation epidemiology in France].

Science.gov (United States)

Hiesse, Christian

2013-11-01

Kidney transplantation activity in France is among the most important worldwide: in 2011, 2976 transplants have been performed (47.5 per million population), and the number of patients living with a functional graft is estimated around 30,000, representing 44.7% of all patients (n = 67,270) treated for end-stage renal failure. However, the rate of preemptive kidney transplants remains very low, only 3.3% of incident patients starting renal replacement therapy. The analysis of demand showed a progressive increase in recent years, as demonstrated by the registration rate on the kidney transplantation waiting list, increasing by 5% yearly between 2006 and 2010, but with huge differences according to age categories and regional registration areas, reflecting discrepant appreciations in indications for kidney transplantation. The median waiting time between registration and transplantation increased progressively in recent years, reaching 22.3 months with considerable variations according to regional areas and transplantation teams. Kidney transplantation activity, while increasing continuously, is far to cover the rising demand, and inexorably patients accumulate on the waiting list (around 9000 patients were registered by January 2012). This situation is the consequence of insufficient organ procurement activity. The deceased organ procurement rate remained high: 1572 harvested donors in 2011 (24.1 per million population), but the proportion of older donors rose in recent years, to reach the rate of 26% of donors older than 65 years in 2011. The procurement activity of donors after cardiac arrest was reintroduced in 2006, but increased slowly: 65 transplants were performed in 2011 using kidney procured in non heart-beating donors. The living donor kidney transplantation activity has markedly increased recently: 302 living donor transplantations were performed in 2011, representing 10.1% of the kidney transplantations. Facing the predictable increase in the number of

Implementing a Cardiac Skills Orientation and Simulation Program.

Science.gov (United States)

Hemingway, Maureen W; Osgood, Patrice; Mannion, Mildred

2018-02-01

Patients with cardiac morbidities admitted for cardiac surgical procedures require perioperative nurses with a high level of complex nursing skills. Orienting new cardiac team members takes commitment and perseverance in light of variable staffing levels, high-acuity patient populations, an active cardiac surgical schedule, and the unpredictability of scheduling patients undergoing cardiac transplantation. At an academic medical center in Boston, these issues presented opportunities to orient new staff members to the scrub person role, but hampered efforts to provide active learning opportunities in a safe environment. As a result, facility personnel created a program to increase new staff members' skills, confidence, and proficiency, while also increasing the number of staff members who were proficient at scrubbing complex cardiac procedures. To address the safe learning requirement, personnel designed a simulation program to provide scrubbing experience, decrease orientees' supervision time, and increase staff members' confidence in performing the scrub person role. © AORN, Inc, 2018.

Evaluation of Exercise Performance, Cardiac Function, and Quality of Life in Children After Liver Transplantation.

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Vandekerckhove, Kristof; Coomans, Ilse; De Bruyne, Elke; De Groote, Katya; Panzer, Joseph; De Wolf, Daniel; Boone, Jan; De Bruyne, Ruth

2016-07-01

In children, after having liver transplantation (LT), it is important to assess the quality of life (QOL). Physical fitness is an important determinant of QOL, and because cardiac function can influence exercise performance, it is the purpose of the present study to assess these factors. Children in stable follow-up for more than 6 months post-LT were invited to participate in a case control study. Patients underwent cardiopulmonary exercise testing and echocardiography to assess systolic and diastolic function, and left ventricular wall dimensions. Health-related QOL was evaluated using child- and adolescent-reported PedsQL questionnaire. Twenty-eight of 31 included patients performed a maximal exercise test (15 boys, 11.6 ± 2.9 years, weight, 40.9 ± 13.1 kg; length, 148.6 ± 17.3 cm; body mass index, 17.6 ± 2.3). Liver transplantation patients had lower maximal oxygen consumption (VO2max/kg) (37.5 ± 9.3 mL/kg per minute vs 44.1 ± 8.8 mL/kg per minute), shorter exercise duration (9.3 ± 2.8 minutes vs 13.3 ± 3 minutes) and lower load (71 ± 14 vs 85 ± 20%). They reached the ventilatory anaerobic threshold earlier (81.4 ± 9.5 vs 88.3 ± 11.9%). Echocardiography demonstrated increased interventricular septal wall thickness (interventricular septum in diastole Z value, +0.45 ± 0.49, P exercise testing. Health-related QOL showed lower overall, emotional, psychosocial, and school functioning scores. Children on antihypertensive medication had impaired physical functioning compared with other LT patients. Lower physical fitness level, more deconditioning and lower health-related QOL in children after LT emphasize the importance of exercise stimulation and fitness programs. Patients on antihypertensive medication seem to be the most vulnerable group suffering from decreased physical fitness.

Novel immunological strategies for islet transplantation.

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Tezza, Sara; Ben Nasr, Moufida; Vergani, Andrea; Valderrama Vasquez, Alessandro; Maestroni, Anna; Abdi, Reza; Secchi, Antonio; Fiorina, Paolo

2015-08-01

Islet transplantation has been demonstrated to improve glycometabolic control, to reduce hypoglycemic episodes and to halt the progression of diabetic complications. However, the exhaustion of islet function and the side effects related to chronic immunosuppression limit the spread of this technique. Consequently, new immunoregulatory protocols have been developed, with the aim to avoid the use of a life-time immunosuppression. Several approaches have been tested in preclinical models, and some are now under clinical evaluation. The development of new small molecules and new monoclonal or polyclonal antibodies is continuous and raises the possibility of targeting new costimulatory pathways or depleting particular cell types. The use of stem cells and regulatory T cells is underway to take advantage of their immunological properties and to induce tolerance. Xenograft islet transplantation, although having severe problems in terms of immunological compatibility, could theoretically provide an unlimited source of donors; using pigs carrying human immune antigens has showed indeed promising results. A completely different approach, the use of encapsulated islets, has been developed; synthetic structures are used to hide islet alloantigen from the immune system, thus preserving islet endocrine function. Once one of these strategies is demonstrated safe and effective, it will be possible to establish clinical islet transplantation as a treatment for patients with type 1 diabetes long before the onset of diabetic-related complications. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cardiac transplant in a family pedigree of hypertrophic cardiomyopathy secondary to a mutation in the AMP gene.

LENUS (Irish Health Repository)

Schofield, Rebecca Sally

2013-01-01

The phenotype of this unique condition comprises left ventricular hypertrophy (LVH), accessory pathways, atrial arrhythmia and premature failure of the atrioventricular node. At age 11, his ECG showed marked voltage criteria for LVH but his echocardiography was negative. He declined further screening but was reassessed at 21 years of age. By this time he had developed significant LVH. He had an implantable cardioventer defibrillator (ICD) in 2001. He developed atrial flutter and fibrillation which was initially treated with medical therapy and then radiofrequency ablation.Unfortunately, his condition deteriorated. He was New York Heart Association (NYHA) class 3-4 for most of 2011 and spent the latter part of the year and most of 2012 as an in-patient. An attempt to upgrade his ICD to a cardiac resynchronisation therapy-defibrillator was unsuccessful.In March 2012 he was placed on the transplant waiting list. He received an organ in June. He is now NHYA class 1 and has returned to work part-time.

Biliary strictures and liver transplantation : clinical and biomedical aspects

NARCIS (Netherlands)

Sebib Korkmaz, Kerem

2014-01-01

The current thesis describes short and long term results of orthotopic liver transplantation (OLT) performed with livers from donation after brain death (DBD) and livers from donation after cardiac death (DCD) with an emphasis on biliary complications, especially nonanastomotic biliary strictures

Effect of infectious diseases on outcome after heart transplant

NARCIS (Netherlands)

van de Beek, Diederik; Kremers, Walter K.; del Pozo, Jose L.; Daly, Richard C.; Edwards, Brooks S.; McGregor, Christopher G. A.; Patel, Robin

2008-01-01

OBJECTIVE: To determine how often cardiac allograft recipients develop infectious diseases and how the infections affect these patients. PATIENTS AND METHODS: We retrospectively studied 313 patients who underwent heart transplant at Mayo Clinic's site in Rochester, MN, from January 1, 1988, through

The effects of compound danshen dripping pills and human umbilical cord blood mononuclear cell transplant after acute myocardial infarction.

Science.gov (United States)

Jun, Yi; Chunju, Yuan; Qi, Ai; Liuxia, Deng; Guolong, Yu

2014-04-01

The low frequency of survival of stem cells implanted in the myocardium after acute myocardial infarction may be caused by inflammation and oxidative stress in the myocardial microenvironment. We evaluated the effects of a traditional Chinese medicine, Compound Danshen Dripping Pills, on the cardiac microenvironment and cardiac function when used alone or in combination with human umbilical cord blood mononuclear cell transplant after acute myocardial infarction. After surgically induced acute myocardial infarction, rabbits were treated with Compound Danshen Dripping Pills alone or in combination with human umbilical cord blood mononuclear cell transplant. Evaluation included histology, measurement of left ventricular ejection fraction and fractional shortening, leukocyte count, count of green fluorescent protein positive cells, superoxide dismutase activity, and malondialdehyde content. Combination treatment with Compound Danshen Dripping Pills and human umbilical cord blood mononuclear cell transplant significantly increased the survival of implanted cells, inhibited cardiac cell apoptosis, decreased oxidative stress, decreased the inflammatory response, and improved cardiac function. Rabbits treated with either Compound Danshen Dripping Pills or human umbilical cord blood mononuclear cells alone had improvement in these effects compared with untreated control rabbits. Combination therapy with Compound Danshen Dripping Pills and human umbilical cord blood mononuclear cells may improve cardiac function and morphology after acute myocardial infarction.

Allografts versus Equine Xenografts in Calcaneal Fracture Repair.

Science.gov (United States)

Sonmez, Mehmet Mesut; Armagan, Raffi; Ugurlar, Meric; Eren, Tugrul

Displaced intra-articular calcaneal fractures are difficult to treat. We determined the functional results and complications of using allografts or equine xenografts in treating these fractures. We reviewed patients seen at our center from May 2011 to December 2014 with Sanders type III or IV unilateral calcaneal fractures treated with locking plates and an additional bone allograft or equine xenograft. A minimum of 1 year after surgery, a history of infection and functional outcomes were assessed using the American Orthopaedic Foot and Ankle Society clinical rating system. Changes in the Gissane angle (GA) and Böhler angle were assessed from radiographs. Of the 91 eligible patients, 15 were lost to follow-up, leaving a sample of 76 patients (42 males): 45 received allografts (19 for type III and 26 for type IV fractures) and 31 received xenografts (20 for type III and 11 for type IV fractures). The mean age was about 40 years in both groups. After ≥1 year of follow-up, the proportion of patients in the American Orthopaedic Foot and Ankle Society scoring categories did not differ significantly between the 2 groups (mean ankle score, 86.5 in the allograft group and 85.1 in the xenograft group), and the American Orthopaedic Foot and Ankle Society functional outcomes were good or excellent in 69% and 68%, respectively (p = .986). The groups did not differ in the incidence of superficial or deep infection (p = 1.000). The Böhler angles were significantly decreased in the xenograft group. Xenografts might be preferred for repairing intra-articular calcaneal fractures because they can perform as well as allografts, avoid donor site morbidities, and are more available and less expensive than allografts. Copyright © 2017 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Retrospective review of bone mineral metabolism management in end-stage renal disease patients wait-listed for renal transplant

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Chavlovski A

2012-09-01

Full Text Available Anna Chavlovski,1 Greg A Knoll,1–3 Timothy Ramsay,4 Swapnil Hiremath,1–3 Deborah L Zimmerman1–31University of Ottawa, 2Ottawa Hospital, 3Kidney Research Centre, Ottawa Hospital Research Institute, 4Ottawa Methods Centre, Ottawa, ON, CanadaBackground: In patients with end-stage renal disease, use of vitamin D and calcium-based phosphate binders have been associated with progression of vascular calcification that might have an impact on renal transplant candidacy. Our objective was to examine management of mineral metabolism in patients wait-listed for renal transplant and to determine the impact on cardiac perfusion imaging.Methods: Data was collected retrospectively on patients wait-listed for a renal transplant (n = 105, being either active (n = 73 and on hold (n = 32. Demographic data, medications, serum concentrations of calcium, phosphate, parathyroid hormone, and cardiac perfusion imaging studies were collected from the electronic health record. Chi-square and Student’s t-tests were used to compare active and on-hold patients as appropriate. Logistic regression was used to examine variables associated with worsening cardiac imaging studies.Results: The wait-listed patients were of mean age 56 ± 14 years and had been on dialysis for 1329 ± 867 days. On-hold patients had received a significantly greater total dose of calcium (2.35 ± .94 kg versus 1.49 ± 1.52 kg; P = 0.02 and were more likely to have developed worsening cardiovascular imaging studies (P = 0.03. Total doses of calcium and calcitriol were associated with worsening cardiovascular imaging studies (P = 0.05.Conclusion: Patients on hold on the renal transplant waiting list received higher total doses of calcium. A higher total dose of calcium and calcitriol was also associated with worsening cardiovascular imaging. Time on dialysis before transplant has been associated with worse post-transplant outcomes, and it is possible that the total calcium and calcitriol dose

Drug-Induced Rhabdomyolysis with Elevated Cardiac Troponin T

DEFF Research Database (Denmark)

Egholm, Gro; Pareek, Manan

2015-01-01

for myocardial injury. This case report describes a 48-year-old woman, who, two years after cardiac transplantation, presented with rhabdomyolysis. During the course of the disease, her troponin T level was elevated on repeated occasions, but other definitive evidence of myocardial injury was not found...

Improving recovery time following heart transplantation: the role of the multidisciplinary health care team

Directory of Open Access Journals (Sweden)

Roussel MG

2013-08-01

Full Text Available Maureen G Roussel,1 Noreen Gorham,2 Lynn Wilson,2 Abeel A Mangi2 1Heart and Vascular Center, Yale-New Haven Hospital, New Haven, CT, USA; 2Center for Advanced Heart Failure, Mechanical Circulatory Support and Cardiac Transplantation, Yale New Haven Heart and Vascular Institute, Yale-New Haven Hospital, New Haven, CT, USA Background: The care of cardiac transplant patients is complex requiring a finely orchestrated endeavor to save a patient’s life. Given the chronic and complex nature of these patients, multiple disciplines are involved in their care. Recognizing difficulties with communication among team members and striving for improved efficiencies in our pretransplant listing process and in our inpatient care, our team was prompted to change the existing approach to patient care related to heart transplantation. Methods: Daily multidisciplinary rounds were instituted and the format of the weekly Multidisciplinary Review Committee (MDRC meetings was modified with the list of attendees broadened to include a larger interdisciplinary team. Additionally, the approach to patient care was analyzed for process improvement. Results: The quality improvements are improved communication and throughput, quantified in an 85% decrease in time to complete transplant evaluation, a 37% decrease in median length of stay posttransplantation, and a 33% reduction in the 30 day readmission rate. In addition, pre- and posttransplant caregivers now participate in MDRC in person or via an electronic meeting platform to support the continuum of care. Quality metrics were chosen and tracked via a transparent electronic platform allowing all involved to assess progress toward agreed upon goals. These were achieved in an 18 month time period following the recruitment of new leadership and invested team members working together as a multidisciplinary team to improve the quality of cardiac transplant care. Discussion: Implementation of daily multidisciplinary rounds and

A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies

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Jody E. Hooper

2015-01-01

Full Text Available Embryonal rhabdomyosarcoma (eRMS is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

Bipolar Disorder and Heart Transplantation: A Case Report.

Science.gov (United States)

Ramírez-Giraldo, Ana María; Restrepo, Diana

Bipolar disorder is a chronic and recurrent mood disease that includes symptoms that fluctuate from euphoria to depression. As a mood disorder, itis one of the main contraindications for transplantation procedures. The case is presented of a patient with bipolar disorder who had a heart transplant after a cardiac arrest. Heart transplantation is the treatment of choice in patients with heart failure and arrhythmias that do not respond to conventional treatment. Case report and narrative review of literature. A 34-year-old woman with bipolar disorder diagnosed when she was 13, treated with lithium and aripiprazole. She required a heart transplant as the only therapeutic option, after presenting with ventricular tachycardia refractory to conventional treatment. The patient did not suffer an emotional decompensation with the removal of the lithium and aripiprazole that were associated with prolonged QTc interval, and remained eurhythmic throughout the process. Heart transplantation can be performed safely and successfully in patients with bipolar disorder, when suitably followed-up by a liaison psychiatry group. Bipolar disorder should not be considered as an absolute contraindication for heart transplantation. Copyright © 2017 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Peripheral blood transcriptome sequencing reveals rejection-relevant genes in long-term heart transplantation.

Science.gov (United States)

Chen, Yan; Zhang, Haibo; Xiao, Xue; Jia, Yixin; Wu, Weili; Liu, Licheng; Jiang, Jun; Zhu, Baoli; Meng, Xu; Chen, Weijun

2013-10-03

Peripheral blood-based gene expression patterns have been investigated as biomarkers to monitor the immune system and rule out rejection after heart transplantation. Recent advances in the high-throughput deep sequencing (HTS) technologies provide new leads in transcriptome analysis. By performing Solexa/Illumina's digital gene expression (DGE) profiling, we analyzed gene expression profiles of PBMCs from 6 quiescent (grade 0) and 6 rejection (grade 2R&3R) heart transplant recipients at more than 6 months after transplantation. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) was carried out in an independent validation cohort of 47 individuals from three rejection groups (ISHLT, grade 0,1R, 2R&3R). Through DGE sequencing and qPCR validation, 10 genes were identified as informative genes for detection of cardiac transplant rejection. A further clustering analysis showed that the 10 genes were not only effective for distinguishing patients with acute cardiac allograft rejection, but also informative for discriminating patients with renal allograft rejection based on both blood and biopsy samples. Moreover, PPI network analysis revealed that the 10 genes were connected to each other within a short interaction distance. We proposed a 10-gene signature for heart transplant patients at high-risk of developing severe rejection, which was found to be effective as well in other organ transplant. Moreover, we supposed that these genes function systematically as biomarkers in long-time allograft rejection. Further validation in broad transplant population would be required before the non-invasive biomarkers can be generally utilized to predict the risk of transplant rejection. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia

International Nuclear Information System (INIS)

Saland, E; Boutzen, H; Castellano, R; Pouyet, L; Griessinger, E; Larrue, C; Toni, F de; Scotland, S; David, M; Danet-Desnoyers, G; Vergez, F; Barreira, Y; Collette, Y; Récher, C; Sarry, J-E

2015-01-01

Relevant preclinical mouse models are crucial to screen new therapeutic agents for acute myeloid leukemia (AML). Current in vivo models based on the use of patient samples are not easy to establish and manipulate in the laboratory. Our objective was to develop robust xenograft models of human AML using well-characterized cell lines as a more accessible and faster alternative to those incorporating the use of patient-derived AML cells. Five widely used AML cell lines representing various AML subtypes were transplanted and expanded into highly immunodeficient non-obese diabetic/LtSz-severe combined immunodeficiency IL2Rγ c null mice (for example, cell line-derived xenografts). We show here that bone marrow sublethal conditioning with busulfan or irradiation has equal efficiency for the xenotransplantation of AML cell lines. Although higher number of injected AML cells did not change tumor engraftment in bone marrow and spleen, it significantly reduced the overall survival in mice for all tested AML cell lines. On the basis of AML cell characteristics, these models also exhibited a broad range of overall mouse survival, engraftment, tissue infiltration and aggressiveness. Thus, we have established a robust, rapid and straightforward in vivo model based on engraftment behavior of AML cell lines, all vital prerequisites for testing new therapeutic agents in preclinical studies

Everolimus in Heart Transplantation: An Update

Directory of Open Access Journals (Sweden)

Stephan W. Hirt

2013-01-01

Full Text Available The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into account, all de novo heart transplant patients can be regarded as potential candidates for immunosuppression with everolimus and reduced-exposure calcineurin inhibitor therapy. Caution about the use of everolimus immediately after transplantation should be exercised in certain patients with the risk of severe proteinuria, with poor wound healing, or with uncontrolled severe hyperlipidemia. Initiation of everolimus in the early phase aftertransplant is not advisable in patients with severe pretransplant end-organ dysfunction or in patients on a left ventricular assist device beforetransplant who are at high risk of infection or of wound healing complications. The most frequent reason for introducing everolimus in maintenance heart transplant patients is to support minimization or withdrawal of calcineurin inhibitor therapy, for example, due to impaired renal function or malignancy. Due to its potential to inhibit the progression of cardiac allograft vasculopathy and to reduce cytomegalovirus infection, everolimus should be initiated as soon as possible after heart transplantation. Immediate and adequate reduction of CNI exposure is mandatory from the start of everolimus therapy.

Global Conservation of Protein Status between Cell Lines and Xenografts

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Julian Biau

2016-08-01

Full Text Available Common preclinical models for testing anticancer treatment include cultured human tumor cell lines in monolayer, and xenografts derived from these cell lines in immunodeficient mice. Our goal was to determine how similar the xenografts are compared with their original cell line and to determine whether it is possible to predict the stability of a xenograft model beforehand. We studied a selection of 89 protein markers of interest in 14 human cell cultures and respective subcutaneous xenografts using the reverse-phase protein array technology. We specifically focused on proteins and posttranslational modifications involved in DNA repair, PI3K pathway, apoptosis, tyrosine kinase signaling, stress, cell cycle, MAPK/ERK signaling, SAPK/JNK signaling, NFκB signaling, and adhesion/cytoskeleton. Using hierarchical clustering, most cell culture-xenograft pairs cluster together, suggesting a global conservation of protein signature. Particularly, Akt, NFkB, EGFR, and Vimentin showed very stable protein expression and phosphorylation levels highlighting that 4 of 10 pathways were highly correlated whatever the model. Other proteins were heterogeneously conserved depending on the cell line. Finally, cell line models with low Akt pathway activation and low levels of Vimentin gave rise to more reliable xenograft models. These results may be useful for the extrapolation of cell culture experiments to in vivo models in novel targeted drug discovery.

Nkx2.5 enhances the efficacy of mesenchymal stem cells transplantation in treatment heart failure in rats.

Science.gov (United States)

Deng, Bo; Wang, Jin Xin; Hu, Xing Xing; Duan, Peng; Wang, Lin; Li, Yang; Zhu, Qing Lei

2017-08-01

The aim of this study is to determine whether Nkx2.5 transfection of transplanted bone marrow mesenchymal stem cells (MSCs) improves the efficacy of treatment of adriamycin-induced heart failure in a rat model. Nkx2.5 was transfected in MSCs by lentiviral vector transduction. The expressions of Nkx2.5 and cardiac specific genes in MSCs and Nkx2.5 transfected mesenchymal stem cells (MSCs-Nkx2.5) were analyzed with quantitative real-time PCR and Western blot in vitro. Heart failure models of rats were induced by adriamycin and were then randomly divided into 3 groups: injected saline, MSCs or MSCs-Nkx2.5 via the femoral vein respectively. Four weeks after injection, the cardiac function, expressions of cardiac specific gene, fibrosis formation and collagen volume fraction in the myocardium as well as the expressions of GATA4 and MEF2 in rats were analyzed with echocardiography, immunohistochemistry, Masson staining, quantitative real-time PCR and Western blot, respectively. Nkx2.5 enhanced cardiac specific gene expressions including α-MHC, TNI, CKMB, connexin-43 in MSCs-Nkx2.5 in vitro. Both MSCs and MSCs-Nkx2.5 improved cardiac function, promoted the differentiation of transplanted MSCs into cardiomyocyte-like cells, decreased fibrosis formation and collagen volume fraction in the myocardium, as well as increased the expressions of GATA4 and MEF2 in adriamycin-induced rat heart failure models. Moreover, the effect was much more remarkable in MSCs-Nkx2.5 than in MSCs group. This study has found that Nkx2.5 enhances the efficacy of MSCs transplantation in treatment adriamycin-induced heart failure in rats. Nkx2.5 transfected to transplanted MSCs provides a potential effective approach to heart failure. Copyright © 2017 Elsevier Inc. All rights reserved.

Detection of mediastinitis after heart transplantation by gallium-67 scintigraphy

International Nuclear Information System (INIS)

Quirce, R.; Serano, J.; Arnal, C.; Banzo, I.; Carril, J.M.

1991-01-01

We report the findings of a patient with post-cardiac transplant mediastinitis detected by 67 Ga-citrate imaging. Fever and leukocytosis were the first clinical signs suggesting infection. The usual diagnostic modalities, including CT and ultrasound, failed to identify the site of infection. A 67 Ga scan showed intense abnormal uptake behind the sternum. The site of uptake was shown by necropsy to be necrotic tissue involving cardiac sutures, pulmonary arteries, and the aorta due to infection with Haemophilus aphrophilus

Cardiorespiratory functional assessment after pediatric heart transplantation.

Science.gov (United States)

Pastore, E; Turchetta, A; Attias, L; Calzolari, A; Giordano, U; Squitieri, C; Parisi, F

2001-12-01

Limited data are available on the exercise capacity of young heart transplant recipients. The aim of this study was therefore to assess cardiorespiratory responses to exercise in this group of patients. Fourteen consecutive heart transplant recipients (six girls and eight boys, age-range 5-15 yr) and 14 healthy matched controls underwent a Bruce treadmill test to determine: duration of test; resting and maximum heart rates; maximum systolic blood pressure; peak oxygen consumption (VO2 peak); and cardiac output. Duration of test and heart rate increase were then compared with: time since transplantation, rejections per year, and immunosuppressive drugs received. The recipients also underwent the following lung function tests: forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). When compared with healthy controls, transplant recipients had tachycardia at rest (126 +/- 3.7 beats/min; p physical activity, possibly owing to over-protective parents and teachers and to a lack of suitable supervised facilities. The authors stress the importance of a cardiorespiratory functional evaluation for assessment of health status and to encourage recipients, if possible, to undertake regular physical activity.

Uterine-derived progenitor cells are immunoprivileged and effectively improve cardiac regeneration when used for cell therapy.

Science.gov (United States)

Ludke, Ana; Wu, Jun; Nazari, Mansoreh; Hatta, Kota; Shao, Zhengbo; Li, Shu-Hong; Song, Huifang; Ni, Nathan C; Weisel, Richard D; Li, Ren-Ke

2015-07-01

Cell therapy to prevent cardiac dysfunction after myocardial infarction (MI) is less effective in aged patients because aged cells have decreased regenerative capacity. Allogeneic transplanted stem cells (SCs) from young donors are usually rejected. Maintaining transplanted SC immunoprivilege may dramatically improve regenerative outcomes. The uterus has distinct immune characteristics, and we showed that reparative uterine SCs home to the myocardium post-MI. Here, we identify immunoprivileged uterine SCs and assess their effects on cardiac regeneration after allogeneic transplantation. We found more than 20% of cells in the mouse uterus have undetectable MHC I expression by flow cytometry. Uterine MHC I((neg)) and MHC I((pos)) cells were separated by magnetic cell sorting. The MHC I((neg)) population expressed the SC markers CD34, Sca-1 and CD90, but did not express MHC II or c-kit. In vitro, MHC I((neg)) and ((pos)) SCs show colony formation and endothelial differentiation capacity. In mixed leukocyte co-culture, MHC I((neg)) cells showed reduced cell death and leukocyte proliferation compared to MHC I((pos)) cells. MHC I((neg)) and ((pos)) cells had significantly greater angiogenic capacity than mesenchymal stem cells. The benefits of intramyocardial injection of allogeneic MHC I((neg)) cells after MI were comparable to syngeneic bone marrow cell transplantation, with engraftment in cardiac tissue and limited recruitment of CD4 and CD8 cells up to 21 days post-MI. MHC I((neg)) cells preserved cardiac function, decreased infarct size and improved regeneration post-MI. This new source of immunoprivileged cells can induce neovascularization and could be used as allogeneic cell therapy for regenerative medicine. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pancreas preservation for pancreas and islet transplantation

Science.gov (United States)

Iwanaga, Yasuhiro; Sutherland, David E.R.; Harmon, James V.; Papas, Klearchos K.

2010-01-01

Purpose of review To summarize advances and limitations in pancreas procurement and preservation for pancreas and islet transplantation, and review advances in islet protection and preservation. Recent findings Pancreases procured after cardiac death, with in-situ regional organ cooling, have been successfully used for islet transplantation. Colloid-free Celsior and histidine-tryptophan-ketoglutarate preservation solutions are comparable to University of Wisconsin solution when used for cold storage before pancreas transplantation. Colloid-free preservation solutions are inferior to University of Wisconsin solution for pancreas preservation prior to islet isolation and transplantation. Clinical reports on pancreas and islet transplants suggest that the two-layer method may not offer significant benefits over cold storage with the University of Wisconsin solution: improved oxygenation may depend on the graft size; benefits in experimental models may not translate to human organs. Improvements in islet yield and quality occurred from pancreases treated with inhibitors of stress-induced apoptosis during procurement, storage, isolation or culture. Pancreas perfusion may be desirable before islet isolation and transplantation and may improve islet yields and quality. Methods for real-time, noninvasive assessment of pancreas quality during preservation have been implemented and objective islet potency assays have been developed and validated. These innovations should contribute to objective evaluation and establishment of improved pancreas preservation and islet isolation strategies. Summary Cold storage may be adequate for preservation before pancreas transplants, but insufficient when pancreases are processed for islets or when expanded donors are used. Supplementation of cold storage solutions with cytoprotective agents and perfusion may improve pancreas and islet transplant outcomes. PMID:18685343

Next-generation sequence analysis of cancer xenograft models.

Directory of Open Access Journals (Sweden)

Fernando J Rossello

Full Text Available Next-generation sequencing (NGS studies in cancer are limited by the amount, quality and purity of tissue samples. In this situation, primary xenografts have proven useful preclinical models. However, the presence of mouse-derived stromal cells represents a technical challenge to their use in NGS studies. We examined this problem in an established primary xenograft model of small cell lung cancer (SCLC, a malignancy often diagnosed from small biopsy or needle aspirate samples. Using an in silico strategy that assign reads according to species-of-origin, we prospectively compared NGS data from primary xenograft models with matched cell lines and with published datasets. We show here that low-coverage whole-genome analysis demonstrated remarkable concordance between published genome data and internal controls, despite the presence of mouse genomic DNA. Exome capture sequencing revealed that this enrichment procedure was highly species-specific, with less than 4% of reads aligning to the mouse genome. Human-specific expression profiling with RNA-Seq replicated array-based gene expression experiments, whereas mouse-specific transcript profiles correlated with published datasets from human cancer stroma. We conclude that primary xenografts represent a useful platform for complex NGS analysis in cancer research for tumours with limited sample resources, or those with prominent stromal cell populations.

The outcomes of simultaneous liver and kidney transplantation using donation after cardiac death organs.

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Alhamad, Tarek; Spatz, Christin; Uemura, Tadahiro; Lehman, Eric; Farooq, Umar

2014-12-15

There has been a remarkable increase in simultaneous liver and kidney transplantations (SLK). As organ demand has increased, so has the use of donation after cardiac death (DCD). However, little is known about the outcomes of DCD in SLK. We performed a retrospective analysis using the United Network for Organ Sharing database to compare the outcomes of DCD SLK to donation after brain death (DBD) and determine the impact of donor and recipient factors on allograft and patient survival. Between 2002 and 2011, a total of 3,026 subjects received SLK from DBD and 98 from DCD. Kidney, liver, and patient survival from DCD donors were inferior to DBD at 1, 3, and 5 years (P=0.0056, P=0.0035, and P=0.0205, respectively). With the use of the Cox model, DCD was a significant risk factor for kidney and liver allograft failure and patient mortality. Recipient factors that were associated with worse allograft and patient outcomes included black race, diabetes, being on a ventilator, hospitalization, delayed graft function, hepatocellular carcinoma, and intensive care unit stay. Older age of the donor was also associated with worse outcomes. Despite the decreased allograft and patient survival compared with DBD, DCD SLK provides an acceptable option for SLK, with a survival probability of more than 50% at 5 years.

Radiosensitivity of four human tumor xenografts. Influence of hypoxia and cell-cell contact

International Nuclear Information System (INIS)

Guichard, M.; Dertinger, H.; Malaise, E.P.

1983-01-01

Contact effect (CE) and hypoxia have been studied in human tumor cell lines transplanted in athymic nude mice. Four cell lines - one melanoma (Bell) and three colorectal adenocarcinomas (HT29, HRT18, and HCT8) - were studied. Cell survival was determined with an in vivo in vitro colony-forming assay. Survival curves were obtained under three different conditions: (1) tumor cells irradiated in air-breathing mice, (2) tumor cells irradiated in animals asphyxiated for 10 min, and (3) tumor cells plated and irradiated either immediately or 5 hr later. For all cell lines, radiosensitivity appeared to be lower when cells were irradiated in vivo than when they were irradiated in vitro. Only in the case of the HCT8 tumor did the relative in vivo radioresistance seem to be linked to hypoxia; in the other cell lines, hypoxia alone could not account for the lower in vivo radiosensitivity. Our results suggest that a CE plays an important role in the response of human xenografts to irradiation

Integrated genomics of ovarian xenograft tumor progression and chemotherapy response

International Nuclear Information System (INIS)

Stuckey, Ashley; Brodsky, Alexander S; Fischer, Andrew; Miller, Daniel H; Hillenmeyer, Sara; Kim, Kyu K; Ritz, Anna; Singh, Rakesh K; Raphael, Benjamin J; Brard, Laurent

2011-01-01

Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c. In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth. These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival. We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number

Induction Therapy With Antithymocyte Globulin in Patients Undergoing Cardiac Transplantation Is Associated With Decreased Coronary Plaque Progression as Assessed by Intravascular Ultrasound.

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Azarbal, Babak; Cheng, Richard; Vanichsarn, Christopher; Patel, Jignesh K; Czer, Lawrence S; Chang, David H; Kittleson, Michelle M; Kobashigawa, Jon A

2016-01-01

Antithymocyte globulin (ATG) is used as induction therapy after cardiac transplant for enhancing immunosuppression and delaying the initiation of nephrotoxic drugs. It is unknown if ATG induction is associated with decreased coronary plaque progression by intravascular ultrasound (IVUS). Patients transplanted between March 2010 and December 2012 with baseline and 1-year IVUS were included. All patients transplanted were included in a secondary analysis. Change in plaque progression was measured in a blinded fashion on matched coronary segments and contrasted between patients induced with ATG and those who were not. One hundred and three patients were included in IVUS arms. Mean age at transplant was 55.8 ± 12.6 years, and 33.0% were female. Patients induced with ATG were more sensitized (54.3% versus 14.3%). Plaque progression was attenuated in patients who received ATG by changes in maximal intimal area (1.0 ± 1.2 versus 2.3 ± 2.6 mm(2); P = 0.001), maximal percent stenosis (6.3 ± 7.9 versus 12.8 ± 12.3%; = 0.003), maximal intimal thickness (0.2 ± 0.2 versus 0.3 ± 0.3 mm; P = 0.035), and plaque volume (0.5 ± 0.7 versus 1.0 ± 1.3 mm(3)/mm; P = 0.016). Rapid plaque progression by maximal percent stenosis (≥ 20%) occurred less frequently in the ATG arm (4.3% versus 26.3; P = 0.003). Survival (P = 0.242) and any treated rejection (P = 0.166) were not statistically different between groups. Patients receiving ATG had a higher rate of first-year infection (P = 0.003), perhaps related to increased intravenous antibiotic use immediately postoperatively, and a trend toward more biopsy-proven rejection (P = 0.073). Induction therapy with ATG is associated with reduced first-year coronary plaque progression as assessed by IVUS, despite an increased prevalence of sensitized patients with a trend toward more rejection. © 2016 American Heart Association, Inc.

Renal transplantation in high cardiovascular risk patients.

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Bittar, Julio; Arenas, Paula; Chiurchiu, Carlos; de la Fuente, Jorge; de Arteaga, Javier; Douthat, Walter; Massari, Pablo U

2009-10-01

Current transplant success allows recipients with previous contraindications to transplant to have access to this procedure with more frequency and safety. The concept of high-risk patient has changed since the first stages of transplantation. In the first studies, the high-risk concept was based on probability of early graft failure or on a patient's clinical condition to cope with high perioperatory morbimortality. Later on, this concept implied immunological factors that were crucial to ensure transplant success because hypersensitized or polytransfused patients experienced a higher risk of acute rejection and subsequent graft loss. Afterward, the presence of various comorbidities would redefine the high-risk concept for renal transplant mainly considering recipient's clinical aspects. Currently, the change in epidemiological characteristics of patients starting dialysis causes that we now deal with a greater increase of elderly patients, diabetic patients, and patients with history of cardiovascular disease. Today, high-risk patients are those with clinical features that predict an increase in the risk of perioperative morbimortality or death with functioning graft. In this review, we will attempted to analyze currents results of renal transplant outcomes in terms of patients and graft survival in elderly patients, diabetic patients, and patients with previous cardiovascular disease from the most recent experiences in the literature and from experiences in our center. In any of the groups previously analyzed, survival offered by renal transplant is significantly higher compared to dialysis. Besides, these patients are the recipient group that benefit the most with the transplant because their mortality while remaining on dialysis is extremely high. Hence, renal transplantation should be offered more frequently to older patients, diabetic patients, and patients with pretransplant cardiac and peripheral vascular disease. A positive attitude toward renal

Variation of heart transplant rates in the United States during holidays.

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Grodin, Justin L; Ayers, Colby R; Thibodeau, Jennifer T; Mishkin, Joseph D; Mammen, Pradeep P A; Markham, David W; Drazner, Mark H; Patel, Parag C

2014-08-01

Some cardiac transplant programs may upgrade listed patients to United Network for Organ Sharing (UNOS) 1A-status during the holidays. Whether more transplants actually occur during holidays is unknown. We assessed rates of single-organ heart transplantation from 2001 to 2010 for recipients age ≥18 yr using the UNOS database. Patients were stratified by transplantation during holiday (±3 d, n = 2375) and non-holiday periods (n = 16 112). Holidays included Easter/Spring break, Memorial Day, July 4th, Labor Day, Thanksgiving, and Christmas/New Years (winter holidays). Secondary analysis assessing transplant rates across seasons was also completed. Donor and recipient characteristics were similar between groups. Compared with non-holidays, July 4th had higher transplant rates (5.69 vs. 5.09 transplants/d, p = 0.03) while the winter holiday had lower transplant rates (4.50 vs. 5.09 transplants/d, p < 0.01). There was a trend toward lower transplant rates for all holidays compared with non-holidays (p = 0.06). Transplant rates were significantly different across seasons with greater rates in spring and summer (p < 0.01). Heart transplant rates were higher during the July 4th and lower during the winter holidays. Although there was a higher likelihood of transplantation during the spring and summer seasons, upgrading patients to 1A status during most holidays may not improve their chances for transplantation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Intragraft interleukin 2 mRNA expression during acute cellular rejection and left ventricular total wall thickness after heart transplantation

NARCIS (Netherlands)

de Groot-Kruseman, H A; Baan, C C; Hagman, E M; Mol, W M; Niesters, H G; Maat, A P; Zondervan, P E; Weimar, W; Balk, A H

OBJECTIVE: To assess whether diastolic graft function is influenced by intragraft interleukin 2 (IL-2) messenger RNA (mRNA) expression in rejecting cardiac allografts. DESIGN: 16 recipients of cardiac allografts were monitored during the first three months after transplantation. The presence of IL-2

Recipient origin of neointimal vascular smooth muscle cells in cardiac allografts with transplant arteriosclerosis

NARCIS (Netherlands)

Hillebrands, JL; van den Hurk, BMH; Klatter, FA; Popa, ER; Nieuwenhuis, P; Rozing, J

2000-01-01

Background: Coronary artery disease is today's most important post-heart transplantation problem after the first perioperative year. Histologically, coronary artery disease is characterized by transplant arteriosclerosis. The current view on this vasculopathy is that vascular smooth muscle (VSM)

Full-root aortic valve replacement with stentless xenograft achieves superior regression of left ventricular hypertrophy compared to pericardial stented aortic valves.

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Tavakoli, Reza; Auf der Maur, Christoph; Mueller, Xavier; Schläpfer, Reinhard; Jamshidi, Peiman; Daubeuf, François; Frossard, Nelly

2015-02-03

Full-root aortic valve replacement with stentless xenografts has potentially superior hemodynamic performance compared to stented valves. However, a number of cardiac surgeons are reluctant to transform a classical stented aortic valve replacement into a technically more demanding full-root stentless aortic valve replacement. Here we describe our technique of full-root stentless aortic xenograft implantation and compare the early clinical and midterm hemodynamic outcomes to those after aortic valve replacement with stented valves. We retrospectively compared the pre-operative characteristics of 180 consecutive patients who underwent full-root replacement with stentless aortic xenografts with those of 80 patients undergoing aortic valve replacement with stented valves. In subgroups presenting with aortic stenosis, we further analyzed the intra-operative data, early postoperative outcomes and mid-term regression of left ventricular mass index. Patients in the stentless group were younger (62.6 ± 13 vs. 70.3 ± 11.8 years, p regression of the left ventricular mass index in the stentless (p replacement can be performed without adversely affecting the early morbidity or mortality in patients operated on for aortic valve stenosis provided that the coronary ostia are not heavily calcified. The additional time necessary for the full-root stentless compared to the classical stented aortic valve replacement is therefore not detrimental to the early clinical outcomes and is largely rewarded in patients with aortic stenosis by lower transvalvular gradients at mid-term and a better regression of their left ventricular mass index.

A human lung xenograft mouse model of Nipah virus infection.

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Gustavo Valbuena

2014-04-01

Full Text Available Nipah virus (NiV is a member of the genus Henipavirus (family Paramyxoviridae that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%. NiV can cause Acute Lung Injury (ALI in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecular mechanisms of NiV-associated ALI in the human respiratory tract are unknown. Thus, there is an urgent need for models of henipavirus infection of the human respiratory tract to study the pathogenesis and understand the host responses. Here, we describe a novel human lung xenograft model in mice to study the pathogenesis of NiV. Following transplantation, human fetal lung xenografts rapidly graft and develop mature structures of adult lungs including cartilage, vascular vessels, ciliated pseudostratified columnar epithelium, and primitive "air" spaces filled with mucus and lined by cuboidal to flat epithelium. Following infection, NiV grows to high titers (10(7 TCID50/gram lung tissue as early as 3 days post infection (pi. NiV targets both the endothelium as well as respiratory epithelium in the human lung tissues, and results in syncytia formation. NiV infection in the human lung results in the production of several cytokines and chemokines including IL-6, IP-10, eotaxin, G-CSF and GM-CSF on days 5 and 7 pi. In conclusion, this study demonstrates that NiV can replicate to high titers in a novel in vivo model of the human respiratory tract, resulting in a robust inflammatory response, which is known to be associated with ALI. This model will facilitate progress in the fundamental understanding of henipavirus pathogenesis and virus-host interactions; it will also provide biologically relevant models for other respiratory viruses.

Cost Evaluation of a Donation after Cardiac Death Program: How Cost per Organ Compares to Other Donor Types.

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Lindemann, Jessica; Dageforde, Leigh Anne; Vachharajani, Neeta; Stahlschmidt, Emily; Brockmeier, Diane; Wellen, Jason R; Khan, Adeel; Chapman, William C; Doyle, Mb Majella

2018-05-01

Donation after cardiac death (DCD) is one method of organ donation. Nationally, more than half of evaluated DCD donors do not yield transplantable organs. There is no algorithm for predicting which DCD donors will be appropriate for organ procurement. Donation after cardiac death program costs from an organ procurement organization (OPO) accounting for all evaluated donors have not been reported. Hospital, transportation, and supply costs of potential DCD donors evaluated at a single OPO from January 2009 to June 2016 were collected. Mean costs per donor and per organ were calculated. Cost of DCD donors that did not yield a transplantable organ were included in cost analyses resulting in total cost of the DCD program. Donation after cardiac death donor costs were compared with costs of in-hospital donation after brain death (DBD) donors. There were 289 organs transplanted from 264 DCD donors evaluated. Mean cost per DCD donor yielding transplantable organs was $9,306. However, 127 donors yielded no organs, at a mean cost of $8,794 per donor. The total cost of the DCD program was $32,020 per donor and $15,179 per organ. Mean cost for an in-hospital DBD donor was $33,546 and $9,478 per organ transplanted. Mean organ yield for DBD donors was 3.54 vs 2.21 for DCD donors (p organ 63% of the cost of a DCD organ. Mean cost per DCD donor is comparable with DBD donors, however, individual cost of DCD organs increases by almost 40% when all costs of an entire DCD program are included. Published by Elsevier Inc.

Exploratory use of cardiovascular magnetic resonance imaging in liver transplantation: a one-stop shop for preoperative cardiohepatic evaluation.

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Reddy, Sahadev T; Thai, Ngoc L; Fakhri, Asghar A; Oliva, Jose; Tom, Kusum B; Dishart, Michael K; Doyle, Mark; Yamrozik, June A; Williams, Ronald B; Grant, Saundra B; Poydence, Jacqueline; Shah, Moneal; Singh, Anil; Nathan, Swami; Biederman, Robert W W

2013-11-15

Preoperative cardiovascular risk stratification in orthotopic liver transplantation candidates has proven challenging due to limitations of current noninvasive modalities. Additionally, the preoperative workup is logistically cumbersome and expensive given the need for separate cardiac, vascular, and abdominal imaging. We evaluated the feasibility of a "one-stop shop" in a magnetic resonance suite, performing assessment of cardiac structure, function, and viability, along with simultaneous evaluation of thoracoabdominal vasculature and liver anatomy. In this pilot study, patients underwent steady-state free precession sequences and stress cardiac magnetic resonance (CMR), thoracoabdominal magnetic resonance angiography, and abdominal magnetic resonance imaging (MRI) on a standard MRI scanner. Pharmacologic stress was performed using regadenoson, adenosine, or dobutamine. Viability was assessed using late gadolinium enhancement. Over 2 years, 51 of 77 liver transplant candidates (mean age, 56 years; 35% female; mean Model for End-stage Liver Disease score, 10.8; range, 6-40) underwent MRI. All referred patients completed standard dynamic CMR, 98% completed stress CMR, 82% completed late gadolinium enhancement for viability, 94% completed liver MRI, and 88% completed magnetic resonance angiography. The mean duration of the entire study was 72 min, and 45 patients were able to complete the entire examination. Among all 51 patients, 4 required follow-up coronary angiography (3 for evidence of ischemia on perfusion CMR and 1 for postoperative ischemia), and none had flow-limiting coronary disease. Nine proceeded to orthotopic liver transplantation (mean 74 days to transplantation after MRI). There were six ascertained mortalities in the nontransplant group and one death in the transplanted group. Explant pathology confirmed 100% detection/exclusion of hepatocellular carcinoma. No complications during CMR examination were encountered. In this proof-of-concept study, it

A simple technique can reduce cardiopulmonary bypass use during lung transplantation

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Marcos N. Samano

2016-04-01

Full Text Available Cardiopulmonary bypass causes an inflammatory response and consumption of coagulation factors, increasing the risk of bleeding and neurological and renal complications. Its use during lung transplantation may be due to pulmonary hypertension or associated cardiac defects or just for better exposure of the pulmonary hilum. We describe a simple technique, or open pericardium retraction, to improve hilar exposure by lifting the heart by upward retraction of the pericardial sac. This technique permits lung transplantation without cardiopulmonary bypass when bypass use is recommended only for better exposure.

MR-evaluation of left myocardial function in transplanted hearts

International Nuclear Information System (INIS)

Rienmuller, R.K.; Lioret, J.; Kemkes, B.; Erdmann, E.; Gartner, C.; Hacker, H.; Tilling, R.

1988-01-01

Of 60 heart transplant recipients, 25 were restudied with magnetic resonance (MR) imaging after 1 year to evaluate the left ventricular myocardial (LVM) function, Seven healthy subjects and 15 patients with dilated cardiomyopathy (DCM) served as controls. EDV, ejection fraction (EF), LVMM, wall stress (T-diastolic, T-systolic), and LVM contraction and relaxation (LVMC, LVMR) were measured over a cardiac cycle and compared with angiocardiographic and clinical data. The results showed that EDV and EF were normal in heart transplant recipients both initially and at follow-up, and in healthy subjects. LVMM was significantly increased in patients with DCM and less so in transplant recipients. T-diastolic wall stress was increased in transplant recipients and patients with DCM. The isovolumetric part of LVMC and the LVMR were reduced in these groups, corresponding to restrictive hemodynamics. In transplant recipients at follow-up, a progressive reduction in LVMR was found. In transplant recipients with global myocardial ischemia, LVMM,LVMC,LVMR, and EF are continuously decreasing, in contrast to acute or subacute rejection, where LVMM was found unchanged or increased. In conclusion, LVMM, LVMR, and LVMC as determined by MR imaging are sensitive quantitative indexes of various causes of altered LVM function that result from (sub) acute, chronic rejection or graft atherosclerosis

Intracardiac tromboembolism during liver transplantation.

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Longo, S; Palacios, M; Tinti, M E; Siri, J; de Brahi, J I; Cabrera Shulmeyer, M C

2018-03-20

We describe a case of intraoperative cardiac trombosis during orthotopic liver transplant surgery that resulted in intraoperative death. By using transesophageal echocardiography, the cause of the descompensation of the patient could be determined and the mechanism of trombus migration from thrombi from the venous circulation to the left heart was accurately observed. Copyright © 2018 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

The Changing Financial Landscape of Renal Transplant Practice: A National Cohort Analysis.

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Axelrod, D A; Schnitzler, M A; Xiao, H; Naik, A S; Segev, D L; Dharnidharka, V R; Brennan, D C; Lentine, K L

2017-02-01

Kidney transplantation has become more resource intensive as recipient complexity has increased and average donor quality has diminished over time. A national retrospective cohort study was performed to assess the impact of kidney donor and recipient characteristics on transplant center cost (exclusive of organ acquisition) and Medicare reimbursement. Data from the national transplant registry, University HealthSystem Consortium hospital costs, and Medicare payments for deceased donor (N = 53 862) and living donor (N = 36 715) transplants from 2002 to 2013 were linked and analyzed using multivariate linear regression modeling. Deceased donor kidney transplant costs were correlated with recipient (Expected Post Transplant Survival Score, degree of allosensitization, obesity, cause of renal failure), donor (age, cause of death, donation after cardiac death, terminal creatinine), and transplant (histocompatibility matching) characteristics. Living donor costs rose sharply with higher degrees of allosensitization, and were also associated with obesity, cause of renal failure, recipient work status, and 0-ABDR mismatching. Analysis of Medicare payments for a subsample of 24 809 transplants demonstrated minimal correlation with patient and donor characteristics. In conclusion, the complexity in the landscape of kidney transplantation increases center costs, posing financial disincentives that may reduce organ utilization and limit access for higher-risk populations. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Use of Prothrombin Complex Concentrate in Patients during Heart Transplantation after Implantation of a Left Ventricular Mechanical Support System

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V. V. Lomivorotov

2012-01-01

Full Text Available Heart transplantation in patients after implantation of mechanical cardiac support devices entails an extremely high risk for perioperative bleeding. Recombinant activated coagulation factor VII is presently used to reduce the volume of bleeding in this patient group. There are parallel data on its administration-induced thromboembolic events in the literature. This paper describes a case of using a prothrombin complex concentrate in a patient during explantation of a left ventricular bypass system and subsequent orthotopic heart transplantation in the presence of significant hypocoagulation. At the end of a surgery, 1200 IU of the agent was used at a remaining bleeding rate of more than 1000 ml/hour. Within the first 24 hours after surgery, the rate of discharge drainage was less than 100 ml/hour. A control plain chest X-ray study revealed massive left-sided hydrothorax on day 2 postsurgery. The left pleural cavity was revised under thoracoscopic guidance and 1000 ml of blood clots were evacuated. Although the administration of prothrombin complex concentrate did not guard against re-intervention, its use seems a promising strategy in life-threatening bleedings in patients after explantation of mechanical cardiac support devices. Further multicenter investigations are required to determine the efficacy and safety of prothrom-bin complex concentration in cardiac surgery. Key words: Recombinant activated coagulation factor VII, prothrombin complex concentration, mechanical cardiac support device, orthotopic heart transplantation.

Intestinal transplantation: The anesthesia perspective.

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Dalal, Aparna

2016-04-01

Intestinal transplantation is a complex and challenging surgery. It is very effective for treating intestinal failure, especially for those patients who cannot tolerate parenteral nutrition nor have extensive abdominal disease. Chronic parental nutrition can induce intestinal failure associated liver disease (IFALD). According to United Network for Organ Sharing (UNOS) data, children with intestinal failure affected by liver disease secondary to parenteral nutrition have the highest mortality on a waiting list when compared with all candidates for solid organ transplantation. Intestinal transplant grafts can be isolated or combined with the liver/duodenum/pancreas. Organ Procurement and Transplantation Network (OPTN) has defined intestinal donor criteria. Living donor intestinal transplant (LDIT) has the advantages of optimal timing, short ischemia time and good human leukocyte antigen matching contributing to lower postoperative complications in the recipient. Thoracic epidurals provide excellent analgesia for the donors, as well as recipients. Recipient management can be challenging. Thrombosis and obstruction of venous access maybe common due to prolonged parenteral nutrition and/or hypercoaguability. Thromboelastography (TEG) is helpful for managing intraoperative product therapy or thrombosis. Large fluid shifts and electrolyte disturbances may occur due to massive blood loss, dehydration, third spacing etc. Intestinal grafts are susceptible to warm and cold ischemia and ischemia-reperfusion injury (IRI). Post-reperfusion syndrome is common. Cardiac or pulmonary clots can be monitored with transesophageal echocardiography (TEE) and treated with recombinant tissue plasminogen activator. Vasopressors maybe used to ensure stable hemodynamics. Post-intestinal transplant patients may need anesthesia for procedures such as biopsies for surveillance of rejection, bronchoscopy, endoscopy, postoperative hemorrhage, anastomotic leaks, thrombosis of grafts etc. Asepsis

The relation between serum testosterone levels and cardiovascular risk factors in patients with kidney transplantation

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Hulya Colak

2014-01-01

Full Text Available The objective of the study is to evaluate the relationship between serum testos-terone levels and cardiovascular risk factors (CVRF in patients after kidney transplantation and with chronic kidney disease (CKD. Seventy-five male patients, aged between 18 and 68 years, who had kidney transplantation at least six months earlier, were enrolled into the study. Only renal transplant recipients and CKD patients with a creatinine level of 0.05. Serum testosterone levels were independent risk factors affecting IVC collapse index, systolic BP and LA. m-TORi and CNIs drugs might have no negative effect on serum testosterone levels, and improvement of the serum testosterone levels after transplantation might have a positive contribution on cardiac risk factors.

Bone Marrow Mononuclear Cell Transplantation Restores Inflammatory Balance of Cytokines after ST Segment Elevation Myocardial Infarction.

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Kirsi Alestalo

Full Text Available Acute myocardial infarction (AMI launches an inflammatory response and a repair process to compensate cardiac function. During this process, the balance between proinflammatory and anti-inflammatory cytokines is important for optimal cardiac repair. Stem cell transplantation after AMI improves tissue repair and increases the ventricular ejection fraction. Here, we studied in detail the acute effect of bone marrow mononuclear cell (BMMNC transplantation on proinflammatory and anti-inflammatory cytokines in patients with ST segment elevation myocardial infarction (STEMI.Patients with STEMI treated with thrombolysis followed by percutaneous coronary intervention (PCI were randomly assigned to receive either BMMNC or saline as an intracoronary injection. Cardiac function was evaluated by left ventricle angiogram during the PCI and again after 6 months. The concentrations of 27 cytokines were measured from plasma samples up to 4 days after the PCI and the intracoronary injection.Twenty-six patients (control group, n = 12; BMMNC group, n = 14 from the previously reported FINCELL study (n = 80 were included to this study. At day 2, the change in the proinflammatory cytokines correlated with the change in the anti-inflammatory cytokines in both groups (Kendall's tau, control 0.6; BMMNC 0.7. At day 4, the correlation had completely disappeared in the control group but was preserved in the BMMNC group (Kendall's tau, control 0.3; BMMNC 0.7.BMMNC transplantation is associated with preserved balance between pro- and anti-inflammatory cytokines after STEMI in PCI-treated patients. This may partly explain the favorable effect of stem cell transplantation after AMI.

Cardiac Restoration Stemming From the Placenta Tree: Insights From Fetal and Perinatal Cell Biology

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Sveva Bollini

2018-04-01

Full Text Available Efficient cardiac repair and ultimate regeneration still represents one of the main challenges of modern medicine. Indeed, cardiovascular disease can derive from independent conditions upsetting heart structure and performance: myocardial ischemia and infarction (MI, pharmacological cardiotoxicity, and congenital heart defects, just to name a few. All these disorders have profound consequences on cardiac tissue, inducing the onset of heart failure over time. Since the cure is currently represented by heart transplantation, which is extremely difficult due to the shortage of donors, much effort is being dedicated to developing innovative therapeutic strategies based on stem cell exploitation. Among the broad scenario of stem/progenitor cell subpopulations, fetal and perinatal sources, namely amniotic fluid and term placenta, have gained interest due to their peculiar regenerative capacity, high self-renewal capability, and ease of collection from clinical waste material. In this review, we will provide the state-of-the-art on fetal perinatal stem cells for cardiac repair and regeneration. We will discuss different pathological conditions and the main therapeutic strategies proposed, including cell transplantation, putative paracrine therapy, reprogramming, and tissue engineering approaches.

Effect of blood transfusion and cyclophosphamide on cardiac allograft survival in sensitized mice

International Nuclear Information System (INIS)

Lasek, Witold; Sora, Magdalena; Jakobisiak, Marek

1994-01-01

In the H-2-incompatible donor-recipient model in mice (BALB/c → CBA/H), combination of donor-specific blood transfusion (DST) on the day -9 before transplantation with both pre- and post transplant immunosuppression with cyclophosphamide (CY) interacted beneficially to produce significant donor-specific prolongation of cardiac graft survival. However, in recipients presensitized with donor-specific blood on the day -21, combination of DST with pre- and post transplant CY immunosuppression did not act synergistically and graft survival in this group did not differ from that in presentized mice treated with 2 doses of CY alone. (author). 21 refs, 1 fig., 3 tabs

Machine perfusion for improving outcomes following renal transplant: current perspectives

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Cannon RM

2016-03-01

Full Text Available Robert M Cannon,1 Glen A Franklin1,2 1The Hiram C Polk Jr MD Department of Surgery, University of Louisville, 2Kentucky Organ Donor Affiliates, Louisville, KY, USAAbstract: There is a disparity between the number of kidneys available for transplantation and the number of patients awaiting an organ while on dialysis. The current kidney waiting list in the US contains more than 100,000 patients. This need has led to the inclusion of older donors with worsening renal function, as well as greater utilization of kidneys from non-heartbeating (donation after cardiac death donors. Coinciding with this trend has been a growing interest in technology to improve the function of these more marginal organs, the most important of which currently is machine perfusion (MP of donated kidneys after procurement. While this technology has no standard guidelines currently for comprehensive use, there are many studies that demonstrate higher organ yield and function after a period of MP. Particularly with the older donor and during donation after cardiac death cases, MP may offer some significant benefits. This manuscript reviews all of the current literature regarding MP and its role in renal transplantation. We will discuss both the experience in Europe and the US using machine perfusion for donated kidneys.Keywords: machine perfusion, renal transplantation, kidney pumping, renal failure, organ donation

Monitoring of cardiac antirejection therapy with 111In lymphocytes

International Nuclear Information System (INIS)

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

1982-01-01

To determine whether lymphocytes labeled with 111 In permit noninvasive assessment of antirejection therapy, we performed 40 allogeneic heterotopic cardiac transplants in rats. Antirejection therapy with azathioprine (30 mg/kg) and sodium salicylate (200 mg/kg) prolonged contractile function of the graft from 7.5 +/- 1.5 (s.d.) days in controls to 19.4 +/- 3.7 days in treated animals. Six to seven days after transplantation, autologous lymphocytes labeled with 111 In were injected intravenously in seven untreated and eight treated rats. Scintigraphy and organ counting were performed 24 hr after administration of labeled cells. At sacrifice all grafts in untreated rats exhibited contractile failure, whereas grafts in all treated rats were beating well. Transplants in untreated recipients exhibited marked accumulation of 111 In lymphocytes detectable scintigraphically, with ratios of 7.7 +/- 1.9 for the activity in the transplant over that in the native heart (HT/HO), as obtained by well counting. In contrast, accumulation was not scintigraphically detectable in transplants of treated rats, with HT/HO ratios of 2.6 +/- 1.8 (p less than 0.005). The results suggested that imaging with 111 In-labeled lymphocytes will permit noninvasive assessment of antirejection therapy

Ultrasound-targeted microbubble destruction enhances delayed BMC delivery and attenuates post-infarction cardiac remodelling by inducing engraftment signals.

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Chen, Yanmei; Zhang, Chuanxi; Shen, Shuxin; Guo, Shengcun; Zhong, Lintao; Li, Xinzhong; Chen, Guojun; Chen, Gangbin; He, Xiang; Huang, Chixiong; He, Nvqin; Liao, Wangjun; Liao, Yulin; Bin, Jianping

2016-12-01

Delayed administration of bone marrow cells (BMCs) at 2-4 weeks after successful reperfusion in patients with acute myocardial infarction (MI) does not improve cardiac function. The reduction in engraftment signals observed following this time interval might impair the effects of delayed BMC treatment. In the present study, we aimed to determine whether ultrasound-targeted microbubble destruction (UTMD) treatment could increase engraftment signals, enhance the delivery of delayed BMCs and subsequently attenuate post-infarction cardiac remodelling. A myocardial ischaemia/reperfusion (I/R) model was induced in Wistar rats via left coronary ligation for 45 min followed by reperfusion. Western blotting revealed that engraftment signals peaked at 7 days post-I/R and were dramatically lower at 14 days post-I/R. The lower engraftment signals at 14 days post-I/R could be triggered by UTMD treatment at a mechanical index of 1.0-1.9. The troponin I levels in the 1.9 mechanical index group were higher than in the other groups. Simultaneous haematoxylin and eosin staining and fluorescence revealed that the number of engrafted BMCs in the ischaemic zone was greater in the group treated with both UTMD and delayed BMC transplantation than in the control groups (PBMC transplantation improved cardiac function and decreased cardiac fibrosis at 4 weeks after treatment, as compared with control groups (both PBMC transplantation increased capillary density, myocardial cell proliferation and c-kit + cell proliferation. These findings indicated that UTMD treatment could induce engraftment signals and enhance homing of delayed BMCs to ischaemic myocardium, attenuating post-infarction cardiac remodelling by promoting neovascularization, cardiomyogenesis and expansion of cardiac c-kit + cells. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Unusual rapid evolution of type B aortic dissection in a marfan patient following heart transplantation: successful endovascular treatment.

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Botta, L; Russo, V; Grigioni, F; Arpesella, G; Rocchi, G; Di Bartolomeo, R; Fattori, R

2006-10-01

A patient with Marfan syndrome with previous Bentall operation for mitral and tricuspid valve repair, required orthotopic cardiac transplantation for end stage cardiomyopathy. Postoperatively he suffered type-B aortic dissection, despite normal aortic diameters. Following sudden increase of aortic diameters, two years later, he underwent successful stent graft implantation. In patients with Marfan syndrome, post transplantation morbidity is high, with a 40% incidence of thoracic aortic dissection. This case highlights the potential of endovascular approach for treating post-transplantation aortic dissection.

Noninvasive detection of rejection of transplanted hearts with indium-111-labeled lymphocytes

International Nuclear Information System (INIS)

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

1987-01-01

To determine whether cardiac transplant rejection can be detected noninvasively with indium-111 ( 111 In)-labeled lymphocytes, we studied 11 dogs with thoracic heterotopic cardiac transplants without immunosuppression and five dogs with transplants treated with cyclosporine (10 mg/kg/day) and prednisone (1 mg/kg/day). All were evaluated sequentially with gamma scintigraphy after administration of 150 to 350 muCi of autologous 111 In-lymphocytes. Technetium-99m-labeled red blood cells (1 to 3 mCi) were used for correction of radioactivity in the blood pool attributable to circulating labeled lymphocytes. Lymphocyte infiltration was quantified as the ratio of indium in the myocardium of the transplant or native heart compared with that in blood (indium excess, IE). Results were correlated with mechanical and electrical activity of allografts and with histologic findings in sequential biopsy specimens. In untreated dogs (n = 11), IE was 15.5 +/- 7.0 (SD) in transplanted hearts undergoing rejection and 0.4 +/- 1.1 in native hearts on the day before animals were killed. In dogs treated with cyclosporine and prednisone (n = 5), IE was minimal in allografts during the course of immunosuppression (0.8 +/- 0.4) and increased to 22.9 +/- 11.1 after immunosuppression was stopped. Scintigraphic criteria of rejection (IE greater than 2 SD above that in native hearts) correlated with results of biopsies indicative of rejection and appeared before electrophysiologic or mechanical manifestations of dysfunction. Thus infiltration of labeled lymphocytes in allografts, indicative of rejection, is detectable noninvasively by gamma scintigraphy and provides a sensitive approach potentially applicable to clinical monitoring for early detection of rejection and guidance for titration of immunosuppressive measures

Usefulness and limitations of transthoracic echocardiography in heart transplantation recipients

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Galderisi Maurizio

2008-01-01

Full Text Available Abstract Transthoracic echocardiography is a primary non-invasive modality for investigation of heart transplant recipients. It is a versatile tool which provides comprehensive information about cardiac structure and function. Echocardiographic examinations can be easily performed at the bedside and serially repeated without any patient's discomfort. This review highlights the usefulness of Doppler echocardiography in the assessment of left ventricular and right ventricular systolic and diastolic function, of left ventricular mass, valvular heart disease, pulmonary arterial hypertension and pericardial effusion in heart transplant recipients. The main experiences performed by either standard Doppler echocardiography and new high-tech ultrasound technologies are summarised, pointing out advantages and limitations of the described techniques in diagnosing acute allograft rejection and cardiac graft vasculopathy. Despite the sustained efforts of echocardiographic technique in predicting the biopsy state, endocardial myocardial biopsies are still regarded as the gold standard for detection of acute allograft rejection. Conversely, stress echocardiography is able to identify accurately cardiac graft vasculopathy and has a recognised prognostic in this clinical setting. A normal stress-echo justifies postponement of invasive studies. Another use of transthoracic echocardiography is the monitorisation and the visualisation of the catheter during the performance of endomyocardial biopsy. Bedside stress echocardiography is even useful to select appropriately heart donors with brain death. The ultrasound monitoring is simple and effective for monitoring a safe performance of biopsy procedures.

Perspectives on stem cell therapy for cardiac regeneration. Advances and challenges.

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Choi, Sung Hyun; Jung, Seok Yun; Kwon, Sang-Mo; Baek, Sang Hong

2012-01-01

Ischemic heart disease (IHD) accelerates cardiomyocyte loss, but the developing stem cell research could be useful for regenerating a variety of tissue cells, including cardiomyocytes. Diverse sources of stem cells for IHD have been reported, including embryonic stem cells, induced pluripotent stem cells, skeletal myoblasts, bone marrow-derived stem cells, mesenchymal stem cells, and cardiac stem cells. However, stem cells have unique advantages and disadvantages for cardiac tissue regeneration, which are important considerations in determining the specific cells for improving cell survival and long-term engraftment after transplantation. Additionally, the dosage and administration method of stem cells need to be standardized to increase stability and efficacy for clinical applications. Accordingly, this review presents a summary of the stem cell therapies that have been studied for cardiac regeneration thus far, and discusses the direction of future cardiac regeneration research for stem cells.

Diagnostic and prognostic role of myocardial perfusion scintigraphy in kidney transplant candidates: narrative review

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Alberto Bestetti

2016-10-01

Full Text Available PurposeCardiac screening in adult kidney transplant candidates with myocardial perfusion scintigraphy (MPS can reveal findings associated with increased risk for coronary heart disease events, but the exact value of this screening test is still undetermined.MethodsNarrative review based on the available literature and guidelines on the yield, benefits, and harms of MPS screening in kidney transplant candidates.ResultsAlthough coronary angiography carries low risk in general population, it is not without risk particularly in patients with complex comorbid disease and the use of intravenous contrast media may precipitate a need for hospitalization and death. We could avoid invasive coronary angiography in patients with chronic kidney disease, although with high coronary calcium score, but good left ventricle function and normal perfusion, evaluated by Gated single-photon emission computed tomographic (SPECT MPS. In fact, although Gated SPECT MPS has not a high sensitivity, it provides some variables that are closely related to sudden death: post-stress and rest-ejection fraction and left ventricular volumes, left ventricle muscle mass, extent of ischemia and scar.ConclusionsGated SPECT MPS is a valid noninvasive cardiac screening test. It can be used as alternative to stress echocardiography in kidney transplant candidates with high cardiovascular risk and a positive or inconclusive exercise tolerance ECG test.Patients with abnormal perfusion and cardiac dysfunction should undergo invasive coronary artery imaging and endovascular treatment, while angiography could be avoided in patients with normal MPI, having good long-term prognosis.

Current State and Future Perspectives of Energy Sources for Totally Implantable Cardiac Devices.

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Bleszynski, Peter A; Luc, Jessica G Y; Schade, Peter; PhilLips, Steven J; Tchantchaleishvili, Vakhtang

There is a large population of patients with end-stage congestive heart failure who cannot be treated by means of conventional cardiac surgery, cardiac transplantation, or chronic catecholamine infusions. Implantable cardiac devices, many designated as destination therapy, have revolutionized patient care and outcomes, although infection and complications related to external power sources or routine battery exchange remain a substantial risk. Complications from repeat battery replacement, power failure, and infections ultimately endanger the original objectives of implantable biomedical device therapy - eliminating the intended patient autonomy, affecting patient quality of life and survival. We sought to review the limitations of current cardiac biomedical device energy sources and discuss the current state and trends of future potential energy sources in pursuit of a lifelong fully implantable biomedical device.

Total donor ischemic time: relationship to early hemodynamics and intensive care morbidity in pediatric cardiac transplant recipients.

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Rodrigues, Warren; Carr, Michelle; Ridout, Deborah; Carter, Katherine; Hulme, Sara Louise; Simmonds, Jacob; Elliott, Martin; Hoskote, Aparna; Burch, Michael; Brown, Kate L

2011-11-01

Single-center studies have failed to link modest increases in total donor ischemic time to mortality after pediatric orthotopic heart transplant. We aimed to investigate whether prolonged total donor ischemic time is linked to pediatric intensive care morbidity after orthotopic heart transplant. Retrospective cohort review. Tertiary pediatric transplant center in the United Kingdom. Ninety-three pediatric orthotopic heart transplants between 2002 and 2006. Total donor ischemic time was investigated for association with early post-orthotopic heart transplant hemodynamics and intensive care unit morbidities. Of 43 males and 50 females with median age 7.2 (interquartile range 2.2, 13.0) yrs, 62 (68%) had dilated cardiomyopathy, 20 (22%) had congenital heart disease, and nine (10%) had restrictive cardiomyopathy. The mean total donor ischemic time was 225.9 (sd 65.6) mins. In the first 24 hrs after orthotopic heart transplant, age-adjusted mean arterial blood pressure increased (p total donor ischemic time was significantly associated with lower mean arterial blood pressure (p care unit (p = .004), and longer post-orthotopic heart transplant stay in hospital (p = .02). Total donor ischemic time was not related to levels of mean pulmonary arterial pressure (p = .62), left atrial pressure (p = .38), or central venous pressure (p = .76) early after orthotopic heart transplant. Prolonged total donor ischemic time has an adverse effect on the donor organ, contributing to lower mean arterial blood pressure, as well as more prolonged ventilation and intensive care unit and hospital stays post-orthotopic heart transplant, reflecting increased morbidity.

Use of I-123 MIBG cardiac scintigraphy to assess the impact of carvedilol on cardiac adrenergic neuronal function in childhood dilated cardiomyopathy

International Nuclear Information System (INIS)

Maunoury, C.; Acar, P.; Sidi, D.

2006-01-01

I-123 MIBG cardiac scintigraphy is a useful tool to assess cardiac adrenergic neuronal function, which is impaired in children with dilated cardiomyopathy (DCM). In adults with DCM, long-term treatment with carvedilol improves both cardiac adrenergic neuronal function and left ventricular function. The aim of this prospective study was to evaluate the impact of carvedilol on cardiac adrenergic neuronal function and on left ventricular function in seventeen patients (11 female, 6 male, mean age 39 ± 57 months, range 1 - 168 months) with DCM. All patients underwent I-123 MIBG cardiac scintigraphy and equilibrium radio-nuclide angiography before and after a 6 month period of carvedilol therapy. A static anterior view of the chest was acquired 4 hours after intravenous injection of 20 to 75 MBq of I-123 MIBG. Cardiac neuronal uptake of I-123 MIBG was measured using the heart to mediastinum count ratio (HMR). Radionuclide left ventricular ejection fraction (LVEF) was assessed following a standard protocol. There was no major cardiac events (death or transplantation) during the follow-up period. I-123 MIBG cardiac uptake and left ventricular function respectively increased by 38% and 65% after 6 months of treatment with carvedilol (HMR 223 ± 49% vs 162 ± 26%, p < 0.0001 and LVEF = 43 ± 17% vs 26 ± 11%, p < 0.0001). Carvedilol can improve cardiac adrenergic neuronal function and left ventricular function in children with DCM. Further studies are needed to assess the relationship between improvement in I-123 MIBG cardiac uptake and the beneficial effects of carvedilol on morbidity and mortality. (authors)

Desensitization strategies in adult heart transplantation-Will persistence pay off?

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Chih, Sharon; Patel, Jignesh

2016-08-01

Strategies are needed to enable successful heart transplantation in highly sensitized patients. Immunologic challenges from sensitization to human leukocyte antigen (HLA) reduce access to compatible donors, extend waiting times to transplant, and increase the risks of antibody-mediated rejection and cardiac allograft vasculopathy after transplant. The prime goal of desensitization is to increase access to transplantation through expansion of the donor organ pool. Existing therapies are directed at key components of the humoral immune response with newer biologically based regimens able to target plasma cells as the source of antibody production, as well as complement activation that has a central role in antibody-mediated injury. Despite the emergence of early promising results for these agents, a significant knowledge gap remains with the current data for desensitization, extrapolated mostly from non-heart solid-organ transplants and small observational studies. Notably, no approach has demonstrated significant and sustainable reductions in HLA antibody pre-transplant, and the ideal desensitization strategy remains elusive. In addition, clinical tools to evaluate the humoral response and efficacy of therapy are limited, focusing almost exclusively on HLA antibody detection. Importantly, desensitization is associated with significant costs and potential risks, and overall long-term outcomes and cost-effectiveness have not been sufficiently evaluated. Investigation is ongoing into the development of a clinically effective desensitization strategy in heart transplantation. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Organizing Thrombus Mimicking a Cardiac Tumor Located at the Mitral-Aortic Intervalvular Fibrosa

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Ji Seong Lee

2016-02-01

Full Text Available Thrombosis at the left ventricular outflow tract occurs without any detectable heart disease or predisposing factors only extremely rarely. A 48-year-old male visited Konkuk University Medical Center with loss of consciousness one month prior to presentation. Before he visited our hospital, he had been diagnosed with a cardiac tumor, which was located between the left atrium and posterior aortic root, and which was adjacent to both the aortic and mitral valves. Cardiac transplantation was recommended at the other hospital because of the high risk of cardiac dysfunction induced by both aortic and mitral valvular dysfunction after surgical resection. Based on preoperative transthoracic echocardiography, cardiac computed tomography, cardiac magnetic resonance imaging, and intraoperative transesophageal echocardiography, we considered it to be a benign tumor. Complete resection was achieved and the pathology confirmed organizing thrombus. We report a case of organizing thrombus mimicking a cardiac tumor, which was located at the mitral-aortic intervalvular fibrosa of the left ventricular outflow tract without any heart disease.

Effect of a single intraoperative high-dose ATG-Fresenius on delayed graft function in donation after cardiac-death donor renal allograft recipients: a randomized study

NARCIS (Netherlands)

Hoogen, M.W.F. van den; Kho, M.M.; Abrahams, A.C.; Zuilen, A.D. van; Sanders, J.S.; Dijk, M.; Hilbrands, L.B.; Weimar, W.; Hoitsma, A.J.

2013-01-01

OBJECTIVES: Reducing the incidence of delayed graft function after transplant with donation after cardiac death donor renal allografts would facilitate managing recipients during their first weeks after a transplant. To reduce this incidence, in most studies, induction therapy with depleting

Effect of a single intraoperative high-dose ATG-fresenius on delayed graft function in donation after cardiac-death donor renal allograft recipients: A randomized study

NARCIS (Netherlands)

M.W.F. van den Hoogen (M. W F); M.M.L. Kho (Marcia); A.C. Abrahams (Alferso); A.D. van Zuilen (Arjan); J.-S. Sanders (Jan-Stephan); M. van Dijk (Marja); L.B. Hilbrands (Luuk); W. Weimar (Willem); A.J. Hoitsma (Andries)

2013-01-01

textabstractObjectives: Reducing the incidence of delayed graft function after transplant with donation after cardiac death donor renal allografts would facilitate managing recipients during their first weeks after a transplant. To reduce this incidence, in most studies, induction therapy with

Effect of a Single Intraoperative High-Dose ATG-Fresenius on Delayed Graft Function in Donation After Cardiac-Death Donor Renal Allograft Recipients : A Randomized Study

NARCIS (Netherlands)

van den Hoogen, Martijn W. F.; Kho, Marcia M. L.; Abrahams, Alferso C.; van Zuilen, Arjan D.; Sanders, Jan Stephan; van Dijk, Marja; Hilbrands, Luuk B.; Weimar, Willem; Hoitsma, Andries J.

Objectives: Reducing the incidence of delayed graft function after transplant with donation after cardiac death donor renal allografts would facilitate managing recipients during their first weeks after a transplant. To reduce this incidence, in most studies, induction therapy with depleting

Transplantation of Immortalized CD34+ and CD34- Adipose-Derived Stem Cells Improve Cardiac Function and Mitigate Systemic Pro-Inflammatory Responses.

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Jong-Ho Kim

Full Text Available Adipose-derived stem cells (ADSCs have the potential to differentiate into various cell lineages and they are easily obtainable from patients, which makes them a promising candidate for cell therapy. However, a drawback is their limited life span during in vitro culture. Therefore, hTERT-immortalized CD34+ and CD34- mouse ADSC lines (mADSCshTERT tagged with GFP were established. We evaluated the proliferation capacity, multi-differentiation potential, and secretory profiles of CD34+ and CD34- mADSCshTERT in vitro, as well as their effects on cardiac function and systemic inflammation following transplantation into a rat model of acute myocardial infarction (AMI to assess whether these cells could be used as a novel cell source for regeneration therapy in the cardiovascular field. CD34+ and CD34- mADSCshTERT demonstrated phenotypic characteristics and multi-differentiation potentials similar to those of primary mADSCs. CD34+ mADSCshTERT exhibited a higher proliferation ability compared to CD34- mADSCshTERT, whereas CD34- mADSCshTERT showed a higher osteogenic differentiation potential compared to CD34+ mADSCshTERT. Primary mADSCs, CD34+, and CD34- mADSCshTERT primarily secreted EGF, TGF-β1, IGF-1, IGF-2, MCP-1, and HGFR. CD34+ mADSCshTERT had higher secretion of VEGF and SDF-1 compared to CD34- mADSCshTERT. IL-6 secretion was severely reduced in both CD34+ and CD34- mADSCshTERT compared to primary mADSCs. Transplantation of CD34+ and CD34- mADSCshTERT significantly improved the left ventricular ejection fraction and reduced infarct size compared to AMI-induced rats after 28 days. At 28 days after transplantation, engraftment of CD34+ and CD34- mADSCshTERT was confirmed by positive Y chromosome staining, and differentiation of CD34+ and CD34- mADSCshTERT into endothelial cells was found in the infarcted myocardium. Significant decreases were observed in circulating IL-6 levels in CD34+ and CD34- mADSCshTERT groups compared to the AMI

Identification of Differentially Expressed Genes between Original Breast Cancer and Xenograft Using Machine Learning Algorithms

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Deling Wang

2018-03-01

Full Text Available Breast cancer is one of the most common malignancies in women. Patient-derived tumor xenograft (PDX model is a cutting-edge approach for drug research on breast cancer. However, PDX still exhibits differences from original human tumors, thereby challenging the molecular understanding of tumorigenesis. In particular, gene expression changes after tissues are transplanted from human to mouse model. In this study, we propose a novel computational method by incorporating several machine learning algorithms, including Monte Carlo feature selection (MCFS, random forest (RF, and rough set-based rule learning, to identify genes with significant expression differences between PDX and original human tumors. First, 831 breast tumors, including 657 PDX and 174 human tumors, were collected. Based on MCFS and RF, 32 genes were then identified to be informative for the prediction of PDX and human tumors and can be used to construct a prediction model. The prediction model exhibits a Matthews coefficient correlation value of 0.777. Seven interpretable interactions within the informative gene were detected based on the rough set-based rule learning. Furthermore, the seven interpretable interactions can be well supported by previous experimental studies. Our study not only presents a method for identifying informative genes with differential expression but also provides insights into the mechanism through which gene expression changes after being transplanted from human tumor into mouse model. This work would be helpful for research and drug development for breast cancer.

Identification of Differentially Expressed Genes between Original Breast Cancer and Xenograft Using Machine Learning Algorithms.

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Wang, Deling; Li, Jia-Rui; Zhang, Yu-Hang; Chen, Lei; Huang, Tao; Cai, Yu-Dong

2018-03-12

Breast cancer is one of the most common malignancies in women. Patient-derived tumor xenograft (PDX) model is a cutting-edge approach for drug research on breast cancer. However, PDX still exhibits differences from original human tumors, thereby challenging the molecular understanding of tumorigenesis. In particular, gene expression changes after tissues are transplanted from human to mouse model. In this study, we propose a novel computational method by incorporating several machine learning algorithms, including Monte Carlo feature selection (MCFS), random forest (RF), and rough set-based rule learning, to identify genes with significant expression differences between PDX and original human tumors. First, 831 breast tumors, including 657 PDX and 174 human tumors, were collected. Based on MCFS and RF, 32 genes were then identified to be informative for the prediction of PDX and human tumors and can be used to construct a prediction model. The prediction model exhibits a Matthews coefficient correlation value of 0.777. Seven interpretable interactions within the informative gene were detected based on the rough set-based rule learning. Furthermore, the seven interpretable interactions can be well supported by previous experimental studies. Our study not only presents a method for identifying informative genes with differential expression but also provides insights into the mechanism through which gene expression changes after being transplanted from human tumor into mouse model. This work would be helpful for research and drug development for breast cancer.

Renal blood flow investigations with 133xenon and the anger scintillation camera in the hyperacute xenograft rejection of the rabbit kidney

International Nuclear Information System (INIS)

Heidenreich, P.; Oberdorfer, M.; Hoer, G.; Erhardt, W.; Krueger, P.; Pielsticker, K.

1976-01-01

The aim of this study was to demonstrate the advantage and validity of 133 Xe-washout externally monitored by the scintillation camera. Until now there were no reports on quantitative blood flow studies in hyperacute rejection of transplanted kidneys using a scintillation camera. Within 35 minutes after e-vivo hemoperfusion of rabbit kidneys by cats we found a simultaneous progressive decrease of renal blood flow, renal cortical blood flow as well as of the intrarenal distribution of renal cortical blood flow in all cases. The hyperacute rejection of xenografts could be verified in every case histologically. Using the scintillation camera we were able to detect regional perfusion defects caused by artifical air embolism as well as by preexisting cortical infarction. (orig.) [de

Total lymphoid irradiation in the treatment of early or recurrent heart transplant rejection

International Nuclear Information System (INIS)

Salter, Susan P.; Salter, Merle M.; Kirklin, James K.; Bourge, Robert C.; Naftel, David C.

1995-01-01

Purpose: Recurrent acute cardiac allograft rejection is an important cause of repeat hospitalization and a major mode of mortality, particularly during the 6 months immediately following transplant. Total lymphoid irradiation (TLI) has been shown experimentally to induce a state of partial tolerance when administered prior to transplantation. Anecdotal reports of clinical experience have also suggested efficacy of TLI in treatment of recurrent cardiac rejection. The purpose of this study is to evaluate the safety and efficacy of TLI for treatment of early or recurrent heart transplant rejection. Materials and Methods: Between January 1990 and June 1992, 49 patients postallograft cardiac transplant were given courses of TLI for treatment of early or recurrent rejection after conventional therapy with Methylprednisolone, antithymocyte globulin, OKT3, and methotrexate. Two patients failed to complete their therapy and were not evaluated. Two other patients received a second TLI course, making a total of 49 courses delivered. Indications for TLI were early rejection (n = 5), recurrent rejection (n = 38), and recurrent rejection with vasculitis (n = 6). The dose goal of the TLI protocol was 8 Gy in 10 fractions given twice weekly. Three separate fields were used to encompass all major lymph node-bearing areas. The actual mean dose was 7 Gy (range 2.4-8.4 Gy), and the duration of treatment was 8 to 106 days. These variations were secondary to leukopenia or thrombocytopenia. Results: The mean posttransplant follow-up is 15 ± 1.2 months (maximum 27 months). Among patients initiating TLI within 1 month posttransplant (n = 15), the rejection frequency decreased from 1.83 episodes/patient/month pre-TLI to 0.13 episodes/patient/month post-TLI (p < 0.0001). For those who began TLI 1-3 months after transplant (n = 21), rejection decreased from 1.43 to 0.10 episodes/patient/month (p < 0.0001). When TLI was started more than 3 months posttransplant (n = 11), the pre-TLI and post

[Chronic kidney disease and kidney transplantation].

Science.gov (United States)

Thuret, R; Timsit, M O; Kleinclauss, F

2016-11-01

To report epidemiology and characteristics of end-stage renal disease (ESRD) patients and renal transplant candidates, and to evaluate access to waiting list and results of renal transplantation. An exhaustive systematic review of the scientific literature was performed in the Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of the following keywords: "chronic kidney disease, epidemiology, kidney transplantation, cost, survival, graft, brain death, cardiac arrest, access, allocation". French legal documents have been reviewed using the government portal (http://www.legifrance.gouv.fr). Articles were selected according to methods, language of publication and relevance. The reference lists were used to identify additional historical studies of interest. Both prospective and retrospective series, in French and English, as well as review articles and recommendations were selected. In addition, French national transplant and health agencies (http://www.agence-biomedecine.fr and http://www.has-sante.fr) databases were screened using identical keywords. A total of 3234 articles, 6 official reports and 3 newspaper articles were identified; after careful selection 99 publications were eligible for our review. The increasing prevalence of chronic kidney disease (CKD) leads to worsen organ shortage. Renal transplantation remains the best treatment option for ESRD, providing recipients with an increased survival and quality of life, at lower costs than other renal replacement therapies. The never-ending lengthening of the waiting list raises issues regarding treatment strategies and candidates' selection, and underlines the limits of organ sharing without additional source of kidneys available for transplantation. Allocation policies aim to reduce medical or geographical disparities regarding enrollment on a waiting list or access to an allotransplant. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

ES-cell derived hematopoietic cells induce transplantation tolerance.

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Sabrina Bonde

Full Text Available BACKGROUND: Bone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. However, their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. Alternatively, embryonic stem (ES cells have emerged as a potential source of less immunogenic hematopoietic progenitor cells (HPCs. Up till now, however, it has been difficult to generate stable hematopoietic cells from ES cells. METHODOLOGY/PRINCIPAL FINDINGS: Here, we derived CD45(+ HPCs from HOXB4-transduced ES cells and showed that they poorly express MHC antigens. This property allowed their long-term engraftment in sublethally irradiated recipients across MHC barriers without the need for immunosuppressive agents. Although donor cells declined in peripheral blood over 2 months, low level chimerism was maintained in the bone marrow of these mice over 100 days. More importantly, chimeric animals were protected from rejection of donor-type cardiac allografts. CONCLUSIONS: Our data show, for the first time, the efficacy of ES-derived CD45(+ HPCs to engraft in allogenic recipients without the use of immunosuppressive agents, there by protecting cardiac allografts from rejection.

Prevalence of nursing diagnosis of decreased cardiac output and the predictive value of defining characteristics in patients under evaluation for heart transplant Prevalencia del diagnóstico de enfermería de disminución del gasto cardíaco y valor predictivo de las características definidoras en pacientes en fase de evaluación para trasplante cardíaco Prevalência do diagnóstico de enfermagem de débito cardíaco diminuído e valor preditivo das características definidoras em pacientes em avaliação para transplante cardíaco

OpenAIRE

Lígia Neres Matos; Tereza Cristina Felippe Guimarães; Marcos Antônio Gomes Brandão; Deyse Conceição Santoro

2012-01-01

The purposes of the study were to identify the prevalence of defining characteristics (DC) of decreased cardiac output (DCO) in patients with cardiac insufficiency under evaluation for heart transplantation, and to ascertain the likelihood of defining characteristics being predictive factors for the existence of reduction in cardiac output. Data was obtained by retrospective documental analysis of the clinical records of right-sided heart catheterizations in 38 patients between 2004 and 2009....

Hypothermic Oxygenated Machine Perfusion in Porcine Donation After Circulatory Determination of Death Liver Transplant

NARCIS (Netherlands)

Fondevila, Constantino; Hessheimer, Amelia J.; Maathuis, Mark-Hugo J.; Munoz, Javier; Taura, Pilar; Calatayud, David; Leuvenink, Henri; Rimola, Antoni; Garcia-Valdecasas, Juan C.; Ploeg, Rutger J.

2012-01-01

Background. Livers from donation after circulatory determination-of-death (DCD) donors suffer ischemic injury during a preextraction period of cardiac arrest and are infrequently used for transplantation; they have the potential, however, to considerably expand the donor pool. We aimed to determine

Radiation Exposure from Diagnostic Imaging in a Cohort of Pediatric Transplant Recipients.

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Alexandra Seal

Full Text Available Recipients of solid organ transplants (SOT have extensive diagnostic imaging (DI. The purpose of this study was to quantify this exposure. Children from northern Alberta with SOTs at Stollery Children's Hospital, Edmonton, Alberta January 1, 2006, to July 31, 2012, were included. Effective doses of radiation were estimated using published norms for DI performed post-transplant up to October 16, 2014. The 54 eligible children had 6215 DI studies (5628 plain films, 293 computerized tomography (CT scans, 149 positron emission topography (PET -CT scans, 47 nuclear medicine scans and 98 cardiac catheterizations. Children less than 5 years of age underwent more DI studies than did older children (median (IQR 140 (66-210 vs 49 (19-105, p = 0.010. Children with post-transplant lymphoproliferative disorder (N = 8 had more CT scans (median (IQR 13 (5.5-36 vs 1 (0-5, p100 mSv. In conclusion, a significant proportion of pediatric transplant recipients have sufficient radiation exposure post-transplant for DI to be at potential risk for radiation-induced malignancies.

Transplantation immunity in the American cockroach, Periplaneta americana: the rejection of integumentary grafts from Blatta orientalis.

Science.gov (United States)

Karp, R D; Meade, C C

1993-01-01

The results from several previous studies have indicated that the American cockroach is able to respond to integumentary xenografts, but doubt remained as to whether cockroaches could effectively discriminate between self and allogeneic differences. This was emphasized by the fact that while one study reported that Periplaneta americana responded to grafts donated by the closely related genus Blatta orientalis, the data reported elsewhere, using a different assay system, found no such reactivity. Since we have subsequently reported, using a direct histological assay, that Periplaneta can in fact recognize and destroy integumentary allografts, we initiated a study to hopefully sort out the enigma presented by previous data using Blatta as a transplant donor. Integument from Blatta orientalis was transplanted orthotopically onto Periplaneta americana, and at various time points post-transplant, scored histologically for the survival of the subcuticular epidermal layer. The results clearly demonstrated that Periplaneta reacted to the Blatta tissue, because approximately 82% of the grafts had the epidermal layer destroyed by day 7 posttransplant. The kinetics of the response to Blatta was more in line with our allograft data, which would be in agreement with other work indicating that the closer the donor and recipient are on the phylogenetic tree, the less intense the reactivity to the foreign transplant.

Endothelial dysfunction after non-cardiac surgery

DEFF Research Database (Denmark)

Søndergaard, E S; Fonnes, S; Gögenur, I

2015-01-01

was to systematically review the literature to evaluate the association between non-cardiac surgery and non-invasive markers of endothelial function. METHODS: A systematic search was conducted in MEDLINE, EMBASE and Cochrane Library Database according to the PRISMA guidelines. Endothelial dysfunction was described only...... transplantation and vascular surgery respectively) had an improvement in endothelial dysfunction 1 month after surgery. CONCLUSION: Endothelial function changes in relation to surgery. Assessment of endothelial function by non-invasive measures has the potential to guide clinicians in the prevention or treatment...

Methylene Blue for Vasoplegia When on Cardiopulmonary Bypass During Double-Lung Transplantation.

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Carley, Michelle; Schaff, Jacob; Lai, Terrance; Poppers, Jeremy

2015-10-15

Vasoplegia syndrome, characterized by hypotension refractory to fluid resuscitation or high-dose vasopressors, low systemic vascular resistance, and normal-to-increased cardiac index, is associated with increased morbidity and mortality after cardiothoracic surgery. Methylene blue inhibits inducible nitric oxide synthase and guanylyl cyclase, and has been used to treat vasoplegia during cardiopulmonary bypass. However, because methylene blue is associated with increased pulmonary vascular resistance, its use in patients undergoing lung transplantion has been limited. Herein, we report the use of methylene blue to treat refractory vasoplegia during cardiopulmonary bypass in a patient undergoing double-lung transplantation.

Assessment of potential heart donors: A statement from the French heart transplant community.

Science.gov (United States)

Dorent, Richard; Gandjbakhch, Estelle; Goéminne, Céline; Ivanes, Fabrice; Sebbag, Laurent; Bauer, Fabrice; Epailly, Eric; Boissonnat, Pascale; Nubret, Karine; Amour, Julien; Vermes, Emmanuelle; Ou, Phalla; Guendouz, Soulef; Chevalier, Philippe; Lebreton, Guillaume; Flecher, Erwan; Obadia, Jean-François; Logeart, Damien; de Groote, Pascal

2018-02-01

Assessment of potential donors is an essential part of heart transplantation. Despite the shortage of donor hearts, donor heart procurement from brain-dead organ donors remains low in France, which may be explained by the increasing proportion of high-risk donors, as well as the mismatch between donor assessment and the transplant team's expectations. Improving donor and donor heart assessment is essential to improve the low utilization rate of available donor hearts without increasing post-transplant recipient mortality. This document provides information to practitioners involved in brain-dead donor management, evaluation and selection, concerning the place of medical history, electrocardiography, cardiac imaging, biomarkers and haemodynamic and arrhythmia assessment in the characterization of potential heart donors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

PREDICTIVE SIGNIFICANCE OF ANTI-HLA AUTOANTIBODIES IN HEART TRANSPLANT RECIPIENTS

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O. P. Shevchenko

2013-01-01

Full Text Available Aim. The aim of this study was to define the role of preformed anti-HLA antibodies (anti-HLA in antibody-mediated rejection (AMR and cardiac allograft vasculopathy (CAV after heart transplantation. Materials and Methods. 140 heart transplant recipients were followed after heart transplantation performed for 106 dilated and 34 – ischemic cardiomyopathy. Anti-HLA was determined before transplantation by ELISA. Results. Recipients were divided into 2 groups: anti-HLA positive (n = 45, 32,1% and anti-HLA negative (n = 95, 67,9%. The incidence of AMR in anti-HLA positive group was 12 (26,67% and 11 (11,58% in anti-HLA negative group. Risk of AMR was significantly higher in anti-HLA positive recipients (RR 2,3: 95% CI 1,02–4,81, р = 0,03. During first three years after transplantation CAV was diagnosed in 9 (20% of anti-HLA positive recipients and in 7 (6,8% of patients without anti-HLA. (RR 2,7: 95% CI 1,08–6,82, р = 0,03. Survival in freedom from CAV in anti-HLA negative recipients was much higher than in anti-HLA positive recipients (0,89 ± 0,07, 0,72 ± 0,06, resp. (p = 0,02.Conclusions. The presence of preformed anti-HLA antibodies in candidates for heart transplantation increase the risk of AMR and CAV post transplantation in 2,3 and 2,7 times, respectively. 

The Intestinal Microbiome and the Liver Transplant Recipient: What We Know and What We Need to Know.

Science.gov (United States)

Doycheva, Iliana; Leise, Michael D; Watt, Kymberly D

2016-01-01

The intestinal microbiome and immune system are in close symbiotic relationship in health. Gut microbiota plays a role in many chronic liver diseases and cirrhosis. However, alterations in the gut microbiome after liver transplantation and the implications for liver transplant recipients are not well understood and rely mainly on experimental animal studies. Recent advances in molecular techniques have identified that increased intestinal permeability, decreased beneficial bacteria, and increased pathogenic species may play important roles in the early posttransplant period. The associations between microbiota perturbation and postliver transplant infections and acute rejection are evolving. The link with metabolic syndrome, obesity, and cardiac disease in the general population require translation into the transplant recipient. This review focuses on our current knowledge of the known and potential interaction of the microbiome in the liver transplant recipient. Future human studies focused on microbiota changes in liver transplant patients are warranted and expected.

Mechanisms of cardiac transplantation tolerance in syngeneic rat radiation chimeras

International Nuclear Information System (INIS)

Moran, T.M.

1981-01-01

Seventy-five percent of adult LEW rats, lethally irradiated (860 R), transplanted with an RT-1 incompatible Wistar Furth (WF) heart or kidney and repopulated on day 2 with a 4:1 mixture of syngeneic thymus and bone marrow cells accept these grafts. In order to look at the ability of animals tolerating WF organ grafts to respond against WF spleen cells in vitro we developed a rat mixed lymphocyte culture. Tolerant animals were tested for the ability to respond to donor antigens and approximately half of the 50 animals tested, were responsive. We attempted to demonstrate suppressor cells which might be responsible for maintaining tolerance in the nonresponders. Neither mixtures at the sensitization or the effector level suggested that tolerance was being maintained by a suppressor cell. An in vivo assay which tested the ability of various cell populations to affect the survival of allogeneic hearts transplanted into sublethally irradiated recipients was then employed. Tolerance is induced using this protocol in a manner similar or identical to tolerance produced by neonatal injection of antigen. This tolerance might be maintained in part by suppressor cells which prevents the generation of clones of cells reactive against the heart donor. The mechanism of tolerance in rats with demonstrable clones of reactive cells remains to be determined

Human adipose stem cell and ASC-derived cardiac progenitor cellular therapy improves outcomes in a murine model of myocardial infarction

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Davy PMC

2015-10-01

Full Text Available Philip MC Davy,1 Kevin D Lye,2,3 Juanita Mathews,1 Jesse B Owens,1 Alice Y Chow,1 Livingston Wong,2 Stefan Moisyadi,1 Richard C Allsopp1 1Institute for Biogenesis Research, 2John A. Burns School of Medicine, University of Hawaii at Mānoa, 3Tissue Genesis, Inc., Honolulu, HI, USA Background: Adipose tissue is an abundant and potent source of adult stem cells for transplant therapy. In this study, we present our findings on the potential application of adipose-derived stem cells (ASCs as well as induced cardiac-like progenitors (iCPs derived from ASCs for the treatment of myocardial infarction. Methods and results: Human bone marrow (BM-derived stem cells, ASCs, and iCPs generated from ASCs using three defined cardiac lineage transcription factors were assessed in an immune-compromised mouse myocardial infarction model. Analysis of iCP prior to transplant confirmed changes in gene and protein expression consistent with a cardiac phenotype. Endpoint analysis was performed 1 month posttransplant. Significantly increased endpoint fractional shortening, as well as reduction in the infarct area at risk, was observed in recipients of iCPs as compared to the other recipient cohorts. Both recipients of iCPs and ASCs presented higher myocardial capillary densities than either recipients of BM-derived stem cells or the control cohort. Furthermore, mice receiving iCPs had a significantly higher cardiac retention of transplanted cells than all other groups. Conclusion: Overall, iCPs generated from ASCs outperform BM-derived stem cells and ASCs in facilitating recovery from induced myocardial infarction in mice. Keywords: adipose stem cells, myocardial infarction, cellular reprogramming, cellular therapy, piggyBac, induced cardiac-like progenitors

Imaging mass spectrometry identifies prognostic ganglioside species in rodent intracranial transplants of glioma and medulloblastoma.

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Leonardo Ermini

Full Text Available Matrix-assisted laser desorption ionization (MALDI imaging mass spectrometry (MALDI-MSI allows us to investigate the distribution of lipid molecules within tissues. We used MALDI-MSI to identify prognostic gangliosides in tissue sections of rat intracranial allografts of rat glioma and mouse intracranial xenografts of human medulloblastoma. In the healthy adult rodent brain, GM1 and GD1 were the main types of glycolipids. Both gangliosides were absent in both intracranial transplants. The ganglioside GM3 was not present in the healthy adult brain but was highly expressed in rat glioma allografts. In combination with tandem mass spectrometry GM3 (d18:1/C24:0 was identified as the most abundant ganglioside species in the glioma allotransplant. By contrast, mouse xenografts of human medulloblastoma were characterized by prominent expression of the ganglioside GM2 (d18:0/C18:0. Together, these data demonstrate that tissue-based MALDI-MSI of gangliosides is able to discriminate between different brain tumors and may be a useful clinical tool for their classification and grading.

The use of lyophilised bovine bone xenograft in mandibular reconstructive surgery - an animal experimental surgery

International Nuclear Information System (INIS)

Samsudin, A.R.; Meor Kamal, M. Z.; Afifi Abu Bakar

1999-01-01

The aim of this study is to look at the effectiveness of using lyophillised bovine bone xenograft in mandibular reconstructive surgery. Six adult merino sheep underwent bilateral marginal block resection of the mandible under general anaesthesia. The defect on the right body of mandible was left alone while the similar mandibulectomy defect on the left body of mandible was reconstructed using a cortico-cancellous block of radiosterilised lyophillised bovine bone xenograft which was procured from a calve femur. The bone xenograft was fixed and immobilized using titanium mini plates and screws. All the sheep returned to the controlled grazing ground on the 7th. Postoperative day. One sheep was sacrificed every month and the mandible was retrieved for postmortem gross and microscopical histological examination. Clinical results showed no evidence of tissue rejection in the mandible of the sheep and all the wounds healed well. All sheep showed no problem with normal eating habits. Histological examination showed resorption of the xenograft very early at one month postoperative and xenograft resorption together with new host bone deposition started at 2 months postoperative and maximise at 6 months postoperative. There is also evidence showing that the cancellous portion resorp more than the cortical portion of the xenograft. In conclusion, cortico-cancellous blocks of bovine bone xenograft may be use in mandibular reconstructive surgery giving esthetically acceptable, functional, biocompatible and overall clinically predictable results

Accuracy of multidetector row computed tomography for the detection of transplant vasculopathy: comparison with invasive coronary angiography and intravascular ultrasound

International Nuclear Information System (INIS)

Carrascosa, P.; Capunay, C.; Carrascosa, J.; Perrone, S.; Deviggiano, A.; Lopez, E.M.; Lev, G.; Garcia, M.J.

2009-01-01

Objective: To evaluate the diagnostic accuracy of multidetector computed tomography (MDCT) for detection of luminal stenosis and cardiac allograft vasculopathy in comparison with coronary angiography (CA) and intravascular ultrasound (IVUS) respectively. Material and methods: Nineteen cardiac transplant patients scheduled for follow-up CA were included. MDCT coronary angiography was performed using a 16-row CT scanner within 7-14 days after CA and IVUS. Studies were analyzed by independent readers; two observers evaluated the CT datasets for the presence of coronary artery stenosis > 50% and allograft vasculopathy. Results: The sensitivity for detecting > 50% luminal stenosis was 80-88% and specificity, 98-99% and for detection of cardiac allograft vasculopathy, the sensitivity was 91-96% and specificity, 88-91%. Conclusion: In this preliminary series, our results indicate that MDCT coronary angiography was capable of detecting both significant coronary stenosis as well as diffuse intimal proliferation. This non-invasive procedure could be an alternative to CA and IVUS in the surveillance of heart transplant patients. (authors) [es

Two-photon induced collagen cross-linking in bioartificial cardiac tissue

Science.gov (United States)

Kuetemeyer, Kai; Kensah, George; Heidrich, Marko; Meyer, Heiko; Martin, Ulrich; Gruh, Ina; Heisterkamp, Alexander

2011-08-01

Cardiac tissue engineering is a promising strategy for regenerative therapies to overcome the shortage of donor organs for transplantation. Besides contractile function, the stiffness of tissue engineered constructs is crucial to generate transplantable tissue surrogates with sufficient mechanical stability to withstand the high pressure present in the heart. Although several collagen cross-linking techniques have proven to be efficient in stabilizing biomaterials, they cannot be applied to cardiac tissue engineering, as cell death occurs in the treated area. Here, we present a novel method using femtosecond (fs) laser pulses to increase the stiffness of collagen-based tissue constructs without impairing cell viability. Raster scanning of the fs laser beam over riboflavin-treated tissue induced collagen cross-linking by two-photon photosensitized singlet oxygen production. One day post-irradiation, stress-strain measurements revealed increased tissue stiffness by around 40% being dependent on the fibroblast content in the tissue. At the same time, cells remained viable and fully functional as demonstrated by fluorescence imaging of cardiomyocyte mitochondrial activity and preservation of active contraction force. Our results indicate that two-photon induced collagen cross-linking has great potential for studying and improving artificially engineered tissue for regenerative therapies.

Pretransplant portal venous administration of donor antigen and portal venous allograft drainage synergistically prolong rat cardiac allograft survival

International Nuclear Information System (INIS)

Kamei, T.; Callery, M.P.; Flye, M.W.

1990-01-01

The effect of antigen given through the portal vein (PV) before transplantation or continuous drainage of a graft into the PV results in moderate prolongation of allograft survival. This study examines these treatment modalities further. Pretransplant donor antigen as 25 x 10(6) ultraviolet B-irradiated (12,000 joules/m2) donor spleen cells was given 7 days before heart transplantation through either the PV or systemic venous (IV) routes. On day 0, Lewis-to-Buffalo rat cardiac allografts were drained either into the PV or IV. Pretransplant PV donor antigen administration (p less than 0.005), but not by IV administration, significantly prolonged cardiac allograft survival across the strong RT 1 rat histoincompatibility barrier. Similarly PV, but not IV, drainage of the graft prolonged graft survival (p less than 0.005). Pretransplant IV antigen administration had no additive effect on PV drainage graft survival. In contrast, when pretransplant PV donor antigen was combined with PV drainage, 11 of 14 allografts (p less than 0.001) continued to function, free of rejection, after 150 days. Therefore for rat cardiac transplants a clearly synergistic graft-prolonging effect results when pretransplant PV donor antigen is combined with PV drainage of the allografts. These data clarify the potent tolerogenic effects of alloantigen not only administered into the PV but also continuously shed intraportally so that it is first processed by the liver

Regional differences in prognostic value of cardiac valve plane displacement in systemic light-chain amyloidosis.

Science.gov (United States)

Ochs, Marco M; Fritz, Thomas; Arenja, Nisha; Riffel, Johannes; Andre, Florian; Mereles, Derliz; Siepen, Fabian Aus dem; Hegenbart, Ute; Schönland, Stefan; Katus, Hugo A; Friedrich, Matthias G W; Buss, Sebastian J

2017-11-09

To compare the prognostic value of cardiac valve plane displacement (CVPD) on various locations in cardiac light chain (AL) amyloidosis. Consecutive patients with biopsy-proven cardiac involvement in AL amyloidosis who had undergone cardiovascular magnetic resonance (CMR) between 2005 and 2014 in our institution, were retrospectively identified and data analyzed. The primary combined endpoint was all-cause mortality or heart transplantation. Systolic CVPD were obtained from standard cine bSSFP in 2-, 3- and 4-chamber views at anterior aortic plane systolic excursion (AAPSE); anterior, anterolateral, inferolateral, inferior, inferoseptal mitral (MAPSE); and lateral tricuspid (TAPSE) annular segments. We identified 68 patients (58 ± 10 years; 59% male). Median follow-up period was 1.2 years (IQR, 0.3-4.1). Significant differences in CVPD between patients who reached a primary endpoint (n = 44) and transplant-free survivors were found only for AAPSE (6.1 mm (IQR, 4.6-9.4) vs. 8.8 mm (IQR, 6.9-10.4); p = 0.02) and MAPSE anterolateral (7.3 mm (IQR, 5.4-11.7) vs. 10.5 mm (IQR, 8.1-13.4); p = 0.03). AAPSE (χ 2  = 15.6; p = 0.0002) provided the best predictive value for transplant-free survival compared to all other valvular plane locations. A high-risk cutoff (AAPSE ≤ 7.6 mm) was calculated by ROC analysis to predict all-cause death or heart transplantation within 6 months from index examination (AUC = 0.80; CI: 0.68 to 0.89; p model of late gadolinium enhancement and global longitudinal strain (GLS) (∆χ 2  = 5.8, p = 0.02) as well as to a clinical model including Karnofsky index and NT-proBNP (∆χ 2  = 6.2, p = 0.01). In patients with cardiac involvement in AL amyloidosis, systolic CVPD obtained from standard long axis cine views appear to indicate outcome better, when obtained in the anterior aortic plane (AAPSE) and provide incremental prognostic value to LGE and strain measurements.

Coronary microvasculopathy in heart transplantation: Consequences and therapeutic implications.

Science.gov (United States)

Vecchiati, Alessandra; Tellatin, Sara; Angelini, Annalisa; Iliceto, Sabino; Tona, Francesco

2014-06-24

Despite the progress made in the prevention and treatment of rejection of the transplanted heart, cardiac allograft vasculopathy (CAV) remains the main cause of death in late survival transplanted patients. CAV consists of a progressive diffuse intimal hyperplasia and the proliferation of vascular smooth muscle cells, ending in wall thickening of epicardial vessels, intramyocardial arteries (50-20 μm), arterioles (20-10 μm), and capillaries (system. The non-immunological factors are older donor age, ischemia-reperfusion time, hyperlipidemia and CMV infections. Diagnostic techniques that are able to assess microvascular function are lacking. Intravascular ultrasound and fractional flow reserve, when performed during coronary angiography, are able to detect epicardial coronary artery disease but are not sensitive enough to assess microvascular changes. Some authors have proposed an index of microcirculatory resistance during maximal hyperemia, which is calculated by dividing pressure by flow (distal pressure multiplied by the hyperemic mean transit time). Non-invasive methods to assess coronary physiology are stress echocardiography, coronary flow reserve by transthoracic Doppler echocardiography, single photon emission computed tomography, and perfusion cardiac magnetic resonance. In this review, we intend to analyze the mechanisms, consequences and therapeutic implications of microvascular dysfunction, including an extended citation of relevant literature data.

Changes in the action potential and transient outward potassium current in cardiomyocytes during acute cardiac rejection in rats.

Science.gov (United States)

Luo, Wenqi; Jia, Yixin; Zheng, Shuai; Li, Yan; Han, Jie; Meng, Xu

2017-01-01

Acute cardiac rejection contributes to the changes in the electrophysiological properties of grafted hearts. However, the electrophysiological changes of cardiomyocytes during acute cardiac rejection are still unknown. An understanding of the electrophysiological mechanisms of cardiomyocytes could improve the diagnosis and treatment of acute cardiac rejection. So it is important to characterize the changes in the action potential ( AP ) and the transient outward potassium current ( I to ) in cardiomyocytes during acute cardiac rejection. Heterotopic heart transplantation was performed in allogeneic [Brown Norway (BN)-to-Lewis] and isogeneic (BN-to-BN) rats. Twenty models were established in each group. Ten recipients were sacrificed at the 2nd day and the other ten recipients were sacrificed at the 4 th day after the operation in each group. Histopathological examinations of the grafted hearts were performed in half of the recipients in each group randomly. The other half of the grafted hearts were excised rapidly and enzymatically dissociated to obtain single cardiomyocytes. The AP and I to current were recorded using the whole cell patch-clamp technique. Forty grafted hearts were successfully harvested and used in experiments. Histologic examination showed mild rejection at the 2 nd day and moderate rejection at the 4 th day in the allogeneic group after cardiac transplantation, while no evidence of histologic lesions of rejection were observed in the isogeneic group. Compared with the isogeneic group, the action potential duration ( APD ) of cardiomyocytes in the allogeneic group was significantly prolonged ( APD 90 was 49.28±5.621 mV in the isogeneic group and 88.08±6.445 mV in the allogeneic group at the 2 nd day, P=0.0016; APD 90 was 59.34±5.183 mV in the isogeneic group and 104.0±9.523 mV in the allogeneic group at the 4 th day, P=0.0064). The current density of I to was significantly decreased at the 4 th day after cardiac transplantation. The APD of

Dual-source cardiac computed tomography angiography (CCTA) in the follow-up of cardiac transplant: comparison of image quality and radiation dose using three different imaging protocols

Energy Technology Data Exchange (ETDEWEB)

Beitzke, D.; Berger-Kulemann, V.; Unterhumer, S.; Loewe, C.; Wolf, F. [Medical University Vienna, Department of Biomedical Imaging and Image Guided Therapy, Division of Cardiovascular and Interventional Radiology, Vienna (Austria); Schoepf, V. [Medical University Vienna, Department of Biomedical Imaging and Image Guided Therapy, Division of Neuroradiology and Musculoskeletal Radiology, Vienna (Austria); Spitzer, E. [Bern University Hospital, Department of Cardiology, Bern (Switzerland); Feuchtner, G.M. [Innsbruck Medical University, Department of Radiology II, Innsbruck (Austria); Gyoengyoesi, M. [Medical University Vienna, Department of Cardiology, Vienna (Austria); Uyanik-Uenal, K.; Zuckermann, A. [Medical University Vienna, Department of Cardiac Surgery, Vienna (Austria)

2015-08-15

To prospectively evaluate image quality (IQ) and radiation dose of dual-source cardiac computed tomography (CCTA) using different imaging protocols. CCTA was performed in 150 patients using the retrospective ECG-gated spiral technique (rECG) the prospective ECG-gated technique (pECG), or the prospective ECG-gated technique with systolic imaging and automated tube voltage selection (pECGsys). IQ was rated using a 16-segment coronary artery model. Techniques were compared for overall IQ, IQ of the large and the small coronary artery segments. Effective dose was used for comparison of radiation dose. Overall IQ and IQ of the large segments showed no differences between the groups. IQ analysis of the small segments showed lowered IQ in pECGsys compared to rECG (p = 0.02), but not to pECG (p = 0.6). Effective dose did not differ significantly between rECG and pECG (p = 0.13), but was significantly lower for pECGsys (p < 0.001 vs. rECG and pECG). Radiation dose of dual-source CCTA in heart transplant recipients is significantly reduced by using prospective systolic scanning and automated tube voltage selection, while overall IQ and IQ of the large coronary segments are maintained. IQ appears to be lower compared to retrospective techniques with regard to small coronary segments. (orig.)

Dual-source cardiac computed tomography angiography (CCTA) in the follow-up of cardiac transplant: comparison of image quality and radiation dose using three different imaging protocols

International Nuclear Information System (INIS)

Beitzke, D.; Berger-Kulemann, V.; Unterhumer, S.; Loewe, C.; Wolf, F.; Schoepf, V.; Spitzer, E.; Feuchtner, G.M.; Gyoengyoesi, M.; Uyanik-Uenal, K.; Zuckermann, A.

2015-01-01

To prospectively evaluate image quality (IQ) and radiation dose of dual-source cardiac computed tomography (CCTA) using different imaging protocols. CCTA was performed in 150 patients using the retrospective ECG-gated spiral technique (rECG) the prospective ECG-gated technique (pECG), or the prospective ECG-gated technique with systolic imaging and automated tube voltage selection (pECGsys). IQ was rated using a 16-segment coronary artery model. Techniques were compared for overall IQ, IQ of the large and the small coronary artery segments. Effective dose was used for comparison of radiation dose. Overall IQ and IQ of the large segments showed no differences between the groups. IQ analysis of the small segments showed lowered IQ in pECGsys compared to rECG (p = 0.02), but not to pECG (p = 0.6). Effective dose did not differ significantly between rECG and pECG (p = 0.13), but was significantly lower for pECGsys (p < 0.001 vs. rECG and pECG). Radiation dose of dual-source CCTA in heart transplant recipients is significantly reduced by using prospective systolic scanning and automated tube voltage selection, while overall IQ and IQ of the large coronary segments are maintained. IQ appears to be lower compared to retrospective techniques with regard to small coronary segments. (orig.)

Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

Energy Technology Data Exchange (ETDEWEB)

Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Ballestas, Mary E. [Department of Pediatrics Infectious Disease, Children' s of Alabama, School of Medicine, University of Alabama at Birmingham, AL (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., Suite 2114, Bethesda, MD 20892 (United States); Elmets, Craig A. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

2013-01-15

Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

International Nuclear Information System (INIS)

Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C.; Ballestas, Mary E.; Kopelovich, Levy; Elmets, Craig A.; Athar, Mohammad

2013-01-01

Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

Colorectal cancer patient-derived xenografted tumors maintain characteristic features of the original tumors.

Science.gov (United States)

Cho, Yong Beom; Hong, Hye Kyung; Choi, Yoon-La; Oh, Ensel; Joo, Kyeung Min; Jin, Juyoun; Nam, Do-Hyun; Ko, Young-Hyeh; Lee, Woo Yong

2014-04-01

Despite significant improvements in colon cancer outcomes over the past few decades, preclinical development of more effective therapeutic strategies is still limited by the availability of clinically relevant animal models. To meet those clinical unmet needs, we generated a well-characterized in vivo preclinical platform for colorectal cancer using fresh surgical samples. Primary and metastatic colorectal tumor tissues (1-2 mm(3)) that originate from surgery were implanted into the subcutaneous space of nude mice and serially passaged in vivo. Mutation status, hematoxylin and eosin staining, short tandem repeat profiling, and array comparative genomic hybridization were used to validate the similarity of molecular characteristics between the patient tumors and tumors obtained from xenografts. From surgical specimens of 143 patients, 97 xenograft models were obtained in immunodeficient mice (establish rate = 67%). Thirty-nine xenograft models were serially expanded further in mice with a mean time to reach a size of 1000-1500 mm(3) of 90 ± 20 d. Histologic and immunohistochemical analyses revealed a high degree of pathologic similarity including histologic architecture and expression of CEA, CK7, and CD20 between the patient and xenograft tumors. Molecular analysis showed that genetic mutations, genomic alterations, and gene expression patterns of each patient tumor were also well conserved in the corresponding xenograft tumor. Xenograft animal models derived from fresh surgical sample maintained the key characteristic features of the original tumors, suggesting that this in vivo platform can be useful for preclinical development of novel therapeutic approaches to colorectal cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

Radiation doses to Norwegian heart-transplanted patients undergoing annual coronary angiography

International Nuclear Information System (INIS)

Seierstad, T.; Friberg, E. G.; Lervag, C.; Widmark, A.; Wilhelmsen, N.; Stranden, E.

2012-01-01

Heart-transplanted patients in Norway undergo annual coronary angiography (CA). The aims of this study were to establish a conversion factor between dose-area product and effective dose for these examinations and to use this to evaluate the accumulated radiation dose and risks associated with annual CA. An experienced cardiac interventionist performed a simulated examination on an Alderson phantom loaded with thermoluminescence dosemeters. The simulated CA examination yielded a dose-area product of 17 Gy cm 2 and an effective dose of 3.4 mSv: the conversion factor between dose-area product and effective dose was 0.20 mSv Gy cm -2 . Dose-area product values from 200 heart-transplanted patients that had undergone 906 CA examinations between 2001 and 2008 were retrieved from the institutional database. Mean dose-area product from annual CA was 25 Gy cm 2 , ranging from 2 to 140 Gy cm 2 . Mean number of CA procedure was 8 (range, 1-23). Mean accumulated effective dose for Norwegian heart-transplanted patients between 2001 and 2008 was 34 mSv (range, 5-113 mSv). Doses and radiation risks for heart-transplanted patients are generally low, because most heart transplantations are performed on middle-aged patients with limited life expectancy. Special concern should however be taken to reduce doses for young heart-transplanted patients who are committed to lifelong follow-up of their transplanted heart. (authors)

Heart Transplant in Patients with Predominantly Rheumatic Valvular Heart Disease.

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Rosa, Vitor E E; Lopes, Antonio S S A; Accorsi, Tarso A D; Fernandes, Joao Ricardo C; Spina, Guilherme S; Sampaio, Roney O; Bacal, Fernando; Tarasoutchi, Flavio

2015-09-01

International records indicate that only 2.6% of patients with heart transplants have valvular heart disease. The study aim was to evaluate the epidemiological and clinical profile of patients with valvular heart disease undergoing heart transplantation. Between 1985 and 2013, a total of 569 heart transplants was performed at the authors' institution. Twenty patients (13 men, seven women; mean age 39.5 +/- 15.2 years) underwent heart transplant due to structural (primary) valvular disease. Analyses were made of the patients' clinical profile, laboratory data, echocardiographic and histopathological data, and mortality and rejection. Of the patients, 18 (90%) had a rheumatic etiology, with 85% having undergone previous valve surgery (45% had one or more operations), and 95% with a normal functioning valve prosthesis at the time of transplantation. Atrial fibrillation was present in seven patients (35%), while nine (45%) were in NYHA functional class IV and eight (40%) in class III. The indication for cardiac transplantation was refractory heart failure in seven patients (35%) and persistent NYHA class III/IV in ten (50%). The mean left ventricular ejection fraction (LVEF) was 26.6 +/- 7.9%. The one-year mortality was 20%. Histological examination of the recipients' hearts showed five (27.7%) to have reactivated rheumatic myocarditis without prior diagnosis at the time of transplantation. Univariate analysis showed that age, gender, LVEF, rheumatic activity and rejection were not associated with mortality at one year. Among the present patient cohort, rheumatic heart disease was the leading cause of heart transplantation, and a significant proportion of these patients had reactivated myocarditis diagnosed in the histological analyses. Thus, it appears valid to investigate the existence of rheumatic activity, especially in valvular cardiomyopathy with severe systolic dysfunction before transplantation.

Long-term use of amiodarone before heart transplantation significantly reduces early post-transplant atrial fibrillation and is not associated with increased mortality after heart transplantation

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Rivinius R

2016-02-01

Full Text Available Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Bastian Schmack,2 Christian Erbel,1 Christian A Gleissner,1 Mohammadreza Akhavanpoor,1 Lutz Frankenstein,1 Fabrice F Darche,1 Patrick A Schweizer,1 Dierk Thomas,1 Philipp Ehlermann,1 Tom Bruckner,3 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, Angiology and Pneumology, 2Department of Cardiac Surgery, Heidelberg University Hospital, 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany Background: Amiodarone is a frequently used antiarrhythmic drug in patients with end-stage heart failure. Given its long half-life, pre-transplant use of amiodarone has been controversially discussed, with divergent results regarding morbidity and mortality after heart transplantation (HTX.Aim: The aim of this study was to investigate the effects of long-term use of amiodarone before HTX on early post-transplant atrial fibrillation (AF and mortality after HTX.Methods: Five hundred and thirty patients (age ≥18 years receiving HTX between June 1989 and December 2012 were included in this retrospective single-center study. Patients with long-term use of amiodarone before HTX (≥1 year were compared to those without long-term use (none or <1 year of amiodarone. Primary outcomes were early post-transplant AF and mortality after HTX. The Kaplan–Meier estimator using log-rank tests was applied for freedom from early post-transplant AF and survival.Results: Of the 530 patients, 74 (14.0% received long-term amiodarone therapy, with a mean duration of 32.3±26.3 months. Mean daily dose was 223.0±75.0 mg. Indications included AF, Wolff–Parkinson–White syndrome, ventricular tachycardia, and ventricular fibrillation. Patients with long-term use of amiodarone before HTX had significantly lower rates of early post-transplant AF (P=0.0105. Further, Kaplan–Meier analysis of freedom from early post-transplant AF showed significantly lower rates of AF in this

Effectiveness of YouTube as a Source of Medical Information on Heart Transplantation.

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Chen, He-Ming; Hu, Zhong-Kai; Zheng, Xiao-Lin; Yuan, Zhao-Shun; Xu, Zhao-Bin; Yuan, Ling-Qing; Perez, Vinicio A De Jesus; Yuan, Ke; Orcholski, Mark; Liao, Xiao-Bo

2013-11-21

In this digital era, there is a growing tendency to use the popular Internet site YouTube as a new electronic-learning (e-learning) means for continuing medical education. Heart transplantation (HTx) remains the most viable option for patients with end-stage heart failure or severe coronary artery disease. There are plenty of freely accessible YouTube videos providing medical information about HTx. The aim of the present study is to determine the effectiveness of YouTube as an e-learning source on HTx. In order to carry out this study, YouTube was searched for videos uploaded containing surgical-related information using the four keywords: (1) "heart transplantation", (2) "cardiac transplantation", (3) "heart transplantation operation", and (4) "cardiac transplantation operation". Only videos in English (with comments or subtitles in English language) were included. Two experienced cardiac surgeons watched each video (N=1800) and classified them as useful, misleading, or recipients videos based on the HTx-relevant information. The kappa statistic was used to measure interobserver variability. Data was analyzed according to six types of YouTube characteristics including "total viewership", "duration", "source", "days since upload", "scores" given by the viewers, and specialized information contents of the videos. A total of 342/1800 (19.00%) videos had relevant information about HTx. Of these 342 videos, 215 (62.8%) videos had useful information about specialized knowledge, 7/342 (2.0%) were found to be misleading, and 120/342 (35.1%) only concerned recipients' individual issues. Useful videos had 56.09% of total viewership share (2,175,845/3,878,890), whereas misleading had 35.47% (1,375,673/3,878,890). Independent user channel videos accounted for a smaller proportion (19% in total numbers) but might have a wider impact on Web viewers, with the highest mean views/day (mean 39, SD 107) among four kinds of channels to distribute HTx-related information. You

Mechanostimulation Protocols for Cardiac Tissue Engineering

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Marco Govoni

2013-01-01

Full Text Available Owing to the inability of self-replacement by a damaged myocardium, alternative strategies to heart transplantation have been explored within the last decades and cardiac tissue engineering/regenerative medicine is among the present challenges in biomedical research. Hopefully, several studies witness the constant extension of the toolbox available to engineer a fully functional, contractile, and robust cardiac tissue using different combinations of cells, template bioscaffolds, and biophysical stimuli obtained by the use of specific bioreactors. Mechanical forces influence the growth and shape of every tissue in our body generating changes in intracellular biochemistry and gene expression. That is why bioreactors play a central role in the task of regenerating a complex tissue such as the myocardium. In the last fifteen years a large number of dynamic culture devices have been developed and many results have been collected. The aim of this brief review is to resume in a single streamlined paper the state of the art in this field.

Metabolic syndrome definitions and components in predicting major adverse cardiovascular events after kidney transplantation.

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Prasad, G V Ramesh; Huang, Michael; Silver, Samuel A; Al-Lawati, Ali I; Rapi, Lindita; Nash, Michelle M; Zaltzman, Jeffrey S

2015-01-01

Metabolic syndrome (MetS) associates with cardiovascular risk post-kidney transplantation, but its ambiguity impairs understanding of its diagnostic utility relative to components. We compared five MetS definitions and the predictive value of constituent components of significant definitions for major adverse cardiovascular events (MACE) in a cohort of 1182 kidney transplant recipients. MetS definitions were adjusted for noncomponent traditional Framingham risk factors and relevant transplant-related variables. Kaplan-Meier, logistic regression, and Cox proportional hazards analysis were utilized. There were 143 MACE over 7447 patient-years of follow-up. Only the World Health Organization (WHO) 1998 definition predicted MACE (25.3 vs 15.5 events/1000 patient-years, P = 0.019). Time-to-MACE was 5.5 ± 3.5 years with MetS and 6.8 ± 3.9 years without MetS (P < 0.0001). MetS was independent of pertinent MACE risk factors except age and previous cardiac disease. Among MetS components, dysglycemia provided greatest hazard ratio (HR) for MACE (1.814 [95% confidence interval 1.26-2.60]), increased successively by microalbuminuria (HR 1.946 [1.37-2.75]), dyslipidemia (3.284 [1.72-6.26]), hypertension (4.127 [2.16-7.86]), and central obesity (4.282 [2.09-8.76]). MetS did not affect graft survival. In summary, although the WHO 1998 definition provides greatest predictive value for post-transplant MACE, most of this is conferred by dysglycemia and is overshadowed by age and previous cardiac disease. © 2014 Steunstichting ESOT.

Heart Transplantation in Congenital Heart Disease: In Whom to Consider and When?

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Attenhofer Jost, Christine H.; Schmidt, Dörthe; Huebler, Michael; Balmer, Christian; Noll, Georg; Caduff, Rosmarie; Greutmann, Matthias

2013-01-01

Due to impressive improvements in surgical repair options, even patients with complex congenital heart disease (CHD) may survive into adulthood and have a high risk of end-stage heart failure. Thus, the number of patients with CHD needing heart transplantation (HTx) has been increasing in the last decades. This paper summarizes the changing etiology of causes of death in heart failure in CHD. The main reasons, contraindications, and risks of heart transplantation in CHD are discussed and underlined with three case vignettes. Compared to HTx in acquired heart disease, HTx in CHD has an increased risk of perioperative death and rejection. However, outcome of HTx for complex CHD has improved over the past 20 years. Additionally, mechanical support options might decrease the waiting list mortality in the future. The number of patients needing heart-lung transplantation (especially for Eisenmenger's syndrome) has decreased in the last years. Lung transplantation with intracardiac repair of a cardiac defect is another possibility especially for patients with interatrial shunts. Overall, HTx will remain an important treatment option for CHD in the near future. PMID:23577237

Bibliometric analysis of the top-cited articles on islet transplantation.

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Pu, Qiang-Hong; Lyu, Qiu-Ju; Liu, Huan; Fan, Kai-Hua

2017-11-01

To identify and characterize the top-cited articles in the field of islet transplantation. We used the Science Citation Index Expanded database to identify the most frequently cited articles published after 1900. Articles were evaluated using the following characteristics: citation number, publication year, study design, references, country and institution of origin, authorship, and journal. Keyword analysis and citation networks were used to analyze research trends. The most frequently cited articles received between 146 and 2988 citations; the median was 291. All of the most frequently cited articles were published between 1972 and 2012, and 85 articles were published after 1990. The most popular study design involved basic science (75 articles). The leading countries were the United States (US) and Canada, and the leading institutions were the University of Alberta, Canada, and the University of Minnesota, in the US. Journals specializing in diabetes or transplantation published more than half of the articles (n = 53, 52%), with the journal Diabetes publishing the largest number (n = 30). No association was found between a journal's impact factor and the number of top-cited articles it published. There was no correlation between the number of citations and the number of years since publication, authors, participating institutions, or countries involved. Top-cited articles focused on 2 themes: the use of antirejection immunotherapy or biocompatible encapsulations to prolong graft survival, and assessments of the efficacy of islet transplants, in particular, islet allografts. Our study can help researchers to identify and decipher the characteristics of top-cited articles in the field of islet transplantation. Just as clinically successful allografts are carried out using the Edmonton protocol, autografts and xenografts should be similarly strengthened to solve problems relating to immune rejection and islet sources, respectively.

Balancing rejection and infection with respect to age, race, and gender: clues acquired from 17 years of cardiac transplantation data.

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George, James F; Pamboukian, Salpy V; Tallaj, José A; Naftel, David C; Myers, Susan L; Foushee, Margaret T; Brown, Robert N; Pajaro, Octavio E; McGiffin, David C; Kirklin, James K

2010-09-01

Donor and recipient risk factors for rejection and infection have been well characterized. The contribution of demographic factors, especially age at the time of transplantation to morbidity and mortality due to rejection and infection, is much less well understood. Using parametric hazard analysis and multivariate risk-factor equations for infection and rejection events, we quantitatively determined the relationship of fundamental demographic variables (age, race and gender) to infection and rejection. These analyses were conducted with respect to date of transplant and age at the time of transplantation. The patient group consisted of all primary heart transplants performed at the University of Alabama at Birmingham during the years 1990 to 2007 (n = 526). Risk factors for rejection within 12 months post-transplantation were date of transplant (p < 0.0001) and age at the time of transplantation (young adults 10 to 30 years of age, p < 0.0001). Risk factors for infection were date of transplant (p < 0.0001) and age at the time of transplantation (young children and older adults, p < 0.0001). There were three immunosuppressive eras in 1990 to 2007. Notably, although the proportion of patients experiencing rejection and infection events decreased during each successive immunosuppressive era, the relative relationship of infection to rejection, as well as age at the time of transplantation, remained similar into the most recent era. The maximal frequency of rejection events and rejection death occurred among patients transplanted at ages 10 to 30 years. Conversely, the frequency of infection events was minimal within the same group. In the oldest and youngest patients receiving transplants, infection was the predominant cause of death and rates of rejection events decreased. These data show that evolving immunosuppressive strategies have successfully reduced rejection and infection frequencies, and those patients transplanted at 30 to 60 years of age have the lowest

Anti-EGFR therapy radiosensitizes human lung adenocarcinoma xenograft in nude mouse

International Nuclear Information System (INIS)

Wang Hui; Li Tianran; Tian Jiahe; Qu Baolin; Zhu Hui

2008-01-01

Objective: To investigate the effect of Gefitinib on radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. Methods: Human lung adenocarcinoma cell line A549 was used to establish nude mouse xenograft tumor model. The mice were derided into 4 groups: control, irradiation alone, Gefinitib alone and radiation combined with Genifitib. Radiation schedule was 3 fractions of 5 Gy, once daily. Gefitinib was daily administered by gavage at 100 mg/(kg·day -1 ) for 14 days. In the combination group, radiotherapy was performed 2 hours after Gefitinib administration. Tumor diameter was measured every other day. Percentage of tumor growth inhibition, growth delay time and regrowth delay time were evaluated. Results: For A549 xenografts in radiation alone, gefitinib alone and combination therapy groups, the percentage of tumor growth inhibition was 22.7%, 12.4% and 38.2%, respectively (F=25.75, P=0.000). Tumor growth delay time was 6.0, 7.8 and 21.6 days, respectively (F=70.49, P=0.000). Tumor regrowth delay time in combination therapy and irradiation alone groups was 23.4 and 10.2 days. (F=174.24, P= 0.000). Sensitizing enhancement ratio of combination group was 1.5 in growth and 1.7 in regrowth. Conclusions: Anti-EGFR therapy enhances the radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. (authors)

Guillain-Barré Syndrome due to CMV Reactivation after Cardiac Transplantation

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Christina Maria Steger

2012-01-01

Full Text Available A 40-year-old male patient suffered from end-stage heart failure due to ischemic cardiomyopathy and received orthotopiccardiac transplantation in June 2005. The instantaneous postoperative course was uneventful, but, seven months later, he suffered from paralysis in the lower extremities finally resulting in quadriplegia and was admitted to hospital. After laboratory testings the diagnosis of a Guillain-Barré syndrome due to cytomegalovirus reactivation was confirmed.

Early radiation effects in highly apoptotic murine lymphoma xenografts monitored by 31P magnetic resonance spectroscopy

International Nuclear Information System (INIS)

Sakurai, Hideyuki; Mitsuhashi, Norio; Murata, Osamu; Kitamoto, Yoshizumi; Saito, Yoshihiro; Hasegawa, Masatoshi; Akimoto, Tetsuo; Takahashi, Takeo; Nasu, Sachiko; Niibe, Hideo

1998-01-01

Purpose: Phosphorus-31 magnetic resonance spectra ( 31 P-MRS) were obtained from highly apoptotic murine lymphoma xenografts before and up to 24 hr following graded doses of radiation ranging from 2 to 30 Gy. Radiation-induced apoptosis was also estimated up to 24 hr by scoring apoptotic cells in tumor tissue. Methods and Materials: Highly apoptotic murine lymphoma cells, EL4, were subcutaneously transplanted into C57/BL mice. At 7 days after transplantation, radiation was given to the tumor with a single dose at 3, 10, and 30 Gy. The β-ATP/Pi, PME/Pi, and β-ATP/PME values were calculated from the peak area of each spectrum. Radiation-induced apoptosis was scored with counting apoptotic cells on hematoxylin and eosin stained specimens (%apoptosis). Results: The values of % apoptosis 4, 8, and 24 hr after radiation were 21.8, 19.6, and 4.6% at 3 Gy, 35.1, 25.6, and 14.8% at 10 Gy, 38.4, 38.0, and 30.6% at 30 Gy, respectively (cf. 4.4% in control). There was no correlation between early change in β-ATP/Pi and % apoptosis at 4 hr after radiation when most of the apoptosis occurred. An early decrease in PME/Pi was observed at 4 hr after radiation dose at 30 Gy. For each dose, the values of β-ATP/Pi 24 hr after radiation were inversely related to radiation dose. Conclusion: The increase in β-ATP/Pi observed by 31 P-MRS was linked to the degree of histological recovery from radiation-induced apoptosis

High-Intensity Interval Training in Heart Transplant Recipients: A Systematic Review with Meta-Analysis

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Raphael José Perrier-Melo

2018-02-01

Full Text Available Abstract Heart transplantation (HTx is considered an efficient and gold-standard procedure for patients with end-stage heart failure. After surgery, patients have lower aerobic power (VO2max and compensatory hemodynamic responses. The aim of the present study was to assess through a systematic review with meta-analysis whether high-intensity interval training (HIIT can provide benefits for those parameters. This is a systematic review with meta-analysis, which searched the databases and data portals PubMed, Web of Science, Scopus, Science Direct and Wiley until December 2016 (pairs. The following terms and descriptors were used: “heart recipient” OR “heart transplant recipient” OR ”heart transplant” OR “cardiac transplant” OR “heart graft”. Descriptors via DeCS and Mesh were: “heart transplantation’’ OR “cardiac transplantation”. The words used in combination (AND were: “exercise training” OR “interval training” OR “high intensity interval training” OR “high intensity training” OR “anaerobic training” OR “intermittent training” OR “sprint training”. The initial search identified 1064 studies. Then, only those studies assessing the influence of HIIT on the post-HTx period were added, resulting in three studies analyzed. The significance level adopted was 0.05. Heart transplant recipients showed significant improvement in VO2peak, heart rate and peak blood pressure in 8 to 12 weeks of intervention.

[Short-term outcomes of lung transplant recipients using organs from brain death donors].

Science.gov (United States)

He, W X; Jiang, C; Liu, X G; Huang, W; Chen, C; Jiang, L; Yang, B; Wu, K; Chen, Q K; Yang, Y; Yu, Y M; Jiang, G N

2016-12-01

Objective: To assess short-term outcomes after lung transplantation with organs procured following brain death. Methods: Between April 2015 and July 2016, all 17 recipients after lung transplantation using organs from brain death donors (DBD) at Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine were enrolled in this study. All patients were male, aging (60±7) years, including 11 chronic obstructive pulmonary disease, 5 idiopathic pulmonary fibrosis, 1 silicosis. Seventeen donors were 16 males and 1 female, with 10 traumatic brain injury, 5 cerebrovascular accident and 2 sudden cardiac death. Of 17 recipients receiving DBD lung transplant, 16 were single lung transplant. Data were collected including intubation duration of mechanical ventilation, hospital length of stay, incidence of pulmonary infection bronchus anastomosis complications, primary graft dysfunction (PGD), and acute rejection, bronchiolitis obliterans syndrome (BOS) as well as mortality of 90-day after lung transplantation. Results: Median duration of intubation were 2 (2) days ( M ( Q R )) in recipients after lung transplantation. The incidence of pulmonary infection and bronchus anastomosis complications were 15/17 and 5/17, respectively. Median length of stay in hospital were 56 (19) days. The ratio of readmission 1 month after discharge were 10/17. Mortality of 90-day post-transplant were 2/17. The incidence of PGD and BOS were 1/17 and 2/17, respectively. Conclusion: Recipients with DBD lung transplantation have an acceptable survival during short-term follow-up, but with higher incidences of complications related to infection post-transplantation.

Thallium stress testing does not predict cardiovascular risk in diabetic patients with end-stage renal disease undergoing cadaveric renal transplantation

International Nuclear Information System (INIS)

Holley, J.L.; Fenton, R.A.; Arthur, R.S.

1991-01-01

This study assessed the usefulness of thallium stress testing as a predictor of perioperative cardiovascular risk in diabetic patients with end-stage renal disease undergoing cadaveric renal transplantation. Demographic factors influencing the exercise performance in these patients were also examined. The medical records of 189 consecutive patients with diabetic nephropathy who were evaluated for cadaveric renal transplantation were reviewed. Thallium stress testing was the initial examination of cardiovascular status in 141 patients. An adequate examination was one in which at least 70% of maximum heart rate was achieved. A thallium stress test was normal if there were no ST segment depressions on the electrocardiogram and no perfusion abnormalities on the thallium scan. Forty-four patients underwent cardiac catheterization as the initial evaluation (Group C) and four patients underwent transplantation without a formal cardiovascular evaluation (Group D). Sixty-four of the 141 patients undergoing thallium stress testing had an adequate and normal examination (Group A). The incidence of perioperative cardiac events in this group was 2%. Seventy-seven patients (Group B) had an abnormal (n = 41) or an inadequate (n = 36) thallium stress test and most (n = 61) then underwent coronary angiography. The use of beta-blockers was the only predictor of an abnormal or inadequate thallium stress test. Forty-three percent of patients with inadequate or abnormal thallium stress tests had significant coronary artery disease on cardiac catheterization. The perioperative risk of cardiac events was not different in Group A versus Groups B, C, and D combined. Survival of Group A and B patients was not different but was significantly longer than that of Group C patients

[Melanoma in organ transplant patients].

Science.gov (United States)

Lévêque, L; Dalac, S; Dompmartin, A; Louvet, S; Euvrard, S; Catteau, B; Hazan, M; Schollhamer, M; Aubin, F; Dreno, B; Daguin, P; Chevrant-Breton, J; Frances, C; Bismuth, M J; Tanter, Y; Lambert, D

2000-02-01

The incidence of cutaneous melanoma has rapidly increased in the white population over the last decades. It has been estimated that the incidence doubles world-wide every 10 years. Different risk factors have been identified, including immunosuppression. The aim of our study-was to determine the relative risk of developing melanoma in the organ transplant population and the clinical and histological features of their melanomas. This retrospective study was conducted with the collaboration of 9 University Hospital Centers: Besançon, Brest, Caen, Dijon, Lille, Lyon, Nantes, Paris (Pitié-Salpétrière) and Rennes. A questionnaire was sent to the different departments of dermatology of these hospitals to obtain information on patients who had presented a melanoma after a transplantation between 1971 and 1997. During this period, there were 12,477 organ transplant recipients in the transplantation units of these 9 hospitals. Average follow-up for these patients was about 5 years and the average duration of immunosuppressive therapy was about 4.5 years. Among 12,477 organ transplant recipients, we found 17 cases of melanoma but no data could be obtain on one case: 14 occurred in renal transplant recipients and 3 in cardiac transplant recipients. Clinical and histological data were only available in 16 patients. The average time between transplantation and diagnosis of melanoma was 63 months, but it was 5 times shorter for 2 patients who had a past history of melanoma before transplantation. Two patients had a mucosal melanoma; for the cutaneous melanomas, 2 appeared on Dubreuilh melanosis, 2 were in situ melanomas, 7 were superficial spreading melanomas and 3 were nodular melanomas. The histological review of 11 cutaneous melanomas revealed a precursor nevus in 6 cases and a weak or no stroma reaction in 7/7 cases. Complete excision of the melanoma was performed in all patients except one with anorectal melanoma. Four patients died of visceral metastasis within a mean

Tricuspid valve regurgitation after heart transplantation.

Science.gov (United States)

Kwon, Murray H; Shemin, Richard J

2017-05-01

Tricuspid valve regurgitation (TVR) in the orthotopic heart transplant (OHT) recipient is quite common and has varied clinical sequelae. In its severest forms, it can lead to right-sided failure symptoms indistinguishable from that seen in native heart TVR disease. While certain implantation techniques are widely recognized to reduce the risk of TVR in the cardiac allograft, concomitant tricuspid annuloplasty, while having advocates, is not currently accepted as a routinely established adjunct. Decisions to surgically correct TVR in the OHT recipient must be made carefully, as certain clinical scenarios have high risk of failure. Like in the native heart, anatomic etiologies typically have the greatest chances for success compared to functional etiologies. While repair options have been utilized, there is emerging data to support replacement as the more durable option. While mechanical prostheses are impractical in the heart transplant recipient, biologic valves offer the advantage of continued access to the right ventricle for biopsies in addition to acceptable durability in the low pressure system of the right side.

Efficient non-viral reprogramming of myoblasts to stemness with a single small molecule to generate cardiac progenitor cells.

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Zeeshan Pasha

Full Text Available The current protocols for generation of induced pluripotent stem (iPS cells involve genome integrating viral vectors which may induce tumorgenesis. The aim of this study was to develop and optimize a non-viral method without genetic manipulation for reprogramming of skeletal myoblasts (SMs using small molecules.SMs from young male Oct3/4-GFP(+ transgenic mouse were treated with DNA methyltransferase (DNMT inhibitor, RG108. Two weeks later, GFP(+ colonies of SM derived iPS cells (SiPS expressing GFP and with morphological similarity of mouse embryonic stem (ESCs were formed and propagated in vitro. SiPS were positive for alkaline phosphatase activity, expressed SSEA1, displayed ES cell specific pluripotency markers and formed teratoma in nude mice. Optimization of culture conditions for embryoid body (EBs formation yielded spontaneously contracting EBs having morphological, molecular, and ultra-structural similarities with cardiomyocytes and expressed early and late cardiac markers. miR profiling showed abrogation of let-7 family and upregulation of ESCs specific miR-290-295 cluster thus indicating that SiPS were similar to ESCs in miR profile. Four weeks after transplantation into the immunocompetent mice model of acute myocardial infarction (n = 12 per group, extensive myogenesis was observed in SiPS transplanted hearts as compared to DMEM controls (n = 6 per group. A significant reduction in fibrosis and improvement in global heart function in the hearts transplanted with SiPS derived cardiac progenitor cells were observed.Reprogramming of SMs by DNMT inhibitor is a simple, reproducible and efficient technique more likely to generate transgene integration-free iPS cells. Cardiac progenitors derived from iPS cells propagated extensively in the infarcted myocardium without tumorgenesis and improved cardiac function.

Systematic analysis of a xenograft mice model for KSHV+ primary effusion lymphoma (PEL.

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Lu Dai

Full Text Available Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL, which arises preferentially in the setting of infection with human immunodeficiency virus (HIV. Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV(+ PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells propagated in vivo exhibit unique biology, differing from one another or from their parental cell lines propagated through in vitro culture. Therefore, we used a KSHV(+ PEL/BCBL-1 xenograft model involving non-obese diabetic/severe-combined immunodeficient (NOD/SCID mice, and compared characteristics of effusion and solid tumors with their parent cell culture-derived counterparts. Our results indicate that although this xenograft model can be used for study of effusion and solid lymphoma observed in patients, tumor cells in vivo display unique features to those passed in vitro, including viral lytic gene expression profile, rate of solid tumor development, the host proteins and the complex of tumor microenvironment. These items should be carefully considered when the xenograft model is used for testing novel therapeutic strategies against KSHV-related lymphoma.

CARDIAC TRANSPLANTATION IN YOUNG PATIENT WITH DILATED CARDIOMYOPATHY AND SECONDARY ANTIPHOSPHOLIPID SYNDROME

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E. V. Shlyakhto

2013-01-01

Full Text Available Patients with congestive heart failure have an increased incidence of thromboembolic events. The choice of me- dical management in patients with antiphospholipid antibodies and generalized thrombosis due to hypercoagula- bility is complex issue. We report heart transplant outcome in 15 years old patient with dilated cardiomyopathy and secondary anti-phospholipid syndrome. 

Screening for heart transplantation and left ventricular assist system

DEFF Research Database (Denmark)

Lund, Lars H; Trochu, Jean-Noel; Meyns, Bart

2018-01-01

BACKGROUND: Heart transplantation (HTx) and implantable left ventricular assist systems (LVAS) improve outcomes in advanced heart failure but may be underutilized. We hypothesized that screening can identify appropriate candidates. METHODS AND RESULTS: The ScrEEning for advanced Heart Failure...... treatment (SEE-HF) study was a multicentre prospective study screening patients with existing cardiac resynchronization therapy (CRT) and/or implantable cardioverter-defibrillator (ICD) for ejection fraction ≤40% and New York Heart Association (NYHA) class III-IV, and subsequently for guideline-based HTx...

Effect of 34 kinds of traditional Japanese herbal medicines on prolongation of cardiac allograft survival.

Science.gov (United States)

Jin, X; Uchiyama, M; Zhang, Q; Harada, T; Otsuka, K; Shimokawa, T; Niimi, M

2014-05-01

Herbal medicines have been used for over 3,000 years in Asian as alternative therapy for their variety effects and have recently become popular in Europe and the United States. In the last 30 years, Japanese herbal medicines were widely used for treatment of diseases after been recognized officially by Japanese government. In this study, we investigated the effect of 34 kinds of traditional Japanese herbal medicines on alloimmune responses in a murine model of cardiac allograft transplantation. CBA mice (H2(k)) underwent transplantation of a C57BL/6 (H2(b)) heart and received oral administration of 2 g/kg/d of the 34 kinds of herbal medicines from the day of transplantation until 7 days afterward. Naïve CBA mice rejected B6 cardiac grafts acutely (median survival time [MST], 7 days). CBA transplant recipients given 2 g/kg/d of Sairei-to (TJ-114) and Tokishakuyaku-san (TJ-23) had prolonged C57BL/6 allograft survival indefinitely (both MSTs > 100 days). Moreover, CBA transplant recipients given Seisinrensiin (TJ-111), Tokishigyakukagoshuyushokyoto (TJ-38), Rikkunshito (TJ-43), Maobushisaishinto (TJ-127), Ninjin-yoei-to (TJ-108), Ryokan-kyomi-shinge-nin-to (TJ-119), Inchingorei-san (TJ-117), Hochuekkito (TJ-41), Kihi-to (TJ-65), and Sinbu-to (TJ-30) had also prolonged C57BL/6 allograft survival significantly (MSTs of 28, 22, 16, 14, 14, 13, 12, 9.5, 9 and 9 days, respectively). However, none of other 22 kinds of herbal medicines could prolong the allograft survival. Furthermore, oral administration of 2 g/kg/d of Daikenchuto (TJ-100) induced sudden death (within 1 minute) in CBA mice. In conclusion, 12 kinds of Japanese herbal medicines prolonged allograft survival and one showed toxic effect in mice. Copyright © 2014 Elsevier Inc. All rights reserved.

SUPPLEMENTAL CARDIOPLEGIA IMMEDIATELY BEFORE GRAFT IMPLANTATION MAY IMPROVE EARLY POST-TRANSPLANTATION OUTCOME

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Hendrik eTevaearai Stahel

2014-11-01

Full Text Available Background: Preservation of cardiac grafts for transplantation is not standardized and most centers use a single administration of crystalloid solution at the time of harvesting. We investigated possible benefits of an additional dose of cardioplegia dispensed immediately before implantation.Methods: Consecutive adult cardiac transplantations (2005-2012 were reviewed. Hearts were harvested following a standard protocol (Celsior 2L, 4-8oC. In 2008, 100mL crystalloid cardioplegic solution was added and administered immediately before implantation. Univariate and logistic regression analyses were used to investigate risk factors for post-operative graft failure and mid-term outcome. Results: A total of 81 patients, 44 standard (Cardio - versus 37 with additional cardioplegia (Cardio + were analyzed. Recipients and donors were comparable in both groups. Cardio + patients demonstrated a reduced need for defibrillation (24% vs. 48%, p=0.03, post-operative ratio of CK-MB/CK (10.1±3.9% vs. 13.3±4.2%, p=0.001, intubation time (2.0±1.6 vs. 7.2±11.5 days, p=0.05 and ICU stay (3.9±2.1 vs. 8.5±7.8 days, p=0.001. Actuarial survival was reduced when graft ischemic time was >180 minutes in Cardio – but not in Cardio + patients (p=0.033. Organ ischemic time >180 minutes (OR:5.48, CI:1.08-27.75, donor female gender (OR:5.84, CI:1.13-33.01 and recipient/donor age >60 (OR:6.33, CI:0.86-46.75, but not the additional cardioplegia nor the observation period appeared independent predictors of post-operative acute graft failure.Conclusion: An additional dose of cardioplegia administered immediately before implantation may be a simple way to improve early and late outcome of cardiac transplantation, especially in situations of prolonged graft ischemia. A large, ideally multicentric, randomized study is desirable to verify this preliminary observation.

Improvement of Radiation-Mediated Immunosuppression of Human NSCLC Tumour Xenografts in a Nude Rat Model

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Sergey V. Tokalov

2010-01-01

Full Text Available Human tumour xenografts in a nude rat model have consistently been used as an essential part of preclinical studies for anticancer drugs activity in human. Commonly, these animals receive whole body irradiation to assure immunosuppression. But whole body dose delivery might be inhomogeneous and the resulting incomplete bone marrow depletion may modify tumour behaviour. To improve irradiation-mediated immunosuppression of human non-small cell lung cancer (NSCLC xenografts in a nude rat model irradiation (2 + 2 Gy from opposite sides of animals has been performed using a conventional X-ray tube. The described modification of whole body irradiation improves growth properties of human NSCLC xenografts in a nude rat model. The design of the whole body irradiation mediated immunosuppression described here for NSCLC xenografts may be useful for research applications involving other types of human tumours.

Psychological assessment of patients undergoing cardiac transplant in a teaching hospital (2004 to 2012

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Sara dos Santos Cunha

2014-09-01

Full Text Available Objective: To analyze the psychological evaluations of patients with heart failure waiting for heart transplantation. Methods: The data were obtained from patient records containing pre-surgery psychological evaluations performed by psychologists from the multidisciplinary cardiology team. The evaluation protocol included the Quality of Life Questionnaire (SF-36, Beck Depression Inventory, and an interview script. Results: The results of psychological evaluations performed between 2004 and 2012 for 60 candidates for heart transplantation were analyzed: 43 men and 17 women aged between 16 and 66 years (Mean=45.18; SD=11.91, predominantly from the São José do Rio Preto area (São Paulo state, Brazil (83%, with incomplete elementary education (68%, and who were in stable relationships (73%. Although women presented higher mean scores for depression (21.41 than men (14.61, there was no significant difference between genders. Women's quality of life was impaired in all domains compared to men (below 50% and was significantly poorer in the physical functioning (P=0.01, vitality (P=0.00, emotional role functioning (P=0.04, and mental health (P=0.02 domains. Conclusion: Patients with psychosocial vulnerability (e.g., depression identified before transplantation should receive psychological treatment.

Long-term results of vaginal repairs with and without xenograft reinforcement

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Mouritsen, Lone; Kronschnabl, M.; Lose, G.

2010-01-01

INTRODUCTION AND HYPOTHESIS: The aim of this paper is to study if xenograft reinforcement of vaginal repair reduces recurrence of prolapse. METHODS: Results 1-5 years after vaginal repair were studied in 41 cases with xenograft and in 82 matched controls without. Symptoms were evaluated...... as POPQ > -1 plus symptoms revealed recurrence in 3% of cases and 12% controls. None of the recurrence rates was significantly different for cases versus controls. No vaginal erosions were seen. Previous surgery was a significant risk factor with odds ratio 7.3 for another recurrence. CONCLUSIONS...

Radiosensitivity of drug-resistant human tumour xenografts

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Mattern, J.; Bak, M. Jr.; Volm, M.; Hoever, K.H.

1989-01-01

The radiosensitivity of three drug-resistant sublines of a human epidermoid lung carcinoma growing as xenografts in nude mice was investigated. Drug resistance to vincristine, actinomycin D and cisplatin was developed in vivo by repeated drug treatment. It was found that all three drug-resistant tumour lines were not cross-resistant to irradiation. (orig.) [de

Improvement of Heart Failure by Human Amniotic Mesenchymal Stromal Cell Transplantation in Rats.

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Razavi Tousi, Seyed Mohammad Taghi; Faghihi, Mahdieh; Nobakht, Maliheh; Molazem, Mohammad; Kalantari, Elham; Darbandi Azar, Amir; Aboutaleb, Nahid

2016-07-06

Background: Recently, stem cells have been considered for the treatment of heart diseases, but no marked improvement has been recorded. This is the first study to examine the functional and histological effects of the transplantation of human amniotic mesenchymal stromal cells (hAMSCs) in rats with heart failure (HF). Methods: This study was conducted in the years 2014 and 2015. 35 male Wistar rats were randomly assigned into 5 equal experimental groups (7 rats each) as 1- Control 2- Heart Failure (HF) 3- Sham 4- Culture media 5- Stem Cell Transplantation (SCT). Heart failure was induced using 170 mg/kg/d of isoproterenol subcutaneously injection in 4 consecutive days. The failure confirmed by the rat cardiac echocardiography on day 28. In SCT group, 3×10 6 cells in 150 µl of culture media were transplanted to the myocardium. At the end, echocardiographic and hemodynamic parameters together with histological evaluation were done. Results: Echocardiography results showed that cardiac ejection fraction in HF group increased from 58/73 ± 9% to 81/25 ± 6/05% in SCT group (p value < 0.001). Fraction shortening in HF group was increased from 27/53 ± 8/58% into 45/55 ± 6/91% in SCT group (p value < 0.001). Furthermore, hAMSCs therapy significantly improved mean diastolic blood pressure, mean arterial pressure, left ventricular systolic pressure, rate pressure product, and left ventricular end-diastolic pressure compared to those in the HF group, with the values reaching the normal levels in the control group. A marked reduction in fibrosis tissue was also found in the SCT group (p value < 0.001) compared with the animals in the HF group. Conclusion: The transplantation of hAMSCs in rats with heart failure not only decreased the level of fibrosis but also conferred significant improvement in heart performance in terms of echocardiographic and hemodynamic parameters.

[Artificial muscle and its prospect in application for direct cardiac compression assist].

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Dong, Jing; Yang, Ming; Zheng, Zhejun; Yan, Guozheng

2008-12-01

Artificial heart is an effective device in solving insufficient native heart supply for heart transplant, and the research and application of novel actuators play an important role in the development of artificial heart. In this paper, artificial muscle is introduced as the actuators of direct cardiac compression assist, and some of its parameters are compared with those of native heart muscle. The open problems are also discussed.

Heart transplantation for adults with congenital heart disease: current status and future prospects.

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Matsuda, Hikaru; Ichikawa, Hajime; Ueno, Takayoshi; Sawa, Yoshiki

2017-06-01

Increased survival rates after corrective or palliative surgery for complex congenital heart disease (CHD) in infancy and childhood are now being coupled with increased numbers of patients who survive to adulthood with various residual lesions or sequelae. These patients are likely to deteriorate in cardiac function or end-organ function, eventually requiring lifesaving treatment including heart transplantation. Although early and late outcomes of heart transplantation have been improving for adult survivors of CHD, outcomes and pretransplant management could still be improved. Survivors of Fontan procedures are a vulnerable cohort, particularly when single ventricle physiology fails, mostly with protein-losing enteropathy and hepatic dysfunction. Therefore, we reviewed single-institution and larger database analyses of adults who underwent heart transplantation for CHD, to enable risk stratification by identifying the indications and outcomes. As the results, despite relatively high early mortality, long-term results were encouraging after heart transplantation. However, further investigations are needed to improve the indication criteria for complex CHD, especially for failed Fontan. In addition, the current system of status criteria and donor heart allocation system in heart transplantation should be arranged as suitable for adults with complex CHD. Furthermore, there is a strong need to develop ventricular assist devices as a bridge to transplantation or destination therapy, especially where right-sided circulatory support is needed.

MULTIPLEX ANALYSIS OF BIOMARKERS OF NEOANGIOGENESIS AND INFLAMMATION IN HEART TRANSPLANT RECIPIENTS

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O. P. Shevchenko

2015-01-01

Full Text Available Aim of study: multiplex analysis of the levels of biomarkers of neoangiogenesis and inflammation in cardiac transplant recipients. Materials and methods. 59 pts. with heart failure III–IV according to NYHA FC, waiting for a heart transplant, aged 22 to 73 years, 48 males and 11 females. 41 recipient (30 men and 11 women had dilated cardiomyopathy, 18 – coronary heart disease (CHD. The concentration of VEGF-A, VEGF-D, PlGF, PDGF-BB, FGF, sCD40L, MCP-1 was measured using xMAP technology, the sets of reagents Simplex ProcartaPlexTM (Affymetrix, USA. Results. There are four levels of seven biomarkers of neoangiogenesis and inflammation method for multiplex analysis in patients with heart failure. A year after transplantation, the mean levels of biomarkers VEGF-A (p = 0.001, PDGF-BB (p = 0.018, MCP-1 (p = 0.003 was significantly decreased, and the others had a tendency to decrease relative to the level before transplantation. It was shown individual differences of levels of VEGF-A, VEGF-D and PlGF before and after transplantation. There were found different dynamics of the concentrations of biomarkers and growth factors before and after heart transplantation in patients with cardiovascular complications and without them. Conclusion. Multiplex analysis allows to measure the concentration range of analyte biomarkers of neoangiogenesis, inflammation in one sample of blood serum of patients with severe heart failure and after transplantation. There are marked individual differences in the concentration of biomarkers in different clinical situations that may have clinical significance in the conduct and supervision of recipients after transplantation.

Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification.

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Pillai, Indulekha C L; Li, Shen; Romay, Milagros; Lam, Larry; Lu, Yan; Huang, Jie; Dillard, Nathaniel; Zemanova, Marketa; Rubbi, Liudmilla; Wang, Yibin; Lee, Jason; Xia, Ming; Liang, Owen; Xie, Ya-Hong; Pellegrini, Matteo; Lusis, Aldons J; Deb, Arjun

2017-02-02

Mammalian tissues calcify with age and injury. Analogous to bone formation, osteogenic cells are thought to be recruited to the affected tissue and induce mineralization. In the heart, calcification of cardiac muscle leads to conduction system disturbances and is one of the most common pathologies underlying heart blocks. However the cell identity and mechanisms contributing to pathological heart muscle calcification remain unknown. Using lineage tracing, murine models of heart calcification and in vivo transplantation assays, we show that cardiac fibroblasts (CFs) adopt an osteoblast cell-like fate and contribute directly to heart muscle calcification. Small-molecule inhibition of ENPP1, an enzyme that is induced upon injury and regulates bone mineralization, significantly attenuated cardiac calcification. Inhibitors of bone mineralization completely prevented ectopic cardiac calcification and improved post injury heart function. Taken together, these findings highlight the plasticity of fibroblasts in contributing to ectopic calcification and identify pharmacological targets for therapeutic development. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison of Two Xenograft Materials Used in Sinus Lift Procedures: Material Characterization and In Vivo Behavior

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María Piedad Ramírez Fernández

2017-06-01

Full Text Available Detailed information about graft material characteristic is crucial to evaluate their clinical outcomes. The present study evaluates the physico-chemical characteristics of two xenografts manufactured on an industrial scale deproteinized at different temperatures (non-sintered and sintered in accordance with a protocol previously used in sinus lift procedures. It compares how the physico-chemical properties influence the material’s performance in vivo by a histomorphometric study in retrieved bone biopsies following maxillary sinus augmentation in 10 clinical cases. An X-ray diffraction analysis revealed the typical structure of hydroxyapatite (HA for both materials. Both xenografts were porous and exhibited intraparticle pores. Strong differences were observed in terms of porosity, crystallinity, and calcium/phosphate. Histomorphometric measurements on the bone biopsies showed statistically significant differences. The physic-chemical assessment of both xenografts, made in accordance with the protocol developed on an industrial scale, confirmed that these products present excellent biocompatibilitity, with similar characteristics to natural bone. The sintered HA xenografts exhibited greater osteoconductivity, but were not completely resorbable (30.80 ± 0.88% residual material. The non-sintered HA xenografts induced about 25.92 ± 1.61% of new bone and a high level of degradation after six months of implantation. Differences in the physico-chemical characteristics found between the two HA xenografts determined a different behavior for this material.

In search of better spermatogonial preservation by supplementation of cryopreserved human immature testicular tissue xenografts with N-acetylcysteine and testosterone

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Jonathan ePoels

2014-12-01

Full Text Available Controlled slow-freezing is the procedure currently applied for immature testicular tissue cryobanking in clinical practice. Vitrification has been proposed as a promising alternative, with a view to better preserving spermatogonial stem cells for future fertility restoration by autografting in young boys suffering from cancer. It appears that besides the potential influence of the cryopreservation technique used, the transplantation procedure itself has a significant impact on spermatogonial loss observed in ITT xenografts. Eighteen immature testicular tissue pieces issuing from 6 patients aged 2-15 years were used. Fragments of fresh tissue (serving as ungrafted controls, frozen-thawed tissue, frozen-thawed tissue supplemented with N-acetylcysteine and frozen-thawed tissue supplemented with testosterone xenografted to nude mice for 5 days were compared. Upon graft removal, histological and immunohistochemical analyses were performed to evaluate spermatogonia, intratubular proliferation and intrinsic and extrinsic apoptosis. A significant decrease in the integrity of intact seminiferous tubules was found in all three grafted groups. Spermatogonia were observed by immunohistochemistry in all grafted groups, with recovery rates of 67%, 63% and 53% respectively for slow-frozen tissue, slow-frozen tissue supplemented with N-acetylcysteine and slow-frozen tissue supplemented with testosterone. Apoptosis evidenced by active caspase-3 and TUNEL was similar in all grafts. The study is limited by the low availability of immature testicular tissue samples of human origin, and no clear impact of graft supplementation was found. The mouse xenotransplantation model needs to be refined to investigate human spermatogenesis in human immature testicular tissue grafts.

Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model.

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Kurundkar, Deepali; Srivastava, Ritesh K; Chaudhary, Sandeep C; Ballestas, Mary E; Kopelovich, Levy; Elmets, Craig A; Athar, Mohammad

2013-01-15

Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. Copyright © 2012 Elsevier Inc. All rights reserved.

Uptake of perfusion imaging agents by transplanted hearts: an experimental study in rats

International Nuclear Information System (INIS)

Bergsland, J.; Carr, E.A. Jr.; Carroll, M.; Feldman, M.J.; Kung, H.; Wright, J.R.

1989-01-01

There is a need for a reliable noninvasive marker of rejection in transplanted hearts. Endomyocardial biopsy is now the universally accepted diagnostic method of choice, but the invasiveness of the procedure and the limited size of the sample obtained makes this method far from ideal. As coronary blood flow may be expected to decrease during acute rejection, there has been interest in thallium-201 chloride (T1), a perfusion marker, as an imaging agent for diagnosing cardiac rejection. Hexakis(t-butylisonitrile)-technetium (Tc-TBI) is a representative of a new class of radiopharmaceuticals proposed as perfusion markers. We have compared the uptake of these imaging agents in a rat model of cardiac transplantation. Uptake of Tc-TBI as well as of T1 was significantly lower in rejecting than in nonrejecting hearts. This change was found in both left (LV) and right (RV) ventricles. Allografts in animals treated with cyclosporine (CyA) showed less severe rejection and higher uptakes of both imaging agents as compared to unmodified rejection. Our results suggest that perfusion imaging with these radionuclides is a potentially useful approach to the problem of detecting allograft rejection

Halofuginone suppresses growth of human uterine leiomyoma cells in a mouse xenograft model.

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Koohestani, Faezeh; Qiang, Wenan; MacNeill, Amy L; Druschitz, Stacy A; Serna, Vanida A; Adur, Malavika; Kurita, Takeshi; Nowak, Romana A

2016-07-01

Does halofuginone (HF) inhibit the growth of human uterine leiomyoma cells in a mouse xenograft model? HF suppresses the growth of human uterine leiomyoma cells in a mouse xenograft model through inhibiting cell proliferation and inducing apoptosis. Uterine leiomyomas are the most common benign tumors of the female reproductive tract. HF can suppress the growth of human uterine leiomyoma cells in vitro. The mouse xenograft model reflects the characteristics of human leiomyomas. Primary leiomyoma smooth muscle cells from eight patients were xenografted under the renal capsule of adult, ovariectomized NOD-scid IL2Rγ(null) mice (NSG). Mice were treated with two different doses of HF or vehicle for 4 weeks with six to eight mice per group. Mouse body weight measurements and immunohistochemical analysis of body organs were carried out to assess the safety of HF treatment. Xenografted tumors were measured and analyzed for cellular and molecular changes induced by HF. Ovarian steroid hormone receptors were evaluated for possible modulation by HF. Treatment of mice carrying human UL xenografts with HF at 0.25 or 0.50 mg/kg body weight for 4 weeks resulted in a 35-40% (P leiomyoma cells in an in vivo model, HF was administered to mice whose tolerance and metabolism of the drug may differ from that in humans. Also, the longer term effects of HF treatment are yet unclear. The results of this study showing the effectiveness of HF in reducing UL tumor growth by interfering with the main cellular processes regulating cell proliferation and apoptosis are in agreement with previous studies on the effects of HF on other fibrotic diseases. HF can be considered as a candidate for reducing the size of leiomyomas, particularly prior to surgery. This project was funded by NIH PO1HD057877 and R01 HD064402. Authors report no competing interests. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights

Influence of prostaglandin analogues on epithelial cell proliferation and xenograft growth.

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Tutton, P J; Barkla, D H

1980-01-01

The influence of two prostaglandin (PG) analogues, 16,16-dimethyl PG E2 and 16,16-dimethyl PG F2 alpha and of the cyclo-oxygenase inhibitor, flurbiprofen, on epithelial cell proliferation was assessed using a stathmokinetic technique. The epithelia examined were those of the jejunal crypts, the colonic crypts and that of dimethylhydrazine-induced adenocarcinomas of rat colon. The influence of the two prostaglandin analogues, and of flurbiprofen, on the growth of a human colorectal tumour propagated as xenografts in immune-deprived mice was also assessed. The PG E2 analogue transiently inhibited xenograft growth, but was without effect on the mitotic rate in the rat tissues. The PG F2 alpha analogue was also found to inhibit xenograft growth but, unlike the PG E2 analogue, it was found to be a strong inhibitor of cell proliferation in rat colonic tumours, and an accelerator of proliferation in jejunal-crypt cells. The only statistically significant effect of flurbiprofen was to accelerate cell division in the rat colonic tumours.

Heart transplantation in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

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Groh, Matthieu; Masciocco, Gabriella; Kirchner, Elizabeth; Kristen, Arnt; Pellegrini, Carlo; Varnous, Shaïda; Bortman, Guillermo; Rosenberg, Mark; Brucato, Antonio; Waterworth, Paul; Bonacina, Edgardo; Facchetti, Fabio; Calabrese, Leonard; Gregorini, Gina; Scali, Juan Jose; Starling, Randall; Frigerio, Maria; D'Armini, Andrea Maria; Guillevin, Loïc

2014-08-01

Heart involvement is the leading cause of death of patients with eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome) and is more frequent in anti-neutrophil cytoplasm antibody (ANCA)-negative patients. Post-transplant outcome has only been reported once. We conducted a retrospective international multicenter study. Patients satisfying the criteria of the American College of Rheumatology and/or revised Chapel Hill Consensus Conference Nomenclature were identified by collaborating vasculitis and transplant specialists, and the help of the Churg-Strauss Syndrome Association. Nine ANCA(-) patients who received transplants between October 1987 and December 2009 were identified. The vasculitis and cardiomyopathy diagnoses were concomitant for 5 patients and separated by 12 to 288 months for the remaining 4 patients. Despite ongoing immunosuppression, histologic examination of 7 (78%) patients' explanted hearts showed histologic patterns suggestive of active vasculitis. The overall 5-year survival rate was low (57%), but rose to 80% when considering only the 6 patients transplanted during the last decade. After survival lasting 3 to 60 months, 4 (44%) patients died sudden deaths. The search for EGPA-related cardiomyopathy is mandatory early in the course of this type of vasculitis. Indeed, prompt treatment with corticosteroids and cyclophosphamide may achieve restore cardiac function. Most patients in this series were undertreated. For patients with refractory EGPA, heart transplantation should be performed, which carries a fair prognosis. No optimal immunosuppressive strategy has yet been identified. Copyright © 2014 International Society for Heart and Lung Transplantation. All rights reserved.

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

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

2017-08-01

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

Matrigel alters the pathophysiology of orthotopic human breast adenocarcinoma xenografts with implications for nanomedicine evaluation.

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Shuhendler, Adam J; Prasad, Preethy; Cai, Ping; Hui, Kelvin K W; Henderson, Jeffrey T; Rauth, Andrew M; Wu, Xiao Yu

2013-08-01

Matrigel, a mouse sarcoma-derived basement membrane protein mixture, is frequently used to facilitate human tumor xenograft growth in rodents. Despite its known effects on tumor growth and metastasis, its impact on tumor pathophysiology and preclinical evaluation of nanomedicines in tumor xenografts has not been reported previously. Herein bilateral MDA435 tumors were established orthotopically with (Mat+) or without (Mat-) co-injection of Matrigel. Tumor perfusion, morphology and nanoparticle retention were evaluated. As compared to Mat- tumors, Mat+tumors exhibited enhanced vascular perfusion and lymphatic flow, greater blood vessel and lymphatic growth within the tumor core, and more deformation and collapse of lymphatics in tumor-associated lymph nodes. These changes were accompanied by reduced nanoparticle retention in Mat+tumors. The results suggest that Matrigel is not a passive medium for tumor growth, but rather significantly alters long-term tumor architecture. These findings have significant implications for the evaluation of therapeutic nanomedicine in xenograft mouse models. Matrigel is utilized in facilitating human tumor xenograft growth in rodents. The authors demonstrate that Matrigel is not a passive medium for tumor growth; instead it significantly alters long-term tumor architecture, with major implications in the evaluation of therapeutic nanomedicine in xenograft mouse models. Copyright © 2013 Elsevier Inc. All rights reserved.

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

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

1993-01-01

Transplantation has become an accepted treatment of many cardiac end-stage diseases. Acute cellular rejection accounts for 15% to 20% of all graft failures. The first grading system of acute cellular rejection, the Stanford Classification, was introduced in 1979, and since then many other grading...

Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure

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Ullmann Cris

2006-06-01

Full Text Available Abstract Background Since only little is known on stem cell therapy in non-ischemic heart failure we wanted to know whether a long-term improvement of cardiac function in non-ischemic heart failure can be achieved by stem cell transplantation. Methods White male New Zealand rabbits were treated with doxorubicine (3 mg/kg/week; 6 weeks to induce dilative non-ischemic cardiomyopathy. Thereafter, we obtained autologous bone marrow stem cells (BMSC and injected 1.5–2.0 Mio cells in 1 ml medium by infiltrating the myocardium via a left anterolateral thoracotomy in comparison to sham-operated rabbits. 4 weeks later intracardiac contractility was determined in-vivo using a Millar catheter. Thereafter, the heart was excised and processed for radioligand binding assays to detect β1- and β2-adrenoceptor density. In addition, catecholamine plasma levels were determined via HPLC. In a subgroup we investigated cardiac electrophysiology by use of 256 channel mapping. Results In doxorubicine-treated animals β-adrenoceptor density was significantly down-regulated in left ventricle and septum, but not in right ventricle, thereby indicating a typical left ventricular heart failure. Sham-operated rabbits exhibited the same down-regulation. In contrast, BMSC transplantation led to significantly less β-adrenoceptor down-regulation in septum and left ventricle. Cardiac contractility was significantly decreased in heart failure and sham-operated rabbits, but was significantly higher in BMSC-transplanted hearts. Norepinephrine and epinephrine plasma levels were enhanced in heart failure and sham-operated animals, while these were not different from normal in BMSC-transplanted animals. Electrophysiological mapping revealed unaltered electrophysiology and did not show signs of arrhythmogeneity. Conclusion BMSC transplantation improves sympathoadrenal dysregualtion in non-ischemic heart failure.

Human reconstructed skin xenografts on mice to model skin physiology.

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Salgado, Giorgiana; Ng, Yi Zhen; Koh, Li Fang; Goh, Christabelle S M; Common, John E

Xenograft models to study skin physiology have been popular for scientific use since the 1970s, with various developments and improvements to the techniques over the decades. Xenograft models are particularly useful and sought after due to the lack of clinically relevant animal models in predicting drug effectiveness in humans. Such predictions could in turn boost the process of drug discovery, since novel drug compounds have an estimated 8% chance of FDA approval despite years of rigorous preclinical testing and evaluation, albeit mostly in non-human models. In the case of skin research, the mouse persists as the most popular animal model of choice, despite its well-known anatomical differences with human skin. Differences in skin biology are especially evident when trying to dissect more complex skin conditions, such as psoriasis and eczema, where interactions between the immune system, epidermis and the environment likely occur. While the use of animal models are still considered the gold standard for systemic toxicity studies under controlled environments, there are now alternative models that have been approved for certain applications. To overcome the biological limitations of the mouse model, research efforts have also focused on "humanizing" the mice model to better recapitulate human skin physiology. In this review, we outline the different approaches undertaken thus far to study skin biology using human tissue xenografts in mice and the technical challenges involved. We also describe more recent developments to generate humanized multi-tissue compartment mice that carry both a functioning human immune system and skin xenografts. Such composite animal models provide promising opportunities to study drugs, disease and differentiation with greater clinical relevance. Copyright © 2017 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Combined administration of mesenchymal stem cells overexpressing IGF-1 and HGF enhances neovascularization but moderately improves cardiac regeneration in a porcine model.

Science.gov (United States)

Gómez-Mauricio, Guadalupe; Moscoso, Isabel; Martín-Cancho, María-Fernanda; Crisóstomo, Verónica; Prat-Vidal, Cristina; Báez-Díaz, Claudia; Sánchez-Margallo, Francisco M; Bernad, Antonio

2016-07-16

Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are among the most promising growth factors for promoting cardiorepair. Here, we evaluated the combination of cell- and gene-based therapy using mesenchymal stem cells (MSC) genetically modified to overexpress IGF-1 or HGF to treat acute myocardial infarction (AMI) in a porcine model. Pig MSC from adipose tissue (paMSC) were genetically modified for evaluation of different therapeutic strategies to improve AMI treatment. Three groups of infarcted Large White pigs were compared (I, control, non-transplanted; II, transplanted with paMSC-GFP (green fluorescent protein); III, transplanted with paMSC-IGF-1/HGF). Cardiac function was evaluated non-invasively using magnetic resonance imaging (MRI) for 1 month. After euthanasia and sampling of the animal, infarcted areas were studied by histology and immunohistochemistry. Intramyocardial transplant in a porcine infarct model demonstrated the safety of paMSC in short-term treatments. Treatment with paMSC-IGF-1/HGF (1:1) compared with the other groups showed a clear reduction in inflammation in some sections analyzed and promoted angiogenic processes in ischemic tissue. Although cardiac function parameters were not significantly improved, cell retention and IGF-1 overexpression was confirmed within the myocardium. The simultaneous administration of IGF-1- and HGF-overexpressing paMSC appears not to promote a synergistic effect or effective repair. The combined enhancement of neovascularization and fibrosis in paMSC-IGF-1/HGF-treated animals nonetheless suggests that sustained exposure to high IGF-1 + HGF levels promotes beneficial as well as deleterious effects that do not improve overall cardiac regeneration.

First pediatric transatlantic air ambulance transportation on a Berlin Heart EXCOR left ventricular assist device as a bridge to transplantation.

Science.gov (United States)

Tissot, Cecile; Buchholz, Holger; Mitchell, Max B; da Cruz, Eduardo; Miyamoto, Shelley D; Pietra, Bill A; Charpentier, Arnaud; Ghez, Olivier

2010-03-01

Mechanical circulatory devices are indicated in patients with refractory cardiac failure as a bridge to recovery or to transplantation. Whenever required, transportation while on mechanical support is a challenge and still limited by technical restrictions or distance. We report the first pediatric case of transatlantic air transportation on a Berlin Heart EXCOR ventricular assist device (Berlin Heart, Berlin, Germany) of a 13-yr-old American female who presented in cardiogenic shock with severe systolic dysfunction while vacationing in France. Rapid hemodynamic deterioration occurred despite maximal medical treatment, and she was supported initially with extracorporeal membrane oxygenation converted to a Berlin Heart EXCOR left ventricular assist device. Long-distance air transportation of the patient was accomplished 3 wks after implantation from Marseille, France, to Denver, Colorado. No adverse hemodynamic effects were encountered during the 13.5-hr flight (8770 km). The patient did not recover sufficient cardiac function and underwent successful orthotopic heart transplantation 3 months after the initial event. Our experience suggests that long-distance air transportation of pediatric patients using the Berlin Heart EXCOR mobile unit as a bridge to recovery or transplantation is feasible and appears safe.

Machine Perfusion Versus Cold Storage for the Preservation of Kidneys Donated After Cardiac Death A Multicenter, Randomized, Controlled Trial

NARCIS (Netherlands)

Jochmans, Ina; Moers, Cyril; Smits, Jacqueline M.; Leuvenink, Henri G. D.; Treckmann, Juergen; Paul, Andreas; Rahmel, Axel; Squifflet, Jean-Paul; van Heurn, Ernest; Monbaliu, Diethard; Ploeg, Rutger J.; Pirenne, Jacques

2010-01-01

Objective: Hypothermic machine perfusion may improve outcome after transplantation of kidneys donated after cardiac death (DCD), but no sufficiently powered prospective studies have been reported. Because organ shortage has led to an increased use of DCD kidneys, we aimed to compare hypothermic

Long-term results of vaginal repairs with and without xenograft reinforcement

DEFF Research Database (Denmark)

Mouritsen, Lone; Kronschnabl, M.; Lose, G.

2010-01-01

The aim of this paper is to study if xenograft reinforcement of vaginal repair reduces recurrence of prolapse. Results 1-5 years after vaginal repair were studied in 41 cases with xenograft and in 82 matched controls without. Symptoms were evaluated by a validated questionnaire and anatomy...... in 3% of cases and 12% controls. None of the recurrence rates was significantly different for cases versus controls. No vaginal erosions were seen. Previous surgery was a significant risk factor with odds ratio 7.3 for another recurrence. Recurrence rates defined by POPQ plus symptoms were low compared...

Impacto da variabilidade de peso na estabilidade metabólica dos pacientes transplantados cardíacos no Ceará Impact of weight variation on the metabolic stability of cardiac transplant patients in the state of Ceara

Directory of Open Access Journals (Sweden)

Daniele Maria de Oliveira Carlos

2008-04-01

Full Text Available FUNDAMENTO: As alterações de peso após o transplante cardíaco (TC freqüentemente ocorrem e aumentam os riscos de doenças secundárias. OBJETIVO: Determinar o impacto da variabilidade do peso nos níveis séricos de glicose, triglicérides, colesterol total e frações dos pacientes transplantados cardíacos. MÉTODOS: Estudo retrospectivo documental realizado com 82 pacientes adultos submetidos a TC entre outubro de 1997 e dezembro de 2005 no Ceará, sendo 83% do sexo masculino e a idade média de 45,06±12,04 anos. As variáveis estudadas foram o perfil biopatológico, o peso e o índice de massa corporal (IMC relacionadas às alterações bioquímico-metabólicas. Os dados foram descritos usando freqüências, medidas de tendência central, teste t de Student e coeficiente de correlação de Pearson. RESULTADOS: A média global do IMC aumentou de 23,77±3,68kg/m² antes do TC, para 25,48±3,92kg/m² no primeiro ano e para 28,38±4,97kg/m² no quinto. Os pacientes com sobrepeso/obesidade (IMC > 25 kg/m² apresentaram valores médios de glicose, colesterol total, lipoproteína de baixa densidade (LDL e triglicérides maiores que os pacientes com eutrofia/desnutrição (IMC BACKGROUND: Weight alterations post cardiac transplant (CT frequently occur and increase the risks of secondary diseases. OBJECTIVE: This study aimed at determining the impact of weight variability on serum levels of glucose, triglycerides, total cholesterol and its fractions of cardiac transplant patients. METHODS: This was a retrospective documental study held with 82 patients submitted to CT between October, 1997 and December, 2005 in Ceará, Brazil. 83% were male and the average age was 45.06±12.04 years. The studied variables were: biopathology profile, the weight and the body mass index (BMI related to the biochemical-metabolic alterations and to the survival. Data were described using frequencies, measures of central tendency, t-Student test and Pearson

ISSLS PRIZE IN BASIC SCIENCE 2018: Growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model.

Science.gov (United States)

Miyazaki, Shingo; Diwan, Ashish D; Kato, Kenji; Cheng, Kevin; Bae, Won C; Sun, Yang; Yamada, Junichi; Muehleman, Carol; Lenz, Mary E; Inoue, Nozomu; Sah, Robert L; Kawakami, Mamoru; Masuda, Koichi

2018-04-01

To elucidate the effects of growth differentiation factor-6 (GDF6) on: (i) gene expression of inflammatory/pain-related molecules and structural integrity in the rabbit intervertebral disc (IVD) degeneration model, and (ii) sensory dysfunction and changes in pain-marker expression in dorsal nerve ganglia (DRGs) in the rat xenograft radiculopathy model. Forty-six adolescent rabbits received anular-puncture in two non-consecutive lumbar IVDs. Four weeks later, phosphate-buffered saline (PBS) or GDF6 (1, 10 or 100 µg) was injected into the nucleus pulposus (NP) of punctured discs and followed for 4 weeks for gene expression analysis and 12 weeks for structural analyses. For pain assessment, eight rabbits were sacrificed at 4 weeks post-injection and NP tissues of injected discs were transplanted onto L5 DRGs of 16 nude rats to examine mechanical allodynia. The rat DRGs were analyzed immunohistochemically. In GDF6-treated rabbit NPs, gene expressions of interleukin-6, tumor necrosis factor-α, vascular endothelial growth factor, prostaglandin-endoperoxide synthase 2, and nerve growth factor were significantly lower than those in the PBS group. GDF6 injections resulted in partial restoration of disc height and improvement of MRI disc degeneration grades with statistical significance in rabbit structural analyses. Allodynia induced by xenograft transplantation of rabbit degenerated NPs onto rat DRGs was significantly reduced by GDF6 injection. Staining intensities for ionized calcium-binding adaptor molecule-1 and calcitonin gene-related peptide in rat DRGs of the GDF6 group were significantly lower than those of the PBS group. GDF6 injection may change the pathological status of degenerative discs and attenuate degenerated IVD-induced pain.

Hemodynamic and ADH responses to central blood volume shifts in cardiac-denervated humans

Science.gov (United States)

Convertino, V. A.; Thompson, C. A.; Benjamin, B. A.; Keil, L. C.; Savin, W. M.; Gordon, E. P.; Haskell, W. L.; Schroeder, J. S.; Sandler, H.

1990-01-01

Hemodynamic responses and antidiuretic hormone (ADH) were measured during body position changes designed to induce blood volume shifts in ten cardiac transplant recipients to assess the contribution of cardiac and vascular volume receptors in the control of ADH secretion. Each subject underwent 15 min of a control period in the seated posture, then assumed a lying posture for 30 min at 6 deg head down tilt (HDT) followed by 20 min of seated recovery. Venous blood samples and cardiac dimensions (echocardiography) were taken at 0 and 15 min before HDT, 5, 15, and 30 min of HDT, and 5, 15, and 30 min of seated recovery. Blood samples were analyzed for hematocrit, plasma osmolality, plasma renin activity (PRA), and ADH. Resting plasma volume (PV) was measured by Evans blue dye and percent changes in PV during posture changes were calculated from changes in hematocrit. Heart rate (HR) and blood pressure (BP) were recorded every 2 min. Results indicate that cardiac volume receptors are not the only mechanism for the control of ADH release during acute blood volume shifts in man.

Intraoperative hemodynamic monitoring during liver transplantation: goals and devices

DEFF Research Database (Denmark)

Nissen, Peter; Frederiksen, H J; Secher, N H

2010-01-01

With the introduction of orthotopic liver transplantation (OLT) almost 40 years ago, changes in the cardiovascular system that manifest during the different phases of the operation combined, sometimes with massive hemorrhage in likely critically ill patients have been a challenge. Here hemodynamic...... monitoring of the patients during OLT is addressed with focus on maintaining the patients' central blood volume (CBV) and methods and devices that can serve that purpose are listed. It is considered that a stable CBV maintains cerebral blood flow and oxygenation and thereby the well-being of the patient......, while even a small reduction in blood pressure affects cerebral blood flow and oxygenation if it reflects a reduced CBV and thereby cardiac output. In that regard it is accepted that for the patient going through OLT cardiac output (~8 L/min-1) and also venous oxygen saturation (~85%) are larger than...

Dynamic low dose I-123-iodophenylpentadecanoic acid metabolic cardiac imaging

International Nuclear Information System (INIS)

Murray, G.L.; Magill, H.L.; Schad, N.C.

1993-01-01

Recognition of stunned and hibernating myocardium is essential in this era of cardiac revascularization. Positron emission tomography (PET) accurately identifies viability but is costly and unavailable to most patients. Dynamic low dose I-123-iodophenylpentadecanoic acid (IPPA) metabolic cardiac imaging is a potentially cost-effective alternative to PET. Using transmural myocardial biopsies obtained during coronary bypass surgery as the viability gold standard, resting IPPA imaging agreed with 39/43 (91%) biopsies, with a sensitivity for viability of 33/36(92%) and a specificity of 6/7 (86%) in patients with severe ischemic cardiomyopathy. Eighty percent of IPPA viable, infarcted segments improved wall motion postoperatively. Furthermore, when compared to reinjection thallium (SPECT-Tl) scans after myocardial infarction, there was IPPA-Tl concordance in 27/35 (77%)(Kappa=0.536, p=0.0003). Similar to PET, IPPA demonstrated more viability than SPECT-Tl, 26/35 (74%) vs. 18/35 (51%)(p=0.047). Finally, when compared to transvenous endomyocardial biopsy for detecting rejection following cardiac transplantation, IPPA sensitivity for ≥Grade II rejection was 100%, and IPPA screening assessment for the necessity of biopsy could result in a 31% cost-savings. Therefore, IPPA metabolic cardiac imaging is a safe, inexpensive technique with a promising future. (author)

Transplante de intestino delgado Small intestine transplantation

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Flávio Henrique Ferreira Galvão

2003-06-01

Full Text Available RACIONAL: Avanços da biotecnologia e o desenvolvimento de novas drogas imunossupressoras melhoraram os resultados do transplante de intestino delgado. Esse transplante é atualmente indicado para casos especiais da falência intestinal. OBJETIVO: A presente revisão realça os recentes desenvolvimentos na área do transplante de intestino delgado. MATERIAL E MÉTODO: Mais de 600 publicações de transplante de intestino delgado foram revisadas. O desenvolvimento da pesquisa, novas estratégias de imunossupressão, monitorização do enxerto e do receptor, e avanços na técnica cirúrgica são discutidos. RESULTADOS: Realizaram-se cerca de 700 transplante de intestino delgado em 55 centros: 44% intestino-fígado, 41% enxerto intestinal isolado e 15% transplante multivisceral. Rejeição e infecção são as principais limitações desse transplante. Sobrevida de 5 anos na experiência internacional é de 46% para o transplante de intestino isolado, 43% para o intestino-fígado e de cerca de 30% para o transplante multivisceral. Sobrevidas prolongadas são mais freqüentes nos centros com maior experiência. Em série de 165 transplantes intestinais na Universidade de Pittsburgh, PA, EUA, foi relatada sobrevida do paciente maior do que 75% no primeiro ano, 54% em 5 anos e 42% em 10 anos. Mais de 90% desses pacientes assumem dieta oral irrestrita. CONCLUSÃO: O transplante de intestino delgado evoluiu de estratégia experimental para uma alternativa viável no tratamento da falência intestinal permanente. Promover o refinamento da terapia imunossupressora, do manejo e prevenção de infecções, da técnica cirúrgica e da indicação e seleção adequada dos pacientes é crucial para melhorar a sobrevida desse transplante.BACKGROUND: Significant progress has been made in clinical small bowel transplantation over the last decade mainly due advances in biotechnology and new immunosuppressive regiments. This transplantation has now been indicated

Suicidal hanging donors for lung transplantation: Is this chapter still closed? Midterm experience from a single center in United Kingdom.

Science.gov (United States)

Ananiadou, Olga; Schmack, Bastian; Zych, Bartlomiej; Sabashnikov, Anton; Garcia-Saez, Diana; Mohite, Prashant; Weymann, Alexander; Mansur, Ashham; Zeriouh, Mohamed; Marczin, Nandor; De Robertis, Fabio; Simon, Andre Rüdiger; Popov, Aron-Frederik

2018-04-01

In the context of limited donor pool in cardiothoracic transplantation, utilization of organs from high risk donors, such as suicidal hanging donors, while ensuring safety, is under consideration. We sought to evaluate the outcomes of lung transplantations (LTx) that use organs from this group.Between January 2011 and December 2015, 265 LTx were performed at our center. Twenty-two recipients received lungs from donors after suicidal hanging (group 1). The remaining 243 transplantations were used as a control (group 2). Analysis of recipient and donor characteristics as well as outcomes was performed.No statistically significant difference was found in the donor characteristics between analyzed groups, except for higher incidence of cardiac arrest, younger age and smoking history of hanging donors (P donor cause of death is not associated with poor mid-term survival or chronic lung allograft dysfunction following transplantation. These results encourage assessment of lungs from hanging donors, and their consideration for transplantation.

HEPATIC FUNCTION AFTER GENETICALLY-ENGINEERED PIG LIVER TRANSPLANTATION IN BABOONS

Science.gov (United States)

Ekser, Burcin; Echeverri, Gabriel J.; Hassett, Andrea Cortese; Yazer, Mark H.; Long, Cassandra; Meyer, Michael; Ezzelarab, Mohamed; Lin, Chih Che; Hara, Hidetaka; van der Windt, Dirk J.; Dons, Eefje M.; Phelps, Carol; Ayares, David; Cooper, David K.C.; Gridelli, Bruno

2010-01-01

Background If ‘bridging’ to allotransplantation is to be achieved by a pig liver xenograft, adequate hepatic function needs to be assured. Methods We have studied hepatic function in baboons after transplantation of livers from α1,3-galactosyltransferase gene-knockout (GTKO,n=1) or GTKO pigs transgenic for CD46 (GTKO/CD46,n=5). Monitoring was by liver function tests and coagulation parameters. Pig-specific proteins in the baboon serum/plasma were identified by Western blot. In 4 baboons, coagulation factors were measured. The results were compared with values from healthy humans, baboons, and pigs. Results Recipient baboons died or were euthanized after 4-7 days following internal bleeding associated with profound thrombocytopenia. However, parameters of liver function, including coagulation, remained in the near-normal range, except for some cholestasis. Western blot demonstrated that pig proteins (albumin, fibrinogen, haptoglobin, plasminogen) were produced by the liver from day 1. Production of several pig coagulation factors was confirmed. Conclusions After the transplantation of genetically-engineered pig livers into baboons (1) many parameters of hepatic function, including coagulation, were normal or near-normal; (2) there was evidence for production of pig proteins, including coagulation factors, and (3) these appeared to function adequately in baboons, though inter-species compatibility of such proteins remains to be confirmed. PMID:20606605

Liver transplant

Science.gov (United States)

Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

Hair Transplants

Science.gov (United States)

... Search Skin Experts Skin Treatments Hair Transplants Share » HAIR TRANSPLANTS Before (left) and after (right) - front of ... transplant. Photo courtesy of N. Sadick What are hair transplants? In punch transplanting, a plug containing hair ...

Cellular basis for accumulation of 111In-labeled leukocytes and platelets in rejecting cardiac allografts: concise communication

International Nuclear Information System (INIS)

Wang, T.S.; Oluwole, S.; Fawwaz, R.A.; Wolff, M.; Kuromoto, N.; Satake, K.; Hardy, M.A.; Alderson, P.O.

1982-01-01

Biodistribution and imaging studies in rats showed that 111 In-labeled leukocytes and platelets accumulate progressively with time after transplantation in cardiac allografts undergoing rejection, but do not accumulate in normal syngeneic heart grafts. Maximum heart allograft-to-blood ratios of 9:1 were obtained, and allograft-to-native heart ratios of 17:1. Microscopic studies of the rejecting cardiac allografts showed that histologic findings paralleled the cellular changes predicted by the radionuclide studies. Intravenously administered 67 Ga citrate and /sup 99m/Tc sulfur colloid failed to show significant accumulation in rejecting grafts. The findings suggest that cellular rejection, rather than nonspecific inflammatory changes, is the primary basis for accumulation of 111 In leukocytes and platelets in rejecting cardiac allografts

Cellular basis for accumulation of In-111-labeled leukocytes and platelets in rejecting cardiac allografts: concise communication

International Nuclear Information System (INIS)

Wang, T.S.T.; Oluwole, S.; Fawwaz, R.A.; Wolff, M.; Kuromoto, N.; Satake, K.; Hardy, M.A.; Alderson, P.O.

1982-01-01

Biodistribution and imaging studies in rats showed that In-111-labeled leukocytes and platelets accumulate progressively with time after transplantation in cardiac allografts undergoing rejection, but do not accumulate in normal syngeneic heart grafts. Maximum heart allograft-to-blood ratios of 9:1 were obtained, and allograft-to-native heart ratios of 17:1. Microscopic studies of the rejecting cardiac allografts showed that histologic findings paralleled the cellular changes predicted by the radionuclide studies. Intravenously administered Ga-67 citrate and Tc-99m sulfur colloid failed to show significant accumulation in rejecting grafts. The findings suggest that cellular rejection, rather than nonspecific inflammatory changes, is the primary basis for accumulation of In-111 leukocytes and platelets in rejecting cardiac allografts

Exosomal secretion of cytoplasmic prostate cancer xenograft-derived proteins

NARCIS (Netherlands)

F.H. Jansen (Flip); J. Krijgsveld (Jeroen); A.L. Rijswijk (Angelique); G.J.C.M. van den Bemd (Gert-Jan); M.S. van den Berg (Mirella); W.M. van Weerden (Wytske); R. Willemsen (Rob); L.J.M. Dekker (Lennard); T.M. Luider (Theo); G.W. Jenster (Guido)

2009-01-01

textabstractNovel markers for prostate cancer (PCa) are needed because current established markers such as prostate-specific antigen lack diagnostic specificity and prognostic value. Proteomics analysis of serum from mice grafted with human PCa xenografts resulted in the identification of 44

Localization of indium-111 in human malignant tumor xenografts and control by chelators

International Nuclear Information System (INIS)

Watanabe, Naoyuki; Oriuchi, Noboru; Endo, Keigo; Inoue, Tomio; Tanada, Shuji; Murata, Hajime; Kim, E. Edmund; Sasaki, Yasuhito

1999-01-01

The kinetics of soluble indium-111 ( 111 In) in human malignant tumor xenografts and cells was investigated in combination with chelators. Firstly, without chelator, the kinetics of 111 In-chloride was investigated in vitro and in vivo using four human malignant neuroblastoma SK-N-MC, pulmonary papillary adenocarcinoma NCI-H441, pulmonary squamous cell carcinoma PC 9, and colon adenocarcinoma LS 180 cells and xenografts. 111 In was incorporated into tumor cells in vitro to a maximum level during a 60-min incubation. A maximum level of radioactivity was demonstrated in vivo in four human malignant tumors xenografted into nude mice at 24 h postinjection of 111 In-chloride. Secondly, the effect of edetate calcium disodium (CaNa 2 EDTA) on radioactivity in 111 In-labeled tumors xenografts and cells was studied in vitro and in vivo. CaNa 2 EDTA significantly reduced 111 In-activity from the labeled tumor xenografts, whereas it had no affect on the radioactivity in the labeled cells. Thirdly, the effect of CaNa 2 EDTA on radioactivity in human malignant tumors xenografted into nude mice injected with 111 In-chloride was investigated. In one group of mice CaNa 2 EDTA administered intraperitoneally at 1, 22, 34, 46, 58, and 70 h after injection of 111 In-chloride (postadministration), the localization of 111 In at the tumors was significantly decreased at 72 h compared with the control in all four tumor types. In the other group of mice, CaNa 2 EDTA administered intraperitoneally at 12 and 1 h before injection of 111 In-chloride and 1, 22, 34, 46, 58, and 70 h postinjection (pre- and postadministration), the radioactivity of tumors was also significantly decreased at 72 h, and the reduction was greater than that with use of postadministration. In a comparative study, CaNa 3 DTPA had a more powerful effect than CaNa 2 EDTA. In conclusion, 111 In-activity in tumors consists of intracellular and extracellular components, and the extracellular 111 In may be cleared by

Immediate re-transplantation following early kidney transplant thrombosis.

LENUS (Irish Health Repository)

Phelan, Paul J

2012-02-01

Allograft thrombosis is a devastating early complication of renal transplantation that ultimately leads to allograft loss. We report here on our experience of nine cases of immediate re-transplantation following early kidney transplant thrombosis at a single centre between January 1990 and June 2009. The mean age was 42.9 years at time of transplant. For seven patients, the allograft thrombosis was their first kidney transplant and seven of the nine cases had a deceased donor transplant. The initial transplants functioned for a mean of 1.67 days and the patients received a second allograft at a mean of 3.1 days after graft failure. All of the re-transplants worked immediately. Four allografts failed after a mean of 52.5 months (2-155 months). Two of these died with a functioning allograft, one failed owing to chronic allograft nephropathy and one owing to persistent acute cellular rejection. The remaining five patients still have a functioning allograft after a mean of 101.8 months (7-187 months). One year allograft and patient survival after re-transplantation were 87.5% and 100% respectively (after 5 years, both were 57%). Immediate re-transplantation following early kidney transplant thrombosis can be a success. It may be considered in selected cases after allograft thrombosis.

Transplantes cardiopulmonar e pulmonar com doador em localidade distante Distant donor procurement for heart-lung and lung transplantation

Directory of Open Access Journals (Sweden)

Luis Sérgio Fragomeni

1988-12-01

Full Text Available Em situações específicas, os transplantes clínicos cardiopulmonar e pulmonar são, hoje, formas estabelecidas de tratamento para estágio final de doença cardiopulmonar e pulmonar. A obtenção de doadores adequados permanece o maior problema e a remoção de órgãos em localidades distantes é, hoje, uma necessidade. Embora muitos métodos de preservação pulmonar possam ser empregados, para períodos isquémicos de até 5 horas, a hipotermia e o uso de solução cardioplégica com infusão da solução de Collins modificada no tronco pulmonar tem sido método simples e eficiente para preservação do bloco coração-pulmão. Descrevemos, aqui, o método corrente que empregamos, com o qual os transplantes cardiopulmonar e pulmonar combinados foram sucedidos de excelente função cárdio-respiratória.In special situations, clinical heart-lung and lung transplantation are today established methods of therapy for end stage cardiopulmonary and pulmonary disease. Adequate donor availability remains a major problem and distant organ procurement is today a necessity. Although many methods of lung preservation can be used, for periods of up to 5 hours, hypothermic storage with cardioplegic arrest and pulmonary artery flush with modified Collins solution has proven to be a simple and reliable method of heart-lung preservation. We here describe our current method of heart-lung block protection, in which heart-lung and double lung transplantation were performed followed by excelent cardiac and pulmonary function.

Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.

Directory of Open Access Journals (Sweden)

Lorin Dodbiba

Full Text Available The high morbidity and mortality of patients with esophageal (E and gastro-esophageal junction (GEJ cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR, and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55 in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32. Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04 and older patients (p=0.01. Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.

Cardiac output-based fluid optimization for kidney transplant recipients: a proof-of-concept trial.

Science.gov (United States)

Corbella, Davide; Toppin, Patrick Jason; Ghanekar, Anand; Ayach, Nour; Schiff, Jeffery; Van Rensburg, Adrian; McCluskey, Stuart A

2018-04-10

Intravenous fluid management for deceased donor kidney transplantation is an important, modifiable risk factor for delayed graft function (DGF). The primary objective of this study was to determine if goal-directed fluid therapy using esophageal Doppler monitoring (EDM) to optimize stroke volume (SV) would alter the amount of fluid given. This randomized, proof-of-concept trial enrolled 50 deceased donor renal transplant recipients. Data collected included patient characteristics, fluid administration, hemodynamics, and complications. The EDM was used to optimize SV in the EDM group. In the control group, fluid management followed the current standard of practice. The groups were compared for the primary outcome of total intraoperative fluid administered. There was no difference in the mean (standard deviation) volume of intraoperative fluid administered to the 24 control and 26 EDM patients [2,307 (750) mL vs 2,675 (842) mL, respectively; mean difference, 368 mL; 95% confidence interval (CI), - 87 to + 823; P = 0.11]. The incidence of complications in the control and EDM groups was similar (15/24 vs 17/26, respectively; P = 0.99), as was the incidence of delayed graft failure (8/24 vs 11/26, respectively; P = 0.36). Goal-directed fluid therapy did not alter the volume of fluid administered or the incidence of complications. This proof-of-concept trial provides needed data for conducting a larger trial to determine the influence of fluid therapy on the incidence in DGF in deceased donor kidney transplantation. www.clinicaltrials.gov (NCT02512731). Registered 31 July 2015.

Xenograft tumors derived from malignant pleural effusion of the patients with non-small-cell lung cancer as models to explore drug resistance.

Science.gov (United States)

Xu, Yunhua; Zhang, Feifei; Pan, Xiaoqing; Wang, Guan; Zhu, Lei; Zhang, Jie; Wen, Danyi; Lu, Shun

2018-05-09

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions show dramatic responses to specific tyrosine kinase inhibitors (TKIs); however, after 10-12 months, secondary mutations arise that confer resistance. We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK- and EGFR-targeted TKIs crizotinib and osimertinib, respectively. Genotypes of patient biopsies and xenograft tumors were determined by whole exome sequencing (WES), and patients and xenograft-bearing mice received targeted treatment (crizotinib or osimertinib) accordingly. Xenograft mice were also treated for prolonged periods to identify whether the development of drug resistance and/or treatment responses were associated with tumor size. Finally, the pathology of patients biopsies and xenograft tumors were compared histologically. The histological characteristics and chemotherapy responses of xenograft tumors were similar to the actual patients. WES showed that the genotypes of the xenograft and patient tumors were similar (an echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) gene fusion (patient/xenograft: CTC15035 EML4-ALK ) and EGFR L858R and T790M mutations (patient/xenograft: CTC15063 EGFR L858R, T790M )). After continuous crizotinib or osimertinib treatment, WES data suggested that acquired ALK E1210K mutation conferred crizotinib resistance in the CTC15035 EML4-ALK xenograft, while decreased frequencies of EGFR L858R and T790M mutations plus the appearance of v-RAF murine sarcoma viral oncogene homolog B (BRAF) G7V mutations and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (PIK3C2A) A86fs frame shift mutations led to osimertinib resistance in the CTC15063 EGFR L858R, T790M xenografts. We successfully developed a new method of generating

Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts

Directory of Open Access Journals (Sweden)

Zhu Y

2014-12-01

Full Text Available Yin Zhu,1,* Ming Cheng,2,* Zhen Yang,3 Chun-Yan Zeng,3 Jiang Chen,3 Yong Xie,3 Shi-Wen Luo,3 Kun-He Zhang,3 Shu-Feng Zhou,4 Nong-Hua Lu1,31Department of Gastroenterology, 2Department of Orthopedics, 3Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China; 4Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA*These authors contributed equally to this workAbstract: Mesenchymal stem cells (MSCs have been recognized as promising delivery vehicles for gene therapy of tumors. Gastric cancer is the third leading cause of worldwide cancer mortality, and novel treatment modalities are urgently needed. NK4 is an antagonist of hepatocyte growth factor receptors (Met which are often aberrantly activated in gastric cancer and thus represent a useful candidate for targeted therapies. This study investigated MSC-delivered NK4 gene therapy in nude mice bearing gastric cancer xenografts. MSCs were transduced with lentiviral vectors carrying NK4 complementary DNA or enhanced green fluorescent protein (GFP. Such transduction did not change the phenotype of MSCs. Gastric cancer xenografts were established in BALB/C nude mice, and the mice were treated with phosphate-buffered saline (PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4. The tropism of MSCs toward gastric cancer cells was determined by an in vitro migration assay using MKN45 cells, GES-1 cells and human fibroblasts and their presence in tumor xenografts. Tumor growth, tumor cell apoptosis and intratumoral microvessel density of tumor tissue were measured in nude mice bearing gastric cancer xenografts treated with PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4 via tail vein injection. The results showed that MSCs migrated preferably to gastric cancer cells in vitro. Systemic MSCs-NK4 injection significantly suppressed the growth of gastric cancer xenografts. MSCs-NK4 migrated and accumulated in tumor

Immediate re-transplantation following early kidney transplant thrombosis.

LENUS (Irish Health Repository)

Phelan, Paul J

2011-08-01

Allograft thrombosis is a devastating early complication of renal transplantation that ultimately leads to allograft loss. We report here on our experience of nine cases of immediate re-transplantation following early kidney transplant thrombosis at a single centre between January 1990 and June 2009. The mean age was 42.9 years at time of transplant. For seven patients, the allograft thrombosis was their first kidney transplant and seven of the nine cases had a deceased donor transplant. The initial transplants functioned for a mean of 1.67 days and the patients received a second allograft at a mean of 3.1 days after graft failure. All of the re-transplants worked immediately. Four allografts failed after a mean of 52.5 months (2-155 months). Two of these died with a functioning allograft, one failed owing to chronic allograft nephropathy and one owing to persistent acute cellular rejection. The remaining five patients still have a functioning allograft after a mean of 101.8 months (7-187 months). One year allograft and patient survival after re-transplantation were 87.5% and 100% respectively (after 5 years, both were 57%). Immediate re-transplantation following early kidney transplant thrombosis can be a success. It may be considered in selected cases after allograft thrombosis.

[B-type natriuretic peptide assessment in the diagnosis of rejection after pediatric heart transplant].

Science.gov (United States)

Sylos, Cristina de; Azeka, Estela; Kajita, Luis; Benvenutti, Luis; Strunz, Célia Cassaro; Branco, Klébia Castello; Riso, Arlindo Almeida; Tanamati, Carla; Jatene, Marcelo; Barbero-Marcial, Miguel

2009-03-01

Rejection is one of the major causes of mortality following pediatric heart transplant. B-type natriuretic peptide (BNP) has been studied as a method for the diagnosis of acute rejection, especially in adult patients undergoing heart transplant. To correlate serum BNP levels with acute rejection as diagnosed by endomyocardial biopsy in patients of the pediatric heart transplant group. A total of 50 BNP samples were collected from 33 children in the postoperative period of heart transplant, and data on age, gender, skin color, blood group, immune panel, follow-up time after transplant, functional class, immunosuppressive regimen used and number of rejections were analyzed. Thirty three children with median age of 10.13 years were analyzed; of these, 54% were females and 78% were Caucasians. BNP levels were determined at a mean time from transplant of 4.25 years. Nine episodes of rejection were diagnosed in eight patients (27%) by means of endomyocardial biopsy; of these, three were grade 3A, five were grade 2, and one had humoral rejection. At the moment of biopsy, most patients were asymptomatic. The mean serum BNP level was 77.18 pg/ml, with 144.22 pg/ml in the group with rejection and 62.46 pg/ml in the group without rejection, with p = 0.02. Asymptomatic children can present acute rejection in the postoperative period of heart transplant. Serum BNP levels show a statistically significant difference in the group with rejection and thus can be an additional method in the diagnosis of cardiac rejection.

Blunt traumatic cardiac rupture: therapeutic options and outcomes.

Science.gov (United States)

Nan, Yu-Yun; Lu, Ming-Shian; Liu, Kuo-Sheng; Huang, Yao-Kuang; Tsai, Feng-Chun; Chu, Jaw-Ji; Lin, Pyng Jing

2009-09-01

the cardiac rupture. The in-hospital mortality was 27.3% (3/11) with 1 intra-operative death, 1 multiple organ failure, and 1 death while waiting for cardiac transplantation. Another patient with morbid neurological defects died on the thirty-third postoperative day; the overall survival was 63.6% (7/11). Compared with the surviving patients, the fatalities had higher RTS and TRISS scores, serum creatinine levels, had received greater blood transfusions, and had a worse preoperative conscious state. We proposed a protocol combining various diagnostic tools, including FAST, CT, transthoracic echocardiography, and TEE, to manage suspected blunt traumatic cardiac rupture. Pericardial defects can mask the cardiac lesion and complicate definite cardiac repair. Comorbid trauma, particularly neurological injury, may have an impact on the survival of such patients, despite timely repair of the cardiac lesions.

Gallium-67 imaging in human heart transplantation: correlation with endomyocardial biopsy

International Nuclear Information System (INIS)

Meneguetti, J.C.; Camargo, E.E.; Soares, J. Jr.

1987-01-01

Endomyocardial biopsy seems to be the most accurate method to use for diagnosis and follow-up of acute rejection of the transplanted heart. This investigation compared a noninvasive procedure, gallium-67 imaging, with endomyocardial biopsy in the detection of acute rejection in heart transplantation. Seven male patients (aged 41 to 54 years) sequentially had 46 gallium-67 scintigrams and 46 endomyocardial biopsies between 1 week and 8 months after transplantation. Both studies were obtained in the same day, 48 hours after the administration of an intravenous injection of gallium-67 citrate. Cardiac uptake was graded as negative, mild, moderate, and marked according to an increasing count ratio with rib and sternal uptakes. Histologic findings were graded as negative, mild acute rejection, moderate acute rejection, severe acute rejection, resolving rejection, and nonspecific reaction. Negative biopsies were not found with moderate uptake, and neither moderate nor severe acute rejection were found with negative scintigrams. Imaging sensitivity was 83% with 17% false negatives and 9% false positives. Of seven studies with moderate uptake, five showed moderate acute rejection, and the patients had specific therapy with a decline in uptake, which correlated with resolving rejection. It is conceivable that in the future this technique may be used as a screening procedure for sequential endomyocardial biopsies in the follow-up of heart transplant patients

Patient with a total artificial heart maintained on outpatient dialysis while listed for combined organ transplant, a single center experience.

Science.gov (United States)

Hanna, Ramy M; Hasnain, Huma; Kamgar, Mohammad; Hanna, Mina; Minasian, Raffi; Wilson, James

2017-10-01

Advanced mechanical circulatory support is increasingly being used with more sophisticated devices that can deliver pulsatile rather than continuous flow. These devices are more portable as well, allowing patients to await cardiac transplantation in an outpatient setting. It is known that patients with renal failure are at increased risk for developing worsening acute kidney injury during implantation of a ventricular assist device (VAD) or more advanced modalities like a total artificial heart (TAH). Dealing with patients who have an implanted TAH who develop renal failure has been a challenge with the majority of such patients having to await a combined cardiac and renal transplant prior to transition to outpatient care. Protocols do exist for VAD implanted patients to be transitioned to outpatient dialysis care, but there are no reported cases of TAH patients with end stage renal disease (ESRD) being successfully transitioned to outpatient dialysis care. In this report, we identify a patient with a TAH and ESRD transitioned successfully to outpatient hemodialysis and maintained for more than 2 years, though he did not survive to transplant. It is hoped that this report will raise awareness of this possibility, and assist in the development of protocols for similar patients to be successfully transitioned to outpatient dialysis care. © 2017 International Society for Hemodialysis.

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

Science.gov (United States)

Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A; Gong, Yongquan; Fischbein, Michael P; Robbins, Robert C; Naesens, Maarten; Butte, Atul J; Sarwal, Minnie M

2013-10-21

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.

Relationship between natriuretic peptides and inflammation: proteomic evidence obtained during acute cellular cardiac allograft rejection in humans.

Science.gov (United States)

Meirovich, Yael F; Veinot, John P; de Bold, Mercedes L Kuroski; Haddad, Haissam; Davies, Ross A; Masters, Roy G; Hendry, Paul J; de Bold, Adolfo J

2008-01-01

Cardiac natriuretic peptides (NPs) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are polypeptide hormones secreted by the heart. Previously, we found that BNP, but not ANF, plasma levels may increase during an acute cellular cardiac allograft rejection episode. In vitro, the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced a selective increase of BNP gene expression and secretion. Other pro-inflammatory cytokines had no such effects. We identified cytokines associated with the selective upregulation of BNP during cardiac allograft rejection using a proteomics approach to measure 120 cytokines and related substances in the plasma of 16 transplant patients before, during and after an acute rejection episode. The values obtained were correlated with BNP plasma levels. Cytokines identified as being significantly related to BNP plasma levels were tested in neonatal rat ventricular cardiocytes in culture for their ability to selectively promote BNP secretion. The signaling pathway related to this phenomenon was pharmacologically characterized. Regulated-on-activation, normal T-expressed and secreted (RANTES), neutrophil-activating protein-2 (NAP-2) and insulin growth factor binding protein-1 (IGFBP-1) had significant correlations with BNP plasma levels during Grade 3A (Grade 2 revised [2R]) or above rejection as diagnosed by endomyocardial biopsy score according to the International Society for Heart and Lung Transplantation (ISHLT) grading system. In rat neonatal ventricular cardiocyte cultures, IGFBP-1 and RANTES were capable of promoting BNP, but not ANF secretion, as observed in rejecting patients. The BNP-promoting secretion activity of the identified cytokines was abolished by SB203580, a specific p38 MAP kinase inhibitor. This work shows that cytokines other than pro-inflammatory cytokines correlate with BNP plasma levels observed during acute cardiac allograft rejection, and that

Everolimus: a proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology.

Science.gov (United States)

Gabardi, Steven; Baroletti, Steven A

2010-10-01

Everolimus, a proliferation signal inhibitor in the mammalian target of rapamycin (mTOR) drug class, has many clinical applications, including in organ transplantation, oncology, and cardiology. It currently has United States Food and Drug Administration (FDA) approval for prophylaxis against rejection in de novo renal transplant recipients, treatment of renal cell carcinoma, and use as a drug-eluting stent. To review the pharmacology, pharmacokinetics, efficacy, and safety of everolimus, we performed a search of the MEDLINE database (January 1997-April 2010) for all English-language articles of in vitro and in vivo studies that evaluated everolimus, as well as abstracts from recent scientific meetings and the manufacturer. In transplantation, everolimus demonstrates immunosuppressive properties and has been used to prevent acute rejection in cardiac, liver, lung, and renal transplant recipients. It appears that this agent may be potent enough to allow for the minimization or removal of calcineurin inhibitors in the long-term management of renal transplant recipients. In oncology, everolimus has been proven effective for the management of treatment-resistant renal cell carcinoma. In cardiology, everolimus is available as a drug-coated stent and is used in percutaneous coronary interventions for prevention of restenosis. In transplant recipients and patients with renal cell carcinoma, everolimus appears to have an extensive adverse-event profile. The pharmacologic properties of everolimus differentiate this agent from other drugs used in these clinical areas, and its pharmacokinetic properties differentiate it from sirolimus.

Role of Soluble ST2 as a Marker for Rejection after Heart Transplant

OpenAIRE

Lee, Ga Yeon; Choi, Jin-Oh; Ju, Eun-Seon; Lee, Yoo-Jung; Jeon, Eun-Seok

2016-01-01

Background and Objectives Endomyocardial biopsy is obligatory during the first year after heart transplant (HTx) for the surveillance of acute rejection. Previous attempts using cardiac biomarkers for the detection of rejection failed to show enough evidence to substitute endomyocardial biopsy. Therefore, this study sought the possibility of using soluble ST2 (sST2), a novel cardiovascular marker, as a surrogate marker for acute allograft rejection after HTx. Subjects and Methods A total of 4...

Pre-liver transplant psychosocial evaluation predicts post-transplantation outcomes.

Science.gov (United States)

Benson, Ariel A; Rowe, Mina; Eid, Ahmad; Bluth, Keren; Merhav, Hadar; Khalaileh, Abed; Safadi, Rifaat

2018-08-01

Psychosocial factors greatly impact the course of patients throughout the liver transplantation process. A retrospective chart review was performed of patients who underwent liver transplantation at Hadassah-Hebrew University Medical Center between 2002 and 2012. A composite psychosocial score was computed based on the patient's pre-transplant evaluation. Patients were divided into two groups based on compliance, support and insight: Optimal psychosocial score and Non-optimal psychosocial score. Post-liver transplantation survival and complication rates were evaluated. Out of 100 patients who underwent liver transplantation at the Hadassah-Hebrew University Medical Center between 2002 and 2012, 93% had a complete pre-liver transplant psychosocial evaluation in the medical record performed by professional psychologists and social workers. Post-liver transplantation survival was significantly higher in the Optimal group (85%) as compared to the Non-optimal group (56%, p = .002). Post-liver transplantation rate of renal failure was significantly lower in the Optimal group. No significant differences were observed between the groups in other post-transplant complications. A patient's psychosocial status may impact outcomes following transplantation as inferior psychosocial grades were associated with lower overall survival and increased rates of complications. Pre-liver transplant psychosocial evaluations are an important tool to help predict survival following transplantation.

Verification of Heart Disease: Implications for a New Heart Transplantation Allocation System.

Science.gov (United States)

Raeisi-Giglou, Pejman; Rodriguez, E Rene; Blackstone, Eugene H; Tan, Carmela D; Hsich, Eileen M

2017-12-01

This study sought to determine the accuracy of the pre-transplantation clinical diagnosis of heart disease in the United Network for Organ Sharing (UNOS) database. Because survival on the heart transplantation waitlist depends on underlying heart disease, a new allocation system will include the type of heart disease. Accuracy of the pre-transplantation clinical diagnosis and the effect of misclassification are unknown. We included all adults who received transplants at our center between January 2009 to December 2015. We compared the pre-transplantation clinical diagnosis at listing with pathology of the explanted heart and determined the potential effect of misclassification with the proposed allocation system. A total of 334 patients had the following clinical cardiac diagnoses at listing: 148 had dilated cardiomyopathy, 19 had restrictive cardiomyopathy, 103 had ischemic cardiomyopathy, 24 had hypertrophic cardiomyopathy, 11 had valvular disease, 16 had congenital heart disease (CHD), and 13 patients had a diagnosis of "other." Pathology of the explanted hearts revealed 82% concordance and 18% discordance (10% coding errors and 8% incorrect diagnosis). The most common incorrect diagnoses were sarcoidosis (66%), arrhythmogenic right ventricular dysplasia (60%), and other causes of predominately right-sided heart failure (33%). Among the misclassified diagnoses, 40% were listed as UNOS status 2, 8% remained at status 2 at transplantation, and only sarcoidosis and CHD were potentially at a disadvantage with the new allocation. There is high concordance between clinical and pathologic diagnosis, except for sarcoidosis and genetic diseases. Few misclassifications result in disadvantages to patients based on the new allocation system, but rare diseases like sarcoidosis remain problematic. To improve the UNOS database and enhance outcome research, pathology of the explanted hearts should be required post-transplantation. Copyright © 2017 American College of

Organ donation in cardiac arrest patients treated with extracorporeal CPR: A single centre observational study.

Science.gov (United States)

Casadio, Maria Chiara; Coppo, Anna; Vargiolu, Alessia; Villa, Jacopo; Rota, Matteo; Avalli, Leonello; Citerio, Giuseppe

2017-09-01

In a consecutive cohort of cardiac arrest (CA) treated with extracorporeal cardiopulmonary resuscitation (eCPR), we describe the incidence of brain death (BD), the eligibility for organ donation and the short-term follow-up of the transplanted organs. All refractory in- and out-of-hospital CA admitted to our Cardiac Intensive Care Unit between January 2011 and September 2016 treated with eCPR were enrolled in the study. 112 CA patients received eCPR. 82 (73.2%) died in hospital, 25 BD (22.3%) and 57 for other causes (50.9%). At the time of first neurological evaluation after rewarming, variables related to evolution to BD were a lower GCS (3 [3-3] vs. 8 [3-11], pdonation in BD patients was 56%, with 39 donated organs: 23 kidneys, 12 livers, and 4 lungs. 89.74% of the transplanted organs reached an early good functional recovery. In refractory CA patients treated with eCPR, the prevalence of BD is high. This population has a high potential for considering organ donation. Donated organs have a good outcome. Copyright © 2017 Elsevier B.V. All rights reserved.

Ventriculectomia parcial esquerda: ponte para transplante em pacientes com insuficiência cardíaca refratária e hipertensão pulmonar

Directory of Open Access Journals (Sweden)

Fernando A. LUCCHESE

1997-07-01

Full Text Available A insuficiência cardíaca congestiva refratária a tratamento clínico tem no transplante cardíaco ortotópico a sua melhor opção cirúrgica. Escassez de doadores, morbidade significativa associada com a terapêutica anti-rejeição, aterosclerose coronária e custos consideráveis associados com o transplante são fatores responsáveis pela sua limitada aplicação. Para os que se encontram na lista para transplante, o período de espera de 6 meses a 1 ano pode levar à deterioração hemodinâmica e expressivo número de mortes. A sobrevida, na lista de espera, pode ser de 46% em 1 ano (1. Afora isso, um significativo número de pacientes tem contra-indicação para transplante, por apresentar hipertensão e resitência pulmonar elevadas. A ventriculectomia parcial esquerda (VPE (2, 3, restaurando o raio do ventrículo esquerdo e melhorando, assim, a relação massa-volume e o desempenho sistólico, pode propiciar diminuição da pressão e da resistência arterial pulmonar, em alguns pacientes.Medically refractory heart failure is traditionally managed with cardiac transplantation although some limited success has also been obtained in selected patients with alternative surgical options. Scarce donors, significant morbidity secondary to the antirejection therapy, post-transplantation coronary disease and the high costs of transplantation programs, all together are limiting factors. For those on the waiting list of transplantation the one year mortality may be as high as 46%. Furthermore, a significant number of patients have contraindication to transplantation due to severe pulmonary arterial hypertension and elevated pulmonary vascular resistance. Partial Left Ventriculectomy (PLV attempts to relieve symptoms of congestive heart failure by reducing left ventricular dimensions and mass and restoring the normal mass-to-volume ratio of the left ventricle. As a consequence, cardiac index and forward ejection fraction increase thus unloading

Three-year post-transplant medicare payments in kidney transplant recipients: Associations with pre-transplant comorbidities

Directory of Open Access Journals (Sweden)

Gerardo Machnicki

2011-01-01

Full Text Available Little is known about the influence of pre-transplant comorbidities on post-transplant expenditures. We estimated the associations between pre-transplant comorbidities and post-transplant Medicare costs, using several comorbidity classification systems. We included recipients of first-kidney deceased donor transplants from 1995 through 2002 for whom Medicare was the primary payer for at least one year pre-transplant (N = 25,175. We examined pre-transplant comorbidities as classified by International Classification of Diseases (ICD-9-CM codes from Medicare claims with the Clinical Cla-ssifications Software (CCS and Charlson and Elixhauser algorithms. Post-transplant costs were calcu-lated from payments on Medicare claims. We developed models considering Organ Procurement and Transplantation Network (OPTN variables plus: 1 CCS categories, 2 Charlson, 3 Elixhauser, 4 num-ber of Charlson and 5 number of Elixhauser comorbidities, independently. We applied a novel regression methodology to account for censoring. Costs were estimated at individual and population levels. The comorbidities with the largest impact on mean Medicare payments included cardiovascular disease, ma-lignancies, cerebrovascular disease, mental conditions and functional limitations. Skin ulcers and infec-tions, rheumatic and other connective tissue disease and liver disease also contributed to payments and have not been considered or described previously. A positive graded relationship was found between costs and the number of pre-transplant comorbidities. In conclusion, we showed that expansion beyond the usually considered pre-transplant comorbidities with inclusion of CCS and Charlson or Elixhauser comorbidities increased the knowledge about comorbidities related to augmented Medicare payments. Our expanded methodology can be used by others to assess more accurately the financial implications of renal transplantation to Medicare and individual transplant centers.

Yogurt Feeding Induced the Prolongation of Fully Major Histocompatibility Complex-Mismatched Murine Cardiac Graft Survival by Induction of CD4+Foxp3+ Cells.

Science.gov (United States)

Uchiyama, M; Yin, E; Yanagisawa, T; Jin, X; Hara, M; Matsuyama, S; Imazuru, T; Uchida, K; Kawamura, M; Niimi, M

Yogurt is a nutrient-rich food and the beneficial effects of yogurt on both health and immunomodulatory effects are well documented. In this pilot study, we investigated the effects of commercially produced yogurt R-1 on alloimmune responses in a murine cardiac transplantation model. The R-1 is produced by Meiji Co., Ltd., and contains live and active lactic acid bacteria (lactobacillus bulgaricus OLL1073R-1) mainly. CBA (H2 k ) mice underwent transplantation of a C57BL/6 (H2 b ; B6) heart and received oral administration of 1 mL, 0.1 mL, and 0.01 mL of R-1 from the day of transplantation until 7 days afterward. Additionally, we prepared one group of CBA recipients given 1 mL of R-1 sterilized by microwave for 7 days. Histological and immunohistochemical studies were performed. Naïve CBA mice rejected B6 cardiac graft acutely (median survival time [MST]: 7 days). CBA recipients given of 1 mL of R-1 had significantly prolonged B6 allograft survival (MST, 27 days). However, other doses of 0.1 mL and 0.01 mL of R-1 did not prolonged allograft survival (MSTs, 9 days and 8.5 days, respectively). Also, CBA recipients administered microwaved R-1 had no prolongation of B6 allograft (MST, 9 days). Histological and immunohistochemical studies showed the cardiac allograft from R-1-exposed CBA recipients had preserved graft and vessel structure and the number of infiltrated CD4 + , CD8 + , and Foxp3 + cells in R-1-exposed CBA recipients increased, respectively. In conclusion, our findings imply that yogurt containing active lactic acid bacteria could change alloimmune responses partially and induce the prolongation of cardiac allograft survival via CD4 + Foxp3 + regulatory cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Donor-specific anti-HLA antibodies with antibody-mediated rejection and long-term outcomes following heart transplantation.

Science.gov (United States)

Clerkin, Kevin J; Farr, Maryjane A; Restaino, Susan W; Zorn, Emmanuel; Latif, Farhana; Vasilescu, Elena R; Marboe, Charles C; Colombo, Paolo C; Mancini, Donna M

2017-05-01

Donor-specific anti-HLA antibodies (DSA) are common after heart transplantation and are associated with rejection, cardiac allograft vasculopathy, and mortality. A noninvasive diagnostic test for pathologic antibody-mediated rejection (pAMR) does not exist. From January 1, 2010, through August 31, 2013, 221 consecutive adult patients underwent heart transplantation and were followed through October 1, 2015. The primary objective was to determine whether the presence of DSA could detect AMR at the time of pathologic diagnosis. Secondary analyses included association of DSA (stratified by major histocompatibility complex class and de novo status) during AMR with new graft dysfunction, graft loss (mortality or retransplantation), and development of cardiac allograft vasculopathy. During the study period, 69 patients (31.2%) had DSA (24% had de novo DSA), and there were 74 episodes of pAMR in 38 patients. Sensitivity of DSA at any mean fluorescence intensity to detect concurrent pAMR was only 54.3%. The presence of any DSA during pAMR increased the odds of graft dysfunction (odds ratio = 5.37; 95% confidence interval [CI], 1.34-21.47; p = 0.018), adjusting for age, sex, and timing of AMR. Circulating class II DSA after transplantation increased risk of future pAMR (hazard ratio = 2.97; 95% CI, 1.31-6.73; p = 0.009). Patients who developed de novo class II DSA had 151% increased risk of graft loss (contingent on 30-day survival) compared with patients who did not have DSA (95% CI, 1.11-5.69; p = 0.027). DSA were inadequate to diagnose pAMR. Class II DSA provided prognostic information regarding future pAMR, graft dysfunction with pAMR, and graft loss. Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

IL-34 is a Treg-specific cytokine and mediates transplant tolerance

OpenAIRE

Bézie, Séverine; Picarda, Elodie; Ossart, Jason; Tesson, Laurent; Usal, Claire; Renaudin, Karine; Anegon, Ignacio; Guillonneau, Carole

2015-01-01

Cytokines and metabolic pathway–controlling enzymes regulate immune responses and have potential as powerful tools to mediate immune tolerance. Blockade of the interaction between CD40 and CD40L induces long-term cardiac allograft survival in rats through a CD8+CD45RClo Treg potentiation. Here, we have shown that the cytokine IL-34, the immunoregulatory properties of which have not been previously studied in transplantation or T cell biology, is expressed by rodent CD8+CD45RClo Tregs and huma...

Glomerular Filtration Rate Estimation in Renal and Non-Renal Solid Organ Transplantation

DEFF Research Database (Denmark)

Hornum, Mads; Feldt-Rasmussen, Bo

2017-01-01

Following transplantation (TX) of both renal and non-renal organs, a large proportion of patients have renal dysfunction. There are multiple causes for this. Chronic nephrotoxicity and high doses of calcineurin inhibitors are important factors. Preoperative and perioperative factors like hyperten......Following transplantation (TX) of both renal and non-renal organs, a large proportion of patients have renal dysfunction. There are multiple causes for this. Chronic nephrotoxicity and high doses of calcineurin inhibitors are important factors. Preoperative and perioperative factors like...... hypertension, hypotension, drugs and infections may play a causative role as well. Organ-specific causes include hepatorenal syndrome, cirrhosis, low cardiac function, low respiratory function and diabetes developed both before and after TX. It is important to be able to perform precise and valid measurements...... rate methods for use in renal and non-renal TX....

Physicochemical characterization of porcine bone-derived grafting material and comparison with bovine xenografts for dental applications.

Science.gov (United States)

Lee, Jung Heon; Yi, Gyu Sung; Lee, Jin Woong; Kim, Deug Joong

2017-12-01

The physicochemical properties of a xenograft are very important because they strongly influence the bone regeneration capabilities of the graft material. Even though porcine xenografts have many advantages, only a few porcine xenografts are commercially available, and most of their physicochemical characteristics have yet to be reported. Thus, in this work we aimed to investigate the physicochemical characteristics of a porcine bone grafting material and compare them with those of 2 commercially available bovine xenografts to assess the potential of xenogenic porcine bone graft materials for dental applications. We used various characterization techniques, such as scanning electron microscopy, the Brunauer-Emmett-Teller adsorption method, atomic force microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, and others, to compare the physicochemical properties of xenografts of different origins. The porcine bone grafting material had relatively high porosity (78.4%) and a large average specific surface area (SSA; 69.9 m 2 /g), with high surface roughness (10-point average roughness, 4.47 µm) and sub-100-nm hydroxyapatite crystals on the surface. Moreover, this material presented a significant fraction of sub-100-nm pores, with negligible amounts of residual organic substances. Apart from some minor differences, the overall characteristics of the porcine bone grafting material were very similar to those of one of the bovine bone grafting material. However, many of these morphostructural properties were significantly different from the other bovine bone grafting material, which exhibited relatively smooth surface morphology with a porosity of 62.0% and an average SSA of 0.5 m 2 /g. Considering that both bovine bone grafting materials have been successfully used in oral surgery applications in the last few decades, this work shows that the porcine-derived grafting material possesses most of the key physiochemical characteristics required for its

An integrated analysis of miRNA and gene copy numbers in xenografts of Ewing's sarcoma

Directory of Open Access Journals (Sweden)

Mosakhani Neda

2012-03-01

Full Text Available Abstract Background Xenografts have been shown to provide a suitable source of tumor tissue for molecular analysis in the absence of primary tumor material. We utilized ES xenograft series for integrated microarray analyses to identify novel biomarkers. Method Microarray technology (array comparative genomic hybridization (aCGH and micro RNA arrays was used to screen and identify copy number changes and differentially expressed miRNAs of 34 and 14 passages, respectively. Incubated cells used for xenografting (Passage 0 were considered to represent the primary tumor. Four important differentially expressed miRNAs (miR-31, miR-31*, miR-145, miR-106 were selected for further validation by real time polymerase chain reaction (RT-PCR. Integrated analysis of aCGH and miRNA data was performed on 14 xenograft passages by bioinformatic methods. Results The most frequent losses and gains of DNA copy number were detected at 9p21.3, 16q and at 8, 15, 17q21.32-qter, 1q21.1-qter, respectively. The presence of these alterations was consistent in all tumor passages. aCGH profiles of xenograft passages of each series resembled their corresponding primary tumors (passage 0. MiR-21, miR-31, miR-31*, miR-106b, miR-145, miR-150*, miR-371-5p, miR-557 and miR-598 showed recurrently altered expression. These miRNAS were predicted to regulate many ES-associated genes, such as genes of the IGF1 pathway, EWSR1, FLI1 and their fusion gene (EWS-FLI1. Twenty differentially expressed miRNAs were pinpointed in regions carrying altered copy numbers. Conclusion In the present study, ES xenografts were successfully applied for integrated microarray analyses. Our findings showed expression changes of miRNAs that were predicted to regulate many ES associated genes, such as IGF1 pathway genes, FLI1, EWSR1, and the EWS-FLI1 fusion genes.

Post-transplant lymphoproliferative disorder following kidney transplantation

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Maksten, Eva Futtrup; Vase, Maja Ølholm; Kampmann, Jan

2016-01-01

after long-term post-transplantation follow-up. A retrospective population-based cohort study including all kidney transplant recipients at two Danish centres (1990-2011; population covered 3.1 million; 2175 transplantations in 1906 patients). Pathology reports were reviewed for all patient biopsies...

Aggravated Cardiac Remodeling post Aortocaval Fistula in Unilateral Nephrectomized Rats.

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Jie Wu

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

A survey of nine years heart transplantation at Erasme Hospital, University of Brussels.

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Primo, G; Le Clerc, J L; Antoine, M; De Smet, J M; Joris, M

1991-01-01

Between March 1982 and March 1991, 225 heart transplantations (HTx) have been performed in 220 patients suffering end stage cardiac disease. Thirteen percent were females and 87% were males. Age range was from 5 to 68 years. The underlying cardiac disease was ischemic cardiopathy in 51.5%, congestive dilated cardiomyopathy in 42%, valvular cardiomyopathy in 3.5%, toxic myocarditis (post-adriamycin) in 1.5% and chronic rejection in 2.5% (retransplantation). Selection of the recipients was done following the currently well established criteria also taking into account the absolute major contraindications for HTx. Due to the still increasing demand of donor organs, currently donor age has been extended up to 50 years for male and 55 years for female donors. One quarter of the grafts were harvested on site in our institution, two other quarters were harvested somewhere else in Belgium and the last quarter provided by other countries cooperating with Eurotransplant. All patients have undergone orthotopic cardiac transplantation using the standard Lower and Shumway technique. Immunosuppression protocols have changed four times throughout the years. Nevertheless all were based on the use of Ciclosporine variously combined with other current immunosuppressive drugs. Rejection monitoring relied on routine endocardiac biopsy and was diagnosed according to the Billingham criteria. The in-hospital mortality is currently 11%. Infection, early right heart graft failure and acute rejection were the leading causes of death. The major causes of early morbidity were several curable infections, reversible rejection episodes, transient acute renal failure and controllable arterial hypertension. Among the survivors followed for at least one month up to nine years, half of late mortality was caused by chronic rejection followed by infection, sudden death, metabolic disorders, stroke and malignancy. Late morbidity involves cases of mild coronary graft diseases, biological renal

The decreased influence of overall treatment time on the response of human breast tumor xenografts following prolongation of the potential doubling time (T{sub pot})

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Sarkaria, Jann N; Fowler, John F; Lindstrom, Mary J; Jordan, V Craig; Mulcahy, R Timothy

1995-02-15

Purpose: Repopulation during fractionated radiotherapy has been postulated to result in a significant loss in local control in rapidly proliferating tumors. Clinical data suggest that accelerated fractionation schedules can overcome the influence of repopulation by limiting the overall treatment time. Unfortunately, accelerated therapy frequently leads to increased acute reactions, which may become dose limiting. An alternative to accelerated fractionation would be to decrease the rate of repopulation during therapy. To test the potential efficacy of this alternative, we examined the effect of reducing tumor proliferation rate on the response of MCF-7 human breast carcinoma xenografts treated with a short vs. a long course of fractionated therapy. To reduce the proliferation rate, we deprived nude mice transplanted with MCF-7 xenografts of the growth-stimulating hormone estradiol (E{sub 2}). We have previously reported that E{sub 2} deprivation increases the potential doubling time (T{sub pot}) for MCF-7 xenografts from a mean of 2.6 days to 5.3 days (p < 0.001). Methods and Materials: E{sub 2}-stimulated and E{sub 2}-deprived MCF-7 breast carcinoma xenografts were clamped hypoxically and irradiated with four fractions of 5 Gy each, using either a short (3-day) or long (9-day) treatment course. E{sub 2} stimulation was restored in all animals at the completion of irradiation. Radiation response was determined by regrowth time and regrowth delay of the irradiated tumors as compared to unirradiated controls. Results: Prolongation of therapy in rapidly proliferating, E{sub 2}-stimulated tumors (T{sub pot} {approx} 2.6 days) resulted in a significant decrease in regrowth time in two identical experiments. With results pooled for analysis, the regrowth times for the short and long treatments were 62 and 32 days, respectively (combined p < 0.001). The shorter regrowth times suggest that there was less overall tumor damage with the longer fractionated radiotherapy course

Diffuse myocardial fibrosis among healthy pediatric heart transplant recipients: Correlation of histology, cardiovascular magnetic resonance, and clinical phenotype.

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Feingold, Brian; Salgado, Cláudia M; Reyes-Múgica, Miguel; Drant, Stacey E; Miller, Susan A; Kennedy, Mark; Kellman, Peter; Schelbert, Erik B; Wong, Timothy C

2017-08-01

Fibrosis is commonly described in heart allografts lost late after transplantation. CMR-derived ECV is a validated measure of DMF in native adult hearts that may predict heart failure and mortality. We explored associations of ECV with histologic myocardial fibrosis and clinical features after pediatric heart transplantation. Twenty-five recipients (7.0±6.3 years at transplant and 10.7±6.5 years post-transplant) were prospectively recruited for CMR and BNP measurement at the time of surveillance biopsy. All had normal ejection fractions and lacked heart failure symptoms. Fibrosis was quantified on biopsy after picrosirius red staining as CVF. ECV was quantified using contemporaneous hematocrit on basal and mid-short-axis slices. ECV was moderately correlated with CVF (r=.47; P=.019). We found no associations of ECV with hemodynamics, ischemic time, time since transplantation, or number of prior biopsies or acute rejections. Compared to healthy non-transplant controls, there was no significant difference in ECV (25.1±3.0 vs 23.7±2.0%, P=.09). Log-transformed BNP was correlated with ECV (recipients: r=.46, P=.02; recipients and controls: r=.45, P=.006). These findings suggest ECV quantifies DMF and relates to biological indicators of cardiac function after pediatric heart transplantation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Optimal specific radioactivity of anti-HER2 Affibody molecules enables discrimination between xenografts with high and low HER2 expression levels

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Tolmachev, Vladimir [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Uppsala University, Department of Medical Sciences, Nuclear Medicine, Uppsala (Sweden); Waallberg, Helena [Royal Institute of Technology, School of Biotechnology, Stockholm (Sweden); Sandstroem, Mattias [Uppsala University Hospital, Section of Hospital Physics, Department of Oncology, Uppsala (Sweden); Hansson, Monika; Wennborg, Anders [Affibody AB, Stockholm (Sweden); Orlova, Anna [Uppsala University, Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden)

2011-03-15

Overexpression of the HER2 receptor is a biomarker for predicting those patients who may benefit from trastuzumab therapy. Radiolabelled Affibody molecules can be used to visualize HER2 expression in tumour xenografts with high sensitivity. However, previous studies demonstrated that the difference in uptake in xenografts with high and low HER2 expression levels is not proportional to the difference in expression levels. We hypothesized that discrimination between tumours with high and low HER2 expression may be improved by increasing the injected dose (reducing the specific activity) of the tracer. The influence of injected dose of anti-HER2 {sup 111}In-DOTA-Z{sub HER2} {sub 342} Affibody molecule on uptake in SKOV-3 (high HER2 expression) and LS174T (low expression) xenografts was investigated. The optimal range of injected doses enabling discrimination between xenografts with high and low expression was determined. To verify this, tumour uptake was measured in mice carrying both SKOV-3 and LS174T xenografts after injection of either 1 or 15 {mu}g {sup 111}In-DOTA-Z{sub HER2:342}. An increase in the injected dose caused a linear decrease in the radioactivity accumulation in the LS174T xenografts (low HER2 expression). For SKOV-3 xenografts, the dependence of the tumour uptake on the injected dose was less dramatic. The injection of 10-30 {mu}g {sup 111}In-DOTA-Z{sub HER2:342} per mouse led to the largest difference in uptake between the two types of tumour. Experiments in mice bearing two xenografts confirmed that the optimized injected dose enabled better discrimination of expression levels. Careful optimization of the injected dose of Affibody molecules is required for maximum discrimination between xenografts with high and low levels of HER2 expression. This information has potential relevance for clinical imaging applications. (orig.)

Sugammadex to reverse neuromuscular blockade in a child with a past history of cardiac transplantation

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Karen Miller

2017-01-01

Full Text Available Sugammadex is a novel agent for the reversal of neuromuscular blockade. The speed and efficacy of reversal with sugammadex are significantly faster than acetylcholinesterase inhibitors, such as neostigmine. Sugammadex also has a limited adverse profile when compared with acetylcholinesterase inhibitors, specifically in regard to the incidence of bradycardia. This adverse effect may be particularly relevant in the setting of a heart transplant recipient with a denervated heart. The authors present a case of an 8-year-old child, status postcardiac transplantation, who required anesthetic care for laparoscopy and lysis of intra-abdominal adhesions. Sugammadex was used to reverse neuromuscular blockade and avoid the potential adverse effects of neostigmine. The unique mechanism of action of sugammadex is discussed, previous reports of its use in this unique patient population are reviewed, and its potential benefits compared to traditional acetylcholinesterase inhibitors are presented.

Sugammadex to reverse neuromuscular blockade in a child with a past history of cardiac transplantation.

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Miller, Karen; Hall, Brian; Tobias, Joseph D

2017-01-01

Sugammadex is a novel agent for the reversal of neuromuscular blockade. The speed and efficacy of reversal with sugammadex are significantly faster than acetylcholinesterase inhibitors, such as neostigmine. Sugammadex also has a limited adverse profile when compared with acetylcholinesterase inhibitors, specifically in regard to the incidence of bradycardia. This adverse effect may be particularly relevant in the setting of a heart transplant recipient with a denervated heart. The authors present a case of an 8-year-old child, status postcardiac transplantation, who required anesthetic care for laparoscopy and lysis of intra-abdominal adhesions. Sugammadex was used to reverse neuromuscular blockade and avoid the potential adverse effects of neostigmine. The unique mechanism of action of sugammadex is discussed, previous reports of its use in this unique patient population are reviewed, and its potential benefits compared to traditional acetylcholinesterase inhibitors are presented.

An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia

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Zhisheng Her

2017-10-01

Full Text Available Abstract Background Xenotransplantation of patient-derived AML (acute myeloid leukemia cells in NOD-scid Il2rγ null (NSG mice is the method of choice for evaluating this human hematologic malignancy. However, existing models constructed using intravenous injection in adult or newborn NSG mice have inferior engraftment efficiency, poor peripheral blood engraftment, or are difficult to construct. Methods Here, we describe an improved AML xenograft model where primary human AML cells were injected into NSG newborn pups intrahepatically. Results Introduction of primary cells from AML patients resulted in high levels of engraftment in peripheral blood, spleen, and bone marrow (BM of recipient mice. The phenotype of engrafted AML cells remained unaltered during serial transplantation. The mice developed features that are consistent with human AML including spleen enlargement and infiltration of AML cells into multiple organs. Importantly, we demonstrated that although leukemic stem cell activity is enriched and mediated by CD34+CD117+ subpopulation, CD34+CD117− subpopulation can acquire CD34+CD117+ phenotype through de-differentiation. Lastly, we evaluated the therapeutic potential of Sorafenib and Regorafenib in this AML model and found that periphery and spleen AML cells are sensitive to these treatments, whereas BM provides a protective environment to AML. Conclusions Collectively, our improved model is robust, easy-to-construct, and reliable for pre-clinical AML studies.

Application of a Patient Derived Xenograft Model for Predicative Study of Uterine Fibroid Disease.

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Martin Fritsch

Full Text Available Human uterine fibroids, benign tumors derived from the smooth muscle layers of the uterus, impose a major health burden to up to 50% of premenopausal women in their daily life. To improve our understanding of this disease, we developed and characterized a patient-derived xenograft model by subcutaneous transplantation of pieces of human uterine fibroid tissue into three different strains of severe combined immunodeficient mice. Engrafted uterine fibroid tissue preserved the classical morphology with interwoven bundles of smooth muscle cells and an abundant deposition of collagenous matrix, similar to uterine fibroids in situ. The grafts expressed both estrogen receptor 1 and progesterone receptor. Additionally, both receptors were up-regulated by estrogen treatment. Growth of the fibroid grafts was dependent on 17β-estradiol and progesterone supplementation at levels similar to women with the disease and was studied for up to 60 days at maximum. Co-treatment with the antiprogestin mifepristone reduced graft growth (four independent donors, p<0.0001 two-sided t-test, as did treatment with the mTOR inhibitor rapamycin (three independent donors, p<0.0001 two-sided t-test. This in vivo animal model preserves the main histological and functional characteristics of human uterine fibroids, is amenable to intervention by pharmacological treatment, and can thus serve as an adequate model for the development of novel therapies.

Mechanical circulatory support as a bridge to cardiac retransplantation: a single center experience.

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Clerkin, Kevin J; Thomas, Sunu S; Haythe, Jennifer; Schulze, P Christian; Farr, Maryjane; Takayama, Hiroo; Jorde, Ulrich P; Restaino, Susan W; Naka, Yoshifumi; Mancini, Donna M

2015-02-01

Cardiac retransplantation is increasing in frequency. Recent data have shown that retransplantation outcomes are now comparable with primary transplantation. The use of mechanical circulatory support (MCS) as a bridge to retransplantation has similar post-retransplant outcomes to those without MCS, but the success of bridging patients to retransplant with MCS has not been well studied. From January 2000 to February 2014 at Columbia University Medical Center, 84 patients were listed for retransplantation. Of this cohort, 48 patients underwent retransplantation, 15 were bridged with MCS, 24 died, and 6 clinically improved. A retrospective analysis was performed examining waiting list time, survival to retransplantation, and survival after retransplant. The effect of the United Network of Organ Sharing (UNOS) allocation policy change in 2006 on waiting list time and MCS use was also investigated. Of 48 patients who underwent retransplantation, 11 were bridged with MCS. Overall 1-year survival to retransplantation was 81.3%. There was no significant difference in waiting list survival (p = 0.71) in those with and without MCS. Death from cardiac arrest or multiorgan failure with infection was more frequent in the medically managed group (p = 0.002). After the UNOS 2006 allocation policy change, waiting list time (599 ± 936 days in Era 1 vs 526 ± 498 days in Era 2, p = 0.65) and waiting list survival (p = 0.22) between eras were comparable, but there was a trend toward greater use of MCS (p = 0.13). Survival after retransplant was acceptable. The use of MCS as a bridge to cardiac retransplantation is a reasonable strategy. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Right ventricular longitudinal strain and right ventricular stroke work index in patients with severe heart failure: left ventricular assist device suitability for transplant candidates.

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Cameli, M; Bernazzali, S; Lisi, M; Tsioulpas, C; Croccia, M G; Lisi, G; Maccherini, M; Mondillo, S

2012-09-01

Right ventricular (RV) systolic function has a critical role in determining the clinical outcome and the success of using left ventricular assist devices in patients with refractory heart failure. RV deformation analysis by speckle tracking echocardiography (STE) has recently allowed the analysis of RV longitudinal function. Using cardiac catheterization as the reference standard, this study aimed to explore the correlation between RV longitudinal function by STE and RV stroke work index (RVSWI) among patients referred for cardiac transplantation. Right heart catheterization and transthoracic echo-Doppler were simultaneously performed in 47 patients referred for cardiac transplant assessment due to refractory heart failure (ejection fraction 25.1 ± 4.5%). Thermodilution RV stroke volume and invasive pulmonary pressures were used to obtain RVSWI. RV longitudinal strain (RVLS) by STE was assessed averaging RV free-wall segments (free-wall RVLS). We also calculated. Tricuspid S' and tricuspid annular plane systolic excursion (TAPSE). No significant correlation was observed for TAPSE on tricuspid S' with RV stroke volume (r = 0.14 and r = 0.06, respectively). A close negative correlation between free-wall RVLS and RVSWI was found (r = -0.82; P rights reserved.

Retinal progenitor cell xenografts to the pig retina

DEFF Research Database (Denmark)

Warfvinge, Karin; Kiilgaard, Jens Folke; Lavik, Erin B

2005-01-01

To investigate the survival, integration, and differentiation of mouse retinal progenitor cells after transplantation to the subretinal space of adult pigs.......To investigate the survival, integration, and differentiation of mouse retinal progenitor cells after transplantation to the subretinal space of adult pigs....

The Impact of Ischemia/Reperfusion Injury on Liver Allografts from Deceased after Cardiac Death versus Deceased after Brain Death Donors.

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Jin Xu

Full Text Available The shortage of organs for transplantation has led to increased use of organs procured from donors after cardiac death (DCD. The effects of cardiac death on the liver remain poorly understood, however. Using livers obtained from DCD versus donors after brain death (DBD, we aimed to understand how ischemia/reperfusion (I/R injury alters expression of pro-inflammatory markers ceramides and influences graft leukocyte infiltration.Hepatocyte inflammation, as assessed by ceramide expression, was evaluated in DCD (n = 13 and DBD (n = 10 livers. Allograft expression of inflammatory and cell death markers, and allograft leukocyte infiltration were evaluated from a contemporaneous independent cohort of DCD (n = 22 and DBD (n = 13 livers.When examining the differences between transplant stages in each group, C18, C20, C24 ceramides showed significant difference in DBD (p<0.05 and C22 ceramide (p<0.05 were more pronounced for DCD. C18 ceramide is correlated to bilirubin, INR, and creatinine after transplant in DCD. Prior to transplantation, DCD livers have reduced leukocyte infiltration compared to DBD allografts. Following reperfusion, the neutrophil infiltration and platelet deposition was less prevalent in DCD grafts while cell death and recipients levels of serum aspartate aminotransferase (AST of DCD allografts had significantly increased.These data suggest that I/R injury generate necrosis in the absence of a strong inflammatory response in DCD livers with an appreciable effect on early graft function. The long-term consequences of increased inflammation in DBD and increased cell death in DCD allografts are unknown and warrant further investigation.

PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models

NARCIS (Netherlands)

Meehan, Terrence F.; Conte, Nathalie; Goldstein, Theodore; Inghirami, Giorgio; Murakami, Mark A.; Brabetz, Sebastian; Gu, Zhiping; Wiser, Jeffrey A.; Dunn, Patrick; Begley, Dale A.; Krupke, Debra M.; Bertotti, Andrea; Bruna, Alejandra; Brush, Matthew H.; Byrne, Annette T.; Caldas, Carlos; Christie, Amanda L.; Clark, Dominic A.; Dowst, Heidi; Dry, Jonathan R.; Doroshow, James H.; Duchamp, Olivier; Evrard, Yvonne A.; Ferretti, Stephane; Frese, Kristopher K.; Goodwin, Neal C.; Greenawalt, Danielle; Haendel, Melissa A.; Hermans, Els; Houghton, Peter J.; Jonkers, Jos; Kemper, Kristel; Khor, Tin O.; Lewis, Michael T.; Lloyd, K. C. Kent; Mason, Jeremy; Medico, Enzo; Neuhauser, Steven B.; Olson, James M.; Peeper, Daniel S.; Rueda, Oscar M.; Seong, Je Kyung; Trusolino, Livio; Vinolo, Emilie; Wechsler-Reya, Robert J.; Weinstock, David M.; Welm, Alana; Weroha, S. John; Amant, Frédéric; Pfister, Stefan M.; Kool, Marcel; Parkinson, Helen; Butte, Atul J.; Bult, Carol J.

2017-01-01

Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models

Textile-templated electrospun anisotropic scaffolds for regenerative cardiac tissue engineering.

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Şenel Ayaz, H Gözde; Perets, Anat; Ayaz, Hasan; Gilroy, Kyle D; Govindaraj, Muthu; Brookstein, David; Lelkes, Peter I

2014-10-01

For patients with end-stage heart disease, the access to heart transplantation is limited due to the shortage of donor organs and to the potential for rejection of the donated organ. Therefore, current studies focus on bioengineering approaches for creating biomimetic cardiac patches that will assist in restoring cardiac function, by repairing and/or regenerating the intrinsically anisotropic myocardium. In this paper we present a simplified, straightforward approach for creating bioactive anisotropic cardiac patches, based on a combination of bioengineering and textile-manufacturing techniques in concert with nano-biotechnology based tissue-engineering stratagems. Using knitted conventional textiles, made of cotton or polyester yarns as template targets, we successfully electrospun anisotropic three-dimensional scaffolds from poly(lactic-co-glycolic) acid (PLGA), and thermoplastic polycarbonate-urethane (PCU, Bionate(®)). The surface topography and mechanical properties of textile-templated anisotropic scaffolds significantly differed from those of scaffolds electrospun from the same materials onto conventional 2-D flat-target electrospun scaffolds. Anisotropic textile-templated scaffolds electrospun from both PLGA and PCU, supported the adhesion and proliferation of H9C2 cardiac myoblasts cell line, and guided the cardiac tissue-like anisotropic organization of these cells in vitro. All cell-seeded PCU scaffolds exhibited mechanical properties comparable to those of a human heart, but only the cells on the polyester-templated scaffolds exhibited prolonged spontaneous synchronous contractility on the entire engineered construct for 10 days in vitro at a near physiologic frequency of ∼120 bpm. Taken together, the methods described here take advantage of straightforward established textile manufacturing strategies as an efficient and cost-effective approach to engineering 3D anisotropic, elastomeric PCU scaffolds that can serve as a cardiac patch. Copyright �

Retinal progenitor cell xenografts to the pig retina

DEFF Research Database (Denmark)

Warfvinge, Karin; Kiilgaard, Jens Folke; Klassen, Henry

2006-01-01

We evaluated the host response to murine retinal progenitor cells (RPCs) following transplantation to the subretinal space (SRS) of the pig. RPCs from GFP mice were transplanted subretinally in 18 nonimmunosuppressed normal or laser-treated pigs. Evaluation of the SRS was performed on hematoxylin-eosin...

Outside-in HLA class I signaling regulates ICAM-1 clustering and endothelial cell-monocyte interactions via mTOR in transplant antibody-mediated rejection.

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Salehi, Sahar; Sosa, Rebecca A; Jin, Yi-Ping; Kageyama, Shoichi; Fishbein, Michael C; Rozengurt, Enrique; Kupiec-Weglinski, Jerzy W; Reed, Elaine F

2018-05-01

Antibody-mediated rejection (AMR) resulting in transplant allograft vasculopathy (TAV) is the major obstacle for long-term survival of solid organ transplants. AMR is caused by donor-specific antibodies to HLA, which contribute to TAV by initiating outside-in signaling transduction pathways that elicit monocyte recruitment to activated endothelium. Mechanistic target of rapamycin (mTOR) inhibitors can attenuate TAV; therefore, we sought to understand the mechanistic underpinnings of mTOR signaling in HLA class I Ab-mediated endothelial cell activation and monocyte recruitment. We used an in vitro model to assess monocyte binding to HLA I Ab-activated endothelial cells and found mTOR inhibition reduced ezrin/radixin/moesin (ERM) phosphorylation, intercellular adhesion molecule 1 (ICAM-1) clustering, and monocyte firm adhesion to HLA I Ab-activated endothelium. Further, in a mouse model of AMR, in which C57BL/6. RAG1 -/- recipients of BALB/c cardiac allografts were passively transferred with donor-specific MHC I antibodies, mTOR inhibition significantly reduced vascular injury, ERM phosphorylation, and macrophage infiltration of the allograft. Taken together, these studies indicate mTOR inhibition suppresses ERM phosphorylation in endothelial cells, which impedes ICAM-1 clustering in response to HLA class I Ab and prevents macrophage infiltration into cardiac allografts. These findings indicate a novel therapeutic application for mTOR inhibitors to disrupt endothelial cell-monocyte interactions during AMR. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Impact of MLH1 expression on tumor evolution after curative surgical tumor resection in a murine orthotopic xenograft model for human MSI colon cancer.

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Meunier, Katy; Ferron, Marianne; Calmel, Claire; Fléjou, Jean-François; Pocard, Marc; Praz, Françoise

2017-09-01

Colorectal cancers (CRCs) displaying microsatellite instability (MSI) most often result from MLH1 deficiency. The aim of this study was to assess the impact of MLH1 expression per se on tumor evolution after curative surgical resection using a xenograft tumor model. Transplantable tumors established with the human MLH1-deficient HCT116 cell line and its MLH1-complemented isogenic clone, mlh1-3, were implanted onto the caecum of NOD/SCID mice. Curative surgical resection was performed at day 10 in half of the animals. The HCT116-derived tumors were more voluminous compared to the mlh1-3 ones (P = .001). Lymph node metastases and peritoneal carcinomatosis occurred significantly more often in the group of mice grafted with HCT116 (P = .007 and P = .035, respectively). Mlh1-3-grafted mice did not develop peritoneal carcinomatosis or liver metastasis. After surgical resection, lymph node metastases only arose in the group of mice implanted with HCT116 and the rate of cure was significantly lower than in the mlh1-3 group (P = .047). The murine orthotopic xenograft model based on isogenic human CRC cell lines allowed us to reveal the impact of MLH1 expression on tumor evolution in mice who underwent curative surgical resection and in mice whose tumor was left in situ. Our data indicate that the behavior of MLH1-deficient CRC is not only governed by mutations arising in genes harboring microsatellite repeated sequences but also from their defect in MLH1 as such. © 2017 Wiley Periodicals, Inc.

Differential gene expression of cardiac ion channels in human dilated cardiomyopathy.

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Maria Micaela Molina-Navarro

Full Text Available BACKGROUND: Dilated cardiomyopathy (DCM is characterized by idiopathic dilation and systolic contractile dysfunction of the cardiac chambers. The present work aimed to study the alterations in gene expression of ion channels involved in cardiomyocyte function. METHODS AND RESULTS: Microarray profiling using the Affymetrix Human Gene® 1.0 ST array was performed using 17 RNA samples, 12 from DCM patients undergoing cardiac transplantation and 5 control donors (CNT. The analysis focused on 7 cardiac ion channel genes, since this category has not been previously studied in human DCM. SCN2B was upregulated, while KCNJ5, KCNJ8, CLIC2, CLCN3, CACNB2, and CACNA1C were downregulated. The RT-qPCR (21 DCM and 8 CNT samples validated the gene expression of SCN2B (p < 0.0001, KCNJ5 (p < 0.05, KCNJ8 (p < 0.05, CLIC2 (p < 0.05, and CACNB2 (p < 0.05. Furthermore, we performed an IPA analysis and we found a functional relationship between the different ion channels studied in this work. CONCLUSION: This study shows a differential expression of ion channel genes involved in cardiac contraction in DCM that might partly underlie the changes in left ventricular function observed in these patients. These results could be the basis for new genetic therapeutic approaches.

Leukocyte and platelet depletion improves blood flow and function in a renal transplant model.

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Yates, Phillip J; Hosgood, Sarah A; Nicholson, Michael L

2012-01-01

Donation after cardiac death (DCD) donors are an important source of organs for transplantation. Due to warm and cold ischemic injury, DCD kidneys undergo a significant reperfusion insult when transplanted. This is manifested clinically as a high incidence of delayed graft function (DGF) and primary non-function (PNF). The importance of leukocytes in the generation of reperfusion injury is pivotal. Using an ex vivo porcine model of kidney transplantation, the effects of reperfusion with leukocyte and platelet depleted blood (LDB) and whole blood (WB) on renal blood flow and function were compared. Hemodynamic measurements were recorded, and biochemical, hematological, and histologic samples taken at set time-points. Reperfusion with LDB improved renal blood flow significantly compared with WB reperfusion. In addition, there was a significant improvement in creatinine clearance and renal oxygen consumption, but not fractional excretion of sodium, acid-base homeostasis, urinary nitric oxide (NO), or 8-isoprostane levels. This study represents a good model for the initial reperfusion period in renal transplantation. Improvement in only some functional markers and neither urinary NO nor 8-isoprostane levels indicates that improved blood flow alone is not sufficient to reverse the severe ischemic insult endured by DCD kidneys. Copyright © 2012 Elsevier Inc. All rights reserved.

Assessment of cardiotoxicity during haemopoietic stem cell transplantation with plasma brain natriuretic peptide.

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Snowden, J A; Hill, G R; Hunt, P; Carnoutsos, S; Spearing, R L; Espiner, E; Hart, D N

2000-08-01

Cardiac failure is a known complication of haemopoietic stem cell transplantation (HSCT) and is often difficult to diagnose as patients may have multiple medical problems. Since brain natriuretic peptide (BNP) is largely a hormone of cardiac ventricular origin and is released early in the course of ventricular dysfunction, we have examined the value of serial plasma BNP levels for detecting cardiac failure in patients undergoing cytotoxic conditioning for HSCT. Fifteen patients undergoing HSCT were evaluated (10 undergoing autologous HSCT; five undergoing allogeneic HSCT). BNP was measured by radioimmunoassay prior to therapy and weekly for 5 weeks. Seven patients had a significant rise in BNP level (above a previously established threshold of 43 pmol/l associated with cardiac failure), occurring 1-4 weeks post commencement of conditioning. In three of these patients, cardiac failure was subsequently diagnosed clinically 3, 9 and 23 days after a BNP level of 43 pmol/l had been detected. These three patients had the highest peak BNP levels for the group and in each case elevation in BNP level occurred for a period exceeding 1 week. Although numbers were relatively small, a BNP >43 pmol/l was significantly associated with the inclusion of high-dose cyclophosphamide in the preparative regimen (P = 0.02). BNP levels showed no relationship to febrile episodes. In conclusion, these results show that plasma BNP may be used as a marker for early detection of cardiac dysfunction in patients undergoing HSCT, particularly if levels are increased for periods exceeding 1 week. Measurement of BNP during HSCT may be helpful in patients at risk of cardiac failure, in complex clinical situations and in monitoring the cardiotoxicity of preparative regimens.

PERFORMANCE EVALUATION OF ENDOVASCULAR MYOCARDIUM REVASCULARIZATION IN RENAL TRANSPLANT RECIPIENTS

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I. G. Ryadovoy

2012-01-01

Full Text Available Coronary artery stenting was performed at 75 renal transplant recipients. Diffuse multiple and expressed calcified coronary artery disease took place that created many difficulties during the procedures. In result of endovascular treatments positive dynamics of clinical condition in the nearest postoperative period was marked, tolerance to physical exercise was increased and according to this the functional class of angina was reduced. Cardiac and general mortality after treatment in comparison to the data of foreign authors was lower and comparable with demographic death rate of the population for persons of the same sex and age. 

Kidney transplant

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... always take your medicine as directed. Alternative Names Renal transplant; Transplant - kidney Patient Instructions Kidney removal - discharge Images Kidney anatomy Kidney - blood and urine flow Kidneys Kidney transplant - ...

Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

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Lohse, Ines; Lourenco, Corey; Ibrahimov, Emin; Pintilie, Melania [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Tsao, Ming-Sound [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON M5G2C4 (Canada); Department of Laboratory Medicine and Pathobiology, 27 King’s College Circle, University of Toronto, Toronto, ON M5S1A1 (Canada); Hedley, David W., E-mail: david.hedley@uhn.ca [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medical Biophysics University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medicine, University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, 610 University Ave., Toronto, ON M5G2M9 (Canada)

2014-02-26

The unusually dense stroma of pancreatic cancers is thought to play an important role in their biological aggression. The presence of hypoxia is also considered an adverse prognostic factor. Although it is usually assumed that this is the result of effects of hypoxia on the epithelial component, it is possible that hypoxia exerts indirect effects via the tumor stroma. We therefore measured hypoxia in the stroma of a series of primary pancreatic cancer xenografts. Nine patient-derived pancreatic xenografts representing a range of oxygenation levels were labeled by immunohistochemistry for EF5 and analyzed using semi-automated pattern recognition software. Hypoxia in the tumor and stroma was correlated with tumor growth and metastatic potential. The extent of hypoxia varied from 1%–39% between the different models. EF5 labeling in the stroma ranged from 0–20% between models, and was correlated with the level of hypoxia in the tumor cell area, but not microvessel density. Tumor hypoxia correlated with spontaneous metastasis formation with the exception of one hypoxic model that showed disproportionately low levels of hypoxia in the stroma and was non-metastatic. Our results demonstrate that hypoxia exists in the stroma of primary pancreatic cancer xenografts and suggest that stromal hypoxia impacts the metastatic potential.

Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

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Francis Richard W

2010-04-01

Full Text Available Abstract Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL. However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models.

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Zhang, Libo; Vines, Douglass C; Scollard, Deborah A; McKee, Trevor; Komal, Teesha; Ganguly, Milan; Do, Trevor; Wu, Bing; Alexander, Natasha; Vali, Reza; Shammas, Amer; Besanger, Travis; Baruchel, Sylvain

2017-01-01

Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68 Ga-DOTA-TATE and 177 Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2) expression with 68 Ga-DOTA-TATE uptake and 177 Lu-DOTA-TATE therapy in neuroblastoma (NB) xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68 Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15) compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2)). Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68 Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177 Lu-DOTA-TATE (20 MBq/animal), tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro , NB cells showed variable expression levels of norepinephrine transporter (NET), a molecular target for 131 I-MIBG therapy, low 123 I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68 Ga-DOTA-TATE uptake and antitumor efficacy of 177 Lu-DOTA-TATE. 68 Ga-DOTA-TATE PET is superior to 123 I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177 Lu-DOTA-TATE therapy.

Correlation of Somatostatin Receptor-2 Expression with Gallium-68-DOTA-TATE Uptake in Neuroblastoma Xenograft Models

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Libo Zhang

2017-01-01

Full Text Available Peptide-receptor imaging and therapy with radiolabeled somatostatin analogs such as 68Ga-DOTA-TATE and 177Lu-DOTA-TATE have become an effective treatment option for SSTR-positive neuroendocrine tumors. The purpose of this study was to evaluate the correlation of somatostatin receptor-2 (SSTR2 expression with 68Ga-DOTA-TATE uptake and 177Lu-DOTA-TATE therapy in neuroblastoma (NB xenograft models. We demonstrated variable SSTR2 expression profiles in eight NB cell lines. From micro-PET imaging and autoradiography, a higher uptake of 68Ga-DOTA-TATE was observed in SSTR2 high-expressing NB xenografts (CHLA-15 compared to SSTR2 low-expressing NB xenografts (SK-N-BE(2. Combined autoradiography-immunohistochemistry revealed histological colocalization of SSTR2 and 68Ga-DOTA-TATE uptake in CHLA-15 tumors. With a low dose of 177Lu-DOTA-TATE (20 MBq/animal, tumor growth inhibition was achieved in the CHLA-15 high SSTR2 expressing xenograft model. Although, in vitro, NB cells showed variable expression levels of norepinephrine transporter (NET, a molecular target for 131I-MIBG therapy, low 123I-MIBG uptake was observed in all selected NB xenografts. In conclusion, SSTR2 expression levels are associated with 68Ga-DOTA-TATE uptake and antitumor efficacy of 177Lu-DOTA-TATE. 68Ga-DOTA-TATE PET is superior to 123I-MIBG SPECT imaging in detecting NB tumors in our model. Radiolabeled DOTA-TATE can be used as an agent for NB tumor imaging to potentially discriminate tumors eligible for 177Lu-DOTA-TATE therapy.

Pancreatic Islet Cell Transplantation: A new era in transplantation

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Warnock, Garth L.; Rajotte, Ray V.

1992-01-01

Transplantation of insulin-producing tissue offers a physiologic approach to restoration of glycemic control. Whereas transplantation of vascularized pancreatic grafts has recently achieved encouraging results, pancreatic islet cell transplantation holds the promise of low morbidity and reduced requirements for agressive immunosuppression for recipients. Islet cell transplantation was recently demonstrated to induce euglycemia with insulin independence.

Expression of a Chimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potency of Human Regulatory T Cells in Preventing Human Skin Transplant Rejection.

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Boardman, D A; Philippeos, C; Fruhwirth, G O; Ibrahim, M A A; Hannen, R F; Cooper, D; Marelli-Berg, F M; Watt, F M; Lechler, R I; Maher, J; Smyth, L A; Lombardi, G

2017-04-01

Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens. We used CAR technology to redirect human polyclonal Tregs toward donor-MHC class I molecules, which are ubiquitously expressed in allografts. Two novel HLA-A2-specific CARs were engineered: one comprising a CD28-CD3ζ signaling domain (CAR) and one lacking an intracellular signaling domain (ΔCAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or ΔCAR Tregs in the presence of HLA-A2, without eliciting cytotoxic activity. Furthermore, CAR and ΔCAR Tregs preferentially transmigrated across HLA-A2-expressing endothelial cell monolayers. In a human skin xenograft transplant model, adoptive transfer of CAR Tregs alleviated the alloimmune-mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs. Our results demonstrated that the use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Placental Growth Factor Promotes Cardiac Muscle Repair via Enhanced Neovascularization

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Jianfeng Zhang

2015-06-01

Full Text Available Background/Aims: Transplantation of mesenchymal stem cells (MSCs improves post-injury cardiac muscle repair using ill-defined mechanisms. Recently, we have shown that production and secretion of placental growth factor (PLGF by MSCs play a critical role in the MSCs-mediated post-injury cardiac muscle repair. In this study, we addressed the underlying molecular mechanisms, focusing specifically on the interactions between MSCs, macrophages and endothelial cells. Methods: We isolated macrophages (BM-MΦ from mouse bone-marrow derived cells based on F4/80 expression by flow cytometry. BM-MΦ were treated with different doses of PLGF. Cell number was analyzed by a MTT assay. Macrophage polarization was examined based on CD206 expression by flow cytometry. PLGF levels in macrophage subpopulations were analyzed by RT-qPCR and ELISA. Effects of macrophages on vascularization were evaluated by a collagen gel assay using Human umbilical vein endothelial cells (HUVECs co-cultured with PLGF-treated macrophages. Results: PLGF did not increase macrophage number, but dose-dependently polarized macrophages into a M2 subpopulation. M2 macrophages expressed high levels of PLGF. PLGF-polarized M2 macrophages significantly increased tubular structures in the collagen gel assay. Conclusion: Our data suggest that MSCs-derived PLGF may induce macrophage polarization into a M2 subpopulation, which in turn releases more PLGF to promote local neovascularization for augmenting post-injury cardiac muscle repair. This study thus sheds novel light on the role of PLGF in cardiac muscle regeneration.

Delayed revascularization of islets after transplantation by IL-6 blockade in pig to non-human primate islet xenotransplantation model.

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Min, Byoung-Hoon; Shin, Jun-Seop; Kim, Jong-Min; Kang, Seong-Jun; Kim, Hyun-Je; Yoon, Il-Hee; Park, Su-Kyoung; Choi, Ji-Won; Lee, Min-Suk; Park, Chung-Gyu

2018-01-01

Pancreatic islet transplantation is currently proven as a promising treatment for type 1 diabetes patients with labile glycemic control and severe hypoglycemia unawareness. Upon islet transplantation, revascularization is essential for proper functioning of the transplanted islets. As IL-6 is important for endothelial cell survival and systemic inflammation related to xenograft, the effect of IL-6 receptor antagonist, tocilizumab, on revascularization of the transplanted islets was examined in pig to non-human primate islet xenotransplantation model. Also, the endothelial cell origin in a new vessel of the transplanted pig islets was determined. Pig islets were isolated from designated pathogen-free (DPF) SNU miniature pigs and transplanted via portal vein into five streptozotocin-induced diabetic monkeys. One group (n = 2, basal group) was treated with anti-thymoglobulin (ATG), anti-CD40 antibody (2C10R4), sirolimus, and tacrolimus, and the other group was additionally given tocilizumab on top of basal immunosuppression (n = 3, Tocilizumab group). To confirm IL-6 blocking effect, C-reactive protein (CRP) levels and serum IL-6 concentration were measured. Scheduled biopsy of the margin of the posterior segment right lobe inferior of the liver was performed at 3 weeks after transplantation to assess the degree of revascularization of the transplanted islets. Immunohistochemical staining using anti-insulin, anti-CD31 antibodies, and lectin IB4 was conducted to find the origin of endothelial cells in the islet graft. CRP significantly increased at 1~2 days after transplantation in Basal group, but not in Tocilizumab group, and higher serum IL-6 concentration was measured in latter group, showing the biological potency of tocilizumab. In Basal group, well-developed endothelial cells were observed on the peri- and intraislet area, whereas the number of CD31 + cells in the intraislet space was significantly reduced in Tocilizumab group. Finally, new endothelial

Prevention of Human Lymphoproliferative Tumor Formation in Ovarian Cancer Patient-Derived Xenografts

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Kristina A. Butler

2017-08-01

Full Text Available Interest in preclinical drug development for ovarian cancer has stimulated development of patient-derived xenograft (PDX or tumorgraft models. However, the unintended formation of human lymphoma in severe combined immunodeficiency (SCID mice from Epstein-Barr virus (EBV–infected human lymphocytes can be problematic. In this study, we have characterized ovarian cancer PDXs which developed human lymphomas and explore methods to suppress lymphoproliferative growth. Fresh human ovarian tumors from 568 patients were transplanted intraperitoneally in SCID mice. A subset of PDX models demonstrated atypical patterns of dissemination with mediastinal masses, hepatosplenomegaly, and CD45-positive lymphoblastic atypia without ovarian tumor engraftment. Expression of human CD20 but not CD3 supported a B-cell lineage, and EBV genomes were detected in all lymphoproliferative tumors. Immunophenotyping confirmed monoclonal gene rearrangements consistent with B-cell lymphoma, and global gene expression patterns correlated well with other human lymphomas. The ability of rituximab, an anti-CD20 antibody, to suppress human lymphoproliferation from a patient's ovarian tumor in SCID mice and prevent growth of an established lymphoma led to a practice change with a goal to reduce the incidence of lymphomas. A single dose of rituximab during the primary tumor heterotransplantation process reduced the incidence of CD45-positive cells in subsequent PDX lines from 86.3% (n = 117 without rituximab to 5.6% (n = 160 with rituximab, and the lymphoma rate declined from 11.1% to 1.88%. Taken together, investigators utilizing PDX models for research should routinely monitor for lymphoproliferative tumors and consider implementing methods to suppress their growth.

Generation of Antigen Microarrays to Screen for Autoantibodies in Heart Failure and Heart Transplantation.

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Andrzej Chruscinski

Full Text Available Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen. Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this technique using two sets of samples that were obtained at our institution. In the first retrospective study, we profiled pre-transplant sera from 24 heart failure patients who subsequently received heart transplants. We identified 8 antibody reactivities that were higher in patients who developed cellular rejection (2 or more episodes of grade 2R rejection in first year after transplant as defined by revised criteria from the International Society for Heart and Lung Transplantation compared with those who did have not have rejection episodes. In a second retrospective study with 31 patients, we identified 7 IgM reactivities that were higher in heart transplant recipients who developed antibody-mediated rejection (AMR compared with control recipients, and in time course studies, these reactivities appeared prior to overt graft dysfunction. In conclusion, we demonstrated that the autoantibody microarray technique outperforms traditional ELISAs as it uses less patient

Human Sulfatase 2 inhibits in vivo tumor growth of MDA-MB-231 human breast cancer xenografts

International Nuclear Information System (INIS)

Peterson, Sarah M; Concino, Michael F; Liaw, Lucy; Martini, Paolo GV; Iskenderian, Andrea; Cook, Lynette; Romashko, Alla; Tobin, Kristen; Jones, Michael; Norton, Angela; Gómez-Yafal, Alicia; Heartlein, Michael W

2010-01-01

Extracellular human sulfatases modulate growth factor signaling by alteration of the heparin/heparan sulfate proteoglycan (HSPG) 6-O-sulfation state. HSPGs bind to numerous growth factor ligands including fibroblast growth factors (FGF), epidermal growth factors (EGF), and vascular endothelial growth factors (VEGF), and are critically important in the context of cancer cell growth, invasion, and metastasis. We hypothesized that sulfatase activity in the tumor microenvironment would regulate tumor growth in vivo. We established a model of stable expression of sulfatases in the human breast cancer cell line MDA-MB-231 and purified recombinant human Sulfatase 2 (rhSulf2) for exogenous administration. In vitro studies were performed to measure effects on breast cancer cell invasion and proliferation, and groups were statistically compared using Student's t-test. The effects of hSulf2 on tumor progression were tested using in vivo xenografts with two methods. First, MDA-MB-231 cells stably expressing hSulf1, hSulf2, or both hSulf1/hSulf2 were grown as xenografts and the resulting tumor growth and vascularization was compared to controls. Secondly, wild type MDA-MB-231 xenografts were treated by short-term intratumoral injection with rhSulf2 or vehicle during tumor growth. Ultrasound analysis was also used to complement caliper measurement to monitor tumor growth. In vivo studies were statistically analyzed using Student's t test. In vitro, stable expression of hSulf2 or administration of rhSulf2 in breast cancer cells decreased cell proliferation and invasion, corresponding to an inhibition of ERK activation. Stable expression of the sulfatases in xenografts significantly suppressed tumor growth, with complete regression of tumors expressing both hSulf1 and hSulf2 and significantly smaller tumor volumes in groups expressing hSulf1 or hSulf2 compared to control xenografts. Despite significant suppression of tumor volume, sulfatases did not affect vascular

Clinical application of l-123 MlBG cardiac imaging

International Nuclear Information System (INIS)

Kang, Do Young

2004-01-01

Cardiac neurotransmission imaging allows in vivo assessment of presynaptic reuptake, neurotransmitter storage and postsynaptic receptors. Among the various neurotransmitter, I-123 MlBG is most available and relatively well-established. Metaiodobenzylguanidine (MIBG) is an analogue of the false neurotransmitter guanethidine. It is taken up to adrenergic neurons by uptake-1 mechanism as same as norepinephrine. As tagged with I-123, it can be used to image sympathetic function in various organs including heart with planar or SPECT techniques. I-123 MIBG imaging has a unique advantage to evaluate myocardial neuronal activity in which the heart has no significant structural abnormality or even no functional derangement measured with other conventional examination. In patients with cardiomyopathy and heart failure, this imaging has most sensitive technique to predict prognosis and treatment response of betablocker or ACE inhibitor. In diabetic patients, it allow very early detection of autonomic neuropathy. In patients with dangerous arrhythmia such as ventricular tachycardia or fibrillation, MIBG imaging may be only an abnormal result among various exams. In patients with ischemic heart disease, sympathetic derangement may be used as the method of risk stratification. In heart transplanted patients, sympathetic reinnervation is well evaluated. Adriamycin-induced cardiotoxicity is detected earlier than ventricular dysfunction with sympathetic dysfunction. Neurodegenerative disorder such as Parkinson's disease or dementia with Lewy bodies has also cardiac sympathetic dysfunction. Noninvasive assessment of cardiac sympathetic nerve activity with l-123 MlBG imaging may be improve understanding of the pathophysiology of cardiac disease and make a contribution to predict survival and therapy efficacy

Clinical application of l-123 MlBG cardiac imaging

Energy Technology Data Exchange (ETDEWEB)

Kang, Do Young [College of Medicine, Donga Univ., Busan (Korea, Republic of)

2004-10-01

Cardiac neurotransmission imaging allows in vivo assessment of presynaptic reuptake, neurotransmitter storage and postsynaptic receptors. Among the various neurotransmitter, I-123 MlBG is most available and relatively well-established. Metaiodobenzylguanidine (MIBG) is an analogue of the false neurotransmitter guanethidine. It is taken up to adrenergic neurons by uptake-1 mechanism as same as norepinephrine. As tagged with I-123, it can be used to image sympathetic function in various organs including heart with planar or SPECT techniques. I-123 MIBG imaging has a unique advantage to evaluate myocardial neuronal activity in which the heart has no significant structural abnormality or even no functional derangement measured with other conventional examination. In patients with cardiomyopathy and heart failure, this imaging has most sensitive technique to predict prognosis and treatment response of betablocker or ACE inhibitor. In diabetic patients, it allow very early detection of autonomic neuropathy. In patients with dangerous arrhythmia such as ventricular tachycardia or fibrillation, MIBG imaging may be only an abnormal result among various exams. In patients with ischemic heart disease, sympathetic derangement may be used as the method of risk stratification. In heart transplanted patients, sympathetic reinnervation is well evaluated. Adriamycin-induced cardiotoxicity is detected earlier than ventricular dysfunction with sympathetic dysfunction. Neurodegenerative disorder such as Parkinson's disease or dementia with Lewy bodies has also cardiac sympathetic dysfunction. Noninvasive assessment of cardiac sympathetic nerve activity with l-123 MlBG imaging may be improve understanding of the pathophysiology of cardiac disease and make a contribution to predict survival and therapy efficacy.

Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts

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Rémy Nicolle

2017-11-01

Full Text Available Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively. Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

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Clemens Krepler

2017-11-01

Full Text Available Summary: Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups. : Krepler et al. have established a collection of melanoma patient-derived xenografts (PDX. Melanoma is a very heterogeneous cancer, and this large collection includes even rare subtypes and genetic aberrations in sufficient numbers. Multiple PDX from therapy-resistant patients are characterized and tested in pre-clinical trials for second line therapies. Keywords: melanoma, patient-derived xenografts, targeted therapy, immune checkpoint blockade, melanoma brain metastasis, in vivo models, BRAF inhibitor resistance, ERK inhibitor, MDM2 inhibitor, PI3K beta inhibitor

Identification of Biomarkers of Necrosis in Xenografts Using Imaging Mass Spectrometry.

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Fernández, Roberto; Garate, Jone; Lage, Sergio; Terés, Silvia; Higuera, Mónica; Bestard-Escalas, Joan; López, Daniel H; Guardiola-Serrano, Francisca; Escribá, Pablo V; Barceló-Coblijn, Gwendolyn; Fernández, José A

2016-02-01

Xenografts are commonly used to test the effect of new drugs on human cancer. However, because of their heterogeneity, analysis of the results is often controversial. Part of the problem originates in the existence of tumor cells at different metabolic stages: from metastatic to necrotic cells, as it happens in real tumors. Imaging mass spectrometry is an excellent solution for the analysis of the results as it yields detailed information not only on the composition of the tissue but also on the distribution of the biomolecules within the tissue. Here, we use imaging mass spectrometry to determine the distribution of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and their plasmanyl- and plasmenylether derivatives (PC-P/O and PE-P/O) in xenografts of five different tumor cell lines: A-549, NCI-H1975, BX-PC3, HT29, and U-87 MG. The results demonstrate that the necrotic areas showed a higher abundance of Na(+) adducts and of PC-P/O species, whereas a large abundance of PE-P/O species was found in all the xenografts. Thus, the PC/PC-ether and Na(+)/K(+) ratios may highlight the necrotic areas while an increase on the number of PE-ether species may be pointing to the existence of viable tumor tissues. Furthermore, the existence of important changes in the concentration of Na(+) and K(+) adducts between different tissues has to be taken into account while interpreting the imaging mass spectrometry results. Graphical Abstract ᅟ.

Effect of human leukocyte antigen-C and -DQ matching on pediatric heart transplant graft survival.

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Butts, Ryan J; Savage, Andrew J; Nietert, Paul J; Kavarana, Minoo; Moussa, Omar; Burnette, Ali L; Atz, Andrew M

2014-12-01

A higher degree of human leukocyte antigen (HLA) matching at the A, B, and DR loci has been associated with improved long-term survival after pediatric heart transplantation in multiple International Society for Heart and Lung Transplantation registry reports. The aim of this study was to investigate the association of HLA matching at the C and DQ loci with pediatric graft survival. The United Network of Organ Sharing database was queried for isolated heart transplants that occurred from 1988 to 2012 with a recipient age of 17 or younger and at least 1 postoperative follow-up encounter. When HLA matching at the C or DQ loci were analyzed, only transplants with complete typing of donor and recipient at the respective loci were included. Transplants were divided into patients with at least 1 match at the C locus (C-match) vs no match (C-no), and at least 1 match at the DQ (DQ-match) locus vs no match (DQ-no). Primary outcome was graft loss. Univariate analysis was performed with the log-rank test. Cox regression analysis was performed with the following patient factors included in the model: recipient age, ischemic time; recipient on ventilator, extracorporeal membrane oxygenation, ventricular assist device, or inotropes at transplant; recipient serum bilirubin and creatinine closest to transplant, ratio of donor weight to recipient weight, underlying cardiac diagnosis, crossmatch results, transplant year, and HLA matching at the A, B, and DR loci. Complete typing at the C locus occurred in 2,429 of 4,731 transplants (51%), and complete typing at the DQ locus occurred in 3,498 of 4,731 transplants (74%). Patient factors were similar in C-match and C-no, except for year of transplant (median year, 2007 [interquartile range, 1997-2010] vs year 2005 [interquartile range, 1996-2009], respectively; p = 0.03) and the degree of HLA matching at the A, B, and DR loci (high level of HLA matching in 11.9% vs 3%, respectively; p HLA matching at the C locus or the DQ locus

Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide.

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Amanda E Hargrove

Full Text Available Pyrrole-imidazole (Py-Im polyamides are high affinity DNA-binding small molecules that can inhibit protein-DNA interactions. In VCaP cells, a human prostate cancer cell line overexpressing both AR and the TMPRSS2-ERG gene fusion, an androgen response element (ARE-targeted Py-Im polyamide significantly downregulates AR driven gene expression. Polyamide exposure to VCaP cells reduced proliferation without causing DNA damage. Py-Im polyamide treatment also reduced tumor growth in a VCaP mouse xenograft model. In addition to the effects on AR regulated transcription, RNA-seq analysis revealed inhibition of topoisomerase-DNA binding as a potential mechanism that contributes to the antitumor effects of polyamides in cell culture and in xenografts. These studies support the therapeutic potential of Py-Im polyamides to target multiple aspects of transcriptional regulation in prostate cancers without genotoxic stress.

Intestine Transplant

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... After the transplant Preventing rejection Post-transplant medications Types of immunosuppressants Switching immunosuppressants Side effects Other medications Generic and brand name drugs Post-transplant tests Infections and immunity Lifestyle changes Health concerns Back to work or ...

Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression.

Science.gov (United States)

Aron Badin, R; Vadori, M; Vanhove, B; Nerriere-Daguin, V; Naveilhan, P; Neveu, I; Jan, C; Lévèque, X; Venturi, E; Mermillod, P; Van Camp, N; Dollé, F; Guillermier, M; Denaro, L; Manara, R; Citton, V; Simioni, P; Zampieri, P; D'avella, D; Rubello, D; Fante, F; Boldrin, M; De Benedictis, G M; Cavicchioli, L; Sgarabotto, D; Plebani, M; Stefani, A L; Brachet, P; Blancho, G; Soulillou, J P; Hantraye, P; Cozzi, E

2016-07-01

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Interrogating open issues in cancer precision medicine with patient-derived xenografts

NARCIS (Netherlands)

Byrne, Annette T; Alférez, Denis G; Amant, Frédéric; Annibali, Daniela; Arribas, Joaquín; Biankin, Andrew V; Bruna, Alejandra; Budinská, Eva; Caldas, Carlos; Chang, David K; Clarke, Robert B; Clevers, Hans; Coukos, George; Dangles-Marie, Virginie; Eckhardt, S Gail; Gonzalez-Suarez, Eva; Hermans, Els; Hidalgo, Manuel; Jarzabek, Monika A; de Jong, Steven; Jonkers, Jos; Kemper, Kristel; Lanfrancone, Luisa; Mælandsmo, Gunhild Mari; Marangoni, Elisabetta; Marine, Jean-Christophe; Medico, Enzo; Norum, Jens Henrik; Palmer, Héctor G; Peeper, Daniel S; Pelicci, Pier Giuseppe; Piris-Gimenez, Alejandro; Roman-Roman, Sergio; Rueda, Oscar M; Seoane, Joan; Serra, Violeta; Soucek, Laura; Vanhecke, Dominique; Villanueva, Alberto; Vinolo, Emilie; Bertotti, Andrea; Trusolino, Livio

Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer

Interrogating open issues in cancer precision medicine with patient-derived xenografts

NARCIS (Netherlands)

Byrne, Annette T.; Alférez, Denis G.; Amant, Frédéric; Annibali, Daniela; Arribas, Joaquín; Biankin, Andrew V.; Bruna, Alejandra; Budinská, Eva; Caldas, Carlos; Chang, David K.; Clarke, Robert B.; Clevers, Hans; Coukos, George; Dangles-Marie, Virginie; Eckhardt, S. Gail; Gonzalez-Suarez, Eva; Hermans, Els; Hidalgo, Manuel; Jarzabek, Monika A.; de Jong, Steven; Jonkers, Jos; Kemper, Kristel; Lanfrancone, Luisa; Mælandsmo, Gunhild Mari; Marangoni, Elisabetta; Marine, Jean-Christophe; Medico, Enzo; Norum, Jens Henrik; Palmer, Héctor G.; Peeper, Daniel S.; Pelicci, Pier Giuseppe; Piris-Gimenez, Alejandro; Roman-Roman, Sergio; Rueda, Oscar M.; Seoane, Joan; Serra, Violeta; Soucek, Laura; Vanhecke, Dominique; Villanueva, Alberto; Vinolo, Emilie; Bertotti, Andrea; Trusolino, Livio

2017-01-01

Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer

Human cardiac stem cells exhibit mesenchymal features and are maintained through Akt/GSK-3β signaling

International Nuclear Information System (INIS)

Tateishi, Kento; Ashihara, Eishi; Honsho, Shoken; Takehara, Naofumi; Nomura, Tetsuya; Takahashi, Tomosaburo; Ueyama, Tomomi; Yamagishi, Masaaki; Yaku, Hitoshi; Matsubara, Hiroaki; Oh, Hidemasa

2007-01-01

Recent evidence suggested that human cardiac stem cells (hCSCs) may have the clinical application for cardiac repair; however, their characteristics and the regulatory mechanisms of their growth have not been fully investigated. Here, we show the novel property of hCSCs with respect to their origin and tissue distribution in human heart, and demonstrate the signaling pathway that regulates their growth and survival. Telomerase-active hCSCs were predominantly present in the right atrium and outflow tract of the heart (infant > adult) and had a mesenchymal cell-like phenotype. These hCSCs expressed the embryonic stem cell markers and differentiated into cardiomyocytes to support cardiac function when transplanted them into ischemic myocardium. Inhibition of Akt pathway impaired the hCSC proliferation and induced apoptosis, whereas inhibition of glycogen synthase kinase-3 (GSK-3) enhanced their growth and survival. We conclude that hCSCs exhibit mesenchymal features and that Akt/GSK-3β may be crucial modulators for hCSC maintenance in human heart

Cardiac imaging : X-ray, magnetic resonance and ultrasound in congenital heart diseases

International Nuclear Information System (INIS)

Rigby, M.L.

1991-01-01

In many instances, the management of simple or common congenital cardiac anomalies, such as patient arterial duct, atrial septal defect or ventricular septal defect, can be based upon clinical evaluation, the chest radiograph and conventional transthoracic echocardiography and Doppler investigation. Angiography is usually required for those conditions, such as the tetralogy of Fallot, in which the size and anatomy of the pulmonary arteries influence the timing or the type of surgical intervention. Interventional cardiac catheterization, however, requires high quality X-ray screening and, frequently, transesophageal echocardiography. The investigation of more complex anomalies, such as those in hearts with a univentricular atrioventricular connection, often involves several methods of investigation. These complex anomalies require complete morphological and physiological assessment in order to provide optimum medical and surgical management. Increasingly, the diagnosis is established in utero. Should termination of pregnancy then be encouraged? Or, should all patients be subjected to an aggressive medical and surgical treatment regimen to optimize the chances of a later successful Fontan operation? Finally, what is the role of cardiac transplantation or the Norwood operation in those infants in whom the long term prognosis of conventional treatment is considered to be poor? (author). 20 refs.; 6 figs

Islet alloautotransplantation: Allogeneic pancreas transplantation followed by transplant pancreatectomy and islet transplantation.

Science.gov (United States)

Nijhoff, M F; Dubbeld, J; van Erkel, A R; van der Boog, P J M; Rabelink, T J; Engelse, M A; de Koning, E J P

2018-04-01

Simultaneous pancreas-kidney (SPK) transplantation is an important treatment option for patients with type 1 diabetes (T1D) and end-stage renal disease (ESRD). Due to complications, in up to 10% of patients, allograft pancreatectomy is necessary shortly after transplantation. Usually the donor pancreas is discarded. Here, we report on a novel procedure to rescue endocrine tissue after allograft pancreatectomy. A 39-year-old woman with T1D and ESRD who had undergone SPK transplantation required emergency allograft pancreatectomy due to bleeding at the vascular anastomosis. Islets were isolated from the removed pancreas allograft, and almost 480 000 islet equivalents were infused into the portal vein. The patient recovered fully. After 3 months, near-normal mixed meal test (fasting glucose 7.0 mmol/L, 2-hour glucose 7.5 mmol/L, maximal stimulated C-peptide 3.25 nmol/L, without insulin use in the preceding 36 hours) was achieved. Glycated hemoglobin while taking a low dose of long-acting insulin was 32.7 mmol/mol hemoglobin (5.3%). When a donor pancreas is lost after transplantation, rescue β cell therapy by islet alloautotransplantation enables optimal use of scarce donor pancreata to optimize glycemic control without additional HLA alloantigen exposure. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Transplant tourism among kidney transplant patients in Eastern Nigeria.

Science.gov (United States)

Okafor, U H

2017-07-05

Transplant tourism entails movement of recipient, donor or both to a transplant centre outside their country of residence. This has been reported in many countries; and has variously been associated with organ trade. The objective of this study is to determine the frequency and pattern of transplant tourism among transplant patients in Eastern Nigeria. This is a non randomized cross sectional study. All kidney transplant patients who presented at Enugu State University Teaching Hospital Parklane Enugu and Hilton Clinics Port Harcourt in Nigeria were recruited. The clinical parameters including the transplant details of all the patients were documented. The data obtained was analysed using SPSS package. A total of one hundred and twenty six patients were studied, 76.2% were males with M:F ratio of 3.2:1 and mean age of 46.9 ± 13.3 years. Fifty four and 58.7% of the patients were managed in a tertiary hospital and by a nephrologist respectively before referral for kidney transplant. Only 15.8% of the patients had their kidney transplant without delay: finance, lack of donor, logistics including delay in obtaining travelling documents were the common causes of the delay. Ninety percent of the patients had their transplant in India with majority of them using commercial donors. India was also the country with cheapest cost ($18,000.00). 69.8% were unrelated donors, 68.2% were commercial donors and 1.6% of the donors were spouse. All the commercial donors received financial incentives and each commercial donor received mean of 7580 ± 1280 dollars. Also 30.2% of the related donors demanded financial incentive. Transplant tourism is prevalent in eastern Nigeria.

G-CSF treatment after myocardial infarction: impact on bone marrow-derived vs cardiac progenitor cells.

Science.gov (United States)

Brunner, Stefan; Huber, Bruno C; Fischer, Rebekka; Groebner, Michael; Hacker, Marcus; David, Robert; Zaruba, Marc-Michael; Vallaster, Marcus; Rischpler, Christoph; Wilke, Andrea; Gerbitz, Armin; Franz, Wolfgang-Michael

2008-06-01

Besides its classical function in the field of autologous and allogenic stem cell transplantation, granulocyte colony-stimulating factor (G-CSF) was shown to have protective effects after myocardial infarction (MI) by mobilization of bone marrow-derived progenitor cells (BMCs) and in addition by activation of multiple signaling pathways. In the present study, we focused on the impact of G-CSF on migration of BMCs and the impact on resident cardiac cells after MI. Mice (C57BL/6J) were sublethally irradiated, and BM from green fluorescent protein (GFP)-transgenic mice was transplanted. Coronary artery ligation was performed 10 weeks later. G-CSF (100 microg/kg) was daily injected for 6 days. Subpopulations of enhanced GFP(+) cells in peripheral blood, bone marrow, and heart were characterized by flow cytometry. Growth factor expression in the heart was analyzed by quantitative real-time polymerase chain reaction. Perfusion was investigated in vivo by gated single photon emission computed tomography (SPECT). G-CSF-treated animals revealed a reduced migration of c-kit(+) and CXCR-4(+) BMCs associated with decreased expression levels of the corresponding growth factors, namely stem cell factor and stromal-derived factor-1 alpha in ischemic myocardium. In contrast, the number of resident cardiac Sca-1(+) cells was significantly increased. However, SPECT-perfusion showed no differences in infarct size between G-CSF-treated and control animals 6 days after MI. Our study shows that G-CSF treatment after MI reduces migration capacity of BMCs into ischemic tissue, but increases the number of resident cardiac cells. To optimize homing capacity a combination of G-CSF with other agents may optimize cytokine therapy after MI.

Anterior cruciate ligament reconstruction with a novel porcine xenograft: the initial Italian experience

Science.gov (United States)

ZAFFAGNINI, STEFANO; GRASSI, ALBERTO; MUCCIOLI, GIULIO MARIA MARCHEGGIANI; DI SARSINA, TOMMASO ROBERTI; RAGGI, FEDERICO; BENZI, ANDREA; MARCACCI, MAURILIO

2015-01-01

At the current state of the art in anterior cruciate ligament (ACL) reconstruction, multiple techniques have been presented but none has given clearly defined and improved results. One of the main issues concerns the choice of graft. The concept of using xenograft tissue, defined as a graft tissue from one species and destined for implantation in an unlike species, was introduced in order to try to overcome the mechanical and biological concerns associated with synthetic materials and the safety and quality concerns and availability problems of allograft tissue. Xenograft tissue carries the risk of producing an immunological reaction. In order to try to overcome or attenuate the immune response against porcine xenograft tissue, the Z-Process® (Aperion Biologics Inc, San Antonio, Texas, USA) has been developed and used to produce the Z-Lig® family of devices for ACL reconstruction procedures. Z-Lig® is a tendon graft with or without bone blocks, sourced from animal tissue in a manner consistent with what has normally been sourced from human tissue, and processed to overcome anti-Gal-mediated rejection and to attenuate other immunological recognition in humans. All this while ensuring sterility, viral inactivation and preservation of mechanical proprieties appropriate for an ACL reconstruction device. The Z-Lig® device has been tested in skeletally mature monkeys and given interesting and promising results from the preclinical performance and safety profile point of view. On this basis, it was possible to proceed with the first clinical trial involving humans, which gave similar encouraging results. The Z-Lig® device has also been implanted in Italy at the Rizzoli Orthopaedic Institute in Bologna, as a part of international multicenter prospective randomized blinded controlled study aimed at comparing xenograft with allograft tissue. PMID:26605257

Patient-Derived Xenograft Models : An Emerging Platform for Translational Cancer Research

NARCIS (Netherlands)

Hidalgo, Manuel; Amant, Frederic; Biankin, Andrew V.; Budinska, Eva; Byrne, Annette T.; Caldas, Carlos; Clarke, Robert B.; de Jong, Steven; Jonkers, Jos; Maelandsmo, Gunhild Mari; Roman-Roman, Sergio; Seoane, Joan; Trusolino, Livio; Villanueva, Alberto

Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These

Activity of a new nitrosourea (TCNU) in human lung cancer xenografts.

Science.gov (United States)

Fergusson, R. J.; Anderson, L. E.; Macpherson, J. S.; Robins, P.; Smyth, J. F.

1988-01-01

The activity of a new nitrosourea (TCNU) based on the endogenous amino acid taurine was assessed in three human lung cancer xenografts growing in immunodeficient mice. Moderate activity (specific growth delays of 0.63 and 1.13 compared with controls) was seen in two non-small cell tumours after a single oral administration of 20 mg-1kg. This dose was curative in a small cell xenograft. By using high performance liquid chromatography it was possible to detect parent drug in the tumours as well as the plasma and tissues after oral administration of TCNU. Drug sensitivity was correlated inversely with the amount of the DNA repair enzyme 0(6)-methylguanine-DNA methyltransferase assayed from extracts of the tumour cells but not with the levels of parent drug within the tumour. This compound appears to have unique pharmacokinetic properties compared with other chloroethylnitrosoureas. PMID:3390369

Perfusion device for liver preservation ex vivo before transplantation: first experimental study

Directory of Open Access Journals (Sweden)

O. N. Reznik

2017-01-01

Full Text Available Introduction. Successful liver transplantation including from donors with a sudden irreversible cardiac arrest requires the use of modern hardware and technical support to maintain, select and sustain organ viability for the period from harvesting to transplantation to the recipient.Materials and methods. Hardware-software system (HSS developed by the Russian State Scientific Center for Robotics and Technical Cybernetics (RTC was used for testing of normothermic perfusion of donor’s liver ex vivo. The experiment was conducted on the isolated pig liver (Duroc breed in accordance with the ethical principles.Result. During perfusion spontaneous recovery of bile outflow through the cannula installed in the common bile duct (volume of bile released – 240 ml was observed, and the color and uniformity of the perfused liver did not differ from the normal parameters. Biochemical indicators were stabilized at the physiological values after 40 minutes of perfusion procedure.Conclusion. Isolated liver transplant was completely restored after 30 minutes of warm ischemia and was functioning well due to ex vivo perfusion procedure on the new perfusion device. The first case of the new device usage for normothermic liver ex vivo demonstrated hopeful results to be further investigated.

The Eurotransplant High-Urgency Heart Transplantation Program: an option for patients in acute heart failure?

Science.gov (United States)

Koch, A; Tochtermann, U; Remppis, A; Dengler, T J; Schnabel, P A; Hagl, S; Sack, F U

2006-09-01

The Eurotransplant High-Urgency (HU) Heart Transplantation Program allows urgent heart transplants to be carried out in rapidly deteriorating patients with acute-to-chronic heart failure on the elective waiting list. But do the results of HU heart transplantation justify performing primary heart transplantation in these critically ill patients and offer an acceptable outcome? Between 2000 and 2004, 64 heart transplantations (HTx) (32 elective and 32 HU-HTx) were performed in our department. After having been accepted in an auditing process based on HU criteria, intensive care patients in NYHA functional class IV (cardiac index 1.7 l/min/qm BS), in end-organ failure (creatinine 1.5 mg/dl), and with catecholamine dependence (dobutamine 8 microg/kg/min), are given priority with respect to organ allocation, and their data were compared to data from elective patients from the same period. HU requests were accepted in 97 % of cases. Two requests were not accepted, and both patients with contraindications for assist device implantation died within one week. The HU patients were 100 % in NYHA class IV, 93 % of the elective patients were in NYHA class III. Waiting time on the HU list was 13 days, and 7 of these patients died before HTx. Following heart transplantation, survival rates at 30 days and at one year of the HU group were 88 % and 85 % versus 94 % and 93 % in the elective group. This study shows that end-stage heart failure patients in the HU program can be transplanted primarily with good results if an organ is available in time. We are still in the position where the HU program only manages the organ shortage; there are still too many patients on the waiting list who die before receiving a donor organ.