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R Margreiter

Publications and source records attributed to R Margreiter.

At least 19 recordsLinked to original sources
PubMed1999

Gemcitabine--a novel immunosuppressive agent--prevents rejection in a rat cardiac transplantation model.

BACKGROUND: 2',2' -difluorodeoxycytidine (dFdC, gemcitabine) is a pyrimidine antimetabolite with antineoplastic activity against a wide range of solid tumors. The immunosuppressive activities of this compound have not been described to date. METHODS: The in vitro effects on activated T lymphocytes were studied with a lymphocyte colony-forming assay in a microagar culture system. Heart transplantations were performed in the fully allogeneic Lewis/ Brown Norway combination. dFdC was administered once daily at various dosages from the time of surgery until day 50. RESULTS: Phytohemagglutinin-induced lymphocyte proliferation was inhibited 50% by dFdC at a concentration of 3.25+/-0.9 nmol/L. Allografts of untreated animals survived for 7.5 (7-8) days and those with 25, 50, and 75 microg/kg body weight dFdC for 7.3 (7-8), 9.3 (8-10), and 16.3 (10-38) days, respectively. Treatment with 100 or 125 microg/kg body weight of dFdC, however, prolonged allograft survival until day 152.8 (129-178). Dose-dependent leukopenia was the main toxicity. CONCLUSIONS: DFdC is a new immunosuppressive agent that can successfully prevent cardiac rejection in a rat transplantation model.

Animals↗
PubMed1999

Cytomegalovirus infections after treatment with daclizumab, an anti IL-2 receptor antibody, for prevention of renal allograft rejection. Roche Study Group.

Daclizumab is a newly developed humanized anti-IL-2 receptor monoclonal antibody. We describe the effect of adding daclizumab to conventional dual or triple cyclosporine A immunosuppressive therapy on the incidence and nature of cytomegalovirus (CMV) infections in patients receiving a first cadaveric renal graft. In the triple therapy study there was no evidence of any difference in CMV rate or course of disease between the two treatment arms, although in the dual therapy study a decrease in the incidence of CMV infection was observed in the patients treated with daclizumab. The onset of CMV disease was markedly delayed in the daclizumab groups in both studies. Daclizumab can effectively reduce the risk of acute rejection without causing a concomitant increase in opportunistic infections, and by decreasing the need for antirejection therapy may also have a beneficial effect on CMV infection rates.

Adult↗
PubMed1999

Expression of stress proteins, adhesion molecules, and interleukin-8 in endothelial cells after preservation and reoxygenation.

Endothelial activation is a central feature of preservation-induced allograft injury. The present study aims at a quantitative assessment of stress proteins, adhesion molecules, and interleukin-8 in a cell culture-based model of organ preservation. Human umbilical vein endothelial cells were exposed to cold, hypoxic storage in University of Wisconsin (UW), histidine-tryptophane-ketoglutarate (HTK), and EuroCollins solutions for 8 h with subsequent rewarming/reoxygenation (rew/reox) for 1 and 4 h. A cell-based ELISA was designed for detection of heat shock proteins (HSP) 60 and 70, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1). Immunohistochemical staining was performed for comparison. Interleukin-8 was quantified by ELISA. HSP 70 was expressed after cold storage in HTK and EuroCollins solution and after rew/reox in all groups. A constitutive expression of HSP 60 was observed with further upregulation after rew/reox following cold storage in all experimental groups. ICAM-1 was clearly upregulated, but VCAM-1 showed only weak expression after cold storage and rew/reox. ELAM-1 was detectable in minimal amounts after cold storage but was considerably upregulated after 4 h of rew/reox. A significant increase of interleukin-8 release could be found after 4 h of rew/reox following storage in EuroCollins solution. Expression of stress proteins can be considered as a new parameter of preservation-associated endothelial activation. Apart from possible protective effects, allograft vasculopathy could be in part a consequence of the antigeneic potential of heat shock proteins connected with effects caused by adhesion molecules and inflammatory cytokines.

Adenosine↗
PubMed1999

Ultrastructural analysis of human endothelial cells after hypothermic storage in organ preservation solutions.

BACKGROUND: Protection of vascular endothelium is a critical factor in organ preservation for transplantation. This study aims at a morphological assessment of endothelial cell injury in a comparison of storage solutions, using a cell culture model of cold preservation and rewarming. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were cultured in monolayer and exposed to hypothermic storage in University of Wisconsin (UW), histidine-tryptophane-ketoglutarate (HTK), and EuroCollins solutions for 6 h and subsequent rewarming for 30 min or 6 h. Alterations of subcellular structures and cell-cell contacts were analyzed by transmission electron microscopy (TEM) and light microscopic assessment after actin and nuclear staining. RESULTS: Structural alterations of mitochondria, endoplasmic reticulum, nuclei, and cytoskeletal fibers as well as disruption of intercellular contacts were found after cold storage in HTK and EuroCollins solutions. In contrast, storage in UW solution resulted in minimum changes of stress fibers only. A rapid rearrangement of structural alterations was achieved during rewarming in cell culture medium in all experimental groups. CONCLUSIONS: Preservation of endothelial cell structure is best achieved by UW solution. Ultrastructural cell damage is a direct consequence of hypothermic storage and is fully reversible during rewarming after short storage times.

Adenosine↗
PubMed1999

Pancreas transplantation modulates reverse cholesterol transport.

Hyperinsulinemia secondary to insulin resistance in type-II diabetes or in the metabolic syndrome is associated with the "atherogenetic lipoprotein phenotype": high triglycerides, small, dense low-density lipoprotein (LDL) cholesterol, and low high-density lipoprotein (HDL) cholesterol. In contrast, hyperinsulinemia in pancreas-kidney transplant recipients (PKT-R), secondary to systemic venous drainage of the heteropically implanted pancreas graft, leads to high lipoprotein lipase (LPL) activity and a presumably antiatherogenic lipoprotein profile with very attenuated postprandial lipemia, high HDL cholesterol, and a preponderance of large-sized HDL (HDL(2)) and large buoyant LDL particles. We interpret these findings to suggest that in PKT-R, peripheral hyperinsulinemia upregulates LPL activity in peripheral tissues, which induces rapid clearance of chylomicron triglycerides from plasma and, thus, attenuates postprandial lipemia. Low postprandial lipemia allows little net cholesteryl ester transfer from HDL to triglyceride-rich lipoproteins, keeping the levels of the antiatherogenic lipoprotein HDL high and potentially increasing, thereby reverse cholesterol transport. The type of lipoprotein metabolism and pattern present in PKT-R is associated with a low cardiovascular risk in the general population; it cannot be excluded, however, that hyperinsulinemia as found in PKT-R may contribute to atherosclerosis by effects unrelated to lipoprotein metabolism.

Adult↗
PubMed1999

Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up.

The highly atherogenic lipoprotein(a) [Lp(a)] is significantly elevated in patients with renal disease. It is discussed controversially whether Lp(a) concentrations decrease after renal transplantation and whether the mode of immunosuppressive therapy influences the Lp(a) concentrations. In a prospective study the Lp(a) concentrations before and on average 48 months after renal transplantation were measured in 145 patients. The determinants of the relative changes of Lp(a) concentrations were investigated in a multivariate analysis. Patients treated by CAPD showed a larger decrease of Lp(a) than hemodialysis patients, reflecting their markedly higher Lp(a) levels before transplantation. The relative decrease of Lp(a) was higher with increasing Lp(a) concentrations before transplantation in combination with an increasing molecular weight of apolipoprotein(a) [apo(a)]. That means that the relative decrease of Lp(a) is related to the Lp(a) concentration and the apo(a) size polymorphism. With increasing proteinuria and decreasing glomerular filtration rate, the relative decrease of Lp(a) became less pronounced. Neither prednisolone nor cyclosporine (CsA) had a significant impact on the Lp(a) concentration changes. Azathioprine (Aza) was the only immunosuppressive drug which had a dose-dependent influence on the relative decrease of Lp(a) levels. These data clearly demonstrate a decrease of Lp(a) following renal transplantation which is caused by the restoration of kidney function. The relative decrease is influenced by Aza but not by CsA or prednisolone.

Adult↗
PubMed1999

Bronchiolitis obliterans organizing pneumonia associated with Pneumocystis carinii infection in a liver transplant patient receiving tacrolimus.

We report on a case of bronchiolitis obliterans organizing pneumonia (BOOP) associated with Pneumocystis carinii pneumonia (PCP) after liver transplantation and tacrolimus based immunosuppression. Radiologically, bilateral diffuse interstitial shadowing and patchy alveolar infiltrates developed after switching the patient from cyclosporin A to tacrolimus for persistent rejection. Bronchoalveolar lavage (BAL) fluid showed inflammatory cells but no pathogenic organisms. Open lung biopsy revealed BOOP with granulomatous PCP. Thus, even in the case of negative BAL the possibility of an atypical P. carinii infection has to be considered for differential diagnosis of pneumonia in immunocompromised patients after organ transplantation. The combination of BOOP with PCP after liver transplantation and tacrolimus medication has not been reported previously.

Cryptogenic Organizing Pneumonia↗
PubMed1999

Bilateral nephrectomy, peritoneal dialysis and subsequent cadaveric renal transplantation for treatment of renal failure due to polycystic kidney disease requiring continuous ventilation.

We report here on a newborn with end-stage renal failure due to autosomal recessive polycystic kidney disease, also causing ventilation-requiring respiratory distress. Peritoneal dialysis was able to keep the newborn alive but not wean it from the respirator. After removal of both huge kidneys, dialysis became more effective and allowed the neonate to be extubated only 5 days later. It was decided to register the baby for a pediatric cadaveric kidney transplant when it reached 6 kg/body wt or to perform a living related transplant if no such kidney became available and the baby grew to 7 kg/body wt. At the age of 9 months and a weight of 6 kg a cadaveric kidney from a 20-month-old donor became available and was transplanted extraperitoneally. Prophylactic immunosuppression included cyclosporin, mycophenolate mofetil and steroids. Pneumonia on post-operative day 10 required respiratory care for several days and acute rejection requiring peritoneal dialysis. Both complications were controlled with antibiotics and conversion from cyclosporin to tacrolimus and a temporary increase in steroids. Thirteen months later the child is alive and well with a serum creatinine of 0.6 mg%. From this experience we would recommend early removal of both polycystic kidneys causing end-stage renal failure and respiratory insufficiency, starting peritoneal dialysis and performing a renal transplant as soon as possible. This therapeutic strategy seems appropriate for this complex situation.

Age Factors↗
PubMed1999

Cutaneous lesions as the presenting sign of acute graft-versus-host disease following liver transplantation.

Acute graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation but is only rarely observed after solid organ transplantation. We describe a 68-year-old man who developed a maculopapular eruption 7 days following orthotopic liver transplantation for cirrhosis with malignant transformation due to haemochromatosis. At day 20, the patient complained of nausea, vomiting, diarrhoea and fever. Skin biopsy revealed a lymphocytic infiltrate at the dermoepidermal interface, vacuolization of basal cells and epidermal dyskeratosis. Immunohistochemistry showed HLA-DR and intercellular adhesion molecule-1 expression of lesional keratinocytes. HLA-typing of peripheral blood lymphocytes demonstrated circulating lymphocytes of donor origin. Endoscopy revealed extensive erosions of the oesophagus, stomach and duodenum that on histology disclosed multifocal loss of crypts, lymphocytic infiltrates and epithelial cell death. A diagnosis of acute GVHD was made, and high-dose immunosuppressive therapy with azathioprine and methylprednisolone was instituted. The skin and gastrointestinal symptoms subsided within 4 weeks, but the patient died from severe infectious complications 105 days after transplantation. We conclude that acute GVHD is a rare but potentially fatal complication of liver transplantation. Skin lesions are an early sign of acute GVHD and thus represent an important tool for early diagnosis.

Acute Disease↗
PubMed1999

Comparison of two quality-of-life instruments for cancer patients: the functional assessment of cancer therapy-general and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30.

PURPOSE: To compare two quality-of-life (QOL) questionnaires for cancer patients, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy-General (Fact-G), on the basis of empirical data. PATIENTS AND METHODS: Two hundred forty-four patients with a diagnosis of breast cancer or Hodgkin's disease completed both the EORTC QLQ-C30 and the FACT-G (German language version) during the same session. Questionnaire data were analyzed on a subscale basis using correlation analysis, canonical correlation, and multiple linear regression. RESULTS: Correlations between corresponding subscales of the FACT-G and the EORTC QLQ-C30 ranged from r =.14 for the social domain (very poor agreement) to r =.66 for the physical domain (good agreement), with r values for the other domains lying between these extremes. Canonical correlation analysis for the two sets of subscales revealed that overall agreement between the two instruments was only moderate (first canonical correlation coefficient r =.85, but overall redundancy less than 40%). Of the five FACT-G subscales, only one, physical well-being, was well represented by the EORTC QLQ-C30 subscales (multiple linear regression, R(2) =.67). Only three of eight EORTC QLQ-C30 subscales (physical functioning, global QOL, general symptoms) were represented fairly well by FACT-G subscales (R(2) =.43 to.60). The lowest R(2) values (<.15; ie, virtually no representation by the other instrument) were found for the FACT-G social well-being and relation with doctors and EORTC QLQ-C30 cognitive functioning subscales. CONCLUSION: For the sample investigated, the EORTC QLQ-C30 and the FACT-G were found to measure markedly different aspects of QOL, despite considerable overlap. Replicability provided, this implies that neither of the two QOL instruments can be replaced by the other and that a direct comparison of results obtained with the two instruments is not possible.

Adult↗
PubMed1998

Mitochondrial respiration in the low oxygen environment of the cell. Effect of ADP on oxygen kinetics.

Oxygen levels in the intracellular microenvironment of tissues such as heart are extremely low, at 1-2% of standard atmospheric oxygen pressure. Kinetic studies with isolated mitochondria suggest a regulatory role of oxygen under these conditions, particularly in active states at high ADP concentration, when oxygen affinity was lower than in the resting state at ADP limitation. The oxygen pressure at 50% of maximum flux, p50, was 0.035 and 0.057 kPa in heart and liver mitochondria, respiring in state 3 on substrates for complex I or II and II, respectively. p50 in the resting state 4 was 0.02 kPa. The apparent kinetic efficiency, Jmax/p50, increased from the resting to the active state, despite the decrease of oxygen affinity, 1/p50. Consequently, the relative increase of respiratory flux by ADP activation, expressed as the adenylate control ratio, declined under hypoxia, but not to the extreme of a complete loss of the scope for activation, which would occur at constant Jmax/p50. High oxygen affinity is achieved by an excess capacity of cytochrome c oxidase relative to the respiratory chain and a correspondingly low turnover rate of this enzyme, consistent with the concept of kinetic trapping of oxygen [1].

Adenosine Diphosphate↗
PubMed1998

Myocardial fatty acid metabolism during acute cardiac allograft rejection.

Fatty acids are promptly taken up, metabolised and eliminated by healthy cardiomyocytes. Cardiomyopathy, coronary heart disease and chronic rejection are known to be associated with an impaired fatty acid metabolism. It was the aim of this study to investigate fatty acid metabolism in a rat heart transplant model and to correlate scintigraphic findings with histological changes. After right-side nephrectomy of Lewis recipients Brown Norway cardiac allografts were anastomosed to the renal vessels. Animals were given no immunosuppression. The metabolism of carrier-free 17-123 jodo-heptadecanoic acid (123J-HDA) with a specific activity of > 2 x 10(17) Bq/ml was scintigraphically measured between days 1 and 11. An increase in the grade of rejection was observed over time. Fifty-six frames of 30 s duration each were recorded. For the region of interest (native heart, transplanted heart, left kidney) frames 10-56 were superimposed, time-activity curves generated and monoexponentially fitted. Furthermore, elimination half-life and intercepts were calculated. Following scintigraphic evaluation the animals were killed and graft as well as native hearts excised for histological examination. The uptake of the tracer identified severe grades of rejection. Elimination half-life of the tracer was twice as long from hearts with mild rejection and more than 14 times as long in severe rejection compared with no rejection. Elimination half-life and amplitude did not permit discrimination between grades 1, 2 and 3 a, but significantly decreased in groups 3 b and 4. This method therefore seems to be a valuable tool for the noninvasive detection of severe acute cardiac allograft rejection. Since fatty acid metabolism is clearly stress-dependent it remains to be seen whether this method allows detection of earlier rejection in loaded hearts.

Animals↗
PubMed1998

Influence of hyperinsulinemia on lipoproteins after pancreas transplantation with systemic insulin drainage.

Successful pancreas transplantation with systemic drainage is followed by a normalization of carbohydrate and lipid metabolism with low levels of plasma cholesterol and triglycerides. HDL cholesterol concentration and CETP plasma levels were found to be increased and the composition of lipoproteins altered in that LDL and HDL2/HDL3 were enriched in UC, HDL2 enriched in PL, and LDL depleted in PL. The mechanisms by which hyperinsulinemia may cause the observed changes in surface composition of plasma lipoproteins are unknown, as is their clinical relevance. It remains to be seen whether these changes counterbalance the favorable effects of an increased triglyceride clearance capacity on the cardiovascular risk of diabetic patients.

Adult↗
PubMed1998

2-Chlorodeoxyadenosine (cladribine) in combination with low-dose cyclosporin prevents rejection after allogeneic heart and liver transplantation in the rat.

The purine analogue 2-chlorodeoxyadenosine (2-CDA) has been shown to possess synergistic immunosuppressive properties when given together with cyclosporin (CSA) in a rat small bowel transplant model. The present study investigated the immunosuppressive potency of 2-CDA alone and in combination after liver or heart transplantation in a fully allogeneic rat model with 5 animals in each group. Immunosuppression was provided with CSA 10 mg/kg body weight (BW)/day orally or 2-CDA 0.1 mg/kg/BW day intravenously or both compounds together in the dosages mentioned. Animals were sacrificed on day 10 following transplantation, and graft histology was assessed. In addition, cardiac graft function was evaluated by palpation immediately prior to sacrificing the animal. CSA given alone was able to mitigate but not prevent rejection. 2-CDA alone did not exhibit any detectable immunosuppressive effect. When CSA was combined with 2-CDA, no rejection was seen in 80% of the liver allografts and in 60% of heart allografts, and only mild rejection was observed in the remaining animals. All hearts of the combined treatment group, however, beat strongly. From these findings it is concluded that 2-CDA alone has no, but together with CSA a strong immunosuppressive effect in preventing solid organ allograft rejection.

Animals↗