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Biomedical subjects

F Mühlbacher

Publications and source records attributed to F Mühlbacher.

At least 19 recordsLinked to original sources
PubMed2006

Tail-induced attraction between nucleosome core particles.

We study a possible electrostatic mechanism underlying the compaction of DNA inside the nuclei of eucaryotes: the tail-bridging effect between nucleosomes, the fundamental DNA packaging units of the chromatin complex. As a simple model of the nucleosome we introduce the eight-tail colloid, a charged sphere with eight oppositely charged, flexible, grafted chains that represent the terminal histone tails. We show that our complexes attract each other via the formation of chain bridges and contrast this to the effect of attraction via charge patches. We demonstrate that the attraction between eight-tail colloids can be tuned by changing the fraction of charged monomers on the tails. This suggests a physical mechanism of chromatin compaction where the degree of DNA condensation is controlled via biochemical means, namely the acetylation and deacetylation of lysines in the histone tails.

Animals↗
PubMed2006

Long-term outcomes in liver transplant patients with hepatic C infection receiving tacrolimus or cyclosporine.

Choice of calcineurin inhibitor may be a contributing factor to deteriorating patient and graft survival following liver transplantation for hepatitis C virus (HCV). In our multicenter, open-label LIS2T study, de novo liver transplant patients stratified by HCV status were randomized to cyclosporine or tacrolimus. Follow-up data were obtained in an observational study of 95 patients. Mean follow-up was 34 and 37 months, respectively, for cyclosporine-treated (n = 47) and tacrolimus-treated (n = 48) patients. In patients not receiving antiviral therapy, 22 of 31 given cyclosporine (72%) and 24 of 29 given tacrolimus (83%) had biochemical recurrence of HCV. In 68 patients with at least one biopsy, histological evidence of HCV-related hepatitis was present in 27 of 31 (87%) cyclosporine-treated patients and 37 of 37 (100%) tacrolimus-treated patients (P = .02, chi-square test). Three-year actuarial risk of fibrosis stage 2 was 66% with cyclosporine and 90% with tacrolimus; for fibrosis stage 3 or 4 it was 46% and 80%, respectively. Three graft losses were attributed to HCV recurrence in cyclosporine-treated patients and six in tacrolimus-treated patients. Tacrolimus may be associated with increased risk of histological HCV disease recurrence compared to cyclosporine.

Adult↗
PubMed2002

Fresh arterial homograft transplantation: a novel concept for critical limb ischaemia.

INTRODUCTION: homografts have been used since the early days of vascular surgery, but have failed to provide long-term success. Arteries supplying organ transplants seldom show signs of biodegradation. We therefore introduced fresh arterial homograft repair with consecutive immunosuppression (ATX). AIM: to assess feasibility and clinical usefulness of ATX. SETTING: university teaching hospital. MATERIAL AND METHOD: conduits were harvested during multi-organ procurement and stored in Custodiol. Implantation followed immediately. Viability of the transplant was documented in all cases. Patients received immunosuppression for the duration of bypass function. RESULTS: thirteen patients received ATX for critical limb ischaemia (M/F: 11/2, age: 62yr, previous revascularisations: 4.5 (1-8), median run-off index 5, previous organ transplant: n=2. Most bypasses were anastomosed to single tibial or pedal vessels. There was no early failure. Within an average follow up of 12 months there were 6 graft thromboses in 5 patients, successfully revised in 4. Three limbs were lost after 2, 5 and 6 months due to graft failure. Graft rejection was shown in 1 out of 3 explanted grafts. CONCLUSION: we report a concept, which may circumvent the problem of biologic graft degeneration. Limb salvage was possible in 75% at 12 months in otherwise difficult circumstances.

Adolescent↗
PubMed2001

Waking the dead.

Explore the source record for details and available documents.

Brain Death↗
PubMed2001

Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.

BACKGROUND: Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. METHODS: Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. RESULTS: At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05). CONCLUSIONS: Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

Adrenal Cortex Hormones↗
PubMed2001

Multiorgan donation from a donor with unrecognized ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency, the most common inherited urea cycle disorder, shows a spectrum of severity ranging from severe neonatal hyperammonemic coma to no symptoms among adults. We report on the multiorgan procurement from a donor who died of cerebral edema due to unrecognized late-onset OTC deficiency. The donor's OTC deficiency was diagnosed retrospectively since the liver graft recipient developed cerebral edema postoperatively due to hyperammonemia. Plasma ammonia was extremely elevated (3793 micromol/l), but was not accompanied by general liver dysfunction. Post mortem, the diagnosis of OTC deficiency was established by enzyme and molecular analysis in a biopsy of the transplanted liver. In contrast to the fatal course of the liver graft recipient, the kidney, lung, and heart transplantations were successful. Ten months after transplantation these recipients were alive and showed good graft function. This case demonstrates the importance of careful donor evaluation, particularly if the donor's cause of death is obscure.

Adult↗
PubMed2001

Use of absorbable mesh in the treatment of parenchymal liver injuries during orthotopic liver transplantation.

OBJECTIVE: To find out whether packing or wrapping with polyglactin 910 mesh was more effective in stopping bleeding in livers that had been damaged during transplantation. DESIGN: Retrospective study. SETTING: University hospital, Austria. SUBJECTS AND INTERVENTIONS: 15 of 27 livers that had been damaged during transplantation bled sufficiently to warrant either packing (n = 6) or wrapping (n = 9). MAIN OUTCOME MEASURES: Arrest of bleeding; other complications. RESULTS: Both packing and wrapping succeeded in stopping the bleeding, and neither caused infections. Packing may theoretically cause an increase in intra-abdominal pressure and impair organ function. CONCLUSION: It is preferable to wrap rather than pack a bleeding liver that has been damaged during transplantation.

Adult↗
PubMed2000

Successful treatment of a patient suffering from severe acute potassium dichromate poisoning with liver transplantation.

BACKGROUND: Oral ingestion of potassium dichromate produces a complex spectrum of complications. It has an extremely poor prognosis and usually leads to rapid death. METHODS: We report the case of a 16-year-old male patient who was admitted to hospital after oral ingestion of potassium dichromate with suicidal intention. RESULTS: The patient's condition deteriorated, and he became comatose within 5 days in spite of immediate attempts at detoxification. Because of irreversible liver failure, which occurred within 2 days after admission, and because of cerebral edema, the decision to perform a liver transplantation was made. On day 6 after admission, a compatible donor liver was transplanted. The course of liver transplantation and the patient's subsequent recovery were uneventful. CONCLUSION: The rationale for the delayed transplantation was to avoid damage of the new organ because of high serum chromium levels. Despite severe organ damage, the chromium content of the liver was increased. To the authors' knowledge, this is the first case report of acute toxic liver failure, caused by potassium dichromate poisoning, treated successfully by means of liver transplantation.

Acute Disease↗
PubMed2000

Thrombopoietin induces rapid resolution of thrombocytopenia after orthotopic liver transplantation through increased platelet production.

Thrombopoietin (TPO) deficiency has been proposed as an important etiologic factor for thrombocytopenia in advanced-stage liver disease. To clarify the contributions of platelet production, platelet consumption, coagulation activation, and splenic sequestration to thrombocytopenia in liver disease, we studied TPO serum levels and markers of platelet production, platelet activation, and coagulation activation before and 14 days after orthotopic liver transplantation (OLT) in 18 patients with advanced liver cirrhosis. Thrombocytopenia before transplantation occurred with low-normal serum levels of TPO, normal levels of platelet and coagulation activation markers, and no increase in bone marrow production of platelets. TPO serum levels increased significantly on the first day after OLT, preceding the increase of reticulated platelets by 3 days and peripheral platelets by 5 days. Normalization of the peripheral platelet count occurred in most patients within 14 days of OLT, irrespective of the change in spleen size assessed by computed tomography volumetry. Normalization of platelet counts was not hampered by a certain degree of platelet activation observed during the steepest increase in the peripheral platelet count. Bone marrow production of platelets increased significantly within 2 weeks of transplantation. Low TPO serum levels with low platelet counts and without platelet consumption suggests low TPO production in end-stage liver disease. The rapid increase in TPO serum levels after transplantation induces an increase in the bone marrow production of platelets. Decreased TPO production in the cirrhotic liver is an important etiologic factor for thrombocytopenia in liver disease that is rapidly reversed by transplantation.

Adult↗
PubMed2000

Increased apoptosis of hepatocytes in vascular occlusion after orthotopic liver transplantation.

Early vascular occlusion is liable to cause graft failure, and differential diagnosis between this condition and primary nonfunction (PNF) caused by preservation injury may be difficult. Apoptosis has been detected in immunomediated cytotoxicity and is known to be triggered by mild ischemia. In a retrospective analysis we investigated the role of apoptosis in vascular occlusion, PNF, and acute allograft rejection to improve the differential diagnosis of early graft failure. The liver graft histology of 75 patients (46 male, 29 female) a median 47 (1-64) years of age was screened semiquantitatively for the rate of apoptosis on the hematoxylin-eosin stain (HE) and by the in situ end nick labeling technique (TUNEL). This cohort included all patients who developed PNF (n = 9) or vascular occlusion (n = 11) after orthotopic liver transplantation (OLT) in the years 1992 to 1996. Within this period of time we performed 205 OLTs on 189 patients. We further included 22 patients with early acute rejection and 11 controls. The highest rates of apoptotic hepatocytes were seen in vascular occlusion (P < 0.001). Grafts with PNF were explanted 1-3 days after OLT and showed hepatocytes that were 100% necrotic. Cases of acute early rejection showed a significantly higher apoptotic cell count than did normal controls (P < 0.003), increasing in direct proportion to the severity of rejection. Screening biopsies for the rate of apoptosis can improve the efficacy and accuracy of differential diagnosis of early graft failure.

Adolescent↗
PubMed2000

General compliance after liver transplantation for alcoholic cirrhosis.

In recent years, alcoholic cirrhosis has been accepted as an indication for OLT, compliance of patients suffering from alcoholic cirrhosis is still under discussion, however. 118 patients who had undergone OLT for alcoholic cirrhosis were considered for analysis. The mean follow-up time of the study population was 53.7 +/- 38.9 months. Compliance was defined by 3 parameters: 1. Sobriety. Fifteen (13%) out of 118 recipients suffered an alcohol relapse during the observation period. There was no difference between the groups with or without alcohol relapse concerning compliance with medication, incidence of rejection, or adherence to check-ups. 2. Drug-compliance. Nineteen recipients (16 %) were not within the target range with the immunosuppressive medication. Comparison of the compliant- and non-compliant groups produced a significant difference for late acute rejection, the other parameters being similar in the subgroups. 3. Adherence to appointments. Nearly all patients in the study population ( > 95 %) were compliant with both transplant and psychological appointments in the outpatient clinic. In conclusion, analysis of our data indicates that patients with OLT for alcoholic cirrhosis are compliant, although alcohol relapse occurs in 13 % of recipients.

Follow-Up Studies↗
PubMed2000

Long-term evaluation of proliferative donor antigen-specific reactivity in cadaveric kidney transplant recipients.

Development of donor-specific proliferative hyporeactivity has been evaluated in many studies for its usefulness in identifying transplant recipients at low risk of immunological complications. These studies often result in controversial conclusions, however. The authors claim that the discrepancy in the predictive value of mixed lymphocyte culture- (MLC) reactivity might partly be due to differences in presentation and interpretation of results. The purpose of this study is to investigate the usefulness of a normalized evaluation of antigen-specific donor-reactivity in a small number of kidney transplant recipients. This could then serve as a basis for an extended clinical study. Ten cadaveric kidney recipients were tested for proliferative reactivity to donor- and third-party antigens up to 20 months posttransplantation. Expressing donor-specific reactivity as a relation between the percentage of pretransplant responses towards donor splenocytes and the percentage of pretransplant responses towards third-party donor cells should minimize influences of e. g. uremia, current immunosuppression or infections on the evaluation of specific reactivity and thus should allow an evaluation of the donor-specificity of T-cell alloresponses independently of fluctuations in global responsiveness. Four of ten recipients acquired a state of donor-specific hyporeactivity ( < 75 % relative specific reactivity) at 20 months post-transplantation (61 +/- 12%, mean +/- SD). Six patients were classified non-hyporeactive (98 +/- 10% mean relative specific reactivity). Relative specific reactivity did not correlate with the levels of general reactivity. Three of the four hyporeactive and four of the six non-hyporeactive patients developed acute rejection. Stable graft function at 20 months posttransplantation (serum creatinine < or = 2 mg/dl) was not closely related to the reactivity status, as five of eight patients with well-functioning grafts did not develop relative specific hyporeactivity. One recipient with chronic rejection was classified hyporeactive. One non-hyporeactive patient lost his graft due to non-immunological causes. Our data suggest that post-transplant relative specific reactivity does not predict acute rejection. Downregulation of donor-specific reactivity might not be a prerequisite for stable graft function but could help identifying recipients who require less immunosuppression. This, however, remains to be established in a prospective immunosuppression-weaning study.

Adult↗
PubMed2000

Catecholamines up-regulate lipopolysaccharide-induced IL-6 production in human microvascular endothelial cells.

The catecholamine-mediated modulation of the cytokine network has primarily been demonstrated for leukocytes. Whereas catecholamines decrease the LPS-induced production of IL-6 by leukocytes, serum levels of IL-6 are dramatically increased by the catecholamine epinephrine in animal endotoxemia models. We now demonstrate that epinephrine as well as norepinephrine can induce IL-6 in an endothelial cell line (HMEC-1). Furthermore, these catecholamines could even potentiate the LPS-induced IL-6 protein production. The synergistic effect of catecholamines and LPS could be reproduced in primary human skin microvascular endothelial cells. The catecholamine-induced IL-6 stimulation is based on increased IL-6 mRNA levels. RNA stability assays revealed that this regulation is not a result of enhanced RNA stability and therefore is most likely due to an increased transcription. Treatment with cycloheximide indicated that new protein synthesis is not necessary for this transcriptional up-regulation of IL-6 mRNA. Preincubation with alpha and beta receptor antagonists showed that the effect is mediated by beta(1)- and beta(2)-adrenergic receptors. Thus, endothelial cells might be a possible source of increased IL-6 production observed in situations such as stress or septic shock, in which catecholamines are elevated due to endogenous production or exogenous application.

Adrenergic beta-Antagonists↗
PubMed1999

Carbohydrate deficient transferrin for detection of alcohol relapse after orthotopic liver transplantation for alcoholic cirrhosis.

Early diagnosis and monitoring of an alcohol relapse in patients after orthotopic liver transplantation for alcoholic cirrhosis is of importance for the long-term outcome. A prospective study of 97 patients who underwent orthotopic liver transplant for alcoholic cirrhosis has been performed. All of the recipients considered for analysis survived for at least 3 months and were under the care of one specialist psychologist. Mean follow-up amounted to 48.5+/-1.4 months. The rates of alcohol relapse at 1 and 3 years after orthotopic liver transplant were 6 and 9%, respectively. Carbohydrate-deficient transferrin is a biological marker for alcohol abuse independently of liver disease and has been used for the first time ever in liver graft recipients. A total of 830 values were included prospectively in the study population. Detection of alcohol relapse had a sensitivity of 92% and a specificity of 98%. Changes in carbohydrate-deficient transferrin levels indicated clandestine and sporadic drinking after transplantation. Furthermore, clinical events were not found to influence carbohydrate-deficient transferrin, either in patients with or without alcoholic relapse. In our opinion, carbohydrate-deficient transferrin is a useful screening marker for alcohol relapse in patients after orthotopic liver transplant for alcoholic cirrhosis, to select those patients who need special attention from the psychologist.

Adult↗
PubMed1999

Preservation solutions for transplantation.

Eurocollins has almost been abandoned because of the glucose disadvantage. UW is certainly the most used preservation solution for livers, kidneys, and pancreases with excellent clinical and experimental preservation data. UW can certainly be considered the current golden standard solution. However, the disadvantage of high viscosity, high price, uneasy handling of many 1-L bags, and the fact that the radical scavenger glutathion cannot be detected in the bags by chemical analysis (presumably due to diffusion) encourage competitors to produce new compounds with better cost to effect ratios. HTK has a firm place in cardiac preservation; by demonstration of equal safety and efficacy in preserving livers and kidneys, at least in the middle and lower range of cold ischemia time, HTK will be sued more frequently, particularly with the consideration of lower price and more easy handling aspects. The suggested high volume perfusion is not really necessary, calculation based on a total volume of 10 L for a multiorgan donor show significant cost reductions. Celsior is current only used for cardiac preservation. Beyond all aspects of conservation and preservation potencies of all these fluids, it must not be forgotten that cold ischemia itself is a risk factor for organ function. Therefore, cold ischemia time should be kept as short as possible. People are willing to accept 24 hours or more cold ischemia time in kidney transplantation because organ failure can be treated by dialysis. In other organs, where immediate organ function is essential, like in clinical heart transplantation, cold ischemia is hardly ever extended beyond 6 hours. Why are hearts and kidneys so different? Very likely, there is no difference, and the outstanding results in living unrelated kidney transplants is mostly due to short cold ischemia time.

Adenosine↗
PubMed1999

Stable prodrugs of n-butyric acid: suppression of T cell alloresponses in vitro and prolongation of heart allograft survival in a fully allogeneic rat strain combination.

n-Butyric acid has previously been shown in vitro to suppress T cell alloresponses and beyond that to induce a state of alloantigen-specific hyporesponsiveness suggesting a potential relevance for suppressing alloresponses also in vivo. The clinical use of butyrate salt derivatives, however, is limited by an extremely short half-life due to rapid metabolism. This prompted us to investigate the effect of butyric acid derivatives with prolonged residence time in vivo on T cell alloresponses in vitro and further to explore the immunosuppressive capacity of esterified n-butyric acid in vivo. First, the effect of three butyric acid esters, i.e. glucose pentabutyrate, diacetone glucose butyrate and tributyrin on T cell proliferation in a human mixed lymphocyte culture (MLC) was evaluated. All three derivatives were found to inhibit T cell alloresponses in a concentration-dependent manner. Based on the ED50 values, glucose pentabutyrate was found to be most effective in inhibiting T cell alloreactivity in vitro (11 microM), followed by diacetone glucose butyrate (122 microM), tributyrin (146 microM) and sodium butyrate (539 microM). Because of its favourable in vitro properties, glucose pentabutyrate was chosen for in vivo experiments. To test the effect of this compound on allograft survival in vivo, in the second part of this study, heterotopic heart transplants were performed in a high responder fully allogeneic rat strain combination (Brown Norway to Lewis strain rats). We found that intraperitoneal (i.p.) injection of glucose pentabutyrate at 500 mg/kg/day (day 0 and daily up to 12 days posttransplant) induced a significant prolongation of allograft survival as compared to animals treated with vehicle (glycerol formal, i.p.) alone (14.1+/-6.3 versus 9.6+/-3.2 days, p = 0.036), whereby at lower dosage (100 mg/kg/day) no such effect was observed (10.2+/-2.1 days, p = 0.21). Our findings suggest that stable prodrugs of n-butyric acid might have potential clinical relevance for inhibiting alloresponses in vivo.

Animals↗