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Digestive Diseases and Sciences 12/2010; 55(12):3627-9. · 2.12 Impact Factor
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ABSTRACT: Pretransplant screening in living donor kidney transplantation includes human leukocyte antigen matching, and panel reactive antibody analysis, whereas T cell mediated anti-donor reactivity is not assessed routinely. We investigated T cell reactivity after living related kidney transplantation between two monocygotic twins and in consequence correlated the withdrawal of individual immunosuppressive medication with immunological findings.
Immunosuppression consisted of mycophenolate mofetil, glucocorticoid single shot, and induction therapy with antithymocyte immunoglobulin.
FACS analysis of recipient peripheral blood cells revealed a normal haemogram after transplantation, showing non-activated CD4 and CD8 cells. Mixed lymphocyte reaction did not reveal donor-specific T cell activity. IFN-gamma and IL-10 ELISA of supernatants of recipient cells cocultivated with donor cells support the lack of Th1 and Th2 cell differentiation.
Based on immunological findings on days 5 and 20 MMF-therapy was reduced and stopped. Immunological monitoring on day 90 confirmed the absence of immune reactions directed against donor tissue.
Transplant Immunology 09/2009; 22(1-2):38-43. · 1.46 Impact Factor
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ABSTRACT: Effective immunosuppressive therapy is essential to prevent transplant rejection but renders patients vulnerable to opportunistic infections. The present study investigates the effects of common immunosuppressive drugs on the course of septic peritonitis in an experimental mouse model. We show that treatment with a combination of tacrolimus, mycophenolate mofetil, and methylprednisolone resulted in highly elevated lethality of septic peritonitis. When immunosuppressive drugs were combined with antibiotic therapy, however, mice were almost completely protected. The combination of mycophenolate mofetil and methylprednisolone was shown to be required and sufficient to improve outcome of septic peritonitis in the presence of antibiotic therapy. Combined immunosuppressive and antibiotic therapy, but not antibiotic therapy alone, resulted in enhanced bacterial clearance. These beneficial effects were linked to an elevated expression of activation markers and an increased production of reactive oxygen metabolites by peritoneal neutrophils and correlated with a reduced messenger RNA expression of the inhibitory cytokine IL-22. In contrast, systemic or peritoneal levels of IL-10, IL-12, TNF-alpha, keratinocyte chemoattractant, and monocyte chemoattractant protein 1, and splenic messenger RNA levels of IFN-gamma were not influenced by the immunosuppressive therapy. These results therefore suggest that combined immunosuppressive and antibiotic therapy may improve bacterial clearance and survival of septic peritonitis by a mechanism that involves enhanced activation and antimicrobial activity of neutrophils and reduced production of IL-22.
Shock (Augusta, Ga.) 06/2009; 33(2):155-61. · 2.87 Impact Factor
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ABSTRACT: Dysfunction of the graft after liver transplantation caused by ischaemia-/reperfusion (I/R) injury is a serious clinical problem. The aim of this study was to evaluate the influence of different kinds of reperfusion on I/R injury in a rat model. Arterialized orthoptic rat liver treatment was performed on male LEWIS-(RT(1))-rats. Three groups (n = 7) were formed. Group I: antegrade reperfusion with a 6-min delayed reperfusion via the hepatic artery. Group II: Antegrade reperfusion, simultaneously, via the portal vein and the hepatic artery. Group III: Retrograde reperfusion via the vena cava. Serum parameters were determined one, 24 and 48 h after operation. Furthermore, after 48 h, the liver was taken for histological assessment. After 48 h, rats of group III showed significantly lower aspartate amino transferase and alanine amino transferase serum levels compared with group I and group II rats. Forty-eight hours after transplantation, glutamate dehydrogenase serum level was significantly lower in group III than in group II. In histology, group III livers showed significantly less necrotic spots than group I and group II livers. Maximum size of the necrotic spots was significantly lower in group III than in group I. Also, significantly more necrotic spots were seen in the 'Rappaport's zone' 1 and 2 of group I than in group III. Our data suggested that the expression of I/R-injury correlates with the type of reperfusion. Furthermore, under standard conditions, this study was able to demonstrate that in a rat model, the retrograde reperfusion leads to a lower expression of I/R-injury than the antegrade reperfusion.
International Journal of Experimental Pathology 01/2009; 89(6):433-7. · 2.57 Impact Factor
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Michael Gerg,
Charlotte Kopitz,
Susanne Schaten,
Alexander Tschukes,
Christoph Kahlert, Manfred Stangl,
Claus W Hann von Weyhern,
Björn L D M Brücher,
Dylan R Edwards,
Karsten Brand,
Achim Krüger
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ABSTRACT: The specific spatiotemporal role of the matrix metalloproteinase 2 (MMP-2) and MMP-9 (gelatinase) during metastasis is still under debate. Host cells have been described as major contributors to these MMPs during metastasis. Here, we show strong overexpression of MMP-2 and MMP-9 by tumor cells of clinical liver specimen of recurrent metachronous metastases, leading us to address the importance of tumor cell-derived MMP-2 or MMP-9 during liver metastasis. Thus far, distinction of their roles was impossible due to lack of inhibitors which can act exclusively on tumor cells or distinguish MMP-2 from MMP-9. We therefore used short hairpin RNA interference technology in the well-established syngeneic L-CI.5s lymphoma model, in which we could analyze the time course of experimental liver colonization (arrest/invasion of single tumor cells, outgrowth, and invasion within the parenchyma) in immunocompetent mice and correlate these steps with MMP-2 or MMP-9 expression levels. In parental tumor cells, MMP-9 expression closely correlated with the invasive phases of liver colonization, whereas MMP-2 expression remained unaltered. Specific knockdown of MMP-9 revealed a close correlation between invasion-dependent events and tumor cell-derived MMP-9 expression. In contrast, knockdown of MMP-2 did not significantly alter the metastatic potential of the cells but led to a marked inhibition of metastatic foci growth. These findings explain the efficacy of gelatinase-specific synthetic inhibitors on invasion and growth of tumor cells and attribute distinct functions of MMP-2 and MMP-9 to aspects of liver metastasis.
Molecular Cancer Research 04/2008; 6(3):341-51. · 4.29 Impact Factor
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Transplant International 12/2007; 20(11):991-2. · 2.92 Impact Factor
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Charlotte Kopitz,
Michael Gerg,
Obul Reddy Bandapalli,
Dilek Ister,
Caroline J Pennington,
Stephanie Hauser,
Christin Flechsig,
Hans-Willi Krell,
Dalibor Antolovic,
Keith Brew,
Hideaki Nagase, Manfred Stangl,
Claus W Hann von Weyhern,
Björn L D M Brücher,
Karsten Brand,
Lisa M Coussens,
Dylan R Edwards,
Achim Krüger
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ABSTRACT: Balanced expression of proteases and their inhibitors is one prerequisite of tissue homeostasis. Metastatic spread of tumor cells through the organism depends on proteolytic activity and is the death determinant for cancer patients. Paradoxically, increased expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of several endometalloproteinases, including matrix metalloproteinases and a disintegrin and metalloproteinase-10 (ADAM-10), in cancer patients is negatively correlated with their survival, although TIMP-1 itself inhibits invasion of some tumor cells. Here, we show that elevated stromal expression of TIMP-1 promotes liver metastasis in two independent tumor models by inducing the hepatocyte growth factor (HGF) signaling pathway and expression of several metastasis-associated genes, including HGF and HGF-activating proteases, in the liver. We also found in an in vitro assay that suppression of ADAM-10 is in principle able to prevent shedding of cMet, which may be one explanation for the increase of cell-associated HGF receptor cMet in livers with elevated TIMP-1. Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon.
Cancer Research 10/2007; 67(18):8615-23. · 7.86 Impact Factor
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ABSTRACT: To evaluate the long-term outcome and prognostic factors of patients with hilar cholangiocarinoma.
Ninety-six consecutive patients underwent treatment for malignant hilar bile duct tumors during 1995-2005. Of the 96 patients, 20 were initially treated with surgery (n = 2 R0 / n = 18 R1). In non-operated patients, data analysis was performed retrospectively.
Among the 96 patients, 76 were treated with endoscopic transpapillary (ERC, n = 45) and/or percutaneous transhepatic biliary drainage (PTBD, n = 31). The mean survival time of these 76 patients undergoing palliative endoscopic and/or percutaneous drainage was 359 +/- 296 d. The mean survival time of patients with initial bilirubin levels > 10 mg/dL was significantly lower (P < 0.001) than patients with bilirubin levels < 10 mg/dL. The mean survival time of patients with Bismuth stage II (n = 8), III (n = 28) and IV (n = 40) was 496 +/- 300 d, 441 +/- 385 d and 274 +/- 218 d, respectively. Thus, patients with advanced Bismuth stage showed a reduced mean survival time, but the difference was not significant. The type of biliary drainage had no significant beneficial effect on the mean survival time (ERC vs PTBD, P = 0.806).
Initial bilirubin level is a significant prognostic factor for survival of patients. In contrast, age, tumor stage according to the Bismuth-Corlette classification, and types of intervention are not significant prognostic parameters for survival. Palliative treatment with endoscopic or percutaneous biliary drainage is still suboptimal, new diagnostic and therapeutic tools need to be evaluated.
World Journal of Gastroenterology 03/2007; 13(9):1422-6. · 2.47 Impact Factor
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European Radiology 02/2006; 16(1):238-9. · 3.22 Impact Factor
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ABSTRACT: In high-critical medical fields instant information delivery is essential. Task-flow analyses within the transplantation unit of the Technische Universität München revealed that valuable time could be saved in pre-transplantation management being able to retrieve data of organ receivers ubiquitously. Inspired by this clinical scenario, a mobile application was designed and implemented providing surgeons with decision-relevant information on potential organ receivers. It assists them in considering the prospects of forthcoming organ transplantations and facilitates decision making and documentation with regard to high security demands. The described system services three organ receiver lists and is used by the surgeons in every transplantation procedure. After a 6-month period of clinical usage, the system has been evaluated in terms of handling, clinical benefit and total time savings. Intuitive, ubiquitous access to decision-relevant patient data and authenticated documentation were the major improvements with average total time savings of 50 min in comparison to the old system.
International Journal of Medical Informatics 07/2004; 73(5):461-4. · 2.41 Impact Factor
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ABSTRACT: Crigler-Najjar syndrome type 1 (CNS1) is characterized by severe unconjugated hyperbilirubinemia from birth, caused by total failure of UDP-glucuronyltransferase activity. Only orthotopic liver transplantation (OLT) offers the prospect of cure. However, because the onset of neurologic deficits is unpredictable, timing of OLT remains difficult.
In our transplant center, 3 patients underwent early OLT for CNS1. Two of them (7 yr, 12 yr) showed mild to moderate neurologic deficits only few weeks before OLT, another patient (4 yr) had no signs of bilirubin encephalopathy. All patients required extensive phototherapy to control bilirubin levels. Thus, OLT was performed shortly after the onset of neurologic symptoms or as a prophylactic procedure, respectively.
OLT was uneventful in all recipients. One of the symptomatic patients (7 yr) completely recovered from neurologic deficits at 36 months on OLT, whereas the other patient (12 yr) significantly improved symptoms at 27 months of OLT. These patients, including the 4-year-old boy, attend school at appropriate grades now.
Irreversible brain damage (kernicterus) may occur in the course of CNS1 disease. Because no alternative treatment options are available at this time, OLT should be performed as a preventive procedure to counteract severe CNS-related complications.
Journal of Pediatric Surgery 09/2003; 38(8):1227-31. · 1.45 Impact Factor
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Mobiles Computing in der Medizin, 2. Workshop der Projektgruppe Mobiles Computing in der Medizin (MoCoMed) GMDS-Fachbereich Medizinische Informatik, GI-Fachausschuss 4.7, 9. April 2003, Dortmund; 01/2003
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ABSTRACT: Laparoscopic donor nephrectomy decreases disincentives to donation frequently associated with the disadvantages of open surgery. However, concerns have been raised regarding graft quality, since the incidence of delayed graft function is higher when compared with open procedures. This may be caused by amelioration of kidney perfusion due to the elevated intraabdominal pressure and to a mechanically induced renal angiospasm during donation. This study was addressed to reveal whether the renal periarterial application of papaverine is able to enhance renal blood flow during laparoscopic nephrectomy.
Twelve male piglets underwent left laparoscopic donor nephrectomy after endoscopic occlusion of the right renal vessels and ureter. Urine output and creatinine clearance were determined as indicators of renal blood flow. In the treatment group (n = 6) papaverine hydrochloride was administered to the tissue surrounding the renal artery prior to preparation of the vessels and results were compared with those of controls (n = 6). Free sodium excretion was measured to preclude prerenal failure.
In the control group the mean urine output was 0.015 ml/min/kg and the mean creatinine clearance was 0.95 ml/min/kg. In pigs treated with papaverine the mean urine output was 0.052 ml/min/kg and the mean creatinine clearance was 2.22 ml/min/kg. The differences were significant (urine output, P = 0.02; creatinine clearance, P = 0.038).
Papaverine improves renal function during laparoscopic kidney harvest when applied in the vicinity of the renal artery prior to vascular preparation.
Journal of Surgical Research 05/2002; 103(2):268-71. · 2.25 Impact Factor
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ABSTRACT: Crigler-Najjar type 1 disease (CNS1) is the result of a genetic defect, leading to complete functional loss of an enzyme which glucuronidates bilirubin. As a consequence, unconjugated bilirubin accumulates and may cause kernicterus, the most serious complication in adolescents. Phototherapy effectively adjusts bilirubin levels less than critical concentrations over many years but become less effective in elder children. Therefore, liver transplantation must be performed as definite therapy in these patients to avoid irreversible neurological deficits. Two brothers with CNS1, one without neurological deficits and one with moderate brain injury underwent orthotopic split liver transplantation from the same donor. The intra- and postoperative course of both patients was uneventful. Bilirubin levels normalized after transplantation in both recipients. Furthermore, mental and physical development considerably improved upon transplantation in the brother with neurological dysfunction. Therefore, orthotopic liver transplantation in CNS1 patients should be performed early enough to avoid irreversible brain damage, i.e., as a prophylactic procedure.
Transplantation 02/2002; 73(1):67-9. · 4.00 Impact Factor
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ABSTRACT: We describe the case of a 37-year-old pregnant woman, who was admitted to hospital for suspicion of chorioamnionitis. An emergency C-section was performed. Four days later, the patient suffered from abdominal pain and fever. Computed tomographic scanning demonstrated only a thrombosis of the right ovarian vein. Anticoagulation and antibiotic therapy was started immediately. Color duplex imaging performed 3 days later revealed a free-floating caval thrombus reaching the confluence of hepatic veins while the patient was fully anticoagulated. Emergency thrombectomy was performed by laparotomy, and the thrombus was removed by caval incision during suprahepatic clamping of the inferior vena cava. The patient recovered rapidly from surgery and was discharged on the tenth postoperative day.
Annals of Vascular Surgery 23(5):688.e7-9. · 1.03 Impact Factor
