Medizin - Open Access LMU - Teil 13/22 Archiv

Anti-Saccharomyces cerevisiae antibodies (ASCA) have been described as specific markers in Crohn's disease and their healthy first-degree relatives. 171 patients with Crohn's disease, their 105 first-degree relatives, 145 patients with ulcerative colitis and 101 first-degree relatives of patients with ulcerative colitis, 50 patients with infectious enterocolitis and 100 healthy controls were tested for ASCA employing the ELISA technique. When compared with the healthy controls (p < 0.0001) and patients with infectious enterocolitis (p < 0.0001) the prevalence of ASCA was significantly increased in patients with Crohn's disease and their first-degree relatives (p < 0.01). Further significant differences concerning the frequency of ASCA within the different groups of our study population were not observed. In particular, ASCA were not found in increased prevalence in infectious enterocolitis. These observations are compatible with a role of ASCA as a marker of genetic predisposition to Crohn's disease. Copyright (C) 2002 S. Karger AG, Basel.

Cancers of the gastrointestinal tract, including the liver, bile ducts, and pancreas, constitute the largest group of malignant tumors. Colorectal cancer is one of the most common neoplastic diseases in Western countries and one of the leading causes of cancer-related deaths. Inactivation of the adenomatous polyposis coli (APC) tumor-suppressor gene during early adenoma formation is thought to be the first genetic event in the process of colorectal carcinogenesis followed by mutations in oncogenes like K-Ras and tumor-suppressor genes like p53. Identification of the interaction of APC with the proto-oncogene beta-catenin has linked colorectal carcinogenesis to the Wnt-signal transduction pathway. The main function of APC is thought to be the regulation of free beta-catenin in concert with the glycogen synthase kinase 3beta (GSK-3beta) and Axin proteins. Loss of APC function, inactivation of Axin or activating beta-catenin mutations result in the cellular accumulation of beta-catenin. Upon translocation to the nucleus beta-catenin serves as an activator of T-cell factor (Tcf)-dependent transcription leading to an increased expression of several specific target genes including c-Myc, cyclin D1, MMP-7, and ITF-2. While APC mutations are almost exclusively found in colorectal cancers, deregulation of Wnt/beta-catenin/Tcf signaling is also common in other gastrointestinal and extra-gastrointestinal human cancers. In a fraction of hepatocellular carcinomas the Writ pathway is deregulated by inactivation of Axin or stabilizing mutations of beta-catenin. The majority of hepatoblastomas and a group of gastric cancers also carry beta-catenin mutations. Clearly, this pathway harbors great potential for future applications in cancer diagnostics, staging, and therapy. Copyright (C) 2002 S. Karger AG, Basel.

Background and Aims: The genes encoding for tumor necrosis factor-alpha (TNF-alpha), epidermal growth factor receptor (EGFR) and the vitamin D receptor (VDR) are colocalized to inflammatory bowel disease-associated linkage regions on chromosomes 6, 7 and 12. An association study of these gene polymorphisms with ulcerative colitis or Crohn's disease and a stratification according to disease phenotypes was performed in order to identify gentically homogenous subgroups. Patients and Methods: 119 healthy, unrelated controls, 95 patients with Crohn's disease and 93 patients with ulcerative colitis were genotyped for the (G to A) -308 TNF-alpha promoter polymorphism on chromosome 6, the codon 497 EGFR polymorphism on chromosome 7 and the Taql polymorphism of the VDR gene on chromosome 12. After genotyping, patients were stratified according to the respective disease phenotype. Results: A disequilibrium in the distribution of the VDR genotypes was found in patients with ulcerative colitis compared to controls (p = 0.024). In fistulizing and fibrostenotic Crohn's disease the `TT' genotype was significantly reduced compared with other phenotypes (p = 0.006), whereas the `tt' genotype was found more frequently (p = 0.04). The frequency of the WT allele of the EGFR gene was significantly higher in ulcerative colitis (p = 0.04) than in controls. Further significant differences, concerning the associations of the different polymorphisms and disease susceptibility or clinical phenotypes, were not observed. Conclusions: Regardless of the disease phenotype, the associations between the polymorphisms and inflammatory bowel disease investigated herein are modest, even after stratification for the disease phenotypes. Hence, these polymorphisms are unlikely to confer the reported linkage between inflammatory bowel disease and chromosomes 6, 7 and 12. Copyright (C) 2002 S. Karger AG, Basel.

Background/Aim: The generation of reactive oxygen species by activated Kupffer cells (KC) may contribute to reperfusion injury of the liver during liver transplantation or resection. The aim of our present studies was to investigate (1) prevention of hepatic reperfusion injury after warm ischemia by administration of the antioxidant glutathione (GSH) and (2) whether GSH confers protection through influences on KC toxicity. Methods: Isolated perfused rat livers were subjected to 1 h of warm ischemia followed by 90 min of reperfusion without (n = 5) or with GSH or catalase (n = 4-5 each). Selective KC activation by zymosan (150 mug/ml) in continuously perfused rat livers was used to investigate KC-related liver injury. Results: Postischemic infusion of 0.1, 0.5, 1.0 and 2.0 mM GSH, but not 0.05 mM GSH prevented reperfusion injury after warm ischemia as indicated by a marked reduction of sinusoidal LDH efflux by up to 83 +/- 13% (mean +/- SD; p < 0.05) and a concomitant significant improvement of postischemic bile flow by 58 +/- 27% (p < 0.05). A similar protection was conveyed by KC blockade with gadolinium chloride indicating prevention of KC-related reperfusion injury by postischemic GSH treatment. Postischemic treatment with catalase (150 U/ml) resulted in a reduction of LDH efflux by 40 +/- 9% (p < 0.05). Accordingly, catalase as well as GSH (0.1-2.0 mM) nearly completely prevented the increase in LDH efflux following selective :KC activation by zymosan in continously perfused rat livers. Conclusion: Postischemic administration of GSH protects the liver against reperfusion injury after warm ischemia. Detoxification of KC-derived hydrogen peroxide seem to be an important feature of the protective mechanisms. Copyright (C) 2002 S. Karger AG, Basel.

Personality disorders, and particularly antisocial personality disorder (ASPD), frequently co-occur with alcohol dependence. ASPD is considered to be an important cofactor in the pathogenesis and clinical course of alcohol dependence. The chronological relationship between the onset of symptoms of ASPD and alcohol-dependence characteristics has not yet been studied in great detail and the role of ASID in classification schemes of alcohol dependence as suggested by Cloninger and Schuckit has yet to be determined. We studied 55 alcohol-dependent patients to assess the prevalence and age at manifestation of ASPD, conduct disorder characteristics as well as alcohol dependence by employing the Semi-Structured Assessment for the Genetics of Alcoholism and the Structured Clinical Interview for DSM-IIIR. Results indicate that the onset of ASPD characteristics precede that of alcohol dependence by some 4 years. This finding suggests that in patients with ASPD, alcohol dependence might be a secondary syndrome as suggested by previous research. Copyright (C) 2002 S. Karger AG, Basel.

Today, the technique to directly administer vasodilators via the airway to treat pulmonary hypertension and to improve pulmonary gas exchange is widely accepted among clinicians. The flood of scientific work focussing on this new therapeutic concept had been initiated by a fundamental new observation by Pepke-Zaba {[}1] and Frostell in 1991 {[}2]: Both scientists reported, that inhalation of exogenous nitric oxide (NO) gas selectively dilates pulmonary vessels without a concomittant systemic vasodilation. No more than another decade ago NO was identified as an important endogenous vasodilator {[}3] while having merely been regarded an environmental pollutant before that time. Although inhaled NO proved to be efficacious, alternatives were sought-after due to NO's potential side-effects. In search for the ideal inhaled vasodilator another group of endogenous mediators - the prostanoids - came into the focus of interest. The evidence for safety and efficacy of inhaled prostanoids is - among a lot of other valuable work - based on a series of experimental and clinical investigations that have been performed or designed at the Institute for Surgical Research under the guidance and mentorship of Prof. Dr. med. Dr. h.c. mult. K. Messmer {[}4-19]. In the following, the current and newly emerging clinical applications of inhaled prostanoids and the experimental data which they are based on, will be reviewed. Copyright (C) 2002 S. Karger AG, Basel.

Intraoperative surgical blood loss is initially replaced by infusion of red cell-free, cristalloidal or colloidal solutions. When normovolemia is maintained the ensuing dilutional anemia is compensated by an increase of cardiac output and of arterial oxygen extraction. In the ideal case, a surgical blood loss can entirely be `bridged' without transfusion by intraciperative normovolemic hemodilution. However major blood loss results in extreme hemodilution and the transfusion of red blood cells may finally become necessary to increase arterial oxygen content and to preserve tissue oxygenation. When transfusion has to be started before surgical control of bleeding has been achieved, parts of the red blood cells transfused will get lost, thereby increasing intraoperative transfusion needs. Beside red blood cell transfusion, arterial oxygen content can be rapidly increased by ventilating the patient with 100% oxygen (hyperoxic ventilation), thus enhancing the amount of physically dissolved oxygen in plasma (hyperoxia). In experimental and clinical studies hyperoxic ventilation has emerged as a simple, safe and effective intervention to enlarge the margin of safety for hemodynamic compensation and tissue oxygenation in hemodiluted subjects experiencing major bleeding. The hyperoxia-associated microcirculatory dysregulation and impaired tissue oxygenation known to take place in the presence of a physiologic hemoglobin concentration are not encountered in hemodiluted subjects. Hyperoxic hemodilution i.e. the combination of intraoperative extreme hemodilution and hyperoxic ventilation may therefore be considered a cost-effective, safe and efficient supplement to reduce allogeneic transfusion during surgical interventions associated with high blood losses. The vast majority of the experimental and clinical investigations this new concept is based on was initiated and performed under the guidance of Prof. Konrad Messmer. Copyright (C) 2002 S. Karger AG, Basel.

Background. The OPS imaging technique has been introduced for in vivo assessment of microcirculation in humans. The aim of this study was to validate the new technique against intravital fluorescence microscopy (IFM) for the visualization of colon microcirculation in a murine model of inflammatory bowel disease (IBD). Method. IBD was induced in Balb/c mice by dextran sulfate sodium, controls received normal water. In each animal, both the CYTOSCAN(TM) A/R and IFM were used to image the microcirculation (n = 7 in each group). The postcapillary venular diameter was analyzed on the colon muscularis and mucosa. Results: The venular diameter correlated significantly between both methods representing the good correspondence between both methods. Conclusion: Our study demonstrates that the new technique for visualization of microcirculation without use of fluorescent dyes, the OPS imaging, allows for quantitative measurement of a key microcirculatory parameters of the mouse colon. Copyright (C) 2002 S. Karger AG, Basel.

The development of hemoglobin-based oxygen carriers has been propagated for replacement of the oxygen carrying properties of red blood cells for almost one century. Using a Clark-type multi-wire oxygen surface electrode and the dorsal skin fold chamber model of the awake Syrian golden hamster, local tissue pO(2) was analyzed in the thin striated skin muscle before and after administration of an ultrapurified polymerized bovine hemoglobin solution (U-PBHb(R), Biopure Corp., Boston, Mass., USA) under the following experimental conditions: (a) hypervolemic infusion with U-PBHb at similar to 10% of calculated blood volume, and (b) isovolemic exchange transfusion with U-PBHb by replacing similar to50% of calculated blood volume. Control animals of group a received equivalent treatment with either isotonic saline or dextran 60, control animals of group b received dextran 60. Local tissue pO(2) was found slightly decreased after both hypervolemic infusion and isovolemic exchange transfusion with U-PBHb, while frequency distribution curves of local tissue pO(2) were found more narrow (less values 25 mm Hg), suggesting a more homogeneous tissue pO(2) distribution. The data thus indicate that U-PBHb slightly decreases mean tissue pO(2) after both hypervolemic infusion and isovolemic exchange transfusion which is accompanied by an effective homogenization of local tissue pO(2) distribution as compared to dextran 60. Copyright (C) 2002 S. Karger AG, Basel.

The pulmonary circulation harbors a large intravascular reservoir of leukocytes refered to as the Marginated Pool. This marginated pool is balanced by propeling and retaining forces acting on leukocytes during their passage through the pulmonary circulation. The present paper discusses these factors and their underlying mechanisms. Copyright (C) 2002 S. Karger AG, Basel.

Background. Reperfusion injury represents a severe early complication following lung transplantation. Among the pathogenetic factors, the high potassium content of Euro-Collins(R) solution is discussed. Material and Methods: In a pig model of orthotopic left-sided lung transplantation we investigated the effect of Euro-Collins solution (EC: n=6) versus low potassium dextran (LPD: Perfadex(R): n = 6). Sham-operated (n = 6) animals served as control. Transplant function, cellular energy metabolism and endothelial morphology served as parameters. In a clinical investigation, 124 patients were evaluated following single (EC: n = 31; LPD n = 37) or double (EC: n = 17; LPD n = 39) lung transplantation, whose organs where preserved with EC (n = 48) or LPD (n = 76). Duration of ischemia, duration of ventilation and stay on ICU were registered. Primary transplant function was evaluated according to AaDO(2) values. Cause of early death (30 days) was declared. Results: Experimental results: After flush with EC and 18 h ischemia, a reduction of tissue ATP content (p < 0.01 vs inital value and LPD) was noted. Endothelial damage after ischemia was severe (p < 0.05 vs control), paO(2) was significantly decreased. Clinical results: In the LPD group, duration of ischemia was longer for the grafts transplanted first (SLTx and DLTx: p = 0.0009) as well as second (2. organ DLTx: p = 0.045). Primary transplant function was improved (day 0: SLTx: p = 0.0015; DLTx: p = 0.0095, both vs EC). Duration of ventilation and stay on ICU were shorter (n.s.). Reperfusion injury-associated death was reduced from 8% (EC) to 0 (LPD). Conclusion: In experimental lung preservation, LPD lead to an improved graft function. These results were confirmed in clinical lung transplantation. Clinical lung preservation, therefore, should be carried out by use of LPD. Copyright (C) 2002 S. Karger AG, Basel.

Objective: To determine whether L-arginine has any salutary effects on wound immune cell function following trauma-hemorrhage. Background. Depressed wound immune function contributes to an increased incidence of wound infections following hemorrhage. Although administration of L-arginine has been shown to restore depressed cell-mediated immune responses following hemorrhage potentially by maintaining organ blood flow, it remains unknown whether Larginine has any salutary effects on the depressed local immune response at the wound site. Methods: Male mice were subjected to a midline laparotomy and polyvinyl sponges were implanted subcutaneously in the abdominal wound prior to hemorrhage (35 +/- 5 mm Hg for 90 min and resuscitation) or sham operation. During resuscitation mice received 300 mg/kg body weight L-arginine or saline (vehicle). Sponges were harvested 24 h thereafter, wound fluid collected and wound immune cells cultured for 24 h in the presence of LPS. Pro- (IL-1beta, IL-6) and anti-inflammatory (IL-10) cytokines were determined in the supernatants and the wound fluid. In addition, wounds were stained for IL-6 immunohistochemically. In a separate set of animals, skin and muscle blood flow was determined by microspheres. Results: The capacity of wound immune cells to release IL-1beta and IL-6 in vitro was significantly depressed in hemorrhaged mice receiving vehicle. Administration of L-arginine, however, improved wound immune cell function. In contrast, in vivo the increased IL-6 release at the wound site was decreased in L-arginine-treated mice following hemorrhage. Moreover, IL-10 levels were significantly increased in the wound fluid in hemorrhaged animals receiving L-arginine compared to vehicle-treated mice. In addition, the depressed skin and muscle blood flow after hemorrhage was restored by L-arginine. Conclusions: Thus, L-arginine might improve local wound cell function by decreasing the inflammatory response at the wound site. Since L-arginine protected wound immune cell function this amino acid might represent a novel and useful adjunct to fluid resuscitation for decreasing wound complications following hemorrhage. Copyright beta 2002 S. Karger AG, Basel.