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Hintergrund: Verschiedene Faktoren der Lebensführung spielen eine zentrale Rolle in der Primär- und Tertiärprävention des kolorektalen Karzinoms (CRC). Das Ziel dieser Übersichtsarbeit ist es, die Datenlage zu den Auswirkungen der Lifestyle-Faktoren körperliche Aktivität (KA) und Ernährung in der Primär- und insbesondere der Tertiärprävention des CRC zusammenzufassen. Methoden: Mit Blick auf den Einfluss der Lifestyle-Faktoren auf die Prognose und die Lebensqualität (LQ) der Patienten wurde eine umfassende Literaturrecherche in Publikationen zu klinischen Studien vor allem aus den Jahren 2000 bis 2015 durchgeführt und der aktuelle Wissensstand auf der Grundlage dieser klinischen Studien zusammengefasst. Ergebnisse: Neben der Vermeidung von Risikofaktoren (wie Rauchen und übermäßiger Alkoholgenuss) können ein gesundes Körpergewicht, regelmäßige und moderate KA sowie eine mediterrane Ernährung mit viel Obst, Gemüse, Geflügel und Fisch das Erkrankungsrisiko signifikant verringern. Patienten mit bereits diagnostiziertem CRC können auch aktiv ihre CRC-Prognose und ihre LQ verbessern, indem sie ihre Lebensgewohnheiten umstellen. Patienten, die ein moderates Trainingsprogramm aufnehmen und ihre Essgewohnheiten im Sinne der mediterranen Ernährung ändern, können die krebsspezifische und die Gesamtmortalität um bis zu 40% senken und schon während der Chemotherapie ihre LQ signifikant erhöhen. Daher sollten Ärzte, die CRC-Patienten behandeln, diesen Patienten moderate KA, Kalorienrestriktion und ein mediterranes Ernährungsmuster empfehlen. Die systematische Literaturrecherche des World Cancer Research Fund/American Institute for Cancer Research (AICR/WCRF) von 2007 zeigt zudem, dass nach der Diagnosestellung dieselben Empfehlungen zur Lebensführung gelten wie für die Prävention der Krankheit. Schlussfolgerung: Faktoren der Lebensführung wie moderate KA und mediterrane Ernährung verbessern die LQ und die Prognose von Patienten mit CRC. Die Erkenntnisse zur Wirkung der Umstellung von Lebensgewohnheiten beruhen jedoch hauptsächlich auf Beobachtungsstudien; es gibt nur wenige prospektive Studien und keine randomisierten. Daher rechtfertigen die Beobachtungsstudien kontrollierte randomisierte Studien, die die Wirkung einer solchen Umstellung auf LQ und Krebsrezidivierung nachweisen. Übersetzung aus Visc Med 2016;32:199-204 (DOI:10.1159/000446492)

Background: Lifestyle factors play a pivotal role in the primary and tertiary prevention of colorectal cancer. The purpose of this review article is to summarize data concerning the effect of the lifestyle factors physical activity (PA) and nutrition in primary and, more importantly, tertiary prevention of colorectal cancer (CRC). Methods: Focusing on the influence of lifestyle factors on prognosis und quality of life (QOL), a comprehensive literature search of clinical studies published mainly in the years 2000 until 2015 was performed and the current knowledge based on these clinical studies reviewed. Results: Besides avoiding risk factors (such as smoking and overindulgence in alcohol), healthy weight, regular and moderate PA as well as a diet which contains fruit, vegetables, poultry, and fish (so-called ‘Mediterranean' diet) may reduce the risk of the disease significantly. Patients already diagnosed with CRC can also actively improve the prognosis of CRC and QOL by changing their lifestyle. Patients commencing moderate exercise and modifying their eating habits in terms of a ‘Mediterranean' diet can reduce cancer-specific and overall mortality by up to 40% and significantly increase their quality of life already during chemotherapy. Therefore, moderate physical exercise, calorie restriction, and a Mediterranean dietary pattern for patients with CRC should be recommended by physicians treating these patients. In fact, the World Cancer Research Fund/American Institute for Cancer Research (AICR/WCRF) systematic literature review from 2007 shows that the lifestyle changes recommended after diagnosis are the same for primary prevention of this disease. Conclusion: Lifestyle changes such as moderate PA and a Mediterranean diet significantly improve the QOL as well as the prognosis of patients suffering from colorectal disease. However, the effect of lifestyle changes is mostly based on observational studies, while only few studies are prospective and none are randomized. Therefore, these observational studies warrant controlled randomized trials to prove the effectiveness of lifestyle interventions on QOL and cancer recurrence.

Summary Background There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery. Methods This randomised, controlled, double-blind, parallel-group, superiority trial was done in 18 hospitals across Europe. Patients with chronic pancreatitis who were planned for elective surgical treatment were randomly assigned to DPPHR or partial pancreatoduodenectomy with a central web-based randomisation tool. The primary endpoint was mean quality of life within 24 months after surgery, measured with the physical functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Primary analysis included all patients who underwent one of the assigned procedures; safety analysis included all patients who underwent surgical intervention (categorised into groups as treated). Patients and outcome assessors were masked to group assignment. The trial was registered, ISRCTN38973832. Recruitment was completed on Sept 3, 2013. Findings Between Sept 10, 2009, and Sept 3, 2013, 250 patients were randomly assigned to DPPHR (n=125) or partial pancreatoduodenectomy (n=125), of whom 226 patients (115 in the DPPHR group and 111 in the partial pancreatoduodenectomy group) were analysed. No difference in quality of life was seen between the groups within 24 months after surgery (75·3 [SD 16·4] for partial pancreatoduodenectomy vs 73·0 [16·4] for DPPHR; mean difference −2·3, 95% CI −6·6 to 2·0; p=0·284). The incidence and severity of serious adverse events did not differ between the groups. 70 (64%) of 109 patients in the DPPHR group and 61 (52%) of 117 patients in the partial pancreatoduodenectomy group had at least one serious adverse event, with the most common being reoperations (for reasons other than chronic pancreatitis), gastrointestinal problems, and other surgical morbidity. Interpretation No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting. Funding German Research Foundation (DFG).

The aim of this study was to compare single-port access cholecystectomy (SPA) with the standard laparoscopic technique (LC) regarding the duration of the operation, complications, learning curve, late postoperative quality of life (QoL) and the incidence of incisional hernias. Between June 2009 and December 2011, a total of 122 SPA cholecystectomies were performed in our hospital. Simultaneously, 310 patients were operated on with the LC technique. In the LC group, 100 patients met the same criteria defined for SPA surgery. The two groups (SPA and LC) were compared by multivariable regression analysis. Endpoints of this study were quality of life (QoL) after 6 months by the EQ-5D questionnaire 5L and the incidence of incisional hernia 1 year after surgery. Operating time, hospital stay, and perioperative complications were also measured and compared. The median follow-up was 9.2 months (3–25 months). The patients in the SPA group were younger and more often female. The mean operating time for group SPA was 73 min (35–136 min)—significantly longer than that for group LC with 60 min (33–190 min) (p

The use of isolated human liver cells in research and development has gained increasing interest during the past years. The possible application may vary between elucidation of new biochemical pathways in liver diseases, drug development, safety issues, and new therapeutic strategies up to direct clinical translation for liver support. However, the isolation of human liver cells requires a well-developed logistic network among surgeons, biologists, and technicians to obtain a high quality of cells. Our laboratories have been involved in various applications of human liver cells and we have long-lasting experiences in human liver cell isolation and their application in R&D. We here summarize the present protocol of our laboratories for cell isolation from normal resected liver tissue, the most common tissue available. In addition, we discuss the necessary network in the clinic and quality controls to maintain human liver cells in culture and the effect of 3D extracellular matrix in cultured cells which results in preservation of hepatocyte epithelial polarity in the form of bile canaliculi and repression of epithelial to mesenchymal transitions occurring in 2D cultures.

To find out whether wide local resection is adequate treatment for patients with benign tumours of the papilla of Vater.Retrospective study.University hospital, Germany.31 patients with benign tumours out of a total of 129 with lesions of the ampulla of Vater treated between May 1978 and February 1995.Histological examination of specimens before, during, and after the operation.Sensitivity and positive predictive value of histological examination, and outcome of treatment.Histological examination before and during the operation had a sensitivity of 89% and 97%, respectively. 28 patients were treated by wide excision of the ampulla and 3 by pylorus-preserving partial pancreaticoduodenectomy. At a median follow up of 43 months (range 6-156) there was no evidence of recurrent disease.Wide excision of the ampulla with reconstruction and reimplantation of the duct is adequate treatment for benign lesions. If the histological picture is uncertain, partial pancreaticoduodenectomy is justified in patients at low risk.

Oxidative stress is an important factor in the pathogenesis of acute pancreatitis, as shown in vivo by the beneficial effects of scavenger treatment and in vitro by the potential of free radicals to induce acinar cell damage. However, it is still unclear whether oxygen free radicals (OFR) act only as mediators of tissue damage or represent the initiating event in acute pancreatitis in vivo as well. In the present study the authors aimed to address this issue in an experimental set-up.Two hundred male Wistar rats were randomly assigned to one of the following experimental groups. In two groups, acute necrotizing pancreatitis was induced by retrograde intraductal infusion of 3% sodium taurocholate. Through the abdominal aorta, a catheter was advanced to the origin of the celiac artery for continuous regional arterial (CRA) pretreatment with isotonic saline (NP-S group) or superoxide dismutase/catalase (NP-SOD/CAT group). In another group, oxidative stress was generated by CRA administration of xanthine oxidase and intravenous administration of hypoxanthine (HX/XOD group). Sham-operated rats received isotonic saline both arterially and intraductally. After observation periods of 5 and 30 minutes and 3 and 6 hours, the pancreas was removed for light microscopy and determination of reduced glutathione (GSH), oxidized glutathione (GSSG), conjugated dienes (CD), and malondialdehyde as a marker for OFR-induced lipid peroxidation as well as myeloperoxidase as a parameter for polymorphonuclear leukocyte accumulation.A significant decrease of GSH was paralleled by an increased ratio of GSSG per total glutathione and elevated CD levels after 5 minutes in the NP-S group versus the sham-operated group. Thereafter, the percentage of GSSG and GSH returned to normal levels until the 6-hour time point. After a temporary decrease after 30 minutes, CD levels increased again at 3 hours and were significantly higher at 6 hours in contrast to sham-operated rats. Myeloperoxidase levels were significantly elevated at 3 and 6 hours after pancreatitis induction. In contrast to NP-S rats, treatment with SOD/CAT significantly attenuated the changes in glutathione metabolism within the first 30 minutes and the increase of CDs after 6 hours. HX/XOD administration lead to changes in levels of GSH, GSSG, and CDs at 5 minutes as well as to increased myeloperoxidase levels at 3 hours; these changes were similar to those observed in NP-S rats. Acinar cell damage including necrosis was present after 5 minutes in both NP groups, but did not develop in HX/XOD rats. In addition, serum amylase and lipase levels did not increase in the latter group. SOD/CAT treatment significantly attenuated acinar cell damage and inflammatory infiltrate compared with NP-S animals during the later time intervals.OFRs are important mediators of tissue damage. However, extracellular OFR generation alone does not induce the typical enzymatic and morphologic changes of acute pancreatitis. Factors other than OFRs must be involved for triggering acute pancreatitis in vivo.

Using a retrograde infusion sodium taurocholate pancreatitis model in the rat treatment with oxygen radical scavengers or monoclonal anti-ICAM-1 antibody decreased tissue damage and polymorphonuclear leukocytes (PMN) infiltration. Scavengers or anti-ICAM-1 treatment attenuated the activating capacity of blood PMNs following zymosan stimulation. The local production of oxygen free radicals in the pancreas by systemic infusion of hypoxanthine and regional infusion of xanthine oxidase did not induce acute pancreatitis, although an increase of infiltrating PMNs was observed. Our data suggest that oxygen free radicals and infiltrating PMNs aggravate acute pancreatitis and that both are important mediators of local destruction and systemic activation of PMNs.

Background: The indications for a resective procedure in chronic pancreatitis are severe pain and local complications. The aim of this study, based on prospectively assessed data, was to evaluate distal pancreatectomy in patients suffering from chronic pancreatitis localized in the corpus and cauda of the pancreatic gland. Methods: Seventy-four patients undergoing distal pancreatectomy were evaluated pre- and postoperatively (after a median observation period of 58 months) for pain, professional status, alcohol consumption, and endocrine function as measured by the glucose tolerance test preoperatively. Results: The indication for operation was severe therapy-resistant pain in nearly all patients and an inflammatory tumor or pancreatic pseudocysts in over 50% of the patients. One fourth of the patients were operated in order to exclude malignancy. Ninety-five percent of the patients underwent distal pancreatectomy, only in 4 cases (5%) was a subtotal (Child) resective procedure performed. In 34% of patients undergoing distal pancreatectomy a splenectomy could be avoided. The early postoperative complications were few and mostly due to the severe comorbidity of the patients. During the median observation period of 58 months 14.7% of the patients died due to diseases not related to distal pancreatectomy. Six percent of the patients could not be reevaluated and were lost to follow-up. In the remaining 59 patients 88% had significantly less pain and 66% had an increase in median body weight of 8 kg. Fifty percent of the patients had full or partial professional rehabilitation, one fourth was unemployed and 24% had retired due to age. 51.7% had a normal endocrine function as assessed by the glucose tolerance test, 16.2 and 21.6% had a latent or manifest diabetes mellitus, respectively. In 74.5% of all patients the endocrine function did not worsen during the observation period. Conclusion: In comparison to conservative treatment distal pancreatectomy is a suitable therapeutic measure in patients with severe pain and local complications. It significantly improves the quality of life of patients without compromising endocrine function. Postoperative lethality is lower than in conservatively treated patients and is not related to distal pancreatectomy.

It has been suggested that endotoxin triggers translocation of intestinal bacteria in vivo, either by directly damaging intestinal mucosa or by inducing a systemic inflammatory reaction that leads to mucosal disruption. To address this issue, we examined the immediate effect of extraluminal endotoxin on structure and function of isolated rat cecal mucosa without other inflammatory cells in vitro. The cecal mucosa of 12 male Wistar rats was mounted in modified Ussing chambers filled with Dulbecco's modified Eagle's medium and the ampicillin-resistant Escherichia coli HB101:K12 incubated on the mucosal side. Endotoxin was added to the submucosal side at concentrations of 1 and 10 EU/ml, respectively. Under gassing with carbogene at 37 degreesC, the potential difference across the mucosa was measured continuously. Samples of the mucosal and submucosal solutions were removed at 60, 120, and 180 min and plated out on McConkey ampicillin-agar. After 180 min, the mucosal specimens were retrieved and examined by light and scanning electron microscopy. No significant change in potential difference was observed in control or endotoxin-incubated mucosa within the observation period. Neither light nor scanning electron microscopy showed a significant change in the structure of the epithelium, mucosa, or submucosa. No significant translocation of the E. coli across the mucosa was seen. We concluded that endotoxin alone does not induce immediate structural and functional damage to rat cecal mucosa in vitro. Therefore, it seems unlikely that a short endotoxemia alone directly triggers bacterial translocation by disrupting intestinal mucosa, but rather, entotoxin induces a local and systemic inflammatory reaction that leads to mucosal disruption.

Anhand einer Studie mit prospektiv erhobenen Daten wurde die Wertigkeit der pyloruserhaltenden partiellen Duodenopankreatektomie (PPPD) im Vergleich zur partiellen Duodenopankreatektomie nach Whipple (PD) bei Patienten mit einem duktalen Pankreascarcinom bzgl. postoperativer Morbiditat, Letalitat und Prognose verglichen. Von Mai 1990 bis April 1995 gingen 130 Patienten in die Studie ein, wobei 61 eine PD bzw. 69 Patienten eine PPPD erhielten. Alle Patienten wurden in 6monatigen Abstanden im Rahmen der Tumornachsorge nachuntersucht. Das mediane Nachuntersuchungsintervall lag bei den Patienten bei 36 Monaten; die Uberlebenskurven wurden nach Kaplan-Meier errechnet. Es zeigte sich, das die PPPD bei Patienten mit duktalem Pankreaskopfcarcinom ohne Infiltration des Duodenums die technisch einfachere, blutsparendere, schnellere Operationsmethode ist, die zu keinen erhohten perioperativen Komplikationen fuhrt. Magenentleerungsstorungen waren allenfalls temporar und unterschieden sich nicht signifikant von der Standardoperation nach Whipple (PD). Die mediane Uberlebenszeit der Patienten in der PD-Gruppe lag in bezug auf alle Stadien bei 10,8 Monaten, in der PPPD-Gruppe bei 21 Monaten. Dieser an sich signifikante Unterschied erklart sich jedoch aus der etwas unterschiedlichen Verteilung der UICC-Stadien in beiden Behandlungsgruppen. Betrachtet man das haufigste Stadium (UICC-Stadium III), so konnte kein Unterschied in den medianen Uberlebenszeiten zwischen den Gruppen festgestellt werden: Sie liegen bei 10,1 bzw. 11,2 Monaten. Die PPPD stellt somit eine radikale Operationsmethode dar, die die Prognose der Erkrankung nicht verschlechtert.

Die Gruppe der Phospholipasen A2 (PLA2) umfast sekretorische und intracellulare Enzyme, die Phospholipide spalten und eine physiologische Funktion bei Entzundungsprozessen sowie der Verdauung wahrnimmt. Beim Menschen wird die Gruppe der sekretorischen, niedermolekularen PLA2 (sPLA2) von der Gruppe der cytosolischen, hohermolekularen PLA2 (cPLA2) unterschieden. Die beiden bekannten cPLA2 steuern die intracellulare Reaktion auf einen Entzundungsreiz, indem sie Arachidonsaure aus Membranphospholipiden freisetzen. Die pankreatische sekretorische PLA2 (sPLA2-I) ist ein Verdauungsenzym, das als inaktives Zymogen von den Acinuszellen des Pankreas sezerniert wird. Bei der akuten Pankreatitis zeigt die zirkulierende, aber katalytisch inaktive sPLA2-I das Ausmas der Pankreasschadigung an. Die sPLA2-II ist bei verschiedenen entzundlichen Erkrankungen und Infektionen, nach operativen Eingriffen oder schweren Traumen erhoht. Sie vermittelt die schwere systemische Entzundungsreaktion und ist an der Ausbildung schwerer Komplikationen beteiligt, indem sie die Bildung von Leukotrienen, Prostaglandinen und Plattchen-Aggregations-Faktor reguliert. Hochste sPLA2-II-Werte im Serum finden sich bei Sepsis und Multiorganversagen. Eine diagnostische Bedeutung kommt der sPLA2-II zu, da sie als fruher Marker die schwere systemische Entzundungsreaktion und drohende Organkomplikationen anzeigt.

Bei Patienten mit chronischer Pankreatitis ist der entzundliche Prozes im Pankreaskopf haufig Schrittmacher der Krankheit; der entzundliche Pankreaskopftumor verursacht das Schmerzsyndrom und fuhrt bei der Halfte der Patienten zu lokalen Komplikationen. Die duodenumerhaltende Pankreaskopfresektion bietet gegenuber den in der Vergangenheit praktizierten Verfahren den Vorteil der Erhaltung von Magen, Duodenum und Gallenwegen sowie der Erhaltung der Insulinsekretionskapazitat. Die duodenumerhaltende Pankreaskopfresektion entspricht einer minimalisierten subtotalen Resektion des Pankreaskopfes. Bei 380 Patienten war die Krankenhausletalitat 0,8 %, die Reoperationsfrequenz 5,3 %. Die mittlere postoperative Krankenhausliegezeit war 13,9 Tage. Fruhpostoperativ war der Glucosestoffwechsel bei 2 % verschlechtert und bei 9 % verbessert. Nach einer medianen Nachbeobachtungszeit von 6 Jahren sind 88 % der Patienten vollstandig schmerzfrei bzw. haben selten Bauchschmerzen; 63 % sind wieder voll berufstatig; die Spatletalitat betragt 8,9 %. Nur 10 % der Patienten erlitten weitere Pankreatitisschube. Der entscheidende Vorteil der duodenumerhaltenden Pankreaskopfresektion besteht in der Erhaltung der endokrinen Funktion der Bauchspeicheldruse bei Schonung der Pankreasnachbarorgane.

We investigated the effects of endogenously produced and exogenously applied nitric oxide (NO) on cell proliferation rates and cell cycle regulation in senescent human fibroblasts (WI38). Induction of inducible nitric oxide synthase by tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta inhibited cell proliferation and led to a G1 arrest. These effects were partially reversible by N(G)-monomethyl-arginine (NMA). Addition of the NO donors sodium nitroprusside (SNP) or S-nitroso-N-acetylpenicillamine (SNAP) increased cell proliferation rates as well as the S/G2 fraction. This points to a functional role of NO in cell cycle regulation and cell proliferation in human fibroblasts which depends on the mode of NO generation as well as the culture conditions used.

Bei der chronischen Pankreatitis kommt es oft zu einer entzundlichen Raumforderung im Pankreaskopf mit lokalen Komplikationen durch Obstruktion benachbarter Organstrukturen und Schmerzen. Die chirurgischen Behandlungsverfahren sind der endoskopischen Therapie und resezierende Operationen einer Drainageoperation uberlegen. Die Pankreaskopfresektion ist eine sichere und effektive Methode in der Therapie der chronischen Pankreatitis. Bei gleichwertigen Langzeitergebnissen ist die duodenumerhaltende Pankreaskopfresektion (DEPKR) der Whipple-Operation im Sinne eines schonenderen, organerhaltenden Eingriffs vorzuziehen. Die totale Pankreatektomie sollte nur in Einzelfallen bei chronischer Pankreatitis nach strenger Indikationsstellung durchgefuhrt werden. Insgesamt sollte das Resektionsausmas nach dem Grundsatz „So viel wie notig, so wenig wie moglich“ durchgefuhrt werden.

Oxygen radicals mediate an important step in the initiation of acute pancreatitis. These reactive oxygen metabolites are generated at an early stage of the disease. The source of the enhanced production of oxygen radicals, however, still remains unclear. Experimentally, the effectiveness of antioxidant treatment varies from one model to the other, the differences depending on the experimental model and not on the form of pancreatitis that was induced. In most studies, the experimental animals were pretreated before acute pancreatitis was induced. This does not mirror clinical reality because patients are admitted to the hospital after the onset of the disease. It was shown in cerulein-induced pancreatitis, however, that scavenger treatment also mitigated the pancreatic tissue damage after induction of acute pancreatitis. Moreover, antioxidant treatment also attenuated the extrapancreatic complications, thus improving the final outcome of the disease. Initial indirect observations also suggest that in human acute, acute recurrent, and chronic pancreatitis, oxygen free radicals are generated and add to the damage. Concomitantly, these patients suffer from a severe depletion of oxidative stress. Whether or not this disbalance is instrumental in the development and course of disease remains unanswered. Supplementation with antioxidants that are deficient in patients with acute pancreatitis might be a feasible option to the present therapy to avoid extrapancreatic complications. Well-defined, controlled clinical trials involving patients suffering from acute pancreatitis are therefore needed to validate the role of oxygen radicals in this disease.

Hemorrhagic mucosal lesions are produced during intestinal ischemia and after reperfusion due at least in part to the accumulation and activation of polymorphonuclear leukocytes in the tissue. It has been shown in vitro that adenosine is instrumental in attenuating this pathophysiological process. Acadesine [5-amino-4-imidazolecarboxamide (AICA) riboside], a purine nucleoside analogue, increases the availability of adenosine in the tissue. The aim of the study was therefore to assess the influence of acadesine treatment on neutrophil accumulation, purine metabolism, and mucosal damage after intestinal ischemia and reperfusion. Intestinal ischemia was induced in cats by partial occlusion of the superior mesenteric artery for 2 h. Samples of the small intestine were exercised before and at the end of the hypotensive period as well as 10 and 60 min after reperfusion. Conjugated dienes, myeloperoxidase, and reduced and oxidized glutathione, as well as the purine metabolites, were determined in the tissue samples. The tissue was also examined histologically. Six cats received saline, and six cats were treated initially before ischemia with acadesine (2.5 mg/kg body wt i.v.) over 5 min as a bolus. Thereafter, acadesine (0.5 mg.kg-1.min- i.v.) was given continuously during ischemia and 30 min after reperfusion. Acadesine treatment significantly attenuated the mucosal lesions seen during reperfusion. This improvement was due at least in part to the inhibition of neutrophil accumulation, as judged by low myeloperoxidase levels. The prevention of neutrophil activation resulted most likely from increased adenosine concentrations in the intestinal tissue in the early reperfusion period.(ABSTRACT TRUNCATED AT 250 WORDS)

Background/Aim : In spite of the interest in free radicals as mediators of ischemic damage, most information on these species in biological systems is derived from indirect measurements. Our aim was to obtain more direct information concerning sources of free radical production during ischemia and reperfusion. Methods : We have performed simultaneous measurement of radical generation, purine metabolites, reduced glutathione, neutrophil infiltration and morphological appearance in the cat small intestine in vivo during 60 minutes of ischemia followed by 60 minutes of reperfusion. Results : Radical formation increased abruptly on reperfusion and remained elevated in untreated animals. Inhibition by a monoclonal antibody (IB4) against the neutrophil and by allopurinol treatment was paralleled by improvement of biochemical and morphological parameters. The radicals detected during reperfusion could be divided into one component arising directly from the neutrophils, one due to the xanthine oxidase reaction, and one unknown source. Conclusions : Neutrophils are a major source of radical production during reperfusion after ischemia. Radicals formed in the xanthine oxidase reaction seem to function as a primer for the neutrophils. The nonsignificant linear correlation between radical formation and morphological appearance suggests that factors other than free radicals are important for the development of intestinal damage after a period of ischemia.

Review the histologic and pathophysiologic alterations seen after intestinal ischemia and reperfusion.Current literature review.The most pertinent, current, and representative articles describing results from both animal and human investigations are utilized and discussed.Postischemic intestinal tissue damage appears to be due to the formation of oxygen radicals and the activation of phospholipase A2. The initial source of oxygen radicals seems to be the hypoxanthine-xanthine oxidase system. Oxygen radicals react directly with poly-unsaturated fatty acids, leading to lipid peroxidation within the cell membranes. Indirectly, the radicals trigger the accumulation of neutrophils within the affected tissue initiating inflammatory processes that lead to severe mucosal lesions. Similarly, phospholipase A2 also initiates postischemic mucosal lesions. Phospholipase A2 is a hydrolytic enzyme capable of increasing formation of cytotoxic lysophospholipids within the tissue. Enhanced activity of phospholipase A2 also stimulates the production of prostaglandins and leukotrienes. Various substances (superoxide dismutase, catalase, dimethyl sulfoxide, allopurinol, and deferoxamine, etc.) are able to detoxify oxygen radicals or inhibit the mechanisms leading to their enhanced generation, thus attenuating the postischemic lesions of the mucosa.Oxygen radicals and the activation of phospholipase A2 during reperfusion seem to be instrumental for the development of hemorrhagic mucosal lesions after intestinal ischemia. Radical scavengers and phospholipase A2 inhibitors may prevent reperfusion damage of the intestine, even when the treatment starts during ischemia but before reperfusion.

SUMMARY Background: After pancreatic surgery, some patients have complica tions that require treatment. Method: Review article based on a selective literature search and the German S3 guideline on pancreatic carcinoma. Results: Detailed knowledge of the surgical procedure and its potential early and late complications is a prerequisite for the recognition and treatment of problems occurring after pancreatic surgery. These may be due either to the operation itself or to the progression of the underlying pancreatic disease. Both diabetes mellitus and exocrine insufficiency are common long-term sequelae. If persistent pain should arise, its cause must be identified and treated. To prevent malnutrition and vitamin deficiency after pancreatic resection, patients should be given a diet with an increased fat content and with supplemental enzymes.

SUMMARY Summary Background: Colorectal carcinoma is the most common type of tumor in Western countries. The risk of developing colorectal carcinoma depends both on genetic factors (familial predisposition) and on lifestyle-related factors such as body-mass index, level of physical activity, and nutritional behavior. Regular physical activity is important in primary prevention, and there is also evidence that the prognosis after treatment of a colorectal carcinoma can be improved by exercise. Methods: The PubMed database was searched for relevant articles that appeared in the last 10 years, and selected articles were evaluated. Results: Cross-sectional studies have shown that regular physical activity (ca. 7 hours of brisk walking per week) lowers the risk of colon carcinoma by 40%. Physical activity also improves the outcome of patients already diagnosed with colorectal carcinoma: for example, patients with advanced disease (UICC stage II or III) have been found to survive significantly longer if they perform 4 hours of brisk walking per week, or the equivalent degree of physical exercise. Conclusions: Cross-sectional studies show that physically active persons are less likely to develop colorectal carcinoma than physically inactive persons, and that they have better outcomes in the event that they do develop the disease. The positive findings with respect to secondary prevention still need to be confirmed in interventional trials, but in primary prevention, at least, physical activity should be actively promoted, along with other beneficial lifestyle habits and screening measures.

The purpose of this study was to assess the involvement of oxygen radicals in acute edematous and hemorrhagic panreatitis. Acute pancreatitis was induced in rats by the CCK-analogue cerulein (5 μg/kg/h) and by retrograde injection of 5% sodium taurocholate for 30 min, 3.5 h, and 12 h. At the end of the infusion and observation time, serum enzymes, conjugated dienes, and malondialdehyde in the tissue were measured. Moreover, the tissue samples underwent light microscopical examination. In cerulein pancreatitis, an interstitial edema and intravascular margination of granulocytes in the pancreatic gland were observed after 3.5 h. After 12 h, the histological evaluation revealed a pronounced zymogen degranulation, extensive tissue necrosis and migration of granulocytes into the tissue. Parallelly, amylase and lipase increased by 15 and 35 times, respectively. In contrast, conjugated dienes and malondialdehyde increased in cerulein pancreatitis and reached their highest level after 3.5 h and decreased to normal levels after 12 h. The development of the histological damages and serum enzyme levels with sodium taurocholate pancreatitis was similar as compared to the cerulein pancreatitis, however, the development was faster and more traumatic. Already after 3.5 h an extensive zymogen degranulation and cell necrosis was observed. Concomitantly, the amylase and lipase levels increased by 90 and 30 times, respectively. Treatment with superoxide dismutase (100000 U/kg/h) and catalase (400 000 U/kg/h) prevented lipid peroxidation and reduced zymogen degranulation and tissue necrosis. Tissue edema and inflammatory response were not affected in both models of acute pancreatitis. Moreover, scavenger treatment improved the survival rate in sodium taurocholate pancreatitis. It is therefore concluded that oxygen free radicals seem to be instrumental for the development of the disease. Scavenger treatment can mitigate the pancreatic tissue damages and the extrapancreatic complications.

Background & Aims Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSCs), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Signaling through sonic hedgehog and mammalian target of rapamycin (mTOR), respectively, may be essential for CSC self-renewal and could represent putative targets for novel treatment modalities. Methods We used in vitro and in vivo models of pancreatic cancer to examine the effects of sonic hedgehog inhibition (cyclopamine/CUR199691) and mTOR blockade (rapamycin) on the tumorigenic CSC population. Results Surprisingly, neither cyclopamine nor rapamycin alone or as supplements to chemotherapy were capable of effectively diminishing the CSC pool. Only the combined inhibition of both pathways together with chemotherapy reduced the number of CSCs to virtually undetectable levels in vitro and in vivo. Most importantly, in vivo administration of this triple combination in mice with established patient-derived pancreatic tumors was reasonably tolerated and translated into significantly prolonged long-term survival. Conclusions The combined blockade of sonic hedgehog and mTOR signaling together with standard chemotherapy is capable of eliminating pancreatic CSCs. Further preclinical investigation of this promising approach may lead to the development of a novel therapeutic strategy to improve the devastating prognosis of patients with pancreatic cancer.

Objective: The authors performed a prospective evaluation of staging laparoscopy with laparoscopic ultrasonography in predicting surgical resectability in patients with carcinomas of the pancreatic head and periampullary region.Summary Background Data: Pancreatic resection with curative intent is possible in a select minority of patients who have carcinomas of the pancreatic head and periampullary region. Patient selection is important to plan appropriate therapy and avoid unnecessary laparotomy in patients with unresectable disease. Laparoscopic ultrasonography is a novel technique that combines the proven benefits of staging laparoscopy with high resolution intraoperative ultrasound of the liver and pancreas, but which has yet to be evaluated critically in the staging of pancreatic malignancy.Methods: A cohort of 40 consecutive patients referred to a tertiary referral center and with a diagnosis of potentially resectable pancreatic or periampullary cancer underwent staging laparoscopy with laparoscopic ultrasonography. The diagnostic accuracy of staging laparoscopy alone and in conjunction with laparoscopic ultrasonography was evaluated in predicting tumor resectability (absence of peritoneal or liver metastases; absence of malignant regional lymphadenopathy; tumor confined to pancreatic head or periampullary region).Results: “Occult” metastatic lesions were demonstrated by staging laparoscopy in 14 patients (35%). Laparoscopic ultrasonography demonstrated factors confirming unresectable tumor in 23 patients (59%), provided staging information in addition to that of laparoscopy alone in 20 patients (53%), and changed the decision regarding tumor resectability in 10 patients (25%). Staging laparoscopy with laparoscopic ultrasonography was more specific and accurate in predicting tumor resectability than laparoscopy alone (88% and 89% versus 50% and 65%, respectively).Conclusions: Staging laparoscopy is indispensable in the detection of “occult” intraabdominal metastases. Laparoscopic ultrasonography improves the accuracy of laparoscopic staging in patients with potentially resectable pancreatic and periampullary carcinomas.

In patients with chronic renal failure, hyperparathyroidism is a common problem and surgical parathyroidectomy (PTX) is frequently required. The three different surgical approaches are subtotal PTX, total PTX with autotransplantation, and total PTX without autotransplantation. Recurrence of hyperparathyroidism varies from 5% to 80% in different studies for the first two surgical approaches. To minimize the risk for recurrence, and because we fear severe relapses with calciphylaxia, we perform total PTX without autotransplantation. From October 1993 to October 1997, 20 patients (9 men and 11 women) underwent total PTX without autotransplantation (median age, 52 years; range, 23 to 74 years; median dialysis time before PTX, 6.5 years; range, 1 to 22 years). All patients were supplemented with vitamin D analogues postoperatively. Patients were followed up for 1 to 48 months (median, 20 months). Bone pain, when present, disappeared within the first week after total PTX. Postoperatively, most patients had temporary hypocalcemia. In the long term, five patients had asymptomatic hypocalcemia. One patient, however, repeatedly had hypocalcemic seizures. Five patients developed asymptomatic hypercalcemia when supplemented with calcitriol. At the end of the individual's observation time, parathyroid hormone (PTH) levels were less than normal in six patients, normal in seven patients, and increased in seven patients despite total PTX. We conclude that total PTX should be reconsidered an option for the treatment of hyperparathyroidism secondary to renal failure. There was no evidence of clinical bone disease after total PTX. Apparently, remaining ectopic parathyroid tissue accounts for PTH levels after total PTX.

Secretory synovial-type PLA 2 (sPLA 2 -II) in peripheral blood is known to be associated with systemic complications in patients with severe diseases. Being the pacemaking enzyme in eicosanoid synthesis, sPLA 2 -II is a mediator of the inflammatory response and plays a role in host defense against bacterial infection. We evaluated the clinical role of systemic sPLA 2 -II in bacterial infection of pancreatic necroses in severe acute pancreatitis. In 58 patients with acute pancreatitis, pancreatic and sPLA 2 -I and sPLA 2 -II were measured daily for the first 14 days of hospital treatment by a time-resolved fluoroimmunoassay. All 36 patients with necrotizing pancreatitis underwent regular fine needle aspiration (FNA) to monitor bacterial infection. In 10 patients, infected necroses were found on FNA and postoperative examination. On admission and at most days throughout the observation period, systemic sPLA 2 -II was significantly higher in patients with infected necroses than in patients with sterile necroses or interstitial pancreatitis. This difference was not found for sPLA 2 -I, but values were higher in necrotizing pancreatitis than in interstitial pancreatitis at the first 2 days of hospital treatment. If sPLA 2 -II was >300 ng/ml on 2 successive days within the first 4 days, infected necroses could be predicted with a sensitivity of 89%, a specificity of 88%, and a negative predictive value of 95%. Systemic sPLA 2 -II has the potential to identify patients at risk of bacterial infection of pancreatic necroses and its routine measurement may therefore, in combination with FNA, offer a valuable tool in monitoring patients with acute necrotizing pancreatitis.

Early assessment of severity in acute pancreatitis (AP) has a major impact on further treatment. Previous studies have shown that human pancreas-specific protein (hPASP)/procarboxypeptidase B (PCPB) is a new diagnostic and prognostic marker in AP. In the present study we focused on the prognostic properties of this parameter and analyzed the clinical value of hPASP in discriminating edematous from necrotizing AP. The results were compared to those for C-reactive protein (CRP) and lactate dehydrogenase (LDH). A total of 70 patients was enrolled in this prospective study. Based on contrast-enhanced computed tomography or intraoperative results, 39 patients (27 male, 12 female; median age, 42 years; median Ranson score, 6) suffered from necrotizing pancreatitis (NP) and 31 patients (12 male, 19 female; median age, 57; median Ranson score, 1.5) from acute interstitial-edematous pancreatitis (AIP). Serum concentrations of hPASP/PCPB, CRP, and LDH were measured at 24-h intervals over 14 days after admission by a radioimmunoassay (upper normal value, 60 ng/ ml), a lasernephelometric assay (upper normal value, 4 mg/L), and an enzymekinetic method (upper normal value, 240 U/L), respectively. During the overall observation period concentrations of hPASP/PCPB, CRP, and LDH were significantly higher in patients with NP compared to those with AIP. Based on receiver operating characteristics, the best cutoff levels for predicting NP were >200 ng/ml for hPASP/PCPB, >140 mg/L for CRP, and >290 U/L for LDH. Discrimination between AIP and NP was best on day 3 for both hPASP/PCPB (sensitivity, 91%; specificity, 64%; accuracy, 79%) and CRP (sensitivity, 83%; specificity, 84%; accuracy, 83%) and on day 5 of AP for LDH (sensitivity, 88%; specificity, 100%; accuracy, 91%). The overall accuracy in differentiating AIP from NP within the first 4 days after onset of symptoms was 74% for hPASP/PCPB, 75% for CRP, and 76% for LDH. None of the parameters correlated with the extent of necrosis or the etiology of AP. hPASP/PCPB provides good discrimination between AIP and NP at an early stage of the disease, with results comparable to those for CRP and LDH. Although hPASP/PCPB is both disease specific and predictive for necrosis, the clinical use of this test in its present form is limited due to drawbacks in terms of test performance and cost factors.

Background Carcinoma located in the uncinate process (CUP) of the pancreatic head is considered to be rare. Exact epidemiological data, however, are not available because the series published so far consist of fewer than ten patients. The purpose of this prospective study was to evaluate the clinical appearance of CUP and to compare findings with those of patients with carcinoma in the ventral aspect of the pancreatic head (VPC), which represents the most frequent localization. Results Some 39 (8 per cent) of 506 evaluated patients suffered from CUP. Mean age was 63·3 years. The most frequent complaints were upper abdominal pain (n = 32) and weight loss (n = 35). Jaundice was seen in only five patients and was never an early symptom. The level of CA19-9 was raised in 33 patients. The best diagnostic procedure to detect CUP was computed tomography (CT) (sensitivity 93 per cent), whereas endoscopic retrograde cholangiopancreatography was not useful (sensitivity 21 per cent). Vascular involvement was significantly (P < 0·01) more common in CUP (n = 19) than in VPC (48 versus 19 per cent). This finding and the fact that most patients with CUP were diagnosed at a late stage with distant metastasis or severe vascular involvement present (n = 21) are responsible for the significantly lower rate of operation (n = 25) (64 versus 92 per cent, P < 0·05) and the significantly shorter median survival time (5 versus 11 months, P < 0·05). Conclusion Patients with CUP have a poor prognosis as a result of the lack of early symptoms (jaundice) and early vascular involvement due to the proximity of the uncinate process to the mesenteric root. A raised level of CA19-9, together with weight loss and/or upper abdominal pain, should prompt CT.

Sauerstoffradikale (OR) und Stickstoffmonoxid (NO) spielen bei einer Vielzahl physiologischer bzw. pathophysiologischer Prozesse eine wichtige Rolle. Neben der Radikalart scheinen die beobachteten Effekte vor allem von der Radikalenkonzentration, dem Zelltyp und dem Generationsmodus der Radikale bestimmt zu sein. So konnte fur exogen appliziertes NO gezeigt werden, das Gefasmuskelzellen und Endothelzellen in ihrer Proliferation gehemmt werden [1, 2], wohingegen die Proliferation von K562 Zellen nicht beeinflust wurde [3]. Kontrar hierzu hat NO zytoprotektive Funktionen in Hepatozyten [4], wohingegen NO in Monozyten Apoptose induziert [5]. Wir konnten kurzlich zeigen, das NO in humanen Fibroblasten je nach Generierungsmodus unterschiedliche Effekte bewirkt. Wahrend exogen zugefuhrtes NO zu einer Erhohung der S/G2-Fraktion fuhrte, bewirkte endogen produziertes NO einen G1-Arrest [6]. Ahnlich wie NO haben auch Sauerstoffradikale (OR) neben direkt zytoziden Wirkungen spezifische Effekte wie zum Beispiel die Induktion von Zytokinfreisetzung und Histaminfreisetzung [7, 8]. Auch sind OR in der Lage in bestimmten Zelltypen in hoheren Konzentrationen Apoptose zu erzeugen [9].

Fur die Ausbildung von Mukosaschaden am Dunndarm wahrend der Reperfusion nach begrenzter intestinaler Ischamie werden vor allem Sauerstoffradikale (OR) verantwortlich gemacht [3]. Bislang bekannte und als wesentlich angesehene Quellen dieser uberschiesenden OR-Produktion sind das Hypoxanthin/Xanthinoxidasesystem (HX/XO) und aktivierte neutrophile Granulozyten (PMN’s). Es fehlen experimentelle Untersuchungen, welche die Bedeutung dieser OR-produzierenden Systeme wahrend der Reperfusionsphase zeitlich und quantitativ untersuchen. Aus diesem Grund haben wir an einem standardisierten Modell der intestinalen Ischamie und Reperfusion bei Katzen direkte Messungen der OR, der Akkumulation von neutrophilen Granulozyten (PMN) und der Harnsaurekonzentration (HS) im Gewebe durchgefuhrt. Ziel dieser Untersuchungen war es, uber die Blockierung der Xanthinoxidase (XO) durch Allopurinol (All) und der Leukozytenadhasion uber Hemmung des CD1lb/CD18-Komplexes mit IB4 die OR-Freisetzung der PMN’s und des HX/XO-Systems zeitlich zu differenzieren und zu quantifizieren.

Die Pankreatitis ist gepragt von schweren progredienten Azinuszellschaden, starkem Odem sowie einer im Verlauf zunehmenden Akkumulation und Migration von Entzundungszellen [1]. In einer Vielzahl von Studien in verschiedenen Modellen der experimentellen akuten Pankreatitis konnte eine fruhe Freisetzung von freien Sauerstoffradikalen (OR) nachgewiesen werden [2]. Die daraus resultierende Lipidperoxidation der Zellmembran kann zum Zelluntergang fuhren, falls die antioxidative Kapazitat zur Neutralisierung dieses erhohten Anfalles von freien Radikalen nicht ausreicht. Neben ihrer direkt gewebschadigenden Wirkung stimulieren Sauerstoffradikale den Arachnidonsaurestoffwechsel, was zu einem konsekutiven Anstieg der Prostaglandinmetaboliten und Leukotrienen fuhrt. Durch diese direkten und indirekten Wirkungen dieser hochreaktiven Sauerstoffmolekule kann man sie als molekulare Trigger der Entzundungsreaktion bezeichnen. Im klinischen Alltag ist die Erforschung der Fruhphase dieser Erkrankung sehr problematisch, da zum Zeitpunkt der Klinikeinweisung meist die Initialphase der akuten Pankreatitis bereits durchschritten ist und diese fruhen Phanomene nicht mehr vorhanden oder durch den fulminanten Verlauf der akuten Pankreatitis maskiert werden. So konnten die experimentellen Daten und gezogenen Schlusfolgerungen aus der Fruhphase klinisch bisher nicht zufriedenstellend uberpruft werden.

Pancreatic hyperstimulation with simultaneous duct obstruction does not cause the typical features of acute pancreatitis, therefore the role of an additional challenge, such as either ethanol intoxication or short-term ischemia, was studied. Alcoholic pancreatitis was induced in 28 rats by acute ethanol intoxication (0.25 LD 50 ) and an obstruction/ hyperstimulation mechanism (clip of the biliopancreatic duct for 20 min and intravenous stimulation with 5 U of cholecystokinin and secretin each). Ischemic pancreatitis was performed by obstruction/hyperstimulation and subsequent pancreatic ischemia by clamping the supplying arteries for 40 min. The macro- and microscopic alterations were evaluated and graded by a scoring system. Additionally, the pancreas was removed in 50% of the animals and the pancreatic acini were prepared. From those acini the intracellular enzymes trypsinogen, kallikreinogen, amylase, lipase, glucuronidase, and acidic phosphatases were determined. While obstruction/hyperstimulation, 40 min of ischemia, or ethanol alone did not induce acute pancreatitis, a combination of obstruction/hyperstimulation with either ethanol or ischemia resulted in acute pancreatitis in 68 and 60% of treated rats, respectively. Similarly, both models were characterized by extrapancreatic fat necrosis and acinar necrosis at the periphery of the lobules. Almost all intracellular enzymes were elevated in both pancreatitis models compared to sham-operated controls. Both alcohol and ischemia were insults that sensitize the pancreas to develop acute pancreatitis after obstruction/hyperstimulation. Since the observed morphologic and enzymatic alterations in both models are very similar, alcohol and ischemia might have some common pathways by which they make the pancreas vulnerable to enzymatic attacks.

Sauerstoffradikale (OR) spielen in vielen pathologischen Prozessen wie zum Beispiel Ischamie — Reperfusionsschaden oder Entzundungsprozessen eine wichtige Rolle [1]. Sie wirken durch Lipidperoxidation und Membrandesintegration direkt toxisch. In letzter Zeit wurde gezeigt, das OR neben diesen direkt passiv toxischen Effekten auch spezifische aktive Prozesse, wie zum Beispiel die Freisetzung von Histamin, bewirken konnen [2].

Oxygen derived free radicals are involved in many pathological processes such as postischemic reperfusion injuries, hepatotoxicity of drugs and inflammatory processes. Thereby these oxygen radicals induce lipid peroxidation and perturbation of cellular membranes. The aim of our present study was to determine whether oxygen radicals generated by the xanthine oxidase/ hypoxanthine system cause a release of histamine in human blood cell cultures. Stimulation of blood cell cultures with oxygen radicals induced a histamine liberation which was mainly due to calcium independent processes during the first 30 min, whereas then calcium requiring processes took part in the release of histamine. The regulation of the leukocyte selection LECAM-1 was altered by oxygen radicals whereas histamine, which is known to modulate vascular selectin expression, did not affect the expression of LECAM-1. Our data indicate that oxygen radicals induce a direct calcium independent release of histamine which is due to membrane pertubating processes during the first phase but also induce a specific reaction leading to a further indirect histamine liberation which is probably mediated by PAF.

Die Toxizitat hochreaktiver Sauerstoffradikale (OR) ist heute unbestritten. Trotzdem haben diese pathophysiologischen Erkentnisse bislang nur zu wenigen, therapierelevanten Konsequenzen gefuhrt. Klinische Studien (z. B. Sepsisstudien), welche sich mit der Wirkung von OR beschaftigen scheitern oft an der komplexen, klinischen Situation. Auch unter starker, anaerober korperlicher Belastung entsteht ein Ungleichgewicht zwischen Sauerstoffbedarf und Sauerstoffangebot und hierdurch moglicherweise Sauerstoffradikale [5, 6]. Diese konnte durchaus als standardisierbares, reproduzierbares und klinisches Modell zur Untersuchung der Wirkung von OR und deren therapeutische Beeinflusbarkeit Verwendung finden. Indirekte Wirkungen von OR, z. B. erhohte Lipidperoxidationsprodukte nach extensiver Belastung liesen sich sowohl im Tierexperiment [1], als auch im klinischen Belastungsversuch am Menschen [3, 4] nachweisen. DNA Veranderungen nach sportlicher Belastung wurden nachgewiesen, sobald die anaerobe Schwelle wahrend der sportlichen Aktivitat uberschritten wurde [6]. Bei einigen Untersuchungen konnte ein protektiver Effekt einer antioxidativen Therapie aufgezeigt werden [5]. Dies sind indirekte Hinweise dafur, das OR ursachlich fur diese Schaden sind. Die direkte Messung freier Sauerstoffradikale, bzw. freier, reaktiver Elektronen nach und unter anaerober Belastung wurde bislang nicht durchgefuhrt. Deshalb versuchten wir OR nicht nur indirekt sondern auch direkt und quantitativ uber die Elektronenresonanz-spektroskopie im Serum nach korperlicher Belastung nachzuweisen. Zum weiteren Beweis einer Beteiligung von OR untersuchten wir den Einflus einer hochdosierten Vitamin-E-Prophylaxe auf die Folgen des oxidativen Streses nach sportlicher Betatigung.

In experimental models of pancreatitis lipid peroxidation products are increased possibly because of an enhanced generation of oxygen radicals. The purpose of this study was to determine whether lipid peroxidation products are increased in pancreatic tissue and serum of patients suffering from chronic or acute pancreatitis. In 20 patients undergoing operative treatment for chronic (n = 11) and acute pancreatitis (n = 9) the levels of malondialdehyde, conjugated dienes, and reduced and oxidized glutathione were determined in resected tissue samples. The excised tissue was examined and evaluated by light microscopy. Shortly before operation the serum concentrations of malondialdehyde, alpha-amylase, and lipase were measured. Pancreatic tissue from eight organ donors who had no abdominal trauma or pancreatic disease served as control. In chronic pancreatitis, conjugated dienes as well as malondialdehyde concentrations in the tissue were significantly elevated. Reduced glutathione was significantly decreased, suggesting glutathione depletion due to oxidative stress. In acute pancreatitis only the tissue and serum malondialdehyde levels were significantly high, whereas conjugated dienes remained within the normal range. Serum malondialdehyde levels correlated significantly with tissue concentrations (r = 0.76; p0.05) but not with the clinical course or the enzyme levels. In chronic pancreatitis, the increased tissue levels of lipid peroxidation products and the changes in glutathione metabolism suggest ongoing peroxidation of lipids due to an enhanced generation of oxygen radicals. In hemorrhagic necrotizing pancreatitis, however, oxygen radical-induced lipid peroxidation cannot be proven. Apparently, other pathomechanisms are involved in the development of the severe tissue damage.

Freie Sauerstoffradikale (OR) spielen eine wichtige Rolle in vielen pathophysiologischen Prozessen, wie z.B. Hepatotoxizitat von Medikamenten und Entzundungsreaktionen [1]. Die Akkumulation dieser Radikale im Gewebe fuhrt zur Lipidperoxidation und Denaturierung von Proteinen, was den Verlust von Enzymfunktionen bedeuten kann [2]. Histamin ist in basophilen Granulozyten an Heparin-Protein Komplexe gebunden. Histamin kann aus diesen Komplexen durch extrazellulare Kationen gelost werden [3]. Diese Exposition kann entweder durch Fusion der Granula mit dem Plasmalemm uber eine aktiven, energieabhangigen Weg geschehen oder nicht energieabhangig durch Storung der Membranintegritat oder Zellyse. Im Falle der aktiven Exozytose vermutet man regulativ wirkende Membranrezeptoren, die Kalziumkanale offnen konnen [4]. Beim passiven oder zytotoxischen Weg wird die Histaminfreisetzung durch eine Storung der Membranintegritat bewirkt. Ziel unserer Untersuchungen war es festzustellen, ob OR zu einer Freisetzung von Histamin fuhren und ob diese Freisetzung auf unspezifische membranschadigende oder spezifische, durch OR induzierte Prozesse zuruckzufuhren ist. Desweiteren untersuchten wir, ob das durch OR induzierte „shedding“des leukozytaren Selectins CD62L durch Histamin mediiert wird.

The purpose of this study was to evaluate the effect of free radical ablation therapy in acute hemorrhagic pancreatitis. Acute pancreatitis was induced in 64 rats by retrograde injection of 5% sodium taurocholate. Thirty animals were pretreated with 100,000 units/kg/hr of superoxide dismutase (SOD) and 400,000 units/kg catalase within the first 3 hr. After 0.5, 3.5, and 12 hr of observation time, serum enzymes and the tissue content of conjugated dienes, malondialdehyde, reduced and oxidized glutathione, as well as ATP, ADP and AMP were measured. In addition, tissue samples were examined by light microscopy. Untreated rats (N = 34) developed within 12 hr an acute hemorrhagic necrotizing pancreatitis with a concomitant increase in serum enzyme levels and a decrease in reduced glutathione and ATP. Within the 12-hr observation period, 57% of the animals died. Scavenger treatment improved the tissue damage and attenuated the increase of the serum enzyme levels and the decrease in reduced glutathione and ATP. Moreover, the lethality rate was significantly lower. Oxygen radicals seem to be instrumental for the development of acute hemorrhagic pancreatitis. Thereby, antioxidant treatment reduces tissue damage, biochemical alterations and extrapancreatic complications, thus improving the final outcome.

Die Akkumulation von polymorph nuklearen Neutrophilen (PMN) spielt eine wichtige Rolle bei diversen Entzundungsgeschehen wie z.B. rheumatoider Arthritis, acute respiratory distress syndrome (ARDS) und Ischamie-Reperfusion bedingten Schaden [1]. Durch eine Aktivierung kommt es zu einer Freisetzung von gewebstoxischen Substanzen wie Sauerstoffradikalen (OR) und Proteasen durch PMN. OR wirken durch eine Lipidperoxidation und Membrandesintegration direkt und unspezifisch zeilschadigend. Es konnte bisher gezeigt werden, das OR allein zu einer Degranulation und Aktivierupg der PMN fuhren [2] und spezifisch die Expression der leukozytaren Adhasionsmolekule modulieren [3]. Ziel dieser Untersuchung war es, in vitro festzustellen, ob es durch niedrige Sauerstoffradikalkonzentrationen in Vollblut zu einer Freisetzung von Akutphase Entzundungsmediatoren wie Eicosanoiden (TxB2, LTb4, LTC4) und den Zytokinen TNF-α, IL-1β und IL-6 kommt.

Schleimhautveranderungen nach intestinaler Ischamie und Reperfusion sind von wesentlicher klinischer Bedeutung. Es konnte in den letzten Jahren gezeigt werden, das der Grosteil dieser Schaden nicht in der Ischamie- sondern erst in der Reperfusions- phase entstehen. Verantwortlich hierfur sind freie Sauerstoffradikale (OR): Hypoxan- thin (HX) akkumuliert wahrend der Ischamiephase im Gewebe. Nach der Reperfusion wird Hypoxanthin zu Harnsaure (HS) verstoffwechselt. Hierbei fallen vermehrt OR an und uberfordern die naturlichen Schutzmechanismen der Zelle. Katalysiert wird dieser Abbau uber die Xanthinoxidase (XO). Es konnte gezeigt werden, das nur ein geringerer Teil der Schleimhautschaden durch OR direkt verursacht wird, wahrend der Grosteil der Veranderungen auf aktivierte PMN-Leukozyten zuruckzufuhren sind. Durch Blockierung der XO mit Allopurinol (ALP) lassen sich die Reperfusionsschaden nahezu vollstandig verhindern [1]. Ungeklart ist bislang, ob PMN-Leukozyten durch OR im Blut direkt, oder uber Gewebemediatoren aktiviert werden. Ziel dieser Untersuchung wasr es, in vitro festzustellen, ob OR PMN-Leukozyten direkt erregen konnen. Als Mas der Aktivierung der Leukozyten wurden deren Granulaveranderungen gewertet.

Das Redoxsystem Glutathionperoxidase (GPO) und sein Cosubstrat Glutathion (GSH) stellen einen wichtigen Schutzmechanismus gegen Sauerstoffradikale dar. GPO ist ein selenhaltiges Enzym, das vornehmlich im Cytosol und den Mitochondrien der Zellen nachgewiesen wird. Dieses Enzym katalysiert den Abbau von H2O2 zu Wasser. Dabei wird das Cosubstrat reduziertes Glutathion (GSH), zu dem die GPO eine hohe Affinitat besitzt, oxidiert.

A growing body of evidence suggests that oxygen radicals are generated in all forms of experimental pancreatitis at an early stage of disease. Moreover, first indirect observations assume that also in human acute recurrent and chronic pancreatitis oxygen free radicals are generated and add to the damages seen. The source of the enhanced production of oxygen radicals remains still unclear. Experimentally, the efficiency of scavenger treatment varies between three different models, whereby these differences depend more on the design of the experimental models than on the form of pancreatitis which was induced. Antioxidant treatment with radical scavengers should therefore interrupt these deleterious pathomechanisms or at least mitigate the damages normally seen. Most studies, however, pretreated the experimental animals before inducing acute pancreatitis, which does not mirror the clinical reality. Patients, however, are admitted after onset of the disease. Therefore, well-defined, controlled clinical studies are needed to validate the involvement of oxygen radicals in acute and chronic pancreatitis and the effect of scavenger treatment in patients with pancreatitis.

Oxygen-derived free radicals mediate an important step in the initiation of experimental acute pancreatitis. Thereby, it seems that these reactive oxygen metabolites are generated at an early stage of disease. The source of the enhanced production of oxygen radicals still remains unclear. Experimentally, the efficiency of scavenger treatment varied between different models, whereby these differences depended on the experimental model and not on the form of pancreatitis which was induced. Most studies pretreated the experimental animals before inducing acute pancreatitis. This does not mirror the clinical reality, since patients are admitted to the hospital after onset of the disease. It was shown in Cerulein pancreatitis, however, that scavenger treatment also mitigated the pancreatic tissue damages after induction of acute pancreatitis. Moreover, antioxidant treatment also attenuated the extrapancreatic complications, thus improving the final outcome of the disease. The first indirect observations also suggest that in human acute recurrent and chronic pancreatitis, oxygen free radicals are generated and add to the damages seen. Therefore, well-defined controlled clinical studies with patients suffering from acute pancreatitis are needed to validate the role of oxygen radicals in this disease.

Es konnte an verschiedenen Modellen gezeigt werden [2, 5], das Sauerstoffradikale schon in der Fruhphase der akute odematosen Pankreatitis beteiligt sind und wesentlich zu den auftretenden Schadigungen beitragen. Bei der hamorrhagisch-nekrotisierenden Pankreatitis gibt es in der Literatur jedoch widerspruchliche Angaben.