A common pathway in the pathogenesis of acute pancreatitis is the generation of free oxygen radicals. The most important defense mechanisms are free radical scavengers, especially glutathione. This study evaluates the influence of the inhibition of glutathione synthesis with L-buthionine-(S,R)-sulfoximine (BSO) on the course of experimentally induced acute pancreatitis in rats and the effects on isolated pancreatic acini and their secretion pattern. Thus acute necrotizing pancreatitis was induced with intraductal infusion of low-dose glycodeoxycholic acid and subsequent hyperstimulation with cerulein with and without pretreatment with BSO. In vitro pancreatic acini were isolated and stimulated with different concentrations of cerulein with and without BSO. The BSO-treated group showed a significantly reduced survival, more necrosis, and a decreased secretion of amylase in vivo. No effect on secretion pattern in either groups was seen in vitro and BSO did not exert toxic effects. Based on the data presented, this study demonstrates deleterious effects of scavenger depletion on the course of experimental pancreatitis. This is due to the systemic effects of free oxygen radicals rather than to local effects.

Acute Disease↗

PubMed2002

Introduction. Complications of pancreatic surgery and pancreatitis.

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Humans↗

PubMed2001

Desmopressin impairs microcirculation in donor pancreas and early graft function after experimental pancreas transplantation.

BACKGROUND: Protective effects of desmopressin in brain dead organ donors oppose reports on a hypercoagulatory potential and an increased leukocyte-endothelial interaction (LEI) after application of the drug. The aim was to evaluate the effect of desmopressin on organ donor's pancreas and early graft function. METHODS: Donor microcirculation was evaluated via intra-vital microscopy (IVM) in 24 BR (di/di) rats with central diabetes insipidus, randomly assigned to groups I (control without desmopressin application), II (single i.v. application, no pretreatment) or group III (single i.v. desmopressin application, s.c. pretreatment for 3 days). Microcirculation in recipients was evaluated 1 hr and 6 hr after syngenic pancreas transplantation. Groups III and I served as organ donors. After IVM specimens were taken for histology and immunohistochemistry. RESULTS: Desmopressin in II vs. I led to temporarily (30') increased LEI (Sticker 274.3+/-87.7 vs. 76.5+/-31.1/mm2 endothelial surface; P<0.01) and impaired microcirculation (MCEV 0.43+/-0.07 vs. 0.99+/-0.06 mm/s; P<0.01). Repeated application reduced MCEV and increased LEI for up to 12 hr. Histology in I vs. III showed increased inflammation (n.s.), necrosis (P<0.05) and vacuolization (P<0.01). Immunohistochemistry revealed increased endothelial P-selectin 20' after application. 6 hr after reperfusion organs from III showed reduced MCEV and increased LEI (P<0.01). CONCLUSION: Repeated application of desmopressin impairs graft microcirculation. Perfusion of the pancreas is significantly reduced at the beginning of organ tissue conservation as well as after reperfusion. These disturbances might partly be due to observed endothelial P-selectin expression. Application of desmopressin up to 12 hr prior to organ explantation may impact graft quality.

Animals↗

PubMed2001

Expression of the multidrug resistance proteins MRP2 and MRP3 in human hepatocellular carcinoma.

Treatment of hepatocellular carcinoma (HCC) by chemotherapy is often impeded by the intrinsic multidrug resistance (MDR) of this frequent primary cancer of the liver. The MDR phenotype can be caused by ATP-dependent export of chemotherapeutic drugs across the plasma membrane being mediated by transporters of the MDR P-glycoprotein family or of the multidrug resistance protein (MRP) family. To elucidate the role of MRP family members in HCC, we analyzed the expression and subcellular localization of MRP1 (ABCC1), MRP2 (ABCC2) and MRP3 (ABCC3); all 3 isoforms have been shown to confer resistance to chemotherapeutic drugs. Semiquantitative RT-PCR demonstrated that MRP2 and MRP3 mRNA expression in HCC was at least 10-fold higher than MRP1 mRNA expression. MRP2 immunostaining was observed in 87% (33/38) of HCC samples. MRP2 was localized in the plasma membrane in a polarized fashion, either in trabecular structures resembling the canalicular membrane or in the luminal membrane when cells had a pseudoglandular arrangement. MRP3 was detected in all samples examined (9/9) by RT-PCR and by immunofluorescence microscopy. MRP3 was localized to the basolateral membrane of carcinoma cells. Double-label immunofluorescence microscopy with antibodies specific for MRP2 or MRP3 indicated that carcinoma cells expressed both MRP isoforms simultaneously. When MRP1 was detected by immunofluorescence microscopy, it was localized on the intracellular membranes of carcinoma cells. Thus, plasma membrane expression of MRP2 and MRP3, but not of MRP1, can contribute to the MDR phenotype of HCC.

Adenosine Triphosphate↗

PubMed2001

Minimal residual disease in thyroid carcinoma.

The detection of disseminated tumor cells in differentiated (DTC) and medullary thyroid carcinomas (MTC) is one of the main topics in current thyroid cancer research. Immunocytochemistry and polymerase chain reaction (PCR) provide the tools for the identification of a small number of thyroid cancer cells in peripheral blood and cervical lymph nodes. Thyroid-specific markers, such as thyroglobulin (Tg) mRNA and thyroid peroxidase (TPO) mRNA, have been detected with RT-PCR in blood samples of tumor patients and healthy control subjects. To prevent false-positive results, quantitative PCR systems were established. Tumor-specific markers, such as telomerase activity and cytokeratin 20 (CK20), have been detected in various epithelial tumors. Amplification products of these markers were found in blood samples and in fine-needle aspiration (FNA) biopsies of patients with thyroid carcinomas. Using molecular detection of disseminated tumor cells in cervical lymph nodes with CK20 RT-PCR, a higher percentage of involved lymph nodes was detected compared to immunohistochemistry. The results of the presented studies may help researchers to develop more sensitive methods for early tumor cell dissemination, and refine risk groups that might benefit from more extensive surgical procedures or adjuvant therapy. However, the prognostic value of minimal residual disease (MRD) in thyroid carcinoma has to be confirmed in large or multicenter prospective studies.

Humans↗

PubMed2001

Impact of inhibition of complement by sCR1 on hepatic microcirculation after warm ischemia.

Recent observations provide evidence that complement is implicated as an important factor in the pathophysiology of ischemia/reperfusion injury (IRI). Here, we assessed the effects of complement inhibition on hepatic microcirculation by in vivo microscopy (IVM) using a rat model of warm hepatic ischemia clamping the left pedicle for 70 min. Ten animals received the physiological complement regulator soluble complement receptor type 1 (sCR1) intravenously 1 min prior to reperfusion. Controls were given an equal amount of Ringer's solution (n = 10). Microvascular perfusion and leukocyte adhesion were studied 30 to 100 min after reperfusion by IVM. Microvascular perfusion in hepatic sinusoids was significantly improved in the sCR1 group (80.6 +/- 0.6% of all observed sinusoids were perfused [sCR1] vs 67.3 +/- 1.2% [controls]). The number of adherent leukocytes was reduced in sinusoids (49.9 +/- 3.4 [sCR1] vs 312.3 +/- 14.2 in controls [adherent leukocytes per square millimeter of liver surface]; P < 0.001) as well as in postsinusoidal venules after sCR1 treatment (230.9 +/- 21.7 [sCR1] vs 1906.5 +/- 93.5 [controls] [adherent leukocytes per square millimeter of endothelial surface]; P < 0.001). Reflecting reduced hepatocyte injury, liver transaminases were decreased significantly upon sCR1 treatment compared to controls. Our results provide further evidence that complement plays a decisive role in warm hepatic IRI. Therefore, we conclude that complement inhibition by sCR1 is effective as a therapeutical approach to reduce microcirculatory disorders after reperfusion following warm organ ischemia.

Animals↗

PubMed2001

[Definition of surgical degree of freedom by functional anatomy in liver resection surgery].

Liver resections have developed to very complex and differentiated operations, clearly adapted to individual anatomical and physiological conditions. In parallel, perioperative morbidity has been dramatically reduced. Intraoperative strict consideration of various details of hepatic anatomy, particularly of functional liver anatomy, has proved to be of particular importance when liver surgery reaches indication and technical limits. The term "functional anatomy" stands for a form of hepatic substructurization, which is primarily based on the existence of hemodynamically independent regions of liver parenchyma. A selection of some of the most important details and facts of functional liver anatomy and secondary derived guidelines for surgical strategy and technique is presented in an overview, with special focus on liver resection.

Hepatectomy↗

PubMed2001

Characterization of renal parenchymal perfusion during experimental infrarenal aortic clamping and declamping with enhanced thermodiffusion electrodes.

Despite multiple previous experimental and clinical investigations, it has not been fully clarified until now whether infrarenal aortic cross-clamping (IRAC) induces a significant disturbance of renal parenchymal perfusion. Most renal cortical flow data collected thus far have been heterogenous because of inherent limitations of available measurement technology. The enhanced thermal diffusion (TD) electrode is a newly developed and previously validated prototype device that allows continuous quantification of parenchymal kidney perfusion after local probe implantation. We monitored renal perfusion during experimental IRAC with TD for the first time, thereby also evaluating the potential applicability of the method in clinical aortic surgery. IRAC (20 min) followed by sudden declamping was performed in pigs under general anesthesia (n = 14). Renal cortical blood flow (RCBF) was continuously quantified by TD, total aortic flow (TABF) and renal artery flow (RABF) were measured by ultrasonic flow probes, and parameters of systemic circulation were determined by Swan-Ganz catheter. Our results showed that kidney perfusion can be continuously quantified using TD electrodes during experimental aortic surgery in a porcine model. IRAC does not lead to a significant impairment of RCBF in young pigs as measured by TD. Renal perfusion appears to be predominantly pressure driven. Consequently, abrubt aortic declamping can bring about prolonged renal ischemia. Transfer of the TD method to RCBF monitoring during clinical aortic surgery appears to be feasible and should be investigated in selected cases.

Animals↗

PubMed2001

Insulin sensitivity and beta-cell secretion after liver transplantation in patients with acute liver failure.

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Acute Disease↗

PubMed2001

N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation.

In orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P < or = 0.02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment.

Acetylcysteine↗

PubMed2001

Expression and localization of the multidrug resistance proteins MRP2 and MRP3 in human gallbladder epithelia.

BACKGROUND & AIMS: The multidrug resistance protein (MRP) isoforms MRP2 (ABCC2) and MRP3 (ABCC3) play a decisive role in the hepatic secretion of endogenous and xenobiotic conjugates and are differentially expressed in hepatocytes and cholangiocytes. The epithelium of the gallbladder considerably modifies the composition of primary hepatic bile by absorption and secretion; however, the underlying transport mechanisms were largely unknown. Localization of MRP2 and MRP3 may provide an explanation of how the products of phase II conjugation are effluxed from gallbladder epithelia. METHODS: Expression and localization of MRP2 and MRP3 were analyzed by reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence microscopy of human gallbladder tissue. RESULTS: Expression of MRP2 and MRP3 was identified in all gallbladders by RT-PCR followed by sequencing of the amplified fragments. Double immunofluorescence microscopy using 2 specific antibodies for the respective MRP isoform showed the simultaneous expression of MRP2 in the apical membrane and MRP3 in the basolateral membrane of gallbladder epithelia. MRP1 protein expression was not detectable. CONCLUSIONS: Our findings show the expression of MRP2 and MRP3 in distinct plasma membrane domains of gallbladder epithelia and provide evidence for the capacity of the gallbladder to secrete xenobiotic and endogenous anionic conjugates into blood via MRP3 and into bile via MRP2.

Aged↗

PubMed2001

Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas.

BACKGROUND: This study evaluated the outcome of total thyroidectomy and modified radical neck dissection in primary treatment of patients with medullary thyroid carcinoma (MTC). METHODS: Thirty-six patients with sporadic (n = 16) and hereditary (n = 20) MTC underwent thyroidectomy and systematic central and lateral lymph node dissection (unilateral, 23; bilateral, 13) between 1994 and 2000. Postoperative serum calcitonin levels were correlated with immediate or delayed surgery, tumor categories, and lymph node metastases. RESULTS: Sixteen of 36 (44%) patients with clinically evident MTC treated with central and lateral neck dissection exhibited normal basal and stimulated calcitonin levels at a median follow-up of 3.7 years. Lymph node involvement was detected in 75% of these patients and correlated with the TNM stages. Biochemical cure was achieved according to the T categories in 83% of the patients in stage T1, 42% in stage T2, and none of the patients in stage T4 (P = .011). Basal and stimulated calcitonin levels were found to be normal in 89% of the patients without lymph node involvement and in 30% of the patients with lymph node metastases (P = .005). CONCLUSIONS: Screening for MTC and primary treatment with total thyroidectomy and modified radical neck dissection are essential for biochemical cure of MTC.

Adolescent↗

PubMed2001

Endothelin-1 and big-endothelin concentrations are elevated in liver graft tissue during cold storage and reperfusion.

Endothelin (ET) and its precursor big-ET were synchronously analyzed by RIA in liver biopsies and systemic plasma during porcine orthotopic liver transplantation (OLT) before graft harvesting (phase A), after cold storage (phase B), and early (phase C) and late reperfusion (phase D). Tissue and plasma concentrations were correlated with length of survival and reperfusion. Increased tissue ET/big-ET levels were already detected during phase B (ET: 46 +/- 20; big-ET: 245 +/- 119 pg/mg cytosolic protein) and remained elevated in phase C (ET: 49 +/- 16; big-ET: 306 +/- 144 pg/mg) compared to baseline (ET: 32 +/- 13; big-ET: 185 +/- 164 pg/mg; p < 0.05). In phase D, a rapid concentration decline was detected (ET: 36 +/- 26; big-ET: 163 +/- 138 pg/mg). Systemic ET levels were elevated in phase B (3.4 +/- 3.0 pg/ml), C, (2.8 +/- 1.2 pg/ml) and D (2.6 +/- 2.0 pg/ml), compared to baseline (1.7 +/- 1.1 pg/ml; p < 0.05). ET/big-ET kinetics in liver tissue and systemic plasma showed analogous characteristics. Intrahepatic ET accumulation during storage and early reperfusion could be of relevance for harvest-related disturbances of hepatic microcirculation.

Animals↗

PubMed2001

Attenuation by fibrates of plasminogen activator inhibitor type-1 expression in human arterial smooth muscle cells.

Human atherosclerotic lesions exhibit increased expression of plasminogen activator inhibitor type-1 (PAI-1) that has been implicated in atherogenesis. Although vascular smooth muscle cells are a predominant source of PAI-1 expression potentially favorable modulation of PAI-1 expression by fibrates has not yet been characterized in these cells. Human aortic smooth muscle cells were exposed to selected growth factors. PAI-1 expression was stimulated most powerfully by TGF-beta (EC50 = 0.2 ng/ml, up to 12-fold increase). Gemfibrozil inhibited basal PAI-1 expression by 23% (p = ns) and TGF-beta-induced PAI-1 expression by 52% (p = 0.017) whereas t-PA and total protein synthesis was not affected. Changes in PAI-1 protein accumulation reflected PAI-1 gene expression attributable to modulation of half-life of PAI-1 mRNA by gemfibrozil. Inhibition by other fibrates was less. Gemfibrozil specifically attenuates TGF-beta-induced PAI-1 expression in human arterial smooth muscle cells. Thus, fibrates are promising agents for normalizing increased PAI-1 expression in arterial walls in patients in whom PAI-1 expression is increased.

Aorta↗