Search PubMed⌕ Search

Biomedical subjects

C Niederau

Publications and source records attributed to C Niederau.

At least 55 records · Page 3Linked to original sources
PubMed1998

Trypsinogen activation and glutathione content are linked to pancreatic injury in models of biliary acute pancreatitis.

CONCLUSION: In models of biliary acute pancreatitis, which might resemble the situation in humans, premature activation of trypsinogen inside the pancreas ("autodigestion") occurs and is correlated with the extent of ductal and parenchymal injury. It is accompanied by a critical spending of protease inhibitors and glutathione, compromising important acinar cell defense and maintenance mechanisms. BACKGROUND: Premature activation of pancreatic digestive enzymes and profound changes of levels of certain biochemical compounds have been implicated in the pathophysiology of acute pancreatitis. Hitherto, little information on their role in biliary acute pancreatitis has been available. METHODS: Three types of injury to the pancreaticobiliary duct system of various severity were induced in rats--ligation of the common bile-pancreatic duct, retrograde infusion of electrolyte, or retrograde infusion of taurocholate solution--and were compared to sham-operated animals. Trypsin, trypsin inhibitory capacity (TIC), reduced glutathione (GSH), and other compounds were measured in pancreatic tissue. Histopathology, as well as serum amylase, lipase, and gamma-glutamyl transferase (gamma GT) were assessed. RESULTS: Histopathology and elevated activity of gamma GT in the serum revealed increasing severity of pancreatic injury from sham operation through retrograde duct infusion with taurocholate. GSH was diminished even in macroscopically normal-appearing tissue, but significantly lower in altered (hemorrhagic)-looking sections. Conversely, tissue levels of trypsin were significantly increased. TIC was elevated only in the duct obstruction model, whereas it was reduced in the retrograde duct infusion models.

Acute Disease↗
PubMed1998

Long-term effects of CCK-agonist and -antagonist on food intake and body weight in Zucker lean and obese rats.

The present study evaluates long-term effects of the CCK-agonist caerulein and the CCK-A antagonist loxiglumide in obese and lean Zucker rats. Caerulein and loxiglumide altered food intake neither in obese nor in lean rats. By as yet unknown mechanisms, however, weight increase was accelerated by loxiglumide and reduced by caerulein in obese and lean rats. Caerulein increased pancreatic weight only in lean but not in obese rats. Thus, obese rats show a resistance of pancreatic CCK-A receptors. The failure of CCK-agonist and -antagonist to alter food intake suggests that this CCK-resistance is not responsible for obesity in the genetically altered rats.

Animals↗
PubMed1998

Value of liver biopsy prior to interferon therapy for chronic viral hepatitis.

The present study prospectively evaluated the value of liver biopsy in patients with chronic hepatitis B (N=75) and C (N=135) prior to interferon therapy. Biopsy specimens revealed cirrhosis in 26% of patients with hepatitis B and 30% with hepatitis C. Although cirrhosis was not predictable by laboratory values in individual patients mean gamma-GT, alkaline phosphatase, and bilirubin levels were significantly higher in patients with cirrhosis compared to those without. Since cirrhosis significantly impairs the response rate to interferon therapy in hepatitis C but not in hepatitis B, liver biopsy is important for the management of chronic hepatitis C infection. In 88% of patients with serum HBV-DNA, irrespective of the serum HBeAg status, chronic active hepatitis was seen. Similarly, chronic active hepatitis was found in 84% of patients with elevated aminotransferases and hepatitis C antibodies. Thus, chronic active hepatitis was diagnosed in the majority of cases with chronic viral hepatitis, showing that this histopathological diagnosis is of little additional value for the recommendation on interferon treatment in these patients. However, none of the other grading systems of liver biopsy specimens described so far have been evaluated for their ability to predict overall prognosis or response rates to interferon therapy. Therefore, the physician is presently left with the questionable value of a procedure with well-known risks and costs in patients suitable for interferon treatment. Hence, prospective randomized controlled studies to evaluate histopathological grading systems are urgently needed to redefine the necessity of liver biopsy in this routine clinical setting.

Antiviral Agents↗
PubMed1998

Inhibition of cathepsin B does not affect the intracellular activation of trypsinogen by cerulein hyperstimulation in isolated rat pancreatic acinar cells.

Activation of trypsinogen is thought to trigger the autodigestive process in acute pancreatitis. The lysosomal enzyme cathepsin B was suggested to cause the activation of trypsinogen because it is known that cathepsin B is able to activate trypsinogen in special circumstances and that lysosomal and digestive enzymes are colocalized within intracellular vacuoles in the early stage of pancreatitis. As yet this hypothesis has been difficult to prove because activated trypsin is difficult to quantify in pancreatitis by conventional enzymatic measurements. We therefore employed an ELISA for trypsin activating peptide (TAP), which is a small peptide cleaved during the activation of trypsinogen and can be determined reliably. Supraphysiological concentrations of cerulein (1 nM-1 microM) resulted in a marked increase in TAP in freshly isolated pancreatic acinar cells, indicating activation of trypsinogen. This activation as determined by the TAP increase was significantly reduced by the serine protease inhibitor Fut-175 but not by the cathepsin B inhibitors E-64 and NCO-700. The concentrations of NCO-700 and E-64 abolished the cathepsin B activity of pancreatic acinar cells but did not significantly reduce the trypsin activity (after enterokinase preincubation); correspondingly the concentrations of Fut-175 used abolished the trypsin activity but did not reduce the cathepsin B activity. The results indicate that an autoactivation of trypsin rather than an activation of trypsinogen by cathepsin B triggers trypsin activation by supramaximal cerulein concentrations.

Animals↗
PubMed1998

Premature trypsinogen activation during cerulein pancreatitis in rats occurs inside pancreatic acinar cells.

Although it is widely accepted that trypsinogen activation is an initiating event in the development of acute pancreatitis, its location inside the pancreas is not known. In our studies, acute edematous pancreatitis was induced in rats by one or two intraperitoneal injections of 50 microg cerulein/kg body weight. The pancreas was removed for examination 1 or 2 h after the first and the second cerulein injection, respectively. The cleavage product of trypsinogen activation, trypsinogen activation peptide, was specifically labeled on pancreatic tissue sections by a corresponding antibody, the signal enhanced by a biotin-avidin conjugate, and the site then visualized by coupled peroxidase activity on diaminobenzidine. The sections were examined by light microscopy. Trypsinogen activation peptide, reflecting activation of the pancreatic digestive enzyme trypsinogen, was detected inside pancreatic acinar cells in this animal model of acute pancreatitis. As early as 1 h after the first injection of cerulein, protease activation was seen within the apical pole of acinar cells. Protease activation was increased 2 h after the latter of two injections of cerulein and more evenly distributed within the cells. For the first time morphologic evidence confirms that the activation originates within the acinar cell, rather than from the interstitium or the duct lumen. The location of this activation at the apical site of the acinar cell indicates its origin from subcellular compartments involving the late steps in the secretory pathway.

Animals↗
PubMed1997

Cardiac troponin T in patients with clinically suspected myocarditis.

OBJECTIVES: The present study investigated whether myocyte injury can be assessed sensitively by measurement of serum levels of cardiac troponin T (cTnT) in patients with clinically suspected myocarditis and whether cTnT levels may predict the results of histologic and immunohistologic analysis of endomyocardial biopsy specimens. BACKGROUND: Conventionally used laboratory variables often fail to show myocyte injury in patients with clinically suspected myocarditis, possibly because of a low extent of myocardial injury in these patients. Sensitive variables for myocyte injury have not yet been investigated. METHODS: Eighty patients with clinically suspected myocarditis were screened for creatine kinase (CK) activity, MB isoform of CK (CK-MB) activity and cTnT. Endomyocardial biopsy specimens were examined histologically and immunohistologically. RESULTS: cTnT was elevated in 28 of 80 patients with clinically suspected myocarditis, CK in 4 and CK-MB in 1. Histologic analysis alone of the endomyocardial biopsy specimen revealed evidence of myocarditis in only five patients, all with elevated cTnT levels. Twenty-three of 28 patients with elevated cTnT levels had histologically negative findings for myocarditis. Additional immunohistologic analysis revealed evidence of myocarditis in 26 (93%) of 28 patients with elevated cTnT levels and in 23 (44%) of 52 patients with normal cTnT levels. Mean cTnT levels were higher in patients with myocarditis proved histologically or immunohistologically, or both, than in patients without myocarditis (0.59 +/- 1.68 vs. 0.04 +/- 0.05, p < 0.001). CONCLUSIONS: Measurement of serum levels of cTnT provides evidence of myocyte injury in patients with clinically suspected myocarditis more sensitively than does conventional determination of cardiac enzyme levels. Myocardial cell damage may be present even in the absence of histologic signs of myocarditis. Additional immunohistologic analysis often shows lymphocytic infiltrates in these patients. Elevated levels of cTnT are highly predictive for myocarditis in this group.

Adolescent↗
PubMed1997

CCK-resistance in Zucker obese versus lean rats.

Obese Zucker rats are less sensitive to the satiety effect of CCK than lean litter mates. The present studies further characterised this CCK resistance. Subcutaneous injection of the CCK agonist caerulein dose-dependently decreased food intake in Zucker obese and lean rats whereas the CCK-B agonist gastrin-17 did not. Caerulein at 4 microg/kg, which resulted in CCK plasma bioactivity slightly above postprandial levels, decreased food intake in lean rats but not in obese rats. The decrease in food intake was also more marked at higher caerulein doses (20-100 microg/kg) in lean versus obese rats. In lean animals the satiety effects of the "near physiological" 4 microg/kg caerulein dose was abolished after blockade of vagal afferents with capsaicin, whereas the effects of higher caerulein doses were not. CCK-stimulated amylase secretion from pancreatic acini and binding capacity of 125I-labelled CCK-8 were decreased in obese versus lean rats. The CCK-A antagonist loxiglumide at 20 mg/kg, a dose which abolished the action of all caerulein doses on food intake, failed to alter the food intake either in obese or in lean rats when given without an agonist. The results suggest that the satiety effects of "near physiological" doses of caerulein in lean rats are mediated by vagal afferents whereas pharmacological doses act via non-vagal mechanisms. The differences in CCK's satiety effect between lean and obese rats may be due to differences in CCK-receptor binding and action at peripheral vagal sites. However, the failure of the CCK-A antagonist to increase food intake questions whether any of the effects of exogenous CCK are of physiological relevance.

Amylases↗
PubMed1997

[Current aspects in the pathogenesis of acute pancreatitis].

Alcohol abuse and gallstones are the most important factors in the pathogenesis of acute pancreatitis. Other factors are less frequent, and in some patients one is unable to identify any risk factor. Even in the most frequent forms of alcoholic or biliary pancreatitis little is known about the cellular and molecular mechanisms which lead to severe pancreatitis. New experimental studies have shown that many biochemical and morphological events are similar in different experimental models of pancreatitis as well as in human disease. These changes include intracellular premature activation of trypsin, blockade of luminal enzyme secretion and appearance of intracellular vacuoles. Although activated trypsin triggers the activation of other proteases, it is not trypsin but other proteases (e.g. elastase, chymotrypsin and phospholipase) which damage the pancreatic acinar cell. These pathogenetic findings may lead to the development of inhibitors which more effectively inhibit the latter cell-toxic proteases and may thereby help to improve the therapy.

Acute Disease↗
PubMed1997

Erythropoietin in patients with acute renal failure and continuous veno-venous haemofiltration.

Erythropoietin (Epo) is a glycoprotein hormone produced in the kidney in response to hypoxia or anaemia. In acute renal failure (ARF) anaemia also occurs and current opinion is that Epo production is depressed with inappropriately low plasma levels throughout the uraemic phase. Our study was designed to determine the excretion of Epo in patients with ARF. Fifty-nine ventilated patients were studied, 39 with ARF and continuous veno-venous haemofiltration therapy (group 1) and 13 patients with normal renal function who served as a control group (group 2). All patients with ARF were anaemic and needed a mean transfusion of 0.6 units/day. Values for vitamin B12, folic acid, serum iron and ferritin were normal. While patients with normal renal function had Epo values within the normal range, patients with ARF had significantly higher values at the onset of haemofiltration therapy. Mean Epo (mean +/- SEM) values on days 0-2 were 92.6 +/- 11.7 mU/ml in group 1 and 16.5 +/- 6.4 mU/ml in group 2 (p < 0.0002). Epo levels declined in group 1 to 49 +/- 10.5 mU/ml on days 9 and 10 compared to 23 +/- 9.1 mU/ml in group 2 (ns). These values were maintained until the end of the observation period. No differences were seen between oliguric and non-oliguric patients. Our data show that patients with ARF have increased Epo levels at the beginning of the disease with a strong tendency to decrease, suggesting that there might be inadequate Epo levels during the course of acute renal failure.

Acute Kidney Injury↗
PubMed1997

Beneficial effects of L-2-oxothiazolidine-4-carboxylate on cerulein pancreatitis in mice.

BACKGROUND & AIMS: Disturbances of the thiol metabolism of acinar cells may play a role in the pathophysiology of acute pancreatitis. Cerulein-induced pancreatitis causes depletion of glutathione. The entire pancreatic thiol status was assessed in this model. The potential benefit of augmentation of pancreatic glutathione by L-2-oxothiazolidine-4-carboxylate (OTC) for the course of pancreatitis was determined. METHODS: Mice were treated with cerulein (50 microg/kg) and with or without administration of OTC (6.5 and 20 mmol/kg, respectively). Pancreatic tissue was analyzed for reduced and oxidized glutathione, nonprotein thiol, mixed disulfide, protein thiol, and protein disulfide. Histopathology and serum amylase were also assessed. RESULTS: Levels of all thiol compounds were altered profoundly at a different rate during pancreatitis. OTC caused an increase of 60% in pancreatic glutathione. Its administration at 20 mmol/kg attenuated the decrease of pancreatic glutathione and protein thiol until 8 hours and blunted the cerulein-induced increase in amylase activity and histopathologic damage. At 6.5 mmol/kg, OTC failed to show effects on all parameters. CONCLUSIONS: OTC administered in a prophylactic protocol dose-dependently exerted beneficial effects in cerulein-induced pancreatitis in mice despite only transient influence on pancreatic thiol compounds. Thiols (e.g., reduced glutathione) and their corresponding disulfides are critically involved in the pathophysiology of cerulein-induced pancreatitis.

Amylases↗
PubMed1997

Menadione induces both necrosis and apoptosis in rat pancreatic acinar AR4-2J cells.

This study evaluated the action of menadione on cell proliferation and integrity of the rat pancreatic acinar cell line, AR4-2J. Menadione at 1-20 microM dose- and time-dependently inhibited cell proliferation of AR4-2J cells. In contrast, a high concentration of menadione (100 microM) caused rapid cell death (> 90% of cells took up trypan blue within 4-h). While the high concentration of menadione (100 microM) induced DNA smear in electrophoresis indicative of necrosis, lower concentrations (10-20 microM) induced a DNA ladder indicative of apoptosis. Similar results were obtained using a DNA fragmentation ELISA. Glutathione (1 mM), the calcium chelator EGTA (500 microM), and the cysteine protease inhibitor NCO-700 (5 mM) partly inhibited the effect of 1-10 microM menadione on cell proliferation and DNA fragmentation. Menadione at 1-20 microM induced wild-type P53, whereas the 100 microM menadione had a minor effect on wild-type P53. It is concluded that menadione induced necrosis at high concentrations and apoptosis at low concentrations in AR4-2J cells. Apoptosis induced by lower concentrations of menadione may be mediated by wild-type P53, intracellular calcium, and mechanisms which decrease the intracellular concentration of reduced glutathione.

Animals↗
PubMed1997

Cell volume changes modulate cholecystokinin- and carbachol-stimulated amylase release in isolated rat pancreatic acini.

BACKGROUND & AIMS: Changes in cell volume have been recently identified as modulators of cell function and gene expression. This study evaluated the regulation of exocrine secretion by pancreatic acini on the basis of changes in cell hydration. METHODS: Acini were exposed to hypotonicity or hypertonicity. The effects of corresponding changes in cell volume on various cell functions were analyzed. RESULTS: Hypertonicity and hypotonicity caused a stepwise cell shrinkage and swelling, respectively. Cell shrinkage decreased and cell swelling increased amylase secretion stimulated by cholecystokinin (CCK) and carbachol but not by secretin. Changes in cell volume did not alter basal or CCK-stimulated calcium concentrations or CCK-stimulated inositol triphosphate generation. The regulation of secretion by cell volume is not mediated via changes in CCK receptor binding or protein kinase C. The increase of amylase release caused by hypotonicity was completely inhibited by cytochalasin B, colchicine, and genistein. Hypotonicity as well as CCK caused activation of mitogen-activated protein kinases. CONCLUSIONS: Changes in cell volume regulate exocrine secretion of pancreatic acini. The effects were found only for secretagogues that act via the calcium/inositol-trisphosphate pathway. However, the mechanisms involved are located at luminal parts of the signal-transduction cascade and involve the cytoskeleton, protein phosphorylation, and activation of mitogen-activated protein kinases.

Adenosine Triphosphate↗
PubMed1997

Intestinal protein leakage in the acquired immunodeficiency syndrome.

Body wasting, protein catabolism, and hypoalbuminemia are complicating features of the acquired immunodeficiency syndrome (AIDS). Given their multifactorial causes, the contributing role of intestinal protein loss has not yet been fully elucidated. To quantify enteric protein leakage, determination of fecal alpha 1-antitrypsin (AAT) excretion has been established as an accurate and reliable endogenous marker. We estimated AAT concentration by standard immune nephelometry in duplicate random stool samples of 49 patients with AIDS, and we compared it to that of 43 patients with chronic inflammatory bowel disease and to 34 healthy controls. When compared with healthy persons, patients with AIDS had increased fecal AAT excretion regardless of current opportunistic intestinal infections and fecal AAT excretion similar to that of patients with quiescent chronic inflammatory bowel disease. The ratio of fecal and serum AAT concentration was not different between AIDS patients and healthy controls, although it was consistently increased in those with chronic inflammatory bowel disease. Significant intestinal protein leakage occurs in patients with AIDS, probably due to primary impairment of gut permeability. Enteric protein loss may be an important feature of human immunodeficiency virus-associated enteropathy with altered mucosal barrier function.

AIDS-Related Opportunistic Infections↗
PubMed1997

Cytotoxicity of peroxynitrite in rat pancreatic acinar AR4-2J cells.

Peroxynitrite (0.5-50 microM) induced dose-dependent cytotoxic effects in rat pancreatic acinar AR4-2J cells. Glutathione (2 mM) and ebselen (10 microM) partially reduced the cytotoxicity caused by 1-10 microM concentrations of peroxynitrite. Higher concentrations (10-50 microM) of peroxynitrite induced DNA smear suggestive of necrosis, while lower concentrations (2-5 microM) induced DNA fragmentations suggestive of apoptosis. The effects of peroxynitrite on [Ca2+]i showed a similar dose dependency. Peroxynitrite concentrations > 10 microM rapidly increased [Ca2+]i in a dose-dependent manner, while concentrations < 5 microM did not affect [Ca2+]i. In contrast, the presentation of wild-type P53 was accelerated at lower concentrations of peroxynitrite (< or = 10 microM) but not at higher concentrations (50 microM). The present study suggests that peroxynitrite at lower concentrations (2-5 microM) induces wildtype P53 and apoptosis, which is potentially a protective response toward the DNA damage caused by peroxynitrite. On the other hand, higher concentrations of peroxynitrite (10-50 microM) rapidly increase [Ca2+]i and eventually induce necrosis.

Animals↗
PubMed1997

Effect of oxidative stress on cellular functions and cytosolic free calcium of rat pancreatic acinar cells.

The present study evaluates the effect of free radicals generated by xanthine oxidase-catalyzed oxidation of hypoxanthine on cellular function of isolated rat pancreatic acinar cells. The results show that a rapid and sustained increase in intracellular Ca2+ concentration ([Ca2+]i) preceded all other morphological and functional alterations investigated. Radical-induced [Ca2+]i increase was largely inhibited by 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester, which prevents Ca2+ release from intracellular stores, but not by Ca2(+)-depleted medium. Radicals released Ca2+ from thapsigargin-insensitive, ryanodine-sensitive intracellular stores, whereas the secretagogue caerulein at physiological concentrations mainly released Ca2+ from thapsigargin-sensitive stores. In contrast to effects of the secretagogue, radical-induced Ca2+ changes did not cause luminal protein secretion but cell death. In single-cell measurements, both secretagogue and radicals induced oscillations of [Ca2+]i. Radical-induced oscillations had a lower frequency but similar amplitude when compared with caerulein-induced oscillations. 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and ryanodine, which prevented the radical-induced Ca2+ increase without altering the generation of radicals, markedly reduced the radical-induced cell damage. These results suggest that the Ca2+ increase mediates the radical-induced cell injury. The studies also indicate that not only the extent and duration but also the origin of [Ca2+]i release as well as the frequency of Ca2+ oscillations may determine whether a pancreatic acinar cell will secrete or die.

Adenosine Triphosphate↗