Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The levels of pancreatic digestive enzymes, lysosomal hydrolases, and protease inhibitors were evaluated in ascites fluid from 24 patients with acute pancreatitis diagnosed as alcoholic, gallstone-induced, or idiopathic. In this group the concentrations of amylase (354 +/- 98 ng/ml), immunoreactive cationic trypsinogen (1840 +/- 238 ng/ml), and immunoreactive elastase 2 (1492 +/- 262 ng/ml) were greatly elevated in comparison to the corresponding serum values. Enzyme levels in ascites from the idiopathic pancreatitis group tended to be higher than the levels from the other two groups. Activity of acid phosphatase and beta-glucuronidase was significantly higher in ascites compared to serum in all groups. On the other hand, levels of immunoreactive alpha 1-protease inhibitor and alpha 2-macroglobulin in ascites fluid were about half the average concentrations reported for normal serum. Significant amounts of tryptic amidase activity (61.7 +/- 13.7 micrograms/ml) were observed, indicating a trypsin-alpha 2-macroglobulin complex. These data indicate an imbalance in the protease-to-inhibitor ratio in ascites fluid from patients with acute pancreatitis. Coupled with elevated ribonuclease activity (27.4 +/- 3.4 units), a positive methemalbumin test in 23 of 24 patients (1.1 +/- 0.4 mg hematin/100 ml), and an average protein concentration of 4.0 +/- 0.2 g/100 ml, these observations demonstrate that abdominal paracentesis and the biochemical analyses of ascites fluid provide useful information related to the biochemical events in acute pancreatitis and may be useful in the diagnosis of difficult cases, but their predictive value of severity remains to be established.
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PMID:Biochemical studies in peritoneal fluid from patients with acute pancreatitis. Relationship to etiology. 381 84

Radioimmunoassays for anionic and cationic dog trypsins are described. Characterization of the immunoreactivities in sera from fasting dogs demonstrated the presence of the two proenzymes only. Fasting sera from 10 dogs contained anionic and cationic trypsinogen in concentrations between 17-110 micrograms/l and 7-19 micrograms/l, respectively. Induction of experimental pancreatitis in dogs was accompanied by a large increase of immunoreactive anionic and cationic trypsins in the circulation. During the progress of the pancreatitis, immunoreactive trypsin with larger molecular weight than trypsinogen appeared. This high molecular weight immunoreactive trypsin was not seen in serum after intravenous injection of pancreatic juice in dogs. The high molecular weight immunoreactive trypsin probably consists of trypsin in complex with protease inhibitors. In vitro studies showed that the immunoreactivity of trypsin decreased considerably after binding to alpha 1-antitrypsin or alpha-macroglobulins.
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PMID:Immunoreactive trypsins in sera from dogs before and after induction of experimental pancreatitis. 615 94

Protein analysis of intraductal precipitates and calculi is important to elucidate the mechanism of stone formation in chronic pancreatitis. We revealed human cationic trypsin immunoreactivity in protein extracts of pancreatic stones from 11 of 13 patients with chronic calcified pancreatitis, ranging from 0 to 42.3 ng/micrograms protein. On gel filtration the immunoreactivity eluted as one peak, which is identical to that of human cationic trypsinogen. On immunostaining of pancreatic stone, using an immunogold technic and scanning electron microscopy, the immunoreactivity was observed more densely in the amorphous portion of the center of the stones than in the concentric laminar layer of the periphery. Only negligible activity was detected for elastase 1 or amylase in the stone extracts. These results suggest that the presence of trypsinogen in pancreatic stone is not due to coprecipitation or adsorption of pancreatic enzymes but that trypsinogen is more likely involved in an initial step of intraductal precipitate formation than in a subsequent step of stone formation. However, the absence of trypsinogen in the stones from two of the 13 patients also suggests that trypsinogen is not the sole protein initiating precipitate formation.
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PMID:Trypsin(ogen) content of pancreatic calculi in chronic calcified pancreatitis in man. 820 Feb 69

A porcine pancreatic transplantation model was used to investigate possible protease activation in the pancreatic graft during preservation. After perfusion with Perfadex and cold ischemia for 24 h, but prior to reperfusion, activated carboxypeptidase B was demonstrated in tissue samples from the graft parenchyma with a Western blot technique, indicating that graft pancreatitis may already be initiated during the preservation phase. A higher degree of carboxypeptidase B activation was observed in grafts perfused at a pressure of 130 cm H20 than after perfusion at 70 cm H20. During reperfusion, the fraction of activated carboxypeptidase B gradually declined but was still detectable after 2 h. One group of pigs received aprotinin intravenously during reperfusion, but the protease inhibitor did not influence the degree of carboxypeptidase B activation in the biopsy specimen. Immunoblotting against cationic trypsinogen/trypsin was also performed. When activated trypsin was detectable, it never presented more than a few percent of the total amount of uncomplexed immunoreactive trypsinogen/trypsin.
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PMID:Protease activation in the porcine pancreatic allograft during preservation. 857 79

Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder characterized by epigastric pain and often more serious complications. We now report that an Arg-His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype. This mutation was observed in all HP affected individuals and obligate carriers from five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site. Cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis.
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PMID:Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. 884 Nov 72

Our understanding of the molecular genetics of pancreatic cancer has advanced spectacularly over the last 5 years so that this tumour type is now one of the best characterised of all malignancies. A small proportion of cases results from inherited predisposition due to germline transmission of a mutated CDKN2 or BRCA2 gene, while patients with familial pancreatitis due to a mutated cationic trypsinogen gene have a greatly increased risk of developing pancreatic cancer. The majority of cases are sporadic and are characterised at the molecular level by several key genetic abnormalities. The most frequent of these is point mutation of the dominant oncogene KRAS, a lesion which occurs as an early and possibly initiating event in tumourigenesis. Inactivating mutations of the tumour suppressor genes TP53, CDKN2 and SMAD4 are also frequently observed and this constellation of genetic defects sets pancreatic cancer apart from other types of cancer, a feature which could have important implications for molecular diagnosis. Genetic intervention for cancer prevention and therapy is becoming a clinical reality and several approaches are being pursued for pancreatic cancer. As well as tumour suppressor gene replacement and oncogene blockade, strategies with a potential bystander effect are showing promise. These include genetic prodrug activation therapy using selective expression of suicide genes and genetic immunomodulation with cytokines and tumour-associated antigens.
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PMID:Molecular advances in pancreatic cancer. 943 1

Important advances in the understanding of pancreatic diseases have taken place through the application of molecular methods in the study of the inherited form of pancreatitis and pancreas cancer. Mutations of the cationic trypsinogen gene have been found to be causative for hereditary pancreatitis with important implications for the molecular pathogenesis of acute and chronic pancreatitis. A variety of cancer syndromes involving the P16 and BRCA2 genes, for example, also lead to pancreatic cancer, but the gene responsible for familial pancreatic cancer has not been identified so far. The establishment of a European Registry of Hereditary Pancreatitis and Pancreatic Cancer (EUROPAC) will facilitate future developments.
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PMID:Hereditary pancreatitis and familial pancreatic cancer. 943 3

Hereditary pancreatitis (HP) is the most common form of chronic relapsing pancreatitis in childhood, and may account for approximately 25% of adult cases with chronic idiopathic pancreatitis. Recently, an arginine-histidine (R117H) mutation within the cationic trypsinogen gene was found in 5/5 families studied with HP. In this study we report on the results of linkage and direct mutational analysis for the common R117H mutation examined in 8 nonrelated families with hereditary pancreatitis. Two-point linkage analysis with the 7q35 marker D7S676, done initially in 4 families, yielded lod scores that were positive in 2, negative in one, and weakly positive in one. Direct mutational analysis of exon 3 of the cationic trypsinogen gene in 6 families showed that all symptomatic individuals tested were heterozygous for the R117H mutation. Also, several asymptomatic but at-risk relatives were found to be heterozygous for this mutation. Affected individuals in the remaining 2 families did not have the mutation. Radiation hybrid mapping using the Genebridge 4 panel assigned the trypsinogen gene to chromosome region 7q35, 2.9 cR distal to ETS WI-9353 and 3.8 cR proximal the dinucleotide repeat marker D7S676. The negative linkage and absence of the trypsinogen mutation in 2/8 families suggest locus heterogeneity in HP. Analysis of the R117H mutation is useful in identifying presymptomatic "at-risk" relatives and in genetic counseling. Also, it can be useful in identifying children and adults with isolated chronic idiopathic pancreatitis.
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PMID:Heterogeneity in hereditary pancreatitis. 955 94

Hereditary pancreatitis (OMIM 167800) is thought to be associated with a mutation of the exon 3 of cationic trypsinogen (Nature Genet (1996): 14:141-145). This paper reports sequence data of two independent families suffering from this disease. PCR amplificates from leukocyte or buccal swab DNA showed no mutation of exon 3 of cationic trypsinogen. Instead, in exon 2, an A-to-T tranversion was found that led to the substitution of Asn by Ile in the sixth amino acid of the active trypsin. In exons 4 and 5, silent mutations were found. In the other expressed trypsinogens, several homozygous alterations not associated to hereditary pancreatitis were identified. As a model of pathogenesis, we hypothesize that mutation of trypsinogen in exon 2 could lead to premature cleavage of the activation peptide of trypsinogen or to altered intracellular transport.
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PMID:Mutations of the cationic trypsinogen in hereditary pancreatitis. 963 18

Hereditary pancreatitis is an autosomal dominant disorder with incomplete penetrance. It is characterised by recurring episodes of severe abdominal pain and often presents in childhood. Recently, a mutation in the cationic trypsinogen gene was identified in this disease. Previously, only one mutation at residue 117 of the trypsinogen gene has been found in the five separate hereditary pancreatitis families, four from the USA and one from Italy. Alteration of the Arg117 site is believed to disrupt a fail-safe mechanism for the inactivation of trypsin, leading to autodigestion of the pancreas under certain conditions. Molecular analysis of the trypsinogen gene was carried out on a hereditary pancreatitis family from the UK. The same G to A mutation at residue 117 was identified in this family, suggesting that this is a common mutation in hereditary pancreatitis.
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PMID:Evidence for a common mutation in hereditary pancreatitis. 971 98


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