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Biomedical subjects

V Keim

Publications and source records attributed to V Keim.

At least 37 records · Page 2Linked to original sources
PubMed2001

Ofloxacin and ursodeoxycholic acid versus ursodeoxycholic acid alone to prevent occlusion of biliary stents: a prospective, randomized trial.

BACKGROUND AND STUDY AIMS: Biliary plastic stents are highly effective in the treatment of malignant biliary obstruction, but may become occluded over time, leading to jaundice and cholangitis. Stent occlusion is thought to be caused by bacterial adhesion and formation of biofilm. This study was carried out to assess whether treatment with ofloxacin in combination with ursodeoxycholic acid is superior to ursodeoxycholic acid alone in preventing stent occlusion. PATIENTS AND METHODS: Patients with obstructive jaundice due to inoperable malignant disease underwent placement of a straight 11.5-Fr polyethylene stent. After stent insertion, the patients were randomly assigned to receive either ofloxacin (200 mg b.i.d.) with ursodeoxycholic acid (250 mg t.i.d.) or ursodeoxycholic acid alone. The end points of the study were the frequency of stent occlusions, the time to stent occlusion, and the safety of the two regimens. RESULTS: Fifty-two patients were enrolled, of whom 26 were assigned to the combined therapy group and 26 to the control group. Thirty patients were suffering from pancreatic cancer, 13 from gallbladder or bile duct cancer, and nine had metastases from other malignant tumors. Eight stent occlusions (31%) occurred in the ofloxacin group and six (23 %) in the control group (P = 0.76). The mean times to stent occlusion were 95 +/- 9 days and 101 +/- 9 days, respectively (P = 0.91). No significant differences regarding survival time or safety were observed between the two groups. CONCLUSIONS: Ofloxacin in combination with ursodeoxycholic acid is not superior to ursodeoxycholic acid alone in preventing stent occlusion in patients with malignant obstructive jaundice.

Aged↗
PubMed2001

[Pathogenetic concepts of chronic pancreatitis].

Summary. The understanding of the pathogenesis of chronic pancreatitis is limited. Several theories (i. e. obstruction hypothesis) were suggested in the past but could not be confirmed by experimental data. As a formal description of the course of the disease, the necrosis-fibrosis concept seems to be very attractive. According to this theory, there is no significant difference in the pathogenesis of acute and chronic pancreatitis. A major step was the identification of mutations of the cationic trypsinogen, the secretory trypsin inhibitor (SPINK 1) and the cystic-fibrosis protein (CFTR) in some patients. Investigation of these mutations may significantly contribute to a better understanding of the pathogenesis of chronic pancreatitis.

Adult↗
PubMed2000

Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation.

BACKGROUND & AIMS: Mutations of the cationic trypsinogen have been described in hereditary pancreatitis. We report a new trypsinogen mutation in the activation peptide of the proenzyme in a family with chronic pancreatitis. METHODS: The coding region of the cationic trypsinogen gene was sequenced after polymerase chain reaction amplification. The following peptides homologous to the N-terminal end of cationic trypsinogen were synthesized (one-letter code, mutated amino acid underlined): wild-type peptide, APFDDDDKIVGG; pD22G, APFDDDGKIVGG; pK23R, APFDDDDRIVGG. The sequences of pD22G and pK23R correspond to the recently identified mutation K23R and to the mutation described here (D22G). To mimic trypsinogen activation, these peptides were digested with trypsin for 30 minutes at pH 5.0-8. 0, and the fragments were analyzed by high-performance liquid chromatography. RESULTS: In a family with clinical evidence of hereditary chronic pancreatitis, a missense mutation of codon 22 (GAC-->GGC) of the cationic trypsinogen was found. This mutation results in a substitution of aspartic acid by glycine; therefore, the mutation was called D22G. Chromatographic analysis of tryptic digests of the peptides pD22G and pK23R showed hydrolysis rates of 22% and 75%, respectively, whereas the wild-type peptide was hydrolyzed at only 6%. The cleavage rates were reduced at lower pH, and no hydrolysis occurred without trypsin. CONCLUSIONS: The activation peptides of the trypsinogen variants D22G and K23R could be released at a higher rate than in wild-type trypsinogen, resulting in increased amounts of trypsin in the pancreas, which could initiate pancreatitis.

Adult↗
PubMed2000

Decrease of CA 19-9 during chemotherapy with gemcitabine predicts survival time in patients with advanced pancreatic cancer.

Chemotherapy with gemcitabine has been shown to be an effective regimen in advanced or metastatic pancreatic cancer with improvement of both quality of life and survival time. The response of the tumour marker CA 19-9 to chemotherapy with gemcitabine was studied in order to find out whether it is related to survival time of patients. Forty-three consecutive patients (median age 61 years, range 39-76 years; 20 males, 23 females) suffering from histologically proven locally advanced or metastatic pancreatic adenocarcinoma and a baseline Karnofsky-index > or = 60 were treated with gemcitabine in a dose of 1,000 mg/m(-2) weekly x 7 followed by 1 week of rest during the first cycle and thereafter 1,000 mg/m(-2) weekly x 3 followed by 1 week of rest until progression. In 36 of 43 patients serial measurements of CA 19-9 could be performed. Patients with a decrease of > 20% of the baseline CA 19-9 level after 8 weeks of treatment (n = 25) had a significantly better median survival than patients with a rise or a decrease < or = 20% (n = 11) (268 vs 110 days; P < 0.001). The response of CA 19-9 was the strongest independent predictor of survival (P < 0.001) in the multivariate analysis. In conclusion, a decrease of CA 19-9 > 20% during the first weeks of chemotherapy with gemcitabine is associated with a better survival of patients with locally advanced or metastatic pancreatic cancer. Serial measurements of CA 19-9 are useful to decide whether further chemotherapy after the first weeks of treatment is indicated.

Adult↗
PubMed2000

Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis.

OBJECTIVE: We investigated whether mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and cationic trypsinogen gene are associated with recurrent acute, or chronic idiopathic pancreatitis. METHODS: Twenty patients with idiopathic pancreatitis (11 women, nine men; mean age, 30 yr) were studied for the presence of a CFTR mutation by screening the genomic DNA for more than 30 mutations and variants in the CFTR gene. Selected mutations of the cationic trypsinogen gene were screened by Afl III restriction digestion or by a mutation-specific polymerase chain reaction (PCR). In each patient exons 1, 2, and 3 of the cationic trypsinogen gene were sequenced. Patients with a CFTR mutation underwent evaluation of further functional electrophysiological test (intestinal current measurement). RESULTS: No mutation of the cationic trypsinogen gene was detected. A CFTR mutation was detected in 6/20 (30.0%) patients. Three patients (15.0%) had a cystic fibrosis (CF) mutation on one chromosome (deltaF508, I336K, Y1092X), which is known to cause phenotypical severe cystic fibrosis. One patient was heterozygous for the 5T allele. In addition, two possibly predisposing CFTR variants (R75Q, 1716G-->A) were detected on four patients, one of these being a compound heterozygous for the missense mutation I336K and R75Q. No other family member (maternal I336K; paternal R75Q; sister I1336K) developed pancreatitis. An intestinal current measurement in rectum samples of patients with a CFTR mutation revealed no CF-typical constellations. CONCLUSIONS: CFTR mutations are associated with recurrent acute, or chronic idiopathic pancreatitis, whereas mutations of the cationic trypsinogen mutation do not appear to be a frequent pathogenetic factor.

Adult↗
PubMed2000

Role of various phospholipases A2 and inhibitors in the pathogenesis and prevention of pancreatic acinar cell necrosis: studies with isolated rat pancreatic acini.

BACKGROUND: Phospholipase A2 (PLA2) may play a central role in the pathogenesis of pancreatic acinar cell necrosis. Several questions, however, are unsolved: Is acinar cell necrosis caused by PLA2 derived from infiltrating leukocytes or from pancreatic PLA2 itself? Does PLA2 cause cellular lysis by the release of lysolecithin from lecithin or by generation of free radicals? The aims of this study were to determine which form of PLA2 is responsible for cellular damage and how to inhibit its action. METHODS: Isolated rat pancreatic acini were prepared by collagenase digestion. Newly synthesized proteins were labeled by 35S-methionine. Acini were incubated in buffer to which various factors, such as porcine pancreatic PLA2 or bee venom PLA2, homogenates of either leukocytes or pancreatic homogenates, all with or without lecithin and with or without potential inhibitors (aprotinin, 4-bromophenacylbromide, BM 16.2115, quinacrine, various analogs of arachidonic acid), or free radicals (hydrogen peroxide, xanthine/ xanthine oxidase) with or without allo-purinol or dismutase/catalase were added. Cellular destruction was measured by the release of radiolabeled proteins. RESULTS: PLA2 alone, free radicals, and granulocytes were not harmful to acini within 30 min of incubation. Free radicals caused significant release of radiolabeled proteins only after 3 h of incubation; this release could be inhibited by scavengers. Incubation of pancreatic acini with PLA2 in combination with lecithin caused rapid release of radiolabeled proteins. Addition of high concentrations of enterokinase activated pancreatic homogenates both alone and with lecithin caused release of cellular proteins, suggesting that pancreatic PLA2 uses lecithin from pancreatic membranes as substrate. Almost all tested potential inhibitors of PLA2 were unable to prevent the destruction caused by either pancreatic or bee venom PLA2 and lecithin. However, HK 42, a polyunsaturated fatty acid analog, was able to reduce dose dependently the release of acinar proteins caused by pancreatic PLA2 and lecithin. CONCLUSION: Pancreatic PLA2 and not PLA2 from infiltrating leukocytes may play a role in pancreatic acinar cell necrosis. Cellular lysis is caused upon the action of lysolecithin and probably not via the action of free radicals.

Animals↗
PubMed1999

The pancreatitis-associated protein in hereditary and chronic alcoholic pancreatitis.

The pancreatitis-associated protein (PAP) was investigated in patients with hereditary and chronic alcoholic pancreatitis. Blood levels of pancreatic enzymes and PAP were measured in nine families with hereditary pancreatitis; in three of them, the mutation N21I, and in six, the R117H variant of the cationic trypsinogen were present. In all family members, similar to controls, only normal values of the PAP were found. There was no evidence for polymorphism of the PAP gene in patients with hereditary or alcoholic pancreatitis. Immunohistochemically PAP was detected in the apical parts of the acinar cells but not in ducts, interstitial tissue, islets, or blood vessels. Intensity of PAP labeling was directly related to the deterioration of the acinar units, and its concentration was inversely related to chymotrypsinogen immunoreactivity in the same tissue. Similar immunohistochemical findings were present in chronic alcoholic and hereditary pancreatitis. We conclude that there is a lack of PAP polymorphism in hereditary and alcoholic pancreatitis and that expression of the PAP in both groups of patients is related to the degree of cellular damage of the pancreas.

Acute-Phase Proteins↗
PubMed1999

Hereditary pancreatitis and mutation of the trypsinogen gene.

Hereditary pancreatitis is a rare form of chronic recurrent pancreatitis. A family, in which 11 members had chronic pancreatitis, five had diabetes, and two had pancreatic cancer, was studied, and hereditary pancreatitis was diagnosed in all patients by demonstrating the mutation in exon 3 of the cationic trypsinogen gene (R117H). The clinical implications of genotypic analysis in hereditary pancreatitis are discussed.

Adolescent↗
PubMed1999

Screening for mutations of the cationic trypsinogen gene: are they of relevance in chronic alcoholic pancreatitis?

BACKGROUND: In hereditary pancreatitis mutations of exons 2 (N21I) and 3 (R117H) of the cationic trypsinogen gene have been described. AIMS: To investigate whether the same mutations can also be found in patients with chronic alcoholic pancreatitis. METHODS: Leucocyte DNA was prepared from 23 patients with chronic alcoholic pancreatitis, 21 with alcoholic liver cirrhosis, 34 individuals from seven independent families with hereditary pancreatitis, and 15 healthy controls. DNA was also obtained from pancreatic tissue (n=7) and from pancreatic juice (n=5) of patients suffering from chronic alcoholic pancreatitis. R117H was detected by restriction digestion with Afl III. N21I was identified by an allele specific polymerase chain reaction (PCR). RESULTS: R117H was detected in four families with hereditary pancreatitis. The N21I mutation was identified in three families. All mutations were confirmed by sequencing of the corresponding DNAs. In patients with chronic alcoholic pancreatitis neither the exon 2 nor exon 3 mutations were present in blood leucocytes, pancreatic juice, or pancreatic tissue. DNA of the patients with alcoholic liver cirrhosis as well as all controls was of wild type. CONCLUSIONS: The allele specific PCR may be used to screen for the N21I mutation of cationic trypsinogen. Both trypsinogen mutations were found in hereditary pancreatitis but do not seem to be major pathogenic factors in chronic alcoholic pancreatitis.

Adult↗
PubMed1999

The endothelin antagonist bosentan does not improve survival in severe experimental pancreatitis in rats.

BACKGROUND: Severity of pancreatitis seems to be aggravated by impairment of vascular perfusion of the gland. Early mortality occurs within the first few days from the acute consequences of pancreatic injury with subsequent inflammatory response. Because vasoactive substances, including endothelin, seem to contribute to early mortality in acute pancreatitis, we tested the hypothesis that the inhibition of endothelin action could alter the outcome after severe experimental pancreatitis. METHODS: In two groups of rats, pancreatitis was induced by intraductal infusion into the pancreatic duct of 1 microL/g body weight (b.w.) of either a 4% or a 5% sodium taurocholate solution. The mixed endothelin A and endothelin B receptor antagonist bosentan (20 mg/kg b.w.) or vehicle was injected intravenously in 12-h intervals for 3 d starting 1 h after induction of bile acid pancreatitis. This dose of bosentan is known to completely inhibit the effect of exogenous endothelin. The survival rate was monitored for 7 d. Thereafter, the surviving rats were sacrificed and the pancreas was prepared for histological and biochemical evaluation. RESULTS: Irrespective of the treatment protocol (bosentan versus saline), survival was not different in animals challenged with either 4% or 5% sodium taurocholate. The corresponding survival rates were 62% with bosentan and 77% without bosentan in the 4% sodium taurocholate group. In the 5% sodium taurocholate group, the survival rates were 20% with and 27% without bosentan. Morphological and biochemical alterations were identical in control as well as in endothelin-antagonist-treated rats. CONCLUSION: Therapy with the mixed endothelin A and endothelin B receptor antagonist bosentan does not influence the outcome after severe experimental pancreatitis. Therefore, blockade of endothelin A and B receptor subtypes may not be of major importance as a therapeutic principle in this model of experimental pancreatitis.

Animals↗
PubMed1999

[Secondary diabetes in chronic pancreatitis].

In the majority of patients suffering from chronic pancreatitis an endocrine pancreatic insufficiency is correlated with exocrine dysfunction. The prevalence of impaired or diabetic glucose tolerance is 40-70%, half of these patients suffer from an insulin-dependent diabetes mellitus. In general the probability of endocrine insufficiency progressively increases within the ten years following diagnosis of chronic pancreatitis. Onset and severity of the endocrine dysfunction depend on parenchymal destruction of the pancreas but are also influenced by ongoing alcohol consumption. Pathological findings in the endocrine pancreas are a loss of B-cells with decrease in secretion of insulin but also a loss of B-cell responsiveness to glucose by impaired perisinusoidal diffusion. Disturbances of the enteroinsulinar axis with diminished levels of incretins due to an exocrine insufficiency are also discussed. In addition, an impaired A-cell function may be important, that is characterized by diminished levels of stimulated glucagon. Increased plasma levels of somatostatin were found, the source of which is unknown. The susceptibility to severe hypoglycemia in patients with diabetes mellitus secondary to chronic pancreatitis is higher than in Type I diabetics. This is mainly caused by the impaired glucagon secretion but also influenced by malnutrition and concomitant hepatic dysfunction due to the toxic affect of alcohol. Diagnostic procedures are the measurement of C-peptide-concentrations and profiles of blood glucose after fasting and stimulation with L-arginine or glucose. Especially in the beginning of the endocrine insufficiency the determination of basal levels of blood glucose or C-peptide are not useful. Unless treatment by diet is effective, the therapy of diabetes secondary to chronic pancreatitis should be done by insulin replacement. A certain degree of hyperglycemia may be tolerated due to the risk of hypoglycemia and the persistent alcohol consumption in these patients. Intensified insulin therapy should only be done in selected patients with good compliance. Long-term complications in patients with pancreatogenic diabetes are comparable to diabetes Type I and largely depend on the duration of the diabetes. Life expectancy is reduced, death in these patients is mainly due to persistent alcohol and nicotine abuse (cardiovascular disease, malignant tumors, etc.), in only a minority pancreatitis or diabetes (mainly hypoglycaemia) are relevant risk factors.

Chronic Disease↗