Search PubMed⌕ Search

Biomedical subjects

G Paumgartner

Publications and source records attributed to G Paumgartner.

At least 37 records · Page 2Linked to original sources
PubMed1999

Prevention of Kupffer cell-induced oxidant injury in rat liver by atrial natriuretic peptide.

The generation of reactive oxygen species (ROS) by activated Kupffer cells contributes to liver injury following liver preservation, shock, or endotoxemia. Pharmacological interventions to protect liver cells against this inflammatory response of Kupffer cells have not yet been established. Atrial natriuretic peptide (ANP) protects the liver against ischemia-reperfusion injury, suggesting a possible modulation of Kupffer cell-mediated cytotoxicity. Therefore, we investigated the mechanism of cytoprotection by ANP during Kupffer cell activation in perfused rat livers of male Sprague-Dawley rats. Activation of Kupffer cells by zymosan (150 microgram/ml) resulted in considerable cell damage, as assessed by the sinusoidal release of lactate dehydrogenase and purine nucleoside phosphorylase. Cell damage was almost completely prevented by superoxide dismutase (50 U/ml) and catalase (150 U/ml), indicating ROS-related liver injury. ANP (200 nM) reduced Kupffer cell-induced injury via the guanylyl cyclase-coupled A receptor (GCA receptor) and cGMP: mRNA expression of the GCA receptor was found in hepatocytes, endothelial cells, and Kupffer cells, and the cGMP analog 8-bromo-cGMP (8-BrcGMP; 50 microM) was as potent as ANP in protecting from zymosan-induced cell damage. ANP and 8-BrcGMP significantly attenuated the prolonged increase of hepatic vascular resistance when Kupffer cell activation occurred. Furthermore, both compounds reduced oxidative cell damage following infusion of H2O2 (500 microM). In contrast, superoxide anion formation of isolated Kupffer cells was not affected by ANP and only moderately reduced by 8-BrcGMP. In conclusion, ANP protects the liver against Kupffer cell-related oxidant stress. This hormonal protection is mediated via the GCA receptor and cGMP, suggesting that the cGMP receptor plays a critical role in controlling oxidative cell damage. Thus ANP signaling should be considered as a new pharmacological target for protecting liver cells against the inflammatory response of activated Kupffer cells without eliminating the vital host defense function of these cells.

Animals↗
PubMed1998

Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain.

Dehydroepiandrosterone sulfate (DHEAS) is the major circulating steroid in man. Pharmacologically, it exerts marked neuropsychiatric effects. Since no target receptor has been identified, we investigated whether the organic anion transporting polypeptide (OATP), a multispecific steroid carrier, transports DHEAS. Expression of the human liver OATP in Xenopus laevis oocytes resulted in high-affinity, partially Na+-dependent uptake of [3H]DHEAS (Km: 6.6 micromol/l). DHEAS transport was inhibited by bromosulfophthalein, bile acids, sulfated estrogens and dexamethasone. Northern blot analysis showed widespread expression of OATP in human brain. These data identify OATP as the first known target protein of DHEAS in human liver and brain.

Animals↗
PubMed1998

A scientific relational database combined with a report generator for endoscopy in networks: EndoNet.

BACKGROUND AND STUDY AIMS: The flexibility required in academic endoscopy units is not provided by the available database systems. In a project involving substantial cooperation between endoscopists and computer scientists, we have developed an adaptable database, combined with a report generator embedded in the hospital's intranet. PATIENTS AND METHODS: Six workstations in different areas of the hospital were clustered with a UNIX operating system to implement multi-user capability and access control. A relational database was used to design an application appropriate to the specific needs of the endoscopy unit in a teaching hospital engaged in scientific research. Both the terminology used in standardized endoscopy nomenclature and a free text block facility were included. A graphical user interface was developed to assemble pertinent data, generate the reports, and supervise the database. RESULTS: A total of 4936 examinations including 2988 patients were entered consecutively during continuous routine operation of the system. Complete report generation required five minutes (median; range 1-9 minutes). Both structured items and free text were used in all the reports. Querying of the database was possible, concerning matters such as the need for repeated endoscopic therapy in acute gastrointestinal bleeding (4%), the search for Helicobacter pylori in appropriate patients (64%), the rate of accidental pancreatic duct visualization in endoscopic retrograde cholangiography (24%), and links between examinations and active trials (2%). Indicating improved report quality, the number and the diameter of esophageal varices in patients with varices were more frequently reported with the new report system than with previous typed reports (P<0.001). An anonymous questionnaire revealed that the readability of the computer-generated reports was better than that of the previous typewritten reports (P=0.01). CONCLUSIONS: This report describes the creation of a database application and a report generator meeting the needs of scientific and routine use, and the successful application of this system in an academic endoscopy unit.

Computer Communication Networks↗
PubMed1998

Fibrotic entrapment of the small bowel in congenital intestinal lymphangiectasia.

Congenital intestinal lymphangiectasia is a rare protein-losing enteropathy that is characterized by diarrhea and peripheral edema. This report presents a 37-yr-old woman who had suffered from recurrent diarrhea and peripheral edema since her early childhood and who was admitted for severe attacks of abdominal pain. A diagnosis of intestinal lymphangiectasia was made endoscopically, histologically, and radiographically. Laparotomy revealed complete fibrotic entrapment of the small bowel, which caused partial mechanical bowel obstruction. Surgical decortication led to recovery. To the best of our knowledge, this is the first report on fibrotic entrapment of the small bowel in a patient with long lasting intestinal lymphangiectasia.

Adult↗
PubMed1998

Breath-hold MR cholangiography with snapshot techniques: prospective comparison with endoscopic retrograde cholangiography.

PURPOSE: To compare findings with magnetic resonance (MR) cholangiography with rapid acquisition with relaxation enhancement (RARE) and half-Fourier acquisition with single-shot turbo spin-echo (hereafter, half Fourier RARE) snapshot imaging techniques to those with endoscopic retrograde cholangiography (ERC). MATERIALS AND METHODS: Heavily T2-weighted thick-section (RARE) and thin-section (half-Fourier RARE) MR cholangiography were performed prospectively, on a 1.5-T imager, in the biliary tree of 61 consecutive patients before ERC. Findings at ERC were considered the standard of reference. The radiologist and endoscopist were blinded to each other's report. On- and off-site MR cholangiographic readings were performed to detect stones (n = 24), biliary dilatation (n = 34), or stenosis (n = 36). RESULTS: The sensitivity and specificity of MR cholangiography, respectively, calculated on a lesion-by-lesion basis, were 92.3% and 95.8% for cholangiolithiasis, 94.1% and 92.6% for duct dilatation, and 88.8% and 84.0% for stenosis. With snapshot MR cholangiography, on a patient-by-patient basis, differentiation between normal (n = 15) and abnormal (n = 46) results yielded a sensitivity of 92.4%, a specificity of 83.4%, and a positive predictive value of 95.6%. Pitfalls were caused by flow artifacts, compression by vessels, and low contrast between calculi and surrounding parenchyma. CONCLUSION: Snapshot MR cholangiography allowed noninvasive, accurate detection of biliary stones, strictures, and dilatation similar to that with ERC. Discrepancies regarding low-grade dilatation and strictures had no clinical relevance at retrospective review.

Bile Duct Diseases↗
PubMed1998

[Successful conservative therapy of hepatorenal syndrome with vasopressin-1-receptor antagonist ornipressin].

A 47-year-old male patient with alcoholic cirrhosis Child-Pugh grade C was admitted to our center for evaluation of liver transplantation. Serum creatinine had increased from 1.6 to 4.3 mg/100 ml within the previous two weeks, creatinine clearance was 12 ml/min, and urinary sodium 12 mmol/24 h. The diagnosis of HRS type I was established. Diuretic treatment was discontinued. Following albumin infusion, central venous pressure was increased to above 10 cm H2O and dopamine (2 micrograms/kg/min) infusion was started. However, renal function did not improve. An i.v. infusion of ornipressin (POR8, Sandoz; 6 IU/h) was started and dopamine infusion continued. During a four-hour interval, urinary volume and sodium excretion doubled. Therefore treatment was continued for three weeks. After 22 days, renal function had normalized (creatinine 1.2 mg/100 ml, creatinine clearance 65 ml/min, urinary sodium 62 mmol/24 h) and diuretic therapy was resumed. No adverse effects were observed. Ornipressin/dopamine infusion was discontinued and renal function remained normal. Three weeks later, the patient underwent liver transplantation with normal renal function. Ornipressin infusion had no effect on circulating endothelin, but decreased the activation of the renin-aldosterone system and of the sympathetic activity. So far, no noninvasive therapy of hepatorenal syndrome has been established. This is the first report of successful medical treatment of HRS type I with a three-week infusion of the vasopressin-l-receptor agonist ornipressin.

Dose-Response Relationship, Drug↗
PubMed1997

Identification and functional characterization of the promoter region of the human organic anion transporting polypeptide gene.

The organic anion transporting polypeptide (OATP) of the basolateral hepatocyte membrane mediates multispecific uptake of anionic and other amphipathic substrates from sinusoidal blood plasma. To investigate the mechanisms controlling OATP expression, the 5'-flanking region of the human OATP gene was isolated from a P1-derived artificial chromosome genomic clone. Sequence analysis of the OATP promoter showed a number of consensus binding sites for both ubiquitous and liver-enriched transcription factors. Transfection of HepG2 cells with a series of 5'-deleted promoter-luciferase constructs identified the minimal promoter region within 91 base pairs relative to the transcription initiation site. A putative silencer element was localized in the -662/-440 region. The minimal promoter was also active in Chang liver, Madin-Darby canine kidney, and Chinese hamster ovary cells, indicating that basal promoter function is independent of liver-specific regulatory mechanisms. In transfected HepG2 cells, taurocholate (100 micromol/L) stimulated and triiodothyronine (1 micromol/L) inhibited OATP promoter activity, whereas hydrocortisone, dexamethasone, beta-estradiol, estrone-3-sulfate, and testosterone had no significant effect. Reverse-transcription polymerase chain reaction analysis showed an increase in OATP messenger RNA in the livers of four patients with chronic cholestatic liver disease compared with three noncholestatic controls. The up-regulation of OATP expression by taurocholate could serve to enhance the sinusoidal efflux of toxic intracellular compounds during chronic cholestasis.

Amino Acid Sequence↗
PubMed1997

Safety and efficacy of repeated shockwave lithotripsy of gallstones with and without adjuvant bile acid therapy.

BACKGROUND & AIMS: The value of adjuvant bile acid dissolution therapy after extracorporeal shockwave lithotripsy (ESWL) of gallbladder stones is under debate. A double-blind, randomized, multicenter trial was conducted to determine the safety and efficacy of repeated ESWL with and without adjuvant bile acid therapy. METHODS: At five centers, 153 patients with gallstones and good gallbladder emptying were randomized to undergo up to six high-energy lithotripsy sessions combined with ursodeoxycholic acid (UDCA, 750 mg/day; n = 77) or placebo (n = 76). RESULTS: Six months after the initial treatment, 77% of patients with small single stones (< or = 20 mm in diameter), 60% with large single stones (> 20 mm in diameter), and 41% with multiple stones were free of stones. Administration of UDCA had no effect on stone disappearance in the whole study group but tended to improve stone disappearance rates in patients with large single stones and tended to decrease biliary adverse effects in patients with multiple stones. CONCLUSIONS: Repeated high-energy ESWL without adjuvant bile acid therapy represents a safe and effective treatment in patients with small single stones and good gallbladder emptying. In patients with large single stones and multiple stones, adjuvant bile acid therapy may be beneficial.

Adjuvants, Pharmaceutic↗
PubMed1997

Physical laws of cholesterol gallstone fragmentation.

Efficient fragmentation is the most important prerequisite for successful treatment of gallstones by extracorporeally induced shock waves. No data are available on the amount of energy necessary for stone disintegration and on the threshold energy below which no further fragmentation occurs. We therefore performed an in vitro investigation on human cholesterol gallstones to elucidate physical laws governing shock-wave lithotripsy. First, the focal pressure of the lithotripter was measured to calculate the energy traversing a stone. Second, 96 gallstones from 16 gall bladders were analysed with respect to physicochemical composition, radiological features and ultrasound before fragmentation was performed. Energy for stone disintegration was constant within each stone family but varied between 4.6 mL-1 and 36.8J mL-1 in different families. This energy correlated linearly with stone volume. None of the radiological and physicochemical factors revealed a clear-cut correlation of the different energies necessary for similar stone disintegration. The threshold energy differed between 0.26 mJ and 1.04 mJ per pulse. In conclusion, stone volume was the best parameter predicting stone fragmentation. However, in cholesterol stones with a similar composition the required energy per volume varies considerably together with the threshold energy. Radiological and ultrasound parameters appear to be of minor importance in explaining these differences.

Acoustics↗
PubMed1997

Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas.

BACKGROUND & AIMS: Chemotherapy of hepatocellular carcinomas is hampered by the insufficient accumulation of cytostatic drugs within the tumor cells. The aim of this study was to evaluate the feasibility of therapeutic strategies using antineoplastic agents coupled to bile acids. METHODS: Expression of the Na(+)-taurocholate-cotransporting polypeptide (NTCP) was analyzed in six hepatocellular carcinomas and in nonmalignant liver tissue. Uptake of the cytostatic drug [3H]-chlorambucil-taurocholate (S2676) was measured in Xenopus laevis oocytes injected with total messenger RNA (mRNA) from the carcinomas or peritumor tissue or with complementary RNA encoding the NTCP or the organic anion-transporting polypeptide (OATP) of human liver. RESULTS: Expression of hepatocellular carcinoma mRNA in oocytes resulted in mainly Na(+)-dependent uptake of chlorambucil-taurocholate. The level of NTCP mRNA in carcinomas amounted to 56% +/- 27% compared with peritumor tissue. Immunofluorescence studies confirmed the expression of NTCP on the surface of hepatocellular carcinoma cells. OATP expression, determined by immunoblotting, was similar in hepatocellular carcinomas and surrounding liver tissue (n = 3). NTCP mediated Na(+)-dependent uptake of chlorambucil-taurocholate (Michaelis constant, 11 mumol/L), whereas OATP mediated Na(+)-independent uptake. CONCLUSIONS: Hepatocellular carcinomas express the Na(+)-dependent bile acid transporter NTCP. Because NTCP mediates high-affinity uptake of chlorambucil-taurocholate, targeting of cytostatic bile acids to hepatocellular carcinomas could become a feasible therapeutic strategy.

Animals↗
PubMed1997

Differential gene expression of the three natriuretic peptides and natriuretic peptide receptor subtypes in human liver.

BACKGROUND: Various effects of atrial natriuretic peptide (ANP) on the liver have been observed. However, there is limited information about the types of receptors for natriuretic peptides expressed by the human liver. AIM: To investigate gene expression of the three NP receptor types (NPR) as well as of the NP in human liver. METHODS: Presence of mRNA coding for all three NPR and for ANP, brain and C-type natriuretic peptide (BNP, CNP) was investigated by reverse transcription-polymerase chain reaction (RT-PCR). Human liver tissues and hepatocellular carcinoma tissues were examined. RESULTS: Specific PCR products for all three NPR, namely NPR-A, B, and C, could be detected. Moreover, ANP and CNP, but not BNP mRNA was detectable. The concentration of ANP transcripts was up to fivefold higher in hepatocellular carcinoma compared with non-tumorous liver tissue of the same subjects. No difference in the expression of NP receptors relative to GAPDH mRNA of tumorous and non-tumorous tissue was observed except of slightly increased NPR-A transcripts. CONCLUSION: These data show that NPR transcripts are coexpressed with ANP and CNP mRNA in the human liver. This provides evidence for a local NP system in the human liver.

Aged↗
PubMed1996

Formation of cholic acid and chenodeoxycholic acid from 7 alpha-hydroxycholesterol and 27-hydroxycholesterol by primary cultures of human hepatocytes.

It has been suggested that chenodeoxycholic acid is preferentially formed by the alternative or 'acidic' pathway of bile acid biosynthesis starting with 27-hydroxylation of cholesterol, while cholic acid is derived from 7 alpha-hydroxycholesterol which initiates the 'neutral' pathway. We have studied bile acid formation from each of these precursors using human hepatocytes cultured in a novel sandwich collagen configuration. Culture supernatants were analyzed using capillary gas chromatography and gas chromatography-mass spectrometry. 27-Hydroxycholesterol and 7 alpha-hydroxycholesterol were both found to be efficiently converted to cholic acid as well as chenodeoxycholic acid. Analysis of acidic intermediates after addition of 7 alpha-hydroxycholesterol to the cultures revealed a significant increase of side-chain oxygenated C24- and C27-steroids with a 3-oxo-7 alpha-hydroxy-delta 4-ring structure. These data indicate that (i) the 'neutral' pathway is connected to the 'acidic' pathway by side-chain oxidation of C27-steroids with a 3-oxo-7 alpha-hydroxy-delta 4-ring structure and that (ii) the relative formation of cholic acid and chenodeoxycholic acid is regulated by metabolic events distal to the initial hydroxylation at either position 7 or position 27 of the cholesterol molecule.

Adult↗
PubMed1996

Molecular and functional characterization of bile acid transport in human hepatoblastoma HepG2 cells.

Bile acids are taken up into human liver by Na+-dependent and Na+-independent transport mechanisms. In hepatocarcinogenesis, numerous liver-specific functions are lost and the uptake of organic anions is markedly reduced. We have investigated the molecular and functional derangements of bile acid transport in the human hepatoblastoma cell line HepG2. Uptake of [3H]-taurocholic acid was saturable and entirely Na+ independent, with the kinetic characteristics of the human liver organic anion transporting polypeptide (OATP). OATP, but not the Na+-dependent bile acid transporter (Na+-taurocholate-cotransporting polypeptide [NTCP]), was detectable by reverse-transcription polymerase chain reaction (RT-PCR) analysis of HepG2 RNA. The level of OATP expression in HepG2 cells was determined by Northern blot analysis and was found to be 40% in comparison with normal liver. Transfection of an OATP-derived phosphorothioate (PTO)-antisense oligonucleotide into HepG2 cells resulted in 77% inhibition of temperature-dependent bile acid uptake. Injection of HepG2 messenger RNA (mRNA) into Xenopus laevis oocytes significantly stimulated Na+-independent taurocholate uptake, indicating the expression of a bile acid transport protein. We conclude that bile acid uptake into human hepatoblastoma HepG2 cells is mediated by the multi-specific organic anion transporting polypeptide OATP. Therapeutic strategies employing bile acid-derived cytostatic agents for the treatment of hepatocellular carcinomas may therefore depend upon the expression of the Na+-independent bile acid transporter OATP in hepatic malignancies.

Animals↗