Helmut Denk — Page 3 | PubMed Health

PubMed2002

Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice.

Cholestasis is associated with retention of bile acids and reduced expression of the Na(+)/taurocholate cotransporter (Ntcp), the major hepatocellular bile acid uptake system. This study aimed to determine whether downregulation of Ntcp in obstructive cholestasis 1) is a consequence of bile acid retention and 2) is mediated by induction of the transcriptional repressor short heterodimer partner 1 (SHP-1). To study the time course for the changes in serum bile acid levels as well as SHP-1 and Ntcp steady-state mRNA levels, mice were subjected to common bile duct ligation (CBDL) for 3, 6, 12, 24, 72, and 168 h and compared with sham-operated controls. Serum bile acid levels were determined by radioimmunoassay. SHP-1 and Ntcp steady-state mRNA expression were assessed by Northern blotting. In addition, Ntcp protein expression was studied by Western blotting and immunofluorescence microscopy. Increased SHP-1 mRNA expression paralleled elevations of serum bile acid levels and was followed by downregulation of Ntcp mRNA and protein expression in CBDL mice. Maximal SHP-1 mRNA expression reached a plateau phase after 6-h CBDL (12-fold; P < 0.001) and preceded the nadir of Ntcp mRNA levels (12%, P < 0.001) by 6 h. In conclusion, bile acid-induced expression of SHP-1 may, at least in part, mediate downregulation of Ntcp in CBDL mice. These findings support the concept that downregulation of Ntcp in cholestasis limits intracytoplasmatic accumulation of potentially toxic bile acids.

Animals↗

PubMed1999

Long-term results of early gastric cancer accomplished in a European institution by Japanese-type radical resection.

BACKGROUND: Long-term survival following Japanese-type radical surgery for 130 consecutively performed early gastric cancers (EGC) in a single Austrian institution between January 1, 1984 and May 31, 1998 was analyzed in terms of long-term survival, postoperative morbidity, and mortality.METHODS: Extended D2 lymphadenectomy as defined by the JRSGC was performed in 129 patients with EGC. The surgical process was consistent as nearly all patients were operated on by only two surgeons. Overall survival and factors influencing survival were analyzed with particular regard to the depth of tumor infiltration, histological type, tumor grading, Lauren classification, tumor diameter, macroscopic appearance, localization, and lymph node involvement.RESULTS: Of 678 gastric cancer patients surgically treated in the mentioned period, 130 patients (19.2%) were qualified as EGC. In 70 patients the tumor was limited to the mucosa and in 60 patients the tumor had not yet invaded the submucosa. The percentage of patients with positive lymph nodes increased from 2.9% with mucosal invasion to 21.7% with submucosal tumor involvement. The overall 5- and 10-year observed survival rate, postoperative mortality not excluded, was 74.6% and 62.1%, respectively, and 91.1% and 91.1%, respectively, when calculated as tumor specific. The 5- and 10-year observed survival rate of tumors limited to the mucosa was 77.2% and 72.1%, respectively, and 98.1% and 98.1%, respectively, when calculated as tumor specific. The respective values for submucosal invasion were 71.6% and 51.7%, and 82.7% and 82.7%. Postoperative complications occurred in 17 patients (13.1%) and postoperative hospital mortality totaled 1.5% (2/130). In multivariate analysis, only lymph node metastases were found to have independent prognostic influence on survival ( P < 0.001; hazard ratio, 8.25).CONCLUSION: Japanese-type radical lymph node dissection for EGC in a European surgical institution yielded long-term survival nearly identical to that reported repeatedly by Japanese authors. Postoperative morbidity and mortality was not sacrificed by our comparatively radical surgical approach.

Journal Article↗