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Copyright of Der Nervenarzt is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Der Gastroenterologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective. VEGF is a glycoprotein with various (e.g. angiogenic) activities. So far, research has focused on its angiogenic properties. VEGF receptors are localized on epithelial cells of patients with inflammatory bowel disease (IBD) and also on Caco-2 and IEC-18 cells. Our aim was to evaluate the role of VEGF on intestinal epithelial cell (IEC) migration and proliferation by utilizing an established in vitro model. Methods. IEC-18 and Caco-2 monolayers were wounded with a razor blade as described previously. Cells were incubated in medium w/o rat VEGF 164 . After 24  h, migration was assessed by counting cells across the wound edge. Migration was blocked with neutralizing TGF-β 1 antibodies. IEC proliferation was assessed using the MTT (3-[4, 5-Dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide) test. Semi-quantitative changes of the TGF-β 1 mRNA expression were evaluated before and after stimulation of the cells with VEGF 164 by RT-PCR. Statistical analysis was performed with ANOVA and the Wilcoxon test. Results. VEGF 164 significantly induced epithelial cell migration in Caco-2 and IEC-18 cells compared to control. TGF-β 1 antibodies completely abolished this VEGF-induced cell migration. TGF-β 1 mRNA significantly increased in IEC-18 and Caco-2 cells after stimulation with VEGF. VEGF significantly inhibited epithelial cell proliferation in IEC-18 and in Caco-2 cells, indicating that the observed effects on cell migration were not due to any proliferate effects. Conclusion. VEGF effects on epithelial cell migration play an important part in epithelial cell restitution by maintaining mucosal homeostasis after mucosal injury. This effect is mediated by TGF-β 1 . Our results obtain another possible role for increased VEGF levels in the intestinal mucosa of patients with IBD as reported recently by others. [ABSTRACT FROM AUTHOR]

Objective . In 2003 we identified a family with familial hypocalciuric hypercalcemia (FHH) (heterozygous CASR gene mutation L173P) and a mutation in the pancreatic secretory trypsin inhibitor gene ( SPINK1 ) (N34S). While family members with an isolated calcium-sensing receptor gene ( CASR ) mutation remained healthy, a combination of the CASR and SPINK1 gene mutation caused chronic pancreatitis (CP). We thus speculate that the combination of two genetic defects affecting calcium homeostasis and pancreatic enzyme activation might represent a novel approach in chronic inherited pancreatic disease. We therefore sought to explore whether CASR gene mutations were prevalent in a cohort of patients with CP and confirmed SPINK1 mutations. Material and methods . A cohort of 19 families ( n =170) with a history of idiopathic CP (ICP) was screened for mutations within the CASR gene; 104 members of that cohort had a mutation (N34S) within the SPINK1 gene and 66 of those were suffering from CP. The entire CASR gene was screened for single strand conformation polymorphism under varying polyacrylamide gel conditions and subjected to direct dideoxy nucleotide sequencing of amplified cDNA. Results . Single-strand conformation polymorphisms were observed in 59 samples, clustering of exons 3, 4 and 7. DNA sequence analysis revealed a yet unreported missense mutation in exon 7 (R896H) and two conservative mutations in exon 4 (F391F) and exon 7 (E790E). Furthermore, an intronic polymorphism in nucleotide position 493-19 G?>?A was detected in 19 out of 170 members of that cohort. Conclusions . We identified three novel calcium-sensing receptor gene mutations (1 missense mutation, 2 silent mutations and 1 intronic polymorphism) in a cohort of 19 families with ICP. In particular, the kindred with the R896H mutation presenting with a similar pedigree to the family described above may indicate a role for CASR gene mutations in SPINK1 -related CP. Again, only the patient with the combination of both CASR and N34S SPINK1 gene mutation developed pancreatitis, whereas in the healthy parents and children only an isolated CASR or N34S SPINK1 gene mutation could be detected. We suggest that the CASR gene is a novel yet undetected co-factor in a multifactorial genetic setting of SPINK1- related pancreatitis that alters the susceptibility for pancreatitis in these patients. [ABSTRACT FROM AUTHOR]

Introduction: In pancreatic ischemia/reperfusion (IR) injury (IRI) the role of nitric oxide (NO) is not completely understood. Using a rat model of normothermic in situ IRI, the effect of endogenous and exogenous NO donors on post-ischemic tissue oxygenation and tissue damage was investigated. Methods: IR was induced by 2-hour normothermic in situ ischemia of a pancreatic tail segment pedunculated on the splenic vessels with 2 h of reperfusion in an untreated, an L-arginine- and a sodium-nitroprusside-treated group (Wistar rats, n = 7/group). Animals without ischemia served as controls. Tissue oxygenation (pO2ti) was monitored using a pO2-sensitive Clark-type electrode. Histological investigation was performed following a semiquantitative score (edema, vacuolization, PMN infiltration, necrosis). Plasma lipase was another marker of organ damage. Results: The administration of L-arginine and sodium nitroprusside caused a significant amelioration of the decrease in pO2ti after reperfusion compared to IR animals (p < 0.05). Histological damage was also reduced in the NO donor groups (p < 0.05). After reperfusion, plasma lipase in the L-arginine-treated animals was significantly lower compared to IR and sodium nitroprusside (p < 0.05). Conclusions: The administration of both endogenous and exogenous NO donors is protective in IRI of the rat pancreas which can be seen by an improvement in post-ischemic tissue oxygenation which indicates better nutritive tissue perfusion, amelioration of the histological tissue injury and, in L-arginine animals, lower lipase levels. NO donors could be useful in the prevention and reduction of the pancreatic IRI. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion injury plays an important role in the development of graft pancreatitis and thrombosis after pancreas transplantation. Up to now there are few therapeutic options for this severe complication because very little is known about pancreatic ischemia/reperfusion injury. The same pathomechanisms may also be involved in the induction and determination of the course of acute pancreatitis. We observed the effect of 2 h of warm in situ ischemia on the postischemic tissue oxygenation, histological organ damage, and pancreatic enzymes. Experiments were performed in 21 male Wistar rats. In sham-operated animals without ischemia, the pancreas was not dissected. In the ischemic/reperfusion group a pancreatic tail-segment was carefully separated from the head, and ischemia was induced by clamping the splenic vessels for 2 h, after flushing the pancreatic tail-segment with heparinized saline. Animals treated similarly, but with opening of the lamps some seconds after induction of ischemia, served as controls. The animals were observed for 2 h after reperfusion. Tissue oxygenation was monitored by a PO2-sensitive probe (LICOX, GMS, Kiel, Germany) which was implanted into the pancreatic tissue. Blood samples were taken before, 5 min, 60 min, and 120 min after reperfusion. At the end of the experiment the pancreatic tail was excises for histological examination; biopsies from the non-ischemic pancreatic head served as intraindividual control to exclude side effects on the non-ischemic pancreatic head. In the ischemia/reperfusion group, PO2ti was significantly lower 1 h (18.0±1.7 mmHg) and 2 h (16.4±1.6 mmHg) after reperfusion compared with baseline conditions (32.8±5.2 mmHg) and the control group (1 h 30.6±1.9 mmHg, 2 h 32.4±2.4 mmHg). Histological injury score and plasma lipase activity were significantly higher in the ischemia/reperfusion group compared with the control group. Thus we describe a new experimental model of complete normothermic in situ ischemia of a pancreatic tail-segment with the possibility of flushing the pancreatic tail-segment and selective local application of drugs to the pancreas. [ABSTRACT FROM AUTHOR]

A C825T polymorphism was recently described in GNB3, the gene encoding the Gβ3 subunit of heterotrimeric G proteins. The 825T allele is associated with the expression of a shorter splice variant (Gβ3-s) and enhanced signal transduction via pertussis toxin (PTX)-sensitive G proteins. Given the pivotal role of G protein βγ dimers in chemotaxis, we related the genotype at the GNB3 locus as a marker for Gβ3-s expression to chemotaxis of human neutrophils in response to stimulation with interleukin-8 (IL-8). IL-8, which activates a CXC receptor coupled to PTX-sensitive G proteins, induced at 10 nM an enhanced maximum chemotaxis of neutrophils from individuals with TC/TT genotype compared to CC genotype. Furthermore, migration of neutrophils from 825T allele carriers was 2.5-fold higher at 0.1 nM and 1 nM IL-8. At these concentrations of IL-8, no significant chemotaxis was observed in neutrophils from homozygous C825 allele carriers, indicating a genotype-dependent, different potency of IL-8 to chemoattract neutrophils. In contrast, IL-8-induced Ca2+ signals and O2– generation were independent of genotype. The role of Gβ3-s in enhanced chemotaxis could be confirmed by determination of chemotaxis of COS-7 cells following transfection with either Gβ3-s or "wild-type" Gβ3. Upon stimulation of the transfected cells with the chemoattractant lysophosphatidic acid (LPA), we observed an enhanced chemotactic response of Gβ3-s-transfected compared to Gβ3-transfected COS-7 cells, confirming that Gβ3-s actually causes enhanced chemotaxis. [ABSTRACT FROM AUTHOR]