Das internationale Subventionskarussell: Dabeisein oder Abspringen?

Vergeltungsmaßnahmen der Bundesrepublik Deutschland gegen Subventionen zugunsten einzelner Industriebranchen im Ausland lassen sich aus gesamtwirtschaftlicher Sicht nicht rechtfertigen. Aktion und Reaktion verringern den internationalen Warenaustausch und führen zu Einkommensverlusten bei allen am Welthandel beteiligten Ländern. Subventionen zugunsten einzelner Industriebranchen verursachen Wachstumsverluste, indem sie - eine Fehlspezialisierung auf strukturschwache Branchen oder vermeintliche Zukunftsindustrien fördern, - die Kostenkontrollfunktion des Wettbewerbs teilweise außer Kraft setzen und - Interessengruppen wie Unternehmer und Gewerkschaften ermutigen, reale Ressourcen in die Beeinflussung des politischen Entscheidungsprozesses zu investieren, um Vorteile zu erlangen (rent seeking). Die Verhaltensweise des "rent seeking", die sowohl für inländische als auch für ausländische Interessengruppen charakteristisch ist, hat dazu beigetragen, daß im vergangenen Jahrzehnt immer mehr Länder und immer mehr Produktionsbereiche in das internationale Subventionskarussell einbezogen worden sind. Durch diesen Lawineneffekt kumulieren sich die volkswirtschaftlichen Kosten, die die am Subventionswettlauf beteiligten Länder zu tragen haben. Die beste Lösung dieses Dilemmas wäre ein international vereinbarter Abbau von Branchensubventionen. Erweist sich eine solche Lösung als unerreichbar, so lohnt sich aus gesamtwirtschaftlicher Sicht immer noch ein einseitiger Ausstieg aus dem Subventionskarussell. Eine derartige Revision der bisherigen Wirtschaftspolitik wäre in der Bundesrepublik auch politisch durchsetzbar, wenn über Steuersenkungen das Wählerpotential der Steuerzahler mobilisiert würde. --

Multiphoton microscopy for the investigation of dermal penetration of nanoparticle-borne drugs

Multiphoton microscopy of a dually fluorescence-labeled model system in excised human skin is employed for high resolution three dimensional visualization in order to study the release, accumulation and penetration properties of drugs released from nanoscale carrier particles in dermal administration. Polymer particles were covalently labeled with fluorescein while Texas Red as a drug-model was dissolved in the particle to be released to the formulation matrix. Single nanoparticles on skin could easily be localized and imaged with diffraction limited resolution. The temporal evolution of the fluorescent drug-model concentration in various skin compartments over more than five hours was investigated by multiphoton spectral imaging of the same area of the specimen. The three dimensional penetration profile of the drug-model in correlation with skin morphology and particle localization information are obtained by a multiple laser line excitation experiment. Multiphoton microscopy combined with spectral imaging was found to allow non invasive long term studies of particle-borne drug-model penetration into the skin with sub cellular resolution. By dual color labeling a clear discrimination between particle-bound and released drug-model was possible. The introduced technique was shown to be a powerful tool in revealing the dermal penetration properties and pathways of drugs and nanoscale drug vehicles on microscopic level

Surgical Trauma Leads to a Shorter Survival in a Murine Orthotopic Pancreatic Cancer Model

Background: Abdominal surgery is frequently followed by immune dysfunction usually lasting for several days. This is especially important in cases with tumour diseases as an intact immune function is essential in this situation. Therefore, we analysed the outcome of tumour-bearing mice in a mouse model of surgically induced immune dysfunction (SID). Methods: In male C57BL/6 mice, a pancreatic tumour was implanted orthotopically. Following tumour implantation, the model of SID was applied. The control groups were either laparotomised or underwent no surgical procedure. The survival rate was determined by observation for >60 days. The tumour growth progress was imaged by a 7-tesla small animal MRI. Results: On day 60 after tumour implantation, the survival rate in SID mice was reduced to 41%. In the laparotomised group, 81% of mice survived, while the control group had a survival rate of 75%. These differences were significant (SID vs. control: p < 0.02, and SID vs. laparotomy: p < 0.002). The tumour volume was not influenced by the degree of surgical trauma. Conclusion: In pancreatic cancer, the SID model is ideally suited to investigate the influence of SID on this tumour entity

Absence of the neutrophil serine protease cathepsin G decreases neutrophil granulocyte infiltration but does not change the severity of acute pancreatitis

Acute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Cathepsins constitute a large group of lysosomal enzymes, that have been shown to modulate trypsinogen activation and neutrophil infiltration. Cathepsin G (CTSG) is a neutrophil serine protease of the chymotrypsin C family known to degrade extracellular matrix components and to have regulatory functions in inflammatory disorders. The aim of this study was to investigate the role of CTSG in pancreatitis. Isolated acinar cells were exposed to recombinant CTSG and supramaximal cholezystokinin stimulation. In CTSG(-/-) mice and corresponding controls acute experimental pancreatitis was induced by serial caerulein injections. Severity was assessed by histology, serum enzyme levels and zymogen activation. Neutrophil infiltration was quantified by chloro-acetate ersterase staining and myeloperoxidase measurement. CTSG was expessed in inflammatory cells but not in pancreatic acinar cells. CTSG had no effect on intra-acinar-cell trypsinogen activation. In CTSG(-/-) mice a transient decrease of neutrophil infiltration into the pancreas and lungs was found during acute pancreatitis while the disease severity remained largely unchanged. CTSG is involved in pancreatic neutrophil infiltration during pancreatitis, albeit to a lesser degree than the related neutrophil (PMN) elastase. Its absence therefore leaves pancreatitis severity essentially unaffected

Common variants in the CLDN2-MORC4 and PRSS1-PRSS2 loci confer susceptibility to acute pancreatitis

BACKGROUND/OBJECTIVES: Acute pancreatitis (AP) is one of the most common gastrointestinal disorders often requiring hospitalization. Frequent aetiologies are gallstones and alcohol abuse. In contrast to chronic pancreatitis (CP) few robust genetic associations have been described. Here we analysed whether common variants in the CLDN2-MORC4 and the PRSS1-PRSS2 locus that increase recurrent AP and CP risk associate with AP. METHODS: We screened 1462 AP patients and 3999 controls with melting curve analysis for SNPs rs10273639 (PRSS1-PRSS2), rs7057398 (RIPPLY), and rs12688220 (MORC4). Calculations were performed for the overall group, aetiology, and gender sub-groups. To examine genotype-phenotype relationships we performed several meta-analyses. RESULTS: Meta-analyses of all AP patients depicted significant (p-value<0.05) associations for rs10273639 (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.81-0.97, p-value 0.01), rs7057398 (OR 1.27, 95% CI 1.07-1.5, p-value 0.005), and rs12688220 (OR 1.32, 95% CI 1.12-1.56, p-value 0.001). For the different aetiology groups a significant association was shown for rs10273639 (OR 0.76, 95% CI 0.63-0.92, p-value 0.005), rs7057398 (OR 1.43, 95% CI 1.07-1.92, p-value 0.02), and rs12688220 (OR 1.44, 95% CI 1.07-1.93, p-value 0.02) in the alcoholic sub-group only. CONCLUSIONS: The association of CP risk variants with different AP aetiologies, which is strongest in the alcoholic AP group, might implicate common pathomechanisms most likely between alcoholic AP and CP

Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

OBJECTIVE: Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. DESIGN: 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. RESULTS: We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. CONCLUSION: An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders

Cathepsin D Expression and Gemcitabine Resistance in Pancreatic Cancer.

BackgroundCathepsin-D (CatD), owing to its dual role as a proteolytic enzyme and as a ligand, has been implicated in cancer progression. The role of CatD in pancreatic ductal adenocarcinoma is unknown.MethodsCatD expression quantified by immunohistochemistry of tumor-tissue microarrays of 403 resected pancreatic cancer patients from the ESPAC-Tplus trial, a translational study within the ESPAC (European Study Group for Pancreatic Cancer) trials, was dichotomously distributed to low and high H scores (cut off 22.35) for survival and multivariable analysis. The validation cohort (n = 69) was recruited based on the hazard ratio of CatD from ESPAC-Tplus. 5-fluorouracil-, and gemcitabine-resistant pancreatic cancer cell lines were employed for mechanistic experiments. All statistical tests were two-sided.ResultsMedian overall survival was 23.75 months and median overall survival for patients with high CatD expression was 21.09 (95% confidence interval [CI] = 17.31 to 24.80) months vs 27.20 (95% CI = 23.75 to 31.90) months for low CatD expression (χ2 LR, 1DF = 4.00; P = .04). Multivariable analysis revealed CatD expression as a predictive marker in gemcitabine-treated (z stat = 2.33; P = .02) but not in 5-fluorouracil-treated (z stat = 0.21; P = .82) patients. An independent validation cohort confirmed CatD as a negative predictive marker for survival (χ2 LR, 1DF = 6.80; P = .009) and as an independent predictive marker in gemcitabine-treated patients with a hazard ratio of 3.38 (95% CI = 1.36 to 8.38, P = .008). Overexpression of CatD was associated with a concomitant suppression of the acid sphingomyelinase, and silencing of CatD resulted in upregulation of acid sphingomyelinase with rescue of gemcitabine resistance.ConclusionsAdjuvant gemcitabine is less effective in pancreatic ductal adenocarcinoma with high CatD expression, and thus CatD could serve as a marker for biomarker-driven therapy