Genetic polymorphisms of manganese-superoxide dismutase and glutathione-S-transferase in chronic alcoholic pancreatitis

Chronic alcohol consumption is a major risk factor for the development of chronic pancreatitis. However, chronic pancreatitis occurs only in a minority of heavy drinkers. This variability may be due to yet unidentified genetic factors. Several enzymes involved in the degradation of reactive oxidants and xenobiotics, such as glutathione-S-transferase P1 (GSTP1) and manganese-superoxide dismutase (MnSOD) reveal functional polymorphisms that affect the antioxidative capacity and may therefore modulate the development of chronic pancreatitis and long-term complications like endocrine and exocrine pancreatic insufficiency. Two functional polymorphisms of the MnSOD and the GSTP1 gene were assessed by polymerase chain reaction and restriction fragment length polymorphism in 165 patients with chronic alcoholic pancreatitis, 140 alcoholics without evidence of pancreatic disease and 160 healthy control subjects. The distribution of GSTP1 and MnSOD genotypes were in Hardy-Weinberg equilibrium in the total cohort. Genotype and allele frequencies for both genes were not statistically different between the three groups. Although genotype MnSOD Ala/Val was seemingly associated with the presence of exocrine pancreatic insufficiency, this subgroup was too small and the association statistically underpowered. None of the tested genotypes affected the development of endocrine pancreatic insufficiency. Polymorphisms of MnSOD and GSTP1 are not associated with chronic alcoholic pancreatitis. The present data emphasize the need for stringently designed candidate gene association studies with well-characterized cases and controls and sufficient statistical power to exclude chance observation

Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer (PaCa) is a fatal human cancer due to its exceptional resistance to all current anticancer therapies. The cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly overexpressed in PaCa and seems to play an important role in cancer resistance to anticancer treatment. The inhibition of HO-1 sensitized PaCa cells to chemo- and radiotherapy <it>in vitro</it>.</p> <p>Therefore, we investigated the effects of HO-1 and its metabolites biliverdin, carbon monoxide and iron on PaCa cells.</p> <p>PaCa cell lines with divergent HO-1 expression patterns were used in a murine orthotopic cancer model. HO-1 expression and activity was regulated by zinc (inhibition) and cobalt (induction) protoporphyrin. Furthermore, the influence of cellular HO-1 levels and its metabolites on effects of standard chemotherapy with gemcitabine was tested <it>in vivo </it>and <it>in vitro</it>.</p> <p>Results</p> <p>High HO-1 expression in PaCa cell lines was associated with increased chemoresistance <it>in vitro</it>. Chemoresistance to gemcitabine was increased during HO-1 induction in PaCa cells expressing low levels of HO-1. The inhibition of HO-1 activity in pancreatic tumors with high HO-1 boosted chemotherapeutic effects <it>in vivo </it>significantly. Furthermore, biliverdin and iron promoted PaCa resistance to chemotherapy. Consequently, specific iron chelation by desferrioxamine revealed profound anticancerous effects.</p> <p>Conclusion</p> <p>In summary, the inhibition of HO-1 and the chelation of iron in PaCa cells were associated with increased sensitivity and susceptibility of pancreatic tumors to chemotherapy <it>in vivo</it>. The metabolites biliverdin and iron seem to be involved in HO-1-mediated resistance to anticancer treatment. Therefore, HO-1 inhibition or direct interference with its metabolites may evolve new PaCa treatment strategies.</p

SAPALDIA: Methods and participation in the cross-sectional part of the Swiss Study on Air Pollution and Lung Diseases in Adults

Summary: SAPALDIA-the Swiss Study on Air Pollution and Lung Diseases in Adults-focuses on the long term health effects of low to moderate levels of air pollutants as typically seen in different parts of Switzerland. The aim of the SAPALDIA cross-sectional study carried out in 1991 was to determine the prevalence of bronchial asthma, chronic bronchitis and allergic conditions in the adult population of Switzerland and to identify and to determine the respective importance of potentially influencing factors. These could be both personal (smoking habits, allergy status, family history, occupation) and environmental (outdoor and indoor pollution, aeroallergens, climate). A further aim of the cross-sectional study consisted in the identification of individuals susceptible to present symptoms during a two year observation period and to be included in the SAPALDIA follow-up study. This technical report represents the methodological documentation for the cross-sectional study of SAPALDIA. The instruments and the methods of standardisation are presented and discussed. The medical examination consisted of a computerised interview using a standardised questionnaire, the taking of a blood sample for serological tests, allergy skin testing, the measurement of endexpiratory CO and body height, and pulmonary function testing followed by methacholine challenge testing or bronchodilatation testing. The pattern of participation and the 9651 participants of the study, representing 59.3% of the sample, are described. Based on information on non-participants gained by telephone interviews and mailed short questionnaires, possible selection biases are quantified and discusse

«Transversales Unterrichten». – Interdisziplinäre Module als Studienschwerpunkt in der Schuleingangsphase

Die Lehrerinnen- und Lehrerbildung der Schuleingangsstufe basiert wesentlich auf fachwissenschaftlichen und fachdidaktischen Grundlagen, während der Vorschul- und Unterstufenunterricht in der Regel wenig fachlich organisiert ist. Insofern stellt das Verhältnis von Fachlichkeit und Interdisziplinarität eine Besonderheit und eine Herausforderung dar, die in der Modulgruppe «Transversales Unterrichten» aufgenommen werden. Da sich lebensweltliche bzw. gesamtgesellschaftliche Fragestellungen selten einzelfachlich aufgreifen und bearbeiten lassen, werden im Modul mehrere Fachwissenschaften und Fachdidaktiken aufeinander bezogen und bildungstheoretisch reflektierte, stufenspezifische transversale Lerngelegenheiten ent-wickelt, umgesetzt und evaluiert. Aus hochschuldidaktischer Sicht sollen Studierende zur Multiperspektivität angeleitet werden, um diese in Form sich ergänzender Weisen der Weltaneignung an die Schülerinnen und Schüler weiterzuvermitteln.Preparation programs for preschool teachers (kindergarten and first years of primary school) are based on subject-specific scientific basics and pedagogy, while classroom teaching is less subject-oriented. Hence, the relationship between subjects/disciplines and interdisciplinarity constitutes a special challenge which is addressed in the modules on «transversal teaching». Fundamental questions about the world and modern society can rarely be dealt with by one single subject. This is why the pluridisciplinary module integrates theory of education, planning of level-specific transversal learning opportunities as well as their implementation and evaluation. In the context of higher education, students should be trained in multi-perspective views in order be able to teach children a variety of ways of approaching the world

A bipartite butyrate-responsive element in the human calretinin (CALB2) promoter acts as a repressor in colon carcinoma cells but not in mesothelioma cells

The short-chain fatty acid butyrate plays an essential role in colonic mucosa homeostasis through the capacity to block the cell cycle, regulate differentiation and to induce apoptosis. The beneficial effect of dietary fibers on preventing colon cancer is essentially mediated through butyrate, derived from luminal fermentation of fibers by intestinal bacteria. In epithelial cells of the colon, both in normal and colon cancer cells, the expression of several genes is positively or negatively regulated by butyrate likely through modulation of histone acetylation and thereby affecting the transcriptional activity of genes. Calretinin (CALB2) is a member of the EF-hand family of Ca²⁺-binding proteins and is expressed in a majority of poorly differentiated colon carcinoma and additionally in mesothelioma of the epithelioid and mixed type. Since CALB2 is one of the genes negatively regulated by butyrate in colon cancer cells and butyrate decreases calretinin protein expression levels in those cells, we investigated whether expression is regulated via putative butyrate-responsive elements (BRE) in the human CALB2 promoter. We identified two elements that act as butyrate-sensitive repressors in all colon cancer cell lines tested (CaCo-2, HT-29, Co-115/3). In contrast, in cells of mesothelial origin, MeT-5A and ZL34, the same two elements do not operate as butyrate-sensitive repressors and calretinin expression levels are insensitive to butyrate indicative of cell type-specific regulation of the CALB2 promoter. Calretinin expression in colon cancer cells is negatively regulated by butyrate via a bipartite BRE flanking the TATA box and this may be linked to butyrate's chemopreventive activity

Ticlopidine in Its Prodrug Form Is a Selective Inhibitor of Human NTPDase1

Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), like other ectonucleotidases, controls extracellular nucleotide levels and consequently their (patho)physiological responses such as in thrombosis, inflammation, and cancer. Selective NTPDase1 inhibitors would therefore be very useful. We previously observed that ticlopidine in its prodrug form, which does not affect P2 receptor activity, inhibited the recombinant form of human NTPDase1 (Ki=14 μM). Here we tested whether ticlopidine can be used as a selective inhibitor of NTPDase1. We confirmed that ticlopidine inhibits NTPDase1 in different forms and in different assays. The ADPase activity of intact HUVEC as well as of COS-7 cells transfected with human NTPDase1 was strongly inhibited by 100 µM ticlopidine, 99 and 86%, respectively. Ticlopidine (100 µM) completely inhibited the ATPase activity of NTPDase1 in situ as shown by enzyme histochemistry with human liver and pancreas sections. Ticlopidine also inhibited the activity of rat and mouse NTPDase1 and of potato apyrase. At 100 µM ticlopidine did not affect the activity of human NTPDase2, NTPDase3, and NTPDase8, nor of NPP1 and NPP3. Weak inhibition (10–20%) of NTPDase3 and -8 was observed at 1 mM ticlopidine. These results show that ticlopidine is a specific inhibitor of NTPDase1 that can be used in enzymatic and histochemistry assays

Radiofrequency ablation of liver tumors: Actual limitations and potential solutions in the future

Over the past decade, radiofrequency ablation (RFA) has evolved into an important therapeutical tool for the treatment of non resectable primary and secondary liver tumors. The clinical benefit of RFA is represented in several clinical studies. They underline the safety and feasibility of this new and modern concept in treating liver tumors. RFA has proven its clinical impact not only in hepatocellular carcinoma (HCC) but also in metastatic disease such as colorectal cancer (CRC). Due to the increasing number of HCC and CRC, RFA might play an even more important role in the future. Therefore, the refinement of RFA technology is as important as the evaluation of data of prospective randomized trials that will help define guidelines for good clinical practice in RFA application in the future. The combination of hepatic resection and RFA extends the feasibility of open surgical procedures in patients with extensive tumors. Adverse effects of RFA such as biliary tract damage, liver failure and local recurrence remain an important task today but overall the long term results of RFA application in treating liver tumors are promising. Incomplete ablation of liver tumors due to insufficient technology of ablation needles, tissue cooling by the neighbouring blood vessels, large tumor masses and ablation of tumors in close vicinity to heat sensitive organs remain difficult tasks for RFA. Future solutions to overcome these limitations of RFA will include refinement of ultrasonographic guidance (accuracy of probe placement), improvements in needle technology (e.g. needles preventing charring) and intraductal cooling techniques

Liver resections can be performed safely without Pringle maneuver: A prospective study

AIM: To evaluate liver resections without Pringle maneuver, i.e., clamping of the portal triad. METHODS: Between 9/2002 and 7/2013, 175 consecutive liver resections (n = 101 major anatomical and n = 74 large atypical > 5 cm) without Pringle maneuver were performed in 127 patients (143 surgeries). Accompanying, 37 wedge resections (specimens < 5 cm) and 43 radiofrequency ablations were performed. Preoperative volumetric calculation of the liver remnant preceeded all anatomical resections. The liver parenchyma was dissected by water-jet. The median central venous pressure was 4 mmHg (range: 5-14). Data was collected prospectively. RESULTS: The median age of patients was 60 years (range: 16-85). Preoperative chemotherapy was used in 70 cases (49.0%). Liver cirrhosis was present in 6.3%, and liver steatosis of ≥ 10% in 28.0%. Blood loss was median 400 mL (range 50-5000 mL). Perioperative blood transfusions were given in 22/143 procedures (15%). The median weight of anatomically resected liver specimens was 525 g (range: 51-1850 g). One patient died postoperatively. Biliary leakages (n = 5) were treated conservatively. Temporary liver failure occurred in two patients. CONCLUSION: Major liver resections without Pringle maneuver are feasible and safe. The avoidance of liver inflow clamping might reduce liver damage and failure, and shorten the hospital stay