Showing papers by "Andreas Pfeiffer published in 2003"

Geant4—a simulation toolkit

Abstract: G eant 4 is a toolkit for simulating the passage of particles through matter. It includes a complete range of functionality including tracking, geometry, physics models and hits. The physics processes offered cover a comprehensive range, including electromagnetic, hadronic and optical processes, a large set of long-lived particles, materials and elements, over a wide energy range starting, in some cases, from 250 eV and extending in others to the TeV energy range. It has been designed and constructed to expose the physics models utilised, to handle complex geometries, and to enable its easy adaptation for optimal use in different sets of applications. The toolkit is the result of a worldwide collaboration of physicists and software engineers. It has been created exploiting software engineering and object-oriented technology and implemented in the C++ programming language. It has been used in applications in particle physics, nuclear physics, accelerator design, space engineering and medical physics.

Inflammatory Cytokines and the Risk to Develop Type 2 Diabetes: Results of the Prospective Population-Based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study

Abstract: A subclinical inflammatory reaction has been shown to precede the onset of type 2 (non-insulin-dependent) diabetes. We therefore examined prospectively the effects of the central inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) on the development of type 2 diabetes. We designed a nested case-control study within the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study including 27,548 individuals. Case subjects were defined to be those who were free of type 2 diabetes at baseline and subsequently developed type 2 diabetes during a 2.3-year follow-up period. A total of 192 cases of incident type 2 diabetes were identified and matched with 384 non-disease-developing control subjects. IL-6 and TNF-alpha levels were found to be elevated in participants with incident type 2 diabetes, whereas IL-1beta plasma levels did not differ between the groups. Analysis of single cytokines revealed IL-6 as an independent predictor of type 2 diabetes after adjustment for age, sex, BMI, waist-to-hip ratio (WHR), sports, smoking status, educational attainment, alcohol consumption, and HbA(1c) (4th vs. the 1st quartile: odds ratio [OR] 2.6, 95% CI 1.2-5.5). The association between TNF-alpha and future type 2 diabetes was no longer significant after adjustment for BMI or WHR. Interestingly, combined analysis of the cytokines revealed a significant interaction between IL-1beta and IL-6. In the fully adjusted model, participants with detectable levels of IL-1beta and elevated levels of IL-6 had an independently increased risk to develop type 2 diabetes (3.3, 1.7-6.8), whereas individuals with increased concentrations of IL-6 but undetectable levels of IL-1beta had no significantly increased risk, both compared with the low-level reference group. These results were confirmed in an analysis including only individuals with HbA(1c) <5.8% at baseline. Our data suggest that the pattern of circulating inflammatory cytokines modifies the risk for type 2 diabetes. In particular, a combined elevation of IL-1beta and IL-6, rather than the isolated elevation of IL-6 alone, independently increases the risk of type 2 diabetes. These data strongly support the hypothesis that a subclinical inflammatory reaction has a role in the pathogenesis of type 2 diabetes.

Association Between Adiponectin and Mediators of Inflammation in Obese Women

Abstract: Low plasma levels of the anti-inflammatory factor adiponectin characterize obesity and insulin resistance. To elucidate the relationship between plasma levels of adiponectin, adiponectin gene expression in adipose tissue, and markers of inflammation, we obtained blood samples, anthropometric measures, and subcutaneous adipose tissue samples from 65 postmenopausal healthy women. Adiponectin plasma levels and adipose-tissue gene expression were significantly lower in obese subjects and inversely correlated with obesity-associated variables, including high-sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6). Despite adjustment for obesity-associated variables, plasma levels of adiponectin were significantly correlated to adiponectin gene expression (partial r = 0.38, P < 0.05). Furthermore, the inverse correlation between plasma levels of hs-CRP and plasma adiponectin remained significant despite correction for obesity-associated variables (partial r = -0.32, P < 0.05), whereas the inverse correlation between adiponectin plasma levels or adiponectin gene expression in adipose tissue with plasma IL-6 were largely dependent on the clustering of obesity-associated variables. In conclusion, our data suggest a transcriptional mechanism leading to decreased adiponectin plasma levels in obese women and demonstrate that low levels of adiponectin are associated with higher levels of hs-CRP and IL-6, two inflammatory mediators and markers of increased cardiovascular risk.

Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass.

Abstract: Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. We have disrupted expression of the mitochondrial protein frataxin selectively in pancreatic beta cells. Mice were born healthy but subsequently developed impaired glucose tolerance progressing to overt diabetes mellitus. These observations were explained by impairment of insulin secretion due to a loss of beta cell mass in knockout animals. This phenotype was preceded by elevated levels of reactive oxygen species in knockout islets, an increased frequency of apoptosis, and a decreased number of proliferating beta cells. Hence, disruption of the frataxin gene in pancreatic beta cells causes diabetes following cellular growth arrest and apoptosis, paralleled by an increase in reactive oxygen species in islets. These observations might provide insight into the deterioration of beta cell function observed in different subtypes of diabetes in humans.

Universal pion freeze-out in heavy-ion collisions.

Abstract: Based on an evaluation of data on pion interferometry and on particle yields at midrapidity, we propose a universal condition for thermal freeze-out of pions in heavy-ion collisions We show that freeze-out occurs when the mean free path of pions lambda(f) reaches a value of about 1 fm, which is much smaller than the spatial extent of the system at freeze-out This critical mean free path is independent of the centrality of the collision and beam energy from the Alternating Gradient Synchrotron to the Relativistic Heavy Ion Collider

Clinical implications of the EGF receptor/ligand system for tumor progression and survival in gastrointestinal carcinomas: evidence for new therapeutic options.

Abstract: The epidermal growth factor (EGF) receptor and its various ligands (EGF, TGF-α, amphiregulin, heparin-binding (HB)-EGF, heregulin, betacellulin) seem to be involved in the growth regulation of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors However, few quantitative data investigating the impact of tumor-EGF receptor levels in gastrointestinal carcinomas on tumor stage and prognosis are available Therefore, EGF receptors were quantitatively determined in colorectal carcinomas in comparison to adjacent normal mucosa by 125I[EGF]-binding studies EGFR capacity was increased in advanced invasive colorectal carcinomas (Tl/2 vs T3/4 tumors, p<0001) and advanced UICC stages (UICC I vs UICC II/III, p<0001) These findings were confirmed with quantitative 125 [I]EGF autoradiography performed on frozen tissue slides and analyzed by laser densitometry (p=0020) EGF receptor analysis with immunohistochemistry with EGFR antibodies directed against the extracellular domain of the receptor was not correlated with tumor invasion or prognosis mRNA-expression of EGFR ligands was investigated using semiquantitative RT-PCR amplification using specific primers RT-PCR transcripts of EGFR ligands (EGF, TGF- α, HB-EGF, and amphiregulin) were detected in both carcinomas and normal mucosa, indicating that autocrine growth stimulation of colorectal carcinomas is mediated by coexpression of EGF receptor ligands and upregulation of EGF receptors Survival of colorectal cancer patients with increased tumor EGF receptor levels was significantly reduced in comparison to patients with low/unchanged tumor EGF receptor levels (mean survival±SD, 362±40 vs 468±43 months; p=0017) Further studies investigating EGF receptor levels in gastric cancer patients have shown that increased tumor EGF receptor levels were associated with poor prognosis in gastric cancer patients with tumors localized distal from the cardia Several specific EGF receptor tyrosine kinase inhibitors have recently entered clinical phase I–III studies, with promisingantitumor effects in several tumors, including gastrointestinal cancer Therefore, patients with invasive gastric or colorectal carcinomas might benefit from therapies specifically blocking EGFR-mediated signal transduction

Reduced survival of rectal cancer patients with increased tumor epidermal growth factor receptor levels.

Abstract: PURPOSE: The epidermal growth factor receptor and its various ligands (epidermal growth factor, transforming growth factor-alpha, amphiregulin, heparin-binding epidermal growth factor, heregulin, and betacellulin) have been implicated in growth and regeneration of intestinal mucosa and might be related to the development and progression of gastrointestinal tumors. Although some studies have investigated levels of epidermal growth factor receptor by radioligand binding studies, none of them have further analyzed these levels in patients with rectal cancer and investigated their prognostic value. METHODS: We quantitatively determined tumor epidermal growth factor receptor levels in 38 patients with colorectal cancer compared with adjacent normal mucosa by iodine-125–labeled epidermal growth factor binding studies and Scatchard analysis. Patients were followed up for 49.5 ± 32.2 (range, 2–120) months. RESULTS: Epidermal growth factor receptor capacity was increased in invasive colorectal carcinomas according to T classification (P < 0.001), tumors with lymph node infiltration (P = 0.038), and advanced International Union Against Cancer stage (P < 0.001). Survival of colorectal cancer was reduced in patients with advanced International Union Against Cancer stage (P < 0.001), tumors with positive lymph nodes (P < 0.001), and tumors with elevated epidermal growth factor receptor levels (P = 0.024). In rectal cancer patients, poor prognosis was associated with advanced International Union Against Cancer stage (P = 0.029), tumors with lymph node infiltration (P = 0.040), and increased epidermal growth factor receptor levels (P = 0.002). Multivariate Cox regression analysis indicated that elevated levels of epidermal growth factor receptor were an independent predictor of reduced survival in patients with rectal cancer (P = 0.005). CONCLUSION: The epidermal growth factor receptor/ligand system appears to be involved in tumor development and tumor progression of colorectal carcinomas, with prognostic implication especially in patients with invasive rectal carcinomas. These patients might take advantage of therapies that specifically block epidermal growth factor receptor–mediated signal transduction.

Post-prandial decrease of human plasma ghrelin in the absence of insulin.

Abstract: Ghrelin is the most powerful orexigenic hormone in mammalian physiology. Ghrelin plasma concentrations increase prior to meal onset, but decrease post-prandially. We and others reported previously that insulin reduces circulating ghrelin levels and might therefore be a driving force for post-prandial suppression of ghrelin. To test the influence of insulin on post-prandial ghrelin regulation, a patient with Type I diabetes with complete insulin deficiency received a low glycemic index meal and subsequently an additional high glycemic index meal in the absence of insulin substitution. Subsequently, a sc injection of 0.08 IU Lispro insulin per kg body weight was given. Results were compared to those of a healthy control subject matched for sex, age and body mass index, which was undergoing the same test series (without Lispro bolus) in the presence of endogenous post-prandial insulin secretion. A substantial decrease of plasma ghrelin levels was observed in the insulin-deficient patient following low glycemic index carbohydrate load (27% plasma ghrelin decrease). The subsequent exposure to a high glycemic index meal resulted in a slight additional reduction of ghrelin levels (32% from baseline), while Lispro bolus did not induce further changes in circulating ghrelin (27% of baseline at termination). This post-prandial response was comparable to that of the healthy control subject (33% reduction after the first meal, 40% after the second meal). These data tentatively suggest that post-prandial secretion of ghrelin is not exclusively regulated by plasma insulin or plasma glucose but may depend on other metabolic factors yet to be identified.

Precision validation of Geant4 electromagnetic physics

Abstract: The Geant4 toolkit provides an ample set of physics models for electromagnetic interactions. Results from a series of detailed tests with respect to well established reference data sources and experiments are presented, focusing on the precision validation of cross sections and angular distributions of various alternative physics models available in Geant4. Such precision tests are especially relevant for critical applications of simulation models, such as tracking detectors, calorimetry, neutrino and other astroparticle experiments, medical physics.

Protein kinase C-α attenuates cholinergically stimulated gastric acid secretion of rabbit parietal cells

Abstract: The phorbolester 12-O-tetradecanoyl phorbol-13-acetate (TPA), an activator of protein kinase C (PKC), inhibits cholinergic stimulation of gastric acid secretion. We observed that this effect strongly correlated with the inhibition of Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity in rabbit parietal cells. The aim of this study was to specify the function of PKC-α in cholinergically stimulated H+ secretion. PKC-α represents the only calcium-dependent PKC isoenzyme that has been detected in rabbit parietal cells. Go 6976, an inhibitor of calcium-dependent PKC, concentration-dependently antagonized the inhibitory effect of TPA, and, therefore, revealed the action of PKC-α on carbachol-induced acid secretion in rabbit parietal cells. TPA exerted no additive inhibition of carbachol-stimulated acid secretion if acid secretion was partially inhibited by the potent CaMKII inhibitor 1-[N,O-bis(5-isoquinolinsulfonyl)-N-methyl-L-tyrosyl]-4-phenyl-piperazine (KN-62). Since both kinase modulators, TPA and KN-62, affected no divergent signal transduction pathways in the parietal cell, an in vitro model has been used to study if PKC directly targets CaMKII. CaMKII purified from parietal cell-containing gastric mucosa of pig, was transphosphorylated by purified cPKC containing PKC-α up to 1.8 mol Pi per mol CaMKII in vitro. The autonomy site of CaMKII was not transphosphorylated by PKC. The phosphotransferase activity of the purified CaMKII was in vitro inhibited after transphosphorylation by PKC if calmodulin was absent during transphosphorylation. Attenuation of CaMKII activity by PKC showed strong similarity to the downregulation of CaMKII by basal autophosphorylation. Our results suggest that PKC-α and CaMKII are closely functionally linked in a cholinergically induced signalling pathway in rabbit parietal cells. We assume that in cholinergically stimulated parietal cells PKC-α transinhibits CaMKII activity, resulting in an attenuation of acid secretion. British Journal of Pharmacology (2003) 139, 545–554. doi:10.1038/sj.bjp.0705211

Beam energy and centrality dependence of two-pion Bose-Einstein correlations at SPS energies / CERES Collaboration

Abstract: Abstract Results are presented of a two-pion interferometry (HBT) analysis in Pb+Au collisions at 40, 80, and 158 A GeV. A detailed study of the Bertsch–Pratt HBT radius parameters has been performed as function of the mean pair transverse momentum kt and in bins of the centrality of the collision. From these results we extract model-dependent information about the space–time evolution of the reaction. An investigation of the effective volume of the pion emitting system provides an important tool to study the properties of thermal pion freeze-out.

Data analysis in HEP a statistical toolkit

Abstract: Statistical methods play a significant role throughout the life-cycle of HEP experiments, being an essential component of physics analysis. Only a few basic tools for statistical analysis were available in the public domain FORTRAN libraries for HEP. Nowadays the situation is hardly unchanged even among the libraries of the new generation. The present project in progress aims to develop an object-oriented software toolkit for statistical data analysis. More in particular, the Statistical Comparison component of the toolkit provides algorithms for the comparison of data distributions in a variety of use cases typical of HEP experiments, as regression testing (in various phases of the software life-cycle), validation of simulation through comparison to experimental data, comparison of expected versus reconstructed distributions, comparison of data from different sources - such as different sets of experimental data, or experimental with respect to theoretical distributions. The toolkit contains a variety of goodness-of-fit tests, from chi-squared to Kolmogorov-Smirnov, to less known, but generally much more powerful tests such as Anderson-Darling, Lilliefors, Cramer-von Mises, Kuiper. Thanks to the component-based design and the usage of the standard AIDA interfaces, this tool can be used by other data analysis systems or integrated in experimental software frameworks. We present the architecture of the system, the statistics methods implemented and the results of its first applications to the validation of the Geant4 Simulation Toolkit and to experimental data analysis.

Tools for simulation and analysis

Abstract: Software plays an incrwasingly important role in the design and operation of large-scale HEP detectors, as well as in the analysis of experimental data. In the recent past, new software technologies have emerged in the HEP domain, and new software systems, in particular for detector simulation (Geant4) and data analysis (Anaphe), have been developed to address the challenging requirements of new-generation HEP experiments.

A software toolkit for statistical data analysis

Abstract: We present a project in progress to develop a software toolkit for statistical data analysis. The toolkit is based on advanced software technologies, integrating generic programming techniques with object oriented methods, and adopts a rigorous software process, to ensure a high quality of the product. Thanks to the component-based architecture and the usage of the standard AIDA interfaces, this tool can be easily used by other data analysis systems or integrated in experimental frameworks. The initial component of the system addresses goodness of fit tests; its applications include the comparisons of data distributions in a variety of use cases typical of HEP experiments: regression testing (in various phases of the software life-cycle), validation of simulation through comparison to experimental data, comparison of expected versus reconstructed distributions, comparison of dierent experimental distributions - or of experimental with respect to theoretical ones - in physics analysis, monitoring detector behavior with respect to a reference in online DAQ. The system will provide the user the option to choose among a wide set of goodness-of-fit tests (chi-squared, KolmogorovSmirnov, Anderson-Darling, Lilliefors, Kuiper, Cramer-von Mises, etc.), specialised for various types of binned and unbinned distributions. Its flexible design makes it open to further extension to implement other tests. This system would represent a significant improvement with respect to the current availability of comparison tests in HEP libraries, limited to the chi-squared and Kolmogorov-Smirnov algorithms. We present the architecture of the toolkit, the detailed design of the basic statistical testing component and preliminary results of its application, in particular concerning the physics validation of the Geant4 Simulation Toolkit. We discuss the openness of the project, welcoming contributions from experts and user requirements from experiments.

Substitutionstherapie mit Hormonen. Was ist gesichert

Abstract: Die Behandlung von Patienten mit Hormonausfallen und ihre Substitution ist fur den endokrinologisch tatigen Arzt eine wesentliche Aufgabe. Dabei kann der Substitutionsbedarf einzelne oder, z. B. bei Erkrankungen der Hypophyse, mehrere Hormone betreffen. Die Frage, ob eine Hormonsubstitution erfolgen sollte, ist von zahlreichen Faktoren wie Alter, Geschlecht und Begleiterkrankungen des Patienten abhangig. Unumstritten ist die Notwendigkeit einer Substitution mit Hydrokortison bei Nachweis einer Nebennierenrindeninsuffizienz oder mit L-Thyroxin bei einer Hypothyreose bei allen Patienten. Die Substitution mit Ostrogen- oder Testosteronpraparaten ist im jungeren Alter fur das physische und psychische Wohlbefinden und fur den Erhalt der Knochenmasse wesentlich. Bei Patienten mit gesichertem Wachstumshormonmangel sollte die Therapie moglichst im Rahmen von Verlaufsbeobachtungen erfolgen. Der Einsatz der postmenopausalen Hormonersatztherapie mit Ostrogenen muss nach aktuellen Untersuchungen kritisch gesehen werden und ist im Wesentlichen auf die Beseitigung der Symptome in den Wechseljahren gerichtet.

A SoftwareToolkit for Statistical Data Analysis

Abstract: We present a project in progress to develop a software toolkit for statistical data analysis. The toolkit is based on advanced software technologies, integrating generic programming techniques with object oriented methods, and adopts a rigorous software process, to ensure a high quality of the product. Thanks to the component-based architecture and the usage of the standard AIDA interfaces, this tool can be easily used by other data analysis systems or integrated in experimental frameworks. The initial component of the system addresses goodness of fit tests; its applications include the comparisons of data distributions in a variety of use cases typical of HEP experiments: regression testing (in various phases of the software life-cycle), validation of simulation through comparison to experimental data, comparison of expected versus reconstructed distributions, comparison of different experimental distributions - or of experimental with respect to theoretical ones - in physics analysis, monitoring detector behavior with respect to a reference in online DAQ. The system will provide the user the option to choose among a wide set of goodness-of-fit tests (chi-squared, KolmogorovSmirnov, Anderson-Darling, Lilliefors, Kuiper, Cramer-von Mises, etc.), specialised for various types of binned and unbinned distributions. Its flexible design makes it open to further extension to implement other tests. This system would represent a significant improvement with respect to the current availability of comparison tests in HEP libraries, limited to the chi-squared and Kolmogorov-Smirnov algorithms. We present the architecture of the toolkit, the detailed design of the basic statistical testing component and preliminary results of its application, in particular concerning the physics validation of the Geant4 Simulation Toolkit. We discuss the openness of the project, welcoming contributions from experts and user requirements from experiments.