Saarland University Research Articles

Erratum to “A Continuous Model for Multistore Competitive Location”

In Dasci and Laporte (2005), we present a model in a multi tore competitive l cation environment. W develop the model by shifting the issue from competition on pre cise location decisions to competition over location density decisions. The intent of this note is to correct an error in one of the intermediate calculations and its impact on some of the subsequent results. We thank Hans-Peter Ziegler and Stefan Nickel of Saarland University, who discovered the error and brought it to our attention. To describe the error and its correction, we reconsider the leader's problem and its proposed solution given in Equations (18) and (19) of Dasci and Laporte (2005). The leader's problem is given as

Behavioral Comorbidity Differs in Subtypes of Enuresis and Urinary Incontinence

The aim of this prospective study is to describe the association of comorbid behavioral and somatic factors in children with different forms of nocturnal enuresis and daytime incontinence referred to a tertiary center. A total of 166 consecutive children 5.1 to 16.4 years old were referred for detailed assessment between January 2004 and July 2006. Evaluation included a detailed history, pediatric examination, 24 to 48-hour voiding protocols, sonography and uroflow. Parents filled out the Child Behavior Checklist, a standardized parental questionnaire consisting of 113 problem items. ICD-10 diagnoses were given based on standardized mental state examination and mutual consensus conferences. In the full sample externalizing disorders were more than twice as common as internalizing disorders. Differences were found between children with nocturnal enuresis and daytime incontinence regarding parent reported externalizing behavior scores as well as rates of "at least 1 ICD-10 psychiatric diagnosis" and comorbid encopresis. Children with monosymptomatic nocturnal enuresis showed fewer internalizing disorders and lower rates of "at least 1 ICD-10 psychiatric diagnosis" and comorbid encopresis compared to those with nonmonosymptomatic nocturnal enuresis, urge incontinence and voiding postponement. The results of sonography and uroflow measures also differed between groups. Different subtypes of enuresis and urinary incontinence demonstrate differences in behavioral problems and psychiatric comorbidity. The highest rates of psychiatric comorbidity were found in the group of children with voiding postponement and the lowest were in children with monosymptomatic nocturnal enuresis. We recommend screening for comorbid psychiatric disorders in children with enuresis and urinary incontinence. Further investigations in a larger group of children are necessary.

Phänotyp des visuellen Systems bei okulokutanem und okulärem Albinismus

In spite of albinism being one of the visual impairments which has been known for over a century, it has only been known for a few decades that albinism is correlated to severe cerebral morphological developmental alterations. The increasing knowledge about the role of melanin in the development and orientation of cerebral neurons not only renders more insight into albinism, but also a greater insight in the physiological neuronal and cerebral development in man. Concerning the morphological and visual phenotype there are new clinical findings which enlarge the known spectrum of albinism. In a representative group of 506 persons with oculocutaneous and ocular albinism who are in care at the Department of Ophthalmology at the University of Saarland (UKS), we present a staging of morphological findings of the iris, retinal pigment epithelium and macula, and of the optic nerve head which has been in use for 10 years. Albinism may present with a remarkably mild ocular phenotype and a near to normal functional phenotype. We present correlations between molecular genetic types of albinism, ocular phenotype and visual function. Of great importance concerning later visual acuity is the dysplasia of the optic nerve head (ONH), which is a frequent finding in albinism. The appearance of the ONH should always be included in any clinical description of an albinism patient. It is highly possible that due to a moderate phenotype there are still many patients who have not been diagnosed yet. Visual acuity of 30/20 to 20/20 and no nystagmus do not rule out albinism. In addition, when performing albino VEPs in phenotypically normal children with infantile strabismus, small ONHs, but normal visual acuity and no nystagmus, the classical atypical chiasmal crossing is sometimes found. Therefore, the number of persons having undiagnosed albinism is probably quite high, perhaps there even is a very broad transition zone from normal to albinotic.

Applications of Electron Microscopy in Medicine

Applications of electron microscopy, stand-alone and in combination with other microscopy methods, in diverse fields of biological and medical research as well as in medical diagnosis will be one of the main topics at the Microscopy Conference (MC 2007), to be held from 2 to 7 September 2007 at the Saarland University in Saarbrucken (Germany). This is the 33rd Conference of the Deutsche Gesellschaft fur Elektronenmikroskopie e. V. (DGE), which was initially conceived as a national meeting but has achieved in recent years a remarkable international character. Based on the experiences in past conferences, approximately 500 participants and over 20 exhibitors are expected in Saarbrucken. This conference is an important scientific highlight for the Saarland University, coinciding with the celebrations of the 60th anniversary of its foundation by the French administration in 1947. Information about the program, commercial exhibition, deadlines, etc. is available on the meeting homepage: http: www.uni-saarland.de/mc2007.

Melatonin preconditioning improves liver function after hemorrhagic shock

Department of Anesthesiology and Critical Care Medicine, Saarland University Hospital, Homburg, Germany

Norditerpenoid alkaloids from Delphinium cinereum

alimer@istanbul.edu.tr; 2) Marmara University, Faculty of Pharmacy, Department of Pharmacognosy, 34668 HaydarpasaIstanbul-Turkey; 3) Suleyman Demirel University, Faculty of Science and Literature, Department of Botany, Isparta-Turkey; 4) Saarland University, Institute of Pharmacognosy and Analytical Phytochemistry, P.O.151150, 6604 Saarbrucken-Germany. Published in Khimiya Prirodnykh Soedinenii, No. 3, pp. 301-302, May-June, 2007. Original article submitted February 14, 2006.

T-cell activation requires mitochondrial translocation towards the immunological synapse (87.32)

Abstract Activation of the adaptive immune response requires the interaction between antigen-presenting cells and T-cells. This cell-cell interaction, called the immunological synapse (IS), facilitates the activation of several T-cell receptor (TCR)-mediated signalling cascades including a rise in the cytosolic Ca2+ concentration ([Ca2+]i) through the activation of CRAC/ORAI1 channels. These channels are opened after depletion of intracellular Ca2+ stores and inactivated by the inflowing Ca2+ itself. We show by epifluorescence, 2-photon and total internal reflection microscopy, that a large fraction of mitochondria was moved to the immediate vicinity of the IS, a process highly dependent on the actin cytoskeleton. Mitochondrial movement to the IS was required to sustain the CRAC/ORAI1-mediated Ca2+ influx. Disruption of the actin cytoskeleton prevented mitochondrial movement and subsequent [Ca2+]i rises. The increased [Ca2+]i signals following interaction of the IS with mitochondria correlated with an enhanced T-cell proliferation. Our results show that actin cytoskeleton-mediated movement of mitochondria into the vicinity of the IS is required to sustain Ca2+ influx and permit efficient T-cell activation. This project was funded by the Deutsche Forschungsgemeinschaft (SFB 530 and GRK 845) and a grant from the Saarland University (HOMFOR).

Dynamic Hepatitis C Virus Genotypic and Phenotypic Changes in Patients Treated With the Protease Inhibitor Telaprevir

Telaprevir (VX-950), a hepatitis C virus (HCV) NS3.4A protease inhibitor, has shown strong antiviral activity in phase 1 clinical studies. Because of high levels of HCV replication and the low fidelity of HCV polymerase, selection of resistant isolates during therapy may occur. A highly sensitive sequencing method was developed in which approximately 80 clones/sample were analyzed to identify mutations in the NS3 protease catalytic domain in HCV genotype-1-infected patients dosed with 450 mg every 8 hours, 750 mg every 8 hours, or 1250 mg every 12 hours of telaprevir for 14 days. Mutations that confer low-level resistance (V36A/M, T54A, R155K/T, and A156S) and high-level resistance (A156V/T, 36+155, 36+156) to telaprevir were detected and correlated with telaprevir exposure and virologic response. Changes in the frequency of mutations after the end of dosing showed an inverse relationship between in vivo viral fitness and resistance. In the absence of telaprevir selective pressure the majority of resistant variants were replaced by wild-type virus within 3-7 months. Resistant HCV isolates are selected rapidly during therapy with the highly active protease inhibitor telaprevir. Combination therapy with pegylated interferon-alfa or other direct antiviral drugs seem mandatory to avoid developing resistance.

Impact of disease severity on outcome of antiviral therapy in treatment‐naïve patients with chronic hepatitis C†

We read with interest the article by Everson et al.1 The authors convincingly demonstrate that disease severity, as measured by both degree of liver fibrosis and platelet count, has a major impact on the rate of sustained viral response (SVR) following therapy with peginterferon α-2a and ribavirin among patients with advanced chronic HCV infection who have formerly not responded to interferon therapy. Previous reports indicate SVR rates of 43%–75% among treatment-naïve patients with cirrhosis and/or bridging fibrosis after combination therapy with peginterferon and ribavirin,2-4 with the highest response rates noted among patients infected with genotypes 2 or 3.3 The impact of portal hypertension with splenomegaly as reflected by the platelet count was, however, not reported in these studies. In a European HCV multicenter treatment study,5 we treated 270 treatment-naïve HCV-infected patients with peginterferon α-2a and ribavirin. Eighty of these patients had either bridging fibrosis (Ishak stage 3–4) or cirrhosis (Ishak stage 5–6) in their pretreatment liver biopsies. Their SVR rates with regards to genotype and baseline platelet counts and fibrosis stage are summarized in Table 1. Interestingly, patients infected with genotype 1 who had both bridging fibrosis and platelet count ≤125,000/mm3 achieved SVR, compared to none of 5 patients infected with genotype 1 who had cirrhosis and low platelet count (P = 0.0476, Fisher's exact test). Disease severity, however, had less impact on SVR among patients infected with genotypes 2 or 3. In conclusion, these findings support the results presented by Everson et al. that disease severity as measured by both fibrosis stage and platelet count is a major determinant of treatment outcome in patients with advanced chronic hepatitis C, especially those infected with genotype 1, even in patients previously naïve to treatment. Johan Westin*, Kristoffer Hellstrand*, Åsa Alsiö*, Magdalena Ydreborg*, Carlo Ferrari , Avidan U. Neumann , Jean-Michel Pawlotsky?, Solko W. Schalm?, Stefan Zeuzem**, Elke Verhey-Hart?, Martin Lagging*, * Department of Infectious Diseases, University of Göteborg, Sweden, Azienda Ospedaliera di Parma, Parma, Italy, Bar-Ilan University, Ramat-Gan, Israel, ? Hôpital Henri Mondor—Université Paris XII, Creteil, France, ? University Hospital Rotterdam Dijkzigt, Rotterdam, The Netherlands, ** Saarland University Hospital, Homburg/Saar, Germany.

Septic shock therapy: The recipe or the cook?

Department of Anesthesiology and Intensive Care Therapy, Friedrich-Schiller-University, Jena, Germany (Kortgen, Bauer) Department of Anesthesiology and Intensive Care Medicine, University of Saarland, Homburg/Saar, Germany (Niederprüm)

Selective cyclo-oxygenase-2 inhibition induces regression of autologous endometrial grafts by down-regulation of vascular endothelial growth factor-mediated angiogenesis and stimulation of caspase-3-dependent apoptosis

To investigate the effects of selective cyclo-oxygenase-2 (COX-2) inhibition on the angiogenesis and proliferation of endometrial grafts. Intravital fluorescence microscopic study. Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany. Syrian golden hamsters. Endometrial fragments were transplanted into dorsal skinfold chambers of Syrian golden hamsters. Animals were treated daily with the selective COX-2-inhibitor NS398; controls received the vehicle dimethyl sulfoxide only. Angiogenesis was analyzed for 2 weeks with the use of intravital fluorescence microscopy. Protein expression of vascular endothelial growth factor, proliferating cell nuclear antigen, caspase-3, and activated caspase-3 was measured by Western blot analysis. Histological sections were scanned for local microthrombosis. COX-2 inhibition induced a marked regression of endometrial grafts due to inhibition of angiogenesis, as indicated by significantly reduced microvessel density within grafts compared to controls. This effect was associated with a decreased expression of vascular endothelial growth factor. Moreover, COX-2 inhibition suppressed cell proliferation and induced apoptosis-associated caspase-3 expression. Interestingly, microthrombus formation could not be observed. Our study demonstrates that selective COX-2 inhibition induces regression of endometrial grafts by suppression of angiogenesis and stimulation of apoptosis. Accordingly, COX-2 inhibition may represent a novel therapeutic strategy for the treatment of endometriosis.

The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor-β and Mediates Stimulation of Collagen Gene Expression

Transforming growth factor-beta (TGF-beta) stimulates collagen synthesis and accumulation, and aberrant TGF-beta signaling is implicated in pathological organ fibrosis. Regulation of type I procollagen gene (COL1A2) transcription by TGF-beta involves the canonical Smad signaling pathway as well as additional protein and lipid kinases, coactivators, and DNA-binding transcription factors that constitute alternate non-Smad pathways. By using Affymetrix microarrays to detect cellular genes whose expression is regulated by Smad3, we identified early growth response factor-1 (EGR-1) as a novel Smad3-inducible gene. Previous studies implicated Egr-1 in cell growth, differentiation, and survival. We found that TGF-beta induced rapid and transient accumulation of Egr-1 protein and mRNA in human skin fibroblasts. In transient transfection assays, TGF-beta stimulated the activity of the Egr-1 gene promoter, as well as that of a minimal Egr-1-responsive reporter construct. Furthermore, TGF-beta enhanced endogenous Egr-1 interaction with a consensus Egr-1-binding site element and with GC-rich DNA sequences of the human COL1A2 promoter in vitro and in vivo. Forced expression of Egr-1 by itself caused dose-dependent up-regulation of COL1A2 promoter activity and further enhanced the stimulation induced by TGF-beta. In contrast, the TGF-beta response was abrogated when the Egr-1-binding sites of the COL1A2 promoter were mutated or deleted. Furthermore, Egr-1-deficient embryonic mouse fibroblasts showed attenuated TGF-beta responses despite intact Smad activation, and forced expression of ectopic EGR-1 in these cells could restore COL1A2 stimulation in a dose-dependent manner. Taken together, these findings identify Egr-1 as a novel intracellular TGF-beta target that is necessary for maximal stimulation of collagen gene expression in fibroblasts. The results therefore implicate Egr-1 in the profibrotic responses elicited by TGF-beta and suggest that Egr-1 may play a new and important role in the pathogenesis of fibrosis.

Complete long-term survival data from a trial of adjuvant chemotherapy vs control after radical cystectomy for locally advanced bladder cancer: Lehmann J, Franzaring L, Thüroff J, Wellek S, Stöckle M, Departments of Urology and Paediatric Urology, Saarland University, Homburg/Saar, Germany

Objectives To report the long-term follow-up of patients with locally advanced bladder cancer treated with either adjuvant combined chemotherapy with methotrexate, vinblastine, doxorubicin/epirubicin, and cisplatin (MVAC/MVEC) or no additional treatment after radical cystectomy, to examine various survival endpoints and factors associated with long-term survival. Patients and Methods Between May 1987 and December 1990, 49 patients undergoing radical cystectomy for locally advanced bladder cancer were randomized to observation only or adjuvant systemic chemotherapy with three cycles of MVAC/MVEC (methotrexate 30 mg/m 2 on day 1, 15 and 22; vinblastine 3 mg/m 2 on day 2, 15 and 22; doxorubicin 30 mg/m 2 or epirubicin 45 mg/m 2 on day 2; and cisplatin 70 mg/m 2 on day 2 of a 28-day cycle). Data were obtained for progression-free, overall and tumour-specific survival. Results In all, 23 patients were randomized to the control arm and 26 to treatment with adjuvant chemotherapy. The trial intended to accrue 100 patients but was stopped after an interim analysis showed a marked difference in progression free-survival when these first 49 patients had been randomized. The intent-to-treat analysis, including hazard ratios (HR) with 95% confidence intervals and point estimates at 10 years for control vs adjuvant chemotherapy, was as follows: progression-free survival HR 2.84 (1.46–5.54; P = 0.002), 13.0% vs 43.7%; overall survival HR 1.75 (0.95–3.23; P = 0.069), 17.4% vs 26.9%; and tumour-specific survival HR 2.52 (1.28–4.99; P = 0.007), 17.4% vs 41.7%, respectively. Conclusions The long-term results further support the use of adjuvant-combined chemotherapy with cisplatin-based regimens after radical cystectomy for locally advanced bladder cancer, as this significantly improves progression-free and tumour-specific survival.

PsyDok: Electronic full-text archive for psychological documents

The Saarland University and State Library (Saarlaendische Universitaets- und Landesbibliothek SULB) runs the Special Subject Collection Psychology which is part of an information system for the supra-regional literature supply in Germany. With the increasing opportunities for electronic information the following question emerged for the Special Subject Collection: how can a contribution to the availability and preservation of electronic documents particularly with regards to grey literature be made? Giving an answer SULB established the repository PsyDok in autumn 2002. PsyDok is one of the few subject-specific digital repositories in Germany. It is a registered data provider of the Open Archives Initiative (OAI) and certified by the German Initiative for Networkinformation (DINI), which developed a variety of standards digital repositories have to comply with to achieve this mark of quality. PsyDok offers many interfaces to disciplinary and multidisciplinary retrieval and information systems. The allocation of Uniform Resource Names (URN) guarantees persistent availability and citeability of the documents. Several services and mechanisms guarantee not only a maximum of visibility and a rapid and global scientific exchange and flow of information stored on PsyDok but also its long term availability and its scientific utilization. PsyDok fits the principles of "Open Access": Many different document types may be published, but PsyDok focuses particularly on diploma theses, dissertations, professorial dissertations and grey literature. Regarding aspects of visibility, information exchange and scientific utilization producers of scientific literature benefit from PsyDok.

News Briefs

German researchers have developed a chip that can render complex graphics in real time. The chip could allow individuals or small organizations to easily perform complex graphics work. Currently, they must either use a single computer, which takes a long time to produce sophisticated graphics, or they must spend the money to have a cluster of computers yield results quickly. Saarland University scientists have developed an algorithm that lets a chip rapidly perform ray tracing. This approach is an alternative to the rasterization techniques - used in most of today's graphics chips - that convert mathematical and digital information into a matrix of pixels. Ray tracing is a sophisticated approach that renders images in 3D environments by tracing the paths that light rays would take through a scene and calculating the reflection, refraction, or absorption that would occur when they hit an object. Unlike rasterization, ray tracing yields the information needed to compute shadows, reflections, and other effects necessary for high-quality images

Limit distributions of least squares estimators in linear regression models with vague concepts

Linear regression models with vague concepts extend the classical single equation linear regression models by admitting observations in form of fuzzy subsets instead of real numbers. They have lately been introduced (cf. [V. Krätschmer, Induktive Statistik auf Basis unscharfer Meßkonzepte am Beispiel linearer Regressionsmodelle, unpublished postdoctoral thesis, Faculty of Law and Economics of the University of Saarland, Saarbrücken, 2001; V. Krätschmer, Least squares estimation in linear regression models with vague concepts, Fuzzy Sets and Systems, accepted for publication]) to improve the empirical meaningfulness of the relationships between the involved items by a more sensitive attention to the problems of data measurement, in particular, the fundamental problem of adequacy. The parameters of such models are still real numbers, and a method of estimation can be applied which extends directly the ordinary least squares method. In another recent contribution (cf. [V. Krätschmer, Strong consistency of least squares estimation in linear regression models with vague concepts, J. Multivar. Anal., accepted for publication]) strong consistency and n -consistency of this generalized least squares estimation have been shown. The aim of the paper is to complete these results by an investigation of the limit distributions of the estimators. It turns out that the classical results can be transferred, in some cases even asymptotic normality holds.

Strong consistency of least-squares estimation in linear regression models with vague concepts

Linear regression models with vague concepts extend the classical single equation linear regression models by admitting observations in form of fuzzy subsets instead of real numbers. They have recently been introduced [cf. Krätschmer, Induktive statistik auf basis unscharfer meßkonzepte am beispiel linearer regressionsmodelle, Unpublished Habilitation Monograph, Faculty of Law and Economics of the University of Saarland, Saarbrücken, 2001] to improve the empirical meaningfulness of the relationship between the involved items by a more sensitive attention to the problems of data measurement, in particular the fundamental problem of adequacy. The parameters of such models are still real numbers, and a method of estimation can be applied which extends directly the ordinary least-squares method. This paper deals with some first asymptotic properties of estimators obtained by the method. Firstly, strong consistency will be shown, and secondly, the convergence rate will be investigated. The later result will be the starting point for a future study which will calculate the limit distributions of the estimators.

Model-independent calculation of ke0 values

Department of Anaesthesiology and Intensive Care Medicine, University of Saarland, Homburg/Saar, Germany

Effects of i.v. mannitol and hemofiltration on CD 14 expression density after cardiopulmonary-bypass

Department of Anesthesiology and Intensive Care Medicine, University of Saarland, Homburg/Saar, Germany

THE ET INTERVIEW: PROFESSOR JAN KMENTA

Jan Kmenta is the author of the internationally respected text The Elements of Econometrics [1] and co-editor of several books related to econometric model building. His published research over 40 years relates to many facets of econometric theory and practice, including the estimation of production functions, the evaluation of structural econometric models, and estimation in the face of missing data. This work has appeared in the leading journals of the profession. A 1966 paper [11] is of historical interest for being the second econometric model constructed of the Australian economy. In his work, through both constructive contributions and methodological critique, he has always sought to highlight and advance the evidently close connection between economics and econometrics.Kmenta was born on January 3, 1928, in Prague, the Czech Republic. He was educated at the Jirasek State Gymnasium in Prague (1939–47) and the Czech University of Technology in Prague (1947–49). At the University of Sydney (1952–55), Australia, he graduated with a Bachelor of Economics degree (First Class Honors). He obtained a Master of Arts degree (1959) and a Doctor of Philosophy degree (1964) from Stanford University with a doctoral dissertation entitled “Australian Postwar Immigration: An Econometric Study.” After teaching stints in Australia, Stanford, and Wisconsin, he taught at Michigan State from 1965 to 1973 and at the University of Michigan from 1973 to 1993. He is currently Professor Emeritus of Economics and Statistics, University of Michigan, and Visiting Professor, CERGE-EI, Charles University, Prague.His various academic awards and prizes include the Alexander von Humboldt Foundation Award for Senior U.S. Scientists, the Michigan Economic Society Best Professor Award, the Royal Economic Society Lecturer at the University of Leicester, and the Karel Englis Medal of the Academy of Sciences of the Czech Republic. He was awarded an honorary doctorate from the University of Saarland, Germany, and served as associate editor, Journal of the American Statistical Association (1973–1979 and 1985–1992), associate editor, Review of Economics and Statistics (1975–1992), and associate editor, Metrika (1981–1985). Kmenta was listed as 40th among all economists ranked by the total number of citations (Medoff 1989).This is an edited transcript of two tape-recorded interviews conducted with Professor Kmenta in Sydney on March 12, 2004, as he visited the University of New South Wales to present the seminar Econometrics: A Failed Science? I am indebted to one of Kmenta's former students, Eric Sowey, for suggesting this project and for his enthusiasm and support throughout.