Institute For Umweltmedizinische Forschung

Düsseldorf, Germany

Institute For Umweltmedizinische Forschung

Düsseldorf, Germany
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Breier J.M.,University of North Carolina at Chapel Hill | Gassmann K.,Institute For Umweltmedizinische Forschung | Kayser R.,TNO | Stegeman H.,TNO | And 3 more authors.
Neurotoxicology and Teratology | Year: 2010

In vitro, high-throughput methods have been widely recommended as an approach to screen chemicals for the potential to cause developmental neurotoxicity and prioritize them for additional testing. The choice of cellular models for such an approach will have important ramifications for the accuracy, predictivity and sensitivity of the screening assays. In recent years neuroprogenitor cells from rodents and humans have become more widely available and may offer useful models having advantages over primary neuronal cultures and/or transformed cell lines. To date, these models have been utilized in only a limited number of toxicity studies. This review summarizes the state of the science regarding stem and neuroprogenitor models that could be used for screening assays, provides researchers in this field with examples of how these cells have been utilized to date, and discusses the advantages, limitations and knowledge gaps regarding these models. Data are available from both rodent and human stem and neuroprogenitor cell models that indicate that these models will be a valid and useful tool for developmental neurotoxicity testing. Full potential of these models will only be achieved following advances in neurobiology that elucidate differentiation pathways more clearly, and following further evaluation of larger sets of developmentally neurotoxic and non-toxic chemicals to define the sensitivity and predictivity of assays based on stem or progenitor cell models.


Moors M.,Institute For Umweltmedizinische Forschung | Moors M.,Karolinska Institutet | Vudattu N.K.,Microbiology | Abel J.,Institute For Umweltmedizinische Forschung | And 7 more authors.
Genes and Immunity | Year: 2010

Alternative splicing of pre-mRNA increases proteomic diversity, a crucial mechanism in defining tissue identity. We demonstrate differentially spliced interleukin (IL)-7 in distinct anatomic areas in the adult, in developing human brains and in normal human neuronal progenitor (NHNP) cells. IL-7c (c, the canonical form spanning all six exons) or its variants IL-75, 4 or 4/5 were cloned and expressed as recombinant proteins. IL-7 and splice variants were able to shift the differentiation of NHNP cells as compared with the diluent control (P0.01) defined by anti-Β (III)-tubulin and glial fibrillary acidic protein expression, with different degrees (IL-7c4/5IL-75); IL-74 exhibited a significantly weaker potency. Differentiation was confirmed by transcriptome analysis of IL-7c-stimulated neural NHNP cells, resulting in 58 differentially expressed genes; some of these are involved in neural differentiation, for example, the developmentally regulated transcription factor krüppel-like factor 12, musashi 2, a translational regulator of cell fate or the sonic hedgehog receptor patch 1. This suggests that IL-7 influences neural development at a molecular level by participating in human brain architecture through glia cell formation: a paradigm that alternative splicing in cytokines, for example, for IL-7, has a physiological role in human organ development and progenitor cell differentiation. © 2010 Macmillan Publishers Limited. All rights reserved.


Berdel D.,Marien Hospital Wesel | Beckmann C.,Marien Hospital Wesel | Von Berg A.,Marien Hospital Wesel | Gappa M.,Marien Hospital Wesel | And 7 more authors.
Atemwegs- und Lungenkrankheiten | Year: 2010

Background: Lung function testing plays an important role in the diagnosis in management of respiratory diseases. During childhood and adolescence, there is continuous growth of both, lung parenchyma and airways; it is mandatory that test results are interpreted in relation to a normal population of similar age and height. The quality of the reference data may influence interpretation of clinical lung function data. Currently, old reference data obtained during the 70s and 80s are commonly used, although there has been considerable change in somatic growth and development over the last decades. Aims: Collection of spirometric reference data in girls and boys between 4 and 17 years of age. Methods: Measurements were performed in randomly selected schools and kindergartens from 3 regions in Germany (Wesel, Düsseldorf, Hannover). The ISAAC questionnaire was used to identify children with pre-existing respiratory diseases. Trained technicians performed spirometry under field conditions, according to international standards, using the the EasyOne spirometer (ndd Medizintechnik AG, Zürich, Schweiz). All data were stored in a central data base and visually inspected for quality control before they were included into the final analysis. Results: Between August 2007 and June 2009, n = 5,397 children and adolescents between 4 and 18 years of age performed spirometry, of which n = 3,228 measurements were technically acceptable. Of these, n = 1,941 healthy subjects remained for final analysis. © 2010 Dustri-Verlag Dr. Karl Feistle.


Berdel D.,Marien Hospital Wesel | Beckmann C.,Marien Hospital Wesel | Von Berg A.,Marien Hospital Wesel | Gappa M.,Marien Hospital Wesel | And 7 more authors.
Pravention und Rehabilitation | Year: 2010

Background: Lung function testing plays an important role in the diagnosis in management of respiratory diseases. During childhood and adolescence, there is continuous growth of both, lung parenchyma and airways; it is mandatory that test results are interpreted in relation to a normal population of similar age and height. The quality of the reference data may influence interpretation of clinical lung function data. Currently, old reference data obtained during the 70s and 80s are commonly used, although there has been considerable change in somatic growth and development over the last decades. Aims: Collection of spirometric reference data in girls and boys between 4 and 17 years of age. Methods: Measurements were performed in randomly selected schools and kindergartens from 3 regions in Germany (Wesel, Dusseldorf, Hannover). The ISAAC questionnaire was used to identify children with pre-existing respiratory diseases. Trained technicians performed spirometryunderfield conditions, according to international standards, using the the EasyOne spirometer (ndd Medizintechnik AG, Zurich, Schweiz). All data were stored in a central data base and visually inspected for quality control before they were included into the final analysis. Results: Between August 2007 and June 2009, n = 5,397 children and adolescents between 4 and 18 years of age performed spirometry, of which n = 3,228 measurements were technically acceptable. Of these, n = 1,941 healthy subjects remained for final analysis. © 2010 Dustri-Verlag Dr. Karl Feistle ISSN 0937-552X.


Huls A.,Institute For Umweltmedizinische Forschung | Kramer U.,Institute For Umweltmedizinische Forschung | Gappa M.,Marienhospital | Muller-Brandes C.,Abteilung fur Anasthesiologie und Intensivmedizin | And 7 more authors.
Pneumologie | Year: 2013

Background: Comparing children's lung function with reference values is important for diagnosing respiratory diseases. The values by Zapletal et al., commonly used nowadays, are not appropriate for the current stage of children's development. We have now developed new reference values and a lower limit of normal (LLN) for children in Germany, divided into small-range age and height categories. Material and Methods: We examined 4- to 18-year-old children in 3 German communities under field conditions. 1943 children were healthy and had a visually acceptable lung function which also fulfilled international quality criteria. We used the regression model LMS, which was introduced by Stanojevic and Quanjer in this context. Results: There were significant differences between the measured lung function and the predicted values according to Zapletal et al. The lung function did not only depend on the child's height, but also in a non-linear way on the age. The variation coefficient did not depend on age. Conclusions: To avoid diagnostic errors, the currently often used reference values according to Zapletal et al. should no longer be used. The non-linear dependence on age corresponds to the recently published results by Stanojevic and Quanjer. © Georg Thieme Verlag KG Stuttgart · New York.


Gerber P.A.,Heinrich Heine University Düsseldorf | Hevezi P.,University of California at Irvine | Buhren B.A.,Heinrich Heine University Düsseldorf | Martinez C.,Heinrich Heine University Düsseldorf | And 6 more authors.
PLoS ONE | Year: 2013

Through bioinformatics analyses of a human gene expression database representing 105 different tissues and cell types, we identified 687 skin-associated genes that are selectively and highly expressed in human skin. Over 50 of these represent uncharacterized genes not previously associated with skin and include a subset that encode novel secreted and plasma membrane proteins. The high levels of skin-associated expression for eight of these novel therapeutic target genes were confirmed by semi-quantitative real time PCR, western blot and immunohistochemical analyses of normal skin and skin-derived cell lines. Four of these are expressed specifically by epidermal keratinocytes; two that encode G-protein-coupled receptors (GPR87 and GPR115), and two that encode secreted proteins (WFDC5 and SERPINB7). Further analyses using cytokine-activated and terminally differentiated human primary keratinocytes or a panel of common inflammatory, autoimmune or malignant skin diseases revealed distinct patterns of regulation as well as disease associations that point to important roles in cutaneous homeostasis and disease. Some of these novel uncharacterized skin genes may represent potential biomarkers or drug targets for the development of future diagnostics or therapeutics. © 2013 Gerber et al.


Stabenow D.,University of Bonn | Frings M.,University of Bonn | Truck C.,University of Bonn | Gartner K.,University of Bonn | And 8 more authors.
Hepatology | Year: 2010

In vivo evaluation of CD8 T cell effector (cytotoxic T lymphocyte [CTL]) function in peripheral organs such as the liver is currently not possible but would greatly improve our understanding of local immune regulation, because simple determination of antigen-specific CTL numbers does not predict the outcome of immune responses. In particular, measurement of alanine aminotransferase serum levels is not sensitive enough to detect T cell immunity against low numbers of target hepatocytes. We developed a procedure that detects virus-specific effector function of CTLs in the liver after simultaneous adenoviral transfer of reporter and immune target genes into hepatocytes, followed by bioluminescence imaging of reporter genes. Bioluminescence imaging enabled detection of as few as 10,000 infected hepatocytes in vivo, and even more importantly, quantification of antiviral effector function of as few as 50,000 CTLs. Conclusion: Our results provide evidence that low numbers of antigen-specific CTLs are sufficient to control viral gene expression and eliminate viral infection from hepatocytes. The experimental system established here is a highly sensitive method to simultaneously detect viral infection of hepatocytes and to quantify antiviral CTL function in the liver in vivo and will help in characterizing principles of hepatic immune regulation. Copyright © 2010 by the American Association for the Study of Liver Diseases.


Gotic M.,Ruder Boskovic Institute | Jurkin T.,Ruder Boskovic Institute | Music S.,Ruder Boskovic Institute | Unfried K.,Institute For Umweltmedizinische Forschung | And 2 more authors.
Journal of Molecular Structure | Year: 2013

Mn-oxide microstructures were investigated by XRD, FT-IR, TEM, FE SEM and EDS techniques. The oxidation of the aqueous solutions of manganese (II) chloride by hydrogen peroxide was employed to synthesize pure 20-30-nm pseudospherical hausmannite (Mn3O4) nanoparticles and manganite (γ-MnOOH) nanowires. The α-MnO2 nanotubes and nanorods were hydrothermally synthesized starting from a KMnO4 precursor, then modified with the addition of divalent metal cations Mn 2+, Cu2+, Ni2+ and Fe2+. The modification with Mn2+ induced the transformation of α-MnO 2 nanotube into 3D β-MnO2 (pyrolusite) prismatic nanoparticles, whereas the low-crystalline α-MnO2 nanorods were transformed into disk-like γ-MnO2 nanoparticles. The modification with Cu2+ and Ni2+ induced the structural transformation of α-MnO2 into a mixture of MnO2 polymorphs. The modification with Cu2+ decreased, whereas the modification with Ni2+ improved the crystallinity of MnO2. The modification with Fe2+ induced the structural transformation of α-MnO2 into γ-MnO2, a decrease in crystallinity and the segregation of α-Fe2O3 (hematite). Thus the modification of MnO2 with Fe2+ (Mn2+) divalent metal cations that can be oxidized into Fe 3+ (Mn4+) by a KMnO4 precursor differs significantly in comparison with, in this case, non-oxidizable cations such as Cu2+ and Ni2+. On the other hand, the advantage that the modification of MnO2 with Mn2+ produces chemically identical compounds with different morphology can be used as a model system for toxicity studies. In this work the preliminary measurements of intracellular oxidative stress in epithelial cells induced by manganese oxide nanoparticles are reported. © 2012 Elsevier B.V. All rights reserved.


Weissenberg A.,Institute For Umweltmedizinische Forschung | Sydlik U.,Institute For Umweltmedizinische Forschung | Peuschel H.,Institute For Umweltmedizinische Forschung | Schroeder P.,Institute For Umweltmedizinische Forschung | And 4 more authors.
Free Radical Biology and Medicine | Year: 2010

Cell-membrane-dependent proliferative signal transduction activated by ultrafine carbon particles in lung epithelial cells involves the specific induction of Akt and ERK1/2 phosphorylation. Particle-induced generation of reactive oxygen species (ROS) and oxidative stress are regarded as initial molecular mechanisms leading to the induction of diverse cellular responses. Therefore, we aimed to analyze the ROS dependence of the induced activation of the Akt/ERK1/2 signaling pathway upon exposure to ultrafine particulate matter (UPM). For this, ultrafine carbon black (ufCB) and ferric sulfate (FS) were used as a model representing the carbonaceous core and a nonparticulate Fenton-reactive transition metal salt often found in combustion-derived UPM. Cell-free as well as intracellular particle-induced ROS generation was assessed and related to the induced Akt and ERK1/2 phosphorylation by inhibiting oxidative stress with catalase, superoxide dismutase, and N-acetylcysteine. We show here that the activation of this signal transduction pathway was mainly due to intracellular, rather than extracellular, ROS production induced by both ufCB and FS. Further inhibitor studies on the role of cell membrane receptors pointed to the epidermal growth factor receptor as a common mediator for particle- as well as transition metal-induced signaling, whereas integrin-dependent Akt and ERK1/2 activation seems to be particle-specific. © 2010 Elsevier Inc.


PubMed | Institute For Umweltmedizinische Forschung
Type: Journal Article | Journal: Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete | Year: 2010

For many decades, cutaneous biology research has primarily focused on the dermis and epidermis. In recent years the subcutaneous far has attracted the attention of basic science, cosmetology and industry. Numerous new approaches are in the process of development, enabling us to better understand assembly, differentiation and function of adipose tissue. To understand these developments a background in the cellular and molecular basics of adipose tissue is indispensable. This state-of the art article provides the needed information.

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