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PubMed | Vivotecnia Research S.L., AnaPath GmbH, EPL Inc., Olympus Schweiz AG and 2 more.
Type: Journal Article | Journal: International journal of toxicology | Year: 2014

Sperm analysis is one of the end points in reproductive toxicology studies. Different methods for quantitative sperm analysis have been described. For qualitative morphological sperm analysis, either such techniques or smears of sperm and histological sperm staging are in use. Any of these methods provides morphological results on a light microscopy level. Laser scanning microscopy is a technique using a focused laser for scanning an object. The Olympus 3D Laser Scanning Microscope LEXT OLS4000 with optional possibilities of differential interference contrast provides a microscopic method for visualizing microasperities, which are far beyond the resolving power of a typical light or laser microscope. This technique was applied to sperm of mice, rats, rabbits, and cynomolgus monkeys at magnifications up to 17 090. The obtained images are comparable to those of a scanning electron microscope under relatively low-power magnifications. Measurements on sperm parameters were taken by an integrated image analysis software tool. Abnormalities were easily detectable.


Geletneky K.,University of Heidelberg | Geletneky K.,German Cancer Research Center | Leoni A.-L.,BSL BIOSERVICE Scientific Laboratories GmbH | Pohlmeyer-Esch G.,KALEIDIS Consultancy in Histopathology | And 11 more authors.
Comparative Medicine | Year: 2015

Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated. Copyright 2015 by the American Association for Laboratory Animal Science.


Geiser M.,University of Bern | Quaile O.,University of Bern | Wenk A.,Helmholtz Center Munich | Wigge C.,University of Bern | And 9 more authors.
Particle and Fibre Toxicology | Year: 2013

Background: Inhalative nanocarriers for local or systemic therapy are promising. Gold nanoparticles (AuNP) have been widely considered as candidate material. Knowledge about their interaction with the lungs is required, foremost their uptake by surface macrophages and epithelial cells.Diseased lungs are of specific interest, since these are the main recipients of inhalation therapy. We, therefore, used Scnn1b-transgenic (Tg) mice as a model of chronic obstructive pulmonary disease (COPD) and compared uptake and localization of inhaled AuNP in surface macrophages and lung tissue to wild-type (Wt) mice.Methods: Scnn1b-Tg and Wt mice inhaled a 21-nm AuNP aerosol for 2 h. Immediately (0 h) or 24 h thereafter, bronchoalveolar lavage (BAL) macrophages and whole lungs were prepared for stereological analysis of AuNP by electron microscopy.Results: AuNP were mainly found as singlets or small agglomerates of ≤ 100 nm diameter, at the epithelial surface and within lung-surface structures. Macrophages contained also large AuNP agglomerates (> 100 nm). At 0 h after aerosol inhalation, 69.2±4.9% AuNP were luminal, i.e. attached to the epithelial surface and 24.0±5.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 35.3±32.2% AuNP were on the epithelium and 58.3±41.4% in macrophages. The percentage of luminal AuNP decreased from 0 h to 24 h in both groups. At 24 h, 15.5±4.8% AuNP were luminal, 21.4±14.2% within epithelial cells and 63.0±18.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 9.5±5.0% AuNP were luminal, 2.2±1.6% within epithelial cells and 82.8±0.2% in macrophages. BAL-macrophage analysis revealed enhanced AuNP uptake in Wt animals at 0 h and in Scnn1b-Tg mice at 24 h, confirming less efficient macrophage uptake and delayed clearance of AuNP in Scnn1b-Tg mice.Conclusions: Inhaled AuNP rapidly bound to the alveolar epithelium in both Wt and Scnn1b-Tg mice. Scnn1b-Tg mice showed less efficient AuNP uptake by surface macrophages and concomitant higher particle internalization by alveolar type I epithelial cells compared to Wt mice. This likely promotes AuNP depth translocation in Scnn1b-Tg mice, including enhanced epithelial targeting. These results suggest AuNP nanocarrier delivery as successful strategy for therapeutic targeting of alveolar epithelial cells and macrophages in COPD. © 2013 Geiser et al.; licensee BioMed Central Ltd.


PubMed | DMPKORE, IASON Consulting, University of Heidelberg, ORYX GmbH and Co KG and 3 more.
Type: Journal Article | Journal: Comparative medicine | Year: 2015

Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated.


PubMed | DMPKORE, IASON Consulting, University of Heidelberg, ORYX GmbH and Co KG and 3 more.
Type: Journal Article | Journal: Comparative medicine | Year: 2015

The autonomous parvovirus H1 (H1PV) is transmitted in rodent populations. The natural host is the rat, in which H1PV infection is pathogenic only in fetuses and newborns. H1PV infection of human cancer cells leads to strong oncolytic effects in preclinical models. In preparation for a clinical trial of H1PV injection in patients with malignant brain tumors, H1PV had to be prepared to Good Manufacturing Practice standards, including extensive toxicology testing in rats. Because the trial involves direct intracerebral injection of H1PV into the tumor and around the resection cavity, possible toxicity to CNS tissue had to be investigated. In addition, quantitative blood levels and the tissue distribution of H1PV after single intracerebral or intravenous injection were measured. Direct injection of H1PV into rat brain at 3 dose levels (maximum, 7.96 107 pfu) did not cause any macroscopic or histologic pathology. Furthermore, H1PV infection of the brain did not alter central or autonomous nervous system function. H1PV DNA was detected in almost all organs at 6 h, 48 h, and 14 d after intravenous and intracerebral injection, with the highest levels in liver and spleen. H1PV concentrations in most organs were similar after intravenous and intracerebral injection, indicating high permeability of the blood-brain barrier for this small virus. The current results demonstrate wide organ distribution of H1PV after intravenous or intracerebral injection, confirm that H1PV is nonpathogenic in adult rats even after direct injection into the brain, and form the basis for the ongoing ParvOryx01 clinical trial.


Dolan L.C.,Burdock Group | Hofman-Huther H.,BSL BIOSERVICE Scientific Laboratories GmbH | Amann N.,Wacker Chemie AG
BMC Research Notes | Year: 2014

Background: Hydroxytyrosol is naturally found in olives, olive oil and wine, and is consumed as part of a normal diet.The substance may have utility as a preservative in a wide variety of foods due to its antioxidant, antimicrobial and amphipathic properties.The potential for hydroxytyrosol to cause chromosome aberrations in vitro had been tested previously, with positive results at high concentrations. An OECD Guideline 475 study (mammalian bone marrow chromosome aberration test) was conducted in rats with the oral limit dose of 2000 mg/kg bw to determine whether hydroxytyrosol is a clastogen in vivo. Results: The oral limit dose of 2000 mg/kg hydroxytyrosol was well tolerated by most rats; however, some rats exhibited clinical signs that abated within 24 hours. Treatment with hydroxytyrosol did not significantly enhance the number of aberrant cells or the mitotic index 24 or 48 hours post-dose.The positive control (cyclophosphamide) induced the expected increase in chromosomal aberrations and a decrease in the mitotic index, confirming the validity of the assay. Conclusion: An oral limit dose of 2000 mg/kg hydroxytyrosol does not induce chromosome aberrations in bone marrow cells of the rat. Accordingly, hydroxytyrosol is not a clastogen in vivo. © 2014 Dolan et al.


Schleh C.,BSL BIOSERVICE Scientific Laboratories GmbH | Leoni A.-L.,BSL BIOSERVICE Scientific Laboratories GmbH
Journal of Occupational Medicine and Toxicology | Year: 2013

Exposure at the working place to various substances, that may affect semen quality is possible and should be investigated in detail. One appropriate method for this is computer-assisted sperm analysis (CASA) which offers multiple benefits in comparison to manual evaluation. However, several pitfalls exist, which make the evaluation of data obtained from CASA difficult to interpret. In the present commentary, we focus on these problems, show some examples, and try to define minimum standards which should be taken into consideration whenever working with computer-assisted sperm analysis. © 2013 Schleh and Leoni; licensee BioMed Central Ltd.


Lynch B.,Intertek | Lau A.,Intertek | Baldwin N.,Intertek | Hofman-Huther H.,BSL Bioservice Scientific Laboratories GmbH | And 2 more authors.
Food and Chemical Toxicology | Year: 2013

Hoodia parviflora is being developed commercially for use in weight loss food and dietary supplement products. Its effects are ascribed to a number of glycosides that have been shown to be present in plant extracts from several Hoodia species, the best known of which is H. gordonii. H. parviflora has been identified as an alternative to H. gordonii, and, as part of the process to develop H. parviflora, in vitro genotoxicity tests, as recommended by recent European Food Safety Authority guidance, were conducted on a dried powder preparation of H. parviflora aerial parts. The preparation was tested for reverse mutation at doses up to 5,000 μg/plate in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, and in Escherichia coli WP2 uvrA TA, both in the presence and in the absence of an exogenous source of metabolic activation (rat liver S9). In addition, the dried powder was evaluated in an in vitro cytotoxicity chromosome aberration assay using human lymphocytes. Test conditions included both a 4 (up to 2500 μg/mg) and 44-h exposure period (up to 1000 μg/mg) and the incorporation of an exogenous source of metabolic activation (4-h exposure only). H. parviflora dried powder was non-genotoxic in both in vitro assays. © 2013 Elsevier Ltd.


Ahuja V.,Charité - Medical University of Berlin | Ahuja V.,BSL Bioservice Scientific Laboratories GmbH | Platzek T.,German Federal Institute for Risk Assessment | Fink H.,Free University of Berlin | And 2 more authors.
Archives of Toxicology | Year: 2010

Disperse dyes, which are suitable for dyeing synthetic fibres, are responsible for the great majority of allergic contact dermatitis (ACD) cases to textile dyes. The aim of the present study was to investigate the sensitising potential of various disperse dyes using a biphasic protocol of the local lymph node assay (LLNA). Briefly, mice were shaved over a surface of approximately 2 cm2 on their backs and treated using a "sensitisation-challenge protocol". The shaved surface was treated once daily on days 1-3 with 50 μl of the test solution. Animals remained untreated on days 4-14. On days 15-17, mice were treated with 25 μl of the test solution on the dorsum of both ears. Mice were killed on day 19 with deep CO2 anaesthesia, the lymph nodes prepared and various end points, such as ear thickness, ear punch weight, lymph node weight, lymph node cell count and the proportion of various lymphocyte subpopulations, were determined by flow cytometry. The results were compared to control group treated with the vehicle alone. Our results showed that almost all of the tested textile dyes caused a significant increase in lymph node cell count and lymph node weight. We also observed an increase in ear thickness and ear punch weight in most of the concentrations tested for various textile dyes. We observed a decrease in CD4+ and CD8+ cells and an increase in CD19+, CD45+ and CD45+/1A+ cells in most of the cases, which is characteristic for allergens. The CD4+/CD69+ cells increased in only few experiments mainly with Disperse Blue 124 and Disperse Blue 106. Based on our results, the disperse dyes could be arranged in four groups on the basis of their sensitising potency in the following decreasing order (in parenthesis: lowest concentration causing a significant increase in lymph node cell number): group 1, strong: Disperse Blue 124 and Disperse Blue 106 (0.003%); group 2, moderate: Disperse Red 1 and Disperse Blue 1 (3%); group 3, weak: Disperse Orange 37 and Disperse Blue 35 (10%); and group 4, very weak: Disperse yellow 3 and Disperse Orange 3 (increase at 30% or no increase at 30%). In conclusion, our study shows that the biphasic LLNA protocol was proficient enough to study the sensitisation potential of tested textile dyes and provides data allowing to discriminate them according to their potency. © 2010 Springer-Verlag.


PubMed | BSL BIOSERVICE Scientific Laboratories GmbH
Type: Editorial | Journal: Journal of occupational medicine and toxicology (London, England) | Year: 2013

Exposure at the working place to various substances, that may affect semen quality is possible and should be investigated in detail. One appropriate method for this is computer-assisted sperm analysis (CASA) which offers multiple benefits in comparison to manual evaluation. However, several pitfalls exist, which make the evaluation of data obtained from CASA difficult to interpret. In the present commentary, we focus on these problems, show some examples, and try to define minimum standards which should be taken into consideration whenever working with computer-assisted sperm analysis.

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