Untersuchungen zum Metabolismus von Vitamin A / Retinoiden im Hinblick auf eine Risikoabschätzung ihrer teratogenen Wirkung beim Menschen

Vitamin-A-Alkohol (Retinol) und seine Metaboliten sind essentiell für verschiedene physiologische Prozesse (Sehvorgang, Reproduktion, Wachstum und Differenzierung von Zellen, embryonale Entwicklung). Auf der anderen Seite besteht beim Menschen der Verdacht, daß die Aufnahme hoher Vitamin-A-Mengen während der Schwangerschaft mit einem erhöhten Risiko für embryonale Mißbildungen verbunden ist. Verschiedene nationale und internationale Organisationen haben Empfehlungen zur Vitamin-A-Supplementierung schwangerer Frauen herausgegeben. Die empfohlene tägliche Aufnahme liegt bei 2.000-3.000 IU Vitamin A, ein erhöhtes Risiko ist auf Basis von epidemiologischen Daten bereits bei einer täglicher Aufnahme von 10.000-25.000 IU zu befürchten (Rosa 1993, Rothman et al. 1995). Nachdem in Großbritannien im Jahre 1990 erhöhte Vitamin-A-Gehalte in Schlachttierlebern festgestellt wurden, haben auch durch das Bundesinstitut für gesundheitlichen Verbraucherschutz und Veterinärmedizin angestrebte Untersuchungen ergeben, daß die Vitamin-A-Gehalte in Schlachttierlebern deutscher Provenienz deutlich über den in den einschlägigen Nährwerttabellen angegebenen Werten lagen (Anonymus 1995). Eine Lebermahlzeit kann demzufolge mit der Aufnahme der 10- bis 30-fachen Menge des Risikogrenzwertes einhergehen. Die teratogene Wirkung von Vitamin A, aber auch seine essentiellen Funktionen werden zum größten Teil durch den Metabolismus zu aktiven Retinoiden vermittelt. Retinsäuren, Oxidationsprodukte des Vitamin-A-Alkohols, spielen hierbei eine zentrale Rolle, da sie als an die nukleären Transkriptionsfaktoren RAR und RXR binden und die Expression bestimmter Gene beeinflussen können.Vitamin A alcohol (retinol) and its metabolites (retinoids) are essential for a variety of physiological processes, including vision, reproduction, growth and differentiation of cells, and embryonic development. On the other hand, the uptake of excessive amounts of vitamin A during human pregnancy is suspected to be correlated with an increased risk for embryonic malformations. Various national and international authorities have published recommendations concerning vitamin A supplementation during pregnancy. The recommended daily allowance was estimated to be 2000-3000 International Units (IU) Vitamin A (corresponding to 0.6-0.9 mg Retinol). On the basis of epidemiologic data, an increased risk seems to exist at a daily intake of 10000-25000 IU. An average liver meal can contain 10- to 30-fold higher amounts of vitamin A than the recommended daily intake. The teratogenic effects of vitamin A but also its essential functions are mediated mainly by active metabolites of vitamin A. Retinoic acid isomers, the major oxidation products of vitamin A, play a central role, since they are ligands of the nuclear transcription factors RAR and RXR. These transcription factors have an influence on the expression of a variety of genes. To date, only one study has addressed the question, wether consumption of a vitamin A rich meal during pregnancy may be associated with a teratogenic risk. Buss et al. (1995) compared kinetic profiles and concentrations of retinol and its metabolites in human plasma after giving vitamin A as supplement or liver (50 mg and 150 mg vitamin A, respectively). They found that retinyl ester concentrations in plasma were similarly increased, while the concentrations of the biologically active metabolite all-trans-retinoic acid (all-trans-RA) were up to 20-fold higher after supplementation as compared to liver consumption. Based on this difference, the authors concluded that liver consumption is not of equivalent teratogenic potential as

Application of a Rapid and Integrated Analysis System (RIAS) as a High-Throughput Processing Tool for In Vitro ADME Samples by Liquid Chromatography/Tandem Mass Spectrometry

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Over the past decade, drug discovery programs have started to address the optimization of key ADME properties already at an early stage of the process. Hence, analytical chemists have been confronted with tremendously rising sample numbers and have had to develop methodologies accelerating quantitative liquid chromatography/tandem mass spectrometry (LC/MS/MS). This article focuses on the application of a generic and fully automated LC/MS/MS, named Rapid and Integrated Analysis System (RIAS), as a high-throughput platform for the rapid quantification of drug-like compounds in various in vitro ADME assays. Previous efforts were dedicated to the setup and feasibility study of a workflow-integrated platform combining a modified high-throughput liquid handling LC/MS/MS system controlled by a customized software interface and a customized data-processing and reporting tool. Herein the authors present an extension of this previously developed basic application to a broad set of ADME screening campaigns, covering CYP inhibition, Caco-2, and PAMPA assays. The platform is capable of switching automatically between various ADME assays, performs MS compound optimization if required, and provides a speed of 8 s from sample to sample, independently of the type of ADME assay. Quantification and peak review are adopted to the high-throughput environment and tested against a standard HPLC-ESI technology

Ambulante Fachversorgung: Wie sieht ambulante Fachversorgung international aus?

Die ambulante Fachversorgung ist über die einzelnen Länder hinweg heterogen gestaltet. In vielen Ländern werden fachärztliche Leistungen nur in Krankenanstalten oder Behandlungszentren angeboten, wobei in einem Teil der Länder dort auch selbständige Ärzt*innen tätig sein können. Die Primärversorgung ist dabei in vielen Ländern umfassender und beinhaltet teilweise bei uns von Fachärzt*innen erbrachte Leistungen. Fast in allen Ländern sehen wir ein Gatekeeping zur ambulanten Fachversorgung, und überall wird versucht, mehr Leistungen in den ambulanten Bereich zu verschieben. Wesentliche Themen sind dabei die Integration der Versorgung sowie die digitale Vernetzung, welche die Integration und Ambulantisierung unterstützen soll. Die Integration der Versorgung spiegelt sich auch in Bezahlsystemen wider, die stärker sektorenübergreifend und auf Qualität ausgerichtet sind

Measuring Information Transfer

An information theoretic measure is derived that quantifies the statistical coherence between systems evolving in time. The standard time delayed mutual information fails to distinguish information that is actually exchanged from shared information due to common history and input signals. In our new approach, these influences are excluded by appropriate conditioning of transition probabilities. The resulting transfer entropy is able to distinguish driving and responding elements and to detect asymmetry in the coupling of subsystems.Comment: 4 pages, 4 Figures, Revte

The Grizzly, November 29, 2007

Goodbye Scripted TV: Writer\u27s Guild Takes a Stand • Shooting for the Cure: Teams Raise Money for Coalition • Dr. von Schlegell Discusses Islamic Thought, Movements • Jazzman\u27s Cafe Gets Into the Holiday Spirit at Ursinus • A New STAR on Campus • Moritomo: Konichiwa, Hai Hai! • Focus the Nation: Cornucopia of Action and Awareness • Book Review: A Natural History of the Senses • Opinions: Giving Thanks This Holiday; UN Considers Ban on Human Cloning • Field Hockey Frenzy • Men\u27s Basketball Preview • Bears Take the Path Less Traveledhttps://digitalcommons.ursinus.edu/grizzlynews/1751/thumbnail.jp

The Grizzly, September 6, 2007

The Car Share Revolution • Ursinus Initiates Film Fest • Facilities Makes Renovation Waves • Stopping the Stork: Emergency Contraception • A Look at The Rising Suns • Spotlight on Sustain UC • Book Review: What is What by Dave Eggers • Opinions: With Gonzales\u27 Resignation, Exodus Continues; Harry Potter and the Satanic Pre-Teens; Don\u27t Paint Over Our Freedom of Expression • Intramural Intervention • Field Hockey Flavor • Football Sets the Bar High with 28-0 Rout of LaSalle • Fight for the Tophttps://digitalcommons.ursinus.edu/grizzlynews/1741/thumbnail.jp

The Tumorigenicity of Mouse Embryonic Stem Cells and In Vitro Differentiated Neuronal Cells Is Controlled by the Recipients' Immune Response

Embryonic stem (ES) cells have the potential to differentiate into all cell types and are considered as a valuable source of cells for transplantation therapies. A critical issue, however, is the risk of teratoma formation after transplantation. The effect of the immune response on the tumorigenicity of transplanted cells is poorly understood. We have systematically compared the tumorigenicity of mouse ES cells and in vitro differentiated neuronal cells in various recipients. Subcutaneous injection of 1×106 ES or differentiated cells into syngeneic or allogeneic immunodeficient mice resulted in teratomas in about 95% of the recipients. Both cell types did not give rise to tumors in immunocompetent allogeneic mice or xenogeneic rats. However, in 61% of cyclosporine A-treated rats teratomas developed after injection of differentiated cells. Undifferentiated ES cells did not give rise to tumors in these rats. ES cells turned out to be highly susceptible to killing by rat natural killer (NK) cells due to the expression of ligands of the activating NK receptor NKG2D on ES cells. These ligands were down-regulated on differentiated cells. The activity of NK cells which is not suppressed by cyclosporine A might contribute to the prevention of teratomas after injection of ES cells but not after inoculation of differentiated cells. These findings clearly point to the importance of the immune response in this process. Interestingly, the differentiated cells must contain a tumorigenic cell population that is not present among ES cells and which might be resistant to NK cell-mediated killing

Protection of Visual Functions by Human Neural Progenitors in a Rat Model of Retinal Disease

BACKGROUND: A promising clinical application for stem and progenitor cell transplantation is in rescue therapy for degenerative diseases. This strategy seeks to preserve rather than restore host tissue function by taking advantage of unique properties often displayed by these versatile cells. In studies using different neurodegenerative disease models, transplanted human neural progenitor cells (hNPC) protected dying host neurons within both the brain and spinal cord. Based on these reports, we explored the potential of hNPC transplantation to rescue visual function in an animal model of retinal degeneration, the Royal College of Surgeons rat. METHODOLOGY/PRINCIPAL FINDINGS: Animals received unilateral subretinal injections of hNPC or medium alone at an age preceding major photoreceptor loss. Principal outcomes were quantified using electroretinography, visual acuity measurements and luminance threshold recordings from the superior colliculus. At 90–100 days postnatal, a time point when untreated rats exhibit little or no retinal or visual function, hNPC-treated eyes retained substantial retinal electrical activity and visual field with near-normal visual acuity. Functional efficacy was further enhanced when hNPC were genetically engineered to secrete glial cell line-derived neurotrophic factor. Histological examination at 150 days postnatal showed hNPC had formed a nearly continuous pigmented layer between the neural retina and retinal pigment epithelium, as well as distributed within the inner retina. A concomitant preservation of host cone photoreceptors was also observed. CONCLUSIONS/SIGNIFICANCE: Wild type and genetically modified human neural progenitor cells survive for prolonged periods, migrate extensively, secrete growth factors and rescue visual functions following subretinal transplantation in the Royal College of Surgeons rat. These results underscore the potential therapeutic utility of hNPC in the treatment of retinal degenerative diseases and suggest potential mechanisms underlying their effect in vivo