Model-Informed Target Morning 17α-Hydroxyprogesterone Concentrations in Dried Blood Spots for Pediatric Congenital Adrenal Hyperplasia Patients

Monitoring cortisol replacement therapy in congenital adrenal hyperplasia (CAH) patients is vital to avoid serious adverse events such as adrenal crises due to cortisol underexposure or metabolic consequences due to cortisol overexposure. The less invasive dried blood spot (DBS) sampling is an advantageous alternative to traditional plasma sampling, especially in pediatric patients. However, target concentrations for important disease biomarkers such as 17α-hydroxyprogesterone (17-OHP) are unknown using DBS. Therefore, a modeling and simulation framework, including a pharmacokinetic/pharmacodynamic model linking plasma cortisol concentrations to DBS 17-OHP concentrations, was used to derive a target morning DBS 17-OHP concentration range of 2–8 nmol/L in pediatric CAH patients. Since either capillary or venous DBS sampling is becoming more common in the clinics, the clinical applicability of this work was shown by demonstrating the comparability of capillary and venous cortisol and 17-OHP concentrations collected by DBS sampling, using a Bland-Altman and Passing-Bablok analysis. The derived target morning DBS 17-OHP concentration range is a first step towards providing improved therapy monitoring using DBS sampling and adjusting hydrocortisone (synthetic cortisol) dosing in children with CAH. In the future, this framework can be used to assess further research questions, e.g., target replacement ranges for the entire day

Quantifying uncertainty, variability and likelihood for ordinary differential equation models

<p>Abstract</p> <p>Background</p> <p>In many applications, ordinary differential equation (ODE) models are subject to uncertainty or variability in initial conditions and parameters. Both, uncertainty and variability can be quantified in terms of a probability density function on the state and parameter space.</p> <p>Results</p> <p>The partial differential equation that describes the evolution of this probability density function has a form that is particularly amenable to application of the well-known method of characteristics. The value of the density at some point in time is directly accessible by the solution of the original ODE extended by a single extra dimension (for the value of the density). This leads to simple methods for studying uncertainty, variability and likelihood, with significant advantages over more traditional Monte Carlo and related approaches especially when studying regions with low probability.</p> <p>Conclusions</p> <p>While such approaches based on the method of characteristics are common practice in other disciplines, their advantages for the study of biological systems have so far remained unrecognized. Several examples illustrate performance and accuracy of the approach and its limitations.</p

Proteomic Interrogation of Human Chromatin

Chromatin proteins provide a scaffold for DNA packaging and a basis for epigenetic regulation and genomic maintenance. Despite understanding its functional roles, mapping the chromatin proteome (i.e. the “Chromatome”) is still a continuing process. Here, we assess the biological specificity and proteomic extent of three distinct chromatin preparations by identifying proteins in selected chromatin-enriched fractions using mass spectrometry-based proteomics. These experiments allowed us to produce a chromatin catalog, including several proteins ranging from highly abundant histone proteins to less abundant members of different chromatin machinery complexes. Using a Normalized Spectral Abundance Factor approach, we quantified relative abundances of the proteins across the chromatin enriched fractions giving a glimpse into their chromosomal abundance. The large-scale data sets also allowed for the discovery of a variety of novel post-translational modifications on the identified chromatin proteins. With these comparisons, we find one of the probed methods to be qualitatively superior in specificity for chromatin proteins, but inferior in proteomic extent, evidencing a compromise that must be made between biological specificity and broadness of characterization. Additionally, we attempt to identify proteins in eu- and heterochromatin, verifying the enrichments by characterizing the post-translational modifications detected on histone proteins from these chromatin regions. In summary, our results provide insights into the value of different methods to extract chromatin-associated proteins and provide starting points to study the factors that may be involved in directing gene expression and other chromatin-related processes

Abschlussbericht Modellversuch „Unterstützung der KMU des Einzelhandels bei der Umsetzung der neuen gestaltungsoffenen Ausbildung“

Hagedorn U, Huisinga R. Abschlussbericht Modellversuch „Unterstützung der KMU des Einzelhandels bei der Umsetzung der neuen gestaltungsoffenen Ausbildung“.; 2007

Zur Notwendigkeit eines Perspektivwechsels beim selbstorganisierten Lernen

Hagedorn U, Huisinga R. Zur Notwendigkeit eines Perspektivwechsels beim selbstorganisierten Lernen. In: Westhoff G, ed. Gestaltung der Flexibilitätsspielräume in der Berufsausbildung. Bd.1: Ausbildende Fachkräfte und selbstorganisiertes Lernen. Materialien für Ausbilder. Konstanz: Christiani; 2006: 232-240

Berufsausbildung als Spiegel der Veränderungen im Verhältnis von Gesellschaft und Individuum: Laufbahn-Identität

Hagedorn U, Huisinga R. Berufsausbildung als Spiegel der Veränderungen im Verhältnis von Gesellschaft und Individuum: Laufbahn-Identität. In: Westhoff G, ed. Gestaltung der Flexibilitätsspielräume in der Berufsbildung. Bd. 2: Gestaltungsoffene Aus- und Weiterbildung durch Handlungsforschung fördern. Konstanz: Christiani; 2008: 114-123