In Vitro and in Vivo Anti-Inflammatory Activity of the New Glucocorticoid Ciclesonide

ABSTRACT The glucocorticoid ciclesonide is the 2ЈR-epimer of 2Ј-cyclohexyl-11␤-hydroxy-21-isobutyryloxy-16bH-dioxolo [5Ј,4Ј:16,17]pregna-1,4-diene-3,20-dione. The active metabolite desisobutyrylciclesonide (des-CIC) is derived from ciclesonide by esterase cleavage of isobutyrate at the C21 position. The relative binding affinities at the rat glucocorticoid receptor were dexamethasone, 100; ciclesonide, 12; des-CIC, 1212; and budesonide, 905. Des-CIC potently inhibited the activation of murine and human lymphocytes in a series of different in vitro systems. With the exception of concanavalin A-stimulated rat spleen cells, des-CIC was more potent than the parent compound. Des-CIC compared well with budesonide in all in vitro systems. Furthermore, the respective 2ЈS-epimers were always significantly less potent than the 2ЈR-epimers. In vivo, ciclesonide (intratracheal administration), des-CIC, and budesonide inhibited antigen-induced accumulation of eosinophils, protein, and tumor necrosis factor-␣ into the bronchoalveolar lavage fluid of ovalbumin-sensitized and -challenged Brown Norway rats with an ED 50 value ranging from 0.4 to 1.3 mg/kg, indicating similar potency, which suggests in vivo activation of the parent compound. Ciclesonide and budesonide inhibited the bradykinin-induced protein leakage into the rat trachea. In the rat cotton pellet model, ciclesonide inhibited granuloma formation (ED 50 :ϭ of 2 g/pellet), whereas budesonide and des-CIC were 15-and 20-fold less active; thymus involution was induced with an ED 50 of 303, 279, and 154 g/pellet, respectively. When applied orally to rats for 28 days, ciclesonide showed low potency in reducing weight of thymus and adrenals, suggesting low oral bioavailability. The in vivo data on ciclesonide highlight its effective local action and a reduced potential for side effects

Resurrecting melancholia

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65798/1/j.1600-0447.2007.00958.x.pd

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes(1). Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel(2)) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants

A saturated map of common genetic variants associated with human height.

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries

Practice-related examinations are feasible

The 9th Revision of the German Federal Medical Training Regulations demands a practice-related assessment of medical students. On the way to these new regulations German faculties face as well problems related to a lack of experience of lecturers, tutors, examiners, and students with the required examination procedures as strains of a financial and logistic kind. How to succeed in introducing suitable examinations at short notice and which positive effects can be achieved is shown by the Faculty of Medicine of the university of Tübingen.Die neue Approbationsordnung (ÄAppO) fordert, dass Medizinstudierende klinisch-praktisch geprüft werden. Probleme der Fakultäten hierbei sind mangelnde Erfahrung der Lehrverantwortlichen, Prüfer und Studierenden mit den nötigen Prüfungsformen sowie logistische und finanzielle Belastungen der Fakultäten. Wie die Einführung geeigneter Prüfungen kurzfristig gelingen kann und welche positiven Effekte erreicht werden können, zeigt das Beispiel der Medizinischen Fakultät Tübingen