Biomarker discovery by imaging mass spectrometry: transthyretin is a biomarker for gentamicin-induced nephrotoxicity in rat

Adverse drug effects are often associated with pathological changes in tissue. An accurate depiction of the undesired affected area, possibly supported by mechanistic data, is important to classify the effects with regard to relevance for human patients. MALDI imaging MS represents a new analytical tool to directly provide the spatial distribution and the relative abundance of proteins in tissue. Here we evaluate this technique to investigate potential toxicity biomarkers in kidneys of rats that were administered gentamicin, a well known nephrotoxicant. Differential analysis of the mass spectrum profiles revealed a spectral feature at 12,959 Da that strongly correlates with histopathology alterations of the kidney. We unambiguously identified this spectral feature as transthyretin (Ser(28)-Gln(146)) using an innovative combination of tissue microextraction and fractionation by reverse-phase liquid chromatography followed by a top-down tandem mass spectrometric approach. Our findings clearly demonstrate the emerging role of imaging MS in the discovery of toxicity biomarkers and in obtaining mechanistic insights concerning toxicity mechanisms.     

Learning of submissive behavior in mice: A new model

The experience of winning or loosing fights plays an important role in subsequent aggressive or submissive behaviors. In this study agonistic behavior of male mice was chosen to investigate learning mechanisms in the context of a biologically meaningful situation.An ICR mouse introduced into a group of five C57BL/6 mice was attacked by mice of high social status (Fighter, F), but not by lower ranking animals (Non-Fighter, NF). On this basis the following model was developed to study learning of submissive behavior. Day 1 (baseline trial): An ICR mouse was introduced to a single NF-C57 mouse. Few submissive behaviors (crouch) were observed in naive ICR mice upon contact with NF-C57 mice. Day 2 (learning trial): The same ICR mouse was defeated by an F-C57 mouse until it showed defensive upright posture upon approach. This criterion was reached after a mean latency of 3.5 min and after being exposed to a mean number of 14 bites. Day 3 (retest trial): The same pairs as on day 1 confronted each other. Without being attacked, the ICR mouse showed a significant increase of submissive behavior (crouch, defensive sideways and upright) upon mere contact with the NF-C57 mouse when compared to day 1 and to control mice on day 3. Controls, confronted on all three days with NF-C57 mice, showed no increase in submissive behaviors.The results are discussed in terms of acquisition, memory, retrieval and extinction of learned submissive behavior. It is suggested that the mechanisms underlying learning of submissive behavior include generalization of conditioning and specific extinction processes. The further use of the learning scheme to assess drug effects is illustrated.     

Hormonelle Korrelate zur Gesangsentwicklung der Kanarienv?gel

Ohne Zusammenfassung     

Die Beeinflussung des Gesangs- und Brutverhaltens von Kanarienweibchen durch Steroidmanipulationen

Summary To assess the organizing effects of steroids on singing and breeding behaviour of female canaries, 11 females were treated with estradiol and testosterone until day 300. Unlike controls, treated females sing regularly. However, 30 days after the termination of steroid therapy, they exhibit normal female behaviour towards males. Lowered reproductive activity was only detectable in those females which where treated with testosterone during very early development (day 30–60).     

Lack of Gastric Inhibitory Polypepetide (GIP) response to vagal stimulation in the rat

The effect of sham feeding on the plasma concentration of gastric inhibitory polypeptide (GIP) was studied in unrestrained rats bearing chronic gastric fistulas and jugular catheters. While no increase of plasma GIP concentration could be detected during sham feeding (fistula open), during normal feeding (fistula closed), plasma GIP concentrations rose rapidly. In contrast to GIP, plasma insulin concentrations showed a rapid and phasic response during sham feeding in the absence of changes of glycemia. In anesthetized rats electrical stimulation of the vagus nerve was without any effect on plasma GIP concentration, while plasma insulin increased rapidly by as much as 150 percent. It is concluded that under the conditions used, the full gastric and/or intestinal phases of food ingestion are necessary to trigger GIP release, and that vagal activation alone is unable to stimulate GIP release in the rat.