Homozygous CREM-IbΔC-X Overexpressing Mice Are a Reliable and Effective Disease Model for Atrial Fibrillation

Background: Atrial fibrillation (AF) is a significant cause of morbidity and mortality with foreseeably increasing prevalence. While large animal models of the disease are well established but resource intensive, transgenic AF mouse models are not yet widely used to develop or validate novel therapeutics for AF. Hemizygous mice with a cardiomyocyte-specific overexpression of the human cAMP response element modulator (CREM) isoform IbΔC-X spontaneously develop AF on grounds of an arrhythmogenic substrate consisting of alterations in structure, conduction, and calcium handling.Objective: We investigated if homozygous expression of the CREM-IbΔC-X transgene in mice alters the time course of AF development, and if homozygous CREM-IbΔC-X transgenics could be suitable as a disease model of AF.Methods: Southern Blot, quantitative real-time PCR, and immunoblotting were used to identify and verify homozygous transgenics. Cardiac gravimetry, quantitative real-time RT-PCR, histology, survival analysis, and repeated ECG recordings allowed assessment of phenotypic development and effects of antiarrhythmic drugs.Results: Homozygous animals could be identified by Southern blot and quantitative PCR, showing a strong trend to increased transgenic protein expression. In homozygous animals, atrial hypertrophy appeared earlier and more pronounced than in hemizygous animals, going along with an earlier onset of spontaneous AF, while no increased early mortality was observed. Application of a rate-controlling drug (esmolol) led to the expected result of a decreased heart rate. Application of a rhythm-controlling drug (flecainide) showed effects on heart rate variability, but did not lead to a definitive conversion to sinus rhythm.Conclusion: We suggest homozygous CREM-IbΔC-X overexpressing mice as a reliable model of early onset, rapidly progressive AF

Key Learning Outcomes for Clinical Pharmacology and Therapeutics Education in Europe: A Modified Delphi Study.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of a uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. A total of 129 experts from 27 European countries were asked to rate 307 learning outcomes. In all, 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired

Untersuchungen zum Einfluss der cAMP-regulierten Transkriptionsfaktoren Activator Protein 2Alpha (AP-2Alpha) und cAMP Response Element Modulator (CREM) auf die Apoptose in isolierten Herzen

Im Rahmen der Herzinsuffizienz kommt es zu einer Störung der Signalübertragung über cAMP sowie zu einer gesteigerten Apoptose von Kardiomyozyten. AP-2alpha und CREM sind zwei cAMP-regulierte Transkriptionsfaktoren, die im menschlichen Herzen exprimiert werden. AP-2alpha ist bei der dilatativen Kardiomyopathie heraufreguliert und löst bei Überexpression in Kardiomyozyten Apoptose aus. Die dominant negative CREM-Isoform ICER stimuliert Apoptose in Kardiomyozyten. In dieser Arbeit wurde gezeigt, dass eine heterozygote Ausschaltung des AP-2alpha-Gens (eine homozygote ist letal) sowie eine vollständige Ausschaltung des CREM-Gens keinen Einfluss auf durch Ischämie/Reperfusion ausgelöste Apoptose in isolierten Herzen haben. Möglicherweise ist dieser fehlende Einfluss jedoch durch das intakte AP-2alpha-Allel bzw. durch Kompensation durch CREM-ähnliche Transkriptionsfaktoren erklärt, was lohnende Ziele für weitere Untersuchungen bietet

Erhöhung des Testbemühens im Progresstest Medizin durch Steigerung der Transparenz gegenüber den Studierenden – eine kontrollierte Studie

Stümpel FT, Marschall B, Friederichs H. Erhöhung des Testbemühens im Progresstest Medizin durch Steigerung der Transparenz gegenüber den Studierenden – eine kontrollierte Studie. Presented at the Jahrestagung der Gesellschaft für Medizinische Ausbildung (GMA), Zürich.Progresstests (PTM) haben sich als formatives Feedback-Instrument im Medizinstudium etabliert, sind aber sehr von dem Bemühen der Teilnehmenden abhängig. Es wird postuliert, dass sich das Testbemühen v.a. durch eine Erhöhung der Bekanntheit des Prinzips PTM und durch eine vermehrt wahrgenommene Nützlichkeit steigern lässt. In einer kontrollierten Studie soll die Wirksamkeit einer Transparenzsteigerung auf das Testbemühen am PTM gemessen werden

Mice without the Regulator Gene Rsc1A1 Exhibit Increased Na+-D-Glucose Cotransport in Small Intestine and Develop Obesity

The product of the intronless single copy gene RSC1A1, named RS1, is an intracellular 617-amino-acid protein that is involved in the regulation of the Na+-D-glucose cotransporter SGLT1. We generated and characterized RS1 knockout (RS1−/−) mice. In the small intestines of RS1−/− mice, the SGLT1 protein was up-regulated sevenfold compared to that of wild-type mice but was not changed in the kidneys. The up-regulation of SGLT1 was posttranscriptional. Small intestinal D-glucose uptake measured in jointly perfused small bowel and liver was increased twofold compared to that of the wild-type, with increased peak concentrations of D-glucose in the portal vein. At birth, the weights of RS1−/− and wild-type mice were similar. At the age of 3 months, male RS1−/− mice had 5% higher weights and 15% higher food intakes, whereas their energy expenditures and serum leptin concentrations were similar to those of wild-type mice. At the age of 5 months, male and female RS1−/− mice were obese, with 30% increased body weight, 80% increased total fat, and 30% increased serum cholesterol. At this age, serum leptin was increased, whereas food intake was the same as for wild-type mice. The data suggest that the removal of RS1 leads to leptin-independent up-regulation of food intake, which causes obesity

Phenotyping of Mice with Heart Specific Overexpression of A2A-Adenosine Receptors: Evidence for Cardioprotective Effects of A2A-Adenosine Receptors

Background: Adenosine can be produced in the heart and acts on cardiac adenosine receptors. One of these receptors is the A2A-adenosine receptor (A2A-AR).Methods and Results: To better understand its role in cardiac function, we generated and characterized mice (A2A-TG) which overexpress the human A2A-AR in cardiomyocytes. In isolated atrial preparations from A2A-TG but not from WT, CGS 21680, an A2A-AR agonist, exerted positive inotropic and chronotropic effects. In ventricular preparations from A2A-TG but not WT, CGS 21680 increased the cAMP content and the phosphorylation state of phospholamban and of the inhibitory subunit of troponin in A2A-TG but not WT. Protein expression of phospholamban, SERCA, triadin, and junctin was unchanged in A2A-TG compared to WT. Protein expression of the α-subunit of the stimulatory G-protein was lower in A2A-TG than in WT but expression of the α-subunit of the inhibitory G-protein was higher in A2A-TG than in WT. While basal hemodynamic parameters like left intraventricular pressure and echocardiographic parameters like the systolic diameter of the interventricular septum were higher in A2A-TG than in WT, after β-adrenergic stimulation these differences disappeared. Interestingly, A2A-TG hearts sustained global ischemia better than WT.Conclusion: We have successfully generated transgenic mice with cardiospecific overexpression of a functional A2A-AR. This receptor is able to increase cardiac function per se and after receptor stimulation. It is speculated that this receptor may be useful to sustain contractility in failing human hearts and upon ischemia and reperfusion