Adenosine is a powerful trigger for ischemic preconditioning (IPC). Myocardial ischemia induces intracellular and extracellular ATP degradation to adenosine, which then activates adenosine receptors and elicits cardioprotection. Conventionally extracellular adenosine formation by ecto-5'-nucleotidase (CD73) during ischemia was thought to be negligible compared to the massive intracellular production, but controversial reports in the past demand further evaluation. In this study we evaluated the relevance of ecto-5'-nucleotidase (CD73) for infarct size reduction by ischemic preconditioning in in vitro and in vivo mouse models of myocardial infarction, comparing CD73-/- and wild type (WT) mice.3x5 minutes of IPC induced equal cardioprotection in isolated saline perfused hearts of wild type (WT) and CD73-/- mice, reducing control infarct sizes after 20 minutes of ischemia and 90 minutes of reperfusion from 46 ± 6.3% (WT) and 56.1 ± 7.6% (CD73-/-) to 26.8 ± 4.7% (WT) and 25.6 ± 4.7% (CD73-/-). Coronary venous adenosine levels measured after IPC stimuli by high-pressure liquid chromatography showed no differences between WT and CD73-/- hearts. Pharmacological preconditioning of WT hearts with adenosine, given at the measured venous concentration, was evenly cardioprotective as conventional IPC. In vivo, 4x5 minutes of IPC reduced control infarct sizes of 45.3 ± 8.9% (WT) and 40.5 ± 8% (CD73-/-) to 26.3 ± 8% (WT) and 22.6 ± 6.6% (CD73-/-) respectively, eliciting again equal cardioprotection. The extent of IPC-induced cardioprotection in male and female mice was identical.The infarct size limiting effects of IPC in the mouse heart in vitro and in vivo are not significantly affected by genetic inactivation of CD73. The ecto-5'-nucleotidase derived extracellular formation of adenosine does not contribute substantially to adenosine's well known cardioprotective effect in early phase ischemic preconditioning.

BACKGROUND:By means of the revision of the Medical Licensure Act for Physicians (ÄAppO) in 2009, undergraduate palliative care education (UPCE) was incorporated as a mandatory cross sectional examination subject (QB13) in medical education in Germany. Its implementation still constitutes a major challenge for German medical faculties. There is a discrepancy between limited university resources and limited patient availabilities and high numbers of medical students. Apart from teaching theoretical knowledge and skills, palliative care education is faced with the particular challenge of imparting a professional and adequate attitude towards incurably ill and dying patients and their relatives.PROJECT DESCRIPTION:Against this background, an evidence-based longitudinal UPCE curriculum was systematically developed following Kern's Cycle [1] and partly implemented and evaluated by the students participating in the pilot project. Innovative teaching methods (virtual standardised/simulated patient contacts, e-learning courses, interdisciplinary and interprofessional collaborative teaching, and group sessions for reflective self-development) aim at teaching palliative care-related core competencies within the clinical context and on an interdisciplinary and interprofessional basis.RESULTS:After almost five years of development and evaluation, the UPCE curriculum comprises 60 teaching units and is being fully implemented and taught for the first time in the winter semester 2014/15. The previous pilot phases were successfully concluded. To date, the pilot phases (n=26), the subproject "E-learning in palliative care" (n=518) and the blended-learning elective course "Communication with dying patients" (n=12) have been successfully evaluated.CONCLUSION:All conducted development steps and all developed programmes are available for other palliative care educators (Open Access). The integrated teaching formats and methods (video, e-learning module, interprofessional education, group sessions for reflexive self-development) and their evaluations are intended to make a contribution to an evidence-based development of palliative care curricula in Germany.

Introduction: Core competencies have progressively gained importance in medical education. In other contexts, especially personnel selection and development, assessment centers (ACs) are used to assess competencies, but there is only a limited number of studies on competency-based ACs in medical education. To the best of our knowledge, the present study provides the first data on the criterion-related validity of a competency-based AC in medical education. Methods: We developed an AC tailored to measure core competencies relevant to medical education (social-ethical, communicative, self, and teaching) and tested its validity in n=30 first-year medical students using 3- to 4-year follow-up measures such as (a) objective structured clinical examinations (OSCE) on basic clinical skills (n=26), (b) OSCE on communication skills (n=21), and (c) peer feedback (n=18). The AC contained three elements: interview, group discussion, and role play. Additionally, a self-report questionnaire was provided as a basis for the interview. Results: Baseline AC average score and teaching competency correlated moderately with the communication OSCE average score (r=0.41, p=0.03, and r=0.38, p=0.04, respectively). Social-ethical competency in the AC showed a very strong convergent association with the communication OSCE average score (r=0.60, p<0.01). The AC total score also showed a moderate correlation with the overall peer feedback score provided in Year 4 (r=0.38, p=0.06). In addition, communicative competency correlated strongly with the overall peer feedback (r=0.50, p=0.02). We found predominantly low and insignificant correlations between the AC and the OSCE on basic clinical skills (r=−0.33 to 0.30, all p's>0.05). Conclusion: The results showed that competency-based ACs can be used at a very early stage of medical training to successfully predict future performance in core competencies.

BACKGROUND:A mission statement (MS) sets out the long-term goals of an institution and is supposed to be suited for studying learning environments. Yet, hardly any study has tested this issue so far. The aim of the present study was the development and psychometric evaluation of an MS-Questionnaire (MSQ) focusing on explicit competencies. We investigated to what extent the MSQ captures the construct of learning environment and how well a faculty is following--in its perception--a competency orientation in a competency-based curriculum.METHODS:A questionnaire was derived from the MS "teaching" (Medical Faculty, Heinrich-Heine University Düsseldorf) which was based on (inter-) nationally accepted goals and recommendations for a competency based medical education. The MSQ was administered together with the Dundee Ready Education Environment Measure (DREEM) to 1119 students and 258 teachers. Cronbach's alpha was used to analyze the internal consistency of the items. Explorative factor analyses were performed to analyze homogeneity of the items within subscales and factorial validity of the MSQ. Item discrimination was assessed by means of part-whole corrected discrimination indices, and convergent validity was analyzed with respect to DREEM. Demographic variations of the respondents were used to analyze the inter-group variations in their responses.RESULTS:Students and teachers perceived the MS implementation as "moderate" and on average, students differed significantly in their perception of the MS. They thought implementation of the MS was less successful than faculty did. Women had a more positive perception of educational climate than their male colleagues and clinical students perceived the implementation of the MS on all dimensions significantly worse than preclinical students. The psychometric properties of the MSQ were very satisfactory: Item discrimination was high. Similarly to DREEM, the MSQ was highly reliable among students (α = 0.92) and teachers (α = 0.93). In both groups, the MSQ correlated highly positively with DREEM (r = 0.79 and 0.80, p < 0.001 each). Factor analyses did not reproduce the three areas of the MS perfectly. The subscales, however, could be identified as such both among teachers and students.CONCLUSIONS:The perceived implementation of faculty-specific goals can be measured in an institution to some considerable extent by means of a questionnaire developed on the basis of the institution's MS. Our MSQ provides a reliable instrument to measure the learning climate with a strong focus on competencies which are increasingly considered crucial in medical education. The questionnaire thus offers additional information beyond the DREEM. Our site-specific results imply that our own faculty is not yet fully living up to its competency-based MS. In general, the MSQ might prove useful for faculty development to the increasing number of faculties seeking to measure their perceived competency orientation in a competency-based curriculum.

AIMS:The teachers' perspectives of the educational environment have as yet only been sparsely considered. This study aimed at validating the first German version of the Dundee Ready Education Environment Measure (DREEM) from the points of view of both students and teachers.METHODS:Data from 1119 students and 258 teachers were available for analysis. Psychometric validation included the analysis of homogeneity and discrimination at item level as well as reliability (Cronbach's α), criterion and construct validity at test level. Effect sizes were calculated and the independent samples t-test was used for statistical inference testing of mean differences between two groups.RESULTS:Item characteristics were satisfactory in both samples. Reliability was high with α = 0.92 (students) and 0.94 (teachers), respectively. Factor analyses revealed five dimensions which slightly diverged from the five subscales postulated by the DREEM authors though. The environment was evaluated significantly (p < 0.001) more positively by teachers (M = 117.63) than by students (M = 109.75). Further significant differences were observed with regard to gender, mother language, stage of studies and previous professional training among others.CONCLUSIONS:With convincing psychometric properties at item and test levels, the suitability of DREEM not only for students but also for teachers to assess the educational environment has been demonstrated.

TASK-1, a member of the recently identified K2P channel family, is mainly expressed in the heart and the nervous system. TASK-1 is regulated by several physiological and pathological conditions and functions as a background potassium channel. However, there are limited data concerning the significance of TASK-1 in cardiac physiology. We studied the functional role of TASK-1 in the heart by cardiac phenotyping the TASK-1-deficient mouse (TASK-1−/−). TASK-1 was predominantly expressed in the ventricles of control animals. Real-time PCR and immunoblot demonstrated that the expression of seven other K2P channels was unchanged in TASK-1−/− mice. No structural or functional abnormalities were found by histology and echocardiography. Electrophysiological studies recording monophasic action potentials (MAPs) showed a significant prolongation of action potential duration in spontaneously beating and atrially paced hearts, respectively. Surface ECGs of TASK-1−/− mice revealed a significant prolongation of the rate corrected QT interval. Telemetric ECG recordings for 24 h, during physical and pharmacological stress testing and after ischemia/reperfusion injury did not result in a higher incidence of arrhythmias. Infarct size was comparable in both genotypes. However, TASK-1−/− mice had a higher mean heart rate and significantly reduced heart rate variability (HRV). Time and frequency domain measurements as well as baroreceptor reflex testing revealed a sympathovagal imbalance with a shift to an increase in sympathetic influence in TASK-1−/− mice. In conclusion, TASK-1 plays a functional role in the repolarization of the cardiac action potential in vivo and contributes to the maintenance of HRV.

Acta PhysiologicaVolume 194, Issue 2 p. 171-173 Teaching workshop on ‘Implications of the Bologna Declaration for Teaching Physiology in Medical Education’ at the joint meeting of the German Physiological Society and the Federation of European Physiological Societies, Cologne, 2–5 March 2008 L. H. E. H. Snoeckx, L. H. E. H. Snoeckx Department of Physiology, Maastricht University, Maastricht, the NetherlandsSearch for more papers by this authorT. Ivanics, T. Ivanics Institute of Human Physiology and Clinical Experimental Research, Semmelweiss University, Budapest, HungarySearch for more papers by this authorL. Peltonen, L. Peltonen Department of Biomedicine/Physiology, University of Helsinki, Helsinki, FinlandSearch for more papers by this authorU. Decking, U. Decking Department of Cardiovascular Physiology, University of Düsseldorf, Düsseldorf, GermanySearch for more papers by this authorJ. H. Ravesloot, J. H. Ravesloot Department of Physiology, Academic Medical Center of the University of Amsterdam, Amsterdam, the NetherlandsE-mail: l.snoeckx@fys.unimaas.nlSearch for more papers by this author L. H. E. H. Snoeckx, L. H. E. H. Snoeckx Department of Physiology, Maastricht University, Maastricht, the NetherlandsSearch for more papers by this authorT. Ivanics, T. Ivanics Institute of Human Physiology and Clinical Experimental Research, Semmelweiss University, Budapest, HungarySearch for more papers by this authorL. Peltonen, L. Peltonen Department of Biomedicine/Physiology, University of Helsinki, Helsinki, FinlandSearch for more papers by this authorU. Decking, U. Decking Department of Cardiovascular Physiology, University of Düsseldorf, Düsseldorf, GermanySearch for more papers by this authorJ. H. Ravesloot, J. H. Ravesloot Department of Physiology, Academic Medical Center of the University of Amsterdam, Amsterdam, the NetherlandsE-mail: l.snoeckx@fys.unimaas.nlSearch for more papers by this author First published: 05 September 2008 https://doi.org/10.1111/j.1748-1716.2008.01886.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume194, Issue2October 2008Pages 171-173 RelatedInformation

AIMS In the heart, there is not only a transmural gradient of left ventricular perfusion and action potential duration (APD), but also spatial heterogeneity within each myocardial layer, where local blood flow and energy turnover vary more than three-fold between individual regions. We analysed at high spatial resolution whether a corresponding heterogeneity also extends to ion channel gene expression and APD. METHODS AND RESULTS In the open-chest beagle dog, left ventricular 300 microL samples of very low or high flow were identified by radioactive microspheres and expression levels determined by quantitative PCR. The distribution of epicardial APD was assessed by mapping local activation repolarization intervals (ARIs) and QT interval (QT). ERG, the potassium channel mediating IKr, and KChIP2, the interacting protein modulating Ito, were increased in Low flow (3.3- and 2.5-fold, P < 0.001 and <0.05, respectively; n = 6 hearts, 30-31 samples each) as compared with High flow areas. This suggested enhanced repolarizing currents in Low flow areas, and in consequence, mathematical model analysis predicted a shorter local APD upon enhanced ERG and IKr. Epicardial mapping revealed a patchy, temporally stable APD pattern (n = 11), a small apico-basal gradient and an APD prolongation induced by the ERG blocker dofetilide predominantly in areas of short basal ARI or QT, respectively (n = 9). In addition, in Short QT areas, ERG expression was three-fold increased (P < 0.05, n = 4). CONCLUSION The spatial pattern of perfusion is matched by the novel patterns of K+ channel expression and APD. Whenever this newly recognized intramural dispersion of APD increases, it may contribute to arrhythmogenesis.

High resolution analysis (300 μl) reveals a temporally stable, patchy pattern of perfusion in the LV free wall. Low flow areas (LowF) receive <60% of the average flow and display decreased energy turnover and enhanced fatty acid content, while the mechanism of this spatial heterogeneity is unknown. Lipid profile analysis of canine LowF showed an elevated triglyceride content (+212%) when compared to High flow samples (HighF). In LowF, mRNA expression of PPARα was reduced to ¼ and the same was true for 5 key enzymes or transporters in lipid metabolism (p<0.05 – 0.001), suggesting preferential glycolysis in LowF. Potassium ion channel expression also displayed flow-related differences, with enhanced expression of ERG (3.5-fold, p<0.001) and KChIP2 (2.1-fold) in LowF, mediating resp. governing IKr and Ito. Model analysis predicted a shorter local APD in LowF, which was confirmed by epicardial mapping of local QT intervals. This revealed a patchy, temporally stable pattern and a QT prolongation upon ERG blockade predominantly in areas of short basal QT (p<0.01). In short QT areas, ERG expression was increased and basal perfusion decreased. Thus, within the apparently homogenous left ventricular wall, distinct metabolic and electrophysiological phenotypes exist. In LowF, both downregulation of fatty acid oxidation and APD shortening will reduce O2 consumption in these regions and may thus partially explain the spatial heterogeneity of perfusion. Supported by DFG.

CD73/ecto-5'-nucleotidase, which catalyzes the conversion of adenosine monophosphate to adenosine, has been implicated in vascular homeostasis. The aim of the present study was to evaluate the role of CD73 in erythropoietin (EPO) production and to determine its influence on basal kidney perfusion using a CD73 knockout mutant recently generated by us. Of all organs investigated, kidneys showed the most prominent CD73 activity, preferentially located in peritubular fibroblasts of the renal cortex and the glomerular mesangium. In the absence of CD73, alkaline phosphatase remained unchanged, but tissue adenosine was reduced under control conditions (by 76%) and during normobaric hypoxia (by 72%). Despite the loss of CD73 activity, EPO mRNA and plasma protein concentrations were not different under basal conditions as well as after normobaric hypoxia (8% O2) and carbon monoxide (0.1% CO) inhalation (both for 4 h). Although there were no differences in blood pressure and urine flow volume, average weight of both kidneys was reduced by 21% in the knockout (wild type 7.17+/-1.18 mg g-1 body wt, CD73-/- 5.70+/-1.91 mg g-1 body wt). Measurement of renal plasma flow and glomerular filtration revealed no significant differences when related to respective kidney weights. We conclude that adenosine derived by the extracellular CD73 pathway has no impact on EPO production under basal conditions and after hypoxic challenge but may determine kidney weight.

PURPOSE. Adenosine is increasingly released in metabolic stress conditions, like hypoxia or ischemia, and regulates many physiologic processes, such as aqueous humor secretion and intraocular pressure, via activation of four adenosine receptors. In the current study, the role of the adenosine system in the pathophysiology of pseudoexfoliation (PEX) syndrome, which is typically associated with anterior chamber hypoxia and elevated intraocular pressure, was examined.METHODS. RT-PCR, Northern hybridization, in situ hybridization, and immunohistochemistry were applied to analyze the mRNA and protein expression of the adenosine receptor subtypes A1, A2A, A2B, and A3 in anterior segment tissues of PEX eyes, without and with glaucoma, in comparison to eyes with primary open-angle or angle-closure glaucoma and normal control eyes. Real-time PCR was used to study the effect of hypoxia and oxidative stress on adenosine receptor expression by nonpigmented ciliary epithelial cells in vitro. Levels of adenosine and its catabolites inosine, hypoxanthine, and xanthine were measured in cell culture supernatants and aqueous humor samples by HPLC.RESULTS. All four adenosine receptor subtypes (A2A > A1 > A2B > A3) were coexpressed but differently distributed in the ciliary epithelium of control eyes, with the A3 receptor being localized to the basolateral membrane infoldings of the nonpigmented epithelial cells. A selective, approximately 10-fold upregulation of A3 receptor mRNA and protein was consistently found in the nonpigmented ciliary epithelium of all PEX eyes, with and without glaucoma, compared with the normal and glaucomatous control eyes. Significant upregulation of A3 receptor message in nonpigmented epithelial cells was induced by both hypoxia and oxidative stress in vitro, together with increased levels of inosine, hypoxanthine, and xanthine in the supernatants. Levels of adenosine and its catabolites, however, were not significantly elevated in the aqueous humor of patients with PEX.CONCLUSIONS. Considering the known role of the A3 adenosine receptor in modulating aqueous humor secretion, its selective, probably hypoxia-induced upregulation in the ciliary epithelium may not only confer cytoprotection but also influence aqueous humor dynamics and may be accessible to therapeutic intervention in patients with PEX.

Exposure of rat liver epithelial cells to doxorubicin, an anthraquinone derivative widely employed in cancer chemotherapy, led to a dose-dependent decrease in gap junctional intercellular communication (GJC). Gap junctions are clusters of inter-cellular channels consisting of connexins, the major connexin in the cells used being connexin-43 (Cx43). Doxorubicin-induced loss of GJC was mediated by activation of extracellular signal-regulated kinase (ERK)-1 and ERK-2, as demonstrated using inhibitors of ERK activation. Furthermore, activation of the epidermal growth factor (EGF) receptor by doxorubicin was responsible for ERK activation and the subsequent attenuation of GJC. Inhibition of GJC, however, was not by direct phosphorylation of Cx43 by ERK-1/2, whereas menadione, a 1,4-naphthoquinone derivative that was previously demonstrated to activate the same EGF receptor-dependent pathway as doxorubicin, resulting in downregulation of GJC, caused strong phos-phorylation of Cx43 at serines 279 and 282. Thus, ERK-dependent downregulation of GJC upon exposure to quinones may occur both by direct phosphorylation of Cx43 and in a phosphorylation-independent manner.