The dopamine-D2-receptor agonist ropinirole dose-dependently blocks the Ca2+-triggered permeability transition of mitochondria

AbstractRopinirole, an agonist of the post-synaptic dopamine D2-receptor, exerts neuroprotective activity. The mechanism is still under discussion. Assuming that this neuroprotection might be associated with inhibition of the apoptotic cascade underlying cell death, we examined a possible effect of ropinirole on the permeability transition pore (mtPTP) in the mitochondrial inner membrane. Using isolated rat liver mitochondria, the effect of ropinirole was studied on Ca2+-triggered large amplitude swelling, membrane depolarization and cytochrome c release. In addition, the effect of ropinirole on oxidation of added, membrane-impermeable NADH was investigated. The results revealed doubtlessly, that ropinirole can inhibit permeability transition. In patch-clamp experiments on mitoplasts, we show directly that ropinirole interacts with the mtPTP. Thus, ropinirole reversibly inhibits the opening of mtPTP with an IC50 of 3.4µM and a Hill coefficient of 1.3. In both systems (i.e. energized mitochondria and mitoplasts) the inhibitory effect on permeability transition was attenuated by increasing concentrations of inorganic phosphate. In addition, we showed with antimycin A-treated mitochondria that ropinirole failed to suppress respiratory chain-linked reactive oxygen species release. In conclusion, our data suggest that the neuroprotective activity of ropinirole is due to the blockade of the Ca2+-triggered permeability transition

Primary skin fibroblasts as a model of Parkinson's disease

Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues

Mitochondria and Energetic Depression in Cell Pathophysiology

Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED), which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell’s ability to do work and control the intracellular Ca2+ homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS), mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD). However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect) is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis

Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

Mitochondrial abnormalities have been identified as a central mechanism in multiple neurodegenerative diseases and, therefore, the mitochondria have been explored as a therapeutic target. This review will focus on the evidence for mitochondrial abnormalities in the two most common neurodegenerative diseases, Parkinson's disease and Alzheimer's disease. In addition, we discuss the main strategies which have been explored in these diseases to target the mitochondria for therapeutic purposes, focusing on mitochondrially targeted antioxidants, peptides, modulators of mitochondrial dynamics and phenotypic screening outcomes

Vom HAM-Nat bis zum "Physikum" - Analyse der Studienerfolgsparameter vor und nach Einführung eines Naturwissenschaftstests im Zulassungsverfahren

Background/Objectives: For the winter semester 2012/13, the Medical School of Otto-von-Guericke University Magdeburg introduced the HAM-Nat test (Hamburg Assessment Test for Medical Degrees - Natural Sciences Section) for the selection of its study applicants with the aim of improving the academic success of their students in the pre-clinical part which has a heavy emphasis on natural sciences. The study examines the extent to which the new University Selection Procedure (AdH) influences two criteria for measuring students' success, compliance with the standard period of study up until the first part of the medical state exam (M1) and its result.Methodology: A comparison of above-mentioned parameters for measuring student success for the matriculation years 2008-2011 (no HAM-Nat test, Pre-Matriculation) and those of the matriculation years 2012-2014 (Nat-Matriculation), whose students have passed the HAM-Nat test in the selection process of the university. In addition, it was taken into account the number of course certificates gained within the standard time period. In the Nat-Matriculation, the HAM-Nat results were merged with the associated M1 exam results.Results: The proportion of AdH students who were admitted to the Physikum (first part of the medical state exam (M1)) within the standard period of study only increased slightly in the period studied. Within the AdH group, 70% of the Pre-Matriculation group gained entry to the second phase of studies without delay, rising to 78% in the AdH-group of the Nat-Matriculation. For all admission groups taken together, the overall grades for the first section of the medical state exam 2010-2016 show a positive trend, regardless of the selection procedure. The proportion of correctly answered questions in the nationwide M1 increased accordingly in the period studied. The better those matriculating had performed in the HAM-Nat test, the better their results were in the written and oral parts of the first part of the medical state exam. Conclusion: Although a significant proportion of students in the AdH group had obtained their place of study only on the basis of their test result and the score in the HAM-Nat test only weakly correlated with the school leaving grade (Abitur), the quantifiable study success parameters to date - in an albeit short observation period before and after introduction of the test - improved slightly. The number of Nat-Matriculations is too low to be able to assess the effect of the HAM-Nat test bearing in mind natural fluctuations. Nevertheless, the HAM-Nat test as an instrument of selection also made it possible for candidates with originally insufficient Abitur grades to gain admission without negative effects on the study success of the AdH cohort.Hintergrund/Zielsetzung: Die Medizinische Fakultät der Otto-von-Guericke Universität Magdeburg hat zum Wintersemester 2012/13 den HAM-Nat-Test (Hamburger Auswahlverfahren für Medizinische Studiengänge - Naturwissenschaftsteil) zur Auswahl ihrer Studienbewerber mit dem Ziel eingeführt, den Studienerfolg ihrer Studierenden im vorrangig naturwissenschaftlich geprägten vorklinischen Studienabschnitt zu verbessern. Untersucht wird, inwieweit das neue Auswahlverfahren der Hochschule (AdH) zwei Kriterien des Studienerfolgs beeinflusst, nämlich die Einhaltung der Regelstudienzeit bis zum 1. Abschnitt der Ärztlichen Prüfung (M1) und dessen Ergebnis.Methodik: Die genannten Studienerfolgsparameter der Matrikel 2008-2011 (ohne HAM-Nat-Test, Vor-Matrikel) werden mit denen der Matrikel 2012-2014 (Nat-Matrikel) verglichen, deren Studierende im Auswahlverfahren der Hochschule den HAM-Nat-Test abgelegt haben. Außerdem wurde die Anzahl der in der Regelzeit bestandenen Leistungsnachweise berücksichtigt. In der Nat-Matrikel wurden die HAM-Nat-Ergebnisse mit den zugehörigen M1-Prüfungsergebnissen zusammengeführt.Ergebnisse: Der Anteil der AdH-Studierenden, der in der Regelstudienzeit zur M1-Prüfung zugelassen werden konnte, ist in der untersuchten Zeitreihe nur gering gestiegen. Innerhalb der AdH Gruppe erreichten 70% der Vor-Matrikel verzögerungsfrei den zweiten Studienabschnitt, in der AdH-Gruppe der Nat-Matrikel 78%. Für alle Zulassungsquoten zusammengenommen ist bzgl. der Gesamtprädikate im 1. Abschnitt der Ärztlichen Prüfung von 2010-2016 unabhängig vom Auswahlverfahren ein positiver Trend zu verzeichnen. Der Anteil der richtig beantworteten Fragen in der bundesweiten M1-Prüfung stieg dazu passend im Beobachtungszeitraum. Je besser die Immatrikulierten im HAM-Nat-Test abgeschnitten hatten, desto besser waren ihre Ergebnisse im schriftlichen und im mündlichen Teil des 1. Abschnitts der ärztlichen Prüfung. Schlussfolgerung: Obwohl ein nennenswerter Teil der Studierenden in der AdH-Quote ihren Studienplatz erst aufgrund ihres Testergebnisses erhalten hatte und die Punktzahl im HAM-Nat-Test nur schwach mit der Abiturnote korreliert, haben sich die bisher quantifizierbaren Studienerfolgsparameter im allerdings nur kurzen Beobachtungszeitraum vor und nach Einführung des Tests gering positiv verändert. Die Zahl der Nat-Matrikel ist zu gering, um den Effekt des HAM-Nat-Tests in seinen natürlichen Schwankungen beurteilen zu können. Dennoch ermöglicht der HAM-Nat-Test als Auswahlinstrument auch Bewerbern mit primär unzureichend zulassungsfähigen Abiturdurchschnittsnoten Erfolg im Zulassungsverfahren, ohne den Studienerfolg der AdH-Kohorte zu verschlechtern

Introduction of the HAM-Nat examination – applicants and students admitted to the Medical Faculty in 2012-2014

Background/aim: In the 2012/13 winter semester, the Magdeburg Medical Faculty introduced a test of knowledge for the selection of applicants. The Hamburg Assessment Test for Medicine - Natural Sciences (HAM-Nat) comprises a multiple-choice test with questions on the aspects of biology, physics, chemistry and mathematics relevant to medicine, which was specifically developed for the selection of medicine applicants. The aim is to study how the HAM-Nat influences student selection, the reasons why students decide to take the test as part of their application procedure and what expectations they have of their course of study.Methods: The selection procedures applied at the university in 2011 (without HAM-Nat) and in 2012-2014 (with HAM-Nat) are compared. On the basis of the results of exploratory interviews, university entrants in winter semester 2013/2014 participated in a written survey on why they chose their subject and place of study and their expectations of their course of study. Results: No problems were encountered in introducing the extended selection procedure that included the HAM-Nat Test. The HAM-Nat had a great influence on the selection decision. About 65% of the students admitted would not have obtained a place if the decision had been based exclusively on their Abitur grade [grade obtained in the German school-leaving examination]. On average, male applicants obtained better HAM-Nat results than female ones. The questionnaire was answered by 147 out of 191 university entrants (77%). In the case of applicants from Saxony-Anhalt, the principle reasons for choosing the regional capital are its proximity, the social environment offered, good conditions for studying and the feel-good factor at the university. For the majority of applicants, however, particularly applicants from other federal states, the relatively good chances of admission in Magdeburg were the main reason. Conclusion: The Magdeburg Medical Faculty regards the HAM-Nat as a suitable tool for selecting applicants with outstanding knowledge of natural sciences and thus of increasing and harmonising levels of knowledge at the start of the course. Completion of the standard period of study and success in the 1st part of the German Medical Examination will be the subject of further observation of the students. The HAM-Nat, as a performance-related selection procedure, is not suitable for giving active preference to natives of Saxony-Anhalt in the application procedure but their number has increased since it was introduced. Applicants primarily use the selection procedure tactically to obtain the university place they want to study medicine. Specifics relating to curricula and university profile and research areas are not critical to their choice

First Contact: interprofessional education based on medical students' experiences from their nursing internship

Goal: The aim of the course “interprofessional communication and nursing” is to reflect medical students’ experiences from the nursing internship. The content of the course focuses on barriers and support of interprofessional communication as a foundation for teamwork between nursing professionals and physicians. The nursing internship is for most medical students the first contact with nursing professionals and can lead to perceptions about the other group that might hinder interprofessional teamwork and consequently harm patients. To meet the demographic challenges ahead it is important to emphasize interprofessional education in the study of medicine and better prepare future physicians for interprofessional collaboration. Method: The design of the course includes an assessment of a change in the students’ perceptions about nursing and interprofessional communication. The first class meeting presents the starting point of the assessment and visualizes students’ perceptions of nursing and medicine. The content of the following class meetings serve to enhance the students’ knowledge about nursing as a profession with its own theories, science and scholarship. In addition, all students have to write a research paper that entails to interview one nursing professional and one physician about their ideas of interprofessional communication and to compare the interviews with their own experiences from the nursing internship. To access what students learned during the course a reflective discussion takes place at the last meeting combined with an analysis of the students’ research papers. Results: The assessment of the students’ perceptions about the nursing profession and the importance of successful interprofessional communication showed a new and deeper understanding of the topic. They were able to identify barriers and support measures of interprofessional communication and their own responsibilities as part of a team.Conclusion: Interprofessional education is an important part of medical education and should be a topic from the beginning. The assessment of the course shows that it is possible and important to integrate the topic early in the curriculum