Progressive Degeneration of Human Mesencephalic Neuron Derived Cells Triggered by Dopamine-Dependent Oxidative Stress Is Dependent on the Mixed-Lineage Kinase Pathway

Models of Parkinson's disease (PD) based on selective neuronal death have been used to study pathogenic mechanisms underlying nigral cell death and in some instances to develop symptomatic therapies. For validation of putative neuroprotectants, a model is desirable in which the events leading to neurodegeneration replicate those occurring in the disease.Wedeveloped ahumanin vitro model ofPDbased on the assumption that dysregulated cytoplasmic dopamine levels trigger cell loss in this disorder. Differentiated human mesencephalic neuron-derived cells were exposed to methamphetamine (METH) to promote cytoplasmic dopamine accumulation. In the presence of elevated iron concentrations, as observed in PD, increased cytosolic dopamine led to oxidative stress, c-Jun N-terminal kinase (JNK) pathway activation, neurite degeneration, and eventually apoptosis. We examined the role of the mixed lineage kinases (MLKs) in this complex degenerative cascade by using the potent inhibitor 3,9-bis[(ethylthio)methyl]-K-252a (CEP1347). Inhibition of MLKs not only prevented FeCl2+/METH-induced JNK activation and apoptosis but also early events such as neurite degeneration and oxidative stress. This broad neuroprotective action of CEP1347 was associated with increased expression of an oxidative stress-response modulator, activating transcription factor 4. As a functional consequence, transcription of the cystine/glutamate and glycine transporters, cellular cystine uptake and intracellular levels of the redox buffer glutathione were augmented. In conclusion, this new human model of parkinsonian neurodegeneration has the potential to yield new insights into neurorestorative therapeutics and suggests that enhancement of cytoprotective mechanisms, in addition to blockade of apoptosis, may be essential for disease modulation

The TRI 2007 and CMP 2013 Surveys of Members of Parliament

The study was conducted in two waves of interviews among members of parliament in two old and five new democracies as part of a larger comparative study of democratic development. While the TRI 2007 elite survey did not only include members of parliament, but also media elites, the integrated data file includes parliamentarians only. During the survey period 04.11.2006 to 16.12.2013, members of parliament were interviewed in face-to-face interviews and telephone interviews on the following topics: democracy, religion and the church, and the impact of the global financial and economic crisis. Respondents were selected by random sampling (Chile: full survey (Total universe/Complete enumeration).Satisfaction with life; trusting most people vs. need to be very careful; groups of people the respondent would not like to have as neighbors (people of a different race, people who have AIDS, immigrants or foreign workers, people of a different religion); estimated proportion of the population who would not want immigrants or foreign workers as neighbors; estimated proportion of voters or supporters of own party who would not want immigrants or foreign workers as neighbors; no freedom of choice vs. great deal of control over own life; people taking advantage of you if the got a chance vs. people try to be fair; country’s most important aim (first choice and second choice: maintaining order in the nation, giving people mor say in important government decisions, fighting rising prices, protecting freedom of speech); respondent`s position on a Left-right scale; estimated position of respondents party on a Left-right scale; estimated position of party`s voters on a Left-right scale; estimated position of population as a whole on a Left-right scale; income equality vs. income differences as incentives for individual effort; private vs. government ownership of business and industry; private vs. government responsibility for provision; competition is good and stimulates people to work hard vs. competition is harmful and brings out the worst in people; confidence in different organizations (religious communities, armed forces, press, television, labor unions, police, courts, government, political parties, parliament, the civil service, banks, environmental organizations, women`s organizations, charitable or humanitarian organizations, country specific regional organization (e.g. African Union, EU), United Nations, Constitutional Court; rating of various types of political systems (having a strong leader who does not have to bother with parliament and elections, having experts, not government, make decisions according to what they think is best for the country, having the army rule, having a democratic political system); essential characteristics of democracy (governments tax the rich and subsidize the poor, the individual human right to dignity (e.g. respect of others) is upheld, people choose their leaders in free elections, People receive state aid for unemployment, Civil rights protect people’s liberty against oppression, the economy is prospering, women have the same rights as men, complete freedom for anyone to criticize the government, equality of the vote in elections, basic necessities like shelter, food and water for everyone, jobs for everyone, equal opportunity in education, minority rights); rating of the current governments performance in handling the above mentioned matters; agreement with the following statement: Although democracy has many shortcomings, it is still better than any other political system; extend to which the country is democratically governed today; satisfaction with the development of democracy in the country; extent of respect for individual human rights nowadays in the country; likelihood that authorities could enforce the law if a person committed a serious crime and if a person did not pay tax on some of the earned income; likelihood that court will punish elected public office holders, civil servants and managers of private businesses who take bribes; prevalence of corruption in the country amongst elected public office holders, amongst civil servants, and amongst managers of private businesses; agreement with the following statements about the current political system (people have freedom of speech and association, nobody needs to be afraid of arbitrary arrest, people have the freedom to choose who to vote for without being pressured); rating of the communication between various political groups (governing and opposition parties, governing parties and mass media, opposition parties and mass media, governing parties and NGOs, and between the opposition parties and NGOs). Frequency of thinking about the meaning of life; religion or religious denomination; frequency of attending religious services; self-evaluation as religious person; opinion on churches (are giving adequate answers to the moral problems and needs of the individual, to the problems of family life, to people`s spiritual needs and to the social problems facing the society); importance of God in life; justification of homosexuality, of prostitution, of abortion, of divorce and of death penalty; proud to be citizen of the country. Global financial and economic crisis: evaluation of the current state of economy; evaluation of the state of economy compared to 12 months ago; evaluation of the state of economy over the next 12 months; impact of financial and economic crisis on the country in general, on country´s economy, on country´s banking system, on the people´s standard of living, and on the quality of democracy in the country; rating of the performance of different actors in handling the impact of the crisis (national government, parties (country specific), International Monetary Fund (IMF), G20, and the EU); personal involvement in government decision-making dealing with the crisis; parties that benefited or suffered from the crisis (country specific); crisis as a consequence of neo-liberal economic policies; impact of the crisis has already reached its peak vs. the worst is yet to come; position of different parties (country specific) on economic and welfare policies; respondents position on welfare state dealing with the crisis; rating of the contribution of national policy measures to overcoming the crisis; fairness of income distribution in the country; impact of the crisis on income distribution ; frequency of: public procurement contracts for most favorable kickbacks, public sector employees treat some groups unfairly, public sectors favor applicants with whom the have strong personal contacts, public sector employees act impartially); economic policy should be run by politicians or experts; economic policy in the country is run by politicians or experts; evaluation of globalization; more important in a democracy: equality or freedom; closer to own vision of state: guaranteeing political freedoms or equalizing citizens` welfare; perceived conflict between different groups in society (between the rich and the poor, young and old, religious believers and non-believers (atheists), women and men, employees and employers, public and private sector employees, educated and uneducated, working and middle classes, and between farmers and urban population). Demography: country of birth; highest level of formal education, father´s and mother´s highest level of formal education, party of respondent (country specific). Additionally coded was: survey wave; unique ID, case ID; country of interview; date of interview; weighting factors.Die Studie wurde in zwei Befragungswellen unter Parlamentsmitgliedern in zwei alten und fünf neuen Demokratien im Rahmen einer größeren vergleichenden Studie zur demokratischen Entwicklung durchgeführt. Während in der Elitenerhebung des TRI 2007 nicht nur Parlamentarier, sondern auch Medieneliten erfasst wurden, sind im integrierte Datensatz nur die Daten der Parlamentarier enthalten. Im Erhebungszeitraum 04.11.2006 bis 16.12.2013 wurden Parlamentsmitglieder in persönlichen und telefonischen Interviews zu folgenden Themen befragt: Demokratie, Religion und Kirche sowie Einfluss der weltweiten Finanz- und Wirtschaftskrise. Die Auswahl der Befragten erfolgte durch Wahrscheinlichkeitsauswahl (Chile: Vollerhebung).Lebenszufriedenheit; Vertrauen in die meisten Menschen vs. Notwendigkeit, sehr vorsichtig zu sein; Personengruppen, die der Befragte ungern als Nachbarn hätte (Menschen anderer Hautfarbe, Menschen mit AIDS, Immigranten/Gastarbeiter, Menschen anderer Religion); geschätzter Anteil der Bevölkerung, der Immigranten/Gastarbeiter als Nachbarn ablehnt; geschätzter Anteil der Wähler oder Anhänger der eigenen Partei, die Immigranten/Gastarbeiter als Nachbarn ablehnen; keine Wahlfreiheit vs. viel Kontrolle über das eigene Leben; Menschen, die einen ausnutzen, wenn sie die Chance dazu haben vs. Menschen versuchen, fair zu sein; wichtigstes Ziel des Landes (erste und zweite Wahl: Aufrechterhaltung der Ordnung im Land, mehr Mitsprache bei wichtigen Regierungsentscheidungen, Kampf gegen steigende Preise, Schutz der Redefreiheit); Position des Befragten auf einer Links-Rechts-Skala; geschätzte Position der Partei des Befragten auf einer Links-Rechts-Skala; geschätzte Position der Wähler der Partei auf einer Links-Rechts-Skala; geschätzte Position der Bevölkerung insgesamt auf einer Links-Rechts-Skala; Einkommensgleichheit vs. Einkommensunterschiede als Anreiz für individuelle Anstrengungen; privates vs. staatliches Eigentum an Unternehmen und Industrie; private vs. staatliche Verantwortung für die Versorgung; Wettbewerb ist gut und stimuliert die Menschen zu harter Arbeit vs. Wettbewerb ist schädlich und bringt das Schlechteste im Menschen hervor; Vertrauen in verschiedene Organisationen (Religionsgemeinschaften, Streitkräfte, Presse, Fernsehen, Gewerkschaften, Polizei, Gerichte, Regierung, politische Parteien, Parlament, öffentlicher Dienst, Banken, Umweltorganisationen, Frauenorganisationen, karitative oder humanitäre Organisationen, länderspezifische regionale Organisationen (z. B. Afrikanische Union, Europäische Union), Vereinte Nationen, Verfassungsgericht; Bewertung verschiedener Arten politischer Systeme (ein starker Führer, der sich nicht um Parlament und Wahlen kümmern muss, Experten, nicht die Regierung, die Entscheidungen treffen, die sie am besten für das Land halten, die Armee als Herrscher, ein demokratisches politisches System); wesentliche Merkmale der Demokratie (Regierungen besteuern Reiche und subventionieren Arme, das individuelle Menschenrecht auf Würde (z. B. Respekt vor anderen) wird gewahrt, die Menschen wählen ihre Führer in freien Wahlen, die Menschen erhalten staatliche Hilfe bei Arbeitslosigkeit, die Bürgerrechte schützen die Freiheit der Menschen vor Unterdrückung, die Wirtschaft floriert, Frauen haben die gleichen Rechte wie Männer, völlige Freiheit für jeden, die Regierung zu kritisieren, Gleichheit der Stimmen bei Wahlen, Grundbedürfnisse wie Unterkunft, Nahrung und Wasser für alle, Arbeitsplätze für alle, Chancengleichheit im Bildungswesen, Minderheitenrechte); Bewertung der Leistung der gegenwärtigen Regierung im Umgang mit den oben genannten Merkmalen; Zustimmung zu folgender Aussage: Obwohl die Demokratie viele Mängel hat, ist sie immer noch besser als jedes andere politische System; Ausmaß, in dem das Land heute demokratisch regiert wird; Zufriedenheit mit der Entwicklung der Demokratie im Land; Ausmaß der Achtung der individuellen Menschenrechte heutzutage im Land; Wahrscheinlichkeit, dass die Behörden das Gesetz durchsetzen können, wenn eine Person ein schweres Verbrechen begangen hat und wenn eine Person einen Teil ihres Einkommens nicht versteuert hat; Wahrscheinlichkeit, dass Gerichte gewählte Amtsträger, Beamte und Manager von Privatunternehmen bestrafen, die Bestechungsgelder annehmen; Verbreitung von Korruption im Land unter gewählten Amtsträgern, unter Beamten und unter Managern von Privatunternehmen; Zustimmung zu den folgenden Aussagen über das derzeitige politische System (die Menschen haben Rede- und Vereinigungsfreiheit, niemand muss Angst vor willkürlicher Verhaftung haben, die Menschen haben die Freiheit zu wählen, wen sie wählen wollen, ohne unter Druck gesetzt zu werden); Bewertung der Kommunikation zwischen verschiedenen politischen Gruppen (Regierungs- und Oppositionsparteien, Regierungsparteien und Massenmedien, Oppositionsparteien und Massenmedien, Regierungsparteien und NRO sowie zwischen den Oppositionsparteien und NRO). Häufigkeit des Nachdenkens über den Sinn des Lebens; Religion oder Konfession; Häufigkeit des Besuchs von Gottesdiensten; Selbsteinschätzung als religiöse Person; Meinung über Kirchen (geben angemessene Antworten auf die moralischen Probleme und Bedürfnisse des Einzelnen, auf die Probleme des Familienlebens, auf die spirituellen Bedürfnisse der Menschen und auf die sozialen Probleme der Gesellschaft); Bedeutung von Gott im Leben; Rechtfertigung von Homosexualität, Prostitution, Abtreibung, Scheidung und Todesstrafe; Stolz darauf, Bürger des Landes zu sein. Globale Finanz- und Wirtschaftskrise: Bewertung der aktuellen Wirtschaftslage; Bewertung der Wirtschaftslage im Vergleich zu vor 12 Monaten; Bewertung der Wirtschaftslage in den nächsten 12 Monaten; Auswirkungen der Finanz- und Wirtschaftskrise auf das Land im Allgemeinen, auf die Wirtschaft des Landes, auf das Bankensystem des Landes, auf den Lebensstandard der Bevölkerung und auf die Qualität der Demokratie im Land; Bewertung der Leistung der verschiedenen Akteure bei der Bewältigung der Auswirkungen der Krise (nationale Regierung, Parteien (länderspezifisch), Internationaler Währungsfonds (IWF), G20 und EU); Persönliche Beteiligung an der Entscheidungsfindung der Regierung im Umgang mit der Krise; Parteien, die von der Krise profitiert oder darunter gelitten haben (länderspezifisch); Krise als Folge der neoliberalen Wirtschaftspolitik; Auswirkungen der Krise haben ihren Höhepunkt bereits erreicht bzw. das Schlimmste steht noch bevor; Position der verschiedenen Parteien (länderspezifisch) zur Wirtschafts- und Sozialpolitik; Position der Befragten zum Umgang des Sozialstaates mit der Krise; Bewertung des Beitrags nationaler politischer Maßnahmen zur Überwindung der Krise; Gerechtigkeit der Einkommensverteilung im Land; Auswirkungen der Krise auf die Einkommensverteilung; Häufigkeit von: Vergabe öffentlicher Aufträge gegen Schmiergelder, Angestellte des öffentlichen Sektors behandeln einige Gruppen unfair, Angestellte des öffentlichen Sektors bevorzugen Bewerber, zu denen sie starke persönliche Kontakte haben, Angestellte des öffentlichen Sektors handeln unparteiisch; Wirtschaftspolitik sollte von Politikern oder Experten betrieben werden; Wirtschaftspolitik im Land wird von Politikern oder Experten betrieben; Bewertung der Globalisierung; wichtiger in einer Demokratie: Gleichheit oder Freiheit; näher an der eigenen Vorstellung vom Staat: Gewährleistung politischer Freiheiten oder Ausgleich des Wohlergehens der Bürger; wahrgenommener Konflikt zwischen verschiedenen Gruppen in der Gesellschaft (zwischen Reichen und Armen, Jungen und Alten, Gläubigen und Nicht-Gläubigen (Atheisten), Frauen und Männern, Arbeitnehmern und Arbeitgebern, Angestellten des öffentlichen und privaten Sektors, Gebildeten und Ungebildeten, Arbeitern und Mittelschicht sowie zwischen Landwirten und städtischer Bevölkerung). Demografie: Geburtsland; höchster formaler Bildungsgrad; höchster formaler Bildungsgrad von Vater und Mutter; Partei des Befragten (länderspezifisch). Zusätzlich kodiert wurden: Erhebungswelle; eindeutige ID; Fall-ID; Land der Befragung; Interviewdatum; Gewichtungsfaktoren

Formation of α clusters in dilute neutron-rich matter

International audienceThe surface of neutron-rich heavy nuclei, with a neutron skin created by excess neutrons, provides an important terrestrial model system to study dilute neutron-rich matter. By using quasi-free α cluster–knockout reactions, we obtained direct experimental evidence for the formation of α clusters at the surface of neutron-rich tin isotopes. The observed monotonous decrease of the reaction cross sections with increasing mass number, in excellent agreement with the theoretical prediction, implies a tight interplay between α-cluster formation and the neutron skin. This result, in turn, calls for a revision of the correlation between the neutron-skin thickness and the density dependence of the symmetry energy, which is essential for understanding neutron stars. Our result also provides a natural explanation for the origin of α particles in α decay.</jats:p

Early rhythm-control therapy in patients with atrial fibrillation

BACKGROUND Despite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk. METHODS In this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed ≤1 year before enrollment) and cardiovascular conditions to receive either early rhythm control or usual care. Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation–related symptoms. The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome; the second primary outcome was the number of nights spent in the hospital per year. The primary safety outcome was a composite of death, stroke, or serious adverse events related to rhythm-control therapy. Secondary outcomes, including symptoms and left ventricular function, were also evaluated. RESULTS In 135 centers, 2789 patients with early atrial fibrillation (median time since diagnosis, 36 days) underwent randomization. The trial was stopped for efficacy at the third interim analysis after a median of 5.1 years of follow-up per patient. A first-primary-outcome event occurred in 249 of the patients assigned to early rhythm control (3.9 per 100 person-years) and in 316 patients assigned to usual care (5.0 per 100 person-years) (hazard ratio, 0.79; 96% confidence interval, 0.66 to 0.94; P=0.005). The mean (±SD) number of nights spent in the hospital did not differ significantly between the groups (5.8±21.9 and 5.1±15.5 days per year, respectively; P=0.23). The percentage of patients with a primary safety outcome event did not differ significantly between the groups; serious adverse events related to rhythm-control therapy occurred in 4.9% of the patients assigned to early rhythm control and 1.4% of the patients assigned to usual care. Symptoms and left ventricular function at 2 years did not differ significantly between the groups. CONCLUSIONS Early rhythm-control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with early atrial fibrillation and cardiovascular conditions

Post-anaesthesia pulmonary complications after use of muscle relaxants (POPULAR): a multicentre, prospective observational study

Background Results from retrospective studies suggest that use of neuromuscular blocking agents during general anaesthesia might be linked to postoperative pulmonary complications. We therefore aimed to assess whether the use of neuromuscular blocking agents is associated with postoperative pulmonary complications. Methods We did a multicentre, prospective observational cohort study. Patients were recruited from 211 hospitals in 28 European countries. We included patients (aged ≥18 years) who received general anaesthesia for any in-hospital procedure except cardiac surgery. Patient characteristics, surgical and anaesthetic details, and chart review at discharge were prospectively collected over 2 weeks. Additionally, each patient underwent postoperative physical examination within 3 days of surgery to check for adverse pulmonary events. The study outcome was the incidence of postoperative pulmonary complications from the end of surgery up to postoperative day 28. Logistic regression analyses were adjusted for surgical factors and patients’ preoperative physical status, providing adjusted odds ratios (ORadj) and adjusted absolute risk reduction (ARRadj). This study is registered with ClinicalTrials.gov, number NCT01865513. Findings Between June 16, 2014, and April 29, 2015, data from 22803 patients were collected. The use of neuromuscular blocking agents was associated with an increased incidence of postoperative pulmonary complications in patients who had undergone general anaesthesia (1658 [7·6%] of 21694); ORadj 1·86, 95% CI 1·53–2·26; ARRadj –4·4%, 95% CI –5·5 to –3·2). Only 2·3% of high-risk surgical patients and those with adverse respiratory profiles were anaesthetised without neuromuscular blocking agents. The use of neuromuscular monitoring (ORadj 1·31, 95% CI 1·15–1·49; ARRadj –2·6%, 95% CI –3·9 to –1·4) and the administration of reversal agents (1·23, 1·07–1·41; –1·9%, –3·2 to –0·7) were not associated with a decreased risk of postoperative pulmonary complications. Neither the choice of sugammadex instead of neostigmine for reversal (ORadj 1·03, 95% CI 0·85–1·25; ARRadj –0·3%, 95% CI –2·4 to 1·5) nor extubation at a train-of-four ratio of 0·9 or more (1·03, 0·82–1·31; –0·4%, –3·5 to 2·2) was associated with better pulmonary outcomes. Interpretation We showed that the use of neuromuscular blocking drugs in general anaesthesia is associated with an increased risk of postoperative pulmonary complications. Anaesthetists must balance the potential benefits of neuromuscular blockade against the increased risk of postoperative pulmonary complications