Regional governance and local school development policy in the process of de- or reconstructing regional structures of educational institutions

Der politikwissenschaftliche und ökonomische Diskurs über Governance und neue Steuerung dominiert seit einigen Jahren auch die schulpolitischen und erziehungswissenschaftlichen Debatten über Schulentwicklung. In dem Beitrag werden die Chancen und Grenzen dieses Politikmodells - sowohl als bildungspolitische Strategie wie auch als analytisches Instrumentarium - an einem konkreten empirischen Fall überprüft und diskutiert. Empirische Grundlage sind ausgewählte Daten und Teilergebnisse eines Forschungsprojekts zur wissenschaftlichen Begleitung von kommunalen Schulentwicklungsinitiativen in Westfalen. Im Prozess des Rück- und Umbaus regionaler Schulangebotsstrukturen, der heute durch den demographischen Wandel erzwungen wird, erweisen sich die interkommunale Standortkonkurrenz und die etablierten kommunalpolitischen Akteure als bestimmende Faktoren, wenn dabei politische Handlungsstrategien verfolgt werden, die als Local Governance bezeichnet werden können. (DIPF/Orig.)For several years now, the political-scientific and economic discourse on governance has also dominated the school-political and educational-scientific debates on school development. Drawing on a concrete empirical example, the authors examine and discuss the opportunities and limitations of this political model - both as an educational-political strategy and as analytical instrument. The study\u27s empirical basis is formed by selected data and partial results from a research project for the scientific monitoring of local school development initiatives in Westphalia. In the process of de- and reconstructing regional structures of educational institutions - a process forced by present-day demographic change - inter-communal competition between locations and the established players on the local political field prove to be the decisive factors if strategies of political action are pursued which can be described as local governance. (DIPF/Orig.

Oxidative Stress and Inflammatory Modulation of Ca2+ Handling in Metabolic HFpEF-Related Left Atrial Cardiomyopathy

Metabolic syndrome-mediated heart failure with preserved ejection fraction (HFpEF) is commonly accompanied by left atrial (LA) cardiomyopathy, significantly affecting morbidity and mortality. We evaluate the role of reactive oxygen species (ROS) and intrinsic inflammation (TNF-α, IL-10) related to dysfunctional Ca2+ homeostasis of LA cardiomyocytes in a rat model of metabolic HFpEF. ZFS-1 obese rats showed features of HFpEF and atrial cardiomyopathy in vivo: increased left ventricular (LV) mass, E/e' and LA size and preserved LV ejection fraction. In vitro, LA cardiomyocytes exhibited more mitochondrial-fission (MitoTracker) and ROS-production (H2DCF). In wildtype (WT), pro-inflammatory TNF-α impaired cellular Ca2+ homeostasis, while anti-inflammatory IL-10 had no notable effect (confocal microscopy; Fluo-4). In HFpEF, TNF-α had no effect on Ca2+ homeostasis associated with decreased TNF-α receptor expression (western blot). In addition, IL-10 substantially improved Ca2+ release and reuptake, while IL-10 receptor-1 expression was unaltered. Oxidative stress in metabolic syndrome mediated LA cardiomyopathy was increased and anti-inflammatory treatment positively affected dysfunctional Ca2+ homeostasis. Our data indicates, that patients with HFpEF-related LA dysfunction might profit from IL-10 targeted therapy, which should be further explored in preclinical trials

Left ventricular dysfunction in heart failure with preserved ejection fraction-molecular mechanisms and impact on right ventricular function

The current classification of heart failure (HF) based on left ventricular (LV) ejection fraction (EF) identifies a large group of patients with preserved ejection fraction (HFpEF) with significant morbidity and mortality but without prognostic benefit from current HF therapy. Co-morbidities and conditions such as arterial hypertension, diabetes mellitus, chronic kidney disease, adiposity and aging shape the clinical phenotype and contribute to mortality. LV diastolic dysfunction and LV structural remodeling are hallmarks of HFpEF, and are linked to remodeling of the cardiomyocyte and extracellular matrix. Pulmonary hypertension (PH) and right ventricular dysfunction (RVD) are particularly common in HFpEF, and mortality is up to 10-fold higher in HFpEF patients with vs. without RV dysfunction. Here, we review alterations in cardiomyocyte function (i.e., ion homeostasis, sarcomere function and cellular metabolism) associated with diastolic dysfunction and summarize the main underlying cellular pathways. The contribution and interaction of systemic and regional upstream signaling such as chronic inflammation, neurohumoral activation, and NO-cGMP-related pathways are outlined in detail, and their diagnostic and therapeutic potential is discussed in the context of preclinical and clinical studies. In addition, we summarize prevalence and pathomechanisms of RV dysfunction in the context of HFpEF and discuss mechanisms connecting LV and RV dysfunction in HFpEF. Dissecting the molecular mechanisms of LV and RV dysfunction in HFpEF may provide a basis for an improved classification of HFpEF and for therapeutic approaches tailored to the molecular phenotype

Right‐ventricular dysfunction in HFpEF is linked to altered cardiomyocyte Ca2+ homeostasis and myofilament sensitivity

Aim Heart failure with preserved ejection fraction (HFpEF) is frequently (30%) associated with right ventricular (RV) dysfunction, which increases morbidity and mortality in these patients. Yet cellular mechanisms of RV remodelling and RV dysfunction in HFpEF are not well understood. Here, we evaluated RV cardiomyocyte function in a rat model of metabolically induced HFpEF. Methods: and results Heart failure with preserved ejection fraction-prone animals (ZSF-1 obese) and control rats (Wistar Kyoto) were fed a high-caloric diet for 13 weeks. Haemodynamic characterization by echocardiography and invasive catheterization was performed at 22 and 23 weeks of age, respectively. After sacrifice, organ morphometry, RV histology, isolated RV cardiomyocyte function, and calcium (Ca2+) transients were assessed. ZSF-1 obese rats showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV diastolic dysfunction (including increased LV end-diastolic pressures and E/e ' ratio), and preserved LV ejection fraction. ZSF-1 obese animals developed RV dilatation (50% increased end-diastolic area) and mildly impaired RV ejection fraction (42%) with evidence of RV hypertrophy. In isolated RV cardiomyocytes from ZSF-1 obese rats, cell shortening amplitude was preserved, but cytosolic Ca2+ transient amplitude was reduced. In addition, augmentation of cytosolic Ca2+ release with increased stimulation frequency was lost in ZSF-1 obese rats. Myofilament sensitivity was increased, while contractile kinetics were largely unaffected in intact isolated RV cardiomyocytes from ZSF-1 obese rats. Western blot analysis revealed significantly increased phosphorylation of cardiac myosin-binding protein C (Ser282 cMyBP-C) but no change in phosphorylation of troponin I (Ser23, 24 TnI) in RV myocardium from ZSF-1 obese rats. Conclusions: Right ventricular dysfunction in obese ZSF-1 rats with HFpEF is associated with intrinsic RV cardiomyocyte remodelling including reduced cytosolic Ca2+ amplitudes, loss of frequency-dependent augmentation of Ca2+ release, and increased myofilament Ca2+ sensitivity

Effects of different exercise modalities on cardiac dysfunction in heart failure with preserved ejection fraction

Aims: Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent disease. Physical exercise has been shown to alter disease progression in HFpEF. We examined cardiomyocyte Ca2+ homeostasis and left ventricular function in a metabolic HFpEF model in sedentary and trained rats following 8 weeks of moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT). Methods and results: Left ventricular in vivo function (echocardiography) and cardiomyocyte Ca2+ transients (CaTs) (Fluo-4, confocal) were compared in ZSF-1 obese (metabolic syndrome, HFpEF) and ZSF-1 lean (control) 21- and 28-week-old rats. At 21 weeks, cardiomyocytes from HFpEF rats showed prolonged Ca-2(+) reuptake in cytosolic and nuclear CaTs and impaired Ca2+ release kinetics in nuclear CaTs. At 28 weeks, HFpEF cardiomyocytes had depressed CaT amplitudes, decreased sarcoplasmic reticulum (SR) Ca2+ content, increased SR Ca2+ leak, and elevated diastolic [Ca2+] following increased pacing rate (5 Hz). In trained HFpEF rats (HIIT or MICT), cardiomyocyte SR Ca2+ leak was significantly reduced. While HIIT had no effects on the CaTs (1-5 Hz), MICT accelerated early Ca-2(+) release, reduced the amplitude, and prolonged the CaT without increasing diastolic [Ca2+] or cytosolic Ca2+ load at basal or increased pacing rate (1-5 Hz). MICT lowered pro-arrhythmogenic Ca2+ sparks and attenuated Ca2+-wave propagation in cardiomyocytes. MICT was associated with increased stroke volume in HFpEF. Conclusions: In this metabolic rat model of HFpEF at an advanced stage, Ca2+ release was impaired under baseline conditions. HIIT and MICT differentially affected Ca2+ homeostasis with positive effects of MICT on stroke volume, end-diastolic volume, and cellular arrhythmogenicity

Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF

Background: Sodium-glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF. Methods: 17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca2+ transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca2+ release were recorded by ratiometric microscopy using Ca2+-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca2+ buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student's t-test, as applicable. Results: Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca2+ release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca2+] of CaT at baseline and in response to glucose influx, possibly related to a similar to 50% increase of sodium sodium-calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca2+ buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca2+ accumulation upon glycolytic inhibition. Conclusion: The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca2+-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca2+ buffer capacity, diastolic Ca2+ accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials

Radiotherapy for hormone-sensitive prostate cancer with synchronous low burden of distant metastases.

PURPOSE The DEGRO Expert Commission on Prostate Cancer has revised the indication for radiation therapy of the primary prostate tumor in patients with synchronous distant metastases with low metastatic burden. METHODS The current literature in the PubMed database was reviewed regarding randomized evidence on radiotherapy of the primary prostate tumor with synchronous low metastatic burden. RESULTS In total, two randomized trials were identified. The larger study, the STAMPEDE trial, demonstrated an absolute survival benefit of 8% after 3 years for patients with low metastatic burden treated with standard of care (SOC) and additional radiotherapy (RT) (EQD2 ≤ 72 Gy) of the primary tumor. Differences in the smaller Horrad trial were not statistically significant, although risk reduction in the subgroup (< 5 bone metastases) was equal to STAMPEDE. The STOPCAP meta-analysis of both trials demonstrated the benefit of local radiotherapy for up to 4 bone lesions and an additional subanalysis of STAMPEDE also substantiated this finding in cases with M1a-only metastases. CONCLUSION Therefore, due to the survival benefit after 3 years, current practice is changing. New palliative SOC is radiotherapy of the primary tumor in synchronously metastasized prostate cancer with low metastatic burden (defined as ≤ 4 bone metastases, with or without distant nodes) or in case of distant nodes only detected by conventional imaging

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Studies on fire spread in road tunnels

Im Rahmen des Forschungsprojektes wurden für verschiedene Tunnel mit Rechteck- und Gewölbequerschnitt mit dem Regelquerschnitt RG 31t (bzw. RQ 10,5), die orts- und zeitabhängigen Verteilungen der Gastemperatur, der Gasgeschwindigkeit und Gaszusammensetzung, der adiabaten Decken- und Wandtemperaturen sowie der zeitliche Verlauf der Wärmefreisetzungsrate und des Durchwärmungsverhaltens bestimmt werden. Betrachtet wurden Tunnel mit konstanter Längsneigung von 3 % sowie ein Tunnel mit muldenfoermigem Längsprofil (Richtungs- und Gegenverkehr). Bezüglich der Austrittgeschwindigkeit wurden die Szenarien 20,6 kg/s und 300 kg/s unterschieden. Zusätzlich im Fall A ein mit Holzpaletten beladenen LKW und im Fall B zusätzlich noch weitere PKW und LKW berücksichtigt. In einem originalmaßstäblichen Großbrandversuch wurde zur Klärung offener, aus der Modellierung resultierender Fragen ein Unfall in einem Richtungsverkehrstunnel zwischen einem LKW, der mit ca. 3,7 t Europoolpaletten beladen war, und einem PKW nachgebildet. Insgesamt wurden 3 Mittelklasse-PKW im Versuchstunnel positioniert. Die Brandlast betrug ca. 123 GJ. Anhand durchgeführter Plattenbrandversuche wurde festgestellt, dass die Schichten aus spritzbarem Faserbeton des Systems RUB sowie die Fertigteilschutzschichten des Systems HOCHTIEF ein relativ geringes bzw. kein Abplatzverhalten aufweisen und bei Brandbeanspruchung jeweils einen signifikanten thermischen Schutz der Stahlbetonkonstruktion gewährleisten können. Es konnte gezeigt werden, dass Auswirkungen auf die Tragstruktur nicht größer sind als infolge eines Brands, dessen Temperatur-Zeit-Verlauf dem ZTV-ING-Verlauf entspricht. Es sei aber angemerkt, dass aus den Szenarien unter noch ungünstigeren Bedingungen (z.B. im Falle eingeschränkt funktionsfähiger Schlitzrinnen) Auswirkungen entstehen könnten, die nur durch den verlängerten ZTV-ING-Temperatur-Zeit-Verlauf abgedeckt wären.As part of the research project, various tunnels with rectangular or arched cross sections and the standard cross-section RG 31t (or RQ 10.5), the site- and time-dependent distributions of the gas temperature, the gas velocity and gas composition, the adiabatic wall and ceiling temperatures as well as the heat release rate and the propagation of the heat shall be determined. Tunnels with a continuous longitudinal slope of 3% and a tunnel with a bowl-shaped longitudinal profile (unidirectional and bi-directional traffic) shall be examined. For the exhaust velocity, the scenarios can differ between 20.6 kg/s and 300 kg/s. Furthermore, a truck loaded with wooden pallets was taken into account for case A and further cars and trucks for case B. In a full-scale large fire test an accident was simulated in a unidirectional tunnel between a truck loaded with approx. 3.7 t of Euro pallets and car to clarify unanswered questions from modelling. A total of 3 medium-sized cars were positioned in the test tunnel. The fire load was approx. 123 GJ. On the basis of fire tests carried out with plates it was determined that the layer of sprayable fibre concrete from the RUB system and the prefabricated protective layers from the HOCHTIEF system display a relatively or even no spalling and each can provide a significant thermal protection of the reinforced concrete structure in case of fire. It could be shown that the impact on the supporting structure is not greater than in case of a fire having a temperature-time curve according to the ZTV-ING curve. However, it should be noted that scenarios under even more unfavourable conditions (e.g. in the case of limited functional drainage channels) could have a negative effect that can only be covered by the extended ZTV-ING temperature-time curve