Aufstieg und Scheitern der intellektuellen Revolution des Iran Akteur*innen und Ideen der Reformbewegung

Seit der Islamischen Revolution 1979 setzte das Regime unter dem Revolutionsführer Ayatollah Khomeini seine Herrschaftsauffassung mit Gewalt und gegen großen Widerstand anderer Revolutionär*innen durch. Nach Khomeinis Tod 1989 war es erstmals möglich, den Absolutheitsanspruch der ¬Rechtsgelehrten in Frage zu stellen. Es entstand eine Reformbewegung, die mit dem Wahlsieg Mohammad Khatamis als Präsident im Jahre 1997 ihre größte Chance auf einen Systemwandel hatte. Ihre Anhänger*innen forderten eine zivilgesellschaftliche Wende auf der Basis von Toleranz und Pluralismus, welche sich islamisch begründen ließ oder einem säkularen Staatsverständnis unterlag. Die Arbeit beschäftigt sich mit der Frage, wieso die Reformbewegung unter Präsident Khatami keine Demokratisierung und zivilgesellschaftliche Wende des iranischen Systems herbeiführen konnte und wie der konservative Klerus es vermochte, die Machtzentren weiterhin zu besetzen und zu kontrollieren. Das Scheitern der Reformbewegung wird dabei auf drei Ebenen betrachtet: institutionell, personenbezogen und ideologisch. Zudem wird dieses Scheitern im Spannungsdreieck aus den Widersprüchlichkeiten des politischen Systems, der Ohnmacht der Reformer*innen und dem Aufstieg der Konservativen verortet (vgl. Akbari, 2007, S.1)

N-acetyl-b-D-glucosaminidase: A potential cardiorenal biomarker with a relevant impact on ICD shock therapies and mortality

Aims Chronic heart failure may lead to chronic kidney disease. Previous studies suggest tubular markers N-acetyl-b-D-glucosaminidase (NAG) and Kidney-injury-molecule-1 (KIM-1) as potential markers for the cardiorenal syndrome (CRS). The prognostic value of NAG and KIM-1 regarding implantable cardioverter defibrillator (ICD) shock therapies is unknown. Methods We included 314 patients with an ICD and collected plasma and urine samples. Urine-values of NAG and KIM-1 got related to urinary creatinine. Outcomes of interest were sustained adequate shock therapies and a combined endpoint of all-cause mortality, rehospitalisation due to congestive heart failure and adequate shock therapies. Follow up time was 32 months (IQR 6-35 months). Results KIM-1 and NAG were positively correlated with NT-proBNP (KIM-1:r= .34,P < .001; NAG:r= .47,P < .001). NAG was significantly elevated in patients with primary prevention compared with secondary prevention ICD indication (P= .003). According to Kaplan Meier analysis, NAG as well as NT-proBNP were significant predictors for adequate ICD shock therapies and for the combined endpoint (eachP < .001). Elevated KIM-1 showed no significant differences (eachP= n.s.). In multivariate cox regression analysis, NAG as well as NT-proBNP were both independent predictors for adequate ICD shock therapies as well as the combined endpoint, beside ejection fraction <35% (eachP < .05). Diabetes, primary prevention ICD indication, coronary artery disease, eGFR and age were no significant predictors for both endpoints (eachP= n.s.). Conclusion Similar to NT-proBNP, NAG showed promising value for overall prognostication in ICD patients. Especially, NAG seems to incorporate an additional prognostic value regarding occurrence of ICD shock therapies

The adipo‐fibrokine activin A is associated with metabolic abnormalities and left ventricular diastolic dysfunction in obese patients

Aims Left ventricular diastolic dysfunction (LVDD) is common in obese subjects, and a relationship between epicardial adipose tissue (EAT), increased adipocytokines, and cardiovascular diseases has been reported. This study sought to examine as to whether the adipo-fibrokine activin A is a link between increased EAT, the metabolic syndrome (MetS), and LVDD in severely obese subjects. Methods and results In 236 obese subjects (empty set body mass index 39.8 +/- 7.9 kg/m(2) ) with a variable degree of the MetS and in 60 healthy non-obese controls (empty set body mass index 24.8 +/- 3.4 kg/m(2)), serum activin A levels were measured and correlated with parameters of the MetS, epicardial fat thickness (EFT), and echocardiographic parameters of LVDD. Activin A levels were higher in obese than in non-obese subjects (362 +/- 124 vs. 301 +/- 94 pg/mL, P = 0.0004), increased with the number of MetS components (from 285 +/- 82 with no MetS component, 323 +/- 94 with one or two MetS components, to 403 +/- 131 pg/ml with >= 3 MetS components, P < 0.0001) and correlated with EFT (r = 0.41, P < 0.001). Furthermore, activin A levels were related to several parameters of LVDD [e.g. left atrial size (382 +/- 117 vs. 352 125 pg/ml, P = 0.024), E/e' (394 +/- 108 vs. 356 +/- 127 pg/mL, P = 0.005)]. LVDD was highest in MetS obese subjects with high EFT (44.3%) compared with MetS obese subjects with low EFT (27.0%), non-MetS obese subjects with high EFT (24.2%), and non-MetS obese subjects with low EFT (10.6%, P < 0.0001). Conclusions In severe obesity, activin A was significantly related to EFT, MetS, and LVDD, implicating MetS-related alterations in the secretory profile of EAT in the pathogenesis of obesity-related heart disease

Improvement of obstructive sleep apnea does not rescue left atrial enlargement in obese participants of a multimodal weight reduction program

The aim of our study was to investigate the effect of obstructive sleep apnea (OSA) and its weight loss related improvement on left atrial (LA) area in individuals with severe obesity participating in a multimodal weight reduction (WR) program. Participants with obesity (body mass index, BMI, 40.2 ± 7.3 kg/m2) underwent a 1-year WR program. Phenotyping was performed at baseline and after 12 months. Individuals were categorized according to their baseline apnea-hypopnea-index (AHI) into “no OSA” (AHI < 5) and “OSA” (AHI ≥ 5). From a total of 84 study participants, 69 completed the program. Average WR was 19.0 ± 15.7 kg after 12 months. Participants with obesity and OSA had a larger LA area at baseline as compared to participants with obesity but without OSA (22.4 ± 5.6 vs 18.8 ± 3.8 cm2; P = .008). Linear regression showed significant associations of AHI and BMI with LA area. In contrast, despite a significant decrease of AHI in participants with OSA as compared to those without OSA at 1 year follow up (ΔAHI was −12 ± 14) ΔLA area did not significantly differ between groups. Multivariable linear regression showed no significant association of ΔAHI or ΔBMI with ΔLA. In conclusion, the presence of obstructive sleep apnea contributes to LA enlargement on top of obesity in our study cohort. Yet, successful WR with subsequently improved OSA was not associated with an improvement of LA area

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Effects of Vitamin D3, Butyrate and Intestamin® on expression of Cathelicidin gene camp

In ständigem Kontakt mit zahlreichen Mikroorganismen benötigt unser Körper eine Vielzahl an Mechanismen zur Abwehr krankheitserregender Keime. Antimikrobielle Peptide unterstützen als Effektormoleküle die einzellige Epithelschicht des Darms, die als Mukosabarriere unseren Körper vor dem Eindringen pathogener Keime bewahrt. Die Expression des antimikrobiellen Peptids LL-37, auch Cathelicidin genannt, stellt eine Strategie des angeborenen Immunsystems zur Abwehr von Mikroorganismen im Kolon dar. Die Expression des Cathelicidin Gens camp kann, wie in der vorliegenden Arbeit untersucht wurde, durch exogene Faktoren, wie die biologisch aktive Form des Vitamin D3, das 1,25(OH)2D3, die kurzkettige Fettsäure Butyrat und das Ernährungssupplement Intestamin®, angeregt werden. Die Stimulation der Zellen mit den genannten Substanzen führte in allen gestesteten Zelllinien zeit- und dosisabhängig zu einer Steigerung der Expression des Cathelicidin Gens. Die Induktion der camp-Expression durch 1,25(OH)2D3 wird durch die Existenz eines Vitamin D Response Elements (VDRE) in der Promoterrregion des camp-Gens begründet, an das der Vitamin D-Rezeptor Komplex als ligandenabhängiger Transkriptionsfaktor bindet und die Genexpression vermittelt. Die Auswirkungen von Butyrat auf die Genexpression des Cathelicidins werden auf die Modifikation des Acetylierungsstatus der Histonproteine zurückgeführt. Butyrat bewirkt durch eine reversible Hemmung der Histondeacetylase die Hyperacetylierung bestimmter Kernhistone und greift auf diese Weise in die Regulation der Gentranskription ein. Das enterale Ernährungssupplement Intestamin®, das als Pharmakonutrition speziell für schwerkranke Patienten entwickelt wurde, ist reich an Glutamin-Dipeptiden, Tributyrin und Antioxidantien. Der Effekt, den Intestamin® auf die Expression des Cathelicidin Gens ausübt, ist wahrscheinlich auf Tributyrin zurückzuführen. Tributyrin, der Ester aus Glycerin und Butyrat, wird durch Hydrolyse zu Butyrat umgesetzt und bewirkt vermutlich die Steigerung der camp-Expression. Eine Co-Stimulation von GEKI 02 Zellen mit 1,25(OH)2D3 plus Butyrat erzielte nach 48 Stunden eine weitere Steigerung der Expression des Cathelicidin Gens gegenüber beiden Einzelsubstanzen. In allen anderen getesteten Zelllinien zeigte sich keine synergetische Wirkung der beiden Substanzen. Auch eine Co-Stimulation mit Intestamin® plus Butyrat konnte nicht zu einer stärkeren Zunahme der camp-Expression führen als eine Behandlung mit beiden Einzelsubstanzen. Eine synergetische Wirkung der Substanzen 1,25(OH)2D3 und Butyrat in GEKI 02 Zellen könnte durch die Acetylierung der Histone bedingt sein, die eine Auflockerung der Chromatinstruktur bewirkt, was wiederum die Bindung von Transkriptionsfaktoren wie dem Vitamin D-Rezeptor Komplex erleichtert. Die fehlende synergetische Wirkung in allen anderen getesteten Zelllinien könnte mit der Tatsache in Zusammenhang stehen, dass die Induktion der camp-Expression zeitabhängig ist: Vitamin D3 erzielte nach 24 Stunden, Butyrat nach 48 Stunden die deutlichsten Auswirkungen auf die Genexpression des Cathelicidins. Der Einfluss des MEK/ERK Signalweges auf die durch 1,25(OH)2D3, Butyrat und Intestamin® induzierte camp-Expression wurde in den durchgeführten Versuchen mittels des spezifischen MEK 1/2 Inhibitors U0126 untersucht. U0126 blockierte die Induktion des Cathelicidin Gens durch Intestamin® und Butyrat, was die Beteiligung des Signalweges MEK/ERK belegt. Vitamin D3 dagegen übt seinen Einfluss auf LL-37 nicht über den Signalweg MEK/ERK aus. Obwohl Vitamin D3 und Butyrat die Expression des Cathelicidin Gens camp induzieren, konnte die Inkubation der Zellen mit beiden Substanzen die antimikrobielle Aktivität der Kolonepithelzellen gegenüber E.coli im Vergleich zu unbehandelten Kontrollzellen nicht steigern. Ursächlich hierfür könnte neben der Wahl eines apathogenen Bakterienstammes das Mikromilieu der Umgebung sein. Außer der Konzentration des Peptids spielen insbesondere der pH-Wert und die Salzkonzentration des Kulturmediums eine wichtige Rolle, da sie die Ausbildung der Sekundärstruktur, nämlich der &#945;-helikalen Konformation, des LL-37 beeinflussen, die für die Interaktion mit Biomembranen erforderlich ist. Aufgrund der zunehmenden Resistenzentwicklung von Bakterien gegenüber herkömmlichen Antibiotika, wächst das Interesse an der Erforschung antimikrobieller Peptide. Exogene Faktoren wie 1,25(OH)2D3, Butyrat und Intestamin® können eine Steigerung der Expression des Cathelicidin Gens erzielen. Ob sich dieser Effekt allerdings auch in-vivo zeigt und eventuell therapeutischen Einsatz finden könnte, müssen weitere Studien klären.Defence of mucosal and epithelial surfaces against microbial pathogens involves the innate and adaptive immune response. The single cell layer of the colonic epithelium produces an array of immune modulators, including antimicrobial peptides, such as cathelicidins, that participate in the innate immune system. The aim of the present study was to analyse the effect of calcitriol, the histon-deacetylase inhibitor butyrate and the enteral pharmaconutrition supplement Intestamin® on the expression of the cathlicidin gene camp. After exposure to these stimuli a time and dose dependent induction of the expression of the cathelicidin gene was found in all investigated colorectal cell lines. The effect of calcitriol, 1,25(OH)2D3, is mediated by the vitamin D response element (VDRE) in the camp promoter that was bound by the vitamin D receptor (VDR). The induction of cathelicidin expression after treatment with butyrate is attributed to a reversible inhibition of histone deacetylases resulting in modulation of core histone and non-histone proteins and subsequent regulation of the gene transcription. The enteral pharmaconutrition supplement Intestamin® contains glutamine, antioxidant vitamins and tributyrin. The increased cathelicidin level after treatment with Intestamin® are ascribed to tributyrin because tributyrin is a novel structured lipid composed of three molecules of butyrate esterified with glycerol that induces the cathelicidin gene camp after hydrolysis to butyrate. When colorectal cells GEKI 02 were stimulated with 1,25(OH)2D3 plus butyrate, a further increase of cathelicidin expression was seen after 48 hours. This effect was not seen for the incubation with Intestamin® plus butyrate. Changes in the acetylation status of core histone and non-histone proteins caused by butyrate that enhance binding of the vitamin D receptor complex as a transcription factor might be responsible for the synergistic effect of butyrate and calcitriol. To determine the influence of the MEK/ERK signalling pathway in the investigated cell lines the specific MEK/ERK inhibitor U0126 was utilized. Inhibition of the MEK/ERK pathway blocked butyrate- and Intestamin®-induced cathelicidin expression while no effect was observed for calcitriol. Although incubation with vitamin D3 and butyrate increased cathelicidin expression, the antimicrobial activity against E.coli could not be enhanced in the investigated colorectal cells. This might be caused by selection of a commensal bacterium and the absence of relevant microenvironmental stimuli because the antibacterial activity correlates with the extent of &#945;-helicity, which is influenced by ion composition, pH, and peptide concentration. Due to the fast development of bacterial resistance to traditional antibiotics, there is increasing interest in the research on antimicrobial peptides. Exogenic factors like 1,25(OH)2D3, butyrate and Intestamin® can enhance an expression of the cathelicidin gene. Further in vivo studies, however, are necessary to verify this effect for the potential future therapeutic application

Successful weight reduction improves left ventricular diastolic function and physical performance in severe obesity

Obesity and the metabolic syndrome (MetS) are risk factors for left ventricular diastolic dysfunction (LVDD). However, little is known about the impact of successful weight reduction (WR) on diastolic function and physical performance. Obese subjects (øBMI 40.2 ± 8.6 kg/m2) underwent a 1-year WR program comprising diet and lifestyle components. Echocardiography and exercise capacity (6-minute walk) were performed at baseline and after 1 year. The distribution of weight reduction was split at the sample median and subjects were dichotomized in “successful WR” (% WR ≥ median, corresponding to a weight loss of 8%) and “failed-WR” (% WR < median). From a total of 188 obese subjects, 71 had LVDD at baseline. Obese patients with successful WR improved their MetS alterations, including fasting glucose, insulin, lipids, adipokines, blood pressure levels, and epicardial fat thickness. The same was not true for obesity with failed WR. Subjects with successful WR demonstrated significant improvement in echocardiographic LVDD parameters (median [interquartile range]): Δe’ (2,5 [-1.0, 4.7], P < 0.01), Δe’/a’ (0.34 [0.07, 079], P < 0.01), ΔE/e’ (-1.14 [-2.72, -0.54], P < 0.05), ΔE/A (0.08 [-0.04, 0.26], P < 0.05), ΔArd-Ad (-28 [-54, -4], P < 0.01), and 6-minute walk distance (65 [19, 135], P < 0.01). Improvement of ≥ 2 LVDD criteria was accomplished in 30% of subjects with WR versus 10% without (P = 0.009). Using multivariable regression analysis, reduction of epicardial fat thickness was particularly predictive for the improvement of diastolic function. In summary, in severe obesity, successful long-term WR was associated with improved LV diastolic function and exercise capacity

N-acetyl-ß-D-glucosaminidase is predictive of mortality in chronic heart failure: a 10-year follow-up

Aim: The study focused on biomarkers of kidney injury as predictors of mortality in patients with chronic heart failure (CHF) in a long-term follow-up (median 104 months). Methods/results: KIM-1, NAG and NGAL were assessed from urine, NT-proBNP from blood samples. 149 patients (age 62 +/- 12 years) with CHF (mean EF 30% [IQR 24-40%]) were enrolled. 79 (53%) patients died. Cox regression analysis revealed Log2NAG (HR: 1.46, CI: 1.12-1.89), Log2KIM-1 (HR: 1.23, CI: 1.02-1.49) and Log2NT-proBNP (HR: 1.50, CI: 1.32-1.72) as significant predictors of all-cause mortality as opposed to Log2NGAL (HR: 1.04, CI: 0.90-1.20). Log2NAG remained a significant predictor of all-cause mortality in a multivariate Cox regression model but lost its predictive value in combination with Log2NT-proBNP. Conclusion: The 10-year follow-up suggests NAG as a predictive tubular marker in CHF patients

Evaluation of a multimarker panel in chronic heart failure: a 10-year follow-up

Aim: We assessed the 10-year prognostic role of 11 biomarkers with different pathophysiological backgrounds. Materials & methods/results: Blood samples from 144 patients with heart failure were analyzed. After 10 years of follow-up (median follow-up was 104 months), data regarding all-cause mortality were acquired. Regarding Kaplan-Meier analysis, all markers, except TIMP-1 and GDF-15, were significant predictors for all-cause mortality. We created a multimarker model with nt-proBNP, hsTnT and IGF-BP7 and found that patients in whom all three markers were elevated had a significantly worse long-time-prognosis than patients without elevated markers. Conclusion: In a 10-year follow-up, a combination of three biomarkers (NT-proBNP, hs-TnT, IGF-BP7) identified patients with a high risk of mortality

Relation between obesity, the metabolic syndrome, successful long-term weight reduction and right ventricular function

This study sought to examine the relationships between right ventricular (RV) function and geometry, morbid obesity with and without the metabolic syndrome, and the effect of long-term weight loss. Obese (n = 153, BMI 41.2 ± 8.7 kg/m2) and healthy non-obese control subjects (n = 38, BMI 25.5 ± 3.3 kg/m2) of similar age and gender distribution were prospectively studied during the course of a 1-year weight reduction program with echocardiography at baseline and after one year of follow up. Function and geometry of the right heart were evaluated by tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (TDI S’), RV myocardial performance index (TEI), RV end-diastolic (RVEDD) and end-systolic diameter (RVESD), area of the right atrium (RAA), and systolic pulmonary artery pressure (PAP). Whereas parameters of systolic and diastolic LV function were significantly worse in the obese subjects than those in the non-obese subjects (EF 66 ± 6 versus 69 ± 6%, P = 0.004; E/E’ 7.4 ± 2.5 versus 6.3 ± 2.6, P = 0.010), parameters of RV function (TAPSE 25.6 ± 4.5 versus 25.1 ± 3.5 mm, P = 0.528; TDI S’ 13.5 ± 2.9 versus 13.8 ± 2.9 mm/second, P = 0.553; TEI 0.25 ± 0.13 versus 0.28 ± 0.09, P = 0.283) as well as geometry measurements were comparable between the obese and non-obese participants and also in obese subjects with full blown metabolic syndrome. Additionally, successful weight reduction did not alter the RV parameters. Nevertheless, in the few obese subjects with RV dysfunction (n = 7), metabolic syndrome parameters were more pronounced than in obese with normal RV function. Morbid obesity with and without the metabolic syndrome is accompanied by an impaired LV systolic and diastolic function. In contrast, RV function appears to be less affected by obesity independent of the presence of the metabolic syndrome