Robert H G Schwinger

Universität Regensburg, Ratisbon, Bavaria, Germany

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Publications (293)1082.99 Total impact

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    Full-text · Dataset · Aug 2015
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    ABSTRACT: End of life is an unfortunate but inevitable phase of the heart failure patients' journey. It is often preceded by a stage in the progression of heart failure defined as advanced heart failure, and characterised by poor quality of life and frequent hospitalisations. In clinical practice, the efficacy of treatments for advanced heart failure is often assessed by parameters such as clinical status, haemodynamics, neurohormonal status, and echo/MRI indices. From the patients' perspective, however, quality-of-life-related parameters, such as functional capacity, exercise performance, psychological status, and frequency of re-hospitalisations, are more significant. The effects of therapies and interventions on these parameters are, however, underrepresented in clinical trials targeted to assess advanced heart failure treatment efficacy, and data are overall scarce. This is possibly due to a non-universal definition of the quality-of-life-related endpoints, and to the difficult standardisation of the data collection. These uncertainties also lead to difficulties in handling trade-off decisions between quality of life and survival by patients, families and healthcare providers. A panel of 34 experts in the field of cardiology and intensive cardiac care from 21 countries around the world convened for reviewing the existing data on quality-of-life in patients with advanced heart failure, discussing and reaching a consensus on the validity and significance of quality-of-life assessment methods. Gaps in routine care and research, which should be addressed, were identified. Finally, published data on the effects of current i.v. vasoactive therapies such as inotropes, inodilators, and vasodilators on quality-of-life in advanced heart failure patients were analysed. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Full-text · Article · May 2015 · International Journal of Cardiology
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    Full-text · Dataset · Oct 2014
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    ABSTRACT: Background The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. Methods and results A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. Conclusions The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.
    Full-text · Article · Jun 2014
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    ABSTRACT: The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.
    Full-text · Article · Apr 2014 · International journal of cardiology
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    Full-text · Dataset · Apr 2014
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    ABSTRACT: BACKGROUND: Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms. METHODS: In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS: The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001). CONCLUSIONS: Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).
    No preview · Dataset · Mar 2014
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    Full-text · Article · Oct 2013 · European Heart Journal
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    ABSTRACT: Aim: The present study investigated whether eNOS-activation may be dysregulated in cardiac tissue of patients suffering from type 2 diabetes (T2D). Main methods: We performed immunohistochemical measurements of translocated eNOS-activation as well as eNOS-phosphorylation at Ser1177, Thr495, Ser 635, Ser114 and of the protein kinase B (Akt) in isolated right atrial trabeculae of patients undergoing cardiac bypass or valve surgery with (n=12, 68.1 ± 2.5 years) and without T2D (n=12, 64.7 ± 2.7 years). In addition, we investigated oxidative (8-isoprostane) and nitrosative stress markers (nitrotyrosine) as well as the effect of pharmacological stimulation of angiotensin (AT)-receptors on eNOS-phosphorylation. Key findings: Translocation-dependent eNOS-activation was similar in both groups. The same holds true for eNOS-phosphorylation at Ser114. eNOS-phosphorylation at Ser635 was significantly increased, whereas eNOS-phosphorylation of Ser1177 was significantly decreased in the diabetic group paralleled by a decrease in phosphorylation of Akt and Thr495. These alterations were accompanied by a significant decrease in nitrotyrosine. After application of angiotensin II (10 µM, 2 min.) for investigation of the AT-receptor-dependent eNOS-stimulation, we did not find differences between the increases in eNOS-Ser1177-phosphorylation in the non-diabetic (+39.7% ± 23.5%) and in the diabetic group (32.22% ± 11.45%). A simultaneous increase in Akt-phosphorylation could not be observed. Significance: The present study indicates that T2D goes along with a decrease in eNOS-phosphorylation at Ser1177 under basal conditions in cardiac tissue. Whether this may be attributed to the insulin resistance of cardiac muscle has to be further investigated. Receptor-stimulated eNOS-activation still works at least for angiotensin II-dependent eNOS-activation.
    Preview · Article · Dec 2012 · Journal of Applied Physiology
  • Hannes Reuter · Robert H G Schwinger
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    ABSTRACT: The fast cycling of calcium between internal stores and the myofilaments with rapid diffusion down steep concentration gradients provides the cellular basis for cardiac contraction and relaxation. In heart failure, the intracellular Ca(2) (+) dynamics are impaired showing reduced systolic peak Ca(2) (+), elevated diastolic Ca(2) (+) levels, and prolonged diastolic Ca(2) (+) decay. The recognition that defects in the function of Ca(2) (+) handling proteins are central to the pathogenesis of heart failure has attracted attention to these proteins as potential targets for therapy. Besides pharmacologic interventions including digitalis, ranolazine, levosimendan and others, cardiac gene therapy holds great promise and the recent clinical studies have proven the feasibility of this therapeutic approach. In this review, the rationale underlying modern therapies that modulate intracellular Ca(2) (+) handling for the treatment of human heart failure are presented and discussed.
    No preview · Article · Jun 2012 · Wiener Medizinische Wochenschrift
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    ABSTRACT: The Glasgow-Pittsburgh cerebral performance categories (GP-CPC) and the Glasgow Outcome Score (GOS) have been used to categorize patients according to their neurological outcome for prognostic predictors in patients after cardiac arrest (CA). We postulated that inclusion of deaths without knowing the cerebral status into the group of patients with poor outcome after CA using the GP-CPC and GOS will lead to dilution of the prognostic power of the investigated biochemical marker. The present study was conducted to verify this issue by employing a modified outcome score, which we termed as Modified Glasgow Outcome Score (MGOS). In the present study, 97 patients were enrolled in a prospective manner. Serum NSE and S100B levels were measured daily for 7 days after admission to the intensive care unit. Neurological outcome was assessed by employing the GOS and MGOS after 6 months. By employing the GOS, 46 patients were categorized into the group of patients with poor outcome and 51 patients survived with good neurological outcome. Patients who died without certified brain damage or with unknown cerebral status after CA (n = 20) were separated from patients with poor outcome in the MGOS. The magnitude of NSE (S100B) elevation in patients with poor outcome categorized by the MGOS was approximately 1.7-fold (1.5) higher as compared with patients divided by the GOS. The mean calculated sensitivities and area under the curve values of NSE and S100B predicting poor outcome classified by the MGOS were significantly higher as compared with the GOS. Conclusively, inclusion of deaths without certified brain damage or with unknown cerebral status into the group of patients with poor outcome will lead to underestimation of the prognostic power of investigated biochemical markers such as NSE and S100B. The MGOS will help to avoid this bias.
    Full-text · Article · Feb 2012 · Clinical Research in Cardiology
  • Dennis Ladage · Robert H.G. Schwinger · Klara Brixius
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    ABSTRACT: SUMMARY  For the past 40 years, beta-blockers have been widely used in cardiovascular medicine, reducing morbidity as well as mortality. Beta-blockers are currently used in a number of cardiovascular conditions such as systolic heart failure, postmyocardial infarction, and in prevention and treatment of arrhythmias. They are not recommended as the first line antihypertensive therapy, particularly in the elderly, unless there are specific indications. Despite the benefits of beta-blockers, tolerability concerns in patients with co-morbidities have limited their use. Some of these problems were overcome with the discovery of cardioselective beta-blockers. The third generation beta-blockers have additional properties of vasodilatation and advantages in terms of minimizing the adverse effects of beta-blockers. Some of the advantages include improvement of insulin resistance, decrease in cholesterol as well as alleviation of erectile dysfunction. Acute treatment with beta-blockers modifies local muscular metabolic properties and impairs endurance exercise capacity whereas the influence of chronic is debated controversially.
    No preview · Article · Jan 2012 · Cardiovascular Therapeutics
  • Eva Rieckeheer · Robert H.G. Schwinger · Wilhelm Bloch · Klara Brixius
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    ABSTRACT: WS(®) 1442 is a special extract of hawthorn leaves with flowers used for the treatment of mild cardiac failure. The activation of endothelial nitric oxide synthase (eNOS) has been shown to contribute to its vasodilating properties. Quite recently it has been demonstrated that red blood cells (RBCs) express a functional NO-synthase (rbcNOS) and rbcNOS activation has been associated with increased RBC deformability. The aim of the present study was to determine whether WS(®) 1442 is able to activate rbcNOS, to induce NO-formation in RBC and to alter RBC-deformability. Blood from healthy volunteers was incubated with WS(®) 1442 (25-100 μg/ml) for up to 30 min. RbcNOS activation was detected by immunohistochemical staining of phosphorylated rbcNOS and NO-formation was examined by diaminofluorescein (DAF) fluorescence. RBC deformability was measured by a laser assisted optical rotational cell analyzer. Serine 1177 of RbcNOS (rbcNOS Ser(1177)) was time- and concentration-dependently phosphorylated by WS(®) 1442. Rates of rbcNOS Ser(1177) phosphorylation were up to 149% higher in RBCs treated with WS(®) 1442 in comparison to control (DMSO 0.05%). WS(®) 1442 induced a time-dependent increase in NO-formation in RBCs which reached its maximum after 5 min. An increase in shear stress (0.3-50 Pa) caused an increase in RBC deformability. WS(®) 1442 did not change either basal or maximal RBC-deformability or shear stress sensitivity of RBC at normoxia. CONCLUSION: WS(®) 1442 activates rbcNOS and causes NO-formation in RBCs. WS(®) 1442-dependent NO-formation however does not affect RBC-deformability at normoxia.
    No preview · Article · Sep 2011 · Phytomedicine: international journal of phytotherapy and phytopharmacology
  • Christian Brinkmann · Robert H. G. Schwinger · Klara Brixius
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    ABSTRACT: Type 2 diabetic patients have an increased level of systemic free radicals, which severely restrict the bioavailability of endothelium-derived nitric oxide (NO) and thus contribute to the development of an endothelial dysfunction. This review analyses the influence of physical training on molecular development mechanisms of the endothelial dysfunction and determines the significance of regular physical exercise for the endothelial function in type 2 diabetic patients. Systematic training reinforces the endogenic antioxidative capacity and results in a reduction in oxidative stress. Training – also combined with a change in diet – furthermore reduces hyperglycaemic blood sugar levels, thus curbing a major source of free radicals in diabetes. Moreover, physical exercise enhances vascular NO synthesis through an increased availability/activity of endothelial NO synthases (eNOS). Endurance, as well as resistance training with submaximal intensity or a combination of both forms of training is suitable to effectively improve the endothelial function in type 2 diabetic patients in the long term.
    No preview · Article · Sep 2011 · Wiener Medizinische Wochenschrift
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    Christian Brinkmann · Robert H G Schwinger · Klara Brixius

    Preview · Article · Sep 2011 · Wiener Medizinische Wochenschrift
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    ABSTRACT: Recently, increased cardiac norepinephrine levels were observed in patients who were exposed to irregular stimulation during electrophysiological testing. The molecular mechanisms remain unclear. Intrinsic cardiac adrenergic (ICA) cells are present in mammalian hearts and contain catecholamine-synthesizing enzymes sufficient to produce biologically active norepinephrine levels. Thus, we aimed to investigate the expression of catecholamine-synthesizing enzymes by ICA cells exposed to irregular pacing. Co-cultures of cardiomyocytes and ICA cells were exposed to irregular pacing for 48h (standard deviation (SD)=5%, 25% and 50% of mean cycle length) at a constant rate of 5Hz. The expression of catecholamine-synthesizing enzymes including tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DBH) were analyzed on mRNA and protein levels. First, immunolabeling identified ICA cells presenting TH and DBH staining around the cell nucleus. Irregular pacing with 25% SD at a constant rate of 5Hz significantly increased the expression of TH and DBH enzyme synthesis. Pharmacological approaches have shown that both metoprolol and losartan reversed the irregular pacing induced DBH increase, whereas the expression of TH was only blocked by metoprolol in a significant manner. Blockade of the endothelin-A receptor by BQ123 or the calcineurin-NFAT pathway by cyclosporine-A, 11R-VIVIT or FK506 revealed a potential role of both cascades in irregular pacing induced catecholamine-synthesizing enzyme expression. ICA cells respond to irregular electrical activation with an increase in catecholamine-synthesizing enzymes. Drugs commonly used in clinical routine significantly influence the expression of TH and DBH by ICA cells via different signaling routes.
    No preview · Article · Aug 2011 · Biochemical and Biophysical Research Communications
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    ABSTRACT: An irregular ventricular response during atrial fibrillation (AF) has been shown to mediate an increase in sympathetic nerve activity in human subjects. The molecular mechanisms remain unclear. This study aimed to investigate the impact of rate and irregularity on nerve growth factor (NGF) expression in cardiomyocytes, since NGF is known to be the main contributor to cardiac sympathetic innervation density. Cell cultures of neonatal rat ventricular myocytes were electrically stimulated for 48 h with increasing rates (0, 5 and 50 Hz) and irregularity (standard deviation (SD)=5%, 25% and 50% of mean cycle length). Furthermore, we analyzed the calcineurin-NFAT and the endothelin-1 signalling pathways as possible contributors to NGF regulation during arrhythmic stimulation. We found that the increase of NGF expression reached its maximum at the irregularity of 25% SD by 5 Hz (NGF: 5 Hz 0% SD=1 vs. 5Hz 25% SD=1.57, P<0.05). Specific blockade of the ET-A receptor by BQ123 could abolish this NGF increase (NGF: 5 Hz 25% SD+BQ123=0.66, P<0.05). High frequency electrical field stimulation (HFES) with 50 Hz decreased the NGF expression in a significant manner (NGF: 50Hz=0.55, P<0.05). Inhibition of calcineurin-NFAT signalling with cyclosporine-A or 11R-VIVIT abolished the HFES induced NGF down-regulation (NGF: 50 Hz+CsA=1.14, P<0.05). In summary, this study reveals different signalling routes of NGF expression in cardiomyocytes exposed to increasing rates and irregularity. Whether this translates into different degrees of NGF expression and possibly neural sympathetic growth in various forms of ventricular rate control during AF remains to be elucidated in further studies.
    No preview · Article · Aug 2011 · Cellular Signalling
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    ABSTRACT: The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators.
    Full-text · Article · Jul 2011 · International journal of cardiology
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    ABSTRACT: Mechanical stretch has been shown to increase vascular endothelial growth factor (VEGF) expression in cultured myocytes. Sympathetic neurons (SN) also possess the ability to express and secrete VEGF, which is mediated by the NGF/TrkA signaling pathway. Recently, we demonstrated that SN respond to stretch with an upregulation of nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF). Whether stretch increases neuronal VEGF expression still remains to be clarified. Therefore, SN from the superior cervical ganglia of neonatal Sprangue Dawley rats were exposed to a gradual increase of stretch from 3% up to 13% within 3days (3%, 7% and 13%). Under these conditions, the expression and secretion of VEGF was analyzed. Mechanical stretch significantly increased VEGF mRNA and protein expression (mRNA: control=1 vs. stretch=3.1; n=3/protein: control=1 vs. stretch=2.7; n=3). ELISA experiments to asses VEGF content in the cell culture supernatant showed a time and dose dependency in VEGF increment due to stretch. NGF and CNTF neutralization decreased stretch-induced VEGF augmentation in a significant manner. This response was mediated in part by TrkA receptor activation. The stretch-induced VEGF upregulation was accompanied by an increase in HIF-1α expression. KDR levels remained unchanged under conditions of stretch, but showed a significant increase due to NGF neutralization. In summary, SN respond to stretch with an upregulation of VEGF, which is mediated by the NGF/CNTF and TrkA signaling pathway paralleled by HIF-1α expression. NGF signaling seems to play an important role in regulating neuronal KDR expression.
    No preview · Article · Jun 2011 · Biochemical and Biophysical Research Communications
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    ABSTRACT: Age has been identified as an independent risk factor for cardiovascular diseases. A shift of the cardiac autonomic nervous system towards an increase in sympathetic tone has been reported in the elderly. Nerve growth factor (NGF) is the main neurotrophic factor that increases the sympathetic activity of the heart. If there is a shift of NGF expression in old compared to young cardiomyocytes and whether there are regional differences in the heart still remain unclear. Therefore, we chose a rat model of different-aged rats (3-4 days = neonatal, 6-8 weeks = young, 20-24 months = old), and isolated cardiomyocytes from the left and the right atrium (LA, RA), as well as from the left and the right ventricle (LV, RV), were used to determine NGF expression on mRNA and protein levels. In neonatal, young, and old rats, NGF amount in LA and RA was significantly lower as compared to LV and RV. In young and old rats, we found significant higher NGF protein levels in LA compared to RA. In addition, both atria showed an increase in NGF expression between age groups neonatal, young, and old. In both ventricles, we observed a significant decrease in NGF expression from neonatal to young rats and a significant increase from young to old rats. The highest NGF amount in LV and RV was observed in neonatal rats. Regarding tyrosine kinase A receptor (TrkA) expression, the main receptor for NGF signaling, both atria showed the largest expression in old rats; while in LV and RV, TrkA was expressed mainly in young rats. These results point to a contribution of nerve growth factors to the change of autonomic tone observed in elderly patients.
    Full-text · Article · May 2011 · Age

Publication Stats

6k Citations
1,082.99 Total Impact Points

Institutions

  • 2009-2015
    • Universität Regensburg
      Ratisbon, Bavaria, Germany
  • 2011-2012
    • University Hospital Regensburg
      • Klinik und Poliklinik für Innere Medizin II
      Ratisbon, Bavaria, Germany
  • 2007-2012
    • Klinikum Weiden
      Weyden, Bavaria, Germany
  • 2006-2011
    • Deutsche Sporthochschule Köln
      • Abteilung molekulare und zelluläre Sportmedizin
      Köln, North Rhine-Westphalia, Germany
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
  • 1993-2009
    • University of Cologne
      • • Division of Cardiology, Pneumology, Angiology and Intensive Care
      • • Department of Internal Medicine
      • • Department of Cardiothoracic Surgery
      Köln, North Rhine-Westphalia, Germany
  • 1990-1991
    • University Hospital München
      München, Bavaria, Germany