Delivery of viral vectors to the heart represents a challenging endeavor. Besides vector design, the route of substrate administration is significantly influencing gene delivery success. The ...selective retrograde venous injection (SRVI) represents one of the most efficient percutaneous delivery strategies for transduction of the anterior left ventricular myocardium. In this chapter, we discuss the advantages and limitations of this vector delivery approach and provide a protocol for selective retrograde venous injection in a preclinical large animal model. As limited transgene expression frequently hampers generation of reliable proof-of-principle data and thus translation, this technique provides a valuable tool to ensure high myocardial transduction in preclinical research.
Learning from connectomics on the fly Schlegel, Philipp; Costa, Marta; Jefferis, Gregory SXE
Current opinion in insect science,
December 2017, 2017-12-00, Letnik:
24
Journal Article
Recenzirano
Odprti dostop
•Whole brain EM connectomics will revolutionise neuroscience.•Insects are at the forefront of this revolution.•Mapping between light and EM image data can integrate anatomy and function.•Quantitative ...definitions of cell type will promote experiments and communication.•Tools and resources that integrate big neuroscience data are critical for neurobiologists.
Parallels between invertebrates and vertebrates in nervous system development, organisation and circuits are powerful reasons to use insects to study the mechanistic basis of behaviour. The last few years have seen the generation in Drosophila melanogaster of very large light microscopy data sets, genetic driver lines and tools to report or manipulate neural activity. These resources in conjunction with computational tools are enabling large scale characterisation of neuronal types and their functional properties. These are complemented by 3D electron microscopy, providing synaptic resolution data. A whole brain connectome of the fly larva is approaching completion based on manual reconstruction of electron-microscopy data. An adult whole brain dataset is already publicly available and focussed reconstruction is under way, but its 40× greater volume would require ∼500–5000 person-years of manual labour. Nevertheless rapid technical improvements in imaging and especially automated segmentation will likely deliver a complete adult connectome in the next 5 years. To enhance our understanding of the circuit basis of behaviour, light and electron microscopy outputs must be integrated with functional and physiological information into comprehensive databases. We review presently available data, tools and opportunities in Drosophila. We then consider the limits and potential of future progress and how this may impact neuroscience in rich model systems provided by larger insects and vertebrates.
Direct volume rendering has become a popular method for visualizing volumetric datasets. Even though computers are continually getting faster, it remains a challenge to incorporate sophisticated ...illumination models into direct volume rendering while maintaining interactive frame rates. In this paper, we present a novel approach for advanced illumination in direct volume rendering based on GPU ray-casting. Our approach features directional soft shadows taking scattering into account, ambient occlusion and color bleeding effects while achieving very competitive frame rates. In particular, multiple dynamic lights and interactive transfer function changes are fully supported. Commonly, direct volume rendering is based on a very simplified discrete version of the original volume rendering integral, including the development of the original exponential extinction into a-blending. In contrast to a-blending forming a product when sampling along a ray, the original exponential extinction coefficient is an integral and its discretization a Riemann sum. The fact that it is a sum can cleverly be exploited to implement volume lighting effects, i.e. soft directional shadows, ambient occlusion and color bleeding. We will show how this can be achieved and how it can be implemented on the GPU.
Recurrent episodes of decompensated heart failure (HF) represent an emerging cause of hospitalizations in developed countries with an urgent need for effective therapies. Recently, the ...pregnancy-related hormone relaxin (RLN) was found to mediate cardio-protective effects and act as a positive inotrope in the cardiovascular system. RLN binds to the RLN family peptide receptor 1 (RXFP1), which is predominantly expressed in atrial cardiomyocytes. We therefore hypothesized that ventricular RXFP1 expression might exert potential therapeutic effects in an in vivo model of cardiac dysfunction. Thus, mice were exposed to pressure overload by transverse aortic constriction and treated with AAV9 to ectopically express RXFP1. To activate RXFP1 signaling, RLN was supplemented subcutaneously. Ventricular RXFP1 expression was well tolerated. Additional RLN administration not only abrogated HF progression but restored left ventricular systolic function. In accordance, upregulation of fetal genes and pathological remodeling markers were significantly reduced. In vitro, RLN stimulation of RXFP1-expressing cardiomyocytes induced downstream signaling, resulting in protein kinase A (PKA)-specific phosphorylation of phospholamban (PLB), which was distinguishable from β-adrenergic activation. PLB phosphorylation corresponded to increased calcium amplitude and contractility. In conclusion, our results demonstrate that ligand-activated cardiac RXFP1 gene therapy represents a therapeutic approach to attenuate HF with the potential to adjust therapy by exogenous RLN supplementation.
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The hormone relaxin and its receptor RXFP1 mediate several beneficial cardiovascular effects. This report demonstrates that AAV-mediated expression of RXFP1 combined with relaxin administration rescues ventricular function in a pressure-overload model. The results suggest that ligand-activated cardiac RXFP1 gene therapy might represent a therapeutic approach to attenuate heart failure.
We developed an automatic method for synaptic partner identification in insect brains and use it to predict synaptic partners in a whole-brain electron microscopy dataset of the fruit fly. Those ...predictions can be used to infer a connectivity graph with high accuracy, thus allowing fast identification of neural pathways. To facilitate circuit reconstruction using our results, we developed CircuitMap, a user interface add-on for the circuit annotation tool Catmaid.
Background
Sacubitril/valsartan (S/V) improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Data about the immediate, short-, and intermediate-term hemodynamic ...effects of S/V are limited.
Methods
In this prospective observational study, 37 outpatients with chronic HFrEF were treated with S/V according to current guideline recommendations. Next to clinical, laboratory and echocardiographic parameters, haemodynamic variables were assessed non-invasively by use of inert gas rebreathing and bioimpedance cardiography at baseline and at 2-week, 3-month and 6-month follow-up. The course of variables throughout the study and the relationship between variables were analysed using fractional polynomials.
Results
S/V treatment resulted in short- and intermediate-term improvements in NYHA functional class (2.3 ± 0.6 at baseline vs. 1.9 ± 0.5 at 6-month follow-up,
p =
0.14), 6-min walk test (453 ± 110 vs. 528 ± 98 m,
p =
0.02), ejection fraction (31 ± 9 vs. 36 ± 12%,
p =
0.13), pulmonary artery pressure (39 ± 10 vs. 31 ± 10 mmHg,
p =
0.02), and NT-proBNP values (1702 (782–2897 vs. 1004 (599–1627) ng/L,
p =
0.03). In addition, S/V caused immediate decreases in systemic vascular resistance index (SVRI) and systolic blood pressure (SBP), which were associated with a simultaneous drop in stroke volume (SV) and cardiac index (CI). However, while SVRI and SBP remained at low levels during further treatment, SV and CI restored rapidly and increased to slightly higher levels thereafter.
Conclusion
The vasodilative effects of S/V result in immediate reductions in SVRI, SBP, SV and CI. However, S/V induces reverse cardiac remodelling, which is apparent shortly after treatment initiation and leads to improvements of clinical, functional, echocardiographic, laboratory and haemodynamic variables.
The trend towards electrification in the energy and transportation sector requires the build-up of new production capacities for the next generation of high-end battery cells and packs. Consistent ...high quality products, minimum manufacturing costs and modularity of the production system are considered central planning targets. Here we present a multi-level-simulation approach that is able to complement conventional planning targets while assessing the usage of energy within battery cell manufacturing considering machine availability and site locations. The energy assessment combines simulation models at machine and process level with a model that specifies technical building systems and the building shell. The simulation model was parameterized based on insights from scientific literature, equipment manufacturer data sheets and was checked for plausability through expert interviews. Our results show that improving the energy efficiency of the coating / drying process can reduce total energy consumption of the battery manufacturing system by 13 to 30 % depending on machine availability. Considering the location of the reference factory, Germany performed best in terms of primary energy demand, Sweden best in terms of energy related CO2 emissions and China achieved superior results in terms of energy related costs.
Transcatheter edge-to-edge repair (TEER) using the MitraClip™ device has been established as a suitable alternative to mitral valve surgery in patients with severe mitral regurgitation (MR) and high ...or prohibitive surgical risk. Only limited information regarding the impact of TEER on ventricular arrhythmias (VA) has been reported. The aim of the present study was to assess the impact of TEER using the MitraClip
device on the burden of VA and ICD (Implantable Cardioverter Defibrillator) therapies. Among 600 MitraClip
implantations performed in our clinic between September 2009 and October 2018, we identified 86 patients with successful TEER and an active implantable cardiac device (pacemaker, ICD, CRT-P/D (Cardiac Resynchronization Therapy-Pacemaker/Defibrillator)) eligible for retrospective VA analyses. These patients presented with mainly functional MR (81.4%) and severely reduced left ventricular ejection fraction (mean LVEF 22.1% ± 10.3%). The observation period comprised 456 ± 313 days before and 424 ± 287 days after TEER. The burden of ventricular arrhythmias (sustained ventricular tachycardia (sVT) and ventricular fibrillation (VF)) was significantly reduced after TEER (0.85 ± 3.47 vs. 0.43 ± 2.03 events per patient per month,
= 0.01). Furthermore, the rate of ICD therapies (anti-tachycardia pacing (ATP) and ICD shock) decreased significantly after MitraClip
implantation (1.0 ± 3.87 vs. 0.32 ± 1.41,
= 0.014). However, reduction of VA burden did not result in improved two-year survival in this patient cohort with severely reduced LVEF. Mitral valve TEER using the MitraClip™ device was associated with a significant reduction of ventricular arrhythmias and ICD therapies.
Sachkunde Interventionelle Echokardiographie Rudolph, Volker; von Bardeleben, Ralph Stephan; Hagendorff, Andreas ...
Der Kardiologe,
09/2022, Letnik:
16, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Die interventionelle Therapie struktureller Herzerkrankungen hat eine immense Entwicklung durchlaufen, und viele innovative Ansätze sind mittlerweile fester Bestandteil der klinischen Routine. ...Hierdurch gewinnt die Standardisierung der Prozeduren zur Sicherung der Versorgungsqualität eine immer größere Bedeutung. Die interventionelle Echokardiographie spielt für die Qualität der Prozeduren eine herausragende Bedeutung. Dabei setzt das echokardiographische Guiding höchste Ansprüche an den Echokardiographeur und erfordert zudem Kenntnisse über die verwendeten Devices und Abläufe der Prozeduren. Das vorliegende Positionspapier fasst diese Inhalte der interventionellen Echokardiographie zusammen. Die aufgeführten Inhalte dienen als Grundlage für künftig von der Deutschen Gesellschaft für Kardiologie angebotene Kurse, die zur Erlangung der Sachkunde Interventionelle Echokardiographie absolviert werden müssen. Neben dem wichtigen Aspekt der Qualitätssicherung ist es Ziel der vorliegenden Sachkunde, die Wahrnehmung der interventionellen Echokardiographie als neu entstandene, eigenständige, der interventionellen Tätigkeit gleichwertige Kompetenz zu fördern.
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