Zusammenfassung
Die Technik der Transkatheteraortenklappenimplantation (TAVI) hat einen festen Platz in der Therapie von inoperablen und Hochrisikopatienten mit symptomatischer, hochgradiger ...Aortenklappenstenose eingenommen. Eine Indikationsausweitung hin zu Patienten mit intermediärem Risikoprofil ist für die Zukunft wahrscheinlich. Inzwischen steht eine Vielzahl moderner, optimierter TAVI-Systeme zur Verfügung, mit denen eine differenzierte Therapie unter Berücksichtigung individueller klinischer und anatomischer Patientencharakteristika möglich ist. Dies hat, zusammen mit einer optimierten Prozedurplanung und gewachsener Anwendererfahrung, zu einer stetigen Verbesserung klinischer und hämodynamischer Ergebnisse nach TAVI geführt. Ein interdisziplinärer Heart-Team-Ansatz ist eine unverzichtbare Voraussetzung für die optimale Patientenversorgung.
ESA’s Design 2 produces cross-cutting initiative includes digitalisation, process automation, interoperability, and harnessing smart embedded sensors to achieve a seamless data cycle (SDC). The SDC ...in digital engineering covers requirements and design, production, assembly, integration, and testing as well as in-flight operations including recycling. Nevertheless, central data and legal challenges lie in the joint research addressed Europe-wide (geo-return) and the partner network constraints covering agency, large system integrator (LSI), research and development (R&D), and high-tech SME interests. Either way, a legal enabler for digitization of the European space business can be seen in ESA's strict compliance policy with regard to the acceptance of their general terms and conditions. In fact, it is reasonable to assume that ESA declares data to be a common deliverable in the future and that the contractors accept this too. However, there are technical challenges like portability, interoperability, interconnectivity, and the need for a federated infrastructure, while all these aspects have to be solved across company and national borders. The European Gaia-X project tackles the aforementioned challenges while targeting an open, transparent, and secure digital ecosystem in which data are stored, processed, and used while retaining data sovereignty. This paper deepens these framework conditions, addresses them from the perspective of real space applications, and presents key opportunities and challenges at the implementation level. Moreover, it shows how the seamless data cycle contributes to increase freedom of design, improve overall performance, and reduce cost and lead time from concept to manufacturing while creating new high-performance space products.
Many publications have shown that imidazoline derivatives such as clonidine, moxonidine or rilmenidine reduce sympathetic tone via a central mechanism and that as a result they reduce plasma ...catecholamines and blood pressure. This reduction in blood pressure appears not to be regulated via peripheral, presynaptically localized receptors, since neither catecholamine depletion by reserpine, or since neither catecholamine destruction of the nerve endings with 6-hydroxydopamine produces a notable weakening of the clonidine-induced blood pressure reduction.
Heart contraction depends on a complicated array of interactions between sarcomeric proteins required to convert chemical energy into mechanical force. Cyclic interactions between actin and myosin ...molecules, controlled by troponin and tropomyosin, generate the sliding force between the actin-based thin and myosin-based thick filaments. Alterations in this sophisticated system due to missense mutations can lead to cardiovascular diseases. Numerous structural studies proposed pathological mechanisms of missense mutations at the myosin-myosin, actin-tropomyosin, and tropomyosin-troponin interfaces. However, despite the central role of actomyosin interactions a detailed structural description of the cardiac actomyosin interface remained unknown. Here, we report a cryo-EM structure of a cardiac actomyosin complex at 3.8 Å resolution. The structure reveals the molecular basis of cardiac diseases caused by missense mutations in myosin and actin proteins.
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•The structure of cardiac actomyosin complex is resolved at near-atomic 3.8 Å resolution•Resultant pseudo-atomic model provides molecular details of actomyosin interface•The structure reveals how mutations in actin and myosin may lead to cardiac diseases
Heart contraction depends on interactions between actin and myosin molecules. The cardiac actomyosin interface remained unknown. The structure of cardiac actomyosin complex at near-atomic resolution by Risi et al. provides molecular details of the actomyosin interface and reveals molecular basis of cardiac diseases caused by mutations in actin and myosin.
The use of nanoparticles for targeted oral drug delivery to the inflamed gut tissue in inflammatory bowel disease was examined. Such a strategy of local drug delivery would be a distinct improvement ...compared with existing colon delivery devices for this disease. An experimental colitis was induced by trinitrobenzenesulfonic acid to male Wistar rats. Rolipram, an anti-inflammatory model drug, was incorporated within poly(lactic-coglycolic acid) nanoparticles, which were administered once a day orally for five consecutive days. A clinical activity score and myeloperoxidase activity were determined to assess the inflammation, whereas an adverse effect index reflected the remaining neurotropic effect of rolipram resulting from its systemic absorption. All nanoparticle formulations proved to be as efficient as the drug in solution in mitigating the experimental colitis. The clinical activity score and myeloperoxidase activity decreased significantly after the oral administration of rolipram nanoparticles or solution. During the next 5 days when animals were kept without drug treatment the drug solution group displayed a strong relapse, whereas the nanoparticle groups continued to show reduced inflammation levels. The rolipram solution group had a high adverse effect index, whereas the rolipram nanoparticle groups proved their potential to retain the drug from systemic absorption as evidenced by a significantly reduced index. This new delivery system enabled the drug to accumulate in the inflamed tissue with higher efficiency than when given as solution. The nanoparticle deposition in the inflamed tissue should be given particular consideration in the design of new carrier systems for the treatment of inflammatory bowel disease.
The potential of confocal laser scanning microscope (CLSM) has been evaluated for characterizing microcapsules. The aim was to visualize the polymer distribution within the particle wall, and to ...localize and to quantify the encapsulated oil phase. Microcapsules were prepared by complex coacervation: the oil phase, gelatine, and arabic gum were labelled with fluorescent markers. For all compounds it was proved that fluorescence labelling did not alter physico-chemical properties critical to the encapsulation process. Labelling of the inner oil phase allowed us to identify and to localize, three-dimensionally, the encapsulated compound. A homogeneous distribution for both gelatine and arabic gum throughout the capsule wall was observed. The addition of fluorescently labelled casein as a macromolecular model compound to the coacervate resulted in an inhomogeneous distribution of casein within the wall material, the highest concentration of casein was found at the oil–wall interface. To determine the encapsulation rate, CLSM pictures of the microcapsule samples were acquired using different fluorescence labels for the microcapsule wall polymers and the incorporated oil phase, respectively. By applying computational image analysis, the volumes of the different phases were calculated. Comparing the results of non-destructive image analysis with those obtained by degradation, extraction and chemical analysis, a linear relation was found with correlation coefficients better than 0.980.
Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation to optimize pulmonary gas exchange. However, it remains unclear whether acute HPV (occurring within seconds) and the ...vasoconstrictor response to sustained alveolar hypoxia (developing over several hours) are triggered by identical mechanisms. We investigated the effect of mitochondrial and NADPH oxidase inhibitors on both phases of HPV in intact rabbit lungs. These studies revealed that the sustained HPV is largely dependent on mitochondrial complex I and totally dependent on complex IV, whereas NADPH oxidase dependence was only observed for acute HPV. These findings were reinforced by an alternative approach employing lungs from mice deficient in the NADPH oxidase subunit p 47(phox). In these mice (which lack a subunit suggested to be important for the function of most NADPH oxidase isoforms), but not in gp 91(phox)-deficient mice (which represent only one isoform of NADPH oxidases), acute HPV was significantly reduced, while non-hypoxia-induced vasoconstrictions elicited by the thromboxane mimetic U46619 were not affected. We concluded that the acute phase and the sustained phase of HPV are differentially regulated, with NADPH oxidase activity predominating in the acute phase, while a strong dependence on mitochondrial participation was observed for the second phase.
The substitution of selenium activates the selenium-dependent enzyme glutathione peroxidase, which is important for scavenging free radicals. To date, only limited data are available about the ...clinical impact of selenium regarding the toxicities due to free radical producing therapies, e.g. irradiation or chemotherapy, and therefore the objective of this study was to investigate the clinical impact of selenium in such therapies.
39 patients (8 female, 31 male) with advanced head and neck cancer were included in a randomised phase II study. The mean age was 63.52+/-9.31 years. Tumour localizations: oral cavity 15 patients, oropharynx 19 patients, hypopharynx 5 patients, carcinoma of unknown primary 1 patient. Group A (n=22) received 500 microg sodium selenite on the days of radiotherapy and 300 microg sodium selenite on days without radiotherapy. Group B (17) was irradiated without any selenium substitution. Both groups were well balanced according to age, gender, localization and stage of the tumour. The RTOG grade of radiation-associated toxicities was evaluated once per week.
The following serious toxicities were observed (group A vs. group B): dysphagia 22.7% vs. 35.3%, loss of taste 22.7% vs. 47.1%, dry mouth 22.7% vs. 23.5%, and stomatitis 36.4% vs. 23.5%. A statistical trend (Fisher's exact test) was only seen for the loss of taste (p=0.172). The weekly patient analysis (Student's t-test) showed a significant reduction of dysphagia in the selenium group (Group 1) at the last week of irradiation.
This small randomised trial showed limited effects of selenium in the prevention of ageusia (loss of taste) and dysphagia due to radiotherapy of head and neck cancer.
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