Transapical aortic valve implantation with a self-expanding anatomically oriented valve

Aims The Medtronic Engager™ aortic valve bioprosthesis is a self-expanding valve with support arms facilitating anatomically correct positioning and axial fixation. Valve leaflets, made of bovine pericardium, are mounted on a Nitinol frame. Here, we report the first in man study with this new implant (Trial Identifier NCT00677638). Methods and results Thirty patients (mean age 83.4 ± 3.8 years; 83% female) with tricuspid aortic valve stenosis were included in the study. Mean logistic EuroSCORE was 23.4 ± 11.9. Mean aortic annulus diameter was 21.8 ± 1.4 mm. For this study, the Engager was available in only one size (23 mm), to fit aortic annuli of 19-23 mm. Standard transapical valve implantation was performed using predilation of the aortic valve and rapid ventricular pacing during ballon valvuloplasty and most valve deployments. Accurate valve placement was achieved in 29/30 cases (97%). Post-implant peak-to-peak gradient was 13.3 ± 9.3 mmHg. In 80% of the patients, no more than grade I paravalvular leakage was observed, in 13% grades I-II and in 3% grade II. Three patients (10%) required permanent pacemaker implantation for higher-degree or complete atrioventricular block. Four dissections (13%) occurred during positioning of the valve and were treated surgically in three cases. Thirty-day and in-hospital mortality were 20% and 23%, respectively, and 6-month survival was 56.7%. No structural failure occurred for up to 1 year. Conclusion This series established the feasibility of implanting a novel self-expanding transapical aortic valve prosthesis predictably into an anatomically correct position. Observed complications led to complete redesign of the delivery system for upcoming clinical studies with the goal of establishing safety and performanc

Mechanistic interrogation of combination Bevacizumab/dual PI3K/mTOR inhibitor response in Glioblastoma implementing novel MR and PET imaging biomarkers.

Purpose: Resistance to bevacizumab (BEV) in glioblastoma (GBM) is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Implementing an MRI/PET molecular imaging biomarker approach, we sought to interrogate response to combining BEV with the mTOR/PI3K inhibitor BEZ235. Methods: Tumors were established by orthotopically implanting U87MG-luc2 in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion weighted-MRI, T2 weighted (T2w), and T2* weighted (T2*w) before and following delivery of superparamagnetic iron oxide (SPIO) contrast. Maps for changes in relaxation rates: ΔR2, ΔR2* and apparent diffusion coefficient (ADC) were calculated. Vessel Size Index (VSI) and micro vessel density index (MDI) were derived. 3´-deoxy-3´-[18F]fluorothymidine ([18F]FLT)- and O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) PET was further performed and tumor endothelium/proliferation markers assessed by immunohistochemistry. Results: Treatment with BEV resulted in a pronounced decrease in tumor volume (T2w MRI). No additive effect on tumour volume was observed in BEV/BEZ235 combination compared with BEV monotherapy. Ki67 proliferation index staining and [18F]FLT uptake studies were used to support observations. Using ΔR2* and ΔR2 values respectively, BEZ235 + BEV combination significantly reduced tumor microvessel volume in comparison to BEV alone. Decreased MDI was further observed in the combination group; supported by von Willebrand Factor (vWF) immunohistochemistry. We observed decreased [18F]FET uptake following BEV, but failed to observe further reduced [18F]FET uptake in the combination cohort. vWF IHC analysis showed mean tumor vessel size increased in all cohorts. Conclusions: Assessing MR imaging biomarker parameters together with [18F]FET and [18F]FLT PET, informed drug combination mechanism of action and provided clues as to potential clinical response. Translation of a BEZ35/BEV combination regimen could support reduction of peritumoral edemaobviating the requirement for steroids. Implementing hypothesis driven molecular imaging studies facilitates the interrogation of drug response in the pre-clinic. These data may more accurately predict the clinical potential of novel therapeutic approaches in oncology

Die Europäisierung der öffentlichen Aufgaben

Die zunehmende Europäisierung der öffentlichen Aufgaben ist einer der wichtigsten Trends im Wandel der Staatstätigkeit in der Bundesrepublik Deutschland und in anderen Mitgliedstaaten der Europäischen Union. In diesem Essay werden die Stufen der Europäisierung der Staatstätigkeit nachgezeichnet, in Weiterführung von Lindberg/Scheingold (1970) und Schmitter (1996) quantifiziert und hinsichtlich ihrer Kosten und ihres Nutzen erörtert. Inhalt: Stufen der Europäisierung der öffentlichen Aufgaben Der Europäisierungsgrad der öffentlichen Aufgaben von 1950 bis zum Ende des 20. Jahrhunderts Vom Nutzen und von den Kosten der Europäisierung der öffentlichen Angelegenheiten Verzeichnis der zitierten Literatu

Role of TNF-alpha during central sensitization in preclinical studies

Tumor necrosis factor-alpha (TNF-α) is a principal mediator in pro-inflammatory processes that involve necrosis, apoptosis and proliferation. Experimental and clinical evidence demonstrate that peripheral nerve injury results in activation and morphological changes of microglial cells in the spinal cord. These adjustments occur in order to initiate an inflammatory cascade in response to the damage. Between the agents involved in this reaction, TNF-α is recognized as a key player in this process as it not only modulates lesion formation, but also because it is suggested to induce nociceptive signals. Nowadays, even though the function of TNF-α in inflammation and pain production seems to be generally accepted, diverse sources of literature point to different pathways and outcomes. In this review, we systematically searched and reviewed original articles from the past 10 years on animal models of peripheral nervous injury describing TNF-α expression in neural tissue and pain behavior

Hg 5d and 6s: Multichannel quantum-defect analysis of experimental data

Schäfers F, Heckenkamp C, Müller M, Radojevic V, Heinzmann U. Hg 5d and 6s: Multichannel quantum-defect analysis of experimental data. Physical Review, A: Atomic, Molecular and Optical Physics. 1990;42(5):2603-2613.Experimental spin-polarization data for the Hg 6s Cooper minimum and dipole-transition amplitudes and phase-shift differences for photoionization of the Hg 5d and 6s shells (eight channels) in the photon-energy region from the 2D3/2 threshold up to 35 eV (kinetic energies from 0 to 20 eV) are presented and compared with new relativistic random-phase approximation calculations. The data were evaluated from an experimental data set, quantum mechanically complete, consisting of cross-section and photoelectron spin-polarization data. For the 5d subshells the results show strong interchannel coupling between the outgoing p and f continuum channels. The results for Hg 6s could be used for an independent determination of the photoelectron angular distribution parameter [Beta] in the Cooper-minimum region. This region is shown to be perturbed by numerous two-electron excitations, which might be a possible explanation for the controversy on its location

The future of hybrid imaging—part 2: PET/CT

Since the 1990s, hybrid imaging by means of software and hardware image fusion alike allows the intrinsic combination of functional and anatomical image information. This review summarises the state-of-the-art of dual-modality imaging with a focus on clinical applications. We highlight selected areas for potential improvement of combined imaging technologies and new applications. In the second part, we briefly review the background of dual-modality PET/CT imaging, discuss its main applications and attempt to predict technological and methodological improvements of combined PET/CT imaging. After a decade of clinical evaluation, PET/CT will continue to have a significant impact on patient management, mainly in the area of oncological diseases. By adopting more innovative acquisition schemes and data processing PET/CT will become a fast and dose-efficient imaging method and an integral part of state-of-the-art clinical patient management

Differential transcriptional profiling of damaged and intact adjacent dorsal root ganglia neurons in neuropathic pain

Neuropathic pain, caused by a lesion in the somatosensory system, is a severely impairing mostly chronic disease. While its underlying molecular mechanisms are not thoroughly understood, neuroimmune interactions as well as changes in the pain pathway such as sensitization of nociceptors have been implicated. It has been shown that not only are different cell types involved in generation and maintenance of neuropathic pain, like neurons, immune and glial cells, but, also, intact adjacent neurons are relevant to the process. Here, we describe an experimental approach to discriminate damaged from intact adjacent neurons in the same dorsal root ganglion (DRG) using differential fluorescent neuronal labelling and fluorescence-activated cell sorting (FACS). Two fluorescent tracers, Fluoroemerald (FE) and 1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate (DiI), were used, whose properties allow us to distinguish between damaged and intact neurons. Subsequent sorting permitted transcriptional analysis of both groups. Results and qPCR validation show a strong regulation in damaged neurons versus contralateral controls as well as a moderate regulation in adjacent neurons. Data for damaged neurons reveal an mRNA expression pattern consistent with established upregulated genes like galanin, which supports our approach. Moreover, novel genes were found strongly regulated such as corticotropinreleasing hormone (CRH), providing novel targets for further research. Differential fluorescent neuronal labelling and sorting allows for a clear distinction between primarily damaged neuropathic neurons and "bystanders," thereby facilitating a more detailed understanding of their respective roles in neuropathic processes in the DRG