Recent Submissions

  • Journal Article

    CaosDB—Research Data Management for Complex, Changing, and Automated Research Workflows 

    Fitschen, Timm; Schlemmer, Alexander; Hornung, Daniel; tom Wörden, Henrik; Parlitz, Ulrich; Luther, Stefan
    Data 2019; 4(2)
    We present CaosDB, a Research Data Management System (RDMS) designed to ensure seamless integration of inhomogeneous data sources and repositories of legacy data in a FAIR way. Its primary purpose is the management of data from biomedical sciences, both from simulations and experiments during the complete research data lifecycle. An RDMS for this domain faces particular challenges: research data arise in huge amounts, from a wide variety of sources, and traverse a highly branched path of further processing. To be accepted by its users, an RDMS must be built around workflows of the scientists and practices and thus support changes in workflow and data structure. Nevertheless, it should encourage and support the development and observation of standards and furthermore facilitate the automation of data acquisition and processing with specialized software. The storage data model of an RDMS must reflect these complexities with appropriate semantics and ontologies while offering simple methods for finding, retrieving, and understanding relevant data. We show how CaosDB responds to these challenges and give an overview of its data model, the CaosDB Server and its easy-to-learn CaosDB Query Language. We briefly discuss the status of the implementation, how we currently use CaosDB, and how we plan to use and extend it.
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  • Journal Article

    MP2RAGE multispectral voxel‐based morphometry in focal epilepsy 

    Kotikalapudi, Raviteja; Martin, Pascal; Erb, Michael; Scheffler, Klaus; Marquetand, Justus; Bender, Benjamin; Focke, Niels K.
    Human Brain Mapping 2019; 40(17) p.5042-5055
    We assessed the applicability of MP2RAGE for voxel-based morphometry. To this end, we analyzed its brain tissue segmentation characteristics in healthy subjects and the potential for detecting focal epileptogenic lesions (previously visible and nonvisible). Automated results and expert visual interpretations were compared with conventional VBM variants (i.e., T1 and T1 + FLAIR). Thirty-one healthy controls and 21 patients with focal epilepsy were recruited. 3D T1-, T2-FLAIR, and MP2RAGE images (consisting of INV1, INV2, and MP2 maps) were acquired on a 3T MRI. The effects of brain tissue segmentation and lesion detection rates were analyzed among single- and multispectral VBM variants. MP2-single-contrast gave better delineation of deep, subcortical nuclei but was prone to misclassification of dura/vessels as gray matter, even more than conventional-T1. The addition of multispectral combinations (INV1, INV2, or FLAIR) could markedly reduce such misclassifications. MP2 + INV1 yielded generally clearer gray matter segmentation allowing better differentiation of white matter and neighboring gyri. Different models detected known lesions with a sensitivity between 60 and 100%. In non lesional cases, MP2 + INV1 was found to be best with a concordant rate of 37.5%, specificity of 51.6% and concordant to discordant ratio of 0.60. In summary, we show that multispectral MP2RAGE VBM (e.g., MP2 + INV1, MP2 + INV2) can improve brain tissue segmentation and lesion detection in epilepsy.
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  • Journal Article

    Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study 

    Wachter, Rolf; Senni, Michele; Belohlavek, Jan; Straburzynska‐Migaj, Ewa; Witte, Klaus K.; Kobalava, Zhanna; Fonseca, Candida; Goncalvesova, Eva; Cavusoglu, Yuksel; Fernandez, Alberto; et al.
    Chaaban, SaidBøhmer, EllenPouleur, Anne‐CatherineMueller, ChristianTribouilloy, ChristopheLonn, EvaA.L. Buraiki, JehadGniot, JacekMozheiko, MariaLelonek, MalgorzataNoè, AdeleSchwende, HeikeBao, WeibinButylin, DmytroPascual‐Figal, DomingoGniot, JacekMozheiko, MariaLelonek, MalgorzataDominguez, Antonio ReyesHoracek, Thomasdel Rio, Enrique GarciaKobalava, ZhannaMueller, Christian EugenCavusoglu, YukselStraburzynska-Migaj, EwaSlanina, Miroslavvom Dahl, JuergenSenni, MicheleRyding, AlisdairMoriarty, AndrewRobles, Manuel BeltranVillota, Julio NunezQuintana, Antonio GarciaNitschke, ThorstenManuel Garcia Pinilla, JoseBonet, Luis AlmenarChaaban, SaidFilali zaatari, MD, SamiaSpinar, JindrichMusial, WlodzimierzAbdelbaki, KhaledBelohlavek, JanFehske, WolfgangBott, Michael CarlosHoegalmen, GeirLeiro, Marisa CrespoOzcan, Ismail TurkayMullens, WilfriedKryza, RadimAl-Ani, RiadhLoboz-Grudzien, KrystynaErmoshkina, LyudmilaHojerova, SilviaFernandez, Alberto AlfredoSpinarova, LenkaLapp, HaraldBulut, EfraimAlmeida, FilipaVishnevsky, AlexanderBelicova, MargitaPascual, DomingoWitte, KlausWong, KennethDroogne, WalterDelforge, MarcPeterka, MartinOlbrich, Hans‐GeorgCarugo, StefanoNessler, JadwigaMcGill, Thao HuynhHuegl, BurkhardAkin, IbrahimMoreira, IlidioBaglikov, AndreyThambyrajah, JeetendraHayes, ChrisBarrionuevo, Marcelo RaulYigit, ZerrinKaya, HakkiKlimsa, ZdenekRadvan, MartinKadel, ChristophLandmesser, UlfDi Tano, GiuseppeLisik, Malgorzata BuksinskaFonseca, CandidaOliveira, LuisMarques, IreneSantos, Luis MiguelLenner, EgonLetavay, PeterBueno, Manuel GomezMota, PaulaWong, AaronBailey, KristianFoley, PaulHasbani, EduardoVirani, SeanMassih, Tony AbdelAl‐Saif, ShukriTaborsky, MilosKaislerova, MartaMotovska, ZuzanaPrahaCohen, Aron ArielLogeart, DamienEndemann, DierkFerreira, DanielBrito, DulceKycina, PeterBollano, EntelaBasilio, Enrique GalveRubio, Lorenzo FacilaAguado, Marcos GarciaSchiavi, Lilia BeatrizZivano, Daniel FranciscoLonn, EvaSayed, Ali ElPouleur, Anne‐CatherineHeyse, AlexSchee, AlexandrPolasek, RostislavHoura, MarekTribouilloy, ChristopheSeronde, Marie FranceGalinier, MichelNoutsias, MichelSchwimmbeck, PeterVoigt, IngoWestermann, DirkPulignano, GiovanniVegsundvaag, JohnnyAlexandre Da Silva Antunes, JoseMonteiro, PedroStevlik, JanGoncalvesova, EvaHulkoova, BeataJuan Castro Fernandez, AntonioDavies, CeriSquire, IainMeyer, PhilippeSheppard, RichardSahin, TayfunSochor, KarelDe Geeter, GuillaumeWachter, RolfSchmeisser, AlexanderWeil, JoachimSoares, Ana OliveiraVasilevna, Olga BulashovaOshurkov, AndreySunderland, Shahid JunejoGlover, JasonExequiel, TomasDecoulx, EricMeyer, SvenMuenzel, ThomasFrioes, FernandoArbolishvili, GeorgyTokarcikova, AnnaKarlstrom, PatricCarles Trullas Vila, JoanPerez, Gonzalo PenaSankaranarayanan, RajivNageh, ThuraiaAlasia, Diego CristianRefaat, MarwanDemirkan, BurcuAl-Buraiki, JehadKarabsheh, Shadi
    European Journal of Heart Failure 2019; 21(8) p.998-1007
    AIMS: To assess tolerability and optimal time point for initiation of sacubitril/valsartan in patients stabilised after acute heart failure (AHF). METHODS AND RESULTS: TRANSITION was a randomised, multicentre, open-label study comparing two treatment initiation modalities of sacubitril/valsartan. Patients aged ≥ 18 years, hospitalised for AHF were stratified according to pre-admission use of renin-angiotensin-aldosterone system inhibitors and randomised (n = 1002) after stabilisation to initiate sacubitril/valsartan either ≥ 12-h pre-discharge or between Days 1-14 post-discharge. Starting dose (as per label) was 24/26 mg or 49/51 mg bid with up- or down-titration based on tolerability. The primary endpoint was the proportion of patients attaining 97/103 mg bid target dose after 10 weeks. Median time of first dose of sacubitril/valsartan from the day of discharge was Day -1 and Day +1 in the pre-discharge group and the post-discharge group, respectively. Comparable proportions of patients in the pre- and post-discharge initiation groups met the primary endpoint [45.4% vs. 50.7%; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.79-1.02]. The proportion of patients who achieved and maintained for ≥ 2 weeks leading to Week 10, either 49/51 or 97/103 mg bid was 62.1% vs. 68.5% (RR 0.91; 95% CI 0.83-0.99); or any dose was 86.0% vs. 89.6% (RR 0.96; 95% CI 0.92-1.01). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90-2.46). CONCLUSIONS: Initiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02661217. © 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons
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  • Journal Article

    Strategy to enhance transgene expression in proximity of amyloid plaques in a mouse model of Alzheimer's disease 

    Weber-Adrian, Danielle; Kofoed, Rikke Hahn; Chan, Josephine Wing Yee; Silburt, Joseph; Noroozian, Zeinab; Kügler, Sebastian; Hynynen, Kullervo; Aubert, Isabelle
    Theranostics 2019; 9(26) p.8127-8137
    Gene therapy can be designed to efficiently counter pathological features characteristic of neurodegenerative disorders. Here, we took advantage of the glial fibrillary acidic protein (GFAP) promoter to preferentially enhance transgene expression near plaques composed of amyloid-beta peptides (Aβ), a hallmark of Alzheimer’s disease (AD), in the TgCRND8 mouse model of amyloidosis. Methods: The delivery of intravenously injected recombinant adeno-associated virus mosaic serotype 1/2 (rAAV1/2) to the cortex and hippocampus of TgCRND8 mice was facilitated using transcranial MRI-guided focused ultrasound in combination with microbubbles (MRIgFUS), which transiently and locally increases the permeability of the blood-brain barrier (BBB). rAAV1/2 expression of the reporter green fluorescent protein (GFP) under a GFAP promoter was compared to GFP expression driven by the constitutive human beta actin (HBA) promoter. Results: MRIgFUS targeting the cortex and hippocampus facilitated the entry of rAAV1/2 and GFP expression under the GFAP promoter was localized to GFAP-positive astrocytes. Adjacent to Aβ plaques where GFAP is upregulated, the volume, surface area, and fluorescence intensity of the transgene GFP were greater in rAAV1/2-GFAP-GFP compared to rAAV1/2-HBA-GFP treated animals. In peripheral organs, GFP expression was particularly strong in the liver, irrespective of the promoter. Conclusion: The GFAP promoter enhanced transgene expression in proximity of Aβ plaques in the brain of TgCRND8 mice, and it also resulted in significant expression in the liver. Future gene therapies for neurological disorders could benefit from using a GFAP promoter to regulate transgene expression in response to disease-induced astrocytic reactivity.
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  • Journal Article

    A facile oxygen-17 NMR method to determine effective viscosity in dilute, molecularly crowded and confined aqueous media 

    Rezaei-Ghaleh, Nasrollah; Munari, Francesca; Becker, Stefan; Assfalg, Michael; Griesinger, Christian
    Chemical Communications 2019; 55(82) p.12404-12407
    We present an NMR method based on natural abundance 17O relaxation of water to determine effective viscosity in biological aqueous samples. The method accurately captures viscosity of dilute and crowded protein solutions and offers a fairly simple way to quantify the internal fluidity of biological condensates formed through phase separation.
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  • Journal Article

    Real‐time multi‐directional flow MRI using model‐based reconstructions of undersampled radial FLASH – A feasibility study 

    Kollmeier, Jost M.; Tan, Zhengguo; Joseph, Arun A.; Kalentev, Oleksandr; Voit, Dirk; Merboldt, K. Dietmar; Frahm, Jens
    NMR in Biomedicine: Art. ;e4184
    The purpose of this work was to develop an acquisition and reconstruction technique for two- and three-directional (2d and 3d) phase-contrast flow MRI in real time. A previous real-time MRI technique for one-directional (1d) through-plane flow was extended to 2d and 3d flow MRI by introducing in-plane flow sensitivity. The method employs highly undersampled radial FLASH sequences with sequential acquisitions of two or three flow-encoding datasets and one flow-compensated dataset. Echo times are minimized by merging the waveforms of flow-encoding and radial imaging gradients. For each velocity direction individually, model-based reconstructions by regularized nonlinear inversion jointly estimate an anatomical image, a set of coil sensitivities and a phase-contrast velocity map directly. The reconstructions take advantage of a dynamic phase reference obtained by interpolating consecutive flow-compensated acquisitions. Validations include pulsatile flow phantoms as well as in vivo studies of the human aorta at 3 T. The proposed method offers cross-sectional 2d and 3d flow MRI of the human aortic arch at 53 and 67 ms resolution, respectively, without ECG synchronization and during free breathing. The in-plane resolution was 1.5 × 1.5 mm2 and the slice thickness 6 mm. In conclusion, real-time multi-directional flow MRI offers new opportunities to study complex human blood flow without the risk of combining differential phase (i.e., velocity) information from multiple heartbeats as for ECG-gated data. The method would benefit from a further reduction of acquisition time and accelerated computing to allow for extended clinical trials.
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  • Journal Article

    The spectrum of involuntary vocalizations in humans: A video atlas 

    Mainka, Tina; Balint, Bettina; Gövert, Felix; Kurvits, Lille; Riesen, Christoph; Kühn, Andrea A.; Tijssen, Marina A.J.; Lees, Andrew J.; Müller‐Vahl, Kirsten; Bhatia, Kailash P.; et al.
    Ganos, Christos
    Movement Disorders
    Left ventricular assist device (LVAD) therapy is a promising option for patients with advanced heart failure (HF), refractory to guideline‐mandated medical treatment either as a bridge to heart transplantation or as lifelong therapy. Functional capacity improves after LVAD implantation but remains reduced in patients with long‐term LVAD therapy. Exercise training (ET) improves functional capacity and quality of life (QoL) in HF and may provide incremental benefits in patients supported with LVAD therapy. Methods The primary objective of Ex‐VAD is to investigate whether a 12‐week supervised ET can improve peak oxygen uptake (peakVO2) measured by cardiopulmonary exercise testing (CPET) on an ergometer. The study is powered to demonstrate a group difference of 3 mL/min/kg in peakVO2 at week 12, with a power of 0.9 and a standard deviation of 5 mL/min/kg. After baseline assessments to determine whether ET is safe, 66 patients at six trial sites with advanced HF and LVAD therapy will be randomized 2:1 to supervised ET or to the control arm of usual care alone. Patients randomized to ET will perform supervised aerobic endurance and resistance ET (three times/week) for 12 weeks. At baseline and during follow‐up, anthropometry, CPET, echocardiography (at rest and exercise), and QoL evaluation will be performed. Blood samples will be collected to examine cardiac‐specific relevant biomarkers. Overall physical activity, training sessions, and adherence will be monitored and documented throughout the study using accelerometers and patient diaries. Conclusions The Ex‐VAD trial will assess the effects of a supervised ET programme on peakVO2 and QoL in patients with LVAD. As LVAD therapy moves from crisis support to ambulatory functional enhancement, this trial will provide a rationale to improve functional capacity and, in perspective, cardiovascular outcomes in LVAD‐supported patients with advanced HF.
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  • Journal Article

    Exercise training in patients with a left ventricular assist device (Ex‐VAD): rationale and design of a multicentre, prospective, assessor‐blinded, randomized, controlled trial 

    Bobenko, Anna; Schoenrath, Felix; Knierim, Jan H.; Friede, Tim; Verheyen, Nicolas; Mehra, Mandeep R.; Haykowsky, Mark; Herrmann‐Lingen, Christoph; Duvinage, André; Pieske‐Kraigher, Elisabeth; et al.
    Halle, MartinFalk, VolkmarPieske, BurkertEdelmann, Frank
    European Journal of Heart Failure 2019; 21(9) p.1152-1159
    AIMS: Left ventricular assist device (LVAD) therapy is a promising option for patients with advanced heart failure (HF), refractory to guideline-mandated medical treatment either as a bridge to heart transplantation or as lifelong therapy. Functional capacity improves after LVAD implantation but remains reduced in patients with long-term LVAD therapy. Exercise training (ET) improves functional capacity and quality of life (QoL) in HF and may provide incremental benefits in patients supported with LVAD therapy. METHODS: The primary objective of Ex-VAD is to investigate whether a 12-week supervised ET can improve peak oxygen uptake (peakVO2 ) measured by cardiopulmonary exercise testing (CPET) on an ergometer. The study is powered to demonstrate a group difference of 3 mL/min/kg in peakVO2 at week 12, with a power of 0.9 and a standard deviation of 5 mL/min/kg. After baseline assessments to determine whether ET is safe, 66 patients at six trial sites with advanced HF and LVAD therapy will be randomized 2:1 to supervised ET or to the control arm of usual care alone. Patients randomized to ET will perform supervised aerobic endurance and resistance ET (three times/week) for 12 weeks. At baseline and during follow-up, anthropometry, CPET, echocardiography (at rest and exercise), and QoL evaluation will be performed. Blood samples will be collected to examine cardiac-specific relevant biomarkers. Overall physical activity, training sessions, and adherence will be monitored and documented throughout the study using accelerometers and patient diaries. CONCLUSIONS: The Ex-VAD trial will assess the effects of a supervised ET programme on peakVO2 and QoL in patients with LVAD. As LVAD therapy moves from crisis support to ambulatory functional enhancement, this trial will provide a rationale to improve functional capacity and, in perspective, cardiovascular outcomes in LVAD-supported patients with advanced HF.
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  • Journal Article

    The clinical significance of interleukin‐6 in heart failure: results from the BIOSTAT‐CHF study 

    Markousis‐Mavrogenis, George; Tromp, Jasper; Ouwerkerk, Wouter; Devalaraja, Matt; Anker, Stefan D.; Cleland, John G.; Dickstein, Kenneth; Filippatos, Gerasimos S.; Harst, Pim; Lang, Chim C.; et al.
    Metra, MarcoNg, Leong L.Ponikowski, PiotrSamani, Nilesh JZannad, FaiezZwinderman, Aeilko H.Hillege, Hans L.Veldhuisen, Dirk J.Kakkar, RahulVoors, Adriaan A.Meer, Peter
    European Journal of Heart Failure 2019; 21(8) p.965-973: Art.
    AIMS: Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)-α were largely unsuccessful. Interleukin (IL)-6 is an important inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL-6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations. METHODS AND RESULTS: Interleukin-6 was measured in 2329 patients [89.4% with a left ventricular ejection fraction (LVEF) ≤ 40%] of the BIOSTAT-CHF cohort. The primary outcome was all-cause mortality and HF hospitalization during 2 years, with all-cause, cardiovascular (CV), and non-CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL-6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N-terminal pro-brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF-α/IL-1-related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL-6 levels. IL-6 independently predicted the primary outcome [HR (95% confidence interval) per doubling: 1.16 (1.11-1.21), P < 0.001], all-cause mortality [1.22 (1.16-1.29), P < 0.001] and CV as well as non-CV mortality [1.16 (1.09-1.24), P < 0.001; 1.31 (1.18-1.45), P < 0.001], but did not improve discrimination in previously published risk models. CONCLUSIONS: In a large, heterogeneous cohort of HF patients, elevated IL-6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL-6 as a potential therapeutic target in specific HF subpopulations.
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  • Journal Article

    Spontaneous Left Cardiac Isomerism in Chick Embryos: Case Report, Review of the Literature, and Possible Significance for the Understanding of Ventricular Non-Compaction Cardiomyopathy in the Setting of Human Heterotaxy Syndromes 

    Männer, Jörg
    Journal of Cardiovascular Development and Disease 2019; 6(4): Art. 40
    The outer shape of most vertebrates is normally characterized by bilateral symmetry. The inner organs, on the other hand, are normally arranged in bilaterally asymmetric patterns. Congenital deviations from the normal organ asymmetry can occur in the form of mirror imagery of the normal arrangement (situs inversus), or in the form of arrangements that have the tendency for the development of bilateral symmetry, either in a pattern of bilateral left-sidedness (left isomerism) or bilateral right-sidedness (right isomerism). The latter two forms of visceral situs anomalies are called “heterotaxy syndromes”. During the past 30 years, remarkable progress has been made in uncovering the genetic etiology of heterotaxy syndromes. However, the pathogenetic mechanisms causing the spectrum of cardiovascular defects found in these syndromes remain poorly understood. In the present report, a spontaneous case of left cardiac isomerism found in an HH-stage 23 chick embryo is described. The observations made in this case confirmed the existence of molecular isomerism in the ventricular chambers previously noted in mouse models. They, furthermore, suggest that hearts with left cardiac isomerism may have the tendency for the development of non-compaction cardiomyopathy caused by defective development of the proepicardium.
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  • Journal Article

    The Calmodulin Binding Region of the Synaptic Vesicle Protein Mover Is Required for Homomeric Interaction and Presynaptic Targeting 

    Akula, Asha Kiran; Zhang, Xin; Viotti, Julio S.; Nestvogel, Dennis; Rhee, Jeong-Seop; Ebrecht, Rene; Reim, Kerstin; Wouters, Fred; Liepold, Thomas; Jahn, Olaf; et al.
    Bogeski, IvanDresbach, Thomas
    Frontiers in Molecular Neuroscience 2019; 12: Art. 249
    Neurotransmitter release is mediated by an evolutionarily conserved machinery. The synaptic vesicle (SV) associated protein Mover/TPRGL/SVAP30 does not occur in all species and all synapses. Little is known about its molecular properties and how it may interact with the conserved components of the presynaptic machinery. Here, we show by deletion analysis that regions required for homomeric interaction of Mover are distributed across the entire molecule, including N-terminal, central and C-terminal regions. The same regions are also required for the accumulation of Mover in presynaptic terminals of cultured neurons. Mutating two phosphorylation sites in N-terminal regions did not affect these properties. In contrast, a point mutation in the predicted Calmodulin (CaM) binding sequence of Mover abolished both homomeric interaction and presynaptic targeting. We show that this sequence indeed binds Calmodulin, and that recombinant Mover increases Calmodulin signaling upon heterologous expression. Our data suggest that presynaptic accumulation of Mover requires homomeric interaction mediated by regions distributed across large areas of the protein, and corroborate the hypothesis that Mover functionally interacts with Calmodulin signaling.
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  • Journal Article

    Sarcopenia: A Time for Action. An SCWD Position Paper 

    Bauer, Juergen; Morley, John E.; Schols, Annemie M.W.J.; Ferrucci, Luigi; Cruz‐Jentoft, Alfonso J.; Dent, Elsa; Baracos, Vickie E.; Crawford, Jeffrey A.; Doehner, Wolfram; Heymsfield, Steven B.; et al.
    Jatoi, AminahKalantar‐Zadeh, KamyarLainscak, MitjaLandi, FrancescoLaviano, AlessandroMancuso, MichelangeloMuscaritoli, MaurizioPrado, Carla M.Strasser, FlorianHaehling, StephanCoats, Andrew J.S.Anker, Stefan D.
    Journal of Cachexia, Sarcopenia and Muscle 2019; 10(5) p.956-961
    The term sarcopenia was introduced in1988. The original definition was a“muscle loss”of the appendicular muscle mass inthe older people as measured by dual energy x-ray absorptiometry (DXA). In2010, the definition was altered to be low musclemass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society ofSarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. thatrapid screening, such as with the SARC-F questionnaire, should be utilized with a formal diagnosis being made by measuringgrip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessmentsof the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Pri-mary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease-related sarcopenia) haspredominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause musclewasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Managementof sarcopenia should consist of resistance exercise in combination with a protein intake of1to1.5g/kg/day. There is insuffi-cient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age-related)sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of theunderlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age-re-lated and disease-related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physicalactivity and sedentary behavior in the general population, using a life-long approach. There is a need for more clinical researchinto the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statementprovides recommendations on the management of sarcopenia and how to progress the knowledge and recognition ofsarcopenia.
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  • Journal Article

    Secretion of functionally active complement factor H related protein 5 (FHR5) by primary tumour cells derived from Glioblastoma Multiforme patients 

    DeCordova, Syreeta; Abdelgany, Amr; Murugaiah, Valarmathy; Pathan, Ansar A.; Nayak, Annapurna; Walker, Tom; Shastri, Abhishek; Alrokayan, Salman H.; Khan, Haseeb A.; Singh, Shiv K.; et al.
    De Pennington, NickSim, Robert B.Kishore, Uday
    Immunobiology 2019; 224(5) p.625-631
    The complement system is an important humoral immune surveillance mechanism against tumours. However, many malignant tumours are resistant to complement mediated lysis. Here, we report secretion of complement factor H related protein 5 (FHR5) by primary tumour cells derived from Glioblastoma multiforme (GBM) patients. We investigated whether the secreted FHR5 exhibited functional activity similar to factor H, including inhibition of complement mediated lysis, acting as a co-factor for factor I mediated cleavage of C3b, and decay acceleration of C3 convertase. Immunoblotting analysis of primary GBM cells (B30, B31 and B33) supernatant showed the active secretion of FHR5, but not of Factor H. ELISA revealed that the secretion of soluble GBM-FHR5 by cultured GBM cells increased in a time-dependent manner. Primary GBM-FHR5 inhibited complement mediated lysis, possessed co-factor activity for factor I mediated cleavage and displayed decay acceleration of C3 convertase. In summary, we detected the secretion of FHR5 by primary GBM cells B30, B31 and B33. The results demonstrated that GBM-FHR5 shares biological function with FH as a mechanism primary GBM cells potentially use to resist complement mediated lysis.
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  • Journal Article

    Cardiac arrest in takotsubo syndrome: results from the InterTAK Registry 

    Gili, Sebastiano; Cammann, Victoria L.; Schlossbauer, Susanne A.; Kato, Ken; D’Ascenzo, Fabrizio; Di Vece, Davide; Jurisic, Stjepan; Micek, Jozef; Obeid, Slayman; Bacchi, Beatrice; et al.
    Szawan, Konrad A.Famos, FlurinaSarcon, AnnahitaLevinson, RenaDing, Katharina J.Seifert, BurkhardtLenoir, OliviaBossone, EduardoCitro, RodolfoFranke, JenniferNapp, L ChristianJaguszewski, MiloszNoutsias, MichelMünzel, ThomasKnorr, MaikeHeiner, SusanneKatus, Hugo A.Burgdorf, ChristofSchunkert, HeribertThiele, HolgerBauersachs, JohannTschöpe, CarstenPieske, Burkert M.Rajan, LawrenceMichels, GuidoPfister, RomanCuneo, AlessandroJacobshagen, ClaudiusHasenfuß, GerdKarakas, MahirKoenig, WolfgangRottbauer, WolfgangSaid, Samir M.Braun-Dullaeus, Ruediger C.Banning, AdrianCuculi, FlorimKobza, RichardFischer, Thomas A.Vasankari, TuijaAiraksinen, K.E. JuhaniOpolski, GrzegorzDworakowski, RafalMacCarthy, PhilipKaiser, ChristophOsswald, StefanGaliuto, LeonardaCrea, FilippoDichtl, WolfgangEmpen, KlausFelix, Stephan B.Delmas, ClémentLairez, OlivierEl-Battrawy, IbrahimAkin, IbrahimBorggrefe, MartinGilyarova, EkaterinaShilova, AlexandraGilyarov, MikhailHorowitz, John D.Kozel, MartinTousek, PetrWidimský, PetrWinchester, David E.Ukena, ChristianGaita, FiorenzoDi Mario, CarloWischnewsky, Manfred B.Bax, Jeroen J.Prasad, AbhiramBöhm, MichaelRuschitzka, FrankLüscher, Thomas F.Ghadri, Jelena R.Templin, Christian
    European Heart Journal 2019; 40(26) p.2142-2151
    AIMS: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS). METHODS AND RESULTS: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission. CONCLUSIONS: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.
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  • Journal Article

    The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112 

    van Tran, Nhan; Ernst, Felix G. M.; Hawley, Ben R.; Zorbas, Christiane; Ulryck, Nathalie; Hackert, Philipp; Bohnsack, Katherine E.; Bohnsack, Markus T.; Jaffrey, Samie R.; Graille, Marc; et al.
    Lafontaine, Denis L. J.
    Nucleic Acids Research 2019; 47(15) p.7719-7733
    N6-methyladenosine (m6A) has recently been found abundantly on messenger RNA and shown to regulate most steps of mRNA metabolism. Several important m6A methyltransferases have been described functionally and structurally, but the enzymes responsible for installing one m6A residue on each subunit of human ribosomes at functionally important sites have eluded identification for over 30 years. Here, we identify METTL5 as the enzyme responsible for 18S rRNA m6A modification and confirm ZCCHC4 as the 28S rRNA modification enzyme. We show that METTL5 must form a heterodimeric complex with TRMT112, a known methyltransferase activator, to gain metabolic stability in cells. We provide the first atomic resolution structure of METTL5-TRMT112, supporting that its RNA-binding mode differs distinctly from that of other m6A RNA methyltransferases. On the basis of similarities with a DNA methyltransferase, we propose that METTL5-TRMT112 acts by extruding the adenosine to be modified from a double-stranded nucleic acid.
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  • Journal Article

    Analyses of sphingosine‐1‐phosphate in the context of transfusion: how much is in stored blood products and in patient blood? 

    Poppe, Annika; Moritz, Eileen; Geffken, Maria; Schreiber, Joerg; Greiwe, Gillis; Amschler, Katharina; Wruck, Marie‐Louise; Schwedhelm, Edzard; Daum, Günter; Kluge, Stefan; et al.
    Peine, SvenWinkler, Martin Sebastian
    Transfusion 2019; 59(10) p.3071-3076
    BACKGROUND: Sphingosine-1-phosphate (S1P) is a bloodborne lipid that regulates vascular tone and endothelial permeability. S1P concentrations are reduced in critically ill patients. As hematopoietic cells produce S1P, this study intends to investigate S1P concentrations in blood products during storage and in patient plasma after blood transfusion. STUDY DESIGN AND METHODS: S1P concentrations were measured in 83 red blood cell (RBC) units and 73 platelet concentrates (PCs) before and after storage. In addition, 26 critically ill patients who received one or two RBC units were recruited to measure S1P plasma levels before and three times within 24 hours after transfusion. RESULTS: The highest S1P concentrations were found in fresh PCs. S1P concentrations in PCs are reduced by 60% when stored at room temperature for 4 days, whereas in RBCs S1P concentrations remained stable when stored at 4°C within 35 days. S1P concentrations in PCs and RBCc were 2.5 to 6 times higher compared to patient plasma. Plasma S1P levels in critically ill patients, however, transiently decreased after transfusion of RBCs and recover to pretransfusion values within the following 24 hours. CONCLUSION: S1P concentrations in blood products are significantly higher compared to human plasma S1P levels, even though plasma S1P levels decreased after RBC transfusion in critically ill patients and reached pretransfusion values within 24 hours.
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  • Journal Article

    Breathing and Ventilation during Extracorporeal Membrane Oxygenation: How to Find the Balance between Rest and Load 

    Quintel, Michael; Busana, Mattia; Gattinoni, Luciano
    American Journal of Respiratory and Critical Care Medicine 2019; 200(8) p.954-956
    Comment on Mechanical Ventilation Management during Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome. An International Multicenter Prospective Cohort.
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  • Journal Article

    Predicting Progression in Parkinson’s Disease Using Baseline and 1-Year Change Measures 

    Chahine, Lana M.; Siderowf, Andrew; Barnes, Janel; Seedorff, Nicholas; Caspell-Garcia, Chelsea; Simuni, Tanya; Coffey, Christopher S.; Galasko, Douglas; Mollenhauer, Brit; Arnedo, Vanessa; et al.
    Daegele, NicholeFrasier, MarkTanner, CarolineKieburtz, KarlMarek, Kenneth
    Journal of Parkinson's Disease 2019; 9(4) p.665-679
    BACKGROUND: Improved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials. OBJECTIVES: To examine whether baseline measures and their 1-year change predict longer-term progression in early PD. METHODS: Parkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models. RESULTS: Among 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance. CONCLUSIONS: Baseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding.
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  • Journal Article

    The prognostic role of IDH mutations in homogeneously treated patients with anaplastic astrocytomas and glioblastomas 

    Christians, Arne; Adel-Horowski, Antonia; Banan, Rouzbeh; Lehmann, Ulrich; Bartels, Stephan; Behling, Felix; Barrantes-Freer, Alonso; Stadelmann, Christine; Rohde, Veit; Stockhammer, Florian; et al.
    Hartmann, Christian
    Acta Neuropathologica Communications 2019; 7(1): Art. 156
    The detection of IDH mutations in patients with diffusely infiltrating malignant astrocytomas resulted in substantial modifications in the concept of WHO classification of these tumors. An important underlying observation was that patients with anaplastic astrocytomas (AA) without IDH mutation had a clinical course similar to that of patients with glioblastomas (GBM). The underlying observations of the German Glioma Network and NOA-04, however, were based on mixed patient cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually had radiotherapy or chemotherapy only. This intrinsic shortcoming of the study raised the question of whether patients with AA, IDH wildtype, WHO grade III, might have better prognosis if treated with combined radiochemotherapy than patients with GBM receiving the same combination therapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of an IDH mutation are still important if neither vascular proliferation nor necrosis are detectable. All patients in the cohort investigated here with the diagnosis of AA or GBM were subjected to a combined radiochemotherapy according to the Stupp protocol independently of the histopathological diagnosis. Thus, the analysis of these patients allows to clarify whether patients with AA, IDH wildtype, WHO grade III have a prognosis similar to that of GBM, IDH wildtype, WHO grade IV, even under equivalent therapeutic conditions. We determined the IDH1 and IDH2 status by sequencing, the MGMT status by pyrosequencing after bisulfite treatment and the EGFR status of the patients by FISH. In fact, the patients with the histopathological diagnosis of an AA IDH wild-type under similar aggressive therapy showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a GBM (mOS 13 months). Instead, patients with an AA and an IDH mutation receiving the same therapy had a mOS of 54 months. Thus, it can be concluded that in the absence of an IDH mutation, the established histopathological grading criteria 'necrosis' and 'vascular proliferation' actually lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and an IDH mutation are examined, there is still a difference between patients with necrosis and/or vascular proliferation and those whose tumors do not show such characteristics. Accordingly, in patients with malignant astrocytomas with IDH mutation it can be concluded that a histological differentiation between AA IDH mutated and GBM IDH mutated remains beneficial from a prognostic perspective.
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  • Journal Article

    Circularly Permuted Fluorescent Protein-Based Indicators: History, Principles, and Classification 

    Kostyuk, Alexander I.; Demidovich, Aleksandra D.; Kotova, Daria A.; Belousov, Vsevolod V.; Bilan, Dmitry S.
    International Journal of Molecular Sciences 2019; 20(17): Art. 4200
    Genetically encoded biosensors based on fluorescent proteins (FPs) are a reliable tool for studying the various biological processes in living systems. The circular permutation of single FPs led to the development of an extensive class of biosensors that allow the monitoring of many intracellular events. In circularly permuted FPs (cpFPs), the original N- and C-termini are fused using a peptide linker, while new termini are formed near the chromophore. Such a structure imparts greater mobility to the FP than that of the native variant, allowing greater lability of the spectral characteristics. One of the common principles of creating genetically encoded biosensors is based on the integration of a cpFP into a flexible region of a sensory domain or between two interacting domains, which are selected according to certain characteristics. Conformational rearrangements of the sensory domain associated with ligand interaction or changes in the cellular parameter are transferred to the cpFP, changing the chromophore environment. In this review, we highlight the basic principles of such sensors, the history of their creation, and a complete classification of the available biosensors.
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