Recent Submissions

  • Journal Article

    Effect of alendronate or 8-prenylnaringenin applied as a single therapy or in combination with vibration on muscle structure and bone healing in ovariectomized rats 

    Komrakova, M.; Rechholtz, C.; Pohlmann, N.; Lehmann, W.; Schilling, A. F.; Wigger, R.; Sehmisch, S.; Hoffmann, D. B.
    Bone Reports 2019; 11: Art. 100224
    Bisphosphonate alendronate (ALN), phytoestrogen 8-prenylnaringenin (8-PN) and the whole body vibration exert a favorable effect on osteoporotic bone. However, the impact of these treatments and the combination of pharmacological therapies with biomechanical stimulation on muscle and bone has not yet been explored in detail. The effect of ALN and 8-PN and their combination with the vibration (Vib) on skeletal muscle and bone healing was investigated in ovariectomized (Ovx) rats. Three-month old rats were Ovx (n = 78), or left intact (Non-Ovx; n = 12). Five weeks after Ovx, all rats were treated according to the group assignment (n = 12/13): 1) Non-Ovx; 2) Ovx; 3) Ovx + Vib; 4) Ovx + ALN; 5) Ovx + ALN + Vib; 6): Ovx + 8-PN; 7) Ovx + 8-PN + Vib. Treatments with ALN (0.58 mg/kg BW, in food), 8-PN (1.77 mg/kg BW, daily s.c. injections) and/or with vertical vibration (0.5 mm, 35 Hz, 1 g, 15 min, 2×/day, 5×/week) were conducted for ten weeks. Nine weeks after Ovx, all rats underwent bilateral tibia osteotomy with plate osteosynthesis and were sacrificed six weeks later. Vibration increased fiber size and capillary density in muscle, enlarged callus area and width, and decreased callus density in tibia, and elevated alkaline phosphatase in serum. ALN and ALN + Vib enhanced capillarization and lactate dehydrogenase activity in muscle. In tibia, ALN slowed bone healing, ALN + Vib increased callus width and density, enhanced callus formation rate and expression of osteogenic genes. 8-PN and 8-PN + Vib decreased fiber size and increased capillary density in muscle; callus density and cortical width were reduced in tibia. Vibration worsened 8-PN effect on bone healing decreasing the callus width and area. Our data suggest that Vib, ALN, 8-PN, or 8-PN + Vib do not appear to aid bone healing. ALN + Vib improved bone healing; however application is questionable since single treatments impaired bone healing. Muscle responds to the anti-osteoporosis treatments and should be included in the evaluation of the drugs.
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  • Journal Article

    Rheopheresis for Digital Ulcers and Raynaud's Phenomenon in Systemic Sclerosis Refractory to Conventional Treatments 

    Korsten, Peter; Müller, Gerhard A.; Rademacher, Jan-Gerd; Zeisberg, Michael; Tampe, Björn
    Frontiers in Medicine 2019; 6: Art. 208
    Raynaud's phenomenon (RP) is almost universally present in patients with Systemic Sclerosis (SSc). RP represents a generalized vasculopathy and potentially lead to digital ulcers (DU), which may be complicated by superinfection, tissue necrosis, and limb loss. We report the analysis of an extracorporeal procedure in a 36-year-old female patient with diffuse SSc with refractory RP and DU despite treatment with diltiazem, candesartan, sildenafil, and intravenous iloprost. We performed rheopheresis (RheoP), a variant of double-filtration plasmapheresis, as a potential new treatment option for refractory patients despite optimal medical therapy. We performed two RheoP per week every 4 weeks for a total of 3 months. Clinical improvement in DU healing occurred with no adverse events directly related to the treatment. While there was no reduction in the number of Raynaud attacks with RheoP, a significant reduction of the duration of attacks from a median of 15 (5–45, 95% CI 10–15) to 7 (3–30, 95% CI 6–10) minutes with an improvement of the Raynaud Condition Score (RCS) improved from 4 to 2. In conclusion, RheoP is a feasible and potentially beneficial treatment modality in patients with refractory RP and DU. We propose that RheoP should be investigated in a larger number of patients in a clinical trial setting.
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  • Journal Article

    Present criteria for prophylactic ICD implantation: Insights from the EU-CERT-ICD (Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators in EUrope) project 

    Zabel, Markus; Schlögl, Simon; Lubinski, Andrzej; Svendsen, Jesper Hastrup; Bauer, Axel; Arbelo, Elena; Brusich, Sandro; Conen, David; Cygankiewicz, Iwona; Dommasch, Michael; et al.
    Flevari, PanagiotaGaluszka, JanKatsimardos, AndreasHansen, JimHasenfuß, GerdHatala, RobertHuikuri, Heikki V.Kenttä, TuomasKuczejko, TomaszHaarmann, HelgeHarden, MarkusIovev, SvetoslavKääb, StefanKaliska, GabrielaKatsimardos, AndreasKasprzak, Jaroslaw D.Qavoq, DariuszLüthje, LarsMalik, MarekNovotný, TomášPavlović, NikolaPerge, PeterRöver, ChristianSchmidt, GeorgShalganov, TchavdarSritharan, RajeevaSvetlosak, MartinSallo, ZoltanSzavits-Nossan, JankoTraykov, VassilVandenberk, BertVelchev, VasilVos, Marc A.Willich, Stefan N.Friede, TimWillems, RikMerkely, BélaSticherling, Christian
    Journal of Electrocardiology
    BACKGROUND. The clinical effectiveness of primary prevention implantable cardioverter defibrillator (ICD) therapy is under debate. It is urgently needed to better identify patients who benefit from prophylactic ICD therapy. The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD) completed in 2019 will assess this issue. SUMMARY. The EU-CERT-ICD is a prospective investigator-initiated non-randomized, controlled, multicenter observational cohort study done in 44 centers across 15 European countries. A total of 2327 patients with heart failure due to ischemic heart disease or dilated cardiomyopathy indicated for primary prophylactic ICD implantation were recruited between 2014 and 2018 (>1500 patients at first ICD implantation, >750 patients non-randomized non-ICD control group). The primary endpoint was all-cause mortality, first appropriate shock was co-primary endpoint. At baseline, all patients underwent 12-lead ECG and Holter-ECG analysis using multiple advanced methods for risk stratification as well as documentation of clinical characteristics and laboratory values. The EU-CERT-ICD data will provide much needed information on the survival benefit of preventive ICD therapy and expand on previous prospective risk stratification studies which showed very good applicability of clinical parameters and advanced risk stratifiers in order to define patient subgroups with above or below average ICD benefit. CONCLUSION. The EU-CERT-ICD study will provide new and current data about effectiveness of primary prophylactic ICD implantation. The study also aims for improved risk stratification and patient selection using clinical risk markers in general, and advanced ECG risk markers in particular.
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  • Journal Article

    CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays 

    Windpassinger, Christian; Piard, Juliette; Bonnard, Carine; Alfadhel, Majid; Lim, Shuhui; Bisteau, Xavier; Blouin, Stéphane; Ali, Nur’Ain B.; Ng, Alvin Yu Jin; Lu, Hao; et al.
    Tohari, SumantyTalib, S. Zakiah A.van Hul, NoémiCaldez, Matias J.Van Maldergem, LionelYigit, GökhanKayserili, HülyaYoussef, Sameh A.Coppola, Vincenzode Bruin, AlainTessarollo, LinoChoi, HyungwonRupp, VerenaRoetzer, KatharinaRoschger, PaulKlaushofer, KlausAltmüller, JanineRoy, SudiptoVenkatesh, ByrappaGanger, RudolfGrill, FranzBen Chehida, FaridWollnik, BerndAltunoglu, UmutAl Kaissi, AliReversade, BrunoKaldis, Philipp
    The American Journal of Human Genetics 2017; 101(3) p.391-403
    In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development.
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  • Journal Article

    Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex 

    Guadalupe, Tulio; Mathias, Samuel R.; vanErp, Theo G. M.; Whelan, Christopher D.; Zwiers, Marcel P.; Abe, Yoshinari; Abramovic, Lucija; Agartz, Ingrid; Andreassen, Ole A.; Arias-Vásquez, Alejandro; et al.
    Aribisala, Benjamin S.Armstrong, Nicola J.Arolt, VolkerArtiges, EricAyesa-Arriola, RosaBaboyan, Vatche G.Banaschewski, TobiasBarker, GarethBastin, Mark E.Baune, Bernhard T.Blangero, JohnBokde, Arun L.W.Boedhoe, Premika S.W.Bose, AnushreeBrem, SilviaBrodaty, HenryBromberg, UliBrooks, SamanthaBüchel, ChristianBuitelaar, JanCalhoun, Vince D.Cannon, Dara M.Cattrell, AnnaCheng, YuqiConrod, Patricia J.Conzelmann, AnnetteCorvin, AidenCrespo-Facorro, BenedictoCrivello, FabriceDannlowski, Udode Zubicaray, Greig I.de Zwarte, Sonja M.C.Deary, Ian J.Desrivières, SylvaneDoan, Nhat TrungDonohoe, GaryDørum, Erlend S.Ehrlich, StefanEspeseth, ThomasFernández, GuillénFlor, HertaFouche, Jean-PaulFrouin, VincentFukunaga, MasakiGallinat, JürgenGaravan, HughGill, MichaelSuarez, Andrea GonzalezGowland, PennyGrabe, Hans J.Grotegerd, DominikGruber, OliverHagenaars, SaskiaHashimoto, RyotaHauser, Tobias U.Heinz, AndreasHibar, Derrek P.Hoekstra, Pieter J.Hoogman, MartineHowells, Fleur M.Hu, HaoHulshoff Pol, Hilleke E.Huyser, ChaimIttermann, BerndJahanshad, NedaJönsson, Erik G.Jurk, SarahKahn, Rene S.Kelly, SineadKraemer, BerndKugel, HaraldKwon, Jun SooLemaitre, HerveLesch, Klaus-PeterLochner, ChristineLuciano, MichelleMarquand, Andre F.Martin, Nicholas G.Martínez-Zalacaín, IgnacioMartinot, Jean-LucMataix-Cols, DavidMather, KarenMcDonald, ColmMcMahon, Katie L.Medland, Sarah E.Menchón, José M.Morris, Derek W.Mothersill, OmarManiega, Susana MunozMwangi, BensonNakamae, TakashiNakao, TomohiroNarayanaswaamy, Janardhanan C.Nees, FraukeNordvik, Jan E.Onnink, A. Marten H.Opel, NilsOphoff, RoelPaillère Martinot, Marie-LaurePapadopoulos Orfanos, DimitriPauli, PaulPaus, TomášPoustka, LuiseReddy, Janardhan YC.Renteria, Miguel E.Roiz-Santiáñez, RobertoRoos, AnnerineRoyle, Natalie A.Sachdev, PerminderSánchez-Juan, PascualSchmaal, LianneSchumann, GunterShumskaya, ElenaSmolka, Michael N.Soares, Jair C.Soriano-Mas, CarlesStein, Dan J.Strike, Lachlan T.Toro, RobertoTurner, Jessica A.Tzourio-Mazoyer, NathalieUhlmann, AnneHernández, Maria Valdésvan den Heuvel, Odile A.van der Meer, Dennisvan Haren, Neeltje E.M .Veltman, Dick J.Venkatasubramanian, GanesanVetter, Nora C.Vuletic, DaniellaWalitza, SusanneWalter, HenrikWalton, EstherWang, ZhenWardlaw, JoannaWen, WeiWestlye, Lars T.Whelan, RobertWittfeld, KatharinaWolfers, ThomasWright, Margaret J.Xu, JianXu, XiufengYun, Je-YeonZhao, JingJingFranke, BarbaraThompson, Paul M.Glahn, David C.Mazoyer, BernardFisher, Simon E.Francks, Clyde
    Brain Imaging and Behavior 2016; 11(5) p.1497-1514
    The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.
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  • Journal Article

    Cardiac optogenetics: using light to monitor cardiac physiology 

    Koopman, Charlotte D.; Zimmermann, Wolfram H.; Knöpfel, Thomas; de Boer, Teun P.
    Basic Research in Cardiology 2017; 112(5): Art. 56
    Our current understanding of cardiac excitation and its coupling to contraction is largely based on ex vivo studies utilising fluorescent organic dyes to assess cardiac action potentials and signal transduction. Recent advances in optogenetic sensors open exciting new possibilities for cardiac research and allow us to answer research questions that cannot be addressed using the classic organic dyes. Especially thrilling is the possibility to use optogenetic sensors to record parameters of cardiac excitation and contraction in vivo. In addition, optogenetics provide a high spatial resolution, as sensors can be coupled to motifs and targeted to specific cell types and subcellular domains of the heart. In this review, we will give a comprehensive overview of relevant optogenetic sensors, how they can be utilised in cardiac research and how they have been applied in cardiac research up to now.
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  • Journal Article

    Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: A randomized trial 

    Trenkwalder, Claudia; Winkelmann, Juliane; Oertel, Wolfgang; Virgin, Garth; Roubert, Bernard; Mezzacasa, Anna
    Movement Disorders 2017; 32(10) p.1478-1482
    BACKGROUND: Compromised iron status is important in restless legs syndrome pathophysiology. We compared the efficacy and tolerability of ferric carboxymaltose (single intravenous dose) versus placebo for restless legs syndrome treatment in iron-deficient nonanemic patients. METHODS: Patients with moderate to severe restless legs syndrome and serum ferritin < 75 μg/L (or serum ferritin 75-300 μg/L and transferrin saturation < 20%) were randomized to ferric carboxymaltose (1000 mg iron) or placebo. Mean change difference between ferric carboxymaltose and placebo in International Restless Legs Syndrome Severity Scale score from baseline to week 4 was the primary end point; week 12 was a secondary end point. RESULTS: Ferric carboxymaltose treatment (n = 59) led to nonsignificant improvement over placebo (n = 51) in International Restless Legs Syndrome Severity Scale score at week 4 (difference [95% confidence interval], -2.5 [-5.93 to 1.02], P = 0.163), reaching significance by week 12 (-4.66 [-8.59 to -0.73], P = 0.021). CONCLUSIONS: In patients who responded to treatment, ferric carboxymaltose may require more time to stabilize restless legs syndrome than previously assumed. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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  • Journal Article

    Low‐flow/low‐gradient aortic stenosis—Still a diagnostic and therapeutic challenge 

    Vogelgesang, Anja; Hasenfuss, Gerd; Jacobshagen, Claudius
    Clinical Cardiology 2017; 40(9) p.654-659
    Aortic stenosis (AS) is the most frequently observed valvular heart disease. During the symptomatic stage, the rate of death increases dramatically, so that a precise diagnostic approach is taken to guide therapeutic options. Of patients with severe AS, 30% to 50% present with low-flow/low-gradient AS (LF/LGAS) status. This review focuses on LF/LGAS and the best diagnostic and therapeutic management in either classic LF/LGAS with reduced left ventricular ejection fraction (LVEF) or paradoxical LF/LGAS with preserved LVEF. Current literature demonstrates that in classic LF/LGAS it is crucial to rule out a pseudo-severe AS, because reduced LVEF may result in an incomplete opening of the valve. This can be done by low-dose dobutamine stress echocardiography. Classic LF/LGAS has poor clinical outcomes when managed conservatively; therefore, surgical or interventional aortic valve replacement should be performed. In paradoxical LF/LGAS, the LVEF is preserved (>50%), but impaired filling of the concentric hypertrophied ventricle leads to reduced stroke volume. Therefore, diagnostic and therapeutic decisions in paradoxical LF/LGAS are even more challenging. It is a heterogeneous disease entity, and it is crucial to rule out any diagnostic errors because numerous potential confounders might lead to misdiagnosis. As in classic stenosis, pseudo-severe stenosis must be ruled out as well. Evaluation via multidetector computed tomography or transesophageal echocardiography can help to evaluate the morphologic alterations of the valve (eg, calcification). Further studies are necessary to understand this disease entity and to evaluate the optimal diagnostic and therapeutic approach for these patients.
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  • Journal Article

    Proteomic Comparison of Malignant Human Germ Cell Tumor Cell Lines 

    Bremmer, Felix; Bohnenberger, Hanibal; Küffer, Stefan; Oellerich, Thomas; Serve, Hubert; Urlaub, Henning; Strauss, Arne; Maatoug, Yasmine; Behnes, Carl Ludwig; Oing, Christoph; et al.
    Radzun, Heinz JoachimStröbel, PhilippBalabanov, StefanHonecker, Friedemann
    Disease Markers 2019; 2019 p.1-14
    Malignant germ cell tumors (GCT) are the most common malignant tumors in young men between 18 and 40 years. The correct identification of histological subtypes, in difficult cases supported by immunohistochemistry, is essential for therapeutic management. Furthermore, biomarkers may help to understand pathophysiological processes in these tumor types. Two GCT cell lines, TCam-2 with seminoma-like characteristics, and NTERA-2, an embryonal carcinoma-like cell line, were compared by a quantitative proteomic approach using high-resolution mass spectrometry (MS) in combination with stable isotope labelling by amino acid in cell culture (SILAC). We were able to identify 4856 proteins and quantify the expression of 3936. 347 were significantly differentially expressed between the two cell lines. For further validation, CD81, CBX-3, PHF6, and ENSA were analyzed by western blot analysis. The results confirmed the MS results. Immunohistochemical analysis on 59 formalin-fixed and paraffin-embedded (FFPE) normal and GCT tissue samples (normal testis, GCNIS, seminomas, and embryonal carcinomas) of these proteins demonstrated the ability to distinguish different GCT subtypes, especially seminomas and embryonal carcinomas. In addition, siRNA-mediated knockdown of these proteins resulted in an antiproliferative effect in TCam-2, NTERA-2, and an additional embryonal carcinoma-like cell line, NCCIT. In summary, this study represents a proteomic resource for the discrimination of malignant germ cell tumor subtypes and the observed antiproliferative effect after knockdown of selected proteins paves the way for the identification of new potential drug targets.
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  • Monograph

    Die „Humanembryologische Dokumentationssammlung Blechschmidt“: Geschichte einer sensiblen Sammlung, 1939-1973 

    Markert, Michael
    Georg-August-Universität Göttingen, GoeScholar: Göttingen,
    Der Wissenschaftshistoriker Michael Markert untersuchte von 08/2017 bis 07/2019 die Herkunft der 430 Schnittserien menschlicher Embryonen und Föten in der sogenannten „Humanembryologischen Dokumentationssammlung Blechschmidt“. Diese Präparate waren Grundlage für das wissenschaftliche Lebenswerk des Anatomen Erich Blechschmidt (1904-1992), der von 1942 bis 1974 das Anatomische Institut der Universität Göttingen leitete. Aufgabe des gemeinsam von Zentraler Kustodie, Zentrum Anatomie und Medizinischer Fakultät finanzierten Projektes war es, eine umfassende Dokumentation der Schnittserien, ihrer Gewinnung, Integration in die Sammlung und nicht zuletzt Nutzung vorzulegen. Der vorliegende Text bündelt die zentralen Projektergebnisse.
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  • Journal Article

    Does refugee status matter? Medical needs of newly arrived asylum seekers and resettlement refugees - a retrospective observational study of diagnoses in a primary care setting 

    Kleinert, Evelyn; Müller, Frank; Furaijat, Ghefar; Hillermann, Nele; Jablonka, Alexandra; Happle, Christine; Simmenroth, Anne
    Conflict and Health 2019; 13(1): Art. 39
    Background Providing adequate healthcare to newly arrived refugees is considered one of the significant challenges for the German healthcare system. These refugees can be classified mainly into two groups: asylum seekers (who have applied for asylum after arrival in Germany and are waiting for the refugee-status decision) and resettlement refugees (who have already been granted asylum status before arriving in Germany). Whereas earlier studies have explored the health status of asylum seekers especially in terms of mental and behavioural disorders and infectious diseases without distinguishing between these two groups, our study aims to evaluate possible relationships of asylum status and medical needs of these two groups with a special focus on mental and behavioural disorders and infectious diseases. Methods In this retrospective observational study, collected data on all asylum-seeker and resettlement-refugee patients (N = 2252) of a German reception centre (August 2017 to August 2018) is analysed by absolute and relative frequencies and medians. Patient data, collected by chart review, include age, gender, country of origin, asylum status, and diagnoses (ICD-10). To describe the relationship between sociodemographic factors (including asylum status) and diagnoses, we used tests of significance and bivariate correlations with Spearman correlation coefficients. All collected data are pseudonymised. Results Of all 2252 patients, 43% were resettlement refugees. In almost all ICD-10 categories, asylum seekers received significantly more diagnoses than resettlement refugees. According to our data, asylum seekers presented with mental and behavioural disorders nine times more often (9%) than resettlement refugees (1%). In the case of infectious diseases, the results are mixed: asylum seekers were twice as frequently (11%) diagnosed with certain infectious and parasitic diseases than resettlement refugees (5%), but resettlement refugees were treated twice as often (22% of the asylum seekers and 41% of the resettlement refugees) for diseases of the respiratory system, of which 84% were acute respiratory infections (in both groups). Conclusion This study indicates that patients with unregulated migration more frequently present symptoms of psychiatric diseases and somatoform symptoms than resettlement refugees. A health policy approach within migration policy should aim to enable persecuted persons to migrate under regulated and safe conditions.
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  • Journal Article

    Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling 

    Jochmann, Svenja; Elkenani, Manar; Mohamed, Belal A.; Buchholz, Eric; Lbik, Dawid; Binder, Lutz; Lorenz, Kristina; Shah, Ajay M.; Hasenfuß, Gerd; Toischer, Karl; et al.
    Schnelle, Moritz
    ESC Heart Failure
    Aims Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal-regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogenactivated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO-induced cardiac remodelling as this was unknown. Methods and results Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr-Glu-Tyr) motif ( 28% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte-specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6-fold, P < 0.05) and protein level (3.1-fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice. Conclusions VO-induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocytespecific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO.
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  • Journal Article

    Genetic deletion of calcium/calmodulin-dependent protein kinase type II delta does not mitigate adverse myocardial remodeling in volume-overloaded hearts 

    Mohamed, Belal A.; Elkenani, Manar; Jakubiczka-Smorag, Joanna; Buchholz, Eric; Koszewa, Sabrina; Lbik, Dawid; Schnelle, Moritz; Hasenfuss, Gerd; Toischer, Karl
    Scientific Reports 2019; 9(1): Art. 9889
    Calcium/calmodulin-dependent protein kinase type II delta (CaMKIIδ), the predominant CaMKII isoform expressed in the heart, has been implicated in the progression of myocardial infarction- and pressure overload-induced pathological remodeling. However, the role of CaMKIIδ in volume overload (VO) has not been explored. We have previously reported an activation of CaMKII during transition to HF in long-term VO. Here, we address whether CaMKIIδ is critically involved in the mortality, myocardial remodeling, and heart failure (HF) progression in response to VO. CaMKIIδ knockout (δ-KO) and wild-type (WT) littermates were exposed to aortocaval shunt-induced VO, and the progression of adverse myocardial remodeling was assessed by serial echocardiography, histological and molecular analyses. The mortality rates during 10 weeks of VO were similar in δ-KO and WT mice. Both genotypes displayed comparable eccentric myocardial hypertrophy, altered left ventricle geometry, perturbed systolic and diastolic functions after shunt. Additionally, cardiomyocytes hypertrophy, augmented myocyte apoptosis, and up-regulation of hypertrophic genes were also not significantly different in δ-KO versus WT hearts after shunt. Therefore, CaMKIIδ signaling seems to be dispensable for the progression of VO-induced maladaptive cardiac remodeling. Accordingly, we hypothesize that CaMKIIδ-inhibition as a therapeutic approach might not be helpful in the context of VO-triggered HF.
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  • Journal Article

    Dorsale Stabilisation der Halswirbelkörper HWK1/HWK2 modifiziert nach Goel-Harms mit HWK-1-Pedikelschrauben 

    Viezens, Lennart; Sehmisch, Stephan; Weiser, Lukas; Dreimann, Marc; Lehmann, Wolfgang
    Operative Orthopädie und Traumatologie 2019; 31(4) p.275-283
    OBJECTIVE: Stabilization of the atlantoaxial transition by an alternative screw position in C1. INDICATIONS: Instabilities C1/C2 due to inflammation, tumor or trauma. CONTRAINDICATIONS: Presence of a very small pedicle of C1. Variations in the course of the vertebral arteries. SURGICAL TECHNIQUE: The midline approach to the upper cervical spine is used for the modified instrumentation of C1 with pedicle screws instead of Harms screws and for the unaltered instrumentation of C2. Depending on the indication, dorsal spondylodesis is performed by opening the laminae and attaching ceramic bone substitute material. POSTOPERATIVE MANAGEMENT: In mobile patients, additional immobilisation with a soft collar is recommended for 6 weeks. Full recovery is given 3-4 months after surgery. RESULTS: From January 2017 to September 2018, 21 stabilizations of the atlantoaxial transition were performed. The mean age was 72.52 ± 15.45 years. A total of 42 screws were placed in C1. In all, 21 (50%) C1 pedicle screwscould be placed, and in other 21 cases Harms screws were used. Complications were seen in 3 patients. Overall, considering the contraindications, the instrumentation of C1 with pedicle screws appears as a safe alternative to instrumentation with Harms screws
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  • Journal Article

    Techniken zur Steigerung der Pedikelschraubenstabilität im osteoporotischen Knochen 

    Weiser, Lukas; Sehmisch, Stephan; Lehmann, Wolfgang; Viezens, Lennart
    Operative Orthopädie und Traumatologie 2019; 31(4) p.284-292
    OBJECTIVE: Operative stabilisation of osteoporotic vertebral fractures. INDICATIONS: Fractures of the thoracic and lumbar spine. CONTRAINDICATIONS: None. SURGICAL TECHNIQUE: Preoperative determination of expected bone mineral density. Implantation of pedicle screws in special trajectories, cement augmentation of the screws and use of alternative implants. POSTOPERATIVE MANAGEMENT: Early functional mobilisation and initiation of osteoporosis therapy if indicated. RESULTS: A biomechanical cadaver study with human vertebral bodies was performed. There was a highly significant correlation between bone mineral density and the fatigue load (r2 = 0.839, p < 0.001). Specimens with bone mineral density below 80 mg/cm3 only reached 60% of the fatigue load compared to the specimens with adequate bone quality (>120 mg/cm3) and therefore stability mightbe insufficient and an additional stabilisation should be considered. In osteoporotic vertebrae, the fatigue strength of cement augmented screws was increased by 52% compared to the non-augmented screws (fatigue load non-augmented: 173 N, augmented: 263 N; p = 0.001). Studies conducted by other research groups have demonstrated the effect of various screw trajectories and alternative implants to improve stability in the treatment of osteoporotic vertebral body fractures.
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  • Journal Article

    Intraoperative Revision von primär ausgerissenen Pedikelschrauben 

    Weiser, Lukas; Sehmisch, Stephan; Viezens, Lennart; Lehmann, Wolfgang
    Operative Orthopädie und Traumatologie 2019; 31(4) p.293-300
    OBJECTIVE: Intraoperative revision of initially loosened pedicle screws. INDICATIONS: Intraoperatively loosened/stripped pedicle screws. CONTRAINDICATIONS: None. SURGICAL TECHNIQUE: Removal of the loosened/stripped pedicle screw. Checking the screw channel and re-implantation using a different trajectory, a larger screw diameter or a cement-augmented pedicle screw. POSTOPERATIVE MANAGEMENT: Early functional mobilization and initiation of osteoporosis therapy if indicated. RESULTS: A biomechanical study with human vertebral bodies was performed. Augmented and not augmented pedicle screws were tested until loosening using a fatigue testing setup. After loosening occurred a subsequent augmentation of the loosened, not augmented screw was performed, and it was tested using a fatigue test again. Both the initial (p = 0.009) and the augmentation after loosening (p = 0.001) showed a significant increase in failure load compared to the non-augmented pedicle screws. In our own patient collective from April 2016 to August 2018, 11 of 524 patients treated with pedicle screws showed intraoperative screw loosening. This was revised in 6 cases with a subsequent augmentation and in 5 cases with a larger screw diameter. In the postoperative control at 6 weeks, none of these screws showed loosening again.
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  • Journal Article

    Decline of COPD exacerbations in clinical trials over two decades - a systematic review and meta-regression 

    Andreas, Stefan; Röver, Christian; Heinz, Judith; Straube, Sebastian; Watz, Henrik; Friede, Tim
    Respiratory Research 2019; 20: Art. 186
    BACKGROUND: An important goal of chronic obstructive pulmonary disease (COPD) treatment is to reduce the frequency of exacerbations. Some observations suggest a decline in exacerbation rates in clinical trials over time. A more systematic understanding would help to improve the design and interpretation of COPD trials. METHODS: We performed a systematic review and meta-regression of the placebo groups in published randomized controlled trials reporting exacerbations as an outcome. A Bayesian negative binomial model was developed to accommodate results that are reported in different formats; results are reported with credible intervals (CI) and posterior tail probabilities (pB). RESULTS: Of 1114 studies identified by our search, 55 were ultimately included. Exacerbation rates decreased by 6.7% (95% CI (4.4, 9.0); pB < 0.001) per year, or 50% (95% CI (36, 61)) per decade. Adjusting for available study and baseline characteristics such as forced expiratory volume in 1 s (FEV1) did not alter the observed trend considerably. Two subsets of studies, one using a true placebo group and the other allowing inhaled corticosteroids in the "placebo" group, also yielded consistent results. CONCLUSIONS: In conclusion, this meta-regression indicates that the rate of COPD exacerbations decreased over the past two decades to a clinically relevant extent independent of important prognostic factors. This suggests that care is needed in the design of new trials or when comparing results from older trials with more recent ones. Also a considerable effect of adjunct therapy on COPD exacerbations can be assumed.
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  • Journal Article

    Epigenome Mapping Identifies Tumor-Specific Gene Expression in Primary Rectal Cancer 

    Flebbe, Hannah; Hamdan, Feda H.; Kari, Vijayalakshmi; Kitz, Julia; Gaedcke, Jochen; Ghadimi, B. Michael; Johnsen, Steven A.; Grade, Marian
    Cancers 2019; 11(8): Art. 1142
    Epigenetic alterations play a central role in cancer development and progression. The acetylation of histone 3 at lysine 27 (H3K27ac) specifically marks active genes. While chromatin immunoprecipitation (ChIP) followed by next-generation sequencing (ChIP-seq) analyses are commonly performed in cell lines, only limited data are available from primary tumors. We therefore examined whether cancer-specific alterations in H3K27ac occupancy can be identified in primary rectal cancer. Tissue samples from primary rectal cancer and matched mucosa were obtained. ChIP-seq for H3K27ac was performed and differentially occupied regions were identified. The expression of selected genes displaying differential occupancy between tumor and mucosa were examined in gene expression data from an independent patient cohort. Differential expression of four proteins was further examined by immunohistochemistry. ChIP-seq for H3K27ac in primary rectal cancer and matched mucosa was successfully performed and revealed differential binding on 44 regions. This led to the identification of genes with increased H3K27ac, i.e., RIPK2, FOXQ1, KRT23, and EPHX4, which were also highly upregulated in primary rectal cancer in an independent dataset. The increased expression of these four proteins was confirmed by immunohistochemistry. This study demonstrates the feasibility of ChIP-seq-based epigenome mapping of primary rectal cancer and confirms the value of H3K27ac occupancy to predict gene expression differences.
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  • Journal Article

    B cell depletion can be effective in multiple sclerosis but failed in a patient with advanced childhood cerebral X-linked adrenoleukodystrophy 

    Rosewich, Hendrik; Nessler, Stefan; Brück, Wolfgang; Gärtner, Jutta
    Therapeutic Advances in Neurological Disorders 2019; 12
    Rituximab exerts its clinical efficacy by its specific pattern of depletion of CD20+ B lymphocytes and it has been demonstrated that rituximab is an effective treatment for relapsing remitting multiple sclerosis. X-linked adrenoleukodystrophy (X-ALD), the most common monogenetic neuroinflammatory disorder, shares substantial overlap with multiple sclerosis in the neuropathological changes found in brain tissues in advanced stages of the disease. While there is no effective therapy for these patients, we hypothesized that rituximab might be effective in arresting the neuroinflammatory process. Our detailed clinical, imaging and immunological data revealed that rituximab is not effective in advanced stages of X-ALD and consequently should not be applied for compassionate use in these patients.
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  • Journal Article

    Expression and prognostic impact of alpha thalassemia/mental retardation X-linked and death domain-associated protein in human lung cancer 

    Buentzel, Judith; Yao, Sha; Elakad, Omar; Lois, Anna-Maria; Brünies, Jana; König, Julia; Hinterthaner, Marc; Danner, Bernhard C.; Ströbel, Philipp; Emmert, Alexander; et al.
    Bohnenberger, Hanibal
    Medicine 2019; 98(31): Art. e16712
    Molecular characterization of lung cancer specimens after radical surgery offers additional prognostic information and may help to guide adjuvant therapeutic procedures. The transcriptional regulators alpha thalassemia/mental retardation X-linked (ATRX) and death domain-associated protein (DAXX) have recently been described in different cancer entities as a useful prognostic biomarker. This study was initiated to explore their protein expression patterns and prognostic value in patients with operable lung cancer disease.The protein abundance (in the following text also named protein expression) of ATRX and DAXX were analyzed by immunohistochemistry in 194 samples of squamous cell lung carcinoma (SQCLC), 111 samples of pulmonary adenocarcinoma (AC) and 40 samples of small cell lung cancer (SCLC). The protein levels of ATRX and DAXX were correlated with clinicopathological characteristics and patient outcome.ATRX showed strong protein expression in 16.2% of AC, 11.9% of SQCLC, and 42.5% of SCLC. DAXX was highly expressed in 54.9% of AC, 76.2% of SQCLC, and 82.5% of SCLC. Immunostaining of both ATRX and DAXX were seen in 14.4% of AC, 11.3% of SQCLC, and 42.5% of SCLC. High protein expression of ATRX was a favorable prognostic marker for patients with AC (hazard ratio 0.38, P = .02). Sub-group analyses showed a significant correlation between ATRX and the clinical stage of SQCLC and SCLC. Histological grading and ATRX were also significantly associated in cases of SQCLC.The presence of ATRX and DAXX are correlated with lung cancer histology. Strong ATRX protein expression is associated with a significantly longer overall survival in patients with AC.
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