Items 1-20 of 4411

    • Journal Article

      Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression? 

      Geladaris, Anastasia; Häusler, Darius; Weber, Martin S.
      International Journal of Molecular Sciences 2021; 22(7): Art. 3461
      Therapeutically controlling chronic progression in multiple sclerosis (MS) remains a major challenge. MS progression is defined as a steady loss of parenchymal and functional integrity of the central nervous system (CNS), occurring independent of relapses or focal, magnetic resonance imaging (MRI)-detectable inflammatory lesions. While it clinically surfaces in primary or secondary progressive MS, it is assumed to be an integral component of MS from the very beginning. The exact mechanisms causing progression are still unknown, although evolving evidence suggests that they may substantially differ from those driving relapse biology. To date, progression is assumed to be caused by an interplay of CNS-resident cells and CNS-trapped hematopoietic cells. On the CNS-resident cell side, microglia that are phenotypically and functionally related to cells of the monocyte/macrophage lineage may play a key role. Microglia function is highly transformable. Depending on their molecular signature, microglia can trigger neurotoxic pathways leading to neurodegeneration, or alternatively exert important roles in promoting neuroprotection, downregulation of inflammation, and stimulation of repair. Accordingly, to understand and to possibly alter the role of microglial activation during MS disease progression may provide a unique opportunity for the development of suitable, more effective therapeutics. This review focuses on the current understanding of the role of microglia during disease progression of MS and discusses possible targets for therapeutic intervention.
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    • Journal Article

      Characterization of Methacrylate-Based Resins Containing Methacryl-Polyhedral Oligomeric Silsesquioxanes (MA-POSS-8) 

      Kreutz, Marietta; Wiegand, Annette; Stawarczyk, Bogna; Lümkemann, Nina; Rizk, Marta
      Materials 2021; 14(7): Art. 1680
      The use of functionalized dental adhesives that might prevent degradation of the dentin hybrid layer has been proposed. The aim of the study was to characterize the physicochemical properties and the potential to induce mineral precipitation of methacrylate-based resins containing methacryl-functionalized polyhedral oligomeric silsesquioxane (MA-POSS-8). In total, six different compositions of resins based on bisphenol A glycerolate dimethacrylate (BisGMA, 40 to 60 wt.%), triethylene glycol dimethacrylate (TEGDMA, 5 to 35 wt.%) and 2-hydroxyethyl methacrylate (HEMA, 25 or 35 wt.%) were prepared and infiltrated with 5 wt.% MA-POSS-8. Unfilled resins served as control. Degree of conversion, viscosity, Martens hardness, indentation modulus, water sorption, and sol fraction were investigated. Polymerized specimens were examined by SEM/EDX for the presence of Ca/P precipitates after immersion in artificial saliva for 28 days at 37 °C. Statistical analysis was performed with two-way ANOVA and Tukey’s post-hoc test (p < 0.05). The degree of conversion ranged from 55.0 to 59.8% and was not affected by the addition of MA-POSS-8. Viscosity ranged from 60.0 to 422.3 mPa*s and was not affected by MA-POSS-8 except for one methacrylate-based resin with 60 wt.% BisGMA. Martens hardness and indentation modulus ranged from 161.3 to 138.1 N/mm2 and 4.2 to 3.9 kN/mm2 and were affected by MA-POSS-8 in only one resin (50 wt.% BisGMA, 25 wt.% TEGDMA, 25 wt.% HEMA). Water sorption was not affected by MA-POSS-8; sol fraction was below the detection limit. Formation of Ca/P precipitates was observed on all specimens of test and control groups. Material properties were not affected adversly by MA-POSS-8 except for slight differences in Martens Hardness, indentation modulus, viscosity, in some groups.
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    • Journal Article

      Evaluation of ustekinumab trough levels during induction and maintenance therapy with regard to disease activity status in difficult to treat Crohn disease patients 

      Mechie, Nicolae-Catalin; Burmester, Merle; Mavropoulou, Eirini; Pilavakis, Yiannis; Kunsch, Steffen; Ellenrieder, Volker; Amanzada, Ahmad
      Medicine 2021; 100(11): Art. e25111
      Ustekinumab (UST) is approved for the treatment of moderate and severe Crohn disease (CD). Therapeutic drug monitoring (TDM) can help monitor the therapeutic effects of biologics. Therefore, the aim of this study was to evaluate the clinical outcomes of UST-treated CD patients and to determine the UST trough level in clinical and corticosteroid-free remission. This retrospective study included patients with moderate and severe active disease (AD) treated intravenously with a weight-adapted induction dose of UST. The maintenance therapy consisted of 90 mg UST subcutaneously at week 8 and thereafter every 8 or 12 weeks, depending on the clinical response. Clinical and corticosteroid-free remission, Harvey-Bradshaw-Index (HBI), UST trough level, and further laboratory parameters were measured just before the injection of UST at each follow-up evaluation until week 40. 37 CD patients with a median HBI of 9 at week 0 were included in the study. Starting from 24% at the beginning of the monitoring period, and 38% of patients at the end of the monitoring period were treated with an 8-week interval (P = .18). There was a significant improvement in clinical (P = .0004), corticosteroid-free remission (P = .03), and HBI (P < .0001) from week 0 until the end of the observation period. The serum UST trough level decreased significantly from 2.0 at week 8 to 0.3, in the maintenance therapy and 0.4 μg/ml at the end of the therapy (P < .0001). Neither UST trough level nor levels of C-reactive protein (CRP) or fecal calprotectin (FC) were associated with disease outcome. Concomitant immunomodulator therapy did not appear to affect the UST trough level or clinical course. UST is an effective treatment option for difficult-to-treat patients with CD. UST trough levels may not be associated with treatment efficacy or the prediction of treatment outcomes in patients with CD. Further prospective randomized trials should be conducted to evaluate whether UST trough levels are associated with treatment outcomes in patients with CD.
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    • Journal Article

      Case Report: Interferon-γ Restores Monocytic Human Leukocyte Antigen Receptor (mHLA-DR) in Severe COVID-19 With Acquired Immunosuppression Syndrome 

      Dickel, Steffen; Grimm, Clemens; Amschler, Katharina; Schnitzler, Sebastian Uwe; Schanz, Julie; Moerer, Onnen; Payen, Didier; Tampe, Bjoern; Winkler, Martin Sebastian
      Frontiers in Immunology 2021; 12: Art. 645124
      Background: The major histocompatibility complex (MHC) class II characterized by monocytes CD14+ expression of human leukocyte antigen receptors (HLA-DR), is essential for the synapse between innate and adaptive immune response in infectious disease. Its reduced expression is associated with a high risk of secondary infections in septic patients and can be safely corrected by Interferon-y (IFNy) injection. Coronavirus disease (COVID-19) induces an alteration of Interferon (IFN) genes expression potentially responsible for the observed low HLA-DR expression in circulating monocytes (mHLA-DR). Methods: We report a case of one-time INFy injection (100 mcg s.c.) in a superinfected 61-year-old man with COVID-19–associated acute respiratory distress syndrome (ARDS), with monitoring of mHLA-DR expression and clinical tolerance. Observations: Low mHLA-DR pretreatment expression (26.7%) was observed. IFNy therapy leading to a rapid increase in mHLA-DR expression (83.1%). Conclusions: Severe ARDS in a COVID-19 patient has a deep reduction in mHLA-DR expression concomitantly with secondary infections. The unique IFNy injection was safe and led to a sharp increase in the expression of mHLA-DR. Based on immune and infection monitoring, more cases of severe COVID-19 patients with low mHLA-DR should be treated by IFNy to test the clinical effectiveness.
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    • Journal Article

      Electrophysiology Echoes Brain Dynamics in Children and Adolescents With Tourette Syndrome—A Developmental Perspective 

      Rothenberger, Aribert; Heinrich, Hartmut
      Frontiers in Neurology 2021; 12: Art. 587097
      The development of the complex clinical picture of motor and vocal tics in children and adolescents with Tourette syndrome (TS) must be paralleled by changes in the underlying pathophysiology. Electrophysiological methods such as EEG and event-related potentials (ERPs) are non-invasive, safe and easy to apply and thus seem to provide an adequate means to investigate brain dynamics during this brain maturational period. Also, electrophysiology is characterized by a high time resolution and can reflect motor, sensory and cognitive aspects as well as sleep behavior. Hence, this narrative review focuses on how electrophysiology echoes brain dynamics during development of youngsters with TS and might be useful for the treatment of tics. A comprehensive picture of developmental brain dynamics could be revealed showing that electrophysiological parameters evolve concurrently with clinical characteristics of TS. Specifically, evidence for a maturational delay of motor inhibition related to cortico-spinal hyper-excitability and brain mechanisms for its cognitive compensation could be shown. Moreover, deviant sleep parameters and probably a stronger perception-action binding were reported. For neuromodulatory treatments (e.g., neurofeedback; repetitive transcranial magnetic stimulation, rTMS/transcranial direct current stimulation, tDCS) targeting neuronal deficits and/or strengthening compensatory brain mechanisms, pilot studies support the possibility of positive effects regarding tic reduction. Finally, attention-deficit/hyperactivity disorder (ADHD), as a highly frequent co-existing disorder with TS, has to be considered when using and interpreting electrophysiological measures in TS. In conclusion, application of electrophysiology seems to be promising regarding clinical and research aspects in youngsters with TS.
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    • Journal Article

      Different Forms of Tumor Vascularization and Their Clinical Implications Focusing on Vessel Co-option in Colorectal Cancer Liver Metastases 

      Haas, Gwendolyn; Fan, Shuang; Ghadimi, Michael; De Oliveira, Tiago; Conradi, Lena-Christin
      Frontiers in Cell and Developmental Biology 2021; 9: Art. 612774
      In modern anti-cancer therapy of metastatic colorectal cancer (mCRC) the anti-angiogenic treatment targeting sprouting angiogenesis is firmly established for more than a decade. However, its clinical benefits still remain limited. As liver metastases (LM) represent the most common metastatic site of colorectal cancer and affect approximately one-quarter of the patients diagnosed with this malignancy, its treatment is an essential aspect for patients' prognosis. Especially in the perioperative setting, the application of anti-angiogenic drugs represents a therapeutic option that may be used in case of high-risk or borderline resectable colorectal cancer liver metastases (CRCLM) in order to achieve secondary resectability. Regarding CRCLM, one reason for the limitations of anti-angiogenic treatment may be represented by vessel co-option (VCO), which is an alternative mechanism of blood supply that differs fundamentally from the well-known sprouting angiogenesis and occurs in a significant fraction of CRCLM. In this scenario, tumor cells hijack pre-existing mature vessels of the host organ independently from stimulating new vessels formation. This represents an escape mechanism from common anti-angiogenic anti-cancer treatments, as they primarily target the main trigger of sprouting angiogenesis, the vascular endothelial growth factor A. Moreover, the mechanism of blood supply in CRCLM can be deduced from their phenotypic histopathological growth pattern (HGP). For that, a specific guideline has already been implemented. These HGP vary not only regarding their blood supply, but also concerning their tumor microenvironment (TME), as notable differences in immune cell infiltration and desmoplastic reaction surrounding the CRCLM can be observed. The latter actually serves as one of the central criteria for the classification of the HGP. Regarding the clinically relevant effects of the HGP, it is still a topic of research whether the VCO-subgroup of CRCLM results in an impaired treatment response to anti-angiogenic treatment when compared to an angiogenic subgroup. However, it is well-proved, that VCO in CRCLM generally relates to an inferior survival compared to the angiogenic subgroup. Altogether the different types of blood supply result in a relevant influence on the patients' prognosis. This reinforces the need of an extended understanding of the underlying mechanisms of VCO in CRCLM with the aim to generate more comprehensive approaches which can target tumor vessels alternatively or even other components of the TME. This review aims to augment the current state of knowledge on VCO in CRCLM and other tumor entities and its impact on anti-angiogenic anti-cancer therapy.
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    • Journal Article

      Adipose‐derived mesenchymal stem cells reduce autophagy in stroke mice by extracellular vesicle transfer of miR‐25 

      Kuang, Yaoyun; Zheng, Xuan; Zhang, Lin; Ai, Xiaoyu; Venkataramani, Vivek; Kilic, Ertugrul; Hermann, Dirk M.; Majid, Arshad; Bähr, Mathias; Doeppner, Thorsten R.
      Journal of Extracellular Vesicles 2020; 10(1): Art. e12024
      Grafted mesenchymal stem cells (MSCs) yield neuroprotection in preclinical stroke models by secreting extracellular vesicles (EVs). The neuroprotective cargo of EVs, however, has not yet been identified. To investigate such cargo and its underlying mechanism, primary neurons were exposed to oxygen-glucose-deprivation (OGD) and cocultured with adipose-derived MSCs (ADMSCs) or ADMSC-secreted EVs. Under such conditions, both ADMSCs and ADMSC-secreted EVs significantly reduced neuronal death. Screening for signalling cascades being involved in the interaction between ADMSCs and neurons revealed a decreased autophagic flux as well as a declined p53-BNIP3 activity in neurons receiving either treatment paradigm. However, the aforementioned effects were reversed when ADMSCs were pretreated with the inhibitor of exosomal secretion GW4869 or when Hrs was knocked down. In light of miR-25-3p being the most highly expressed miRNA in ADMSC-EVs interacting with the p53 pathway, further in vitro work focused on this pathway. Indeed, a miR-25-3p oligonucleotide mimic reduced cell death, whereas the anti-oligonucleotide increased autophagic flux and cell death by modulating p53-BNIP3 signalling in primary neurons exposed to OGD. Likewise, native ADMSC-EVs but not EVs obtained from ADMSCs pretreated with the anti-miR-25-3p oligonucleotide (ADMSC-EVsanti-miR-25-3p) confirmed the aforementioned in vitro observations in C57BL/6 mice exposed to cerebral ischemia. The infarct size was reduced, and neurological recovery was increased in mice treated with native ADMSC-EVs when compared to ADMSC-EVsanti-miR-25-3p. ADMSCs induce neuroprotection by improved autophagic flux through secreted EVs containing miR-25-3p. Hence, our work uncovers a novel key factor in naturally secreted ADMSC-EVs for the regulation of autophagy and induction of neuroprotection in a preclinical stroke model.
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    • Journal Article

      Non‐invasive hemodynamic profile of early COVID‐19 infection 

      Busana, Mattia; Schiavone, Marco; Lanfranchi, Antonio; Battista Forleo, Giovanni; Ceriani, Elisa; Beatrice Cogliati, Chiara; Gasperetti, Alessio
      Physiological Reports 2020; 8(20): Art. e14628
      Introduction Little is known about the systemic and pulmonary macrohemodynamics in early COVID-19 infection. Echocardiography may provide useful insights into COVID-19 physiopathology. Methods Twenty-three COVID-19 patients were enrolled in a medical ward. Gas exchange, transthoracic echocardiographic, and hemodynamic variables were collected. Results Mean age was 57 ± 17 years. The patients were hypoxemic (PaO2/FiO2 = 273.0 ± 102.6 mmHg) and mildly hypocapnic (PaCO2 = 36.2 ± 6.3 mmHg, pH = 7.45 ± 0.03). Mean arterial pressure was decreased (86.7 [80.0–88.3] mmHg). Cardiac index was elevated (4.32 ± 0.90 L∙min-1∙m-2) and the resulting systemic vascular resistance index low (1,458 [1358–1664] dyn∙s∙cm-5∙m-2). The right heart was morphologically and functionally normal, with pulmonary artery pressure (PAPm, 18.0 ± 2.9 mmHg) and Total Pulmonary Resistances (TPR, 2.3 [2.1–2.7] mmHg∙l-1∙min-1) within normal limits. When stratifying for SVRI, patients with an SVRI value below the cohort median had also more severe oxygenation impairment and lower TPR, despite a similar degree of CXR infiltrates. Oxygen delivery index in this group resulted supranormal. Conclusions In the early stages of COVID-19 infection the hemodynamic profile is characterized by a hyperdynamic circulatory state with high CI and low SVRI, while the right heart is functionally unaffected. Our findings suggest that hypoxemia, viral sepsis or peripheral shunting are possible mechanisms for the vasodilation that dominates at this stage of the disease and may itself worsen the gas exchange.
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    • Journal Article

      Cardiotoxicity and Cardiovascular Biomarkers in Patients With Breast Cancer: Data From the GeparOcto‐GBG 84 Trial 

      Rüger, Alexandra Maria; Schneeweiss, Andreas; Seiler, Sabine; Tesch, Hans; van Mackelenbergh, Marion; Marmé, Frederik; Lübbe, Kristina; Sinn, Bruno; Karn, Thomas; Stickeler, Elmar; et al.
      Müller, VolkmarSchem, ChristianDenkert, CarstenFasching, Peter A.Nekljudova, ValentinaGarfias‐Macedo, TaniaHasenfuß, GerdHaverkamp, WilhelmLoibl, Sibyllevon Haehling, Stephan
      Journal of the American Heart Association 2020; 9(23): Art. e018143
      Background Patients with breast cancer can be affected by cardiotoxic reactions through cancer therapies. Cardiac biomarkers, like NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and high‐sensitivity cardiac troponin T, might have predictive value. Methods and Results Echocardiography, ECG, hemodynamic parameters, NT‐proBNP and high‐sensitivity cardiac troponin T were assessed in 853 patients with early‐stage breast cancer randomized in the German Breast Group GeparOcto‐GBG 84 phase III trial. Patients received neo‐adjuvant dose‐dense, dose‐intensified epirubicin, paclitaxel, and cyclophosphamide (iddEPC group, n=424) or paclitaxel, non‐pegylated doxorubicin, and in triple negative breast cancer, (paclitaxel, non‐pegylated doxorubicin, carboplatin group, n=429) treatment for 18 weeks. Patients positive for human epidermal growth receptor 2 (n=354, 41.5%) received monoclonal antibodies on top of allocated therapy; 119 (12.9%) of all patients showed a cardiotoxic reaction during therapy (15 [1.8%] using a more strict definition). Presence of cardiotoxic reactions was irrespective of treatment allocation (P=0.31). Small but significant increases in NT‐proBNP developed early in patients with a cardiotoxic reaction as compared with those without in whom NT‐proBNP rose only towards the end of therapy (P=0.04). High‐sensitivity cardiac troponin T rose early in both groups. Logistic regression showed that NT‐proBNP (odds ratio [OR], 1.03; 95% CI, 1.008–1.055; P=0.01) and hemoglobin (OR, 1.31; 95% CI, 1.05–1.63; P=0.02) measured at 6 weeks after treatment initiation were significantly associated with cardiotoxic reactions. Conclusions NT‐proBNP and hemoglobin are significantly associated with cardiotoxic reactions in patients with early‐stage breast cancer undergoing dose‐dense and dose‐intensified chemotherapy, but high‐sensitivity cardiac troponin T is not.
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    • Journal Article

      Bounds for the weight of external data in shrinkage estimation. 

      Röver, Christian; Friede, Tim
      Biometrical journal. Biometrische Zeitschrift 2021-02-25; 63(5) p.1131-1143
      Shrinkage estimation in a meta-analysis framework may be used to facilitate dynamical borrowing of information. This framework might be used to analyze a new study in the light of previous data, which might differ in their design (e.g., a randomized controlled trial and a clinical registry). We show how the common study weights arise in effect and shrinkage estimation, and how these may be generalized to the case of Bayesian meta-analysis. Next we develop simple ways to compute bounds on the weights, so that the contribution of the external evidence may be assessed a priori. These considerations are illustrated and discussed using numerical examples, including applications in the treatment of Creutzfeldt-Jakob disease and in fetal monitoring to prevent the occurrence of metabolic acidosis. The target study's contribution to the resulting estimate is shown to be bounded below. Therefore, concerns of evidence being easily overwhelmed by external data are largely unwarranted.
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      Identification of drivers of breast cancer invasion by secretome analysis: insight into CTGF signaling 

      Hellinger, Johanna W.; Schömel, Franziska; Buse, Judith V.; Lenz, Christof; Bauerschmitz, Gerd; Emons, Günter; Gründker, Carsten
      Scientific Reports 2020; 10(1)
      An altered consistency of tumor microenvironment facilitates the progression of the tumor towards metastasis. Here we combine data from secretome and proteome analysis using mass spectrometry with microarray data from mesenchymal transformed breast cancer cells (MCF-7-EMT) to elucidate the drivers of epithelial-mesenchymal transition (EMT) and cell invasion. Suppression of connective tissue growth factor (CTGF) reduced invasion in 2D and 3D invasion assays and expression of transforming growth factor-beta-induced protein ig-h3 (TGFBI), Zinc finger E-box-binding homeobox 1 (ZEB1) and lysyl oxidase (LOX), while the adhesion of cell-extracellular matrix (ECM) in mesenchymal transformed breast cancer cells is increased. In contrast, an enhanced expression of CTGF leads to an increased 3D invasion, expression of fibronectin 1 (FN1), secreted protein acidic and cysteine rich (SPARC) and CD44 and a reduced cell ECM adhesion. Gonadotropin-releasing hormone (GnRH) agonist Triptorelin reduces CTGF expression in a Ras homolog family member A (RhoA)-dependent manner. Our results suggest that CTGF drives breast cancer cell invasion in vitro and therefore could be an attractive therapeutic target for drug development to prevent the spread of breast cancer.
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    • Journal Article

      A double-Flp-in method for stable overexpression of two genes 

      Jensen, Ole; Ansari, Salim; Gebauer, Lukas; Müller, Simon F.; Lowjaga, Kira A. A. T.; Geyer, Joachim; Tzvetkov, Mladen V.; Brockmöller, Jürgen
      Scientific Reports 2020; 10(1)
      Overexpression of single genes in mammalian cells is widely used to investigate protein function in basic and applied biosciences and in drug research. A better understanding of interactions of two proteins is an important next step in the advancement of our understanding of complex biological systems. However, simultaneous and robust overexpression of two or more genes is challenging. The Flp-In system integrates a vector into cell lines at a specific genomic locus, but has not been used for integration of more than one gene. Here we present a modification of the Flp-In system that enables the simultaneous targeted integration of two genes. We describe the modification and generation of the vectors required and give the complete protocol for transfection and validation of correct genomic integration and expression. We also provide results on the stability and reproducibility, and we functionally validated this approach with a pharmacologically relevant combination of a membrane transporter facilitating drug uptake and an enzyme mediating drug metabolism.
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      Continuous lengthening potential after four years of magnetically controlled spinal deformity correction in children with spinal muscular atrophy 

      Lorenz, Heiko M.; Hecker, Marina M.; Braunschweig, Lena; Badwan, Batoul; Tsaknakis, Konstantinos; Hell, Anna K.
      Scientific Reports 2020; 10(1)
      Magnetically controlled growing rods (MCGR) are commonly implanted for the treatment of early-onset scoliosis. While most authors report favorable short-term results, little is known about long-term deformity correction. This prospective cohort study assesses spinal deformity control in a homogeneous spinal muscular atrophy (SMA) patient group treated with MCGR implants, a standardized lengthening protocol and a minimum follow-up of four years. 17 SMA patients with progressive scoliosis were treated with MCGR implanted parallel to the spine with rib-to-pelvis fixation. Radiologic measurements were performed before and after MCGR implantation and during external lengthening procedures. These included measurements of the scoliotic curve, kyphosis, lordosis, pelvic obliquity and the spinal length. Additional clinical data of the complications were also analyzed. 17 children (mean age 7.4 years) were surgically treated and underwent a total of 376 lengthenings. Complication rates were 3.5% in respect to all interventions or 41% of the patients had complications during 3.5% of the lengthening sessions. The initial implantation significantly reduced the main scoliotic curve by 59%, with the correction remaining constant throughout the follow-up. Pelvic obliquity was also significantly and permanently corrected by 72%, whereas kyphosis and lordosis were not influenced. The spinal length could be significantly increased mostly during the first year of treatment. Bilateral implantation of MCGRs for correction of spinal deformity in children with SMA showed no decrease of the lengthening potential during a four-year follow-up. Therefore, the previously described ‘law of diminishing returns’ could not be applied to this patient population.
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      Accuracy of zero-heat-flux thermometry and bladder temperature measurement in critically ill patients 

      Bräuer, Anselm; Fazliu, Albulena; Perl, Thorsten; Heise, Daniel; Meissner, Konrad; Brandes, Ivo Florian
      Scientific Reports 2020; 10(1)
      Core temperature (TCore) monitoring is essential in intensive care medicine. Bladder temperature is the standard of care in many institutions, but not possible in all patients. We therefore compared core temperature measured with a zero-heat flux thermometer (TZHF) and with a bladder catheter (TBladder) against blood temperature (TBlood) as a gold standard in 50 critically ill patients in a prospective, observational study. Every 30 min TBlood, TBladder and TZHF were documented simultaneously. Bland–Altman statistics were used for interpretation. 7018 pairs of measurements for the comparison of TBlood with TZHF and 7265 pairs of measurements for the comparison of TBlood with TBladder could be used. TBladder represented TBlood more accurate than TZHF. In the Bland Altman analyses the bias was smaller (0.05 °C vs. − 0.12 °C) and limits of agreement were narrower (0.64 °C to − 0.54 °C vs. 0.51 °C to – 0.76 °C), but not in clinically meaningful amounts. In conclusion the results for zero-heat-flux and bladder temperatures were virtually identical within about a tenth of a degree, although TZHF tended to underestimate TBlood. Therefore, either is suitable for clinical use.
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      Memory guidance of value-based decision making at an abstract level of representation 

      Liashenko, Anna; Dizaji, Aslan S.; Melloni, Lucia; Schwiedrzik, Caspar M.
      Scientific Reports 2020; 10(1)
      Value-based decisions about alternatives we have never experienced can be guided by associations between current choice options and memories of prior reward. A critical question is how similar memories need to be to the current situation to effectively guide decisions. We address this question in the context of associative learning of faces using a sensory preconditioning paradigm. We find that memories of reward spread along established associations between faces to guide decision making. While memory guidance is specific for associated facial identities, it does not only occur for the specific images that were originally encountered. Instead, memory guidance generalizes across different images of the associated identities. This suggests that memory guidance does not rely on a pictorial format of representation but on a higher, view-invariant level of abstraction. Thus, memory guidance operates on a level of representation that neither over- nor underspecifies associative relationships in the context of obtaining reward.
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      Vimentin protects differentiating stem cells from stress 

      Pattabiraman, Sundararaghavan; Azad, Gajendra Kumar; Amen, Triana; Brielle, Shlomi; Park, Jung Eun; Sze, Siu Kwan; Meshorer, Eran; Kaganovich, Daniel
      Scientific Reports 2020; 10(1)
      Vimentin is one of the first cytoplasmic intermediate filaments to be expressed in mammalian cells during embryogenesis, but its role in cellular fitness has long been a mystery. Vimentin is acknowledged to play a role in cell stiffness, cell motility, and cytoplasmic organization, yet it is widely considered to be dispensable for cellular function and organismal development. Here, we show that Vimentin plays a role in cellular stress response in differentiating cells, by recruiting aggregates, stress granules, and RNA-binding proteins, directing their elimination and asymmetric partitioning. In the absence of Vimentin, pluripotent embryonic stem cells fail to differentiate properly, with a pronounced deficiency in neuronal differentiation. Our results uncover a novel function for Vimentin, with important implications for development, tissue homeostasis, and in particular, stress response.
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      X-ray diffraction and second harmonic imaging reveal new insights into structural alterations caused by pressure-overload in murine hearts 

      Nicolas, Jan-David; Khan, Amara; Markus, Andrea; Mohamed, Belal A.; Toischer, Karl; Alves, Frauke; Salditt, Tim
      Scientific Reports 2020; 10(1)
      We demonstrate a label-free imaging approach to study cardiac remodeling of fibrotic and hypertrophic hearts, bridging scales from the whole organ down to the molecular level. To this end, we have used mice subjected to transverse aortic constriction and imaged adjacent cardiac tissue sections by microfocus X-ray diffraction and second harmonic generation (SHG) imaging. In this way, the acto-myosin structure was probed in a spatially resolved manner for entire heart sections. From the recorded diffraction data, spatial maps of diffraction intensity, anisotropy and orientation were obtained, and fully automated analysis depicted the acto-myosin filament spacing and direction. X-ray diffraction presented an overview of entire heart sections and revealed that in regions of severe cardiac remodeling the muscle mass is partly replaced by connective tissue and the acto-myosin lattice spacing is increased at these regions. SHG imaging revealed sub-cellular structure of cardiac tissue and complemented the findings from X-ray diffraction by revealing micro-level distortion of myofibrils, immune cell infiltration at regions of cardiac remodeling and the development of fibrosis down to the scale of a single collagen fibril. Overall, our results show that both X-ray diffraction and SHG imaging can be used for label-free and high-resolution visualization of cardiac remodeling and fibrosis progression at different stages in a cardiac pressure-overload mouse model that cannot be achieved by conventional histology.
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      Rapid direct detection of pathogens for diagnosis of joint infections by MALDI-TOF MS after liquid enrichment in the BacT/Alert blood culture system 

      Noll, Christine; Nasruddin-Yekta, Azadda; Sternisek, Pia; Weig, Michael; Groß, Uwe; Schilling, Arndt F.; Beil, Frank Timo; Bader, Oliver
      PLOS ONE 2020; 15(12)
      Pathogen identification is a critical step during diagnosis of infectious diseases. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight mass spectrometry (MALDI-TOF-MS) has become the gold standard for identification of microorganisms cultured on solid media in microbiology laboratories. Direct identification of microbes from liquid specimen, circumventing the need for the additional overnight cultivation step, has been successfully established for blood culture, urine and liquor. Here, we evaluate the ability of MALDI-TOF MS for direct identification of pathogens in synovial fluid after liquid enrichment in BacT/Alert blood culture bottles. Influence of synovial specimen quality on direct species identification with the MALDI BioTyper/Sepsityper was tested with samples inoculated from pretested native synovia with concomitant inoculation of blood or pus, or highly viscous fluid. Here, we achieved >90% concordance with culture on solid medium, and only mixed-species samples posed significant problems. Performance in routine diagnostics was tested prospectively on bottles inoculated by treating physicians on ward. There, we achieved >70% concordance with culture on solid media. The major contributors to test failure were the absence of a measurable mass signal and mixed-specimen samples. The Sepsityper workflow worked well on samples derived from BacT/Alert blood culture bottles inoculated with synovial fluid, giving concordant results to identification from solid media. Host remnant material in the inoculum, such as blood or pus, had no detrimental effect on identification score values of the BioTyper system after processing with the Sepsityper workflow, and neither had the initial viscosity of the synovial sample.
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      Comparison of the double loop knot stitch and Kessler stitch for Achilles tendon repair: A biomechanical cadaver study 

      Frosch, Stephan; Buchhorn, Gottfried; Hawellek, Thelonius; Walde, Tim Alexander; Lehmann, Wolfgang; Hubert, Jan
      PLOS ONE 2020; 15(12)
      Tendon elongation after Achilles tendon (AT) repair is associated with the clinical outcome. Reliable suture techniques are essential to reduce gap formations and to allow early mobilization. Cyclic loading conditions represent the repetitive loading in rehabilitation. The aim of this study was to compare the Kessler stitch and double loop knot stitch (DLKS) in a cyclic loading program focussing on gap formation. Sixteen human cadaveric ATs were transected and sutured using either the Kessler stitch or DLKS (eight matched pairs). The suture-tendon configurations were subjected to cyclic loading and additional ultimate load to failure testing using the Zwick 1446 universal testing machine. Each AT survived cyclic loading, with a mean gap formation less than 5 mm after 1000 cycles. The mechanical properties of the Kessler stitch and DLKS were not significantly different after cyclic loading with a mean displacement of 4.57 mm (± 1.16) for the Kessler stitch and 4.85 mm (± 1.14) for the DLKS (P = .76). There were no significant differences in the ultimate load testing (P = .85). Both bioprotective techniques prevent excessive gaping in cyclic testing when tendon loading is moderate. Our data and those from literature of gap formation in cyclic and ultimate loading allow the conclusion, that early aggressive AT loading after repair (e.g. full weightbearing) overstrain simple as well as complex suture configurations. Initial intraoperative tightening of the knots (preloading) before locking is important to decrease postoperative elongation.
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    • Journal Article

      Genetic structure of coast redwood (Sequoia sempervirens [D. Don] Endl.) populations in and outside of the natural distribution range based on nuclear and chloroplast microsatellite markers 

      Breidenbach, Natalie; Gailing, Oliver; Krutovsky, Konstantin V.
      PLOS ONE 2020; 15(12)
      Coast redwood (Sequoia sempervirens) naturally growing in southern Oregon and northern California is one of the few conifer tree species that are polyploid. Despite its unique ecological and economic importance, its population genetic structure is still insufficiently studied. To obtain additional data on its population genetic structure we genotyped 317 samples collected from populations in California (data set C) and 144 trees growing in a provenance trial in France (data set F) using 12 nuclear (five random nuclear genomic nSSRs and seven expressed sequence tag EST-SSRs) and six chloroplast (cpSSRs) microsatellite or simple sequence repeat (SSR) markers, respectively. These data sets were also used as reference to infer the origin of 147 coast redwood trees growing in Germany (data set G). Coast redwood was introduced to Europe, including Germany as an ornamental species, decades ago. Due to its fast growth and high timber quality, it could be considered as a potential commercial timber species, especially in perspective to climate warming that makes more regions in Germany suitable for its growing. The well performing trees in colder Germany could be potential frost resistant genotypes, but their genetic properties and origin are mostly unknown. Within the natural range in southern Oregon and northern California, only two relatively weak clusters were identified, one northern and one southern, separated by the San Francisco Bay. High genetic diversity, but low differentiation was found based on the 12 nuclear SSR markers for all three data sets F, C and G. We found that investigated 147 German trees represented only 37 different genotypes. They showed genetic diversity at the level less than diversity observed within the natural range in the northern or southern cluster, but more similar to the diversity observed in the southern cluster. It was difficult to assign German trees to the original single native populations using the six cpSSR markers, but rather to either the northern or southern cluster. The high number of haplotypes found in the data sets based on six cpSSR markers and low genetic differentiation based on 12 nuclear SSRs found in this study helps us study and better understand population genetic structure of this complex polyploid tree and supports the selection of potential genotypes for German forestry.
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