Recent Submissions

  • Journal Article

    The long noncoding RNA neuroLNC regulates presynaptic activity by interacting with the neurodegeneration-associated protein TDP-43 

    Keihani, S.; Kluever, V.; Mandad, S.; Bansal, V.; Rahman, R.; Fritsch, E.; Gomes, L. Caldi; Gärtner, A.; Kügler, S.; Urlaub, H.; et al.
    Wren, J. D.Bonn, S.Rizzoli, S. O.Fornasiero, E. F.
    Science Advances 2019; 5(12): Art. eaay2670
    The cellular and the molecular mechanisms by which long noncoding RNAs (lncRNAs) may regulate presynaptic function and neuronal activity are largely unexplored. Here, we established an integrated screening strategy to discover lncRNAs implicated in neurotransmitter and synaptic vesicle release. With this approach, we identified neuroLNC, a neuron-specific nuclear lncRNA conserved from rodents to humans. NeuroLNC is tuned by synaptic activity and influences several other essential aspects of neuronal development including calcium influx, neuritogenesis, and neuronal migration in vivo. We defined the molecular interactors of neuroLNC in detail using chromatin isolation by RNA purification, RNA interactome analysis, and protein mass spectrometry. We found that the effects of neuroLNC on synaptic vesicle release require interaction with the RNA-binding protein TDP-43 (TAR DNA binding protein-43) and the selective stabilization of mRNAs encoding for presynaptic proteins. These results provide the first proof of an lncRNA that orchestrates neuronal excitability by influencing presynaptic function.
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  • Journal Article

    Dynamically borrowing strength from another study through shrinkage estimation 

    Röver, Christian; Friede, Tim
    Statistical Methods in Medical Research 2020-01-22; 29(1) p.293-308
    Meta-analytic methods may be used to combine evidence from different sources of information. Quite commonly, the normal-normal hierarchical model (NNHM) including a random-effect to account for between-study heterogeneity is utilized for such analyses. The same modeling framework may also be used to not only derive a combined estimate, but also to borrow strength for a particular study from another by deriving a shrinkage estimate. For instance, a small-scale randomized controlled trial could be supported by a non-randomized study, e.g. a clinical registry. This would be particularly attractive in the context of rare diseases. We demonstrate that a meta-analysis still makes sense in this extreme case, effectively based on a synthesis of only two studies, as illustrated using a recent trial and a clinical registry in Creutzfeld-Jakob disease. Derivation of a shrinkage estimate within a Bayesian random-effects meta-analysis may substantially improve a given estimate even based on only a single additional estimate while accounting for potential effect heterogeneity between the studies. Alternatively, inference may equivalently be motivated via a model specification that does not require a common overall mean parameter but considers the treatment effect in one study, and the difference in effects between the studies. The proposed approach is quite generally applicable to combine different types of evidence originating, e.g. from meta-analyses or individual studies. An application of this more general setup is provided in immunosuppression following liver transplantation in children.
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  • Journal Article

    Chronic hyponatremia in patients with proximal femoral fractures after low energy trauma: A retrospective study in a level-1 trauma center 

    Hoffmann, Daniel Bernd; Popescu, Christian; Komrakova, Marina; Welte, Lena; Saul, Dominik; Lehmann, Wolfgang; Hawellek, Thelonius; Beil, Frank Timo; Dakna, Mohammed; Sehmisch, Stephan
    Bone Reports 2020; 12: Art. 100234
    Introduction: We evaluated the prevalence and influence of chronic hyponatremia in patients with low energy trauma. We also investigated the influence of medication and diseases on hyponatremia. Material and methods: This retrospective study included 314 cases of proximal femoral fracture due to low energy trauma. Patients were treated in the University Medical Center Goettingen within 3 years. Hyponatremia was defined as serum sodium <135 mmol/L at admission. Results: Overall, 15.6% of patients in the low energy trauma group had hyponatremia. Among patients older than 80 years, women showed distinctly higher rates of hyponatremia (female: 16.4%; male: 5.9%). In contrast only 4.7% of patients who underwent elective hip arthroplasty showed hyponatremia. Patients on sartanes and aldosterone antagonists showed significantly higher rates of hyponatremia. Alcoholism was significantly associated with hyponatremia. Conclusions: We confirmed a high prevalence of chronic hyponatremia in patients with fractures due to low energy trauma. Our data underscore chronic hyponatremia as a contributing factor to hip fractures. Women older than 80 have a higher risk of developing hyponatremia. Sartanes, aldosterone antagonists, and alcohol disease are associated with hyponatremia. Treating hyponatremia may decrease the risk of fracture after low energy trauma. Therefore, physicians of different specialties should focus on treatment of chronic hyponatremia to reduce the fracture rate associated with low energy trauma.
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  • Journal Article

    The HPQ-Development and First Administration of a Questionnaire for Hypoparathyroid Patients 

    Wilde, Deborah; Wilken, Lara; Stamm, Bettina; Blaschke, Martina; Heppner, Christina; Chavanon, Mira-Lynn; Leha, Andreas; Herrmann-Lingen, Christoph; Siggelkow, Heide
    JBMR Plus 2019; 4(1): Art. e10245
    Hypoparathyroidism patients suffer a variety of complaints often leading to reduced quality of life. Currently, no specific standard instrument exists to measure corresponding disease manifestations. We therefore aimed to develop a disease-characteristic questionnaire for hypoparathyroid patients. We used an analytical-empirical approach for questionnaire construction based on retrospective analysis of four well-established but non-disease-specific questionnaires (Symptom Checklist 90, revised [SCL-90-R]; Giessen Complaint List [GBB]; Short-Form-36 Health Survey [SF-36]; von Zerssen Symptom List [B-L Zerssen]) and two additional unpublished or local questionnaires (SHGdQ and GPQ) in a German hypoparathyroidism self-help group (n = 60). Retrospective data were compared with corresponding general population norms. The new questionnaire was administered prospectively over 1 year to patients with postoperative hypoparathyroidism and two control groups to validate specificity. Exploratory factor analysis (EFA) and reliability testing were applied to identify relevant scales and reduce overlapping items. In the self-help group, SCL-90-R revealed elevated symptom load in four complaint areas (p = 0.003 to p < 0.001). The SF-36 mental summary score (p < 0.001) and further scales were lowered. In the GBB, four of five scales (p = 0.009 to p < 0.001) were elevated. In the B-L Zerssen, 6 of 24 items revealed complaint areas. Based on these findings, the new 40-item "Hypoparathyroid Patient Questionnaire" (HPQ 40) was developed, tested prospectively, and further analyzed. EFA revealed five scales (pain and cramps, gastrointestinal symptoms, depression and anxiety, neurovegetative symptoms, loss of vitality), all with Cronbach's alpha >0.7. The questionnaire was revised accordingly and shortened to 28 questions to avoid redundancy. We present a new disease-characteristic questionnaire for hypoparathyroidism patients. Prospective testing revealed five major complaint areas and promising psychometric properties. This questionnaire can be tested for usefulness in further clinical trials. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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  • Journal Article

    Regeneration competent satellite cell niches in rat engineered skeletal muscle 

    Tiburcy, Malte; Markov, Alex; Kraemer, Lena K.; Christalla, Peter; Rave‐Fraenk, Margret; Fischer, Henrike J.; Reichardt, Holger M.; Zimmermann, Wolfram‐Hubertus
    FASEB BioAdvances 2019; 1(12) p.731-746
    Satellite cells reside in defined niches and are activated upon skeletal muscle injury to facilitate regeneration. Mechanistic studies of skeletal muscle regeneration are hampered by the inability to faithfully simulate satellite cell biology in vitro. We sought to overcome this limitation by developing tissue engineered skeletal muscle (ESM) with (1) satellite cell niches and (2) the capacity to regenerate after injury. ESMs contained quiescent Pax7‐positive satellite cells in morphologically defined niches. Satellite cells could be activated to repair (i) cardiotoxin and (ii) mechanical crush injuries. Activation of the Wnt‐pathway was essential for muscle regeneration. Finally, muscle progenitors from the engineered niche developed de novo ESM in vitro and regenerated skeletal muscle after cardiotoxin‐induced injury in vivo. We conclude that ESM with functional progenitor niches reminiscent of the in vivo satellite cell niches can be engineered in vitro. ESM may ultimately be exploited in disease modeling, drug screening, or muscle regeneration.
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  • Journal Article

    Are There Any Biomarkers for Pedophilia and Sexual Child Abuse? A Review 

    Jordan, Kirsten; Wild, Tamara Sheila Nadine; Fromberger, Peter; Müller, Isabel; Müller, Jürgen Leo
    Frontiers in Psychiatry 2020; 10: Art. 940
    The use of biomarkers in medicine is a common and valuable approach in several clinical fields. Understanding the relationship between measurable biological processes and clinical outcomes not only is indispensable in the face of understanding physiological processes in healthy as well as in diseased organisms but also for understanding and evaluating treatment effects. Therefore, also in the context of forensic psychiatry, biomarkers and their potentially beneficial effects are of growing interest. The objective of this review is to examine if there are biomarkers that may serve as a tool to support diagnostic process, treatment evaluation, and risk assessment of pedophilic individuals and child sexual offenders. In the first part, we present an overview of the current neurobiological, as well as physiological and psychophysiological approaches to characterize pedophilia and child sexual offending. Secondly, we discuss and evaluate the impact of these approaches on the development of biomarkers for diagnosis, therapy, and risk assessment in pedophilic subjects and child sexual offenders. We conclude that a lot of research has already enhanced our neurobiological knowledge about pedophilia and child sexual offending. Although there surely exist promising parameters and approaches, in our view currently none of these is ready yet to serve as a clinically applicable diagnostic, response, or predictive biomarker for pedophilia and child sexual offending. Therefore, further work remains to be done. The development of a composite diagnostic biomarker to assess deviant sexual interest, combining several measures like functional magnetic resonance imaging, electroencephalogram, eye tracking, and behavioral approaches seems to be most promising. A valid and reliable measurement of deviant sexual interest, insensitive to manipulations could significantly support clinical diagnostic process. Similarly, regarding therapy evaluation and risk assessment, a composite biomarker to assess inhibitory control functions seems to be promising. Furthermore, the application of the Research Domain Criteria-approach, a new approach for investigating and classifying mental disorders, offers the possibility to take research to a new level.
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  • Journal Article

    DCAF1 (VprBP): emerging physiological roles for a unique dual-service E3 ubiquitin ligase substrate receptor 

    Schabla, N Max; Mondal, Koushik; Swanson, Patrick C
    Journal of Molecular Cell Biology 2018; 11(9) p.725-735
    Cullin-RING ligases (CRLs) comprise a large group of modular eukaryotic E3 ubiquitin ligases. Within this family, the CRL4 ligase (consisting of the Cullin4 [CUL4] scaffold protein, the Rbx1 RING finger domain protein, the DNA damage-binding protein 1 [DDB1], and one of many DDB1-associated substrate receptor proteins) has been intensively studied in recent years due to its involvement in regulating various cellular processes, its role in cancer development and progression, and its subversion by viral accessory proteins. Initially discovered as a target for hijacking by the human immunodeficiency virus accessory protein r, the normal targets and function of the CRL4 substrate receptor protein DDB1-Cul4-associated factor 1 (DCAF1; also known as VprBP) had remained elusive, but newer studies have begun to shed light on these questions. Here, we review recent progress in understanding the diverse physiological roles of this DCAF1 in supporting various general and cell type-specific cellular processes in its context with the CRL4 E3 ligase, as well as another HECT-type E3 ligase with which DCAF1 also associates, called EDD/UBR5. We also discuss emerging questions and areas of future study to uncover the dynamic roles of DCAF1 in normal physiology.
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  • Journal Article

    Adjuvant Radiotherapy and/or Chemotherapy for Endometrial Cancer, Status as at 2019 

    Emons, Günter; Tempfer, Clemens; Battista, Marco Johannes; Mustea, Alexander; Vordermark, Dirk
    Geburtshilfe und Frauenheilkunde 2019; 79(12) p.1273-1277
    The role of adjuvant radiotherapy and/or chemotherapy in the primary treatment of endometrial cancer with a high risk of recurrence has still not been conclusively determined. The results of 3 large randomized controlled studies on different aspects of this issue have been published in full in recent months, and the relevant results are analyzed here.
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  • Journal Article

    Variations in concerns reported on the patient concerns inventory in patients with head and neck cancer from different health settings across the world 

    Rogers, Simon N.; Alvear, Alvaro; Anesi, Alexandre; Babin, Emmanuel; Balik, Ali; Batstone, Martin; Brockmeyer, Phillipp; Carrasco, Claudia Celedon; Chien, Chih‐Yen; Chirila, Magdalena; et al.
    Dholam, Kanchan P.Doss, Jennifer G.Finizia, CaterinaGhani, Wan M. NabilahGurav, Sandeep V.Kadir, KathreenaKolator, MateuszLima, RobertoLin, Yu‐TsaiNhongo, SimonOzdemir‐Karatas, MeltemPeker, KadriyePesic, ZoranRansy, PierreSantos, IzabellaSchliephake, HenningShah, KetanSouza, FernandaSunil, GeethuThankappan, KrishnakumarEhrsson, Ylva TiblomTiple, CristinaTuomi, LisaValerini, SaraLara, Pablo VasquezZatoński, TomaszLowe, Derek
    Head & Neck p.1-15
    BACKGROUND: The aim was to collate and contrast patient concerns from a range of different head and neck cancer follow-up clinics around the world. Also, we sought to explore the relationship, if any, between responses to the patient concerns inventory (PCI) and overall quality of life (QOL). METHODS: Nineteen units participated with intention of including 100 patients per site as close to a consecutive series as possible in order to minimize selection bias. RESULTS: There were 2136 patients with a median total number of PCI items selected of 5 (2-10). "Fear of the cancer returning" (39%) and "dry mouth" (37%) were most common. Twenty-five percent (524) reported less than good QOL. CONCLUSION: There was considerable variation between units in the number of items selected and in overall QOL, even after allowing for case-mix variables. There was a strong progressive association between the number of PCI items and QOL.
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  • Journal Article

    Dose-dependent effect of cannabinoid WIN-55,212-2 on myelin repair following a demyelinating insult 

    Tomas-Roig, J.; Agbemenyah, H. Y.; Celarain, N.; Quintana, E.; Ramió-Torrentà, Ll.; Havemann-Reinecke, U.
    Scientific Reports 2020; 10(1): Art. 590
    Dysfunctions in the endocannabinoid system have been associated with experimental animal models and multiple sclerosis patients. Interestingly, the endocannabinoid system has been reported to confer neuroprotection against demyelination. The present study aims to assess the effects of the cannabinoid agonist WIN-55,212-2 in cuprizone fed animals on myelin repair capacity. Animals exposed to cuprizone were simultaneously treated withWIN-55,212-2, behaviorally tested and finally the corpus callosum was exhaustively studied by Western blotting, qRT-PCR and a myelin staining procedure. We report that the long-term administration of WIN-55,212-2 reduced the global amount of CB1 protein. Histological analysis revealed clear demyelination after being fed cuprizone for three weeks. However, cuprizone-fed mice subjected to 0.5 mg/Kg of WIN-55,212-2 displayed no differences when compared to controls during demyelination, although there was a robust increase in the myelinated axons during the remyelination phase. These animals displayed better performance on contextual fear conditioning which was in turn non-attributable to an antinociceptive effect. In contrast, a 1 mg/Kg dosage caused a remarkable demyelination accompanied by limited potential for myelin repair. Upon drug administration while mice ongoing demyeliniation, the expression of Aif1 (microglia) and Gfap (astrocytes) followed a dose-dependent manner whereas the expression of both markers was apparently attenuated during remyelination. Treatment with vehicle or 0.5 mg/Kg of the drug during demyelination increased the expression of Pdgfra (oligodendrocyte precursor cells) but this did not occur when 1 mg/Kg was administered. In conclusion, the drug at 0.5 mg/Kg did not alter myelin architecture while 1 mg/Kg had a deleterious effect in this model.
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  • Journal Article

    Pathway-, layer- and cell-type-specific thalamic input to mouse barrel cortex 

    Sermet, B .Semihcan; Truschow, Pavel; Feyerabend, Michael; Mayrhofer, Johannes M.; Oram, Tess B.; Yizhar, Ofer; Staiger, Jochen F.; Petersen, Carl C.H.
    eLife 2019; 8: Art. e52665
    Mouse primary somatosensory barrel cortex (wS1) processes whisker sensory information, receiving input from two distinct thalamic nuclei. The first-order ventral posterior medial (VPM) somatosensory thalamic nucleus most densely innervates layer 4 (L4) barrels, whereas the higher-order posterior thalamic nucleus (medial part, POm) most densely innervates L1 and L5A. We optogenetically stimulated VPM or POm axons, and recorded evoked excitatory postsynaptic potentials (EPSPs) in different cell-types across cortical layers in wS1. We found that excitatory neurons and parvalbumin-expressing inhibitory neurons received the largest EPSPs, dominated by VPM input to L4 and POm input to L5A. In contrast, somatostatin-expressing inhibitory neurons received very little input from either pathway in any layer. Vasoactive intestinal peptide-expressing inhibitory neurons received an intermediate level of excitatory input with less apparent layer-specificity. Our data help understand how wS1 neocortical microcircuits might process and integrate sensory and higher-order inputs.
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  • Journal Article

    Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo 

    Yambire, King Faisal; Rostosky, Christine; Watanabe, Takashi; Pacheu-Grau, David; Torres-Odio, Sylvia; Sanchez-Guerrero, Angela; Senderovich, Ola; Meyron-Holtz, Esther G; Milosevic, Ira; Frahm, Jens; et al.
    West, A PhillipRaimundo, Nuno
    eLife 2019; 8: Art. e51031
    Lysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain poorly understood. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and non-apoptotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified by in vivo magnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking impaired lysosomal acidification, mitochondrial malfunction and inflammation in vivo
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  • Journal Article

    IVIVC Assessment of Two Mouse Brain Endothelial Cell Models for Drug Screening 

    Puscas, Ina; Bernard-Patrzynski, Florian; Jutras, Martin; Lécuyer, Marc-André; Bourbonnière, Lyne; Prat, Alexandre; Leclair, Grégoire; Roullin, V. Gaëlle
    Pharmaceutics 2019; 11(11): Art. 587
    Since most preclinical drug permeability assays across the blood-brain barrier (BBB) are still evaluated in rodents, we compared an in vitro mouse primary endothelial cell model to the mouse b.End3 and the acellular parallel artificial membrane permeability assay (PAMPA) models for drug screening purposes. The mRNA expression of key feature membrane proteins of primary and bEnd.3 mouse brain endothelial cells were compared. Transwell® monolayer models were further characterized in terms of tightness and integrity. The in vitro in vivo correlation (IVIVC) was obtained by the correlation of the in vitro permeability data with log BB values obtained in mice for seven drugs. The mouse primary model showed higher monolayer integrity and levels of mRNA expression of BBB tight junction (TJ) proteins and membrane transporters (MBRT), especially for the efflux transporter Pgp. The IVIVC and drug ranking underlined the superiority of the primary model (r2 = 0.765) when compared to the PAMPA-BBB (r2 = 0.391) and bEnd.3 cell line (r2 = 0.019) models. The primary monolayer mouse model came out as a simple and reliable candidate for the prediction of drug permeability across the BBB. This model encompasses a rapid set-up, a fair reproduction of BBB tissue characteristics, and an accurate drug screening.
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  • Journal Article

    Post-Concussion Symptoms in Complicated vs. Uncomplicated Mild Traumatic Brain Injury Patients at Three and Six Months Post-Injury: Results from the CENTER-TBI Study 

    Voormolen, Daphne C.; Haagsma, Juanita A.; Polinder, Suzanne; Maas, Andrew I.R.; Steyerberg, Ewout W.; Vuleković, Petar; Sewalt, Charlie A.; Gravesteijn, Benjamin Y.; Covic, Amra; Andelic, Nada; et al.
    Plass, Anne Marievon Steinbuechel, Nicole
    Journal of Clinical Medicine 2019; 8(11): Art. 1921
    The aim of this study was to assess the occurrence of post-concussion symptoms and post-concussion syndrome (PCS) in a large cohort of patients after complicated and uncomplicated mild traumatic brain injury (mTBI) at three and six months post-injury. Patients were included through the prospective cohort study: Collaborative European NeuroTrauma Effectiveness Research (CENTER-TBI). Patients enrolled with mTBI (Glasgow Coma Scale 13-15) were further differentiated into complicated and uncomplicated mTBI based on the presence or absence of computed tomography abnormalities, respectively. The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) assessed post-concussion symptoms and PCS according to the mapped ICD-10 classification method. The occurrence of post-concussion symptoms and syndrome at both time points was calculated. Chi square tests were used to test for differences between and within groups. Logistic regression was performed to analyse the association between complicated versus uncomplicated mTBI and the prevalence of PCS. Patients after complicated mTBI reported slightly more post-concussion symptoms compared to those after uncomplicated mTBI. A higher percentage of patients after complicated mTBI were classified as having PCS at three (complicated: 46% vs. uncomplicated: 35%) and six months (complicated: 43% vs. uncomplicated 34%). After adjusting for baseline covariates, the effect of complicated versus uncomplicated mTBI at three months appeared minimal: odds ratio 1.25 (95% confidence interval: 0.95-1.66). Although patients after complicated mTBI report slightly more post-concussion symptoms and show higher PCS rates compared to those after uncomplicated mTBI at three and six months, complicated mTBI was only found a weak indicator for these problems.
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  • Journal Article

    Cerebral Palsy: Early Markers of Clinical Phenotype and Functional Outcome 

    Einspieler, Christa; Bos, Arend F.; Krieber-Tomantschger, Magdalena; Alvarado, Elsa; Barbosa, Vanessa M.; Bertoncelli, Natascia; Burger, Marlette; Chorna, Olena; Del Secco, Sabrina; DeRegnier, Raye-Ann; et al.
    Hüning, BrittaKo, JooyeonLucaccioni, LauraMaeda, TomokiMarchi,VivianaMartín, ErikaMorgan, CatherineMutlu, AkmerNogolová, AlicePansy, JasminPeyton, ColleenPokorny, Florian B.Prinsloo, Lucia R.Ricci, EileenSaini, LokeshScheuchenegger, AnnaSilva, Cinthia R.Soloveichick, MarinaSpittle, Alicia J.Toldo, MorenoUtsch, Fabianavan Zyl, JeanettaViñals, CarlosWang, JunYang, HongYardımcı-Lokmanoğlu, Bilge N.Cioni, GiovanniFerrari, FabrizioGuzzetta, AndreaMarschik, Peter B.
    Journal of Clinical Medicine 2019; 8(10): Art. 1616
    The Prechtl General Movement Assessment (GMA) has become a cornerstone assessment in early identification of cerebral palsy (CP), particularly during the fidgety movement period at 3-5 months of age. Additionally, assessment of motor repertoire, such as antigravity movements and postural patterns, which form the Motor Optimality Score (MOS), may provide insight into an infant's later motor function. This study aimed to identify early specific markers for ambulation, gross motor function (using the Gross Motor Function Classification System, GMFCS), topography (unilateral, bilateral), and type (spastic, dyskinetic, ataxic, and hypotonic) of CP in a large worldwide cohort of 468 infants. We found that 95% of children with CP did not have fidgety movements, with 100% having non-optimal MOS. GMFCS level was strongly correlated to MOS. An MOS > 14 was most likely associated with GMFCS outcomes I or II, whereas GMFCS outcomes IV or V were hardly ever associated with an MOS > 8. A number of different movement patterns were associated with more severe functional impairment (GMFCS III-V), including atypical arching and persistent cramped-synchronized movements. Asymmetrical segmental movements were strongly associated with unilateral CP. Circular arm movements were associated with dyskinetic CP. This study demonstrated that use of the MOS contributes to understanding later CP prognosis, including early markers for type and severity.
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  • Journal Article

    From Tumor Metastasis towards Cerebral Ischemia—Extracellular Vesicles as a General Concept of Intercellular Communication Processes 

    Zheng, Xuan; Bähr, Mathias; Doeppner, Thorsten R.
    International Journal of Molecular Sciences 2019; 20(23): Art. 5995
    Extracellular vesicles (EVs) have been tremendous carriers in both experimental and translational science. These vesicles-formerly regarded as artifacts of in vitro research-have a heterogeneous population of vesicles derived from virtually all eukaryotic cells. EVs consist of a bilayer lipid structure with a diameter of about 30 to 1000 nm and have a characteristic protein and non-coding RNA content that make up different forms of EVs such as exosomes, microvesicles, and others. Despite recent progress in the EV field, which is known to serve as potential biomarkers and therapeutic tools under various pathological conditions, fundamental questions are yet to be answered. This short review focuses on recently reported data regarding EVs under pathological conditions with a particular emphasis on the role of EVs under such different conditions like tumor formation and cerebral ischemia. The review strives to point out general concepts of EV intercellular communication processes that might be vital to both diagnostic and therapeutic strategies in the long run.
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  • Journal Article

    Micronutrient Depletion in Heart Failure: Common, Clinically Relevant and Treatable 

    Cvetinovic, Natasa; Loncar, Goran; Isakovic, Andjelka M.; von Haehling, Stephan; Doehner, Wolfram; Lainscak, Mitja; Farkas, Jerneja
    International Journal of Molecular Sciences 2019; 20(22)
    Heart failure (HF) is a chronic condition with many imbalances, including nutritional issues. Next to sarcopenia and cachexia which are clinically evident, micronutrient deficiency is also present in HF. It is involved in HF pathophysiology and has prognostic implications. In general, most widely known micronutrients are depleted in HF, which is associated with symptoms and adverse outcomes. Nutritional intake is important but is not the only factor reducing the micronutrient availability for bodily processes, because absorption, distribution, and patient comorbidity may play a major role. In this context, interventional studies with parenteral micronutrient supplementation provide evidence that normalization of micronutrients is associated with improvement in physical performance and quality of life. Outcome studies are underway and should be reported in the following years.
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  • Journal Article

    Pediatric Healthcare Utilization in a Large Cohort of Refugee Children Entering Western Europe During the Migrant Crisis 

    Happle, Christine; Dopfer, Christian; Ernst, Diana; Kleinert, Evelyn; Vakilzadeh, Annabelle; Hellms, Susanne; Evlampidou, Iro; Hillermann, Nele; Schmidt, Reinhold E.; Behrens, Georg M. N.; et al.
    Müller, FrankWetzke, MartinJablonka, Alexandra
    International Journal of Environmental Research and Public Health 2019; 16(22): Art. 4415
    Background: Currently, half of the population displaced worldwide is children and adolescents. Little is known on healthcare demand in underage migrants. MATERIALS AND METHODS: We analyzed healthcare utilization in n = 1.411 children and adolescents living in a large German refugee reception in 2015-2016. RESULTS: The mean age of all included refugees was 9 years (60.8% male). The majority came from the eastern Mediterranean region. During a mean camp inhabitance of 34 days, 57.6% needed primary healthcare, with a significant inverse correlation of healthcare seeking frequency with age and duration of camp inhabitance. Infants and unaccompanied minors displayed particular high demands for medical help. DISCUSSION: Our analysis showed that pediatric primary healthcare in pediatric and adolescent refugees are most sought during the first period upon arrival with particular demand in infants, toddlers, and unaccompanied minors. Based on this data, future care taking strategies should be adapted accordingly.
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  • Journal Article

    The Hypomorphic Variant p.(Gly624Asp) in COL4A5 as a Possible Cause for an Unexpected Severe Phenotype in a Family With X-Linked Alport Syndrome 

    Macheroux, Eva Pauline; Braunisch, Matthias C.; Pucci Pegler, Stephanie; Satanovskij, Robin; Riedhammer, Korbinian M.; Günthner, Roman; Gross, Oliver; Nagel, Mato; Renders, Lutz; Hoefele, Julia
    Frontiers in Pediatrics 2019; 7: Art. 485
    Background: Alport syndrome (AS) is a progressive kidney disorder leading to end stage renal disease (ESRD). Extrarenal symptoms like hearing loss and ocular changes can be observed. Approximately 85% of the patients carry pathogenic variants in COL4A5 (X-linked inheritance). The variant c.1871G>A, p.(Gly624Asp) in COL4A5 is described in the literature as a hypomorphic variant associated with thin basement membrane nephropathy (TBMN). ESRD was only seen rarely at a median age of 50 years and extrarenal manifestations have only been described in single cases. Case report and Methods: This is a report on a family with X-linked AS. In the female index patient, microscopic hematuria, and proteinuria were observed beginning at the age of 20 years and 41 years, respectively. Microscopic hematuria was also present in the daughter (from 6th month of life), the son (from 22nd month of life), the mother and the maternal grandniece. Proteinuria was observed in the maternal aunt and paternal grandmother. The father of the index patient, a paternal uncle and a second cousin presented with ESRD at the age of 49, 34, and 70 years of life, respectively. Extrarenal manifestations were absent in the whole family. In the index patient, her children and her mother molecular diagnostics were performed using Sanger and exome sequencing. Results: In all examined family members the variant c.1871G>A, p.(Gly624Asp) in COL4A5 was identified. With the exception of the index patient, who was homozygous for this variant, all family members carried the variant heterozygously, or hemizygously. A different or additional monogenic hereditary nephropathy could not be detected by exome sequencing of the index patient. Discussion: This is the first report of a patient with the variant p.(Gly624Asp) in COL4A5 in a homozygous state. The variant was previously reported as a mild variant requiring dialysis in less than 10%. The family presented, however, with a more severe clinical course. We therefore suggest to question the term "hypomorphic" in the context of the variant p.(Gly624Asp) although molecular diagnostics could not be done in all affected family members.
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  • Journal Article

    GABA-Glycine Cotransmitting Neurons in the Ventrolateral Medulla: Development and Functional Relevance for Breathing 

    Hirrlinger, Johannes; Marx, Grit; Besser, Stefanie; Sicker, Marit; Köhler, Susanne; Hirrlinger, Petra G.; Wojcik, Sonja M.; Eulenburg, Volker; Winkler, Ulrike; Hülsmann, Swen
    Frontiers in Cellular Neuroscience 2019; 13: Art. 517
    Inhibitory neurons crucially contribute to shaping the breathing rhythm in the brain stem. These neurons use GABA or glycine as neurotransmitter; or co-release GABA and glycine. However, the developmental relationship between GABAergic, glycinergic and cotransmitting neurons, and the functional relevance of cotransmitting neurons has remained enigmatic. Transgenic mice expressing fluorescent markers or the split-Cre system in inhibitory neurons were developed to track the three different interneuron phenotypes. During late embryonic development, the majority of inhibitory neurons in the ventrolateral medulla are cotransmitting cells, most of which differentiate into GABAergic and glycinergic neurons around birth and around postnatal day 4, respectively. Functional inactivation of cotransmitting neurons revealed an increase of the number of respiratory pauses, the cycle-by-cycle variability, and the overall variability of breathing. In summary, the majority of cotransmitting neurons differentiate into GABAergic or glycinergic neurons within the first 2 weeks after birth and these neurons contribute to fine-tuning of the breathing pattern.
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