Recent Submissions

  • 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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  • Journal Article

    Molecular profiling of stem cell-like female germ line cells in Drosophila delineates networks important for stemness and differentiation 

    Tiwari, Manu D.; Zeitler, Daniela M.; Meister, Gunter; Wodarz, Andreas
    Biology Open 2019; 8(11): Art. bio046789
    Stem cells can self-renew and produce daughter cells destined for differentiation. The precise control of the balance between these two outcomes is essential to ensure tissue homeostasis and to prevent uncontrolled proliferation resulting in tumor formation. As self-renewal and differentiation are likely to be controlled by different gene expression programs, unraveling the underlying gene regulatory networks is crucial for understanding the molecular logic of this system. In this study, we have characterized by next generation RNA sequencing (RNA-seq) the transcriptome of germline stem cell (GSC)-like cells isolated from bag of marbles (bam) mutant Drosophila ovaries and compared it to the transcriptome of germ line cells isolated from wild-type ovaries. We have complemented this dataset by utilizing an RNA-immunoprecipitation strategy to identify transcripts bound to the master differentiation factor Bam. Protein complex enrichment analysis on these combined datasets allows us to delineate known and novel networks essential for GSC maintenance and differentiation. Further comparative transcriptomics illustrates similarities between GSCs and primordial germ cells and provides a molecular footprint of the stem cell state. Our study represents a useful resource for functional studies on stem cell maintenance and differentiation.
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  • Journal Article

    Alzheimer’s disease-associated (hydroxy)methylomic changes in the brain and blood 

    Lardenoije, Roy; Roubroeks, Janou A. Y.; Pishva, Ehsan; Leber, Markus; Wagner, Holger; Iatrou, Artemis; Smith, Adam R.; Smith, Rebecca G.; Eijssen, Lars M. T.; Kleineidam, Luca; et al.
    Kawalia, AmitHoffmann, PerLuck, TobiasRiedel-Heller, SteffiJessen, FrankMaier, WolfgangWagner, MichaelHurlemann, RenéKenis, GunterAli, Muhammaddel Sol, AntonioMastroeni, DiegoDelvaux, ElaineColeman, Paul D.Mill, JonathanRutten, Bart P. F.Lunnon, KatieRamirez, Alfredovan den Hove, Daniël L. A.
    Clinical Epigenetics 2019; 11(1): Art. 164
    BACKGROUND: Late-onset Alzheimer's disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. RESULTS: We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (- 3.76% 5mC, pŠidák = 1.07E-06), CHRNB1 (+ 1.46% 5hmC, pŠidák = 4.01E-04), RHBDF2 (- 3.45% UC, pŠidák = 4.85E-06), and C3 (- 1.20% UC, pŠidák = 1.57E-03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, pŠidák = 7.14E-04). CONCLUSIONS: The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.
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  • Journal Article

    Clinical and imaging features of myeloid sarcoma: a German multicenter study 

    Meyer, Hans-Jonas; Pönisch, Wolfram; Schmidt, Stefan Andreas; Wienbeck, Susanne; Braulke, Friederike; Schramm, Dominik; Surov, Alexey
    BMC Cancer 2019; 19(1): Art. 1150
    BACKGROUND: Myeloid sarcoma (MS), also known as chloroma, is an extramedullary manifestation of malignant primitive myeloid cells. Previously, only small studies investigated clinical and imaging features of MS. The purpose of this study was to elucidate clinical and imaging features of MS based upon a multicenter patient sample. METHODS: Patient records of radiological databases of 4 German university hospitals were retrospectively screened for MS in the time period 01/2001 and 06/2019. Overall, 151 cases/76 females (50.3%) with a mean age of 55.5 ± 15.1 years and 183 histopathological confirmation or clinically suspicious lesions of MS were included into this study. The underlying hematological disease, localizations, and clinical symptoms as well as imaging features on CT and MRI were investigated. RESULTS: In 15 patients (9.9% of all 151 cases) the manifestation of MS preceded the systemic hematological disease. In 43 cases (28.4%), first presentation of MS occurred simultaneously with the initial diagnosis of leukemia, and 92 (60.9%) patients presented MS after the initial diagnosis. In 37 patients (24.5%), the diagnosis was made incidentally by imaging. Clinically, cutaneous lesions were detected in 35 of 151 cases (23.2%). Other leading symptoms were pain (n = 28/151, 18.5%), neurological deficit (n = 27/151, 17.9%), swelling (n = 14/151, 9.3%) and dysfunction of the affected organ (n = 10/151, 6.0%). Most commonly, skin was affected (n = 30/151, 16.6%), followed by bone (n = 29/151, 16.0%) and lymphatic tissue (n = 21/151, 11.4%). Other localizations were rare. On CT, most lesions were homogenous. On T2-weighted imaging, most of the lesions were hyperintense. On T1-weighted images, MS was hypointense in n = 22/54 (40.7%) and isointense in n = 30/54 (55.6%). A diffusion restriction was identified in most cases with a mean ADC value of 0.76 ± 0.19 × 10- 3 mm2/s. CONCLUSIONS: The present study shows clinical and imaging features of MS based upon a large patient sample in a multicenter design. MS occurs in most cases meta-chronous to the hematological disease and most commonly affects the cutis. One fourth of cases were identified incidentally on imaging, which needs awareness of the radiologists for possible diagnosis of MS.
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  • Journal Article

    Global EEG coherence as a marker for cognition in older adults at risk for dementia 

    Laptinskaya, Daria; Fissler, Patrick; Küster, Olivia Caroline; Wischniowski, Jakob; Thurm, Franka; Elbert, Thomas; Arnim, Christine A. F.; Kolassa, Iris‐Tatjana
    Psychophysiology
    Quantitative electroencephalography (EEG) provides useful information about neurophysiological health of the aging brain. Current studies investigating EEG coherence and power for specific brain areas and frequency bands have yielded inconsistent results. This study assessed EEG coherence and power indices at rest measured over the whole skull and for a wide frequency range as global EEG markers for cognition in a sample at risk for dementia. Since global markers are more reliable and less error-prone than region- and frequency-specific indices they might help to overcome previous inconsistencies. Global EEG coherence (1-30 Hz) and an EEG slowing score were assessed. The EEG slowing score was calculated by low-frequency power (1-8 Hz) divided by high-frequency power (9-30 Hz). In addition, the prognostic value of the two EEG indices for cognition and cognitive decline was assessed in a 5-year follow-up pilot study. Baseline global coherence correlated positively with cognition at baseline, but not with cognitive decline or with cognition at the 5-year follow-up. The EEG slowing ratio showed no significant association, neither with cognition at baseline or follow-up, nor with cognitive decline over a period of 5 years. The results indicate that the resting state global EEG coherence might be a useful and easy to assess electrophysiological correlate for neurocognitive health in older adults at risk for dementia. Because of the small statistical power for the follow-up analyses, the prognostic value of global coherence could not be determined in the present study. Future studies should assess its prognostic value with larger sample sizes.
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  • Journal Article

    Burden of illness in not adequately controlled chronic hypoparathyroidism: Findings from a 13‐country patient and caregiver survey 

    Siggelkow, Heide; Clarke, Bart L.; Germak, John; Marelli, Claudio; Chen, Kristina; Dahl‐Hansen, Helen; Glenister, Elizabeth; Bent‐Ennakhil, Nawal; Judge, Davneet; Mycock, Katie; et al.
    Bollerslev, Jens
    Clinical Endocrinology 2020; 92(2) p.159-168
    OBJECTIVE: To address knowledge gaps regarding burdens associated with not adequately controlled chronic hypoparathyroidism. DESIGN: Global patient and caregiver survey. STUDY POPULATIONS: Patients with chronic hypoparathyroidism not adequately controlled on conventional therapy and their caregivers. MEASUREMENTS: Health-related quality of life (HRQoL) and health status were evaluated using the 36-item Short Form version 2 (SF-36 v2.0) and Five-Level EuroQoL 5 Dimensions (EQ-5D-5L) instruments, respectively. Hypoparathyroidism-associated symptoms were assessed by a disease-specific Hypoparathyroidism Symptom Diary and caregiver burden via the Modified Caregiver Strain Index (MCSI). RESULTS: Data were obtained from 398 patients and 207 caregivers. Patients' self-rated hypoparathyroidism-related symptom severity was none (3%), mild (32%), moderate (53%) or severe (12%). Per the Hypoparathyroidism Symptom Diary, patients reported moderate, severe or very severe symptoms of physical fatigue (73%), muscle cramps (55%), heaviness in limbs (55%) and tingling (51%) over a 7-day recall period. Impacts (rated 'somewhat' or 'very much') were reported by 84% of patients for ability to exercise, 78% for sleep, 75% for ability to work and 63% for family relationships. Inverse relationships were observed between patient self-rated overall symptom severity and HRQoL and health status assessment scores-the greater the symptom severity, the lower the SF-36 and EQ-5D-5L scores. Caregiver burden increased with patient self-rated symptom severity: none, 1.7 MCSI; mild, 5.4 MCSI; moderate, 9.5 MCSI; and severe, 12.5 MCSI. CONCLUSION: Patients with not adequately controlled hypoparathyroidism reported substantial symptoms and impacts. Greater patient symptom severity was associated with decreased patient HRQoL and health status assessments and increased caregiver burden.
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  • Journal Article

    Short interruptions between pre‐warming and intraoperative warming are associated with low intraoperative hypothermia rates 

    Grote, Rolf; Wetz, Anna; Bräuer, Anselm; Menzel, Matthias
    Acta Anaesthesiologica Scandinavica p.1-5
    BACKGROUND: Prevention of inadvertent hypothermia is recommended for procedures >30 minutes because hypothermia increases the risk of myocardial ischemia, intraoperative blood loss, transfusion and wound complications. Therefore, short warming interruptions between pre-warming and intraoperative warming might result in lower hypothermia rates. The aim of this retrospective investigation was to determine whether the incidence of inadvertent intraoperative hypothermia was affected by the warming interruption. METHODS: The lowest intraoperative body core temperature value and the warming interruption time were taken from anaesthesia records. Body core temperature was recorded continuously, and a patient was classified to be hypothermic if the lowest recorded temperature value was <36°C. Hypothermia rates and the correlation between warming interruption times and intraoperative hypothermia rates were calculated. RESULTS: Five thousand eighty-four patients were analysed. The intraoperative hypothermia rate was 15.3%. Nineteen patients (0.4%) had a recorded temperature of <35.0°C. An increase in forced-air warming interruption time was significantly associated with an increase in intraoperative hypothermia rates (P < .0001). Patients with interruptions in forced-air warming >20 minutes showed significantly higher hypothermia rates than those with interruptions of ≤20 minutes (P < .0001). CONCLUSION: Intraoperative hypothermia rates increased significantly with longer forced-air warming interruptions between pre-warming and intraoperative warming. Short warming interruptions can preserve the effect of pre-warming and are associated with low intraoperative hypothermia rates.
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