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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS German Medical Science; VOL: 17; DOC02 /20190222/
    Publication Date: 2019-02-22
    Description: The current gold standard for assessment of most sleep disorders is the in-laboratory polysomnography (PSG). This approach produces high costs and inconveniences for the patients. An accessible and simple preliminary screening method to diagnose the most common sleep disorders and to decide whether a PSG is necessary or not is therefore desirable. A minimalistic type-4 monitoring system which utilized tracheal body sound and actigraphy to accurately diagnose the obstructive sleep apnea syndrome was previously developed. To further improve the diagnostic ability of said system, this study aims to examine if it is possible to perform automated sleep staging utilizing body sound to extract cardiorespiratory features and actigraphy to extract movement features.A linear discriminant classifier based on those features was used for automated sleep staging using the type-4 sleep monitor. For validation 53 subjects underwent a full-night screening at Ulm University Hospital using the developed sleep monitor in addition to polysomnography. To assess sleep stages from PSG, a trained technician manually evaluated EEG, EOG, and EMG recordings. The classifier reached 86.9% accuracy and a Kappa of 0.69 for sleep/wake classification, 76.3% accuracy and a Kappa of 0.42 for Wake/REM/NREM classification, and 56.5% accuracy and a Kappa of 0.36 for Wake/REM/light sleep/deep sleep classification. For the calculation of sleep efficiency (SE), a coefficient of determination r2 of 0.78 is reached. Additionally, subjects were classified into groups of SEs (SE〉=40%, SE〉=60% and SE〉=80%). A Cohen's Kappa 〉0.61 was reached for all groups, which is considered as substantial agreement.The presented method provides satisfactory performance in sleep/wake and wake/REM/NREM sleep staging while maintaining a simple setup and offering high comfort. This minimalistic approach may address the need for a simple yet reliable preliminary sleep screening in an ambulatory setting.
    Description: Der aktuelle Goldstandard für die Beurteilung der meisten Schlafstörungen ist die Polysomnographie (PSG). Diese Methode der Diagnose ist mit hohen Kosten und Unannehmlichkeiten für die Patienten verbunden. Eine einfache Methode der Diagnose der häufigsten Schlafstörungen ist daher wünschenswert. Hierzu wurde ein minimalistischer Typ-4-Schlafmonitor, welcher Körperschall und Aktigraphie zur Diagnose des obstruktiven Schlafapnoe-Syndroms einsetzt, entwickelt. Um die Diagnosefähigkeit dieses Systems zu erweitern, soll in dieser Studie untersucht werden, ob der Schlafmonitor automatisiert Schlafstadien klassifizieren kann. Hierbei wird Körperschall verwendet, um kardiorespiratorische Merkmale zu extrahieren, und Aktigraphie, um Bewegungsmerkmale zu extrahieren.Ein auf diesen Merkmalen basierender linearer Diskriminanzklassifizierer wurde für die automatisierte Klassifizierung von Schlafstadien mit dem vorgestellten Typ-4-Schlafmonitor verwendet. Zur Validierung wurden 53 Probanden am Universitätsklinikum Ulm zusätzlich zur PSG einem nächtlichen Screening mit dem entwickelten Schlafmonitor unterzogen. Zur Beurteilung der Schlafstadien der PSG hat ein geschulter Techniker EEG-, EOG- und EMG-Aufnahmen manuell ausgewertet. Der Klassifikator erreichte eine Genauigkeit von 86,9% und ein Kappa von 0,69 für Schlaf/Wach-Klassifizierung, 76,3% Genauigkeit und ein Kappa von 0,42 für Wach/REM/NREM-Klassifizierung, und 56,5% Genauigkeit und ein Kappa von 0,36 für Wach/REM/Leichtschlaf/Tiefschlaf-Klassifizierung. Für die Berechnung der Schlafeffizienz (SE) wird ein Bestimmtheitsmaß r2 von 0,78 erreicht. Zusätzlich wurden die Probanden in Gruppen von SEs eingeteilt (SE〉=40%, SE〉=60% und SE〉=80%). Ein Cohen's Kappa 〉0,61 wurde für alle Gruppen erreicht, was als substantielle Übereinstimmung angesehen wird.Die vorgestellte Methode bietet eine zufriedenstellende Leistung in der Schlaf/Wach- und Wach/REM/NREM-Schlaf-Klassifizierung bei einfachem Aufbau und hohem Patientenkomfort. Dieser minimalistische Ansatz kann den Bedarf an einem einfachen aber zuverlässigen Vorab-Schlaf-Screening im ambulanten Bereich abdecken.
    Keywords: sleep staging ; monitoring ; respiratory sounds ; movement analysis ; ddc: 610
    Language: English
    Type: article
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  • 2
    Abstract: RATIONALE: The intercalated disc (ID) is a highly specialized cell-cell contact structure that ensures mechanical and electric coupling of contracting cardiomyocytes. Recently, the ID has been recognized to be a hot spot of cardiac disease, in particular inherited cardiomyopathy. OBJECTIVE: Given its complex structure and function we hypothesized that important molecular constituents of the ID still remain unknown. METHODS AND RESULTS: Using a bioinformatics screen, we discovered and cloned a previously uncharacterized 54 kDa cardiac protein which we termed Myozap (Myocardium-enriched zonula occludens-1-associated protein). Myozap is strongly expressed in the heart and lung. In cardiac tissue it localized to the ID and directly binds to desmoplakin and zonula occludens-1. In a yeast 2-hybrid screen for additional binding partners of Myozap we identified myosin phosphatase-RhoA interacting protein (MRIP), a negative regulator of Rho activity. Myozap, in turn, strongly activates SRF-dependent transcription through its ERM (Ezrin/radixin/moesin)-like domain in a Rho-dependent fashion. Finally, in vivo knockdown of the Myozap ortholog in zebrafish led to severe contractile dysfunction and cardiomyopathy. CONCLUSIONS: Taken together, these findings reveal Myozap as a previously unrecognized component of a Rho-dependent signaling pathway that links the intercalated disc to cardiac gene regulation. Moreover, its subcellular localization and the observation of a severe cardiac phenotype in zebrafish, implicate Myozap in the pathogenesis of cardiomyopathy.
    Type of Publication: Journal article published
    PubMed ID: 20093627
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  • 3
    Keywords: MODEL ; SEQUENCE ; VARIANTS ; IDENTIFICATION ; genetics ; MUTATIONS ; DILATED CARDIOMYOPATHY ; CARDIOVASCULAR-DISEASE ; genetic testing ; BINDING PROTEIN-C ; CARDIAC MYOSIN ; cardiomyopathy dilated ; cardiomyopathy hypertrophic ; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY ; heart diseases
    Abstract: Background-Today, mutations in more than 30 different genes have been found to cause inherited cardiomyopathies, some associated with very poor prognosis. However, because of the genetic heterogeneity and limitations in throughput and scalability of current diagnostic tools up until now, it is hardly possible to genetically characterize patients with cardiomyopathy in a fast, comprehensive, and cost-efficient manner. Methods and Results-We established an array-based subgenomic enrichment followed by next-generation sequencing to detect mutations in patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). With this approach, we show that the genomic region of interest can be enriched by a mean factor of 2169 compared with the coverage of the whole genome, resulting in high sequence coverage of selected disease genes and allowing us to define the genetic pathogenesis of cardiomyopathies in a single sequencing run. In 6 patients, we detected disease-causing mutations, 2 microdeletions, and 4 point mutations. Furthermore, we identified several novel nonsynonymous variants, which are predicted to be harmful, and hence, might be potential disease mutations or modifiers for DCM or HCM. Conclusions-The approach presented here allows for the first time a comprehensive genetic screening in patients with hereditary DCM or HCM in a fast and cost-efficient manner.
    Type of Publication: Journal article published
    PubMed ID: 21252143
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  • 4
    Keywords: GENE ; VARIANTS ; HEALTH ; HEART-FAILURE ; SOCIETY ; susceptibility loci ; CORONARY-ARTERY-DISEASE ; Myocarditis ; HLA-C ; CARDIOLOGY
    Abstract: Aims Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. Methods and reuslts Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 x 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. Conclusion The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.
    Type of Publication: Journal article published
    PubMed ID: 23853074
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  • 5
    Keywords: EXPRESSION ; Germany ; human ; SUPPORT ; DEATH ; DISEASE ; MORTALITY ; POPULATION ; GENE ; GENES ; GENOME ; PATIENT ; FAMILY ; DISORDER ; LINKAGE ; PATHOGENESIS ; REGION ; LINKAGE DISEQUILIBRIUM ; MUSCLE ; PHENOTYPE ; POPULATIONS ; UNITED-STATES ; DILATED CARDIOMYOPATHY ; SINGLE ; FAMILIES ; DETERMINANTS ; REARRANGEMENT ; CARDIOMYOPATHY ; LOCI ; VERTEBRATE GENOMES ; GENOMES ; DYSFUNCTION ; STATE ; Genetic ; FUNCTIONAL ASSESSMENT ; Case-Control Studies Cell Line Chrom
    Abstract: Human dilated cardiomyopathy (DCM), a disorder of the cardiac muscle, causes considerable morbidity and mortality and is one of the major causes of sudden cardiac death. Genetic factors play a role in the etiology and pathogenesis of DCM. Disease-associated genetic variations identified to date have been identified in single families or single sporadic patients and explain a minority of the etiology of DCM. We show that a 600-kb region of linkage disequilibrium (LD) on 5q31.2-3, harboring multiple genes, is associated with cardiomyopathy in three independent Caucasian populations (combined P-value = 0.00087). Functional assessment in zebrafish demonstrates that at least three genes, orthologous to loci in this LD block, HBEGF, IK, and SRA1, result independently in a phenotype of myocardial contractile dysfunction when their expression is reduced with morpholino antisense reagents. Evolutionary analysis across multiple vertebrate genomes suggests that this heart failure-associated LD block emerged by a series of genomic rearrangements across amphibian, avian, and mammalian genomes and is maintained as a cluster in mammals. Taken together, these observations challenge the simple notion that disease phenotypes can be traced to altered function of a single locus within a haplotype and suggest that a more detailed assessment of causality can be necessary
    Type of Publication: Journal article published
    PubMed ID: 19064678
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  • 6
    Keywords: CANCER ; EXPRESSION ; miRNAs ; MICRORNA SIGNATURES
    Abstract: In a multicenter study, we determined the expression profiles of 863 microRNAs by array analysis of 454 blood samples from human individuals with different cancers or noncancer diseases, and validated this 'miRNome' by quantitative real-time PCR. We detected consistently deregulated profiles for all tested diseases; pathway analysis confirmed disease association of the respective microRNAs. We observed significant correlations (P = 0.004) between the genomic location of disease-associated genetic variants and deregulated microRNAs
    Type of Publication: Journal article published
    PubMed ID: 21892151
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  • 7
    Keywords: quality control ; SKELETAL-MUSCLE ; MYOCARDIAL-INFARCTION ; DILATED CARDIOMYOPATHY ; HEART-FAILURE ; HYPERTROPHY ; UBIQUITIN-PROTEASOME SYSTEM ; MUSCLE RING FINGER-1 ; LIGASE COMPLEX ; ATROGIN-1
    Abstract: Rationale: The emerging role of the ubiquitin-proteasome system in cardiomyocyte function and homeostasis implies the necessity of tight regulation of protein degradation. However, little is known about cardiac components of this machinery. Objective: We sought to determine whether molecules exist that control turnover of cardiac-specific proteins. Methods and Results: Using a bioinformatic approach to identify novel cardiac-enriched sarcomere proteins, we identified F-box and leucine-rich repeat protein 22 (Fbxl22). Tissue-specific expression was confirmed by multiple tissue Northern and Western Blot analyses as well as quantitative reverse-transcriptase polymerase chain reaction on a human cDNA library. Immunocolocalization experiments in neonatal and adult rat ventricular cardiomyocytes as well as murine heart tissue located Fbxl22 to the sarcomeric z-disc. To detect cardiac protein interaction partners, we performed a yeast 2-hybrid screen using Fbxl22 as bait. Coimmunoprecipitation confirmed the identified interactions of Fbxl22 with S-phase kinase-associated protein 1 and Cullin1, 2 critical components of SCF (Skp1/Cul1/F-box) E3- ligases. Moreover, we identified several potential substrates, including the z-disc proteins alpha-actinin and filamin C. Consistently, in vitro overexpression of Fbxl22-mediated degradation of both substrates in a dose-dependent fashion, whereas proteasome inhibition with MG-132 markedly attenuated degradation of both alpha-actinin and filamin C. Finally, targeted knockdown of Fbxl22 in rat cardiomyocytes as well as zebrafish embryos results in the accumulation of alpha-actinin associated with severely impaired contractile function and cardiomyopathy in vivo. Conclusions: These findings reveal the previously uncharacterized cardiac-specific F-box protein Fbxl22 as a component of a novel cardiac E3 ligase. Fbxl22 promotes the proteasome-dependent degradation of key sarcomeric proteins, such as alpha-actinin and filamin C, and is essential for maintenance of normal contractile function in vivo.
    Type of Publication: Journal article published
    PubMed ID: 22972877
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  • 8
    Keywords: IN-VITRO ; DISEASES ; GENE ; WILD-TYPE ; INTERMEDIATE-FILAMENTS ; DILATED CARDIOMYOPATHY ; MICE LACKING DESMIN ; SKELETAL MYOPATHY ; VENTRICULAR-TACHYCARDIA ; CYCLOHEXIMIDE
    Abstract: Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies. We generated R349P desmin knock-in mice, which harbor the ortholog of the most frequently occurring human desmin missense mutation R350P. These mice develop age-dependent desmin-positive protein aggregation pathology, skeletal muscle weakness, dilated cardiomyopathy, as well as cardiac arrhythmias and conduction defects. For the first time, we report the expression level and subcellular distribution of mutant versus wild-type desmin in our mouse model as well as in skeletal muscle specimens derived from human R350P desminopathies. Furthermore, we demonstrate that the missense-mutant desmin inflicts changes of the subcellular localization and turnover of desmin itself and of direct desmin-binding partners. Our findings unveil a novel principle of pathogenesis, in which not the presence of protein aggregates, but disruption of the extrasarcomeric intermediate filament network leads to increased mechanical vulnerability of muscle fibers. These structural defects elicited at the myofiber level finally impact the entire organ and subsequently cause myopathy and cardiomyopathy.
    Type of Publication: Journal article published
    PubMed ID: 25394388
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  • 9
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    Abstract: Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein. Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure. To evaluate the role of nexilin in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found several mutations in NEXN associated with the disease. Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish. Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations. Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma.
    Type of Publication: Journal article published
    PubMed ID: 19881492
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