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| 2. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
- Nicolas, Aude, et al.
(författare)
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- 2018
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Ingår i: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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| 6. |
- Priori, Silvia G., et al.
(författare)
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Task Force on Sudden Cardiac Death, European Society of Cardiology
- 2002
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 4:1, s. 3-18
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Tidskriftsartikel (refereegranskat)abstract
- The European Society of Cardiology has convened a Task Force on Sudden Cardiac Death in order to provide a comprehensive, educational document on this important topic. The main document has been published in the European Heart Journal in August 2001[1]. The Task Force has now summarized the most important clinical issues on sudden cardiac death and provided tables with recommendations for risk stratification and for prophylaxis of sudden cardiac death. The present recommendations are specifically intended to encourage the development and revision of national guidelines on prevention of sudden cardiac death. The common challenge for cardiologists, physicians of other medical specialties and health professionals throughout Europe is to realize the potential for sudden cardiac death prevention and to contribute to public health efforts to reduce its burden.
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| 9. |
- Kenna, Kevin P., et al.
(författare)
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NEK1 variants confer susceptibility to amyotrophic lateral sclerosis
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:9, s. 1037-1042
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261 His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261 His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
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| 11. |
- Corrado, Domenico, et al.
(författare)
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Proposed diagnostic criteria for arrhythmogenic cardiomyopathy : European Task Force consensus report
- 2024
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Ingår i: International Journal of Cardiology. - : Elsevier. - 0167-5273 .- 1874-1754. ; 395
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Tidskriftsartikel (refereegranskat)abstract
- Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right-and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late-gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnor-malities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients.
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| 12. |
- Elliott, Perry, et al.
(författare)
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Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases.
- 2008
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 29:2, s. 270-6
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Tidskriftsartikel (refereegranskat)abstract
- In biology, classification systems are used to promote understanding and systematic discussion through the use of logical groups and hierarchies. In clinical medicine, similar principles are used to standardise the nomenclature of disease. For more than three decades, heart muscle diseases have been classified into primary or idiopathic myocardial diseases (cardiomyopathies) and secondary disorders that have similar morphological appearances, but which are caused by an identifiable pathology such as coronary artery disease or myocardial infiltration (specific heart muscle diseases). In this document, The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases presents an update of the existing classification scheme. The aim is to help clinicians look beyond generic diagnostic labels in order to reach more specific diagnoses.
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| 13. |
- Holmqvist, Fredrik, et al.
(författare)
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Variable interatrial conduction illustrated in a hypertrophic cardiomyopathy population
- 2007
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Ingår i: Annals of Noninvasive Electrocardiology. - 1082-720X. ; 12:3, s. 227-236
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with hypertrophic cardiomyopathy (HCM) have a high incidence of atrial fibrillation. They also have a longer P-wave duration than healthy controls, indicating conduction alterations. Previous studies have demonstrated orthogonal P-wave morphology alterations in patients with paroxysmal atrial fibrillation. In the present study, the P-wave morphology of patients with HCM was compared with that of matched controls in order to explore the nature of the atrial conduction alterations. Methods and Results: A total of 65 patients (45 men, mean age 49 +/- 15) with HCM were included. The control population (n = 65) was age and gender matched (45 men, mean age 49 +/- 15). Five minutes of 12-lead ECG was recorded. The data were subsequently transformed to orthogonal lead data, and unfiltered signal-averaged P-wave analysis was performed. The P-wave duration was longer in the HCM patients compared to the controls (149 +/- 22 vs 130 +/- 16 ms, P < 0.0001). Examination of the P-wave morphology demonstrated changes in conduction patterns compatible with interatrial conduction block of varying severity in both groups, but a higher degree of interatrial block seen in the HCM population. These changes were most prominent in the Leads Y and Z. Conclusion: The present study suggests that the longer P-wave duration observed in HCM patients may be explained by a higher prevalence of block in one or more of the interatrial conduction routes.
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| 14. |
- Potter, Samara L. Poplack, et al.
(författare)
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Detection of hypertrophic cardiomyopathy is improved when using advanced rather than strictly conventional 12-lead electrocardiogram
- 2010
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Ingår i: Journal of Electrocardiology. - : Elsevier BV. - 1532-8430 .- 0022-0736. ; 43:6, s. 713-718
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Twelve-lead electrocardiogram (ECG) is used to screen for hypertrophic cardiomyopathy (HCM), but up to 25% of HCM patients do not have distinctly abnormal ECGs, whereas up to 5% to 15% of healthy athletes do. We hypothesized that an approximately 5-minute resting advanced 12-lead ECG test ("A-ECG score") could detect HCM with greater sensitivity than pooled conventional ECG criteria and distinguish healthy athletes from HCM with greater specificity. Materials and methods: Five-minute 12-lead ECGs were obtained from 56 HCM patients, 56 age/sex-matched healthy controls, and 69 younger endurance-trained athletes. Electrocardiograms were analyzed using recently suggested pooled conventional ECG criteria and also A-ECG scoring techniques that considered results from multiple advanced and conventional ECG parameters. Results: Compared with pooled criteria from the strictly conventional ECG, an A-ECG logistic score incorporating results from just 3 advanced ECG parameters (spatial QRS-T angle, unexplained portion of QT variability, and T-wave principal component analysis ratio) increased the sensitivity of ECG for identifying HCM from 89% (78%-96%) to 98% (89%-100%; P = .025), while increasing specificity from 90% (83%-94%) to 95% (92%-99%; P = .020). Conclusions: Resting 12-lead A-ECG scores that are simultaneously more sensitive than pooled conventional ECG criteria for detecting HCM and more specific for distinguishing healthy athletes and other healthy controls from HCM can be constructed. Pending further prospective validation, such scores may lead to improved ECG-based screening for HCM. Published by Elsevier Inc.
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