TY - JOUR A1 - Petritsch, B. A1 - Köstler, H. A1 - Weng, A. M. A1 - Horn, M. A1 - Gassenmaier, T. A1 - Kunz, A. S. A1 - Weidemann, F. A1 - Wanner, C. A1 - Bley, T. A. A1 - Beer, M. T1 - Myocardial lipid content in Fabry disease: a combined \(^1\)H-MR spectroscopy and MR imaging study at 3 Tesla JF - BMC Cardiovascular Disorders N2 - Background Fabry disease is characterized by a progressive deposition of sphingolipids in different organ systems, whereby cardiac involvement leads to death. We hypothesize that lysosomal storage of sphingolipids in the heart as occurring in Fabry disease does not reflect in higher cardiac lipid concentrations detectable by \(^1\)H magnetic resonance spectroscopy (MRS) at 3 Tesla. Methods Myocardial lipid content was quantified in vivo by \(^1\)H-MRS in 30 patients (12 male, 18 female; 18 patients treated with enzyme replacement therapy) with genetically proven Fabry disease and in 30 healthy controls. The study protocol combined \(^1\)H-MRS with cardiac cine imaging and LGE MRI in a single examination. Results Myocardial lipid content was not significantly elevated in Fabry disease (p = 0.225). Left ventricular (LV) mass was significantly higher in patients suffering from Fabry disease compared to controls (p = 0.019). Comparison of patients without signs of myocardial fibrosis in MRI (LGE negative; n = 12) to patients with signs of fibrosis (LGE positive; n = 18) revealed similar myocardial lipid content in both groups (p > 0.05), while the latter showed a trend towards elevated LV mass (p = 0.076). Conclusions This study demonstrates the potential of lipid metabolic investigation embedded in a comprehensive examination of cardiac morphology and function in Fabry disease. There was no evidence that lysosomal storage of sphingolipids influences cardiac lipid content as measured by \(^1\)H-MRS. Finally, the authors share the opinion that a comprehensive cardiac examination including three subsections (LGE; \(^1\)H-MRS; T\(_1\) mapping), could hold the highest potential for the final assessment of early and late myocardial changes in Fabry disease. KW - late gadolinium enhancement KW - myocardial lipid content KW - magnetic resonance spectroscopy KW - Morbus Fabry KW - rare diseases KW - lysosomal storage disease Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146693 VL - 16 IS - 205 ER - TY - JOUR A1 - Biederer, J. A1 - Beer, M. A1 - Hirsch, W. A1 - Wild, J. A1 - Fabel, M. A1 - Puderbach, M. A1 - Van Beek, E. J. R. T1 - MRI of the lung (2/3). Why … when … how? JF - Insights into Imaging N2 - Background Among the modalities for lung imaging, proton magnetic resonance imaging (MRI) has been the latest to be introduced into clinical practice. Its value to replace X-ray and computed tomography (CT) when radiation exposure or iodinated contrast material is contra-indicated is well acknowledged: i.e. for paediatric patients and pregnant women or for scientific use. One of the reasons why MRI of the lung is still rarely used, except in a few centres, is the lack of consistent protocols customised to clinical needs. Methods This article makes non-vendor-specific protocol suggestions for general use with state-of-the-art MRI scanners, based on the available literature and a consensus discussion within a panel of experts experienced in lung MRI. Results Various sequences have been successfully tested within scientific or clinical environments. MRI of the lung with appropriate combinations of these sequences comprises morphological and functional imaging aspects in a single examination. It serves in difficult clinical problems encountered in daily routine, such as assessment of the mediastinum and chest wall, and even might challenge molecular imaging techniques in the near future. Conclusion This article helps new users to implement appropriate protocols on their own MRI platforms. Main Messages • MRI of the lung can be readily performed on state-of-the-art 1.5-T MRI scanners. • Protocol suggestions based on the available literature facilitate its use for routine • MRI offers solutions for complicated thoracic masses with atelectasis and chest wall invasion. • MRI is an option for paediatrics and science when CT is contra-indicated KW - magnetic resonance imaging KW - lung KW - sequence imaging protocol Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124268 VL - 3 IS - 4 ER - TY - JOUR A1 - Biederer, Jürgen A1 - Mirsadraee, S. A1 - Beer, M. A1 - Molinari, F. A1 - Hintze, C. A1 - Bauman, G. A1 - Both, M. A1 - Van Beek, E. J. R. A1 - Wild, J. A1 - Puderbach, M. T1 - MRI of the lung (3/3)—current applications and future perspectives JF - Insights into Imaging N2 - Background MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. Methods Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. Results In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a “buffet” of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. Conclusion New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations. KW - functional imaging KW - magnetic resonance imaging KW - cystic fibrosis KW - pulmonary embolism KW - tumor KW - infiltrate Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124348 VL - 3 IS - 4 ER - TY - JOUR A1 - Heise, Ruth A1 - Amann, Philipp M. A1 - Ensslen, Silke A1 - Marquardt, Yvonne A1 - Czaja, Katharina A1 - Joussen, Sylvia A1 - Beer, Daniel A1 - Abele, Rupert A1 - Plewnia, Gabriele A1 - Tampé, Robert A1 - Merk, Hans F. A1 - Hermanns, Heike M. A1 - Baron, Jens M. T1 - Interferon Alpha Signalling and Its Relevance for the Upregulatory Effect of Transporter Proteins Associated with Antigen Processing (TAP) in Patients with Malignant Melanoma JF - PLoS ONE N2 - Introduction Interferon alpha (IFNα) is routinely used in the clinical practice for adjuvant systemic melanoma therapy. Understanding the molecular mechanism of IFNα effects and prediction of response in the IFNα therapy regime allows initiation and continuation of IFNα treatment for responder and exclusion of non-responder to avoid therapy inefficacy and side-effects. The transporter protein associated with antigen processing-1 (TAP1) is part of the MHC class I peptide-loading complex, and important for antigen presentation in tumor and antigen presenting cells. In the context of personalized medicine, we address this potential biomarker TAP1 as a target of IFNα signalling. Results We could show that IFNα upregulates TAP1 expression in peripheral blood mononuclear cells (PBMCs) of patients with malignant melanoma receiving adjuvant high-dose immunotherapy. IFNα also induced expression of TAP1 in mouse blood and tumor tissue and suppressed the formation of melanoma metastasis in an in vivo B16 tumor model. Besides its expression, TAP binding affinity and transport activity is induced by IFNα in human monocytic THP1 cells. Furthermore, our data revealed that IFNα clearly activates phosphorylation of STAT1 and STAT3 in THP1 and A375 melanoma cells. Inhibition of Janus kinases abrogates the IFNα-induced TAP1 expression. These results suggest that the JAK/STAT pathway is a crucial mediator for TAP1 expression elicited by IFNα treatment. Conclusion We suppose that silencing of TAP1 expression provides tumor cells with a mechanism to escape cytotoxic T-lymphocyte recognition. The observed benefit of IFNα treatment could be mediated by the shown dual effect of TAP1 upregulation in antigen presenting cells on the one hand, and of TAP1 upregulation in ‘silent’ metastatic melanoma cells on the other hand. In conclusion, this work contributes to a better understanding of the mode of action of IFNα which is essential to identify markers to predict, assess and monitor therapeutic response of IFNα treatment in the future. KW - interferon alpha signalling KW - interferon alpha (IFNα) KW - transporter protein associated with antigen processing-1 (TAP1) KW - melanoma therapy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167409 VL - 11 IS - 1 ER - TY - JOUR A1 - Weidemann, F. A1 - Niemann, M. A1 - Stork, S. A1 - Breunig, F. A1 - Beer, M. A1 - Sommer, C. A1 - Herrmann, S. A1 - Ertl, G. A1 - Wanner, C. T1 - Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications JF - Journal of Internal Medicine N2 - The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease. METHODS: A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. RESULTS: During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. CONCLUSION: Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease. KW - Fabry disease KW - α-galactosidase A KW - dialysis KW - prognosis KW - stroke KW - sudden cardiac death Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132075 VL - 247 IS - 4 ER - TY - JOUR A1 - Fazeli, Gholamreza A1 - Beer, Katharina B. A1 - Geisenhof, Michaela A1 - Tröger, Sarah A1 - König, Julia A1 - Müller-Reichert, Thomas A1 - Wehman, Ann M. T1 - Loss of the Major Phosphatidylserine or Phosphatidylethanolamine Flippases Differentially Affect Phagocytosis JF - Frontiers in Cell and Developmental Biology N2 - The lipids phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEth) are normally asymmetrically localized to the cytosolic face of membrane bilayers, but can both be externalized during diverse biological processes, including cell division, cell fusion, and cell death. Externalized lipids in the plasma membrane are recognized by lipid-binding proteins to regulate the clearance of cell corpses and other cell debris. However, it is unclear whether PtdSer and PtdEth contribute in similar or distinct ways to these processes. We discovered that disruption of the lipid flippases that maintain PtdSer or PtdEth asymmetry in the plasma membrane have opposite effects on phagocytosis in Caenorhabditis elegans embryos. Constitutive PtdSer externalization caused by disruption of the major PtdSer flippase TAT-1 led to increased phagocytosis of cell debris, sometimes leading to two cells engulfing the same debris. In contrast, PtdEth externalization caused by depletion of the major PtdEth flippase TAT-5 or its activator PAD-1 disrupted phagocytosis. These data suggest that PtdSer and PtdEth externalization have opposite effects on phagocytosis. Furthermore, externalizing PtdEth is associated with increased extracellular vesicle release, and we present evidence that the extent of extracellular vesicle accumulation correlates with the extent of phagocytic defects. Thus, a general loss of lipid asymmetry can have opposing impacts through different lipid subtypes simultaneously exerting disparate effects. KW - phagocytosis KW - lipid asymmetry KW - flippase KW - phosphatidylserine KW - phosphatidylethanolamine KW - extracellular vesicle Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208771 SN - 2296-634X VL - 8 ER -