@article{KampfBauerReiter2018, author = {Kampf, Thomas and Bauer, Wolfgang Rudolf and Reiter, Theresa}, title = {Improved post-processing strategy for MOLLI based tissue characterization allows application in patients with dyspnoe and impaired left ventricular function}, series = {Zeitschrift f{\"u}r Medizinische Physik}, volume = {28}, journal = {Zeitschrift f{\"u}r Medizinische Physik}, doi = {10.1016/j.zemedi.2017.07.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325481}, pages = {25-35}, year = {2018}, abstract = {Contrast and non-contrast MRI based characterization of myocardium by T1-mapping will be of paramount importance to obtain biomarkers, e.g. fibrosis, which determines the risk of heart failure patients. T1-mapping by the standard post-processing of the modified look-locker inversion recovery (MOLLI) lacks of accuracy when trying to reduce its duration, which on the other hand, is highly desirable in patients with heart failure. The recently suggested inversion group fitting (IGF) technique, which considers more parameters for fitting, has a superior accuracy for long T1 times despite a shorter duration. However, for short T1 values, the standard method has a superior precision. A conditional fitting routine is proposed which ideally takes advantage of both algorithms. Materials and methods All measurements were performed on a 1.5 T clinical scanner (ACHIEVA, Philips Healthcare, The Netherlands) using a MOLLI 5(n)3(n)3 prototype with n(heart beats) being a variable waiting time between inversion experiments. Phantom experiments covered a broad range of T1 times, waiting times and heart rates. A saturation recovery experiment served as a gold standard for T1 measurement. All data were analyzed with the standard MOLLI, the IGF fit and the conditional fitting routine and the obtained T1 values were compared with the gold standard. In vivo measurements were performed in a healthy volunteer and a total of 34 patients with normal findings, dilative cardiomyopathy and amyloidosis. Results Theoretical analysis and phantom experiments provided a threshold value for an apparent IGF determining processing with IGF post processing for values above, or switching to the standard technique for values below. This was validated in phantoms and patients measurements. A reduction of the waiting time to 1 instead of 3 heart beats between the inversion experiments showed reliable results. The acquisition time was reduced from 17 to 13 heart beats. The in vivo measurements showed ECV values between 25\% (18-33\%; SD 0.03) in the healthy, 30\% (22-40\%; SD 0.04) in patients with DCM and 45\% (30-60\%; SD 0.9) in patients with amyloidosis. Conclusion The adopted post-processing algorithm determines long T1 values with high accuracy and short T1 values while maintaining a high precision. Based on reduction of waiting time, and independence of heart rate, it shortens breath hold duration and allows fast T1-mapping, which is frequently a prerequisite in patients with cardiac diseases.}, language = {en} } @article{GermainElliottFalissardetal.2019, author = {Germain, Dominique P. and Elliott, Perry M. and Falissard, Bruno and Fomin, Victor V. and Hilz, Max J. and Jovanovic, Ana and Kantola, Ilkka and Linhart, Aleš and Renzo, Mignani and Namdar, Mehdi and Nowak, Albina and Oliveira, Jo{\~a}o-Paulo and Pieroni, Maurizio and Viana-Baptista, Miguel and Wanner, Christoph and Spada, Marco}, title = {The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts}, series = {Molecular Genetics and Metabolism Reports}, volume = {19}, journal = {Molecular Genetics and Metabolism Reports}, doi = {10.1016/j.ymgmr.2019.100454}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232987}, year = {2019}, abstract = {Background Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations. Methods We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients. Results Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes. Conclusions ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.}, language = {en} } @article{UeceylerUrlaubMayeretal.2019, author = {{\"U}{\c{c}}eyler, Nurcan and Urlaub, Daniela and Mayer, Christine and Uehlein, Sabrina and Held, Melissa and Sommer, Claudia}, title = {Tumor necrosis factor-α links heat and inflammation with Fabry pain}, series = {Molecular Genetics and Metabolism}, volume = {127}, journal = {Molecular Genetics and Metabolism}, doi = {https://doi.org/10.1016/j.ymgme.2019.05.009}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229190}, pages = {200-206}, year = {2019}, abstract = {Fabry disease (FD) is an X-linked lysosomal storage disorder associated with pain triggered by heat or febrile infections. We modelled this condition by measuring the cytokine expression of peripheral blood mononuclear cells (PBMC) from FD patients in vitro upon stimulation with heat and lipopolysaccharide (LPS). We enrolled 67 FD patients and 37 healthy controls. We isolated PBMC, assessed their gene expression of selected pro- and anti-inflammatory cytokines, incubated them with heat, LPS, globotriaosylceramide (Gb3), and tumor necrosis factor-α (TNF), and measured TNF secretion in the supernatant and intracellular Gb3 accumulation, respectively. We found increased TNF, interleukin (IL-)1β, and toll-like receptor 4 (TLR4) gene expression in FD men (p < .05 to p < .01). TNF and IL-10 were higher, and IL-4 was lower in the subgroup of FD men with pain compared to controls (p < .05 to p < .01). Hereby, TNF was only increased in FD men with pain and classical mutations (p < .05) compared to those without pain. PBMC from FD patients secreted more TNF upon stimulation with LPS (p < .01) than control PBMC. Incubation with Gb3 and an additional α-galactosidase A inhibitor did not further increase TNF secretion, but incubation with TNF greatly increased the Gb3 load in FD PBMC compared to controls (p < .01). Also, LPS incubation and heat challenge (40 °C) increased Gb3 accumulation in PBMC of patients compared to baseline (p < .05 each), while no alterations were observed in control PBMC. Our data show that TNF holds a crucial role in the pathophysiology of FD associated pain, which may open a novel perspective for analgesic treatment in FD pain.}, language = {en} } @article{GermainAradBurlinaetal.2019, author = {Germain, Dominique P. and Arad, Michael and Burlina, Alessandro and Elliott, Perry M. and Falissard, Bruno and Feldt-Rasmussen, Ulla and Hilz, Max J. and Hughes, Derralynn A. and Ortiz, Alberto and Wanner, Christoph and Weidemann, Frank and Spada, Marco}, title = {The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease - A systematic literature review by a European panel of experts}, series = {Molecular Genetics and Metabolism}, volume = {126}, journal = {Molecular Genetics and Metabolism}, doi = {10.1016/j.ymgme.2018.09.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232963}, pages = {224-235}, year = {2019}, abstract = {Background Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients. Methods A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type. Results Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease. Conclusions This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results.}, language = {en} } @article{SpadaBaronElliottetal.2019, author = {Spada, Marco and Baron, Ralf and Elliott, Perry M. and Falissard, Bruno and Hilz, Max J. and Monserrat, Lorenzo and T{\o}ndel, Camilla and Tylki-Szymańska, Anna and Wanner, Christoph and Germain, Dominique P.}, title = {The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease - A systematic literature review by a European panel of experts}, series = {Molecular Genetics and Metabolism}, volume = {126}, journal = {Molecular Genetics and Metabolism}, doi = {10.1016/j.ymgme.2018.04.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239287}, pages = {212-223}, year = {2019}, abstract = {Background Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease. Methods A comprehensive systematic review of published literature on ERT in Fabry disease was conducted in January 2017. The literature analysis included all original articles reporting outcomes of ERT in paediatric patients. Results Treatment-related outcomes in the paediatric population were reported in six publications derived from open-label clinical trials and in 10 publications derived from observational or registry-based studies. ERT was shown to significantly reduce plasma and urine GL-3 levels in paediatric patients with Fabry disease. The effect of ERT on GL-3 clearance from renal podocytes appeared to be agalsidase dose-dependent. ERT relieved pain and improved gastrointestinal symptoms and quality of life. Conclusions Based on the published literature, the use of ERT in paediatric patients can significantly clear GL-3 accumulation, ameliorate the early symptoms of Fabry disease, and improve quality of life. Treatment with ERT in paediatric patients with Fabry disease may be important to prevent further disease progression and overt organ damage.}, language = {en} } @article{FazziniLaminaFendtetal.2019, author = {Fazzini, Federica and Lamina, Claudia and Fendt, Liane and Schultheiss, Ulla T. and Kotsis, Fruzsina and Hicks, Andrew A. and Meiselbach, Heike and Weissensteiner, Hansi and Forer, Lukas and Krane, Vera and Eckardt, Kai-Uwe and K{\"o}ttgen, Anna and Kronenberg, Florian}, title = {Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease}, series = {Kidney International}, volume = {96}, journal = {Kidney International}, organization = {GCKD Investigators}, doi = {10.1016/j.kint.2019.04.021}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227662}, pages = {480-488}, year = {2019}, abstract = {Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95\% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95\% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95\% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95\% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD.}, language = {en} } @article{StoreyStaplinHaynesetal.2018, author = {Storey, Benjamin C. and Staplin, Natalie and Haynes, Richard and Reith, Christina and Emberson, Jonathan and Herrington, William G. and Wheeler, David C. and Walker, Robert and Fellstr{\"o}m, Bengt and Wanner, Christoph and Landray, Martin J. and Baigent, Colin}, title = {Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation}, series = {Kidney International}, volume = {93}, journal = {Kidney International}, organization = {The SHARP Collaborative Group}, doi = {10.1016/j.kint.2017.09.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240067}, pages = {1000-1007}, year = {2018}, abstract = {Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95\% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.}, language = {en} } @article{ElliotGermainHilzetal.2019, author = {Elliot, Perry M. and Germain, Dominique P. and Hilz, Max J. and Spada, Marco and Wanner, Christoph and Falissard, Bruno}, title = {Why systematic literature reviews in Fabry disease should include all published evidence}, series = {European Journal of Medical Genetics}, volume = {62}, journal = {European Journal of Medical Genetics}, doi = {10.1016/j.ejmg.2019.103702}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226654}, year = {2019}, abstract = {Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of ERT. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of ERT on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of ERT in patients with Fabry disease; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods, ERT regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of ERT outcomes in Fabry disease, highlighting that in a rare genetic disorder like Fabry disease, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies.}, language = {en} } @article{EisenhoferPeitzschKadenetal.2019, author = {Eisenhofer, Graeme and Peitzsch, Mirko and Kaden, Denise and Langton, Katharina and Mangelis, Anastasios and Pamporaki, Christina and Masjkur, Jimmy and Geroula, Aikaterini and Kurlbaum, Max and Deutschbein, Timo and Beuschlein, Felix and Prejbisz, Aleksander and Bornstein, Stefan R. and Lenders, Jacques W. M.}, title = {Reference intervals for LC-MS/MS measurements of plasma free, urinary free and urinary acid-hydrolyzed deconjugated normetanephrine, metanephrine and methoxytyramine}, series = {Clinica Chimica Acta}, volume = {490}, journal = {Clinica Chimica Acta}, doi = {10.1016/j.cca.2018.12.019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226598}, pages = {46-54}, year = {2019}, abstract = {Background Plasma or urinary metanephrines are recommended for screening of pheochromocytomas and paragangliomas (PPGLs). Measurements of urinary free rather than deconjugated metanephrines and additional measurements of methoxytyramine represent other developments. For all measurements there is need for reference intervals. Methods Plasma free, urinary free and urinary deconjugated O-methylated catecholamine metabolites were measured by LC-MS/MS in specimens from 590 hypertensives and normotensives. Reference intervals were optimized using data from 2,056 patients tested for PPGLs. Results Multivariate analyses, correcting for age and body surface area, indicated higher plasma and urinary metanephrine in males than females and sex differences in urinary normetanephrine and free methoxytyramine that largely reflected body size variation. There were positive associations of age with plasma metabolites, but negative relationships with urinary free metanephrine and methoxytyramine. Plasma and urinary normetanephrine were higher in hypertensives than normotensives, but differences were small. Optimization of reference intervals using the data from patients tested for PPGLs indicated that age was the most important consideration for plasma normetanephrine and sex most practical for urinary metabolites. Conclusion This study clarifies impacts of demographic and anthropometric variables on catecholamine metabolites, verifies use of age-specific reference intervals for plasma normetanephrine and establishes sex-specific reference intervals for urinary metabolites.}, language = {en} } @article{SiebertCiatoMurakamietal.2019, author = {Siebert, Claudia and Ciato, Denis and Murakami, Masanori and Frei-Stuber, Ludwig and Perez-Rivas, Luis Gustavo and Monteserin-Garcia, Jos{\´e} Luis and N{\"o}lting, Svenja and Maurer, Julian and Feuchtinger, Annette and Walch, Axel K. and Haak, Harm R. and Bertherat, J{\´e}r{\^o}me and Mannelli, Massimo and Fassnacht, Martin and Korpershoek, Esther and Reincke, Martin and Stalla, G{\"u}nter K. and Hantel, Constanze and Beuschlein, Felix}, title = {Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma}, series = {Frontiers in Endocrinology}, volume = {10}, journal = {Frontiers in Endocrinology}, doi = {10.3389/fendo.2019.00487}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238029}, year = {2019}, abstract = {Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is fundamental for cell survival and contributes to different oncogenic signaling pathways. Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several cancer types. We have examined the expression of HSP90 in different adrenal tumors and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC. Methods: Immunohistochemical expression of HSP90 isoforms was investigated in different adrenocortical tumors and associated with clinical features. Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines. Results: Within adrenocortical tumors, ACC samples exhibited the highest expression of HSP90β. Within a cohort of ACC patients, HSP90β expression levels were inversely correlated with recurrence-free and overall survival. In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2—and AKT—pathways by luminespib and ganetespib treatment. Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC.}, language = {en} }