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958 Publications visible to you, out of a total of 958
Recorded and Reported Sleepiness: The Association Between Brain Arousal in Resting State and Subjective Daytime Sleepiness.
LIFE Adult

Abstract (Expand)

Objectives: Daytime sleepiness is a significant public health concern. Early evidence points toward the computerized VIGALL (Vigilance Algorithm Leipzig) as time-efficient tool to assess sleepiness … objectively. In the present study, we investigated the association between VIGALL variables of EEG vigilance (indicating brain arousal in resting state) and subjective daytime sleepiness in the LIFE cohort study. Additionally, we validated VIGALL against the self-rated likelihood of having fallen asleep during the conducted resting EEG and against heart periods. Methods: Participants of the primary sample LIFE 60+ (N = 1927, 60-79 years) and replication sample LIFE 40+ (N = 293, 40-56 years) completed the Epworth Sleepiness Scale (ESS). After an average interval of 3 weeks (LIFE 60+) and 65 weeks (LIFE 40+), respectively, participants underwent a single 20-minute resting EEG, analyzed using VIGALL 2.1. Results: Analyses revealed significant associations between ESS and EEG vigilance in LIFE 60+ (rho = -0.17, p = 1E-14) and LIFE 40+ (rho = -0.24, p = 2E-5). Correlations between EEG vigilance and self-rated sleep likelihood reached rho = -0.43 (p = 2E-91) in LIFE 60+ and rho = -0.50 (p = 5E-20) in LIFE 40+. Overall, strongest correlations were obtained for EEG vigilance variable "slope index." Furthermore, lower EEG vigilance was consistently associated with longer heart periods. Conclusions: The present study contributes to the validation of VIGALL. Despite the considerable interval between ESS and EEG assessment dates, the strength of ESS-VIGALL association approximates prior ESS-Multiple Sleep Latency Test results. In this light, VIGALL might constitute an economical choice for the objective assessment of daytime sleepiness in large cohort studies. The discriminative power to identify disorders of hypersomnolence, however, remains to be addressed.

Authors: P. Jawinski, J. Kittel, C. Sander, J. Huang, J. Spada, C. Ulke, K. Wirkner, T. Hensch, U. Hegerl

Date Published: 1st Jul 2017

Publication Type: Journal article

Disentangling the neural correlates of corticobasal syndrome and corticobasal degeneration with systematic and quantitative ALE meta-analyses.
LIFE Adult

Abstract (Expand)

Corticobasal degeneration is a scarce neurodegenerative disease, which can only be confirmed by histopathological examination. Reported to be associated with various clinical syndromes, its classical … clinical phenotype is corticobasal syndrome. Due to the rareness of corticobasal syndrome/corticobasal degeneration and low numbers of patients included in single studies, meta-analyses are particularly suited to disentangle features of the clinical syndrome and histopathology. Using PubMed, we identified 11 magnetic resonance imaging studies measuring atrophy in 22 independent cohorts with 200 patients contrasted to 318 healthy controls. The anatomic likelihood estimation method was applied to reveal affected brain regions across studies. Corticobasal syndrome was related to gray matter loss in the basal ganglia/thalamus, frontal, parietal, and temporal lobes. In corticobasal degeneration patients, atrophy in the thalamus, frontal, temporal, and occipital lobes were found. Finally, in a conjunction analysis, the bilateral thalamus, the bilateral posterior frontomedian cortex, posterior midcingulate cortex and premotor area/supplementary motor area, and the left posterior superior and middle frontal gyrus/precentral gyrus were identified as areas associated with both, corticobasal syndrome and corticobasal degeneration. Remarkably, atrophy in the premotor area/supplementary motor area and posterior midcingulate/frontomedian cortex seems to be specific for corticobasal syndrome/corticobasal degeneration, whereas atrophy in the thalamus and the left posterior superior and middle frontal gyrus/precentral gyrus are also associated with other neurodegenerative diseases according to anatomic likelihood estimation method meta-analyses. Our study creates a new conceptual framework to understand, and distinguish between clinical features (corticobasal syndrome) and histopathological findings (corticobasal degeneration) by powerful data-driven meta-analytic approaches. Furthermore, it proposes regional-specific atrophy as an imaging biomarker for diagnosis of corticobasal syndrome/corticobasal degeneration ante-mortem.

Authors: F. Albrecht, S. Bisenius, R. Morales Schaack, J. Neumann, M. L. Schroeter

Date Published: 27th Jun 2017

Publication Type: Journal article

Human Diseases: neurodegenerative disease

Multilineage communication regulates human liver bud development from pluripotency.
Leipzig Melanoma Studies

Abstract (Expand)

Conventional two-dimensional differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. Three-dimensional organoids generate complex organ-like tissues; … however, it is unclear how heterotypic interactions affect lineage identity. Here we use single-cell RNA sequencing to reconstruct hepatocyte-like lineage progression from pluripotency in two-dimensional culture. We then derive three-dimensional liver bud organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during liver bud development. We find that liver bud hepatoblasts diverge from the two-dimensional lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark three-dimensional liver buds against fetal and adult human liver single-cell RNA sequencing data, and find a striking correspondence between the three-dimensional liver bud and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signalling in liver buds, and show that vascular endothelial growth factor (VEGF) crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.

Authors: J. G. Camp, K. Sekine, T. Gerber, H. Loeffler-Wirth, H. Binder, M. Gac, S. Kanton, J. Kageyama, G. Damm, D. Seehofer, L. Belicova, M. Bickle, R. Barsacchi, R. Okuda, E. Yoshizawa, M. Kimura, H. Ayabe, H. Taniguchi, T. Takebe, B. Treutlein

Date Published: 22nd Jun 2017

Publication Type: Not specified

Human Diseases: liver disease

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Importance The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives To estimate age-specific risks of breast, ovarian, and contralateral …ral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for \geq2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P\textless.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P\textless.001). Conclusions and Relevance These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

Authors: Karoline B. Kuchenbaecker, John L. Hopper, Daniel R. Barnes, Kelly-Anne Phillips, Thea M. Mooij, Marie-José Roos-Blom, Sarah Jervis, Flora E. van Leeuwen, Roger L. Milne, Nadine Andrieu, David E. Goldgar, Mary Beth Terry, Matti A. Rookus, Douglas F. Easton, Antonis C. Antoniou, Lesley McGuffog, D. Gareth Evans, Daniel Barrowdale, Debra Frost, Julian Adlard, Kai-Ren Ong, Louise Izatt, Marc Tischkowitz, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Steve Ellis, Catherine Nogues, Christine Lasset, Dominique Stoppa-Lyonnet, Jean-Pierre Fricker, Laurence Faivre, Pascaline Berthet, Maartje J. Hooning, Lizet E. van der Kolk, Carolien M. Kets, Muriel A. Adank, Esther M. John, Wendy K. Chung, Irene L. Andrulis, Melissa Southey, Mary B. Daly, Saundra S. Buys, Ana Osorio, Christoph Engel, Karin Kast, Rita K. Schmutzler, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Michael L. Friedlander, Sue-Anne McLachlan, Eva Machackova, Lenka Foretova, Yen Y. Tan, Christian F. Singer, Edith Olah, Anne-Marie Gerdes, Brita Arver, Håkan Olsson

Date Published: 20th Jun 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Model-based individual managing of thrombocytopenia during multi-cyclic chemotherapy
HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles

Abstract (Expand)

Background: Thrombocytopenia is a major side-effect of cytotoxic cancer therapies. The aim of precision medicine is to develop therapy modifications accounting for the individual’s risk. Methodology/Principle … Findings: To solve this task, we develop an individualized bio-mechanistic model of the dynamics of bone marrow thrombopoiesis, circulating platelets and therapy effects thereon. Comprehensive biological knowledge regarding cell differentiation, amplification, apoptosis rates, transition times and corresponding regulations are translated into ordinary differential equations. A model of osteoblast/osteoclast interactions was incorporated to mechanistically describe bone marrow support of quiescent cell stages. Thrombopoietin (TPO) as a major regulator is explicitly modelled including pharmacokinetics and –dynamics of TPO injections. Effects of cytotoxic drugs are modelled by transient depletions of proliferating cells. To calibrate the model, we used population data from the literature and close-meshed individual data of N=135 high-grade non-Hodgkin’s lymphoma patients treated with CHOP-like chemotherapies. To limit the number of free parameters, several parsimony assumptions were derived from biological data and tested via Likelihood methods. Heterogeneity of patients was explained by a few model parameters. The over-fitting issue of individual parameter estimation was successfully dealt with a virtual participation of each patient in population-based experiments. The model qualitatively and quantitatively explains a number of biological observations such as the role of osteoblasts in explaining long-term toxic effects, megakaryocyte-mediated feedback on stem cells, bi-phasic stimulation of thrombopoiesis by TPO, dynamics of megakaryocyte ploidies and non-exponential platelet degradation. Almost all individual time series could be described with high precision. We demonstrated how the model can be used to provide predictions regarding individual therapy adaptations. Conclusions: We propose a mechanistic thrombopoiesis model of unprecedented comprehensiveness in both, biological mechanisms considered and experimental data sets explained. Our innovative method of parameter estimation allows robust determinations of individual parameter settings facilitating the development of individual treatment adaptations during chemotherapy.

Authors: Y. Kheifetz, Markus Scholz, Markus Löffler

Date Published: 9th Jun 2017

Publication Type: Not specified

Human Diseases: thrombocytopenia

Stability of BDNF in Human Samples Stored Up to 6 Months and Correlations of Serum and EDTA-Plasma Concentrations.
LIFE Adult

Abstract (Expand)

Brain-derived neurotrophic factor (BDNF), an important neural growth factor, has gained growing interest in neuroscience, but many influencing physiological and analytical aspects still remain unclear. … In this study we assessed the impact of storage time at room temperature, repeated freeze/thaw cycles, and storage at -80 degrees C up to 6 months on serum and ethylenediaminetetraacetic acid (EDTA)-plasma BDNF. Furthermore, we assessed correlations of serum and plasma BDNF concentrations in two independent sets of samples. Coefficients of variations (CVs) for serum BDNF concentrations were significantly lower than CVs of plasma concentrations (n = 245, p = 0.006). Mean serum and plasma concentrations at all analyzed time points remained within the acceptable change limit of the inter-assay precision as declared by the manufacturer. Serum and plasma BDNF concentrations correlated positively in both sets of samples and at all analyzed time points of the stability assessment (r = 0.455 to rs = 0.596; p < 0.004). In summary, when considering the acceptable change limit, BDNF was stable in serum and in EDTA-plasma up to 6 months. Due to a higher reliability, we suggest favoring serum over EDTA-plasma for future experiments assessing peripheral BDNF concentrations.

Authors: M. Polyakova, H. Schlogl, J. Sacher, M. Schmidt-Kassow, J. Kaiser, M. Stumvoll, J. Kratzsch, M. L. Schroeter

Date Published: 3rd Jun 2017

Publication Type: Journal article

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term … mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung fur Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

Authors: S. Zewinger, M. E. Kleber, V. Tragante, R. O. McCubrey, A. F. Schmidt, K. Direk, U. Laufs, C. Werner, W. Koenig, D. Rothenbacher, U. Mons, L. P. Breitling, H. Brenner, R. T. Jennings, I. Petrakis, S. Triem, M. Klug, A. Filips, S. Blankenberg, C. Waldeyer, C. Sinning, R. B. Schnabel, K. J. Lackner, E. Vlachopoulou, O. Nygard, G. F. T. Svingen, E. R. Pedersen, G. S. Tell, J. Sinisalo, M. S. Nieminen, R. Laaksonen, S. Trompet, R. A. J. Smit, N. Sattar, J. W. Jukema, H. V. Groesdonk, G. Delgado, T. Stojakovic, A. P. Pilbrow, V. A. Cameron, A. M. Richards, R. N. Doughty, Y. Gong, R. Cooper-DeHoff, J. Johnson, M. Scholz, F. Beutner, J. Thiery, J. G. Smith, R. O. Vilmundarson, R. McPherson, A. F. R. Stewart, S. Cresci, P. A. Lenzini, J. A. Spertus, O. Olivieri, D. Girelli, N. I. Martinelli, A. Leiherer, C. H. Saely, H. Drexel, A. Mundlein, P. S. Braund, C. P. Nelson, N. J. Samani, D. Kofink, I. E. Hoefer, G. Pasterkamp, A. A. Quyyumi, Y. A. Ko, J. A. Hartiala, H. Allayee, W. H. W. Tang, S. L. Hazen, N. Eriksson, C. Held, E. Hagstrom, L. Wallentin, A. Akerblom, A. Siegbahn, I. Karp, C. Labos, L. Pilote, J. C. Engert, J. M. Brophy, G. Thanassoulis, P. Bogaty, W. Szczeklik, M. Kaczor, M. Sanak, S. S. Virani, C. M. Ballantyne, V. V. Lee, E. Boerwinkle, M. V. Holmes, B. D. Horne, A. Hingorani, F. W. Asselbergs, R. S. Patel, B. K. Kramer, H. Scharnagl, D. Fliser, W. Marz, T. Speer

Date Published: 2nd Jun 2017

Publication Type: Journal article

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