cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.5122930.v1
title: Supplementary Material for: Differentiation of Multipotent Adult Germline Stem Cells Derived from Mouse Testis into Functional Endothelial Cells

description: Pluripotent stem cells hold great promise for the treatment of cardiovascular disease. We previously described multipotent adult germline stem cells (maGSCs) from mouse testis with differentiation potential similar to embryonic stem cells. The aim of this work was to differentiate maGSCs into functional endothelial cells and to study their potential for vasculogenesis. MaGSCs were cocultivated with OP9 stromal cells to induce differentiation into cardiovascular progenitors, i.e. fetal liver kinase 1-positive (Flk-1<sup>+</sup>) cells. Five days later, Flk-1<sup>+</sup> cells were separated using fluorescence-activated cell sorting, followed by cultivation on collagen type IV under endothelial differentiation conditions. At different time points, maGSC-derived endothelial-like cells were characterized using RT-PCR, flow cytometry, immunofluorescence and functional assays. Cultivation of Flk-1<sup>+</sup> cells resulted in the progressive upregulation of endothelial cell markers, including VE-cadherin, von Willebrand factor and endothelial nitric oxide synthase. Moreover, Flk-1<sup>+</sup> maGSC-derived endothelial-like cells were able to branch and form networks in vitro and promoted functional blood vessel formation in vivo. Importantly, Flk-1<sup>+</sup> cells retained their potential to proliferate and could be continuously expanded, while the ability of contact inhibition was preserved. Thus, maGSCs may provide a useful source of endothelial-like cells to study the basic mechanisms of vasculogenesis or endothelial differentiation.
DOI: 10.6084/m9.figshare.5122933.v1
title: Supplementary Material for: A Generalized Sequential Bonferroni Procedure Using Smoothed Weights for Genome-Wide Association Studies Incorporating Information on Hardy-Weinberg Disequilibrium among Cases

description: <i>Background/Objectives:</i> For genome-wide association studies (GWAS) with case-control designs, one of the most widely used association tests is the Cochran-Armitage (CA) trend test assuming an additive mode of inheritance. The CA trend test often has higher power than other association tests under additive and multiplicative disease models. However, it can have very low power under a recessive disease model in GWAS. Although tests (such as MAX3) robust to different genetic models have been developed, they often have relatively lower power than the CA trend test under additive and multiplicative models. The goal of this study is to propose an efficient method that not only has higher power than the CA trend test under dominant and recessive models but also maintains the power of the CA trend test under additive and multiplicative models. <i>Methods:</i> We employed the generalized sequential Bonferroni (GSB) procedure of Holm to incorporate information from a Hardy-Weinberg disequilibrium (HWD) test into the CA trend test based on estimating weights from the p values of the HWD test. We proposed to smooth the weights to reduce possible noise. <i>Results and Conclusions:</i> Results from extensive simulation studies showed that the proposed GSB procedure can achieve the goal described above.
DOI: 10.6084/m9.figshare.5122927
title: Supplementary Material for: Missing Heritability in the Tails of Quantitative Traits? A Simulation Study on the Impact of Slightly Altered True Genetic Models

description: <i>Objective:</i> Genome-wide association studies have identified robust associations between single nucleotide polymorphisms and complex traits. As the proportion of phenotypic variance explained is still limited for most of the traits, larger and larger meta-analyses are being conducted to detect additional associations. Here we investigate the impact of the study design and the underlying assumption about the true genetic effect in a bimodal mixture situation on the power to detect associations. <i>Methods:</i> We performed simulations of quantitative phenotypes analysed by standard linear regression and dichotomized case-control data sets from the extremes of the quantitative trait analysed by standard logistic regression. <i>Results:</i> Using linear regression, markers with an effect in the extremes of the traits were almost undetectable, whereas analysing extremes by case-control design had superior power even for much smaller sample sizes. Two real data examples are provided to support our theoretical findings and to explore our mixture and parameter assumption. <i>Conclusions:</i> Our findings support the idea to re-analyse the available meta-analysis data sets to detect new loci in the extremes. Moreover, our investigation offers an explanation for discrepant findings when analysing quantitative traits in the general population and in the extremes.
DOI: 10.6084/m9.figshare.5122921
title: Supplementary Material for: Endothelial Dysfunction of the Peripheral Vascular Bed in the Acute Phase after Ischemic Stroke

description: <i>Background:</i> Endothelial dysfunction (ED) is relevant for the development of cerebrovascular and cardiovascular diseases. Asymmetric dimethylarginine (ADMA) competes with <i>L</i>-arginine and has been implicated in the development of ED. Increased levels of ADMA have been found in chronic heart failure (CHF). We hypothesized that peripheral ED in acute ischemic stroke is associated with increased ADMA levels. <i>Methods:</i> We evaluated 60 patients with acute stroke in the territory of the middle cerebral artery. Stroke patients were classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. We compared these patients with patients of similar age without known cardiovascular disease (negative controls, n = 23) and patients with stable, ambulatorily treated CHF (n = 46, left ventricular ejection fraction = 33.8 ± 10.9) with known ED (positive controls). Peripheral endothelial function was assessed by EndoPAT2000 technology using the reactive hyperemia index (RHI). <i>Results:</i> RHI was significantly decreased in stroke and in CHF compared to controls (1.8 ± 0.3 vs. 1.8 ± 0.4 vs. 2.2 ± 0.4, respectively, ANOVA p = 0.01). A decreased RHI was observed in cardioembolic and lacunar infarcts and stroke of undetermined etiology (1.7 ± 0.4, 1.8 ± 0.5 and 1.7 ± 0.3, p &lt; 0.0001). The <i>L</i>-arginine/ADMA ratio was significantly decreased in stroke and in CHF (147.6 ± 31.7 and 126.1 ± 37.9 vs. controls: 161.5 ± 26.1, p &lt; 0.0001) and was lowest in stroke patients in the cardioembolic group (133.0 ± 29.4, p &lt; 0.0001). A lower <i>L</i>-arginine/ADMA ratio was associated with ED in cardioembolic stroke and CHF (r = 0.324, p &lt; 0.05 and r = 0.429, p &lt; 0.0001). <i>Conclusion:</i> Peripheral ED occurs to a similar degree in acute ischemic stroke and CHF. The impaired vasodilator capacity of peripheral arteries reflects the TOAST classification. ADMA may play a role in ED in both acute ischemic stroke and CHF.
DOI: 10.6084/m9.figshare.5122924
title: Supplementary Material for: Correlation of Levels of Neuronal and Glial Markers with Radiological Measures of Infarct Volume in Ischaemic Stroke: A Systematic Review

description: <i>Background:</i> A blood test that quantified the extent of brain damage following ischaemic stroke might be a useful surrogate outcome measure in trials of acute stroke treatments. Measures of neuronal and glial damage, such as neuron-specific enolase (NSE), glial fibrillary acidic protein, tau-protein, myelin-basic protein and S100-β are potential candidate biomarkers. <i>Aim:</i> We systematically reviewed the relevant literature to find studies that correlated blood levels of neuronal and glial damage markers with imaging measures of infarct volume. <i>Methods:</i> We identified studies with a comprehensive search of databases and the reference lists of relevant studies. We included studies that: (1) measured the highest level, or area under the curve (AUC) over time of markers of cerebral damage, (2) calculated infarct volume, and (3) correlated the two measures. <i>Results:</i> Seventeen studies met the criteria for the systematic review. There were sufficient data to provide summary estimates for S100-β and NSE. The peak level and AUC over time of both markers correlated with subacute infarct volume. Measurements of S100-β later than 24 h after stroke were better correlated with subacute infarct size than earlier measurements. However, scan times varied, and none was later than 8 days after stroke. <i>Conclusion:</i> Peak and AUC levels of NSE and S100-β levels correlated with subacute infarct volume. Correlations of S100-β with infarct volume were stronger when measured after 24 h than closer to admission. Exploratory studies within clinical trials are necessary before blood markers of cerebral tissue damage can be recommended as surrogate endpoints.
DOI: 10.6084/m9.figshare.5122918
title: Supplementary Material for: Characteristics of Spinal Cord Stroke in Clinical Neurology

description: Spinal cord stroke accounts for about 0.3% of all strokes in our department. Thirty-two patients (15 males, 17 females; mean age 63.3 years) treated in the period 1995–2010 were included. Patients underwent thorough investigation including the use of different stroke scales (National Institute of Health Stroke Scale, Barthel Index and modified Rankin Scale). Twenty-eight patients had infarctions, 3 had hemorrhages, and 1 had arterio-venous fistula. Twenty-eight spinal cord strokes were spontaneous, 2 were secondary to aorta aneurysms, and 2 post surgery. Biphasic ictus was seen in 17% of all spontaneous infarctions. Younger age, male gender, hypertension, diabetes mellitus, and higher blood glucose on admission regardless of diabetes mellitus, were risk factors associated with more severe spinal cord stroke. Treatment and prevention of these risk factors should be essential in spinal cord stroke. We recommend a clinical classification into upper (cervical) and lower (thoracic or medullary conus) spinal cord strokes. Patients with upper strokes in this study had more severe strokes initially, but they had a better prognosis. Therefore it is important to identify this patient group.Acute sensory spinal cord deficit symptoms, common initial symptoms in biphasic spinal cord strokes, should be considered as possible spinal cord stroke, especially when preceded by radiating pain between the shoulders.
DOI: 10.6084/m9.figshare.5122924.v1
title: Supplementary Material for: Correlation of Levels of Neuronal and Glial Markers with Radiological Measures of Infarct Volume in Ischaemic Stroke: A Systematic Review

description: <i>Background:</i> A blood test that quantified the extent of brain damage following ischaemic stroke might be a useful surrogate outcome measure in trials of acute stroke treatments. Measures of neuronal and glial damage, such as neuron-specific enolase (NSE), glial fibrillary acidic protein, tau-protein, myelin-basic protein and S100-β are potential candidate biomarkers. <i>Aim:</i> We systematically reviewed the relevant literature to find studies that correlated blood levels of neuronal and glial damage markers with imaging measures of infarct volume. <i>Methods:</i> We identified studies with a comprehensive search of databases and the reference lists of relevant studies. We included studies that: (1) measured the highest level, or area under the curve (AUC) over time of markers of cerebral damage, (2) calculated infarct volume, and (3) correlated the two measures. <i>Results:</i> Seventeen studies met the criteria for the systematic review. There were sufficient data to provide summary estimates for S100-β and NSE. The peak level and AUC over time of both markers correlated with subacute infarct volume. Measurements of S100-β later than 24 h after stroke were better correlated with subacute infarct size than earlier measurements. However, scan times varied, and none was later than 8 days after stroke. <i>Conclusion:</i> Peak and AUC levels of NSE and S100-β levels correlated with subacute infarct volume. Correlations of S100-β with infarct volume were stronger when measured after 24 h than closer to admission. Exploratory studies within clinical trials are necessary before blood markers of cerebral tissue damage can be recommended as surrogate endpoints.
DOI: 10.6084/m9.figshare.5122927.v1
title: Supplementary Material for: Missing Heritability in the Tails of Quantitative Traits? A Simulation Study on the Impact of Slightly Altered True Genetic Models

description: <i>Objective:</i> Genome-wide association studies have identified robust associations between single nucleotide polymorphisms and complex traits. As the proportion of phenotypic variance explained is still limited for most of the traits, larger and larger meta-analyses are being conducted to detect additional associations. Here we investigate the impact of the study design and the underlying assumption about the true genetic effect in a bimodal mixture situation on the power to detect associations. <i>Methods:</i> We performed simulations of quantitative phenotypes analysed by standard linear regression and dichotomized case-control data sets from the extremes of the quantitative trait analysed by standard logistic regression. <i>Results:</i> Using linear regression, markers with an effect in the extremes of the traits were almost undetectable, whereas analysing extremes by case-control design had superior power even for much smaller sample sizes. Two real data examples are provided to support our theoretical findings and to explore our mixture and parameter assumption. <i>Conclusions:</i> Our findings support the idea to re-analyse the available meta-analysis data sets to detect new loci in the extremes. Moreover, our investigation offers an explanation for discrepant findings when analysing quantitative traits in the general population and in the extremes.
DOI: 10.6084/m9.figshare.5122912
title: Supplementary Material for: Gastric Wash-Based Molecular Testing for Antibiotic Resistance in <i>Helicobacter pylori</i>

description: <i>Background:</i> A number of noninvasive tests have been developed to establish the presence of <i>Helicobacter pylori</i> infection. However, thus far these tests have only been capable of detecting its presence. An increasing number of antibiotic-resistant <i>H. pylori</i> infections have been reported and they are known to be correlated with 23S rRNA single nucleotide polymorphisms (SNPs). We hypothesized that genomic analysis of <i>H. pylori</i> recovered from gastric washes could not only be less invasive, but also useful as a screening test and for assessing the outcome of eradication therapy. <i>Methods:</i> Biopsy specimens and gastric washes were collected from 100 patients during endoscopic examination. Then we analyzed 23S rRNA, <i>ureA</i>, and <i>cagA</i> genes using PCR and high-throughput pyrosequencing analysis. <i>Results:</i> Forty-five percent (44/97) of patients tested positive for <i>ureA</i> and 42.3% (41/97) tested positive by a rapid urease test. One hundred percent (35/35) of patients who tested positive by both methods were observed to have the <i>cagA</i> gene. Among these 35 patients, 23S rRNA SNPs were present in 34.3% (12/35). <i>Conclusions:</i> Gastric wash-based PCR and a pyrosequencing assay were used to rapidly detect and estimate the number of 23S rRNA SNPs in clinical isolates of <i>H. pylori</i>. Not only is this a less invasive technique, but it can also diagnose drug resistance.
DOI: 10.6084/m9.figshare.5122918.v1
title: Supplementary Material for: Characteristics of Spinal Cord Stroke in Clinical Neurology

description: Spinal cord stroke accounts for about 0.3% of all strokes in our department. Thirty-two patients (15 males, 17 females; mean age 63.3 years) treated in the period 1995–2010 were included. Patients underwent thorough investigation including the use of different stroke scales (National Institute of Health Stroke Scale, Barthel Index and modified Rankin Scale). Twenty-eight patients had infarctions, 3 had hemorrhages, and 1 had arterio-venous fistula. Twenty-eight spinal cord strokes were spontaneous, 2 were secondary to aorta aneurysms, and 2 post surgery. Biphasic ictus was seen in 17% of all spontaneous infarctions. Younger age, male gender, hypertension, diabetes mellitus, and higher blood glucose on admission regardless of diabetes mellitus, were risk factors associated with more severe spinal cord stroke. Treatment and prevention of these risk factors should be essential in spinal cord stroke. We recommend a clinical classification into upper (cervical) and lower (thoracic or medullary conus) spinal cord strokes. Patients with upper strokes in this study had more severe strokes initially, but they had a better prognosis. Therefore it is important to identify this patient group.Acute sensory spinal cord deficit symptoms, common initial symptoms in biphasic spinal cord strokes, should be considered as possible spinal cord stroke, especially when preceded by radiating pain between the shoulders.
DOI: 10.6084/m9.figshare.5122921.v1
title: Supplementary Material for: Endothelial Dysfunction of the Peripheral Vascular Bed in the Acute Phase after Ischemic Stroke

description: <i>Background:</i> Endothelial dysfunction (ED) is relevant for the development of cerebrovascular and cardiovascular diseases. Asymmetric dimethylarginine (ADMA) competes with <i>L</i>-arginine and has been implicated in the development of ED. Increased levels of ADMA have been found in chronic heart failure (CHF). We hypothesized that peripheral ED in acute ischemic stroke is associated with increased ADMA levels. <i>Methods:</i> We evaluated 60 patients with acute stroke in the territory of the middle cerebral artery. Stroke patients were classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. We compared these patients with patients of similar age without known cardiovascular disease (negative controls, n = 23) and patients with stable, ambulatorily treated CHF (n = 46, left ventricular ejection fraction = 33.8 ± 10.9) with known ED (positive controls). Peripheral endothelial function was assessed by EndoPAT2000 technology using the reactive hyperemia index (RHI). <i>Results:</i> RHI was significantly decreased in stroke and in CHF compared to controls (1.8 ± 0.3 vs. 1.8 ± 0.4 vs. 2.2 ± 0.4, respectively, ANOVA p = 0.01). A decreased RHI was observed in cardioembolic and lacunar infarcts and stroke of undetermined etiology (1.7 ± 0.4, 1.8 ± 0.5 and 1.7 ± 0.3, p &lt; 0.0001). The <i>L</i>-arginine/ADMA ratio was significantly decreased in stroke and in CHF (147.6 ± 31.7 and 126.1 ± 37.9 vs. controls: 161.5 ± 26.1, p &lt; 0.0001) and was lowest in stroke patients in the cardioembolic group (133.0 ± 29.4, p &lt; 0.0001). A lower <i>L</i>-arginine/ADMA ratio was associated with ED in cardioembolic stroke and CHF (r = 0.324, p &lt; 0.05 and r = 0.429, p &lt; 0.0001). <i>Conclusion:</i> Peripheral ED occurs to a similar degree in acute ischemic stroke and CHF. The impaired vasodilator capacity of peripheral arteries reflects the TOAST classification. ADMA may play a role in ED in both acute ischemic stroke and CHF.
DOI: 10.6084/m9.figshare.5122906
title: Supplementary Material for: A Lentiviral CXCR4 Overexpression and Knockdown Model in Colorectal Cancer Cell Lines Reveals Plerixafor-Dependent Suppression of SDF-1α-Induced Migration and Invasion

description: <i>Background:</i> The development of distant metastasis is associated with poor outcome in patients with colorectal cancer (CRC). The stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) have pivotal roles in the chemotaxis of migrating tumor cells during metastasis. Thus, hampering the SDF-1/CXCR4 cross-talk is a promising strategy to suppress metastasis. <i>Methods:</i> We investigated the invasive behavior of the lentivirally CXCR4overexpressing CRC cell lines SW480, SW620 and RKO in chemotaxis and invasion assays toward an SDF-1α gradient. Low endogenous CXCR4 expression levels were determined by quantitative realtime polymerase chain reaction (PCR) and fluorescence-activated cell sorting (FACS) analyses. <i>Results:</i> A lentiviral CXCR4 overexpression and knockdown model was established in these CRC cells. In transwell migration assays, CXCR4 overexpression favored chemotaxis and invasion of cells in all 3 lines depending on an SDF-1α gradient (p &lt; 0.001 vs. untransduced cells). Functional CXCR4 knockdown using lentiviral short hairpin RNA (shRNA) vectors significantly decreased the migration behavior in CRC cell lines (p &lt; 0.001), confirming a CXCR4-specific effect. Pharmacologic inhibition of the SDF-1α/CXCR4 interaction by the bicyclam Plerixafor<sup>TM</sup> at 100 µM significantly abrogated CXCR4-dependent migration and invasion through Matrigel<sup>TM</sup> (SW480, SW620, RKO; p &lt; 0.05). Conclusion: Our results indicate that a CXCR4-antagonistic therapy might prevent tumor cell dissemination and metastasis in CRC patients, consequently improving survival.
DOI: 10.6084/m9.figshare.5122909
title: Supplementary Material for: Zur Wirksamkeit pharmakologischer und psychotherapeutischer Therapien bei Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) im Erwachsenenalter: Eine empirische Metaanalyse

description: Verlaufsstudien über die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) dokumentieren eine Persistenz von Kardinalsymptomen in ca. 1/3 der Fälle bis ins Erwachsenenalter. Somit stellt sich die Frage der Wirksamkeit der gängigen ADHS-Therapien für Erwachsene. Zur Beantwortung dieser Frage werden die Ergebnisse einer empirischen Metaanalyse vorgestellt. Einbezogen wurden 12 Wirksamkeitsstudien über psychotherapeutische Interventionen sowie 43 pharmakologische Studien. Im Ergebnis wurde für die psychotherapeutischen Studien eine gewichtete gemittelte Effektstärke von 0,84 (Konfidenzintervall 95%: 0,64–1,04) berechnet und für die pharmakologischen Behandlungsformen eine gewichtete gemittelte Effektgröße von 0,44 (Konfidenzintervall 95%: 0,37–0,50). Die Ergebnisse werden kritisch, unter Berücksichtigung methodischer (z.B. Einsatz unterschiedlicher Messinstrumente, unterschiedliche abhängige Variablen) und weiterführender inhaltlicher Gesichtspunkte, diskutiert.
DOI: 10.6084/m9.figshare.5122912.v1
title: Supplementary Material for: Gastric Wash-Based Molecular Testing for Antibiotic Resistance in <i>Helicobacter pylori</i>

description: <i>Background:</i> A number of noninvasive tests have been developed to establish the presence of <i>Helicobacter pylori</i> infection. However, thus far these tests have only been capable of detecting its presence. An increasing number of antibiotic-resistant <i>H. pylori</i> infections have been reported and they are known to be correlated with 23S rRNA single nucleotide polymorphisms (SNPs). We hypothesized that genomic analysis of <i>H. pylori</i> recovered from gastric washes could not only be less invasive, but also useful as a screening test and for assessing the outcome of eradication therapy. <i>Methods:</i> Biopsy specimens and gastric washes were collected from 100 patients during endoscopic examination. Then we analyzed 23S rRNA, <i>ureA</i>, and <i>cagA</i> genes using PCR and high-throughput pyrosequencing analysis. <i>Results:</i> Forty-five percent (44/97) of patients tested positive for <i>ureA</i> and 42.3% (41/97) tested positive by a rapid urease test. One hundred percent (35/35) of patients who tested positive by both methods were observed to have the <i>cagA</i> gene. Among these 35 patients, 23S rRNA SNPs were present in 34.3% (12/35). <i>Conclusions:</i> Gastric wash-based PCR and a pyrosequencing assay were used to rapidly detect and estimate the number of 23S rRNA SNPs in clinical isolates of <i>H. pylori</i>. Not only is this a less invasive technique, but it can also diagnose drug resistance.