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The National Institutes of Health Stroke Scale (NIHSS) score is the most frequently used score worldwide for assessing the clinical severity of a stroke. Prior research suggested an association between acute symptomatic seizures after stroke and poorer outcome. We determined the frequency of acute seizures after ischemic stroke in a large population-based registry in a central European region between 2004 and 2016 and identified risk factors for acute seizures in univariate and multivariate analyses. Additionally, we determined the influence of seizures on morbidity and mortality in a matched case–control design. Our analysis of 135,117 cases demonstrated a seizure frequency of 1.3%. Seizure risk was 0.6% with an NIHSS score at admission <3 points and increased up to 7.0% with >31 score points. Seizure risk was significantly higher in the presence of acute non-neurological infections (odds ratio: 3.4; 95% confidence interval: 2.8–4.1). A lower premorbid functional level also significantly increased seizure risk (OR: 1.7; 95%CI: 1.4–2.0). Mortality in patients with acute symptomatic seizures was almost doubled when compared to controls matched for age, gender, and stroke severity. Acute symptomatic seizures increase morbidity and mortality in ischemic stroke. Their odds increase with a higher NIHSS score at admission.
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired antimicrobial activity in phagocytic cells. As a monogenic disease affecting the hematopoietic system, CGD is amenable to gene therapy. Indeed in a phase I/II clinical trial, we demonstrated a transient resolution of bacterial and fungal infections. However, the therapeutic benefit was compromised by the occurrence of clonal dominance and malignant transformation demanding alternative vectors with equal efficacy but safety-improved features. In this work we have developed and tested a self-inactivating (SIN) gammaretroviral vector (SINfes.gp91s) containing a codon-optimized transgene (gp91(phox)) under the transcriptional control of a myeloid promoter for the gene therapy of the X-linked form of CGD (X-CGD). Gene-corrected cells protected X-CGD mice from Aspergillus fumigatus challenge at low vector copy numbers. Moreover, the SINfes.gp91s vector generates substantial amounts of superoxide in human cells transplanted into immunodeficient mice. In vitro genotoxicity assays and longitudinal high-throughput integration site analysis in transplanted mice comprising primary and secondary animals for 11 months revealed a safe integration site profile with no signs of clonal dominance.
Recent advances in the diagnostic of myeloproliferative neoplasms (MPNs) discovered CALRETICULIN (CALR) mutations as a major driver in these disorders. In contrast to JAK2 mutations being mainly associated with polycythaemia vera, CALR mutations are only associated with primary myelofibrosis (PMF) and essential thrombocythaemia (ET). CALR mutations are present in the majority of PMF and ET patients lacking JAK2 and MPL mutations. As these CALR mutations are absent from reactive bone marrow (BM) lesions their presence indicates ET or PMF. So far these mutations are detectable only by molecular assays. Their molecular detection is cumbersome because of the great CALR mutation heterogeneity. Therefore, the availability of a simple assay would be of great help. All CALR mutations reported lead to a frameshift generating a new 36 amino-acid C-terminus. We generated a monoclonal antibody (CAL2) to this C-neoterminus by immunizing mice with a representative peptide and compared its performance with Sanger sequencing data in 173 MPNs and other BM diseases. There was a 100% correlation between the molecular and the CAL2 immunohistochemical (IHC) assays. Thus, the detection of CALR mutations by the CAL2 IHC is a specific, sensitive, rapid, simple and low-cost method.
Diese Arbeit trägt dazu bei, die Lutherdarstellung in Lehr- und Schulbüchern der ersten Schulbuchgeneration systematisch zu erschließen. Sie stellt sich der Herausforderung den jeweils spezifischen Akzent der Lutherdarstellung und -konzeption, welcher in den Lehrtexten des Lehrbuchs transportiert wird, herauszuarbeiten und weitergehend im Verbund mit den anderen untersuchten Lehrbüchern auf übergreifende, verbindende und trennende Elemente zu untersuchen. Diese Forschungsarbeit leistet einen Beitrag zur Erschließung Luthers sowie ihrer Art und Intensität in dem Medium des Schulbuchs im Kontext der Aufklärung. Insgesamt werden zehn Werke von acht Autoren im Zeitraum von 1780 bis 1817 untersucht, darunter Schulbücher von Johann Matthias Schröckh, Lorenz von Westenrieder und Jakob Brand.
Observation of enhanced subthreshold K+ production in central collisions between heavy nuclei
(1994)
In the very heavy collision system 197Au+197Au the K+ production process was studied as a function of impact parameter at 1 GeV/nucleon, a beam energy well below the free N-N threshold. The K+ multiplicity increases more than linearly with the number of participant nucleons and the K+/ pi + ratio rises significantly when going from peripheral to central collisions. The measured K+ double differential cross section is enhanced by a factor of 6 compared to microscopic transport calculations if secondary processes (Delta N-->K Lambda N and Delta Delta -->K Lambda N) are ignored.
Background: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma.
Methods: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics.
Results: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on "double-hit" MYC and BCL2 transformed lymphomas.
Conclusions: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.
Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium
(2017)
Um die Lehre an Universitäten maßgeblich zu verbessern, werden neben fachübergreifenden Wei-terbildungs- und Unterstützungsangeboten für Lehrende zunehmend auch fachnahe Weiterbil-dungsangebote gefordert und erprobt. Dieser Beitrag stellt ein Konzept zur Etablierung eines fach-spezifischen Arbeitskreis Hochschuldidaktik vor, in dem die aktive Rolle der MitarbeiterInnen bei der Ausgestaltung von Lehrkonzepten und der Konzipierung von Weiterbildungsangeboten angeregt und die Kommunikation zwischen den Lehrenden eines Fachbereiches gefördert wird. Exemplarisch wird die Entwicklung des „Arbeitskreis Hochschullehre Evangelische Theologie“ an der Goethe-Universität Frankfurt vorgestellt. Darüber hinaus sollen Anregungen gegeben werden, wie die Etablierung ähnlicher Prozesse, die einen ressourcenorientierten Strukturwandel an Fachbereichen anstoßen möchten, gelingen kann. Ziel eines hochschuldidaktischen Arbeitskreises ist es, Lehrende dabei zu unterstützen, Lehre als positive Herausforderung der akademischen Arbeit zu erleben und gemeinsam in einem professionalisierten Rahmen neue Entwicklungen voranzutreiben.
Background: Clinical trial registries increase transparency in medical research by making information and results of planned, ongoing, and completed studies publicly available. However, the registration of clinical trials remains a time-consuming manual task complicated by the fact that the same studies often need to be registered in different registries with different data entry requirements and interfaces.
Objective: This study investigates how Health Level 7 (HL7) Fast Healthcare Interoperability Resources (FHIR) may be used as a standardized format for exchanging and storing clinical trial records.
Methods: We designed and prototypically implemented an open-source central trial registry containing records from university hospitals, which are automatically exported and updated by local study management systems.
Results: We provided an architecture and implementation of a multisite clinical trials registry based on HL7 FHIR as a data storage and exchange format.
Conclusions: The results show that FHIR resources establish a harmonized view of study information from heterogeneous sources by enabling automated data exchange between trial centers and central study registries.
Rationale: Steroid refractory graft-vs-host disease (sr-GvHD) represents a challenging complication after allogeneic hematopoietic cell transplantation (allo-HCT). Intestinal microbiota (IM) diversity and dysbiosis were identified as influencing factors for the development of acute GvHD. Fecal microbiota transfer (FMT) is hypothesized to restore IM dysbiosis, but there is limited knowledge about the significance of FMT in the treatment of sr-GvHD.
Objectives: We studied the effects of FMT on sr-GvHD in allo-HCT patients from two German tertiary clinical centers (n = 11 patients; period: March 2017 until July 2019). To assess safety and clinical efficacy, we analyzed clinical data pre- and post-FMT (day -14 to +30 relative to FMT). Moreover, IM were analyzed in donor samples and in a subset of patients pre- and post-FMT by 16S rRNA sequencing.
Results: Post-FMT, we observed no intervention-associated, systemic inflammatory responses and only minor side effects (5/11 patients: abdominal pain and transformation of peristalsis—each 3/11 and vomiting—1/11). Stool frequencies and volumes were significantly reduced [pre- vs post-FMT (d14): P < .05, respectively] as well as clear attenuation regarding both grading and staging of sr-GvHD was present upon FMT. Moreover, IM analyses revealed an increase of alpha diversity as well as a compositional shifts toward the donor post-FMT.
Conclusions: In our study, we observed positive effects on sr-GVHD after FMT without the occurrence of major adverse events. Although these findings are in line with published data on beneficial effects of FMT in sr-GvHD, further randomized clinical studies are urgently needed to better define the clinical validity including mode of action.