Konsumenten als nationale Systembauer:: Deutsche und niederländische Radfahrerverbände im Vergleich, 1900–1940

Consumers and national System-builder: Comparing German and Dutch cyclists‘ unions, 1900–1940 This article explores the variability and the limits of the political in regard to cyclists‘ unions in Germany and the Netherlands between 1900 and 1940. In both countries, cyclists formed national consumer organizations, mixing consumer demands with social and even political implications. The Dutch Cyclists‘ Union managed to establish herself as an eminent political actor and „system builder“ with lasting impact on traffic legislation and road construction. While liberals were loosing the political majority in Dutch parliament, the Cyclists‘ Union became a stronghold of Dutch liberalism outside the narrow confines of the old institutionalized political arena. In contrast, German cyclists‘ dreams of opening up social elites and fostering social and political change through the bicycle were shattered. The bicycle, which had started off as a luxury good in the 1890s and had become a common means of transport by the 1920s, was more suitable for political communications „from top to bottom“. Old liberal elites in the Netherlands were quite successful in making use of this consumer object in order to reformulate their existing claims to power and create new realms of the political. A transformation of social and political conditions, „from the bottom up“, as it was hoped for by part of the German cyclists‘ movement, however, turned out to be utopian

Editorial — Business and Human Rights: Taking Stock of Trends in International Governance and Domestic Litigation

Business and Human Rights: Taking Stock of Trends in International Governance and Domestic Litigation (Editorial

a versatile tool for the analysis and integrative visualization of DNA copy number variants

Background The analysis of DNA copy number variants (CNV) has increasing impact in the field of genetic diagnostics and research. However, the interpretation of CNV data derived from high resolution array CGH or NGS platforms is complicated by the considerable variability of the human genome. Therefore, tools for multidimensional data analysis and comparison of patient cohorts are needed to assist in the discrimination of clinically relevant CNVs from others. Results We developed GenomeCAT, a standalone Java application for the analysis and integrative visualization of CNVs. GenomeCAT is composed of three modules dedicated to the inspection of single cases, comparative analysis of multidimensional data and group comparisons aiming at the identification of recurrent aberrations in patients sharing the same phenotype, respectively. Its flexible import options ease the comparative analysis of own results derived from microarray or NGS platforms with data from literature or public depositories. Multidimensional data obtained from different experiment types can be merged into a common data matrix to enable common visualization and analysis. All results are stored in the integrated MySQL database, but can also be exported as tab delimited files for further statistical calculations in external programs. Conclusions GenomeCAT offers a broad spectrum of visualization and analysis tools that assist in the evaluation of CNVs in the context of other experiment data and annotations. The use of GenomeCAT does not require any specialized computer skills. The various R packages implemented for data analysis are fully integrated into GenomeCATs graphical user interface and the installation process is supported by a wizard. The flexibility in terms of data import and export in combination with the ability to create a common data matrix makes the program also well suited as an interface between genomic data from heterogeneous sources and external software tools. Due to the modular architecture the functionality of GenomeCAT can be easily extended by further R packages or customized plug-ins to meet future requirements

A Photoreceptor Contributes to the Natural Variation of Diapause Induction in Daphnia magna

Diapause is an adaptation that allows organisms to survive harsh environmental conditions. In species occurring over broad habitat ranges, both the timing and the intensity of diapause induction can vary across populations, revealing patterns of local adaptation. Understanding the genetic architecture of this fitness-related trait would help clarify how populations adapt to their local environments. In the cyclical parthenogenetic crustacean Daphnia magna, diapause induction is a phenotypic plastic life history trait linked to sexual reproduction, as asexual females have the ability to switch to sexual reproduction and produce resting stages, their sole strategy for surviving habitat deterioration. We have previously shown that the induction of resting stage production correlates with changes in photoperiod that indicate the imminence of habitat deterioration and have identified a Quantitative Trait Locus (QTL) responsible for some of the variation in the induction of resting stages. Here, new data allows us to anchor the QTL to a large scaffold and then, using a combination of a new mapping panel, targeted association mapping and selection analysis in natural populations, to identify candidate genes within the QTL. Our results show that variation in a rhodopsin photoreceptor gene plays a significant role in the variation observed in resting stage induction. This finding provides a mechanistic explanation for the link between diapause and day-length perception that has been suggested in diverse arthropod taxa

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2-mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven by tet methylcytosine dioxygenase 2 (Tet2) mutations and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which was associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and replication protein A complex. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies

End-of-life decisions in acute stroke patients: an observational cohort study

Background: Crucial issues of modern stroke care include best practice end-of-life-decision (EOLD)-making procedures and the provision of high-quality palliative care for dying stroke patients. Methods: We retrospectively analyzed records of those patients who died over a 4-year period (2011–2014) on our Stroke Unit concerning EOLD, focusing on the factors that most probably guided decisions to induce limitation of life-sustaining therapy and subsequently end-of-life-care procedures thereafter. Results: Of all patients treated at our Stroke Unit, 120 (2.71 %) died. In 101 (86.3 %), a do-not-resuscitate-order (DNRO) was made during early treatment. A decision to withdraw/withhold further life supportive therapy was made in 40 patients (34.2 %) after a mean of 5.0 days (range 0–29). Overall patient death occurred after a mean time of 7.0 days (range 1–30) and 2.6 days after therapy restrictions. Disturbance of consciousness at presentation, dysphagia on day 1 and large supratentorial stroke were possible indicators of decisions to therapeutic withdrawing/withholding. Proceedings of EOL care in these patients were heterogeneous; in most cases monitoring (95 %), medical procedures (90 %), oral medication (88 %), parenteral nutrition (98 %) and antibiotic therapy (86 %) were either not ordered or withdrawn, however IV fluids were continued in all patients. Conclusions: A high percentage of stroke patients were rated as terminally ill and died in the course of caregiving. Disturbance of consciousness at presentation, dysphagia on day 1 and large supratentorial stroke facilitated decisions to change therapeutic goals thus initiating end-of-life-care. However, there is further need to foster research on this field in order to ameliorate outcome prognostication, to understand the dynamics of EOLD-making procedures and to educate staff to provide high-quality patient-centred palliative care in stroke medicine

Autologous tenocyte injection for the treatment of chronic recalcitrant gluteal tendinopathy: A prospective pilot study

Background: Gluteal tendinopathy is a common cause of lateral hip pain, and existing conservative treatment modalities demonstrate high symptom recurrence rates. Autologous tenocyte injection (ATI) is a promising cell therapy that may be useful for the treatment of gluteal tendinopathy. Purpose: To investigate the safety and effectiveness of ATI, specifically in patients with chronic recalcitrant gluteal tendinopathy. Study Design: Case series; Level of evidence, 4. Methods: Twelve female patients with a clinical and radiological diagnosis of gluteal tendinopathy were recruited. Patients demonstrated a mean duration of symptoms of 33 months (range, 6-144 months), had undergone a mean 3.2 prior corticosteroid injections (range, 2-5), and had failed to respond to existing conservative treatments including physiotherapy and injections. In an initial procedure, tendon cells were harvested from a needle biopsy of the patella tendon and propagated in a certified Good Manufacturing Practice (GMP) laboratory. In a secondary procedure, a single injection of 2 mL autologous tenocytes (2-5 x 106 cells/mL) suspended in patient serum was injected into the site of the pathological gluteal tendons under ultrasound guidance. Patients were assessed preand postinjection (3, 6, 12, and 24 months) using the Oxford Hip Score (OHS), a visual analog pain scale (VAS), the Short Form-36 (SF-36), and a satisfaction scale. Magnetic resonance imaging (MRI) was undertaken at 8.7 months (range, 6-12 months) postinjection. Results: Molecular characterization of autologous tendon cells showed a profile of growth factor production in all cases, including platelet-derived growth factor a, fibroblast growth factor ß, and transforming growth factor ß. The OHS (mean, 24.0 preinjection to 38.9 at 12 months [14.9-point improvement]; 95% CI, 10.6-19.2; P <.001), VAS (mean, 7.2 preinjection to 3.1 at 12 months [4.1-point improvement]; 95% CI, 2.6-5.6; P <.001), and SF-36 (mean, 28.1 preinjection to 43.3 at 12 months [15.2-point improvement]; 95% CI, 9.8-20.5; P <.001) significantly improved to 12 months postinjection, sustained to 24 months. Eight patients were satisfied with their outcomes. Significant MRI-based improvement could not be demonstrated in the majority of cases. Conclusion: ATI for gluteal tendinopathy is safe, with improved and sustained clinical outcomes to 24 months

A Prevalence Estimation of Exstrophy and Epispadias in Germany From Public Health Insurance Data

Introduction: The prevalence of rare diseases is very important for health care research. According to the European Surveillance of Congenital Anomalies (EUROCAT) registers, the live prevalence for exstrophy and/or epispadias (grades 1–3) is reported with 1:23,255 (95% CI: 1:26,316; 1:20,000). A Europe-wide prevalence evaluation based on reports from excellence centers estimates a prevalence for exstrophies of 1:32,200 and for isolated epispadias of 1:96,800 in 2010. However, the frequency of exstrophy [International Statistical Classification of Diseases and Related Health Problems revision 10 (ICD-10): Q64.1] and epispadias (ICD-10: Q64.0) treated in different age groups in Germany remains unclear. Material and Method: Public health insurance data from 71 million people (approximately 87% of the population) were provided by the German Institute for Medical Documentation and Information (DIMDI) in accordance to the German Social Insurance Code for this research purpose. DIMDI analyzed the data source for the ICD diagnoses exstrophy and epispadias between 2009 and 2011. As provided data were robust over the years, averaged data are mentioned. Detailed subgroup analysis of small numbers was forbidden due to privacy protection. Results: Annually, 126 persons of all ages with epispadias and 244 with exstrophy are treated as inpatients. In the observed population, 34 infants (<1 year of age) with epispadias and 19 with exstrophy (58% male) are treated as outpatients each year. This corresponds to an estimated live prevalence of 1:11,000 (95% CI: 1:14,700; 1:8,400) for EEC (exstrophy–epispadias complex), more specifically a prevalence of 1:17,142 for epispadias and of 1:30,675 for exstrophy. The male-to-female ratio for exstrophy is 1.4:1 for infants and 1.6:1 for all minors. In children and adolescents, 349 epispadias and 393 exstrophies (up to the age of 17) are treated annually, whereas adults with exstrophy and even more with epispadias make comparatively less use of medical care. Conclusion: With the help of DIMDI data, the live prevalence of bladder exstrophy and epispadias in Germany could be estimated. The prevalence of epispadias was higher than in previous reports, in which milder epispadias phenotypes (grade 1 or 2) may not have been included. These analyses might enlighten knowledge about nationwide incidence and treatment numbers of rare diseases such as the EEC