H-Diplo Roundtable XXI-28 on Tworek. News from Germany: the competition to control world communications, 1900-1945

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Hildesheimer Geographische Studien, Band 5

In diesem Band enthalten: Hannah Graen, Robin Stadtmann & Martin Sauerwein: Modellierung von Temperaturdaten und Temperaturveränderungen im Nationalpark Asinara, Sardinien (S. 1-27); Sarah Matheis, Nico Herrmann & Martin Sauerwein: Entwicklung eines Monitoringkonzeptes für Niedermoore am Beispiel des Bergen-Weißacker Moores, Süd-Brandenburg (S. 28-63); Martin Sauerwein, Jan-Philip Dieck & Robin Stadtmann: Urbane Böden im Kontext von Ecosystem Services (S. 64-89); Martin Sauerwein, Julia Jaquemotte & Lars Germershausen: Ursachen der Nitratbelastung des Grundwassers im Raum Hannover/Hildesheim (S. 90-110); Sabine Panzer-Krause: Einkaufen in der Hildesheimer Innenstadt. Auswirkungen der Arneken Galerie auf den innerstädtischen Einzelhandel (S. 111-132); Robin Stadtmann, Nico Herrmann, Jasmin Karaschewski & Martin Sauerwein: Bodenbewusstsein: Hildesheimer Aktivitäten zum Jahr des Bodens 2015 (S. 133-140

Mechanisms Underlying Metabolic and Neural Defects in Zebrafish and Human Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)

In humans, mutations in electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH) lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. These results show that mitochondrial dysfunction, leading to an increase in aerobic glycolysis, affects neurogenesis through the PPARG-ERK pathway, a potential target for therapeutic intervention

High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types

OBJECTIVE: To retrospectively determine the frequency of N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia. METHODS: Clinical characterization of 660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age-matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients. RESULTS: Serum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with “unclassified dementia” followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson’s disease-related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA-associated cognitive decline. INTERPRETATION: Serum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy

Outcomes and Satisfaction After Delivery of a Breast Cancer Survivorship Care Plan: Results of a Multicenter Trial

Survivorship care plans (SCPs) have been suggested to reduce fragmentation of care experienced by cancer survivors. Acceptance of SCPs is high, but trials in the United States are few. This pilot study used a quasiexperimental design to examine the outcomes achieved by breast cancer survivors receiving a standardized SCP visit at one of seven comprehensive cancer centers

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

The role of complement in antibody mediated transplant rejection

International audienceAntibody mediated transplant rejection (AMR) is a major cause of long-term allograft failure, and currently available treatments are of limited efficacy for treating the disease. AMR is caused by donor specific antibodies (DSA) that bind to antigens within the transplanted organ. DSA usually activate the classical pathway of complement within the allograft, and complement activation is believed to be an important cause of tissue injury in AMR. Several new clinical assays may improve our ability to identify patients at risk of AMR. Complement inhibitory drugs have also been tested in selected patients and in small series. Better understanding of the role of complement activation in the pathogenesis of AMR will likely improve our ability to diagnose the disease and to develop novel treatments

Predicting interactome networks perturbations in human cancer: application to gene fusions in acute lymphoblastic leukemia.

Genomic variations such as point mutations and gene fusions are directly or indirectly associated with human diseases. They are recognized as diagnostic, prognostic markers and therapeutic targets. However, predicting the functional impact of these genetic alterations beyond affected genes and their products is challenging because diseased phenotypes are likely dependent of complex molecular interaction networks. Using as models three different chromosomal translocations ETV6-RUNX1 (TEL-AML1), BCR-ABL1, and TCF3-PBX1 (E2A-PBX1), frequently found in precursor-B cell acute lymphoblastic leukemia (preB-ALL), we develop an approach to extract perturbed molecular interactions from gene expression changes. We show that the MYC and JunD transcriptional circuits are specifically deregulated following ETV6-RUNX1 and TCF3-PBX1 gene fusions, respectively. We also identified the bulk mRNA NXF1-dependent machinery as a direct target for the TCF3-PBX1 fusion protein. Through a novel approach combining gene expression and interactome data analysis, we provide new insight into TCF3-PBX1 and ETV6-RUNX1 acute lymphoblastic leukemia.Perturbations of interactome network in acute lymphoblastic leukemi

Glomerular C3 Deposition Is an Independent Risk Factor for Allograft Failure in Kidney Transplant Recipients With Transplant Glomerulopathy

Introduction: Transplant glomerulopathy (TG) becomes increasingly prevalent in kidney transplant recipients over time, and it is strongly associated with allograft failure. To date, our prognostic biomarkers and understanding of the processes of immunologic injury in TG are limited. Methods: This is a retrospective cohort analysis of kidney transplant recipients with TG (double contours of the glomerular basement membrane as defined by the chronic glomerulopathy score). Glomerular deposition of the complement protein C3 was determined, and its association with allograft survival was analyzed by Cox regression analysis. Results: Of the 111 patients with TG, 72 (65%) had allograft failure, with a median follow-up time of 3 years from biopsy diagnosis of TG. C3-positive compared to C3-negative patients did not differ with respect to cause of end-stage renal disease, induction or maintenance immunosuppression, or sensitization. A greater proportion of patients with glomerular C3 deposition developed allograft failure compared to those with no C3 deposition (78% vs. 55%, P = 0.01). C3 deposition was independently associated with allograft failure in multivariate analyses (adjusted hazard ratio [HR] = 1.38, 95% confidence interval [CI] = 1.13−1.69, P = 0.002). There was no association between C4d or C1q deposition and allograft failure. Chronicity score was also associated with allograft failure in multivariate analysis (adjusted HR 1.26, 95% CI 1.12-1.41, P = 0.0001). Conclusion: In this cohort of patients with TG, glomerular C3 deposition was independently associated with a higher risk of allograft failure. These findings identify glomerular C3 as a novel prognostic indicator in patients with TG. Keywords: chronic rejection, complement, glomerulopathy, pathology, transplan

Kidney Transplant Recipients With Primary Membranous Glomerulonephritis Have a Higher Risk of Acute Rejection Compared With Other Primary Glomerulonephritides

Background. Despite being the leading cause of graft failure, there is a lack of published data about the rates of rejection in kidney transplant patients with glomerulonephritis as the cause of end-stage renal disease. Methods. We examined all consecutive adult (>18 years) renal transplant recipients with biopsy-proven native renal glomerular disease who underwent kidney transplant between 1994 and 2013. Glomerulonephritis groups included were IgA nephropathy (IgAN) (N = 306), focal segmental glomerulosclerosis (FSGS) (N = 298), membranous nephropathy (MN) (N = 81), and lupus nephritis (LN) (N = 177). Results. In the total cohort of 862 patients, 363 patients had an episode of acute rejection during the follow-up period of 19 years (incidence rate of 7.2% per year). Forty-five of 81 patients with MN had an episode of acute rejection during the follow-up period. Patients with MN had significantly higher incidence of acute rejection (12.1 per 100 person years, P < 0.05) in comparison to IgAN (7.2 per 100 person years), FSGS (7.4 per 100 person years), and LN (7.9 per 100 person years). Patients with MN had 1.9 times higher risk of developing acute rejection after transplant in comparison to IgAN (P < 0.005). In patients with MN, 33 of 45 (73.3%) rejection events were acute cellular rejection, 8 (17.8%) of 45 were acute antibody-mediated rejection and 6 of 45 (13.3%) were combined cellular and antibody-mediated acute rejection. Despite higher rates of acute rejection, 10-year allograft survival was similar in all subgroups. Conclusions. Patients with MN have higher incidence of acute rejection after kidney transplant but have similar 10-year allograft survival in comparison to the other glomerular diseases like IgAN, FSGS, and LN