67 research outputs found
Inflammation, fibrosis and skeletal muscle regeneration in LGMDR9 are orchestrated by macrophages
Aims: Variable degrees of inflammation, necrosis, regeneration and fibrofatty replacement are part of the pathological spectrum of the dystrophic process in alpha dystroglycanopathy LGMDR9 (FKRP-related, OMIM #607155), one of the most prevailing types of LGMDs worldwide. Inflammatory processes and their complex interplay with vascular, myogenic and mesenchymal cells may have a major impact on disease development. The purpose of our study is to describe the specific immune morphological features in muscle tissue of patients with LGMDR9 to enable a better understanding of the phenotype of muscle damage leading to disease progression.
Methods: We have analysed skeletal muscle biopsies of 17 patients genetically confirmed as having LGMDR9 by histopathological and molecular techniques.
Results: We identified CD206+ MHC class II+ and STAT6+ immune-repressed macrophages dominating the endomysial infiltrate in areas of myofibre regeneration and fibrosis. Additionally, PDGFRβ+ pericytes were located around MHC class II+ activated capillaries residing in close proximity to areas of fibrosis and regenerating fibres. Expression of VEGF was found on many regenerating neonatal myosin+ fibres, myofibres and CD206+ macrophages also co-expressed VEGF.
Conclusion: Our results show characteristic immune inflammatory features in LGMDR9 and more specifically shed light on the predominant role of macrophages and their function in vascular organisation, fibrosis and myogenesis. Understanding disease-specific immune phenomena potentially inform about possibilities for anti-fibrotic and anti-inflammatory therapeutic strategies, which may complement Ribitol replacement and gene therapies for LGMDR9 that may be available in the future
Interpreting the Tinnitus Questionnaire (German version): what individual differences are clinically important?
Objective: Reporting of clinical significance is recommended because findings can be statistically significant without being relevant to patients. For aiding clinical interpretation of the Tinnitus Questionnaire (TQ), many investigators use a 5-point change cut-off as a minimal clinically important difference (MCID). But there are shortcomings in how this value was originally determined. Design: The MCID was evaluated by analysing retrospective clinical data on the TQ (German version). Following recommended standards, multiple estimates were computed using anchor- and distribution-based statistical methods. These took into account not only patients’ experience of clinical improvement, but also measurement reliability. Study sample: Pre- and post-intervention scores were assessed for 202 patients. Results: Our six estimates ranged from 5 to 21 points in TQ change score from pre- to post- intervention. The 5-point TQ change score was obtained using a method that considered change between groups, and did not account for measurement error or bias. The size of the measurement error was considerable, and this comprises interpretation of individual patient change scores. Conclusions: To enhance confidence that a TQ change over time in individual patients is clinically meaningful, we advise at least the median MCID of 12 points
Krüppel-like factor 15 regulates BMPER in endothelial cells
Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. Previous studies have shown that BMP endothelial cell precursor-derived regulator (BMPER) plays an important role in endothelial cell function and blood vessel formation. BMPER is a key regulator of BMP4 activity and a prerequisite for BMP pathway activation by BMP4 in endothelial cells. Here, we characterize the BMPER promoter and elucidate mechanisms of BMPER regulation
The intracellular detection of MIP-1beta enhances the capacity to detect IFN-gamma mediated HIV-1-specific CD8 T-cell responses in a flow cytometric setting providing a sensitive alternative to the ELISPOT
<p>Abstract</p> <p>Background</p> <p>T-cell mediated immunity likely plays an important role in controlling HIV-1 infection and progression to AIDS. Several candidate vaccines against HIV-1 aim at stimulating cellular immune responses, either alone or together with the induction of neutralizing antibodies, and assays able to measure CD8 and CD4 T-cell responses need to be implemented. At present, the IFN-γ-based ELISPOT assay is considered the gold standard and it is broadly preferred as primary assay for detection of antigen-specific T-cell responses in vaccine trials. However, in spite of its high sensitivity, the measurement of the sole IFN-γ production provides limited information on the quality of the immune response. On the other hand, the introduction of polychromatic flow-cytometry-based assays such as the intracellular cytokine staining (ICS) strongly improved the capacity to detect several markers on a single cell level.</p> <p>Results</p> <p>The cumulative analysis of 275 samples from 31 different HIV-1 infected individuals using an ICS staining procedure optimized by our laboratories revealed that, following antigenic stimulation, IFN-γ producing T-cells were also producing MIP-1β whereas T-cells characterized by the sole production of IFN-γ were rare. Since the analysis of the combination of two functions decreases the background and the measurement of the IFN-γ+ MIP-1β+ T-cells was equivalent to the measurement of the total IFN-γ+ T-cells, we adopted the IFN-γ+ MIP-1β+ data analysis system to evaluate IFN-γ-based, antigen-specific T-cell responses. Comparison of our ICS assay with ELISPOT assays performed in two different experienced laboratories demonstrated that the IFN-γ+ MIP-1β+ data analysis system increased the sensitivity of the ICS up to levels comparable to the sensitivity of the ELISPOT assay.</p> <p>Conclusion</p> <p>The IFN-γ+ MIP-1β+ data evaluation system provides a clear advantage for the detection of low magnitude HIV-1-specific responses. These results are important to guide the choice for suitable highly sensitive immune assays and to build reagent panels able to accurately characterize the phenotype and function of responding T-cells. More importantly, the ICS assay can be used as primary assay to evaluate HIV-1-specific responses without losing sensitivity in comparison to the ELISPOT assay.</p
ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling
Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.ope
Regionale Standards: Ausgabe 2013
"Die 'Regionalen Standards' gehen zurück auf die Initiative eines gemeinsamen Arbeitskreises, bestehend aus Vertretern des Statistischen Bundesamtes, der Arbeitsgemeinschaft Sozialwissenschaftlicher Institute e.V. (ASI) und des ADM Arbeitskreis Deutscher Markt- und Sozialforschungsinstitute e.V. Sie stellen ein Angebot für die Forschung in der Bundesrepublik Deutschland dar. Die 'Regionalen Standards' beschreiben Gebietsabgrenzungen und Instrumente zur Typisierung von Regionen, wie sie in der Bundesrepublik Deutschland von der amtlichen Statistik und/oder der Markt- und Sozialforschung in gewisser Regelmäßigkeit eingesetzt werden. Zusätzlich werden Datensätze aus unterschiedlichen Quellen vorgestellt, die für die Regionalisierung von Bevölkerungsumfragen genutzt werden können und für die Forschung (teils jedoch mit
Einschränkungen) zur Verfügung stehen. Ergänzt werden die 'Regionalen Standards' durch eine jährlich aktualisierte Tabellenanalyse aus dem Mikrozensus, zu beziehen über die Internetseiten www.destatis.de, www.gesis.org und www.adm-ev.de." (Autorenreferat
The Prospects of the Baby Boomers: Methodological Challenges in Projecting the Lives of an Aging Cohort
Lohnzurueckhaltung und gewerkschaftliche Vernunft: d. polit. Oekonomie d. Arbeitsmarktes in d. Bundesrepublik Deutschland d. 60er Jahre
SIGLEAvailable from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel C 155675 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman
mTOR-induced pneumonitis in a 72-year-old patient after heart transplantation
History A 72-year-old heart transplant recipient presented to the hospital with progressive dyspnea. His immunosuppressive therapy was switched to the mTOR-inhibitor everolimus. A few months before, due to a progressive decline in renal function. Primarily, a community-acquired pneumonia was suspected and an empiric antibiotic therapy was initiated. Despite antimicrobial treatment, an acute respiratory distress syndrome developed and mechanical ventilation became necessary. Investigations During the following extensive diagnostic a transbronchial lung biopsy was performed and histological analysis revealed a drug induced lung injury. Diagnosis Based on the clinical and histological findings an everolimus induced pneumonitis was suspected. Treatment and course The drug was immediately discontinued and a high-dose steroid treatment was started, resulting in a significant improvement of respiratory function. Conclusion Everolimus-related interstitial pneumonitis represents a rare but important adverse effect of everolimus in immunosuppressed patients. Recognition of everolimus induced pneumonitis is of high clinical relevance and should be considered in all patients on everolimus presenting with respiratory symptoms of unknown origin
Histological Diagnosis of Atypical Takayasu Arteritis Using Percutaneous Transluminal Atherectomy
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