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Buscher A.K.,University of Duisburg - Essen | Kranz B.,University of Munster | Buscher R.,University of Duisburg - Essen | Hildebrandt F.,Howard Hughes Medical Institute | And 10 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2010

Background and objectives: Mutations in podocyte genes are associated with steroid-resistant nephrotic syndrome (SRNS), mostly affecting younger age groups. To date, it is unclear whether these patients benefit from intensified immunosuppression with cyclosporine A (CsA). The aim of this study was to evaluate the influence of podocyte gene defects in congenital nephrotic syndrome (CNS) and pediatric SRNS on the efficacy of CsA therapy and preservation of renal function. Design, settings, participants, & measurements: Genotyping was performed in 91 CNS/SRNS patients, irrespective of age at manifestation or response to CsA. Results: Mutations were identified in 52% of families (11 NPHS1, 17 NPHS2, 11 WT1, 1 LAMB2, 3 TRPC6). Sixty-eight percent of patients with nongenetic SRNS responded to CsA, most of them achieved complete remission. In contrast, none of the patients with genetic CNS/SRNS experienced a complete remission and only two (17%) achieved a partial response, both affected by a WT1 mutation. Preservation of renal function was significantly better in children with nongenetic disease after a mean follow-up time of 8.6 years (ESRD in 29% versus 71%). Conclusions: The mutation detection rate in our population was high (52%). Most patients with genetic CNS/SRNS did not benefit from CsA with significantly lower response rates compared with nongenetic patients and showed rapid progression to end-stage renal failure. These data strongly support the idea not to expose CNS/SRNS patients with inherited defects related to podocyte function to intensified immunosuppression with CsA. Copyright © 2010 by the American Society of Nephrology.

Dubose S.N.,Jaeb Center for Health Research | Hermann J.M.,University of Ulm | Tamborlane W.V.,Yale University | Beck R.W.,Jaeb Center for Health Research | And 6 more authors.
Journal of Pediatrics | Year: 2015

Objective To examine the current extent of the obesity problem in 2 large pediatric clinical registries in the US and Europe and to examine the hypotheses that increased body mass index (BMI) z-scores (BMIz) are associated with greater hemoglobin A1c (HbA1c) and increased frequency of severe hypoglycemia in youth with type 1 diabetes (T1D). Study design International (World Health Organization) and national (Centers for Disease Control and Prevention/German Health Interview and Examination Survey for Children and Adolescents) BMI references were used to calculate BMIz in participants (age 2-<18 years and ≥1 year duration of T1D) enrolled in the T1D Exchange (n = 11 435) and the Diabetes Prospective Follow-up (n = 21 501). Associations between BMIz and HbA1c and severe hypoglycemia were assessed. Results Participants in both registries had median BMI values that were greater than international and their respective national reference values. BMIz was significantly greater in the T1D Exchange vs the Diabetes Prospective Follow-up (P <.001). After stratification by age-group, no differences in BMI between registries existed for children 2-5 years, but differences were confirmed for 6- to 9-, 10- to 13-, and 14- to 17-year age groups (all P <.001). Greater BMIz were significantly related to greater HbA1c levels and more frequent occurrence of severe hypoglycemia across the registries, although these associations may not be clinically relevant. Conclusions Excessive weight is a common problem in children with T1D in Germany and Austria and, especially, in the US. Our data suggest that obesity contributes to the challenges in achieving optimal glycemic control in children and adolescents with T1D. © 2015 Elsevier Inc.

Wolf G.,University of Greifswald | Aumann N.,University of Greifswald | Michalska M.,University of Greifswald | Bast A.,University of Greifswald | And 5 more authors.
Journal of Endocrinology | Year: 2010

Type 1 diabetes mellitus is characterized by a progressive autoimmune destruction of insulin-producing β cells. Macrophages and T lymphocytes release cytokines, which induce the synthesis of oxygen and nitrogen radicals in the pancreatic islets. The resulting cellular and mitochondrial damage promotes β cell death. β cells are very sensitive to the autoimmune free radical-dependent attack due to their low content of antioxidant enzymes such as glutathione peroxidase and catalase. A focal point of β cell protection should be the control of the mitochondrial redox status, which will result in the preservation of metabolic stimulus-secretion coupling. For this reason, there is a considerable interest in the mitochondrial peroxiredoxin III (PRX III), a thioredoxin-dependent peroxide reductase, which was shown to be able to protect against both oxidative and nitrosative stress. Using the Tet-On-system, we generated stably transfected rat insulinoma cells over- or under-expressing PRX III in a doxycyclin-dependent manner to analyze the effect of increased or decreased amounts of cellular PRX III, following treatment with several stressors. We provide evidence that PRX III protects pancreatic β cells from cell stress induced by accumulation of hydrogen peroxide, or the induction of inducible nitric oxide synthase or caspase-9 and -3 by pro-inflammatory cytokines or streptozotocin. Basal insulin secretion was markedly decreased in cells expressing lower levels of PRX III. We suggest PRX III may be a suitable target for promoting deceleration or even prevention of stress-associated apoptosis in pancreatic β cells and the manifestation of insulin-dependent diabetes mellitus. © 2010 Society for Endocrinology.

Schmudde M.,University of Greifswald | Friebe E.,University of Greifswald | Sonnemann J.,University Childrens Hospital Jena | Beck J.F.,University Childrens Hospital Jena | Broker B.M.,University of Greifswald
Cancer Letters | Year: 2010

Histone deacetylase inhibitors (HDIs) exert direct tumour-toxic activity and sensitise tumour cells for other therapeutic regimens as well as the cytotoxic effects of activated immune cells. However, the HDI suberoylanilide hydroxamic acid (SAHA; vorinostat) interfered with the IL-2 activation of human NK cells and the priming of human tumour-specific T cells. In contrast, NK or T cells which were activated in the absence of HDIs became resistant to their immunosuppressive action. Therefore, as a therapeutic strategy, first the patient's immune system might be stimulated and then HDIs could sensitise the tumours for the attack of the pre-activated immune effector cells. © 2010 Elsevier Ireland Ltd.

Sonnemann J.,University Childrens Hospital Jena | Sonnemann J.,Friedrich - Schiller University of Jena | Gressmann S.,University Childrens Hospital Jena | Becker S.,University Childrens Hospital Jena | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2010

Purpose: It has recently been recognised that anticancer chemotherapy can elicit an immunogenic form of apoptosis characterised by the exposure of calreticulin (CRT) on the surface of dying tumour cells, entailing an immune response that contributes to the therapeutic outcome. CRT exposure has been found to be induced by anthracyclins and oxaliplatin, but not by other proapoptotic antineoplastic agents including etoposide, camptothecin and cisplatin. In this study, we examined the histone deacetylase inhibitor vorinostat for its capability to stimulate CRT exposure in tumour cells. Methods: Childhood tumour cells, i.e. the brain tumour cell lines PFSK and DAOY and the Ewing's sarcoma cell line CADO-ES-1, were treated with vorinostat, and CRT exposure was determined by flow cytometric analysis of CRT immunofluorescence. Combination effects of vorino-stat/TRAIL and vorinostat/bortezomib were also assessed. Results: Vorinostat treatment induced CRT exposure in PFSK and DAOY cells, but not in caspase-8-deficient CADO-ES-1 cells. CRT exposure could be prevented by the pan-caspase inhibitor z-VAD-fmk and by brefeldin A, an inhibitor of Golgi-mediated transport. Conclusion: Vorinostat has the capacity to elicit CRT exposure, suggesting its usefulness as immunogenic antitu-mour agent. © Springer-Verlag 2010.

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