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Frankfurt am Main, Germany

Doring M.,University of Tubingen | Rohrer K.M.,University of Tubingen | Erbacher A.,University of Tubingen | Gieseke F.,Research Institute Childrens Cancer Center Hamburg | And 5 more authors.
Annals of Hematology | Year: 2015

The human leukocyte antigen DR surface expression on CD14+ monocytes reflects the degree to which these cells have been activated. Given the central role monocytes and macrophages play in the immune system, a decreased human leukocyte antigen DR expression on CD14+ monocytes results in a hallmark of altered immune status during systemic inflammatory response syndrome. We hypothesize that human leukocyte antigen DR expression might be similarly altered after hematopoietic stem cell transplantation and during post-transplant complications. Using flow cytometry, this study investigates the human leukocyte antigen DR surface expression of CD14+ monocytes in 30 pediatric and young adult patients up to 1 year after hematopoietic stem cell transplantation. Normal values were derived from a control group of healthy children, adolescents, and young adults. Human leukocyte antigen DR expression decreased significantly prior and during bacterial infection or sepsis. By contrast, human leukocyte antigen DR expression levels were elevated before and at the time of viremia. Human leukocyte antigen DR expression was also elevated during acute graft-versus-host disease. In contrast, the expression was reduced when patients had hepatic veno-occlusive disease. A significant decrease of human leukocyte antigen DR expression was associated with a relapse of the underlying disease and before death. Human leukocyte antigen DR expression on CD14+ monocytes appears to be a promising parameter that might allow identification of patients at risk after hematopoietic stem cell transplantation. © 2014, Springer-Verlag Berlin Heidelberg.

Doring M.,University Hospital of Tuebingen | Cabanillas Stanchi K.M.,University Hospital of Tuebingen | Haufe S.,University Hospital of Tuebingen | Erbacher A.,University Hospital of Tuebingen | And 4 more authors.
Annals of Hematology | Year: 2015

Human leukocyte antigen DR surface expression in “classical” CD14++CD16− (M1), “intermediate” CD14++CD16+ (M2), and “non-classical” CD14+CD16++ (M3) monocytes reflects the activation state of these cells. The full spectrum of monocyte and its function is still unknown. The present pilot study describes the monocyte subpopulations and their human leukocyte antigen DR expression during the post-transplant period as well as during transplant-related adverse events of 30 pediatric patients and young adults with hemato-oncological malignancies and immunodeficiency disorders in comparison to healthy children and young adults. A significant change of the human leukocyte antigen DR expression in all three monocyte subpopulations during the period after bone marrow transplantation depending on the time after transplantation and adverse events could be recognized. Prior to and during sepsis or bacterial infection, a significant decrease in human leukocyte antigen DR expression occurred. A significant increase on CD14++CD16− monocytes could be observed during graft-versus-host disease. The alterations of human leukocyte antigen DR expression on the monocyte subpopulations during adverse events after hematopoietic stem cell transplantation may be a sign of changes in the capacity of these subpopulations. Moreover, human leukocyte antigen DR expression in monocyte subpopulations may be used to monitor treatment responses in these entities. © 2014, Springer-Verlag Berlin Heidelberg.

Heusch P.,University of Duisburg - Essen | Aker S.,University of Duisburg - Essen | Boengler K.,University of Duisburg - Essen | Deindl E.,Ludwig Maximilians University of Munich | And 10 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2010

Our objective was to address the balance of inducible nitric oxide (NO) synthase (iNOS) and arginase and their contribution to contractile dysfunction in heart failure (HF). Excessive NO formation is thought to contribute to contractile dysfunction; in macrophages, increased iNOS expression is associated with increased arginase expression, which competes with iNOS for arginine. With substrate limitation, iNOS may become uncoupled and produce reactive oxygen species (ROS). In rabbits, HF was induced by left ventricular (LV) pacing (400 beats/min) for 3 wk. iNOS mRNA [quantitative real-time PCR (qRT-PCR)] and protein expression (confocal microscopy) were detected, and arginase II expression was quantified with Western blot; serum arginine and myocardial nitrite and nitrate concentrations were determined by chemiluminescence, and protein S-nitrosylation with Western blot. Superoxide anions were quantified with dihydroethidine staining. HF rabbits had increased LV end-diastolic diameter [20.0 ± 0.5 (SE) vs. 17.2 ± 0.3 mm in sham] and decreased systolic fractional shortening (11.1 ± 1.4 vs. 30.6 ± 0.7% in sham; both P < 0.05). Myocardial iNOS mRNA and protein expression were increased, however, not associated with increased myocardial nitrite or nitrate concentrations or protein S-nitrosylation. The serum arginine concentration was decreased (124.3 ± 5.6 vs. 155.4 ± 12.0 μmol/l in sham; P < 0.05) at a time when cardiac arginase II expression was increased (0.06 ± 0.01 vs. 0.02 ± 0.01 arbitrary units in sham; P < 0.05). Inhibition of iNOS with 1400W attenuated superoxide anion formation and contractile dysfunction in failing hearts. Concomitant increases in iNOS and arginase expression result in unchanged NO species and protein S-nitrosylation; with substrate limitation, uncoupled iNOS produces superoxide anions and contributes to contractile dysfunction. Copyright © 2010 the American Physiological Society.

Grunert S.C.,University of Zurich | Grunert S.C.,University Hospital Freiburg | Stucki M.,University of Zurich | Morscher R.J.,University of Zurich | And 17 more authors.
Orphanet Journal of Rare Diseases | Year: 2012

Background: Isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine metabolism caused by mutations in MCCC1 or MCCC2 encoding the α and β subunit of MCC, respectively. The phenotype is highly variable ranging from acute neonatal onset with fatal outcome to asymptomatic adults. Methods. We report clinical, biochemical, enzymatic and mutation data of 88 MCC deficient individuals, 53 identified by newborn screening, 26 diagnosed due to clinical symptoms or positive family history and 9 mothers, identified following the positive newborn screening result of their baby. Results: Fifty-seven percent of patients were asymptomatic while 43% showed clinical symptoms, many of which were probably not related to MCC deficiency but due to ascertainment bias. However, 12 patients (5 of 53 identified by newborn screening) presented with acute metabolic decompensations. We identified 15 novel MCCC1 and 16 novel MCCC2 mutant alleles. Additionally, we report expression studies on 3 MCCC1 and 8 MCCC2 mutations and show an overview of all 132 MCCC1 and MCCC2 variants known to date. Conclusions: Our data confirm that MCC deficiency, despite low penetrance, may lead to a severe clinical phenotype resembling classical organic acidurias. However, neither the genotype nor the biochemical phenotype is helpful in predicting the clinical course. © 2012 Grünert et al.; licensee BioMed Central Ltd.

Opladen T.,University of Heidelberg | Lindner M.,University of Heidelberg | Lindner M.,University Childrens Hospital Frankfurt | Das A.M.,Hannover Medical School | And 16 more authors.
Molecular Genetics and Metabolism | Year: 2016

Background: The hepatic urea cycle is the main metabolic pathway for detoxification of ammonia. Inborn errors of urea cycle function present with severe hyperammonemia and a high case fatality rate. Long-term prognosis depends on the residual activity of the defective enzyme. A reliable method to estimate urea cycle activity in-vivo does not exist yet. The aim of this study was to evaluate a practical method to quantify 13C-urea production as a marker for urea cycle function in healthy subjects, patients with confirmed urea cycle defect (UCD) and asymptomatic carriers of UCD mutations. Methods: 13C-labeled sodium acetate was applied orally in a single dose to 47 subjects (10 healthy subjects, 28 symptomatic patients, 9 asymptomatic carriers). Results: The oral 13C-ureagenesis assay is a safe method. While healthy subjects and asymptomatic carriers did not differ with regards to kinetic variables for urea cycle flux, symptomatic patients had lower 13C-plasma urea levels. Although the 13C-ureagenesis assay revealed no significant differences between individual urea cycle enzyme defects, it reflected the heterogeneity between different clinical subgroups, including male neonatal onset ornithine carbamoyltransferase deficiency. Applying the 13C-urea area under the curve can differentiate between severe from more mildly affected neonates. Late onset patients differ significantly from neonates, carriers and healthy subjects. Conclusion: This study evaluated the oral 13C-ureagenesis assay as a sensitive in-vivo measure for ureagenesis capacity. The assay has the potential to become a reliable tool to differentiate UCD patient subgroups, follow changes in ureagenesis capacity and could be helpful in monitoring novel therapies of UCD. © 2015 Elsevier Inc.

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