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Hamburg, Germany

Ertl H.,Labor Lademannbogen | Butte W.,Carl von Ossietzky University
Journal of Exposure Science and Environmental Epidemiology

Semi-volatile chemicals like pesticides and polychlorinated biphenyls (PCB) tend to accumulate in house dust. This may result in residues of some parts per million (p.p.m.), closely associated with health impairments and diseases like cancer. To explain these associations, we must establish whether a relevant absorption from house dust into human organisms occurs, and most crucially the release of chemicals, that is, their bioaccessibility. Digestive as well as dermal bioaccessibilities were examined using in-vitro methods. On average, the digestive bioaccessibility was 40% for the pesticides and 60% for the PCB. The dermal penetration availability reached 60% for the pesticides and 70% for the PCB (percentages of the concentrations in the dust). Based on the bioaccessibility, an estimate of internal exposure was calculated and expressed as percentages of acceptable or tolerable daily intake (ADI/TDI) values. Exposure via the respiratory tract proved to be very low. Exposure via the digestive tract had maximum values of 4% for pesticides and 12% for PCB. Dermal exposure was much higher. Even for average concentrations in house dust (0.5 p.p.m.), children exposed to DDT and PCB showed up to 300% of the ADI/TDI values, and adults about 60%. With high concentrations of contaminants in house dust, the maximum doses absorbed through the skin reached 5000%. © 2012 Nature America, Inc. All rights reserved. Source

Fraedrich K.,Universitatsklinikum Hamburg Eppendorf | Schrader J.,Universitatsklinikum Hamburg Eppendorf | Ittrich H.,Universitatsklinikum Hamburg Eppendorf | Keller G.,Universitatsklinikum Hamburg Eppendorf | And 11 more authors.
Clinical Cancer Research

Purpose: Aurora kinases play a crucial role in cell-cycle control. Uncontrolled expression of aurora kinases causes aneuploidy and tumor growth. As conservative treatment options for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) are disappointing, aurora kinases may be an interesting target for novel therapeutic strategies. Experimental Design: Human GEP-NETs were tested for aurora kinase expression. The efficacy of the new aurora kinase inhibitor danusertib was evaluated in two human GEP-NET cell lines (BON1 and QGP) in vitro and in vivo. Results: The majority of ten insulinomas and all 33 nonfunctional pancreatic or midgut GEP-NETs expressed aurora A despite a mostly high degree of cell differentiation. Both human GEP-NET cell lines expressed aurora kinase A and B, and high Ser10 phosphorylation of histone H3 revealed increased aurora B activity. Remarkably, danusertib led to cell-cycle arrest and completely inhibited cell proliferation of the GEP-NET cells in vitro. Decreased phosphorylation of histone H3 indicated effective aurora B inhibition. In a subcutaneous murine xenograft model, danusertib significantly reduced tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil. As a consequence, decreased levels of tumor marker chromogranin A were found in mouse serum samples. In a newly developed orthotopic model for GEP-NET liver metastases by intrasplenic tumor cell transplantation, dynamic MRI proved significant growth inhibition of BON1- and QGP-derived liver metastases. Conclusions: These results show that danusertib may impose a new therapeutic strategy for aurora kinase expressing metastasized GEP-NETs. ©2012 AACR. Source

Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure in the western world but there is still no specific and early diagnosis available. Besides a genetic predisposition and viral infections, autoimmune reactions play an important role in the pathogenesis of DCM. The beta1-adrenergic receptor (beta1-AR) has been described as the major target structure in autoimmune DCM. In this study a recombinant GST-beta1-AR fusion protein comprising the second extracellular loop was generated as a target for the analysis of autoantibodies in sera from 115 patients with different heart failure diseases (41 DCM, 30 non-ischemic secondary cardiomyopathy [NISCM], 44 coronary artery disease [CAD]). Sera were collected from a non-selected population of heart failure patients in consecutive order. Autoantibodies against the beta1-AR were detected in 37% of DCM, 30% of NISCM, and 36% of CAD patients but none of the controls were positive. Furthermore, our data show that cardiomyopathy patients with anti-beta1-AR antibodies are younger (54 years vs. 61 years [DCM], 53 years vs. 56 years [NISCM], 61 years vs. 61 years [CAD]. Regardless of diagnosis antibody-positive patients had lower EF levels (29% vs. 32%, p = 0.0001 [DCM]; 23% vs. 25%, p < 0.0001 [NISCM]; 23% vs. 25%, p < 0.0001 [CAD]) than the antibody-negative counterparts but, nevertheless, also lower NT-proBNP levels compared to antibody negative patients (567 pg/mL vs. 1296 pg/mL, p = 0.0005 [DCM]; 224 pg/mL vs. 1135 pg/mL, p = 0.0002 [NISCM]; 605 pg/mL vs. 940 pg/mL, p = 0.0005 [CAD]). We conclude that DCM patients should be further characterized and differentiated by the detection of autoantibodies against beta1-AR. Autoimmune DCM patients are younger compared with their non-autoimmune counterparts, possibly due to the autoimmune trigger of the disease or reflecting an early stage of the disease. Surprisingly, the autoimmune patients have worse clinical manifestations but show less excessive NT-proBNP levels. It is not clear yet, though, whether these autoantibodies have a direct impact on the NT-proBNP levels. Whether or not these data are a consequence of pathogenic antibodies has to be elucidated in further studies. Source

Ingiliz P.,Medical Center for Infectious Diseases | Krznaric I.,Medical Center for Infectious Diseases | Stellbrink H..-J.,Study Center | Knecht G.,Infectious Diseases Center | And 9 more authors.
HIV Medicine

Objectives: The incidence of sexually transmitted hepatitis C virus (HCV) reinfection is on the rise in HIV-infected men who have sex with men (MSM). Data on natural history of acute hepatitis C and possible factors associated with spontaneous clearance are limited. The aim of this study was to analyse the outcome of HCV reinfections in HIV-positive MSM. Methods: A retrospective analysis was carried out on patients with more than one sexually acquired HCV infection who were diagnosed at four major German HIV and hepatitis care centres. Reinfection was defined by genotype or phylogenetic clade switch, detectable HCV RNA after a sustained virological response (SVR) or after spontaneous clearance (SC). Results: In total, 48 HIV-positive MSM were identified with HCV reinfection, among them 11 with a third episode and one patient with four episodes. At the first episode, 43 and five patients had an SVR and SC, respectively. The second episode was accompanied by a genotype switch in 29 patients (60%). Whereas 30 and nine patients showed an SVR and SC, respectively, eight patients developed chronic hepatitis. Neither HCV genotype switch nor interleukin-28B genotype was associated with SC. However, SC rates at the second episode were higher for patients with SC at the first episode compared with patients without SC (60 vs. 14%, respectively; P=0.03). Two patients with SC at the first episode were reinfected with the same genotype. Conclusions: Multiple reinfections in HIV-infected MSM do occur, with or without genotype switch, and with prior SC of previous episodes. In this large case series, except for SC at the first episode, no factor was of value in clinical decision-making for early therapeutic intervention in acute HCV reinfection. Copyright © 2014 British HIV Association. Source

Frohnauer J.,University of Kiel | Caliebe A.,University of Kiel | Gesk S.,University of Kiel | Partsch C.-J.,Endokrinologikum Labore Hamburg | And 3 more authors.
Molecular Cytogenetics

Background: Typical Williams-Beuren syndrome (WBS) is commonly caused by a ∼1.5 Mb - ∼1.8 Mb heterozygous deletion of contiguous genes at chromosome region 7q11.23. The majority of WBS cases occurs sporadically but few familial cases of autosomal dominant inheritance have been reported. Recent data demonstrated the existence of the paracentric inversion polymorphism at the WBS critical region in 7q11.23 in some of the progenitors transmitting the chromosome which shows the deletion in the affected child. In parents having a child affected by WBS the prevalence of such a structural variant has been reported to be much higher (∼25- ∼30%) than in the general population (∼1- ∼6%). However, in these previously reported studies only a limited number of randomly selected patients and non transmitting parents of WBS patients were used as controls, but without specification of any clinical data. Therefore we have undertaken a German population-based molecular cytogenetic investigation. We evaluated the incidence of the paracentric inversion polymorphism at 7q11.23 analyzing interphase nuclei of lymphocytes using a three color fluorescence in situ hybridization (FISH) probe. Results. FISH analysis was carried out on couples with a child affected by WBS as compared to a population sample composed of different normal individuals: Control group I: couples with two healthy children, control group II: couples with fertility problems, planning ICSI and control group III: couples with two healthy children and one child with a chromosome aberration, not involving region 7q11.23. The three color FISH assay showed that the frequency of the paracentric inversion polymorphism at 7q11.23 in couples with a child affected by WBS was 20.8% (5 out of 24 pairs) as compared to 8.3% (2 out of 24 pairs, control group I), 25% (4 out of 16 pairs, control group II) and 9.1% (1 out of 11 pairs, control group III), respectively (total 7 out of 51 pairs, 13.8%). The frequencies differed between the groups, but this was statistically not significant (p > 0.05, Fisher's test). Conclusion. Our results do not support the hypothesis that the paracentric inversion polymorphism at 7q11.23 is a major predisposing factor for the WBS deletion. © 2010 Frohnauer et al; licensee BioMed Central Ltd. Source

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