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Ulrich R.G.,Institute For Neue Und Neuartige Tierseuchenerreger | Ulrich R.G.,University of Federal Defense Munich | Essbauer S.S.,Charité - Medical University of Berlin | Kruger D.H.,Labor Berlin GmbH | And 2 more authors.
Chirurgische Praxis | Year: 2013

Rodents (and other small mammals) play a major role in the transmission of various zoonotic pathogens. This includes pathogens, directly or indirectly transmitted to humans by urine, indirectly transmitted by aerogen uptake of pathogen-contaminated dust or by arthropod vectors. On the other hand, transmission can be mediated by biting or by contact with the coat of the infected reservoir animal. For additional pathogens it is currently unknown, if they are pathogenic to humans or if rodents have an epidemiological role for their transmission to humans. This manuscript provides an overview for rodentborne zoonotic pathogens present in Germany: Hantaviruses, orthopox viruses, tick-borne encephalitis virus, Leptospira and Rickettsia spp.


Lindenberg L.,Charité - Medical University of Berlin | Spengler L.,Charité - Medical University of Berlin | Bang H.,Orgentec Diagnostika | Dorner T.,Charité - Medical University of Berlin | And 10 more authors.
Arthritis Research and Therapy | Year: 2015

Introduction: Antibodies against mutated citrullinated vimentin (AMCV) represent a useful diagnostic marker with correlation to disease activity in patients with rheumatoid arthritis (RA). Since seropositivity for citrullinated autoantibodies was predictive for response to B-cell depleting therapy (BCDT) with rituximab (RTX), we investigated whether differences in antibody fine reactivity and immunoglobulin (Ig) isotype kinetics among AMCV-positive patients could provide additional information about outcome. Methods: A total of 50 AMCV IgG-positive RA patients (RTX responders (RRs) n = 37 and non-responders (NRRs) n = 13) were analyzed for reactivity against MCV epitopes and co-existent AMCV isotypes IgM and IgA. Antibody titers were determined by enzyme-linked immunosorbent assay at baseline and 24 weeks after the first cycle of RTX, and compared to kinetics of rheumatoid factor (RF) and antibodies against cyclic citrullinated peptide (ACCP). Results: Recognized MCV epitopes by AMCV IgG of RRs and NRRs showed similar baseline patterns, with reducing reactivity in RRs and unchanged or even expanding reactivity in NRRs upon RTX treatment. At baseline, RRs were more frequently negative for AMCV subtypes, especially for IgA (68 %), compared to NRRs (31 %). Being AMCV IgA-negative at baseline indicated a good treatment response to RTX (negative predictive value = 0.86). Co-existence of AMCV IgA and IgG with stable titers upon treatment were associated with poorer responses to RTX. Furthermore, reductions of AMCV IgA levels upon RTX correlated with the improvement of 28-joint Disease Activity Score (DAS28). In comparison, subtypes of RF and ACCP were not of additional value for prediction of RTX response. Conclusions: Restrictive IgG seropositivity against MCV with treatment-associated decline in fine reactivity and titers was predictive for response to RTX. Double-positivity for AMCV IgG and IgA was associated with failure to respond to BCDT, suggesting a pathogenetic and less sensitive IgA-producing B-cell subset in NRRs. © 2015 Lindenberg et al.


Bader A.M.,Charité - Medical University of Berlin | Klose K.,Charité - Medical University of Berlin | Bieback K.,University of Heidelberg | Korinth D.,University of Heidelberg | And 6 more authors.
PLoS ONE | Year: 2015

Hypoxic preconditioning was shown to improve the therapeutic efficacy of bone marrowderived multipotent mesenchymal stromal cells (MSCs) upon transplantation in ischemic tissue. Given the interest in clinical applications of umbilical cord blood-derived MSCs, we developed a specific hypoxic preconditioning protocol and investigated its anti-Apoptotic and pro-Angiogenic effects on cord blood MSCs undergoing simulated ischemia in vitro by subjecting them to hypoxia and nutrient deprivation with or without preceding hypoxic preconditioning. Cell number, metabolic activity, surface marker expression, chromosomal stability, apoptosis (caspases-3/7 activity) and necrosis were determined, and phosphorylation, mRNA expression and protein secretion of selected apoptosis and angiogenesis-regulating factors were quantified. Then, human umbilical vein endothelial cells (HUVEC) were subjected to simulated ischemia in co-culture with hypoxically preconditioned or naive cord blood MSCs, and HUVEC proliferation was measured. Migration, proliferation and nitric oxide production of HUVECs were determined in presence of cord blood MSC-conditioned medium. Cord blood MSCs proved least sensitive to simulated ischemia when they were preconditioned for 24 h, while their basic behavior, immunophenotype and karyotype in culture remained unchanged. Here, "post-ischemic" cell number and metabolic activity were enhanced and caspase-3/7 activity and lactate dehydrogenase release were reduced as compared to non-preconditioned cells. Phosphorylation of AKT and BAD, mRNA expression of BCL-XL, BAG1 and VEGF, and VEGF protein secretion were higher in preconditioned cells. Hypoxically preconditioned cord blood MSCs enhanced HUVEC proliferation and migration, while nitric oxide production remained unchanged. We conclude that hypoxic preconditioning protects cord blood MSCs by activation of anti-Apoptotic signaling mechanisms and enhances their angiogenic potential. Hence, hypoxic preconditioning might be a translationally relevant strategy to increase the tolerance of cord blood MSCs to ischemia and improve their therapeutic efficacy in clinical applications. Copyright: © 2015 Bader et al.


PubMed | Labor Berlin GmbH, Charité - Medical University of Berlin, Deutsches Herzzentrum Berlin, University of Cologne and University of Heidelberg
Type: Journal Article | Journal: PloS one | Year: 2015

Hypoxic preconditioning was shown to improve the therapeutic efficacy of bone marrow-derived multipotent mesenchymal stromal cells (MSCs) upon transplantation in ischemic tissue. Given the interest in clinical applications of umbilical cord blood-derived MSCs, we developed a specific hypoxic preconditioning protocol and investigated its anti-apoptotic and pro-angiogenic effects on cord blood MSCs undergoing simulated ischemia in vitro by subjecting them to hypoxia and nutrient deprivation with or without preceding hypoxic preconditioning. Cell number, metabolic activity, surface marker expression, chromosomal stability, apoptosis (caspases-3/7 activity) and necrosis were determined, and phosphorylation, mRNA expression and protein secretion of selected apoptosis and angiogenesis-regulating factors were quantified. Then, human umbilical vein endothelial cells (HUVEC) were subjected to simulated ischemia in co-culture with hypoxically preconditioned or nave cord blood MSCs, and HUVEC proliferation was measured. Migration, proliferation and nitric oxide production of HUVECs were determined in presence of cord blood MSC-conditioned medium. Cord blood MSCs proved least sensitive to simulated ischemia when they were preconditioned for 24 h, while their basic behavior, immunophenotype and karyotype in culture remained unchanged. Here, post-ischemic cell number and metabolic activity were enhanced and caspase-3/7 activity and lactate dehydrogenase release were reduced as compared to non-preconditioned cells. Phosphorylation of AKT and BAD, mRNA expression of BCL-XL, BAG1 and VEGF, and VEGF protein secretion were higher in preconditioned cells. Hypoxically preconditioned cord blood MSCs enhanced HUVEC proliferation and migration, while nitric oxide production remained unchanged. We conclude that hypoxic preconditioning protects cord blood MSCs by activation of anti-apoptotic signaling mechanisms and enhances their angiogenic potential. Hence, hypoxic preconditioning might be a translationally relevant strategy to increase the tolerance of cord blood MSCs to ischemia and improve their therapeutic efficacy in clinical applications.


Dedieu C.,Charité - Medical University of Berlin | Dedieu C.,University Pierre and Marie Curie | Rohmel J.,Charité - Medical University of Berlin | Kolsch U.,Labor Berlin GmbH | And 8 more authors.
Monatsschrift fur Kinderheilkunde | Year: 2016

Background: Chronic granulomatous disease is an inherited primary immune deficiency characterized by recurrent infections and increased susceptibility to autoimmunity and dysregulated inflammatory response. The prognosis of the disease has been improved by early diagnosis and reduced intensity stem cell transplantation. Case report: An 11-month-old boy was referred to this department with hepatosplenomegaly and recurrent fever of unknown origin. The first febrile episode occurred at 4 months of age and reoccurred at 5, 8 and 11 months of age. He was the first born child of non-consanguineous German parents. Ultrasound revealed an abdominal conglomerate of lymph nodes which led to the suspicion of phagocytic cell dysfunction. The immunological workup revealed chronic granulomatous disease. The patient was successfully treated with intravenous antibiotics for 6 weeks and an early reduced intensity stem cell transplantation was recommended, which was successfully carried out at 14 months of age without any complications. Conclusion: Elective stem cell transplantation is the only curative therapy for chronic granulomatous disease and should be strongly recommended for every newly diagnosed patient before the occurrence of major complications if a fully 10/10 HLA-matched donor is available. © 2015, Springer-Verlag Berlin Heidelberg.


Steinbach C.L.,Charité - Medical University of Berlin | Topper C.,Charité - Medical University of Berlin | Adam T.,Labor Berlin GmbH | Kees M.G.,Charité - Medical University of Berlin
Annals of Clinical Microbiology and Antimicrobials | Year: 2015

Background: Secondary peritonitis requires surgical source control and adequate antimicrobial treatment. Antimicrobial regimens are usually selected according to local susceptibility data of individual pathogens against single agents, but this neglects both the polymicrobial nature of the infection and the use of combination therapy. We analysed the probability of common regimens to cover all relevant pathogens isolated in one patient ("spectrum adequacy rate", SAR) in a real-life data set. Methods: Data from 242 patients with secondary peritonitis (88 community acquired, 154 postoperative cases) treated in our IMCU/ICU were obtained retrospectively. The relative frequency of pathogens, resistance rates and the SAR were analysed using the free software R. Results: Enterococci were isolated in 47.1% of all patients, followed by Escherichia coli (42.6%), other enterobacteriaceae (33.1%), anaerobes (29.8%) and Candida spp. (28.9%). Resistance patterns were consistent with general surveillance data from our hospital. The susceptibility rates and SAR were lower in postoperative than in community acquired cases. The following regimens yielded a SAR > 95% when enterobacteriaceae only were considered: piperacillin/tazobactam+gentamicin, cefotaxim (only for community acquired cases), cefotaxim+gentamicin, meropenem, tigecycline+gentamicin or tigecycline+ciprofloxaxin. When enterococci were also considered, all betalactam based regimens required combination with vancomycin or linezolid for a SAR>95%, whereas TGC based regimens were not compromised. As for Candida spp., the SAR of fluconazole was 81.9-87.5%. Conclusions: This study demonstrates a rational approach to assess the adequacy of antimicrobial regimens in secondary peritonitis, which may help to adjust local guidelines or to select candidate regimens for clinical studies. © 2015 Steinbach et al.


Lobitz S.,Charité - Medical University of Berlin | Frommel C.,Labor Berlin GmbH | Brose A.,Labor Berlin GmbH | Klein J.,Charité - Medical University of Berlin | Blankenstein O.,Charité - Medical University of Berlin
European Journal of Human Genetics | Year: 2014

Sickle cell disease (SCD) does not occur in the indigenous German population. However, with the increasing numbers of immigrants its prevalence is steadily rising. Nevertheless, robust epidemiological data is not available for Germany and, consequently, the German newborn screening (NBS) program does not include SCD. Between 1 September 2011 and 30 November 2012, an unselected cohort of 34 084 Berlin newborns was tested for SCD. The results of 14 newborns were consistent with SCD and 265 babies were identified as hemoglobin S (Hb S) carriers. These data indicate a 95% probability that the incidence of SCD in Berlin is at least 2.5/10 000. © 2014 Macmillan Publishers Limited All rights reserved.


Derganova O.,Charité - Medical University of Berlin | Derganova O.,Voronezh State Medical Academy | Martinez-Gamboa L.,Charité - Medical University of Berlin | Egerer K.,Charité - Medical University of Berlin | And 9 more authors.
Clinical and Experimental Rheumatology | Year: 2014

Objective: Antibodies against citrullinated antigens (ACPA) represent one rheumatoid arthritis (RA) classification criteria. Recently, mutated and citrullinated vimentin (MCV), containing approx. 45 potentially citrullinated sites, was characterised as another modified autoantigenic RA target. Therefore, we wanted to screen, select and validate predominant MCV autoantigenic epitopes (called here MCE) as possible new diagnostic targets. Methods: MCV-derived peptides with citrullinated sites were screened in healthy controls and patients. Based on this, twelve selected MCE were used for validation of ACPA isotypes (IgA/IgG/IgM) with ELISA in early RA (ERA, <12 months) and established RA (>12 months) Russian patients. Sensitivity of MCE reactivity was compared to commercially available ELISAs for anti-CCP IgG, anti-MCV IgG, and anti-RF IgA/IgM/IgG. Results: Anti-MCE IgG/IgA//IgM antibodies were observed in 64.1%, 23.1%, and 15.4% ERA, and 63.9%, 26.7%, and 13.1% established RA patients, respectively. Anti-MCV IgG was present in 64.1% ERA and 55.0% RA patients. Furthermore, anti-CCP IgG and RF IgG/IgA/IgM were detectable in up to 76.9%, 71.8%, 71.8%, and 38.5% ERA, and 80.1%, 72.3%, 67.5%, and 43.0% RA patients. Anti-CCP IgG single positivity was observed in 7.7% ERA and 6.3% RA patients. Only one RA patient was anti-MCE single positive. Conclusion: MCV autoantigenic epitopes were emulated by cyclic citrullinated MCV-derived peptides and recognised by all autoantibody-Ig subclasses in RA. Tested MCE were recognized more frequently by IgG as the original MCV antigen. High antibody prevalence against CCP epitopes suggests a strong CCP-linkage to RA pathogenesis in the investigated Russian cohort. © Clinical and Experimental Rheumatology 2014.


von der Hagen M.,TU Dresden | Hennermann J.B.,Johannes Gutenberg University Mainz | von Bernuth H.,Charité - Medical University of Berlin | von Bernuth H.,Labor Berlin GmbH | And 3 more authors.
Medizinische Genetik | Year: 2016

Microcephaly affects 2–3 % of the population and is often associated with intellectual disability. The underlying reduction in brain volume can result from various exogenous factors or genetic causes. Microcephaly remains a poorly defined condition lacking both uniform diagnostic approaches and classification. A definite etiological diagnosis is the key to predict the prognosis, identify co-morbidities and offer genetic counseling. In addition, the identification of the underlying cause increases our knowledge of brain development and the clinical spectrum of microcephaly. We propose a diagnostic approach for children with microcephaly from a pediatric neurologist point of view. © 2016, Springer-Verlag Berlin Heidelberg.


PubMed | Labor Berlin GmbH and Charité - Medical University of Berlin
Type: | Journal: Annals of clinical microbiology and antimicrobials | Year: 2015

Secondary peritonitis requires surgical source control and adequate antimicrobial treatment. Antimicrobial regimens are usually selected according to local susceptibility data of individual pathogens against single agents, but this neglects both the polymicrobial nature of the infection and the use of combination therapy. We analysed the probability of common regimens to cover all relevant pathogens isolated in one patient (spectrum adequacy rate, SAR) in a real-life data set.Data from 242 patients with secondary peritonitis (88 community acquired, 154 postoperative cases) treated in our IMCU/ICU were obtained retrospectively. The relative frequency of pathogens, resistance rates and the SAR were analysed using the free software R.Enterococci were isolated in 47.1% of all patients, followed by Escherichia coli (42.6%), other enterobacteriaceae (33.1%), anaerobes (29.8%) and Candida spp. (28.9%). Resistance patterns were consistent with general surveillance data from our hospital. The susceptibility rates and SAR were lower in postoperative than in community acquired cases. The following regimens yielded a SAR > 95% when enterobacteriaceae only were considered: piperacillin/tazobactam+gentamicin, cefotaxim (only for community acquired cases), cefotaxim+gentamicin, meropenem, tigecycline+gentamicin or tigecycline+ciprofloxaxin. When enterococci were also considered, all betalactam based regimens required combination with vancomycin or linezolid for a SAR>95%, whereas TGC based regimens were not compromised. As for Candida spp., the SAR of fluconazole was 81.9-87.5%.This study demonstrates a rational approach to assess the adequacy of antimicrobial regimens in secondary peritonitis, which may help to adjust local guidelines or to select candidate regimens for clinical studies.

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