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Borstel-Hohenraden, Germany

Fischer N.,University of Hamburg | Schulz C.,University of Hamburg | Stieler K.,University of Hamburg | Hohn O.,Robert Koch Institute | And 3 more authors.
Emerging Infectious Diseases | Year: 2010

Xenotropic murine leukemia virus-related gammaretrovirus (XMRV) has been recently associated with prostate cancer and chronic fatigue syndrome. To identify nucleic acid sequences, we examined respiratory secretions by using PCR. XMRV-specifi c sequences were detected in 2%-3% of samples from 168 immunocompetent carriers and ≈10% of samples from 161 immunocompromised patients. Source

Yildirim A.O.,University of Marburg | Yildirim A.O.,Institute of Lung Biology and Disease | Muyal V.,University of Marburg | John G.,Justus Liebig University | And 5 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2010

Rationale: Emphysema is characterized by destruction of alveoli with ensuing airspace enlargement and loss of alveoli. Induction of alveolar regeneration is still a major challenge in emphysema therapy. Objectives: To investigate whether therapeutic application of palifermin (ΔN23-KGF) is able to induce a regenerative response in distal lungparenchyma after induction of pulmonaryemphysema. Methods: Mice were therapeutically treated at three occasions by oropharyngeal aspiration of 10 mg ΔN23-KGF per kg body weight after induction of emphysema by porcine pancreatic elastase. Measurements and Main Results: Airflow limitation associated with emphysema was largely reversed as assessed by noninvasive head-out body plethysmography. Porcine pancreatic elastase-induced airspace enlargement and loss of alveoli were partially reversed as assessed by design-based stereology. ΔN23-KGF induced proliferation of epithelium, endothelium, and fibroblasts being associated with enhanceddifferentiation as well as increased expression of vascular endothelial growth factor, vascular endothelial growth factor receptors, transforming growth factor (TGF)-β1, TGF-β2, (phospho-) Smad2, plasminogen activator inhibitor-1, and elastin as assessed by quantitative reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. ΔN23-KGF induced the expression of TGF-β1 in and release of active TGF-β1 from primary mouse alveolar epithelial type 2 (AE2) cells, murine AE2-like cells LA-4, and cocultures of LA-4 and murine lung fibroblasts (MLF), but not in MLF cultured alone. Recombinant TGF-β1 but not ΔN23-KGF induced elastin gene expression in MLF. Blockade of TGF-signaling by neutralizing antibody abolished these effects of ΔN23-KGF in LA-4/MLF cocultures. Conclusions: Our data demonstrate that therapeutic application of ΔN23-KGF has the potential to induce alveolar maintenance programs in emphysematous lungs and suggest that the regenerative effect on interstitial tissue is linked to AE2 cell-derived TGF-β1. Source

Verbeeck R.K.,University of Namibia | Gunther G.,Katutura State Hospital | Gunther G.,Leibniz Center for Medicine and Biosciences | Kibuule D.,University of Namibia | And 2 more authors.
European Journal of Clinical Pharmacology | Year: 2016

Introduction: Tuberculosis (TB) remains one of the world’s deadliest communicable diseases. Although cure rates of the standard four-drug (rifampicin, isoniazid, pyrazinamide, ethambutol) treatment schedule can be as high as 95–98 % under clinical trial conditions, success rates may be much lower in less well resourced countries. Unsuccessful treatment with these first-line anti-TB drugs may lead to the development of multidrug resistant and extensively drug resistant TB. The intrinsic interindividual variability in the pharmacokinetics (PK) of the first-line anti-TB drugs is further exacerbated by co-morbidities such as HIV infection and diabetes. Methods: Therapeutic drug monitoring has been proposed in an attempt to optimize treatment outcome and reduce the development of drug resistance. Several studies have shown that maximum plasma concentrations (Cmax), especially of rifampicin and isoniazid, are well below the proposed target Cmax concentrations in a substantial fraction of patients being treated with the standard four-drug treatment schedule, even though treatment’s success rate in these studies was typically at least 85 %. Discussion: The proposed target Cmax concentrations are based on the concentrations of these agents achieved in healthy volunteers and patients receiving the standard doses. Estimation of Cmax based on one or two sampling times may not have the necessary accuracy since absorption rate, especially for rifampicin, may be highly variable. In addition, minimum inhibitory concentration (MIC) variability should be taken into account to set clinically meaningful susceptibility breakpoints. Clearly, there is a need to better define the key target PK and pharmacodynamic (PD) parameters for therapeutic drug monitoring (TDM) of the first-line anti-TB drugs to be efficacious, Cmax (or area under the curve (AUC)) and Cmax/MIC (or AUC/MIC). Conclusion: Although TDM of first-line anti-TB drugs has been successfully used in a limited number of specialized centers to improve treatment outcome in slow responders, a better characterization of the target PK and/or PK/PD parameters is in our opinion necessary to make it cost-effective. © 2016, Springer-Verlag Berlin Heidelberg. Source

Polansky J.K.,Helmholtz Center for Infection Research | Polansky J.K.,Leibniz Center for Medicine and Biosciences | Schreiber L.,Helmholtz Center for Infection Research | Thelemann C.,Charite - Medical University of Berlin | And 7 more authors.
Journal of Molecular Medicine | Year: 2010

The forkhead-box protein P3 (Foxp3) is a key transcription factor for the development and suppressive activity of regulatory T cells (Tregs), a T cell subset critically involved in the maintenance of self-tolerance and prevention of over-shooting immune responses. However, the transcriptional regulation of Foxp3 expression remains incompletely understood. We have previously shown that epigenetic modifications in the CpG-rich Treg-specific demethylated region (TSDR) in the Foxp3 locus are associated with stable Foxp3 expression. We now demonstrate that the methylation state of the CpG motifs within the TSDR controls its transcriptional activity rather than a Treg-specific transcription factor network. By systematically mutating every CpG motif within the TSDR, we could identify four CpG motifs, which are critically determining the transcriptional activity of the TSDR and which serve as binding sites for essential transcription factors, such as CREB/ATF and NF-κB, which have previously been shown to bind to this element. The transcription factor Ets-1 was here identified as an additional molecular player that specifically binds to the TSDR in a demethylation-dependent manner in vitro. Disruption of the Ets-1 binding sites within the TSDR drastically reduced its transcriptional enhancer activity. In addition, we found Ets-1 bound to the demethylated TSDR in ex vivo isolated Tregs, but not to the methylated TSDR in conventional CD4+ T cells. We therefore propose that Ets-1 is part of a larger protein complex, which binds to the TSDR only in its demethylated state, thereby restricting stable Foxp3 expression to the Treg lineage. © 2010 The Author(s). Source

Claes A.-K.,University of Toronto | Claes A.-K.,Leibniz Center for Medicine and Biosciences | Claes A.-K.,University of Kiel | Zhou J.Y.,University of Toronto | Philpott D.J.,University of Toronto
Physiology | Year: 2015

The NOD-like receptors (NLRs) are cytosolic pattern-recognition receptors, which are critically involved in mucosal immune defense. The association of the NLR, NOD2, with inflammatory bowel disease first pointed to the NLRs potential function as guardians of the intestinal barrier. Since then, several studies have emphasized the importance of NLRs in maintaining gut homeostasis and intestinal infections, and in shaping the microbiota. In this review, we will highlight the function of NLRs in intestinal inflammation. © 2015 Int. Source

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