Both systemic and local application of Granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy

<p>Abstract</p> <p>Background</p> <p>The hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) plays a crucial role in controlling the number of neutrophil progenitor cells. Its function is mediated via the G-CSF receptor, which was recently found to be expressed also in the central nervous system. In addition, G-CSF provided neuroprotection in models of neuronal cell death. Here we used the retinal ganglion cell (RGC) axotomy model to compare effects of local and systemic application of neuroprotective molecules.</p> <p>Results</p> <p>We found that the <it>G-CSF receptor </it>is robustly expressed by RGCs <it>in vivo </it>and <it>in vitro</it>. We thus evaluated G-CSF as a neuroprotectant for RGCs and found a dose-dependent neuroprotective effect of G-CSF on axotomized RGCs when given subcutaneously. As stem stell mobilization had previously been discussed as a possible contributor to the neuroprotective effects of G-CSF, we compared the local treatment of RGCs by injection of G-CSF into the vitreous body with systemic delivery by subcutaneous application. Both routes of application reduced retinal ganglion cell death to a comparable extent. Moreover, G-CSF enhanced the survival of immunopurified RGCs <it>in vitro</it>.</p> <p>Conclusion</p> <p>We thus show that G-CSF neuroprotection is at least partially independent of potential systemic effects and provide further evidence that the clinically applicable G-CSF could become a treatment option for both neurodegenerative diseases and glaucoma.</p

Regulation of mitochondrial fission during neuronal apoptosis

Durch dynamische Teilungs- und Verschmelzungsvorgänge variiert unter physiologischen Bedingungen die Morphologie der Mitochondrien stetig zwischen punktartigen und tubulär vernetzten Formen. Die vorherrschende Morphologie der Mitochondrien ist tubulär und gibt ein Gleichgewicht der beiden Prozesse wieder. Bei der neuronalen Apoptose ist der mitochondriale Apoptoseweg (intrinsisch) von besonderer Bedeutung, wobei die Mitochondrien pro-apoptotische Proteine (z.B. Cytochrome c) ins Zytosol freisetzen und ihre Morphologie zu kleineren punktierten Strukturen verändern. Bis zum heutigen Zeitpunkt ist die Kenntnis der mitochondrialen Zerteilungsvorgänge innerhalb der neuronalen Apoptose und der Signaltransduktionswege, auf denen die mitochondriale Morphologie reguliert wird, gering. Die vorliegenden Studie zeigt, dass die mitochondriale Zerteilung ein zeitlich frühes und invariantes Ereignis innerhalb der neuronalen Apoptose ist. Die Zerteilung der Mitochondrien erwies sich als notwendig für die bereits bekannte Cytochrom c Freisetzung und die Induktion der neuronalen Apoptose. Sowohl die ungestörte Funktion des Aktin- als auch des Tubulinzytoskeletts waren Voraussetzung für die Regulation der morphologischen Veränderungen der Mitochondrien in der Apoptose. Durch Einsatz von Inhibitoren konnte CDK5 als eine Signalkinase identifiziert werden, welche die mitochondrialen Zerteilungsvorgänge während der neuronalen Apoptose reguliert. Als CDK5 Inhibitoren dienten dominant negative Mutanten, anti-CDK5 siRNS und Indolinon A. Durch Beeinflussung der mitochondriale Zerteilung wird die bekannte Neurotoxizität moduliert. Die Resultate erlauben, die CDK5 induzierte Neurotoxizität mittels Zerteilung der Mitochondrien zu erklären, so dass beide in die bekannten Apoptosekaskaden integriert werden können

Incidences of Infectious Events in a Renal Transplant Cohort of the German Center of Infectious Diseases (DZIF)

Background Infectious complications are a major cause of morbidity and mortality after kidney transplantation. Methods In this transplant cohort study at the German Center of Infectious Diseases (DZIF), we evaluated all infections occurring during the first year after renal transplantation. We assessed microbial etiology, incidence rates, and temporal occurrence of these infections. Results Of 804 renal transplant recipients (65.2% male, 51 +/- 14 years), 439 (54.6%) had 972 infections within the first year after transplantation. Almost half of these infections (47.8%) occurred within the first 3 months. Bacteria were responsible for 66.4% (645/972) of all infections, followed by viral (28.9% [281/972]) and fungal (4.7% [46/972]) pathogens. The urinary tract was the most common site of infection (42.4%). Enterococcus was the most frequently isolated bacterium (20.9%), followed by E. coli (17.6%) and Klebsiella (12.5%). E. coli was the leading pathogen in recipients <50 years of age, whereas Enterococcus predominated in older recipients. Resistant bacteria were responsible for at least 1 infection in 9.5% (76/804) of all recipients. Viral infections occurred in 201 recipients (25.0%). Of these, herpes viruses predominated (140/281 [49.8%]), and cytomegalovirus had the highest incidence rate (12.3%). In the 46 fungal infections, Candida albicans (40.8%) was the most commonly isolated. Other fungal opportunistic pathogens, including Aspergillus fumigatus and Pneumocystis, were rare. Conclusions Renal allograft recipients in Germany experience a high burden of infectious complications in the first year after transplantation. Bacteria were the predominating pathogen, followed by opportunistic infections such as cytomegalovirus. Microbial etiology varied between age groups, and resistant bacteria were identified in 10% of recipients

The transplant cohort of the German center for infection research (DZIF Tx-Cohort): study design and baseline characteristics

Infectious complications are the major cause of morbidity and mortality after solid organ and stem cell transplantation. To better understand host and environmental factors associated with an increased risk of infection as well as the effect of infections on function and survival of transplanted organs, we established the DZIF Transplant Cohort, a multicentre prospective cohort study within the organizational structure of the German Center for Infection Research. At time of transplantation, heart-, kidney-, lung-, liver-, pancreas- and hematopoetic stem cell- transplanted patients are enrolled into the study. Follow-up visits are scheduled at 3, 6, 9, 12 months after transplantation, and annually thereafter; extracurricular visits are conducted in case of infectious complications. Comprehensive standard operating procedures, web-based data collection and monitoring tools as well as a state of the art biobanking concept for blood, purified PBMCs, urine, and faeces samples ensure high quality of data and biosample collection. By collecting detailed information on immunosuppressive medication, infectious complications, type of infectious agent and therapy, as well as by providing corresponding biosamples, the cohort will establish the foundation for a broad spectrum of studies in the field of infectious diseases and transplant medicine. By January 2020, baseline data and biosamples of about 1400 patients have been collected. We plan to recruit 3500 patients by 2023, and continue follow-up visits and the documentation of infectious events at least until 2025. Information about the DZIF Transplant Cohort is available at https://www.dzif.de/en/working-group/transplant-cohort