TY - JOUR A1 - Zhang, Nan A1 - Van Crombruggen, Koen A1 - Holtappels, Gabriele A1 - Lan, Feng A1 - Katotomichelakis, Michail A1 - Zhang, Luo A1 - Högger, Petra A1 - Bachert, Claus T1 - Suppression of Cytokine Release by Fluticasone Furoate vs. Mometasone Furoate in Human Nasal Tissue Ex-Vivo JF - PLOS ONE N2 - Background: Topical glucocorticosteroids are the first line therapy for airway inflammation. Modern compounds with higher efficacy have been developed, but head-to-head comparison studies are sparse. Objective: To compare the activity of two intranasal glucocorticoids, fluticasone furoate (FF) and mometasone furoate (MF) with respect to the inhibition of T helper (Th)1, Th2 and Th17 cytokine release in airway mucosa. Methods: We used an ex-vivo human nasal mucosal tissue model and employed pre-and post-Staphylococcus aureus enterotoxin B (SEB)-challenge incubations with various time intervals and drug concentrations to mimic typical clinical situations of preventive or therapeutic use. Results: At a fixed concentration of 10(-10) M, FF had significantly higher suppressive effects on interferon (IFN)-gamma,interleukin (IL)-2 and IL-17 release, but not IL-5 or tumor necrosis factor (TNF)-alpha, vs. MF. While the maximal suppressive activity was maintained when FF was added before or after tissue stimulation, the cytokine suppression capacity of MF appeared to be compromised when SEB-induced cell activation preceded the addition of the drug. In a pre-challenge incubation setting with removal of excess drug concentrations, MF approached inhibition of IL-5 and TNF-alpha after 6 and 24 hours while FF maximally blocked the release of these cytokines right after pre-incubation. Furthermore, FF suppressed a wider range of T helper cytokines compared to MF. Conclusion: The study demonstrates the potential of our human mucosal model and shows marked differences in the ability to suppress the release of various cytokines in pre-and post-challenge settings between FF and MF mimicking typical clinical situations of preventive or therapeutic use. KW - allergic rhinitis KW - human receptor kinetics KW - staphylococcus aureus KW - intranasal corticosteroids KW - cells KW - propionate KW - secretion KW - affinity KW - therapy KW - spray Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116779 VL - 9 IS - 4 ER - TY - THES A1 - Schaefer, Frauke T1 - Diagnosis and therapy of malaria under the conditions of a developing country - the example of Burkina Faso T1 - Diagnose und Therapie der Malaria unter den Bedingungen eines Entwicklungslandes - das Beispiel Burkina Fasos N2 - Malaria is a challenging infection with increasing and wide-spread treatment failure risk due to resistance. With a estimated death toll of 1-3 Million per year, most cases of Malaria affect children under the age of five years in Sub-Saharan Africa. In this thesis, I analyse the current status of malaria control (focussing on diagnosis and therapy) in Burkina Faso to show how this disease burdens public health in endemic countries and to identify possible approaches to improvement. MB is discussed as a therapeutic option under these circumstances. Burkina Faso is used as a representative example for a country in Sub-Saharan Africa with high endemicity for malaria and is here portrayed, its health system characterised and discussed under socioeconomic aspects. More than half of this country’s population live in absolute poverty. The burden that malaria, especially treatment cost, poses on these people cannot be under-estimated. A retrospective study of case files from the university pediatric hospital in Burkina Faso’s capital, Ouagadougou, shows that the case load is huge, and especially the specific diagnosis of severe malaria is difficult to apply in the hospital’s daily routine. Treatment policy as proposed by WHO is not satisfactorily implemented neither in home treatment nor in health services, as data for pretreatment clearly show. In the face of growing resistance in malaria parasites, pharmacological combination therapies are important. Artemisinins currently are the last resort of malaria therapy. As I show with homology models, even this golden bullet is not beyond resistance development. Inconsidered mass use has rendered other drugs virtually useless before. Artemisinins should thus be protected similar to reserve antibiotics against multi-resistant bacteria. There is accumulating evidence that MB is an effective drug against malaria. Here the biological effects of both MB alone and in combination therapy is explored via modeling and experimental data. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, CQ resistance based on Pfmdr1 and PfCRT transporters as well as SP resistance were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs, given their correct application. Also from the economic point of view MB shows great potential: in terms of production price, it can be compared to CQ, which could help to diminuish the costs of malaria treatment to affordable ranges for those most affected and struk by poverty. Malaria control is feasible, but suboptimal diagnosis and treatment are often hindering the achievment of this goal. In order to achieve malaria control, more effort has to be made to implement better adjusted and available primary treatment strategies for uncomplicated malaria that are highly standardised. Unfortunately, campaigns against malaria are chronically underfinanced. In order to maximize the effect of available funds, a cheap treatment option is most important, especially as pharmaceuticals represent the biggest single matter of expense in the fight against malaria. N2 - Malaria ist eine Krankheit, die uns vor große Herausforderungen stellt. Insbesondere die weltweit verbreiteten Resistenzen, die viele Therapieoptionen nutzlos werden lassen, haben den Kampf gegen die Malaria in den letzten Jahrzehnten deutlich verkompliziert. Schätzungen gehen davon aus, dass Malaria jährlich 1 bis 3 Millionen Todesopfer fordert. Mortalität und Morbidität der Erkrankung konzentrieren sich dabei in besonderer Weise auf Kinder unter fünf Jahren in Afrika südlich der Sahara. In der hier vorgestellten Doktorarbeit analysiere ich den aktuellen Stand der Malaria-Kontrolle in Burkina Faso und zeige beispielhaft auf, warum diese Krankheit eine derart große Bürde für die Volksgesundheit darstellt und wo Ansatzpunkte zur Verbesserung der Kontrollmaßnahmen zu sehen sind, mit einem besonderen Fokus auf Diagnostik und Therapieoptionen. Dabei wird MB als Therapieoption genauer beleuchtet. Um die besonderen Gegebenheiten eines Landes wie Burkina Faso - welches hier als repräsentatives Beispiel für einen Staat mit hoher Endemizität für Malaria herangezogen wird - aufzuzeigen, wird ein Porträt des Landes und seines Gesundheitssystems insbesondere unter Sozio- Ökonomischen Gesichtspunkten gezeichnet. Burkina Faso ist ein sehr armes Land, über die Hälfte seiner Bevölkerung lebt unterhalb der Armutsgrenze. Die Kosten von Malaria sind für diese Menschen gigantisch, und insbesondere die Kosten von Medikamenten wiegen schwer. Eine retrospektive Studie aus Fallakten des Universitäts-Kinderkrankenhauses in Burkina Fasos Hauptstadt Ouagadougou zeigt vor allem, dass allein die Fallzahlen überwältigend sind, und vor allem die spezifische Diagnose der schweren Verlaufsform der Malaria ist unter den vorherrschenden Bedingungen eine Mammutaufgabe. Die Behandlungsvorschriften wie von der WHO vorgegeben werden weder vom Gesundheitssystem noch von der Therapie zu Hause erfüllt, wie in den präsentierten Daten für die Vorbehandlung zeigen. Die zur Verfügung stehenden Malaria-wirksamen Therapeutika sind leider dank Resistenzentwicklung - oft durch unbedachten Masseneinsatz verursacht - sehr begrenzt. Artemisinine sind momentan das einzige Mittel gegen welches noch keine Resistenzen im Feld nachgewiesen wurden. Mittels Homologie-Modellierung zeige ich auf wie einfach eine solche Resistenzentwicklung jedoch denkbar wäre. Artemisinine sollten daher durch sehr gezielten Einsatz als ”letzter Trumpf” möglichst lange vor Resistenzentwicklung geschützt werden, ähnlich wie Reserveantibiotika gegen Multi-resistente Keime. MB ist ein hervorragender Kandidat für eine Kombinationsbehandlung gegen Malaria und eventuell eine Option, Artemisinine länger zu ”schonen”. Hier wird dieses Medikament mit bioinformatischen Mitteln genauer in seinen Wirkmechanismen beleuchtet und in Kombination mit anderen Medikamenten getestet mittels einer experimentell gestützten bioinformatischen Pathway-Modellierung. Durch diese Netzwerk-Analyse wurden verschiedene Angriffspunkte von MB auf das Redox-Netzwerk der Malariaerreger identifiziert. Daraufhin wurden CQ und SP-Resistenzen in silico simuliert. Weitere Analysen zeigten dabei, dass MB synergisitische Wirkungen mit anderen Therapeutika gegen Malaria aufzeigt, wenn sie zielgerichtet eingesetzt werden. Finanziell gesehen hat MB Potenzial, ein zweites CQ zu werden, und somit endlich wieder die Kosten der Behandlung für Menschen die in Armut leben erschwinglich zu machen. Malaria Kontrolle ist erreichbar, aber suboptimale Diagnosestellung und Behandlung behindern das Erreichen dieses Zieles. Hierfür muss eine angepasste, dezentrale und hochgradig standardisierte Primärbehandlung unkomplizierter Malaria implementiert werden und für eine bessere Verfügbarkeit dieser gesorgt werden. Leider leidet die Finanzierung der Kampagnen gegen Malaria an chronischer Unterversorgung. Um den maximalen Nutzen aus den vorhandenen Mitteln ziehen zu können ist eine günstigere medikamentöse Therapie ein entscheidender Beitrag, zumal Medikamente den größten Einzelbetrag im Kampf gegen Malaria verbrauchen. KW - Malaria KW - bioinformatic KW - socioeconomic KW - Methylene blue KW - developing country KW - therapy KW - diagnosis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-102863 ER - TY - JOUR A1 - Projahn, Delia A1 - Simsekyilmaz, Sakine A1 - Singh, Smriti A1 - Kanzler, Isabella A1 - Kramp, Birgit K. A1 - Langer, Marcella A1 - Burlacu, Alexandrina A1 - Bernhagen, Jürgen A1 - Klee, Doris A1 - Zernecke, Alma A1 - Hackeng, Tilman M. A1 - Groll, Jürgen A1 - Weber, Christian A1 - Liehn, Elisa A. A1 - Koenen, Roy R. T1 - Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction JF - Journal of Cellular and Molecular Medicine N2 - Myocardial infarction (MI) induces a complex inflammatory immune response, followed by the remodelling of the heart muscle and scar formation. The rapid regeneration of the blood vessel network system by the attraction of hematopoietic stem cells is beneficial for heart function. Despite the important role of chemokines in these processes, their use in clinical practice has so far been limited by their limited availability over a long time-span in vivo. Here, a method is presented to increase physiological availability of chemokines at the site of injury over a defined time-span and simultaneously control their release using biodegradable hydrogels. Two different biodegradable hydrogels were implemented, a fast degradable hydrogel (FDH) for delivering Met-CCL5 over 24hrs and a slow degradable hydrogel (SDH) for a gradual release of protease-resistant CXCL12 (S4V) over 4weeks. We demonstrate that the time-controlled release using Met-CCL5-FDH and CXCL12 (S4V)-SDH suppressed initial neutrophil infiltration, promoted neovascularization and reduced apoptosis in the infarcted myocardium. Thus, we were able to significantly preserve the cardiac function after MI. This study demonstrates that time-controlled, biopolymer-mediated delivery of chemokines represents a novel and feasible strategy to support the endogenous reparatory mechanisms after MI and may compliment cell-based therapies. KW - chemokines KW - therapy KW - cardiovascular pharmacology KW - remodelling KW - endothelial progenitor cells KW - left-ventricular function KW - heart-failure KW - rat model KW - recruitment KW - factor-I Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116597 SN - 1582-4934 VL - 18 IS - 5 ER - TY - JOUR A1 - Hetz, Susan A1 - Acikgoez, Ali A1 - Voss, Ulrike A1 - Nieber, Karen A1 - Holland, Heidrun A1 - Hegewald, Cindy A1 - Till, Holger A1 - Metzger, Roman A1 - Metzger, Marco T1 - In Vivo Transplantation of Neurosphere-Like Bodies Derived from the Human Postnatal and Adult Enteric Nervous System: A Pilot Study JF - PLOS ONE N2 - Recent advances in the in vitro characterization of human adult enteric neural progenitor cells have opened new possibilities for cell-based therapies in gastrointestinal motility disorders. However, whether these cells are able to integrate within an in vivo gut environment is still unclear. In this study, we transplanted neural progenitor-containing neurosphere-like bodies (NLBs) in a mouse model of hypoganglionosis and analyzed cellular integration of NLB-derived cell types and functional improvement. NLBs were propagated from postnatal and adult human gut tissues. Cells were characterized by immunohistochemistry, quantitative PCR and subtelomere fluorescence in situ hybridization (FISH). For in vivo evaluation, the plexus of murine colon was damaged by the application of cationic surfactant benzalkonium chloride which was followed by the transplantation of NLBs in a fibrin matrix. After 4 weeks, grafted human cells were visualized by combined in situ hybridization (Alu) and immunohistochemistry (PGP9.5, GFAP, SMA). In addition, we determined nitric oxide synthase (NOS)-positive neurons and measured hypertrophic effects in the ENS and musculature. Contractility of treated guts was assessed in organ bath after electrical field stimulation. NLBs could be reproducibly generated without any signs of chromosomal alterations using subtelomere FISH. NLB-derived cells integrated within the host tissue and showed expected differentiated phenotypes i.e. enteric neurons, glia and smooth muscle-like cells following in vivo transplantation. Our data suggest biological effects of the transplanted NLB cells on tissue contractility, although robust statistical results could not be obtained due to the small sample size. Further, it is unclear, which of the NLB cell types including neural progenitors have direct restoring effects or, alternatively may act via 'bystander' mechanisms in vivo. Our findings provide further evidence that NLB transplantation can be considered as feasible tool to improve ENS function in a variety of gastrointestinal disorders. KW - Hirschsprung disease KW - benzalkonium chloride KW - progenitors KW - GUT KW - rat KW - colon KW - biology KW - therapy KW - neural stem-cell KW - motility disorders Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116793 VL - 9 IS - 4 ER -