Role of alphaV-integrin in Cardiac Hypertrophic Growth in Response to Pressure Overload

In dieser Arbeit sollen die funktionellen Zusammenhänge zwischen Integrinrezeptoren und myokardialer Hypertrophieentwicklung am Maus-Model nach aortic-banding untersucht werden. Durch den Einsatz eines Integrin-alphaV/Beta3 und alphaV/beta5-Inhibitors (EMD 270179 der Fa. Merck) konnten gezielt diese Integrinrezeptoren gehemmt werden. Mittels morphologischen, histologischen, immunhistochemischen, biochemischen und bildgebenden Verfahren konnten bekannte Signalwegskaskaden reproduziert und eben auch eine mangelhaft einsetzende Hypertrophieentwicklung unter Integrin-Blockade nachgewiesen werden. Innerhalb von 2-7 Tagen (Untersuchungszeitraum) setzte in der Gruppe der behandelten Tiere eine myokardiale Dilatation ein, die mit einer deulich eingeschränkten linksventrikulären Funktion einherging. Nahezu die Hälfte der Tiere verstarben konsekutiv, während die unbehandelten Tiere deutlich bessere Überlebenschancen zeigten. Ein zur transthorakalen Aortenkonstriktion vergleichbares Ereignis beim Menschen wäre eine langjährig bestehende, unbehandelte arterielle Hypertonie oder eine Aortenstenose. Beides sind jedoch Ereignisse, die in der Regel nicht derart akut einsetzen, sondern sich entwickeln. Demnach wäre ein möglicher Einsatz beim Menschen nach entsprechenden Studien zur Ermittlung des optimalen Therapie-Fensters zu diskutieren.We examined the functional connections between integrin-receptors and cardiac hypertrophy development in mouse model after aortic-banding. By application of an alphaV/Beta3 and alphaV/beta5-inhibitor (EMD 270179 Fa Merck) these integin-receptors could be restrained. By means of morphological, histologic, immunhistologic, biochemical and picture-giving procedures known signal way cascades could be reproduced. Also a faultily starting hypertrophy development under integrin-inhibition could be proved. Within 2-7 days (investigation period) in the group of the treated animals, cardiac dilatation started which was associated with a notable depressed leftventricular function. Nearly half of the animals died consecutively, while the untreated animals showed clearly better survival chances. One to aortic-banding comparable event in human would be a for many years existing, untreated arterial hypertension or an valvular aortic stenosis. Nevertheless, both are events which start as a rule not so urgently, but develop. Therefore, a possible application in humans would be to be discussed according to suitable studies to the inquiry of the optimum therapy window

Close geographic association of human neoehrlichiosis and tick populations carrying Candidatus Neoehrlichia mikurensis in Eastern Switzerland

Neoehrlichiosis caused by Candidatus Neoehrlichia mikurensis is an emerging zoonotic disease. In total, 6 patients have been described in Europe with the first case detected in 2008 and 7 patients in China published in October 2012. In 2009, we diagnosed the first human case of C. Neoehrlichia mikurensis infection in the Zurich area (Switzerland). Here, we report two additional human cases from the same region, which were identified by broad-range 16S rRNA gene PCR. Both patients were immunocompromised and presented with a similar clinical syndrome including fever, malaise and weight loss. A diagnostic multiplex real-time PCR was developed for specific detection of C. Neoehrlichia mikurensis infections. The assay is based on the signature sequence of a 282-bp fragment of the C. Neoehrlichia mikurensis 16S rRNA gene and incorporates a C. Neoehrlichia mikurensis species, a Neoehrlichia genus and an Anaplasmataceae family probe for simultaneous screening. The analytical sensitivity of was determined to be below 5 copies of the C. Neoehrlichia mikurensis 16S rRNA gene. Our results show that the assay is suitable for the direct detection of C. Neoehrlichia mikurensis DNA in clinical samples like blood and bone marrow. In addition, it allows for monitoring treatment response during antibiotic therapy. Using the same assay, DNA extracts from 1916 ticks collected in four forests in close proximity to the patients' residences (<3 km) were screened. At all sampling sites, the minimal prevalence of C. Neoehrlichia mikurensis was between 3.5-8% in pools of either nymphs, males or females, showing a strong geographic association between the three patients and the assumed vector