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Background
Riociguat is the first of a new class of drugs, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body’s own NO and can also increase sGC activity in the absence of NO. The NO-sGC-pathway is impaired in many cardiovascular diseases such as heart failure, pulmonary hypertension and diabetic nephropathy (DN). DN leads to high cardiovascular morbidity and mortality. There is still a high unmet medical need. The urinary albumin excretion rate is a predictive biomarker for these clinical events. Therefore, we investigated the effect of riociguat, alone and in combination with the angiotensin II receptor antagonist (ARB) telmisartan on the progression of DN in diabetic eNOS knock out mice, a new model closely resembling human pathology.
Methods
Seventy-six male eNOS knockout C57BL/6J mice were divided into 4 groups after receiving intraperitoneal high-dose streptozotocin: telmisartan (1 mg/kg), riociguat (3 mg/kg), riociguat+telmisartan (3 and 1 mg/kg), and vehicle. Fourteen mice were used as non-diabetic controls. After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were highly increased and similar in all diabetic groups.
Results
Riociguat, alone (105.2 ± 2.5 mmHg; mean±SEM; n = 14) and in combination with telmisartan (105.0 ± 3.2 mmHg; n = 12), significantly reduced blood pressure versus diabetic controls (117.1 ± 2.2 mmHg; n = 14; p = 0.002 and p = 0.004, respectively), whereas telmisartan alone (111.2 ± 2.6 mmHg) showed a modest blood pressure lowering trend (p = 0.071; n = 14). The effects of single treatment with either riociguat (97.1 ± 15.7 µg/d; n = 13) or telmisartan (97.8 ± 26.4 µg/d; n = 14) did not significantly lower albumin excretion on its own (p = 0.067 and p = 0.101, respectively). However, the combined treatment led to significantly lower urinary albumin excretion (47.3 ± 9.6 µg/d; n = 12) compared to diabetic controls (170.8 ± 34.2 µg/d; n = 13; p = 0.004), and reached levels similar to non-diabetic controls (31.4 ± 10.1 µg/d, n = 12).
Conclusion
Riociguat significantly reduced urinary albumin excretion in diabetic eNOS knock out mice that were refractory to treatment with ARB’s alone. Patients with diabetic nephropathy refractory to treatment with ARB’s have the worst prognosis among all patients with diabetic nephropathy. Our data indicate that additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for patients with diabetic nephropathy resistant to ARB treatment.
Due to their optical and electro-conductive attributes, carbazole derivatives are interesting materials for a large range of biosensor applications. In this study, we present the synthesis routes and fluorescence evaluation of newly designed carbazole fluorosensors that, by modification with uracil, have a special affinity for antiretroviral drugs via either Watson–Crick or Hoogsteen base pairing. To an N-octylcarbazole-uracil compound, four different groups were attached, namely thiophene, furane, ethylenedioxythiophene, and another uracil; yielding four different derivatives. Photophysical properties of these newly obtained derivatives are described, as are their interactions with the reverse transcriptase inhibitors such as abacavir, zidovudine, lamivudine and didanosine. The influence of each analyte on biosensor fluorescence was assessed on the basis of the Stern–Volmer equation and represented by Stern–Volmer constants. Consequently we have demonstrated that these structures based on carbazole, with a uracil group, may be successfully incorporated into alternative carbazole derivatives to form biosensors for the molecular recognition of antiretroviral drugs.
Saccades move objects of interest into the center of the visual field for high-acuity visual analysis. White, Stritzke, and Gegenfurtner (Current Biology, 18, 124–128, 2008) have shown that saccadic latencies in the context of a structured background are much shorter than those with an unstructured background at equal levels of visibility. This effect has been explained by possible preactivation of the saccadic circuitry whenever a structured background acts as a mask for potential saccade targets. Here, we show that background textures modulate rates of microsaccades during visual fixation. First, after a display change, structured backgrounds induce a stronger decrease of microsaccade rates than do uniform backgrounds. Second, we demonstrate that the occurrence of a microsaccade in a critical time window can delay a subsequent saccadic response. Taken together, our findings suggest that microsaccades contribute to the saccadic facilitation effect, due to a modulation of microsaccade rates by properties of the background.
Das Reckahner Besucherbuch
(2011)
Der Band setzt sich mit Entwicklungen auseinander, die seit der Mitte des 18. Jahrhunderts das Bild der europäischen Aufklärung nachhaltig prägten. Die durch ein eng geknüpftes Kommunikationsnetz miteinander verbundenen Gelehrten und Gebildeten begannen sich für das Volk und dessen Lebensumstände, für Erziehung und Bildung sowie für vielerlei ökonomische Fragen zu interessieren. Dabei begnügten sie sich nicht mehr mit dem gelehrten Diskurs über diese Gegenstände, sondern widmeten sich zugleich auch der Umsetzung ihrer aufklärerischen Reformvorstellungen.
Aufklärung war also weit mehr als eine abgehobene Geistesbewegung. Diese Tatsache wird mit den Beiträgen des vorliegenden Bandes, der die Ergebnisse einer fächer-, grenzen- und sprachenübergreifenden Tagung dokumentiert, erneut unter Beweis gestellt. Die Erfahrung der beteiligten Wissenschaftler besagt allerdings, dass Erkenntnisse, die in der einen Disziplin als gesichert und selbstverständlich gelten, in benachbarten Fachrichtungen noch keineswegs in der genügenden Breite und Intensität rezipiert sein müssen. Die Herausgeber verstehen die hier präsentierten 24 Aufsätze von Verfassern unterschiedlicher Couleur und verschiedener Nationalität deshalb auch als ein nachdrückliches Plädoyer für ein höheres Maß an Interdisziplinarität in den Geisteswissenschaften.