Combined blockade of AT1-receptors and ACE synergistically potentiates antihypertensive effects in SHR

OBJECTIVES AND DESIGN: To check whether antihypertensive effects are additive or synergistic upon blockade of both angiotensin (AT1)-receptors and angiotensin-converting enzyme (ACE), spontaneously hypertensive rats (SHR) were treated with candesartan-cilexetil (0.1-30 mg/kg per day), ramipril (0.03-10 mg/kg per day), the calcium-antagonist mibefradil (1-150 mg/kg per day) or combinations thereof. Systolic blood pressure (SBP), left ventricular weight (LVW) and the cardiac activity/mRNA levels of ACE were determined. RESULTS: SBP was decreased by candesartan-cilexetil [inhibitory concentration (IC50) (mg/kg): 2.47], ramipril (1.97), mibefradil (4.41), candesartan-cilexetil/ramipril (0.68), and candesartan-cilexetil/mibefradil (5.68). Combining candesartan-cilexetil with ramipril increased SBP reduction synergistically rather than additively, since the dose-response curve was shifted 6.6-fold leftwards compared to a hypothetically generated additive curve, calculated by summing up the doses and corresponding effects of the ramipril and candesartan-cilexetil monotreatment regimes. A total threshold dose < 5.14 mg/kg (derived from dose-response curves) was found to exert synergistic effects when candesartan-cilexetil was combined with ramipril. Antihypertensive effects of mibefradil can not be increased when combined with candesartan-cilexetil. When LVW was correlated with SBP reduction, regression lines of candesartan-cilexetil, ramipril and their combination were congruent, while that for mibefradil was significantly flatter and became steeper under candesartan-cilexetil co-administration. Cardiac ACE activity was greatly reduced by ramipril independently of SBP reduction and dosage. With SBP-ineffective doses of ramipril, cardiac ACE mRNA levels were doubled, indicating a positive feedback mechanism. The increase in ACE mRNA was renormalized when SPB-effective ramipril doses were applied, suggesting a blood pressure-dependent regulation of cardiac ACE expression. CONCLUSIONS: Since synergy was observed only after combining low doses of ramipril and candesartan-cilexetil, prospective clinical trials should be performed on a low-dose combination, revealing the antihypertensive/antiproliferative benefits.     

Erste Erfahrungen mit dem neuen stationären Heilverfahren der Deutschen Gesetzlichen Unfallversicherung

Trauma und Berufskrankheit - Zum 01.01.2013 sind in der gesetzlichen Unfallversicherung die neuen Anforderungen an Krankenhäuser für die Beteiligung am stationären...     

The systems biology of mitochondrial fission and fusion and implications for disease and aging

Mitochondria organize themselves as dynamic populations within a cell, by undergoing continuous cycles of fission and fusion. The spatio-temporal distribution and abundance of mitochondria determines the cell’s energy budget and is thus intimately linked to the cell’s response to environmental stimuli during aging. The dynamic balance of mitochondrial fission and fusion can be studied in terms of antagonistic subpopulations that regulate the mitochondrial responses in space and time. The dynamic nature of these processes motivates mathematical modelling and the simulation of such complex process. In several neurodegenerative and metabolic diseases the dynamic balance of fission and fusion is disturbed. However, how this dynamics plays a role in the progression of diseases is largely unclear. Fission and fusion help mitochondria to regulate cellular energy (ATP) levels, and minimize accumulation of harmful oxidized material called reactive oxygen species which accelerate mutations in mitochondrial DNA (mtDNA) during aging. We discuss how systems biology approaches can be used to investigate the mechanisms controlling the fission–fusion dynamics under two categories: dissecting the design of its molecular regulatory motifs, and understanding complex mitochondrial responses through their population level interactions. This will help us to understand how different regulatory mechanisms regulate the ATP and mutation (mtDNA) landscape of mitochondria to a variety of environmental stimuli in order to maintain their function during aging.     

The impact of elevated serum IgG4 levels in patients with primary sclerosing cholangitis

Background

Elevated IgG4 levels have been reported among patients with primary sclerosing cholangitis. Epidemiological data has only been provided from tertiary centres.

Aims

To investigate the prevalence of elevated IgG4 levels and to compare prognosis between patients with and without elevated IgG4 levels in serum in two European cohorts of patients with primary sclerosing cholangitis.

Methods

Serum IgG4-levels were measured in a consecutive series of patients from Berlin, and retrospectively collected in a population-based cohort from Sweden (total N = 345). Cox's proportional hazard analysis was used to calculate relative risks for liver-related death or liver transplantation and cholangiocarcinoma.

Results

Elevated IgG4 values were demonstrated in 10% of patients. A previous history of pancreatitis, combined intra- and extrahepatic biliary involvement and jaundice were independently associated with elevated IgG4 in multivariate analysis. IgG4 status was not associated with an increased risk for the combined endpoint liver-related death or liver transplantation or cholangiocarcinoma.

Conclusion

The prevalence of elevated IgG4 values among European patients with primary sclerosing cholangitis is similar to what previously has been reported from the United States. Elevated IgG4 was not associated with an increased risk of liver transplantation or liver-related death or cholangiocarcinoma.     

Surface Structure Characterization of Aspergillus fumigatus Conidia Mutated in the Melanin Synthesis Pathway and Their Human Cellular Immune Response

In Aspergillus fumigatus, the conidial surface contains dihydroxynaphthalene (DHN)-melanin. Six-clustered gene products have been identified that mediate sequential catalysis of DHN-melanin biosynthesis. Melanin thus produced is known to be a virulence factor, protecting the fungus from the host defense mechanisms. In the present study, individual deletion of the genes involved in the initial three steps of melanin biosynthesis resulted in an altered conidial surface with masked surface rodlet layer, leaky cell wall allowing the deposition of proteins on the cell surface and exposing the otherwise-masked cell wall polysaccharides at the surface. Melanin as such was immunologically inert; however, deletion mutant conidia with modified surfaces could activate human dendritic cells and the subsequent cytokine production in contrast to the wild-type conidia. Cell surface defects were rectified in the conidia mutated in downstream melanin biosynthetic pathway, and maximum immune inertness was observed upon synthesis of vermelone onward. These observations suggest that although melanin as such is an immunologically inert material, it confers virulence by facilitating proper formation of the A. fumigatus conidial surface.