Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects

OBJECTIVES: We investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure. BACKGROUND: Angiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF. METHODS: Three hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks. RESULTS: Acutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change -7.3 +/- 0.8 mm Hg) and SBP (40 mg: -11.7 +/- 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups. CONCLUSIONS: In CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF.     

A set of specific miRNAs is connected with murine and human gastric cancer

MircoRNAs as a new class of regulatory molecules have been investigated in many specific cells and organs in healthy and diseased conditions. Although miRNA signatures can be directly assessed in patients' affected tissues such as tumor sections, recent studies revealed that miRNA profiles can also be obtained indirectly, that is, from the patients' peripheral blood. For better understanding of miRNA's contribution to gastric carcinoma (one of the leading causes of cancer‐related mortality worldwide), we screened for deregulated miRNAs in blood collected from human cancer patients and compared the expression patterns with a gastric carcinoma mouse model (Tff1 knock‐out). The profiles were assessed using species‐specific miRNA microarrays. Among many dozens of deregulated miRNAs (219 in H. sapiens; 75 in M. musculus), a subset of eight miRNAs comparable in sequence from both species was noted. By in silico analysis, their involvement in targeting neoplastic and MAPkinase pathways was demonstrated. We found a high probability of linkage of all noted miRNAs to pathways in cancer with P‐values of 0.013 and 0.018 in mice and humans, respectively. Linkage to the MAPK‐signaling pathway in mice was observed with a P‐value of 0.01. Moreover, when comparing the 219 deregulated miRNAs obtained from blood with deregulated miRNAs derived from gastric cancer (GC) tissues, as published previously, 24 miRNAs were identical. If confirmed in a larger patient pool, these miRNAs could constitute appropriate blood‐born biomarkers for GC. © 2012 Wiley Periodicals, Inc.     

CT-guided high-dose-rate brachytherapy of unresectable hepatocellular carcinoma

Strahlentherapie und Onkologie - The purpose of the present study was to evaluate the clinical outcome of CT-guided high-dose-rate brachytherapy (CT-HDRBT) in patients with unresectable...     

123I]-phenylpentadecanoic acid uptake in patients with dilated cardiomyopathy

BACKGROUND: The rate constant for global fatty acid influx (k(1)) was studied in 12 male patients with dilated cardiomyopathy (DCM). METHOD: 10 normal subjects served as controls. 201-Thallium (201TI) and [123I]-phenyl-pentadecanoic acid (IPPA) were administered during bicycle exercise under fasting conditions. RESULTS: All patients showed non-homogeneous tracer uptake defects for 201TI and IPPA. k(1) was significantly higher in DCM patients than controls. k(1) showed significant inverse correlation between cardiac index, left-ventricular ejection fraction, left-ventricular enddiastolic pressure and echocardiographic left-ventricular ejection fraction. CONCLUSION: We presume that an increased regional rate constant of IPPA influx into the myocardial tissue in patients with DCM reflects a compensatory mechanism of altered myocardium.     

Preclinical In Vitro Assessment of Submicron-Scale Laser Surface Texturing on Ti6Al4V

Loosening of orthodontic and orthopedic implants is a critical and common clinical problem. To minimize the numbers of revision surgeries due to peri-implant inflammation or insufficient osseointegration, developments of new implant manufacturing strategies are indicated. Ultrafast laser surface texturing is a promising contact-free technology to modify the physicochemical properties of surfaces toward an anti-infectious functionalization. This work aims to texture Ti6Al4V surfaces with ultraviolet (UV) and green (GR) radiation for the manufacturing of laser-induced periodic surface structures (LIPSS). The assessment of these surface modifications addresses key aspects of topography, morphology and chemical composition. Human primary mesenchymal stromal cells (hMSCs) were cultured on laser-textured and polished Ti6Al4V to characterize the surfaces in terms of their in vitro biocompatibility, cytotoxicity, and metal release. The outcomes of the in vitro experiment show the successful culture of hMSCs on textured Ti6Al4V surfaces developed within this work. Cells cultured on LIPSS surfaces were not compromised in terms of their viability if compared to polished surfaces. Yet, the hMSC culture on UV-LIPSS show significantly lower lactate dehydrogenase and titanium release into the supernatant compared to polished. Thus, the presented surface modification can be a promising approach for future applications in orthodontics and orthopedics.     

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.     

Local cooling reduces regional bone blood flow

Local cooling is very common after bone and joint surgery. Therefore the knowledge of bone blood flow during local cooling is of substantial interest. Previous studies revealed that hypothermia leads to vasoconstriction followed by decreased blood flow levels. The aim of this study was to characterize if local cooling is capable of inducing reduced blood flow in bone tissue using a stepwise‐reduced temperature protocol in experimental rabbits. To examine bone blood flow we utilized the fluorescent microsphere (FM) method. In New Zealand white rabbits one randomly chosen hind limb was cooled stepwise from 32 to 2°C, whereas the contra lateral hind limb served as control. Injection of microspheres was performed after stabilization of bone and muscle temperature at each temperature level. Bones were removed, dissected and fluorescence intensity was determined to calculate blood flow values. We found that blood flow of all cooled regions decreased relative to the applied external temperature. At maximum cooling blood flow was almost completely disrupted, indicating local cooling as powerful regulatory mechanism for regional bone blood flow (RBBF). Postoperative cooling therefore may lead to strongly decreased bone blood flow values. As a result external cooling has capacity to both diminish bone healing and reduce bleeding complications. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1820–1827, 2013