Ghrelin inhibits vascular superoxide production in spontaneously hypertensive rats

BACKGROUND: Ghrelin is a novel peptide involved in the control of appetite, but its role in vascular pathologies remains to be elucidated. Ghrelin was shown to decrease blood pressure (BP) and improve endothelial function. Its plasma levels are correlated with BP in humans. Mechanisms of these effects are unknown. Because oxidative stress and increased superoxide production by NAD(P)H oxidases (Nox) are critical in the pathogenesis of hypertension, we aimed to study the effects of ghrelin on vascular superoxide production and NAD(P)H oxidase activity in spontaneously hypertensive rats (SHR). METHODS: Aortic superoxide production and NAD(P)H oxidase activity were measured using lucigenin (5 micromol/L) chemiluminescence. Aortas from Wistar-Kyoto rats (WKY) were used as control. Direct superoxide scavenging properties of ghrelin were tested using xanthine-xanthine oxidase system. RESULTS: Both basal superoxide production and vascular NADPH oxidase activity were significantly higher in aortas from SHR, than from WKY. Preincubation of aortic segments from SHR or WKY with ghrelin caused concentration-dependent (from 50 pg/mL to 5 ng/mL) decrease of basal superoxide production. Vascular NAD(P)H oxidase activity was inhibited by ghrelin, abolishing the difference between SHR and basal WKY. Ghrelin did not affect superoxide release from the in vitro xanthine-xanthine oxidase system, indicating lack of direct superoxide scavenging properties or inhibitory effects on xanthine oxidase in vitro. Nitric oxide synthase (NOS) inhibition, using N(omega)-nitro-L-arginine methyl ester (L-NAME), partially blunted the effects of ghrelin on NADPH oxidase activity indicating potential role of nitric oxide. CONCLUSIONS: Ghrelin inhibits vascular oxidative stress in SHR. This effect is likely related to the inhibition of vascular NAD(P)H oxidases.     

Characterization of focal liver lesions with SonoVue- enhanced sonography： International multicenter-study in comparison to CT and MRI

AIM： To evaluate in a multicenter study whether the sonographic characterization of focal liver lesions can be improved using SonoVue-enhancement; and to compare this method with computed tomography （CT） and magnetic resonance imaging （MRI）.
METHODS： One hundred and thirty four patients withone focal liver lesion detected in baseline ultrasound （US） were examined with conventional US, contrastenhanced US （n = 134）, contrast-enhanced CT （n = 115） and/or dynamic contrast-enhanced MRI （n = 70）. The lesions were classified as malignant, benign or indeterminate and the type of lesion was determined. The final diagnosis based on the combined information of all imaging examinations, clinical information and histology （n = 32） was used. Comparisons were made to see whether the addition of contrast-enhanced US led to the improvement of the characterization of doubtful focal liver lesions.
RESULTS： In comparison with unenhanced US, SonoVue markedly improves sensitivity and specificity for the characterization （malignant/benign） of focal liver lesions. In comparison with CT and/or dynamic MRI, SonoVue -enhanced sonography applied for characterization of focal liver lesions was 30.2% more sensitive in the recognition of malignancy and 16.1% more specific in the exclusion of malignancy and overall 22.9% more accurate. In the subgroup with confirmative histology available （n = 30）, sensitivity was 95.5% （CEUS）, 72.2% （CT） and 81.8% （MRI）, and specificity was 75.0% （CEUS）, 37.5% （CT） and 42.9% （MRI）. The sensitivity and specificity of CEUS for the identification of focal nodular hyperplasia （FNH） and hemangiomas was 100% and 87%, resulting in an accuracy of 94.5%.
CONCLUSION： SonoVue-enhanced sonography emerges as the most sensitive, ost specific and thus most accurate imaging modality for the characterization of focal liver lesions.     

Specialisation and specialist education in prosthetic dentistry in Europe

This presentation reports on the results of a meeting of prosthodontists from selected European countries. The aim of the meeting was to analyse and promote specialisation and specialist education in Prosthetic Dentistry in Europe. Representatives for Europe were selected from the European Prosthodontic Association (EPA) board, the Education and Research Committee of International College of Prosthodontists (ICP), countries with a legally recognised speciality, countries without a recognised speciality but organised training programmes and countries with neither of these situations. Data about specialisation and specialist training in Prosthodontics in Europe was scrutinised and discussed. The programmes for countries with specialist training had relatively similar content, mostly of three years duration. There was strong agreement that a recognised speciality raises the level of care within the discipline for both specialists and non-specialists. In several of the countries where a speciality had been introduced it had been initiated by pressure from public health planning authorities. The conclusions are that from a professional viewpoint an advancement of the speciality over Europe would develop the discipline, improve oral health planning and quality of patient care. A working group for harmonisation was recommended.     

Helicobacter pylori promotes apoptosis, activates cyclooxygenase (COX)-2 and inhibits heat shock protein HSP70 in gastric cancer epithelial cells

Objective

Apoptosis plays an important role in the regulation of gastric epithelial cell number and gastrointestinal disorders induced by Helicobacter pylori (Hp). Heat shock proteins (HSPs) are involved in cell integrity, cell growth and in gastric mucosa colonized by Hp. COX-2 was implicated in Hp-induced carcinogenesis but the effects of this germ and CagA cytotoxin on HSP70, COX-2, Bax and Bcl-2 in gastric cancer epithelial cells have been little studied.

Material and methods

We determined the expression for HSP70, Bax and Bcl-2 in human gastric epithelial MKN7 cells incubated with live strain Hp (cagA?+?vacA+) with or without co-incubation with exogenous CagA and NS-398, the selective COX-2 inhibitor. After 3–48?h of incubation, the expression of HSP70, COX-2, Bax and Bcl-2 mRNA and proteins were determined by RT-PCR and immunoprecipitation.

Results

Hp inhibited expression for HSP70 and this was significantly potentiated by exogenous CagA. Co-incubation of epithelial cells with Hp, without or with CagA increased Bax expression and simultaneously decreased expression for Bcl-2. The increase in COX-2 mRNA and Bax expression were significantly inhibited by NS-398. We conclude that Hp promotes apoptosis in adenocarcinoma gastric epithelial cells in vitro and this is associated with activation of COX-2 and inhibition of HSP70.     

Intrauterine exposure to lead may enhance sensitization to common inhalant allergens in early childhood: a prospective prebirth cohort study

Background

Several in vivo and in vitro studies have shown that metal-rich particles may enhance allergic responses to house dust mites and induce an increased release of allergy-related cytokines.

Objectives

The main goal of this analysis is to define the possible association of intrauterine exposure to lead and mercury with the occurrence of skin sensitization to common aeroallergens in early childhood.

Material and methods

The present study refers to a sample of 224 women in the second trimester of pregnancy recruited from Krakow inner city area who had full term pregnancies and whose children underwent skin prick testing (SPT) at the age of 5. Lead and mercury levels were assessed in cord blood and retested in children at age of 5 years. Aeroallergen concentrations in house dust were measured at the age of 3 years. The main health outcome (atopic status) was defined as the positive SPT to at least one common aeroallergen (Der f1, Der p1, Can f1 and Fel d1) at the age of 5 years. In the statistical analysis of the association between atopic status of children and exposure to metals, the study considered a set of covariates such as maternal characteristics (age, education, atopy), child’s gender, number of older siblings, prenatal (measured via cord blood cotinine) and postnatal environmental tobacco smoke together with exposure to polycyclic aromatic hydrocarbons (PAH) as measured by PAH-DNA adducts.

Results and conclusion

In the binary regression analysis, which controlled for the confounders, the risk ratio (RR) estimate for atopic sensitization was significantly associated with the lead exposure (RR=2.25, 95%CI: 1.21−4.19). In conclusion, the data suggest that even very low-level of prenatal lead exposure may be implicated in enhancing sensitization to common aeroallergens in early childhood.     

The impact of supramolecular nanocarriers to contemporary pharmaceutical and analytical chemistry: a minireview

The paper gives a short review of the most important research results published recently in the field of the applications of supramolecular nanocarriers in modern pharmaceutical and analytical chemistry. The main attention has been paid to the fast developing technology of chemical sensors, ion-selective electrodes and separation methods, in particular to newly designed packing in high-performance liquid chromatography employing supramolecularly aided and membrane mimicking processes.     

Low-Dose Glucose-Insulin-Potassium Is Ineffective in Acute Myocardial Infarction: Results of a Randomized Multicenter Pol-GIK Trial

Summary. We aimed to assess the clinical efficacy of glucose-insulin-potassium (GIK) in acute myocardial infarction. Experimental data provided evidence of the beneficial effects of GIK on ischemic myocardium. The clinical trials, mostly uncontroled and conducted mainly before the thrombolytic era, were inconclusive due to the small number of patients and discrepancies in protocols. In order to evaluate the efficacy of this intervention, we have performed a prospective multicenter randomized study. The study consisted of 954 patients with acute myocardial infarction (MI) randomized within 24 hours from the onset of symptoms to low-dose GIK (n = 494), which consisted of 1000 mL 10% dextrose, 32–20 U insulin, and 80 mEq K+, or to the control group (n = 460), which was given 1000 mL 0.09% sodium chloride, by intravenous 24-hour infusion at a rate of 42 mL/h. Cardiac mortality and the occurrence of cardiac events at 35 days did not differ between GIK and control-allocated patients (32 (6.5%) vs. 21 (4.6%), respectively; OR 1.45, 95% CI 0.79–2.68, P = 0.20; and 214 (43.3%) vs. 192 (41.7%), OR 1.07, 95% CI 0.82–1.38, P = 0.62). Total mortality at 35 days was significantly higher in the GIK than in the control group (44 (8.9%) vs. 22 (4.8%), respectively, OR 1.95, 95% CI 1.12–3.47, P = 0.01). The excess of noncardiac deaths in the GIK group may have occurred by chance. Low-dose GIK treatment does not improve the survival and clinical course in acute MI.     

The Discovery of Conformationally Constrained Bicyclic Peptidomimetics as Potent Hepatitis C NS5A Inhibitors

HCV NS5A inhibitors are the backbone of directly acting antiviral treatments against the hepatitis C virus (HCV). While these therapies are generally highly curative, they are less effective in some specific HCV patient populations. In the search for broader-acting HCV NS5A inhibitors that address these needs, we explored conformational restrictions imposed by the [7,5]-azabicyclic lactam moiety incorporated into daclatasvir (1) and related HCV NS5A inhibitors. Unexpectedly, compound 5 was identified as a potent HCV genotype 1a and 1b inhibitor. Molecular modeling of 5 bound to HCV genotype 1a suggested that the use of the conformationally restricted lactam moiety might have resulted in reorientation of its N-terminal carbamate to expose a new interaction with the NS5A pocket located between amino acids P97 and Y93, which was not easily accessible to 1. The results also suggest new chemistry directions that exploit the interactions with the P97–Y93 site toward new and potentially improved HCV NS5A inhibitors.