Ivabradine (a hyperpolarization activated cyclic nucleotide-gated channel blocker) elevates the threshold for maximal electroshock-induced tonic seizures in mice

BackgroundThe aim of this study was to determine the effect of ivabradine (a hyperpolarization activated cyclic nucleotide-gated channel (HCN) blocker) on the threshold for maximal electroshock (MEST)-induced tonic seizures in mice.MethodsElectroconvulsionswere produced inmice bymeans of a current (sine-wave, 50Hz,maximum500V, strength from3–10mA, ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint).ResultsIvabradine administered intraperitoneally (ip), 60 min before the MEST test, at doses of 5 and 10 mg/kg, did not alter the threshold for maximal electroconvulsions in mice. In contrast, ivabradine at doses of 15 and 20 mg/kg significantly elevated the threshold for maximal electroconvulsions in mice (p < 0.05 and p < 0.001, respectively). Linear regression analysis of ivabradine doses and their corresponding threshold increases allowed determination of the threshold increasing doses by 20 and 50% (TID₂₀ and TID₅₀ values) that elevate the threshold in drug-treated animals over the threshold in control animals. The experimentally derived TID₂₀ and TID₅₀ values for ivabradine were 8.70 and 18.29 mg/kg, respectively.ConclusionsBased on this preclinical study, one can ascertain that ivabradine dose-dependently increased the threshold for MEST-induced seizures, suggesting the antiseizure activity of the compound in this seizure model in mice.     

Dupuytren’s disease and the risk of malignant neoplasms

The object of this study was the investigation of the risk of occurrence of malignant neoplasms in 508 patients with Dupuytren’s disease (DD) and in 2157 of their 1st degree relatives. In the first stage of the study, we evaluated the tumour spectrum as well as the age of the patient at diagnosis of cancers in DD families along with the observed and expected frequencies of malignancies. In the second stage of the study, we examined the distribution of 20 common mutations/polymorphisms in 12 known cancer susceptibility genes among DD patients and 508 matched healthy controls. No such study has been published to date. Results. No significant differences were noted between malignancies diagnosed among members of DD families and the general population. Molecular examination of 20 mutations/polymorphisms in 12 cancer susceptibility genes in Dupuytren’s patients and controls showed a statistically significant association of one mutation with Dupuytren disease: D312M in XPD (OR = 1.75, p = 0.004). We observed a tendency toward changed frequencies of occurrence of central nervous system tumors, laryngeal cancer and non-melanoma skin cancers in DD families. The results of our study indicate a lack of a strong association between Dupuytren disease and familial cancer risk.     

PRL-3 and E-cadherin show mutual interactions and participate in lymph node metastasis formation in gastric cancer

E-cadherin, a transmembrane adhesion molecule, and phosphatase of regenerating liver 3 (PRL-3) protein, a member of the family of tyrosine phosphatases, seem to be responsible for cancer cell migration. Therefore, the study objective was to determine a correlation between PRL-3 and E-cadherin, to assess their expression in neoplastic tissue and normal mucosa of the stomach, to analyze their effect on cancer advancement, and to evaluate their potential as prognostic markers in gastric cancer. The expressions of PRL-3 and E-cadherin were assessed immunohistochemically in 71 patients with gastric cancer. Positive expression of PRL-3 was observed in 42.2 % of gastric cancer cases, whereas E-cadherin expression was abnormal in 38 % of cases. The study revealed that the positive PRL-3 expression and abnormal E-cadherin expression were associated with mucinous gastric carcinoma and lymph node involvement. The former was also related to the infiltrating type of tumor and abnormal E-cadherin expression. The expression of PRL-3, but not of E-cadherin, was associated with shorter survival of patients. PRL-3 and E-cadherin exhibit interactions in gastric cancer and are involved in the formation of lymph node metastases. The PRL-3 protein can be an independent predictive factor of overall survival in gastric cancer patients.     

New insights into impairment of mucosal defense in portal hypertensive gastric mucosa

Portal hypertension (PHT) increases susceptibility of the gastric mucosa to injury. The aim of this study was to investigate whether PHT affects rat gastric mucosal defense mechanisms in vivo at the preepithelial, epithelial, and/or post-epithelial levels. PHT was produced in rats by staged portal vein ligation and sham-operated (SO) rats served as controls. The gastric mucosa was exposed, chambered, and continuously superfused with buffers under in vivo microscopy. We measured gastric mucosal gel layer thickness, surface epithelial cell intracellular pH (pH₁), mucosal blood flow, and mucosal/serosal oxygenation. In PHT rats, gastric mucosal gel layer thickness was significantly reduced (88 ±16 μm in PHT rats vs. 135 ±25 μm in SO rats; P <0.0001), and the surface epithelial cell pH₁ was significantly decreased (6.80 ± 0.11 in PHT rats vs. 7.09 ± 0.21 in SO rats; P <0.01). Although total gastric mucosal blood flow was significantly increased in PHT rats by 72 % (P <0.05), the oxygenation of the gastric mucosal surface was decreased by 42 % (P <0.05) compared with SO rats. PHT impairs pre-epithelial (mucosal gel layer thickness), epithelial (pH₁), and post-epithelial (maldistribution of blood flow) components of the gastric mucosal barrier. These findings can explain the increased susceptibility of portal hypertensive gastric mucosa to injury. Supported by Veterans Affairs Medical Research Service Merit Review Awards (J.D.K., I.J.S., and AS.T.) and a REAP award. Presented at the Fortieth Annual Meeting of The Society for Surgery of the Alimentary Tract, Orlando, Fla., May 16–19, 1999.     

Primary Angioplasty in Patient with St-Segment Elevation Myocardial Infarction in the Setting of Intentional Carbon Monoxide Poisoning

Background

ST-segment elevation myocardial infarction (STEMI) due to coronary artery occlusion in the setting of acute carbon monoxide (CO) poisoning is a very rare presentation.

Objective

Our aim was to report on the use of primary angioplasty in a patient with STEMI in the setting of CO poisoning.

Case Report

A 36-year-old man with retrosternal chest pain was admitted after exposure to CO. The initial electrocardiogram (ECG) showed ST depression in I, aVL, and V3−V4 with slight ST elevation in II, III, aVF leads. Toxic carboxyhemoglobin level of 22% and troponin I of 2.19 μg/L were confirmed. After oxygen therapy the chest pain diminished, but after about 15 h it returned. The repeat ECG revealed normalization of previous ST depression with persistent ST elevation in II, III, aVF leads. The troponin I concentration was 5.94 μg/L. An echocardiogram demonstrated an apex hypokinesia involving the adjacent segments of the anterior and lateral wall. On the coronary angiogram, an acute occlusion of the distal left anterior descending coronary artery was confirmed. Primary percutaneous coronary intervention (PCI) of the infarct-related artery was performed. After PCI, the patient was symptom free and had partial ST-segment elevation resolution. The patient was discharged home after 7 days, with persistent ST-T changes and mild hypokinesia of the apex suggesting myocardial injury.

Conclusions

Patients with toxic CO exposure who have symptoms of STEMI should be carefully evaluated with serial ECG, cardiac necrosis marker measurements, and an echocardiogram. When there is evidence of myocardial injury, a wider use of coronary angiography can identify patients who could benefit from PCI.     

Comparison of diffusion-weighted with T2-weighted imaging for detection of edema in acute myocardial infarction

Background

Recent studies, performed with the use of a commercially available diffusion weighted imaging (DWI) sequence, showed that they are sensitive to the increase of water content in the myocardium and may be used as an alternative to the standard T₂-weighted sequences. The aim of this study was to compare two methods of myocardial edema imaging: DWI and T₂-TIRM.

Methods

The study included 91 acute and post STEMI patients. We applied a qualitative and quantitative image analysis. The qualitative analysis consisted of evaluation of the quality of blood suppression, presence of artifacts and occurrence of high signal (edema) areas. On the basis of edema detection in AMI and control (post STEMI) group, the sensitivity and specificity of TIRM and DWI were determined. Two contrast to noise ratios (CNR) were calculated: CNR₁ - the contrast between edema and healthy myocardium and CNR₂ - the contrast between edema and intraventricular blood pool. The area of edema was measured for both TIRM and DWI sequences and compared with the infarct size in LGE images.

Results

Edema occurred more frequently in the DWI sequence. A major difference was observed in the inferior wall, where an edema-high signal was observed in 46% in T₂-TIRM, whereas in the DWI sequence in 85%. An analysis of the image quality parameters showed that the use of DWI sequence allows complete blood signal suppression in the left ventricular cavity and reduces the occurrence of motion artifacts. However, it is connected with a higher incidence of magnetic susceptibility artifacts and image distortion. An analysis of the CNRs showed that CNR₁ in T₂-TIRM sequence depends on the infarct location and has the lowest value for the inferior wall. The area of edema measured on DWI images was significantly larger than in T₂-TIRM.

Conclusions

DWI is a new technique for edema detection in patients with acute myocardial infarction which may be recommended for the diagnosis of acute injuries, especially in patients with slow-flow artifacts in TIRM images.     

Effect of bosentan on leptin and endothelin‐1 concentration in plasma and brain after cardiac arrest in rats

In previous studies, bosentan was found to decrease plasma leptin concentrations after myocardial infarction (MI) in rats and had decreased mortality. The present study was undertaken to examine the effect of bosentan on leptin and endothelin‐1 (ET‐1) concentrations in plasma and ET‐1 concentrations in the hippocampus after cardiac arrest (CA) in rats. Studies were performed in 72 rats divided into treated and untreated animals in the following experimental groups: control, 3 min, 10 min, 1 h, 24 h, and 7 days after CA. Bosentan was given daily 2 h before CA or decapitation, 7 days, by gavage at a dose of 100 mg/kg. Plasma leptin concentration decreased in the early period after CA, and being elevated in 24 h, normalized 1 week later. Bosentan kept plasma leptin concentration at the control level in the postischemic period. Plasma ET‐1 concentration significantly increased during the postischemic period. Bosentan produced the elevation of plasma ET‐1 concentration in the preischemic period and kept the level of ET‐1 at control values after CA. Concentration of ET‐1 in the hippocampus was significantly lower 24 h after CA and was elevated after 1 week. The most dramatic effect of bosentan on ET‐1 concentration was in the hippocampus, where it significantly decreased during the entire postischemic recovery period. We postulate an important effect of bosentan on concentration of ET‐1 and leptin in plasma and ET‐1 in the brain after global cerebral ischemia caused by CA. Drug Dev Res 64:137–144, 2005. © 2005 Wiley‐Liss, Inc.     

Immunochemical studies of the lipopolysaccharides of Hafnia alvei PCM 1219 and other strains with the O-antigens containing D-glucose 1-phosphate and 2-deoxy-2-[(R)-3-hydroxybutyramido]-D-glucose

Introduction:   Hafnia alveiis the only species of the genus Hafnia, which belongs to the family of Enterobacteriaceae. These Gram-negative bacteria are commonly distributed in the natural environment and are often the cause of human opportunistic infections. Their lipopolysaccharides (LPSs) are important surface antigens which are responsible for the serological specificity and numerous cross-reactions with other enterobacterial genera. So far, 29 different O-polysaccharide (OPS, O-antigen) structures in Hafnias LPSs have been established and for some of them the molecular basis of the serological activity has been elucidated. Materials and Methods:  OPS from H. alvei strain PCM 1219 was obtained by mild acid hydrolysis of the LPS followed by gel permeation chromatography of carbohydrate material on Sephadex G-50 column. The polysaccharide structure was determined using chemical methods as well as ¹³C NMR and ¹H NMR spectroscopy. For serological studies, SDS-PAGE, immunoblotting, and passive hemagglutination tests were used. Results:  The serological studies revealed a cross-reactivity of the LPSs of H. alvei PCM 1219 and a group of H. alvei strains with an O-antigen containing D-glucose 1-phosphate and [(R)-3-hydroxybutyramido]-D-glucose. The following structure of the OPS was established: where Acyl stands for (R)-3-hydroxybutyryl and the degree of O-acetylation is ~70%. The structure of the core oligosaccharide was found to be typical of the genus Hafnia. Conclusions:  Based on the OPS structure and serological results it was concluded that H. alvei strain PCM 1219 should be classified in the same serogroup as the H. alvei type strain ATCC 13337 and five other strains containing D-glucose 1-phosphate and 2-deoxy-2-[(R)-3-hydroxybutyramido]-D-glucose in their O-antigens. Received: 2007.10.10, Accepted: 2008.06.30     

Tuberin-heterozygous cell line TSC2ang1 as a model for tuberous sclerosis-associated skin lesions

Tuberous sclerosis (TS), neurological disorder manifesting with the formation of tumors in numerous organ systems, is a disease associated with the upregulation of mammalian target of rapamycin (mTOR) pathway. It has been found that in healthy individuals two tumor suppressor genes, TSC1 and TSC2, encoding proteins called hamartin and tuberin, respectively, are responsible for the control over mTOR kinase. Loss of one of these genes constitutes the genetic background of TS. In the current study, we aimed at evaluating the fitness of the only TS-associated sarcoma cell line deposited in American Tissue Culture Collection, TSC2ang1, for the in vitro studies on TS. We found that the line shows a stable chromosome pattern with typical Robertsonian translocations. Similarly to primary tumors from TS patients, TSC2ang1 cells respond to rapamycin-induced mTOR inhibition. The cells demonstrate activation of both Akt and Erk pathways, but inhibition of neither of them is as effective as mTOR suppression when considering proliferation potential. Based on these results we propose TSC2ang1 as a good and stable model for pathophysiological and pharmacological studies on skin lesions in TS.