Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca2+ channel and the type 1 ryanodine receptor

Malignant hyperthermia (MH) susceptibility is a dominantly inherited disorder in which volatile anesthetics trigger aberrant Ca(2+) release in skeletal muscle and a potentially fatal rise in perioperative body temperature. Mutations causing MH susceptibility have been identified in two proteins critical for excitation-contraction (EC) coupling, the type 1 ryanodine receptor (RyR1) and Ca(V)1.1, the principal subunit of the L-type Ca(2+) channel. All of the mutations that have been characterized previously augment EC coupling and/or increase the rate of L-type Ca(2+) entry. The Ca(V)1.1 mutation R174W associated with MH susceptibility occurs at the innermost basic residue of the IS4 voltage-sensing helix, a residue conserved among all Ca(V) channels [Carpenter D, et al. (2009) BMC Med Genet 10:104-115.]. To define the functional consequences of this mutation, we expressed it in dysgenic (Ca(V)1.1 null) myotubes. Unlike previously described MH-linked mutations in Ca(V)1.1, R174W ablated the L-type current and had no effect on EC coupling. Nonetheless, R174W increased sensitivity of Ca(2+) release to caffeine (used for MH diagnostic in vitro testing) and to volatile anesthetics. Moreover, in Ca(V)1.1 R174W-expressing myotubes, resting myoplasmic Ca(2+) levels were elevated, and sarcoplasmic reticulum (SR) stores were partially depleted, compared with myotubes expressing wild-type Ca(V)1.1. Our results indicate that Ca(V)1.1 functions not only to activate RyR1 during EC coupling, but also to suppress resting RyR1-mediated Ca(2+) leak from the SR, and that perturbation of Ca(V)1.1 negative regulation of RyR1 leak identifies a unique mechanism that can sensitize muscle cells to MH triggers.     

A three-component biomarker panel for prediction of dengue hemorrhagic fever

Dengue virus infections are a major cause of morbidity in tropical countries. Early detection of dengue hemorrhagic fever (DHF) may help identify individuals that would benefit from intensive therapy. Predictive modeling was performed using 11 laboratory values of 51 individuals (38 DF and 13 DHF) obtained on initial presentation using logistic regression. We produced a robust model with an area under the curve of 0.9615 that retained IL-10 levels, platelets, and lymphocytes as the major predictive features. A classification and regression tree was developed on these features that were 86% accurate on cross-validation. The IL-10 levels and platelet counts were also identified as the most informative features associated with DHF using a Random Forest classifier. In the presence of polymerase chain reaction-proven acute dengue infections, we suggest a complete blood count and rapid measurement of IL-10 can assist in the triage of potential DHF cases for close follow-up or clinical intervention improving clinical outcome.     

The Role of the Epiglottis in the Swallow Process after a Partial or Total Glossectomy Due to a Neoplasm

Repeatable epiglottic movement patterns were recorded during a videofluoroscopic swallow evaluation of 95 patients who had undergone a total or partial glossectomy due to a neoplasm. Because no epiglottic function assessment was performed preoperatively, for the purpose of this study it was assumed that epiglottic mobility was “normal” during this time and that all abnormalities found afterward resulted from the growth of the neoplasm and the glossectomy. It was noted that in the early postoperative period, absence of epiglottic movement was accompanied by aspiration and made swallowing incompetent in a majority of cases (9 of 10). A correlation of movement between the epiglottis and the extent of oral tissue excision was found. Epiglottic mobility was evaluated as “normal” in 72% of the patients, i.e., in 67 of 91 (74%) patients after a partial or nearly total glossectomy and in 1 of 4 people who underwent a total glossectomy. In the subgroup (16%) of patients who underwent a total or nearly total glossectomy and then had videofluoroscopic examinations, 60% of the cases had normal epiglottic movements and 40% had an immobile epiglottis. Compensatory mechanisms implemented by the patients on their own initiative, such as additional swallows and prolonged apnea during deglutition, enabled them to avoid aspiration. However, upward head movement and downward chin tilting during deglutition as compensatory mechanisms used by patients with no epiglottic movement did not reduce the aspiration risk in the early postoperative period and were found to accompany incompetent swallowing attempts.     

Soluble ST2 protein in chronic heart failure is independent of traditional factors

Introduction

ST2 protein is the interleukin 33 (IL-33) receptor, whose serum level depends on the biomechanical strain of cardiac myocytes. The aim of this study was to analyse the relationship between soluble ST2 (sST2) level and traditional factors in patients with chronic heart failure.

Material and methods

Sixty-six patients (mean age 62 years, 75% males) in stable NYHA class I-III with left ventricular ejection fraction < 45% were included in the study. Clinical, biochemical, electrocardiographic, echocardiographic and angiographic data were analysed. Patients were divided into groups depending on sST2 median: > 0.28 ng/ml (n = 31) vs. ≤ 0.28 ng/ml (n = 35). sST2 was measured using a quantitative ELISA kit. In order to define factors associated with sST2 levels uni- and multivariate regression analysis was performed.

Results

There was no relationship between sST2 levels and age (p = 0.67), body mass index (p = 0.19), hsTnT (p = 0.7) or other analysed parameters (all p > 0.05), except for N-terminal prohormone B-type natriuretic peptide (NT-proBNP). A significant positive correlation between sST2 and NT-proBNP was found (p = 0.013, R = 0.395). Multivariate analysis revealed that the stage of coronary artery disease and NT-proBNP were independent factors associated with sST2 concentration (p = 0.04). Intriguing is the fact that the fewer the sclerotic changes present in arteries, the higher was the sST2 level (β = –0.381, p = 0.04).

Conclusions

sST2 protein is independent of traditional factors which usually affect levels of NT-proBNP. In chronic heart failure, sST2 protein may be of greater importance in idiopathic dilated cardiomyopathy than in ischaemic aetiology, which seems to be associated with the molecular mechanism (biomechanical strain) related to sST2.     

Activation of phosphoinositide 3-kinase delta by antipsychotic drugs: Preliminary results

Background

Catalytic subunit delta of phosphoinositide 3-kinase, p110δ, encoded by the PIK3CD gene, was recently proposed as a target for pharmacological treatment of schizophrenia. Current antipsychotic drugs were found to decrease the mRNA expression of PIK3CD, but the mechanism of this process is not known. The aim of the study was to elucidate the mechanism by which antipsychotic drugs affect the mRNA expression of PIK3CD.

Characterization of Graphite Oxide and Reduced Graphene Oxide Obtained from Different Graphite Precursors and Oxidized by Different Methods Using Raman Spectroscopy Statistical Analysis

In this paper, various graphite oxide (GO) and reduced graphene oxide (rGO) preparation methods are analyzed. The obtained materials differed in their properties, including (among others) their oxygen contents. The chemical and structural properties of graphite, graphite oxides, and reduced graphene oxides were previously investigated using Raman spectroscopy (RS), X-ray photoelectron spectroscopy (XPS), and X-ray diffraction (XRD). In this paper, hierarchical clustering analysis (HCA) and analysis of variance (ANOVA) were used to trace the directions of changes of the selected parameters relative to a preparation method of such oxides. We showed that the oxidation methods affected the physicochemical properties of the final products. The aim of the research was the statistical analysis of the selected properties in order to use this information to design graphene oxide materials with properties relevant for specific applications (i.e., in gas sensors).     

High Martensitic Steel after Welding with Micro-Jet Cooling in Microstructural and Mechanical Investigations

Modern means of transport will play a significant role in the smart city. In the automotive industry, high-strength steels such as Docol are employed more often. This kind of material is relatively not very well weldable. The main reason is related to the Heat Affect Zone, the region in which cracks occur. Another disadvantage is connected with differences in values of ultimate strength of parent and weld material. The differences can be diminished using the correct welding process, which employs nickel and molybdenum electrode wires at much lower sulfur content. The weld metal deposit contains mainly martensite and bainite with coarse ferrite, while the parent material contains mainly martensite and rather fine ferrite. New technology, micro-jet cooling after the joining process enables to obtain the microstructure of weld metal deposit at acceptable parameters. Welding with micro-jet cooling could be treated as a very promising welding Docol steels process with high industrial application. Results of non-destructive inspections on macro samples corresponded with further destructive test results (tensile strength, hardness, fatigue, metallographic structure analyses). This article aims to verify fatigue behavior of Docol 1200 M steel after welding supported by the cooling using the micro-jet technique. For the first time, micro-jet cooling was used to weld this kind of steel to check the mechanical properties of the joint, especially to determine the fatigue limit. This study is formulated as follows: investigating fatigue resistance of the Docol 1200 M weld manufactured at the cooling process with micro-jets. The joints were produced in the MAG (Metal Active Gas) technology modified by micro-jet cooling. The results collected in the fatigue test were processed in the form of the Wöhler’s S–N diagram following the fatigue limit of the weld examined. All data have indicated the possibility of obtaining a new method of welded joints with high fatigue limit minimum of 480 MPa. It could be important to achieve a tensile strength of 700 MPa while maintaining the best relative elongation at the level of the base material.