Model for time dependency of cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action.

CHS 828 is a novel drug belonging to the cyanoguanidines. It has shown promising anticancer activity in many preclinical systems and is currently in early clinical trials. Our aim in this study was to assess the growth inhibitory effect of CHS 828 in comparison with paclitaxel, etoposide, and topotecan as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h. Cell survival was measured after 72-h incubation by using the fluorometric microculture cytotoxicity assay. Nonlinear mixed effect modeling was used to model the concentration-effect curves with a modified Hill equation. Patterns of change of drug potency (IC(50)), slope of the concentration-effect curves, and plateau with time were studied. The log IC(50) for CHS 828 decreased with log time in a sigmoid manner for all cell types tested. Although very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC(50) for etoposide and topotecan was decreased with log time in a sigmoid manner. The log IC(50) for paclitaxel decreased linearly with log time. The information obtained from modeling the cytotoxic effect of CHS 828 and changes of IC(50) and slope parameters with exposure time suggests a heterogeneous cell response to CHS 828. This could indicate two distinct mechanisms of induction of cell death.     

Rollerblading and skateboarding injuries in children in northeast England.

OBJECTIVES: To establish the demographic profile and injury characteristics of children presenting with rollerblading or skateboarding associated injuries. This study also examines the circumstances leading to these injuries with a view to suggesting preventive measures. METHODS: A prospective study using a proforma to collect data from each child presenting with rollerblading or skateboarding related injuries. Injury details were obtained from clinical and radiological records. The injury severity score (ISS) was calculated for each child and statistical analysis was done using chi2. RESULTS: Eighty one children presented with rollerblading associated injuries accounting for 7% of childhood injuries seen during the eight month study period. The mean age was 10.3 years and sex distribution was equal. Soft tissue injuries accounted for 51% and fractures for 49% of the injuries. Wrist fractures alone accounted for 86% of all fractures seen. Seventy per cent of soft tissue injuries involved the upper limb. The overall mean ISS was 3.0 with a range from 1 to 9. Injury was attributed to fall secondary to loss of control or collision with an obstacle while rollerblading in the majority of children. Injury occurred while rollerblading in residential or public places in 99% of the children. In contrast skateboarding related injuries were much rarer and caused soft tissue injuries only. CONCLUSION: This study has revealed a higher incidence of rollerblading injuries than previously suspected. Effective management strategies should include not only the treatment of these injuries but also attention to their causes and prevention.     

Interaction of the hepatitis C virus (HCV) core with cellular genes in the development of HCV-induced steatosis

Hepatitis C virus (HCV) has chronically infected a large number of patients, leading to the development of steatosis, cirrhosis and, ultimately, hepatocellular carcinoma. The pathogenesis of HCV has not been fully explained, although steatosis is considered to contribute greatly to liver fibrosis progression, modulating host-cell lipid metabolism. Suspected underlying molecular mechanisms include interactions between HCV proteins and intracellular lipid metabolic pathways. Recent studies have suggested that the nucleocapsid of HCV (core) acts as a pathogenic factor involved in lipid droplet accumulation, changes in lipogenic gene expression and/or the activity of lipogenic proteins in a genotype-specific manner. In this review, we have tried to summarize the current knowledge regarding HCV-induced steatosis and the regulation of expression of host genes and receptors that aid in the viral life cycle and promote liver diseases.     

Estimation of impulse response between electromyogram signals for use in conduction delay distribution estimation

The time delay between two surface electromyograms (EMGs) acquired along the conduction path is used to estimate mean action potential conduction velocity. Modeling the linear impulse response between “upstream” and “downstream” EMG signals permits an estimate of the distribution of velocities, providing more information. In this work, we analyzed EMG from bipolar electrodes placed on the tibialis anterior of 36 subjects, using an inter-electrode distance of 10 mm. Regularized least squares was used to fit the coefficients of a finite impulse response model. We trained the model on one recording, then tested on two others. The optimum correlation between the model-predicted and actual EMG averaged 0.70. We also compared estimation of the mean conduction delay from the peak time of the impulse response to the “gold standard” peak time of the cross-correlation between the upstream and downstream EMG signals. Optimal models differed from the gold standard by 0.02 ms, on average. Model performance was influenced by the regularization parameters. The impulse responses, however, incorrectly contained substantive power at very low time delays, causing delay distribution estimates to exhibit high probabilities at very short conduction delays. Unrealistic distribution estimates resulted. Larger inter-electrode spacing may be required to alleviate this limitation.     

Evaluation of Fluoride Release in Chitosan-Modified Glass Ionomer Cements

ObjectiveThis study assessed the influence of chitosan nanoparticles on the fluoride-releasing ability of 4 glass ionomer cement (GIC) through an in vitro analysis.MethodsFour types of GIC (type II light cure universal restorative, type II universal restorative, GC Fuji VII, and type IX) were modified with nanochitosan particles; 10% chitosan was added to the glass ionomer liquid. Six specimens for each of the 4 groups were created, using expendable Teflon moulds. Discs of each type of GIC (n = 6) were immersed in deionised water at various time intervals. Electrodes selective for fluoride ions were employed to analyse the amount of released fluoride at 1, 7, 14, 21, and 28 days.ResultsChitosan-modified GICs showed greater fluoride release than conventional GICs at all time points. All samples showed an initial high release of fluoride that tapered off with time. The total amount of fluoride released increased from the 1st day to the 28th day on adding chitosan to all the 4 types of GIC. Amongst those, type IX high-strength posterior extra with chitosan released a considerably higher quantity of fluoride at all time intervals.ConclusionsIn all the experimental groups, adding chitosan to the glass ionomer liquid had an accelerating effect on its fluoride-releasing property.     

The adapter proteins of TLRs,TRIF and MYD88, are upregulated in depressed individuals

Background and aims. TRIF and MYD88 are intracellular adaptor proteins for TLR signaling, and altered expression of these molecules can lead to defective or unregulated immune responses. Furthermore, previous studies revealed that depression may alter immune responses, but its mechanisms of action are unclear yet. There is a possibility that immunity and depression are linked through molecules such as TRIF and MYD88, thus, the aim of this study was to evaluate the mRNA levels of TRIF and MYD88 in the PBMCs isolated from depressed medical students. Material and methods. The current study examined 38 depressed medical students studying in Iran and 43 healthy students from the same cohort as a control group. The mRNA levels of TRIF and MYD88 were examined in parallel with a housekeeping gene using real-time PCR. Results. Our results demonstrated that expression of TRIF and MYD88 were significantly elevated in PBMCs isolated from depressed patients when compared to healthy subjects. Conclusions. Based on the current results, it seems that chronic inflammation in depressed patients correlates to the over expression of TRIF and MYD88 genes. Our results show a possible link between the reported increases of chronic inflammation in depressed individuals with unbalanced expression of genes that regulate immunity.