Bored with point and click?

Computers have the potential to be exploited as one of the most exciting examples of instructional media. Yet designers often fail to realize this potential. This is, in part, due to the limitations of hardware and software and, in part, due to the lack of good theory developed through conclusive research. Good examples of computer-based learning may owe more to the imaginative flair of the courseware designer than they do to the application of explicit design guidelines and good learning theory. This paper will therefore consider a variety of issues that may be blocking theoretical development and draw conclusions for future courses of action. This starts with a statement of the problem, first by considering the macro and micro issues, and then by looking at a recent call for help in ComputerBased Learning Environment (CBLE) design. Next, the contribution of instructional design theories will be presented together with a way forward for investigating the issues. Finally the implications for future progress are presented

A proposed psychological model of driving automation

This paper considers psychological variables pertinent to driver automation. It is anticipated that driving with automated systems is likely to have a major impact on the drivers and a multiplicity of factors needs to be taken into account. A systems analysis of the driver, vehicle and automation served as the basis for eliciting psychological factors. The main variables to be considered were: feed-back, locus of control, mental workload, driver stress, situational awareness and mental representations. It is expected that anticipating the effects on the driver brought about by vehicle automation could lead to improved design strategies. Based on research evidence in the literature, the psychological factors were assembled into a model for further investigation

Mapping the methylation status of the miR-145 promoter in saphenous vein smooth muscle cells from individuals with type 2 diabetes

Type 2 diabetes mellitus prevalence is growing globally, and the leading cause of mortality in these patients is cardiovascular disease. Epigenetic mechanisms such as microRNAs (miRs) and DNA methylation may contribute to complications of type 2 diabetes mellitus. We discovered an aberrant type 2 diabetes mellitus–smooth muscle cell phenotype driven by persistent up-regulation of miR-145. This study aimed to determine whether elevated expression was due to changes in methylation at the miR-145 promoter. Smooth muscle cells were cultured from saphenous veins of 22 non-diabetic and 22 type 2 diabetes mellitus donors. DNA was extracted, bisulphite treated and pyrosequencing used to interrogate methylation at 11 CpG sites within the miR-145 promoter. Inter-patient variation was high irrespective of type 2 diabetes mellitus. Differential methylation trends were apparent between non-diabetic and type 2 diabetes mellitus–smooth muscle cells at most sites but were not statistically significant. Methylation at CpGs −112 and −106 was consistently lower than all other sites explored in non-diabetic and type 2 diabetes mellitus–smooth muscle cells. Finally, miR-145 expression per se was not correlated with methylation levels observed at any site. The persistent up-regulation of miR-145 observed in type 2 diabetes mellitus–smooth muscle cells is not related to methylation at the miR-145 promoter. Crucially, miR-145 methylation is highly variable between patients, serving as a cautionary note for future studies of this region in primary human cell types

Manipulation of the spin helix in FeGe thin films and FeGe/Fe multilayers

Magnetic materials without structural inversion symmetry can display the Dzyaloshinskii-Moriya interaction, which manifests itself as chiral magnetic ground states. These chiral states can interact in complex ways with applied fields and boundary conditions provided by finite sample sizes that are of the order of the lengthscale of the chiral states. Here we study epitaxial thin films of FeGe with a thickness close to the helix pitch of the helimagnetic ground state, which is about 70 nm, by conventional magnetometry and polarized neutron reflectometry. We show that the helix in an FeGe film reverses under the application of a field by deforming into a helicoidal form, with twists in the helicoid being forced out of the film surfaces on the way to saturation. An additional boundary condition was imposed by exchange coupling a ferromagnetic Fe layer to one of the interfaces of an FeGe layer. This forces the FeGe spins at the interface to point in the same direction as the Fe, preventing node expulsion and giving a handle by which the reversal of the helical magnet may be controlled

Cardiac fibroblast-specific p38α MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin-6 signaling mechanism

Recent studies suggest that cardiac fibroblast-specific p38α MAPK contributes to the development of cardiac hypertrophy, but the underlying mechanism is unknown. Our study used a novel fibroblast-specific, tamoxifen-inducible p38α knockout (KO) mouse line to characterize the role of fibroblast p38α in modulating cardiac hypertrophy, and we elucidated the mechanism. Myocardial injury was induced in tamoxifen-treated Cre-positive p38α KO mice or control littermates via chronic infusion of the β-adrenergic receptor agonist isoproterenol. Cardiac function was assessed by pressure-volume conductance catheter analysis and was evaluated for cardiac hypertrophy at tissue, cellular, and molecular levels. Isoproterenol infusion in control mice promoted overt cardiac hypertrophy and dysfunction (reduced ejection fraction, increased end systolic volume, increased cardiac weight index, increased cardiomyocyte area, increased fibrosis, and up-regulation of myocyte fetal genes and hypertrophy-associated microRNAs). Fibroblast-specific p38α KO mice exhibited marked protection against myocardial injury, with isoproterenol-induced alterations in cardiac function, histology, and molecular markers all being attenuated. In vitro mechanistic studies determined that cardiac fibroblasts responded to damaged myocardium by secreting several paracrine factors known to induce cardiomyocyte hypertrophy, including IL-6, whose secretion was dependent upon p38α activity. In conclusion, cardiac fibroblast p38α contributes to cardiomyocyte hypertrophy and cardiac dysfunction, potentially via a mechanism involving paracrine fibroblast-to-myocyte IL-6 signaling.-Bageghni, S. A., Hemmings, K. E., Zava, N., Denton, C. P., Porter, K. E., Ainscough, J. F. X., Drinkhill, M. J., Turner, N. A. Cardiac fibroblast-specific p38α MAP kinase promotes cardiac hypertrophy via a putative paracrine interleukin-6 signaling mechanism

Screening for urinary tract colonisation prior to corticosteroid administration in acute multiple sclerosis relapses: Validation of an updated algorithm

INTRODUCTION: To evaluate an updated algorithm in the detection of urinary tract infection (UTI) prior to high-dose corticosteroid treatment in acute relapses in multiple sclerosis (MS). This updated algorithm aimed to decrease the unnecessary use of antibiotics, whilst maintaining accuracy and safety. METHODS: Prospective cohort study of 471 consecutive patients with MS relapses in a hospital-based outpatient acute relapse clinic. 172 patients met exclusion criteria, leaving 299 patients for analysis. Patients underwent urine dipstick and were treated for UTI if 2 or more of: nitrites, leukocyte esterase and cloudy urine were positive. Patients with confirmed acute MS relapse were treated with high dose intravenous or oral methylprednisolone. RESULTS: Significant bacteriuria (>105 colony forming units/mL) was present in 33 (11%, 95% CI 8-15) patients. The algorithm sensitivity and specificity was 24% and 94% respectively; the negative predictive value was 91%. The overall accuracy of the algorithm was 87%. No adverse sequelae were identified in 25 patients who received high dose methylprednisolone in the presence of an untreated UTI. CONCLUSION: With an improved specificity, this updated algorithm addresses previous issues concerning the unnecessary prescription of antibiotics, whilst improving accuracy and maintaining safety

Aberrant phenotype in human endothelial cells of diabetic origin: Implications for saphenous vein graft failure?

Type 2 diabetes (T2DM) confers increased risk of endothelial dysfunction, coronary heart disease, and vulnerability to vein graft failure after bypass grafting, despite glycaemic control. This study explored the concept that endothelial cells (EC) cultured from T2DM and nondiabetic (ND) patients are phenotypically and functionally distinct. Cultured human saphenous vein-(SV-) EC were compared between T2DM and ND patients in parallel. Proliferation, migration, and in vitro angiogenesis assays were performed; western blotting was used to quantify phosphorylation of Akt, ERK, and eNOS. The ability of diabetic stimuli (hyperglycaemia, TNF-α, and palmitate) to modulate angiogenic potential of ND-EC was also explored. T2DM-EC displayed reduced migration (30%) and angiogenesis (40%) compared with ND-EC and a modest, nonsignificant trend to reduced proliferation. Significant inhibition of Akt and eNOS, but not ERK phosphorylation, was observed in T2DM cells. Hyperglycaemia did not modify ND-EC function, but TNF-α and palmitate significantly reduced angiogenic capacity (by 27% and 43%, resp.), effects mimicked by Akt inhibition. Aberrancies of EC function may help to explain the increased risk of SV graft failure in T2DM patients. This study highlights the importance of other potentially contributing factors in addition to hyperglycaemia that may inflict injury and long-term dysfunction to the homeostatic capacity of the endothelium

Tenascin C upregulates interleukin-6 expression in human cardiac myofibroblasts via toll-like receptor 4.

AIM: To investigate the effect of Tenascin C (TNC) on the expression of pro-inflammatory cytokines and matrix metalloproteinases in human cardiac myofibroblasts (CMF). METHODS: CMF were isolated and cultured from patients undergoing coronary artery bypass grafting. Cultured cells were treated with either TNC (0.1 μmol/L, 24 h) or a recombinant protein corresponding to different domains of the TNC protein; fibrinogen-like globe (FBG) and fibronectin type III-like repeats (TNIII 5-7) (both 1 μmol/L, 24 h). The expression of the pro-inflammatory cytokines; interleukin (IL)-6, IL-1β, TNFα and the matrix metalloproteinases; MMPs (MMP1, 2, 3, 9, 10, MT1-MMP) was assessed using real time RT-PCR and western blot analysis. RESULTS: TNC increased both IL-6 and MMP3 (P < 0.01) mRNA levels in cultured human CMF but had no significant effect on the other markers studied. The increase in IL-6 mRNA expression was mirrored by an increase in protein secretion as assessed by enzyme-linked immunosorbant assay (P < 0.01). Treating CMF with the recombinant protein FBG increased IL-6 mRNA and protein (P < 0.01) whereas the recombinant protein TNIII 5-7 had no effect. Neither FBG nor TNIII 5-7 had any significant effect on MMP3 expression. The expression of toll-like receptor 4 (TLR4) in human CMF was confirmed by real time RT-PCR, western blot and immunohistochemistry. Pre-incubation of cells with TLR4 neutralising antisera attenuated the effect of both TNC and FBG on IL-6 mRNA and protein expression. CONCLUSION: TNC up-regulates IL-6 expression in human CMF, an effect mediated through the FBG domain of TNC and via the TLR4 receptor