A comparative study of orthotropic and isotropic bone adaptation in the femur.

Functional adaptation of the femur has been studied extensively by embedding remodelling algorithms in finite element models, with bone commonly assumed to have isotropic material properties for computational efficiency. However, isotropy is insufficient in predicting the directionality of bone's observed microstructure. A novel iterative orthotropic 3D adaptation algorithm is proposed and applied to a finite element model of the whole femur. Bone was modelled as an optimised strain-driven adaptive continuum with local orthotropic symmetry. Each element's material orientations were aligned with the local principal stress directions and their corresponding directional Young's moduli updated proportionally to the associated strain stimuli. The converged predicted density distributions for a coronal section of the whole femur were qualitatively and quantitatively compared with the results obtained by the commonly used isotropic approach to bone adaptation and with ex vivo imaging data. The orthotropic assumption was shown to improve the prediction of bone density distribution when compared with the more commonly used isotropic approach, whilst producing lower comparative mass, structurally optimised models. It was also shown that the orthotropic approach can provide additional directional information on the material properties distributions for the whole femur, an advantage over isotropic bone adaptation. Orthotropic bone models can help in improving research areas in biomechanics where local structure and mechanical properties are of key importance, such as fracture prediction and implant assessment. © 2014 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons, Ltd

A preliminary investigation into the determination of the inaudibility of mechanical plant and music noise in the presence of ambient background noise

Currently there are regulations and guidelines that governing bodies have adopted when dealing with the emission of noise that make reference to or imply the term of inaudibility when setting criteria to be met for mechanical p lant and music noise after restricted hours. However, to date no such criteria has been established that can predict the inaudibility of these sources when combined with ambient backgrounds. As a result, stakeholders are met with uncertainty and designers are left with an inadequate subjective term when attempting to meet location-sp ecific noise criteria. This paper involves an investigation into the possibilities of conducting a psychoacoustic experiment that will test for the inaudibility of mechanical p lant and music noise in the presence of ambient background noise typical of the home environment situated in urban and suburban locations. This paper attempts to provide the framework for future larger scale investigations and provides the relevant findings and a methodology to assist in reducing the subjective nature of the responses observed. Through these future investigations, objective definable criteria from which to establish the inaudibility of mechanical plant and music noise in the presence of ambient background noise may be establishe

Consideration of multiple load cases is critical in modelling orthotropic bone adaptation in the femur

Functional adaptation of the femur has been investigated in several studies by embedding bone remodelling algorithms in finite element (FE) models, with simpli- fications often made to the representation of bone’s material symmetry and mechanical environment. An orthotropic strain-driven adaptation algorithm is proposed in order to predict the femur’s volumetric material property distribution and directionality of its internal structures within a continuum. The algorithm was applied to a FE model of the femur, with muscles, ligaments and joints included explicitly. Multiple load cases representing distinct frames of two activities of daily living (walking and stair climbing) were considered. It is hypothesised that low shear moduli occur in areas of bone that are simply loaded and high shear moduli in areas subjected to complex loading conditions. In addition, it is investigated whether material properties of different femoral regions are stimulated by different activities. The loading and boundary conditions were considered to provide a physiological mechanical environment. The resulting volumetric material property distribution and directionalities agreed with ex vivo imaging data for the whole femur. Regions where non-orthogonal trabecular crossing has been documented coincided with higher values of predicted shear moduli. The topological influence of the different activities modelled was analysed. The influence of stair climbing on the properties of the femoral neck region is highlighted. It is recommended that multiple load cases should be considered when modelling bone adaptation. The orthotropic model of the complete femur is released with this study

May I have your consent? Informed consent in clinical trials- feasibility in emergency situations

Clinical researchers in acute emergency settings are commonly faced with the difficulty of satisfying the conventional ethical requirement of obtaining informed consent, whilst ensuring a representative group of patients is recruited into studies. We discuss our own experience in addressing institutional ethical requirements to obtain informed consent in a multi-centre trial, recruiting highly agitated patients in the emergency setting in Melbourne, Australia. We suggest that, through the application of existing ethical and legal frameworks and pre-emptive communication with the key stakeholders in ethics committees, hospital insurers and legal representatives, a balance can be struck between ethical and legal requirements on the one hand, and the integrity of the research question, on the other.published_or_final_versio

Catalysis by hen egg-white lysozyme proceeds via a covalent intermediate

Hen egg-white lysozyme (HEWL) was the first enzyme to have its three-dimensional structure determined by X-ray diffraction techniques(1). A catalytic mechanism, featuring a long-lived oxo-carbenium-ion intermediate, was proposed on the basis of model-building studies(2). The `Phillips' mechanism is widely held as the paradigm for the catalytic mechanism of beta -glycosidases that cleave glycosidic linkages with net retention of configuration of the anomeric centre. Studies with other retaining beta -glycosidases, however, provide strong evidence pointing to a common mechanism for these enzymes that involves a covalent glycosyl-enzyme intermediate, as previously postulated(3). Here we show, in three different cases using electrospray ionization mass spectrometry, a catalytically competent covalent glycosyl-enzyme intermediate during the catalytic cycle of HEWL. We also show the three-dimensional structure of this intermediate as determined by Xray diffraction. We formulate a general catalytic mechanism for all retaining beta -glycosidases that includes substrate distortion, formation of a covalent intermediate, and the electrophilic migration of C1 along the reaction coordinate

Interpretation of ambiguous situations: evidence for a dissociation between social and physical threat in Williams syndrome

There is increasing evidence that Williams syndrome (WS) is associated with elevated anxiety that is non-social in nature, including generalised anxiety and fears. To date very little research has examined the cognitive processes associated with this anxiety. In the present research, attentional bias for non-social threatening images in WS was examined using a dot-probe paradigm. Participants were 16 individuals with WS aged between 13 and 34 years and two groups of typically developing controls matched to the WS group on chronological age and attentional control ability respectively. The WS group exhibited a significant attention bias towards threatening images. In contrast, no bias was found for group matched on attentional control and a slight bias away from threat was found in the chronological age matched group. The results are contrasted with recent findings suggesting that individuals with WS do not show an attention bias for threatening faces and discussed in relation to neuroimaging research showing elevated amygdala activation in response to threatening non-social scenes in WS

The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone

A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II

During the acquisition of memories, influx of Ca^(2+) into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca^(2+) influx during the first few seconds of activity is interpreted within the Ca^(2+)-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca^(2+) ions. As a first step toward clarifying how the Ca^(2+)-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca^(2+), calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca^(2+) play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing ofCa^(2+) signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca^(2+) is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca^(2+) transients arises from the kinetics of interaction of fluctuating Ca^(2+) with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning