Experimental and computer simulation validation of ultrasound phase interference created by lateral inhomogeneity of transit time in replica bone marrow composite models

Purpose: The measurement of broadband ultrasonic attenuation (BUA) in cancellous bone for the assessment of osteoporosis follows a parabolic-type dependence with bone volume fraction; having minima values corresponding to both entire bone and entire marrow. Langton has recently proposed that the primary BUA mechanism may be significant phase interference due to variations in propagation transit time through the test sample as detected over the phase-sensitive surface of the receive ultrasound transducer. This fundamentally simple concept assumes that the propagation of ultrasound through a complex solid : liquid composite sample such as cancellous bone may be considered by an array of parallel ‘sonic rays’. The transit time of each ray is defined by the proportion of bone and marrow propagated, being a minimum (tmin) solely through bone and a maximum (tmax) solely through marrow. A Transit Time Spectrum (TTS), ranging from tmin to tmax, may be defined describing the proportion of sonic rays having a particular transit time, effectively describing lateral inhomogeneity of transit time over the surface of the receive ultrasound transducer. Phase interference may result from interaction of ‘sonic rays’ of differing transit times. The aim of this study was to test the hypothesis that there is a dependence of phase interference upon the lateral inhomogenity of transit time by comparing experimental measurements and computer simulation predictions of ultrasound propagation through a range of relatively simplistic solid:liquid models exhibiting a range of lateral inhomogeneities. Methods: A range of test models was manufactured using acrylic and water as surrogates for bone and marrow respectively. The models varied in thickness in one dimension normal to the direction of propagation, hence exhibiting a range of transit time lateral inhomogeneities, ranging from minimal (single transit time) to maximal (wedge; ultimately the limiting case where each sonic ray has a unique transit time). For the experimental component of the study, two unfocused 1 MHz ¾” broadband diameter transducers were utilized in transmission mode; ultrasound signals were recorded for each of the models. The computer simulation was performed with Matlab, where the transit time and relative amplitude of each sonic ray was calculated. The transit time for each sonic ray was defined as the sum of transit times through acrylic and water components. The relative amplitude considered the reception area for each sonic ray along with absorption in the acrylic. To replicate phase-sensitive detection, all sonic rays were summed and the output signal plotted in comparison with the experimentally derived output signal. Results: From qualtitative and quantitative comparison of the experimental and computer simulation results, there is an extremely high degree of agreement of 94.2% to 99.0% between the two approaches, supporting the concept that propagation of an ultrasound wave, for the models considered, may be approximated by a parallel sonic ray model where the transit time of each ray is defined by the proportion of ‘bone’ and ‘marrow’. Conclusions: This combined experimental and computer simulation study has successfully demonstrated that lateral inhomogeneity of transit time has significant potential for phase interference to occur if a phase-sensitive ultrasound receive transducer is implemented as in most commercial ultrasound bone analysis devices.

Travelling waves for a velocity–jump model of cell migration and proliferation

Cell invasion, characterised by moving fronts of cells, is an essential aspect of development, repair and disease. Typically, mathematical models of cell invasion are based on the Fisher–Kolmogorov equation. These traditional parabolic models can not be used to represent experimental measurements of individual cell velocities within the invading population since they imply that information propagates with infinite speed. To overcome this limitation we study combined cell motility and proliferation based on a velocity–jump process where information propagates with finite speed. The model treats the total population of cells as two interacting subpopulations: a subpopulation of left–moving cells, $L(x,t)$, and a subpopulation of right–moving cells, $R(x,t)$. This leads to a system of hyperbolic partial differential equations that includes a turning rate, $\Lambda \ge 0$, describing the rate at which individuals in the population change direction of movement. We present exact travelling wave solutions of the system of partial differential equations for the special case where $\Lambda = 0$ and in the limit that $\Lambda \to \infty$. For intermediate turning rates, $0 < \Lambda < \infty$, we analyse the travelling waves using the phase plane and we demonstrate a transition from smooth monotone travelling waves to smooth nonmonotone travelling waves as $\Lambda$ decreases through a critical value $\Lambda_{crit}$. We conclude by providing a qualitative comparison between the travelling wave solutions of our model and experimental observations of cell invasion. This comparison indicates that the small $\Lambda$ limit produces results that are consistent with experimental observations.

Destination branding performance measurement for practitioners

While academic interest in destination branding has been gathering momentum since the field commenced in the late 1990s, one important gap in this literature that has received relatively little attention to date is the measurement of destination brand performance. This paper sets out one method for assessing the performance of a destination brand over time. The intent is to present an approach that will appeal to marketing practitioners, and which is also conceptually sound. The method is underpinned by Decision Set Theory and the concept of Consumer-Based Brand Equity (CBBE), while the key variables mirror the branding objectives used by many destination marketing organisations (DMO). The approach is demonstrated in this paper to measure brand performance for Australia in the New Zealand market. It is suggested the findings provide indicators of both i) the success of previous marketing communications, and ii) future performance, which can be easily communicated to a DMO’s stakeholders.

Prostate gland and extra-capsular tissue 3D reconstruction and measurement

Currently there are little objective parameters that can quantify the success of one form of prostate surgical removal over another. Accordingly, at Old Dominion University (ODU) we have been developing a process resulting in the use of software algorithms to assess the coverage and depth of extra-capsular soft tissue removed with the prostate by the various surgical approaches. Parameters such as the percent of capsule that is bare of soft tissue and where present the depth and extent of coverage have been assessed. First, visualization methods and tools are developed for images of prostate slices that are provided to ODU by the Pathology Department at Eastern Virginia Medical School (EVMS). The visualization tools interpolate and present 3D models of the prostates. Measurement algorithms are then applied to determine statistics about extra-capsular tissue coverage. This paper addresses the modeling, visualization, and analysis of prostate gland tissue to aid in quantifying prostate surgery success. Particular attention is directed towards the accuracy of these measurements and is addressed in the analysis discussions.

Gravity-driven fingering simulations for a thin liquid film flowing down the outside of a vertical cylinder

A numerical study is presented to examine the fingering instability of a gravity-driven thin liquid film flowing down the outer wall of a vertical cylinder. The lubrication approximation is employed to derive an evolution equation for the height of the film, which is dependent on a single parameter, the dimensionless cylinder radius. This equation is identified as a special case of that which describes thin film flow down an inclined plane. Fully three-dimensional simulations of the film depict a fingering pattern at the advancing contact line. We find the number of fingers observed in our simulations to be in excellent agreement with experimental observations and a linear stability analysis reported recently by Smolka & SeGall (Phys Fluids 23, 092103 (2011)). As the radius of the cylinder decreases, the modes of perturbation have an increased growth rate, thus increasing cylinder curvature partially acts to encourage the contact line instability. In direct competition with this behaviour, a decrease in cylinder radius means that fewer fingers are able to form around the circumference of the cylinder. Indeed, for a sufficiently small radius, a transition is observed, at which point the contact line is stable to transverse perturbations of all wavenumbers. In this regime, free surface instabilities lead to the development of wave patterns in the axial direction, and the flow features become perfectly analogous to the two-dimensional flow of a thin film down an inverted plane as studied by Lin & Kondic (Phys Fluids 22, 052105 (2010)). Finally, we simulate the flow of a single drop down the outside of the cylinder. Our results show that for drops with low volume, the cylinder curvature has the effect of increasing drop speed and hence promoting the phenomenon of pearling. On the other hand, drops with much larger volume evolve to form single long rivulets with a similar shape to a finger formed in the aforementioned simulations.

Improving the measurement and surveillance of child abuse in Queensland emergency departments

There are no population studies of prevalence or incidence of child maltreatment in Australia. Child protection data gives some understanding but is restricted by system capacity and definitional issues across jurisdictions. Child protection data currently suggests that numbers of reports are increasing yearly, and the child protection system then becomes focussed on investigating all reports and diluting available resources for those children who are most in need of intervention. A public health response across multiple agencies enables responses to child safety across the entire population. All families are targeted at the primary level; examples include ensuring all parents know the dangers of shaking a baby or teaching children to say no if a situation makes them uncomfortable. The secondary level of prevention targets families with a number of risk factors, for example subsidised child care so children aren't left unsupervised after school when both parents have to be at work or home visiting for drug-addicted parents to ensure children are cared for. The tertiary response then becomes the responsibility of the child protection system and is reserved for those children where abuse and neglect are identified. This model requires that child safety is seen in a broader context than just the child protection system, and increasingly health professionals are being identified as an important component in the public health framework. If all injury is viewed as preventable and considered along a continuum of 'accidental' through to 'inflicted', it becomes possible to conceptualise child maltreatment in an injury context. Parental intent may not be to cause harm to the child, but by lack of insight or concern about risk, the potential for injury is high. The mechanisms for unintentional and intentional injury overlap and some suggest that by segregating child abuse (with the possible exception of sexual abuse) from unintentional injury, child abuse is excluded from the broader injury prevention initiative that is gaining momentum in the community. This research uses a public health perspective, specifically that of injury prevention, to consider the problem of child abuse. This study employed a mixed method design that incorporates secondary data analysis, data linkage and structured interviews of different professional groups. Datasets from the Queensland Injury Surveillance Unit (QISU) and The Department of Child Safety (DCS) were evaluated. Coded injury data was grouped according to intent of injury according to those with a code that indicated the ED presentation was due to child abuse, a code indicating that the injury was possibly due to abuse or, in the third group, the intent code indicated that the injury was unintentional and not due to abuse. Primary data collection from ED records was undertaken and information recoded to assess reliability and completeness. Emergency department data (QISU) was linked to Department of Child Safety Data to examine concordance and data quality. Factors influencing the collection and collation of these data were identified through structured interview methodology and analysed using qualitative methods. Secondary analysis of QISU data indicated that codes lacking specific information on the injury event were more likely to also have an intent code indicating abuse than those records where there was specific information on the injury event. Codes for abuse appeared in only 1.2% of the 84,765 records analysed. Unintentional injury was the most commonly coded intent (95.3%). In the group with a definite abuse code assigned at triage, 83% linked to a record with DCS and cases where documentation indicated police involvement were significantly more likely to be associated with a DCS record than those without such documentation. In those coded with an unintentional injury code, 22% linked to a DCS record with cases assigned an urgent triage category more likely to link than those with a triage category for resuscitation and children who presented to regional or remote hospitals more likely to link to a DCS record than those presenting to urban hospitals. Twenty-nine per cent of cases with a code indicating possible abuse linked to a DCS record. In documentation that indicated police involvement in the case, a code for unspecified activity when compared to cases with a code indicating involvement in a sporting activity and children less than 12 months of age compared to those in the 13-17 year old age group were all variables significantly associated with linkage to a DCS record. Only 13% of records contained documentation indicating that child abuse and neglect were considered in the diagnosis of the injury despite almost half of the sample having a code of abuse or possible abuse. Doctors and nurses were confident in their knowledge of the process of reporting child maltreatment but less confident about identifying child abuse and neglect and what should be reported. Many were concerned about implications of reporting, for the child and family and for themselves. A number were concerned about the implications of not reporting, mostly for the wellbeing of the child and a few in terms of their legal obligations as mandatory reporters. The outcomes of this research will help improve the knowledge of barriers to effective surveillance of child abuse in emergency departments. This will, in turn, ensure better identification and reporting practises; more reliable official statistical collections and the potential of flagging high-risk cases to ensure adequate departmental responses have been initiated.

Measurement error of rearfoot kinematics during running between a 100Hz and 30Hz camera

Background: Measurement accuracy is critical for biomechanical gait assessment. Very few studies have determined the accuracy of common clinical rearfoot variables between cameras with different collection frequencies. Research question: What is the measurement error for common rearfoot gait parameters when using a standard 30Hz digital camera compared to 100Hz camera? Type of study: Descriptive. Methods: 100 footfalls were recorded from 10 subjects ( 10 footfalls per subject) running on a treadmill at 2.68m/s. A high-speed digital timer, accurate within 1ms served as an external reference. Markers were placed along the vertical axis of the heel counter and the long axis of the shank. 2D coordinates for the four markers were determined from heel strike to heel lift. Variables of interest included time of heel strike (THS), time of heel lift (THL), time to maximum eversion (TMax), and maximum rearfoot eversion angle (EvMax). Results: THS difference was 29.77ms (+/- 8.77), THL difference was 35.64ms (+/- 6.85), and TMax difference was 16.50ms (+/- 2.54). These temporal values represent a difference equal to 11.9%, 14.3%, and 6.6% of the stance phase of running gait, respectively. EvMax difference was 1.02 degrees (+/- 0.46). Conclusions: A 30Hz camera is accurate, compared to a high-frequency camera, in determining TMax and EvMax during a clinical gait analysis. However, relatively large differences, in excess of 12% of the stance phase of gait, for THS and THL variables were measured.

An accurate numerical scheme for the contraction of a bubble in a Hele-Shaw cell

We report on an accurate numerical scheme for the evolution of an inviscid bubble in radial Hele-Shaw flow, where the nonlinear boundary effects of surface tension and kinetic undercooling are included on the bubble-fluid interface. As well as demonstrating the onset of the Saffman-Taylor instability for growing bubbles, the numerical method is used to show the effect of the boundary conditions on the separation (pinch-off) of a contracting bubble into multiple bubbles, and the existence of multiple possible asymptotic bubble shapes in the extinction limit. The numerical scheme also allows for the accurate computation of bubbles which pinch off very close to the theoretical extinction time, raising the possibility of computing solutions for the evolution of bubbles with non-generic extinction behaviour.

Sensitivity of edge detection methods for quantifying cell migration assays

Quantitative imaging methods to analyze cell migration assays are not standardized. Here we present a suite of two–dimensional barrier assays describing the collective spreading of an initially–confined population of 3T3 fibroblast cells. To quantify the motility rate we apply two different automatic image detection methods to locate the position of the leading edge of the spreading population after 24, 48 and 72 hours. These results are compared with a manual edge detection method where we systematically vary the detection threshold. Our results indicate that the observed spreading rates are very sensitive to the choice of image analysis tools and we show that a standard measure of cell migration can vary by as much as 25% for the same experimental images depending on the details of the image analysis tools. Our results imply that it is very difficult, if not impossible, to meaningfully compare previously published measures of cell migration since previous results have been obtained using different image analysis techniques and the details of these techniques are not always reported. Using a mathematical model, we provide a physical interpretation of our edge detection results. The physical interpretation is important since edge detection algorithms alone do not specify any physical measure, or physical definition, of the leading edge of the spreading population. Our modeling indicates that variations in the image threshold parameter correspond to a consistent variation in the local cell density. This means that varying the threshold parameter is equivalent to varying the location of the leading edge in the range of approximately 1–5% of the maximum cell density.

SECIS-binding protein 2 promotes cell survival by protecting against oxidative stress

Reactive oxygen species (ROS) are a primary cause of cellular damage that leads to cell death. In cells, protection from ROS-induced damage and maintenance of the redox balance is mediated to a large extent by selenoproteins, a distinct family of proteins that contain selenium in form of selenocysteine (Sec) within their active site. Incorporation of Sec requires the Sec-insertion sequence element (SECIS) in the 3'-untranslated region of selenoproteins mRNAs and the SECIS-binding protein 2 (SBP2). Previous studies have shown that SBP2 is required for the Sec-incorporation mechanism; however, additional roles of SBP2 in the cell have remained undefined. We herein show that depletion of SBP2 by using antisense oligonucleotides (ASOs) causes oxidative stress and induction of caspase- and cytochrome c-dependent apoptosis. Cells depleted of SBP2 have increased levels of ROS, which lead to cellular stress manifested as 8-oxo-7,8-dihydroguanine (8-oxo-dG) DNA lesions, stress granules, and lipid peroxidation. Small-molecule antioxidants N-acetylcysteine, glutathione, and α-tocopherol only marginally reduced ROS and were unable to rescue cells fully from apoptosis, indicating that apoptosis might be directly mediated by selenoproteins. Our results demonstrate that SBP2 is required for protection against ROS-induced cellular damage and cell survival. Antioxid. Redox Signal. 12, 797–808.

Incorporation of exogenous RGD peptide and inter-species blending as strategies for enhancing human corneal limbal epithelial cell growth on Bombyx mori silk fibroin membranes

While fibroin isolated from the cocoons of domesticated silkworm Bombyx mori supports growth of human corneal limbal epithelial (HLE) cells, the mechanism of cell attachment remains unclear. In the present study we sought to enhance the attachment of HLE cells to membranes of Bombyx mori silk fibroin (BMSF) through surface functionalization with an arginine-glycine-aspartic acid (RGD)-containing peptide. Moreover, we have examined the response of HLE cells to BMSF when blended with the fibroin produced by a wild silkworm, Antheraea pernyi, which is known to contain RGD sequences within its primary structure. A procedure to isolate A. pernyi silk fibroin (APSF) from the cocoons was established, and blends of the two fibroins were prepared at five different BMSF/APSF ratios. In another experiment, BMSF surface was modified by binding chemically the GRGDSPC peptide using a water-soluble carbodiimide. Primary HLE were grown in the absence of serum on membranes made of BMSF, APSF, and their blends, as well as on RGD-modified BMSF. There was no statistically significant enhancing effect on the cell attachment due to the RGD presence. This suggests that the adhesion through RGD ligands may have a complex mechanism, and the investigated strategies are of limited value unless the factors contributing to this mechanism become better known.

Numerical solution of an optimal control model of dendritic cell treatment of a growing tumour

A new optimal control model of the interactions between a growing tumour and the host immune system along with an immunotherapy treatment strategy is presented. The model is based on an ordinary differential equation model of interactions between the growing tu- mour and the natural killer, cytotoxic T lymphocyte and dendritic cells of the host immune system, extended through the addition of a control function representing the application of a dendritic cell treat- ment to the system. The numerical solution of this model, obtained from a multi species Runge–Kutta forward-backward sweep scheme, is described. We investigate the effects of varying the maximum al- lowed amount of dendritic cell vaccine administered to the system and find that control of the tumour cell population is best effected via a high initial vaccine level, followed by reduced treatment and finally cessation of treatment. We also found that increasing the strength of the dendritic cell vaccine causes an increase in the number of natural killer cells and lymphocytes, which in turn reduces the growth of the tumour.

Humanised xenograft models of bone metastasis revisited : novel insights into species-specific mechanisms of cancer cell osteotropism

The determinants and key mechanisms of cancer cell osteotropism have not been identified, mainly due to the lack of reproducible animal models representing the biological, genetic and clinical features seen in humans. An ideal model should be capable of recapitulating as many steps of the metastatic cascade as possible, thus facilitating the development of prognostic markers and novel therapeutic strategies. Most animal models of bone metastasis still have to be derived experimentally as most syngeneic and transgeneic approaches do not provide a robust skeletal phenotype and do not recapitulate the biological processes seen in humans. The xenotransplantation of human cancer cells or tumour tissue into immunocompromised murine hosts provides the possibility to simulate early and late stages of the human disease. Human bone or tissue-engineered human bone constructs can be implanted into the animal to recapitulate more subtle, species-specific aspects of the mutual interaction between human cancer cells and the human bone microenvironment. Moreover, the replication of the entire "organ" bone makes it possible to analyse the interaction between cancer cells and the haematopoietic niche and to confer at least a partial human immunity to the murine host. This process of humanisation is facilitated by novel immunocompromised mouse strains that allow a high engraftment rate of human cells or tissue. These humanised xenograft models provide an important research tool to study human biological processes of bone metastasis.

Measurement of a PAGAT gel dosimeter by ultrasound computed tomography

In this work we used a 3D quantitative CT ultrasound imaging system to characterise polymer gel dosimeters. The system comprised of two identical 5 MHz 128 element phased-array ultrasound transducers co-axially aligned and submerged in water as a coupling agent. Rotational and translational movement of the gel dosimeter sample between the transducers were performed using a robotic arm. Ultrasound signals were generated and received using an Olympus Omniscan unit. Dose sensitivity of attenuation and time of flight ultrasonic parameters were assessed using this system.