Mathematical modelling of tumour-induced angiogenesis

The growth of solid tumours beyond a critical size is dependent upon angiogenesis, the formation of new blood vessels from an existing vasculature. Tumours may remain dormant at microscopic sizes for some years before switching to a mode in which growth of a supportive vasculature is initiated. The new blood vessels supply nutrients, oxygen, and access to routes by which tumour cells may travel to other sites within the host (metastasize). In recent decades an abundance of biological research has focused on tumour-induced angiogenesis in the hope that treatments targeted at the vasculature may result in a stabilisation or regression of the disease: a tantalizing prospect. The complex and fascinating process of angiogenesis has also attracted the interest of researchers in the field of mathematical biology, a discipline that is, for mathematics, relatively new. The challenge in mathematical biology is to produce a model that captures the essential elements and critical dependencies of a biological system. Such a model may ultimately be used as a predictive tool. In this thesis we examine a number of aspects of tumour-induced angiogenesis, focusing on growth of the neovasculature external to the tumour. Firstly we present a one-dimensional continuum model of tumour-induced angiogenesis in which elements of the immune system or other tumour-cytotoxins are delivered via the newly formed vessels. This model, based on observations from experiments by Judah Folkman et al., is able to show regression of the tumour for some parameter regimes. The modelling highlights a number of interesting aspects of the process that may be characterised further in the laboratory. The next model we present examines the initiation positions of blood vessel sprouts on an existing vessel, in a two-dimensional domain. This model hypothesises that a simple feedback inhibition mechanism may be used to describe the spacing of these sprouts with the inhibitor being produced by breakdown of the existing vessel's basement membrane. Finally, we have developed a stochastic model of blood vessel growth and anastomosis in three dimensions. The model has been implemented in C++, includes an openGL interface, and uses a novel algorithm for calculating proximity of the line segments representing a growing vessel. This choice of programming language and graphics interface allows for near-simultaneous calculation and visualisation of blood vessel networks using a contemporary personal computer. In addition the visualised results may be transformed interactively, and drop-down menus facilitate changes in the parameter values. Visualisation of results is of vital importance in the communication of mathematical information to a wide audience, and we aim to incorporate this philosophy in the thesis. As biological research further uncovers the intriguing processes involved in tumourinduced angiogenesis, we conclude with a comment from mathematical biologist Jim Murray, Mathematical biology is : : : the most exciting modern application of mathematics.

Computer planning of stereotactic iodine-125 seed brachytherapy for recurrent malignant gliomas

At St Thomas' Hospital, we have developed a computer program on a Titan graphics supercomputer to plan the stereotactic implantation of iodine-125 seeds for the palliative treatment of recurrent malignant gliomas. Use of the Gill-Thomas-Cosman relocatable frame allows planning and surgery to be carried out at different hospitals on different days. Stereotactic computed tomography (CT) and positron emission tomography (PET) scans are performed and the images transferred to the planning computer. The head, tumour and frame fiducials are outlined on the relevant images, and a three-dimensional model generated. Structures which could interfere with the surgery or radiotherapy, such as major vessels, shunt tubing etc., can also be outlined and included in the display. Catheter target and entry points are set using a three-dimensional cursor controlled by a set of dials attached to the computer. The program calculates and displays the radiation dose distribution within the target volume for various catheter and seed arrangements. The CT co-ordinates of the fiducial rods are used to convert catheter co-ordinates from CT space to frame space and to calculate the catheter insertion angles and depths. The surgically implanted catheters are after-loaded the next day and the seeds left in place for between 4 and 6 days, giving a nominal dose of 50 Gy to the edge of the target volume. 25 patients have been treated so far.

The taxation of international maritime leasing profits : has the commissioners ship come in?

In light of McDermott Industries (AUST) Pty Ltd v Commissioner of Taxation, and Draft Taxation Ruling TR 2006/D8, this article considers the current Australian taxation position of profits arising from the cross-border leasing of vessels in the maritime industry. It focuses on the tax treaties to which Australia is a party, in particular the application of the business profits provisions of those treaties, and the deemed existence of a permanent establishment where substantial equipment, owned by a fiscal non-resident, is used within Australian waters.

Molecules, morphology, and ecology indicate a recent, amphibious ancestry for echidnas

The semiaquatic platypus and terrestrial echidnas (spiny anteaters) are the only living egg-laying mammals (monotremes). The fossil record has provided few clues as to their origins and the evolution of their ecological specializations; however, recent reassignment of the Early Cretaceous Teinolophos and Steropodon to the platypus lineage implies that platypuses and echidnas diverged >112.5 million years ago, reinforcing the notion of monotremes as living fossils. This placement is based primarily on characters related to a single feature, the enlarged mandibular canal, which supplies blood vessels and dense electrosensory receptors to the platypus bill. Our reevaluation of the morphological data instead groups platypus and echidnas to the exclusion of Teinolophos and Steropodon and suggests that an enlarged mandibular canal is ancestral for monotremes (partly reversed in echidnas, in association with general mandibular reduction). A multigene evaluation of the echidna–platypus divergence using both a relaxed molecular clock and direct fossil calibrations reveals a recent split of 19–48 million years ago. Platypus-like monotremes (Monotrematum) predate this divergence, indicating that echidnas had aquatically foraging ancestors that reinvaded terrestrial ecosystems. This ecological shift and the associated radiation of echidnas represent a recent expansion of niche space despite potential competition from marsupials. Monotremes might have survived the invasion of marsupials into Australasia by exploiting ecological niches in which marsupials are restricted by their reproductive mode. Morphology, ecology, and molecular biology together indicate that Teinolophos and Steropodon are basal monotremes rather than platypus relatives, and that living monotremes are a relatively recent radiation.

Modeling perceived collision risk in port water navigation

An increase in the likelihood of navigational collisions in port waters has put focus on the collision avoidance process in port traffic safety. The most widely used on-board collision avoidance system is the automatic radar plotting aid which is a passive warning system that triggers an alert based on the pilot’s pre-defined indicators of distance and time proximities at the closest point of approaches in encounters with nearby vessels. To better help pilot in decision making in close quarter situations, collision risk should be considered as a continuous monotonic function of the proximities and risk perception should be considered probabilistically. This paper derives an ordered probit regression model to study perceived collision risks. To illustrate the procedure, the risks perceived by Singapore port pilots were obtained to calibrate the regression model. The results demonstrate that a framework based on the probabilistic risk assessment model can be used to give a better understanding of collision risk and to define a more appropriate level of evasive actions.

Measuring the effect of motorcycle rider training on psychosocial influences for risk taking

Aim: Whilst motorcycle rider training is commonly incorporated into licensing programs in many developed nations, little empirical support has been found in previous research to prescribe it as an effective road safety countermeasure. It has been posited that the lack of effect of motorcycle rider training on crash reduction may, in part, be due to the predominant focus on skills-based training with little attention devoted to addressing attitudes and motives that influence subsequent risky riding. However, little past research has actually endeavoured to measure attitudinal and motivational factors as a function of rider training. Accordingly, this study was undertaken to assess the effect of a commercial motorcycle rider training program on psychosocial factors that have been shown to influence risk taking by motorcyclists. Method: Four hundred and thirty-eight motorcycle riders attending a competency-based licence training course in Brisbane, Australia, voluntarily participated in the study. A self-report questionnaire adapted from the Rider Risk Assessment Measure (RRAM) was administered to participants at the commencement of training, then again at the conclusion of training. Participants were informed of the independent nature of the research and that their responses would in no way effect their chance of obtaining a licence. To minimise potential demand characteristics, participants were instructed to seal completed questionnaires in envelopes and place them in a sealed box accessible only by the research team (i.e. not able to be viewed by instructors). Results: Significant reductions in the propensity for thrill seeking and intentions to engage in risky riding in the next 12 months were found at the end of training. In addition, a significant increase in attitudes to safety was found. Conclusions: These findings indicate that rider training may have a positive short-term influence on riders’ propensity for risk taking. However, such findings must be interpreted with caution in regard to the subsequent safety of riders as these factors may be subject to further influence once riders are licensed and actively engage with peers during on-road riding. This highlights a challenge for road safety education / training programs in regard to the adoption of safety practices and the need for behavioural follow-up over time to ascertain long-term effects. This study was the initial phase of an ongoing program of research into rider training and risk taking framed around Theory of Planned Behaviour concepts. A subsequent 12 month follow-up of the study participants has been undertaken with data analysis pending.

Analysis of involved parties in port water conflicts

With increasing rate of shipping traffic, the risk of collisions in busy and congested port waters is expected to rise. However, due to low collision frequencies it is difficult to analyze such risk in a sound statistical manner. This study aims at examining the occurrence of traffic conflicts in order to understand the characteristics of vessels involved in navigational hazards. A binomial logit model was employed to evaluate the association of vessel attributes and the kinematic conditions with conflict severity levels. Results show a positive association for vessels of small gross tonnage, overall vessel length, vessel height and draft with conflict risk. Conflicts involving a pair of dynamic vessels sailing at low speeds also have similar effects.

Statistical analysis of conflict involvements in port water navigation

With increasing rate of shipping traffic, the risk of collisions in busy and congested port waters is likely to rise. However, due to low collision frequencies in port waters, it is difficult to analyze such risk in a sound statistical manner. A convenient approach of investigating navigational collision risk is the application of the traffic conflict techniques, which have potential to overcome the difficulty of obtaining statistical soundness. This study aims at examining port water conflicts in order to understand the characteristics of collision risk with regard to vessels involved, conflict locations, traffic and kinematic conditions. A hierarchical binomial logit model, which considers the potential correlations between observation-units, i.e., vessels, involved in the same conflicts, is employed to evaluate the association of explanatory variables with conflict severity levels. Results show higher likelihood of serious conflicts for vessels of small gross tonnage or small overall length. The probability of serious conflict also increases at locations where vessels have more varied headings, such as traffic intersections and anchorages; becoming more critical at night time. Findings from this research should assist both navigators operating in port waters as well as port authorities overseeing navigational management.

Combined VEGF and PDGF treatment reduces secondary degeneration after spinal cord injury

Trauma to the spinal cord creates an initial physical injury damaging neurons, glia, and blood vessels, which then induces a prolonged inflammatory response, leading to secondary degeneration of spinal cord tissue, and further loss of neurons and glia surrounding the initial site of injury. Angiogenesis is a critical step in tissue repair, but in the injured spinal cord angiogenesis fails; blood vessels formed initially later regress. Stabilizing the angiogenic response is therefore a potential target to improve recovery after spinal cord injury (SCI). Vascular endothelial growth factor (VEGF) can initiate angiogenesis, but cannot sustain blood vessel maturation. Platelet-derived growth factor (PDGF) can promote blood vessel stability and maturation. We therefore investigated a combined application of VEGF and PDGF as treatment for traumatic spinal cord injury, with the aim to reduce secondary degeneration by promotion of angiogenesis. Immediately after hemisection of the spinal cord in the rat we delivered VEGF and PDGF and to the injury site. One and 3 months later the size of the lesion was significantly smaller in the treated group compared to controls, and there was significantly reduced gliosis surrounding the lesion. There was no significant effect of the treatment on blood vessel density, although there was a significant reduction in the numbers of macrophages/microglia surrounding the lesion, and a shift in the distribution of morphological and immunological phenotypes of these inflammatory cells. VEGF and PDGF delivered singly exacerbated secondary degeneration, increasing the size of the lesion cavity. These results demonstrate a novel therapeutic intervention for SCI, and reveal an unanticipated synergy for these growth factors whereby they modulated inflammatory processes and created a microenvironment conducive to axon preservation/sprouting.

Differential expression and distribution of syndecan-1 and -2 in periodontal wound healing of the rat

Cell-surface proteoglycans participate in several biological functions including interactions with adhesion molecules, growth factors and a variety of other effector molecules. Accordingly, these molecules play a central role in various aspects of cell–cell and cell–matrix interactions. To investigate the expression and distribution of the cell surface proteoglycans, syndecan-1 and -2, during periodontal wound healing, immunohistochemical analyses were carried out using monoclonal antibodies against syndecan-1, or -2 core proteins. Both syndecan-1 and -2 were expressed and distributed differentially at various stages of early inflammatory cell infiltration, granulation tissue formation, and tissue remodeling in periodontal wound healing. Expression of syndecan-1 was noted in inflammatory cells within and around the fibrin clots during the earliest stages of inflammatory cell infiltration. During granulation tissue formation it was noted in fibroblast-like cells and newly formed blood vessels. Syndecan-1 was not seen in newly formed bone or cementum matrix at any of the time periods studied. Syndecan-1 expression was generally less during the late stages of wound healing but was markedly expressed in cells that were close to the repairing junctional epithelium. In contrast, syndecan-2 expression and distribution was not evident at the early stages of inflammatory cell infiltration. During the formation of granulation tissue and subsequent tissue remodeling, syndecan-2 was expressed extracellularly in the newly formed fibrils which were oriented toward the root surface. Syndecan-2 was found to be significantly expressed on cells that were close to the root surface and within the matrix of repaired cementum covering root dentin as well as at the alveolar bone edge. These findings indicate that syndecan-1 and -2 may have distinctive functions during wound healing of the periodontium. The appearance of syndecan-1 may involve both cell–cell and cell–matrix interactions, while syndecan-2 showed a predilection to associate with cell–matrix interactions during hard tissue formation.

Possible comet samples : The NASA Cosmic Dust Program

Beginning in 1974, a limited effort to collect extraterrestrial dust samples from the stratosphere using impactors mounted on NASA U-2 aircraft was initiated at NASA Ames Research Center (1). Subsequent studies (e.g. 1-9) have clearly established an extraterrestrial origin for some of the material. Attrition of comets is considered to be one of the potential sources of extraterrestrial dust(1,5). Additionally, some of the particles appear to represent a type of primitive material not represented in meteorite collections. In order to provide a greater availability of these samples to the scientific community, NASA-Johnson Space Center (JSC) began in May of 1981 a program dedicated to the systematic collection and curation of cosmic dust for scientific investigation. Collections were made at 18 to 20 km altitude by means of collectors mounted under the wings of a WB57F. When the aircraft reaches operating altitude, the collector plates (impactors) are extended into the ambient airstream with the collection surface normal to the airflow. To prevent particles from bouncing off the surface, the impactors are coated with a film of high viscosity silicone oil. The impactors are sealed in canisters to minimize contamination when not collecting.

Revitalising the Australian Shipping Industry through Tax Reform: Alchemy or Piracy?

The Australian Federal Government has recently passed reforms to the shipping industry. These reforms are aimed at removing barriers to investment in Australian shipping, fostering global competitiveness and securing a stable maritime skills base. The shipping reform package adopts a two pronged approach designed to achieve its stated goals by providing both a ‘stick’ and ‘carrot’ to industry participants. First, the ‘stick’ is delivered via the provision of tighter regulation of coastal trading operations through a new licencing system, along with the introduction of a civil penalty regime and an increase in existing penalties. Second, the ‘carrot’ is delivered via taxation incentives available to vessels registered in Australia where the registrant meets certain specified criteria. These incentives, introduced through amendments to the Income Tax Assessment Act 1997 and the Income Tax Assessment Act 1936 and contained in the Tax Laws Amendment (Shipping Reform) Act 2012, provide five key tax incentives to the shipping industry. From 1 July 2012, amendments give effect to an income tax exemption for qualifying ship operators, accelerated depreciation of vessels, roll-over relief from income tax on the sale of a vessel, an employer refundable tax offset, and an exemption from royalty withholding tax for payments made for the lease of certain shipping vessels.

Implementation of the MARPOL Convention in Bangladesh

Vessel-source marine pollution is one of the main sources of marine pollution in Bangladesh. Due to unfettered operation of vessels, the country has been exposed to massive pollution that is causing a serious imbalance in the marine environment. Against this backdrop, this article seeks to demonstrate that the regulatory system of Bangladesh should be strengthened and made more effective in the light of international instruments to ensure the conservation and sustainable management of its marine environment. With this aim the article examines the present status of implementation of the MARPOL Convention in Bangladesh

Inflow cannula design for biventricular assist devices

Cardiovascular diseases are a leading cause of death throughout the developed world. With the demand for donor hearts far exceeding the supply, a bridge-to-transplant or permanent solution is required. This is currently achieved with ventricular assist devices (VADs), which can be used to assist the left ventricle (LVAD), right ventricle (RVAD), or both ventricles simultaneously (BiVAD). Earlier generation VADs were large, volume-displacement devices designed for temporary support until a donor heart was found. The latest generation of VADs use rotary blood pump technology which improves device lifetime and the quality of life for end stage heart failure patients. VADs are connected to the heart and greater vessels of the patient through specially designed tubes called cannulae. The inflow cannulae, which supply blood to the VAD, are usually attached to the left atrium or ventricle for LVAD support, and the right atrium or ventricle for RVAD support. Few studies have characterized the haemodynamic difference between the two cannulation sites, particularly with respect to rotary RVAD support. Inflow cannulae are usually made of metal or a semi-rigid polymer to prevent collapse with negative pressures. However suction, and subsequent collapse, of the cannulated heart chamber can be a frequent occurrence, particularly with the relatively preload insensitive rotary blood pumps. Suction events may be associated with endocardial damage, pump flow stoppages and ventricular arrhythmias. While several VAD control strategies are under development, these usually rely on potentially inaccurate sensors or somewhat unreliable inferred data to estimate preload. Fixation of the inflow cannula is usually achieved through suturing the cannula, often via a felt sewing ring, to the cannulated chamber. This technique extends the time on cardiopulmonary bypass which is associated with several postoperative complications. The overall objective of this thesis was to improve the placement and design of rotary LVAD and RVAD inflow cannulae to achieve enhanced haemodynamic performance, reduced incidence of suction events, reduced levels of postoperative bleeding and a faster implantation procedure. Specific objectives were: * in-vitro evaluation of LVAD and RVAD inflow cannula placement, * design and in-vitro evaluation of a passive mechanism to reduce the potential for heart chamber suction, * design and in-vitro evaluation of a novel suture-less cannula fixation device. In order to complete in-vitro evaluation of VAD inflow cannulae, a mock circulation loop (MCL) was developed to accurately replicate the haemodynamics in the human systemic and pulmonary circulations. Validation of the MCL’s haemodynamic performance, including the form and magnitude of pressure, flow and volume traces was completed through comparisons of patient data and the literature. The MCL was capable of reproducing almost any healthy or pathological condition, and provided a useful tool to evaluate VAD cannulation and other cardiovascular devices. The MCL was used to evaluate inflow cannula placement for rotary VAD support. Left and right atrial and ventricular cannulation sites were evaluated under conditions of mild and severe heart failure. With a view to long term LVAD support in the severe left heart failure condition, left ventricular inflow cannulation was preferred due to improved LVAD efficiency and reduced potential for thrombus formation. In the mild left heart failure condition, left atrial cannulation was preferred to provide an improved platform for myocardial recovery. Similar trends were observed with RVAD support, however to a lesser degree due to a smaller difference in right atrial and ventricular pressures. A compliant inflow cannula to prevent suction events was then developed and evaluated in the MCL. As rotary LVAD or RVAD preload was reduced, suction events occurred in all instances with a rigid inflow cannula. Addition of the compliant segment eliminated suction events in all instances. This was due to passive restriction of the compliant segment as preload dropped, thus increasing the VAD circuit resistance and decreasing the VAD flow rate. Therefore, the compliant inflow cannula acted as a passive flow control / anti-suction system in LVAD and RVAD support. A novel suture-less inflow cannula fixation device was then developed to reduce implantation time and postoperative bleeding. The fixation device was evaluated for LVAD and RVAD support in cadaveric animal and human hearts attached to a MCL. LVAD inflow cannulation was achieved in under two minutes with the suture-less fixation device. No leakage through the suture-less fixation device – myocardial interface was noted. Continued development and in-vivo evaluation of this device may result in an improved inflow cannulation technique with the potential for off-bypass insertion. Continued development of this research, in particular the compliant inflow cannula and suture-less inflow cannulation device, will result in improved postoperative outcomes, life span and quality of life for end-stage heart failure patients.

Association study of the calcitonin gene-related polypeptide-alpha (CALCA) and the receptor activity modifying 1 (RAMP1) genes with migraine

Migraine is a common neurovascular brain disorder characterised by recurrent attacks of severe headache that may be accompanied by various neurological symptoms. Migraine is thought to result from activation of the trigeminovascular system followed by vasodilation of pain-producing intracranial blood vessels and activation of second-order sensory neurons in the trigeminal nucleus caudalis. Calcitonin gene-related peptide (CGRP) is a mediator of neurogenic inflammation and the most powerful vasodilating neuropeptide, and has been implicated in migraine pathophysiology. Consequently, genes involved in CGRP synthesis or CGRP receptor genes may play a role in migraine and/or increase susceptibility. This study investigates whether variants in the gene that encodes CGRP, calcitonin-related polypeptide alpha (CALCA) or in the gene that encodes a component of its receptor, receptor activity modifying protein 1 (RAMP1), are associated with migraine pathogenesis and susceptibility. The single nucleotide polymorphisms (SNPs) rs3781719 and rs145837941 in the CALCA gene, and rs3754701 and rs7590387 at the RAMP1 locus, were analysed in an Australian Caucasian population of migraineurs and matched controls. Although we find no significant association of any of the SNPs tested with migraine overall, we detected a nominally significant association (p = 0.031) of the RAMP1 rs3754701 variant in male migraine subjects, although this is non-significant after Bonferroni correction for multiple testing.