Convergence of regenerative medicine and synthetic biology to develop standardized and validated models of human diseases with clinical relevance

In order to progress beyond currently available medical devices and implants, the concept of tissue engineering has moved into the centre of biomedical research worldwide. The aim of this approach is not to replace damaged tissue with an implant or device but rather to prompt the patient's own tissue to enact a regenerative response by using a tissue-engineered construct to assemble new functional and healthy tissue. More recently, it has been suggested that the combination of Synthetic Biology and translational tissue-engineering techniques could enhance the field of personalized medicine, not only from a regenerative medicine perspective, but also to provide frontier technologies for building and transforming the research landscape in the field of in vitro and in vivo disease models.

The kallikrein-related peptidase family: Dysregulation and functions during cancer progression

Cancer is the second leading cause of death with 14 million new cases and 8.2 million cancer-related deaths worldwide in 2012. Despite the progress made in cancer therapies, neoplastic diseases are still a major therapeutic challenge notably because of intra- and inter-malignant tumour heterogeneity and adaptation/escape of malignant cells to/from treatment. New targeted therapies need to be developed to improve our medical arsenal and counter-act cancer progression. Human kallikrein-related peptidases (KLKs) are secreted serine peptidases which are aberrantly expressed in many cancers and have great potential in developing targeted therapies. The potential of KLKs as cancer biomarkers is well established since the demonstration of the association between KLK3/PSA (prostate specific antigen) levels and prostate cancer progression. In addition, a constantly increasing number of in vitro and in vivo studies demonstrate the functional involvement of KLKs in cancer-related processes. These peptidases are now considered key players in the regulation of cancer cell growth, migration, invasion, chemo-resistance, and importantly, in mediating interactions between cancer cells and other cell populations found in the tumour microenvironment to facilitate cancer progression. These functional roles of KLKs in a cancer context further highlight their potential in designing new anti-cancer approaches. In this review, we comprehensively review the biochemical features of KLKs, their functional roles in carcinogenesis, followed by the latest developments and the successful utility of KLK-based therapeutics in counteracting cancer progression.

Disorganizing educational tropes: Conceptions of dis/ability and curriculum

A study examined the politics of dis/ability and curriculum. Data were obtained from a review of the new disability studies literature, focusing on the areas of history, sociology, anthropology, and critical legal theory. The results indicate that this new literature challenges popular psychoeducational models that assume disability as an objective medical, individual, and pathological deficiency, effectively restricting the systematic study of dis/ability as relational, external, shifting, and socially constituted. The findings suggest ways in which perceptions of “school problems” have to be adjusted to understand how the constant refiguration of normativities in everyday activities creates perceptions of disability-negative ontologies, generates experiences that incite efforts to modify those perceptions in multiple ways, and produces unintended effects from well-intended approaches that in the end remain irreducible to simplistic definitions for the one “ethical” or “politically correct” strategy.

Submission to the External Independent Review of the United Nations Response to Allegations of Sexual Exploitation and Abuse and Other Serious Crimes by Members of Foreign Military Forces Not Under United Nations Command in the Central African Republic

In 2015 the UN Secretary-General established an External Independent Review to review how the United Nations has responded to allegations of child sexual exploitation and child sexual abuse, and to make recommendations concerning how the United Nations should respond to allegations in the future. This submission to the Review Panel draws on literature regarding children's rights, the nature of child sexual abuse, international instruments and policy, the nature of institutional child sexual abuse, and the CAR case itself. It makes recommendations for reform of UN protocols and procedures to better prevent child sexual abuse, and to improve responses to future occurrences.

Cough and ARI outcomes in urban Indigenous Children

Aim To identify cough epidemiology and outcomes in urban Indigenous children Methods An ongoing prospective cohort study of Indigenous children aged <5 years registered with at an urban Indigenous primary health care centre, Brisbane. Detailed baseline data are collected and, children are followed monthly for 12 months to capture ARI events. Children who develop cough as a symptom at any time over the 12 months have weekly follow-up for four weeks to ascertain cough outcomes. Results To date, 118 children have been enrolled (535 child-months of observation); Respiratory illnesses accounted for 23 (19 %) of overall reported reasons for presentation, however respiratory symptoms were present in 41 (35%) of all visits; a dry cough in 22 (18%), wet cough in 31 (26%). To date, 99 ARI’s have been recorded with an incidence of 18.4 episodes/100 child months. Seventeen children (14.4%) had persistent cough at day 28. Conclusion This is the first study to comprehensively describe the incidence and outcomes of cough in urban Indigenous children. Early data suggest respiratory illnesses are the most common illnesses for which these children seek medical advice and there is a high prevalence of wet cough.

A follow up MRI-based geometry and computational fluid dynamics study of carotid bifurcation

Cardiovascular disease is the leading causes of death in the developed world. Wall shear stress (WSS) is associated with the initiation and progression of atherogenesis. This study combined the recent advances in MR imaging and computational fluid dynamics (CFD) and evaluated the patient-specific carotid bifurcation. The patient was followed up for 3 years. The geometry changes (tortuosity, curvature, ICA/CCA area ratios, central to the cross-sectional curvature, maximum stenosis) and the CFD factors (Velocity distribute, Wall Shear Stress (WSS) and Oscillatory Shear Index (OSI)) were compared at different time points.The carotid stenosis was a slight increase in the central to the cross-sectional curvature, and it was minor and variable curvature changes for carotid centerline. The OSI distribution presents ahigh-values in the same region where carotid stenosis and normal border, indicating complex flow and recirculation.The significant geometric changes observed during the follow-up may also cause significant changes in bifurcation hemodynamics.

Effect of inflow and outflow angles on the computational hemodynamics in abdominal aortic aneurysm

To help with the clinical screening and diagnosis of abdominal aortic aneurysm (AAA), we evaluated the effect of inflow angle (IA) and outflow bifurcation angle (BA) on the distribution of blood flow and wall shear stress (WSS) in an idealized AAA model. A 2D incompressible Newtonian flow is assumed and the computational simulation is performed using finite volume method. The results showed that the largest WSS often located at the proximal and the distal end of the AAA. An increase in IA resulted in an increase in maximum WSS. We also found that WSS was maximal when BA was 90°. IA and BA are two important geometrical factors, they may help with AAA risk assessment along with the commonly used AAA diameter.

Study of tracheal collapsibility, compliance and stress by considering its asymmetric geometry

The shape of tracheal cartilage has been widely treated as symmetric in analytical and numerical models. However, according to both histological images and in vivo medical image, tracheal cartilage is of highly asymmetric shape. Taking the cartilage as symmetric structure will induce bias in calculation of the collapse behavior, as well as compliance and muscular stress. However, this has been rarely discussed. In this paper, tracheal collapse is represented by considering its asymmetric shape. For comparison, the symmetric shape, which is reconstructed by half of the cartilage, is also presented. A comparison of cross-sectional area, compliance of airway and stress in the muscular membrane, determined by asymmetric shape and symmetric shape is made. The result indicates that the symmetric assumption brings a small error, around 5% in predicting the cross-sectional area under loading conditions. The relative error of compliance is more than 10%. Particularly when the pressure is close to zero, the error could be more than 50%. The model considering the symmetric shape results in a significant difference in predicting stress in muscular membrane by either under- or over-estimating it. In conclusion, tracheal cartilage should not be treated as a symmetric structure. The results obtained in this study are helpful in evaluating the error induced by the assumption in geometry.

Liquid Chromatography-Mass Spectrometry in Studies of Drug Metabolism and Permeability

Poor pharmacokinetics is one of the reasons for the withdrawal of drug candidates from clinical trials. There is an urgent need for investigating in vitro ADME (absorption, distribution, metabolism and excretion) properties and recognising unsuitable drug candidates as early as possible in the drug development process. Current throughput of in vitro ADME profiling is insufficient because effective new synthesis techniques, such as drug design in silico and combinatorial synthesis, have vastly increased the number of drug candidates. Assay technologies for larger sets of compounds than are currently feasible are critically needed. The first part of this work focused on the evaluation of cocktail strategy in studies of drug permeability and metabolic stability. N-in-one liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods were developed and validated for the multiple component analysis of samples in cocktail experiments. Together, cocktail dosing and LC/MS/MS were found to form an effective tool for increasing throughput. First, cocktail dosing, i.e. the use of a mixture of many test compounds, was applied in permeability experiments with Caco-2 cell culture, which is a widely used in vitro model for small intestinal absorption. A cocktail of 7-10 reference compounds was successfully evaluated for standardization and routine testing of the performance of Caco-2 cell cultures. Secondly, cocktail strategy was used in metabolic stability studies of drugs with UGT isoenzymes, which are one of the most important phase II drug metabolizing enzymes. The study confirmed that the determination of intrinsic clearance (Clint) as a cocktail of seven substrates is possible. The LC/MS/MS methods that were developed were fast and reliable for the quantitative analysis of a heterogenous set of drugs from Caco-2 permeability experiments and the set of glucuronides from in vitro stability experiments. The performance of a new ionization technique, atmospheric pressure photoionization (APPI), was evaluated through comparison with electrospray ionization (ESI), where both techniques were used for the analysis of Caco-2 samples. Like ESI, also APPI proved to be a reliable technique for the analysis of Caco-2 samples and even more flexible than ESI because of the wider dynamic linear range. The second part of the experimental study focused on metabolite profiling. Different mass spectrometric instruments and commercially available software tools were investigated for profiling metabolites in urine and hepatocyte samples. All the instruments tested (triple quadrupole, quadrupole time-of-flight, ion trap) exhibited some good and some bad features in searching for and identifying of expected and non-expected metabolites. Although, current profiling software is helpful, it is still insufficient. Thus a time-consuming largely manual approach is still required for metabolite profiling from complex biological matrices.

The introduction of an Inter-professional learning unit: staff and student perspectives

Background The School of Clinical Sciences comprises a number of health disciplines including podiatry, paramedic science, pharmacy, medical imaging and radiation therapy. A new inter-professional unit was introduced in 2014, which covered key introductory learnings applicable for future health practitioners. This study examined teaching staff and student perspectives about their experience with the new unit for first year students. Methods Qualitative interviews with teaching staff (n=9) and focus group interviews with students (5 groups which ranged in size from 4-30) were conducted. Extensive notes were taken during the interviews Issues emerging from the interviews were identified and organised according to themes and subthemes. Results Four major themes were identified namely: Something new; To be or not to be that is the question; Advantages of the new unit; and Areas for improvement. Previous staff experience with inter-professional learning (IPL) had been ad-hoc, whereas the new unit brought together several disciplines in a planned and deliberate way. There was strong philosophical agreement about the value of IPL but some debate about the extent to which the unit provided IPL experience. The unit was seen as assisting students’ social and academic adjustment to university and provided opportunity for professional socialisation, exposure to macro and micro aspects of the Australian health care system and various types of communication. For podiatry students it was their first opportunity to formally meet and work with other podiatry students and moved their identity from ‘university student’ to ‘podiatry student’. Other positives included providing the opportunity for staff and students to interact at an early stage with the perceived benefit of reducing attrition. Areas for unit improvement included institutional arrangements, unit administration aspects and assessment. Conclusion The unit was seen as beneficial by staff and students however, students were more polarised in their views than staff. There was a tension between feeling apart of and learning about one's own profession and feeling apart of and learning about the roles of other health professionals in relation to patient care and the health care system.

Counter-figures : An Essay on Antimetaphoric Resistance: Paul Celan's Poetry and Poetics at the Limits of Figurality

Titled "An Essay on Antimetaphoric Resistance", the dissertation investigates what is here being called "Counter-figures": a term which has in this context a certain variety of applications. Any other-than-image or other-than-figure, anything that cannot be exhausted by figuration (and that is, more or less, anything at all, except perhaps the reproducible images and figures themselves) can be considered "counter-figurative" with regard to the formation of images and figures, ideas and schemas, "any graven image, or any likeness of any thing". Singularity and radical alterity, as well as temporality and its peculiar mode of uniqueness are key issues here, and an ethical dimension is implied by, or intertwined with, the aesthetic. In terms borrowed from Paul Celan's "Meridian" speech, poetry may "allow the most idiosyncratic quality of the Other, its time, to participate in the dialogue". This connection between singularity, alterity and temporality is one of the reasons why Celan so strongly objects to the application of the traditional concept of metaphor to poetry. As Celan says, "carrying over [übertragen]" by metaphor may imply an unwillingness to "bear with [mittragen]" and to "endure [ertragen]" the poem. The thesis is divided into two main parts. The first consists of five distinct prolegomena which all address the mentioned variety of applications of the term "counter-figures", and especially the rejection or critique of either metaphor (by Aristotle, for instance) or the concept of metaphor (defined by Aristotle, and sometimes deemed "anti-poetic" by both theorists and poets). Even if we restrict ourselves to the traditional rhetorico-poetical terms, we may see how, for instance, metonymy can be a counter-figure for metaphor, allegory for symbol, and irony for any single trope or for any piece of discourse at all. The limits of figurality may indeed be located at these points of intersection between different types of tropes or figures, and even between figures or tropes and the "non-figurative trope" or "pseudo-figure" called catachresis. The second part, following on from the open-ended prolegomena, concentrates on Paul Celan's poetry and poetics. According to Celan, true poetry is "essentially anti-metaphoric". I argue that inasmuch as we are willing to pay attention to the "will" of the poetic images themselves (the tropes and metaphors in a poem) to be "carried ad absurdum", as Celan invites us to do, we may find alternative ways of reading poetry and approaching its "secret of the encounter", precisely when the traditional rhetorical instruments, and especially the notion of metaphor, become inapplicable or suspicious — and even where they still seem to impose themselves.

Image reconstruction with laterally truncated projections in helical cone-beam CT: Linear prediction based projection completion techniques

Lateral or transaxial truncation of cone-beam data can occur either due to the field of view limitation of the scanning apparatus or iregion-of-interest tomography. In this paper, we Suggest two new methods to handle lateral truncation in helical scan CT. It is seen that reconstruction with laterally truncated projection data, assuming it to be complete, gives severe artifacts which even penetrates into the field of view. A row-by-row data completion approach using linear prediction is introduced for helical scan truncated data. An extension of this technique known as windowed linear prediction approach is introduced. Efficacy of the two techniques are shown using simulation with standard phantoms. A quantitative image quality measure of the resulting reconstructed images are used to evaluate the performance of the proposed methods against an extension of a standard existing technique.

Relationship between malnutrition and selected risk factors in two hospitals in Vietnam

Aim: The purpose of this study was to determine the percentage of patients assessed as malnourished using the Subjective Global Assessment in two hospitals in Ho Chi Minh City and Can Tho across multiple wards; and to investigate the association with factors including gender, age, days since admission, medical diagnosis and number of medications used. Methods: This cross-sectional study involved 205 inpatients from a hospital in Ho Chi Minh City and 78 inpatients and 89 outpatients from a hospital in Can Tho. Malnutrition status was assessed using Subjective Global Assessment. Ward, gender, age, medical diagnosis, time since admission and medication number were extracted from medical records. Results: 35.6% of inpatients and 9.0% of outpatients were malnourished. Multivariate analysis revealed factors predicting malnutrition status within inpatients (OR (95%CI)) were: age (OR = 1.03 (1.01-1.06)); cancer diagnosis (OR = 34.25 (3.16-370.89)); respiratory ward (11.49 (1.05-125.92)); or general medicine ward (20.34 (2.10-196.88)). Conclusions: Results indicate that malnutrition is a common problem in hospitals in Vietnam. Further research is needed to confirm this finding across a wider range of hospitals and to investigate the feasibility and efficacy of implementation of nutrition interventions in hospital settings.

The biochemistry of blister fluid from pediatric burn injuries: proteomics and metabolomics aspects

Burn injury is a prevalent and traumatic event for pediatric patients. At present, the diagnosis of burn injury severity is subjective and lacks a clinically relevant quantitative measure. This is due in part to a lack of knowledge surrounding the biochemistry of burn injuries and that of blister fluid. A more complete understanding of the blister fluid biochemistry may open new avenues for diagnostic and prognostic development. Burn insult induces a highly complex network of signaling processes and numerous changes within various biochemical systems, which can ultimately be examined using proteome and metabolome measurements. This review reports on the current understanding of burn wound biochemistry and outlines a technical approach for ‘omics’ profiling of blister fluid from burn wounds of differing severity.

Signifying Angels : Analyses and Interpretations of Rautavaara s Instrumental Compositions

The subject of doctoral thesis is the analysis and interpretation of instrumental pieces composed by Einojuhani Rautavaara (b. 1928) that have been given angelic titles: Archangel Michael Fighting the Antichrist from the suite Icons (1955)/Before the Icons (2006), Angels and Visitations (1978), the Double Bass Concerto Angel of Dusk (1980), Playgrounds for Angels (1981)and the Seventh Symphony Angel of Light (1994). The aim of the work is to find those musical elements common to these pieces that distinguish them from Rautavaara s other works and to determine if they could be thought of as a series. I prove that behind the common elements and titles stands the same extramusical idea the figure of an angel that the composer has described in his commentaries. The thesis is divided into three parts. Since all of the compositions possess titles that refer to the spiritual symbol of an angel, the first part offers a theoretical background to demonstrate the significant role played by angels in various religions and beliefs, and the means by which music has attempted to represent this symbol throughout history. This background traces also Rautavaara s aesthetic attitude as a spiritual composer whose output can be studied with reference to his extramusical interests including literature, psychology, painting, philosophy and myths. The second part focuses on the analysis of the instrumental compositions with angelic titles, without giving consideration to their commentaries and titles. The analyses concentrate in particular on those musical features that distinguish these pieces from Rautavaara s other compositions. In the third part these musical features are interpreted as symbols of the angel through comparison with vocal and instrumental pieces which contain references to the character of an angel, structures of mythical narration, special musical expressions, use of instruments and aspects of brightness. Finally I explore the composer s interpretative codes, drawing on Rilke s cycle of poems Ten Duino Elegies and Jung s theory of archetypes, and analyze the instrumental pieces with angelic titles in the light of the theory of musical ekphrasis.