Development of an integrated metabolomic profiling approach for infectious diseases research

Metabolomic profiling offers direct insights into the chemical environment and metabolic pathway activities at sites of human disease. During infection, this environment may receive important contributions from both host and pathogen. Here we apply an untargeted metabolomics approach to identify compounds associated with an E. coli urinary tract infection population. Correlative and structural data from minimally processed samples were obtained using an optimized LC-MS platform capable of resolving ~2300 molecular features. Principal component analysis readily distinguished patient groups and multiple supervised chemometric analyses resolved robust metabolomic shifts between groups. These analyses revealed nine compounds whose provisional structures suggest candidate infection-associated endocrine, catabolic, and lipid pathways. Several of these metabolite signatures may derive from microbial processing of host metabolites. Overall, this study highlights the ability of metabolomic approaches to directly identify compounds encountered by, and produced from, bacterial pathogens within human hosts.

Development of a rapid and validated method for investigating the metabolism of scoparone in rat using ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry

Scoparone (6,7-dimethoxycoumarin) is known to have a wide range of pharmacological properties. In this study, a rapid and validated ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (UPLC/ESI-QTof-MS) method was developed to investigate the metabolism of scoparone in rat for the first time. The new method reduced the sample handling and analytical time by three- to six-fold, and the detection limit by five- to 1000-fold, compared to published methods. Far more metabolites were detected and identified compared to published data, which were preliminarily identified as scopoletin, isoscopoletin, isofraxidin, and fraxidin, respectively, when subjected to tandem mass spectrometry analyses. It is found that the metabolic trajectory of scoparone in rat focused on phase I metabolism which is obviously different from published results, and revealed a wide range of pharmacological properties of scoparone partly attributed to the bioactivities of its metabolites.

Development status and future prospects for a vaccine against Chlamydia trachomatis infection

Chlamydia trachomatis continues to be the most commonly reported sexually transmitted bacterial infection in many countries with more than 100 million new cases estimated annually. These acute infections translate into significant downstream health care costs, particularly for women, where complications can include pelvic inflammatory disease and other disease sequelae such as tubal factor infertility. Despite years of research, the immunological mechanisms responsible for protective immunity versus immunopathology are still not well understood, although it is widely accepted that T cell driven IFN-g and Th17 responses are critical for clearing infection. While antibodies are able to neutralize infections in vitro, alone they are not protective, indicating that any successful vaccine will need to elicit both arms of the immune response. In recent years, there has been an expansion in the number and types of antigens that have been evaluated as vaccines, and combined with the new array of mucosal adjuvants, this aspect of chlamydial vaccinology is showing promise. Most recently, the opportunities to develop successful vaccines have been given a significant boost with the development of a genetic transformation system for Chlamydia, as well as the identification of the key role of the chlamydial plasmid in virulence. While still remaining a major challenge, the development of a successful C.trachomatis vaccine is starting to look more likely.

Development and validation of a ultra performance LC-ESI/MS method for analysis of metabolic phenotypes of healthy men in day and night urine samples

Ultra-performance LC coupled to quadrupole TOF/MS (UPLC-QTOF/MS) in positive and negative ESI was developed and validated to analyze metabolite profiles for urine from healthy men during the day and at night. Data analysis using principal components analysis (PCA) revealed differences between metabolic phenotypes of urine in healthy men during the day and at night. Positive ions with mass-to-charge ratio (m/z) 310.24 (5.35 min), 286.24 (4.74 min) and 310.24 (5.63 min) were elevated in the urine from healthy men at night compared to that during the day. Negative ions elevated in day urine samples of healthy men included m/z 167.02 (0.66 min), 263.12 (2.55 min) and 191.03 (0.73 min), whilst ions m/z 212.01 (4.77 min) were at a lower concentration in urine of healthy men during the day compared to that at night. The ions m/z 212.01 (4.77 min), 191.03 (0.73 min) and 310.24 (5.35 min) preliminarily correspond to indoxyl sulfate, citric acid and N-acetylneuraminic acid, providing further support for an involvement of phenotypic difference in urine of healthy men in day and night samples, which may be associated with notably different activities of gut microbiota, velocity of tricarboxylic acid cycle and activity of sialic acid biosynthesis in healthy men as regulated by circadian rhythm of the mammalian bioclock.

Development and use of risk adjusted statistical process control tools for the monitoring and improvement of clinical outcomes in interventional cardiology

This thesis explored the development of statistical methods to support the monitoring and improvement in quality of treatment delivered to patients undergoing coronary angioplasty procedures. To achieve this goal, a suite of outcome measures was identified to characterise performance of the service, statistical tools were developed to monitor the various indicators and measures to strengthen governance processes were implemented and validated. Although this work focused on pursuit of these aims in the context of a an angioplasty service located at a single clinical site, development of the tools and techniques was undertaken mindful of the potential application to other clinical specialties and a wider, potentially national, scope.

Peer review : a professional development process for librarians

Peer review is a reflective process which allows us to formalise, and gain maximum benefit from, collegial feedback on our professional performance. It is also a process that encourages us to engage in cycles of planning, acting, recording and reflection which are familiar components of action learning and action research. Entering into these cycles within the peer-review framework is a powerful and cost-effective means of facilitating professional development which is readily adapted to the library context. In 1996, a project implementing peer review, in order to improve client interaction at the reference desk, was completed at the University of Southern Queensland (USQ) Library. For that project we developed a set of guidelines for library staff involved in peer review. These guidelines explained the value of peer review, and described its principles and purposes. We also devised strategies to assist staff as they prepared for the experience of peer review, engaged in the process and reflected on the outcomes. A number of benefits were identified; the peer-review process enhanced team spirit, enhanced client-orientation, and fostered collaborative efforts in improving the reference service. It was also relatively inexpensive to implement. In this paper we will discuss the nature of peer review and its importance to library and information professionals. We will also share the guidelines we developed, and discuss the implementation and outcomes of the peer review project at the University of Southern Queensland. We will conclude by discussing the benefits perceived and the issues that arose in the USQ context, and by suggesting a range of other aspects of library service in which peer-review could be implemented.

Development of an eight gene expression profile implicating human breast tumours of all grade

The goal of improving systemic treatment of breast cancers is to evolve from treating every patient with non-specific cytotoxic chemotherapy/hormonal therapy, to a more individually-tailored direct treatment. Although anatomic staging and histological grade are important prognostic factors, they often fail to predict the clinical course of this disease. This study aimed to develop a gene expression profile associated with breast cancers of differing grades. We extracted mRNA from FFPE archival breast IDC tissue samples (Grades I–III), including benign tumours. Affymetrix GeneChip� Human Genome U133 Plus 2.0 Arrays were used to determine gene expression profiles and validated by Q-PCR. IHC was used to detect the AXIN2 protein in all tissues. From the array data, an independent group t-test revealed that 178 genes were significantly (P B 0.01) differentially expressed between three grades of malignant breast tumours when compared to benign tissues. From these results, eight genes were significantly differentially expressed in more than one comparison group and are involved in processes implicated in breast cancer development and/or progression. The two most implicated candidates genes were CLD10 and ESPTI1 as their gene expression profile from the microarray analysis was replicated in Q-PCR analyses of the original tumour samples as well as in an extended population. The IHC revealed a significant association between AXIN2 protein expression and ER status. It is readily acknowledged and established that significant differences exist in gene expression between different cancer grades. Expansion of this approach may lead to an improved ability to discriminate between cancer grade and other pathological factors.

Knowledge based urban development lessons from a non-western country : the Malaysia experience

Knowledge based urban development (KBUD) is seen as a new paradigm in urban planning and development which is now being implemented across the globe in order to increase the competitiveness of cities and regions. The KBUD concept has been widely applied in western and more developed countries over the last decade, and many have been proven successful. This paper, however, aims to provide an overview of the KBUD exercise in a context of a non western country scenario—Malaysia. Literature suggests that the urban development process in non western countries is different and very much focusing on physical elements. Whether this is the case or otherwise, this paper scrutinises the project of Multimedia Super Corridor (MSC), Malaysia, which is regarded as one of the first large scale manifestations of KBUD exercise in South East Asia. Based on development policies analysis and results of the interviews with the major stakeholders, this paper investigates the application of KBUD concept within the Malaysian context by examining the development and evolution of the city of Cyberjaya—the leading intelligent city of the MSC project. In the light of the literature and case findings, the paper provides recommendations and lessons learned, on the orchestration of KBUD, for other non western cities and regions that are working hard to develop KBUD strategies, strengthening their sustainable socio-spatial policies and seeking a global recognition.

Knowledge-based urban development performance analysis : moving towards an integrated system

Knowledge-based urban development (KBUD) has become the new development paradigm for the cities of the global knowledge economy era. Nevertheless, to date international KBUD performance analysis of prosperous knowledge cities is understudied. This paper, therefore, introduces the methodology and application of a novel performance analysis approach to comprehensively scrutinise the global perspectives on KBUD of cities—i.e., The KBUD Assessment Model (KBUD/AM). This indexing model puts 11 renowned knowledge cities—i.e., Birmingham, Boston, Brisbane, Helsinki, Istanbul, Manchester, Melbourne, San Francisco, Sydney, Toronto, Vancouver—under the KBUD microscope to provide a benchmarked international outlook. The results of the indexing provide internationally benchmarked snapshot of the degree of achievements in various KBUD performance areas. This paper discusses the further development avenues and potentialities of the index to become an integrated system for the policy-making circles of cities to benchmark themselves against their competitors and develop relevant KBUD policies.

The GSTM1 null genotype confers an increased risk for Solar Keratosis Development in an Australian Caucasian Population

Solar keratoses affect approximately 50% of Australian Caucasians aged over 40 y. Solar keratoses can undergo malignant transformation into squamous cell carcinoma followed by possible metastasis and are risk factors for basal cell carcinoma, melanoma, and squamous cell carcinoma. The glutathione-S-transferase genes play a part in detoxification of carcinogens and mutagens, including some produced by ultraviolet radiation. This study examined the role of glutathione-S-transferase M1, T1, P1, and Z1 gene polymorphisms in susceptibility to solar keratoses development. Using DNA samples from volunteers involved in the Nambour Skin Cancer Prevention Trial, allele and genotype frequencies were determined using polymerase chain reaction and restriction enzyme digestion. No significant differences were detected in glutathione-S-transferase P1 and glutathione-S-transferase Z1 allele or genotype frequencies; however, a significant association between glutathione-S-transferase M1 genotypes and solar keratoses development was detected (p=0.003) with null individuals having an approximate 2-fold increase in risk for solar keratoses development (odds ratio: 2.1; confidence interval: 1.3-3.5) and a significantly higher increase in risk in conjunction with high outdoor exposure (odds ratio: 3.4; confidence interval: 1.9-6.3). Also, a difference in glutathione-S-transferase T1 genotype frequencies was detected (p=0.039), although considering that multiple testing was undertaken, this was found not to be significant. Fair skin and inability to tan were found to be highly significant risk factors for solar keratoses development with odds ratios of 18.5 (confidence interval: 5.7-59.9) and 7.4 (confidence interval: 2.6-21.0), respectively. Overall, glutathione-S-transferase M1 conferred a significant increase in risk of solar keratoses development, particularly in the presence of high outdoor exposure and synergistically with known phenotypic risk factors of fair skin and inability to tan.

Investigation of glutathione S-transferase zeta and the development of sporadic breast cancer

Background Certain genes from the glutathione S-transferase superfamily have been associated with several cancer types. It was the objective of this study to determine whether alleles of the glutathione S-transferase zeta 1 (GSTZ1) gene are associated with the development of sporadic breast cancer. Methods DNA samples obtained from a Caucasian population affected by breast cancer and a control population, matched for age and ethnicity, were genotyped for a polymorphism of the GSTZ1 gene. After PCR, alleles were identified by restriction enzyme digestion and results analysed by chi-square and CLUMP analysis. Results Chi-squared analysis gave a χ2 value of 4.77 (three degrees of freedom) with P = 0.19, and CLUMP analysis gave a T1 value of 9.02 with P = 0.45 for genotype frequencies and a T1 value of 4.77 with P = 0.19 for allele frequencies. Conclusion Statistical analysis indicates that there is no association of the GSTZ1 variant and hence the gene does not appear to play a significant role in the development of sporadic breast cancer.

Association of a vitamin D receptor polymorphism with sporadic breast cancer development

Breast cancer is the leading cause of cancer death among Australian women and its incidence is annually increasing. Genetic factors are involved in the complex etiology of breast cancer. The seco-steroid hormone, 1.25 dihydroxy vitamin D3 can influence breast cancer cell growth in vitro. A number of studies have reported correlations between vitamin D receptor (VDR) gene polymorphisms and several diseases including prostate cancer and osteoporosis. In breast cancer, low vitamin D levels in serum are correlated with disease progression and bone metastases, a situation also noted in prostate cancer and suggesting the involvement of the VDR. In our study, 2 restriction fragment length polymorphisms (RFLP) in the 3' region (detected by Apa1 and Taq1) and an initiation codon variant in the 5' end of the VDR gene (detected by Fok1) were tested for association with breast cancer risk in 135 females with sporadic breast cancer and 110 cancer-free female controls. Allele frequencies of the 3' Apa1 polymorphism showed a significant association (p = 0.016; OR = 1.56, 95% CI = 1.09-2.24) while the Taq1 RFLP showed a similar trend (p = 0.053; OR = 1.45, 95% CI = 1.00-2.00). Allele frequencies of the Fok1 polymorphism were not significantly different (p = 0.97; OR = 0.99, 95% CI = 0.69-1.43) in the study population. Our results suggest that specific alleles of the VDR gene located near the 3' region may identify an increased risk for breast cancer and justify further investigation of the role of VDR in breast cancer.

Development and validation of an instrument to measure organizational cultures' support of business process management

The purpose of Business Process Management (BPM) is to increase the efficiency and effectiveness of organizational processes through improvement and innovation. Despite a common understanding that culture is an important element in these efforts, there is a dearth of theoretical and empirical research on culture as a facilitator of successful BPM. We develop the BPM culture construct and propose a validated instrument with which to measure organizational cultures’ support of BPM. The operationalization of the BPM culture concept provides a theoretical foundation for future research and a tool to assist organizations in developing a cultural environment that supports successful BPM.

Local development planning and community empowerment in decentralised Indonesia : the role of local planning in improving self organising capabilities of local communities in Takalar, Indonesia

This study investigates the role of development planning in empowering rural communities in Indonesia’s decentralised era. Evidence is produced that the combination of procedural justice in planning development and social learning in its implementation can assist self-organisation and help empower local communities. Significant benefits are shown to result in: the acquisition and use of collective resources; the development of shared knowledge, skills, values and trust; community leadership; and the development of social networks. Two features of this empowerment model are community-based planning, utilising participatory rural appraisal at the level of the natural village, and the organisation of collective action. These are shown to be effective ways of incorporating procedural justice and social learning in self organisation and community empowerment.

Development and implementation of the Australian universities radiation therapy student clinical assessment form

Purpose: Prior to 2009, one of the problems faced by radiation therapists who supervised and assessed students on placement in Australian clinical centres, was that each of the six Australian universities where Radiation Therapy (RT) programmes were conducted used different clinical assessment and reporting criteria. This paper describes the development of a unified national clinical assessment and reporting form that was implemented nationally by all six universities in 2009. Methods: A four phase methodology was used to develop the new assessment form and user guide. Phase 1 included university consensus around domains of student practice and assessment, and alignment with national competency standards; Phase 2 was a national consensus workshop attended by radiation therapists involved in student supervision and assessment; Phase 3 was an action research re-iterative Delphi technique involving two rounds of a mail-out to gain further expert consensus; and stage 4 was national piloting of the developed assessment form. Results: The new assessment form includes five main domains of practice and 19 sub-domain criteria which students are assessed against during placement. Feedback from the pilot centre participants was positive, with the new form being assessed to be comprehensive and complemented by the accompanying user guide. Conclusion: The new assessment form has improved both the formative and summative assessment of students on placement, as well as enhancing the quality of feedback to students and the universities. The new national form has high acceptance from the Australian universities and has been subject to wide review by the profession.