Evaluation of novel Streptococcus pyogenes vaccine candidates incorporating multiple conserved sequences from the C-repeat region of the M-protein

A major challenge for Streptococcus pyogenes vaccine development is the identification of epitopes that confer protection from infection by multiple S. pyogenes M-types. Here we have identified and characterised the distribution of common variant sequences from individual repeat units of the C-repeat region (CRR) of M-proteins representing 77 different M-types. Three polyvalent fusion vaccine candidates (SV1, SV2 and SV3) incorporating the most common variants were subsequently expressed and purified, and demonstrated to be alpha-helical by Circular Dichroism (CD), a secondary conformational characteristic of the CRR in the M-protein. Antibodies raised against each of these constructs recognise M-proteins that vary in their CRR, and bind to the surface of multiple S. pyogenes isolates. Antibodies raised against SV1, containing five variant sequences, also kill heterologous S. pyogenes isolates in in vitro bactericidal assays. Further structural characterisation of this construct demonstrated the conformation of SV1 was stable at different pHs, and thermal unfolding of SV1 a reversible process. Our findings demonstrate that linkage of multiple variant sequences into a single recombinant construct overcomes the need to embed the variant sequences in foreign helix promoting flanking sequences for conformational stability, and demonstrates the viability of the polyvalent candidates as global S. pyogenes vaccine candidates.

A novel duplication polymorphism in the FANCA promoter and its association with breast and ovarian cancer

The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility gene. A novel allele was identified which has a tandem duplication of a 13 base pair sequence in the promoter region. Methods: We screened germline DNA from 352 breast cancer patients, 390 ovarian cancer patients and 256 normal controls to determine if the presence of either of these two alleles was associated with an increased risk of breast or ovarian cancer. Results: The duplication allele had a frequency of 0.34 in the normal controls. There was a nonsignificant decrease in the frequency of the duplication allele in breast cancer patients. The frequency of the duplication allele was significantly decreased in ovarian cancer patients. However, when malignant and benign tumours were considered separately, the decrease was only significant in benign tumours. Conclusion: The allele with the tandem duplication does not appear to modify breast cancer risk but may act as a low penetrance protective allele for ovarian cancer.

Development of novel vaccine strategies to prevent genital tract chlamydial infections

Chlamydia trachomatis is the most prevalent bacterial sexually transmitted infection in the developed world and the leading cause of preventable blindness worldwide. As reported by the World Health Organization in 2001, there are approximately 92 million new infections detected annually, costing health systems billions of dollars to treat not only the acute infection, but also to treat infection-associated sequelae. The majority of genital infections are asymptomatic, with 50-70% going undetected. Genital tract infections can be easily treated with antibiotics when detected. Lack of treatment can lead to the development of pelvic inflammatory disease, ectopic pregnancies and tubal factor infertility in women and epididymitis and prostatitis in men. With infection rates on the continual rise and the large number of infections going undetected, there is a need to develop an efficacious vaccine which prevents not only infection, but also the development of infection-associated pathology. Before a vaccine can be developed and administered, the pathogenesis of chlamydial infections needs to be fully understood. This includes the kinetics of ascending infection and the effects of inoculating dose on ascension and development of pathology. The first aim in this study was to examine these factors in a murine model. Female BALB/c mice were infected intravaginally with varying doses of C. muridarum, the mouse variant of human C. trachomatis, and the ascension of infection along the reproductive tract and the time-course of infection-associated pathology development, including inflammatory cell infiltration, pyosalpinx and hydrosalpinx, were determined. It was found that while the inoculating dose did affect the rate and degree of infection, it did not affect any of the pathological parameters examined. This highlighted that the sexual transmission dose may have minimal effect on the development of reproductive sequelae. The results of the first section enabled further studies presented here to use an optimal inoculating dose that would ascend the reproductive tract and cause pathology development, so that vaccine efficacy could be determined. There has been a large amount of research into the development of an efficacious vaccine against genital tract chlamydial infections, with little success. However, there have been no studies examining the effects of the timing of vaccination, including the effects of vaccination during an active genital infection, or after clearance of a previous infection. These are important factors that need to be examined, as it is not yet known whether immunization will enhance not only the individual's immune response, but also pathology development. It is also unknown whether any enhancement of the immune responses will cause the Chlamydia to enter a dormant, persistent state, and possibly further enhance any pathology development. The second section of this study aimed to determine if vaccination during an active genital tract infection, or after clearance of a primary infection, enhanced the murine immune responses and whether any enhanced or reduced pathology occurred. Naïve, actively infected, or previously infected animals were immunized intranasally or transcutaneously with the adjuvants cholera toxin and CpG-ODN in combination with either the major outer membrane protein (MOMP) of C. muridarum, or MOMP and ribonucleotide reductase small chain protein (NrdB) of C. muridarum. It was found that the systemic immune responses in actively or previously infected mice were altered in comparison to animals immunized naïve with the same combinations, however mucosal antibodies were not enhanced. It was also found that there was no difference in pathology development between any of the groups. This suggests that immunization of individuals who may have an asymptomatic infection, or may have been previously exposed to a genital infection, may not benefit from vaccination in terms of enhanced immune responses against re-exposure. The final section of this study aimed to determine if the vaccination regimes mentioned above caused in vivo persistence of C. muridarum in the upper reproductive tracts of mice. As there has been no characterization of C. muridarum persistence in vitro, either ultrastructurally or via transcriptome analysis, this was the first aim of this section. Once it had been shown that C. muridarum could be induced into a persistent state, the gene transcriptional profiles of the selected persistent marker genes were used to determine if persistent infections were indeed present in the upper reproductive tracts of the mice. We found that intranasal immunization during an active infection induced persistent infections in the oviducts, but not the uterine horns, and that intranasal immunization after clearance of infection, caused persistent infections in both the uterine horns and the oviducts of the mice. This is a significant finding, not only because it is the first time that C. muridarum persistence has been characterized in vitro, but also due to the fact that there is minimal characterization of in vivo persistence of any chlamydial species. It is possible that the induction of persistent infections in the reproductive tract might enhance the development of pathology and thereby enhance the risk of infertility, factors that need to be prevented by vaccination, not enhanced. Overall, this study has shown that the inoculating dose does not affect pathology development in the female reproductive tract of infected mice, but does alter the degree and rate of ascending infection. It has also been shown that intranasal immunization during an active genital infection, or after clearance of one, induces persistent infections in the uterine horns and oviducts of mice. This suggests that potential vaccine candidates will need to have these factors closely examined before progressing to clinical trials. This is significant, because if the same situation occurs in humans, a vaccine administered to an asymptomatic, or previously exposed individual may not afford any extra protection and may in fact enhance the risk of development of infection-associated sequelae. This suggests that a vaccine may serve the community better if administered before the commencement of sexual activity.

Improving posture and decreasing pain with novel shoe insoles

A single subject longevity study is presented as a case study for the Medical Device Partnering Program (MDPP). The MDPP supports the development of cutting-edge medical devices and assistive technologies, through unique collaborations between researchers, industry, clinical end-users and government. The study aimed to identify what effect the innersole has on specific muscles that may influence stability and whether the innersole had any influence on gait. Three tests were conducted; a standard gait test, dynamic balance test and a standing balance test. Results from the kinematic analysis showed reduced variability in post testing results when compared to pre testing results. Reductions in muscle activation levels were also found across all tests. Further testing with a larger sample size is required to determine if these effects are due to the innersole.

Models of South-East Asian organised crime drug operations in Queensland

In 2002, the United Nations Office on Drugs and Crime (UNODC) issued a report entitled Results of a pilot survey of forty selected organized criminal groups in sixteen countries which established five models of organised crime. This paper reviews these and other common organised crime models and drug trafficking models, and applies them to cases of South East Asian drug trafficking in the Australian state of Queensland. The study tests the following hypotheses: (1) South-East Asian drug trafficking groups in Queensland will operate within a criminal network or core group; (2) Wholesale drug distributors in Queensland will not fit consistently under any particular UN organised crime model; and (3) Street dealers will have no organisational structure. The study concluded that drug trafficking or importation closely resembles a criminal network or core group structure. Wholesale dealers did not fit consistently into any UN organised crime model. Street dealers had no organisational structure as an organisational structure is typically found in mid- to high-level drug trafficking.

The'dream'of multi-agency crime prevention : pitfalls in policy and practice

During the 1980s, terms such as interagency or multi-agency cooperation, collaboration, coordination, and interaction have became permanent features of both crime prevention rhetoric and government crime policy. The concept of having the government, local authorities, and the community working in partnership has characterized both left and right politics for over a decade. The U.S. National Advisory Commission on Criminal Justice Standards and Goals in the U.S.. Circulars 8/84 and 44/90 released by the U.K. Home Office, and the British Morgan Report-coupled with the launch of government strategies in France, the Netherlands, England and Wales, Australia, and, more recently, in Belgium, New Zealand, and Canada-have all emphasized the importance of agencies working together to prevent or reduce crime. This paper draws upon recent Australian research and critically analyzes multi-agency crime prevention. It suggests that agency conflicts and power struggles may be exacerbated by neo-liberal economic theory, by the politics of crime prevention management, and by policies that aim to combine situational and social prevention endeavors. Furthermore, it concludes that indigenous peoples are excluded by crime prevention strategies that fail to define and interpret crime and its prevention in culturally appropriate ways.

Eco-crime and air pollution

This chapter applies emerging discourses of eco-crime and green criminology to issues of air pollution. Of course there are various forms of pollution, but this chapter will focus on the contamination and regulation of 'the air we breathe'.

Crime : Local and Global

Crime: Local and Global covers the way local events (such as prostitution) have wider aspects than previously thought. Links with people traffickers, international organised crime and violence cannot be ignored any longer. Each crime or area of activity selected within this text has a global reach, and is made ever more possible due to the way globalisation has opened up markets, both legitimate and illegitimate. The book's approach and scope emphasises that we can no longer view 'crime' as something which occurs within certain jurisdictions, at certain times and in particular places. For example, the chapter on cybercrime highlights the 'illegal' acts that can be perpetrated by second lifers, anywhere in the world, but are they a crime?

Firearms theft in New Zealand : lessons for crime and injury prevention

In New Zealand, 200,000 licensed shooters (5.5% of the population) own an estimated 1 million firearms, 9 times more guns per capita than in England and Wales and 20% more than in Australia. Based on a 3 year study of firearm theft in New Zealand, this paper concludes that insecure storage of lawfully held weapons by licensed owners poses a significant public health and safety risk. Furthermore, this paper concludes that the failure of the police to enforce New Zealand gun security laws, and the government's hesitancy to develop firearm education and regulation policies, exacerbates insecure firearm storage, a key factor in firearm-related theft, injury, suicide, violence and criminal activity.

Locally oriented crime prevention and the “partnership approach” : politics, practices and prospects

Why have multi-agency or "partnership" approaches to crime prevention and community safety been reported internationally with unfavorable results? Can groups and individuals from disparate government and non-government sectors work together to reduce or prevent crime? This article will address these and other questions by using developments in Belgium as its case study. In 1992, Belgium launched its "safety and crime prevention contracts", a series of locally based crime prevention initiatives which have attempted to contract federal, regional and local governments to a range of social and police oriented crime prevention endeavors. Traces the development of the Belgian crime prevention contracts and examines the difficulties experienced with "multi-agency crime prevention" and suggests that much of the political rhetoric in Belgium calling for local, community and intersectorial "partnerships" has, like several other countries including England and Wales, Canada, Australia and New Zealand, lacked clear practical expression. However, some promising initiatives indicate that this prevention approach may be capable of producing effective crime prevention and community safety outcomes. Further research is needed to describe these initiatives and analyze the conditions under which they are developed.

Crime is in the air : air pollution and regulation in the UK

This latest briefing by Professor Reece Walters in the What is crime? series, draws attention to an area of harm that is often absent from criminological debate. He highlights the human costs of air pollution and failed attempts to adequately regulate and control such harm. Arguing for a cross disciplinary ‘eco-crime’ narrative, the author calls for greater understanding of the far-reaching consequences of air pollution which could set in train changes which may lead to a ‘more robust and meaningful system of justice’. Describing current arrangements in place to control and regulate air pollution, Walters draws attention to the lack of neutrality in current arrangements and the bias ‘towards the economic imperatives of free trade over and above the centrality of environmental protection’. While attention is often given to direct and individualised instances of ‘crime’, the serious consequences of air pollution are frequently neglected. The negative effects of pollution on health and well-being are often borne by people already experiencing a range of other disadvantages. In a global and national context, it is often the poor who are affected most. Ultimately, political and economic imperatives have historically helped to shape legal and regulatory regimes. Whether this is an inherent flaw in current systems or something that can be overcome in favour of dealing with more wide-ranging harms is an area that requires further discussion and debate.

A novel method for the synthesis of monodisperse gold-coated silica nanoparticles

Monodisperse silica nanoparticles were synthesised by the well-known Stober protocol, then dispersed in acetonitrile (ACN) and subsequently added to a bisacetonitrile gold(I) coordination complex ([Au(MeCN)2]?) in ACN. The silica hydroxyl groups were deprotonated in the presence of ACN, generating a formal negative charge on the siloxy groups. This allowed the [Au(MeCN)2]? complex to undergo ligand exchange with the silica nanoparticles and form a surface coordination complex with reduction to metallic gold (Au0) proceeding by an inner sphere mechanism. The residual [Au(MeCN)2]? complex was allowed to react with water, disproportionating into Au0 and Au(III), respectively, with the Au0 adding to the reduced gold already bound on the silica surface. The so-formed metallic gold seed surface was found to be suitable for the conventional reduction of Au(III) to Au0 by ascorbic acid (ASC). This process generated a thin and uniform gold coating on the silica nanoparticles. The silica NPs batches synthesised were in a size range from 45 to 460 nm. Of these silica NP batches, the size range from 400 to 480 nm were used for the gold-coating experiments.

Discovering novel knowledge using granule mining

This paper presents an extended granule mining based methodology, to effectively describe the relationships between granules not only by traditional support and confidence, but by diversity and condition diversity as well. Diversity measures how diverse of a granule associated with the other granules, it provides a kind of novel knowledge in databases. We also provide an algorithm to implement the proposed methodology. The experiments conducted to characterize a real network traffic data collection show that the proposed concepts and algorithm are promising.

A novel CDVM based high-voltage converter using low power solid-state switches and a tuned resonant circuit designed for pulsed power applications

A novel concept of producing high dc voltage for pulsed-power applications is proposed in this paper. The topology consists of an LC resonant circuit supplied through a tuned alternating waveform that is produced by an inverter. The control scheme is based on the detection of variations in the resonant frequency and adjustment of the switching signal patterns for the inverter to produce a square waveform with exactly the same frequencies. Therefore the capacitor voltage oscillates divergently with an increasing amplitude. A simple one-stage capacitor-diode voltage multiplier (CDVM) connected to the resonant capacitor then rectifies the alternating voltage and gives a dc level equal to twice the input voltage amplitude. The produced high voltage appears then in the form of high-voltage pulses across the load. A basic model is simulated by Simulink platform of MATLAB and the results are included in the paper.