Establishment of a mouse model of colitis and its use to evaluate the anti-inflammatory effects of two ghrelin peptides

Ghrelin is a gut-brain peptide hormone that induces appetite, stimulates the release of growth hormone, and has recently been shown to ameliorate inflammation. Recent studies have suggested that ghrelin may play a potential role in inflammation-related diseases such as inflammatory bowel diseases (IBD). A previous study with ghrelin in the TNBS mouse model of colitis demonstrated that ghrelin treatment decreased the clinical severity of colitis and inflammation and prevented the recurrence of disease. Ghrelin may be acting at the immunological and epithelial level as the ghrelin receptor (GHSR) is expressed by immune cells and intestinal epithelial cells. The current project investigated the effect of ghrelin in a different mouse model of colitis using dextran sodium sulphate (DSS) – a luminal toxin. Two molecular weight forms of DSS were used as they give differing effects (5kDa and 40kDa). Ghrelin treatment significantly improved clinical colitis scores (p=0.012) in the C57BL/6 mouse strain with colitis induced by 2% DSS (5kDa). Treatment with ghrelin suppressed colitis in the proximal colon as indicated by reduced accumulative histopathology scores (p=0.03). Whilst there was a trend toward reduced scores in the mid and distal colon in these mice this did not reach significance. Ghrelin did not affect histopathology scores in the 40kDa model. There was no significant effect on the number of regulatory T cells or TNF-α secretion from cultured lymph node cells from these mice. The discovery of C-terminal ghrelin peptides, for example, obestatin and the peptide derived from exon 4 deleted proghrelin (Δ4 preproghrelin peptide) have raised questions regarding their potential role in biological functions. The current project investigated the effect of Δ4 peptide in the DSS model of colitis however no significant suppression of colitis was observed. In vitro epithelial wound healing assays were also undertaken to determine the effect of ghrelin on intestinal epithelial cell migration. Ghrelin did not significantly improve wound healing in these assays. In conclusion, ghrelin treatment displays a mild anti-inflammatory effect in the 5kDa DSS model. The potential mechanisms behind this effect and the disparity between these results and those published previously will be discussed.

Lyprinol : is it a useful anti-inflammatory agent?

The New Zealand green lipped mussel preparation Lyprinol is available without a prescription from a supermarket, pharmacy or Web. The Food and Drug Administration have recently warned Lyprinol USA about their extravagant anti-inflammatory claims for Lyprinol appearing on the web. These claims are put to thorough review. Lyprinol does have anti-inflammatory mechanisms, and has anti-inflammatory effects in some animal models of inflammation. Lyprinol may have benefits in dogs with arthritis. There are design problems with the clinical trials of Lyprinol in humans as an anti-inflammatory agent in osteoarthritis and rheumatoid arthritis, making it difficult to give a definite answer to how effective Lyprinol is in these conditions, but any benefit is small. Lyprinol also has a small benefit in atopic allergy. As anti-inflammatory agents, there is little to choose between Lyprinol and fish oil. No adverse effects have been reported with Lyprinol. Thus, although it is difficult to conclude whether Lyprinol does much good, it can be concluded that Lyprinol probably does no major harm.

Anti-cancer activity of zoledronic acid in breast cancer

Background: Zoledronic acid is used to prevent the bone loss associated with antioestrogen treatments in subjects with breast cancer. Preclinical studies suggest that zoledronic acid may have anticancer activity in its own right. This anticancer possibility with zoledronic acid has not been investigated extensively in clinical trials. Objectives/methods: This evaluation is of a large clinical trial that investigated the effect of zoledronic acid on cancer outcomes in premenopausal women with breast cancer. Results: The trial showed that after 4 years, 94.0% of subjects who were treated with zoledronic acid were disease-free compared with 90.8% of those not treated with zoledronic acid. Recurrence survival was a secondary end point; this occurred in 94.0% with, and 90.9% without, zoledronic acid treatment. Conclusions: Zoledronic acid does have anticancer activity in premenopausal women with cancer.

CTA1-DD is an effective adjuvant for targeting anti-chlamydial immunity to the murine genital mucosa

Chlamydia trachomatis is a significant human pathogen with potentially severe disease sequelae in the genital tract, including infertility. A successful vaccine will need to effectively target immunity to the genital mucosa. Intranasal immunisation with cholera toxin (CT) can target immunity to the genital tract, but has the potential to cause neurological side effects. CTA1-DD is a non-toxic potent mucosal adjuvant which combines the enzymatic properties of CT, with a B cell targeting moiety. Here, we demonstrate that intranasal immunisation with CTA1-DD and chlamydial Major Outer Membrane Protein (MOMP) results in the induction of neutralising systemic and mucosal antibodies, and reduces the level of chlamydial shedding following intravaginal challenge with Chlamydia muridarum. Thus, CTA1-DD is an effective adjuvant for vaccine development against Chlamydia trachomatis, and possibly also a range of other genital pathogens.

Immunogenicity and protective efficacy of an anti-Streptococcus pyogenes vaccine candidate in multiple animal species

Streptococcus pyogenes, also known as Group A Streptococcus (GAS) has been associated with a range of diseases from the mild pharyngitis and pyoderma to more severe invasive infections such as streptococcal toxic shock. GAS also causes a number of non-suppurative post-infectious diseases such as rheumatic fever, rheumatic heart disease and glomerulonephritis. The large extent of GAS disease burden necessitates the need for a prophylactic vaccine that could target the diverse GAS emm types circulating globally. Anti-GAS vaccine strategies have focused primarily on the GAS M-protein, an extracellular virulence factor anchored to GAS cell wall. As opposed to the hypervariable N-terminal region, the C-terminal portion of the protein is highly conserved among different GAS emm types and is the focus of a leading GAS vaccine candidate, J8-DT/alum. The vaccine candidate J8-DT/alum was shown to be immunogenic in mice, rabbits and the non-human primates, hamadryas baboons. Similar responses to J8-DT/alum were observed after subcutaneous and intramuscular immunization with J8-DT/alum, in mice and in rabbits. Further assessment of parameters that may influence the immunogenicity of J8-DT demonstrated that the immune responses were identical in male and female mice and the use of alum as an adjuvant in the vaccine formulation significantly increased its immunogenicity, resulting in a long-lived serum IgG response. Contrary to the previous findings, the data in this thesis indicates that a primary immunization with J8-DT/alum (50ƒÊg) followed by a single boost is sufficient to generate a robust immune response in mice. As expected, the IgG response to J8- DT/alum was a Th2 type response consisting predominantly of the isotype IgG1 accompanied by lower levels of IgG2a. Intramuscular vaccination of rabbits with J8-DT/alum demonstrated that an increase in the dose of J8-DT/alum up to 500ƒÊg does not have an impact on the serum IgG titers achieved. Similar to the immune response in mice, immunization with J8-DT/alum in baboons also established that a 60ƒÊg dose compared to either 30ƒÊg or 120ƒÊg was sufficient to generate a robust immune response. Interestingly, mucosal infection of naive baboons with a M1 GAS strain did not induce a J8-specific serum IgG response. As J8-DT/alum mediated protection has been previously reported to be due to the J8- specific antibody formed, the efficacy of J8-DT antibodies was determined in vitro and in vivo. In vitro opsonization and in vivo passive transfer confirmed the protective potential of J8-DT antibodies. A reduction in the bacterial burden after challenge with a bioluminescent M49 GAS strain in mice that were passively administered J8-DT IgG established that protection due to J8-DT was mediated by antibodies. The GAS burden in infected mice was monitored using bioluminescent imaging in addition to traditional CFU assays. Bioluminescent GAS strains including the ‘rheumatogenic’ M1 GAS could not be generated due to limitations with transformation of GAS, however, a M49 GAS strain was utilized during BLI. The M49 serotype is traditionally a ‘nephritogenic’ serotype associated with post-streptococcal glomerulonephritis. Anti- J8-DT antibodies now have been shown to be protective against multiple GAS strains such as M49 and M1. This study evaluated the immunogenicity of J8-DT/alum in different species of experimental animals in preparation for phase I human clinical trials and provided the ground work for the development of a rapid non-invasive assay for evaluation of vaccine candidates.

(Anti)Queer : introduction

The ‘anti- of ‘(Anti)Queer’ is a queer anti. In particle physics, a domain of science which was for a long time peddled as ultimately knowable, rational and objective, the postmodern turn has made everything queer (or chaotic, as the scientific version of this turn is perhaps more commonly named). This is a world where not only do two wrongs not make a right, but a negative and positive do not calmly cancel each other out to leave nothing, as mathematics might suggest. When matter meets with anti-matter, the resulting explosion can produce not only energy - heat and light? - but new matter. We live in a world whose very basics are no longer the electron and the positron, but an ever proliferating number of chaotic, unpredictable - queer? - subatomic particles. Some are ‘charmed’, others merely ‘strange’ . Weird science indeed. The ‘Anti-’ of ‘Anti-queer’ does not place itself neatly into binaries. This is not a refutation of all that queer has been or will be. It is explicitly a confrontation, a challenge, an attempt to take seriously not only the claims made for queer but the potent contradictions and silences which stand proudly when any attempt is made to write a history of the term. Specifically, ‘Anti-Queer’ is not Beyond Queer, the title of Bruce Bawer’s 1996 book which calmly and self-confidently explains the failings of queer, extols a return to a liberal political theory of cultural change and places its own marker on queer as a movement whose purpose has been served. We are not Beyond Queer. And if we are Anti-Queer, it is only to challenge those working in the arena to acknowledge and work with some of the facts of the movement’s history whose productivity has been erased with a gesture which has, proved, bizarrely, to be reductive and homogenising.

From Deep North to international governance exemplar : Fitzgerald's impact on the international anti-corruption movement

In pre-Fitzgerald Queensland, the existence of corruption was widely known but its extent and modes of operation were not fully evident. The Fitzgerald Report identified the need for reform of the structure, procedures and efficiency in public administration in Queensland. What was most striking in the Queensland reform process was that a new model for combatting corruption had been developed. Rather than rely upon a single law and a single institution, existing institutions were strengthened and new institutions were introduced to create a set of mutually supporting and mutually checking institutions, agencies and laws that jointly sought to improve governmental standards and combat corruption. Some of the reforms were either unique to Queensland or very rare. One of the strengths of this approach was that it avoided creating a single over-arching institution to fight corruption. There are many powerful opponents of reform. Influential institutions and individuals resist any interference with their privileges. In order to cause a mass exodus from an entrenched corruption system, a seminal event or defining process is needed to alter expectations and incentives that are sufficient to encourage significant numbers of individuals to desert the corruption system and assist the integrity system in exposing and destroying it. The Fitzgerald Inquiry was such an event. This article also briefly addresses methods for destroying national corruption systems where they emerge and exist.

From deep North to global governance exemplar : Fitzgerald's impact on the International Anti-corruption Movement

In pre-Fitzgerald Queensland, the existence of corruption was widely known but its extent and modes of operation were not fully evident. The Fitzgerald Report identified the need for reform of the structure, procedures and efficiency in public administration in Queensland. What was most striking in the Queensland reform process was that a new model for combating corruption had been developed. Rather than rely upon a single law and a single institution, existing institutions were strengthened and new institutions were instituted to create a set of mutually supporting and mutually checking institutions, agencies and laws that jointly sought to improve governmental standards and combat corruption. Some of the reforms were either unique to Queensland or very rare. One of the strengths of this approach was that it avoided creating a single overarching institution to fight corruption. There are many powerful opponents of reform. Influential institutions and individuals resist any interference with their privileges. In order to cause a mass exodus from an entrenched corruption system, a seminal event or defining process is needed to alter expectations and incentives that are sufficient to encourage significant numbers of individuals to desert the corruption system and assist the integrity system in exposing and destroying it. The Fitzgerald Inquiry was such an event. The article also briefly addresses methods for destroying national corruption system where they emerge and exist.