Vaccination of healthy and diseased koalas (Phascolarctos cinereus) with a Chlamydia pecorum multi-subunit vaccine : evaluation of immunity and pathology

Chlamydial infections represent a major threat to the long-term survival of the koala and a successful vaccine would provide a valuable management tool. Vaccination however has the potential to enhance inflammatory disease in animals exposed to a natural infection prior to vaccination, a finding in early human and primate trials of whole cell vaccines to prevent trachoma. In the present study, we vaccinated both healthy koalas as well as clinically diseased koalas with a multi-subunit vaccine consisting of Chlamydia pecorum MOMP and NrdB mixed with immune stimulating complex as adjuvant. Following vaccination, there was no increase in inflammatory pathological changes in animals previously infected with Chlamydia. Strong antibody (including neutralizing antibodies) and lymphocyte proliferation responses were recorded in all vaccinated koalas, both healthy and clinically diseased. Vaccine induced antibodies specific for both vaccine antigens were observed not only in plasma but also in ocular secretions. Our data shows that an experimental chlamydial vaccine is safe to use in previously infected koalas, in that it does not worsen infection-associated lesions. Furthermore, the prototype vaccine is effective, as demonstrated by strong levels of neutralizing antibody and lymphocyte proliferation responses in both healthy and clinically diseased koalas. Collectively, this work illustrates the feasibility of developing a safe and effective Chlamydia vaccine as a tool for management of disease in wild koalas.

Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease

Objectives In non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is intricately linked with a number of metabolic alterations. We studied substrate utilisation in NAFLD during basal, insulin-stimulated and exercise conditions, and correlated these outcomes with disease severity. Methods 20 patients with NAFLD (mean±SD body mass index (BMI) 34.1±6.7 kg/m2) and 15 healthy controls (BMI 23.4±2.7 kg/m2) were assessed. Respiratory quotient (RQ), whole-body fat (Fatox) and carbohydrate (CHOox) oxidation rates were determined by indirect calorimetry in three conditions: basal (resting and fasted), insulin-stimulated (hyperinsulinaemic–euglycaemic clamp) and exercise (cycling at an intensity to elicit maximal Fatox). Severity of disease and steatosis were determined by liver histology, hepatic Fatox from plasma β-hydroxybutyrate concentrations, aerobic fitness expressed as , and visceral adipose tissue (VAT) measured by computed tomography. Results Within the overweight/obese NAFLD cohort, basal RQ correlated positively with steatosis (r=0.57, p=0.01) and was higher (indicating smaller contribution of Fatox to energy expenditure) in patients with NAFLD activity score (NAS) ≥5 vs <5 (p=0.008). Both results were independent of VAT, % body fat and BMI. Compared with the lean control group, patients with NAFLD had lower basal whole-body Fatox (1.2±0.3 vs 1.5±0.4 mg/kgFFM/min, p=0.024) and lower basal hepatic Fatox (ie, β-hydroxybutyrate, p=0.004). During exercise, they achieved lower maximal Fatox (2.5±1.4 vs. 5.8±3.7 mg/kgFFM/min, p=0.002) and lower (p<0.001) than controls. Fatox during exercise was not associated with disease severity (p=0.79). Conclusions Overweight/obese patients with NAFLD had reduced hepatic Fatox and reduced whole-body Fatox under basal and exercise conditions. There was an inverse relationship between ability to oxidise fat in basal conditions and histological features of NAFLD including severity of steatosis and NAS

Walking the Coleridge Way : using cultural tourism to change perceptions of Somerset after the foot and mouth epidemic of 2001

This paper explores one of the ways in which the Somerset region in the United Kingdom, devastated by the foot and mouth epidemic in 2001, is trying to free itself from recurring negative representations and create more positive images of the area. After the epidemic projects were sought that would promote a more positive image and draw tourists back to the area. One of these projects drew on literary tourism to reinvigorate the site. A Walking and Bridle trail called the ‘Coleridge Way Walk’ has been implemented to take the images of the area from ones of disease and dirtiness to ones of Romantic longing. The Coleridge Way Walk uses past imaginings to re-energise the area. This energy, in part, comes from ‘re-imagining’ the site through past imaginings. The Coleridge Way Walk uses the past to create future direction for the once tainted area.

The active site residue V266 of Chlamydial HtrA is critical for substrate binding during both in vitro and in vivo conditions

HtrA is a complex, multimeric chaperone and serine protease important for the virulence and survival of many bacteria. Chlamydia trachomatis is an obligate, intracellular bacterial pathogen that is responsible for severe disease pathology. C. trachomatis HtrA (CtHtrA) has been shown to be highly expressed in laboratory models of disease. In this study, molecular modelling of CtHtrA protein active site structure identified putative S1-S3 subsite residues I242, I265, and V266. These residues were altered by site-directed mutagenesis, and these changes were shown to considerably reduce protease activity on known substrates and resulted in a narrower and distinct range of substrates compared to wild type. Bacterial two-hybrid analysis revealed that CtHtrA is able to interact in vivo with a broad range of protein sequences with high affinity. Notably, however, the interaction was significantly altered in 35 out of 69 clones when residue V266 was mutated, indicating that this residue has an important function during substrate binding.

An investigation into the use of human papillomavirus type 16 virus-like particles as a delivery vector system for foreign proteins: N- and C-terminal fusion of GFP to the L1 and L2 capsid proteins

Development of vaccine strategies against human papillomavirus (HPV), which causes cervical cancer, is a priority. We investigated the use of virus-like particles (VLPs) of the most prevalent type, HPV-16, as carriers of foreign proteins. Green fluorescent protein (GFP) was fused to the N or C terminus of both L1 and L2, with L2 chimeras being co-expressed with native L1. Purified chimaeric VLPs were comparable in size (∼55 nm) to native HPV VLPs. Conformation-specific monoclonal antibodies (Mabs) bound to the VLPs, thereby indicating that they possibly retain their antigenicity. In addition, all of the VLPs encapsidated DNA in the range of 6-8 kb. © 2007 Springer-Verlag.

The public health challenges of mental health problems and associated difficulties

Mental health is a major global health issue. Neuropsychiatric conditions are the most significant cause of disability worldwide, and account for 14% of the global burden of disease. Depression in particular places a huge burden on society, with the Global Burden of Disease 2000 study listing it as the fourth leading cause of disease burden worldwide and the largest non-fatal disease burden. In Australia, mental disorders are startlingly common and related to significant disability. The 2007 National Survey of Mental Health and Wellbeing revealed that the lifetime prevalence of any mental disorder was 45%, and within the last 12 months 20% of Australians met criteria for a mental disorder. Many of the articles in this issue explore mental health issues in young people. Indeed, mental health issues account for a large proportion of the disease burden in young people. Across the globe, mental health disorders caused the greatest number of years lost to disability(YLDs) amongst young people aged 10 to 24 years (45% of total YLDs). Depression caused the highest number of disability-adjusted life-years (DALYs) across this age group, accounting for 8. 2% of DALYs alone.6 It is clear that mental health is a critical area of focus for researchers, practitioners, and policy makers.

Tackling the health burden from household air pollution (HAP) : development and implementation of new WHO Guidelines

Household air pollution (HAP), arising mainly from the combustion of solid and other polluting fuels, is responsible for a very substantial public health burden, most recently estimated as causing 3.5 million premature deaths in 2010. These patterns of household fuel use have also important negative impacts on safety, prospects for poverty reduction and the environment, including climate change. Building on previous air quality guidelines, the WHO is developing new guidelines focused on household fuel combustion, covering cooking, heating and lighting, and although global, the key focus is low and middle income countries reflecting the distribution of disease burden. As discussed in this paper, currently in development, the guidelines will include reviews of a wide range of evidence including fuel use in homes, emissions from stoves and lighting, household air pollution and exposure levels experienced by populations, health risks, impacts of interventions on HAP and exposure, and also key factors influencing sustainable and equitable adoption of improved stoves and cleaner fuels. GRADE, the standard method used for guidelines evidence review may not be well suited to the variety and nature of evidence required for this project, and a modified approach is being developed and tested. Work on the guidelines is being carried out in close collaboration with the UN Foundation Global Alliance on Clean cookstoves, allowing alignment with specific tools including recently developed international voluntary standards for stoves, and the development of country action plans. Following publication, WHO plans to work closely with a number of countries to learn from implementation efforts, in order to further strengthen support and guidance. A case study on the situation and policy actions to date in Bhutan provide an illustration of the challenges and opportunities involved, and the timely importance of the new guidelines and associated research, evaluation and policy development agendas.

Menopause as a long-term risk to health : implications of general practitioner accounts of prevention for women’s choice and decision-making

Over the past two decades medical researchers and modernist feminist researchers have contested the meaning of menopause. In this article we examine various meanings of menopause in major medical and feminist literature and the construction of menopause in a semi-structured interview study of general practitioners in rural South Australia. Three discursive themes are identified in these interviews; (i) the hormonal menopause – symptoms, risk, prevention; (ii) the informed menopausal woman; and (iii) decision-making and hormone replacement therapy. By using the discourse of prevention, general practitioners construct menopause in relation to women's health care choices, empowerment and autonomy. We argue that the ways in which these concepts are deployed by general practitioners in this study produces and constrains the options available to women. The implications of these general practitioner accounts are discussed in relation to the proposition that medical and feminist descriptions of menopause posit alternative but equally-fixed truths about menopause and their relationship with the range of responses available to women at menopause. Social and cultural explanations of disease causality (c.f.Germov 1998, Hardey 1998) are absent from the new menopause despite their being an integral part of the framework of the women's health movement and health promotion drawn on by these general practitioners. Further, the shift of responsibility for health to the individual woman reinforces practice claims to empower women, but oversimplifies power relations and constructs menopause as a site of self-surveillance. The use of concepts from the women's health movement and health promotion have nevertheless created change in both the positioning of women as having ‘choices’ and the positioning of some general practitioners in terms of greater information provision to women and an attention to the woman's autonomy. In conclusion, we propose that a new menopause has evolved from a discursive shift in medicine and that there exists within this new configuration, claiming the empowerment of women as an integral part of health care for menopause, the possibility for change in medical practice which will broaden, strengthen, and maintain this position.

Impact of Wolbachia on infection with chikungunya and yellow fever viruses in the mosquito vector Aedes aegypti

Incidence of disease due to dengue (DENV), chikungunya (CHIKV) and yellow fever (YFV) viruses is increasing in many parts of the world. The viruses are primarily transmitted by Aedes aegypti, a highly domesticated mosquito species that is notoriously difficult to control. When transinfected into Ae. aegypti, the intracellular bacterium Wolbachia has recently been shown to inhibit replication of DENVs, CHIKV, malaria parasites and filarial nematodes, providing a potentially powerful biocontrol strategy for human pathogens. Because the extent of pathogen reduction can be influenced by the strain of bacterium, we examined whether the wMel strain of Wolbachia influenced CHIKV and YFV infection in Ae. aegypti. Following exposure to viremic blood meals, CHIKV infection and dissemination rates were significantly reduced in mosquitoes with the wMel strain of Wolbachia compared to Wolbachia-uninfected controls. However, similar rates of infection and dissemination were observed in wMel infected and non-infected Ae. aegypti when intrathoracic inoculation was used to deliver virus. YFV infection, dissemination and replication were similar in wMel-infected and control mosquitoes following intrathoracic inoculations. In contrast, mosquitoes with the wMelPop strain of Wolbachia showed at least a 10(4) times reduction in YFV RNA copies compared to controls. The extent of reduction in virus infection depended on Wolbachia strain, titer and strain of the virus, and mode of exposure. Although originally proposed for dengue biocontrol, our results indicate a Wolbachia-based strategy also holds considerable promise for YFV and CHIKV suppression.

Population Dynamics of RNA viruses

Between 50 and 100 million people are infected with dengue viruses each year and more than 100,000 of these die. Dr Choudhury has demonstrated that populations of dengue viruses in individual patients are genetically and functionally very diverse and that this diversity changes significantly at the time of major outbreaks of disease. The results of his studies may inform strategies which will make dengue vaccines far more effective.

Cost effectiveness of patient education for the prevention of falls in hospital : economic evaluation from a randomized controlled trial

Background Falls are one of the most frequently occurring adverse events that impact upon the recovery of older hospital inpatients. Falls can threaten both immediate and longer-term health and independence. There is need to identify cost-effective means for preventing falls in hospitals. Hospital-based falls prevention interventions tested in randomized trials have not yet been subjected to economic evaluation. Methods Incremental cost-effectiveness analysis was undertaken from the health service provider perspective, over the period of hospitalization (time horizon) using the Australian Dollar (A$) at 2008 values. Analyses were based on data from a randomized trial among n = 1,206 acute and rehabilitation inpatients. Decision tree modeling with three-way sensitivity analyses were conducted using burden of disease estimates developed from trial data and previous research. The intervention was a multimedia patient education program provided with trained health professional follow-up shown to reduce falls among cognitively intact hospital patients. Results The short-term cost to a health service of one cognitively intact patient being a faller could be as high as A$14,591 (2008). The education program cost A$526 (2008) to prevent one cognitively intact patient becoming a faller and A$294 (2008) to prevent one fall based on primary trial data. These estimates were unstable due to high variability in the hospital costs accrued by individual patients involved in the trial. There was a 52% probability the complete program was both more effective and less costly (from the health service perspective) than providing usual care alone. Decision tree modeling sensitivity analyses identified that when provided in real life contexts, the program would be both more effective in preventing falls among cognitively intact inpatients and cost saving where the proportion of these patients who would otherwise fall under usual care conditions is at least 4.0%. Conclusions This economic evaluation was designed to assist health care providers decide in what circumstances this intervention should be provided. If the proportion of cognitively intact patients falling on a ward under usual care conditions is 4% or greater, then provision of the complete program in addition to usual care will likely both prevent falls and reduce costs for a health service.

Designing a continuum of quality external cause of injury information in Queensland : from ambulance to hospital

This study is the first to employ an epidemiological framework to evaluate the ‘fit-for-purpose’ of ICD-10-AM external cause of injury codes, ambulance and hospital clinical documentation for injury surveillance. Importantly, this thesis develops an evidence-based platform to guide future improvements in routine data collections used to inform the design of effective injury prevention strategies. Quantification of the impact of ambulance clinical records on the overall information quality of Queensland hospital morbidity data collections for injury causal information is a unique and notable contribution of this study.

Perianal disease combined with NOD2 genotype predicts need for IBD-related surgery in Crohn’s Disease patients from a population-based cohort

Background: Patients with Crohn’s disease (CD) often require surgery at some stage of disease course. Prediction of CD outcome is influenced by clinical, environmental, serological, and genetic factors (eg, NOD2). Being able to identify CD patients at high risk of surgical intervention should assist clinicians to decide whether or not to prescribe early aggressive treatment with immunomodulators. Methods: We performed a retrospective analysis of selected clinical (age at diagnosis, perianal disease, active smoking) and genetic (NOD2 genotype) data obtained for a population-based CD cohort from the Canterbury Inflammatory Bowel Disease study. Logistic regression was used to identify predictors of complicated outcome in these CD patients (ie, need for inflammatory bowel disease-related surgery). Results: Perianal disease and the NOD2 genotype were the only independent factors associated with the need for surgery in this patient group (odds ratio=2.84 and 1.60, respectively). By combining the associated NOD2 genotype with perianal disease we generated a single “clinicogenetic” variable. This was strongly associated with increased risk of surgery (odds ratio=3.84, P=0.00, confidence interval, 2.28-6.46) and offered moderate predictive accuracy (positive predictive value=0.62). Approximately 1/3 of surgical outcomes in this population are attributable to the NOD2+PA variable (attributable risk=0.32). Conclusions: Knowledge of perianal disease and NOD2 genotype in patients presenting with CD may offer clinicians some decision-making utility for early diagnosis of complicated CD progression and initiating intensive treatment to avoid surgical intervention. Future studies should investigate combination effects of other genetic, clinical, and environmental factors when attempting to identify predictors of complicated CD outcomes.

Genotypes of the MTHFR C677T and MTRR A66G genes act independently to reduce migraine disability in response to vitamin supplementation

BACKGROUND: Migraine is a chronic disabling neurovascular condition that may in part be caused by endothelial and cerebrovascular disruption induced by hyperhomocysteinaemia. We have previously provided evidence indicating that reduction of homocysteine by vitamin supplementation can reduce the occurrence of migraine in women. The current study examined the genotypic effects of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene variants on the occurrence of migraine in response to vitamin supplementation. METHODS: This was a 6-month randomized, double-blinded placebo-controlled trial of daily vitamin B supplementation (B(6), B(9) and B(12)) on reduction of homocysteine and of the occurrence of migraine in 206 female patients diagnosed with migraine with aura. RESULTS: Vitamin supplementation significantly reduced homocysteine levels (P<0.001), severity of headache in migraine (P=0.017) and high migraine disability (P=0.022) in migraineurs compared with the placebo effect (P>0.1). When the vitamin-treated group was stratified by genotype, the C allele carriers of the MTHFR C677T variant showed a higher reduction in homocysteine levels (P<0.001), severity of pain in migraine (P=0.01) and percentage of high migraine disability (P=0.009) compared with those with the TT genotypes. Similarly, the A allele carriers of the MTRR A66G variants showed a higher level of reduction in homocysteine levels (P<0.001), severity of pain in migraine (P=0.002) and percentage of high migraine disability (P=0.006) compared with those with the GG genotypes. Genotypic analysis for both genes combined indicated that the treatment effect modification of the MTRR variant was independent of the MTHFR variant. CONCLUSION: This provided further evidence that vitamin supplementation is effective in reducing migraine and also that both MTHFR and MTRR gene variants are acting independently to influence treatment response in female migraineurs.

A novel immunodeficiency disorder characterized by genetic amplification of interleukin 25

Many primary immunodeficiency disorders of differing etiologies have been well characterized, and much understanding of immunological processes has been gained by investigating the mechanisms of disease. Here, we have used a whole-genome approach, employing single-nucleotide polymorphism and gene expression microarrays, to provide insight into the molecular etiology of a novel immunodeficiency disorder. Using DNA copy number profiling, we define a hyperploid region on 14q11.2 in the immunodeficiency case associated with the interleukin (IL)-25 locus. This alteration was associated with significantly heightened expression of IL25 following T-cell activation. An associated dominant type 2 helper T cell bias in the immunodeficiency case provides a mechanistic explanation for recurrence of infections by pathogens met by Th1-driven responses. Furthermore, this highlights the capacity of IL25 to alter normal human immune responses.