Reduced variance in monozygous twins for multiple MR parameters : implications for disease studies and the genetic basis of brain structure

Twin studies offer the opportunity to determine the relative contribution of genes versus environment in traits of interest. Here, we investigate the extent to which variance in brain structure is reduced in monozygous twins with identical genetic make-up. We investigate whether using twins as compared to a control population reduces variability in a number of common magnetic resonance (MR) structural measures, and we investigate the location of areas under major genetic influences. This is fundamental to understanding the benefit of using twins in studies where structure is the phenotype of interest. Twenty-three pairs of healthy MZ twins were compared to matched control pairs. Volume, T2 and diffusion MR imaging were performed as well as spectroscopy (MRS). Images were compared using (i) global measures of standard deviation and effect size, (ii) voxel-based analysis of similarity and (iii) intra-pair correlation. Global measures indicated a consistent increase in structural similarity in twins. The voxel-based and correlation analyses indicated a widespread pattern of increased similarity in twin pairs, particularly in frontal and temporal regions. The areas of increased similarity were most widespread for the diffusion trace and least widespread for T2. MRS showed consistent reduction in metabolite variation that was significant in the temporal lobe N-acetylaspartate (NAA). This study has shown the distribution and magnitude of reduced variability in brain volume, diffusion, T2 and metabolites in twins. The data suggest that evaluation of twins discordant for disease is indeed a valid way to attribute genetic or environmental influences to observed abnormalities in patients since evidence is provided for the underlying assumption of decreased variability in twins.

Estimation on the mortality and disease burden attributed to selected risk factors in Shandong province [山东省主要危险因素的归因死亡和疾病负担分析]

Objective: To determine the major health related risk factors and provide evidence for policy-making,using health burden analysis on selected factors among general population from Shandong province. Methods: Based on data derived from the Third Death of Cause Sampling Survey in Shandong. Years of life lcrat(YLLs),yearS Iived with disability(YLDs)and disability-adjusted life years(DALYs) were calculated according to the GBD ethodology.Deaths and DALYs attributed to the selected risk factors were than estimated together with the PAF data from GBD 2001 study.The indirect method was employed to estimate the YLDs. Results: 51.09%of the total dearlls and 31.83%of the total DALYs from the Shandong population were resulted from the 19 selected risk factors.High blood pre.ure,smoking,low fruit and vegetable intake,aleohol consumption,indoor smoke from solid fuels,high cholesterol,urban air pollution, physical inactivity,overweight and obesity and unsafe injections in health care settings were identified as the top 10 risk faetors for mortality which together caused 50.21%of the total deaths.Alcohol use,smoking,high blood pressure,Low fruit and vegetable intake, indoor smoke from solid fuels, overweight and obesity,high cholesterol, physical inactivity,urban air pollution and iron-deficiency anemia were proved as the top 10 risk factors related to disease burden and were responsible for 29.04%of the total DALYs. Conclusion: Alcohol use.smoking and high blood pressure were determined as the major risk factors which influencing the health of residents in Shandong. The mortality and burden of disease could be reduced significantly if these major factors were effectively under control.

The role of insulin and IGF2 signalling on metabolic pathways in prostate cancer progression

Prostate cancer (CaP) is the most commonly diagnosed cancer in males in Australia, North America, and Europe. If found early and locally confined, CaP can be treated with radical prostatectomy or radiation therapy; however, 25-40% patients will relapse and go on to advanced disease. The most common therapy in these cases is androgen deprivation therapy (ADT), which suppresses androgen production from the testis. Lack of the testicular androgen supply causes cells of the prostate to undergo apoptosis. However, in some cases the regression initially seen with ADT eventually gives way to a growth of a population of cancerous cells that no longer require testicular androgens. This phenotype is essentially fatal and is termed castrate resistant prostate cancer (CRPC). In addition to eventual regression, there are many undesirable side effects which accompany ADT, including development of a metabolic syndrome, which is defined by the U.S. National Library of Medicine as “a combination of medical disorders that increase the risk of developing cardiovascular disease and diabetes.” This project will focus on the effect of ADT induced hyperinsulinemia, as mimicked by treating androgen receptor positive CaP cells with insulin in a serum (hormone) deprived environment. While this side effect is not widely explored, in this thesis it is demonstrated for the first time that insulin upregulates pathways important to CaP progression. Our group has previously shown that during CaP progression, the enzymes necessary for de novo steroidogenesis are upregulated in the LNCaP xenograft model, total steroid levels are increased in tumours compared to pre castrate levels, and de novo steroidogenesis from radio-labelled acetate has been demonstrated. Because of the CaP dependence on AR for survival, we and other groups believe that CaP cells carry out de novo steroidogenesis to survive in androgen deprived conditions. Because (a) men on ADT often develop metabolic syndrome, and (b) men with lifestyle-induced obesity and hyperinsulinemia have worse prognosis and faster disease progression, and because (c) insulin causes steroidogenesis in other cell lines, the hypothesis that insulin may contribute to CaP progression through upregulation of steroidogenesis was explored. Insulin upregulates steroidogenesis enzymes at the mRNA level in three AR positive cell lines, as well as upregulating these enzymes at the protein level in two cell lines. It has also been demonstrated that insulin increases mitochondrial (functional) levels of steroid acute regulatory protein (StAR). Furthermore, insulin causes increased levels of total steroids in and induction of de novo steroid synthesis by insulin has been demonstrated at levels induced sufficient to activate AR. The effect of insulin analogs on CaP steroidogenesis in LNCaP and VCaP cells has also been investigated because epidemiological studies suggest that some of the analogs developed may have more cancer stimulatory effects than normal insulin. In this project, despite the signalling differences between glargine, X10, and insulin, these analogs did not appear to induce steroidogenesis any more potently that normal insulin. The effect of insulin of MCF7breast cancer cells was also investigated with results suggesting that breast cancer cells may be capable of de novo steroidogenesis, and that increase in estradiol production may be exacerbated by insulin. Insulin has also been long known to stimulate lipogenesis in the liver and adipocytes, and has been demonstrated to increase lipogenesis in breast cancer cells; therefore, investigation of the effect of insulin on lipogenesis, which is a hallmark of aggressive cancers, was investigated. In CaP progression sterol regulatory element binding protein (SREBP) is dysregulated and upregulates fatty acid synthase (FASN), acetyl CoA-carboxylase, and other lipogenesis genes. SREBP is important for steroidogenesis and in this project has been shown to be upregulated by insulin in CaP cells. Fatty acid synthesis provides building blocks of membrane growth, provides substrates for acid oxidation, the main energy source for CaP cells, provides building blocks for anti-apoptotic and proinflammatory molecules, and provides molecules that stimulate steroidogenesis. In this project it has been shown that insulin upregulates FASN and ACC, which synthesize fatty acids, as well as upregulating hormone sensitive lipase (HSL), diazepam-binding inhibitor (DBI), and long-chain acyl-CoA synthetase 3 (ACSL3), which contribute to lipid activation of steroidogenesis. Insulin also upregulates total lipid levels and de novo lipogenesis, which can be suppressed by inhibition of the insulin receptor (INSR). The fatty acids synthesized after insulin treatment are those that have been associated with CaP; furthermore, microarray data suggests insulin may upregulate fatty acid biosynthesis, metabolism and arachidonic acid metabolism pathways, which have been implicated in CaP growth and survival. Pharmacological agents used to treat patients with hyperinsulinemia/ hyperlipidemia have gained much interest in regards to CaP risk and treatment; however, the scientific rationale behind these clinical applications has not been examined. This thesis explores whether the use of metformin or simvastatin would decrease either lipogenesis or steroidogenesis or both in CaP cells. Simvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) inhibitor, which blocks synthesis of cholesterol, the building block of steroids/ androgens. It has also been postulated to down regulate SREBP in other metabolic disorders. It has been shown in this thesis, in LNCaP cells, that simvastatin inhibited and decreased insulin induced steroidogenesis and lipogenesis, respectively, but increased these pathways in the absence of insulin. Conversely, metformin, which activates AMP-activated protein kinase (AMPK) to shut down lipogenesis, cholesterol synthesis, and protein synthesis, highly suppresses both steroidogenesis and lipogenesis in the presence and absence of insulin. Lastly, because it has been demonstrated to increase steroidogenesis in other cell lines, and because the elucidation of any factors affecting steroidogenesis is important to understanding CaP, the effect of IGF2 on steroidogenesis in CaP cells was investigated. In patient samples, as men progress to CRPC, IGF2 mRNA and the protein levels of the receptors it may signal through are upregulated. It has also been demonstrated that IGF2 upregulates steroidogenic enzymes at both the mRNA and protein levels in LNCaP cells, increases intracellular and secreted steroid/androgen levels in LNCaPs to levels sufficient to stimulate the AR, and upregulated de novo steroidogenesis in LNCaPs and VCaPs. As well, inhibition of INSR and insulin-like growth factor 1 receptor (IGF1R), which IGF2 signals through, suggests that induction of steroidogenesis may be occurring predominantly through IGF1R. In summary, this project has illuminated for the first time that insulin is likely to play a large role in cancer progression, through upregulation of the steroidogenesis and lipogenesis pathways at the mRNA and protein levels, and production levels, and demonstrates a novel role for IGF-II in CaP progression through stimulation of steroidogenesis. It has also been demonstrated that metformin and simvastatin drugs may be useful in suppressing the insulin induction of these pathways. This project affirms the pathways by which ADT- induced metabolic syndrome may exacerbate CaP progression and strongly suggests that the monitoring and modulation of the metabolic state of CaP patients could have a strong impact on their therapeutic outcomes.

Interaction of myxomatosis and Rabbit Haemorrhagic Disease in wild rabbit

Increasing resistance of rabbits to myxomatosis in Australia has led to the exploration of Rabbit Haemorrhagic Disease, also called Rabbit Calicivirus Disease (RCD) as a possible control agent. While the initial spread of RCD in Australia resulted in widespread rabbit mortality in affected areas, the possible population dynamic effects of RCD and myxomatosis operating within the same system have not been properly explored. Here we present early mathematical modelling examining the interaction between the two diseases. In this study we use a deterministic compartment model, based on the classical SIR model in infectious disease modelling. We consider, here, only a single strain of myxomatosis and RCD and neglect latent periods. We also include logistic population growth, with the inclusion of seasonal birth rates. We assume there is no cross-immunity due to either disease. The mathematical model allows for the possibility of both diseases to be simultaneously present in an individual, although results are also presented for the case where co infection is not possible, since co-infection is thought to be rare and questions exist as to whether it can occur. The simulation results of this investigation show that it is a crucial issue and should be part of future field studies. A single simultaneous outbreak of RCD and myxomatosis was simulated, while ignoring natural births and deaths, appropriate for a short timescale of 20 days. Simultaneous outbreaks may be more common in Queensland. For the case where co-infection is not possible we find that the simultaneous presence of myxomatosis in the population suppresses the prevalence of RCD, compared to an outbreak of RCD with no outbreak of myxomatosis, and thus leads to a less effective control of the population. The reason for this is that infection with myxomatosis removes potentially susceptible rabbits from the possibility of infection with RCD (like a vaccination effect). We found that the reduction in the maximum prevalence of RCD was approximately 30% for an initial prevalence of 20% of myxomatosis, for the case where there was no simultaneous outbreak of myxomatosis, but the peak prevalence was only 15% when there was a simultaneous outbreak of myxomatosis. However, this maximum reduction will depend on other parameter values chosen. When co-infection is allowed then this suppression effect does occur but to a lesser degree. This is because the rabbits infected with both diseases reduces the prevalence of myxomatosis. We also simulated multiple outbreaks over a longer timescale of 10 years, including natural population growth rates, with seasonal birth rates and density dependent(logistic) death rates. This shows how both diseases interact with each other and with population growth. Here we obtain sustained outbreaks occurring approximately every two years for the case of a simultaneous outbreak of both diseases but without simultaneous co-infection, with the prevalence varying from 0.1 to 0.5. Without myxomatosis present then the simulation predicts RCD dies out quickly without further introduction from elsewhere. With the possibility of simultaneous co-infection of rabbits, sustained outbreaks are possible but then the outbreaks are less severe and more frequent (approximately yearly). While further model development is needed, our work to date suggests that: 1) the diseases are likely to interact via their impacts on rabbit abundance levels, and 2) introduction of RCD can suppress myxomatosis prevalence. We recommend that further modelling in conjunction with field studies be carried out to further investigate how these two diseases interact in the population.

In vitro estimation of foetal liver volume using ultrasound, x-ray computed tomography and magnetic resonance imaging

Sixteen formalin-fixed foetal livers were scanned in vitro using a new system for estimating volume from a sequence of multiplanar 2D ultrasound images. Three different scan techniques were used (radial, parallel and slanted) and four volume estimation algorithms (ellipsoid, planimetry, tetrahedral and ray tracing). Actual liver volumes were measured by water displacement. Twelve of the sixteen livers also received x-ray computed tomography (CT) and magnetic resonance (MR) scans and the volumes were calculated using voxel counting and planimetry. The percentage accuracy (mean ± SD) was 5.3 ± 4.7%, −3.1 ± 9.6% and −0.03 ± 9.7% for ultrasound (radial scans, ray volumes), MR and CT (voxel counting) respectively. The new system may be useful for accurately estimating foetal liver volume in utero.

The relationship between chronic disease self-efficacy and nutritional status, functional ability and quality of life in older adults at risk of hospital readmission

Background and significance: Older adults with chronic diseases are at increasing risk of hospital admission and readmission. Approximately 75% of adults have at least one chronic condition, and the odds of developing a chronic condition increases with age. Chronic diseases consume about 70% of the total Australian health expenditure, and about 59% of hospital events for chronic conditions are potentially preventable. These figures have brought to light the importance of the management of chronic disease among the growing older population. Many studies have endeavoured to develop effective chronic disease management programs by applying social cognitive theory. However, limited studies have focused on chronic disease self-management in older adults at high risk of hospital readmission. Moreover, although the majority of studies have covered wide and valuable outcome measures, there is scant evidence on examining the fundamental health outcomes such as nutritional status, functional status and health-related quality of life. Aim: The aim of this research was to test social cognitive theory in relation to self-efficacy in managing chronic disease and three health outcomes, namely nutritional status, functional status, and health-related quality of life, in older adults at high risk of hospital readmission. Methods: A cross-sectional study design was employed for this research. Three studies were undertaken. Study One examined the nutritional status and validation of a nutritional screening tool; Study Two explored the relationships between participants. characteristics, self-efficacy beliefs, and health outcomes based on the study.s hypothesized model; Study Three tested a theoretical model based on social cognitive theory, which examines potential mechanisms of the mediation effects of social support and self-efficacy beliefs. One hundred and fifty-seven patients aged 65 years and older with a medical admission and at least one risk factor for readmission were recruited. Data were collected from medical records on demographics, medical history, and from self-report questionnaires. The nutrition data were collected by two registered nurses. For Study One, a contingency table and the kappa statistic was used to determine the validity of the Malnutrition Screening Tool. In Study Two, standard multiple regression, hierarchical multiple regression and logistic regression were undertaken to determine the significant influential predictors for the three health outcome measures. For Study Three, a structural equation modelling approach was taken to test the hypothesized self-efficacy model. Results: The findings of Study One suggested that a high prevalence of malnutrition continues to be a concern in older adults as the prevalence of malnutrition was 20.6% according to the Subjective Global Assessment. Additionally, the findings confirmed that the Malnutrition Screening Tool is a valid nutritional screening tool for hospitalized older adults at risk of readmission when compared to the Subjective Global Assessment with high sensitivity (94%), and specificity (89%) and substantial agreement between these two methods (k = .74, p < .001; 95% CI .62-.86). Analysis data for Study Two found that depressive symptoms and perceived social support were the two strongest influential factors for self-efficacy in managing chronic disease in a hierarchical multiple regression. Results of multivariable regression models suggested advancing age, depressive symptoms and less tangible support were three important predictors for malnutrition. In terms of functional status, a standard regression model found that social support was the strongest predictor for the Instrumental Activities of Daily Living, followed by self-efficacy in managing chronic disease. The results of standard multiple regression revealed that the number of hospital readmission risk factors adversely affected the physical component score, while depressive symptoms and self-efficacy beliefs were two significant predictors for the mental component score. In Study Three, the results of the structural equation modelling found that self-efficacy partially mediated the effect of health characteristics and depression on health-related quality of life. The health characteristics had strong direct effects on functional status and body mass index. The results also indicated that social support partially mediated the relationship between health characteristics and functional status. With regard to the joint effects of social support and self-efficacy, social support fully mediated the effect of health characteristics on self-efficacy, and self-efficacy partially mediated the effect of social support on functional status and health-related quality of life. The results also demonstrated that the models fitted the data well with relative high variance explained by the models, implying the hypothesized constructs under discussion were highly relevant, and hence the application for social cognitive theory in this context was supported. Conclusion: This thesis highlights the applicability of social cognitive theory on chronic disease self-management in older adults at risk of hospital readmission. Further studies are recommended to validate and continue to extend the development of social cognitive theory on chronic disease self-management in older adults to improve their nutritional and functional status, and health-related quality of life.

Markers of chronic disease in offenders in a high secure correctional centre in Queensland

This study aimed to gauge the presence of markers of chronic disease, as a basis for food and nutrition policy in correctional facilities. One hundred and twenty offenders, recruited from a Queensland Correctional Centre, provided informed consent and completed both dietary interviews and physical measurements. Mean age of the sample was 35.5 ± 12 years (range = 19–77 yrs); mean age of the total population (n = 945) was 32.8 ± 10 years (range = 19–80 yrs). Seventy-nine participants also provided fasting blood samples. The mean body mass index (BMI) was 27 ± 3.5 kg/m2; 72% having a BMI > 25 kg/m2. Thirty-three percent were classified overweight or obese using waist circumference (mean = 92 ± 10 cm). Mean blood pressure measurement was systolic = 130 ± 14 mmHg and diastolic = 73 ± 10 mmHg. Twenty-four percent were classified as hypertensive of whom three were on antihypertensive medication. Eighteen percent had elevated triglycerides, and 40% unfavourable total cholesterol to HDL ratios. Homeostatic Model Assessment (HOMA scores) were calculated from glucose and insulin. Four participants were insulin resistant, two of whom had known diabetes. Metabolic syndrome, based on waist circumference (adjusted for ethnicity), blood lipids, blood pressure and plasma glucose indicated that 25% (n = 20) were classified with metabolic syndrome. Eighty-four percent (n = 120) reported some physical activity each day, with 51 percent participating ≥two times daily. Fifty-four percent reported smoking with an additional 20% having smoked in the past. Findings suggest that waist circumference rather than weight and BMI only should be used in this group to determine weight status. The data suggest that markers of chronic disease are present and that food and nutrition policy must reflect this. Further analysis is being completed to determine relevant policy initiatives.

The 'obesity paradox' in chronic obstructive pulmonary disease

Poor nutritional status in chronic obstructive pulmonary disease (COPD) is associated with increased mortality independently of disease-severity (Collins et al).1 Epidemiological studies have suggested a protective role of obesity against mortality in COPD (Vestbo et al)2 which is contrary to data from the general population where obesity is associated with decreased life expectancy. This relationship has been referred to as the ‘obesity paradox’ and has been demonstrated in a number of chronic wasting conditions (Kalantar-Zadeh et al).3 This study investigated the existence of the obesity paradox in outpatients with COPD by examining the effect of body mass index (BMI) on 1-year healthcare use and clinical outcome in terms of hospital admission rates, length of hospital stay, outpatient appointments and mortality. BMI was assessed in 424 outpatients with COPD, with measurements performed by specialist respiratory nurses during outpatient clinics. 1-year healthcare use was retrospectively collected from the date of BMI measurement. Abstract S163 Table 1 Patients classified as overweight (25.0–29.9 kg/m2) or obese (>30 kg/m2) experienced significantly fewer emergency hospital admissions, as well as a reduced length of hospital stay, in comparison to normal weight (20.0–24.9 kg/m2) or underweight (<20 kg/m2) outpatients. There was a significant negative trend between BMI classification and mortality. This study supports the existence of the ‘obesity paradox’ in COPD, not only in relation to reduced 1 year mortality rates but also in terms of reduced emergency hospital admissions and reduced length of hospital stay.

P147 Deprivation is associated with increased healthcare utilisation in patients with chronic obstructive pulmonary disease

Deprivation assessed using the index of multiple deprivation (IMD) has been shown to be an independent risk factor for 1-year mortality in outpatients with chronic obstructive pulmonary disease; COPD (Collins et al, 2010). IMD combines a number of economic and social issues (eg, health, education, employment) into one overall deprivation score, the higher the score the higher an individual's deprivation. Whilst malnutrition in COPD has been linked to increased healthcare use it is not clear if deprivation is also independently associated. This study aimed to investigate the influence of deprivation on 1-year healthcare utilisation in outpatients with COPD. IMD was established in 424 outpatients with COPD according to the geographical location for each patient's address (postcode) and related to their healthcare use in the year post-date screened (Nobel et al, 2008). Patients were routinely screened in outpatient clinics for malnutrition using the ‘Malnutrition Universal Screening Tool’, ‘MUST’ (Elia 2003); mean age 73 (SD 9.9) years; body mass index 25.8 (SD 6.3) kg/m2 with healthcare use collected 1 year from screening (Abstract P147 Table 1). Deprivation assessed using IMD (mean 15.9; SD 11.1) was found to be a significant predictor for the frequency and duration of emergency hospital admissions as well as the duration of elective hospital admission. Deprivation was also linked to reduced secondary care outpatient appointment attendance but not an increase in failure to attend and deprivation was not associated with increased disease severity, as classified by the GOLD criteria (p=0.580). COPD outpatients residing in more deprived areas experience increased hospitalisation rates but decreased outpatient appointment attendance. The underlying reason behind this disparity in healthcare use requires further investigation.