Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker.

BACKGROUND: Although we know much about the molecular makeup of the sinus node (SN) in small mammals, little is known about it in humans. The aims of the present study were to investigate the expression of ion channels in the human SN and to use the data to predict electrical activity. METHODS AND RESULTS: Quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence were used to analyze 6 human tissue samples. Messenger RNA (mRNA) for 120 ion channels (and some related proteins) was measured in the SN, a novel paranodal area, and the right atrium (RA). The results showed, for example, that in the SN compared with the RA, there was a lower expression of Na(v)1.5, K(v)4.3, K(v)1.5, ERG, K(ir)2.1, K(ir)6.2, RyR2, SERCA2a, Cx40, and Cx43 mRNAs but a higher expression of Ca(v)1.3, Ca(v)3.1, HCN1, and HCN4 mRNAs. The expression pattern of many ion channels in the paranodal area was intermediate between that of the SN and RA; however, compared with the SN and RA, the paranodal area showed greater expression of K(v)4.2, K(ir)6.1, TASK1, SK2, and MiRP2. Expression of ion channel proteins was in agreement with expression of the corresponding mRNAs. The levels of mRNA in the SN, as a percentage of those in the RA, were used to estimate conductances of key ionic currents as a percentage of those in a mathematical model of human atrial action potential. The resulting SN model successfully produced pacemaking. CONCLUSIONS: Ion channels show a complex and heterogeneous pattern of expression in the SN, paranodal area, and RA in humans, and the expression pattern is appropriate to explain pacemaking.

Clinical efficacy and safety of zoledronic acid in osteoporosis and Paget's disease

Osteoporosis and Paget’s bone disease are the most common diseases of the bone. In addition to glucocorticoid treatment, there are many other secondary causes of osteoporosis. Bisphosphonates are used to treat these bone conditions. Zoledronic acid is the most potent bisphosphonate at inhibiting bone resorption. In osteoporosis, zoledronic acid increases bone mineral density for at least 1 year following a single intravenous administration. The efficacy and safety of zoledronic acid in the treatment of osteoporosis and Paget’s bone disease are reviewed. This article also covers the studies of the effects of zoledronic acid in the bone loss associated with the secondary osteoporosis.

Vitamin D in health and disease : an insight into traditional functions and new roles for the 'sunshine vitamin'

Vitamin D is unique among the vitamins in that humans can synthesize it via the action of UV radiation upon the skin. This combined with its ability to act on specific target tissues via Vitamin D Receptor’s (VDR) make its classification as a steroid hormone more appropriate. While Vitamin D deficiency is a recognized problem in some northern latitude countries, recent studies have shown even in sunny countries such as Australia, vitamin D deficiency may be more prevalent than first thought. Vitamin D is most well known for its role in bone health, however, the discovery of VDR’s on a wide variety of tissue types has also opened up roles for vitamin D far beyond traditional bone health. These include possible associations with autoimmune diseases such as multiple sclerosis and inflammatory bowel diseases, cancer, cardiovascular diseases and muscle strength. Firstly, this paper presents an overview of the two sources of vitamin D: exposure to ultraviolet-B radiation and food sources of vitamin D, with particular focus on both Australian and international studies on dietary vitamin D intake and national fortification strategies. Secondly, the paper reviews recent epidemiological and experimental evidence linking vitamin D and its role in health and disease for the major conditions linked to suboptimal vitamin D, while identifying significant gaps in the research and possible future directions for research.

Inequalities in cardiovascular disease mortality : the role of behavioural, physiological and social risk factors

Background: While the relationship between socioeconomic disadvantage and cardiovascular disease (CVD) is well established, the role that traditional cardiovascular risk factors play in this association remains unclear. We examined the association between education attainment and CVD mortality and the extent to which behavioural, social and physiological factors explained this relationship. Methods: Adults (n=38 355) aged 40-69 years living in Melbourne, Australia were recruited in 1990-1994. Subjects with baseline CVD risk factor data ascertained through questionnaire and physical measurement were followed for an average of 9.4 years with CVD deaths verified by review of medical records and autopsy reports. Results: CVD mortality was higher for those with primary education only compared to those who had completed tertiary education, with a hazard ratio (HR) of 1.66 (95% confidence interval [CI] 1.11-2.49) after adjustment for age, country of birth and gender. Those from the lowest educated group had a more adverse cardiovascular risk factor profile compared to the highest educated group, and adjustment for these risk factors reduced the HR to 1.18 (95% CI 0.78-1.77). In analysis of individual risk factors, smoking and waist circumference explained most of the difference in CVD mortality between the highest and lowest education groups. Conclusions: Most of the excess CVD mortality in lower socioeconomic groups can be explained by known risk factors, particularly smoking and overweight. While targeting cardiovascular risk factors should not divert efforts from addressing the underlying determinants of health inequalities, it is essential that known risk factors are addressed effectively among lower socioeconomic groups.

Resilience in chronic disease : the relationships among risk factors, protective factors, adaptive outcomes, and the level of resilience in adults with diabetes

Background: There are innumerable diabetes studies that have investigated associations between risk factors, protective factors, and health outcomes; however, these individual predictors are part of a complex network of interacting forces. Moreover, there is little awareness about resilience or its importance in chronic disease in adulthood, especially diabetes. Thus, this is the first study to: (1) extensively investigate the relationships among a host of predictors and multiple adaptive outcomes; and (2) conceptualise a resilience model among people with diabetes. Methods: This cross-sectional study was divided into two research studies. Study One was to translate two diabetes-specific instruments (Problem Areas In Diabetes, PAID; Diabetes Coping Measure, DCM) into a Chinese version and to examine their psychometric properties for use in Study Two in a convenience sample of 205 outpatients with type 2 diabetes. In Study Two, an integrated theoretical model is developed and evaluated using the structural equation modelling (SEM) technique. A self-administered questionnaire was completed by 345 people with type 2 diabetes from the endocrine outpatient departments of three hospitals in Taiwan. Results: Confirmatory factor analyses confirmed a one-factor structure of the PAID-C which was similar to the original version of the PAID. Strong content validity of the PAID-C was demonstrated. The PAID-C was associated with HbA1c and diabetes self-care behaviours, confirming satisfactory criterion validity. There was a moderate relationship between the PAID-C and the Perceived Stress Scale, supporting satisfactory convergent validity. The PAID-C also demonstrated satisfactory stability and high internal consistency. A four-factor structure and strong content validity of the DCM-C was confirmed. Criterion validity demonstrated that the DCM-C was significantly associated with HbA1c and diabetes self-care behaviours. There was a statistical correlation between the DCM-C and the Revised Ways of Coping Checklist, suggesting satisfactory convergent validity. Test-retest reliability demonstrated satisfactory stability of the DCM-C. The total scale of the DCM-C showed adequate internal consistency. Age, duration of diabetes, diabetes symptoms, diabetes distress, physical activity, coping strategies, and social support were the most consistent factors associated with adaptive outcomes in adults with diabetes. Resilience was positively associated with coping strategies, social support, health-related quality of life, and diabetes self-care behaviours. Results of the structural equation modelling revealed protective factors had a significant direct effect on adaptive outcomes; however, the construct of risk factors was not significantly related to adaptive outcomes. Moreover, resilience can moderate the relationships among protective factors and adaptive outcomes, but there were no interaction effects of risk factors and resilience on adaptive outcomes. Conclusion: This study contributes to an understanding of how risk factors and protective factors work together to influence adaptive outcomes in blood sugar control, health-related quality of life, and diabetes self-care behaviours. Additionally, resilience is a positive personality characteristic and may be importantly involved in the adjustment process among people living with type 2 diabetes.

Sustainability of a multimodal intervention to promote lifestyle factors associated with the prevention of cardiovascular disease in midlife Australian women : a 5-year follow-up

We evaluated sustainability of an intervention to reduce women’s cardiovascular risk factors, determined the influence of self-efficacy, and described women’s current health. We used a mixed method approach that utilized forced choice and open-ended questionnaire items about health status, habits, and self-efficacy. Sixty women, average age 61, returned questionnaires. Women in the original intervention group continued health behaviors intended to reduce cardiovascular disease (CVD) at a higher rate than the control group, supporting the feasibility of a targeted intervention built around women’s individual goals. The role of self-efficacy in behavior change is unclear. The original intervention group reported higher self-reported health.

Addressing issues in sparseness, ecological bias and formulation of the adjacency matrix in Bayesian spatio-temporal analysis of disease counts

The main objective of this PhD was to further develop Bayesian spatio-temporal models (specifically the Conditional Autoregressive (CAR) class of models), for the analysis of sparse disease outcomes such as birth defects. The motivation for the thesis arose from problems encountered when analyzing a large birth defect registry in New South Wales. The specific components and related research objectives of the thesis were developed from gaps in the literature on current formulations of the CAR model, and health service planning requirements. Data from a large probabilistically-linked database from 1990 to 2004, consisting of fields from two separate registries: the Birth Defect Registry (BDR) and Midwives Data Collection (MDC) were used in the analyses in this thesis. The main objective was split into smaller goals. The first goal was to determine how the specification of the neighbourhood weight matrix will affect the smoothing properties of the CAR model, and this is the focus of chapter 6. Secondly, I hoped to evaluate the usefulness of incorporating a zero-inflated Poisson (ZIP) component as well as a shared-component model in terms of modeling a sparse outcome, and this is carried out in chapter 7. The third goal was to identify optimal sampling and sample size schemes designed to select individual level data for a hybrid ecological spatial model, and this is done in chapter 8. Finally, I wanted to put together the earlier improvements to the CAR model, and along with demographic projections, provide forecasts for birth defects at the SLA level. Chapter 9 describes how this is done. For the first objective, I examined a series of neighbourhood weight matrices, and showed how smoothing the relative risk estimates according to similarity by an important covariate (i.e. maternal age) helped improve the model’s ability to recover the underlying risk, as compared to the traditional adjacency (specifically the Queen) method of applying weights. Next, to address the sparseness and excess zeros commonly encountered in the analysis of rare outcomes such as birth defects, I compared a few models, including an extension of the usual Poisson model to encompass excess zeros in the data. This was achieved via a mixture model, which also encompassed the shared component model to improve on the estimation of sparse counts through borrowing strength across a shared component (e.g. latent risk factor/s) with the referent outcome (caesarean section was used in this example). Using the Deviance Information Criteria (DIC), I showed how the proposed model performed better than the usual models, but only when both outcomes shared a strong spatial correlation. The next objective involved identifying the optimal sampling and sample size strategy for incorporating individual-level data with areal covariates in a hybrid study design. I performed extensive simulation studies, evaluating thirteen different sampling schemes along with variations in sample size. This was done in the context of an ecological regression model that incorporated spatial correlation in the outcomes, as well as accommodating both individual and areal measures of covariates. Using the Average Mean Squared Error (AMSE), I showed how a simple random sample of 20% of the SLAs, followed by selecting all cases in the SLAs chosen, along with an equal number of controls, provided the lowest AMSE. The final objective involved combining the improved spatio-temporal CAR model with population (i.e. women) forecasts, to provide 30-year annual estimates of birth defects at the Statistical Local Area (SLA) level in New South Wales, Australia. The projections were illustrated using sixteen different SLAs, representing the various areal measures of socio-economic status and remoteness. A sensitivity analysis of the assumptions used in the projection was also undertaken. By the end of the thesis, I will show how challenges in the spatial analysis of rare diseases such as birth defects can be addressed, by specifically formulating the neighbourhood weight matrix to smooth according to a key covariate (i.e. maternal age), incorporating a ZIP component to model excess zeros in outcomes and borrowing strength from a referent outcome (i.e. caesarean counts). An efficient strategy to sample individual-level data and sample size considerations for rare disease will also be presented. Finally, projections in birth defect categories at the SLA level will be made.

Examination of social demographic status, disease status, health behaviours and quality of life in older Australians using the theory of planned behaviour model

The increase of life expectancy worldwide during the last three decades has increased age-related disability leading to the risk of loss of quality of life. How to improve quality of life including physical health and mental health for older people and optimize their life potential has become an important health issue. This study used the Theory of Planned Behaviour Model to examine factors influencing health behaviours, and the relationship with quality of life. A cross-sectional mailed survey of 1300 Australians over 50 years was conducted at the beginning of 2009, with 730 completed questionnaires returned (response rate 63%). Preliminary analysis reveals that physiological changes of old age, especially increasing waist circumference and co morbidity was closely related to health status, especially worse physical health summary score. Physical activity was the least adherent behaviour among the respondents compared to eating healthy food and taking medication regularly as prescribed. Increasing number of older people living alone with co morbidity of disease may be the barriers that influence their attitude and self control toward physical activity. A multidisciplinary and integrated approach including hospital and non hospital care is required to provide appropriate services and facilities toward older people.

Future developments in chest pain diagnosis and management

Much of the focus of research on patients with chest pain is directed at technological advances in the diagnosis and management of acute coronary syndrome (ACS), pulmonary embolism (PE), and acute aortic dissection (AAD), despite there being no significant difference at 4 years as regards mortality, ongoing chest pain, and quality of life between patients presenting to the emergency department with noncardiac chest pain and those with cardiac chest pain. This article examines future developments in the diagnosis and management of patients with suspected ACS, PE, AAD, gastrointestinal disease, and musculoskeletal chest pain.

Delirium in early-stage Alzheimer's disease : enhancing cognitive reserve as a possible preventive measure

Delirium is a disorder of acute onset with fluctuating symptoms and is characterized by inattention, disorganized thinking, and altered levels of consciousness. The risk for delirium is greatest in individuals with dementia, and the incidence of both is increasing worldwide because of the aging of our population. Although several clinical trials have tested interventions for delirium prevention in individuals without dementia, little is known about the mechanisms for the prevention of delirium in early-stage Alzheimer’s disease (AD). The purpose of this article is to explore ways of preventing delirium and slowing the rate of cognitive decline in early-stage AD by enhancing cognitive reserve. An agenda for future research on interventions to prevent delirium in individuals with early-stage AD is also presented.

Social Participation of Community Dwelling Stroke Survivors [Published Abstract: From the Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke Conference 2009]

Disability following a stroke can impose various restrictions on patients’ attempts at participating in life roles. The measurement of social participation, for instance, is important in estimating recovery and assessing quality of care at the community level. Thus, the identification of factors influencing social participation is essential in developing effective measures for promoting the reintegration of stroke survivors into the community. Data were collected from 188 stroke survivors (mean age 71.7 years) 12 months after discharge from a stroke rehabilitation hospital. Of these survivors, 128 (61 %) had suffered a first ever stroke, and 81 (43 %) had a right hemisphere lesion. Most (n = 156, 83 %) were living in their own home, though 32 (17 %) were living in residential care facilities. Path analysis was used to test a hypothesized model of participation restriction which included the direct and indirect effects between social, psychological and physical outcomes and demographic variables. Participation restriction was the dependent variable. Exogenous independent variables were age, functional ability, living arrangement and gender. Endogenous independent variables were depressive symptoms, state self-esteem and social support satisfaction. The path coefficients showed functional ability having the largest direct effect on participation restriction. The results also showed that more depressive symptoms, low state self-esteem, female gender, older age and living in a residential care facility had a direct effect on participation restriction. The explanatory variables accounted for 71% of the variance in explaining participation restriction. Prediction models have empirical and practical applications such as suggesting important factors to be considered in promoting stroke recovery. The findings suggest that interventions offered over the course of rehabilitation should be aimed at improving functional ability and promoting psychological aspects of recovery. These are likely to enhance stroke survivors resume or maximize their social participation so that they may fulfill productive and positive life roles.

Disease prevention and control

Globally, the main contributors to morbidity and mortality are chronic diseases, including cardiovascular disease and diabetes. Chronic diseases are costly and partially avoidable, with around sixty percent of deaths and nearly fifty percent of the global disease burden attributable to these conditions. By 2020, chronic illnesses will likely be the leading cause of disability worldwide. Existing health care systems, both national and international, that focus on acute episodic health conditions, cannot address the worldwide transition to chronic illness; nor are they appropriate for the ongoing care and management of those already afflicted with chronic diseases. International and Australian strategic planning documents articulate similar elements to manage chronic disease; including the need for aligning sectoral policies for health, forming partnerships and engaging communities in decision-making. The Australian National Chronic Disease Strategy focuses on four core areas for managing chronic disease; prevention across the continuum, early detection and treatment, integrated and coordinated care, and self-management. Such a comprehensive approach incorporates the entire population continuum, from the ‘healthy’, to those with risk factors, through to people suffering from chronic conditions and their sequelae. This chapter examines comprehensive approach to the prevention, management and care of the population with non-communicable, chronic diseases and communicable diseases. It analyses models of care in the context of need, service delivery options and the potential to prevent or manage early intervention for chronic and communicable diseases. Approaches to chronic diseases require integrated approaches that incorporate interventions targeted at both individuals and populations, and emphasise the shared risk factors of different conditions. Communicable diseases are a common and significant contributor to ill health throughout the world. In many countries, this impact has been minimised by the combined efforts of preventative health measures and improved treatment of infectious diseases. However in underdeveloped nations, communicable diseases continue to contribute significantly to the burden of disease. The aim of this chapter is to outline the impact that chronic and communicable diseases have on the health of the community, the public health strategies that are used to reduce the burden of those diseases and the old and emerging risks to public health from infectious diseases.