A longitudinal study of the impact of chronic psychological stress on health-related quality of life and clinical biomarkers : protocol for the Australian Healthy Aging of Women Study

BACKGROUND: Despite advancements in our understanding of the importance of stress reduction in achieving good health, we still only have limited insight into the impact of stress on cellular function. Recent studies have suggested that exposure to prolonged psychological stress may alter an individual's physiological responses, and contribute to morbidity and mortality. This paper presents an overview of the study protocol we are using to examine the impact of life stressors on lifestyle factors, health-related quality of life and novel and established biomarkers of stress in midlife and older Australian women.The primary aim of this study is to explore the links between chronic psychological stress on both subjective and objective health markers in midlife and older Australian women. The study examines the extent to which exposure frightening, upsetting or stressful events such as natural disasters, illness or death of a relative, miscarriage and relationship conflict is correlated with a variety of objective and subjective health markers.Methods/design: This study is embedded within the longitudinal Healthy Aging of Women's study which has collected data from midlife and older Australian women at 5 yearly intervals since 2001, and uses the Allostastic model of women's health by Groer and colleagues in 2010. The current study expands the focus of the HOW study and will assess the impact of life stressors on quality of life and clinical biomarkers in midlife and older Australian women to explain the impact of chronic psychological stress in women. DISCUSSION: The proposed study hypothesizes that women are at increased risk of exposure to multiple or repeated stressors, some being unique to women, and the frequency and chronicity of stressors increases women's risk of adverse health outcomes. This study aims to further our understanding of the relationships between stressful life experiences, perceived quality of life, stress biomarkers, chronic illness, and health status in women.

Sustainability of a successful health and nutrition program in a remote Aboriginal community

OBJECTIVE: To assess the long term effect of a nutrition program in a remote Aboriginal community (Minjilang). DESIGN: Evaluation of nutritional outcomes over the three years before and the three years after a health and nutrition program that ran from June 1989 to June 1990. Turnover of food items at the community store was used as a measure of dietary intake at Minjilang and a comparison community. SETTING: A community of about 150 Aboriginal people live at Minjilang on Croker Island, 240 km north-east of Darwin. A similar community of about 300 people on another island was used as the comparison. RESULTS: The program produced lasting improvements in dietary intake of most target foods (including fruit, vegetables and wholegrain bread) and nutrients (including folate, ascorbic acid and thiamine). Sugar intake fell in both communities before the program, but the additional decrease in sugar consumption during the program at Minjilang "rebounded" in the next year. Dietary improvements in the comparison community were delayed and smaller than at Minjilang. CONCLUSIONS: The success of the program at Minjilang was linked to an ongoing process of social change, which in turn provided a stimulus for dietary improvement in the comparison community. When Aboriginal people themselves control and maintain ownership of community-based intervention programs, nutritional improvements can be initiated and sustained.

Breast cancer cells induce osteolytic bone lesions in vivo through a reduction in osteoblast activity in mice

Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients.

Metastasis of ovarian cancer is mediated by kallikrein related peptidases

Ovarian cancer, in particular epithelial ovarian cancer (EOC), is commonly diagnosed when the tumor has metastasized into the abdominal cavity with an accumulation of ascites fluid. Combining histopathology and genetic variations, EOC can be sub-grouped into Type-I and Type-II tumors, of which the latter are more aggressive and metastatic. Metastasis and chemoresistance are the key events associated with the tumor microenvironment that lead to a poor patient outcome. Kallikrein-related peptidases (KLKs) are aberrantly expressed in EOC, in particular, in the more metastatic Type-II tumors. KLKs are a family of 15 serine proteases that are expressed in diverse human tissues and involved in various patho-physiological processes. As extracellular enzymes, KLKs function in the hydrolysis of growth factors, proteases, cell membrane bound receptors, adhesion proteins, and cytokines initiating intracellular signaling pathways and their downstream events. High KLK levels are differentially associated with the prognosis of ovarian cancer patients, suggesting that they not only have application as biomarkers but also function in disease progression, and therefore are potential therapeutic targets. Recent studies have demonstrated the function of these proteases in promoting and/or suppressing the invasive behavior of ovarian cancer cells in metastasis in vitro and in vivo. Both conventional cell culture methods and three-dimensional platforms have been applied to mimic the ovarian cancer microenvironment of patients, such as the solid stromal matrix and ascites fluid. Here we summarize published studies to provide an overview of our understanding of the role of KLKs in EOC, and to lay the foundation for future research directions.

A bioengineered 3D ovarian cancer model for the assessment of peptidase-mediated enhancement of spheroid growth and intraperitoneal spread

Cancer-associated proteases promote peritoneal dissemination and chemoresistance in malignant progression. In this study, kallikrein-related peptidases 4, 5, 6, and 7 (KLK4-7)-cotransfected OV-MZ-6 ovarian cancer cells were embedded in a bioengineered three-dimensional (3D) microenvironment that contains RGD motifs for integrin engagement to analyze their spheroid growth and survival after chemotreatment. KLK4-7-cotransfected cells formed larger spheroids and proliferated more than controls in 3D, particularly within RGD-functionalized matrices, which was reduced upon integrin inhibition. In contrast, KLK4-7-expressing cell monolayers proliferated less than controls, emphasizing the relevance of the 3D microenvironment and integrin engagement. In a spheroid-based animal model, KLK4-7-overexpression induced tumor growth after 4 weeks and intraperitoneal spread after 8 weeks. Upon paclitaxel administration, KLK4-7-expressing tumors declined in size by 91% (controls: 87%) and showed 90% less metastatic outgrowth (controls: 33%, P<0.001). KLK4-7-expressing spheroids showed 53% survival upon paclitaxel treatment (controls: 51%), accompanied by enhanced chemoresistance-related factors, and their survival was further reduced by combination treatment of paclitaxel with KLK4/5/7 (22%, P=0.007) or MAPK (6%, P=0.006) inhibition. The concomitant presence of KLK4-7 in ovarian cancer cells together with integrin activation drives spheroid formation and proliferation. Combinatorial approaches of paclitaxel and KLK/MAPK inhibition may be more efficient for late-stage disease than chemotherapeutics alone as these inhibitory regimens reduced cancer spheroid growth to a greater extent than paclitaxel alone.

PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer

The non-canonical Wnt pathway, a regulator of cellular motility and morphology, is increasingly implicated in cancer metastasis. In a quantitative PCR array analysis of 84 Wnt pathway associated genes, both non-canonical and canonical pathways were activated in primary and metastatic tumors relative to normal prostate. Expression of the Wnt target gene PITX2 in a prostate cancer (PCa) bone metastasis was strikingly elevated over normal prostate (over 2,000-fold) and primary prostate cancer (over 200-fold). The elevation of PITX2 protein was also evident on tissue microarrays, with strong PITX2 immunostaining in PCa skeletal and, to a lesser degree, soft tissue metastases. PITX2 is associated with cell migration during normal tissue morphogenesis. In our studies, overexpression of individual PITX2A/B/C isoforms stimulated PC-3 PCa cell motility, with the PITX2A isoform imparting a specific motility advantage in the presence of non-canonical Wnt5a stimulation. Furthermore, PITX2 specific shRNA inhibited PC-3 cell migration toward bone cell derived chemoattractant. These experimental results support a pivotal role of PITX2A and non-canonical Wnt signaling in enhancement of PCa cell motility, suggest PITX2 involvement in homing of PCa to the skeleton, and are consistent with a role for PITX2 in PCa metastasis to soft and bone tissues. Our findings, which significantly expand previous evidence that PITX2 is associated with risk of PCa biochemical recurrence, indicate that variation in PITX2 expression accompanies and may promote prostate tumor progression and metastasis.

Projecting the impact of climate change on dengue transmission in Dhaka, Bangladesh

Weather variables, mainly temperature and humidity influence vectors, viruses, human biology, ecology and consequently the intensity and distribution of the vector-borne diseases. There is evidence that warmer temperature due to climate change will influence the dengue transmission. However, long term scenario-based projections are yet to be developed. Here, we assessed the impact of weather variability on dengue transmission in a megacity of Dhaka, Bangladesh and projected the future dengue risk attributable to climate change. Our results show that weather variables particularly temperature and humidity were positively associated with dengue transmission. The effects of weather variables were observed at a lag of four months. We projected that assuming a temperature increase of 3.3 °C without any adaptation measure and changes in socio-economic condition, there will be a projected increase of 16,030 dengue cases in Dhaka by the end of this century. This information might be helpful for the public health authorities to prepare for the likely increase of dengue due to climate change. The modelling framework used in this study may be applicable to dengue projection in other cities.

The α5 subunit regulates the expression and function of α4*-containing neuronal nicotinic acetylcholine receptors in the ventral-tegmental area

Human genetic association studies have shown gene variants in the α5 subunit of the neuronal nicotinic receptor (nAChR) influence both ethanol and nicotine dependence. The α5 subunit is an accessory subunit that facilitates α4* nAChRs assembly in vitro. However, it is unknown whether this occurs in the brain, as there are few research tools to adequately address this question. As the α4*-containing nAChRs are highly expressed in the ventral tegmental area (VTA) we assessed the molecular, functional and pharmacological roles of α5 in α4*-containing nAChRs in the VTA. We utilized transgenic mice α5+/+(α4YFP) and α5-/-(α4YFP) that allow the direct visualization and measurement of α4-YFP expression and the effect of the presence (α5+/+) and absence of α5 (-/-) subunit, as the antibodies for detecting the α4* subunits of the nAChR are not specific. We performed voltage clamp electrophysiological experiments to study baseline nicotinic currents in VTA dopaminergic neurons. We show that in the presence of the α5 subunit, the overall expression of α4 subunit is increased significantly by 60% in the VTA. Furthermore, the α5 subunit strengthens baseline nAChR currents, suggesting the increased expression of α4* nAChRs to be likely on the cell surface. While the presence of the α5 subunit blunts the desensitization of nAChRs following nicotine exposure, it does not alter the amount of ethanol potentiation of VTA dopaminergic neurons. Our data demonstrates a major regulatory role for the α5 subunit in both the maintenance of α4*-containing nAChRs expression and in modulating nicotinic currents in VTA dopaminergic neurons. Additionally, the α5α4* nAChR in VTA dopaminergic neurons regulates the effect of nicotine but not ethanol on currents. Together, the data suggest that the α5 subunit is critical for controlling the expression and functional role of a population of α4*-containing nAChRs in the VTA.

Self-efficacy partially mediates between social support and health-related quality of life in family caregivers for dementia patients in Shanghai

Background: There is a paucity of research assessing health-related quality of life (HRQoL) and self-efficacy in caregivers of relatives with dementia in mainland China. Aims: To compare the level of HRQoL between caregivers and the general population in mainland China and to assess the role of caregiver self-efficacy in the relationship between caregiver social support and HRQoL. Methods: A cross-sectional study was conducted in Shanghai, China. The caregivers were recruited from the outpatient department of a teaching hospital. A total of 195 participants were interviewed, using a survey package including the Chinese version of the 36-Item Short-Form Health Survey (SF-36), demographic data, the variables associated with the impairments of care recipients, perceived social support and caregiver self-efficacy. The caregivers' SF-36 scores were compared with those of the general population in China. Results: The results indicated that the HRQoL of the caregivers was poorer compared with that of the general population when matched for age and gender. Multiple regression analyses revealed that caregiver self-efficacy is a partial mediator between social support and HRQoL, and a partial mediator between behavioral and psychological symptoms of dementia (BPSD) and caregiver mental health. Conclusion: Assisting with managing BPSD and enhancing caregiver self-efficacy can be considered integral parts of interventions to improve caregiver HRQoL.

Exposure to solar ultraviolet radiation is associated with a decreased folate status in women of childbearing age

In vitro studies indicate that folate in collected human blood is vulnerable to degradation after exposure to ultraviolet (UV) radiation. This has raised concerns about folate depletion in individuals with high sun exposure. Here, we investigate the association between personal solar UV radiation exposure and serum folate concentration, using a three-week prospective study that was undertaken in females aged 18–47 years in Brisbane, Australia (153 E, 27 S). Following two weeks of supplementation with 500 μg of folic acid daily, the change in serum folate status was assessed over a 7-day period of measured personal sun exposure. Compared to participants with personal UV exposures of <200 Joules per day, participants with personal UV exposures of 200–599 and >600 Joules per day had significantly higher depletion of serum folate (p = 0.015). Multivariable analysis revealed personal UV exposure as the strongest predictor accounting for 20% of the overall change in serum folate (Standardised B = −0.49; t = −3.75; p = <0.01). These data show that increasing solar UV radiation exposures reduces the effectiveness of folic acid supplementation. The consequences of this association may be most pronounced for vulnerable individuals, such as women who are pregnant or of childbearing age with high sun exposures.

Matrix metalloproteinases during wound healing - a double edged sword

The extracellular matrix (ECM) provides a framework for cells and gives skin its tensile strength and elasticity. Loss of its integrity necessitates the clearing of damaged components and the deposition of firstly a provisional matrix and later remodelling of the ECM to support a functionally intact tissue. Matrix metalloproteinases (MMPs) are an important family of enzymes that function in the breakdown of the ECM and modulate the function of many biologically active molecules housed in the ECM. Through their enzymatic actions MMPs play a role in fundamental processes such as immune cell infiltration and ECM remodelling during wound repair. Their tight control is necessary for timely wound healing and excessive MMP activity participates in the development and persistence of chronic wounds, while reduced activity contributes to fibrosis. A number of inhibitors have been designed to target this activity and improve wound healing with limited success. Novel strategies are currently being investigated to improve wound healing by targeting MMP modulating molecules.

Improved rural health through a collaborative model of care – qualitative findings

INTRODUCTION Health disparity between urban and rural regions in Australia is well-documented. In the Wheatbelt catchments of Western Australia there is higher incidence and rate of avoidable hospitalisation for chronic diseases. Structured care approach to chronic illnesses is not new but the focus has been on single disease state. A recent ARC Discovery Project on general practice nurse-led chronic disease management of diabetes, hypertension and stable ischaemic heart disease reported improved communication and better medical administration.[1] In our study we investigated the sustainability of such a multi-morbidities general practice –led collaborative model of care in rural Australia. METHODS A QUAN(qual) design was utilised. Eight pairs of rural general practices were matched. Inclusion criteria used were >18 years and capable of giving informed consent, at least one identified risk factor or diagnosed with chronic conditions. Patients were excluded if deemed medically unsuitable. A comprehensive care plan was formulated by the respective general practice nurse in consultation with the treating General Practitioner (GP) and patient based on the individual’s readiness to change, and was informed by available local resource. A case management approach was utilised. Shediaz-Rizkallah and Lee’s conceptual framework on sustainability informed our evaluation.[2] Our primary outcome on measures of sustainability was reduction in avoidable hospitalisation. Secondary outcomes were patients and practitioners acceptance and satisfaction, and changes to pre-determined interim clinical and process outcomes. RESULTS The qualitative interviews highlighted the community preference for a ‘sustainable’ local hospital in addition to general practice. Costs, ease of access, low prioritisation of self chronic care, workforce turnover and perception of losing another local resource if underutilised influenced the respondents’ decision to present at local hospital for avoidable chronic diseases regardless. CONCLUSIONS Despite the pragmatic nature of rural general practice in Australia, the sustainability of chronic multi-morbidities management in general practice require efficient integration of primary-secondary health care and consideration of other social determinants of health. What this study adds: What is already known on this subject: Structured approach to chronic disease management is not new and has been shown to be effective for reducing hospitalisation. However, the focus has been on single disease state. What does this study add: Sustainability of collaborative model of multi-morbidities care require better primary-secondary integration and consideration of social determinants of health.

Expanded scope roles in primary health – what makes them work?

Introduction The demand for better integration between primary and secondary healthcare frequently leads to discussion about expanded scope of practice for nursing, paramedic and allied health professionals and the role these clinicians could play in facilitating improved access to timely and appropriate healthcare. From workforce perspective, expanded scope of practice has also been advocated as a mean of fostering workforce retention. Models of expanded scope roles in nursing and paramedicine have been trialled nationally and internationally in both acute and community care settings. Where they have been successful, trials have resulted in reduction in hospital presentation and admission; improved patient access and timeliness; and patient satisfaction. This paper will examine the characteristics of successful expanded scope programs. Method Exploratory case-study analysis of successful integration of expanded health care roles across primary healthcare settings in rural Australia. Results & Conclusions One size does not fill all. Successful models of integrated expanded health care roles in primary health care settings are built on stakeholder’s capacity and preference; community need; and political will. Collaborative, congruent, multi-disciplinary care teams that prioritise patient-centred care within a dynamic primary care setting have merit and are more likely to foster flexibility and sustainability.