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1.  Barriers and enablers to the delivery of psychological care in the management of patients with type 2 diabetes mellitus in China: a qualitative study using the theoretical domains framework 
Background
China has the largest number of type 2 diabetes mellitus (T2DM) cases globally and individuals with T2DM have an increased risk of developing mental health disorders and functional problems. Despite guidelines recommending that psychological care be delivered in conjunction with standard T2DM care; psychological care is not routinely delivered in China. Community Health Centre (CHC) doctors play a key role in the management of patients with T2DM in China. Understanding the behavioural determinants of CHC doctors in the implementation of psychological care recommendations allows for the design of targeted and culturally appropriate interventions. As such, this study aimed to examine barriers and enablers to the delivery of psychological care to patients with T2DM from the perspective of CHC doctors in China.
Methods
Two focus groups were conducted with 23 CHC doctors from Shenzhen, China. The discussion guide applied the Theoretical Domains Framework (TDF) that examines current practice and identifies key barriers and enablers perceived to influence practice. Focus groups were conducted with an interpreter, and were digitally recorded and transcribed. Two researchers independently coded transcripts into pre-defined themes using deductive thematic analysis.
Results
Barriers and enablers perceived by doctors as being relevant to the delivery of psychological care for patients with T2DM were primarily categorised within eight TDF domains. Key barriers included: CHC doctors’ knowledge and skills; time constraints; and absence of financial incentives. Other barriers included: societal perception that treating psychological aspects of health is less important than physical health; lack of opinion leaders; doctors’ intentional disregard of psychological care; and doubts regarding the efficacy of psychological care. In contrast, perceived enablers included: training of CHC doctors in psychological skills; identification of afternoon/evening clinic times when recommendations could be implemented; introduction of financial incentives; and the creation of a professional role (e.g. diabetes educator), that could implement psychological care recommendations to patients with T2DM.
Conclusions
The utilisation of the TDF allowed for the comprehensive understanding of barriers and enablers to the implementation of psychological care recommendations for patients with T2DM, and consequently, has given direction to future interventions strategies aimed at improving the implementation of such recommendations.
doi:10.1186/s12913-016-1358-x
PMCID: PMC4812648  PMID: 27025727
Type 2 diabetes mellitus; Psychological care; China; Theoretical domains framework; Guideline implementation; Evidence-based practice
2.  Activation of Endothelial Nitric Oxide (eNOS) Occurs through Different Membrane Domains in Endothelial Cells 
PLoS ONE  2016;11(3):e0151556.
Endothelial cells respond to a large range of stimuli including circulating lipoproteins, growth factors and changes in haemodynamic mechanical forces to regulate the activity of endothelial nitric oxide synthase (eNOS) and maintain blood pressure. While many signalling pathways have been mapped, the identities of membrane domains through which these signals are transmitted are less well characterized. Here, we manipulated bovine aortic endothelial cells (BAEC) with cholesterol and the oxysterol 7-ketocholesterol (7KC). Using a range of microscopy techniques including confocal, 2-photon, super-resolution and electron microscopy, we found that sterol enrichment had differential effects on eNOS and caveolin-1 (Cav1) colocalisation, membrane order of the plasma membrane, caveolae numbers and Cav1 clustering. We found a correlation between cholesterol-induced condensation of the plasma membrane and enhanced high density lipoprotein (HDL)-induced eNOS activity and phosphorylation suggesting that cholesterol domains, but not individual caveolae, mediate HDL stimulation of eNOS. Vascular endothelial growth factor (VEGF)-induced and shear stress-induced eNOS activity was relatively independent of membrane order and may be predominantly controlled by the number of caveolae on the cell surface. Taken together, our data suggest that signals that activate and phosphorylate eNOS are transmitted through distinct membrane domains in endothelial cells.
doi:10.1371/journal.pone.0151556
PMCID: PMC4792450  PMID: 26977592
3.  Management of type 2 diabetes in China: the Happy Life Club, a pragmatic cluster randomised controlled trial using health coaches 
BMJ Open  2016;6(3):e009319.
Objective
To assess the effectiveness of a coach-led motivational interviewing (MI) intervention in improving glycaemic control, as well as clinical, psychosocial and self-care outcomes of individuals with type 2 diabetes mellitus (T2DM) compared with usual care.
Design
Pragmatic cluster randomised controlled trial (RCT).
Setting
Community Health Stations (CHSs) in Fengtai district, Beijing, China.
Participants
Of the 41 randomised CHSs (21 intervention and 20 control), 21 intervention CHSs (372 participants) and 18 control CHSs (296 participants) started participation.
Intervention
Intervention participants received telephone and face-to-face MI health coaching in addition to usual care from their CHS. Control participants received usual care only. Medical fees were waived for both groups.
Outcome measures
Outcomes were assessed at baseline, 6 and 12 months. Primary outcome measure was glycated haemoglobin (HbA1c). Secondary outcomes included a suite of anthropometric, blood pressure (BP), fasting blood, psychosocial and self-care measures.
Results
At 12 months, no differential treatment effect was found for HbA1c (adjusted difference 0.02, 95% CI −0.40 to 0.44, p=0.929), with both treatment and control groups showing significant improvements. However, two secondary outcomes: psychological distress (adjusted difference −2.38, 95% CI −4.64 to −0.12, p=0.039) and systolic BP (adjusted difference −3.57, 95% CI −6.08 to −1.05, p=0.005) were robust outcomes consistent with significant differential treatment effects, as supported in sensitivity analyses. Interestingly, in addition to HbA1c, both groups displayed significant improvements in triglycerides, LDL cholesterol and HDL cholesterol.
Conclusions
In line with the current Chinese primary healthcare reform, this study is the first large-scale cluster RCT to be implemented within real-world CHSs in China, specifically addressing T2DM. Although a differential treatment effect was not observed for HbA1c, numerous outcomes (including HbA1c) improved in both groups, supporting the establishment of regular, free clinical health checks for people with T2DM in China.
Trial registration number
ISRCTN01010526; Pre-results.
doi:10.1136/bmjopen-2015-009319
PMCID: PMC4785304  PMID: 26944692
PRIMARY CARE
4.  The PROblem Gambling RESearch Study (PROGRESS) research protocol: a pragmatic randomised controlled trial of psychological interventions for problem gambling 
BMJ Open  2015;5(11):e009385.
Introduction
International prevalence rates for problem gambling are estimated at 2.3%. Problem gambling is a serious global public health concern due to adverse personal and social consequences. Previous research evaluating the effectiveness of psychological interventions for the treatment of problem gambling has been compromised by methodological limitations, including small sample sizes and the use of waitlist control groups. This article describes the study protocol for a pragmatic randomised controlled trial (RCT) evaluating the effectiveness of cognitive-behavioural therapy (CBT), behaviour therapy (BT), motivational interviewing (MI) against a non-directive supportive therapy (NDST) control, in treating problem gambling.
Methods and analysis
This study was a mixed-methods design, with a parallel group, pragmatic RCT as the primary component, and embedded qualitative studies conducted alongside. A total of 297 participants were recruited from the community in Victoria, Australia. Individuals aged 18 years and over, could communicate in English and wished to receive treatment for a gambling problem were eligible. Participants were randomly allocated in to 1 of the 4 psychological interventions: CBT, BT, MI and NDST. Repeated measures were conducted at pretreatment and post-treatment, and 6 and 12 months post-treatment. The statistical analysis will use an intention-to-treat approach. Multilevel mixed modelling will be used to examine changes in the primary outcome measures: gambling symptom severity, using the Gambling Symptom Assessment Scale, and gambling behaviours (frequency, time and expenditure). Secondary outcomes are depression, anxiety, stress and alcohol use. Individual semistructured qualitative interviews were conducted at pretreatment and post-treatment and 12 months post-treatment for a subset of participants (n=66).
Ethics and dissemination
This study was approved by the Victorian Department of Justice, Monash University and the University of Melbourne Human Research Ethics Committees. Findings will be reported in a government report, peer-reviewed publications and conference presentations.
Trial registration number
Current Controlled Trials ISRCTN01629698.
doi:10.1136/bmjopen-2015-009385
PMCID: PMC4663416  PMID: 26603250
PUBLIC HEALTH; PRIMARY CARE; MENTAL HEALTH
5.  Psychological Interventions for the Management of Glycemic and Psychological Outcomes of Type 2 Diabetes Mellitus in China: A Systematic Review and Meta-Analyses of Randomized Controlled Trials 
Introduction
China has the largest number of type 2 diabetes mellitus (T2DM) cases globally, and T2DM management has become a critical public health issue in China. Individuals with T2DM have an increased risk of developing mental health disorders, psychological disturbances, and functional problems associated with living with their condition. Previous systematic reviews have demonstrated that, generally, psychological interventions are effective in the management of T2DM-related outcomes; however, these reviews have predominantly included studies conducted within English-speaking countries and have not determined the efficacy of the varying types of psychological interventions. As such, this paper aims to synthesize evidence and quantify the efficacy of psychological therapies for the management of glycemic and psychological outcomes of T2DM in China, relative to control conditions.
Methods
A systematic search (MEDLINE, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, and Wangfang Data) for all years to December 2014 identified all available literature. Eligibility criteria included: peer-reviewed journal articles, randomized controlled trials (RCTs) assessing the efficacy of a psychological therapy for the management of T2DM, adult participants (≥18 years) diagnosed with T2DM or non-insulin-dependent diabetes mellitus, and Chinese speaking participants only (in mainland China). Outcome measures were glycated hemoglobin, blood glucose concentration, depression, anxiety, and quality of life. Effect sizes were pooled using a random effects model. Negative effect sizes corresponded to positive outcomes favoring the intervention.
Results
Forty-five RCTs were eligible for the meta-analyses. Cognitive behavioral therapy (CBT) and motivational interviewing (MI) were more effective than the control condition in the reduction of glycated hemoglobin [CBT: −0.97 (95% CI −1.37 to −0.57); MI: −0.71 (95% CI −1.00 to −0.43)]. CBT and client-centered therapy (CCT) were also associated with reductions in depression and blood glucose concentration, and CBT was associated with reductions in anxiety.
Conclusion
Psychological interventions, namely, CBT, MI, and CCT are effective in improving certain T2DM-related outcomes in China. Considerable levels of heterogeneity and unclear risk of bias associated with most included RCTs suggest caution when interpreting results. In China, where the burden of T2DM is increasing significantly, psychological interventions may provide promising approaches to assist in the management of T2DM to delay the progression of T2DM related outcomes.
doi:10.3389/fpubh.2015.00252
PMCID: PMC4644788  PMID: 26636054
type 2 diabetes mellitus; psychological intervention; China; therapy; systematic review; meta-analysis; motivational interviewing; cognitive behavioral therapy
6.  Challenges of the Pandemic Response in Primary Care during Pre-Vaccination Period: A Qualitative Study 
Background
During the 2009/A/H1N1 pandemic, the main burden of the patient management fell on primary care physicians (PCPs), and they were the principal implementers of pandemic policies. Broad involvement of PCPs in the pandemic response offered an excellent opportunity to investigate the challenges that they encountered.
Objective
To examine challenges faced by PCPs as they implemented pandemic policies in Australia, Israel and England before the 2009/A/H1N1 pandemic vaccine became available.
Methods
This is a qualitative descriptive study that employed in-depth semi-structured interviews with 65 PCPs from Australia, Israel and England. The data were analysed thematically to provide a detailed account of the themes.
Results
Challenges in three fields of the pandemic response were identified. (i) Consultation of patients was challenged by the high flow of patients, sick and worried-well, the necessity to provide personalised information about the disease during consultations, and unfamiliar antiviral treatment. (ii) Performance of public health responsibilities was complicated in regards to patient segregation and introduction of personal protection measures. (iii) Communication with the health authorities was inefficient, with no established route to provide feedback about the pandemic policies.
Conclusions
The experience of the 2009/A/H1N1 pandemic highlighted the centrality of primary care in the pandemic response. Despite intensive pre-pandemic planning, numerous barriers for implementation of the pandemic policies in primary care were identified. Investigation of three different approaches for involvement of PCPs in the pandemic management showed that none of these approaches worked smoothly.
doi:10.1186/s13584-015-0028-5
PMCID: PMC4606524  PMID: 26473026
Primary Health Care; Pandemics; Disease outbreaks; Public Health; Qualitative research; Health politics; General practice; Influenza; H1N1; Preparedness
7.  Endoglin potentiates nitric oxide synthesis to enhance definitive hematopoiesis 
Biology Open  2015;4(7):819-829.
ABSTRACT
During embryonic development, hematopoietic cells develop by a process of endothelial-to hematopoietic transition of a specialized population of endothelial cells. These hemogenic endothelium (HE) cells in turn develop from a primitive population of FLK1+ mesodermal cells. Endoglin (ENG) is an accessory TGF-β receptor that is enriched on the surface of endothelial and hematopoietic stem cells and is also required for the normal development of hemogenic precursors. However, the functional role of ENG during the transition of FLK1+ mesoderm to hematopoietic cells is ill defined. To address this we used a murine embryonic stem cell model that has been shown to mirror the temporal emergence of these cells in the embryo. We noted that FLK1+ mesodermal cells expressing ENG generated fewer blast colony-forming cells but had increased hemogenic potential when compared with ENG non-expressing cells. TIE2+/CD117+ HE cells expressing ENG also showed increased hemogenic potential compared with non-expressing cells. To evaluate whether high ENG expression accelerates hematopoiesis, we generated an inducible ENG expressing ES cell line and forced expression in FLK1+ mesodermal or TIE2+/CD117+ HE cells. High ENG expression at both stages accelerated the emergence of CD45+ definitive hematopoietic cells. High ENG expression was associated with increased pSMAD2/eNOS expression and NO synthesis in hemogenic precursors. Inhibition of eNOS blunted the ENG induced increase in definitive hematopoiesis. Taken together, these data show that ENG potentiates the emergence of definitive hematopoietic cells by modulating TGF-β/pSMAD2 signalling and increasing eNOS/NO synthesis.
doi:10.1242/bio.011494
PMCID: PMC4571086  PMID: 25979706
Endoglin; Nitric oxide; FLK1; SMAD2; Hemogenic endothelium; Hematopoiesis
8.  Implementing a Chronic Disease Self-Management Program into China: The Happy Life Club™ 
China is experiencing population aging, increased prevalence of chronic diseases, and reductions in the frequency of healthy lifestyle behaviors. In response to these significant transitions, China is implementing major reforms in health care services with a focus on strengthening primary health care. In this paper, we describe a 12-month diabetes management program, the Happy Life Club™ (HLC™), implemented in a primary health care setting in Beijing, that uses doctor and nurse health coaches trained in behavior change techniques and motivational interviewing (MI). This paper reports the results of this pilot study and discusses issues involved in the implementation of Chronic Diseases Self-Management Programs in China. The intervention group showed improvements in HbA1c levels at 6 months and both the control and intervention groups showed reductions in waist circumference over time. Systolic blood pressure improved over time in the intervention group. The intervention group showed improvement in quality of life across the intervention period and both groups showed decreases in psychological distress across the intervention. Doctor visits increased between baseline and 6 months, but there was no change in doctor visits between 6 and 12 months for both groups. The effects were modest, and further investigations are required to evaluate the long-term impact of health coach approaches in China.
doi:10.3389/fpubh.2014.00181
PMCID: PMC4410613  PMID: 25964910
chronic disease self-management; motivational interviewing; diabetes; older people; China
9.  Implementing Chronic Disease Self-Management Approaches in Australia and the United Kingdom 
doi:10.3389/fpubh.2014.00162
PMCID: PMC4410761  PMID: 25964902
chronic illness prevalence; self-management policy and practice; training and workforce needs; Australia; United Kingdom
10.  Performance of Screening Tools in Detecting Major Depressive Disorder among Patients with Coronary Heart Disease: A Systematic Review 
Background
Major depressive disorder (MDD) is common in patients with coronary heart disease (CHD) and there is no consensus on the optimal screening tool for use in identifying MDD. This study aimed to systematically review the performance of various screening tools in the identification of MDD.
Material/Methods
Eligible studies published before 31 Dec 2013 were identified from the following databases: Ovid Medline, EMBASE, PsycINFO, Scopus, Cochrane Library, CINAHL Plus, and Web of Science.
Results
Eight studies aiming to identify MDD in CHD patients were included, and there were 10 self-reporting questionnaires (such as PHQ-2, PHQ-9, PHQ categorical algorithm, HADS-D, BDI, BDI-II, BDI-II-cog, CES-D, SCL-90, 2 simple yes/no items) and 1 observer rating scale (Ham-D). For MDD alone, the sensitivity and specificity of various screening tools at the validity and optimal cut-off point varied from 0.34 [0.19, 0.52] to 0.96 [0.78, 1.00] and 0.69 [0.65, 0.73] to 0.97 [0.93, 0.99]. Results showed PHQ-9 (≥10), BDI-II (≥14 or ≥16), and HADS-D (≥5 or ≥4) were widely used for screening MDD in CHD patients.
Conclusions
There is no consensus on the optimal screening tool for MDD in CHD patients. When evaluating the performance of a screening tool, balancing the high sensitivity and negative predictive value (NPV) between specificity and positive predictive value (PPV) for screening or diagnostic purpose should be considered. After screening, further diagnosis, appropriate management, and necessary referral may also improve cardiovascular outcomes.
doi:10.12659/MSM.892537
PMCID: PMC4354444  PMID: 25725615
Coronary Disease; Depression; Sensitivity and Specificity
11.  Phenazine virulence factor binding to extracellular DNA is important for Pseudomonas aeruginosa biofilm formation 
Scientific Reports  2015;5:8398.
Bacterial resistance to conventional antibiotics necessitates the identification of novel leads for infection control. Interference with extracellular phenomena, such as quorum sensing, extracellular DNA integrity and redox active metabolite release, represents a new frontier to control human pathogens such as Pseudomonas aeruginosa and hence reduce mortality. Here we reveal that the extracellular redox active virulence factor pyocyanin produced by P. aeruginosa binds directly to the deoxyribose-phosphate backbone of DNA and intercalates with DNA nitrogenous base pair regions. Binding results in local perturbations of the DNA double helix structure and enhanced electron transfer along the nucleic acid polymer. Pyocyanin binding to DNA also increases DNA solution viscosity. In contrast, antioxidants interacting with DNA and pyocyanin decrease DNA solution viscosity. Biofilms deficient in pyocyanin production and biofilms lacking extracellular DNA show similar architecture indicating the interaction is important in P. aeruginosa biofilm formation.
doi:10.1038/srep08398
PMCID: PMC4323658  PMID: 25669133
12.  Health, Lifestyle, and Gender Influences on Aging Well: An Australian Longitudinal Analysis to Guide Health Promotion 
A primary societal goal for aging is enabling older people to continue to live well as long as possible. The evidence base around aging well (“healthy,” “active,” and “successful” aging) has been constructed mainly from academic and professional conceptualizations of mortality, morbidity, functioning, and psychological well-being with some attention to lay views. Our study aims to inform action on health promotion to achieve aging well as conceptualized by qualitative research identifying what older Australians themselves value most: continuing to live as long as possible in the community with independence in daily living, and good self-rated health and psychological well-being. Multivariate survival analyses from the Melbourne longitudinal studies on healthy aging program found that important threats to aging well for the total sample over a 12-year period were chronological age, multi-morbidity, low perceived social support, low nutritional score, and being under-weight. For men, threats to aging well were low strain, perceived inadequacy of social activity, and being a current smoker. For women, urinary incontinence, low physical activity and being under-weight were threats to aging well. The findings indicate that healthy lifestyles can assist aging well, and suggest the value of taking gender into account in health promotion strategies.
doi:10.3389/fpubh.2014.00070
PMCID: PMC4078909  PMID: 25072042
healthy aging; life style factors; gender; self-rated health; functional independence; psychological well-being; prospective design
13.  Quality of Care and Quality of Life: Convergence or Divergence? 
The aim of this study was to explore the impact of quality of care (QoC) on patients’ quality of life (QoL). In a cross-sectional study, two domains of QoC and the World Health Organization Quality of Life-Bref questionnaire were combined to collect data from 1,059 pre-discharge patients in four accredited hospitals (ACCHs) and four non-accredited hospitals (NACCHs) in Saudi Arabia. Health and well-being are often restricted to the characterization of sensory qualities in certain settings such as unrestricted access to healthcare, effective treatment, and social welfare. The patients admitted to tertiary health care facilities are generally able to present themselves with a holistic approach as to how they experience the impact of health policy. The statistical results indicated that patients reported a very limited correlation between QoC and QoL in both settings. The model established a positive, but ultimately weak and insignificant, association between QoC (access and effective treatment) and QoL (r = 0.349, P = 0.000; r = 0.161, P = 0.000, respectively). Even though the two settings are theoretically different in terms of being able to conceptualize, adopt, and implement QoC, the outcomes from both settings demonstrated insignificant relationships with QoL as the results were quite similar. Though modern medicine has substantially improved QoL around the world, this paper proposes that health accreditation has a very limited impact on improving QoL. This paper raises awareness of this topic with multiple healthcare professionals who are interested in correlating QoC and QoL. Hopefully, it will stimulate further research from other professional groups that have new and different perspectives. Addressing a transitional health care system that is in the process of endorsing accreditation, investigating the experience of tertiary cases, and analyzing deviated data may limit the generalization of this study. Global interest in applying public health policy underlines the impact of such process on patients’ outcomes. As QoC accreditation does not automatically produce improved QoL outcomes, the proposed study encourages further investigation of the value of health accreditation on personal and social well-being.
doi:10.4137/HSI.S13283
PMCID: PMC4122532  PMID: 25114568
accreditation; quality of care; quality of life; Saudi Arabia
14.  Polymorphisms in the Syntaxin 17 Gene are not Associated with Human Cutaneous Malignant Melanoma 
Melanoma research  2009;19(2):80-86.
The prevalence of cutaneous malignant melanoma (CMM) has increased significantly in most Caucasian populations in recent decades. Both genetic and environment are significant risk factors involved in the development of CMM. A germline mutation in the Syntaxin 17 (STX17) gene was recently identified in horses causing premature hair gray and associated with susceptibility to melanoma. We hypothesized that common germline variants in the STX17 gene might be associated with predisposition to human CMM or might interact with other melanoma risk genes. We conducted a case-control study by genotyping 26 tagging single nucleotide polymorphisms (SNPs) across the STX17 gene region in an Australian sample and performed logistic regression analysis for predicting the possible SNP interactions in a combined dataset. Our results do not support an association between CMM and any of the STX17 SNPs and provide no evidence for interactions between the melanoma risk SNP rs910873 on chromosome 20 and any of the STX17 SNPs. We conclude that common variants in the STX17 gene region do not play a key role in the pathogenesis of human melanoma.
doi:10.1097/CMR.0b013e328322fc45
PMCID: PMC3665505  PMID: 19209086
Syntaxin 17; melanoma; polymorphisms
15.  Kynurenine is a novel endothelium-derived relaxing factor produced during inflammation 
Nature medicine  2010;16(3):279-285.
Control of blood vessel tone is central to vascular homeostasis. Here, we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (IDO) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei), and experimental induction of endotoxemia, caused endothelial expression of IDO, resulting in decreased plasma tryptophan, increased kynurenine, and hypotension. Pharmacological inhibition of IDO increased blood pressure in systemically inflamed mice, but not in mice deficient for IDO or interferon-γ, which is required for IDO induction. Tryptophan dilated pre-constricted porcine coronary arteries only if active IDO and an intact endothelium were both present. Kynurenine dose-dependently decreased blood pressure in spontaneously hypertensive rats, inhibited contraction of arteries, and relaxed pre-constricted rings endothelium-independently. Arterial relaxation by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways.
doi:10.1038/nm.2092
PMCID: PMC3556275  PMID: 20190767
16.  Targeted subendothelial matrix oxidation by myeloperoxidase triggers myosin II-dependent de-adhesion and alters signaling in endothelial cells 
Free Radical Biology & Medicine  2012;53(12):2344-2356.
During inflammation, myeloperoxidase (MPO) released by circulating leukocytes accumulates within the subendothelial matrix by binding to and transcytosing the vascular endothelium. Oxidative reactions catalyzed by subendothelial-localized MPO are implicated as a cause of endothelial dysfunction in vascular disease. While the subendothelial matrix is a key target for MPO-derived oxidants during disease, the implications of this damage for endothelial morphology and signaling are largely unknown. We found that endothelial-transcytosed MPO produced hypochlorous acid (HOCl) that reacted locally with the subendothelial matrix and induced covalent cross-linking of the adhesive matrix protein fibronectin. Real-time biosensor and live cell imaging studies revealed that HOCl-mediated matrix oxidation triggered rapid membrane retraction from the substratum and adjacent cells (de-adhesion). De-adhesion was linked with the alteration of Tyr-118 phosphorylation of paxillin, a key adhesion-dependent signaling process, as well as Rho kinase-dependent myosin light chain-2 phosphorylation. De-adhesion dynamics were dependent on the contractile state of cells, with myosin II inhibition with blebbistatin attenuating the rate of membrane retraction. Rho kinase inhibition with Y-27632 also conferred protection, but not during the initial phase of membrane retraction, which was driven by pre-existing actomyosin tensile stress. Notably, diversion of MPO from HOCl production by thiocyanate or nitrite attenuated de-adhesion and associated signaling responses, despite the latter substrate supporting MPO-catalyzed fibronectin nitration. These data show that subendothelial-localized MPO employs a novel “outside-in” mode of redox signaling, involving HOCl-mediated matrix oxidation. These MPO-catalyzed oxidative events are likely to play a previously unrecognized role in altering endothelial integrity and signaling during inflammatory vascular disorders.
Graphical Abstract
Highlights
► MPO binds to and mediates HOCl-dependent oxidation of the subendothelial matrix. ► HOCl-mediated matrix oxidation disrupts cell-matrix contacts, inducing de-adhesion. ► De-adhesion is driven by unopposed actomyosin contractile forces. ► De-adhesion is linked with rapid changes in adhesion-dependent signaling. ► MPO alters endothelial integrity and signaling by HOCl-mediated matrix oxidation.
doi:10.1016/j.freeradbiomed.2012.10.002
PMCID: PMC3529214  PMID: 23059132
BAH, 4-aminobenzoic acid hydrazide; PP2, 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4–d]pyrimidine; ECs, bovine aortic endothelial cells; FAK, focal adhesion kinase; HBSS, Hank's balanced salt solution; HOCl, hypochlorous acid; HOSCN, hypothiocyanous acid; Met, methionine; MPO, myeloperoxidase; MLC-2, myosin light chain II; NO, nitric oxide; NO2−, nitrite; •NO2, nitrogen dioxide radical; PBS, phosphate-buffered saline, SCN−, thiocyanate; Y-27632, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride; Myeloperoxidase; Extracellular matrix; Endothelial dysfunction; Redox signaling; Free radicals
17.  Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages 
Infiltration of Ly6Chi monocytes from the blood is a hallmark of viral encephalitis. In mice with lethal encephalitis caused by West Nile virus (WNV), an emerging neurotropic flavivirus, inhibition of Ly6Chi monocyte trafficking into the brain by anti-very late antigen (VLA)-4 integrin antibody blockade at the time of first weight loss and leukocyte influx resulted in long-term survival of up to 60% of infected mice, with subsequent sterilizing immunity. This treatment had no effect on viral titers but appeared to be due to inhibition of Ly6Chi macrophage immigration. Although macrophages isolated from the infected brain induced WNV-specific CD4+ T-cell proliferation, T cells did not directly contribute to pathology, but are likely to be important in viral control, as antibody-mediated T-cell depletion could not reproduce the therapeutic benefit of anti-VLA-4. Instead, 70% of infiltrating inflammatory monocyte-derived macrophages were found to be making nitric oxide (NO). Furthermore, aminoguanidine-mediated inhibition of induced NO synthase activity in infiltrating macrophages significantly prolonged survival, indicating involvement of NO in the immunopathology. These data show for the first time the therapeutic effects of temporally targeting pathogenic NO-producing macrophages during neurotropic viral encephalitis.
doi:10.1186/1742-2094-9-246
PMCID: PMC3532418  PMID: 23111065
Neurotropic virus; Flavivirus; Inflammatory monocytes; West Nile virus encephalitis; Macrophage infiltration; VLA-4; Integrins; Nitric oxide
18.  The Happy Life Club™ study protocol: A cluster randomised controlled trial of a type 2 diabetes health coach intervention 
BMC Public Health  2011;11:90.
Background
The Happy Life Club™ is an intervention that utilises health coaches trained in behavioural change and motivational interviewing techniques to assist with the management of type 2 diabetes mellitus (T2DM) in primary care settings in China. Health coaches will support participants to improve modifiable risk factors and adhere to effective self-management treatments associated with T2DM.
Methods/Design
A cluster randomised controlled trial involving 22 Community Health Centres (CHCs) in Fengtai District of Beijing, China. CHCs will be randomised into a control or intervention group, facilitating recruitment of at least 1320 individual participants with T2DM into the study. Participants in the intervention group will receive a combination of both telephone and face-to-face health coaching over 18 months, in addition to usual care received by the control group. Health coaching will be performed by CHC doctors and nurses certified in coach-assisted chronic disease management. Outcomes will be assessed at baseline and again at 6, 12 and 18 months by means of a clinical health check and self-administered questionnaire. The primary outcome measure is HbA1c level. Secondary outcomes include metabolic, physiological and psychological variables.
Discussion
This cluster RCT has been developed to suit the Chinese health care system and will contribute to the evidence base for the management of patients with T2DM. With a strong focus on self-management and health coach support, the study has the potential to be adapted to other chronic diseases, as well as other regions of China.
Trial Registration
Current Controlled Trials ISRCTN01010526
doi:10.1186/1471-2458-11-90
PMCID: PMC3041664  PMID: 21303564
19.  Common sequence variants on 20q11.22 confer melanoma susceptibility 
Nature genetics  2008;40(7):838-840.
We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totalling 2019 cases and 2105 controls. Using pooling we identified a novel melanoma risk locus on chromosome 20 (rs910873, rs1885120), with replication in two further samples (combined P <1 × 10-15). The odds ratio is 1.75 (1.53, 2.01), with evidence for stronger association in early onset cases.
doi:10.1038/ng.163
PMCID: PMC2755512  PMID: 18488026
20.  Suppression of the JNK Pathway by Induction of a Metabolic Stress Response Prevents Vascular Injury and Dysfunction 
Circulation  2008;118(13):1347-1357.
Oxidative injury and dysfunction of the vascular endothelium is an early and causal feature of many vascular diseases and single antioxidant strategies to prevent vascular injury have met with mixed results. Here we report that induction of a metabolic stress response with AMP kinase prevents oxidative endothelial cell injury. This response is characterized by stabilization of the mitochondrion and increased mitochondrial biogenesis resulting in attenuation of oxidative c-Jun N-terminal kinase (JNK) activation. We report that peroxisome proliferator coactivator 1α (PGC-1α) is a key downstream target of AMPK that is both necessary and sufficient for the metabolic stress response and JNK attenuation. Moreover, induction of the metabolic stress response in vivo attenuates ROS-mediated JNK activation and endothelial dysfunction in response to angiotensin II in wild-type mice, but not animals lacking either the endothelial isoform of AMPK or PGC-1α. These data highlight AMPK and PGC-1α as potential therapeutic targets for the amelioration of endothelial dysfunction and, as a consequence, vascular disease.
doi:10.1161/CIRCULATIONAHA.108.784298
PMCID: PMC2756193  PMID: 18809807
22.  Common variation in the fibroblast growth factor receptor 2 gene is not associated with endometriosis risk 
Human Reproduction (Oxford, England)  2008;23(7):1661-1668.
BACKGROUND
Endometriosis is a polygenic disease with a complex and multifactorial aetiology that affects 8–10% of women of reproductive age. Epidemiological data support a link between endometriosis and cancers of the reproductive tract. Fibroblast growth factor receptor 2 (FGFR2) has recently been implicated in both endometrial and breast cancer. Our previous studies on endometriosis identified significant linkage to a novel susceptibility locus on chromosome 10q26 and the FGFR2 gene maps within this linkage region. We therefore hypothesized that variation in FGFR2 may contribute to the risk of endometriosis.
METHODS
We genotyped 13 single nucleotide polymorphisms (SNPs) densely covering a 27 kb region within intron 2 of FGFR2 including two SNPs (rs2981582 and rs1219648) significantly associated with breast cancer and a total 40 tagSNPs across 150 kb of the FGFR2 gene. SNPs were genotyped in 958 endometriosis cases and 959 unrelated controls.
RESULTS
We found no evidence for association between endometriosis and FGFR2 intron 2 SNPs or SNP haplotypes and no evidence for association between endometriosis and variation across the FGFR2 gene.
CONCLUSIONS
Common variation in the breast-cancer implicated intron 2 and other highly plausible causative candidate regions of FGFR2 do not appear to be a major contributor to endometriosis susceptibility in our large Australian sample.
doi:10.1093/humrep/den035
PMCID: PMC2902840  PMID: 18285324
endometriosis; fibroblast growth factor receptor 2; single nucleotide polymorphism; haplotype

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