Cindy Kok

The global burden attributable to low bone mineral density

Introduction The Global Burden of Disease Study 2010 estimated the worldwide health burden of 291 diseases and injuries and 67 risk factors by calculating disability-adjusted life years (DALYs). Osteoporosis was not considered as a disease, and bone mineral density (BMD) was analysed as a risk factor for fractures, which formed part of the health burden due to falls. Objectives To calculate (1) the global distribution of BMD, (2) its population attributable fraction (PAF) for fractures and subsequently for falls, and (3) the number of DALYs due to BMD. Methods A systematic review was performed seeking population-based studies in which BMD was measured by dual-energy X-ray absorptiometry at the femoral neck in people aged 50 years and over. Age- and sex-specific mean ± SD BMD values (g/cm2) were extracted from eligible studies. Comparative risk assessment methodology was used to calculate PAFs of BMD for fractures. The theoretical minimum risk exposure distribution was estimated as the age- and sex-specific 90th centile from the Third National Health and Nutrition Examination Survey (NHANES III). Relative risks of fractures were obtained from a previous meta-analysis. Hospital data were used to calculate the fraction of the health burden of falls that was due to fractures. Results Global deaths and DALYs attributable to low BMD increased from 103 000 and 3 125 000 in 1990 to 188 000 and 5 216 000 in 2010, respectively. The percentage of low BMD in the total global burden almost doubled from 1990 (0.12%) to 2010 (0.21%). Around one-third of falls-related deaths were attributable to low BMD. Conclusions Low BMD is responsible for a growing global health burden, only partially representative of the real burden of osteoporosis.

Glutathionylation mediates angiotensin II-induced eNOS uncoupling, amplifying NADPH oxidase-dependent endothelial dysfunction.

Background Glutathionylation of endothelial nitric oxide synthase (eNOS) “uncouples” the enzyme, switching its function from nitric oxide (NO) to O2•− generation. We examined whether this reversible redox modification plays a role in angiotensin II (Ang II)‐induced endothelial dysfunction. Methods and Results Ang II increased eNOS glutathionylation in cultured human umbilical vein endothelial cells (HUVECs), rabbit aorta, and human arteries in vitro. This was associated with decreased NO bioavailability and eNOS activity as well as increased O2•− generation. Ang II‐induced decrease in eNOS activity was mediated by glutathionylation, as shown by restoration of function by glutaredoxin‐1. Moreover, Ang II‐induced increase in O2•− and decrease in NO were abolished in HUVECs transiently transfected, with mutant eNOS rendered resistant to glutathionylation. Ang II effects were nicotinamide adenine dinucleotide phosphate (NADPH) oxidase dependent because preincubation with gp 91ds‐tat, an inhibitor of NADPH oxidase, abolished the increase in eNOS glutathionylation and loss of eNOS activity. Functional significance of glutathionylation in intact vessels was supported by Ang II‐induced impairment of endothelium‐dependent vasorelaxation that was abolished by the disulfide reducing agent, dithiothreitol. Furthermore, attenuation of Ang II signaling in vivo by administration of an angiotensin converting enzyme (ACE) inhibitor reduced eNOS glutathionylation, increased NO, diminished O2•−, improved endothelium‐dependent vasorelaxation and reduced blood pressure. Conclusions Uncoupling of eNOS by glutathionylation is a key mediator of Ang II‐induced endothelial dysfunction, and its reversal is a mechanism for cardiovascular protection by ACE inhibition. We suggest that Ang II‐induced O2•− generation in endothelial cells, although dependent on NADPH oxidase, is amplified by glutathionylation‐dependent eNOS uncoupling.

Secondary osteoporosis in patients with an osteoporotic fracture.

Secondary osteoporosis is a common cause of osteoporosis, and there are many medical conditions associated with osteoporosis. Many of these present well before osteoporosis develops, and knowledge of these pre-existing conditions may influence the decision about whether to test and/or treat for osteoporosis. Men and premenopausal women with unexplained osteoporosis or a history of fragility fracture should undergo investigation for secondary osteoporosis. Postmenopausal women with risk factors for secondary osteoporosis should also be carefully evaluated. Beyond the well-recognised association with glucocorticoids, an increasing list of drugs has been implicated in causing bone loss and fractures. With appropriate consideration of secondary causes and relevant investigations, many of these conditions are preventable with newer therapies.

Sunlight and health: Attitudes of older people living in intermediate care facilities in southern Australia

Older people have a high prevalence of falls and fractures, partly due to vitamin D deficiency. Sunlight is a major source of vitamin D, but many older people living in intermediate care facilities have inadequate sunlight exposure. The aim of this study was to determine the sun exposure practices and attitudes to sunlight in this population. Fifty-seven older residents of intermediate care facilities in Sydney, Australia were interviewed to determine their sun exposure practices, their views on sunlight and health and whether these have changed over their lives, factors affecting sunlight exposure and their knowledge of vitamin D. Sixty percent of the participants preferred to be outdoors, despite more than 92% believing that sunlight was healthy. In their youth however, almost 90% had preferred to be outdoors. Poor health, physical constraints and a sense of lack of ownership of outdoor spaces were barriers to sunlight exposure. Improved physical access, more outdoor leisure activities and promotion of greater autonomy may improve safe and appropriate sunlight exposure in this population.

Hospital Data Reporting on Postpartum Hemorrhage: Under-Estimates Recurrence and Over-Estimates the Contribution of Uterine Atony

This study aimed to explore whether recording of a prior adverse pregnancy outcome (postpartum hemorrhage) in a medical record increases the likelihood that recurrence of the same event is reported in hospital data. Using a sample of 588 pregnancies [2 consecutive pregnancies for 294 randomly selected women with at least one postpartum hemorrhage (PPH)], we compared ‘coded’ recurrence rates in hospital data with those obtained from medical record audit. ‘Coded’ recurrence in a second pregnancy was also compared for women with or without a documented history of prior PPH. We found a ‘coded’ recurrence rate of 18.5% and an ‘audited’ recurrence rate of 28.4%. The ‘coded’ rate of recurrence among women who had a documented history of PPH was 27.4% compared to 19.1% when the previous PPH was not noted in the second pregnancy medical record. Medical record reporting of uterine atony as the cause for postpartum hemorrhages in first and second births was 37.9 and 34.0% while ‘coded’ hospital data reporting attributed 79.8 and 73.9% respectively to atony. Our study results indicate that a history of postpartum hemorrhage may be a stronger risk factor for subsequent PPH than previously demonstrated. A recorded history of PPH was associated with an increased likelihood of reporting a subsequent PPH, and in such cases recurrence rates approximate true recurrence. The contribution of uterine atony as a cause of postpartum hemorrhage is over-estimated using hospital data.

Trends in calcium and vitamin D usage among older people in nursing care facilities in Australia: still falling short of the guidelines

Objective:  To determine the impact of awareness‐raising strategies of calcium and vitamin D supplements in the active management of bone health of older people living in nursing care facilities in Australia.

Automated Quantification of Myocardial Salvage in a Rat Model of Ischemia-Reperfusion Injury Using 3D High-Resolution Magnetic Resonance Imaging (MRI)

Background Quantification of myocardial “area at risk” (AAR) and myocardial infarction (MI) zone is critical for assessing novel therapies targeting myocardial ischemia–reperfusion (IR) injury. Current “gold‐standard” methods perfuse the heart with Evans Blue and stain with triphenyl tetrazolium chloride (TTC), requiring manual slicing and analysis. We aimed to develop and validate a high‐resolution 3‐dimensional (3D) magnetic resonance imaging (MRI) method for quantifying MI and AAR. Methods and Results Forty‐eight hours after IR was induced, rats were anesthetized and gadopentetate dimeglumine was administered intravenously. After 10 minutes, the coronary artery was re‐ligated and a solution containing iron oxide microparticles and Evans Blue was infused (for comparison). Hearts were harvested and transversally sectioned for TTC staining. Ex vivo MR images of slices were acquired on a 9.4‐T magnet. T2* data allowed visualization of AAR, with microparticle‐associated signal loss in perfused regions. T1 data demonstrated gadolinium retention in infarcted zones. Close correlation (r=0.92 to 0.94; P<0.05) of MRI and Evans Blue/TTC measures for both AAR and MI was observed when the combined techniques were applied to the same heart slice. However, 3D MRI acquisition and analysis of whole heart reduced intra‐observer variability compared to assessment of isolated slices, and allowed automated segmentation and analysis, thus reducing interobserver variation. Anatomical resolution of 81 μm3 was achieved (versus ≈2 mm with manual slicing). Conclusions This novel, yet simple, MRI technique allows precise assessment of infarct and AAR zones. It removes the need for tissue slicing and provides opportunity for 3D digital analysis at high anatomical resolution in a streamlined manner accessible for all laboratories already performing IR experiments.

The NRF2 activator DH404 attenuates adverse ventricular remodeling post-myocardial infarction by modifying redox signalling

Background The novel synthetic triterpenoid, bardoxolone methyl, has the ability to upregulate cytoprotective proteins via induction of the nuclear factor erythroid‐2‐related factor 2 (Nrf2) pathway. This makes it a promising therapeutic agent in disease states characterized by dysregulated oxidative signalling. We have examined the effect of a Nrf2 activator, dihydro‐CDDO‐trifluoroethyl amide (DH404), a derivative of bardoxolone methyl, on post‐infarct cardiac remodeling in rats. Methods/Results DH404, administered from day 2 post myocardial infarction (MI: 30 min transient ischemia followed by reperfusion) resulted in almost complete protection against adverse ventricular remodeling as assessed at day 28 (left ventricular end‐systolic area: sham 0.14±0.01 cm2, MI vehicle 0.29±0.04 cm2 vs. MI DH404 0.18±0.02 cm2, P<0.05); infarct size (21.3±3.4% MI vehicle vs. 10.9±2.3% MI DH404, P<0.05) with associated benefits on systolic function (fractional shortening: sham 71.9±2.6%, MI vehicle 36.2±1.9% vs. MI DH404 58.6±4.0%, P<0.05). These structural and functional benefits were associated with lower myocardial expression of atrial natriuretic peptide (ANP, P<0.01 vs. MI vehicle), and decreased fibronectin (P<0.01 vs. MI vehicle) in DH404‐treated MI rats at 28 days. MI increased glutathionylation of endothelial nitric oxide synthase (eNOS) in vitro ‐ a molecular switch that uncouples the enzyme, increasing superoxide production and decreasing nitric oxide (NO) bioavailability. MI‐induced eNOS glutathionylation was substantially ameliorated by DH404. An associated increase in glutaredoxin 1 (Grx1) co‐immunoprecipitation with eNOS without a change in expression was mechanistically intriguing. Indeed, in parallel in vitro experiments, silencing of Grx1 abolished the protective effect of DH404 against Angiotensin II‐induced eNOS uncoupling. Conclusion The bardoxolone derivative DH404 significantly attenuated cardiac remodeling post MI, at least in part, by re‐coupling of eNOS and increasing the functional interaction of Grx1 with eNOS. This agent may have clinical benefits protecting against post MI cardiomyopathy. HighlightsThe bardoxolone derivative DH404 reduced adverse cardiac remodeling post myocardial infarction.Oral DH404 improved markers of heart failure and fibrosis post myocardial infarction.DH404 increased functional association of glutaredoxin with eNOS.Protection against eNOS glutathionylation is a new mechanism of DH404 benefit.Bardoxolone has potential therapeutic role in ST elevation MI patients. Graphical abstract Figure. No Caption available.

TEXT messages to improve MEDication adherence and Secondary prevention (TEXTMEDS) after acute coronary syndrome: a randomised clinical trial protocol

Background Identifying simple, low-cost and scalable means of supporting lifestyle change and medication adherence for patients following a cardiovascular (CV) event is important. Objective The TEXTMEDS (TEXT messages to improve MEDication adherence and Secondary prevention) study aims to investigate whether a cardiac education and support programme sent via mobile phone text message improves medication adherence and risk factor levels in patients following an acute coronary syndrome (ACS). Study design A single-blind, multicentre, randomised clinical trial of 1400 patients after an ACS with 12 months follow-up. The intervention group will receive multiple weekly text messages that provide information, motivation, support to adhere to medications, quit smoking (if relevant) and recommendations for healthy diet and exercise. The primary endpoint is the percentage of patients who are adherent to cardioprotective medications and the key secondary outcomes are mean systolic blood pressure (BP) and low-density lipoprotein cholesterol. Secondary outcomes will also include total cholesterol, mean diastolic BP, the percentage of participants who are adherent to each cardioprotective medication class, the percentage of participants who achieve target levels of CV risk factors, major vascular events, hospital readmissions and all-cause mortality. The study will be augmented by formal economic and process evaluations to assess acceptability, utility and cost-effectiveness. Summary The study will provide multicentre randomised trial evidence of the effects of a text message-based programme on cardioprotective medication adherence and levels of CV risk factors. Ethics and dissemination Primary ethics approval was received from Western Sydney Local Health District Human Research Ethics Committee (HREC2012/12/4.1 (3648) AU RED HREC/13/WMEAD/15). Results will be disseminated via peer-reviewed publications and presentations at international conferences. Trial registration number ACTRN12613000793718; Pre-results.