Susceptibility-Associated Genetic Variation in NEDD9 Contributes to Prostate Cancer Initiation and Progression.

Although American men of European ancestry represent the largest population of patients with prostate cancer, men of African ancestry are disproportionately affected by prostate cancer, with higher prevalence and worse outcomes. These racial disparities in prostate cancer are due to multiple factors, but variations in genomic susceptibility such as SNP may play an important role in determining cancer aggressiveness and treatment outcome. Using public databases, we have identified a prostate cancer susceptibility SNP at an intronic enhancer of the neural precursor expressed, developmentally downregulated 9 (NEDD9) gene, which is strongly associated with increased risk of patients with African ancestry. This genetic variation increased expression of NEDD9 by modulating the chromatin binding of certain transcription factors, including ERG and NANOG. Moreover, NEDD9 displayed oncogenic activity in prostate cancer cells, promoting prostate cancer tumor growth and metastasis in vitro and in vivo. Together, our study provides novel insights into the genetic mechanisms driving prostate cancer racial disparities. SIGNIFICANCE: A prostate cancer susceptibility genetic variation in NEDD9, which is strongly associated with the increased risk of patients with African ancestry, increases NEDD9 expression and promotes initiation and progression of prostate cancer.See related commentary by Mavura and Huang, p. 3764.

Lower limb immobilisation and venous thromboembolism risk: combined case-control studies.

BACKGROUND: Evidence from randomised controlled trials shows that low-molecular-weight heparin is effective in reducing the risk of venous thromboembolism (VTE) in the clinical setting of temporary lower limb immobilisation. Despite this, international guidelines are non-committal in advocating the use of anticoagulation in this clinical scenario. We determined the risk of VTE associated with lower limb immobilisation and the proportion of VTE events associated with lower limb immobilisation by undertaking a secondary analysis of two case-control studies that had used a similar methodology. METHODS: We undertook logistic regression analysis to investigate the association of risk factors with VTE with the OR and 95% CIs for association between lower limb immobilisation and VTE the primary outcome variable. The proportion of VTE patients with lower limb immobilisation was also calculated. RESULTS: Cases comprised 396 patients aged 18-65 years with radiologically confirmed deep vein thrombosis or pulmonary embolism attending outpatient VTE clinics. Controls, also aged 18-65 years, comprised 197 inpatients in the coronary care unit and 200 outpatients treated for upper limb injuries in the fracture clinic. The OR for association between VTE and lower limb immobilisation was 73.1 (95% CI 10.1 to 530, p<0.001). In 62/396 (16%) cases, patients had undergone lower limb immobilisation within four weeks of their presentation with VTE, representing the most common potentially preventable cause of VTE in this sample. CONCLUSIONS: Lower limb immobilisation is associated with a markedly increased risk of VTE and represents the most common potentially preventable cause in the 18-65-year age group, being present in one in seven cases treated for VTE. Consideration should be given to pharmacological prophylaxis in patients with lower limb immobilisation to reduce the substantial burden of preventable VTE.

Venous thromboembolism risk associated with protracted work- and computer-related seated immobility: A case-control study.

OBJECTIVE: To examine the association between venous thromboembolism and prolonged work- and computer-related seated immobility. DESIGN: A case-control study. PARTICIPANTS AND SETTING: Cases were 200 patients attending venous thromboembolism clinics with a history of deep vein thrombosis and/or pulmonary embolism in the past six months, and controls were 200 patients treated in fracture clinic for an upper limb injury in the past six months. MAIN OUTCOME MEASURES: Logistic regression was used to estimate the association between venous thromboembolism and prolonged work- and computer-related seated immobility in the 28 days before the index event. Prolonged work- and computer-related seated immobility was defined firstly as a categorical variable with at least 10 h seated in a 24-h period, including at least 2 h without getting up; and secondly as the actual time spent seated in a 24-h period. RESULTS: Prolonged work- and computer-related seated immobility (categorical variable) was present in 36 (18%) cases and 31 (15.5%) controls. In multivariate analysis, there was no significant association between prolonged seated immobility and venous thromboembolism, odds ratio 1.18 (95% CI 0.56 to 2.48), P = 0.67. For the mean and maximum number of hours seated in a 24-h period, the odds ratios for the association per additional hour seated with venous thromboembolism were 1.08 (95% CI 1.01 to 1.6), P = 0.02 and 1.04 (95% CI 0.99 to 1.09), P = 0.08, respectively. CONCLUSION: This study found a weak association between venous thromboembolism and prolonged work- and computer-related seated immobility, with increasing mean hours seated associated with a higher risk of venous thromboembolism.

Bisphenol A exposure pathways in early childhood: Reviewing the need for improved risk assessment models.

Bisphenol A (BPA) is a plasticiser found in a number of household plastics, electronics, and food-packaging materials. Over the past 5 years, several human epidemiological studies have reported a positive association between BPA exposure and adverse health outcomes in children, including obesity, asthma, preterm birth, and neuro-behavioural disturbances. These findings are in conflict with international environmental risk assessment models, which predict daily exposure levels to BPA should not pose a risk to child health. The aim of this review is to provide an overview of the evidence for different exposure sources and potential exposure pathways of BPA in early childhood. By collating the findings from experimental models and exposure associations observed in human bio-monitoring studies, we affirm the potential for non-dietary sources to make a substantial contribution to total daily exposure in young children. Infants and toddlers have distinctive exposure sources, physiology, and metabolism of endocrine-disrupting chemicals. We recommend risk-assessment models implement new frameworks, which specifically address exposure and hazard in early childhood. This is particularly important for BPA, which is present in numerous products in the home and day-care environments, and for which animal studies report contradictory findings on its safety at environmentally relevant levels of exposure.

Assessing exposure of young children to common endocrine-disrupting chemicals in the home environment: a review and commentary of the questionnaire-based approach.

BACKGROUND: Although infants and young children are particularly vulnerable to endocrine disrupting chemical (EDC) exposure, there is an absence of comprehensive exposure data for this age group. As young children spend the majority of their time indoors, improved methods of exposure assessment are needed to characterise the health risks from exposures in the home environment. Biologic assessment, which has been considered the gold standard for exposure assessment in recent years, is difficult to conduct in young children. Questionnaires are an alternative and indirect method of predicting exposure, which may overcome some of the limitations of direct exposure assessment. RESEARCH PROBLEM: The feasibility of using a questionnaire-based approach to predict exposure of young children to EDCs in the home has yet to be comprehensively reviewed. Moreover, there is no one questionnaire that has been validated for predicting the exposure of infants to common EDCs in the home. AIMS AND OBJECTIVES: The aim of this review is to discuss the use and validation of the questionnaire-based approach to predict exposure of children to chemicals from three common classes of EDCs in the home, namely, plasticisers, flame retardants, and insecticides. We discuss the strengths and weaknesses of the questionnaire-based approach as well as the important pathways of exposure in the home environment, by which to guide the design and validation of future exposure questionnaires. RESULTS: The findings from our review indicate that the questionnaire-based approach is a valuable tool in the prediction of exposure to persistent organic pollutants, as well as to toxicants that have consistent patterns of exposure. With improvements to the design and validation process, the questionnaire-based approach may also prove to be a reliable instrument in predicting exposure to EDCs with short-half lives, including bisphenol A, phthalates, and pyrethroid and organophosphate insecticides.

Use of nebulised magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in adults: a randomised double-blind placebo-controlled trial.

BACKGROUND: Intravenous magnesium has been shown to cause bronchodilation in acute severe asthma and in small trials in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). There is also some evidence of benefit from nebulised magnesium in acute severe asthma. Our hypothesis was that adjuvant magnesium treatment administered via repeated nebulisation was effective in the management of AECOPD. METHODS: In this randomised double-blind placebo-controlled trial, we approached 161 patients with AECOPD presenting to the emergency departments at two New Zealand hospitals with a forced expiratory volume in 1 s (FEV1) <50% predicted 20 min after initial administration of salbutamol 2.5 mg and ipratropium 500 µg via nebulisation. Patients received 2.5 mg salbutamol mixed with either 2.5 ml isotonic magnesium sulphate (151 mg per dose) or 2.5 ml isotonic saline (placebo) on three occasions at 30 min intervals via nebuliser. The primary outcome measure was FEV1 at 90 min. RESULTS: 116 patients were randomised, 52 of whom were randomly allocated to the magnesium adjuvant group. At 90 min the mean (SD) FEV1 in the magnesium group (N=47) was 0.78 (0.33) l compared with 0.81 (0.30) l in the saline group (N=61) (difference -0.026 l (95% CI -0.15 to 0.095, p=0.67). No patients required non-invasive ventilation. There were 43/48 admissions to hospital in the magnesium group and 56/61 in the saline group (RR 0.98, 95% CI 0.86 to 1.10, p=0.69). CONCLUSIONS: Nebulised magnesium as an adjuvant to salbutamol treatment in the setting of AECOPD has no effect on FEV1. Australian New Zealand Clinical Trials Registry ACTRN12608000167369.

Antineutrophil cytoplasmic autoantibodies and myeloperoxidase autoantibodies in clinical expression of Churg-Strauss syndrome.

BACKGROUND: The clinical significance of antineutrophil cytoplasmic antibodies (ANCAs) in the phenotypic expression of Churg-Strauss syndrome (CSS) is uncertain. OBJECTIVE: We sought to investigate the relationship between ANCA status and the clinical expression of CSS in a case series derived from the US Food and Drug Administration's adverse events database. METHODS: All cases of CSS reported to the US Food and Drug Administration from 1997 to April 2003 were reviewed. Information about basic demographics, suspect medication use, clinical manifestations, histologic findings, ANCA staining patterns, and the presence of antibodies to myeloperoxidase (anti-MPO) or proteinase 3 (anti-PR3) was recorded when available. RESULTS: There were 93 case reports of CSS with sufficient documentation, including ANCA status. There were 38 (40.9%) of 93 cases with positive ANCA results, of which 15 cases reported a positive ELISA, all of which were positive for anti-MPO. ANCA negativity was associated with an increased proportion of cardiac involvement (risk difference [RD], 38.2%; 95% CI, 25.3% to 51.0%), gastrointestinal involvement (RD, 25.5%; 95% CI, 13.9% to 37.0%), pulmonary infiltrates (odds ratio, 4.9; 95% CI, 1.5-16.2), and the outcome of a life-threatening event or death (RD, 30.9%; 95% CI, 18.7% to 43.1%) when compared with anti-MPO-positive cases. ANCA negativity was associated with a decreased proportion of peripheral neuropathy (odds ratio, 0.3; 95% CI, 0.07-0.9). CONCLUSION: These findings support the hypothesis that the presence or absence of autoantibodies influences the clinical expression and severity of CSS.

Randomized controlled trial of high concentration oxygen in suspected community-acquired pneumonia.

OBJECTIVE: To determine whether high concentration oxygen increases the PaCO(2) in the treatment of community-acquired pneumonia. DESIGN: Randomized controlled clinical trial in which patients received high concentration oxygen (8 L/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturations between 93 and 95%) for 60 minutes. Transcutaneous CO(2) (PtCO(2)) was measured at 0, 20, 40 and 60 minutes. SETTING: The Emergency Departments at Wellington, Hutt and Kenepuru Hospitals. PARTICIPANTS: 150 patients with suspected community-acquired pneumonia presenting to the Emergency Department. Patients with chronic obstructive pulmonary disease (COPD) or disorders associated with hypercapnic respiratory failure were excluded. MAIN OUTCOME VARIABLES: The primary outcome variable was the proportion of patients with a rise in PtCO(2) ≥4 mmHg at 60 minutes. Secondary outcome variables included the proportion of patients with a rise in PtCO(2) ≥8 mmHg at 60 minutes. RESULTS: The proportion of patients with a rise in PtCO(2) ≥4 mmHg at 60 minutes was greater in the high concentration oxygen group, 36/72 (50.0%) vs 11/75 (14.7%), relative risk (RR) 3.4 (95% CI 1.9 to 6.2), P < 0.001. The high concentration group had a greater proportion of patients with a rise in PtCO(2) ≥8 mmHg, 11/72 (15.3%) vs 2/75 (2.7%), RR 5.7 (95% CI 1.3 to 25.0), P = 0.007. Amongst the 74 patients with radiological confirmation of pneumonia, the high concentration group had a greater proportion with a rise in PtCO(2) ≥4 mmHg, 20/35 (57.1%) vs 5/39 (12.8%), RR 4.5 (95% CI 1.9 to 10.6) P < 0.001. CONCLUSIONS: We conclude that high concentration oxygen therapy increases the PtCO(2) in patients presenting with suspected community-acquired pneumonia. This suggests that the potential increase in PaCO(2) with high concentration oxygen therapy is not limited to COPD, but may also occur in other respiratory disorders with abnormal gas exchange.

What risks do women face when seeking advice during pregnancy from pharmacies and natural health retailers?

AIM: Potential risks to mother and foetus exist with the incorrect use of complementary and alternative medicine (CAM) products during pregnancy. This study aimed to identify the risks that a woman may face when seeking advice during pregnancy from pharmacies and health food stores (HFS) in Greater Wellington (New Zealand). METHODS: 21 HFS and 21 geographically-matched pharmacies were visited by a researcher who sought advice regarding vitamin supplementation and nausea in early pregnancy using a standardised scenario. Any advice given, including details of recommended products, was documented immediately upon leaving the premises. Proportions were obtained and paired contingency table analysis was used to examine the agreement between the matched pairs. RESULTS: A minority of pharmacies (5/21, 23.8%) and HFS (1/21, 4.8%) made primary recommendations for nausea which were supported by Ministry of Health (MOH) guidelines, and both pharmacies (14/21, 66.7%) and HFS (7/21, 33.3%) recommended products contrary to these guidelines. A greater proportion of pharmacies gave advice consistent with MOH recommended dosage of folic acid supplementation than HFS (20/21, 95.2% vs 10/21, 47.6%). 2/21 (9.5%) of pharmacies and 4/21 (19%) of HFS gave advice with a potential risk of vitamin A overdose. CONCLUSIONS: Pharmacies and HFS in Greater Wellington provided potentially hazardous advice, recommending products, often branded for pregnancy, which contradicted NZ MOH guidelines. Regulatory reform of CAM products and those who sell them is called for in New Zealand.

What risk do consumers face when seeking medical advice from health food stores?

AIM: There is currently no specific legislation to regulate either complementary and alternative medicine (CAM) products or the majority of those promoting them. This study sought to highlight the general risk a consumer may face when they seek help/advice from a pharmacy or health food store (HFS). METHODS: 21 HFS, matched with pharmacies, were visited by a researcher complaining of tiredness, who stated he had been taking warfarin over the previous 2 months. The name, manufacturer and retail price of any products recommended were recorded immediately after leaving the premises. Paired contingency table analysis was used. RESULTS: A pharmacy was significantly more likely to advise the consumer to consult a doctor (13/21) than a HFS (3/21) with a difference in marginal proportions of 47.6% (95% CI 22.5-72.7), p=0.006. A HFS was more likely to recommend more products, and only about one-quarter gave appropriate advice regarding possible interactions with warfarin and management of anticoagulation compared with two-thirds of pharmacies. CONCLUSION: To provide safe and quality advice to consumers, those promoting CAM products need to obtain relevant history and give accurate information regarding possible dug interactions and be prepared to refer back to mainstream medical services. Better regulation of CAM products and those promoting them is called for.

Randomised controlled trial of high concentration versus titrated oxygen therapy in severe exacerbations of asthma.

BACKGROUND: The effect on Paco2 of high concentration oxygen therapy when administered to patients with severe exacerbations of asthma is uncertain. METHODS: 106 patients with severe exacerbations of asthma presenting to the Emergency Department were randomised to high concentration oxygen (8 l/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturations between 93% and 95%) for 60 min. Patients with chronic obstructive pulmonary disease or disorders associated with hypercapnic respiratory failure were excluded. The transcutaneous partial pressure of carbon dioxide (Ptco2) was measured at 0, 20, 40 and 60 min. The primary outcome variable was the proportion of patients with a rise in Ptco2 ≥4 mm Hg at 60 min. RESULTS: The proportion of patients with a rise in Ptco2 ≥4 mm Hg at 60 min was significantly higher in the high concentration oxygen group, 22/50 (44%) vs. 10/53 (19%), RR 2.3 (95% CI 1.2 to 4.4, p<0.006). The high concentration group had a higher proportion of patients with a rise in Ptco2 ≥8 mm Hg, 11/50 (22%) vs. 3/53 (6%), RR 3.9 (95% CI 1.2 to 13.1, p=0.016). All 10 patients with a final Ptco2 ≥45 mm Hg received high concentration oxygen therapy, and in five there was an increase in Ptco2 ≥10 mm Hg. CONCLUSION: High concentration oxygen therapy causes a clinically significant increase in Ptco2 in patients presenting with severe exacerbations of asthma. A titrated oxygen regime is recommended in the treatment of severe asthma, in which oxygen is administered only to patients with hypoxaemia, in a dose that relieves hypoxaemia without causing hyperoxaemia. Clinical trial number ACTRN12607000131459.

Survival of the fittest: capacity building for small nonprofit organizations.

This paper discusses capacity building activities designed for small nonprofits who are members of the Second Harvest Food Bank of Central Florida's ADEPT program. The Second Harvest Food Bank of Central Florida (SHFBCF) is a nonprofit organization that collects, stores and distributes donated food to more than 450 nonprofit partners in Brevard, Lake, Orange, Osceola, Seminole and Volusia counties. This project sought to delineate, design, and implement the capacity building trainings desired by ADEPT member agencies. It also analyzed the relationship between the number of clients served, number of staff, number of volunteers, and the training needs. At the conclusion of the capacity building trainings, data was collected to gauge participants' perceptions of the capacity building trainings and their perceived impact on the effectiveness of the ADEPT Program and its member agencies. The generalizability and applicability of the research results to other small community-based organizations providing social and human services is also discussed.

Merino wool graduated compression stocking increases lower limb venous blood flow: a randomized controlled trial.

INTRODUCTION: Graduated compression stockings represent a nonpharmacological approach to reduce the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) due to prolonged immobility through reducing lower limb venous stasis. A novel merino wool, double-layer, below-knee graduated compression stocking has been developed to reduce the risk of air travel-related DVT and PE. METHODS: Twenty healthy adult participants were randomized to wear the novel graduated compression stocking on either the left or right leg. Doppler ultrasound measurements of popliteal venous blood flow were made on both legs over a 120-minute period. The primary outcome was peak systolic velocity in the popliteal vein at 120 minutes. Secondary outcomes included mean flow velocity, total volume flow, vein cross-sectional area, and change in ankle and calf measurements. RESULTS: The popliteal vein peak systolic velocity was 0.35 cm/s (95% confidence intervals [CI], 0.22 to 0.49, P<0.001) higher with stocking use at 120 minutes, a difference of 24%. Mean flow velocity and total volume flow were also significantly higher with stocking use. Ankle and calf circumference were decreased with stocking use, with an overall difference of -6.3 mm (95% CI, -11.3 to -1.2, P=0.021) and -7.9 mm (95% CI, -13.3 to -2.4, P=0.011), respectively. CONCLUSION: The novel merino wool double-layer, below-knee graduated compression stocking increases lower limb venous blood flow during prolonged seated immobility. Its use is likely to reduce the risk of DVT and PE in situations of prolonged seated immobility, such as long-distance air travel. The reduction in lower limb swelling associated with their use suggests that the stockings are likely to have utility in the treatment of chronic venous insufficiency and lymphedema.

Prolonged work- and computer-related seated immobility and risk of venous thromboembolism.

OBJECTIVE: To determine the risk of venous thromboembolism (VTE) associated with prolonged work- and computer-related seated immobility. DESIGN: Case-control study in which cases were patients aged 18-65 years attending outpatient VTE clinics, and controls were patients aged 18-65 years admitted to CCU with a condition other than VTE. Interviewer-administered questionnaires obtained detailed information on VTE risk factors and clinical details. SETTING: VTE Clinics and Coronary Care Unit (CCU), Wellington and Kenepuru Hospitals, Wellington between February 2007 and February 2009. MAIN OUTCOME MEASURE: The relative risk of VTE associated with prolonged work- and computer-related seated immobility, defined as being seated at work and on the computer at home, at least 10 hours in a 24-hour period and at least 2 hours at a time without getting up, during the four weeks prior to the onset of symptoms that led to VTE diagnosis or CCU admission. RESULTS: There were 197 cases and 197 controls. Prolonged work- and computer-related seated immobility was present in 33/197 (16.8%) and 19/197 (9.6%) cases and controls, respectively. In multivariate analyses, prolonged work- and computer-related seated immobility was associated with an increased risk of VTE, odds ratio 2.8 (95% CI 1.2-6.1, P=0.013). The maximum and average number of hours seated in a 24-hour period were associated with an increased risk of VTE, with odds ratios of 1.1 (95% CI 1.0-1.2, P=0.008) and 1.1 (95% CI 1.0-1.2, P=0.014) per additional hour seated. CONCLUSION: Prolonged work- and computer-related seated immobility increases the risk of VTE. We suggest that there needs to be both a greater awareness of the role of prolonged work-related seated immobility in the pathogenesis of VTE, and the development of occupational strategies to decrease the risk.

An audit of the effect of oxygen prescription charts on clinical practice.

PROBLEM: The need to improve the prescription, administration and monitoring of oxygen therapy. DESIGN: An interventional, prospective audit. BACKGROUND AND SETTING: Wellington Hospital, a teaching and tertiary referral hospital in New Zealand in 2007 and 2008. KEY MEASURES FOR IMPROVEMENT: Demonstration of adequate oxygen prescribing, administration and monitoring of oxygen therapy. STRATEGIES FOR IMPROVEMENT: The introduction of a new drug chart with a specific oxygen prescription section. Targeted educational lectures primarily to medical staff. EFFECTS OF CHANGE: 610 and 566 patients were reviewed in the first and second audits. After introduction of the new oxygen prescription section on the drug chart the proportion of patients whose oxygen therapy was prescribed increased from 15/85 (17.6%) to 39/98 (39.8%), relative risk 2.3 (95% CI 1.3 to 3.9). The proportion with adequate oxygen prescription, with documentation of device, flow rate or inspired oxygen concentration, and the target oxygen saturation increased from 5/85 (5.9%) to 36/98 (36.7%), relative risk 6.2 (95% CI 2.5 to 15.0). Introduction of the new charts was not associated with changes in clinical practice in terms of assessment of oxygen saturations on room air and commencement if < or = 92%, or the titration of oxygen therapy in response to oxygen saturations < or = 92%. LESSONS LEARNT: An oxygen prescription section on hospital drug charts improved the prescription of oxygen but did not improve clinical practice. Additional strategies are required to improve the administration of oxygen therapy in hospitals.

High blood pressure advice given by natural health food stores.

AIM: Complimentary and alternative medicines are widely used but are not registered medicines. The aim of the study was to compare advice given by health food stores and pharmacists for hypertension. METHODS: Twenty-six health food stores and 26 pharmacies were visited by an individual for advise on a hypothetical problem of hypertension. RESULTS: Staff in 25 out of 26 health food stores did not refer the researcher to a medical practitioner; instead they recommended and sold a wide variety of compounds of unproven efficacy. CONCLUSIONS: We recommend the implementation of a formal training programme for health food stores staff and that complimentary and alternative medicines-use in New Zealand is regulated.