Vascular endothelial growth factor promotes physical wound repair and is anti-apoptotic in primary distal lung epithelial and A549 cells

Objective: There is evidence to suggest a beneficial role for growth factors, including vascular endothelial growth factor (VEGF), in tissue repair and proliferation after injury within the lung. Whether this effect is mediated predominantly by actions on endothelial cells or epithelial cells is unknown. This study tested the hypothesis that VEGF acts as an autocrine trophic factor for human adult alveolar epithelial cells and that under situations of pro-apoptotic stress, VEGF reduces cell death. Design: In vitro cell culture study looking at the effects of 0.03% H2O2 on both A549 and primary distal lung epithelial cells.Measurement and Main Results: Primary adult human distal lung epithelial cells express both the soluble and membrane-associated VEGF isoforms and VEGF receptors 1 and 2. At physiologically relevant doses, soluble VEGF isoforms stimulate wound repair and have a proliferative action. Specific receptor ligands confirmed that this effect was mediated by VEGF receptor 1. In addition to proliferation, we demonstrate that VEGF reduces A549 and distal lung epithelial cell apoptosis when administered after 0.03% H2O2 injury. This effect occurs due to reduced caspase-3 activation and is phosphatidylinositol 3′–kinase dependent. Conclusion: In addition to its known effects on endothelial cells, VEGF acts as a growth and anti-apoptotic factor on alveolar epithelial cells. VEGF treatment may have potential as a rescue therapy for diseases associated with alveolar epithelial damage such as acute respiratory distress syndrome.

A randomised controlled trial of the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia:the ECLIPSE trial

BACKGROUND: Heavy menstrual bleeding (HMB) is a common problem, yet evidence to inform decisions about initial medical treatment is limited. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of the levonorgestrel-releasing intrauterine system (LNG-IUS) (Mirena(®), Bayer) compared with usual medical treatment, with exploration of women's perspectives on treatment. DESIGN: A pragmatic, multicentre randomised trial with an economic evaluation and a longitudinal qualitative study. SETTING: Women who presented in primary care. PARTICIPANTS: A total of 571 women with HMB. A purposeful sample of 27 women who were randomised or ineligible owing to treatment preference participated in semistructured face-to-face interviews around 2 and 12 months after commencing treatment. INTERVENTIONS: LNG-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined oestrogen-progestogen or progesterone alone). Women could subsequently swap or cease their allocated treatment. OUTCOME MEASURES: The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period and then again at 5 years. Secondary outcomes included general quality of life (QoL), sexual activity, surgical intervention and safety. Data were analysed using iterative constant comparison. A state transition model-based cost-utility analysis was undertaken alongside the randomised trial. Quality-adjusted life-years (QALYs) were derived from the European Quality of Life-5 Dimensions (EQ-5D) and the Short Form questionnaire-6 Dimensions (SF-6D). The intention-to-treat analyses were reported as cost per QALY gained. Uncertainty was explored by conducting both deterministic and probabilistic sensitivity analyses. RESULTS: The MMAS total scores improved significantly in both groups at all time points, but were significantly greater for the LNG-IUS than for usual treatment [mean difference over 2 years was 13.4 points, 95% confidence interval (CI) 9.9 to 16.9 points; p < 0.001]. However, this difference between groups was reduced and no longer significant by 5 years (mean difference in scores 3.9 points, 95% CI -0.6 to 8.3 points; p = 0.09). By 5 years, only 47% of women had a LNG-IUS in place and 15% were still taking usual medical treatment. Five-year surgery rates were low, at 20%, and were similar, irrespective of initial treatments. There were no significant differences in serious adverse events between groups. Using the EQ-5D, at 2 years, the relative cost-effectiveness of the LNG-IUS compared with usual medical treatment was £1600 per QALY, which by 5 years was reduced to £114 per QALY. Using the SF-6D, usual medical treatment dominates the LNG-IUS. The qualitative findings show that women's experiences and expectations of medical treatments for HMB vary considerably and change over time. Women had high expectations of a prompt effect from medical treatments. CONCLUSIONS: The LNG-IUS, compared with usual medical therapies, resulted in greater improvement over 2 years in women's assessments of the effect of HMB on their daily routine, including work, social and family life, and psychological and physical well-being. At 5 years, the differences were no longer significant. A similar low proportion of women required surgical intervention in both groups. The LNG-IUS is cost-effective in both the short and medium term, using the method generally recommended by the National Institute for Health and Care Excellence. Using the alternative measures to value QoL will have a considerable impact on cost-effectiveness decisions. It will be important to explore the clinical and health-care trajectories of the ECLIPSE (clinical effectiveness and cost-effectiveness of levonorgestrel-releasing intrauterine system in primary care against standard treatment for menorrhagia) trial participants to 10 years, by which time half of the cohort will have reached menopause. TRIAL REGISTRATION: Current Controlled Trials ISRCTN86566246. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 88. See the NIHR Journals Library website for further project information.

Randomised trial of levonorgestrel intrauterine system compared to usual medical treatment for heavy menstrual bleeding:the ECLIPSE Trial

Objective: Heavy menstrual bleeding (menorrhagia) is a common problem, yet evidence is limited to inform therapeutic decisions.We compared the levonorgestrel-releasing intrauterine system(LNG-IUS) to usual medical treatment in a pragmatic randomised trial in primary care. Methods: We randomly assigned 571 women consulting their primary care providers with menorrhagia to LNG-IUS or to usual medical treatment as clinically appropriate (tranexamic acid, mefenamic acid, combined estrogen/progestogen or progestogen only). The primary outcome was a patient-reported measure ofimpact of menorrhagia, the validated Menorrhagia Multi-Attribute Scale (MMAS), assessed over 2 years. Secondary measures included generic quality of life (SF-36), sexual activity and surgical intervention.Results MMAS scores improved from baseline in both the LNG-IUS and usual medical treatment groups by 6 months (mean increases 32.7 points versus 21.4 points, respectively; P < 0.001for both) and were maintained over 2 years, but improvements were significantly greater with LNG-IUS (mean between-group difference 13.4 points, 95%CI, 9.9–16.9; P < 0.001).All domains of MMAS (practical difficulties, social life, family life,work/daily routine, psychological well being and physical health)improved significantly more with LNG-IUS, as were seven of the eight domains of SF-36. More women were still using LNG-IUSthan usual medical treatment at 2 years (64% versus 38%,P < 0.001). There were no significant between-group differences in surgical intervention rates or sexual activity scores. There were no serious adverse events in either group.Conclusions Among women presenting to primary care providers with menorrhagia, LNG-IUS was more effective than usual medical treatment at reducing the impact of this problem on their quality of life. In practice therefore, conventional treatments, such as tranexamic and mefenamic acid, remain helpful choices in women for whom LNG-IUS is considered unsuitable, or due to individual preference. For other women, LNG-IUS can be confidently recommended as an effective initial medical therapy for menorrhagia. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 02/06/02)

Clogging in subsurface-flow treatment wetlands:occurrence and contributing factors

Clogging is a major operational and maintenance issue associated with the use of subsurface flow wetlands for wastewater treatment, and can ultimately limit the lifetime of the system. This review considers over two decades of accumulated knowledge regarding clogging in both vertical and horizontal subsurface flow treatment wetlands. The various physical, chemical and biological factors responsible for clogging are identified and discussed. The occurrence of clogging is placed into the context of various design and operational parameters such as wastewater characteristics, upstream treatment processes, intermittent or continuous operation, influent distribution, and media type. This information is then used to describe how clogging develops within, and subsequently impacts, common variants of subsurface flow treatment wetland typically used in the U.S., U.K., France and Germany. Comparison of these systems emphasized that both hydraulic loading rate and solids loading rate need to be considered when designing systems to operate robustly, i.e. hydraulic overloading makes horizontal-flow tertiary treatment systems in the U.K. more susceptible to clogging problems than vertical-flow primary treatment systems in France. Future research should focus on elucidating the underlying mechanisms of clogging as they relate to the design, operation, and maintenance of subsurface flow treatment wetlands. © 2010 Elsevier B.V.

Is pregnancy a teachable moment for diet and physical activity behaviour change? An interpretative phenomenological analysis of the experiences of women during their first pregnancy

OBJECTIVES: Pregnancy may provide a 'teachable moment' for positive health behaviour change, as a time when women are both motivated towards health and in regular contact with health care professionals. This study aimed to investigate whether women's experiences of pregnancy indicate that they would be receptive to behaviour change during this period. DESIGN: Qualitative interview study. METHODS: Using interpretative phenomenological analysis, this study details how seven women made decisions about their physical activity and dietary behaviour during their first pregnancy. RESULTS: Two women had required fertility treatment to conceive. Their behaviour was driven by anxiety and a drive to minimize potential risks to the pregnancy. This included detailed information seeking and strict adherence to diet and physical activity recommendations. However, the majority of women described behaviour change as 'automatic', adopting a new lifestyle immediately upon discovering their pregnancy. Diet and physical activity were influenced by what these women perceived to be normal or acceptable during pregnancy (largely based on observations of others) and internal drivers, including bodily signals and a desire to retain some of their pre-pregnancy self-identity. More reasoned assessments regarding benefits for them and their baby were less prevalent and influential. CONCLUSIONS: Findings suggest that for women who conceived relatively easily, diet and physical activity behaviour during pregnancy is primarily based upon a combination of automatic judgements, physical sensations, and perceptions of what pregnant women are supposed to do. Health professionals and other credible sources appear to exert less influence. As such, pregnancy alone may not create a 'teachable moment'. Statement of contribution What is already known on this subject? Significant life events can be cues to action with relation to health behaviour change. However, much of the empirical research in this area has focused on negative health experiences such as receiving a false-positive screening result and hospitalization, and in relation to unequivocally negative behaviours such as smoking. It is often suggested that pregnancy, as a major life event, is a 'teachable moment' (TM) for lifestyle behaviour change due to an increase in motivation towards health and regular contact with health professionals. However, there is limited evidence for the utility of the TM model in predicting or promoting behaviour change. What does this study add? Two groups of women emerged from our study: the women who had experienced difficulties in conceiving and had received fertility treatment, and those who had conceived without intervention. The former group's experience of pregnancy was characterized by a sense of vulnerability and anxiety over sustaining the pregnancy which influenced every choice they made about their diet and physical activity. For the latter group, decisions about diet and physical activity were made immediately upon discovering their pregnancy, based upon a combination of automatic judgements, physical sensations, and perceptions of what is normal or 'good' for pregnancy. Among women with relatively trouble-free conception and pregnancy experiences, the necessary conditions may not be present to create a 'teachable moment'. This is due to a combination of a reliance on non-reflective decision-making, perception of low risk, and little change in affective response or self-concept.