Decision-making for active living infrastructure in new communities: a qualitative study in England.

BACKGROUND: Urban design can influence population levels of physical activity and subsequent health impacts. This qualitative study investigates local level decision-making for 'active living' infrastructure (ALI)-walking and cycling infrastructure and open spaces in new communities. METHODS: Thirty-five semi-structured interviews with stakeholders, and limited ethnographic observations, were conducted with local government and private sector stakeholders including urban and transport planners, public health practitioners, elected councillors and developers. Interview transcripts were coded and analysed thematically. RESULTS: Public health practitioners in local government could act as knowledge brokers and leaders to motivate non-health stakeholders such as urban and transport planners to consider health when designing and building new communities. They needed to engage at the earliest stages and be adequately resourced to build relationships across sectors, supporting non-health outcomes such as tackling congestion, which often had greater political traction. 'Evidence' for decision-making identified problems (going beyond health), informed solutions, and also justified decisions post hoc, although case study examples were not always convincing if not considered contextually relevant. CONCLUSION: We have developed a conceptual model with three factors needed to bridge the gap between evidence and ALI being built: influential public health practitioners; supportive policies in non-health sectors; and adequate resources.

Effects of urban motorways on physical activity and sedentary behaviour in local residents: a natural experimental study.

BACKGROUND: There is little evidence on how changing the physical environment changes health-related behaviours. We studied the effects of the new M74 motorway (freeway) - opened in 2011 - and the existing M8 motorway in Glasgow, Scotland, on physical activity and sedentary behaviour among local residents. METHODS: This natural experimental study used baseline (T1; 2005) and follow-up data (T2; 2013) from a longitudinal cohort (N = 365) and two cross-sectional samples (T1 N = 980; T2 N = 978). Adult participants were recruited from three study areas: one surrounding the new motorway, one surrounding the existing motorway, and a third, control, area without a motorway. The outcomes were self-reported time spent sitting, walking, and in moderate-to-vigorous physical activity (MVPA). Motorway exposure was defined in terms of (1) study area and (2) distance from home to the nearest motorway junction. Outcomes were regressed on exposures in two-part (walking and MVPA) or linear (sedentary behaviour) cohort and repeat cross-sectional models, adjusted for baseline behaviour and sociodemographic covariates. RESULTS: Cohort participants living in the M8 area were less likely to participate in MVPA at follow-up than those living in the area without a motorway (OR 0.37; 95%CI 0.15, 0.91). Within the M8 area, those living closer to the motorway were also less likely to do so (OR 0.30; 95%CI 0.09, 0.97). No other statistically significant results were found. CONCLUSIONS: We found some evidence of a negative association between exposure to an existing urban motorway and MVPA. However, the behavioural impacts of motorways are likely to be complex and evolve over time.

Causal pathways linking environmental change with health behaviour change: Natural experimental study of new transport infrastructure and cycling to work.

BACKGROUND: Mechanisms linking changes to the environment with changes in physical activity are poorly understood. Insights into mechanisms of interventions can help strengthen causal attribution and improve understanding of divergent response patterns. We examined the causal pathways linking exposure to new transport infrastructure with changes in cycling to work. METHODS: We used baseline (2009) and follow-up (2012) data (N=469) from the Commuting and Health in Cambridge natural experimental study (Cambridge, UK). Exposure to new infrastructure in the form of the Cambridgeshire Guided Busway was defined using residential proximity. Mediators studied were changes in perceptions of the route to work, theory of planned behaviour constructs and self-reported use of the new infrastructure. Outcomes were modelled as an increase, decrease or no change in weekly cycle commuting time. We used regression analyses to identify combinations of mediators forming potential pathways between exposure and outcome. We then tested these pathways in a path model and stratified analyses by baseline level of active commuting. RESULTS: We identified changes in perceptions of the route to work, and use of the cycle path, as potential mediators. Of these potential mediators, only use of the path significantly explained (85%) the effect of the infrastructure in increasing cycling. Path use also explained a decrease in cycling among more active commuters. CONCLUSION: The findings strengthen the causal argument that changing the environment led to changes in health-related behaviour via use of the new infrastructure, but also show how some commuters may have spent less time cycling as a result.

Towards a differentiated understanding of active travel behaviour: using social theory to explore everyday commuting.

Fostering physical activity is an established public health priority for the primary prevention of a variety of chronic diseases. One promising population approach is to seek to embed physical activity in everyday lives by promoting walking and cycling to and from work ('active commuting') as an alternative to driving. Predominantly quantitative epidemiological studies have investigated travel behaviours, their determinants and how they may be changed towards more active choices. This study aimed to depart from narrow behavioural approaches to travel and investigate the social context of commuting with qualitative social research methods. Within a social practice theory framework, we explored how people describe their commuting experiences and make commuting decisions, and how travel behaviour is embedded in and shaped by commuters' complex social worlds. Forty-nine semi-structured interviews and eighteen photo-elicitation interviews with accompanying field notes were conducted with a subset of the Commuting and Health in Cambridge study cohort, based in the UK. The findings are discussed in terms of three particularly pertinent facets of the commuting experience. Firstly, choice and decisions are shaped by the constantly changing and fluid nature of commuters' social worlds. Secondly, participants express ambiguities in relation to their reasoning, ambitions and identities as commuters. Finally, commuting needs to be understood as an embodied and emotional practice. With this in mind, we suggest that everyday decision-making in commuting requires the tactical negotiation of these complexities. This study can help to explain the limitations of more quantitative and static models and frameworks in predicting travel behaviour and identify future research directions.

A community prevention model to prevent children from inhaling and ingesting harmful legal products.

Children's misuse of harmful legal products (HLPs), including inhaling or ingesting everyday household products, prescription drugs, and over-the-counter drugs, constitutes a serious health problem for American society. This article presents a community prevention model (CPM) focusing on this problem among pre and early adolescents. The model, consisting of a community mobilization strategy and environmental strategies targeting homes, schools, and retail outlets, is designed to increase community readiness and reduce the availability of HLPs, which is hypothesized to reduce HLPs use among children. The CPM is being tested in Alaskan rural communities as part of an inprogress eight-year National Institute on Drug Abuse randomized-controlled trial. This paper presents the CPM conceptual framework, describes the model, and highlights community participation, challenges, and lessons learned from implementation of the model over a 21-month period.

Mothers' experiences of bottle-feeding: a systematic review of qualitative and quantitative studies.

OBJECTIVE: Most babies receive at least some formula milk. Variations in formula-feeding practices can have both short- and long-term health consequences. The literature on parents' experiences of bottle-feeding was systematically reviewed to understand how formula-feeding decisions are made. METHODS: Relevant English-language papers, identified by searching 12 electronic databases, reference lists and related articles and by contacting first authors of included papers, were systematically searched for and appraised. The included studies were analysed and synthesised using a combination of narrative and thematic approaches. Consensus on the final inclusion, interpretation and synthesis of studies was reached across the research team. RESULTS: Six qualitative studies and 17 quantitative studies (involving 13 263 participants) were included. Despite wide differences in study design, context, focus and quality, several consistent themes emerged. Mothers who bottle-fed their babies experienced negative emotions such as guilt, anger, worry, uncertainty and a sense of failure. Mothers reported receiving little information on bottle-feeding and did not feel empowered to make decisions. Mistakes in preparation of bottle-feeds were common. No studies examined how mothers made decisions about the frequency or quantity of bottle-feeds. CONCLUSIONS: Inadequate information and support for mothers who decide to bottle-feed may put the health of their babies at risk. While it is important to promote breastfeeding, it is also necessary to ensure that the needs of bottle-feeding mothers are met.

Population tobacco control interventions and their effects on social inequalities in smoking: systematic review.

OBJECTIVE: To assess the effects of population tobacco control interventions on social inequalities in smoking. DATA SOURCES: Medical, nursing, psychological, social science and grey literature databases, bibliographies, hand-searches and contact with authors. STUDY SELECTION: Studies were included (n = 84) if they reported the effects of any population-level tobacco control intervention on smoking behaviour or attitudes in individuals or groups with different demographic or socioeconomic characteristics. DATA EXTRACTION: Data extraction and quality assessment for each study were conducted by one reviewer and checked by a second. DATA SYNTHESIS: Data were synthesised using graphical ("harvest plot") and narrative methods. No strong evidence of differential effects was found for smoking restrictions in workplaces and public places, although those in higher occupational groups may be more likely to change their attitudes or behaviour. Smoking restrictions in schools may be more effective in girls. Restrictions on sales to minors may be more effective in girls and younger children. Increasing the price of tobacco products may be more effective in reducing smoking among lower-income adults and those in manual occupations, although there was also some evidence to suggest that adults with higher levels of education may be more price-sensitive. Young people aged under 25 are also affected by price increases, with some evidence that boys and non-white young people may be more sensitive to price. CONCLUSIONS: Population-level tobacco control interventions have the potential to benefit more disadvantaged groups and thereby contribute to reducing health inequalities.

Hospital based alternatives to acute paediatric admission: a systematic review.

AIMS: To synthesise published evidence of the impacts of introducing hospital based alternatives to acute paediatric admission. METHODS: Systematic review of studies of interventions for children with acute medical problems. Main outcome measures were: admission or discharge, unscheduled returns to hospital, satisfaction of parents and general practitioners, effects on health service activity, and costs. RESULTS: Twenty five studies were included: one randomised controlled trial, 23 observational or cross-sectional studies, and one qualitative study. Many studies were of uncertain quality or were open to significant potential bias. About 40% of children attending acute assessment units in paediatric departments, and over 60% of those attending acute assessment units in A&E departments, do not require inpatient admission. There is little evidence of serious clinical consequences in children discharged from these units, although up to 7% may subsequently return to hospital. There is some evidence that users are satisfied with these services and that they are associated with reductions in inpatient activity levels and certain hospital costs. Evidence about the impact of urgent outpatient clinics is very limited. CONCLUSIONS: Current evidence supports a view that acute paediatric assessment services are a safe, efficient, and acceptable alternative to inpatient admission, but this evidence is of limited quantity and quality. Further research is required to confirm that this type of service reorganisation does not disadvantage children and their families, particularly where inpatient services are withdrawn from a hospital.

Reducing social inequalities in smoking: can evidence inform policy? A pilot study.

OBJECTIVE: To assess the potential contribution of evidence from existing systematic reviews of effectiveness to answering the question: what works in reducing social inequalities in smoking? DATA SOURCE: The Cochrane Library (2002/4). STUDY SELECTION: Systematic reviews of the effectiveness of community based tobacco control interventions, and all the primary studies included in one of these reviews. DATA EXTRACTION: Reviews and primary studies were assessed for intent to assess the social distribution of intervention effects, information about the social inclusiveness or targeting of interventions, baseline sociodemographic data collected on participants, and estimates of effect size stratified by sociodemographic variables. DATA SYNTHESIS: Only one review aimed to examine outcomes stratified by sex, age or socioeconomic status, and these aims were only achieved with respect to sex. Sociodemographic data about participants were frequently collected in primary studies, but not used to compare intervention effects between social groups. CONCLUSIONS: There may be scope for using existing research more effectively to contribute to evidence based policy to reduce social inequalities in smoking-by explicitly seeking stratified outcome data in new systematic reviews, by re-analysing original datasets, and/or by meta-analysis of individual participant data.

The VEGF receptor tyrosine kinase inhibitor, ZD6474, inhibits angiogenesis and affects microvascular architecture within an orthotopically implanted renal cell carcinoma.

The proangiogenic vascular endothelial growth factor-A (VEGF) is essential for the development of new tumor vessels. ZD6474 is a novel inhibitor of VEGF receptor-2 (VEGFR-2) tyrosine kinase activity, which also has additional activity against epidermal growth factor (EGF) receptor tyrosine kinase. The antitumor activity of different schedules of ZD6474 in a clinically relevant, metastasizing, murine renal cell carcinoma (RENCA) model was evaluated in this study. RENCA cells were inoculated into the left kidney of 24 mice (day 0). Daily ZD6474 (50 mg/kg p.o.) treatment was initiated 1 day or 10 days after tumor cell inoculation and continued until day 21. Following treatment, kidney weight and volume were assessed and blood vessel density determined by CD31 staining. Visible metastases in the lungs, spleen, and lymph nodes were quantified using a dissection microscope. In an additional study, animals were treated according to the same regimen and quantitative three-dimensional microvascular corrosion casting was performed to enable detailed assessment of the tumor vascular architecture. Therapy initiated on day 1 or day 10 resulted in a 79% and 59% reduction in primary tumor volume, a 79% and 60% reduction in the number of lung metastases, and a 58% and 59% reduction in vessel density of primary tumors compared with the control group, respectively. Corrosion casting proved a 5.4- and 3.2-fold lower vascular volume compared with untreated tumors, observations that paralleled with significant architectural alterations. In this RENCA model, ZD6474 was a highly active inhibitor of tumor angiogenesis, primary tumor growth and tumor metastasis.

The angiogenic receptor KDR is widely distributed in human tissues and tumours and relocates intracellularly on phosphorylation. An immunohistochemical study.

AIMS: Angiogenesis is an important factor in tumour growth and metastasis. Vascular endothelial growth factor receptor 2 (VEGFR-2) or KDR plays a crucial role in angiogenesis. The aim of this study was to raise and characterize antibodies against phosphorylated KDR which could be used for studies on human tissues to assess KDR activation and novel inhibitors of KDR activation in clinical trials. METHODS AND RESULTS: Three monoclonal antibodies and one rabbit polyclonal antiserum were produced. The specificity of the antibodies was confirmed by ELISA. One of the mouse antibodies and the rabbit polyclonal antiserum reacted with a 200-kDa band on a Western blot of human umbilical vein endothelial cell (HUVEC) lysates, the molecular weight of KDR. Immunohistochemical staining showed that phosphorylated KDR is present in a wide variety of normal tissues including liver, colon and placenta, and is not restricted to endothelium. It was also present in a number of human tumours including breast carcinomas, colonic carcinomas and non-Hodgkin's lymphomas. The pattern of staining was membranous, cytoplasmic and nuclear. CONCLUSIONS: This study has shown that phosphorylated KDR is present in a wide variety of tumour and tissue types and is not confined to endothelium.

Early discharge of low-risk women from cervical screening.

BACKGROUND: The Scottish Cervical Screening Programme currently offers three-yearly screening to all women between the ages of 20 and 60. However, previous studies have indicated that well-screened women over the age of 50 are likely to be at low risk of cervical neoplasia. This study aimed to explore the implications of discharging these women from screening in a typical area of Scotland. METHODS: A case-control study of the screening histories of women with and without screen-detected cervical neoplasia between ages 50 and 59 in Lanarkshire was carried out, as well as a cross-sectional study of the prevalence of adequate screening histories among women currently aged 50 in Lanarkshire. Routine screening programme statistics were used to estimate the effects of introducing an early discharge policy. RESULTS: Women reaching the age of 50 with two recent, consecutive, negative smears had reduced odds of screen-detected neoplasia in the subsequent decade. The estimated odds ratio for all screen-detected neoplasia (CIN 1-3, adenocarcinoma in situ and invasive carcinoma) was 4.4 [95 per cent confidence interval (CI) 1.6-13.2, p = 0.002]. The estimated odds ratio for screen-detected high-grade CIN and invasive squamous carcinoma was 17.0 (95 per cent CI 2.4-243.0, p = 0.0004). A total of 54.0 per cent (95 per cent CI 47.9-59.9 per cent) of screening participants currently aged 50 fulfilled the definition of adequate screening. Discharging these women might be expected to reduce screening workload by approximately 10 per cent, but those discharged would be at increased risk of neoplasia. CONCLUSION: Now that full screening histories are available in all health board areas since 1990, the identification of a low-risk group within the screened population could be the first step towards a screening programme targeted more closely on those with the greatest capacity to benefit.

ZD4190: an orally active inhibitor of vascular endothelial growth factor signaling with broad-spectrum antitumor efficacy.

There is evidence that vascular endothelial growth factor (VEGF) contributes to solid tumor growth through the promotion of both angiogenesis and tumor vascular permeability. To abrogate VEGF signaling, we developed a small molecular weight inhibitor of VEGF receptor tyrosine kinase (RTK) activity that was compatible with chronic oral administration. ZD4190, a substituted 4-anilinoquinazoline, is a potent inhibitor of KDR and Flt-1 RTK activity, and VEGF stimulated HUVEC proliferation in vitro. Chronic once-daily oral dosing of ZD4190 to young rats produced a dose-dependent increase in the femoral epiphyseal growth plate area, which may be attributed to the inhibition of VEGF signaling in vivo because vascular invasion of cartilage is a prerequisite to the process of ossification. Once-daily oral dosing of ZD4190 to mice bearing established (approximately 0.5 cm3) human tumor xenografts (breast, lung, prostate, and ovarian) elicited significant antitumor activity and at doses that would not be expected to have any direct antiproliferative effect on tumor cells. Prolonged tumor cytostasis was further demonstrated in a PC-3 xenograft model with 10 weeks of ZD4190 dosing, and upon withdrawal of therapy, tumor growth resumed after a short delay. These observations are entirely consistent with the proposed mode of action. ZD4190 is one of a series of VEGF RTK inhibitors that may have utility in the treatment of a range of histologically diverse solid tumor types.

Elucidation of the mechanism of homozygous deletion of 3p12-13 in the U2020 cell line reveals the unexpected involvement of other chromosomes.

Homozygous deletions in tumor cells have been useful in the localization and validation of tumor suppressor genes. We have described a homozygous deletion in a lung cancer cell line (U2020) which is located within the most proximal of the three regions on the short arm of chromosome 3 believed to be lost in lung cancer development. Construction of a YAC contig map indicates that the deletion spans around 8 Mb, but no large deletion was apparent on conventional cytogenetic analysis of the cell line. To investigate this paradox, whole chromosome, arm-specific, and regional paints have been used. This analysis has revealed that genetic loss has occurred by complex rearrangements of chromosomes 3, rather than simple interstitial deletion. These studies emphasize the power of molecular cytogenetics to disclose unsuspected tumor-specific translocations within the extremely complex karyotypes characteristic of solid tumors.

Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors.

A series of substituted 4-anilinoquinazolines and related compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt and KDR) tyrosine kinase activity. Enzyme screening indicated that a narrow structure-activity relationship (SAR) existed for the bicyclic ring system, with quinazolines, quinolines, and cinnolines having activity and with quinazolines and quinolines generally being preferred. Substitution of the aniline was investigated and clearly indicated that small lipophilic substituents such as halogens or methyl were preferred at the C-4' position. Small substituents such as hydrogen and fluorine are preferred at the C-2' position. Introduction of a hydroxyl group at the meta position of the aniline produced the most potent inhibitors of Flt and KDR tyrosine kinases activity with IC(50) values in the nanomolar range (e.g. 10, 12, 13, 16, and 18). Investigation of the quinazoline C-6 and C-7 positions indicates that a large range of substituents are tolerated at C-7, whereas variation at the C-6 is more restricted. At C-7, neutral, basic, and heteroaromatic side chains led to very potent compounds, as illustrated by the methoxyethoxy derivative 13 (IC(50) < 2 nM). Our inhibitors proved to be very selective inhibitors of Flt and KDR tyrosine kinase activity when compared to that associated with the FGF receptor (50- to 3800-fold). Observed enzyme profiles translated well with respect to potency and selectivity for inhibition of growth factor stimulated proliferation of human umbilical vein endothelial cells (HUVECs). Oral administration of selected compounds to mice produced total plasma levels 6 h after dosing of between 3 and 49 microM. In vivo efficacy was demonstrated in a rat uterine oedema assay where significant activity was achieved at 60 mg/kg with the meta hydroxy anilinoquinazoline 10. Inhibition of growth of human tumors in athymic mice has also been demonstrated: compound 34 inhibited the growth of established Calu-6 lung carcinoma xenograft by 75% (P < 0.001, one tailed t-test) following daily oral administration of 100 mg/kg for 21 days.

Homozygous deletions at 3p12 in breast and lung cancer.

We have constructed a physical map of the region homozygously deleted in the U2020 cell line at 3p12, including the location of putative CpG islands. Adjacent to one of these islands, we have identified and cloned a new gene (DUTT1) and used probes from this gene to detect two other homozygous deletions occurring in lung and breast carcinomas: the smallest deletion is within the gene itself and would result in a truncated protein. The DUTT1 gene is a member of the neural cell adhesion molecule family, although its widespread expression suggests it plays a less specialized role compared to other members of the family.

Mapping of the gene encoding the B56 beta subunit of protein phosphatase 2A (PPP2R5B) to a 0.5-Mb region of chromosome 11q13 and its exclusion as a candidate gene for multiple endocrine neoplasia type 1 (MEN1).

The multiple endocrine neoplasia type 1 (MEN1) locus has been previously localised to 11q13 by combined tumour deletion mapping and recombination studies, and a 0.5-Mb region, flanked by PYGM and D11S449, has been defined. In the course of constructing a conting, we have identified the location of the gene encoding the B56 beta subunit of protein phosphatase 2A (PP2A), which is involved in cell signal transduction pathways and thus represents a candidate gene for MEN1. We have searched for mutations in the PP2A-B56 beta coding region, together with the 5' and 3' untranslated regions in six MEN1 patients. DNA sequence abnormalities were not identified and thus the PP2A-B56 beta gene is excluded as the candidate gene for MEN1. However, our precise localisation of PP2A-B56 beta to this region of 11q13 may help in elucidating the basis for other disease genes mapping to this generich region.