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.

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.

Collagenase secretion by human breast neoplasms: a clinicopathologic investigation.

Evidence is presented that biopsy specimens from fibroadenomas, benign cystic lesions, and carcinomas of the human breast can produce in organ culture a neutral protease capable of digesting type I collagen. This enzyme activity, measured with the use of a radioactive release assay, was characterized as true vertebrate collagenase and occurred in both active and latent (requiring trypsin activation) forms. For the two types of benign breast lesion studied, collagenase secretion was significantly higher from fibroadenomas than from benign cystic tissue. Breast carcinomas, however, exhibited a wide quantitative spectrum of collagenase secretion, encompassing the extremes observed for the benign lesions and showing no correlation with histologic type. These results, while providing a plausible mechanism for the marked collagen degradation seen in disseminating neoplasms, demonstrate that high collagenase secretory activity is not pathognomonic of invasive behavior. The findings, however, indicate disordered regulation of collagenase activity in malignant tumors.

Temperature-dependent elaboration of collagenase by the renal adenocarcinoma of the leopard frog, Rana pipiens.

Naturally occurring renal adenocarcinoma in North American leopard frogs, Rana pipiens, metastasize frequently (77%) when these ectothermic animals are kept in a warm environment but not when they are kept cold. We have found that explants of these tumors secrete collagenase, an enzyme capable of dissolving connective tissue fibers and found previously to be closely correlated with metastatic colony-forming capability of murine mammary tumors, and that the amount released sequentially rises and falls as the ambient temperature is shifted between metastasis-permissive and -inhibitory levels. In contrast, normal frog renal tissue has low collagenase output, unaffected by temperature changes.

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.

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.

Amplification and sequencing of genomic breakpoints located within the M-bcr region by Vectorette-mediated polymerase chain reaction.

The polymerase chain reaction (PCR) cannot be used to amplify the breakpoint in the chimaeric BCR-ABL gene in CML and acute leukaemias due to the large variation in the sites of breakpoint in the BCR gene (within a 5.8 kb region) and in the ABL gene (within a 150 kb region). The disease state is usually monitored using RNA-PCR to monitor abnormal transcripts. We have used a new modification of the PCR to amplify breakpoints within zone 3 of the M-bcr. A synthetic oligonucleotide linker, the Vectorette, is ligated to restriction digested DNA, and amplification is carried out between primers for a known target sequence and the Vectorette linker. Three Philadelphia chromosome Ph1-positive CML patients with breakpoints within the ALU region of zone 3 have been amplified and the sequence immediately around the breakpoint determined. The breaks occurred within 70 bp and two were only 14 bp apart. The Vectorette-PCR technique has the potential to rapidly identify and sequence breakpoints, and will enable the design of patient-specific primers to monitor disease progression, particularly following bone marrow transplantation.

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.

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.

Life satisfaction and identity structure in late middle-aged men and women.

A total of 32 retirement-age subjects (17 men and 15 women) provided information about their lives by rating each of their identities in terms of a list of self-generated features. They also rank-ordered their currently enacted identities in terms of time spent in each and completed a life-satisfaction questionnaire. The Identities X Features matrices were analyzed by algorithms that generated a hierarchical model of identity structure for each subject based on feature ratings. The hierarchical levels of identities were combined with time-spent rankings to obtain an index of personal style, a measure that reflected the unique organization of identities for each subject. Personal style indices were then correlated with life-satisfaction scores. Results confirmed the prediction that life satisfaction in this age group is a function of the amount of time spent in identities that give expression to multiple aspects of the self.

Alteration of thermoregulatory behavior in fish by 5-hydroxytryptamine.

Guppies were exposed for 30 min to doses of 5-HT ranging from 20 to 120 mg/l, and then tested in a horizontal temperature gradient. Atlantic salmon injected with 2 microgram/g of 5-HT were similarly tested. The guppies exhibited a biphasic relationship between 5-HT dose and mean selected temperature, i.e., the lowest dose significantly decreased the selected temperature, while the highest dose significantly increased it. In the salmon, injection of 5-HT initially decreased the selected temperature by about 4 degrees C. With time, however, the selected temperature gradually increased until by three hours after injection it exceeded the control value by about 1.5 degrees C. This pattern of temperature change is similar to that observed with rabbits subjected to both systemic and central injection of 5-HT.

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.

Intercellular junctions during development of the definitive kidney in lampreys: freeze fracture and morphometric analyses.

The changing morphology of intercellular junctions in renal morphogenesis during lamprey metamorphosis was followed using freeze-fracture replicas and morphometry. Gap junctions and particle aggregates among strands of occluding junctions are conspicuous in the differentiating podocytes of the renal corpuscle and in the early ciliated neck and proximal segments but not in the distal segment. The cells of the segmented nephron arise from alpha nephrogenic cells which have a focal aggregate (macula occludens) of 4.8 junctional strands. Upon the initiation of metamorphosis the number of strands increases to 8 in undifferentiated cells with either maculae or zonulae occludentes. Differentiation of both neck and proximal segments is accompanied by gradual transformation of a 7-strand zonula occludens to a 4-strand junction but it becomes more shallow in the latter segment. Two types of undifferentiated cell are recognized through five of the seven metamorphic stages. Cells of two types of distal segments begin differentiation at the midpoint of transformation and immediately show zonula occludens of different morphology. Distal segment I (pars recta) has 5 strands and a 0.250 microm depth whereas segment II has 8-9 strands with twice the apical-basal depth. The larval archinephric duct undergoes a moderate transformation in junctional morphology with the addition of 2 strands and no increase in apical-basal depth in zonulae occludentes during metamorphosis. Changes and development of types of intercellular junctions along the nephron in lampreys are discussed with reference to known regional functional specialization in this organism and with the morphology of renal tubular intercellular junctions in other vertebrates.

Ultrastructural features of degeneration of the gallbladder during lamprey biliary atresia.

Thin sections and freeze-fracture replicas were used to examine the fine structural features of degeneration of the gallbladder during lamprey biliary atresia. The cells of the epithelium undergo a progressive accumulation of dense bodies and vacuoles, loss of glycogen, condensation of the filamentous ectoplasm, fragmentation of microvilli, and dilation of cisternae of rough endoplasmic reticulum but eventually disappear by stage 4 of metamorphosis. Zonulae occludentes in the epithelium show a progressive increase in apical-basal depth as the junctional strands fragment. The possibility of an influence of transformed, subepithelial cells on degeneration of epithelial cells is suggested by close contact of the former with the thickened, highly pleated, epithelial basal lamina. The smooth muscle cells of the larval gallbladder are believed to transform during lamprey metamorphosis into these subepithelial cells which shed their external lamina, become intimately associated with collagen and other microfibrils, and which may be capable of phagocytosis. The events of gallbladder degeneration during lamprey metamorphosis show features of apoptosis.

Gap junctions and zonulae occludentes of hepatocytes during biliary atresia in the lamprey.

Gap junctions and zonulae occludentes of hepatocytes were examined in thin sections and freeze-fracture replicas from livers of larval and juvenile adult lampreys and during the phase of metamorphosis when bile ducts and bile canaliculi disappear (biliary atresia). Larvae possess zonulae occludentes at the canaliculi which are composed of one to five (mean = 2.81) junctional strands that provide a bile-blood barrier. Morphometry demonstrates that during biliary atresia the decreases in number of junctional strands and apico-basal depth of the zonulae occludentes are accompanied by an increase in the frequency of gaps or interruptions in the strands and in a breakdown of the bile-blood barrier. The zonulae occludentes completely disappear during metamorphosis and are not found in the adult liver. Gap junctions of the larval liver occupy 1% of the surface of the plasma membrane and have a mean area of 0.167 micron 2 but, following an initial decline in these parameters during early biliary atresia, they rise sharply in later stages of metamorphosis and in adults are 3.2% and 0.502 micron 2, respectively. The events of alteration in junctional morphology during lamprey biliary atresia is in many ways comparable to the changes in gap junctions and zonulae occludentes during experimental and pathological intra- and extrahepatic cholestasis in mammals.

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.