Neighbourhood socio-economic disadvantage and loneliness: the contribution of green space quantity and quality.

Disadvantaged areas experience higher levels of loneliness than advantaged areas, though studies rarely identify environmental determinants of neighbourhood inequity in loneliness. We studied the contribution of the quantity and quality of green space to neighbourhood inequity in loneliness in three buffer sizes (400 m, 800 m, 1600 m), using cross-sectional data from 3778 individuals aged 48-77 years old living in 200 neighbourhoods in Brisbane, Australia. Levels of loneliness were significantly higher in disadvantaged neighbourhoods, and these neighbourhoods had less green space and less access to quality green space. However, there was no evidence that neighbourhood disparities in green space contributed to the association between neighbourhood disadvantage and loneliness. Possible methodological and substantive reasons for this result are discussed.

Outdoor public recreation spaces and social connectedness among adolescents.

BACKGROUND: Outdoor public recreation spaces are important settings for leisure and physical activity. Adolescents' use of these spaces may contribute to social connectedness via social interaction with peers and the community in these settings. However, research on this topic is limited. This exploratory study examined associations of frequency of visitation and physical activity in outdoor public recreation spaces with social connectedness among adolescents in Melbourne, Australia. METHODS: Adolescents self-reported their frequency of visitation to parks, trails, beach/lake, and sports facilities; frequency of physical activity in a park, local street or path, and their street; and social connectedness. Separate analyses were conducted for visitation (n = 349, 15.4 ± 1.6 years, 58% female) and physical activity (n = 441, 15.4 ± 1.6 years, 59% female) using multilevel linear regression models. RESULTS: No significant associations were observed for frequency of visitation to a park (B = 0.86, 95% CI = - 0.26, 1.99), trails (B = 0.41, 95% CI = - 0.61, 1.44), beach/lake (B = - 0.44, 95% CI = - 1.46, 0.57), or sports facilities (B = 0.64, 95% CI = - 0.43, 1.70), nor for frequency of physical activity in their street (B = - 0.07, 95% CI = - 0.46, 0.31), local street/path (B = - 0.05, 95% CI = - 0.43, 0.33) or in a park (B = 0.23, 95% CI = - 0.14, 0.60) with adolescents' social connectedness. CONCLUSIONS: The findings did not support the hypothesis that visiting and being active in outdoor public recreation spaces are associated with adolescents' social connectedness. Future research should consider the duration and context of outdoor public recreation space use (e.g., sports, socialising, relaxing alone) and whether different types and/or a combination of public spaces are more/less conducive to social connectedness.

Correlates of dual trajectories of physical activity and sedentary time in youth: The UP & DOWN longitudinal study.

Trajectories of physical activity and sedentary time (SED) may differ between subgroups of youth. The aim of this study was to identify group-based dual trajectories of physical activity and SED and explore individual, social, and environmental correlates of these trajectories. Longitudinal data (three time points, baseline 2011-2012) of Spanish youth (n = 1597, mean age = 11.94 ± 2.52, 50.9% boys) were used. Moderate-to-vigorous physical activity (MVPA) and SED were assessed objectively at each time point, and 21 potential correlates were self-reported at baseline. Parallel process growth mixture models identified shared categorical latent groups, adjusting for school and age. Multinomial logistic regression models identified baseline correlates of a given trajectory. Four shared categorical latent groups were identified: (1) stable MVPA and decreasing SED (4%); (2) stable MVPA and increasing SED (3%); (3) consistently higher MVPA (18%); and (4) stable low MVPA and slight increase in SED (75%). Multinomial logistic regression models with group 3 as reference found: negative affect (RRR = 0.90, 95% CI 0.84-0.97), parental screen-time rules (RRR = 1.15, 95% CI 1.00-1.33), and household media equipment (RRR = 1.17, 95% CI 1.05-1.30) predicted likelihood of group 1 membership; cons of reducing SED (RRR = 2.70, 95% CI 1.77-4.10) predicted likelihood of group 2 membership; and co-participation in physical activity with friends (RRR = 0.80, 95% CI 0.69-0.94), fathers' modeling of TV viewing (RRR = 1.22, 95% CI 1.02-1.47), and household media equipment (RRR = 1.16, 95% CI 1.02-1.31) predicted likelihood of group 4 membership. Results suggest that strategies to improve MVPA and SED behaviors among youth may need to be multifaceted, targeting all levels of influence.

Eosinophilic Vasculitis.

PURPOSE OF REVIEW: Eosinophilic granulomatosis with polyangiitis (EGPA) represents a rare clinical entity, which is getting increasing attention and relevance in view of our better understanding and newer insights into its pathogenesis. Concomitantly better recognition and understanding of the immune pathophysiologic role of eosinophils provide a solid ground of their role on systemic inflammatory disorders and defense against infectious triggers, especially parasites. This review will focus on describing the physiopathology of eosinophils, as well as providing an in depth description of the natural history, clinical spectrum, and therapy of EGPA. RECENT FINDINGS: Several studies have aimed at finding useful biomarkers to monitor disease activity, and reported data have shown that eotaxin 3, IL25, IL33, and some eicosanoids to be promising options. Regarding therapeutic advances, recently published studies have revealed the efficacy of mepolizumab during induction and maintenance of EGPA. Recently published data confirmed earlier studies that the use of azathioprine during the induction phase is of no benefit during long-term follow-up. In addition, data from the REOVAS study, which uses rituximab, is still ongoing and apparently with promising results. Eosinophils are involved in several systemic inflammatory disorders, and recent gathered data provide support for their role in triggering EGPA. Better understanding of its pathophysiology should generate newer insights into the pathogenesis, biomarkers of disease activity, and therapeutic targets.

Does free public transit increase physical activity and independent mobility in children? Study protocol for comparing children's activity between two Finnish towns with and without free public transit.

BACKGROUND: Children's habitual physical activity, including active travel and catching public transit (walking and cycling to and from destinations), and independent mobility (mobility without an adult) have decreased. Public transit trips are physically active and can provide access to hobbies independent of parents, but there is no device-measured data about children's total physical activity time following the introduction of free public transit. Our aim is to compare physical activity and independent mobility between children living in two Finnish towns, one with a recently introduced free public transit system, and the other without free public transit. METHODS: The city of Mikkeli has provided free public transit for all comprehensive school children since 2017. Various districts from Mikkeli, and the reference town of Kouvola (towns from South-Eastern Finland with a comparative population size and geographical structure), are selected based on their accessibility and the availability of public transit services. Samples of 10-12-year-old children will be recruited through primary schools. We will compare moderate-to-vigorous physical activity time, sitting time (a thigh-worn Fibion® device) and independent mobility (a participatory mapping method, PPGIS) of children: 1) who live in towns with and without free public transit, 2) who live and go to school in districts with high vs. low perceived and objective access to free public transit, and 3) who report using vs. not using free public transit. In addition, ethnography will be used to get insights on the social and cultural effects of the free public transit on children's and parent's everyday life. DISCUSSION: There is a need for scalable solutions that can increase children's physical activity independent of their socioeconomic background or place of residence. This project will give information on how a political action to provide free public transit for children is associated with their total physical activity time and independent mobility patterns, therefore providing highly relevant information for political decision-making and for promoting independent physical activity in children.

Activity-related behavior typologies in youth: a systematic review.

BACKGROUND: Clusters of adolescents differentiated by patterns of physical activity and sedentary behavior (activity-related typologies) are common. Understanding both the characteristics of adolescents and modifiable correlates of these typologies, can help to develop interventions for those most at risk. This systematic review aimed to synthesize the socio-demographic characteristics and modifiable correlates of activity-related behavioral typologies among adolescents. METHODS: A systematic search of seven electronic databases was conducted to identify quantitative studies using person-oriented statistical approaches to identify activity-related behavioral typologies among 12-18 year-olds. This systematic review was registered in Prospero (registration number: CRD42016046879). RESULTS: Thirty-six studies met the inclusion criteria and were classified according to three sub-themes based on behaviors included in the typologies (1. physical activity and sedentary behavior only; 2. physical activity, sedentary behavior and risk-related behaviors; 3. physical activity, sedentary behavior and diet). Studies were mostly cross-sectional and relied on self-report measures. Methods were considerably heterogeneous, however results revealed some consistency in typologies within specific groups. For example, typologies characterized by unhealthy behavior patterns (e.g., characterized by physical inactivity, high sedentary behavior and poor diet or high risk-related behaviors) comprised more older adolescents. With the exception of socio-demographics (age, sex, body mass index and socio-economic status), very few correlates have been studied to date (mostly school-related behavioral factors and intrapersonal influences), with evidence largely from typologies comprised of physical activity, sedentary behavior and diet. CONCLUSIONS: More research is needed to assess a range of modifiable correlates associated with activity-related behavior typologies among adolescents. This will allow for more targeted interventions, to achieve long-lasting, positive behavior change in adolescent populations.

Built environment and physical activity among adolescents: the moderating effects of neighborhood safety and social support.

BACKGROUND: Increasing emphasis has been placed on improving physical activity levels through multilevel interventions. This study aims to examine moderating effects of neighborhood safety (crime and traffic) and social support (from parent and sibling/peer) for physical activity in the relationship between the built environment and moderate-to-vigorous physical activity (MVPA) outside school hours among adolescents in Melbourne. METHODS: Data were from the NEighbourhood Activity in Youth study conducted among adolescents in Melbourne, Australia (n = 358, 15.3 (SD = 1.5) years). MVPA outside school hours was assessed by accelerometer. Built environment features within 1 km and 2 km residential buffers including recreation facilities, park area, and walkability and its components were assessed using Geographic Information Systems. Neighborhood safety, social support for physical activity and sociodemographic information were self-reported by adolescents. Multilevel linear regression models were used to estimate associations. RESULTS: Support for physical activity from sibling/peer positively moderated the relationship between recreation facilities (1 km), residential density (2 km) and MVPA. Recreation facility (count within 2 km), walkability (1 km and 2 km) and residential density (1 km) had significant positive associations with MVPA outside school hours. CONCLUSION: The built environment appeared to have stronger facilitating effects on MVPA among adolescents who had favourable support for physical activity from their sibling or peer. Multilevel interventions that target the built environment and social factors are needed to promote MVPA outside school hours among adolescents.

Ecological correlates of activity-related behavior typologies among adolescents.

BACKGROUND: Adolescents engage in various combinations (typologies) of physical activity and sedentary behaviors, which impact their health and wellbeing in different ways. As such, there is a need to understand the factors that may inhibit or facilitate engagement in combinations of activity-related behaviors to help inform effective intervention strategies targeting those most in need. The aim of this study was to identify ecological correlates of adolescent physical activity and sedentary behavior typologies. METHODS: Cross-sectional study of 473 adolescents (15.0 ± 1.6 years, 41.4% boys) from 18 secondary schools in Melbourne, Australia. Intrapersonal, interpersonal and neighborhood-physical environmental factors were assessed via self-report surveys and Geographic Information Systems. Multinomial logistic regression models determined the relative risk ratio of membership of three homogenous activity-related behavior typologies based on the potential correlates. RESULTS: Higher levels of self-efficacy for physical activity, parental screen-time restriction rules, parental support for physical activity, sibling screen-time co-participation and perceptions of neighborhood pedestrian/traffic safety were associated with greater likelihood of adolescents being in the typology defined as highly active and low sedentary compared to the physically inactive, highly sedentary typology. Higher frequency of co-participation in screen-time with friends was associated with greater likelihood of adolescents being in the typology defined as moderately active, high screen-time compared to physically inactive, highly sedentary. CONCLUSIONS: A range of intrapersonal, interpersonal and environmental correlates appear to play a role in adolescent activity-related typology membership. The findings may inform public health interventions targeting unique adolescent subgroups most at risk of poor health outcomes based on their engagement in combinations of activity-related behaviors.

Is neighbourhood access to tobacco outlets related to smoking behaviour and tobacco-related health outcomes and hospital admissions?

OBJECTIVES: Although the harms of tobacco use are widely accepted, few studies have examined the relationship between access to tobacco outlets and hospital admissions. This study aimed to examine the relationship between neighbourhood access to tobacco outlets, smoking and hospital admissions and self-reported morbidity. METHODS: Responses as to smoking behaviour were obtained from 12,270 adult participants in Western Australia (2003-2009) and individually record-linked to hospital admissions and geographically linked to tobacco outlets. RESULTS: Neighbourhood access to tobacco outlets was marginally positively associated with being a current versus a past smoker. Tobacco outlet access was also positively associated with heart disease for smokers but not non-smokers. For smokers, each additional outlet within 1600m of home was associated with a 2% increase in the odds of heart disease. CONCLUSION: Smokers with greater access to tobacco outlets were more likely to be diagnosed with or admitted to hospital for heart disease. Regulating the density of tobacco outlets in the community has immense potential to improve health benefits and our results motivate the need for future longitudinal studies to confirm this hypothesis.

Does walkable neighbourhood design influence the association between objective crime and walking?

BACKGROUND: Few studies have investigated associations between objectively measured crime and walking, and findings are mixed. One explanation for null or counterintuitive findings emerges from criminology studies, which indicate that the permeable street layouts and non-residential land uses that underpin walkable neighbourhoods are also associated with more crime. This study examined associations between objective crime and walking, controlling for the characteristics of walkable neighbourhoods. METHODS: A population representative sample of adults (25-65 years) (n = 3,487) completed the Western Australian Health and Wellbeing Survey (2006-2008) demographic and walking frequency items. Objective environmental measures were generated for each participant's 400 m and 1600 m neighbourhood areas, including burglary, personal crime (i.e., crimes committed against people) in public space, residential density, street connectivity and local destinations. Log-linear negative binomial regression models were used to examine associations between crime and walking frequency/week, with progressive adjustment for residential density, street connectivity and local destinations. RESULTS: Burglary and personal crime occurring within a participant's 400 m and 1600 m neighbourhoods were positively and significantly associated with walking frequency. For example, for every additional 10 crimes against the person/year within 400 m of a participant's home, walking frequency increased by 8% (relative change = 1.077, p = 0.017). Associations remained constant after controlling for residential density and street connectivity, but attenuated after adjusting for local destinations (e.g., for personal crime in 400 m: relative change = 1.054, p = 0.104). This pattern of attenuation was evident across both crime categories and both neighbourhood sizes. CONCLUSIONS: The observed positive associations between objective crime and walking appear to be a function of living in a more walkable environment, as the presence of destinations has the capacity to both promote walking and attract crime. This study provides a plausible explanation for some mixed findings emerging from studies examining crime as a barrier to walking. In some settings, the hypothesised deterrent effect of crime on walking may be insufficient to outweigh the positive impacts of living in a more walkable environment.

Street connectivity and walking for transport: role of neighborhood destinations.

OBJECTIVE: Built environment attributes may be important determinants of physical activity. Greater street connectivity has been shown in several studies to be associated with adults' walking for transport (WFT). We examined the extent to which this association can be explained by the availability of utilitarian destinations. METHODS: Adults (n=2544) participating in the Physical Activity in Localities and Community Environments (PLACE) study in Adelaide, Australia during 2003-2004, reported their WFT and perceived distances to 16 utilitarian destinations. Connectivity was calculated as the ratio of the number of intersections to Census Collection District land area. Marginal models via generalized estimating equations were used and the product-of-coefficients test was used to test mediation effects. RESULTS: Connectivity was significantly associated with destination availability and with WFT frequency. The connectivity-WFT relationship was attenuated after taking availability of destinations into account, but remained significant. Availability of destinations accounted for 16% of the total effect of connectivity on WFT. CONCLUSIONS: Higher connectivity can be associated with more frequent WFT, partly because more utilitarian destinations are available in areas with well-connected street networks. Further clarification of these relationships and other pathways through which connectivity influences residents' walking can inform urban design initiatives to promote physical activity.

Dog walking is associated with more outdoor play and independent mobility for children.

OBJECTIVE: Dog ownership is positively associated with children's physical activity. It is plausible that dog-facilitated activity rather than dog ownership per se encourages children's physical activity behaviors. We examined relationships between dog walking and children's physical activity, and outdoor play and independent mobility. METHOD: Cross-sectional survey data from the 2007 Perth (Western Australia) TRavel, Environment, and Kids (TREK) project were analyzed for 727 10-12 year olds with a family dog. Weekly minutes of overall physical activity and walking, local walking and outdoor play were collected from children and parents. Children's weekly pedometer steps were measured. Independent mobility was determined by active independent travel to 15 local destinations. RESULTS: Overall, 55% of children walked their dog. After adjustment, more dog walkers than non-dog walkers walked in the neighborhood (75% vs. 47%), played in the street (60% vs. 45%) and played in the yard (91% vs. 84%) (all p ≤ 0.05). Dog walkers were more independently mobile than non-dog walkers (p ≤ 0.001). Dog walking status was not associated with overall physical activity, walking, or pedometer steps (p>0.05). CONCLUSIONS: Dog-facilitated play and physical activity can be an effective strategy for increasing children's physical activity. Dog walking may provide a readily accessible and safe option for improving levels of independent mobility.

The contribution of objective and perceived crime to neighbourhood socio-inequity in loneliness.

Loneliness tends to be more prevalent in socioeconomically disadvantaged neighbourhoods, yet few studies explore the environmental differences contributing to area-based inequity in loneliness. This study examined how perceived and objective crime contributed to differences in loneliness between advantaged and disadvantaged neighbourhoods. The study used cross-sectional data from 3749 individuals aged between 48 and 77 years, residing in 200 neighbourhoods in Brisbane, Australia. We found that participants in disadvantaged neighbourhoods reported higher levels of loneliness and perceived crime, and the most disadvantaged neighbourhoods also had highest prevalence of objective crime. However, while perceived and objective crime were positively correlated with loneliness, only perceived crime accounted for socio-economic inequity in loneliness. Consequently, perceived crime plays an important role in addressing loneliness in disadvantaged communities and requires equitable resourcing for multiple strategies that aim to decrease crime and increase perceived safety.

People living in hilly residential areas in metropolitan Perth have less diabetes: spurious association or important environmental determinant?

BACKGROUND: Variations in 'slope' (how steep or flat the ground is) may be good for health. As walking up hills is a physiologically vigorous physical activity and can contribute to weight control, greater neighbourhood slopes may provide a protective barrier to weight gain, and help prevent Type 2 diabetes onset. We explored whether living in 'hilly' neighbourhoods was associated with diabetes prevalence among the Australian adult population. METHODS: Participants (≥25 years; n = 11,406) who completed the Western Australian Health and Wellbeing Surveillance System Survey (2003-2009) were asked whether or not they had medically-diagnosed diabetes. Geographic Information Systems (GIS) software was used to calculate a neighbourhood mean slope score, and other built environment measures at 1600 m around each participant's home. Logistic regression models were used to predict the odds of self-reported diabetes after progressive adjustment for individual measures (i.e., age, sex), socioeconomic status (i.e., education, income), built environment, destinations, nutrition, and amount of walking. RESULTS: After full adjustment, the odds of self-reported diabetes was 0.72 (95% CI 0.55-0.95) and 0.52 (95% CI 0.39-0.69) for adults living in neighbourhoods with moderate and higher levels of slope, respectively, compared with adults living in neighbourhoods with the lowest levels of slope. The odds of having diabetes was 13% lower (odds ratio 0.87; 95% CI 0.80-0.94) for each increase of one percent in mean slope. CONCLUSIONS: Living in a hilly neighbourhood may be protective of diabetes onset or this finding is spurious. Nevertheless, the results are promising and have implications for future research and the practice of flattening land in new housing developments.

Neighborhood walkability and cardiometabolic risk factors in Australian adults: an observational study.

BACKGROUND: Studies repeatedly highlight associations between the built environment and physical activity, particularly walking. Fewer studies have examined associations with cardiometabolic risk factors, with associations with obesity inconsistent and scarce evidence examining associations with other cardiometabolic risk factors. We aim to investigate the association between neighborhood walkability and the prevalence of obesity, hypertension, hypercholesterolaemia, and type-2 diabetes mellitus. METHODS: Cross-sectional study of 5,970 adults in Western Australia. Walkability was measured objectively for a 1,600 m and 800 m neighborhood buffer. Logistic regression was used to assess associations overall and by sex, adjusting for socio-demographic factors. Mediation by physical activity and sedentary behavior was investigated. RESULTS: Individuals living in high compared with less walkable areas were less likely to be obese (1,600 m OR: 0.84, 95% CI: 0.7 to 1; 800 m OR: 0.75, 95% CI: 0.62 to 0.9) and had lower odds of type-2 diabetes mellitus at the 800 m buffer (800 m OR: 0.69, 95% CI: 0.51 to 0.93). There was little evidence for an association between walkability and hypertension or hypercholesterolaemia. The only significant evidence of any difference in the associations in men and women was a stronger association with type-2 diabetes mellitus at the 800 m buffer in men. Associations with obesity and diabetes attenuated when additionally adjusting for physical activity and sedentary behavior but the overall association with obesity remained significant at the 800 m buffer (800 m OR: 0.78, 95% CI: 0.64 to 0.96). CONCLUSIONS: A protective association between neighborhood walkability and obesity was observed. Neighborhood walkability may also be protective of type-2 diabetes mellitus, particularly in men. No association with hypertension or hypercholesterolaemia was found. This warrants further investigation. Findings contribute towards the accumulating evidence that city planning and policy related strategies aimed at creating supportive environments could play an important role in the prevention of chronic diseases.

Driving down daily step counts: the impact of being driven to school on physical activity and sedentary behavior.

This study investigated whether being driven to school was associated with lower weekday and weekend step counts, less active out-of-school leisure pursuits, and more sedentary behavior. Boys aged 10-13 years (n = 384) and girls aged 9-13 years (n = 500) attending 25 Australian primary schools wore a pedometer and completed a travel diary for one week. Parents and children completed surveys capturing leisure activity, screen time, and sociodemographics. Commute distance was objectively measured. Car travel was the most frequent mode of school transportation (boys: 51%, girls: 58%). After adjustment (sociodemographics, commute distance, and school clustering) children who were driven recorded fewer weekday steps than those who walked (girls: -1,393 steps p < .001, boys: -1,569 steps, p = .009) and participated in fewer active leisure activities (girls only: p = .043). There were no differences in weekend steps or screen time. Being driven to and from school is associated with less weekday pedometer-determined physical activity in 9- to 13-year-old elementary-school children. Encouraging children, especially girls, to walk to and from school (even for part of the way for those living further distances) could protect the health and well-being of those children who are insufficiently active.

Examining the Contribution of the Neighborhood Built Environment to the Relationship Between Neighborhood Disadvantage and Early Childhood Development in 205,000 Australian Children.

OBJECTIVE: We examined associations between neighborhood built environment features and early childhood development (ECD), and tested the contribution of the built environment to associations between neighborhood disadvantage and ECD. METHODS: Spatial neighborhood built environment measures were linked to participant addresses in the 2015 Australian Early Development Census (AEDC) for children ∼5 years old living in Australia's 21 most populous cities. The 2015 AEDC contains teacher-reported national data on five key child development domains for children in their first year of formal full-time schooling (approximately 5 years old). AEDC scores were classified as 'developmentally vulnerable' (≤10th centile). Using multilevel modeling, 44 built environment measures were tested with developmental vulnerability on at least one domain of the AEDC, adjusting for socioeconomic factors and neighborhood disadvantage. RESULTS: The dataset consisted of 205,030 children; 89.2% living in major cities. In major cities, children with more early childhood education and care services (OR 0.997) and preschool services (OR 0.991) exceeding Australian standards, and access to healthier food outlets within 3200 m of their home (OR 0.999) had decreased odds of developmental vulnerability, controlling for socioeconomic factors and neighborhood disadvantage. Neighborhood disadvantage remained significantly associated with developmental vulnerability after adjustment for child/family variables and neighborhood built environment characteristics. CONCLUSIONS: The neighborhood built environment had small effects on the neighborhood disadvantage-ECD relationship at the national level. Few built environment measures were associated with ECD. Small effects at the population level may have wide-ranging impacts; modifying the built environment at scale are promising levers for supporting good child outcomes.

The sequential exposure to jasmonate, salicylic acid and yeast extract promotes sanguinarine accumulation in Argemone mexicana cell cultures.

The effects of the sequential application of methyl jasmonate (MeJa), salicylic acid (SA) and yeast extract (YE) to Argemone mexicana cell cultures were compared to either the sole application of each elicitor, or to the three-partite mixture. The highest sanguinarine accumulation occurred using the sequential treatment (ninefold over unexposed control cultures), followed by the single application of YE (fivefold). The elicitor mixture produced less sanguinarine than sole exposure to YE but higher than MeJa alone. SA did not produce any effect. Transcripts corresponding to tyrosine decarboxylase and berberine bridge enzyme accumulated in treated cells, but did not correlate with alkaloid accumulation. Discrete epifluorescence foci, surrounding the nucleus and scattered throughout the cytoplasm of elicited cells, suggested the presence of alkaloid-accumulating vesicles which could participate in a mechanism to avoid sanguinarine toxicity.