Publications

The Social and Physical Environments

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Neighborhood Walkability and Sedentary Time in Belgian Adults

Background Sedentary behavior (too much sitting) has deleterious health consequences that are distinct from lack of physical activity (too little exercise). Purpose This study aimed to examine the associations of neighborhood walkability and sociodemographic factors with adults' self-reported and objectively assessed sedentary time. Methods This Belgian cross-sectional study was conducted between May 2007 and September 2008. Twenty-four neighborhoods were stratified on GIS-based walkability and neighborhood SES. In all, 1200 adults (aged 20–65 years; 50 per neighborhood; 42.7 [SD=12.6] years; 47.9% men) completed a sociodemographic survey and the International Physical Activity Questionnaire. They also wore an accelerometer for 7 days: Sedentary time was identified as accelerometer counts of less than 100 per minute. Statistical analyses were performed in 2009, using multilevel regression models, adjusted for physical activity levels and individual SES. Results Residents of high-walkable neighborhoods reported more sitting time than those of low-walkable neighborhoods (439.8 vs 403.4 minutes/day of daily sitting time, p<0.05). Living in high-walkable versus low-walkable neighborhoods was also associated with 2.9% more accelerometer-measured overall sedentary time (p<0.001). Being male, younger, unemployed, more highly educated, having a white-collar job (analysis for employed adults only), and living without children were all significantly associated with more sitting time. Conclusions Contrary to expectations, living in a high-walkable neighborhood was associated with higher levels of sedentary time. If future studies in other contexts confirm these associations, environmental and policy innovations aiming to promote physical activity may need to address the potential negative health impact of sedentary behavior.

From death receptor to reactive oxygen species and c‐Jun N‐terminal protein kinase: the receptor‐interacting protein 1 odyssey

Death receptors (DRs) are more than simple killers: they control cell growth, proliferation, and survival, thereby playing a pivotal role in immune and inflammatory responses. Some of these phenomena might be explained by aberrant reactive oxygen species (ROS) production and metabolism, which can lead to oxidative stress. A key signaling molecule of DR-initiated intracellular pathways, receptor-interacting protein 1 (RIP1), orchestrates a complex control of multiple responses and may link DR-associated signaling complexes to ROS production by mitochondria. Yet, RIP1 is also an important regulator of endogenous anti-oxidants and ROS scavenging enzymes, because it is required for nuclear factor kappaB activation that results in expression of anti-apoptotic and anti-oxidant proteins. Alteration of RIP1 function may result in ROS accumulation and abnormal c-Jun N-terminal protein kinase activation, affecting inflammatory responses, innate immunity, stress responses, and cell survival. These molecular mechanisms may be involved in neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases.

Young Adolescents’ Physical Activity In Five Locations As Measured Using GPS And Accelerometry

PURPOSE: To identify youths’ physical activity (PA) in 5 locations and investigate differences by participant factors. METHODS: 616 youth (14.2±1.5 years old; 49.2% girls; 31.6% non-White; 11.2% obese) were recruited from 311 census block groups in the Baltimore, MD and Seattle, WA regions. Participants wore an accelerometer and GPS tracking device for 7±2.6 days. GIS was used to classify GPS points as (1) at home (50 meter radial buffer), (2) at school (15 meter parcel buffer), (3) near home and (4) near school (both 1 kilometer street network buffers), and (5) at all other locations. Accelerometer and GPS data were time-matched and moderate to vigorous PA (MVPA) in each location was assessed using Evenson cut points. Mixed-effects regression tested differences in MVPA minutes in each location by gender, race/ethnicity, and obesity status. RESULTS: Mean daily minutes of MVPA was 38.0±28.1 overall, 7.4±14.1 at home, 11.3±18.2 at school, 5.5±13.7 near home, 2.7±9.5 near school, and 11.7±21.6 at other locations. 5.2±11.9% of time at home, 5.3±7.4% of time at school, 8.6±15.1% of time near home, 9.8±17.7% of time near school, and 6.2±11.5% of time at other locations was spent in MVPA. Boys had 22-56% more MVPA minutes than girls in all locations except near school (Fig 1). Non-White’s had 24-42% more MVPA minutes near home and near school than White non-Hispanics. Normal/overweight youth had 40-56% more MVPA minutes near home and at other locations than obese youth. CONCLUSION: Understanding where PA occurs can provide insight into creating more supportive environments for youth PA. Schools and other locations contributed the most to youths’ overall PA, but these locations were contributors to gender disparities. The low amount of neighborhood PA suggests need and potential for increasing youths’ PA and reducing obesity through interventions to support active travel.

Targeting of TAK1 by the NF-κB protein Relish regulates the JNK-mediated immune response in <i>Drosophila</i>

The molecular circuitry underlying innate immunity is constructed of multiple, evolutionarily conserved signaling modules with distinct regulatory targets. The MAP kinases and the IKK-NF-kappa B molecules play important roles in the initiation of immune effector responses. We have found that the Drosophila NF-kappa B protein Relish plays a crucial role in limiting the duration of JNK activation and output in response to Gram-negative infections. Relish activation is linked to proteasomal degradation of TAK1, the upstream MAP kinase kinase kinase required for JNK activation. Degradation of TAK1 leads to a rapid termination of JNK signaling, resulting in a transient JNK-dependent response that precedes the sustained induction of Relish-dependent innate immune loci. Because the IKK-NF-kappa B module also negatively regulates JNK activation in mammals, thereby controlling inflammation-induced apoptosis, the regulatory cross-talk between the JNK and NF-kappa B pathways appears to be broadly conserved.

Role for IKK2 in muscle: waste not, want not

Activation of transcription factor NF-kappaB, the major regulator of the inflammatory response, depends on the inhibitor of NF-kappaB kinase (IKK) complex, which is composed of 2 catalytic subunits, IKK1 and IKK2 (also known as IKKalpha and IKKbeta), and a regulatory subunit, IKKgamma (also known as NEMO). In this issue of the JCI, Mourkioti et al. show that muscle-specific disruption in mice of the gene encoding IKK2 prevents NF-kappaB activation in response to denervation or toxin-induced injury (see the related article beginning on page 2945). Importantly, this genetic manipulation prevents muscle wasting, thereby providing strong evidence in support of a major pathogenic role for inflammation in a variety of muscular dystrophies characterized by progressive muscle fiber degeneration.

Data from Myeloid IKKβ Promotes Antitumor Immunity by Modulating CCL11 and the Innate Immune Response

&lt;div&gt;Abstract&lt;p&gt;Myeloid cells are capable of promoting or eradicating tumor cells and the nodal functions that contribute to their different roles are still obscure. Here, we show that mice with myeloid-specific genetic loss of the NF-κB pathway regulatory kinase IKKβ exhibit more rapid growth of cutaneous and lung melanoma tumors. In a &lt;i&gt;BRAF&lt;sup&gt;V600E/PTEN&lt;sup&gt;−/−&lt;/sup&gt;&lt;/sup&gt;&lt;/i&gt; allograft model, IKKβ loss in macrophages reduced recruitment of myeloid cells into the tumor, lowered expression of MHC class II molecules, and enhanced production of the chemokine CCL11, thereby negatively regulating dendritic-cell maturation. Elevated serum and tissue levels of CCL11 mediated suppression of dendritic-cell differentiation/maturation within the tumor microenvironment, skewing it toward a Th2 immune response and impairing CD8&lt;sup&gt;+&lt;/sup&gt; T cell–mediated tumor cell lysis. Depleting macrophages or CD8&lt;sup&gt;+&lt;/sup&gt; T cells in mice with wild-type &lt;i&gt;IKKβ&lt;/i&gt; myeloid cells enhanced tumor growth, where the myeloid cell response was used to mediate antitumor immunity against melanoma tumors (with less dependency on a CD8&lt;sup&gt;+&lt;/sup&gt; T-cell response). In contrast, myeloid cells deficient in IKKβ were compromised in tumor cell lysis, based on their reduced ability to phagocytize and digest tumor cells. Thus, mice with continuous IKKβ signaling in myeloid-lineage cells (IKKβ&lt;sup&gt;CA&lt;/sup&gt;) exhibited enhanced antitumor immunity and reduced melanoma outgrowth. Collectively, our results illuminate new mechanisms through which NF-κB signaling in myeloid cells promotes innate tumor surveillance. &lt;i&gt;Cancer Res; 74(24); 7274–84. ©2014 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

Neighborhood built environment and socioeconomic status in relation to physical activity, sedentary behavior, and weight status of adolescents

Introduction The study examined the association of neighborhood walkability to multiple activity-related outcomes and BMI among adolescents and evaluated socioeconomic status as an effect modifier. Method Cross-sectional study, with adolescents recruited from neighborhoods that met criteria for a 2 × 2 matrix defined by high/low GIS-defined walkability and high/low median income. Adolescents aged 12–16 years (n = 928) were recruited from selected neighborhoods in Maryland and King County, Washington regions in 2009–2011. There were 50.4% girls, and 66.3% were non-Hispanic white, with no medical restrictions on physical activity (PA) or diets. Total PA and sedentary time was assessed by 7 days of accelerometer monitoring. Adolescents self-reported active transport, time spent on 6 sedentary behaviors, and height and weight, used to compute BMI percentiles. Mixed model linear and logistic regressions examined outcomes for association with walkability and income, adjusting for demographic covariates and clustering within block groups. Results Walkability was positively and significantly related to objectively-measured PA (p < .001) and more frequent walking for transportation (p < .001). Total self-reported sedentary time (p = .048) and TV time (p < .007) were negatively related to walkability. Time in vehicles was negatively related to walkability only among higher-income adolescents. Conclusions Neighborhood walkability was strongly and consistently associated with adolescents' objectively-assessed total physical activity and reported active transportation. A novel finding was that adolescents living in walkable neighborhoods reported less television time and less time in vehicles. Most results were similar across income categories. Results strengthen the rationale for recommendations to improve walkability.

Childrensʼ Physical Activity Places

Growing empirical evidence documents built environment effects on adults' physical activity, but little is known about environment effects on children's physical activity. Indeed, environments in which adults are active may differ significantly from the environments in which children are active, necessitating a sophisticated approach to public health and environment approaches to increase physical activity across the lifespan. Purpose To examine the relations between the number of places children are active and their levels of physical activity, neighborhood environment, and individual characteristics. Methods Parents of 201 children 4–18 years old were recruited from high and low walkable neighborhoods in King County, WA. Parents reported on the places where their children are active and the places' convenience to their home, their children's activity level, and individual characteristics. Results From a list of 15 potential places in which children could be active in a typical month, friends' homes, own yards, parks, and playgrounds were more frequently visited by children in order to be active than the street and gyms or other paid facilities. The number of places children went to be active was positively related to the number of activity-related facilities convenient to home (<10 minute walk from home) (p<.019), but the number of different children's activity places decreased with child age (p<.007). The number of places a child went to be active was positively related to their level of physical activity (p<.001). In contrast, children went to fewer places to be active when living in neighborhoods marked by environmental factors associated with higher adult physical activity, particularly adults walking for transport (e.g., higher residential density, higher land use mix) (p<.04). Conclusions Children's physical activity appears to benefit from a greater variety of places in which to be active and greater convenience of such activity places. However, the built environment in which adults are more active in the form of walking for transport may not necessarily translate into increased variety in the places in which children are active. Further evaluation of physical activity environments and the potential unique impact of such environments on children is warranted. Supported by NIH grant HL67350.

SUSTAINABILITY OF A HEALTH-RELATED PHYSICAL EDUCATION PROGRAM

Increasing physical activity in physical education (PE) classes is an important public health goal because large numbers of young people participate in PE. Several PE programs have been shown to be effective in promoting physical activity, but the next step is to disseminate programs widely. The present study assessed the sustainability of the SPARK PE program for elementary schools. Two hundred seventy-seven schools were identified that received SPARK training, materials, and follow-up assistance over one year prior to the survey. An independent evaluator sent two mailings to one teacher at all schools and received a 48 percent return rate (N = 111). Seventy-two percent were female, and 25 percent were PE specialists. Seventy-eight percent reported being current users of SPARK, and 75 percent of respondent had used SPARK more than 2 years. SPARK users conducted PE class more often (3.4 d/wk) than non-users (2.7 d/wk; p < 0.002). Use of SPARK was not related to teacher certification type, gender, years teaching, or school socioeconomic level. Physically active teachers were more likely to use SPARK (p < 0.03). Teachers were more likely to use SPARK if sufficient equipment was available (p < 0.03), and there was a trend for SPARK users to report more principal support for PE than non-users (p < 0.08). There was high sustainability of the SPARK program among teachers and schools of all types. Potential self-selection bias is a limitation. Ensuring adequate equipment and principal support for PE, and promoting teacher physical activity, may be ways of enhancing sustainability of health-related PE programs. Supported by International Life Sciences Institute and Childhood Obesity Prevention Initiative.

Objectively Measured Neighborhood Walkability and Change in Physical Activity in Older Japanese Adults: A Five-Year Cohort Study

This study investigated the longitudinal association between changes in older adults' physical activity and neighborhood walkability measured by geographic information systems (GISs, (ArcGIS, ESRI Inc., Redlands, CA, USA)).A mail survey was conducted for Japanese older adults who were randomly selected from three different settlement types. Data on walking, total moderate to vigorous physical activity (MVPA), and sociodemographic characteristics were collected at baseline (in 2010) and follow-up (in 2015). Multiple linear regression analyses were employed to assess the association between MVPA change and neighborhood walkability, adjusted for potential confounders. Effect sizes for independent variables on MVPA change were estimated.Data from 731 community-dwelling older adults (43.7% women) were analyzed. During the follow-up, older adults' MVPA was reduced by 94.4 min/week (-14.2%) on average (675.5 and 579.9 min/week in 2010 and 2015, respectively). Overall, older adults living in highly walkable areas showed a smaller reduction than those in low walkable areas (beta: 99.7 min/week, 95% confidence interval: 28.5⁻171.0). Similar associations were observed among those in the urban and suburban area, but not in the rural area. Walkability had larger effect sizes for explaining MVPA change than demographic characteristics. In addition, the findings for walking were similar to MVPA.Neighborhood walkability mitigated the 5-year reduction of walking and total MVPA among older adults, especially in urban areas.

Predictors of adoption and maintenance of vigorous physical activity in men and women

Background. This study examined predictors of adoption and maintenance of vigorous physical activity over time in a sample of 1,719 randomly selected women and men. Methods. Based on reported frequency of vigorous exercise in a mail survey at baseline, subjects were classified as sedentary (zero sessions per week), intermediate (one to two sessions per week), or active (three or more sessions per week). Results. On the same survey subjects reported on 25 potential determinants of physical activity based on a comprehensive learning model. Twenty-four months later, 85% of subjects were resurveyed, and their physical activity levels were classified. Within each baseline category and gender subgroup, predictors of follow-up physical activity were identified. In multivariate analyses, adoption of vigorous exercise by sedentary men was predicted by self-efficacy, age (inverse), and neighborhood environment (inverse). Adoption by sedentary women was predicted by education, self-efficacy, and friend and family support for exercise. Maintenance of vigorous physical activity was predicted by self-efficacy and age (inverse) for initially active men and by education for initially active women. Conclusion. These results suggest that factors influencing adoption are different for men and women, and there may be different factors influencing adoption versus maintenance of vigorous physical activity.

Nuclear IKKβ Is an Adaptor Protein for IκBα Ubiquitination and Degradation in UV-Induced NF-κB Activation

I kappa B kinase alpha (IKKα) activity is required for functional maturation of dendritic cells and acquired immunity to infection

Outcomes of a 12-Month Web-Based Intervention for Overweight and Obese Men

This study assessed the effect of a 1-year internet-based weight loss intervention for men.Four hundred forty-one overweight and obese men were randomized to intervention or delayed treatment. Participants completed a Web-based assessment of diet and physical activity behaviors and weekly tailored Web modules addressing weight-related behaviors.At 12 months compared to controls, intervention men decreased percent of energy from saturated fat and increased grams of fiber and fruit/vegetable servings per 1.000 kcal (p values < 0.001) and walked 16 min more per day (p < 0.05). No between-group differences in body mass index (BMI), weight, or waist circumference were seen, but among completers, men in the highest tertile of intervention participation had lower weight (98.74 vs. 102.37 kg), BMI (32.38 vs. 33.46), and waist circumference (42.17 vs. 43.47 cm) compared to men who participated less often.The intervention improved diet and activity behaviors, but weight loss occurred only for those with the highest adherence.

Einfluss von BMI und Körper-Kompositionsparametern auf die Effektivität von Immuncheckpoint-Inhibitoren im HCC

The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF

The activation of IkappaB kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-kappaB. IKK is a complex composed of three subunits: IKKalpha, IKKbeta, and IKKgamma (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKalpha and IKKbeta catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKalpha, IKKbeta, and the RING finger domain of TRAF2, and either IKKalpha or IKKbeta alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKgamma is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKgamma-deficient cells. Using TRAF2(-/-) cells, we demonstrated that the TNF-induced interaction between IKKgamma and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

Signal transduction by tumor necrosis factor and its relatives