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Objective: Individuals with type 2 diabetes and depressive symptoms have poorer diabetes outcomes than those with diabetes alone, and there is need for improved understanding of the relationship between illness markers and depressive symptoms. The role of social support is well established; less is known about social comparisons (i.e. comparisons to others in the social environment), which are common and influential in chronic illness. The present study examined the mediating effects of social comparison and social support on the relationship between glycemic control and depressive symptoms., Method and Outcome Measures: Participants with physician-diagnosed type 2 diabetes (N = 185) completed an electronic survey about recent depressive symptoms, glycemic control (HbA1c), perceived social support, and social comparison., Results: Controlling for relevant covariates, social comparison and social support showed independent statistical mediation of the relationship between glycemic control and depressive symptoms (ps < 0.05). Path analysis also showed that including indirect pathways through social comparison and social support reduced the relationship between glycemic control and depressive symptoms to nonsignificance (β = 0.10, p = 0.14)., Conclusion: These findings demonstrate that social comparison plays a role in the relationship between diabetes regulation and depression, independent of social support. Greater attention to this aspect of the social environment may render better diabetes outcomes., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

The synthesis and resolution of a class of chiral organic fluorophores, axially chiral 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (Ax*-BODIPY), is described. Ax*-BODIPYs were prepared through a modular synthesis combined with a late stage Heck functionalisation. Resolution was achieved by preparative chiral HPLC. Absolute stereochemical assignment was performed by comparison of experimental ECD spectra with TD-DFT calculations.

Background: This paper presents two replications of a heuristic model for measuring environment in studies of gene-environment interplay in the etiology of young adult problem behaviors., Methods: Data were drawn from two longitudinal, U.S. studies of the etiology of substance use and related behaviors: the Raising Healthy Children study (RHC; N=1040, 47% female) and the Minnesota Twin Family Study (MTFS; N=1512, 50% female). RHC included a Pacific Northwest, school-based, community sample. MTFS included twins identified from state birth records in Minnesota. Both studies included commensurate measures of general family environment and family substance-specific environments in adolescence (RHC ages 10-18; MTFS age 18), as well as young adult nicotine dependence, alcohol and illicit drug use disorders, HIV sexual risk behavior, and antisocial behavior (RHC ages 24, 25; MTFS age 25)., Results: Results from the two samples were highly consistent and largely supported the heuristic model proposed by Bailey et al. (2011). Adolescent general family environment, family smoking environment, and family drinking environment predicted shared variance in problem behaviors in young adulthood. Family smoking environment predicted unique variance in young adult nicotine dependence. Family drinking environment did not appear to predict unique variance in young adult alcohol use disorder., Conclusions: Organizing environmental predictors and outcomes into general and substance-specific measures provides a useful way forward in modeling complex environments and phenotypes. Results suggest that programs aimed at preventing young adult problem behaviors should target general family environment and family smoking and drinking environments in adolescence., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O(6)-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a "reverse" binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these "reverse" binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.

Background: Although previous studies have revealed that preschool-aged children imitate both aggression and prosocial behaviors on screen, there have been few population-based studies designed to reduce aggression in preschool-aged children by modifying what they watch., Methods: We devised a media diet intervention wherein parents were assisted in substituting high quality prosocial and educational programming for aggression-laden programming without trying to reduce total screen time. We conducted a randomized controlled trial of 565 parents of preschool-aged children ages 3 to 5 years recruited from community pediatric practices. Outcomes were derived from the Social Competence and Behavior Evaluation at 6 and 12 months., Results: At 6 months, the overall mean Social Competence and Behavior Evaluation score was 2.11 points better (95% confidence interval [CI]: 0.78-3.44) in the intervention group as compared with the controls, and similar effects were observed for the externalizing subscale (0.68 [95% CI: 0.06-1.30]) and the social competence subscale (1.04 [95% CI: 0.34-1.74]). The effect for the internalizing subscale was in a positive direction but was not statistically significant (0.42 [95% CI: -0.14 to 0.99]). Although the effect sizes did not noticeably decay at 12 months, the effect on the externalizing subscale was no longer statistically significant (P = .05). In a stratified analysis of the effect on the overall scores, low-income boys appeared to derive the greatest benefit (6.48 [95% CI: 1.60-11.37])., Conclusions: An intervention to reduce exposure to screen violence and increase exposure to prosocial programming can positively impact child behavior.

Substitution at the 7-position of the chromen-4-one pharmacophore of 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one NU7441, a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, with allyl, n-propyl or methyl enabled the resolution by chiral HPLC of atropisomers. Biological evaluation against DNA-PK of each pair of atropisomers showed a marked difference in potency, with biological activity residing exclusively in the laevorotatory enantiomer.

Structure-activity relationships for the MDM2-p53 inhibitory activity of a series of A-ring substituted 2-N-benzyl-3-(4-chlorophenyl)-3-(1-(hydroxymethyl)cyclopropyl)methoxy)isoindolinones have been investigated, giving rise to compounds with improved potency over their unsubstituted counterparts. Isoindolinone A-ring substitution with a 4-chloro group for the 4-nitrobenzyl, 4-bromobenzyl and 4-cyanobenzyl derivatives (10a-c) and substitution with a 6-tert-butyl group for the 4-nitrobenzyl derivative (10j) were found to confer additional potency. Resolution of the enantiomers of 10a showed that potent MDM2-p53 activity resided in the (-)-enantiomer ((-)-10a; IC(50)=44 ± 6 nM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compounds 10a and (-)-10a increase p53 protein levels, activate p53-dependent MDM2 and p21 transcription in MDM2 amplified cells, and show improved selectivity for growth inhibition in wild type p53 cell lines over the parent compound., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 ± 0.01 μM). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)-R-enantiomer (74a; IC(50) = 0.17 ± 0.02 μM). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.

CDK2 inhibitory structure-activity relationships have been explored for a range of 5-substituted O(4)-alkylpyrimidines. Variation of the 5-substituent in the 2,6-diaminopyrimidine series confirmed the 5-nitroso substituent as optimal, and showed that 5-formyl and 5-acetyl substituents were also tolerated at this position. A series of O(4)-alkyl-N(2)-aryl-5-substituted-6-aminopyrimidines revealed interesting structure-activity relationships. In the 5-nitroso series, the optimum O(4)-alkyl substituents were cyclohexylmethyl or sec-butyl, combined with a 2-sulfanilyl group. By contrast, in the N(2)-arylsulfonamido-5-formyl series, the cyclohexylmethyl compound showed relatively poor activity compared with the sec-butyl derivative (22j, (R)-4-(4-amino-6-sec-butoxy-5-formylpyrimidin-2-ylamino)benzenesulfonamide; CDK2 IC(50) = 0.8 nM). Similarly, in the N(2)-arylsulfonamido-5-(hydroxyiminomethyl) series the O(4)-sec-butyl substituent conferred greater potency than the cyclohexylmethyl (23c, (rac)-4-(4-amino-6-sec-butoxy-5-(hydroxyiminomethyl)pyrimidin-2-ylamino)benzenesulfonamide; CDK2 IC(50) = 7.4 nM). The 5-formyl derivatives show selectivity for CDK2 over other CDK family members, and are growth inhibitory in tumour cells (e.g. 22j, GI(50) = 0.57 microM).

Substitution at the 3-position of the dibenzothiophen-4-yl ring of 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one NU7441, a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, with propyl, allyl or methyl enabled the separation by chiral HPLC of atropisomers. This is a consequence of restricted rotation about the dibenzothiophene-chromenone bond. Biological evaluation against DNA-PK of the pairs of atropisomers showed a marked difference in potency, with only one enantiomer being biologically active.

This paper describes the degree to which implementation of the Communities That Care (CTC) prevention operating system was reached in 22 communities in 2 countries: the US (12 communities) and the Netherlands (10 communities). Core elements of CTC and results from two implementation measures conducted in both countries are reported here. Similarities and differences of the implementation process are discussed.

An efficient synthesis of 2-substituted O(4)-cyclohexylmethyl-5-nitroso-6-aminopyrimidines from 6-amino-2-mercaptopyrimidin-4-ol has been developed and used to prepare a range of derivatives for evaluation as inhibitors of cyclin-dependent kinase 2 (CDK2). The structure-activity relationships (SARs) are similar to those observed for the corresponding O(6)-cyclohexylmethoxypurine series with the 2-arylsulfonamide and 2-arylcarboxamide derivatives showing excellent potency. Two compounds, 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2-hydroxyethyl)benzenesulfonamide (7q) and 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7s), were the most potent with IC50 values of 0.7 +/- 0.1 and 0.8 +/- 0.0 nM against CDK2, respectively. The SARs determined in this study are discussed with reference to the crystal structure of 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7j) bound to phosphorylated CDK2/cyclin A.

Raising Healthy Children is a cluster-randomized study of a school-based intervention aimed at preventing problem behaviors among children recruited into the project in the first or second grade of elementary school. Multilevel analysis was used to compare students in intervention and control schools with respect to whether they transferred out of their original schools. Students in intervention schools were less likely to transfer within the first 5 years of the project. A multilevel discrete-time survival model that included both time-varying and contextual variables revealed that the difference in hazard of transfer was greatest in the earlier years of the project.

Like their urban counterparts, adolescents from rural areas are at risk for health and behavior problems, including alcohol and other drug use. This study tested the effects on parenting practices of specific sessions of a parent-training intervention, Preparing for the Drug Free Years, designed to prevent adolescent substance abuse and other problem behaviors. Two hundred and nine rural families were randomly assigned to an intervention or a wait-list control condition. Analyses of covariance comparing adjusted posttest scores revealed that parents in the intervention condition reported significant improvements in parenting behaviors targeted by specific intervention sessions when compared with controls. Effects were most pronounced among mothers. No significant effects were found for nontargeted parenting behaviors, and targeted behaviors were most improved among parents attending relevant program sessions. These results strengthen the internal validity of the study and increase the plausibility that reported improvements were due to the intervention.

George Orwell's 'Big Brother' and Michel Foucault's 'panopticon' have dominated discussion of contemporary developments in surveillance. While such metaphors draw our attention to important attributes of surveillance, they also miss some recent dynamics in its operation. The work of Gilles Deleuze and Felix Guattari is used to analyse the convergence of once discrete surveillance systems. The resultant 'surveillant assemblage' operates by abstracting human bodies from their territorial settings, and separating them into a series of discrete flows. These flows are then reassembled in different locations as discrete and virtual 'data doubles'. The surveillant assemblage transforms the purposes of surveillance and the hierarchies of surveillance, as well as the institution of privacy.

The past decade has seen increasing recognition in prevention science of the need to move away from a black box approach to intervention evaluation and toward an approach that can elaborate on the mechanisms through which changes in the outcomes operate (Chen & Rossi, 1989; Durlak & Wells, 1997; Spoth et al., 1995). An approach that examines issues of program implementation is particularly critical in the design of efficacy studies of school-based preventive interventions. Numerous preventive intervention strategies are now delivered within the schools, often by regular classroom teachers. The extent to which teachers faithfully deliver a particular curriculum or incorporate instructional strategies emphasized by an intervention is a critical question for the overall project evaluation. This article illustrates the utilization of process measures from a multicomponent school-based prevention program to examine implementation of a teaching staff development intervention, and the program's underlying theoretical basis. Given the nested study design, the analyses utilize hierarchical linear models (Bryk & Raudenbush, 1992) to examine changes in teaching strategies by condition and investigate the hypothesized relationships between teaching practices and student behaviors based on the program's theoretical framework. Results suggest that teaching practices in two of the six intervention focus areas were positively impacted in the first 18 months of the project. Findings also support the relationships between teachers' instructional practices and students' behavior.

Aims: Children whose parents abuse drugs are exposed to numerous factors that increase the likelihood of future drug abuse. Despite this heightened risk, few experimental tests of prevention programs with this population have been reported. This article examines whether intensive family-focused interventions with methadone treated parents can reduce parents' drug use and prevent children's initiation of drug use., Design: Parents were assigned randomly into intervention and control conditions and assessed at baseline, post-test, and 6 and 12 months following the intervention. Children were assessed at baseline, and 6- and 12-month follow-up points., Setting: Two methadone clinics in Seattle, Washington., Participants: One hundred and forty-four methadone-treated parents, and their children (n = 178) ranging in age from 3 to 14 years old., Intervention: The experimental intervention supplemented methadone treatment with 33 sessions of family training combined with 9 months of home-based case management. Families in the control condition received no supplemental services., Measurement: Parent measures included: relapse and problem-solving skills, self-report measures of family management practices, deviant peer networks, domestic conflict and drug use. Child measures included self-report measures of rules, family attachment, parental involvement, school attachment and misbehavior, negative peers, substance use and delinquency., Findings: One year after the family skills training, results indicate significant positive changes among parents, especially in the areas of parent skills, parent drug use, deviant peers and family management. Few changes were noted in children's behavior or attitudes., Conclusions: Programs such as this may be an important adjunct to treatment programs, helping to strengthen family bonding and to reduce parents' drug use.

This paper examines the use of specific drugs as longitudinal predictors of violence between domestic partners in a sample of women in methadone treatment for opiate addiction. Crack cocaine use, use of other forms of cocaine, and tranquilizer use are each modestly to moderately positively associated with partner violence victimization. Women who were heavy users of these drugs were more likely to be hit, slapped, or shoved by their partners than light users or nonusers of these drugs. Three possible explanations of these associations are considered.

Aims: Many people treated for opiate addiction continue to use drugs during and after treatment. It may be possible to improve outcomes by addressing patient characteristics that predict continued drug use. This review uses meta-analytic techniques to identify risk factors for continued drug use in patients treated for opiate abuse., Design and Measurements: A thorough search of the published literature yielded 69 studies that reported information on the bivariate association between one or more independent variables and continued use of illicit drugs during and after treatment for opiate addiction., Findings: Most of the patient variables summarized have weak longitudinal relationships with continued drug use, although several variables display moderate longitudinal associations. Ten variables show statistically significant and longitudinally predictive relationships (average r > 0.1) with continued use, including: high level of pretreatment opiate/drug use, prior treatment for opiate addiction, no prior abstinence from opiates, abstinence from/light use of alcohol, depression, high stress, unemployment/employment problems, association with substance abusing peers, short length of treatment, and leaving treatment prior to completion. Several other variables may be potentially longitudinally predictive., Conclusions: To prevent relapse, treatment interventions should address multiple variables because no single variable strongly predicts continued drug use.

Parents in methadone treatment were offered an experimental intervention, Focus on Families, designed to reduce their risk of relapse and their children's risk of substance use. Experimentally assigned volunteers participated in systematic group training in relapse prevention and parenting skills, and received home-based case management services. Immediate posttreatment outcome results reported here include analyses of covariance controlling for baseline measures. Analyses show experimental parents held more family meetings to discuss family fun, displayed stronger refusal/relapse coping skills, demonstrated stronger sense of self-efficacy in role-play situations, and had lower levels of opiate use than control subjects. No significant differences in family bonding, family conflict, or other measures of drug use were found. The utility of intervening with drug-addicted parents in methadone treatment is discussed in light of these findings.

In May 1988, the authors initiated a risk-focused community mobilization project for drug abuse prevention. That project, TOGETHER! Communities for Drug Free Youth, is a state-wide collaboration involving 28 Washington communities. The project uses current research on risk and protective factors for adolescent drug abuse as its foundation. Through training and technical assistance, communities have been mobilized to design and implement comprehensive, risk-focused plans for adolescent drug abuse prevention. This paper describes the design of the project and examines the extent to which the participating communities formed planning teams that utilized an empirically based risk reduction approach in mobilizing to prevent drug abuse.

Evidence indicates that serious and persistent delinquency and the frequent use of illicit drugs emerge from common etiological roots. This suggests that treatment efforts which target risk factors of adolescent drug use and crime may be effective in preventing subsequent antisocial behavior. This paper describes Project ADAPT, a treatment program for juvenile delinquents based on the Social Development Model, which integrates this knowledge of risk factors. Project ADAPT is a 3 1/2-year demonstration project which combines behavioral skill training, supportive network development, and involvement in prosocial activities to facilitate the community reentry of youths following placement in a Washington state correctional facility.