A randomised controlled trial and cost-effectiveness evaluation of "booster" interventions to sustain increases in physical activity in middle-aged adults in deprived urban neighbourhoods

Background: Systematic reviews have identified a range of brief interventions which increase physical activity in previously sedentary people. There is an absence of evidence about whether follow up beyond three months can maintain long term physical activity. This study assesses whether it is worth providing motivational interviews, three months after giving initial advice, to those who have become more active. Methods/Design: Study candidates (n = 1500) will initially be given an interactive DVD and receive two telephone follow ups at monthly intervals checking on receipt and use of the DVD. Only those that have increased their physical activity after three months (n = 600) will be randomised into the study. These participants will receive either a "mini booster" (n = 200), "full booster" (n = 200) or no booster (n = 200). The "mini booster" consists of two telephone calls one month apart to discuss physical activity and maintenance strategies. The "full booster" consists of a face-to-face meeting with the facilitator at the same intervals. The purpose of these booster sessions is to help the individual maintain their increase in physical activity. Differences in physical activity, quality of life and costs associated with the booster interventions, will be measured three and nine months from randomisation. The research will be conducted in 20 of the most deprived neighbourhoods in Sheffield, which have large, ethnically diverse populations, high levels of economic deprivation, low levels of physical activity, poorer health and shorter life expectancy. Participants will be recruited through general practices and community groups, as well as by postal invitation, to ensure the participation of minority ethnic groups and those with lower levels of literacy. Sheffield City Council and Primary Care Trust fund a range of facilities and activities to promote physical activity and variations in access to these between neighbourhoods will make it possible to examine whether the effectiveness of the intervention is modified by access to community facilities. A one-year integrated feasibility study will confirm that recruitment targets are achievable based on a 10% sample.Discussion: The choice of study population, study interventions, brief intervention preceding the study, and outcome measure are discussed

The free moment in walking and its change with foot rotation angle

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Genome Wide Transcriptome Analysis of Dendritic Cells Identifies Genes with Altered Expression in Psoriasis

Activation of dendritic cells by different pathogens induces the secretion of proinflammatory mediators resulting in local inflammation. Importantly, innate immunity must be properly controlled, as its continuous activation leads to the development of chronic inflammatory diseases such as psoriasis. Lipopolysaccharide (LPS) or peptidoglycan (PGN) induced tolerance, a phenomenon of transient unresponsiveness of cells to repeated or prolonged stimulation, proved valuable model for the study of chronic inflammation. Thus, the aim of this study was the identification of the transcriptional diversity of primary human immature dendritic cells (iDCs) upon PGN induced tolerance. Using SAGESeq approach, a tag-based transcriptome sequencing method, we investigated gene expression changes of primary human iDCs upon stimulation or restimulation with Staphylococcus aureus derived PGN, a widely used TLR2 ligand. Based on the expression pattern of the altered genes, we identified non-tolerizeable and tolerizeable genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (Kegg) analysis showed marked enrichment of immune-, cell cycle- and apoptosis related genes. In parallel to the marked induction of proinflammatory mediators, negative feedback regulators of innate immunity, such as TNFAIP3, TNFAIP8, Tyro3 and Mer are markedly downregulated in tolerant cells. We also demonstrate, that the expression pattern of TNFAIP3 and TNFAIP8 is altered in both lesional, and non-lesional skin of psoriatic patients. Finally, we show that pretreatment of immature dendritic cells with anti-TNF-α inhibits the expression of IL-6 and CCL1 in tolerant iDCs and partially releases the suppression of TNFAIP8. Our findings suggest that after PGN stimulation/restimulation the host cell utilizes different mechanisms in order to maintain critical balance between inflammation and tolerance. Importantly, the transcriptome sequencing of stimulated/restimulated iDCs identified numerous genes with altered expression to date not associated with role in chronic inflammation, underlying the relevance of our in vitro model for further characterization of IFNprimed iDCs

Behavioral Inhibition and Attentional Control in Adolescents: Robust Relationships with Anxiety and Depression

Behavioral inhibition (BI) has been associated with the development of internalizing disorders in children and adolescents. It has further been shown that attentional control (AC) is negatively associated with internalizing problems. The combination of high BI and low AC may particularly lead to elevated symptomatology of internalizing behavior. This study broadens existing knowledge by investigating the additive and interacting effects of BI and AC on the various DSM-IV based internalizing dimensions. A sample of non-clinical adolescents (N = 1806, age M = 13.6 years), completed the Behavioral Inhibition System/Behavioral Activation System Scales (BIS/BAS), the attentional control subscale of the Adult Temperament Questionnaire (ATQ) and the Revised Child Anxiety and Depression Scale (RCADS). As expected, BI was positively, and AC was negatively related to internalizing dimensions, with stronger associations of BI than of AC with anxiety symptoms, and a stronger association of AC than of BI with depressive symptoms. AC moderated the association between BI and all measured internalizing dimensions (i.e., symptoms of generalized anxiety disorder, social phobia, separation anxiety disorder, panic disorder, obsessive–compulsive disorder, and major depressive disorder). Since high AC may reduce the impact of high BI on the generation of internalizing symptoms, an intervention focused on changing AC may have potential for prevention and treatment of internalizing disorders

Relapse to smoking during unaided cessation: Clinical, cognitive, and motivational predictors

Rationale: Neurobiological models of addiction suggest that abnormalities of brain reward circuitry distort salience attribution and inhibitory control processes, which in turn contribute to high relapse rates. Objectives: To determine whether impairments of salience attribution and inhibitory control predict relapse in a pharmacologically unaided attempt at smoking cessation. Methods: 141 smokers were assessed on indices of nicotine consumption / dependence (e.g. the FTND, cigarettes per day, salivary cotinine), and three trait impulsivity measures. After overnight abstinence they completed experimental tests of cue reactivity, attentional bias to smoking cues, response to financial reward, motor impulsiveness, and response inhibition (antisaccades). They then started a quit attempt with follow-up after 7 days, 1 month, and 3 months; abstinence was verified via salivary cotinine levels ≤ 20ng/ml. Results: Relapse rates at each point were 52.5%, 64% and 76.3%. The strongest predictor was pre-cessation salivary cotinine; other smoking / dependence indices did not explain additional outcome variance and neither did trait impulsivity. All experimental indices except responsivity to financial reward significantly predicted one week outcome. Salivary cotinine, attentional bias to smoking cues and antisaccade errors explained unique as well as shared variance. At one and three months, salivary cotinine, motor impulsiveness and cue reactivity were all individually predictive; the effects of salivary cotinine and motor impulsiveness were additive. Conclusions: These data provide some support for the involvement of abnormal cognitive and motivational processes in sustaining smoking dependence and suggest that they might be a focus of interventions, especially in the early stages of cessation. Dawkins L, Powell JH, Pickering AD, Powell JF, and West RJ (2009) Addiction 104, 850-

Predictive value of subclinical autistic traits at age 14–15 months for behavioural and cognitive problems at age 3–5 years

It is unclear whether subclinical autistic traits at very young age are transient or stable, and have clinical relevance. This study investigated the relationship between early subclinical autistic traits and the occurrence of later developmental and behavioural problems as well as problems in cognitive and language functioning. Parents of infants aged 14–15 months from the general population completed the Early Screening of Autistic Traits Questionnaire (ESAT). Three groups of children with high, moderate, and low ESAT-scores (total n = 103) were selected. Follow-up assessments included the CBCL 1½–5 at age 3 years, and the SCQ, the ADI-R, the ADOS-G, a non-verbal intelligence test, and language tests for comprehension and production at age 4–5 years. None of the children met criteria for autism spectrum disorder at follow-up. Children with high ESAT-scores at 14–15 months showed significantly more internalizing and externalizing problems at age 3 years and scored significantly lower on language tests at age 4–5 years than children with moderate or low ESAT-scores. Further, significantly more children with high ESAT-scores (14/26, 53.8%) than with moderate and low ESAT-scores (5/36, 13.9% and 1/41, 2.4%, respectively) were in the high-risk/clinical range on one or more outcome domains (autistic symptoms, behavioural problems, cognitive and language abilities). Subclinical autistic traits at 14–15 months predict later behavioural problems and delays in cognitive and language functioning rather than later ASD-diagnoses. The theoretical implications of the findings lie in the pivotal role of early social and communication skills for the development of self-regulation of emotions and impulses. The practical implications bear on the early recognition of children at risk for behavioural problems and for language and cognitive problems

Schizotypy and Behavioural Adjustment and the Role of Neuroticism

In the present study the relationship between behavioural adjustment following cognitive conflict and schizotypy was investigated using a Stroop colour naming paradigm. Previous research has found deficits with behavioural adjustment in schizophrenia patients. Based on these findings, we hypothesized that individual differences in schizotypy, a personality trait reflecting the subclinical expression of the schizophrenia phenotype, would be associated with behavioural adjustment. Additionally, we investigated whether such a relationship would be explained by individual differences in neuroticism, a non-specific measure of negative trait emotionality known to be correlated with schizotypy. 106 healthy volunteers (mean age: 25.1, 60% females) took part. Post-conflict adjustment was measured in a computer-based version of the Stroop paradigm. Schizotypy was assessed using the Schizotypal Personality Questionnaire (SPQ) and Neuroticism using the NEO-FFI. We found a negative correlation between schizotypy and post-conflict adjustment (r = -.30, p<.01); this relationship remained significant when controlling for effects of neuroticism. Regression analysis revealed that particularly the subscale No Close Friends drove the effect. Previous findings of deficits in cognitive control in schizophrenia patients were extended to the subclinical personality expression of the schizophrenia phenotype and found to be specific to schizotypal traits over and above the effects of negative emotionality

Phosphorylation Regulates SIRT1 Function

BACKGROUND: SIR2 is an NAD(+)-dependent deacetylase [1]-[3] implicated in the regulation of lifespan in species as diverse as yeast [4], worms [5], and flies [6]. We previously reported that the level of SIRT1, the mammalian homologue of SIR2 [7], [8], is coupled to the level of mitotic activity in cells both in vitro and in vivo[9]. Cells from long-lived mice maintained SIRT1 levels of young mice in tissues that undergo continuous cell replacement by proliferating stem cells. Changes in SIRT1 protein level were not associated with changes in mRNA level, suggesting that SIRT1 could be regulated post-transcriptionally. However, other than a recent report on sumoylation [10] and identification of SIRT1 as a nuclear phospho-protein by mass spectrometry [11], post-translational modifications of this important protein have not been reported. METHODOLOGY/PRINCIPAL FINDINGS: We identified 13 residues in SIRT1 that are phosphorylated in vivo using mass spectrometry. Dephosphorylation by phosphatases in vitro resulted in decreased NAD(+)-dependent deacetylase activity. We identified cyclinB/Cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates SIRT1. Mutation of two residues phosphorylated by Cyclin B/Cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in SIRT1-deficient cells [12], [13]. CONCLUSIONS/SIGNIFICANCE: Pharmacological manipulation of SIRT1 activity is currently being tested as a means of extending lifespan in mammals. Treatment of obese mice with resveratrol, a pharmacological activator of SIRT1, modestly but significantly improved longevity and, perhaps more importantly, offered some protection against the development of type 2 diabetes mellitus and metabolic syndrome [14]-[16]. Understanding the endogenous mechanisms that regulate the level and activity of SIRT1, therefore, has obvious relevance to human health and disease. Our results identify phosphorylation by cell cycle dependent kinases as a major mechanism controlling the level and function of this sirtuin and complement recent reports of factors that inhibit [17], [18] and activate [19] SIRT1 by protein-protein interactions

Progressive Telomere Dysfunction Causes Cytokinesis Failure and Leads to the Accumulation of Polyploid Cells

Most cancer cells accumulate genomic abnormalities at a remarkably rapid rate, as they are unable to maintain their chromosome structure and number. Excessively short telomeres, a known source of chromosome instability, are observed in early human-cancer lesions. Besides telomere dysfunction, it has been suggested that a transient phase of polyploidization, in most cases tetraploidization, has a causative role in cancer. Proliferation of tetraploids can gradually generate subtetraploid lineages of unstable cells that might fire the carcinogenic process by promoting further aneuploidy and genomic instability. Given the significance of telomere dysfunction and tetraploidy in the early stages of carcinogenesis, we investigated whether there is a connection between these two important promoters of chromosomal instability. We report that human mammary epithelial cells exhibiting progressive telomere dysfunction, in a pRb deficient and wild-type p53 background, fail to complete the cytoplasmatic cell division due to the persistence of chromatin bridges in the midzone. Flow cytometry together with fluorescence in situ hybridization demonstrated an accumulation of binucleated polyploid cells upon serial passaging cells. Restoration of telomere function through hTERT transduction, which lessens the formation of anaphase bridges by recapping the chromosome ends, rescued the polyploid phenotype. Live-cell imaging revealed that these polyploid cells emerged after abortive cytokinesis due to the persistence of anaphase bridges with large intervening chromatin in the cleavage plane. In agreement with a primary role of anaphase bridge intermediates in the polyploidization process, treatment of HMEC-hTERT cells with bleomycin, which produces chromatin bridges through illegimitate repair, resulted in tetraploid binucleated cells. Taken together, we demonstrate that human epithelial cells exhibiting physiological telomere dysfunction engender tetraploid cells through interference of anaphase bridges with the completion of cytokinesis. These observations shed light on the mechanisms operating during the initial stages of human carcinogenesis, as they provide a link between progressive telomere dysfunction and tetraploidy

Symptoms of Anxiety, Depression, and Aggression in Non-clinical Children: Relationships with Self-report and Performance-based Measures of Attention and Effortful Control

This study investigated the relation between the regulative trait of effortful control, and in particular attention control, and psychopathological symptoms in a sample of 207 non-clinical children aged 8–12 years. For this purpose, children completed self-report scales for measuring regulative traits and various types of psychopathological symptoms (i.e., anxiety, depression, and aggression) and were tested with a neuropsychological battery for measuring attention/effortful control capacity. Results indicated that self-report and performance-based measures of attention/effortful control were at best moderately correlated. Further, it was found that self-report indexes of attention/effortful control were clearly negatively related to psychopathological symptoms, which provides support for the notion that low regulation is associated with higher levels of psychopathology. Finally, the performance-based measure of attention/effortful control was not convincingly related to psychopathological symptoms