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OBJECTIVE: During the past decades, a more cautious approach with respect to prescribing medication and physical exercise progressed toward evidence-based guidelines regarding the management of rheumatoid arthritis (RA). Currently, physical activity and other means to improve well-being and functioning are encouraged, and the disease is targeted earlier with more intensive and aggressive pharmacologic treatment. The current study examined whether psychological distress and physical disability in patients with RA reduced over the last 2 decades and whether this is explained by a reduction of disease activity. METHODS: From 1990-2011, consecutive patients with RA (n = 1,151, age range 17-86 years, 68% female, 62% rheumatoid factor positive) were monitored at diagnosis and after 3-5 years of treatment (followup). Depressed mood, anxiety, and physical disability were predicted in multiple linear regression analyses by year of assessment, disease activity, and patient demographics. RESULTS: Over the decades, depressed mood (P = 0.01), anxiety (P = 0.001), and physical disability (P = 0.02) reduced at diagnosis and within-treatment improvement of anxiety (P = 0.04) and physical disability (P < 0.001) increased. Percentages of patients with depressed mood, anxiety, and physical disability at followup changed from 25%, 23%, and 53%, respectively, 2 decades ago to 14%, 12%, and 31%, respectively, currently. After taking account of reduction in disease activity, the decrease in physical disability remained significant (P < 0.001). CONCLUSION: Over the last 2 decades, psychological distress and physical disability decreased. This favorable trend might partly be due to reduced disease activity. The results indicate that patients with RA have a better opportunity to live a valued life currently than 20 years ago.

Rationale Social play behavior is the most characteristic social behavior in young mammals. It is highly rewarding and crucial for proper neurobehavioral development. Despite the importance of genetic factors in normal and pathological social behaviors, little information is available about strain influences on social play. Objective and methods The aim of this study was to investigate differences in social play behavior, 50-kHz ultrasonic vocalizations (USVs) and their modulation by acute morphine and amphetamine administration in two rat strains widely used in behavioral pharmacology studies, i.e.,Wistar and Sprague– Dawley rats. Results Sprague–Dawley rats showed higher levels of social play thanWistar rats. In both strains, no correlation was found between the performance of social behaviors and the emission of 50-kHz USVs. In Wistar and Sprague–Dawley rats, morphine increased and amphetamine decreased social play. The effects of morphine, however, were more pronounced in Wistar than Sprague–Dawley animals. In both strains, morphine did not affect USV emission, while amphetamine increased it during cage exploration. In Sprague–Dawley rats only, amphetamine decreased USVs during social interaction. Conclusions Wistar and Sprague–Dawley rats differ in their absolute levels of social play behavior and 50-kHz USVs, and quantitative differences exist in their response to pharmacological manipulations of social play. The emission of 50-kHz USVs and the behavioral parameters thought to reflect rewarding social interactions in adolescent rats are dissociable.

OBJECTIVES: To examine in patients with early rheumatoid arthritis (RA) whether quality of life (QoL), independently of disease activity, is affected by tight control treatment strategy schemes. METHODS: In the Computer Assisted Management in Early RA (CAMERA) trials, patients with early RA, disease duration

ll volume presenta la condizione postcoloniale come uno dei fattori determinanti che danno forma alla vita quotidiana e alla cultura dell'Italia contemporanea. Esso identifica un'ampia varietà di discorsi, pratiche sociali e forme di produzione culturale specificatamente postcoloniali che trovano espressione nell'Italia di oggi. Questo volume collettaneo non si limita a una rilettura del passato coloniale ma sottolinea come le relazioni di potere poste in essere dal colonialismo siano perpetuate e corroborate nella società attuale. Esso stabilisce inoltre un rapporto di continuità tra il passato coloniale e altri fenomeni centrali per la formazione dell'identità italiana, quali le emigrazioni transoceaniche ed europee, la subalternità del Sud, le migrazioni interne, il rapporto con il Mediterraneo e l'immigrazione contemporanea. Attraverso l'analisi di studiosi e studiose che operano in un contesto internazionale e interdisciplinare, il volume introduce a pieno titolo gli studi postcoloniali come campo di indagine che ampia e arricchisce il dibattito teorico-critico sulla storia e la cultura italiane.

Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (ie, a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10- year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, −1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6–10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.

Social play behavior is the most vigorous and characteristic form of social interaction displayed by developing mammals. The laboratory rat is an ideal species to study this behavior, since it shows ample social play that can be easily recognized and quantified. In this chapter, we will first briefly describe the structure of social play behavior in rats. Next, we will discuss studies that used social isolation rearing during the period in life when social play is most abundant to investigate the developmental functions of social play behavior in rats, focusing on the consequences of play deprivation on social, cognitive, emotional, and sensorimotor development. Last, we will discuss the neural substrates of social play behavior in rats, with emphasis on the limbic corticostriatal circuits that underlie emotions and their influence on behavior.

In medieval towns, examples of personal writing appear more prevalent than in non-urban spaces. Certain urban milieus participating in written culture, however, have been the focus of more scholarship than others. Considering the variety among town dwellers, we may assume that literacy skills differed from one social group to another. This raises several questions: Did attitudes towards the written word result from an experience of the urban educational system? On which levels, and in which registers, did different groups of people have access to writing? The need and the usefulness of written texts may not have been the same for communities and for individuals. In this volume we will concentrate on the town dwellers’ personal documents. These documents include practical uses of writing by individuals for their own professional and religious ends, including testaments and correspondence. Besides written records belonging to the domain of ‘pragmatic literacy’, other kinds of texts were also produced in town. Was there any connection between practical literacy, literary (and historical) creativity and book production?

The shortage of sperm donors in formal settings (i.e., assisted reproduction clinics) and the availability of sperm donors in informal settings (such as through contacts on the internet) motivated us to investigate why men may prefer either a formal or an informal setting for sperm donation. Interviews with ten sperm donors and non-sperm donors yielded 55 reasons for sperm donation in the two settings. These reasons were categorized according to similarity by 14 sperm donors and non-sperm donors. These categorizations were then structured by means of hierarchical cluster analysis. Reasons favouring formal settings included being legally and physically protected, evading paternal feelings or social consequences, and having a simple, standardized procedure in terms of effort and fi nances. Reasons favouring informal settings related to engagement, the possibility to choose a recipient, lack of rules and regulations, having contact with the donor child, and having an (intimate) bond with the recipient. The overview of reasons identifi ed may help potential sperm donors decide on whether to donate in a formal or informal setting, and may fuel discussions by professionals about the most appropriate conditions and legislation for sperm donation in formal settings.

The cholinergic system has been implicated in visuospatial attention but the exact role remains unclear. In visuospatial attention, bias refers to neuronal signals that modulate the sensitivity of sensory cortex, while disengagement refers to the decoupling of attention making reorienting possible. In the current study we investigated the effect of facilitating cholinergic neurotransmission by nicotine (Nicorette Freshmint 2 mg, polacrilex chewing gum) on behavioral and electrophysiological indices of bias and disengagement. Sixteen non-smoking participants performed in a Visual Spatial Cueing (VSC) task while EEG was recorded. A randomized, single-blind, crossover design was implemented. Based on the scarce literature, it was expected that nicotine would specifically augment disengagement related processing, especially manifest as an increase of the modulation of the Late Positive Deflection (LPD) by validity of cueing. No effect was expected on bias related components (cue-locked: EDAN, LDAP; target-locked: P1 and N1 modulations). Results show weak indications for a reduction of the reaction time validity effect by nicotine, but only for half of the sample in which the validity effect on the pretest was largest. Nicotine reduced the result of bias as indexed by a reduced P1 modulation by validity, especially in subjects with strong peripheral responses to nicotine. Nicotine did not affect ERP manifestations of the directing of bias (EDAN, LDAP) or disengagement (LPD).

Early social experiences are of major importance for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause long-lasting behavioural impairments and increase the vulnerability for psychiatric disorders, such as drug addiction.The aim of this study was to investigate whether a lack of social experiences during the juvenile and early adolescent stage, when social play behaviour is highly abundant, alters cocaine self-administration in rats.Rats were socially isolated from postnatal days 21 to 42 followed by re-socialization until adulthood. Cocaine self-administration was then assessed under a fixed ratio and progressive ratio schedule of reinforcement. Next, cue, cocaine and stress-induced reinstatement of cocaine seeking was determined following extinction of self-administration.Early social isolation resulted in an enhanced acquisition of self-administration of a low dose (0.083 mg/infusion) of cocaine, but the sensitivity to cocaine reinforcement, assessed using a dose-response analysis, was not altered in isolated rats. Moreover, isolated rats displayed an increased motivation for cocaine under a progressive ratio schedule of reinforcement. Extinction and reinstatement of cocaine seeking was not affected by early social isolation.Early social isolation causes a long-lasting increase in the motivation to self-administer cocaine. Thus, aberrations in post-weaning social development, such as the absence of social play, enhance the vulnerability for drug addiction later in life.

In medieval towns, examples of personal writing appear more prevalent than in non-urban spaces. Certain urban milieus participating in written culture, however, have been the focus of more scholarship than others. Considering the variety among town dwellers, we may assume that literacy skills differed from one social group to another. This raises several questions: Did attitudes towards the written word result from an experience of the urban educational system? On which levels, and in which registers, did different groups of people have access to writing? The need and the usefulness of written texts may not have been the same for communities and for individuals. In this volume we will concentrate on the town dwellers’ personal documents. These documents include practical uses of writing by individuals for their own professional and religious ends, including testaments and correspondence. Besides written records belonging to the domain of ‘pragmatic literacy’, other kinds of texts were also produced in town. Was there any connection between practical literacy, literary (and historical) creativity and book production?

Impulsivity and compulsivity represent useful conceptualizations that involve dissociable cognitive functions, which are mediated by neuroanatomically and neurochemically distinct components of cortico-subcortical circuitry. The constructs were historically viewed as diametrically opposed, with impulsivity being associated with risk-seeking and compulsivity with harm-avoidance. However, they are increasingly recognized to be linked by shared neuropsychological mechanisms involving dysfunctional inhibition of thoughts and behaviors. In this article, we selectively review new developments in the investigation of the neurocognition of impulsivity and compulsivity in humans, in order to advance our understanding of the pathophysiology of impulsive, compulsive, and addictive disorders and indicate new directions for research.

OBJECTIVES: To examine in patients with early rheumatoid arthritis (RA) whether quality of life (QoL), independently of disease activity, is affected by tight control treatment strategy schemes. METHODS: In the Computer Assisted Management in Early RA (CAMERA) trials, patients with early RA, disease duration

The objectives were to conduct a meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards to determine effect sizes (Cohen's d) for cognitive dysfunction in adults with type 2 diabetes, relative to nondiabetic controls, and to obtain effect sizes for the most commonly reported neuropsychological tests within domains. Twenty-four studies, totaling 26,137 patients (n = 3351 with diabetes), met study inclusion criteria. Small to moderate effect sizes were obtained for five of six domains: motor function (3 studies, n = 2374; d = −0.36), executive function (12 studies, n = 1784; d = −0.33), processing speed (16 studies, n = 3076; d = −0.33), verbal memory (15 studies, n = 4,608; d = −0.28), and visual memory (6 studies, n = 1754; d = −0.26). Effect size was smallest for attention/concentration (14 studies, n = 23,143; d = −0.19). The following tests demonstrated the most notable performance decrements in diabetes samples: Grooved Pegboard (dominant hand) (d = −0.60), Rey Auditory Verbal Learning Test (immediate) (d = −0.40), Trails B (d = −0.39), Rey-Osterreith Complex Figure (delayed) (d = −0.38), Trails A (d = −0.34), and Stroop Part I (d = −0.28). This study provides effect sizes to power future epidemiological and clinical diabetes research studies examining cognitive function and to help inform the selection of neuropsychological tests. (JINS, 2014, 20, 1–14)

Dysregulation of the immune system may play a role in chronic pain, although study findings are inconsistent. This cross-sectional study examined whether basal inflammatory markers and the innate immune response are associated with the presence and severity of chronic multisite musculoskeletal pain. Data were used on 1632 subjects of the Netherlands Study of Depression and Anxiety. The Chronic Pain Grade questionnaire was used to determine the presence and severity of chronic multisite musculoskeletal pain. Subjects were categorized in a chronic multisite musculoskeletal pain group (n = 754) and a control group (n = 878). Blood levels of the basal inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-alpha were determined. To obtain a measure of the innate immune response, 13 inflammatory markers were assessed after lipopolysaccharide (LPS) stimulation in a subsample (n = 707). Subjects with chronic multisite musculoskeletal pain showed elevated levels of basal inflammatory markers compared with controls, but statistical significance was lost after adjustment for lifestyle and disease variables. For some LPS-stimulated inflammatory markers, we did find elevated levels in subjects with chronic multisite musculoskeletal pain both before and after adjustment for covariates. Pain severity was not associated with inflammation within chronic pain subjects. An enhanced innate immune response in chronic multisite musculoskeletal pain may be examined as a potential biomarker for the onset or perpetuation of chronic pain. © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Hemispatial neglect is the failure to report, respond to, or orient to novel or meaningful stimuli presented in the contralesional visual field. This failure cannot be attributed to motor or sensory defects (Heilman and Valenstein, 1979). It constitutes one of the most invalidating neurological disorders that can occur after stroke. As discussed in this Research Topic, patients with neglect are less independent in various activities of daily living compared to patients without neglect (Nijboer et al., 2013). It is therefore important to treat neglect as adequately as possible and much of the research dedicated to neglect therefore focuses on rehabilitation. Here we provide a brief overview of the 29 articles featured in this Research Topic.

This article examines the validity of the assumption that employees' perceptions of those people management activities of their supervisor that impact on employees' abilities, motivation and opportunities to perform influence employee extra-role behaviour. The results of a longitudinal survey with data from 3,368 employees provide support for this assumption. This study's distinctive features - the concept of people management that involves the management of HR implementation, the longitudinal research design, and the use of the AMO framework for specifying the linkages between HRM and performance - make it possible to address the core questions in the HRM-performance debate that still remain unanswered according to Guest. © 2013 John Wiley & Sons Ltd.

Objective: Neuropeptide Y (NPY), given centrally augments food intake and the motivation to work for palatable food. Here, the brain regions were identified through which NPY increases food intake and motivation. Methods: NPY was infused into three brain regions implicated in food intake and motivation: the lateral hypothalamus (LH), nucleus accumbens shell (NAc), and ventral tegmental area (VTA). Motivation for sucrose was assessed using a progressive-ratio schedule of reinforcement in which the effort to obtain successive rewards increased incrementally. To disentangle the effects of NPY on motivation for palatable food from food consumption, free-feeding experiments were performed in which animals had ad libitum access to sucrose pellets. Results: Infusion of NPY into either VTA or NAc increased the motivation to respond for sucrose, whereas infusion of NPY in either NAc or LH increased sucrose consumption. In addition, the effect of intra-VTA NPY on motivation for food was attenuated after pretreatment with the dopamine receptor antagonist alpha-flupenthixol. Conclusions: Specific limbic substrates through which NPY influences consumption of and motivation for palatable food were identified by these data. The motivational effects of NPY are exerted through the VTA, its consummatory effects through the LH, and the NAc is involved in both.

Social play behavior is the most vigorous and characteristic form of social interaction displayed by developing mammals. The laboratory rat is an ideal species to study this behavior, since it shows ample social play that can be easily recognized and quantified. In this chapter, we will first briefly describe the structure of social play behavior in rats. Next, we will discuss studies that used social isolation rearing during the period in life when social play is most abundant to investigate the developmental functions of social play behavior in rats, focusing on the consequences of play deprivation on social, cognitive, emotional, and sensorimotor development. Last, we will discuss the neural substrates of social play behavior in rats, with emphasis on the limbic corticostriatal circuits that underlie emotions and their influence on behavior.

for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause longlasting behavioural impairments and increase the vulnerability for psychiatric disorders, such as drug addiction. Objectives The aim of this study was to investigate whether a lack of social experiences during the juvenile and early adolescent stage, when social play behaviour is highly abundant, alters cocaine self-administration in rats. Methods Rats were socially isolated from postnatal days 21 to 42 followed by re-socialization until adulthood. Cocaine selfadministration was then assessed under a fixed ratio and progressive ratio schedule of reinforcement. Next, cue, cocaine and stress-induced reinstatement of cocaine seeking was determined following extinction of self-administration. Results Early social isolation resulted in an enhanced acquisition of self-administration of a low dose (0.083mg/infusion) of cocaine, but the sensitivity to cocaine reinforcement, assessed using a dose–response analysis, was not altered in isolated rats. Moreover, isolated rats displayed an increased motivation for cocaine under a progressive ratio schedule of reinforcement. Extinction and reinstatement of cocaine seeking was not affected by early social isolation. Conclusions Early social isolation causes a long-lasting increase in the motivation to self-administer cocaine. Thus, aberrations in post-weaning social development, such as the absence of social play, enhance the vulnerability for drug addiction later in life.

Background: The inflammatory hypothesis of schizophrenia is not new, but recently it has regained interest because more data suggest a role of the immune system in the pathogenesis of schizophrenia. If increased inflammation of the brain contributes to the symptoms of schizophrenia, reduction of the inflammatory status could improve the clinical picture. Lately, several trials have been conducted investigating the potential of anti-inflammatory agents to improve symptoms of schizophrenia. This study provides an update regarding the efficacy of anti-inflammatory agents on schizophrenic symptoms in clinical studies performed so far. Methods: An electronic search was performed using PubMed, Embase, the National Institutes of Health web site http://www.clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. Only randomized, double-blind, placebo-controlled studies that investigated clinical outcome were included. Results: Our search yielded 26 double-blind randomized controlled trials that provided information on the efficacy on symptom severity of the following components: aspirin, celecoxib, davunetide, fatty acids such as eicosapentaenoic acids and docosahexaenoic acids, estrogens, minocycline, and N-acetylcysteine (NAC). Of these components, aspirin (mean weighted effect size [ES]: 0.3, n = 270, 95% CI: 0.06–0.537, I2 = 0), estrogens (ES: 0.51, n = 262, 95% CI: 0.043–0.972, I2 = 69%), and NAC (ES: 0.45, n = 140, 95% CI: 0.112–0.779) showed significant effects. Celecoxib, minocycline, davunetide, and fatty acids showed no significant effect. Conclusion: The results of aspirin addition to antipsychotic treatment seem promising, as does the addition of NAC and estrogens. These 3 agents are all very broadly active substances, and it has to be investigated if the beneficial effects on symptom severity are indeed mediated by their anti-inflammatory aspects.

The effects of variables derived from a work stress theory (the effort-reward imbalance theory) on the power in the high frequency (HF_HRV) band of heart rate (0.14-0.40 Hz) throughout a work day, were determined using multilevel analysis. Explanatory variables were analysed at two levels: at the lowest level (within-day level), the effects of positive mood, negative mood, demand, satisfaction, demand-satisfaction ratio, and time of day were assessed. At the highest level (the subject level), the effects of sleep quality, effort, reward, effort-reward imbalance, need for control, type of work (profession), negative affectivity, gender and smoking on HF_HRV were assessed. Need for control has a negative effect on HF_HRV after controlling for time of day effects, i.e. subjects with a high need for control have a lower vagal control of the heart. In the long run, these subjects may be considered to be at increased health risk, because they have less of the health protective effects of vagal tone. The interaction between effort-reward imbalance and time of day has a positive effect on HF_HRV, i.e, the cardiac vagal control of subjects with a high effort-reward imbalance increases as the day progresses. It is discussed that this probably reflects reduced effort allocation, ensuing from disengagement from the work demands. (C) 2001 Elsevier Science B.V. All rights reserved.

The loss of a marital partner results in substantial increases in morbidity and mortality among both men and women, but the effects are relatively greater for widowers than for widows in the acute grieving period. Evidence is reviewed, and explanations of the pattern are examined. An interpretation in terms of gender differences in social support (cf. M. Stroebe & W. Stroebe, 1983 ), although plausible, has not yet been empirically confirmed. Likewise, with respect to gender differences in coping styles, women are more confrontive and expressive of their emotions than men, but there has been little validation of the generally accepted grief work hypothesis (working through grief by women brings about their better recovery). Cognitive processes underlying effective coping with bereavement are analyzed, and a stressor-specific framework, the dual-process model of coping with loss, is suggested to help explain gender differences in health outcomes.

In the public administration discipline, there have been a number of important studies on leadership. However, here, scholarly inquiry still lags behind related disciplines such as psychology and business administration. This article contributes by analyzing the role public leaders can play in making work more meaningful for their employees, which in turn positively influences employees’ job outcomes. More specifically, it analyzes the mediating role of work meaningfulness in the relationships between Leader-Member Exchange (LMX) and organizational commitment, work effort, and work-to-family enrichment. Samples from education, healthcare, and local government are used. Results show firstly that leadership strongly influences work meaningfulness, which in turn influences job outcomes. Secondly, it was found that the impact and extent of leadership and work meaningfulness are higher in healthcare and education than in local government. The results emphasize the importance of leadership and meaningful work in the public sector.

Previous findings have suggested that the nosocomial transmission capacity of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) is lower than that of other MRSA genotypes. We therefore performed a 6-month (June 1–November 30, 2011) nationwide study to quantify the single-admission reproduction number, RA, for LA-MRSA in 62 hospitals in the Netherlands and to compare this transmission capacity to previous estimates. We used spa typing for genotyping. Quantification of RA was based on a mathematical model incorporating outbreak sizes, detection rates, and length of hospital stay. There were 141 index cases, 40 (28%) of which were LA-MRSA. Contact screening of 2,101 patients and 7,260 health care workers identified 18 outbreaks (2 LA-MRSA) and 47 secondary cases (3 LA-MRSA). RA values indicated that transmissibility of LA-MRSA is 4.4 times lower than that of other MRSA (not associated with livestock).

Genetic polymorphisms can shape the global landscape of DNA methylation, by either changing substrates for DNA methyltransferases or altering the DNA binding affinity of cis-regulatory proteins. The interactions between CpG methylation and genetic polymorphisms have been previously investigated by methylation quantitative trait loci (mQTL) and allele-specific methylation (ASM) analysis. However, it remains unclear whether these approaches can effectively and comprehensively identify all genetic variants that contribute to the inter-individual variation of DNA methylation levels. Here we used three independent approaches to systematically investigate the influence of genetic polymorphisms on variability in DNA methylation by characterizing the methylation state of 96 whole blood samples in 52 parent-child trios from 22 nuclear pedigrees. We performed targeted bisulfite sequencing with padlock probes to quantify the absolute DNA methylation levels at a set of 411,800 CpG sites in the human genome. With mid-parent offspring analysis (MPO), we identified 10,593 CpG sites that exhibited heritable methylation patterns, among which 70.1% were SNPs directly present in methylated CpG dinucleotides. We determined the mQTL analysis identified 49.9% of heritable CpG sites for which regulation occurred in a distal cis-regulatory manner, and that ASM analysis was only able to identify 5%. Finally, we identified hundreds of clusters in the human genome for which the degree of variation of CpG methylation, as opposed to whether or not CpG sites were methylated, was associated with genetic polymorphisms, supporting a recent hypothesis on the genetic influence of phenotypic plasticity. These results show that cis-regulatory SNPs identified by mQTL do not comprise the full extent of heritable CpG methylation, and that ASM appears overall unreliable. Overall, the extent of genome-methylome interactions is well beyond what is detectible with the commonly used mQTL and ASM approaches, and is likely to include effects on plasticity.

The position of the spindle apparatus determines the plane of cell cleavage and, therefore, the size and position of daughter cells, as well as the decision between symmetric and asymmetric cell division. We show that asymmetry in cortical actin and, remarkably, an endoplasmic reticulum–localized protein contribute to proper spindle positioning in the Caenorhabditis elegans embryo., The microtubule spindle apparatus dictates the plane of cell cleavage in animal cells. During development, dividing cells control the position of the spindle to determine the size, location, and fate of daughter cells. Spindle positioning depends on pulling forces that act between the cell periphery and astral microtubules. This involves dynein recruitment to the cell cortex by a heterotrimeric G-protein α subunit in complex with a TPR-GoLoco motif protein (GPR-1/2, Pins, LGN) and coiled-coil protein (LIN-5, Mud, NuMA). In this study, we searched for additional factors that contribute to spindle positioning in the one-cell Caenorhabditis elegans embryo. We show that cortical actin is not needed for Gα–GPR–LIN-5 localization and pulling force generation. Instead, actin accumulation in the anterior actually reduces pulling forces, possibly by increasing cortical rigidity. Examining membrane-associated proteins that copurified with GOA-1 Gα, we found that the transmembrane and coiled-coil domain protein 1 (TCC-1) contributes to proper spindle movements. TCC-1 localizes to the endoplasmic reticulum membrane and interacts with UNC-116 kinesin-1 heavy chain in yeast two-hybrid assays. RNA interference of tcc-1 and unc-116 causes similar defects in meiotic spindle positioning, supporting the concept of TCC-1 acting with kinesin-1 in vivo. These results emphasize the contribution of membrane-associated and cortical proteins other than Gα–GPR–LIN-5 in balancing the pulling forces that position the spindle during asymmetric cell division.

Positive social interactions during the juvenile and adolescent phases of life are essential for proper social and cognitive development in mammals, including humans. During this developmental period, there is a marked increase in peer-peer interactions, signified by the abundance of social play behaviour. Despite its importance for behavioural development, our knowledge of the neural underpinnings of social play behaviour is limited. Therefore, the purpose of this study was to map the neural circuits involved in social play behaviour in rats. This was achieved by examining cellular activity after social play using the immediate early gene c-Fos as a marker. After a session of social play behaviour, pronounced increases in c-Fos expression were observed in the medial prefrontal cortex, medial and ventral orbitofrontal cortex, dorsal striatum, nucleus accumbens core and shell, lateral amygdala, several thalamic nuclei, dorsal raphe and the pedunculopontine tegmental nucleus. Importantly, the cellular activity patterns after social play were topographically organized in this network, as indicated by play-specific correlations in c-Fos activity between regions with known direct connections. These correlations suggest involvement in social play behaviour of the projections from the medial prefrontal cortex to the striatum, and of amygdala and monoaminergic inputs to frontal cortex and striatum. The analyses presented here outline a topographically organized neural network implicated in processes such as reward, motivation and cognitive control over behaviour, which mediates social play behaviour in rats.

Neuropeptides are intercellular signal transmitters that play key roles in modulation of many behavioral and physiological processes. Neuropeptide signaling in several nuclei in the hypothalamus contributes to the control of food intake. Additionally, food intake regulation involves neuropeptide signaling in the reward circuitry in the striatum. Here, we analyze neuropeptides extracted from hypothalamus and striatum from rats in four differentially treated dietary groups including a high-fat/high-sucrose diet, mimicking diet-induced obesity. We employ high-resolution tandem mass spectrometry using higher-energy collision dissociation and electron transfer dissociation fragmentation for sensitive identification of more than 1700 unique endogenous peptides, including virtually all key neuropeptides known to be involved in food intake regulation. Label-free quantification of differential neuropeptide expression revealed comparable upregulation of orexigenic and anorexigenic neuropeptides in rats that were fed on a high-fat/high-sucrose diet.

Documentary scholars have presupposed a certain documentary practice, and have ethically evaluated this practice, with a focus on the need for protection for a vulnerable and ignorant participant. But times have changed. By researching the experience of ethical challenges by both documentary filmmakers and participants, through both a quantitative and a qualitative project, a practice surfaces in which the participant is committed to and involved in the project; conflict between filmmaker and participant is recurrent, but non-decisive, as communication, trust, and commitment act as a safety-net. Hence, questions about documentary ethics need to address this contemporary practice, rather than a past one.

Documentary scholars have presupposed a certain documentary practice, and have ethically evaluated this practice, with a focus on the need for protection for a vulnerable and ignorant participant. But times have changed. By researching the experience of ethical challenges by both documentary filmmakers and participants, through both a quantitative and a qualitative project, a practice surfaces in which the participant is committed to and involved in the project; conflict between filmmaker and participant is recurrent, but non-decisive, as communication, trust, and commitment act as a safety-net. Hence, questions about documentary ethics need to address this contemporary practice, rather than a past one.

Documentary scholars have presupposed a certain documentary practice, and have ethically evaluated this practice, with a focus on the need for protection for a vulnerable and ignorant participant. But times have changed. By researching the experience of ethical challenges by both documentary filmmakers and participants, through both a quantitative and a qualitative project, a practice surfaces in which the participant is committed to and involved in the project; conflict between filmmaker and participant is recurrent, but non-decisive, as communication, trust, and commitment act as a safety-net. Hence, questions about documentary ethics need to address this contemporary practice, rather than a past one.

In the aftermath of a traumatic event, many people suffer from psychological distress, but only a minority develops posttraumatic stress disorder (PTSD). Pre-trauma individual differences in fear conditioning, most notably reduced extinction learning, have been proposed as playing an important role in the etiology of PTSD. However, prospective data are lacking. In this study, we prospectively tested whether reduced extinction was a predictor for later posttraumatic stress. Dutch soldiers (N = 249) were administered a conditioning task before their four-month deployment to Afghanistan to asses individual differences in extinction learning. After returning home, posttraumatic stress was measured. Results showed that reduced extinction learning before deployment predicted subsequent PTSD symptom severity, over and beyond degree of pre-deployment stress symptoms, neuroticism, and exposure to stressors on deployment. The findings suggest that reduced extinction learning may play a role in the development of PTSD. © 2012 Elsevier Ltd.

The physicist Neils Bohr allegedly wrote that “Prediction is very difficult, especially about the future”. Many academics believe that serious scholars should never attempt to write about the future, but some awareness of the ways in which the future of e-government may evolve is needed if well-grounded long-term decisions about issues such as infrastructures, institutions and educational programs are to be made. In addition, future-oriented research is of the utmost importance for informed public debate about technological developments with far reaching societal implications. This book marks the 25th anniversary of the permanent study group on e-government of the European Group for Public Administration, and the papers here were first presented at their 2012 meeting in Bucharest, Romania. The invited authors were not asked for rigorous analyses based on systematic empirical research or deeply rooted in a theoretical framework; instead they were challenged to write thoughtful and measured, but provocative, essays about ICT and public administration in the coming decade. Their contributions are reflections on the nature of new and emerging technologies in the public sector and their impact on government and on democracy itself. The book is divided into three sections: the past and present as starting point for thinking about the future of e-government, imagining the future of government, and implications for research and practice. The many questions raised by developments in ICT for future public administration are presented in a clear and thought-provoking manner, and merit more debate. This volume represents a departure from the normal run of academic publications. It is intended both to provoke academics and administrators to think about questions which will affect all of our futures and to offer a range of creative ideas about how the opportunities presented by technology can be exploited to provide better government and governance.

Targeted transparency has become a popular regulatory instrument, but its effects are fuzzy because disclosure does not always lead to better compliance. To understand this fuzziness, it is necessary to study the meanings managers attribute to disclosure systems. An empirical analysis of disclosure systems for food safety in Denmark and for environmental safety in the Netherlands confirms that the range of managerial reactions is broader than expected on the basis of rational-choice theory, but can be explained by focusing on local meanings. The article illustrates the shortcomings of a homogeneous approach to targeted transparency policy. Regulators should adopt a bottom-up rather than a top-down approach and develop differentiated policies based on a more nuanced understanding of the meanings managers attribute to targeted transparency.

This paper starts with the observation that liberal and discursive perspectives have been dominant in academic analyses of the role of technology in the future of democracy. The perspective of democracy as a participatory practice is largely ignored by academic investigations of electronic democracy. This paper argues that new technologies increasingly enable citizens to organize their own forms of public value production in a Do It Yourself (DIY) State: governance without government. The DIY State should not be seen as utopia. Although the DIY State may reflect the hippy ideal of a supportive community, it could also take the form of a 'jungle' where only the fittest survive. A further understanding of this form of democracy, of the way it is affected by new technologies, and of the remaining role for government, is needed to inform public debate and practices.

The emergence of publications on extracellular RNA (exRNA) and extracellular vesicles (EV) has highlighted the potential of these molecules and vehicles as biomarkers of disease and therapeutic targets. These findings have created a paradigm shift, most prominently in the field of oncology, prompting expanded interest in the field and dedication of funds for EV research. At the same time, understanding of EV subtypes, biogenesis, cargo and mechanisms of shuttling remains incomplete. The techniques that can be harnessed to address the many gaps in our current knowledge were the subject of a special workshop of the International Society for Extracellular Vesicles (ISEV) in New York City in October 2012. As part of the ‘‘ISEV Research Seminar: Analysis and Function of RNA in Extracellular Vesicles (evRNA)’’, 6 round-table discussions were held to provide an evidence-based framework for isolation and analysis of EV, purification and analysis of associated RNA molecules, and molecular engineering of EV for therapeutic intervention. This article arises from the discussion of EV isolation and analysis at that meeting. The conclusions of the round table are supplemented with a review of published materials and our experience. Controversies and outstanding questions are identified that may inform future research and funding priorities. While we emphasize the need for standardization of specimen handling, appropriate normative controls, and isolation and analysis techniques to facilitate comparison of results, we also recognize that continual development and evaluation of techniques will be necessary as new knowledge is amassed. On many points, consensus has not yet been achieved and must be built through the reporting of well-controlled experiments.

This chapter characterizes the role of prime ministers as public leaders: of the government, their parties, and the nation. It reviews the current state of knowledge about prime ministers, signals its limitations and sets out the research agenda of the study. It argues that understanding and evaluating how prime ministers perform their leadership function requires delving into the interplay between personal, institutional and contextual factors. It maps out the design of the collaborative and comparative research project the remainder of the book reports on.