Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients

Background: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50 %. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). Methods: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. Results: High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y419) and FAK (Y861) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. Conclusions: Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism

Locomotor activity in relation to dopamine and noradrenaline in the nucleus accumbens, septal and frontalk areas: a 6-hydroxydopamine study

The Study and the Method: The locomotor activity of adult male Sprague-Dawley was automatically recorded in a circular corridor - circadian changes are described as well as the response to the novel situation and its habituation over three hours. Four groups of animals were compared, - those with sham/vehicle operations and those with 6-OHDA dopamine (DA) depleting lesions in - the frontal cortex, the limbic septum, and the ventral tegmental area (VTA - A10). Results: 1/ Lesions of the VTA resulted in increased dark-phase activity, - and a large response to an apomorphine challenge in comparison to other lesion and control groups: 2/ Septal 6-OHDA lesions did not alter locomotion: 3/ After frontal DA depletion there was a small increase of locomotion after the apomorphine challenge, that might reflect increased receptor sensitivity in cortical or sub-cortical areas: (Table 1: HPLC measures of NA, DA and DOPAC for each group in the prefrontal cortex, septum and N. accumbens) Figure 1 illustrates the cumulative photocell counts per hour over 24 hours for the 4 groups:. Figure 2 illustrates the cumulative photocell counts every 10 minutes over 90 minutes post-apomorphine treatment - maximal at 20-30 minutes and habituating over 60 minutes (90 minutes for the VTA group): overall activity VTA >> Frontal > Septal > Controls. Conclusions: Along with correlations found for motor activity with cortical levels of DA and NA, these results are interpreted to support a role for DA, NA and the region of the frontal cortex in modulating locomotion that is primarily mediated by mesolimbic VTA - accumbens - DA activity

Predictability of oppositional defiant disorder and symptom dimensions in children and adolescents with ADHD combined type

Background Oppositional defiant disorder (ODD) is frequently co-occurring with attention deficit hyperactivity disorder (ADHD) in children and adolescents. Because ODD is a precursor of later conduct disorder (CD) and affective disorders, early diagnostic identification is warranted. Furthermore, the predictability of three recently confirmed ODD dimensions (ODD-irritable, ODD-headstrong and ODD-hurtful) may assist clinical decision making. Method Receiver-operating characteristic (ROC) analysis was used in order to test the diagnostic accuracy of the Conners' Parent Rating Scale revised (CPRS-R) and the parent version of the Strength and Difficulties Questionnaire (PSDQ) in the prediction of ODD in a transnational sample of 1093 subjects aged 5-17 years from the International Multicentre ADHD Genetics study. In a second step, the prediction of three ODD dimensions by the same parent rating scales was assessed by backward linear regression analyses. Results ROC analyses showed adequate diagnostic accuracy of the CPRS-R and the PSDQ in predicting ODD in this ADHD sample. Furthermore, the three-dimensional structure of ODD was confirmed by confirmatory factor analysis and the CPRS-R emotional lability scale significantly predicted the ODD irritable dimension. Conclusions The PSDQ and the CPRS-R are both suitable screening instruments in the identification of ODD. The emotional lability scale of the CPRS-R is an adequate predictor of irritability in youth referred for ADH

Genetic analysis of reaction time variability: room for improvement?

Background Increased reaction time variability (RTV) on cognitive tasks requiring a speeded response is characteristic of several psychiatric disorders. In attention deficit hyperactivity disorder (ADHD), the association with RTV is strong phenotypically and genetically, yet high RTV is not a stable impairment but shows ADHD-sensitive improvement under certain conditions, such as those with rewards. The state regulation theory proposed that the RTV difference score, which captures change from baseline to a rewarded or fast condition, specifically measures ‘state regulation'. By contrast, the interpretation of RTV baseline (slow, unrewarded) scores is debated. We aimed to investigate directly the degree of phenotypic and etiological overlap between RTV baseline and RTV difference scores. Method We conducted genetic model fitting analyses on go/no-go and fast task RTV data, across task conditions manipulating rewards and event rate, from a population-based twin sample (n=1314) and an ADHD and control sibling-pair sample (n=1265). Results Phenotypic and genetic/familial correlations were consistently high (0.72-0.98) between RTV baseline and difference scores, across tasks, manipulations and samples. By contrast, correlations were low between RTV in the manipulated condition and difference scores. A comparison across two different go/no-go task RTV difference scores (slow-fast/slow-incentive) showed high phenotypic and genetic/familial overlap (r=0.75-0.83). Conclusions Our finding that RTV difference scores measure largely the same etiological process as RTV under baseline condition supports theories emphasizing the malleability of the observed high RTV. Given the statistical shortcomings of difference scores, we recommend the use of RTV baseline scores for most analyses, including genetic analyse

Roy-Steiner equations for pion-nucleon scattering

Starting from hyperbolic dispersion relations, we derive a closed system of Roy-Steiner equations for pion-nucleon scattering that respects analyticity, unitarity, and crossing symmetry. We work out analytically all kernel functions and unitarity relations required for the lowest partial waves. In order to suppress the dependence on the high-energy regime we also consider once- and twice-subtracted versions of the equations, where we identify the subtraction constants with subthreshold parameters. Assuming Mandelstam analyticity we determine the maximal range of validity of these equations. As a first step towards the solution of the full system we cast the equations for the $\pi\pi\to\bar NN$ partial waves into the form of a Muskhelishvili-Omn\`es problem with finite matching point, which we solve numerically in the single-channel approximation. We investigate in detail the role of individual contributions to our solutions and discuss some consequences for the spectral functions of the nucleon electromagnetic form factors.Comment: 106 pages, 18 figures; version published in JHE

High loading of polygenic risk for ADHD in children with comorbid aggression

Objective: Although attention deficit hyperactivity disorder (ADHD) is highly heritable, genome-wide association studies (GWAS) have not yet identified any common genetic variants that contribute to risk. There is evidence that aggression or conduct disorder in children with ADHD indexes higher genetic loading and clinical severity. The authors examine whether common genetic variants considered en masse as polygenic scores for ADHD are especially enriched in children with comorbid conduct disorder. Method: Polygenic scores derived from an ADHD GWAS meta-analysis were calculated in an independent ADHD sample (452 case subjects, 5,081 comparison subjects). Multivariate logistic regression analyses were employed to compare polygenic scores in the ADHD and comparison groups and test for higher scores in ADHD case subjects with comorbid conduct disorder relative to comparison subjects and relative to those without comorbid conduct disorder. Association with symptom scores was tested using linear regression. Results: Polygenic risk for ADD, derived from the meta-analysis, was higher in the independent ADHD group than in the comparison group. Polygenic score was significantly higher in ADHD case subjects with conduct disorder relative to ADHD case subjects without conduct disorder. ADHD polygenic score showed significant association with comorbid conduct disorder symptoms. This relationship was explained by,the aggression items. Conclusions: Common genetic variation is relevant to ADHD, especially in individuals with comorbid aggression. The findings suggest that the previously published ADHD GWAS meta-analysis contains weak but true associations with common variants, support for which falls below genome-wide significance levels. The findings also highlight the fact that aggression in ADHD indexes genetic as well as clinical severity

The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ

Background Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ. Method Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). Results Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=−0.25 to −0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. Conclusions The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADH

Recovery-based staff training intervention within mental health rehabilitation units: A two-stage analysis using realistic evaluation principles and framework approach

Background - Long-term change in recovery-based practice in mental health rehabilitation is a research priority. Methods - We used a qualitative case study analysis using a blend of traditional 'framework' analysis and 'realist' realist principles toapproaches to carry-out an evaluation of a recovery-focused staff training intervention within three purposively selected mental health rehabilitation units. We tried to ensure the validity of the data by using triangulation of multiple data sources and were collected using different methods. Results - We found that organisational culture and embedding of a change management programme in routine practice were reported as key influences to sustain any change in practice. The qualitative study generated 10 recommendations on how to achieve long-term change in practice including dealing with pre-existing organisational and cultural problems in NHS units. Conclusions - We would propose that a recovery-focused staff training intervention requires leadership, continuity and integration with existing change management programme for long-term change. The intervention must be embedded into routine practice for sustainability

No association between two polymorphisms of the serotonin transporter gene and combined type attention deficit hyperactivity disorder

Several independent studies have reported association between serotonin transporter gene (SLC6A4) polymorphisms and attention deficit hyperactivity disorder (ADHD). Five studies found evidence for association between the long-allele of a 44-bp insertion/deletion polymorphism (5-HTTLPR) and ADHD. Another two studies corroborated this finding while a further six studies did not find such an association. For a second polymorphism within the gene, a variable number tandem repeat (VNTR) within intron 2, one study demonstrated that the 12/12 genotype was significantly less frequent in ADHD cases compared to controls, while a second study found that the 12-allele was preferentially transmitted to offspring affected with ADHD. To provide further clarification of the reported associations, we investigated the association of these two markers with ADHD in a sample of 1,020 families with 1,166 combined type ADHD cases for the International Multi-Centre ADHD Genetics project, using the Transmission Disequilibrium Test. Given the large body of work supporting the association of the promoter polymorphism and mood disorders, we further analyzed the group of subjects with ADHD plus mood disorder separately. No association was found between either of the two markers and ADHD in our large multisite study or with depression within the sample of ADHD cases. © 2008 Wiley-Liss, Inc

Ghrelin Modulates the fMRI BOLD Response of Homeostatic and Hedonic Brain Centers Regulating Energy Balance in the Rat

The orexigenic gut-brain peptide, ghrelin and its G-protein coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1A) are pivotal regulators of hypothalamic feeding centers and reward processing neuronal circuits of the brain. These systems operate in a cooperative manner and receive a wide array of neuronal hormone/transmitter messages and metabolic signals. Functional magnetic resonance imaging was employed in the current study to map BOLD responses to ghrelin in different brain regions with special reference on homeostatic and hedonic regulatory centers of energy balance. Experimental groups involved male, ovariectomized female and ovariectomized estradiol-replaced rats. Putative modulation of ghrelin signaling by endocannabinoids was also studied. Ghrelin-evoked effects were calculated as mean of the BOLD responses 30 minutes after administration. In the male rat, ghrelin evoked a slowly decreasing BOLD response in all studied regions of interest (ROI) within the limbic system. This effect was antagonized by pretreatment with GHS-R1A antagonist JMV2959. The comparison of ghrelin effects in the presence or absence of JMV2959 in individual ROIs revealed significant changes in the prefrontal cortex, nucleus accumbens of the telencephalon, and also within hypothalamic centers like the lateral hypothalamus, ventromedial nucleus, paraventricular nucleus and suprachiasmatic nucleus. In the female rat, the ghrelin effects were almost identical to those observed in males. Ovariectomy and chronic estradiol replacement had no effect on the BOLD response. Inhibition of the endocannabinoid signaling by rimonabant significantly attenuated the response of the nucleus accumbens and septum. In summary, ghrelin can modulate hypothalamic and mesolimbic structures controlling energy balance in both sexes. The endocannabinoid signaling system contributes to the manifestation of ghrelin’s BOLD effect in a region specific manner. In females, the estradiol milieu does not influence the BOLD response to ghrelin