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

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

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

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

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

Promotion of physical activity for adolescents with cystic fibrosis: a qualitative study of UK multi disciplinary cystic fibrosis teams

Background: The Cystic Fibrosis Trust recently published a standards of care document which stated that patients should be given a physical activity (PA) programme based on their motivations, fitness, and willingness to be active. However, there remains much debate regarding the roles and responsibilities for PA promotion, as well as “optimal” recommendations and advice. This study aimed to qualitatively explore cystic fibrosis (CF) multidisciplinary teams (MDTs) advice, recommendations and practices relating to PA promotion for adolescents with CF. / Method: Semi-structured interviews were conducted with fifteen members of CF MDTs (11 physiotherapists, two dieticians and two paediatricians). Thematic analysis was used to analyse the data. / Results: Major themes identified were: (1) structure of MDTs, (2) recommendations relating to intensities, durations and types of PA, and (3) use of exercise testing. Participants reported variation between MDTs in terms of who is responsible for promoting and supporting PA, the nature of advice given to patients, and the use of exercise testing. Participants consistently lacked confidence in their own or others’ knowledge to provide standardised recommendations to patients and highlighted that PA promotion and support was often overlooked during busy periods. / Conclusions: Despite its importance, PA support and promotion is not always prioritised. MDTs lack confidence in their ability to promote PA. Standardised advice and training relating to optimal intensities, durations and types of PA would provide a baseline from which to individualise advice to each patient and could increase confidence in PA promotion among MDTs

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