Mapping the Melatonin Receptor. 8. Selective MT2 Agonists Derived from 5,6-Dihydroindolo[2,1-a]isoquinolines and Related Systems.

A series of substituted indolo[2,1-a]isoquinolines and indolo[1,2-a]benzoxazines have been prepared, as melatonin analogues, to investigate the nature of the binding site of the melatonin receptor. Agonist and antagonist potency of all the analogues was measured using the [35S]GTPγS binding assay protocol. The binding affinity of the analogues were measured by competition binding studies against the human MT1 (hMT1) and MT2 (hMT2) receptors stably transfected in Chinese Hamster Ovarian (CHO) cells, using 2-[125 I]-iodomelatonin, as a ligand. N-Acetyl 2-(10-methoxy-5,6-dihydroindolo[2,1-a]isoquinolin-12-yl)propyl-1-amine (12 a) binds strongly to both the hMT1 and hMT2 receptors, and shows a preference for the hMT2, as does its propanamido counterpart 12 b. The introduction of two methyl groups into their side chain, analogues 15 a and 15 b, leads to antagonism, in the case of the former, and drastically diminishes its hMT1 binding; an analogous profile is seen for 15 b, which, however, is a partial agonist. Introduction of chlorine or methoxy groups into ring 4 gives compounds, that are weakly binding, with a preference for MT2. Substitution of oxygen for carbon at position 5 gives the indolo[1,2-c]benzoxazines 33, 36 a and b, that bind strongly to the human receptors, 33, 36 b being potent agonists at the melatonin receptors, but do not discriminate between hMT1 and hMT2.

NCS Assessments of the Motor, Sensory, and Physical Health Domains.

As part of the National Children's Study (NCS) comprehensive and longitudinal assessment of the health status of the whole child, scientific teams were convened to recommend assessment measures for the NCS. This manuscript documents the work of three scientific teams who focused on the motor, sensory, or the physical health aspects of this assessment. Each domain team offered a value proposition for the importance of their domain to the health outcomes of the developing infant and child. Constructs within each domain were identified and measures of these constructs proposed. Where available extant assessments were identified. Those constructs that were in need of revised or new assessment instruments were identified and described. Recommendations also were made for the age when the assessments should take place.

A comparison of characteristics, developmental disorders and motor progression between children with and without developmental coordination disorder.

BACKGROUND AND AIM: Children with Developmental Coordination Disorder (DCD) have difficulty in the development of motor coordination and with learning new motor skills. Studies demonstrate that children with DCD differ in terms of the nature and severity of their motor difficulties, the incidence of co occurring conditions and family background. However, little is known whether these profiles may relate to motor progression over time. The aim of this study was to describe the profiles of children with and without DCD and track motor progression over time. METHOD: The characteristics of thirty-four 7-14 year old children (M = 10.07, 85.3% boys) with and without DCD were compared and their motor progression monitored over a two academic years. DCD was identified using DSM5 criteria. The Movement Assessment Battery for Children-2 (MABC-2) was used to classify children as TD (≥25th percentile), having moderate motor coordination difficulties (6-16th percentile) or severe motor coordination difficulties (≤ 5th percentile). The Kaufman Brief Intelligence Test - 2 (KBIT-2) was used to measure full scale IQ. Parent questionnaires were used to gather information on socio economic status and co occurrence of other developmental disorders. We used ANOVA to assess whether there were differences in characteristics between the TD children, children with severe motor coordination difficulties and children with moderate motor coordination difficulties. Linear mixed effect modelling was used to estimate any change in motor performance over time and whether this differed between the three groups of children. RESULTS: Children with severe motor coordination difficulties had distinct profiles in motor and non-motor domains, lower IQ and a greater likelihood of having associated characteristics of 2 or more developmental disorders. We found significant differences between the poor motor performance of the severe group compared to the other two groups. Longitudinal analyses revealed stable, persistent and lower motor competence for the severe group. The rate of change in motor proficiency for the typical and severe groups was similar. However, the group with moderate motor difficulties gained on average more points per week compared to the typical group and achieved motor scores in the typically developing range over time. CONCLUSIONS: This is one of the first studies to compare the characteristics and rate of motor progression of children with and without DCD using different motor proficiency cut off scores. The children with severe motor coordination difficulties progressed at the same rate as typically developing peers but remained in the severe group over time, whereas the children with moderate motor coordination difficulties caught up to TDC. The results indicate that different intervention may be required according to the nature and severity of the characteristics in both the motor and non-motor domains of children with DCD.

Cognitive and motor function in developmental coordination disorder.

AIM: To analyse the development of motor skill and executive function in school-aged children with and without developmental coordination disorder (DCD). METHOD: Using a longitudinal design, 186 children (86 males, 100 females) aged 6 to 11 years at Time 1 were tested over a 2-year period, 52 of whom were diagnosed with DCD at Time 1 (27 males, 25 females; mean age 8y 5mo, SD 1y 6mo) using DSM-5 criteria. The McCarron Assessment of Neuromuscular Development assessed motor status at Time 1 and at 2-year follow-up (Time 2). Executive function was assessed using a well-validated measure, the Groton Maze Learning Test. RESULTS: The DCD cohort at Time 1 had moderate incidence of executive function deficit (41%). Most importantly, at a group level, children with persisting DCD (across Times 1 and 2) also showed significantly lower levels of executive function than children with typical motor development at both time points. At an individual level, around 26% of children in this group had persisting executive function deficits relative to normal ranges of performance. INTERPRETATION: Children with persisting DCD are at significant risk of executive function issues. The combination of motor and cognitive issues as a potential risk factor in the longer-term development of children is discussed. WHAT THIS PAPER ADDS: Around half of children initially diagnosed with developmental coordination disorder (DCD) had the same diagnosis at 2-year follow-up. 41% of children with DCD have impaired executive function. Children with persisting DCD show poorer executive function than those with typical motor development or remitting DCD.

Fluorine substituted methoxyphenylalkyl amides as potent melatonin receptor agonists.

A series of fluorine substituted methoxyphenylalkyl amides were prepared with different orientations of the fluorine and methoxy groups with respect to the alkylamide side chain and with alkyl sides of differing lengths (n = 1-3). ß-Dimethyl and α-methyl derivatives were also synthesised. The compounds were tested as melatonin agonists and antagonists using the pigment aggregation of Xenopus melanophores as the biological assay. A number of these compounds were potent melatonin agonists, the potency depending on the length of the alkyl chain, the orientation of the methoxy and fluorine substituents, the amide chain length and, for the ethyl side-chain analogues, the presence of ß-substituents.

Randomised controlled trial comparing uptake of NHS Health Check in response to standard letters, risk-personalised letters and telephone invitations.

BACKGROUND: NHS Health Check is a primary prevention programme offering cardiovascular disease (CVD) risk assessment to adults in England aged 40-74. Uptake remains a challenge and invitation method is a strong predictor of uptake. There is evidence of low uptake when using invitation letters. Telephone invitations might increase uptake, but are not widely used. We explored the potential to improve uptake through personalising letters to patient's CVD risk, and to compare this with generic letters and telephone invitations. METHODS: HEalth Check TRial (HECTR) was a three-arm randomised controlled trial in nine general practices in Staffordshire (UK). Eligible patients were randomised to be invited to a NHS Health Check using one of three methods: standard letter (control); telephone invitation; letter personalised to the patient's CVD risk. The primary outcome was attendance/non-attendance. Data were collected on a range of patient- and practice-level factors (e.g., patient socio-demographics, CVD risk, practice size, Health Checks outside usual working hours). Multi-level logistic regression estimated the marginal effects to explore whether invitation method predicted attendance. Invitation costs were collated from practices to estimate cost benefit. RESULTS: In total, 4614 patients were included in analysis (mean age 50.2 ± 8.0 yr.; 52.4% female). Compared with patients invited by standard letter (30.9%), uptake was significantly higher in those invited by telephone (47.6%, P < .001), but not personalised letter (31.3%, p = .812). In multi-level analysis, compared with the standard letter arm, likelihood of attendance was 18 percentage points higher in the telephone arm and 4 percentage points higher in the personalised letter arm. The effect of telephone calls appeared strongest in patients who were younger and had lower CVD risk. We estimated per 1000 patients invited, risk-personalised letters could result in 40 additional attended Health Checks (at no extra cost) and telephone invitations could result in 180 additional Health Checks at an additional cost of £240. CONCLUSIONS: Telephone invitations should be advocated to address the substantial deficit between current and required levels of NHS uptake, and could be targeted at younger and lower CVD risk adults. Risk-personalised letters should be explored further in a larger sample of high risk individuals. TRIAL REGISTRATION: Registration number: ISRCTN15840751 date of registration: 24/10/2017.

International clinical practice recommendations on the definition, diagnosis, assessment, intervention, and psychosocial aspects of developmental coordination disorder.

AIM: These international clinical practice recommendations (CPR) for developmental coordination disorder (DCD), initiated by the European Academy of Childhood Disability (EACD), aim to address key questions on the definition, diagnosis, assessment, intervention, and psychosocial aspects of DCD relevant for clinical practice. METHOD: Key questions in five areas were considered through literature reviews and formal expert consensus. For recommendations based on evidence, literature searches on 'mechanisms', 'assessment', and 'intervention' were updated since the last recommendations in 2012. New searches were conducted for 'psychosocial issues' and 'adolescents/adults'. Evidence was rated according to the Oxford Centre for Evidence-Based Medicine (level of evidence [LOE] 1-4) and transferred into recommendations. For recommendations based on formal consensus, two meetings of an international, multidisciplinary expert panel were conducted with a further five Delphi rounds to develop good clinical practice (GCP) recommendations. RESULTS: Thirty-five recommendations were made. Eight were based on the evidence from literature reviews (three on 'assessment', five on 'intervention'). Twenty-two were updated from the 2012 recommendations. New recommendations relate to diagnosis and assessment (two GCPs) and psychosocial issues (three GCPs). Additionally, one new recommendation (LOE) reflects active video games as adjuncts to more traditional activity-oriented and participation-oriented interventions, and two new recommendations (one GCP, one LOE) were made for adolescents and adults with DCD. INTERPRETATION: The CPR-DCD is a comprehensive overview of DCD and current understanding based on research evidence and expert consensus. It reflects the state of the art for clinicians and scientists of varied disciplines. The international CPR-DCD may serve as a basis for national guidelines. WHAT THIS PAPER ADDS: Updated international clinical practice guidelines on developmental coordination disorder (DCD). Refined and extended recommendations on clinical assessment and intervention for DCD. A critical synopsis of current research on mechanisms of DCD. A critical synopsis of psychosocial issues in DCD, with implications for clinical practice. The first international recommendations to consider adolescents and adults with DCD.

An evaluation of the Movement ABC-2 Test for use in Italy: A comparison of data from Italy and the UK.

BACKGROUND: The standardized test within the Movement Assessment Battery for Children-2nd edition (MABC-2) is used worldwide to assess motor problems in children. Ideally, any country using a test developed in another country should produce national norms to ensure that it functions effectively in the new context. AIM: The first objective of this study was to explore the differences in motor performance between Italian and British children. The second was to examine the structural validity of the test for the Italian sample. METHOD: A total of 718 Italian (IT) and 765 British (UK) children, aged 3-10 years, were individually tested on the age-appropriate items of the MABC-2 Test. RESULTS: Developmental trends emerged on every task and differences between IT and UK children were obtained on 11 of 27 task comparisons. Interactions between age and country indicated that differences were not consistently in favor of one culture. Confirmatory factor analysis generally supported the proposed structure of the MABC-2 Test. CONCLUSION: Although the differences between the IT and the UK children were relatively few, those that did emerge emphasize the need for population specific norms and suggest that cultural diversity in motor experiences should be considered when evaluating motor abilities in children.

Cognitive and neuroimaging findings in developmental coordination disorder: new insights from a systematic review of recent research.

AIM: To better understand the neural and performance factors that may underlie developmental coordination disorder (DCD), and implications for a multi-component account. METHOD: A systematic review of the experimental literature published between June 2011 and September 2016 was conducted using a modified PICOS (population, intervention, comparison, outcomes, and study type) framework. A total of 106 studies were included. RESULTS: Behavioural data from 91 studies showed a broad cluster of deficits in the anticipatory control of movement, basic processes of motor learning, and cognitive control. Importantly, however, performance issues in DCD were often shown to be moderated by task type and difficulty. As well, we saw new evidence of compensatory processes and strategies in several studies. Neuroimaging data (15 studies, including electroencephalography) showed reduced cortical thickness in the right medial orbitofrontal cortex and altered brain activation patterns across functional networks involving prefrontal, parietal, and cerebellar regions in children with DCD than those in comparison groups. Data from diffusion-weighted magnetic resonance imaging suggested reduced white matter organization involving sensorimotor structures and altered structural connectivity across the whole brain network. INTERPRETATION: Taken together, results support the hypothesis that children with DCD show differences in brain structure and function compared with typically developing children. Behaviourally, these differences may affect anticipatory planning and reduce automatization of movement skill, prompting greater reliance on slower feedback-based control and compensatory strategies. Implications for future research, theory development, and clinical practice are discussed.

Coupling of online control and inhibitory systems in children with atypical motor development: A growth curve modelling study.

INTRODUCTION: Previous research indicates that children with Developmental Coordination Disorder (DCD) show deficits performing online corrections, an issue exacerbated by adding inhibitory constraints; however, cross-sectional data suggests that these deficits may reduce with age. Using a longitudinal design, the aim of the study presented here was to model the coupling that occurs between inhibitory systems and (predictive) online control in typically developing children (TDC) and in those with Developmental Coordination Disorder (DCD) over an extended period of time, using a framework of interactive specialization. We predicted that TDC would show a non-linear growth pattern, consistent with re-organisation in the coupling during the middle childhood period, while DCD would display a developmental lag. METHOD: A group of 196 children (111 girls and 85 boys) aged between 6 and 12years participated in the study. Children were classified as DCD according to research criteria. Using a cohort sequential design, both TDC and DCD groups were divided into age cohorts. Predictive (online) control was defined operationally by performance on a Double-Jump Reaching Task (DJRT), which was assessed at 6-month intervals over two years (5 time points in total). Inhibitory control was examined using an anti-jump condition of the DJRT paradigm whereby children were instructed to touch a target location in the hemispace opposite a cued location. RESULTS: For the TDC group, model comparison using growth curve analysis revealed that a quadratic trend was the most appropriate fit with evidence of rapid improvement in anti-reach performance up until middle childhood (around 8-9years of age), followed by a more gradual rate of improvement into late childhood and early adolescence. This pattern was evident on both chronometric and kinematic measures. In contrast, for children with DCD, a linear function provided the best to fit on the key metrics, with a slower rate of improvement than controls. CONCLUSION: We conclude that children with DCD require a more extended period of development to effectively couple online motor control and executive systems when completing anti-reach movements, whereas TDC show rapid improvement in early and middle childhood. These group differences in growth curves are likely to reflect a maturational lag in the development of motor-cognitive networks in children with DCD.

Mid-Holocene pulse of thinning in the Weddell Sea sector of the West Antarctic ice sheet.

Establishing the trajectory of thinning of the West Antarctic ice sheet (WAIS) since the last glacial maximum (LGM) is important for addressing questions concerning ice sheet (in)stability and changes in global sea level. Here we present detailed geomorphological and cosmogenic nuclide data from the southern Ellsworth Mountains in the heart of the Weddell Sea embayment that suggest the ice sheet, nourished by increased snowfall until the early Holocene, was close to its LGM thickness at 10 ka. A pulse of rapid thinning caused the ice elevation to fall ∼400 m to the present level at 6.5-3.5 ka, and could have contributed 1.4-2 m to global sea-level rise. These results imply that the Weddell Sea sector of the WAIS contributed little to late-glacial pulses in sea-level rise but was involved in mid-Holocene rises. The stepped decline is argued to reflect marine downdraw triggered by grounding line retreat into Hercules Inlet.

Evidence for the stability of the West Antarctic Ice Sheet divide for 1.4 million years.

Past fluctuations of the West Antarctic Ice Sheet (WAIS) are of fundamental interest because of the possibility of WAIS collapse in the future and a consequent rise in global sea level. However, the configuration and stability of the ice sheet during past interglacial periods remains uncertain. Here we present geomorphological evidence and multiple cosmogenic nuclide data from the southern Ellsworth Mountains to suggest that the divide of the WAIS has fluctuated only modestly in location and thickness for at least the last 1.4 million years. Fluctuations during glacial-interglacial cycles appear superimposed on a long-term trajectory of ice-surface lowering relative to the mountains. This implies that as a minimum, a regional ice sheet centred on the Ellsworth-Whitmore uplands may have survived Pleistocene warm periods. If so, it constrains the WAIS contribution to global sea level rise during interglacials to about 3.3 m above present.

New coumarin-based fluorescent melatonin ligands. Design, synthesis and pharmacological characterization.

The design and synthesis of a series of new fluorescent coumarin-containing melatonin analogues is presented. The combination of high-binding affinities for human melatonergic receptors (h-MT1R and h-MT2R) and fluorescent properties, derived from the inclusion of melatonin pharmacophoric elements in the coumarin scaffold, yielded suitable candidates for the development of MT1R and MT2R fluorescent probes for imaging in biological media.

Coupling online control and inhibitory systems in children with Developmental Coordination Disorder: Goal-directed reaching.

For children with Developmental Coordination Disorder (DCD), the real-time coupling between frontal executive function and online motor control has not been explored despite reported deficits in each domain. The aim of the present study was to investigate how children with DCD enlist online control under task constraints that compel the need for inhibitory control. A total of 129 school children were sampled from mainstream primary schools. Forty-two children who met research criteria for DCD were compared with 87 typically developing controls on a modified double-jump reaching task. Children within each skill group were divided into three age bands: younger (6-7 years), mid-aged (8-9), and older (10-12). Online control was compared between groups as a function of trial type (non-jump, jump, anti-jump). Overall, results showed that while movement times were similar between skill groups under simple task constraints (non-jump), on perturbation (or jump) trials the DCD group were significantly slower than controls and corrected trajectories later. Critically, the DCD group was further disadvantaged by anti-jump trials where inhibitory control was required; however, this effect reduced with age. While coupling online control and executive systems is not well developed in younger and mid-aged children, there is evidence of age-appropriate coupling in older children. Longitudinal data are needed to clarify this intriguing finding. The theoretical and applied implications of these results are discussed.

Adaptation and Extension of the European Recommendations (EACD) on Developmental Coordination Disorder (DCD) for the UK context.

BACKGROUND: Developmental Coordination Disorder (DCD) affects the learning and performance of everyday motor skills. It commonly co-occurs with other developmental disorders and a range of associated psycho-social impairments. Recent evidence-based guidelines on diagnosis, assessment, and intervention provide valuable information for practitioners. However these are directed primarily at German-speaking countries and focus on work with children. AIM: The aim of this project was to consider the application of these guidelines in the UK and to extend them for use with adults with DCD. METHODS: Individuals with DCD, parents, and professionals from a wide range of disciplines were invited to two workshops to discuss and debate the guidelines, to adapt them for the UK and produce dissemination materials. RESULTS: A working definition of DCD was agreed, minor revisions were made to the guidelines to reflect the UK context, an extension for adults was compiled and a series of leaflets was produced to disseminate this information to health and education professionals, parents, and employers. CONCLUSIONS: This work will raise awareness of the condition across different professional groups. It provides information to help those working with children and adults with DCD in the UK to assist in the process of diagnosis, assessment, and intervention.

Benzocyclobutane, benzocycloheptane and heptene derivatives as melatonin agonists and antagonists.

Two series of analogues were designed, synthesised and evaluated as potential human melatonin type 1 and 2 receptor (hMT1 and hMT2 ) ligands. Their biological effects were assessed by a well-established, specific model of melatonin action, the pigment response of Xenopus laevis melanophores. Compounds containing a benzocyclobutane scaffold and a methoxy group in the "melatonin" orientation were found to be potent agonists, with one of the analogues exhibiting activity comparable to melatonin. In contrast, analogues with a methoxy group in non-melatonin positions or with multiple methoxy groups showed either weaker agonist activity or were antagonists. Benzocycloheptene derivatives with one methoxy group are found to be weak agonists, whereas those with two methoxy groups were found to be antagonists, as were all of the benzocycloheptane derivatives evaluated. The most active compounds were assessed in a human receptor radio ligand binding assay but showed little discrimination between MT1 and MT2 . These results again show that the indole nitrogen of melatonin is not a necessary component for analogue activity and also illustrate that replacement of the indole ring with a 4-membered carbocycle can provide highly active compounds when the methoxy group is in the melatonin position.

Executive systems constrain the flexibility of online control in children during goal-directed reaching.

We examined the influence of inhibitory load on online motor control in children. A sample of 129 school children was tested: younger, mid-age, and older children. Online control was assessed using a double-step perturbation paradigm across three trail types: non-jump, jump, and anti-jump. Results show that mid-aged children were able to implement online adjustments to jump trials as quickly as older children, but their performance on anti-jump trials regressed toward younger children. This suggests that rapid unfolding of executive systems during middle childhood may constrain the flexibility with which online control can be implemented, particularly when inhibitory demands are imposed.

Diagnosing developmental coordination disorders.

Developmental coordination disorder (DCD) affects around 5% of children and commonly overlaps with other developmental disorders including: attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs) and specific language impairment (SLI). There is evidence to demonstrate the wide-ranging impact on all areas of functioning including psychiatric and learning domains. There is increasing evidence of the continuing impact into adulthood and the long-term negative effects on relationships and employment. There is a need for early identification and intervention to limit the likelihood of these secondary consequences from emerging. This paper addresses the diagnosis of DCD.