Myoclonus-dystonia : distinctive motor and non-motor phenotype from other dystonia syndromes

Background: myoclonus-dystonia (M-D) due to a pathogenic variant of SGCE is an autosomal dominant inherited movement disorder. Apart from motor symptoms, psychiatric disorders are highly prevalent in patients with MD. Previous studies suggest, but never tested directly, that the type of psychiatric disorder differs between dystonia syndromes, probably related to disease specific pathology. Little is known about other non-motor symptoms (NMS) in M.D. Here, we systematically study NMS in M-D in direct comparison to other types of dystonia and healthy controls. Methods: Standardized questionnaires were used to assess type and severity of psychiatric co-morbidity, sleep problems, fatigue and quality of life. Results of M-D patients with a pathogenic variant of SGCE were compared to results of idiopathic cervical dystonia (CD) patients, dopa-responsive dystonia (DRD) patients with a pathogenic variant of GCH1 and controls. Results: We included 164 participants: 41 M-D, 51 CD, 19 DRD patients, 53 controls. Dystonia patients (M-D, CD and DRD) had an increased prevalence of psychiatric disorders compared to controls (56-74% vs. 29%). In M-D we found a significantly increased prevalence of obsessive-compulsive disorder (OCD) and psychosis compared to CD and DRD. All dystonia patients had more sleep problems (49-68% vs. 36%) and fatigue (42-73% vs. 15%) than controls. Compared to other dystonia subtypes, M-D patients reported less excessive daytime sleepiness and fatigue. Conclusion: Psychiatric comorbidity is frequent in all dystonia types, but OCD and psychosis are more common in M-D patients. Further research is necessary to elucidate underlying pathways

Research legitimacy as a precursor to effectiveness: the role of equitable partnerships in transforming aquatic food systems

Competing interests in aquatic food systems pose challenges for small-scale food producers trying to secure their place in the blue economy. These challenges include development aspirations, pressure from conservation interests, climate and environmental change, and blue growth agendas. Research-for-development can contribute to improving outcomes for small-scale actors in aquatic food systems in the face of uneven development, but the legitimacy and effectiveness of research have been found difficult to operationalize. An “engineering mindset” that prioritizes technical innovations, academic definitions of research excellence, unequal research collaborations, and funding constraints currently inhibit conducting strategic and transformative research. Taking ownership, equity, shared analysis, and feedback as key principles for research-in-development can assist in moving from transfer of technology to recognizing and working within the specific political and institutional contexts of aquatic food systems

A pilot study of behavioral, physiological, and subjective responses to varying mental effort requirements in attention-deficit/hyperactivity disorder

Background: Attention-deficit/hyperactivity disorder (ADHD) is presumed to involve mental effort application difficulties. To test this assumption, we manipulated task difficulty and measured behavioral, as well as subjective and psychophysiological indices of effort. Methods: Fifteen adolescent ADHD boys and 16 controls performed two tasks. First, subjective estimates and behavioral and pupillary measures of effort were recorded across five levels of N-back task difficulties. Second, effort discounting was assessed. In the latter, participants made repeated choices between performing a difficult N-back task for a high reward versus an easier N-back task for a smaller reward. Results: Increasing task difficulty led to similar deteriorations in performance for both groups - although ADHD participants performed more poorly at all difficulty levels than controls. While ADHD and control participants rated the tasks equally difficult and discounted effort similarly, those with ADHD displayed slightly different pupil dilation patterns with increasing task difficulty. Conclusion: The behavioral results did not provide evidence for mental effort problems in adolescent boys with ADHD. The subtle physiological effects, however, suggest that adolescents with ADHD may allocate effort in a different way than controls

Crossing barriers:a multidisciplinary approach to children and adults with young-onset movement disorders

Abstract Background Diagnosis of less common young-onset movement disorders is often challenging, requiring a broad spectrum of skills of clinicians regarding phenotyping, normal and abnormal development and the wide range of possible acquired and genetic etiologies. This complexity often leads to considerable diagnostic delays, paralleled by uncertainty for patients and their families. Therefore, we hypothesized that these patients might benefit from a multidisciplinary approach. We report on the first 100 young-onset movement disorders patients who visited our multidisciplinary outpatient clinic. Methods Clinical data were obtained from the medical records of patients with disease-onset before age 18 years. We investigated whether the multidisciplinary team, consisting of a movement disorder specialist, pediatric neurologist, pediatrician for inborn errors of metabolism and clinical geneticist, revised the movement disorder classification, etiological diagnosis, and/or treatment. Results The 100 referred patients (56 males) had a mean age of 12.5 ± 6.3 years and mean disease duration of 9.2 ± 6.3 years. Movement disorder classification was revised in 58/100 patients. Particularly dystonia and myoclonus were recognized frequently and supported by neurophysiological testing in 24/29 patients. Etiological diagnoses were made in 24/71 (34%) formerly undiagnosed patients, predominantly in the genetic domain. Treatment strategy was adjusted in 60 patients, of whom 43 (72%) reported a subjective positive effect. Conclusions This exploratory study demonstrates that a dedicated tertiary multidisciplinary approach to complex young-onset movement disorders may facilitate phenotyping and improve recognition of rare disorders, with a high diagnostic yield and minimal diagnostic delay. Future studies are needed to investigate the cost-benefit ratio of a multidisciplinary approach in comparison to regular subspecialty care

Role-play as responsible robotics: The virtual witness testimony role-play interview for investigating hazardous human-robot interactions

The development of responsible robotics requires paying attention to responsibility within the research process in addition to responsibility as the outcome of research. This paper describes the preparation and application of a novel method to explore hazardous human-robot interactions. The Virtual Witness Testimony role-play interview is an approach that enables participants to engage with scenarios in which a human being comes to physical harm whilst a robot is present and may have had a malfunction. Participants decide what actions they would take in the scenario and are encouraged to provide their observations and speculations on what happened. Data collection takes place online, a format that provides convenience as well as a safe space for participants to role play a hazardous encounter with minimal risk of suffering discomfort or distress. We provide a detailed account of how our initial set of Virtual Witness Testimony role-play interviews were conducted and describe the ways in which it proved to be an efficient approach that generated useful findings, and upheld our project commitments to Responsible Research and Innovation. We argue that the Virtual Witness Testimony role-play interview is a flexible and fruitful method that can be adapted to benefit research in human robot interaction and advance responsibility in robotics

Rare inborn errors of metabolism with movement disorders:a case study to evaluate the impact upon quality of life and adaptive functioning

Background: Inborn errors of metabolism (IEM) form an important cause of movement disorders in children. The impact of metabolic diseases and concordant movement disorders upon children's health-related quality of life (HRQOL) and its physical and psychosocial domains of functioning has never been investigated. We therefore conducted a case study on the HRQOL and development of adaptive functioning in children with an IEM and a movement disorder. Methods: Children with co-existent IEM and movement disorders were recruited from paediatric outpatient clinics. We systematically collected clinical data and videotaped examinations. The movement disorders were diagnosed by a panel of specialists. The Pediatric Quality of Life Inventory 4.0 and the Vineland Adaptive Behavior Scale were used to assess the HRQOL and adaptive functioning, respectively. Results: We recruited 24 children (10 boys, mean age 7y 5 m). Six types of movement disorders were recognised by the expert panel, most frequently dystonia (16/24), myoclonus (7/24) and ataxia (6/24). Mean HRQOL (49.63, SD 21.78) was significantly lower than for other chronic disorders in childhood (e.g. malignancy, diabetes mellitus, rheumatic disease, psychiatric disorders; p Conclusions: A broad spectrum of movement disorders was seen in patients with IEM, although only five were receiving treatment. The overall HRQOL in this population is significantly reduced. Delay in adaptive functioning, most frequently seen in relation to activities of daily living, and the severity of the movement disorder contribute to this lower HRQOL. We plead for a greater awareness of movement disorders and that specialists should be asked to diagnose and treat these wherever possible

Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients

Introduction: In dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations. Methods: Concentrations of metabolites of dopaminergic, serotonergic and noradrenergic pathways were measured in platelet-rich plasma in 41 myoclonus-dystonia (M-D), 25 dopa-responsive dystonia (DRD), 50 cervical dystonia (CD) patients and 55 healthy individuals. (Non-)motor symptoms were assessed using validated instruments, and correlated with concentrations of metabolites. Results: A significantly higher concentration of 3-methoxytyramine (0.03 vs. 0.02 nmol/L, p < 0.01), a metabolite of dopamine, and a reduced concentration of tryptophan (50 vs. 53 μmol/L, p = 0.03), the precursor of serotonin was found in dystonia patients compared to controls. The dopamine/levodopa ratio was higher in CD patients compared to other dystonia groups (p < 0.01). Surprisingly, relatively high concentrations of levodopa were found in the untreated DRD patients. Low concentrations of levodopa were associated with severity of dystonia (rs = −0.3, p < 0.01), depression (rs = −0.3, p < 0.01) and fatigue (rs = −0.2, p = 0.04). Conclusion: This study shows alterations in the dopaminergic and serotonergic metabolism of patients with dystonia, with dystonia subtype specific changes. Low concentrations of levodopa, but not of serotonergic metabolites, were associated with both motor and non-motor symptoms. Further insight into the dopaminergic and serotonergic systems in dystonia with a special attention to the kinetics of enzymes involved in these pathways, might lead to better treatment options

Serotonergic system in vivo with [C-11]DASB PET scans in GTP-cyclohydrolase deficient dopa-responsive dystonia patients

GTP-cyclohydrolase deficiency in dopa-responsive dystonia (DRD) patients impairs the biosynthesis of dopamine, but also of serotonin. The high prevalence of non-motor symptoms suggests involvement of the serotonergic pathway. Our study aimed to investigate the serotonergic system in vivo in the brain of`DRD patients and correlate this to (non-)motor symptoms. Dynamic [(11)C]DASB PET scans, a marker of serotonin transporter availability, were performed. Ten DRD, 14 cervical dystonia patients and 12 controls were included. Univariate- and network-analysis did not show differences in binding between DRD patients compared to controls. Sleep disturbances were correlated with binding in the dorsal raphe nucleus (all participants: r(s) = 0.45, p = 0.04; patients: r(s) = 0.64, p = 0.05) and participants with a psychiatric disorder had a lower binding in the hippocampus (all participants: p = 0.00; patients: p = 0.06). Post-hoc analysis with correction for psychiatric co-morbidity showed a significant difference in binding in the hippocampus between DRD patients and controls (p = 0.00). This suggests that psychiatric symptoms might mask the altered serotonergic metabolism in DRD patients, but definite conclusions are difficult as psychiatry is considered part of the phenotype. We hypothesize that an imbalance between different neurotransmitter systems is responsible for the non-motor symptoms, and further research investigating multiple neurotransmitters and psychiatry in DRD is necessary

A junctional PACSIN2/EHD4/MICAL-L1 complex coordinates VE-cadherin trafficking for endothelial migration and angiogenesis

Angiogenic sprouting relies on collective migration and coordinated rearrangements of endothelial leader and follower cells. VE-cadherin-based adherens junctions have emerged as key cell-cell contacts that transmit forces between cells and trigger signals during collective cell migration in angiogenesis. However, the underlying molecular mechanisms that govern these processes and their functional importance for vascular development still remain unknown. We previously showed that the F-BAR protein PACSIN2 is recruited to tensile asymmetric adherens junctions between leader and follower cells. Here we report that PACSIN2 mediates the formation of endothelial sprouts during angiogenesis by coordinating collective migration. We show that PACSIN2 recruits the trafficking regulators EHD4 and MICAL-L1 to the rear end of asymmetric adherens junctions to form a recycling endosome-like tubular structure. The junctional PACSIN2/EHD4/MICAL-L1 complex controls local VE-cadherin trafficking and thereby coordinates polarized endothelial migration and angiogenesis. Our findings reveal a molecular event at force-dependent asymmetric adherens junctions that occurs during the tug-of-war between endothelial leader and follower cells, and allows for junction-based guidance during collective migration in angiogenesis

Cross-national time trends in adolescent body weight perception and the explanatory role of overweight/obesity prevalence

ABSTRACTIntroduction Body weight perception (BWP) is associated with health behaviors. Current evidence points to an increase over time in both actual and perceived weight status among adolescents, however there is limited evidence on time trends in BWP in cross-national samples of adolescents. Therefore, the aims of this study were to examine time trends in BWP between 2002 and 2018 among adolescents from 41 countries and regions, including gender and country differences and to explore the role of changes over time in country-level overweight/obesity prevalence in these trends.Methods Data were used from five cycles (2002, 2006, 2010, 2014, 2018) of the repeated cross-sectional Health Behavior in School-Aged Children (HBSC) study (n = 746,121; mean±standard deviation age 13.7 ± 1.6 years, 51.0% girls). Multilevel logistic models estimated cross-national linear time trends in adolescent BWP (correct perception, underestimation, or overestimation), adjusted for gender, age, and family affluence. Next, we tested whether country-level changes over time overweight/obesity prevalence could explain these trends in BWP among adolescents.Results Correct weight perception increased over time among girls, while it decreased among boys. Underestimation of weight status increased, and overestimation of weight status decreased over time among both genders, with stronger trends for girls. Furthermore, country differences in trends in both BWP and overweight/obesity were found. Changes over time in country-level overweight/obesity prevalence could not explain these trends.Conclusion The linear increase over time in correct weight perception and the decrease in overestimation may have a positive effect on unhealthy weight reduction behaviors among adolescents. However, the increase in underestimation could signal a need for interventions to strengthen correct weight perception among adolescents. Several implications for policy and practice are discussed