A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs

Narrative Substrates: Reifying and Managing Emergent Narratives in Persistent Game Worlds

International audiencePlayers in modern Massively Multiplayer Online Role-Playing Games progress through ambitiously designed narratives, but have no real influence on the game, since only their characters' data, not the game environment, persists. Although earlier games supported player influence by persisting changes in the world, they relied on players' capacity to form their own stories and lacked guidance for character progression. We explore how persistence and narrative emergence let us build upon players' influence rather than restrict it. We ran four studies and found that players highly value first-time and unique events, and often externalize their experiences to the Web to collaborate and socialize, but unintentionally also disrupt some aspects of in-game play. We introduce Narrative Substrates, a theoretical framework for designing game architec-tures that represent, manage, and persist traces of player activity as unique, interactive content. To illustrate and test the theory, we developed the game We Ride and deployed it as a two-phase technology probe over one year. We identify key benefits and challenges of our approach, and argue that reification of emergent narratives offers new design opportunities for creating truly interactive games

Relating Neuronal to Behavioral Performance: Variability of Optomotor Responses in the Blowfly

Behavioral responses of an animal vary even when they are elicited by the same stimulus. This variability is due to stochastic processes within the nervous system and to the changing internal states of the animal. To what extent does the variability of neuronal responses account for the overall variability at the behavioral level? To address this question we evaluate the neuronal variability at the output stage of the blowfly's (Calliphora vicina) visual system by recording from motion-sensitive interneurons mediating head optomotor responses. By means of a simple modelling approach representing the sensory-motor transformation, we predict head movements on the basis of the recorded responses of motion-sensitive neurons and compare the variability of the predicted head movements with that of the observed ones. Large gain changes of optomotor head movements have previously been shown to go along with changes in the animals' activity state. Our modelling approach substantiates that these gain changes are imposed downstream of the motion-sensitive neurons of the visual system. Moreover, since predicted head movements are clearly more reliable than those actually observed, we conclude that substantial variability is introduced downstream of the visual system

Diagnosis and management of Cornelia de Lange syndrome:first international consensus statement

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning

Character play - The use of game characters in multi-player role-playing games across platforms

Avatars are a commonly used mechanism for representing the player within the world of a game. The avatar forms the main point of interaction between the player and the game, and thus the avatar is an important game design feature. Character-based games combine the concept of an avatar with that of a character, enhancing the avatar with specific features that commonly are changeable, and which can be defined within or outside the framework of the game rules. Within digital games, the rules-based features have received comparatively more attention than, for example, the personalities and background histories of game characters. This article presents results from a comprehensive empirical study of the way complex game characters are utilized by players in multiplayer role-playing games across two different media platforms. The results indicate that adult players are capable of comprehending and utilizing game characters with well-defined personalities and backgrounds, as well as rules-based components. Furthermore, that the game format plays a significant role in the pattern of usage of the character elements. This pattern appears directly linked with variations in the way that the different game formats handle player characters and activate or promote the activation of, different forms of character elements. The degree to which different character elements are activated also has implications for the degree of player engagement in the character. © 2008 ACM