The impact of poor asthma control among asthma patients treated with inhaled corticosteroids plus long-acting β2-agonists in the United Kingdom : a cross-sectional analysis

This study was sponsored by Boehringer Ingelheim Ltd UK, which was involved in all stages of the study conduct and analysis and also funded all costs associated with the development of the manuscript. The authors acknowledge Kantar Health and Errol J Philip for providing medical writing support. Editorial assistance and medical writing support was also provided by Michelle Rebello, PhD, and Suchita Nath-Sain, PhD, of Cactus Communications. This study was sponsored by Boehringer Ingelheim Ltd., UK, which also funded all costs associated with the development of the manuscript. Author Correction, npj Primary Care Respiratory Medicine 27, Article number: 65 (2017) doi:10.1038/s41533-017-0063-5, 05 December 2017 Correction to:npj Primary Care Respiratory Medicine (2017); doi:10.1038/s41533-017-0014-1; Published 09 March 2017Peer reviewedPublisher PD

Relating Dispositional Mindfulness and Long-Term Mindfulness Training with Executive Functioning, Emotion Regulation, and Well-Being in Pre-adolescents

The present study examined whether both dispositional mindfulness without mindfulness training and mindfulness resulting from longer-term mindfulness training are positively associated with pre-adolescents’ well-being, via enhanced executive functioning (EF) and emotion regulation. EF was assessed in a GoNoGo task via behavioral performance and event-related potentials. Study 1 (N = 62) investigated associations of dispositional mindfulness without mindfulness training with EF, well-being and emotion regulation; longitudinal Study 2 with an active control group compared the effects of long-term mindfulness training (N = 28) with a positive psychology intervention (N = 15). Dispositional mindfulness without training was associated with lower EF, unrelated to emotion regulation and the relationship with well-being was mixed. Long-term mindfulness training was positively related to EF and well-being (reduced negative affect), but was uncorrelated with emotion regulation and mindfulness scores. Taken together, long-term mindfulness training was found to have mixed effects. Further research is required in this area

Dissociable effects of mGluR5 allosteric modulation on distinct forms of impulsivity in rats: interaction with NMDA receptor antagonism

Rationale: Impaired N-methyl-D-aspartate (NMDA) receptor signalling underlies several psychiatric disorders that express high levels of impulsivity. Although synergistic interactions exist between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5), the significance of this interaction for impulsivity is unknown. Objective This study aims to investigate the effects of negative and positive allosteric mGluR5 modulation (NAM/PAM) on trait impulsivity and impulsivity evoked by NMDA receptor antagonism in rats. Methods: Motor and choice impulsivity were assessed using the five-choice serial reaction time task (5-CSRTT) and delayeddiscounting task (DDT), respectively. The effects of RO4917523 and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (NAMs) and ADX47273 (PAM) were investigated in non-impulsive rats and in trait high- and low-impulsive rats. The effects of these compounds on impulsivity induced by NMDA receptor antagonism (MK801) in the 5-CSRTT were also investigated. Results: RO4917523 (0.1–1 mg/kg) decreased premature responding and increased omissions but had no effect on locomotor activity up to 0.1 mg/kg. MTEP significantly increased omissions, decreased accuracy and slowed responding but had no effect on premature responding. ADX47273 decreased premature responding at doses that had no effect on locomotor activity. MK801 increased premature responding and impaired attentional accuracy; these deficits were dose dependently rescued by ADX47273 pre-treatment. Allosteric modulation of mGluR5 had no significant effect on choice impulsivity, nor did it modulate general task performance. Conclusions: These findings demonstrate that mGluR5 allosteric modulation selectively dissociates motor and choice impulsivity. We further show that mGluR5 PAMs may have therapeutic utility in selectively targeting specific aspects of impulsivity and executive dysfunction.This research was supported by a Medical Research Council (MRC) grant to JWD (G0701500) and a grant from Boehringer Ingelheim Pharma GmbH & Co. KG. This work was carried out in the Behavioural and Clinical Neuroscience Institute (BCNI) at Cambridge University with joint support from the MRC (G1000183) and Wellcome Trust (093875/Z/10/Z) and at Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. We thank David Theobald, Johannes Freudenreich, Peter Schorn, Alfie Wearn and Benjamin Jaehnke for technical support and Gert Kramer, Dr. Holger Rosenbrock and Dr. Cornelia Dorner-Ciossek for helpful scientific discussions. The authors declare that the experiments performed in this manuscript followed the principles of laboratory animal care and are in compliance with the current laws of the UK and Germany.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-3984-

Dissociable effects of mGluR5 allosteric modulation on distinct forms of impulsivity in rats: interaction with NMDA receptor antagonism.

RATIONALE: Impaired N-methyl-D-aspartate (NMDA) receptor signalling underlies several psychiatric disorders that express high levels of impulsivity. Although synergistic interactions exist between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5), the significance of this interaction for impulsivity is unknown. OBJECTIVE: This study aims to investigate the effects of negative and positive allosteric mGluR5 modulation (NAM/PAM) on trait impulsivity and impulsivity evoked by NMDA receptor antagonism in rats. METHODS: Motor and choice impulsivity were assessed using the five-choice serial reaction time task (5-CSRTT) and delayed-discounting task (DDT), respectively. The effects of RO4917523 and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (NAMs) and ADX47273 (PAM) were investigated in non-impulsive rats and in trait high- and low-impulsive rats. The effects of these compounds on impulsivity induced by NMDA receptor antagonism (MK801) in the 5-CSRTT were also investigated. RESULTS: RO4917523 (0.1-1 mg/kg) decreased premature responding and increased omissions but had no effect on locomotor activity up to 0.1 mg/kg. MTEP significantly increased omissions, decreased accuracy and slowed responding but had no effect on premature responding. ADX47273 decreased premature responding at doses that had no effect on locomotor activity. MK801 increased premature responding and impaired attentional accuracy; these deficits were dose dependently rescued by ADX47273 pre-treatment. Allosteric modulation of mGluR5 had no significant effect on choice impulsivity, nor did it modulate general task performance. CONCLUSIONS: These findings demonstrate that mGluR5 allosteric modulation selectively dissociates motor and choice impulsivity. We further show that mGluR5 PAMs may have therapeutic utility in selectively targeting specific aspects of impulsivity and executive dysfunction.This research was supported by a Medical Research Council (MRC) grant to JWD (G0701500) and a grant from Boehringer Ingelheim Pharma GmbH & Co. KG. This work was carried out in the Behavioural and Clinical Neuroscience Institute (BCNI) at Cambridge University with joint support from the MRC (G1000183) and Wellcome Trust (093875/Z/10/Z) and at Boehringer Ingelheim Pharma GmbH & Co. KG, Germany. We thank David Theobald, Johannes Freudenreich, Peter Schorn, Alfie Wearn and Benjamin Jaehnke for technical support and Gert Kramer, Dr. Holger Rosenbrock and Dr. Cornelia Dorner-Ciossek for helpful scientific discussions. The authors declare that the experiments performed in this manuscript followed the principles of laboratory animal care and are in compliance with the current laws of the UK and Germany.This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00213-015-3984-

Selective and interactive effects of D2 receptor antagonism and positive allosteric mGluR4 modulation on waiting impulsivity

BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. METHODS: Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. RESULTS: Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. CONCLUSIONS: These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes.This research was supported by a Medical Research Council (MRC) grant to JWD (G0701500) and a grant from Boehringer Ingelheim Pharma GmbH & Co. KG. This work was carried out at Boehringer Ingelheim Pharma GmbH & Co. KG in Germany and the Behavioural and Clinical Neuroscience Institute (BCNI) at Cambridge University. The BCNI is jointly supported by the MRC (G1000183) and Wellcome Trust (093875/Z/10/Z)