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-

Environmental conditioning in the control of macrophage thrombospondin-1 production

Thrombospondin-1 (TSP-1) is a multifunctional protein which is secreted into the extracellular matrix during inflammation, where it modulates numerous components of the immune infiltrate. Macrophages are a source of TSP-1, which they produce in response to TLR4 mediated signals. Their production of TSP-1 is regulated by environmental signals that establish a threshold for the level of protein secretion that can be induced by LPS stimulation. Th1 and Th2 cytokines raise this threshold which leads to less TSP-1 production, while signals that promote the generation of regulatory macrophages lower it. TSP-1 plays no direct role in the regulation of its own secretion. In vivo in uveitis, in the presence of TLR-4 ligands, TSP-1 is initially produced by recruited macrophages but this decreases in the presence of inflammatory cytokines. The adaptive immune system therefore plays a dominant role in regulating TSP-1 production in the target organ during acute inflammation

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)

Stream and slope weathering effects on organic-rich mudstone geochemistry and implications for hydrocarbon source rock assessment: a Bowland Shale case study

This study contributes to the exploration and quantification of the weathering of organic-rich mudstones under temperate climatic conditions. Bowland Shales, exposed by a stream and slope, were sampled in order to develop a model for the effects of weathering on the mudstone geochemistry, including major and trace element geochemistry, Rock-Eval pyrolysis and δ13Corg. Four weathering grades (I – IV) are defined using a visual classification scheme; visually fresh and unaltered (I), chemically altered (II, III) and ‘paper shale’ that typifies weathered mudstone on slopes (IV). Bedload abrasion in the stream exposes of visually fresh and geochemically unaltered mudstone. Natural fractures are conduits for oxidising meteoric waters that promote leaching at the millimetre scale and/or precipitation of iron oxide coatings along fracture surfaces. On the slope, bedding-parallel fractures formed (and may continue to form) in response to chemical and/or physical weathering processes. These fractures develop along planes of weakness, typically along laminae comprising detrital grains, and exhibit millimetre- and centimetre-scale leached layers and iron oxide coatings. Fracture surfaces are progressively exposed to physical weathering processes towards the outcrop surface, and results in disintegration of the altered material along fracture surfaces. Grade IV, ‘paper shale’ mudstone is chemically unaltered but represents a biased record driven by initial heterogeneity in the sedimentary fabric. Chemically weathered outcrop samples exhibit lower concentrations of both ‘free’ (S1) (up to 0.6 mgHC/g rock) and ‘bound’ (S2) (up to 3.2 mgHC/g rock) hydrocarbon, reduced total organic carbon content (up to 0.34 wt%), reduced hydrogen index (up to 58 mgHC/gTOC), increased oxygen index (up to 19 mgCO + CO2/gTOC) and increased Tmax (up to 11 °C) compared with unaltered samples. If analysis of chemically weathered samples is unavoidable, back-extrapolation of Rock-Eval parameters can assist in the estimation of pre-weathering organic compositions. Combining Cs/Cu with oxygen index is a proxy for identifying the weathering progression from fresh material (I) to ‘paper shale’ (IV). This study demonstrates that outcrop samples in temperate climates can provide information for assessing hydrocarbon potential of organic-rich mudstones

A live weight-heart girth relationship for accurate dosing of east African shorthorn zebu cattle

The accurate estimation of livestock weights is important for many aspects of livestock management including nutrition, production and appropriate dosing of pharmaceuticals. Subtherapeutic dosing has been shown to accelerate pathogen resistance which can have subsequent widespread impacts. There are a number of published models for the prediction of live weight from morphometric measurements of cattle, but many of these models use measurements difficult to gather and include complicated age, size and gender stratification. In this paper, we use data from the Infectious Diseases of East Africa calf cohort study and additional data collected at local markets in western Kenya to develop a simple model based on heart girth circumference to predict live weight of east African shorthorn zebu (SHZ) cattle. SHZ cattle are widespread throughout eastern and southern Africa and are economically important multipurpose animals. We demonstrate model accuracy by splitting the data into training and validation subsets and comparing fitted and predicted values. The final model is weight0.262 =0.95 + 0.022 × girth which has an R2 value of 0.98 and 95 % prediction intervals that fall within the ±20 % body weight error band regarded as acceptable when dosing livestock. This model provides a highly reliable and accurate method for predicting weights of SHZ cattle using a single heart girth measurement which can be easily obtained with a tape measure in the field setting

CHANGES IN BALANCE AND JOINT POSITION SENSE DURING A 12-DAY HIGH ALTITUDE TREK

The purpose of this study was to investigate changes in postural control and knee joint position sense (KJPS) during a trek to high altitude. Postural control during standing balance and KJPS were measured in 12 participants at sea-level, 3619m, 4600m and 5140m. Total (p = 0.003, d=1.9) and anterior-posterior sway velocity (p= 0.001, d=1.9) during standing balance with eyes open velocity was significantly greater at altitudes of 3619m and 5140m when compared with sea level. Despite a gradual ascent profile, exposure to 3619 m was associated with impairments in postural control. Importantly, these impairments did not worsen at higher altitudes. The present findings should be considered during future trekking expeditions when considering specific strategies to manage impairments in postural control that occur with increasing altitude

Early versus late ureteric stent removal after kidney transplantation.

BACKGROUND: Kidney transplantation is the treatment of choice for patients with end-stage kidney disease. In a previous review we concluded that the routine use of ureteric stents in kidney transplantation reduces the incidence of major urological complications (MUC). Unfortunately, this reduction appears to lead to a concomitant rise in urinary tract infections (UTI). For kidney recipients UTI is now the commonest post-transplant complication. This represents a considerable risk to the immunosuppressed transplant recipient, particularly in the era of increased immunologically challenging transplants. There are a number of different approaches taken when considering ureteric stenting and these are associated with differing degrees of morbidity and hospital cost. OBJECTIVES: This review aimed to look at the benefits and harms of early versus late removal of the ureteric stent in kidney transplant recipients. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 27 March 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All RCTs and quasi-RCTs were included in our meta-analysis. We included recipients of kidney transplants regardless of demography (adults or children) or the type of stent used. DATA COLLECTION AND ANALYSIS: Two authors reviewed the identified studies to ascertain if they met inclusion criteria. We designated removal of a ureteric stent before the third postoperative week (< day 15) or during the index transplant admission as "early" removal. The studies were assessed for quality using the risk of bias tool. The primary outcome of interest was the incidence of MUC. Further outcomes of interest were the incidence of UTI, idiosyncratic stent-related complications, hospital-related costs and adverse events. A subgroup analysis was performed examining the difference in complications reported depending on the type of ureteric stent used; bladder indwelling (BI) versus per-urethral (PU). Statistical analyses were performed using the random effects model and results expressed as relative risk (RR) with 95% confidence intervals (CI). MAIN RESULTS: Five studies (1127 patients) were included in our analysis. Generally the risk of bias of the included studies was judged low or unclear; they addressed the research question and utilised a prospective randomised design. It is uncertain whether early stent removal verus late stent removal improved the incidence of MUC (5 studies, 1127 participants: RR 1.87, 95% CI 0.61 to 5.71; I2 = 21%; low certainty evidence). The incidence of UTI may be reduced in the early stent removal group (5 studies, 1127 participants: RR 0.49 95% CI 0.30 to 0.81; I2 = 59%; moderate certainty evidence). This possible reduction in the UTI incidence was only apparent if a BI stent was used, (3 studies, 539 participants, RR 0.45 95% CI 0.29 to 0.70; I2 = 13%; moderate certainty evidence). However, if an externalised PU stent was used there was no discernible difference in UTI incidence between the early and late group (2 studies, 588 participants: RR 0.60 95% CI 0.17, 2.03; I2 = 83%; low certainty evidence). Data on health economics and quality of life outcomes were lacking. AUTHORS' CONCLUSIONS: Early removal of ureteric stents following kidney transplantation may reduce the incidence of UTI while it uncertain if there is a higher risk of MUC. BI stents are the optimum method for achieving this benefit

Using structure-from-motion to create glacier DEMs and orthoimagery from historical terrestrial and oblique aerial imagery

Jordan R. Mertes acknowledges funding from Michigan Technological University and The Michigan Technological University 2016 Fall Finishing Fellowship. Lindsey Nicholson is supported by the Austrian Science Fund (FWF) Grant V309-N26.Increased resolution and availability of remote sensing products, and advancements in small-scale aerial drone systems, allows observations of glacial changes at unprecedented levels of detail. Software developments, such as Structure from Motion (SfM), now allow users an easy and efficient method to generate 3D models and orthoimages from aerial or terrestrial datasets. While these advancements show promise for current and future glacier monitoring, many regions still suffer a lack of observations from earlier time periods. We report on the use of SfM to extract spatial information from various historic imagery sources. We focus on three geographic regions, the European Alps, High-Arctic Norway and the Nepal Himalaya. We used terrestrial field photos from 1896, high oblique aerial photos from 1936 and aerial handheld photos from 1978 to generate DEMs and orthophotos of the Rhone glacier, Brøggerhalvøya and the lower Khumbu glacier, respectively. Our analysis shows that applying SfM to historic imagery can generate high quality models using only ground control points. Limited camera/orientation information was largely reproduced using self-calibrated model data. Using these data, we calculated mean ground sampling distances across each site which demonstrates the high potential resolution of resulting models. Vertical errors for our models are ±5.4 m, ±5.2 m and ±3.3 m. Differencing shows similar patterns of thinning at lower Rhone (European Alps) and Brøggerhalvøya (Norway) glaciers, which have mean thinning rates of 0.31 m a-1 (1896-2010) to 0.86 m a-1 (1936-2010) respectively. On these clean ice glaciers thinning is highest in the terminus region and decreasing upglacier. In contrast to these glaciers, uneven topography, exposed ice-cliffs and debris cover on the Khumbu glacier create a highly variable spatial distribution of thinning. The mean thinning rate for the Khumbu study area was found to be 0.54±0.9 m a-1 (1978-2015).PostprintPeer reviewe