A lymphoma plasma membrane-associated protein with ankyrin-like properties.

In this study we have used several complementary techniques to isolate and characterize a 72-kD polypeptide that is tightly associated with a major mouse T-lymphoma membrane glycoprotein, gp 85 (a wheat germ agglutinin-binding protein), in a 16 S complex. These two proteins do not separate in the presence of high salt but can be dissociated by treatment with 2 M urea. Further analysis indicates that the 72-kD protein has ankyrin-like properties based on the following criteria: (a) it cross-reacts with specific antibodies raised against erythrocyte and brain ankyrin; (b) it displays a peptide mapping pattern and a pI (between 6.5 and 6.8) similar to that of the 72-kD proteolytic fragment of erythrocyte ankyrin; (c) it competes with erythrocyte ghost membranes (spectrin-depleted preparations) for spectrin binding; and (d) it binds to purified spectrin and fodrin molecules. Most importantly, in intact lymphoma cells this ankyrin-like protein is localized directly underneath the plasma membrane and is found to be preferentially accumulated beneath receptor cap structures as well as associated with a membrane-cytoskeleton complex preparation. It is proposed that the ankyrin-like 72-kD protein may play an important role in linking certain surface glycoprotein(s) to fodrin which, in turn, binds to actin filaments required for lymphocyte cap formation

What is the impact of dexamethasone on postoperative pain in adults undergoing general anaesthesia for elective abdominal surgery: a systematic review and meta-analysis

BACKGROUND: Previous meta-analysis of heterogeneous surgical cohorts demonstrated reduction in postoperative pain with perioperative intravenous dexamethasone, but none have addressed adults undergoing elective abdominal surgery. The aim of this study was to determine the impact of intravenous perioperative dexamethasone on postoperative pain in adults undergoing elective abdominal surgery under general anaesthesia. METHODS: This review was prospectively registered on the international prospective register of systematic reviews (CRD42020176202). Electronic databases Medical Analysis and Retrieval System Online (MEDLINE), Exerpta Medica Database (EMBASE), (CINAHL) Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and trial registries were searched to January 28 2021 for randomised controlled trials, comparing dexamethasone to placebo or alternative antiemetic, that reported pain. The primary outcome was pain score, and secondary outcomes were time to first analgesia, opioid requirements and time to post-anaesthesia care unit (PACU) discharge. RESULTS: Fifty-two studies (5768 participants) were included in the meta-analysis. Pain scores ≤ 4 hour (h) were reduced in patients who received dexamethasone at rest (mean difference (MD), - 0.54, 95% confidence interval (CI) - 0.72 to - 0.35, I2 = 81%) and on movement (MD - 0.42, 95% CI - 0.62 to - 0.22, I2 = 35). In the dexamethasone group, 4-24 h pain scores were less at rest (MD - 0.31, 95% CI - 0.47 to - 0.14, I2 = 96) and on movement (MD - 0.26, 95% CI - 0.39 to - 0.13, I2 = 29) and pain scores ≥ 24 h were reduced at rest (MD - 0.38, 95% CI - 0.52 to - 0.24, I2 = 88) and on movement (MD - 0.38, 95% CI - 0.65 to - 0.11, I2 = 71). Time to first analgesia (minutes) was increased (MD 22.92, 95% CI 11.09 to 34.75, I2 = 98), opioid requirements (mg oral morphine) decreased (MD - 6.66, 95% CI - 9.38 to - 3.93, I2 = 88) and no difference in time to PACU discharge (MD - 3.82, 95% CI - 10.87 to 3.23, I2 = 59%). CONCLUSIONS: Patients receiving dexamethasone had reduced pain scores, postoperative opioid requirements and longer time to first analgesia. Dexamethasone is an effective analgesic adjunct for patients undergoing abdominal surgery

Required duration of mass ivermectin treatment for onchocerciasis elimination in Africa: a comparative modelling analysis.

BACKGROUND: The World Health Organization (WHO) has set ambitious targets for the elimination of onchocerciasis by 2020–2025 through mass ivermectin treatment. Two different mathematical models have assessed the feasibility of reaching this goal for different settings and treatment scenarios, namely the individual-based microsimulation model ONCHOSIM and the population-based deterministic model EPIONCHO. In this study, we harmonize some crucial assumptions and compare model predictions on common outputs. METHODS: Using a range of initial endemicity levels and treatment scenarios, we compared the models with respect to the following outcomes: 1) model-predicted trends in microfilarial (mf) prevalence and mean mf intensity during 25 years of (annual or biannual) mass ivermectin treatment; 2) treatment duration needed to bring mf prevalence below a provisional operational threshold for treatment interruption (pOTTIS, i.e. 1.4 %), and 3) treatment duration needed to drive the parasite population to local elimination, even in the absence of further interventions. Local elimination was judged by stochastic fade-out in ONCHOSIM and by reaching transmission breakpoints in EPIONCHO. RESULTS: ONCHOSIM and EPIONCHO both predicted that in mesoendemic areas the pOTTIS can be reached with annual treatment, but that this strategy may be insufficient in very highly hyperendemic areas or would require prolonged continuation of treatment. For the lower endemicity levels explored, ONCHOSIM predicted that the time needed to reach the pOTTIS is longer than that needed to drive the parasite population to elimination, whereas for the higher endemicity levels the opposite was true. In EPIONCHO, the pOTTIS was reached consistently sooner than the breakpoint. CONCLUSIONS: The operational thresholds proposed by APOC may have to be adjusted to adequately reflect differences in pre-control endemicities. Further comparative modelling work will be conducted to better understand the main causes of differences in model-predicted trends. This is a pre-requisite for guiding elimination programmes in Africa and refining operational criteria for stopping mass treatment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13071-015-1159-9) contains supplementary material, which is available to authorized users

Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity.

Recently, we identified a GTPase-activating protein for the ADP ribosylation factor family of small GTP-binding proteins that we call GIT1. This protein initially was identified as an interacting partner for the G protein-coupled receptor kinases, and its overexpression was found to affect signaling and internalization of the prototypical beta(2)-adrenergic receptor. Here, we report that GIT1 overexpression regulates internalization of numerous, but not all, G protein-coupled receptors. The specificity of the GIT1 effect is not related to the type of G protein to which a receptor couples, but rather to the endocytic route it uses. GIT1 only affects the function of G protein-coupled receptors that are internalized through the clathrin-coated pit pathway in a beta-arrestin- and dynamin-sensitive manner. Furthermore, the GIT1 effect is not limited to G protein-coupled receptors because overexpression of this protein also affects internalization of the epidermal growth factor receptor. However, constitutive agonist-independent internalization is not regulated by GIT1, because transferrin uptake is not affected by GIT1 overexpression. Thus, GIT1 is a protein involved in regulating the function of signaling receptors internalized through the clathrin pathway and can be used as a diagnostic tool for defining the endocytic pathway of a receptor

Comparison of limb kinematics between collected and lengthened (medium/extended) trot in two groups of dressage horses on two different surfaces

Background: Dressage horses are often asked to work in lengthened paces during training and competition, but to date there is limited information about the biomechanics of dressage-specific paces. Preliminary work has shown increased fetlock extension in extended compared with collected paces, but further investigation of the kinematic differences between collected, medium and extended trot in dressage horses is warranted. Objectives: Investigation of the effect of collected versus medium/extended trot on limb kinematics of dressage horses. Study design: Prospective kinematic evaluation. Methods: Twenty clinically sound horses in active dressage training were used: Group 1) ten young horses (≤ 6 years) were assessed at collected and medium trot; Group 2) ten mature horses (≥9 years) were assessed at collected and extended trot. All horses were evaluated on two different surfaces. High-speed motion-capture (240Hz) was used to determine kinematic variables. Forelimb and hindlimb angles were measured at midstance. Descriptive statistics and mixed-effect multilevel-regression analyses were performed. Results: Speed and stride length were reduced and stride duration increased at collected compared with medium/extended trot. Lengthened trot (medium/extended trot) was associated with increased fetlock extension in both the forelimbs and hindlimbs in both groups of horses. Changes were greater in Group 2 compared with Group 1. Shoulder and carpus angles were associated with forelimb fetlock angle. Hock angle was not significantly influenced by pace. Surface had no effect on fetlock or hock angles. Main limitations: Only 2D motion analysis was carried out. Results may have been different in horses with more extreme gait characteristics. Conclusions: Medium/extended trot increases extension of the forelimb and the hindlimb fetlock joints compared with collected trot in both young and mature dressage horses, respectively

Singing and music making: physiological responses across early to later stages of dementia [version 2; peer review: 1 approved with reservations]

Background: Music based interventions have been found to improve the wellbeing of people living with dementia. More recently there has been interest in physiological measures to provide additional information about how music and singing impact this population. / Methods: This multiple-case study design explored physiological responses (heart rate-HR, electrodermal activity-EDA, movement, and skin temperature-ST) of nine people with mild-to-moderate dementia during a singing group, and six people in the later stages of dementia during an interactive music group. The interactive music group was also video recorded to provide information about engagement. Data were analysed using simulation modelling analysis. / Results: The singing group showed an increase in EDA (p < 0.01 for 8/9 participants) and HR (p < 0.01 for 5/9 participants) as the session began. HR (p < 0.0001 for 5/9 participants) and ST (p < 0.0001 for 6/9 participants) increased during faster paced songs. EDA (p < 0.01 all), movement (p < 0.01 for 8/9 participants) and engagement were higher during an interactive music group compared to a control session (music listening). EDA (p < 0.0001 for 14/18 participants) and ST (p < 0.001 for 10/18 participants) increased and in contrast to the responses during singing, HR decreased as the sessions began (p < 0.002 for 9/18 participants). EDA was higher during slower music (p < 0.0001 for 13/18 participants), however this was less consistent in more interactive sessions than the control. There were no consistent changes in HR and movement responses during different styles of music. / Conclusions: Physiological measures may provide valuable information about the experiences of people with dementia participating in arts and other activities, particularly for those with verbal communication difficulties. Future research should consider using physiological measures with video-analysis and observational measures to explore further how engagement in specific activities, wellbeing and physiology interact

Singing and music making: physiological responses across early to later stages of dementia [version 1; peer review: awaiting peer review]

BACKGROUND: Music based interventions have been found to improve the wellbeing of people living with dementia. More recently there has been interest in physiological measures to provide additional information about how music and singing impact this population. METHODS: This multiple-case study design explored physiological responses (heart rate-HR, electrodermal activity-EDA, movement, and skin temperature-ST) of nine people with mild-to-moderate dementia during a singing group, and six people in the later stages of dementia during an interactive music group. The interactive music group was also video recorded to provide information about engagement. Data were analysed using simulation modelling analysis. RESULTS: The singing group showed an increase in EDA (p < 0.01 for 8/9 participants) and HR (p < 0.01 for 5/9 participants) as the session began. HR (p < 0.0001 for 5/9 participants) and ST (p < 0.0001 for 6/9 participants) increased during faster paced songs. EDA (p < 0.01 all), movement (p < 0.01 for 8/9 participants) and engagement were higher during an interactive music group compared to a control session (music listening). EDA (p < 0.0001 for 14/18 participants) and ST (p < 0.001 for 10/18 participants) increased and in contrast to the responses during singing, HR decreased as the sessions began (p < 0.002 for 9/18 participants). EDA was higher during slower music (p < 0.0001 for 13/18 participants), however this was less consistent in more interactive sessions than the control. There were no consistent changes in HR and movement responses during different styles of music. CONCLUSIONS: Physiological measures may provide valuable information about the experiences of people with dementia participating in arts and other activities, particularly for those with verbal communication difficulties. Future research should consider using physiological measures with video-analysis and observational measures to explore further how engagement in specific activities, wellbeing and physiology interact

Genetic Deletion of the Clathrin Adaptor GGA3 Reduces Anxiety and Alters GABAergic Transmission

Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) is a monomeric clathrin adaptor that has been shown to regulate the trafficking of the Beta-site APP-cleaving enzyme (BACE1), which is required for production of the Alzheimer’s disease (AD)-associated amyloid βpeptide. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that depletion of GGA3 results in increased BACE1 levels and activity owing to impaired lysosomal trafficking and degradation. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. We report here that GGA3 deletion results in novelty-induced hyperactivity and decreased anxiety-like behaviors. Given the pivotal role of GABAergic transmission in the regulation of anxiety-like behaviors, we performed electrophysiological recordings in hippocampal slices and found increased phasic and decreased tonic inhibition in the dentate gyrus granule cells (DGGC). Moreover, we found that the number of inhibitory synapses is increased in the dentate gyrus of GGA3 null mice in further support of the electrophysiological data. Thus, the increased GABAergic transmission is a leading candidate mechanism underlying the reduced anxiety-like behaviors observed in GGA3 null mice. All together these findings suggest that GGA3 plays a key role in GABAergic transmission. Since BACE1 levels are elevated in the brain of GGA3 null mice, it is possible that at least some of these phenotypes are a consequence of increased processing of BACE1 substrates

Development of a generic activities model of command and control

This paper reports on five different models of command and control. Four different models are reviewed: a process model, a contextual control model, a decision ladder model and a functional model. Further to this, command and control activities are analysed in three distinct domains: armed forces, emergency services and civilian services. From this analysis, taxonomies of command and control activities are developed that give rise to an activities model of command and control. This model will be used to guide further research into technological support of command and control activities