NAFTA, motor carriers and highway safety

The signing of the NAFTA agreement signaled the beginning of increased efforts to harmonize trade between the U.S., Canada, and Mexico. Unfortunately the harmonization of transportation links is lagging far behind proposed implementation dates. This narrative describes the highway safety, and concerns expressed by highway safety advocates and Teamsters union representatives, and documented by the GAO. The authors propose a market based alternative to restricting transborder traffic to the narrow commercial zone presently in place

Intervention goals for preschoolers with language difficulties and disorders A scoping review using the ICF framework

Purpose: The primary aim of this scoping review was to categorize language therapy goals reported in intervention studies for preschoolers (i.e., children from 0 to 5;0 years old) with language difficulties and disorders within the World Health Organization’s International Classification of Functioning, Disability and Health (ICF) framework. A secondary aim was to determine whether different therapy goals were reported for different language difficulty/disorder subtypes (i.e., comparing language difficulty/disorder associated with a biomedical condition to those without an associated biomedical condition). Method: The scoping review followed Arksey and O’Malley’s (2005) guidelines. Articles were retrieved from speechBITE, with age (under 5), intervention area (language), and study design (all but systematic reviews and clinical practice guidelines) specified as inclusion criteria. Language goals were extracted and categorized into the ICF components. From there, the distributions of these ICF components were compared between intervention studies for different language difficulty/disorder subtype. Results: A total of 287 articles were identified; 140 met inclusion criteria. Of the 293 goals extracted, 48% aligned with the Activities component of the ICF framework, followed by Participation (26%), Environmental Factors (20%), Body Functions and Structures (3%) and Personal Factors (3%). Most participation-focused goals were reported from intervention studies of preschoolers with a language difficulty/disorder associated with a biomedical condition. Conclusions: Few participation-focused goals were reported in intervention studies for preschoolers with language difficulty/disorder without an associated condition. Future work is needed to support integrating the ICF framework in goal setting for both research and practice

A Definition of “Regular Meals” Driven by Dietary Quality Supports a Pragmatic Schedule

Public health guidelines advise eating regular meals without defining “regular.” This study constructed a meaning for “regular” meals congruent with dietary quality. Parents of 4th grade youth in a school-based intervention (Clinicaltrials.gov NCT02491294) completed three, ASA24 online 24-h dietary recalls. Differences in time of intake across days for breakfasts, lunches, dinners were categorized with consistency denoted as always, often/sometimes or rarely/never and assigned values of 3, 2 or 1, respectively. Meal-specific values were summed to form mealtime regularity scores (mReg) ranging from 3 (low) to 9. Healthy eating index (HEI) scores were compared to mReg controlling for weekday/weekend recall pattern. Linear regression predicted HEI scores from mReg. Parents (n = 142) were non-Hispanic white (92%), female (88%) and educated (73%). One mReg version, mReg1 was significantly associated with total HEI, total fruit, whole fruit, tended to correlate with total protein, seafood/plant protein subcomponents. mReg1 predicted total HEI (p = 0.001) and was inversely related to BMI (p = 0.04). A score of three (always) was awarded to breakfasts, lunches or dinners with day-to-day differences of 0–60 min; also, lunches/dinners with one interval of 60–120 min when two meals were ≤60 min apart. More rigid mReg versions were not associated with dietary quality

Protease-activated receptor 2 : are common functions in glial and immune cells linked to inflammation-related CNS disorders?

Protease-activated receptors (PARs) are a novel family of G-protein coupled receptors (GPCRs) whose activation requires the cleavage of the N-terminus by a serine protease. However recent evidence reveals that alternative routes of activation also occur and that PARs signal via multiple pathways and that pathway activation is activator-dependent. Given our increased understanding of PAR function both under physiological and pathophysiological conditions; one aspect that has remained a constant is the link between PAR2 and inflammation. PAR2 is expressed in immune cells of both the innate and adaptive immune system and has been shown to play a role in several peripheral inflammatory conditions. PAR2 is similarly expressed on astrocytes and microglia within the CNS and its activation is either protective or detrimental to CNS function depending on the conditions or disease state investigated. With a clear similarity between the function of PAR2 on both immune cells and CNS glial cells, here we have reviewed their roles in both these systems. We suggest that the recent development of novel PAR2 modulators, including those that show biased signalling, will further increase our understanding of PAR2 function and the development of potential therapeutics for CNS disorders in which inflammation is proposed to play a role

Social prescribing and behaviour change : proposal of a new behaviour change technique concerning the ‘connection’ step

Publisher PDFPeer reviewe

Estradiol effects on the dopamine transporter – protein levels, subcellular location, and function

BACKGROUND: The effects of estrogens on dopamine (DA) transport may have important implications for the increased incidence of neurological disorders in women during life stages when hormonal fluctuations are prevalent, e.g. during menarche, reproductive cycling, pregnancy, and peri-menopause. RESULTS: The activity of the DA transporter (DAT) was measured by the specific uptake of (3)H-DA. We found that low concentrations (10(-14 )to 10(-8 )M) of 17β-estradiol (E(2)) inhibit uptake via the DAT in PC12 cells over 30 minutes, with significant inhibition taking place due to E(2 )exposure during only the last five minutes of the uptake period. Such rapid action suggests a non-genomic, membrane-initiated estrogenic response mechanism. DAT and estrogen receptor-α (ERα) were elevated in cell extracts by a 20 ng/ml 2 day NGFβ treatment, while ERβ was not. DAT, ERα and ERβ were also detectable on the plasma membrane of unpermeabilized cells by immunocytochemical staining and by a fixed cell, quantitative antibody (Ab)-based plate assay. In addition, PC12 cells contained RNA coding for the alternative membrane ER GPR30; therefore, all 3 ER subtypes are candidates for mediating the rapid nongenomic actions of E(2). At cell densities above 15,000 cells per well, the E(2)-induced inhibition of transport was reversed. Uptake activity oscillated with time after a 10 nM E(2 )treatment; in a slower room temperature assay, inhibition peaked at 9 min, while uptake activity increased at 3 and 20–30 min. Using an Ab recognizing the second extracellular loop of DAT (accessible only on the outside of unpermeabilized cells), our immunoassay measured membrane vs. intracellular/nonvesicular DAT; both were found to decline over a 5–60 min E(2 )treatment, though immunoblot analyses demonstrated no total cellular loss of protein. CONCLUSION: Our results suggest that physiological levels of E(2 )may act to sequester DAT in intracellular compartments where the transporter's second extramembrane loop is inaccessible (inside vesicles) and that rapid estrogenic actions on this differentiated neuronal cell type may be regulated via membrane ERs of several types

Quantitative changes in intracellular calcium and extracellular-regulated kinase activation measured in parallel in CHO cells stably expressing serotonin (5-HT) 5-HT2A or 5-HT2C receptors

<p>Abstract</p> <p>Background</p> <p>The serotonin (5-HT) 2A and 2C receptors (5-HT_2AR and 5-HT_2CR) are involved in a wide range of physiological and behavioral processes in the mammalian central and peripheral nervous systems. These receptors share a high degree of homology, have overlapping pharmacological profiles, and utilize many of the same and richly diverse second messenger signaling systems. We have developed quantitative assays for cells stably expressing these two receptors involving minimal cell sample manipulations that dramatically improve parallel assessments of two signaling responses: intracellular calcium (<it>Ca_i</it>⁺⁺) changes and activation (phosphorylation) of downstream kinases. Such profiles are needed to begin to understand the simultaneous contributions from the multiplicity of signaling cascades likely to be initiated by serotonergic ligands.</p> <p>Results</p> <p>We optimized the <it>Ca_i</it>⁺⁺assay for stable cell lines expressing either 5-HT_2AR or 5-HT_2CR (including dye use and measurement parameters; cell density and serum requirements). We adapted a quantitative 96-well plate immunoassay for pERK in the same cell lines. Similar cell density optima and time courses were observed for 5-HT_2AR- and 5-HT_2CR-expressing cells in generating both types of signaling. Both cell lines also require serum-free preincubation for maximal agonist responses in the pERK assay. However, 5-HT_2AR-expressing cells showed significant release of <it>Ca_i</it>⁺⁺in response to 5-HT stimulation even when preincubated in serum-replete medium, while the response was completely eliminated by serum in 5-HT_2CR-expressing cells. Response to another serotonergic ligand (DOI) was eliminated by serum-replete preincubation in both cells lines.</p> <p>Conclusions</p> <p>These data expand our knowledge of differences in ligand-stimulated signaling cascades between 5-HT_2AR and 5-HT_2CR. Our parallel assays can be applied to other cell and receptor systems for monitoring and dissecting concurrent signaling responses.</p

The power of co-ordinate transformations in dynamical interpretations of Galactic structure

$Gaia$ DR2 has provided an unprecedented wealth of information about the positions and motions of stars in our Galaxy, and has highlighted the degree of disequilibria in the disc. As we collect data over a wider area of the disc it becomes increasingly appealing to start analysing stellar actions and angles, which specifically label orbit space, instead of their current phase space location. Conceptually, while $\bar{x}$ and $\bar{v}$ tell us about the potential and local interactions, grouping in action puts together stars that have similar frequencies and hence similar responses to dynamical effects occurring over several orbits. Grouping in actions and angles refines this further to isolate stars which are travelling together through space and hence have shared histories. Mixing these coordinate systems can confuse the interpretation. For example, it has been suggested that by moving stars to their guiding radius, the Milky Way spiral structure is visible as ridge-like overdensities in the $Gaia$ data \citep{Khoperskov+19b}. However, in this work, we show that these features are in fact the known kinematic moving groups, both in the $L_z-\phi$ and the $v_{\mathrm{R}}-v_{\phi}$ planes. Using simulations we show how this distinction will become even more important as we move to a global view of the Milky Way. As an example, we show that the radial velocity wave seen in the Galactic disc in $Gaia$ and APOGEE should become stronger in the action-angle frame, and that it can be reproduced by transient spiral structure.Comment: 12 pages, 10 Figure

Pimavanserin and Lorcaserin Attenuate Measures of Binge Eating in Male Sprague-Dawley Rats

Binge eating disorder (BED) is characterized by dysregulated feeding and reward-related processes, and treatment is often challenged by limited therapeutic options. The serotonin (5-HT) 5-HT2A receptor (5-HT2AR) and 5-HT2CR are implicated in both feeding-related and reward-related behaviors and are thus poised to regulate BED-related behaviors. The purpose of this study was to assess the efficacy of the FDA-approved medications pimavanserin, a 5-HT2AR antagonist/inverse agonist, and lorcaserin, a 5-HT2CR agonist, in a rodent model of binge eating. The effects of pimavanserin (0.3–3.0 mg/kg), lorcaserin (0.25–1.0 mg/kg), and the lowest effective dose of pimavanserin (0.3 mg/kg) plus lorcaserin (1.0 mg/kg) were tested in a high-fat food (HFF) intermittent access binge eating model in adult male Sprague-Dawley rats (n = 64). We assessed three measures related to binge eating – binge episode occurrence, binge intake, and weight gain associated with HFF access. Pimavanserin decreased binge intake and weight gain associated with HFF access, but did not prevent binge episode occurrence. Lorcaserin decreased binge intake, but did not prevent binge episode occurrence or weight gain associated with HFF access. Combined pimavanserin plus lorcaserin prevented binge episode occurrence in addition to decreasing binge intake and weight gain associated with HFF access. These preclinical findings in male rats suggest that pimavanserin and lorcaserin may be effective in treating patients with BED. Our studies further indicate that administration of one or both drugs may be more effective in certain sub-populations of patients with BED because of the unique profile each treatment elicits. These data support future assessment in clinical populations with BED

The power of animation:encouraging doctors to access support for psychological wellbeing

The COVID-19 pandemic has exacerbated already high rates of poor psychological wellbeing in doctors. Many doctors perceive a stigma associated with acknowledging psychological wellbeing concerns, resulting in a reluctance to seek support for those concerns. The aim of this study was to develop a theoretically-informed and evidence-based composite narrative animation (CNA) to encourage doctors to access support for psychological wellbeing, and to evaluate the acceptability of the CNA.A composite narrative was developed from an evidence-base of interviews with 27 GP participants across Scotland (May–July 2020). The Behaviour Change Wheel was used to identify behaviour change techniques (BCTs) to be embedded within the CNA. The narrative was turned into a script in collaboration with an animation company. A brief animation ‘Jane the GP’ was developed reflecting specific BCTs.Scottish doctors (n = 83) were asked for their views on acceptability of the CNA concept, and subsequently asked to provide views on the acceptability of the CNA after viewing it. Participants thought the concept of a CNA was novel but may not appeal to all. After viewing the CNA, the widespread view was that it portrayed an authentic experience, could reduce stigma around seeking support for psychological wellbeing, and highlighted formal routes to access such support.CNAs are a novel and acceptable intervention method for encouraging doctors to access support for psychological wellbeing. The use of a theory driven intervention development framework to create the CNA facilitates the link between theory and practice