Reducing falls in Parkinson’s disease: interactions between donepezil and the 5‐HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements

Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson’s disease (PD), the leading levodopa‐insensitive cause of hospitalization and long‐term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic–dopaminergic losses (“DL rats”) and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5‐HT6 receptor antagonist idalopirdine (Lu AE58054) was reported to exhibit synergistic pro‐cholinergic activity in rats and improved cognition in patients with moderate Alzheimer’s disease, here we assessed the effects of this treatment on MCMCT performance and attention in DL rats. Compared with the vehicle‐treated group, the combined treatment greatly reduced (Cohen’s d = 0.96) falls in DL rats when traversing dynamic surfaces and when exposed to a passive distractor. However, falls associated with a dual task distractor and sustained attentional performance did not benefit from this treatment. Analyses of the behavior in fall‐prone moments suggested that this treatment improved the efficacy and speed of re‐instating forward movement after relatively short stoppages. This treatment may reduce fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait.Following short freezes, rats with dual cortical cholinergic and striatal dopaminergic deafferentation resumed forward movement relatively slowly, generally with the tail positioned relatively low and with a slouched posture, yielding slips and falls. When treated with donepezil and idalopirdine (DON + IDL), such rats resumed forward movement, sometimes starting with a hop, they quickly regaining regular traversal speed and fluid forward movement, with high and firm tail position and upright posture, thereby preventing slips and falls.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135976/1/ejn13354_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135976/2/ejn13354.pd

Public procurement and labour market inequality : conceptualising a multi-faceted relationship

Over the past few decades, policymakers have become increasingly intrigued by public procurement's potential to serve as a policy tool. In line with an increased prevalence of attempts to leverage public procurement for promoting employment-related goals, a growing body of research explores the linkages between public procurement and employment. Yet, while different aspects of the procurement process influence labour market outcomes and the linkages are multiple, current research focuses on individual aspects only. As a result, current understandings of the linkage between public procurement and its labour market effects remain fragmented. Considering choices between the initial identification of an object of purchase and the award and delivery of the contract, this article conceptualises the multi-faceted linkages between public procurement and labour market inequalities understood as issues ofaccess to and (in)equality in employment. It argues that three key aspects (the design of the object, requirements set in the process of buying, and the type of provider) make distinct contributions to the overall impact that procurement processes have on labour market inequality and outlines a framework for analysing the implications of choices at these three core decision points

Marketization, regulation, and equality : towards an analytical framework for understanding the equality impact of public procurement

With the rise of the regulatory welfare state, public procurement gained increasing importance as a tool for the regulation of wages and working conditions and a lever for promoting equality. Yet, despite growing attention to and understanding of public procurement’s relation to equality, existing knowledge remains fragmented. An analytical framework that captures and systematizes the multifaceted interaction between public procurement and equality is still missing. Focusing on conditions of purchasing and obligations set as part of the procurement processes, this article explores the way in which public procurement processes generate equality impacts first through stipulations and practices which are not explicitly linked to equality but generate equality impacts, and second through proactive measures designed to foster equality. It argues that a holistic understanding of public procurement’s equality impact needs to take account of the individual combination of features

‘Hot’ vs. ‘cold’ behavioural‐cognitive styles: motivational‐dopaminergic vs. cognitive‐cholinergic processing of a Pavlovian cocaine cue in sign‐ and goal‐tracking rats

Discrete Pavlovian reward cues acquire more potent incentive motivational properties (incentive salience) in some animals (sign‐trackers; STs) compared to others (goal‐trackers; GTs). Conversely, GTs appear to be better than STs in processing more complex contextual cues, perhaps reflecting their relatively greater bias for goal‐directed cue processing. Here, we investigated the activity of two major prefrontal neuromodulatory input systems, dopamine (DA) and acetylcholine (ACh), in response to a discrete Pavlovian cue that was previously paired with cocaine administration in STs and GTs. Rats underwent Pavlovian training in which light cue presentations were either paired or unpaired with an intravenous cocaine infusion. Following a 10‐day abstinence period, prefrontal dialysates were collected in STs and GTs during cue presentations in the absence of cocaine. In STs, the cue previously paired with cocaine significantly increased prefrontal DA levels. DA levels remained elevated over baseline across multiple cue presentation blocks, and DA levels and approaches to the cue were significantly correlated. In STs, ACh levels were unaffected by cue presentations. In contrast, in GTs, presentations of the cocaine cue increased prefrontal ACh, but not DA, levels. GTs oriented towards the cue at rates similar to STs, but they did not approach it and elevated ACh levels did not correlate with conditioned orientation. The results indicate a double dissociation between the role of prefrontal DA and ACh in STs and GTs, and suggest that these phenotypes will be useful for studying the role of neuromodulator systems in mediating opponent behavioural‐cognitive styles.We investigated the activity of two major prefrontal neuromodulatory input systems, dopamine (DA) and acetylcholine (ACh), in response to a Pavlovian cue that was previously paired with cocaine administration in STs and GTs. Following an abstinence period and in the absence of cocaine, cue presentations (C1–C4) in STs resulted in increases in extracellular DA, but not ACh, levels (left). In contrast, cue presentations in GTs increased ACh, but not DA, levels (NC, no‐cue).Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141035/1/ejn13741_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141035/2/ejn13741-sup-0001-reviewer_comments.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141035/3/ejn13741.pd

The role and impact of employment charters and procurement by subnational authorities to achieve good work standards

The report is based on interviews with local authority procurement leads, and a review of procurement policies and other documents within the local authorities. Some sub-regional governments in England are resorting to 'soft' legislation in order to develop good work practices in their local labour markets. The study analysed the procurement practices of local authorities on four Mayoral Combined authorities, one of which had a Good Work Charter. The study found that a number of cross-cutting themes emerged: good work is commended, not required; legal risk and uncertainty limits what LADs are willing to try through procurement; resources and staffing limit capacity to do more; there are gaps between policy aims and practical realities; and political backing is important. There is an increasing focus and amount of work being undertaken to increase the local value of LAD spend. The focus is usually on social value and increasing spend going to local suppliers. But increasingly there are attempts to secure improvements in local employment conditions and practices through linking good work dimensions to local authority procurement. The biggest challenges to these efforts is the lack of policy coherence and resource constraints. At a national level, whilst social value and good work are identified as Government commitments, there have been delays in legislation to both the procurement and employment aspects of this. Without these, sub national authorities - MCAs and LADs - are wary of the extent of how far they can go in including stipulations in their contracting processes. Where there has been the greatest political coherence, in Greater Manchester, both the MCA and local authorities have been able to make the greatest strides in linking good work conditions to local procurement. The lack of resources, particularly in terms of staffing, posed challenges for the successful implementation, including in particular the monitoring, of social public procurement. Our findings thereby seem to support previous findings that point to the importance of political commitment and leadership and resources and extend these particularly to practices of linking public procurement and good work

Diminished trk A receptor signaling reveals cholinergic‐attentional vulnerability of aging

The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain ( BF ) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno‐associated viral vector‐based RNA interference ( AAV ‐ RNA i) strategy to suppress the expression of tropomyosin‐related kinase A (trk A ) receptors by cholinergic neurons in the nucleus basalis of M eynert/substantia innominata ( nMB / SI ) of adult and aged rats. Suppression of trk A receptor expression impaired attentional performance selectively in aged rats. Performance correlated with trk A levels in the nMB / SI . trk A knockdown neither affected nMB / SI cholinergic cell counts nor the decrease in cholinergic cell size observed in aged rats. However, trk A suppression augmented an age‐related decrease in the density of cortical cholinergic processes and attenuated the capacity of cholinergic neurons to release acetylcholine ( AC h). The capacity of cortical synapses to release AC h in vivo was also lower in aged/trk A ‐ AAV ‐infused rats than in aged or young controls, and it correlated with their attentional performance. Furthermore, age‐related increases in cortical pro NGF and p75 receptor levels interacted with the vector‐induced loss of trk A receptors to shift NGF signaling toward p75‐mediated suppression of the cholinergic phenotype, thereby attenuating cholinergic function and impairing attentional performance. These effects model the abnormal trophic regulation of cholinergic neurons and cognitive impairments in patients with early A lzheimer's disease. This rat model is useful for identifying the mechanisms rendering aging cholinergic neurons vulnerable as well as for studying the neuropathological mechanisms that are triggered by disrupted trophic signaling. The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain ( BF ) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno‐associated viral vector‐based RNA interference ( AAV ‐ RNA i) strategy to suppress the expression of trk A receptors by cholinergic neurons in the nucleus basalis of M eynert/substantia innominata (n MB / SI ) of adult and aged rats. This study provides novel evidence that reduced trkA receptors is not sufficient to trigger cholinergic dysfunction. Rather, aging interacts with disrupted trkA signaling to escalate the vulnerability of BF cholinergic neurons and the manifestation of age‐related attentional impairments.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/96365/1/ejn12090-sup-0001-SupportingInformation.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/96365/2/ejn12090.pd

Communicating product user reviews and ratings in interfaces for e-commerce: a multimodal approach

This paper describes a comparative empirical evaluation study that uses multimodal presentations to communicate review messages in an e-commerce platform. Previous studies demonstrate the effective use of multimodality in different problem domains (e.g. e-learning). In this paper, multimodality and expressive avatars are used to communicate information related to product reviews messages. The data of the reviews was opportunistically collected from Facebook and Twitter. Two independent groups of users were used to evaluate two different presentations of reviews and ratings using as a basis an experimental e- commerce platform. The control group used a text-based with emojis presentation and the experimental group used a multimodal approach based on expressive avatars. Three parameters of usability were measured. These were efficiency, effectiveness, user satisfaction, and user preference. The result showed that the two approaches performed similarly. These findings provide a basis for further experiments in which text, emojis and expressive avatars can be combine to communicate a larger volume of reviews and ratings

Axonal Varicosity Density as an Index of Local Neuronal Interactions

Diffuse transmission is an important non-synaptic communication mode in the cerebral neocortex, in which neurotransmitters released from en passant varicosities interact with surrounding cells. In a previous study we have shown that the cholinergic axonal segments which were in the microproximity with dopaminergic fibers possessed a greater density of en passant varicosities compared to more distant segments, suggesting an activity-dependent level of en passant varicosities in the axonal zone of interaction. To further evaluate this plastic relationship, the density of cholinergic varicosities was quantified on fiber segments within the microproximity of activated or non-activated pyramidal cells of the prefrontal cortex (mPFC). Repetitive 14 days patterned visual stimulation paired with an electrical stimulation of the cholinergic fibers projecting to the mPFC from the HDB was performed to induce persistent axonal plastic changes. The c-Fos early gene immunoreactivity was used as a neuronal activity marker of layer V pyramidal cells, labelled with anti-glutamate transporter EAAC1. Cholinergic fibers were labeled with anti-ChAT (choline acetyltransferase) immunostaining. The density of ChAT+ varicosities on and the length of fiber segments within the 3 µm microproximity of c-Fos positive/negative pyramidal cells were evaluated on confocal images. More than 50% of the pyramidal cells in the mPFC were c-Fos immunoreactive. Density of ChAT+ varicosities was significantly increased within 3 µm vicinity of activated pyramidal cells (0.50±0.01 per µm of ChAT+ fiber length) compared to non-activated cells in this group (0.34±0.001; p≤0.05) or control rats (0.32±0.02; p≤0.05). Different types of stimulation (visual, HDB or visual/HDB) induced similar increase of the density of ChAT+ varicosities within microproximity of activated pyramidal cells. This study demonstrated at the subcellular level an activity-dependent enrichment of ChAT+ varicosities in the axonal zone of interaction with other neuronal elements