Endocannabinoid system alterations in Alzheimer's disease: a systematic review of human studies

Studies investigating alterations of the endocannabinoid system (ECS) in Alzheimer's disease (AD) in humans have reported inconsistent findings so far. We performed a systematic review of studies examining alterations of the ECS specifically within humans with AD or mild cognitive impairment (MCI), including neuroimaging studies, studies of serum and cerebrospinal fluid biomarkers, and post-mortem studies. We attempted to identify reported changes in the expression and activity of: cannabinoid receptors 1 and 2; anandamide (AEA); 2-arachidonoylglycerol (2-AG); monoacylglycerol lipase (MAGL); fatty acid amide hydrolase (FAAH); and transient receptor potential cation channel V1 (TRPV1). Twenty-two studies were identified for inclusion. Mixed findings were reported for most aspects of the ECS in AD, making it difficult to identify a particular profile of ECS alterations characterising AD. The included studies tended to be small, methodologically heterogeneous, and frequently did not control for important potential confounders, such as pathological progression of AD. Eight studies correlated ECS alterations with neuropsychometric performance measures, though studies infrequently examined behavioural and neuropsychiatric correlates. PROSPERO database identifier: CRD42018096249

Complex Shoulder Instability: A combined study of functional MRI, Electromyography and 3-D motion analysis

Purpose of Study : The pathophysiology of type II/III shoulder instability under the Stanmore Classification is not understood. This absence of knowledge prevents treatment strategies being devised or a proper understanding of existing therapies. This is the first study to approach this group of patients from both a cerebral and muscle analysis perspective. Methods : The assessment of shoulder movement was undertaken using two simple movements, forward flexion and abduction. The muscles around the shoulder (AD, MD, PD, UT, SA, BB, TM, LD, PM, SSP, ISP and SUB) were assessed in 21 individuals in the standing and supine position using EMG. In the supine position the movement was restricted to the movement possible in a Siemens 1.5 Tesla MRI Scanner. Patients were recruited with Polar type II/III shoulder instability, with their inclusion confirmed by the senior surgeon and physiotherapist. In total, 16 Polar type II/III patients were recruited along with 16 age-matched controls. The patients and the controls underwent an fMRI and EMG. The fMRI protocol involved movements of forward flexion and abduction in a 1.5 tesla MRI Scanner. The EMG movements tested were forward flexion and abductions to 90 degrees (AD, MD, PD, UT, SA, TM, LD, PM, BB, ISP). Both the patients and the controls completed questionnaires: the Western Ontario Shoulder Instability Index (WOSI), Oxford Shoulder Instability Score (OSIS) and Beck’s Depression Inventory. Results : Analysis of the EMG data in the normal shoulder group confirmed activations in both supine and standing positions; however the activations in the supine position were of a different character. There was increased activation in the patient group compared to the control group. In the patient group, with a voxel level familywise error rate (FWER) p=0.04, there was a unique activation at MNI coordinates -38 -26 56. The cluster FWER p<0.001 showed additional clusters in the patient group in the Primary somatosensory cortex, BA 3, Primary Motor Cortex, BA 4, Premotor cortex, BA 6 and Dorsolateral prefrontal cortex, BA 9. When the WOSI and OSIS were used as a contrast, activations were seen in primary somatosensory cortex, BA 3, supplementary motor cortex, BA 11, orbitofrontal area, BA 26, cingulate gyrus and the amygdala. The WOSI and OSIS showed a dramatically different score in the patient group compared to the controls, save for one patient whose symptoms had largely resolved following muscle patterning physiotherapy. Conclusion : The EMG studies in the standing and the supine position confirmed the validity of the fMRI paradigm. The instability questionnaires, WOSI and OSIS confirmed the patient group selection. The unique activation (MNI -38 -26 56) occurred within the primary motor cortex, with the cluster level voxels stretching between both the somatosensory cortex and the motor cortex. The WOSI and OSI comparisons show similar activations. This is thought to be evidence of compensatory activation. This additional activation was also seen in the EMG analysis, with evidence throughout all of the muscles that greater activation was needed to complete simple movement. Overall, the comparative addition cortical and muscles activations in patient group simultaneously demonstrate dysfunction and compensatory strategies employed to achieve simple shoulder movement

Exploring the length scales, timescales and chemistry of challenging materials (Part 2).

This themed issue explores the different length and timescales that determine the physics and chemistry of a variety of key of materials, explored from the perspective of a wide range of disciplines, including physics, chemistry materials science, Earth science and biochemistry. The topics discussed include catalysis, chemistry under extreme conditions, energy materials, amorphous and liquid structure, hybrid organic materials and biological materials. The issue is in two parts, with this second set of contributions exploring hybrid organic materials, catalysis low-dimensional and graphitic materials, biological materials and naturally occurring, super-hard material as well as dynamic high pressure and new developments in imaging techniques pressure. This article is part of the theme issue 'Exploring the length scales, timescales and chemistry of challenging materials (Part 2)'

Forces between clustered stereocilia minimize friction in the ear on a subnanometre scale

The detection of sound begins when energy derived from acoustic stimuli deflects the hair bundles atop hair cells. As hair bundles move, the viscous friction between stereocilia and the surrounding liquid poses a fundamental challenge to the ear's high sensitivity and sharp frequency selectivity. Part of the solution to this problem lies in the active process that uses energy for frequency-selective sound amplification. Here we demonstrate that a complementary part involves the fluid-structure interaction between the liquid within the hair bundle and the stereocilia. Using force measurement on a dynamically scaled model, finite-element analysis, analytical estimation of hydrodynamic forces, stochastic simulation and high-resolution interferometric measurement of hair bundles, we characterize the origin and magnitude of the forces between individual stereocilia during small hair-bundle deflections. We find that the close apposition of stereocilia effectively immobilizes the liquid between them, which reduces the drag and suppresses the relative squeezing but not the sliding mode of stereociliary motion. The obliquely oriented tip links couple the mechanotransduction channels to this least dissipative coherent mode, whereas the elastic horizontal top connectors stabilize the structure, further reducing the drag. As measured from the distortion products associated with channel gating at physiological stimulation amplitudes of tens of nanometres, the balance of forces in a hair bundle permits a relative mode of motion between adjacent stereocilia that encompasses only a fraction of a nanometre. A combination of high-resolution experiments and detailed numerical modelling of fluid-structure interactions reveals the physical principles behind the basic structural features of hair bundles and shows quantitatively how these organelles are adapted to the needs of sensitive mechanotransduction.Comment: 21 pages, including 3 figures. For supplementary information, please see the online version of the article at http://www.nature.com/natur

Coherent motion of stereocilia assures the concerted gating of hair-cell transduction channels

The hair cell's mechanoreceptive organelle, the hair bundle, is highly sensitive because its transduction channels open over a very narrow range of displacements. The synchronous gating of transduction channels also underlies the active hair-bundle motility that amplifies and tunes responsiveness. The extent to which the gating of independent transduction channels is coordinated depends on how tightly individual stereocilia are constrained to move as a unit. Using dual-beam interferometry in the bullfrog's sacculus, we found that thermal movements of stereocilia located as far apart as a bundle's opposite edges display high coherence and negligible phase lag. Because the mechanical degrees of freedom of stereocilia are strongly constrained, a force applied anywhere in the hair bundle deflects the structure as a unit. This feature assures the concerted gating of transduction channels that maximizes the sensitivity of mechanoelectrical transduction and enhances the hair bundle's capacity to amplify its inputs.Comment: 24 pages, including 6 figures, published in 200

The potential impact of Brexit on the energy, water and food nexus in the UK: A fuzzy cognitive mapping approach

© 2017 The Authors. Energy is one of the cornerstones essential for human life, along with other services such as water and food. Understanding how the different services in the energy-water-food (EWF) nexus interact and are perceived by different actors is key to achieving sustainability. In this paper, we derive a model of the EWF nexus using fuzzy cognitive mapping (FCM). Data were collected in a two-step approach from workshops with researchers and stakeholders involved in the three focal sectors. Four FCMs were developed; one for each of the EWF sectors, and one for the interactions that create the nexus between EWF. The FCM represents the combined views of the groups who participated in the workshops, the importance and limitations of which is discussed. To demonstrate its effectiveness, the aggregated FCM was applied to predict the impacts on the EWF nexus of four scenarios under which the United Kingdom would depart from the European Union (i.e. Brexit). The FCM indicated that energy-related concepts had the largest influence on the EWF nexus and that EWF demand will decrease most under a 'hard-Brexit' scenario. The demand for energy was shown to decline relatively less than other services and was strongly associated with gross domestic product (GDP), whereas UK population size had a stronger effect on water and food demand. Overall, we found a threefold change across all concepts in scenarios without freedom of movement, contribution to the EU budget, and increased policy devolution to the UK

Disrupted reward processing in Parkinson's disease and its relationship with dopamine state and neuropsychiatric syndromes: a systematic review and meta-analysis

Background: Neuropsychiatric symptoms are common in Parkinson’s disease (PD) and predict poorer outcomes. Reward processing dysfunction is a candidate mechanism for the development of psychiatric symptoms including depression and impulse control disorders (ICDs). We aimed to determine whether reward processing is impaired in PD and its relationship with neuropsychiatric syndromes and dopamine replacement therapy. // Methods: The Ovid MEDLINE/PubMed, Embase and PsycInfo databases were searched for articles published up to 5 November 2020. Studies reporting reward processing task performance by patients with PD and healthy controls were included. Summary statistics comparing reward processing between groups were converted to standardised mean difference (SMD) scores and meta-analysed using a random effects model. // Results: We identified 55 studies containing 2578 participants (1638 PD and 940 healthy controls). Studies assessing three subcomponent categories of reward processing tasks were included: option valuation (n=12), reinforcement learning (n=37) and reward response vigour (n=6). Across all studies, patients with PD on medication exhibited a small-to-medium impairment versus healthy controls (SMD=0.34; 95% CI 0.14 to 0.53), with greater impairments observed off dopaminergic medication in within-subjects designs (SMD=0.43, 95% CI 0.29 to 0.57). Within-subjects subcomponent analysis revealed impaired processing off medication on option valuation (SMD=0.57, 95% CI 0.39 to 0.75) and reward response vigour (SMD=0.36, 95% CI 0.13 to 0.59) tasks. However, the opposite applied for reinforcement learning, which relative to healthy controls was impaired on-medication (SMD=0.45, 95% CI 0.25 to 0.65) but not off-medication (SMD=0.28, 95% CI −0.03 to 0.59). ICD was the only neuropsychiatric syndrome with sufficient studies (n=13) for meta-analysis, but no significant impairment was identified compared tonon-ICD patients (SMD=−0.02, 95% CI −0.43 to 0.39). // Conclusion: Reward processing disruption in PD differs according to subcomponent and dopamine medication state, and warrants further study as a potential treatment target and mechanism underlying associated neuropsychiatric syndromes

Methodological and economic evaluations of seven survey modes applied to health service research

Objective: To evaluate methodological outcomes and cost-effectiveness of seven survey modes, using a study of general public views towards pharmacy public health services. Methods: A cross-sectional survey was conducted in North West England among people aged =?18 years, using two approaches. Three interviewer-assisted modes were street, door-to-door and telephone. Four self-completion modes were single-and double-mailing to residential addresses, surveys sent to public/private business by post (postal-business), and questionnaires dropped-off at venues (drop-off). The study compared response rates, demographics and two domains ((a) actual use of and (b) willingness to use pharmacy public health services) between modes. Incremental cost-effectiveness ratios of different modes were assessed against the single-mailing. Key findings: Response rate varied between 5.1% (postal-business) and 34.5% (street). Respondent age, education, employment, socioeconomic and deprivation status varied between different modes. Results for domain (a) were similar for all modes. Interviewer-assisted modes resulted in more positive views on willingness to use advisory services (P < 0.05). The drop-off mode saved ?45.92 (US$72.55) per 1% increase in response rate compared to single mailing, while interviewer-assisted and double-mailing were more costly. At higher response rates, cost-savings by the drop-off mode diminished, but for other survey modes, additional costs decreased. Conclusion: Drop-off mode is cost-effective compared to the standard single mailing, but selection bias is possible. Street surveys are also an efficient method, but may carry a higher risk of social desirability bias. Mixed-modes surveys may reach wider sectors of the population. The similarity in use of services suggests all survey modes reach members of the public relevant to pharmacy researchers

Oscillatory correlates of auditory working memory examined with human electrocorticography

This work examines how sounds are held in auditory working memory (AWM) in humans by examining oscillatory local field potentials (LFPs) in candidate brain regions. Previous fMRI studies by our group demonstrated blood oxygenation level-dependent (BOLD) response increases during maintenance in auditory cortex, inferior frontal cortex and the hippocampus using a paradigm with a delay period greater than 10s. The relationship between such BOLD changes and ensemble activity in different frequency bands is complex, and the long delay period raised the possibility that long-term memory mechanisms were engaged. Here we assessed LFPs in different frequency bands in six subjects with recordings from all candidate brain regions using a paradigm with a short delay period of 3 s. Sustained delay activity was demonstrated in all areas, with different patterns in the different areas. Enhancement in low frequency (delta) power and suppression across higher frequencies (beta/ gamma) were demonstrated in primary auditory cortex in medial Heschl’s gyrus (HG) whilst non-primary cortex showed patterns of enhancement and suppression that altered at different levels of the auditory hierarchy from lateral HG to superior- and middle-temporal gyrus. Inferior frontal cortex showed increasing suppression with increasing frequency. The hippocampus and parahippocampal gyrus showed low frequency increases and high frequency decreases in oscillatory activity. This work demonstrates sustained activity patterns during AWM maintenance, with prominent low-frequency increases in medial temporal lobe regions