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

Establishing consensus of position-specific predictors for elite youth soccer in England

Purpose: To construct a valid and reliable methodology for the development of position- specific predictors deemed appropriate for talent identification purposes within elite youth soccer in England. Method: N = 10 experts participated in a three-step modified e-Delphi poll to generate consensus on a series of generic youth player attributes. A follow up electronic survey completed by coaches, scouts and recruitment staff (n = 99) ranked these attributes to specific player- positions. Results: A final list of 44 player attributes found consensus using the three-step modified e-Delphi poll and the findings indicated that player-positional attributes considered most important at the youth phase are more psychological and technical than physiological or anthropometric. Despite ‘hidden’ attributes (e.g. coachability, flair, versatility, vision etc) finding consensus on the e-Delphi poll, there was no evidence to support these traits when associated with a specific playing position. Conclusion: For those practitioners responsible for talent recruitment, our findings may provide greater understanding of the multiple attributes required for some playing positions. However, new ecological research is required to assess the veracity of our claims

Exercise Training to Target Gait Unsteadiness in People with Diabetes

Balance impairment and an associated high fall rate in people with diabetes is common, and a huge burden to quality of life and healthcare systems. Causes of impaired balance are commonly attributed to both sensory and motor deficits, which includes impaired muscle strength and function. This study investigated the effects of resistance exercise training on balance control during walking over level ground and on stairs. Ten DM people (age: 62 years, BMI: 29kg/m2, VPT: 9V) and 6 DM people with DPN (age: 59 years, BMI: 27kg/m2, VPT: 31V) performed a 16-week intervention of weekly resistance exercise training to increase ankle and knee extensor muscle strength. Six DM controls did not take part in the intervention (age: 50 years, BMI: 26kg/m2, VPT: 12V). Balance during gait was quantified before and after the intervention, by separation between the body centre-of-mass and centre-of-pressure under the feet during both level and stair walking. Knee and ankle extensor muscle strength was assessed using a dynamometer. The exercise intervention increased strength of ankle plantar flexors (22%) and knee extensors (30%). Despite the increases in lower limb muscle strength produced by the intervention, no improvements in balance were seen post training. However, gait speed did increase by 8%, which previous research has shown to be associated with quality of life. Controls showed no training effects in any variables. Although this exercise intervention had a positive effect on gait by increasing walking speed, there was no effect on the control of balance. Previous research has identified that medio-lateral (side-to-side) balance is impaired in people with DPN. The muscles exercised in the present study mainly control the major sagittal plane (forwards-backwards) movements that occur during gait. Interventions targeting the lateral stabilising muscles of the hip and trunk, may show greater potential efficacy in redressing the balance impairment of this population

Altered joint moment strategy during stair walking in diabetes patients with and without peripheral neuropathy

© 2016 The Authors. Aim: To investigate lower limb biomechanical strategy during stair walking in patients with diabetes and patients with diabetic peripheral neuropathy, a population known to exhibit lower limb muscular weakness. Methods: The peak lower limb joint moments of twenty-two patients with diabetic peripheral neuropathy and thirty-nine patients with diabetes and no neuropathy were compared during ascent and descent of a staircase to thirty-two healthy controls. Fifty-nine of the ninety-four participants also performed assessment of their maximum isokinetic ankle and knee joint moment (muscle strength) to assess the level of peak joint moments during the stair task relative to their maximal joint moment-generating capabilities (operating strengths). Results: Both patient groups ascended and descended stairs slower than controls (p < 0.05). Peak joint moments in patients with diabetic peripheral neuropathy were lower (p < 0.05) at the ankle and knee during stair ascent, and knee only during stair descent compared to controls. Ankle and knee muscle strength values were lower (p < 0.05) in patients with diabetic peripheral neuropathy compared to controls, and lower at knee only in patients without neuropathy. Operating strengths were higher (p < 0.05) at the ankle and knee in patients with neuropathy during stair descent compared to the controls, but not during stair ascent. Conclusion: Patients with diabetic peripheral neuropathy walk slower to alter gait strategy during stair walking and account for lower-limb muscular weakness, but still exhibit heightened operating strengths during stair descent, which may impact upon fatigue and the ability to recover a safe stance following postural instability

Lifting the veil of depression and alcoholism in sport coaching: how do we care for carers?

The purpose of this article is to explore the insights of an elite sport coach living with comorbid depression and alcohol misuse. Such consideration is necessary because as coaching is increasingly repositioned as a caring activity the wellbeing of coaches themselves has rarely been considered. To address this gap, a narrative analysis methodology and a story telling approach was used to present the experiences of a case study coach (Steve). The story is derived from Steve’s own perspective and the perspective of his wife, Jane. This novel multi-voiced approach reveals the complex interplay between the sporting environment, Steve’s depression and his alcohol related problems. In doing so, Steve’s story makes an original contribution by unveiling the issue of mental health in elite sport coaching. Steve’s story depicts the significant impact of depressive symptoms, coupled by excessive alcohol use on a coach, their personal life, and their career. Using the work of Goffman and Sartre, the story alludes to how such symptoms can be hidden, to greater and lesser extents, from professional colleagues. This is an important theoretical contribution, because to care for coaches, colleagues, employers, and health professionals will need to understand the needs of individuals such as Steve. Developing an open and supportive culture, which accepts that coaches are fallible, may however be a challenge within professional sport contexts

Sensory-motor mechanisms increasing falls risk in diabetic peripheral neuropathy

Diabetic peripheral neuropathy (DPN) is associated with peripheral sensory and motor nerve damage that affects up to half of diabetes patients and is an independent risk factor for falls. Clinical implications of DPN-related falls include injury, psychological distress and physical activity curtailment. This review describes how the sensory and motor deficits associated with DPN underpin biomechanical alterations to the pattern of walking (gait), which contribute to balance impairments underpinning falls. Changes to gait with diabetes occur even before the onset of measurable DPN, but changes become much more marked with DPN. Gait impairments with diabetes and DPN include alterations to walking speed, step length, step width and joint ranges of motion. These alterations also impact the rotational forces around joints known as joint moments, which are reduced as part of a natural strategy to lower the muscular demands of gait to compensate for lower strength capacities due to diabetes and DPN. Muscle weakness and atrophy are most striking in patients with DPN, but also present in non-neuropathic diabetes patients, affecting not only distal muscles of the foot and ankle, but also proximal thigh muscles. Insensate feet with DPN cause a delayed neuromuscular response immediately following foot–ground contact during gait and this is a major factor contributing to increased falls risk. Pronounced balance impairments measured in the gait laboratory are only seen in DPN patients and not non-neuropathic diabetes patients. Self-perception of unsteadiness matches gait laboratory measures and can distinguish between patients with and without DPN. Diabetic foot ulcers and their associated risk factors including insensate feet with DPN and offloading devices further increase falls risk. Falls prevention strategies based on sensory and motor mechanisms should target those most at risk of falls with DPN, with further research needed to optimise interventions

Evasion of a human cytomegalovirus entry inhibitor with potent cysteine reactivity is concomitant with the utilisation of a heparan sulfate proteoglycan independent route of entry

The dependence of viruses on the host cell to complete their replicative cycle renders cellular functions potential targets for novel anti-virals. We screened a panel of broad acting cellular ion channel inhibitors for activity against human cytomegalovirus (HCMV) and identified the voltage-gated chloride ion channel inhibitor 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) as a potent inhibitor of HCMV replication. Time of addition studies demonstrated that DIDS inhibited entry via a direct interaction with the virion that impeded binding to the plasma membrane. Synthesis and analysis of pharmacological variants of DIDS suggested that intrinsic cysteine, and not lysine, reactivity was important for activity against HCMV.Although sequencing of a DIDS-resistant HCMV revealed enrichment of a mutation within UL100 (encoding for glycoprotein M) and a specific truncation of glycoprotein RL13, these did not explain the DIDS resistance phenotype. Specifically, only the introduction of the RL13 mutant partially pheno-copied the DIDS resistance phenotype. Serendipitously, the entry of DIDS-resistant HCMV also became independent of heparan sulfate proteoglycans (HSPGs) suggesting that evasion of DIDS lowered dependence on an initial interaction with HSPGs. Intriguingly, the DIDS-resistant virus demonstrated increased sensitivity to antibody neutralisation, which mapped, in part, to the presence of the gM mutation.Taken together the data characterise the anti-viral activity of a novel HCMV inhibitor that drives HCMV infection to occur independent of HSPGs and the generation of increased sensitivity to humoral immunity. The data also demonstrate that compounds with cysteine reactivity have the potential to act as anti-viral compounds against HCMV via direct engagement of virions.IMPORTANCE Human cytomegalovirus (HCMV) is major pathogen of non-immunocompetent individuals which remains in need of new therapeutic options. Here we have identified a potent antiviral compound (4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid, DIDS), its mechanism of action and the chemical properties required for its activity. In doing so, the data argue that cysteine-reactive compounds could have the capacity to be developed for anti-HCMV activity. Importantly, the data show that entry of DIDS resistant virus became independent of heparan sulfate proteoglycans (HSPGs) but, concomitantly, became more sensitive to neutralising antibody responses. This serendipitous observation suggests that retention of an interaction with HSPGs during the entry process in vivo may be evolutionarily advantageous through better evasion of humoral responses directed against HCMV virions