NFE2L2, PPARGC1α, and pesticides and Parkinson’s disease risk and progression

ObjectiveTo investigate three expression-altering NFE2L2 SNPs and four PPARGC1α previously implicated SNPs and pesticides on Parkinson's disease (PD) risk and symptom progression.MethodsIn 472 PD patients and 532 population-based controls, we examined variants and their interactions with maneb and paraquat (MB/PQ) pesticide exposure on PD onset (logistic regression) and progression of motor symptoms and cognitive decline (n = 192; linear repeated measures).ResultsNFE2L2 rs6721961 T allele was associated with a reduced risk of PD (OR = 0.70, 95% CI = 0.53, 0.94) and slower cognitive decline (β = 0.095; p = 0.0004). None of the PPARGC1α SNPs were marginally associated with PD risk. We estimate statistical interactions between MB/PQ and PPARGC1α rs6821591 (interaction p = 0.009) and rs8192678 (interaction p = 0.05), such that those with high exposure and the variant allele were at an increased risk of PD (OR ≥ 1.30, p ≤ 0.05). PPARGC1α rs6821591 was also associated with faster motor symptom progression as measured with the UPDRS-III (β = 0.234; p = 0.001).ConclusionOur study provides support for the involvement of both NFE2L2 and PPARGC1α in PD susceptibility and progression, marginally and through pathways involving MB/PQ exposure

Esrrb function is required for proper primordial germ cell development in presomite stage mouse embryos.

Estrogen related receptor beta (Esrrb) is an orphan nuclear receptor that is required for self-renewal and pluripotency in mouse embryonic stem (ES) cells. However, in the early post-implantation mouse embryo, Esrrb is specifically expressed in the extraembryonic ectoderm (ExE) and plays a crucial role in trophoblast development. Previous studies showed that Esrrb is also required to maintain trophoblast stem (TS) cells, the in vitro stem cell model of the early trophoblast lineage. In order to identify regulatory targets of Esrrb in vivo, we performed microarray analysis of Esrrb-null versus wild-type post-implantation ExE, and identified 30 genes down-regulated in Esrrb-mutants. Among them is Bmp4, which is produced by the ExE and known to be critical for primordial germ cell (PGC) specification in vivo. We further identified an enhancer region bound by Esrrb at the Bmp4 locus by performing Esrrb ChIP-seq and luciferase reporter assay using TS cells. Finally, we established a knockout mouse line in which the enhancer region was deleted using CRISPR/Cas9 technology. Both Esrrb-null embryos and enhancer knockout embryos expressed lower levels of Bmp4 in the ExE, and had reduced numbers of PGCs. These results suggested that Esrrb functions as an upstream factor of Bmp4 in the ExE, regulating proper PGC development in mice

A randomised controlled trial of a walking training with simultaneous cognitive demand (dual task) in chronic stroke

Objective. To evaluate the tolerability of, adherence to and efficacy of a community walking training programme with simultaneous cognitive demand (dual‐task) compared to a control walking training programme without cognitive distraction. Methods. Adult stroke survivors, at least 6 months after stroke with a visibly obvious gait abnormality or reduced two‐minute walk distance were included into a 2‐arm parallel randomized controlled trial of complex intervention with blinded assessments. Participants received a 10 week, bi‐weekly, 30 minutes treadmill program at an aerobic training intensity (55‐85% heart rate maximum), either with, or without simultaneous cognitive demands. Outcome measured at 0, 11 and 22 weeks. Primary: two‐minute‐walk tests with and without cognitive distraction, dual task effect on walking and cognition; secondary: SF‐36, EuroQol‐5D‐5L, Physical Activity Scale for Elderly (PASE), and step activity. Results. Fifty stroke patients were included, 43 received allocated training and 45 completed all assessments. The experimental group (n = 26) increased mean (SD) two‐minute walking distance from 90.7 (8.2) to 103.5 (8.2) metres, compared with 86.7 (8.5) to 92.8 (8.6) in the control group, and their PASE score from 74.3 (9.1) to 89.9 (9.4), compared with 94.7 (9.4) to 77.3 (9.9) in the control group. Statistically, only the change in the PASE differed between the groups (p = 0.029), with the dual‐task group improving more. There were no differences in other measures. Conclusions. Walking with specific additional cognitive distraction (dual‐task training) might increase activity more over 12 weeks, but the data are not conclusive

Dual-task walking and automaticity after stroke: Insights from a secondary analysis and imaging sub-study of a randomised controlled trial

Objective. To test the extent to which initial walking speed influences dual-task performance after walking intervention, hypothesising that slow walking speed affects automatic gait control, limiting executive resource availability. Design. A secondary analysis of a trial of dual-task (DT) and single-task (ST) walking interventions comparing those with good (walking speed ⩾0.8 m s−1, n = 21) and limited (walking speed <0.79 m s−1, n = 24) capacity at baseline. Setting. Community. Subjects. Adults six-months post stroke with walking impairment. Interventions. Twenty sessions of 30 minutes treadmill walking over 10 weeks with (DT) or without (ST) cognitive distraction. Good and limited groups were formed regardless of intervention received. Main measures. A two-minute walk with (DT) and without (ST) a cognitive distraction assessed walking. fNIRS measured prefrontal cortex activation during treadmill walking with (DT) and without (ST) Stroop and planning tasks and an fMRI sub-study used ankle-dorsiflexion to simulate walking. Results. ST walking improved in both groups (∆baseline: Good = 8.9 ± 13.4 m, limited = 5.3±8.9 m, Group × time = P < 0.151) but only the good walkers improved DT walking (∆baseline: Good = 10.4 ± 13.9 m, limited = 1.3 ± 7.7 m, Group × time = P < 0.025). fNIRS indicated increased ispilesional prefrontal cortex activation during DT walking following intervention (P = 0.021). fMRI revealed greater DT cost activation for limited walkers, and increased resting state connectivity of contralesional M1 with cortical areas associated with conscious gait control at baseline. After the intervention, resting state connectivity between ipsilesional M1 and bilateral superior parietal lobe, involved in integrating sensory and motor signals, increased in the good walkers compared with limited walkers. Conclusion. In individuals who walk slowly it may be difficult to improve dual-task walking ability

Voices from an edge. Unsettling the practices of youth voice and participation: arts-based practice in The Blue Room, Manchester

The strengths and limitations of approaches to participatory and democratic practice rooted in voice have been discussed in relation to education and also ‘youth voice’. The paper seeks to make critical connection between the two debates, especially in relation to the persistence of practices of exclusion and marginalisation. Drawing on a two-year participant observation of a creativity-based project in Manchester, UK – The Blue Room – which worked with young men in the city centre who may have been engaged in selling sex, the article asks what it might mean for them to have voice. The widely discussed limitations of neo-liberal accounts of voice and choice are evident in this case, for the extent to which such a way of life can be thought to be freely chosen is a matter of intense debate. The possibility explored in this article is that arts-based strategies of pedagogic engagement might offer (to this group of young people and others) a hopeful (because complex, provisional and in process) form of voice rather than a tokenistic and controlling one

Non-formal spaces of socio-cultural accompaniment: Responding to young unaccompanied refugees – reflections from the Partispace project.

Drawing on research in progress in the Partispace project we make a case for the recognition of the importance of non-formal spaces in response to young refugees across three different national contexts: Frankfurt in Germany; Gothenburg in Sweden; and Manchester in the UK. It is argued that recognition of local regulation and national controls of immigration which support climates of hostility makes it important to recognise and affirm the significance of non-formal spaces and ‘small spaces close to home’ which are often developed in the ‘third space’ of civil society and arise from the impulses driven by the solidarity of volunteers. In these contexts it is important that practices of hospitality can develop which symbolically reconstitute refugees as hosts and subjects of a democratic conversation, without which there is no possible administrative solution to the refugee crisis. It is essential that educational spaces such as schools, colleges and universities forge strong bonds with such emergent spaces

‘Is this a time of beautiful chaos?’: reflecting on international feminist legal methods

This article considers how Margaret Jane Radin’s theory of the feminist double bind can bring conceptual clarity to the difficulties feminisms face in engaging with political and legal institutions of global governance. I draw on her theory to reinitiate a conversation on ideal and nonideal theory, in order to answer the call of key proponents in international legal feminism to reevaluate methodologies in critiquing mainstream institutions. By providing an account of how to navigate the double bind, this article brings conceptual clarity to the tension between resistance and compliance that has been argued to lie at the heart of the feminist project in international law. I demonstrate how this theoretical framework can foster greater pluralist perspectives in feminist engagement of ideal theories to temper the deradicalising and conservative risk of navigating feasibility constrained nonideal strategies

Symptoms and risk factors for long COVID in non-hospitalized adults

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02–8.39), hair loss (3.99, 3.63–4.39), sneezing (2.77, 1.40–5.50), ejaculation difficulty (2.63, 1.61–4.28) and reduced libido (2.36, 1.61–3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors