Glial regenerative cell types in the superficial cortex in cortical dysplasia subtypes

PURPOSE: Focal Cortical Dysplasias (FCD) are localized malformative brain lesions in epilepsy. FCD3a associated with hippocampal sclerosis, affects the superficial cortex and is presumed to have an 'acquired' rather than developmental origin. Precursor cells may arise outside neurogenic zones including cortical layer I. Our aim was to characterise subsets of glial progenitor cells in the superficial cortical layers, known to be involved in gliosis and gliogenesis and that could distinguish FCD3a from other subtypes. METHODS: Using immunohistochemistry we quantified the density of glial progenitor subsets in superficial cortex layers using markers against PAX6, GFAP, Olig2 and PDGFRβ and proliferation marker MCM2 in ten FCD3a cases compared to 18 other FCD types and 11 non-FCD controls. KEY FINDINGS: Glial progenitor cells types were present in the cortical layer I and II in all FCD groups. GFAP cells frequently expressed PAX6 and significantly higher GFAP/PAX6 than GFAP/MCM2 cell densities were identified in the FCD3a group (p < 0.05). Olig2 cell densities were significantly higher in FCD3b than FCD3a (p = 0.002) and significantly higher GFAP/MCM2 compared to PDGFRβ/MCM2 cell densities were identified in both FCD3b and FCD2 groups. There was no correlation between cell densities and the age of patients at surgery and between cortical regions. SIGNIFICANCE: Immature and proliferative glial populations across FCD variants reflect reactive cell types and differences may provide insight into underlying pathomechanisms. Higher PAX6 expression in astroglial cells in FCD3a may indicate a switch to astrocytic maturation and enhanced superficial gliosis. Higher Olig2 and GFAP/MCM2 densities in FCD3b may reflect margins of the tumour infiltration zone rather than true cortical dysplasia

Spatiotemporal dynamics of PDGFRβ expression in pericytes and glial scar formation in penetrating brain injuries in adults

AIMS: Understanding the spatiotemporal dynamics of reactive cell types following brain injury is important for future therapeutic interventions. We have previously used penetrating cortical injuries following intracranial recordings as a brain repair model to study scar-forming nestin-expressing cells. We now explore the relationship between nestin-expressing cells, PDGFRβ+ pericytes and Olig2+ glia, including their proliferation and functional maturation. METHODS: In 32 cases, ranging from 3 to 461 days post injury (dpi), immunohistochemistry for PDGFRβ, nestin, GFAP, Olig2, MCM2, Aquaporin 4 (Aq4), Glutamine Synthetase (GS), and Connexin 43 (Cx43) were quantified for cell densities, labelling index (LI) and cellular co-expression at the injury site compared to control regions. RESULTS: PDGFRβ labelling highlighted both pericytes and multipolar parenchymal cells. PDGFRβ LI and PDGFRβ+ /MCM2+ cells significantly increased in injury zones at 10-13 dpi with migration of pericytes away from vessels with increased co-localisation of PDGRFβ with nestin compared to control regions (p < 0.005). Olig2+ /MCM2+ cell populations peaked at 13 dpi with significantly higher cell densities at injury sites than in control regions (p < 0.01) and decreasing with dpi (p < 0.05). Cx43 LI was reduced in acute injuries but increased with dpi (p < 0.05) showing significant cellular co-localisation with nestin and GFAP (p<0.005 and p<0.0001) but not PDGFRβ. CONCLUSIONS: These findings indicate that PDGFRβ+ and Olig2+ cells contribute to the proliferative fraction following penetrating brain injuries, with evidence of pericyte migration. Dynamic changes in Cx43 in glial cell types with dpi suggests functional alterations during temporal stages of brain repair. This article is protected by copyright. All rights reserved

Effectiveness of non-pharmacological interventions on the management of sarcopenic obesity: A systematic review and meta-analysis

Background: Sarcopenic obesity is a combination of both sarcopenia and obesity, which potentiate each other and maximize the negative influences of each, such as physical disability, morbidity, or even mortality. Objectives: To describe the criteria used to identify people with sarcopenic obesity and the components of the non-pharmacological interventions used to manage it, and to evaluate the effectiveness of those interventions.Methods: Randomized controlled trials (RCTs) in Cochrane Library, Scopus, EMBASE, PscyINFO, CINAHL and PubMed were searched. The risk of bias was examined using the Cochrane risk of bias tool. The template for intervention description and replication (TIDieR) checklist was used to summarize the intervention components. Meta-analyses were conducted using random-effect models to pool estimates of the effects of the non-pharmacological interventions on body composition, BMI, grip strength, and gait speed.Results: Sixteen papers (12 RCTs) with 863 participants were included. Diverse diagnostic criteria were used in the studies. Four categories of interventions were used: exercise (aerobic exercises, resistance exercises and exercise machines), nutritional interventions (supplements or dietary control), combined intervention and electrical acupuncture. Intervention durations varied from 8 to 28 weeks. Meta-analyses revealed that exercise with or without nutritional interventions had significant effects on grip strength (exercise: mean difference (MD): 1.63 kg, 95% confidence interval (CI): 0.94, 2.32, P < 0.00001; exercise + nutrition: MD: 1.24 kg, 95% CI: 0.48, 1.99, P = 0.001) and gait speed (exercise: MD: 0.13 m/s, 95% CI: 0.08, 0.18, P < 0.00001, I-2 = 0%; exercise + nutrition: MD: 0.04 m/s, 95% CI: 0.02, 0.06, P = 0.0002). Exercise had significant effects on reducing the percentage of body fat (PBF) compared to usual care (MD: -1.08%, 95% CI: -1.99, -0.17, P = 0.02), while exercise combined with nutritional interventions showed no superiority over exercise solely on decreasing PBF (P = 0.49). Exercise combined with nutritional interventions had significant effects on increasing appendicular skeletal muscle mass (MD: 0.43 kg, 95% CI: 0.20, 0.66, P = 0.0003). Low-caloric high-protein diets showed no superiority over low-caloric low-protein diets in increasing fat-free mass. Subgroup analyses showed that using different formulas to estimate the skeletal muscle mass index may lead to significant differences in determining the effects of exercise on grip strength.Conclusion: The diagnostic criteria for sarcopenic obesity used in future studies should refer to the latest consensus definition. Exercise tended to be the most effective method of improving grip strength and physical performance (e.g. gait speed). The combined effects of exercise and nutritional interventions on muscle mass and muscle strength require further exploration

Granule Cell Dispersion in Human Temporal Lobe Epilepsy: Proteomics Investigation of Neurodevelopmental Migratory Pathways

Granule cell dispersion (GCD) is a common pathological feature observed in the hippocampus of patients with Mesial Temporal Lobe Epilepsy (MTLE). Pathomechanisms underlying GCD remain to be elucidated, but one hypothesis proposes aberrant reactivation of neurodevelopmental migratory pathways, possibly triggered by febrile seizures. This study aims to compare the proteomes of basal and dispersed granule cells in the hippocampus of eight MTLE patients with GCD to identify proteins that may mediate GCD in MTLE. Quantitative proteomics identified 1,882 proteins, of which 29% were found in basal granule cells only, 17% in dispersed only and 54% in both samples. Bioinformatics analyses revealed upregulated proteins in dispersed samples were involved in developmental cellular migratory processes, including cytoskeletal remodeling, axon guidance and signaling by Ras homologous (Rho) family of GTPases (P < 0.01). The expression of two Rho GTPases, RhoA and Rac1, was subsequently explored in immunohistochemical and in situ hybridization studies involving eighteen MTLE cases with or without GCD, and three normal post mortem cases. In cases with GCD, most dispersed granule cells in the outer-granular and molecular layers have an elongated soma and bipolar processes, with intense RhoA immunolabeling at opposite poles of the cell soma, while most granule cells in the basal granule cell layer were devoid of RhoA. A higher percentage of cells expressing RhoA was observed in cases with GCD than without GCD (P < 0.004). In GCD cases, the percentage of cells expressing RhoA was significantly higher in the inner molecular layer than the granule cell layer (P < 0.026), supporting proteomic findings. In situ hybridization studies using probes against RHOA and RAC1 mRNAs revealed fine peri- and nuclear puncta in granule cells of all cases. The density of cells expressing RHOA mRNAs was significantly higher in the inner molecular layer of cases with GCD than without GCD (P = 0.05). In summary, our study has found limited evidence for ongoing adult neurogenesis in the hippocampus of patients with MTLE, but evidence of differential dysmaturation between dispersed and basal granule cells has been demonstrated, and elevated expression of Rho GTPases in dispersed granule cells may contribute to the pathomechanisms underpinning GCD in MTLE

Strong enhancement of phonon scattering through nanoscale grains in lead sulfide thermoelectrics

We present nanocrystalline PbS, which was prepared using a solvothermal method followed by spark plasma sintering, as a promising thermoelectric material. The effects of grains with different length scales on phonon scattering of PbS samples, and therefore on the thermal conductivity of these samples, were studied using transmission electron microscopy and theoretical calculations. We found that a high density of nanoscale grain boundaries dramatically lowered the thermal conductivity by effectively scattering long-wavelength phonons. The thermal conductivity at room temperature was reduced from 2.5 W m1K 1 for ingot-PbS (grain size 4200 lm) to 2.3 W m1K 1 for micro-PbS (grain size 40.4 lm); remarkably, thermal conductivity was reduced to 0.85 W m1 K 1 for nano-PbS (grain size B30 nm). Considering the full phonon spectrum of the material, a theoretical model based on a combination of first-principles calculations and semiempirical phonon scattering rates was proposed to explain this effective enhancement. The results show that the high density of nanoscale grains could cause effective phonon scattering of almost 61%. These findings shed light on developing high-performance thermoelectrics via nanograins at the intermediate temperature range.This contribution was supported primarily by the startup of the South University of Science and Technology of China, supported by the Shenzhen government, and the national 1000 plan for young scientists. This work was also partially supported by a grant-in-aid of ‘985 Project’ from Xi’an Jiaotong University, the National Natural Science Foundation of China (Grant No. 21201138 and 11204228), the National Basic Research Program of China (2012CB619402 and 2014CB644003) and the Fundamental Research Funds for the Central UniversitiesS

Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23

SPG23 is an autosomal-recessive neurodegenerative subtype of lower limb spastic paraparesis with additional diffuse skin and hair dyspigmentation at birth followed by further patchy pigment loss during childhood. Previously, genome-wide linkage in an Arab-Israeli pedigree mapped the gene to an approximately 25 cM locus on chromosome 1q24–q32. By using whole-exome sequencing in a further Palestinian-Jordanian SPG23 pedigree, we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (dual serine-threonine and tyrosine protein kinase) in all four affected family members. DSTYK is located within the established linkage region and we also found the same mutation in the previously reported pedigree and another Israeli pedigree (total of ten affected individuals from three different families). The mutation removes the last two exons and part of the 3′ UTR of DSTYK. Skin biopsies revealed reduced DSTYK protein levels along with focal loss of melanocytes. Ultrastructurally, swollen mitochondria and cytoplasmic vacuoles were also noted in remaining melanocytes and some keratinocytes and fibroblasts. Cultured keratinocytes and fibroblasts from an affected individual, as well as knockdown of Dstyk in mouse melanocytes, keratinocytes, and fibroblasts, were associated with increased cell death after ultraviolet irradiation. Keratinocytes from an affected individual showed loss of kinase activity upon stimulation with fibroblast growth factor. Previously, dominant mutations in DSTYK were implicated in congenital urological developmental disorders, but our study identifies different phenotypic consequences for a recurrent autosomal-recessive deletion mutation in revealing the genetic basis of SPG23.The Centre for Dermatology and Genetic Medicine is supported by a Wellcome Trust Strategic Award (reference 098439/Z/12/Z). The work was supported by the MRC (MR/M018512/1) and the UK National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre (BRC) award to Guy’s and St. Thomas’ NHS Foundation Trust, in partnership with the King’s College London and King’s College Hospital NHS Foundation Trust. This study was also supported by UK Medical Research Council Project Grant (MR/M00046X/1) and Action Research grant SP3706 as well as medical student grants from the Jean Shanks Foundation and the British Association of Dermatologists

The severity and associated factors of participation restriction among community-dwelling frail older people : an application of the International Classification of Functioning, Disability and Health (WHO-ICF)

2016-2017 > Academic research: refereed > Publication in refereed journal201804_a bcmaVersion of RecordPublishe

How the perspectives of nursing assistants and frail elderly residents on their daily interaction in nursing homes affect their interaction : a qualitative study

2015-2016 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Implementation of observational pain management protocol to improve pain management for long-term institutionalized older care residents with dementia: study protocol for a cluster-randomized controlled trial

2013-2014 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe