Fractalkine (CX3CL1) enhances hippocampal N-methyl-D-aspartate receptor (NMDAR) function via D-serine and adenosine receptor type A2 (A2AR) activity.

BACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play fundamental roles in basic brain functions such as excitatory neurotransmission and learning and memory processes. Their function is largely regulated by factors released by glial cells, including the coagonist d-serine. We investigated whether the activation of microglial CX3CR1 induces the release of factors that modulate NMDAR functions. METHODS: We recorded the NMDAR component of the field excitatory postsynaptic potentials (NMDA-fEPSPs) elicited in the CA1 stratum radiatum of mouse hippocampal slices by Shaffer collateral stimulation and evaluated D-serine content in the extracellular medium of glial primary cultures by mass spectrometry analysis. RESULTS: We demonstrated that CX3CL1 increases NMDA-fEPSPs by a mechanism involving the activity of the adenosine receptor type A2 (A2AR) and the release of the NMDAR coagonist D-serine. Specifically (1) the selective A2AR blocker 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261) and the genetic ablation of A2AR prevent CX3CL1 action while the A2AR agonist 5-(6-amino-2-(phenethylthio)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide (VT7) mimics CX3CL1 effect, and (2) the selective blocking of the NMDAR glycine (and D-serine) site by 5,7-dicholorokynurenic acid (DCKA), the enzymatic degradation of D-serine by D-amino acid oxidase (DAAO) and the saturation of the coagonist site by D-serine, all block the CX3CL1 effect. In addition, mass spectrometry analysis demonstrates that stimulation of microglia and astrocytes with CX3CL1 or VT7 increases D-serine release in the extracellular medium. CONCLUSIONS: CX3CL1 transiently potentiates NMDAR function though mechanisms involving A2AR activity and the release of D-serine

LTP impairment by fractalkine/CX3CL1 in mouse hippocampus is mediated through the activity of adenosine receptor type 3 (A3R)

We have examined how the chemokine fractalkine/CX3CL1 influences long-term potentiation (LTP) in CA1 mouse hippocampal slices. Field potentials (fEPSPs) were recorded upon electrical stimulation of Schaffer collaterals. It was found that application of CX3CL1 inhibits LTP when present during the critical induction period. LTP impairment (i) failed to occur in CX3CR1 deficient mice (CX3CR1GFP/GFP) and in the presence of okadaic acid (OA); (ii) required the activation of adenosine receptor 3 (A3R), since it was prevented in A3R-deficient mice or by MRS1523, a selective A3R antagonist. Together, these findings indicate that CX3CL1 inhibits hippocampal LTP through A3R activity. © 2009 Elsevier B.V. All rights reserved

Home-based self-management for sedentary individuals with mild walking disability after stroke: protocol for a randomised pilot study

Abstract Background A Phase I study showed that it is feasible to implement a home-based self-management program aimed at increasing physical activity in individuals after stroke with mild walking disability in Brazil. The next step is to test this program against a control group in order to provide a power analysis for a fully-powered Phase III clinical trial. Methods A Phase II pilot randomised clinical trial with concealed allocation, blinded measurement, and intention-to-treat analyses will be carried out. The inclusion criteria will be individuals diagnosed with stroke, in the acute or subacute phase, with mild walking disability, sedentary, and no significant language impairment. The participants will be randomly allocated to the experimental or control group. The experimental group will receive six sessions of a home-based self-management program based on behaviour change techniques through the Social-Cognitive Theory and Control Theory over 11 weeks. The control group will receive one session of education about stroke (regarding the importance of practising physical activity after a stroke) and usual care. A total of 24 participants will be recruited. The primary outcome will be physical activity, measured through steps taken per day by an activity monitor (Actigraph wGT3X-BT, Pensacola, FL, USA). The mean of daily steps will be analysed to compare groups after intervention. Secondary outcomes will be cardiovascular risk (body mass index, waist circumference, and blood pressure), depressive symptoms (Geriatric Depression Scale), walking ability (6-Minute Walk Test and 10-Meter Walk Test), exercise self-efficacy (Self-Efficacy for Exercise scale), social participation (Stroke Impact Scale) and quality of life (EuroQual-5D). Two-way analyses of variance will be implemented for all parametric outcomes, and the Kruskal–Wallis test for non-parametric outcomes will be used to determine the statistical significance of the between-group differences and reported as mean differences between groups (95% CI). All analyses will be conducted intention-to-treat. All outcomes will be measured at baseline (Week 0), post-intervention (Week 12), and follow-up (Week 24). This pilot clinical trial was registered online at Clinical Trials under number NCT05461976 on 4th April 2022. Discussion If beneficial, this Phase II pilot randomised trial will provide data to plan a fully powered future Phase III clinical trial aimed at verifying the efficacy of this program to promote physical activity after stroke. Trial registration Clinical Trials NCT05461976 on 4th April 2022

Cross-cultural adaptation of the Stroke Upper Limb Capacity Scale (sulcs): an instrument for assessing manual capacity in individuals with hemiparesis

Após a ocorrência do Acidente Vascular Encefálico (AVE), é comum a presença de deficiências residuais, com potencial impacto na utilização dos membros superiores (MMSS) na realização de atividades cotidianas, consideradas essenciais para uma vida independente. O Stroke Upper Limb Capacity Scale (SULCS) avalia a função proximal e distal dos membros superiores de indivíduos pós-AVE por meio de 10 itens, hierarquicamente ordenados, que representam tarefas significativas relacionadas às atividades diárias realizadas em ambiente domiciliar. Objetivo: Adaptar transculturalmente o SULCS para uso no Brasil. Método: O processo de adaptação transcultural foi realizado em cinco estágios, seguindo procedimentos padronizados:  tradução inicial, síntese das traduções, retrotradução, comitê de especialistas e aplicação da versão pré-final em 15 indivíduos pós-AVE. Resultados: As versões original e retrotraduzida apresentaram adequada equivalência semântica. O comitê de especialistas adequou a descrição dos itens às regras gramaticais da língua portuguesa. Em um item da escala, foi acrescentada observação sobre a forma de realização da tarefa, para equivalência experimental, e realizada adaptação do material de teste em três itens, para equivalência cultural. Não foram observadas dificuldades de compreensão dos itens no teste da versão pré-final. Conclusão: O SULCS-Brasil apresentou adequadas equivalências semântica, idiomática, cultural e experimental. Os resultados desse estudo viabilizam o uso do SULCS-Brasil como uma ferramenta para avaliação da capacidade dos membros superiores de indivíduos pós-AVE. Estudos futuros são necessários para continuidade do processo de validação da escala, a partir da investigação de outras propriedades de medida, tais como validade de construto e confiabilidade.After a stroke, the presence of residual impairments has the potential to impact the use of the upper limbs (UL) in carrying-out daily activities, considered essential for an independent life. The Stroke Upper Limb Capacity Scale (SULCS) assesses the proximal and distal functions of the UL of individuals with stroke. Its 10 items, which are hierarchically ordered, represent relevant tasks related to daily activities carried-out within the home environment. Objective: To cross-culturaly adapt the SULCS for its use in Brazil. Method: The process of cross-cultural adaptation was carried-out in five stages, following standardized procedures: translation, synthesis of translations, back-translation, expert committee evaluation, and testing of the pre-final version in 15 post-stroke individuals. Results: The original and back-translated versions showed adequate semantic equivalence. The expert committee adapted the description of the items to the grammatical rules of the  Portuguese-Brazil language. An observation was added in one item of the scale, to better describe the way the task is accomplished, for experimental equivalence. The test material was also adapted in three items of the scale, for cultural equivalence. There were not found any difficulties in understanding the items during the test of the pre-final version. Conclusion: The SULCS-Brazil showed adequate semantic, idiomatic, cultural, and experimental equivalences. The results support the use of the SULCS-Brazil as a tool for the assessement of UL capacity of individuals with stroke. Future studies are necessary for the continuation of the validation process, based upon the investigation of other measurement properties, such as construct validity and reliability

[polymorphisms Gstm1 And Gstt1 And Sporadic Breast Cancer Mammographic Features].

Enzymes of the Glutathione S-transferase system (GST) modulate the effects of exposure to several cytotoxic and genotoxic agents. The GSTM1 and GSTT1 genes are polymorphic in humans and their deletions have been associated to increased risk of many cancers, including breast cancer. To evaluate the occurrence of homozygous deletions of the GSTM1 and GSTT1 genes in women with sporadic breast cancer and in women without cancer and to compare breast cancer mammographic features between patients with and without these deletions. The study evaluated 100 patients with sporadic breast cancer treated from September 2004 to June 2005 and 169 women without cancer, determining the frequency of the above-mentioned deletions by PCR and calculating the odds ratios and their 95% confidence intervals. Medical files and mammograms of 100 patients with breast cancer were evaluated and correlated with mammographic features such as density, mammographic findings and the BI-RADS classification. These findings were correlated with the genetic deletions by the PR (Prevalence-Ratio) with their respective 95% confidence intervals. The GSTM1 gene was deleted in 40% of the cancers and in 44.4% of controls (OR = 1.20; CI 95% 0.70 - 2.04; p=0.5659) while the GSTT1 gene was deleted in 20% and 19.5%, respectively (OR = 0.73; CI 95% 0.37-1.44; p=0.4124). High mammographic density had been associated with GSTM1 deletion (PR 2.43; CI 1.11 to 4.08). GST deletions were not associated with predominant mammographic findings and the BI-RADS classification. GSTM1 homozygous deletion was associated with high mammographic density.5461-

Polymorphisms GSTM1 and GSTT1 and sporadic breast cancer mammographic features

INTRODUCTION: Enzymes of the Glutathione S-transferase system (GST) modulate the effects of exposure to several cytotoxic and genotoxic agents. The GSTM1 and GSTT1 genes are polymorphic in humans and their deletions have been associated to increased risk of many cancers, including breast cancer. OBJECTIVE: To evaluate the occurrence of homozygous deletions of the GSTM1 and GSTT1 genes in women with sporadic breast cancer and in women without cancer and to compare breast cancer mammographic features between patients with and without these deletions. METHODS: The study evaluated 100 patients with sporadic breast cancer treated from September 2004 to June 2005 and 169 women without cancer, determining the frequency of the above-mentioned deletions by PCR and calculating the odds ratios and their 95% confidence intervals. Medical files and mammograms of 100 patients with breast cancer were evaluated and correlated with mammographic features such as density, mammographic findings and the BI-RADS classification. These findings were correlated with the genetic deletions by the PR (Prevalence-Ratio) with their respective 95% confidence intervals. RESULTS: The GSTM1 gene was deleted in 40% of the cancers and in 44.4% of controls (OR = 1.20; CI 95% 0.70 - 2.04; p=0.5659) while the GSTT1 gene was deleted in 20% and 19.5%, respectively (OR = 0.73; CI 95% 0.37-1.44; p=0.4124). High mammographic density had been associated with GSTM1 deletion (PR 2.43; CI 1.11 to 4.08). GST deletions were not associated with predominant mammographic findings and the BI-RADS classification. CONCLUSION: GSTM1 homozygous deletion was associated with high mammographic density.INTRODUÇÃO: As enzimas do sistema da glutationa S-transferase (GST) modulam os efeitos da exposição a vários agentes citotóxicos e genotóxicos. Os genes GSTM1 e GSTT1 são polimórficos em humanos e suas deleções têm sido associadas ao aumento do risco de várias neoplasias, dentre elas o câncer de mama. OBJETIVO: Comparar a freqüência das deleções dos genes GSTM1 e GSTT1 em mulheres sadias e com câncer de mama e comparar as características mamográficas do câncer entre mulheres portadoras e não portadoras das referidas deleções. MÉTODOS: Foram determinadas as freqüências das referidas deleções por PCR em 100 pacientes portadoras de câncer de mama esporádico tratadas de setembro de 2004 a junho de 2005 e em 169 mulheres sadias doadoras de sangue no mesmo período e comparadas através do odds ratio (OR) com seus respectivos IC 95%. Foram revistos os prontuários e as mamografias das pacientes com câncer e avaliadas características mamográficas (padrão de distribuição do parênquima fibro-glandular, achados mamográficos ao diagnóstico e classificação BI-RADS), correlacionando-as às deleções gênicas através do cálculo da RP (razão de prevalência) com seus respectivos IC 95%. RESULTADOS: O GSTM1 esteve deletado em 40% dos cânceres e em 44,4% dos controles (OR=1,20; IC 95% 0,70-2,04; p=0,5659) enquanto o GSTT1 em 20% e 19,5%, respectivamente (OR=0,73; IC 0,37-1,44; p=0,4124). O padrão mamográfico denso esteve associado à deleção homozigótica do GSTM1 (RP= 2,43; IC 1,11-4,08). Não se observou associação entre as deleções do sistema GST e achados mamográficos ao diagnóstico e classificação BI-RADS. CONCLUSÃO: A deleção homozigótica do gene GSTM1 associou-se ao padrão mamográfico denso.616

Synaptic Pruning by Microglia Is Necessary for Normal Brain Development

Microglia are highly motile phagocytic cells that infiltrate and take up residence in the developing brain, where they are thought to provide a surveillance and scavenging function. However, although microglia have been shown to engulf and clear damaged cellular debris after brain insult, it remains less clear what role microglia play in the uninjured brain. Here, we show that microglia actively engulf synaptic material and play a major role in synaptic pruning during postnatal development in mice. These findings link microglia surveillance to synaptic maturation and suggest that deficits in microglia function may contribute to synaptic abnormalities seen in some neurodevelopmental disorders