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1.
J Atheroscler Thromb ; 27(1): 71-99, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31142690

RESUMO

AIM: Studies have suggested that genetic and environmental factors do not account for all risks and mechanisms of intracranial atherosclerotic stenosis (ICAS). DNA methylation may play a role in the progression of ICAS. METHODS: DNA methylation profiles of peripheral blood leucocytes from 7 patients with early-onset ICAS and 7 perfectly matched controls were interrogated for the first time using the Illumina Infinium Human MethylationEPIC BeadChip. Afterward, functional analysis for differentially methylated genes was conducted. In addition, pyrosequencing verification was performed in an independent cohort comprising 21 patients with early-onset ICAS and 21 age- and gender-matched controls. RESULTS: A total of 318 cytosine-phosphate-guanine sites were found to be differentially methylated based on the established standards. Functional analysis annotated differentially methylated sites to atherosclerosis-related processes and pathways, such as the negative regulation of hydrolase activity (GO 0051346), type II diabetes mellitus (KEGG hsa04930), and the insulin signaling pathway (KEGG hsa04910). In addition, a differentially methylated site was also validated, cg22443212 in gene Rnf213, which showed significant hypermethylation in patients with early-onset ICAS compared with controls 59.56% (49.77%, 88.55%) vs. 44.65% (25.07%, 53.21%), respectively; P=0.010). Receiver operating characteristic curve analysis showed that the area under the curve value of cg22443212 was 0.744 (95% confidence interval, 0.586-0.866; P=0.002). CONCLUSIONS: We revealed that altered DNA methylation may play a role in the occurrence and development of ICAS. These results provided new epigenetic insights into ICAS.

2.
Front Neurol ; 10: 1192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798520

RESUMO

Objective: The platelet-to-lymphocyte ratio (PLR) is a new marker of atherosclerotic inflammation and has been identified as a predictive factor in cardiovascular diseases, but its significance in patients with acute ischaemic stroke (AIS) who have undergone intravenous thrombolysis (IVT) is still unknown. Methods: Consecutive patients who were treated with IVT using recombinant tissue plasminogen activator (rtPA) for AIS were included from May 2012 to August 2018. The PLR was calculated according to platelet and lymphocyte counts within 24 h after thrombolysis therapy. Functional outcomes were assessed by the modified Rankin Scale (mRS) at 3 months after thrombolysis. Stroke severity was assessed by National Institutes of Health Stroke Scale (NIHSS) scores. The primary endpoint was an unfavorable outcome (mRS > 2), and the secondary endpoint was death at 3 months. Results: A total of 286 patients were included in the study. The median age was 69.5 (59.0-80.0) years, and 59.1% of patients were men. A total of 120 (42.0%) patients had an unfavorable outcome, and 38 (13.2%) died. Patients with an unfavorable outcome had significantly higher PLR values compared with those with a favorable outcome [172.5 (105.3-239.0) vs. 139 (97.0-194.5), P = 0.008], and the PLR values of the patients who died at 3 months were higher than those of the surviving patients [189.5 (127.5-289.0) vs. 142.0 (98.0-215.5), P = 0.006]. After adjustment for other variables, the PLR was independently associated with the two endpoints: unfavorable outcome (OR 2.220, 95% CI 1.245-3.957, P = 0.007) and death (OR 2.825, 95% CI 1.050-7.601, P = 0.040) at 3 months after thrombolysis. In addition, PLR was correlated with the NIHSS score (R = 0.230, P < 0.001). Conclusions: Higher PLR levels were independently associated with an unfavorable outcome and death at 3 months in AIS patients treated with IVT.

3.
Sci Rep ; 9(1): 16230, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31700074

RESUMO

Seasonal variation of benign paroxysmal positional vertigo (BPPV) occurrence has been reported in recent years. Whether the seasonality of BPPV also exists in Chinese patients and whether it correlates with serum vitamin D levels is unexplored. We retrospectively analyzed the data of 1269 new-onset idiopathic BPPV patients registered in our vertigo outpatient clinic over a six-year period. Additionally, serum 25-hydroxyvitamin D levels during this period were measured in 877 patients by chemiluminescence immunoassay. We delineated the changing trend of the monthly BPPV patient numbers and serum 25-hydroxyvitamin D levels, and the correlation between them was explored. December to next March is the top 4 months with higher BPPV patient numbers. The median BPPV patient numbers in winter group were higher than those in summer group (20 vs. 16 patients, p < 0.05). Median 25-hydroxyvitamin D levels in winter group were much lower than those in summer group (16.3 vs. 20.8 ng/ml, p < 0.001) and autumn group (16.3 vs. 19.3 ng/ml, p < 0.05). A moderate negative correlation was observed between median serum 25-hydroxyvitamin D levels and BPPV patient numbers each month. The onset of BPPV also shows a seasonal fluctuation in Chinese patients. This phenomenon may be related to serum vitamin D levels.

4.
J Headache Pain ; 20(1): 93, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477012

RESUMO

BACKGROUND: Increasing evidence has suggested that the cerebellum is associated with pain and migraine. In addition, the descending pain system of the brainstem is the major site of trigeminal pain processing and modulation and has been discussed as a main player in the pathophysiology of migraine. Cerebellar and brainstem structural changes associated with migraineurs remain to be further investigated. METHODS: Voxel-based morphometry (VBM) (50 controls, 50 migraineurs without aura (MWoAs)) and diffusion tensor imaging (DTI) (46 controls, 46 MWoAs) were used to assess cerebellum and brainstem anatomical alterations associated with MWoAs. We utilized a spatially unbiased infratentorial template toolbox (SUIT) to perform cerebellum and brainstem optimized VBM and DTI analysis. We extracted the average diffusion values from a probabilistic cerebellar white matter atlas to investigate whether MWoAs exhibited microstructure alterations in the cerebellar peduncle tracts. RESULTS: MWoAs showed decreased fractional anisotropy (FA) in the vermis VI extending to the bilateral lobules V and VI of the cerebellum. We also found higher axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) in the right inferior cerebellum peduncle tract in MWoAs. MWoAs exhibited both reduced gray matter volume and increased AD, MD and RD in the spinal trigeminal nucleus (SpV). CONCLUSION: MWoAs exhibited microstructural changes in the cerebellum and the local brainstem. These structural differences might contribute to dysfunction of the transmission and modulation of noxious information, trigeminal nociception, and conduction and integration of multimodal information in MWoAs. These findings further suggest involvement of the cerebellum and the brainstem in the pathology of migraine without aura.


Assuntos
Tronco Encefálico/patologia , Cerebelo/patologia , Enxaqueca sem Aura/patologia , Anisotropia , Tronco Encefálico/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Imagem de Tensor de Difusão , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Masculino , Enxaqueca sem Aura/diagnóstico por imagem , Núcleo Espinal do Trigêmeo/diagnóstico por imagem , Núcleo Espinal do Trigêmeo/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
5.
Eur Neurol ; 81(5-6): 294-301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31484188

RESUMO

INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy -(CADASIL) is the most common familial cerebral small vessel disease caused by notch homolog protein 3 gene mutations and is strongly associated with ischemic stroke and dementia. Patients are characterized by cognitive impairment and widespread white matter (WM) lesions. However, the relationship between WM lesions and cognitive impairment is not very clear. The aim of this study was to investigate WM microstructural abnormalities by diffusion tensor imaging (DTI) and the relationship between WM alterations and cognitive impairment in patients with CADASIL. METHODS: In the present study, we evaluated WM degeneration in 18 patients with CADASIL and 18 controls by fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) based on DTI. RESULTS: Compared with healthy controls, patients with CADASIL showed extensive and significant reductions in FA and increased RD, AD, and MD. These alterations were distributed throughout the entire brain (mainly the inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corpus callosum, internal capsule, external capsule, corona radiata, thalamic radiation, and cingulum). Furthermore, these WM microstructural alterations were significantly correlated with cognitive scores and stroke scale scores. CONCLUSION: Patients with -CADASIL showed widespread WM abnormalities, and WM microstructural integrity and cognitive impairment were significantly correlated. Our results indicated that damage to WM tracts plays an important role in cognitive impairment in CADASIL.

6.
J Pain ; 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31400473

RESUMO

The brainstem has been discussed as the main player in the pathogenesis of migraine. Dysfunctional brainstem nuclei and their abnormal connections to other key brain centers may contribute to headache and other symptoms of migraine. In the present study, 32 patients with migraine without aura (MWoA) and 32 age- and sex-matched healthy controls (HCs) underwent resting-state fMRI scans. We used masked independent analysis (mICA) to investigate whether patients with MWoA exhibited abnormal brainstem nuclei-cortical functional connectivity (FC). The mICA can suppress adjacent physiological noise and prevent results from being driven by the much stronger signals of the surrounding structures. Regional homogeneity (ReHo) was used to investigate whether the brainstem regions with abnormal FC to other brain areas exhibited abnormal regional neuronal activity. Patients with MWoA showed significantly weaker FC between the posterior pons and the left superior parietal lobule, the left middle temporal gyrus, and the left middle frontal gyrus. Furthermore, patients with MWoA exhibited significantly decreased ReHo values in the posterior pons compared with HCs, and the posterior pons ReHo value was significantly negatively correlated with HIT-6 scores in the MWoA group. Patients with MWoA exhibited functional abnormalities in the posterior pons and weakened connections between the posterior pons and several key cortical brain areas involved in pain processing during the resting state. PERSPECTIVE: This study provided increased evidence that the pons is involved in the pathophysiological mechanism of migraine, and weakened connections suggest that the touch and pain sensation of migraine sufferers may not be properly relayed to cortical processing areas, which may be associated with the pathogenesis of MWoA.

7.
Atherosclerosis ; 289: 36-43, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31450012

RESUMO

BACKGROUND AND AIMS: Circulating microRNAs (miRNAs) have recently emerged as promising biomarkers for acute ischaemic stroke (AIS). However, the expression profiles of miRNAs in AIS patients receiving intravenous thrombolysis, and their associations with outcome have not been investigated. METHODS: In a prospective cohort study, a total of 84 AIS patients, who received intravenous thrombolysis (21.4% received combined reperfusion therapy) and completed 3 month follow-up visits, were included. Favourable and unfavourable outcomes were defined as modified Rankin Scale (mRS) scores of 0-1 and 2-6, respectively. Plasma samples were collected at 24 h after thrombolysis. We used RNA sequencing to study miRNA profiles in 5 patients with unfavourable outcomes and 5 matched patients with favourable outcomes. Differentially expressed miRNAs were further validated in all cohorts using quantitative real-time polymerase chain reaction assays. RESULTS: After identification and validation, we found that miR-124-3p, miR-125b-5p and miR-192-5p levels were higher in patients with unfavourable outcomes than in patients with favourable outcomes. Logistic regressions and receiver-operating characteristic curve analyses demonstrated that these altered miRNAs may function as predictive biomarkers for outcome in AIS patients receiving thrombolysis, whether combined with endovascular thrombectomy or not. In addition, miR-124-3p and miR-125b-5p were closely associated with stroke severity. CONCLUSIONS: A set of circulating microRNAs (miR-124-3p, miR-125b-5p and miR-192-5p) are associated with unfavourable 3 month outcomes and might have clinical utility in AIS patients receiving thrombolysis.

8.
Front Neurol ; 10: 696, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312173

RESUMO

There have been few studies about the association between intracranial carotid artery calcification (ICAC) and acute ischemic stroke (AIS) prognosis after intravenous thrombolysis (IVT). We aimed to analyze the association between ICAC and prognosis (including symptomatic intracranial hemorrhage (sICH), functional outcome and death) of AIS patients treated with IVT. In this retrospective study, we consecutively included 232 AIS patients treated with IVT between April 2012 and December 2018. ICAC was evaluated using the modified Woodcock calcification visual score on non-enhanced cranial computed tomography scans. Poor functional outcome was defined as a modified Rankin Scale score > 2 at 3 months. We found that the modified Woodcock calcification score was associated with ICH, poor outcome, and death in univariable analyses on the symptomatic side and/or bilaterally. However, after adjustment for other different covariates, the results showed no significant difference. We documented that the presence and severity of ICAC did not significantly modify the beneficial effects of rtPA treatment in AIS.

9.
Front Aging Neurosci ; 11: 90, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31105552

RESUMO

Background: Urine samples, which capture an individual's metabolic profile, are ideal for the exploration of non-invasive biomarkers to confirm the amnestic mild cognitive impairment (aMCI) status of patients vs. unimpaired ones. Objective: We aimed to detect differentially metabolized amino acids, which are important objectives in metabolomics, garnering particular attention in biomedical pathogenesis from the urine of aMCI patients, which may give clinicians the possibility to intervene with early treatments that curb Alzheimer's disease (AD). Methods: The study included 208 subjects, 98 of whom were aMCI patients, and 110 who were control subjects without dementia. Urine samples were taken from each participant and supernatant was obtained for analysis. The concentrations of amino acids were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Urinary arginine levels in aMCI patients are obviously lower than in normal controls (q < 0.2 and p < 0.05). Meanwhile, aMCI patients had significant reduced urinary global arginine bioavailability ratio (GABR), and GABR in urine displayed a positive correlation with the score of CMMSE. Conclusion: Urinary dysregulated arginine metabolism that may serve as a helpful clinical diagnostic biomarker for aMCI in older adults.

10.
Immun Ageing ; 16: 10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114624

RESUMO

Background: Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent memory deficits in the animal model of Alzheimer's disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker. Results: RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVG-conjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aß levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-ß, and IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-Exo significantly reduced the levels of TNF-α, IL-ß, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13. Conclusions: Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aß levels, and normalized levels of inflammatory cytokines.

11.
Cell Mol Neurobiol ; 39(6): 823-831, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31065924

RESUMO

Severe haemorrhagic transformation (HT), a common complication of recombinant tissue plasminogen activator (rtPA) treatment, predicts poor clinical outcomes in acute ischaemic stroke. The search for agents to mitigate this effect includes investigating biomolecules involved in neovascularization. This study examines the role of Cathepsin K (Ctsk) in rtPA-induced HT after focal cerebral ischaemia in mice. After knockout of Ctsk, the gene encoding Ctsk, the outcomes of Ctsk+/+ and Ctsk-/- mice were compared 24 h after rtPA-treated cerebral ischaemia with respect to HT severity, neurological deficits, brain oedema, infarct volume, number of apoptotic neurons and activated microglia/macrophage, blood-brain barrier integrity, vascular endothelial growth factor (VEGF) expression and Akt-mTOR pathway activation. We observed that haemoglobin levels, brain oedema and infarct volume were significantly greater and resulted in more severe neurological deficits in Ctsk-/- than in Ctsk+/+ mice. Consistent with our hypothesis, the number of NeuN-positive neurons was lower and the number of TUNEL-positive apoptotic neurons and activated microglia/macrophage was higher in Ctsk-/- than in Ctsk+/+ mice. Ctsk knockout mice exhibited more severe blood-brain barrier (BBB) disruption, with microvascular endothelial cells exhibiting greater VEGF expression and lower ratios of phospo-Akt/Akt and phospo-mTOR/mTOR than in Ctsk+/+ mice. This study is the first to provide molecular insights into Ctsk-regulated HT after cerebral ischaemia, suggesting that Ctsk deficiency may disrupt the BBB via Akt/mTOR/VEGF signalling, resulting in neurological deficits and neuron apoptosis. Ctsk administration has the potential as a novel modality for improving the safety of rtPA treatment following stroke.


Assuntos
Isquemia Encefálica/complicações , Catepsina K/deficiência , Hemorragia Cerebral/etiologia , Animais , Apoptose , Barreira Hematoencefálica/patologia , Catepsina K/metabolismo , Infarto da Artéria Cerebral Média/patologia , Macrófagos/patologia , Masculino , Camundongos Knockout , Microglia/patologia , Neurônios/patologia , Permeabilidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Recombinantes , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ativador de Plasminogênio Tecidual , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
J Neurol ; 266(7): 1578-1587, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30923933

RESUMO

Parkinson's disease (PD) is a progressive neurological degenerative disorder characterized by impaired motor function and non-motor dysfunctions. While recent studies have highlighted the role of the cerebellum in PD, our understanding of its role in PD remains limited. In the present study, we used resting-state fMRI to evaluate dysfunctions within the cerebellum in PD patients treated with medication and drug-naïve PD patients. We applied amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) analysis methods. Thirty-one patients with early stage PD (22 drug-naïve and 9 medicated patients) and 31 gender- and age-matched healthy controls were recruited in this study. ALFFs increased in the left cerebellar areas (lobules VI/VIIb/CruI/CruII and the dentate gyrus) and right cerebellar areas (lobules VI/VIIb/VIIIa/CruI/CruII and the dentate gyrus) of all PD patients and in the left and right cerebellar areas (lobules VI/VIIb/CruI and the dentate gyrus) of drug-naive PD patients but were not significantly changed in medicated PD patients. DC increased in the right cerebellar areas of all PD patients and medicated PD patients. All PD patients and all drug-naive PD patients showed significantly weaker functional connectivity (FC) between the left cerebellum and the left medial frontal gyrus. However, FC was significantly stronger between the right cerebellum and the left precentral and right middle occipital gyri in the medicated PD patients than in controls. Furthermore, a correlation analyses revealed that ALFF z scores in the left cerebellum (lobule VI) and right cerebellum (lobule VI/CruI and dentate gyrus) were negatively correlated with Mini-Mental State Examination (MMSE) scores in all PD patients and drug-naive patients. These results indicate that the cerebellum plays an important role in PD, mainly by exerting a compensatory effect in early stage PD. Additionally, antiparkinsonian medication would modified PD-induced changes in local neural activity and FC in PD patients. The results of this study offer novel insights into the roles of the cerebellum in early stage drug-naïve PD.


Assuntos
Antiparkinsonianos/uso terapêutico , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Imagem por Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológico , Idoso , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade
13.
J Stroke Cerebrovasc Dis ; 28(6): 1654-1661, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30878364

RESUMO

INTRODUCTION: Multiple microRNAs (miRNAs) participate in the response to hypoxic/ischemic and ischemia-reperfusion events. However, the expression of these miRNAs in circulation from patients with acute ischemic stroke (AIS) receiving recanalization treatment has not been examined, and whether they are associated with the severity and outcome of stroke is still unknown. MATERIALS AND METHODS: In this prospective cohort study, plasma levels of miR-125b-5p, miR-15a-3p, miR-15a-5p, and miR-206 were measured at 24 hours after thrombolysis with or without endovascular treatment in 94 patients with AIS, as determined by qRT-PCR. Stroke severity was assessed based on National Institutes of Health Stroke Scale (NIHSS) score and infarct lesion. Intracranial haemorrhage (ICH) was recorded. An unfavorable outcome was defined as a modified Rankin Scale score greater than 2 at day 90 after stroke. RESULTS: miR-125b-5p and miR-206 levels were correlated with NIHSS scores (P = .014 and P = .002) and cerebral infarction volumes (P = .025 and P = .030). miR-125b-5p levels were significantly higher in patients with an unfavorable outcome than in patients with a favorable outcome (P = .002) and showed good diagnostic accuracy in discriminating the presence of an unfavorable outcome (area under the curve .735, 95% confidence interval .623-.829, P < .001). No association was found between different miRNAs and ICH. CONCLUSIONS: In AIS patients after thrombolysis with or without endovascular treatment, miR-125b-5p is a novel prognostic biomarker highly associated with an unfavorable outcome. miR-125b-5p and miR-206 levels are associated with stroke severity.


Assuntos
Isquemia Encefálica/terapia , MicroRNA Circulante/sangue , Procedimentos Endovasculares , MicroRNAs/sangue , Acidente Vascular Cerebral/terapia , Terapia Trombolítica , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/genética , MicroRNA Circulante/genética , Imagem de Difusão por Ressonância Magnética , Avaliação da Deficiência , Feminino , Marcadores Genéticos , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Dados Preliminares , Estudos Prospectivos , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/genética , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
Gene ; 697: 184-193, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30797995

RESUMO

BACKGROUNDS: The pathophysiology of hydrocephalus induced brain damage remains unclear. Long non-coding RNAs (lncRNAs) have been demonstrated to be implicated in many central nervous system diseases. However, the roles of lncRNAs in hydrocephalus injury are poorly understood. METHODS: The present study depicted the expression profiles of lncRNAs and messenger RNAs (mRNAs) in C57BL/6 mice with kaolin-induced hydrocephalus and saline controls using high-throughput RNA sequencing. Afterward, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify potential targets that correlated with hydrocephalus. In addition, co-expression networks and cis- and trans-regulation were predicted using bioinformatics methods. Finally, representative lncRNAs and mRNAs were further validation using quantitative real-time polymerase chain reaction. RESULTS: A total of 1575 lncRNAs and 1168 mRNAs were differentially expressed (DE) in hydrocephalus. GO and KEGG analyses indicated several immune and inflammatory response-associated pathways may be important in the hydrocephalus. Besides, functional enrichment analysis based on co-expression network showed several similar pathways, such as chemokine signaling pathway, phagosome, MAPK signaling pathway and complement and coagulation cascade. Cis-regulation prediction revealed 5 novel lncRNAs might regulate their nearby coding genes, and trans-regulation revealed several lncRNAs participate in pathways regulated by transcription factors, including BPTF, FOXM1, NR5A2, P2RX5, and NR6A1. CONCLUSIONS: In conclusion, our results provide candidate genes involved in hydrocephalus and suggest a new perspective on the modulation of lncRNAs in hydrocephalus.


Assuntos
Hidrocefalia/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Animais , Biologia Computacional , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Genoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Hidrocefalia/induzido quimicamente , Caulim/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , RNA Longo não Codificante/análise , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma/genética
15.
Artigo em Inglês | MEDLINE | ID: mdl-30684527

RESUMO

BACKGROUND: Transient receptor potential canonical (TRPC) 6 inhibits Aß in Alzheimer's disease (AD) mouse brain and improves the behavioral performance. AIMS: To evaluate the association of TRPC6 expression in peripheral leucocytes from AD and mild cognitive impairment (MCI) patients and to explore its potential value in early diagnosis of AD. METHODS: TRPC6 mRNA levels in peripheral leucocytes were detected by quantitative real-time PCR. The Spearman correlation test was used to ascertain the associations between TRPC6 and the scores of MMSE, ADL, CSDD, CDR. The Receiver Operating Characteristic (ROC) curve was drawn to evaluate the diagnostic potential of TRPC6 for AD and MCI. RESULTS: There were 108 CE, 136 MCI, 164 Con and 60 PD in the study. The expression of TRPC6 mRNA level in peripheral leucocytes was significantly lower: 1) in patients with AD and MCI compared to Con; 2) in AD compared to MCI; 3) in hospitalized AD compared to AD from communities. There was a significantly positive correlation between TRPC6 mRNA and MMSE score (p = .001, R = 0.327). Significantly inverse correlations were found between TRPC6 and CDR score (p < 0.001, R = -0.303) as well as between TRPC6 and ADL score (p = .001, R = -0.342) for all AD. The area under curve of ROC was 0.881 for the classification of AD, and 0.706 for the classification of MCI, respectively. CONCLUSION: TRPC6 expression is inversely correlated with cognitive performance of AD. TRPC6 in peripheral leucocytes may be a potential biomarker for the diagnosis of AD.


Assuntos
Doença de Alzheimer/metabolismo , Disfunção Cognitiva/metabolismo , Canal de Cátion TRPC6/biossíntese , Idoso , Estudos de Casos e Controles , Diagnóstico Precoce , Feminino , Hospitalização , Humanos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Escalas de Graduação Psiquiátrica/estatística & dados numéricos
16.
Neuroradiology ; 61(1): 103-107, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30488255

RESUMO

PURPOSE: Identifying previous chronic cerebral hemorrhage (PCH), especially asymptomatic cases in patients with ischemic stroke, is essential for proper antithrombotic management. The study aimed to further clarify the prevalence of PCH and the associated factors in patients with acute ischemic stroke using multi-modal neuroimaging including susceptibility-weighted MR imaging (SWI). METHODS: This was a retrospective cross-sectional study of 382 patients with acute ischemic stroke. All patients underwent 3.0-T MRI for cranial SWI, 1.5-T or 3.0-T conventional cranial MRI, and cranial CT. Patients found with PCH were matched 1:4 with patients without PCH. Clinical manifestation, computed tomography, conventional cranial MRI, and cranial SWI were used to determine PCH. Clinical and neuroimaging findings between the patients with symptomatic vs. asymptomatic PCH were compared. RESULTS: Thirty-six patients (36/382, 9.4%) were determined to have had a PCH. Of these 36 patients, 17 (17/36, 47.2%, or 17/382, 4.5%) had asymptomatic PCH. Multivariable analysis showed that serum total cholesterol (OR = 0.510, 95%CI 0.312-0.832, P = 0.007), cerebral microbleeds (OR = 6.251, 95%CI 2.220-17.601, P = 0.001), and antithrombotic drugs history (OR = 3.213, 95%CI 1.018-10.145, P = 0.047) were independently associated with PCH. Asymptomatic PCH had similar clinical and neuroimaging characteristics with symptomatic PCH. CONCLUSION: PCH is not uncommon in acute ischemic stroke patients. Total serum cholesterol, cerebral microbleeds on SWI, and history of antithrombotic drugs were independently associated with PCH in patients with acute ischemic stroke. Asymptomatic PCH, which is easier to be missed and has similar characteristics with symptomatic PCH, should draw much attention.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Imagem Multimodal , Neuroimagem/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Doença Crônica , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
17.
PLoS One ; 13(11): e0207448, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30485326

RESUMO

BACKGROUND: Botulinum toxin type A (BoNT-A) is generally considered safe and is widely used to treat a variety of clinical conditions involving muscle hyperactivity and for cosmetic purposes. However, the effects of BoNT-A poisoning (botulism) on brain function are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we investigated brain functions in 9 patients who received illegal cosmetic injections of botulinum and 18 matched controls by combining the analysis methods of regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) based on resting-state fMRI. Compared with the controls, the patients with botulism exhibited significantly reduced ReHo values in the left posterior lobe of the cerebellum extending to the right anterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum extending to the parahippocampal gyrus and right posterior lobe of the cerebellum. The patients with botulism also showed weakened ALFF values in the right anterior lobe of the cerebellum extending to the left anterior lobe of the cerebellum and right posterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum. CONCLUSIONS/SIGNIFICANCE: The results indicate that BoNT-A may modulate cerebral activation in specific areas, which may play roles in both the adverse effects of botulism and the mechanism underlying clinical treatment with BoNT-A.


Assuntos
Toxinas Botulínicas Tipo A/efeitos adversos , Botulismo , Técnicas Cosméticas/efeitos adversos , Lobo Frontal , Imagem por Ressonância Magnética , Adulto , Toxinas Botulínicas Tipo A/administração & dosagem , Botulismo/induzido quimicamente , Botulismo/diagnóstico por imagem , Botulismo/fisiopatologia , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos
18.
Sci Rep ; 8(1): 7408, 2018 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743683

RESUMO

Managing endovascular thrombectomy (ET) in diabetic ischemic stroke (IS) with novel anticoagulants is challenging due to putative risk of intracerebral hemorrhage. The study evaluates increased hemorrhagic transformation (HT) risk in Rivaroxaban-treated diabetic rats post ET. Diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of 60 mg/kg streptozotocin. After 4-weeks, rats were pretreated orally with 30 mg/kg Rivaroxaban/saline; prothrombin time was monitored. IS and ET was induced after 1 h, by thread-induced transient middle cerebral artery occlusion (tMCAO) that mimicked mechanical ET for proximal MCA occlusion at 60 min. After 24 h reperfusion, infarct volumes, HT, blood-brain barrier (BBB) permeability, tight junction at peri-ischemic lesion and matrix metalloproteinase-9 (MMP-9) activity was measured. Diabetic rats seemed to exhibit increased infarct volume and HT at 24 h after ET than normal rats. Infarct volumes and functional outcomes did not differ between Rivaroxaban and diabetic control groups. A significant increase in HT volumes and BBB permeability under Rivaroxaban treatment was not detected. Compared to diabetic control group, neither the occludin expression was remarkably lower in the Rivaroxaban group nor the MMP-9 activity was higher. Together, Rivaroxaban does not increase HT after ET in diabetic rats with proximal MCA occlusion, since Rivaroxaban has fewer effects on post-ischemic BBB permeability.


Assuntos
Isquemia Encefálica/complicações , Diabetes Mellitus Experimental/complicações , Hemorragias Intracranianas/complicações , Rivaroxabana/farmacologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/cirurgia , Trombectomia , Animais , Barreira Hematoencefálica/metabolismo , Hemorragias Intracranianas/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Ocludina/metabolismo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Risco
19.
FASEB J ; 32(2): 654-668, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28970251

RESUMO

Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia-preconditioned MSCs (PC-MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC-MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR-21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aß levels in the brain; could decrease the activation of astrocytes and microglia; could down-regulate proinflammatory cytokines (TNF-α and IL-1ß); and could up-regulate anti-inflammatory cytokines (IL-4 and -10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC-MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aß levels were lower, and expression of growth-associated protein 43, synapsin 1, and IL-10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, TNF-α, IL-1ß, and activation of STAT3 and NF-κB were sharply decreased. More importantly, exosomes from PC-MSCs effectively increased the level of miR-21 in the brain of AD mice. Additionally, replenishment of miR-21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC-MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR-21.-Cui, G.-H., Wu, J., Mou, F.-F., Xie, W.-H., Wang, F.-B., Wang, Q.-L., Fang, J., Xu, Y.-W., Dong, Y.-R., Liu, J.-R., Guo, H.-D. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Exossomos/metabolismo , Precondicionamento Isquêmico , Células-Tronco Mesenquimais/metabolismo , Sinapses/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Disfunção Cognitiva/patologia , Citocinas/metabolismo , Exossomos/patologia , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Transgênicos , Sinapses/patologia
20.
Sci Rep ; 7(1): 16868, 2017 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-29203874

RESUMO

Long-term headache attacks may cause human brain network reorganization in patients with migraine. In the current study, we calculated the topologic properties of functional networks based on the Brainnetome atlas using graph theory analysis in 29 female migraineurs without aura (MWoA) and in 29 female age-matched healthy controls. Compared with controls, female MWoA exhibited that the network properties altered, and the nodal centralities decreased/increased in some brain areas. In particular, the right posterior insula and the left medial superior occipital gyrus of patients exhibited significantly decreased nodal centrality compared with healthy controls. Furthermore, female MWoA exhibited a disrupted functional network, and notably, the two sub-regions of the right posterior insula exhibited decreased functional connectivity with many other brain regions. The topological metrics of functional networks in female MWoA included alterations in the nodal centrality of brain regions and disrupted connections between pair regions primarily involved in the discrimination of sensory features of pain, pain modulation or processing and sensory integration processing. In addition, the posterior insula decreased the nodal centrality, and exhibited disrupted connectivity with many other brain areas in female migraineurs, which suggests that the posterior insula plays an important role in female migraine pathology.


Assuntos
Encéfalo/metabolismo , Enxaqueca sem Aura/patologia , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Estudos de Casos e Controles , Núcleo Caudado/metabolismo , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Enxaqueca sem Aura/metabolismo , Rede Nervosa/metabolismo , Córtex Pré-Frontal/metabolismo
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