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Urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) is regarded as a biomarker for ß-amyloid protein deposition in Alzheimer disease (AD). The value of AD7c-NTP in predicting post-stroke cognitive recovery was worth exploring. In total, 224 patients with first-ever stroke were enrolled in this retrospective study. Cognitive assessment was evaluated by Mini-Mental State Examination (MMSE), and cognitive improvement was defined as MMSE scores ≥27 or 4-score elevation at 3-month follow-up after stroke. The AD7c-NTP level was 0.68±0.40 ng/mL in the 135 patients with cognitive improvement, while the AD7c-NTP level was 1.49±0.99 ng/mL in the 89 patients without improvement (P<0.001). Those displaying better cognitive recovery also had younger ages, higher MMSE scores, and lower NIHSS scores on admission. In multivariable logistic regression analysis, AD7c-NTP concentration (OR=9.14, 95% CI: 4.52-18.49, P<0.001), age (OR=1.04, 95% CI: 1.01-1.08, P=0.012), and NIHSS score on admission (OR=1.17, 95% CI: 1.07-1.28, P<0.001) remained the independent risk factors affecting cognitive recovery. The area under the receiver operating characteristics curve for AD7c-NTP in predicting unfavorable cognitive function was 0.80 (sensitivity: 0.73 and specificity: 0.84). Urinary AD7c-NTP is a valuable biomarker associated with post-stroke cognitive recovery. It might be adopted to discriminate coexisting AD pathology from vascular cognitive impairment.
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OBJECTIVES: Patients with medication-overuse headache (MOH) are often complicated with anxiety, depression, and sleep disorders and are associated with dependence behavior and substance abuse. Melatonin has physiological properties including analgesia, regulation of circadian rhythms, soporific, and antidepressant and affects drug preference and addiction. This study aimed to investigate the role of melatonin in MOH compared with episodic migraine (EM) and healthy controls and to verify the relationship between plasma melatonin levels and psychiatric symptoms. METHODS: Thirty patients affected by MOH, 30 patients with EM, and 30 matched healthy controls were enrolled. All subjects completed a detailed headache questionnaire and scales including the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index, the Leeds Dependence Questionnaire. Melatonin levels in plasma samples were measured by enzyme immunoassay method. RESULTS: The levels of plasma melatonin were significantly different among 3 groups of subjects (MOH, 7.74 [5.40-9.89]; EM, 9.79 [8.23-10.62]; Control, 10.16 [8.60-17.57]; H = 13.433; P = 0.001). Significantly lower levels of melatonin were found in MOH patients compared with healthy controls ( P = 0.001). The level of plasma melatonin inversely correlated with the scores of HADS-Anxiety ( r = -0.318, P = 0.002), HADS-Depression ( r = -0.368, P < 0.001), Pittsburgh Sleep Quality Index ( r = -0.303, P = 0.004), and Leeds Dependence Questionnaire ( r = -0.312, P = 0.003). CONCLUSIONS: This study innovatively detects the plasma melatonin levels in MOH patients and explores the association between melatonin levels and psychiatric symptoms. Melatonin may be potential complementary therapy in the treatment of MOH considering its comprehensive role in multiple aspects of MOH.
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Transtornos da Cefaleia Secundários , Melatonina , Transtornos de Enxaqueca , Humanos , Estudos Transversais , Melatonina/uso terapêutico , Cefaleia , Transtornos da Cefaleia Secundários/complicações , Transtornos da Cefaleia Secundários/psicologia , Transtornos da Cefaleia Secundários/terapia , Transtornos de Enxaqueca/tratamento farmacológicoRESUMO
Parkinson's disease (PD) is the second most common neurodegenerative disease associated with age. Early diagnosis of PD is key to preventing the loss of dopamine neurons. Peripheral-blood biomarkers have shown their value in recent years because of their easy access and long-term monitoring advantages. However, few peripheral-blood biomarkers have proven useful. This study aims to explore potential peripheral-blood biomarkers for the early diagnosis of PD. Three substantia nigra (SN) transcriptome datasets from the Gene Expression Omnibus (GEO) database were divided into a training cohort and a test cohort. We constructed a protein-protein interaction (PPI) network and a weighted gene co-expression network analysis (WGCNA) network, found their overlapping differentially expressed genes and studied them as the key genes. Analysis of the peripheral-blood transcriptome datasets of PD patients from GEO showed that three key genes were upregulated in PD over healthy participants. Analysis of the relationship between their expression and survival and analysis of their brain expression suggested that these key genes could become biomarkers. Then, animal models were studied to validate the expression of the key genes, and only SSR1 (the signal sequence receptor subunit1) was significantly upregulated in both animal models in peripheral blood. Correlation analysis and logistic regression analysis were used to analyze the correlation between brain dopaminergic neurons and SSR1 expression, and it was found that SSR1 expression was negatively correlated with dopaminergic neuron survival. The upregulation of SSR1 expression in peripheral blood was also found to precede the abnormal behavior of animals. In addition, the application of artificial intelligence technology further showed the value of SSR1 in clinical PD prediction. The three classifiers all showed that SSR1 had high predictability for PD. The classifier with the best prediction accuracy was selected through AUC and MCC to construct a prediction model. In short, this research not only provides potential biomarkers for the early diagnosis of PD but also establishes a possible artificial intelligence model for predicting PD.
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Parkinson's disease is a common neurodegenerative disease. Cell transplantation is a promising therapeutic option for improving the survival and function of dopaminergic neurons, but the mechanisms underlying the interaction between the transplanted cells and the recipient neurons remain to be studied. In this study, we investigated the effects of skin precursor cell-derived Schwann cells (SKP-SCs) directly cocultured with 6-OHDA-injured dopaminergic neurons in vitro and of SKP-SCs transplanted into the brains of 6-OHDA-induced PD mice in vivo. In vitro and in vivo studies revealed that SKP-SCs could reduce the damage to dopaminergic neurons by enhancing self-autophagy and modulating neuronal autophagy. Thus, the present study provides the first evidence that cell transplantation mitigates 6-OHDA-induced damage to dopaminergic neurons by enhancing self-autophagy, suggesting that earlier transplantation of Schwann cells might help alleviate the loss of dopaminergic neurons.
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Autofagia , Encéfalo/patologia , Neurônios Dopaminérgicos/patologia , Transtornos Parkinsonianos/prevenção & controle , Células de Schwann/transplante , Transplante de Células-Tronco , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Fenótipo , Ratos Sprague-Dawley , Células de Schwann/metabolismo , Pele/citologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Mutations in SLC6A1, encoding γ-aminobutyric acid (GABA) transporter 1 (GAT-1), have been recently associated with a spectrum of epilepsy syndromes, intellectual disability and autism in clinic. However, the pathophysiology of the gene mutations is far from clear. Here we report a novel SLC6A1 missense mutation in a patient with epilepsy and autism spectrum disorder and characterized the molecular defects of the mutant GAT-1, from transporter protein trafficking to GABA uptake function in heterologous cells and neurons. The heterozygous missense mutation (c1081C to A (P361T)) in SLC6A1 was identified by exome sequencing. We have thoroughly characterized the molecular pathophysiology underlying the clinical phenotypes. We performed EEG recordings and autism diagnostic interview. The patient had neurodevelopmental delay, absence epilepsy, generalized epilepsy, and 2.5-3 Hz generalized spike and slow waves on EEG recordings. The impact of the mutation on GAT-1 function and trafficking was evaluated by 3H GABA uptake, structural simulation with machine learning tools, live cell confocal microscopy and protein expression in mouse neurons and nonneuronal cells. We demonstrated that the GAT-1(P361T) mutation destabilizes the global protein conformation and reduces total protein expression. The mutant transporter protein was localized intracellularly inside the endoplasmic reticulum (ER) with a pattern of expression very similar to the cells treated with tunicamycin, an ER stress inducer. Radioactive 3H-labeled GABA uptake assay indicated the mutation reduced the function of the mutant GAT-1(P361T), to a level that is similar to the cells treated with GAT-1 inhibitors. In summary, this mutation destabilizes the mutant transporter protein, which results in retention of the mutant protein inside cells and reduction of total transporter expression, likely via excessive endoplasmic reticulum associated degradation. This thus likely causes reduced functional transporter number on the cell surface, which then could cause the observed reduced GABA uptake function. Consequently, malfunctioning GABA signaling may cause altered neurodevelopment and neurotransmission, such as enhanced tonic inhibition and altered cell proliferation in vivo. The pathophysiology due to severely impaired GAT-1 function may give rise to a wide spectrum of neurodevelopmental phenotypes including autism and epilepsy.
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Transtorno Autístico/metabolismo , Retículo Endoplasmático/metabolismo , Epilepsia/metabolismo , Proteínas da Membrana Plasmática de Transporte de GABA/sangue , Ácido gama-Aminobutírico/metabolismo , Sequência de Aminoácidos , Animais , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Linhagem Celular , Criança , Eletroencefalografia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Epilepsia/genética , Epilepsia/fisiopatologia , Epilepsia Tipo Ausência/genética , Epilepsia Tipo Ausência/fisiopatologia , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatologia , Feminino , Proteínas da Membrana Plasmática de Transporte de GABA/química , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Humanos , Aprendizado de Máquina , Camundongos , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Neurônios/metabolismo , Linhagem , Filogenia , Conformação Proteica , Estabilidade Proteica , Transporte Proteico , Tunicamicina/farmacologia , Sequenciamento do ExomaRESUMO
GABRB3 is highly expressed early in the developing brain, and its encoded ß3 subunit is critical for GABAA receptor assembly and trafficking as well as stem cell differentiation in embryonic brain. To date, over 400 mutations or variants have been identified in GABRB3. Mutations in GABRB3 have been increasingly recognized as a major cause for severe paediatric epilepsy syndromes such as Lennox-Gastaut syndrome, Dravet syndrome and infantile spasms with intellectual disability as well as relatively mild epilepsy syndromes such as childhood absence epilepsy. There is no plausible molecular pathology for disease phenotypic heterogeneity. Here we used a very high-throughput flow cytometry assay to evaluate the impact of multiple human mutations in GABRB3 on receptor trafficking. In this study we found that surface expression of mutant ß3 subunits is variable. However, it was consistent that surface expression of partnering γ2 subunits was lower when co-expressed with mutant than with wild-type subunits. Because γ2 subunits are critical for synaptic GABAA receptor clustering, this provides an important clue for understanding the pathophysiology of GABRB3 mutations. To validate our findings further, we obtained an in-depth comparison of two novel mutations [GABRB3 (N328D) and GABRB3 (E357K)] associated with epilepsy with different severities of epilepsy phenotype. GABRB3 (N328D) is associated with the relatively severe Lennox-Gastaut syndrome, and GABRB3 (E357K) is associated with the relatively mild juvenile absence epilepsy syndrome. With functional characterizations in both heterologous cells and rodent cortical neurons by patch-clamp recordings, confocal microscopy and immunoblotting, we found that both the GABRB3 (N328D) and GABRB3 (E357K) mutations reduced total subunit expression in neurons but not in HEK293T cells. Both mutant subunits, however, were reduced on the cell surface and in synapses, but the Lennox-Gastaut syndrome mutant ß3 (N328D) subunit was more reduced than the juvenile absence epilepsy mutant ß3 (E357K) subunit. Interestingly, both mutant ß3 subunits impaired postsynaptic clustering of wild-type GABAA receptor γ2 subunits and prevented γ2 subunits from incorporating into GABAA receptors at synapses, although by different cellular mechanisms. Importantly, wild-type γ2 subunits were reduced and less clustered at inhibitory synapses in Gabrb3+/- knockout mice. This suggests that impaired receptor localization to synapses is a common pathophysiological mechanism for GABRB3 mutations, although the extent of impairment may be different among mutant subunits. The study thus identifies the novel mechanism of impaired targeting of receptors containing mutant ß3 subunits and provides critical insights into understanding how GABRB3 mutations produce severe epilepsy syndromes and epilepsy phenotypic heterogeneity.
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Epilepsia/genética , Receptores de GABA-A/genética , Animais , Encéfalo/embriologia , Linhagem Celular , Membrana Celular/metabolismo , Criança , Pré-Escolar , Análise por Conglomerados , Epilepsia/metabolismo , Síndromes Epilépticas/genética , Feminino , Citometria de Fluxo/métodos , Células HEK293 , Humanos , Masculino , Potenciais da Membrana/fisiologia , Camundongos , Camundongos Knockout , Mutação/genética , Técnicas de Patch-Clamp , Fenótipo , Subunidades Proteicas/genética , Transporte Proteico , Ratos , Receptores de GABA-A/metabolismoRESUMO
BACKGROUND: Mutations in SLC6A1 have been associated mainly with myoclonic atonic epilepsy (MAE) and intellectual disability. We identified a novel missense mutation in a patient with Lennox-Gastaut syndrome (LGS) characterized by severe seizures and developmental delay. METHODS: Exome Sequencing was performed in an epilepsy patient cohort. The impact of the mutation was evaluated by 3H γ-aminobutyric acid (GABA) uptake, structural modeling, live cell microscopy, cell surface biotinylation and a high-throughput assay flow cytometry in both neurons and non neuronal cells. RESULTS: We discovered a heterozygous missense mutation (c700G to A [pG234S) in the SLC6A1 encoding GABA transporter 1 (GAT-1). Structural modeling suggests the mutation destabilizes the global protein conformation. With transient expression of enhanced yellow fluorescence protein (YFP) tagged rat GAT-1 cDNAs, we demonstrated that the mutant GAT-1(G234S) transporter had reduced total protein expression in both rat cortical neurons and HEK 293â¯T cells. With a high-throughput flow cytometry assay and live cell surface biotinylation, we demonstrated that the mutant GAT-1(G234S) had reduced cell surface expression. 3H radioactive labeling GABA uptake assay in HeLa cells indicated a reduced function of the mutant GAT-1(G234S). CONCLUSIONS: This mutation caused instability of the mutant transporter protein, which resulted in reduced cell surface and total protein levels. The mutation also caused reduced GABA uptake in addition to reduced protein expression, leading to reduced GABA clearance, and altered GABAergic signaling in the brain. The impaired trafficking and reduced GABA uptake function may explain the epilepsy phenotype in the patient.
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Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Síndrome de Lennox-Gastaut/genética , Adolescente , Animais , Proteínas da Membrana Plasmática de Transporte de GABA/química , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Células HEK293 , Células HeLa , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Transporte Proteico/genética , RatosRESUMO
OBJECTIVE: to evaluate whether postoperative heart rate variability (HRV) predicts short-term outcomes in patients undergoing coil embolization of ruptured aneurysms. METHODS: Consecutive patients receiving endovascular coiling to treat aneurysmal subarachnoid hemorrhage (SAH) were retrospectively reviewed between November 2011 and December 2014 in the authors' institution. Heart rate (HR) and blood pressure (BP) recorded in the initial 24 h after endovascular treatment were extracted along with other clinical data. HR variability (HRV) and BP variability (BPV) were determined as standard deviation (SD) and successive variation (SV) of every 2-h HR and BP. The correlation between HRV and clinical outcomes as assessed by Glasgow Outcome Scale (GOS) scores at discharge were analyzed statistically. RESULTS: Compared to the 310 patients with favorable outcomes (GOS 4-5), the 35 with unfavorable outcomes (GOS 1-3) had significantly higher HR, HRV, and BPV in the first postoperative day. Furthermore, HRV-SD remained to be an independent predictor of unfavorable recovery in multivariate logistic analysis (OR = 1.14; 95% CI, 1.02-1.29; P = 0.026) after adjusting for age, postoperative fever, and Glasgow Coma Scale scores on admission, which have been identified as predictors of poor prognosis. The area under the receiver operating characteristic curves for HRV-SD and BPV-SV were found to be 0.745 (95% CI, 0.658-0.833) and 0.633 (95% CI, 0.524-0.741), respectively (P < 0.05). CONCLUSIONS: Higher HRV in the first day after coil embolization was associated with unfavorable outcomes in patients with SAH. Early detection and appropriate treatment of the overactive sympathetic activity might promote functional recovery after SAH. Abbreviation: BP: Blood pressure; CI: Confidence interval; DBP: Diastolic blood pressure; GCS: Glasgow coma scale; GOS: Glasgow outcome scale; HR: Heart rate; HRV: Heart rate variability; OR: Odds ratio; ROC: Receiver operating characteristics; SD: Standard deviation; SAH: Subarachnoid hemorrhage; SV: Successive variation; SBP: Systolic blood pressure.
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Embolização Terapêutica/instrumentação , Embolização Terapêutica/métodos , Frequência Cardíaca/fisiologia , Hemorragia Subaracnóidea/fisiopatologia , Hemorragia Subaracnóidea/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/fisiologia , Feminino , Escala de Coma de Glasgow , Escala de Resultado de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Hemorragia Subaracnóidea/psicologia , Resultado do Tratamento , Adulto JovemRESUMO
Delayed administration of kallikrein after cerebral infarction can improve neurological function. However, the appropriate kallkrein treatment time after ischemic stroke has not been illuminated. In this study, we compared the long-term outcome among three kallikrein therapeutic regimens starting at different time points following mouse cerebral ischemia. Furthermore, the protective mechanisms involving neurogenesis, angiogenesis, and AKT-GSK3ß-VEGF signaling pathway were analyzed. Human tissue kallikrein was injected through the tail vein daily starting at 8 h, 24 h, or 36 h after right middle cerebral artery occlusion (MCAO) until the 28th day. Three therapeutic regimens all protected against neurological dysfunction, but kallikrein treatment starting at 8 h after MCAO had the best efficacy. Additionally, kallikrein treatment at 8 h after MCAO significantly enhanced cell proliferation including neural stem cell and induced differentiation of neural stem cell into mature neuron. Kallikrein treatment starting at 8 h also promoted more angiogenesis than other two treatment regimens, which was associated with AKT-GSK3ß-VEGF signaling pathway. Thus, we confirm that three delayed kallikrein treatments provide protection against cerebral infarction and furthermore suggest that kallikrein treatment starting at 8 h had a better effect than that at 24 h and 36 h. These findings provide the experimental data contributing to better clinical application of exogenous kallikrein.
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OBJECTIVE: The present study was conducted to evaluate the effect of postoperative blood pressure (BP) variability on functional outcome in patients after coil embolization of ruptured aneurysms. METHODS: The authors retrospectively reviewed their database of patients undergoing endovascular coiling to treat subarachnoid hemorrhage (SAH) between November 2011 and December 2014. BP values were recorded every 2 hours in the initial 24 hours after endovascular obliteration of ruptured aneurysms. BP variability was determined as standard deviation (SD) and successive variation (SV). Clinical outcome at discharge was assessed by the modified Rankin Scale (mRS) and Glasgow Coma Scale (GCS) Score. BP variability obtained were correlated to patient outcome and analyzed statistically. RESULTS: Favorable outcomes (mRS 0-1) achieved in 308 (83.7%) of the 368 patients. On univariate logistic analysis, postoperative systolic blood pressure variability (SBPV)-SD, SBPV-SV, diastolic blood pressure variability (DBPV)-SD and DBPV-SV were associated with clinical outcome at discharge. SBPV-SV remained to be an independent predictor for functional recovery (OR, 0.93; 95% CI, 0.88-0.98; P = 0.009) after adjusting for age, postoperative fever, and Hunt-Hess grade by multivariate analysis. Furthermore, patients with higher SBPV had lower GCS grade at discharge (P < 0.001). There was no association between clinical outcome and mean systolic BP (SBP) (P = 0.360) or mean diastolic BP (DBP) (P = 0.105) after coiling. CONCLUSION: Postoperative SBPV was a strong predictor of clinical outcome in patients undergoing coil embolization of aneurysms, independent of mean SBP or DBP and seemed to be a potential therapeutic target in aneurysmal SAH.
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Aneurisma Roto/cirurgia , Pressão Sanguínea/fisiologia , Embolização Terapêutica/métodos , Aneurisma Intracraniano/cirurgia , Resultado do Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneurisma Roto/complicações , Feminino , Escala de Coma de Glasgow , Humanos , Aneurisma Intracraniano/complicações , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Hemorragia Subaracnóidea/cirurgia , Adulto JovemRESUMO
OBJECTIVE: Accurate identification of patients who will achieve a favorable outcome is almost impossible preoperatively or postoperatively in poor-grade (Hunt and Hess Grade IV and V) aneurysmal subarachnoid hemorrhage (SAH). Whether characteristics of blood pressure profiles during the first 24 hours after endovascular coiling could predict prognosis in poor grade patients was explored. METHODS: Data were obtained retrospectively on all patients undergoing endovascular treatment with poor-grade SAH from November 2011 to June 2016. Blood pressure during the initial 24 hours was measured at 2-hour intervals after coil embolization. Studied features of mean systolic blood pressure (MSBP) and systolic blood pressure variability (SBPV) as well as demographics, medical history, clinical characteristics, and neurologic outcomes were documented. SBPV was determined as standard deviation and successive variation of systolic blood pressure. Logistic regression analysis was used to identify predictors of favorable outcome assessed on modified Rankin Scale score of 0 to 2. RESULTS: The patients with favorable and unfavorable outcome were comparable with respect to systolic blood pressure on admission and MSBP after coiling. However, MSBP between 120 and 140 mm Hg was one of independent predictors of good outcomes at discharge (odds ratio 7.1; P = 0.002). SBPV-successive variation after embolization was associated with functional recovery (odds ratio 0.87; P = 0.011) in multivariate logistic analysis and mortality by Cox proportional hazard regression (hazard ratio, 1.10; P = 0.001) at 6-month follow-up. CONCLUSIONS: Characteristics of blood pressure profiles after coiling appeared to be simple and convenient indexes for the prognosis of patients with poor-grade SAH.
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Pressão Arterial/fisiologia , Embolização Terapêutica , Hemorragia Subaracnóidea/fisiopatologia , Hemorragia Subaracnóidea/terapia , Adulto , Idoso , Feminino , Frequência Cardíaca/fisiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Razão de Chances , Prognóstico , Estudos Retrospectivos , Hemorragia Subaracnóidea/mortalidade , Resultado do TratamentoRESUMO
OBJECTIVE: This study aimed to evaluate the association of different stenting procedures with the procedure-related complications in stent-assisted coiling (SAC) of ruptured wide-necked aneurysms. METHODS: Consecutive patients undergoing SAC of ruptured wide-necked aneurysms were retrospectively reviewed between December 2011 and June 2016. They received 1 of the 3 stenting procedures during SAC: 1) the coiling microcatheter was "jailed" outside of the stent and the coil embolization proceeded above the stent; 2) initial stent deployment followed by the coils through the stent's strut technique; or 3) the coil-then-stent technique. The effect of different stenting procedures on clinical complications and outcomes was estimated by logistic regression models. RESULTS: Of the 93 patients enrolled in this study, 11 of them (11.8%) suffered from symptomatic thromboembolic events and 10 of them (10.8%) had hemorrhagic complications. SAC with different stenting procedures (odds ratio [OR] = 4.10, 95% confidence interval [CI]: 1.20-13.97, P = 0.024) was the only independent risk factor for symptomatic thromboembolic events. The coil-then-stent technique had a higher ischemic complications rate than the other 2 stenting procedures (P = 0.023). Serum glucose (OR = 1.48, P = 0.014) and systolic blood pressure on admission (OR = 0.97, P = 0.046) were independent predictors of hemorrhagic complications during SAC. However, different stenting procedures and stent types were correlated with neither aneurysm occlusion at the end of procedure (P = 0.498 and 0.176, respectively) nor favorable outcome at discharge (P = 0.710 and 0.928, respectively). CONCLUSION: Different stenting procedures were associated with thromboembolic but not hemorrhagic complications in SAC of ruptured wide-necked aneurysms.
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Aneurisma Roto/terapia , Embolização Terapêutica/instrumentação , Embolia Intracraniana/etiologia , Trombose Intracraniana/etiologia , Complicações Pós-Operatórias/etiologia , Stents , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneurisma Roto/diagnóstico por imagem , Feminino , Humanos , Embolia Intracraniana/diagnóstico por imagem , Trombose Intracraniana/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico por imagem , Estudos Retrospectivos , Fatores de Risco , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/etiologia , VentriculostomiaRESUMO
Transplantation of bone marrow stromal cells (BMSCs) is a promising therapy for ischemic stroke, but the poor oxygen environment in brain lesions limits the efficacy of cell-based therapies. Here, we tested whether hypoxic preconditioning (HP) could augment the efficacy of BMSC transplantation in a rat ischemic stroke model and investigated the underlying mechanism of the effect of HP. In vitro, BMSCs were divided into five passage (P0, P1, P2, P3, and P4) groups, and HP was applied to the groups by incubating the cells with 1% oxygen for 0, 4, 8, 12, and 24 h, respectively. We demonstrated that the expression of hypoxia-inducible factor-1α (HIF-1α) was increased in the HP-treated BMSCs, while their viability was unchanged. We also found that HP decreased the apoptosis of BMSCs during subsequent simulated ischemia-reperfusion (I/R) injury, especially in the 8-h HP group. In vivo, a rat transient focal cerebral ischemia model was established. These rats were administered normal cultured BMSCs (N-BMSCs), HP-treated BMSCs (H-BMSCs), or DMEM cell culture medium (control) at 24 h after the ischemic insult. Compared with the DMEM control group, the two BMSC-transplanted groups exhibited significantly improved functional recovery and reduced infarct volume, especially the H-BMSC group. Moreover, HP decreased neuronal apoptosis and enhanced the expression of BDNF and VEGF in the ischemic brain. Survival and differentiation of transplanted BMSCs were also increased by HP, and the quantity of engrafted BMSCs was significantly correlated with neurological function improvement. These results suggest that HP may enhance the therapeutic efficacy of BMSCs in an ischemic stroke model. The underlying mechanism likely involves the inhibition of caspase-3 activation and an increasing expression of HIF-1α, which promotes angiogenesis and neurogenesis and thereby reduces neuronal death and improves neurological function.
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Isquemia Encefálica/complicações , Hipóxia/patologia , Precondicionamento Isquêmico , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/terapia , Animais , Isquemia Encefálica/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Ativação Enzimática , Hipóxia/complicações , Masculino , Neovascularização Fisiológica , Neurônios/metabolismo , Neurônios/patologia , Neuroproteção , Ratos Sprague-Dawley , Acidente Vascular Cerebral/patologia , Resultado do Tratamento , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: The purpose of this study was to compare the efficacy, stability, and safety of stent-assisted coiling (SAC) and balloon-assisted coiling (BAC) in the treatment of ruptured wide-necked aneurysms in the acute period. METHODS: Consecutive patients including 65 cases treated with SAC and 32 with BAC were reviewed at the authors' institution between November 2011 and December 2014. The efficacy of these 2 approaches and the incidence of periprocedural complications were retrospectively evaluated. RESULTS: Morphologic analysis showed a lower fundus/neck ratio (1.2 vs. 1.6) in the aneurysms treated with SAC versus BAC (P < 0.001). The mean neck width of aneurysms was 4.0 mm in the patients treated with SAC versus 3.4 mm in those treated with BAC (P < 0.04). Coil protrusion into the parent vessels during embolization was an independent risk factor for cerebral ischemic events (odds ratio [OR], 4.08; 95% confidence interval [CI], 1.03-16.2). Neck width (OR, 0.65; 95% CI, 0.44-0.97) and aneurysm perforation during procedure (OR, 6.24; 95% CI, 1.21-32.3) were independent predictors of complete occlusion (Raymond 1) by immediate postembolization angiography. There was no statistical difference between the 2 techniques regarding the rate of aneurysm occlusion at the end of procedure, periprocedural complications, and favorable outcome at discharge and follow-up. CONCLUSIONS: These findings suggested that SAC was more appropriate than BAC for ruptured wide-necked aneurysms with lower fundus/neck ratio or wider neck size. However, periprocedural complications, occlusion rates, and favorable outcomes did not differ between the 2 techniques.
Assuntos
Aneurisma Roto/cirurgia , Embolização Terapêutica/instrumentação , Embolização Terapêutica/métodos , Aneurisma Intracraniano/cirurgia , Stents , Idoso , Aneurisma Roto/complicações , Oclusão com Balão/instrumentação , Oclusão com Balão/métodos , Angiografia Cerebral , Feminino , Seguimentos , Humanos , Aneurisma Intracraniano/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate risk factors to predict postoperative fever after endovascular treatment of ruptured intracranial aneurysms. METHODS: Patients undergoing endovascular coiling to treat subarachnoid hemorrhage in Nantong University between November 2011 and September 2014 were retrospectively reviewed. Postoperative temperature and patient demographic data, admission status, characteristic features of aneurysms, and endovascular coiling procedure were documented and analyzed. There were 336 consecutive patients included in this study, and 111 were classified as febrile (tympanic temperature >38.3°C for at least 2 consecutive days). RESULTS: Univariate analysis demonstrated that age, interval from onset of subarachnoid hemorrhage to operation, history of hypertension and smoking, Hunt and Hess grade, Fisher grade, temperature before coiling, leukocyte count on admission, and infectious complications were correlated with postoperative fever. Five variables were independent risk factors to predict fever by multivariate logistic regression: age >70 years (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.2-5.6), Fisher grade 3 or 4 (OR = 2.2, 95% CI = 1.1-4.3), leukocyte count >10,000/mm(3) on admission (OR = 2.3, 95% CI = 1.3-4.0), temperature >37.5°C before coiling (OR = 4.6, 95% CI = 2.0-10.7), and infectious complications (OR = 4.4, 95% CI = 2.2-8.6). CONCLUSIONS: Postoperative fever after coil embolization was predicted by changeable and unchangeable risk factors in subarachnoid hemorrhage. However, characteristic features of aneurysms and the coiling procedure had no impact on development of postoperative fever. Preventing any infectious complications, lowering temperature before embolization, and draining bloody cerebrospinal fluid may assist in the prevention of subsequent fever.
Assuntos
Aneurisma Roto/epidemiologia , Aneurisma Roto/terapia , Embolização Terapêutica/estatística & dados numéricos , Febre/epidemiologia , Aneurisma Intracraniano/epidemiologia , Aneurisma Intracraniano/terapia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Causalidade , China/epidemiologia , Comorbidade , Embolização Terapêutica/instrumentação , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Sensibilidade e Especificidade , Distribuição por Sexo , Resultado do TratamentoRESUMO
Transplantation of bone marrow stromal cells (BMSCs) reduces astrogliosis, decreases scar thickness and improves neurological functional recovery after brain damage. It is believed that transplanted BMSCs have a profound influence on astrocytes. To obtain the possible mechanism in their interaction, a co-culture system between BMSCs and astrocytes were set to investigate whether BMSCs could modulate cell cycle machinery in reactive astrocytes. The results obtained showed cell cycle regulatory proteins, cdk4 along with its activator cyclin D1, and PCNA increased while p27, an endogenous cyclin-dependent kinase inhibitor, deceased in glutamate-treated astrocytes in vitro. However, BMSCs influenced cell cycle elements in the cocultured astrocytes: cyclin D1, cdk 4 and PCNA were downregulated, while p27 was unregulated. Flow cytometry showed astrocytes in the S phase after glutamate incubation increased to 17.4±2.0% while restored to a level of 7.8±1.1% when cocultured with BMSCs. l-Canavanine, an inhibitor of inducible nitric oxide synthase, partially reversed the S phase to 11.3±0.4% in the cocultured astrocytes. These data indicated that BMSCs might inhibit the cell cycle control system in reactive astrocytes and nitric oxide signaling was involved in this process. The decline of astrogliosis conferred by BMSCs may derive from their effect of inhibiting the cell cycle progression in astrocytes.
Assuntos
Astrócitos/fisiologia , Células da Medula Óssea/fisiologia , Pontos de Checagem do Ciclo Celular , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Canavanina/farmacologia , Células Cultivadas , Técnicas de Cocultura , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Células Estromais/efeitos dos fármacos , Células Estromais/fisiologiaRESUMO
Transplantation of bone marrow stromal cells (BMSCs) improves animal neurological functional recovery after stroke. But the mechanism remains unclear. As cell cycle machinery plays an important role in stroke, we investigated the dynamic changes of cell cycle elements in a rat model of middle cerebral artery occlusion. We found the cell cycle markers, cdk4 along with its activator cyclin D1, and proliferating cell nuclear antigen (PCNA), increased after brain ischemia-reperfusion. Phosphorylation of the retinoblastoma protein (pRb, on ser-795), the cyclin D/cdk4 complex mutual target, was upregulated accordingly. However, intravenously administrated BMSCs facilitated cyclin D1, cdk4, and PCNA decrease in the ischemic cortex. Meanwhile, phospho-pRb (ser-795) was completely inhibited. On the contrary, endogenous cdk inhibitor p27 reduced before but enhanced after BMSCs treatment. These findings suggested BMSCs might modulate cell cycle progression in injured brain via downregulation of the cyclin D1/cdk4/pRb pathway as well as upregulation of p27 level. These results provide another way by which BMSCs may contribute to the recovery from stroke.
Assuntos
Transplante de Medula Óssea , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/cirurgia , Ciclo Celular/fisiologia , Células Estromais/transplante , Animais , Córtex Cerebral/fisiopatologia , Córtex Cerebral/cirurgia , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/cirurgia , Masculino , Fosforilação , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/cirurgiaRESUMO
Two inbred strains of mice, A/J, C57BL/6J and F2 intercross progenies,were used for QTL mapping for weight and cross-sectional area on cervical enlargement of spinal cord in mice. 13 QTLs located on Chromosome 2, 4, 8, 14, 15, 17, 18, 19 and X, respectively, for these two traits were found. Six QTLs were responsible for the cord weight, four for the cross-sectional area and three for both. Among 13 QTLs, three QTLs (P < 0.01) termed SC1 (located near D15Mit158) ,SC2 (DXMit140) and SC3 (DXMit64) accounted for 24%, 19% and 15% of the total variance in weight phenotype, and -3.78, 3.41 and 2.06 mg additive effect, respectively. The P value of other QTLs is between 0.01 and 0.05. SC1 is only one QTL that responsible for both weight and cross-sectional area in three QTLs above. This study revealed the location of major QTLs related size of spinal cord in mice, and may be helpful in fine mapping and ultimate identification of candidate genes.