Gut Dysbiosis Is Associated With the Severity of Cryptogenic Stroke and Enhanced Systemic Inflammatory Response.
Frontiers in immunology
Studies implicate that gut dysbiosis is related with many neurological diseases. However, the potential role of gut dysbiosis in cryptogenic stroke (CS) has not been elucidated yet. In this study, a high prevalence of gastrointestinal (GI) dysfunction and gut inflammation with increased intestinal permeability have been found in CS patients compared with normal controls (NCs). The systemic inflammation in CS patients was also identified by measuring the levels of plasma C-reactive protein (CRP), lipopolysaccharide (LPS), LPS-binding protein (LBP), and white blood cells (WBC) count. Using 16S rRNA sequencing, we found increased alpha diversity, accompanied by a higher abundance of Enterobacteriaceae, Streptococcaceae, and Lactobacillaceae at the family level and , , , and at the genus level in the intestinal microbiota of CS patients compared to NCs. Our results showed that the abundance of was positively correlated with the systemic inflammation, the National Institutes of Health Stroke Scale (NIHSS) scores, and the infarct volumes. In conclusion, gut dysbiosis in CS patients was associated with the severity of CS and the systemic inflammation. Maintaining the intestinal homeostasis may be a potential strategy for the treatment of CS.
A novel risk score for predicting hospital acquired pneumonia in aneurysmal subarachnoid hemorrhage patients.
BACKGROUND:Pneumonia is a common complication in aneurysmal subarachnoid hemorrhage (aSAH) patients and has been confirmed associated with unfavorable outcome of aSAH patients. This study is designed to explore risk factors and develop predictive model of hospital acquired pneumonia in aSAH patients. METHODS:351 aSAH patients received treatments in the neuro-intensive care unit (NICU) of West China hospital were included. Univariate and multivariate logistic regression were performed to explore risk factors of hospital acquired pneumonia. And predictive model for pneumonia was also constructed using logistic regression. Area under the receiver operating characteristics curve (AUC) were calculated to evaluate the accuracy of the constructed model and single markers. RESULTS:96 aSAH patients developed hospital acquired pneumonia with incidence of 27.4%. Logistic regression analysis showed World Federation of Neurosurgical Societies (WFNS) score (0R = 1.677, p = 0.006), neutrophil count (0R = 1.300, p = 0.042), red blood cell transfusion (0R = 3.035, p = 0.030) and tracheostomy (0R = 7.645, p < 0.001) were independent risk factors of pneumonia in aSAH patients. Consisted of these four factors, the constructed model was valuable in predicting pneumonia with AUC of 0.808. The AUC of neutrophil to lymphocyte ratio and lactate dehydrogenase for predicting pneumonia was 0.671 and 0.613, respectively. CONCLUSIONS:WFNS, high neutrophil at admission, need of RBC transfusion and tracheostomy were independent risk factors of hospital acquired pneumonia in aSAH patients. The novel predictive model we constructed is efficient in evaluating possibility of pneumonia in aSAH patients during hospitalizations.
Smartphone navigated endoscopic port surgery of hypertensive basal ganglia hemorrhage.
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
OBJECTIVE:Endoscopic port surgery is a promising alternative for the surgical treatment of intracerebral hypertensive basal ganglia hemorrhage (HBGH). The precise location of hematoma is a crucial step for surgery. The authors developed a simple, low-cost navigation method using an Android smartphone for the localization of HBGH. METHODS:All patients' CT DICOM data were processed with an open-source software (3D Slicer). The volume of hematoma, angle, and length of trajectory were calculated automatically. A smartphone running the Android system and the Compass APP was used to help insert the inner introducer. An endoscopic port system was applied to create a working channel for neuro-endoscopic hematoma evacuation. RESULTS:There were 27 patients enrolled in this study (mean age 56). All patients underwent successful surgical evacuation of HBGH with neuroendoscopic evacuation. The mean time taken for the surgical plan was 4 min. The total operation time from skin incision to final suture was 82.6 min. Compared with standard neuronavigation, mean error of trajectory was 5.1 mm. The mean preoperative hematoma volume was 44.8 ml. The optimal trajectory angle averaged 39.5°and the length was 71 mm. Intraoperative blood loss was about 45 ml. Post-operative hematoma volume was 2.9 ml, and the average evacuation rate was 93.6%. One week after surgery, the mean GCS score was improved from 8.2 to 13.8 (p < 0.01). CONCLUSIONS:This simple, low-cost navigation method using 3D Slicer, an Android smartphone with the Compass APP, helps precisely insert the endoscopic working channel to the desired point, which is crucial for satisfactory evacuation of HBGH.
Decompressive hemicraniectomy after aneurysmal subarachnoid hemorrhage-justifiable in light of long-term outcome?
PURPOSE:Decompressive hemicraniectomy (DHC) is a potentially lifesaving procedure in refractory intracranial hypertension, which can prevent death from brainstem herniation but may cause survival in a disabled state. The spectrum of indications is expanding, and we present long-term results in a series of patients suffering from aneurysmal subarachnoid hemorrhage (SAH). METHODS:We performed a retrospective analysis of previously registered data including all patients treated for SAH between 2010 and 2018 in a single institution. Patients treated with decompressive hemicraniectomy due to refractory intracranial hypertension were identified. Clinical outcome was assessed by means of the Glasgow outcome scale after 12 months. RESULTS:Of all 341 SAH cases, a total of 82 (24.0%) developed intracranial hypertension. Of those, 63 (18.5%) patients progressed into refractory ICP elevation and were treated with DHC. Younger age (OR 0.959, 95% CI 0.933 to 0.984; p = 0.002), anterior aneurysm location (OR 0.253, 95% CI 0.080 to 0.799; 0.019; p = 0.019), larger aneurysm size (OR 1.106, 95% CI 1.025 to 1.194; p = 0.010), and higher Hunt and Hess grading (OR 1.944, 95% CI 1.431 to 2.641; p < 0.001) were independently associated with the need for DHC. After 1 year, 10 (15.9%) patients after DHC were categorized as favorable outcome. Only younger age was independently associated with favorable outcome (OR 0.968 95% CI 0.951 to 0.986; p = 0.001). CONCLUSIONS:Decompressive hemicraniectomy, though lifesaving, has only a limited probability of survival in a clinically favorable condition. We identified young age to be the sole independent predictor of favorable outcome after DHC in SAH.
2,2,6,6-Tetramethylpiperidine-1-oxyl acts as a volatile inhibitor of ferroptosis and neurological injury.
Journal of biochemistry
Ferroptosis, a type of oxidative stress cell death, has been implicated in cell injury in several diseases, and treatments with specific inhibitors have been shown to protect cells and tissues. Here we demonstrated that a treatment with the nitroxide radical, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), prevented the ferroptotic cell death in an airborne manner. Other TEMPO derivatives and lipophilic antioxidants, such as Trolox and ferrostatin-1, also prevented cell death induced by erastin and RSL3; however, only TEMPO exhibited inhibitory activity from a physically distant location. TEMPO vaporized without decomposing, and then dissolved again into a nearby water solution. Volatilized TEMPO inhibited glutamate-induced cell death in mouse hippocampal cell lines, and also reduced neuronal cell death in a mouse ischemia model. These results suggest that TEMPO is a unique cell protective agent that acts in a volatility-mediated manner.
Intertwined Relation between the Endoplasmic Reticulum and Mitochondria in Ischemic Stroke.
Oxidative medicine and cellular longevity
In ischemic stroke (IS), accumulation of the misfolded proteins in the endoplasmic reticulum (ER) and mitochondria-induced oxidative stress (OS) has been identified as the indispensable inducers of secondary brain injury. With the increasing recognition of an association between ER stress and OS with ischemic stroke and with the improved understanding of the underlying molecular mechanism, novel targets for drug therapy and new strategies for therapeutic interventions are surfacing. This review discusses the molecular mechanism underlying ER stress and OS response as both causes and consequences of ischemic stroke. We also summarize the latest advances in understanding the importance of ER stress and OS in the pathogenesis of ischemic stroke and discuss potential strategies and clinical trials explicitly aiming to restore mitochondria and ER dynamics after IS.
Idiopathic Parkinson's disease and chronic pain in the era of deep brain stimulation: a systematic review and meta-analysis.
Journal of neurosurgery
OBJECTIVE:Pain is the most common nonmotor symptom of Parkinson's disease (PD) and is often undertreated. Deep brain stimulation (DBS) effectively mitigates the motor symptoms of this multisystem neurodegenerative disease; however, its therapeutic effect on nonmotor symptoms, especially pain, remains inconclusive. While there is a critical need to help this large PD patient population, guidelines for managing this significant disease burden are absent. Herein, the authors systematically reviewed the literature and conducted a meta-analysis to study the influence of traditional (subthalamic nucleus [STN] and globus pallidus internus [GPi]) DBS on chronic pain in patients with PD. METHODS:The authors performed a systematic review of the literature and a meta-analysis following PRISMA guidelines. Risk of bias was assessed using the levels of evidence established by the Oxford Centre for Evidence-Based Medicine. Inclusion criteria were articles written in English, published in a peer-reviewed scholarly journal, and about studies conducting an intervention for PD-related pain in no fewer than 5 subjects. RESULTS:Twenty-six studies were identified and included in this meta-analysis. Significant interstudy heterogeneity was detected (Cochran's Q test p < 0.05), supporting the use of the random-effects model. The random-effects model estimated the effect size of DBS for the treatment of idiopathic pain as 1.31 (95% CI 0.84-1.79). The DBS-on intervention improved pain scores by 40% as compared to the control state (preoperative baseline or DBS off). CONCLUSIONS:The results indicated that traditional STN and GPi DBS can have a favorable impact on pain control and improve pain scores by 40% from baseline in PD patients experiencing chronic pain. Further trials are needed to identify the subtype of PD patients whose pain benefits from DBS and to identify the mechanisms by which DBS improves pain in PD patients.
Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage.
BACKGROUND:Erythrophagocytosis by reparative monocyte-derived macrophage contributes to hematoma clearance and neurological recovery after intracerebral hemorrhage (ICH). Vitamin D (VitD) is a neuroprotective hormone and regulates the differentiation of monocyte-derived macrophage from monocytes. In this study, we examined the effects of VitD supplementation on monocyte-derived macrophage and hematoma clearance in rodent with ICH. METHODS:Neurobehavioral functions and hematoma volume were assessed using a collagenase injection model in both young- and middle-aged mice with or without VitD treatment given 2 hours post-ICH induction. We used flow cytometry to analyze CD36 expression and macrophage and undifferentiated monocyte cell numbers during in vivo erythrophagocytosis in collagenase and autologous blood injection models. Western blot analysis and immunofluorescence were used to assess the expression levels of the PPAR-γ (peroxisome proliferator-activated receptor γ)-CD36 axis and CD206. A macrophage differentiation study was conducted on murine bone marrow-derived monocytes. RESULTS:VitD promoted neurological recovery and facilitated hematoma clearance in both young- and middle-aged mice after ICH. Within the perihematomal region, mature macrophages, rather than undifferentiated monocytes, expressed higher levels of CD36 in driving erythrocyte clearance. VitD increased the macrophage number but decreased the monocyte number and elevated the levels of CD36 and PPAR-γ in the brain. In vitro, VitD accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. CONCLUSIONS:VitD promotes reparative macrophage differentiation, facilitates hematoma clearance, and improves neurobehavioral performance in mice with ICH, suggesting that VitD should be further examined as a potentially promising treatment for ICH.
Transcription factor ASCL1 acts as a novel potential therapeutic target for the treatment of the Cushing's disease.
The Journal of clinical endocrinology and metabolism
BACKGROUND:The pathogenesis of Cushing's disease (CD) is still not adequately understood despite the identification of somatic driver mutations in USP8, BRAF and USP48. In this multiomics study, we combined RNA sequencing (RNA-seq) with Sanger sequencing to depict transcriptional dysregulation under different gene mutation backgrounds. Furthermore, we evaluated the potential of achaete-scute complex homolog 1 (ASCL1), a pioneer transcription factor, as a novel therapeutic target for treatment of CD and its possible downstream pathway. METHODS:RNA-seq was adopted to investigate the gene expression profile of CD, and Sanger sequencing was adopted to detect gene mutations. Bioinformatics analysis was used to depict transcriptional dysregulation under different gene mutation backgrounds. The function of ASCL1 in hormone secretion, cell proliferation and apoptosis were studied in vitro. The effectiveness of a ASCL1 inhibitor was evaluated in primary CD cells, and the clinical relevance of ASCL1 was examined in 68 patients with CD. RNA-seq in AtT-20 cells upon Ascl1 knockdown combined with published ChIp-seq data and dual luciferase assays were used to explore downstream pathways. RESULTS:ASCL1 was exclusively overexpressed in USP8-mutant and wild type tumors. Ascl1 promoted adrenocorticotrophin hormone overproduction and tumorigenesis and directly regulated Pomc in AtT-20 cells. A ASCL1 inhibitor presented promising efficacy in both AtT-20 and primary CD cells. ASCL1 overexpression was associated with a larger tumor volume and higher adrenocorticotrophin secretion in patients with CD. CONCLUSION:Our findings help to clarify the pathogenesis of CD and suggest that ASCL1 is a potential therapeutic target for treatment of CD.
Association of intraventricular fibrinolysis with clinical outcomes in ICH: an individual participant data meta-analysis.
In patients with intracerebral hemorrhage (ICH) the presence of intraventricular hemorrhage (IVH) constitutes an important therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. This individual participant data (IPD) meta-analysis pooled 1,501 patients from two randomized trials and seven observational studies enrolled during 2004 to 2015. We compared IVF vs standard of care (SoC, including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH and/or IVH. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS, range:0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS:0-3 vs mRS:4-6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random-effects- and doubly-robust-models to calculate odds-ratios (OR) and absolute treatment-effects (ATE). Comparing treatment of 596 with IVF to 905 with SoC resulted in an ATE to achieve the primary outcome of 9.3%[95%CI4.4-14.1]. IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common-OR:1.75[95%CI1.39-2.17], reduced mortality, OR:0.47[95%CI 0.35-0.64], without increased adverse events, absolute difference:1.0%[95%CI-2.7-4.8]. Exploratory analyses provided that early IVF-treatment (≤48 hours) after symptom onset was associated with an ATE:15.2%[95%CI8.6-21.8] to achieve the primary outcome. As compared to SoC, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage significantly improved functional outcome at 6 months. The treatment effect was linked to an early time-window<48h, specifying a target population for future trials.
Machine learning model prediction of 6-month functional outcome in elderly patients with intracerebral hemorrhage.
Spontaneous intracerebral hemorrhage (ICH) has an increasing incidence and a worse outcome in elderly patients. The ability to predict the functional outcome in these patients can be helpful in supporting treatment decisions and establishing prognostic expectations. We evaluated the performance of a machine learning (ML) model to predict the 6-month functional status in elderly patients with ICH leveraging the predictive value of the clinical characteristics at hospital admission. Data were extracted by a retrospective multicentric database of patients ≥ 70 years of age consecutively admitted for the management of spontaneous ICH between January 1, 2014 and December 31, 2019. Relevant demographic, clinical, and radiological variables were selected by a feature selection algorithm (Boruta) and used to build a ML model. Outcome was determined according to the Glasgow Outcome Scale (GOS) at 6 months from ICH: dead (GOS 1), poor outcome (GOS 2-3: vegetative status/severe disability), and good outcome (GOS 4-5: moderate disability/good recovery). Ten features were selected by Boruta with the following relative importance order in the ML model: Glasgow Coma Scale, Charlson Comorbidity Index, ICH score, ICH volume, pupillary status, brainstem location, age, anticoagulant/antiplatelet agents, intraventricular hemorrhage, and cerebellar location. Random forest prediction model, evaluated on the hold-out test set, achieved an AUC of 0.96 (0.94-0.98), 0.89 (0.86-0.93), and 0.93 (0.90-0.95) for dead, poor, and good outcome classes, respectively, demonstrating high discriminative ability. A random forest classifier was successfully trained and internally validated to stratify elderly patients with spontaneous ICH into prognostic subclasses. The predictive value is enhanced by the ability of ML model to identify synergy among variables.
The role of mitochondria-targeting miRNAs in intracerebral hemorrhage.
Non-traumatic intracerebral hemorrhage (ICH) is the most common type of hemorrhagic stroke, most often occurring between the ages of 45 and 60. Arterial hypertension (AH) is most often the cause of ICH, followed by atherosclerosis, blood diseases, inflammatory changes in cerebral vessels, intoxication and vitamin deficiencies. Cerebral hemorrhage can occur by diapedesis or as a result of a ruptured vessel. AH is difficult to treat; requires surgery and can lead to disability or death. One of the important directions in the study of the pathogenesis of ICH is mitochondrial dysfunction and its regulation. The key role of mitochondrial dysfunction in AH and atherosclerosis, as well as in the development of brain damage after hemorrhage, has been acknowledged. MicroRNAs (miRNAs) are a class of non-coding RNAs (about 18-22 nucleotides) that regulate a variety of biological processes including cell differentiation, proliferation, apoptosis, etc., primarily through gene repression. There is growing evidence to support dysregulated miRNAs in various cardiovascular diseases, including ICH. Further, the realization of miRNAs within mitochondrial compartment has challenged the traditional knowledge of signaling pathways involved in the regulatory network of cardiovascular diseases. However, the role of miRNAs in mitochondrial dysfunction for ICH is still under-appreciated, with comparatively much lesser studies and investigations reported, than those in other cardiovascular diseases. In this review, we summarize the up-to-date findings on the published role miRNAs in mitochondrial function for ICH, and the potential use of miRNAs in clinical settings, such as potential therapeutic targets and non-invasive diagnostic/prognostic biomarker tools.