Mitochondrial ferritin upregulation reduced oxidative stress and blood-brain-barrier disruption by maintaining cellular iron homeostasis in a neonatal rat model of germinal matrix hemorrhage.

Germinal matrix hemorrhage (GMH) is a devasting neurological disease in premature newborns. After GMH, brain iron overload associated with hemoglobin degradation contributed to oxidative stress, causing disruption of the already vulnerable blood-brain barrier (BBB). Mitochondrial ferritin (FTMT), a novel mitochondrial outer membrane protein, is crucial in maintaining cellular iron homeostasis. We aimed to investigate the effect of FTMT upregulation on oxidative stress and BBB disruption associated with brain iron overload in rats. A total of 222 Sprague-Dawley neonatal rat pups (7 days old) were used to establish a collagenase-induced GMH model and an iron-overload model of intracerebral FeCl2 injection. Deferiprone was administered via gastric lavage 1 h after GMH and given daily until euthanasia. FTMT CRISPR Knockout and adenovirus (Ad)-FTMT were administered intracerebroventricularly 48 h before GMH and FeCl2 injection, respectively. Neurobehavioral tests, immunofluorescence, Western blot, Malondialdehyde measurement, and brain water content were performed to evaluate neurobehavior deficits, oxidative stress, and BBB disruption, respectively. The results demonstrated that brain expressions of iron exporter Ferroportin (FPN) and antioxidant glutathione peroxidase 4 (GPX4) as well as BBB tight junction proteins including Claudin-5 and Zona Occulta (ZO)-1 were found to be decreased at 72 h after GMH. FTMT agonist Deferiprone attenuated oxidative stress and preserved BBB tight junction proteins after GMH. These effects were partially reversed by FTMT CRISPR Knockout. Iron overload by FeCl2 injection resulted in oxidative stress and BBB disruption, which were improved by Ad-FTMT mediated FTMT overexpression. Collectively, FTMT upregulation is neuroprotective against brain injury associated with iron overload. Deferiprone reduced oxidative stress and BBB disruption by maintaining cellular iron homeostasis partially by the upregulating of FTMT after GMH. Deferiprone may be an effective treatment for patients with GMH.

Fractalkine Enhances Hematoma Resolution and Improves Neurological Function via CX3CR1/AMPK/PPARγ Pathway After GMH.

BACKGROUND: Hematoma clearance has been a proposed therapeutic strategy for hemorrhagic stroke. This study investigated the impact of CX3CR1 (CX3C chemokine receptor 1) activation mediated by r-FKN (recombinant fractalkine) on hematoma resolution, neuroinflammation, and the underlying mechanisms involving AMPK (AMP-activated protein kinase)/PPARγ (peroxisome proliferator-activated receptor gamma) pathway after experimental germinal matrix hemorrhage (GMH). METHODS: A total of 313 postnatal day 7 Sprague Dawley rat pups were used. GMH was induced using bacterial collagenase by a stereotactically guided infusion. r-FKN was administered intranasally at 1, 25, and 49 hours after GMH for short-term neurological evaluation. Long-term neurobehavioral tests (water maze, rotarod, and foot-fault test) were performed 24 to 28 days after GMH with the treatment of r-FKN once daily for 7 days. To elucidate the underlying mechanism, CX3CR1 CRISPR, or selective CX3CR1 inhibitor AZD8797, was administered intracerebroventricularly 24 hours preinduction of GMH. Selective inhibition of AMPK/PPARγ signaling in microglia via intracerebroventricularly delivery of liposome-encapsulated specific AMPK (Lipo-Dorsomorphin), PPARγ (Lipo-GW9662) inhibitor. Western blot, Immunofluorescence staining, Nissl staining, Hemoglobin assay, and ELISA assay were performed. RESULTS: The brain expression of FKN and CX3CR1 were elevated after GMH. FKN was expressed on both neurons and microglia, whereas CX3CR1 was mainly expressed on microglia after GMH. Intranasal administration of r-FKN improved the short- and long-term neurobehavioral deficits and promoted M2 microglia polarization, thereby attenuating neuroinflammation and enhancing hematoma clearance, which was accompanied by an increased ratio of p-AMPK (phosphorylation of AMPK)/AMPK, Nrf2 (nuclear factor erythroid 2-related factor 2), PPARγ, CD36 (cluster of differentiation 36), CD163 (hemoglobin scavenger receptor), CD206 (the mannose receptor), and IL (interleukin)-10 expression, and decreased CD68 (cluster of differentiation 68), IL-1ß, and TNF (tumor necrosis factor) α expression. The administration of CX3CR1 CRISPR or CX3CR1 inhibitor (AZD8797) abolished the protective effect of FKN. Furthermore, selective inhibition of microglial AMPK/PPARγ signaling abrogated the anti-inflammation effects of r-FKN after GMH. CONCLUSIONS: CX3CR1 activation by r-FKN promoted hematoma resolution, attenuated neuroinflammation, and neurological deficits partially through the AMPK/PPARγ signaling pathway, which promoted M1/M2 microglial polarization. Activating CX3CR1 by r-FKN may provide a promising therapeutic approach for treating patients with GMH.

Controlling nutritional status score and prognostic nutrition index predict the outcome after severe traumatic brain injury.

OBJECTIVES: Immune-nutritional status is correlated with a clinical outcome in critical illness. Recently, controlling nutritional status (CONUT) score and prognostic nutrition index (PNI) has been reported to predict prognosis following cancer and other diseases. The aim of this study was to explore the relationship between the CONUT score and PNI and 6-month outcome in patients with severe traumatic brain injury (STBI). METHODS: We retrospectively analyzed the clinical data of 78 patients with STBI, including the CONUT score and PNI. Patients were divided into high CONUT group and low CONUT group. Patients were also divided into high PNI and low PNI group respectively. The 6-month outcome was evaluated by the modified Rankin scale (mRS). The unfavorable outcome was defined as mRS score ≥3. RESULTS: The unfavorable outcome group had lower Glasgow coma scale (GCS) scores, serum albumin, total cholesterol, PNI, and higher CONUT scores (P < 0.05). Both CONUT scores and PNI were strongly correlated with mRS (r = 0.429, P < 0.05; r = -0.590, P < 0.05, respectively). After adjustment for confounding factors, the odds ratios of CONUT scores and PNI for predicting unfavorable outcome were 10.478 (95% CI: 2.793-39.301) and -0.039 (95% CI: 0.008-0.204), respectively. The area under the curve (AUC) of CONUT scores for predicting unfavorable outcome was 0.777 (95% CI: 0.674-0.880, P < 0.01), which was similar to PNI (0.764, 95% CI: 0.657-0.87, P < 0.01). CONCLUSION: Both CONUT scores and PNI might be novel independent predictors of the poor outcome in STBI.

Systemic immune-inflammation index predicts the outcome after aneurysmal subarachnoid hemorrhage.

Systemic inflammatory response is closely related to the pathogenesis and prognosis in critical patients. Recently, systemic immune-inflammation index (SII), an indicator of systemic inflammatory response, was proved to predict the outcome in cancerous and non-cancerous diseases. The aim of this study is to investigate the association between SII on admission and 6-month outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). The clinical data and prognosis of 76 patients with aSAH were analyzed. The 6-month outcome was assessed by the modified Rankin scale(mRS). The unfavorable outcome was defined as mRS score ≥ 3. In addition, multivariate analysis was conducted to investigate factors independently associated with the favorable outcome. Receiver operating characteristic (ROC) curve analysis was undertaken to identify the best cut-off value of SII for the discriminate between favorable and unfavorable outcome in these patients. Thirty-six patients (47.4%) in our study had an unfavorable outcome (mRS ≥ 3) at 6 months, and twenty-four (66.7%) of them were in the high-SII group. A significantly higher SII on admission was observed in patients with unfavorable functional outcome at 6 months. Binary logistic regression analysis showed that there was an independent association between SII on admission and 6-month clinical outcome (adjusted OR = 4.499, 95%CI: 1.242-16.295, P < 0.05). The AUC of the SII for predicting unfavorable outcome was 0.692 (95% CI: 0.571-0.814, P < 0.05). Systemic immune-inflammation index (SII) could be a novel independent prognostic factor for aSAH patients at the early stage of the disease.

Prediction of Hematoma Expansion in Patients With Intracerebral Hemorrhage Using Thromboelastography With Platelet Mapping: A Prospective Observational Study.

Background and Purpose: The purpose of the study was to evaluate the usefulness of thromboelastography with platelet mapping (TEG-PM) for predicting hematoma expansion (HE) and poor functional outcome in patients with intracerebral hemorrhage (ICH). Methods: Patients with primary ICH who underwent baseline computed tomography (CT) and TEG-PM within 6 h after symptom onset were enrolled in the observational cohort study. We performed univariate and multivariate logistic regression models to assess the association of admission platelet function with HE and functional outcome. In addition, a receiver operating characteristic (ROC) curve analysis investigated the accuracy of platelet function in predicting HE. A mediation analysis was undertaken to determine causal associations among platelet function, HE, and outcome. Results: Of 142 patients, 37 (26.1%) suffered HE. Multivariate logistic regression identified arachidonic acid (AA) and adenosine diphosphate (ADP) inhibition as significant independent predictors of HE. The area under the ROC curves was 0.727 for AA inhibition and 0.721 for ADP inhibition. Optimal threshold for AA inhibition was 41.75% (75.7% sensitivity; 67.6% specificity) and ADP inhibition was 65.8% (73.0% sensitivity; 66.7% specificity). AA and ADP inhibition were also associated with worse 3-month outcomes after adjusting for age, admission Glasgow Coma Scale score, intraventricular hemorrhage, baseline hematoma volume, and hemoglobin. The mediation analysis showed that the effect of higher platelet inhibition with poor outcomes was mediated through HE. Conclusions: These findings suggest that the reduced platelet response to ADP and AA independently predict HE and poor outcome in patients with ICH. Platelet function may represent a modifiable target of ICH treatment.

Gint4.T-Modified DNA Tetrahedrons Loaded with Doxorubicin Inhibits Glioma Cell Proliferation by Targeting PDGFRß.

Glioma is one of the deadliest intrinsic brain tumours due to its invasive growth. The effect of glioma treatment is poor because of the presence of the blood-brain barrier and blood tumour barrier and insufficient drug targeting. DNA tetrahedrons (TDN) show great potential for drug delivery and may be a novel therapeutic strategy for glioma. In this study, we used TDN to deliver doxorubicin (DOX) for the glioma therapy. Gint4.T, an aptamer that could recognize platelet-derived growth factor receptor ß on tumour cell, was used to modify TDN (Apt-TDN) for targeted drug delivery. The TDN were self-assembled by one-step synthesis, which showed small size (10 nm) and negative charge. Fetal bovine serum test showed its stability as a drug delivery vehicle. Apt-TDN could be effectively taken up by U87MG cells. Compared with DOX and DOX@TDN (TDN loaded with DOX), the DOX@Apt-TDN (Gint4.T-modified TDN loaded with DOX) showed more early apoptosis rate, higher cell cycle arrest, and greater cytotoxicity towards U87MG cells. In conclusion, our findings indicated that DOX@Apt-TDN provides a novel therapy with promising clinical application for gliomas patients.

Blood Type O Predicts Hematoma Expansion in Patients with Intracerebral Hemorrhage.

BACKGROUND: Hematoma expansion after acute spontaneous intracerebral hemorrhage (ICH) is well established to result in poor prognosis. Recent studies have demonstrated that the ABO blood type system has potential implications on hemostatic properties. The purpose of this study was to explore the potential association of blood type O with hematoma expansion in patients with ICH and validate the usefulness in predicting early hematoma expansion. METHODS: We retrospectively enrolled consecutive patients with ICH who underwent baseline computed tomographic (CT) scan within 6 hours after onset of symptoms. The follow-up CT scan was available within 48 hours after the baseline CT scan. Hematoma expansion was defined as total volume increase more than 33% or more than 6 mL. We performed univariate and multivariate logistic regression analyses to investigate the relationship between the different types of blood (type O versus other types) and hematoma expansion. RESULTS: A total of 210 patients were included in the study. Among them, 72 patients (34.3%) carried blood type O. Hematoma expansion was more common in patients with blood type O (41.7%) than those with other blood types (18.1%; P < .001). Furthermore, the time to baseline CT scan, blood type O, and admission Glasgow Coma Scale score were demonstrated to be independent predictors of hematoma expansion in multivariate logistic regression analysis model. The sensitivity, specificity, positive, and negative predictive values of blood type O for predicting hematoma expansion were 54.5%, 72.9%, 41.6%, and 81.9%, respectively. CONCLUSIONS: Our findings suggest that blood type O represents an independent predictor of hematoma expansion after ICH. Hemostasis seems to be involved in expansion and may represent an important treatment target.

The association of neutrophil-to-lymphocyte ratio and delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage: possible involvement of cerebral blood perfusion.

Background and purpose: Emerging evidence suggests that systemic inflammation is associated with the pathophysiological process of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to investigate the association of white blood cell (WBC) count and neutrophil-to-lymphocyte ratio (NLR) with the occurrence of DCI in SAH patients. Methods: A total of 122 patients diagnosed with aSAH within 72 h of onset were retrospectively enrolled. The count of WBC, neutrophil count (NC), and lymphocyte (LC) was collected on admission. Computed tomography perfusion was performed within 7 days after SAH. The occurrence of DCI was recorded during the hospitalization. Results: Among enrolled patients, 43 (35.2%) developed DCI during hospitalization. Patients who developed DCI had a higher count of WBC, NC, and NLR as well as a lower count of LC. NC and NLR were independently associated with the occurrence of DCI, while NLR was the best predictive parameter according to the receiver operating characteristic curve. Moreover, there was a strong correlation between NLR and mean cerebral blood flow, mean transit time and mean time to peak. Conclusion: Leukocytosis is an early pathology of SAH, and NLR may be a practical predictor for the occurrence of DCI in SAH patients.

Improvement of Deep Brain Stimulation in Dyskinesia in Parkinson's Disease: A Meta-Analysis.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) have been proven to be equally effective in improving motor-symptoms for advanced Parkinson's disease (PD) patients. However, it is unclear that which target stimulation is more effective in reducing dyskinesia. We conducted the meta-analysis to evaluate the efficacy of STN and GPi-DBS in the dyskinesia. Methods: A systematic search was performed in PubMed, Embase, and the Cochrane Library databases. Controlled trials about the dyskinesia comparing the efficacy of GPi and STN DBS were included. Clinical data of dyskinesia and levodopa equivalent doses (LED) were collected for the meta-analysis. Results: Eight eligible trials containing a total of 822 patients were included in this meta-analysis. Our results showed that GPi DBS offered a greater reduction of dyskinesia than STN DBS at 12 months after surgery, with an overall pooled SMD of 0.32 (95% CI = 0.06 to 0.59, P = 0.02). Treatment of STN DBS was associated with a greater reduction of LED compared with GPi DBS, with a change score of -320.55 (95% CI = -401.36 to -239.73, P < 0.00001). Conclusion: GPi DBS is superior to reduce dyskinesia than STN DBS at 12 months after surgery for advanced PD patients. Further studies should focus on the different mechanism for dyskinesia reduction by GPi or STN DBS.

Thromboelastography with Platelet Mapping Detects Platelet Dysfunction in Patients with Aneurysmal Subarachnoid Hemorrhage with Rebleeding.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) has high rates of disability and mortality, and aneurysm rebleeding is associated with poor functional outcomes. Thrombelastography with platelet mapping (TEG-PM) measures platelet function; however, it has not yet been researched in aSAH. We aimed to use TEG-PM to detect changes in platelet function in patients with aSAH and the difference in patients with and without rebleeding. METHODS: We retrospectively included patients with aSAH who underwent a TEG-PM test on admission. Rebleeding was diagnosed according to clinical and imaging data. TEG-PM data of patients with unruptured intracranial aneurysms (UIA) were also obtained as controls. Univariate and multivariate logistic regression models were performed to investigate the relationship between the platelet function and rebleeding. RESULTS: A total of 245 aSAH patients and 32 UIA patients were included in our study. Compared with controls, patients with aSAH demonstrated higher arachidonic acid (AA) and adenosine diphosphate (ADP) inhibition of platelet function (P<0.05). Among them, 27 patients with Hunt-Hess grade IV or V were classified as the severe SAH group. There was a significant correlation between the severe SAH group and the degree of pathway inhibition (P<0.05). Furthermore, AA (Spearman's r=0.264, P<0.001) and ADP (Spearman's r=0.183, P=0.004) inhibition were elevated in Hunt-Hess grade-dependent manners. The AA (Spearman's r=0.169, P=0.008) and ADP (Spearman's r=0.233, P<0.001) inhibition were also significantly correlated with Fisher grade. Thirty-five patients (14.3%) suffered rebleeding. Rebleeding was significantly correlated with systolic blood pressure (P=0.011), diastolic blood pressure (P=0.008), Hunt-Hess grade (P=0.034), Fisher grade (P=0.015), AA inhibition (P<0.001), and ADP inhibition (P<0.001). Multivariate logistic regression analysis model revealed that both AA (P=0.037) and ADP inhibition (P=0.008) were independent determinants for rebleeding. CONCLUSION: TEG-PM may assess platelet dysfunction in patients with aSAH, and the diminished platelet response to ADP and AA may be associated with rebleeding. These findings deserve further investigation.