Identification of blood exosomal metabolomic profiling for high-altitude cerebral edema.

High-altitude cerebral edema (HACE) is a severe neurological condition that can occur at high altitudes. It is characterized by the accumulation of fluid in the brain, leading to a range of symptoms, including severe headache, confusion, loss of coordination, and even coma and death. Exosomes play a crucial role in intercellular communication, and their contents have been found to change in various diseases. This study analyzed the metabolomic characteristics of blood exosomes from HACE patients compared to those from healthy controls (HCs) with the aim of identifying specific metabolites or metabolic pathways associated with the development of HACE conditions. A total of 21 HACE patients and 21 healthy controls were recruited for this study. Comprehensive metabolomic profiling of the serum exosome samples was conducted using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC‒MS/MS). Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify the metabolic pathways affected in HACE patients. Twenty-six metabolites, including ( +)-camphoric acid, choline, adenosine, adenosine 5'-monophosphate, deoxyguanosine 5'-monophosphate, guanosine, and hypoxanthine-9-ß-D-arabinofuranoside, among others, exhibited significant changes in expression in HACE patients compared to HCs. Additionally, these differentially abundant metabolites were confirmed to be potential biomarkers for HACE. KEGG pathway enrichment analysis revealed several pathways that significantly affect energy metabolism regulation (such as purine metabolism, thermogenesis, and nucleotide metabolism), estrogen-related pathways (the estrogen signaling pathway, GnRH signaling pathway, and GnRH pathway), cyclic nucleotide signaling pathways (the cGMP-PKG signaling pathway and cAMP signaling pathway), and hormone synthesis and secretion pathways (renin secretion, parathyroid hormone synthesis, secretion and action, and aldosterone synthesis and secretion). In patients with HACE, adenosine, guanosine, and hypoxanthine-9-ß-D-arabinofuranoside were negatively correlated with height. Deoxyguanosine 5'-monophosphate is negatively correlated with weight and BMI. Additionally, LPE (18:2/0:0) and pregnanetriol were positively correlated with age. This study identified potential biomarkers for HACE and provided valuable insights into the underlying metabolic mechanisms of this disease. These findings may lead to potential targets for early diagnosis and therapeutic intervention in HACE patients.

Associations between tumor and edema volumes with tumor infiltrating lymphocytes in brain metastasis - A preliminary study.

OBJECTIVE: Perifocal edema of brain tumors is associated with survival and neurological symptoms. The present study sought to elucidate the association between edema volume and tumor infiltrating lymphocytes (TIL) in brain metastasis. METHODS: 25 patients with brain metastasis were included into the retrospective study. TILs expressing CD45 was analyzed with leucocyte common antigen staining. MRI was used to semiautomatically estimate tumor and edema volumes. RESULTS: No correlation between tumor volume and edema volume was identified. A positive correlation was identified between tumor volume and TILs expressing CD45 of the stromal compartment (r = 0.46, p = 0.02). No correlations were identified between TILs expressing CD45 and edema volume. CONCLUSIONS: The present study identified correlations between TILs expressing CD45 and volume of BM. The tumor growth of BM might lead to a recruitment of TIL, which could be assessed by MRI.

PaCO2-management in the neuro-critical care of patients with subarachnoid hemorrhage.

The partial pressure of carbon dioxide (PaCO2) in the arterial blood is a strong vasomodulator affecting cerebral blood flow and the risk of cerebral edema and ischemia after acute brain injury. In turn, both complications are related to poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). We aimed to analyze the effect of PaCO2 levels on the course and outcome of aSAH. All patients of a single institution treated for aSAH over 13.5 years were included (n = 633). Daily PaCO2 values from arterial blood gas measurements were recorded for up to 2 weeks after ictus. The study endpoints were: delayed cerebral ischemia (DCI), need for decompressive craniectomy due to increased intracranial pressure > 20 mmHg refractory to conservative treatment and poor outcome at 6-months follow-up (modified Rankin scale > 2). By correlations with the study endpoints, clinically relevant cutoffs for the 14-days mean values for the lowest and highest daily PaCO2 levels were defined by receiver operating characteristic curve analysis. Association with the study endpoints for the identifies subgroups was analyzed using multivariate analysis. The optimal range for PaCO2 values was identified between 30 and 38 mmHg. ASAH patients with poor initial condition (WFNS 4/5) were less likely to show PaCO2 values within the range of 30-38 mmHg (p < 0.001, OR = 0.44). In the multivariate analysis, PaCO2 values between 30 and 38 mmHg were associated with a lower risk for decompressive craniectomy (p = 0.042, aOR = 0.27), DCI occurrence (p = 0.035; aOR = 0.50), and poor patient outcome (p = 0.004; aOR = 0.42). The data from this study shows an independent positive association between low normal mean PaCO2 values during the acute phase of aSAH and patients' outcome. This effect might be attributed to the reduction of intracranial hypertension and alterations in the cerebral blood flow.

Determinants of brain swelling in pediatric and adult cerebral malaria.

Cerebral malaria (CM) affects children and adults, but brain swelling is more severe in children. To investigate features associated with brain swelling in malaria, we performed blood profiling and brain MRI in a cohort of pediatric and adult patients with CM in Rourkela, India, and compared them with an African pediatric CM cohort in Malawi. We determined that higher plasma Plasmodium falciparum histidine rich protein 2 (PfHRP2) levels and elevated var transcripts that encode for binding to endothelial protein C receptor (EPCR) were linked to CM at both sites. Machine learning models trained on the African pediatric cohort could classify brain swelling in Indian children CM cases but had weaker performance for adult classification, due to overall lower parasite var transcript levels in this age group and more severe thrombocytopenia in Rourkela adults. Subgrouping of patients with CM revealed higher parasite biomass linked to severe thrombocytopenia and higher Group A-EPCR var transcripts in mild thrombocytopenia. Overall, these findings provide evidence that higher parasite biomass and a subset of Group A-EPCR binding variants are common features in children and adult CM cases, despite age differences in brain swelling.

Region-specific changes in aquaporin 4 induced by hyperglycemia underlie the differences in cell swelling in the cortex and striatum after cerebral ischemia-reperfusion.

Brain edema is a major cause of death in patients who suffer an ischemic stroke. Diabetes has been shown to aggravate brain edema after cerebral ischemia-reperfusion, but few studies have focused on the heterogeneity of this response across different brain regions. Aquaporin 4 plays an important role in the formation and regression of brain edema. Here, we report that hyperglycemia mainly affects the continuity of aquaporin 4 distribution around blood vessels in the cortical penumbra after ischemia-reperfusion; however, in the striatal penumbra, in addition to affecting the continuity of distribution, it also substantially affects the fluorescence intensity and the polarity distribution in astrocytes. Accordingly, hyperglycemia induces a more significant increase in the number of swelling cells in the striatal penumbra than in the cortical penumbra. These results can improve our understanding of the mechanism underlying the effects of diabetes in cerebral ischemic injury and provide a theoretical foundation for identification of appropriate therapeutic modalities.

Association of Serum IL-6 (Interleukin 6) With Functional Outcome After Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVES: IL-6 (interleukin 6) is a proinflammatory cytokine and an established biomarker in acute brain injury. We sought to determine whether admission IL-6 levels are associated with severity and functional outcome after spontaneous intracerebral hemorrhage (ICH). METHODS: We performed an exploratory analysis of the recombinant activated FAST trial (Factor VII for Acute ICH). Patients with admission serum IL-6 levels were included. Regression analyses were used to assess the associations between IL-6 and 90-day modified Rankin Scale. In secondary analyses, we used linear regression to evaluate the association between IL-6 and baseline ICH and perihematomal edema volumes. RESULTS: Of 841 enrolled patients, we included 552 (66%) with available admission IL-6 levels (mean age 64 [SD 13], female sex 203 [37%]). IL-6 was associated with poor outcome (modified Rankin Scale, 4-6; per additional 1 ng/L, odds ratio, 1.30 [95% CI, 1.04-1.63]; P=0.02) after adjustment for known predictors of outcome after ICH and treatment group. IL-6 was associated with ICH volume after adjustment for age, sex, and ICH location, and this association was modified by location (multivariable interaction, P=0.002), with a stronger association seen in lobar (ß, 12.51 [95% CI, 6.47-18.55], P<0.001) versus nonlobar (ß 5.32 [95% CI, 3.36-7.28], P<0.001) location. IL-6 was associated with perihematomal edema volume after adjustment for age, sex, ICH volume, and ICH location (ß 1.22 [95% CI, 0.15-2.29], P=0.03). Treatment group was not associated with IL-6 levels or outcome. CONCLUSIONS: In the FAST trial population, higher admission IL-6 levels were associated with worse 90-day functional outcome and larger ICH and perihematomal edema volumes.

Ischemic-time associated reductions in equol monosulfate plasma levels in a mouse model of ischemic stroke: support the existence of a 'brain-gut axis'.

BACKGROUND: Interest is growing in the role played by intestinal flora in the pathogeneses of diseases and in the possibility of treating disease by altering intestinal flora compositions. Recent studies have focused on the relationship between the intestinal microbiome and brain function as proposed by the brain-gut axis hypothesis. OBJECTIVES: To investigate the relation between ischemic stroke and plasma equol monosulfate levels (a soy isoflavone metabolite) in a middle cerebral artery occlusion (MCAO) mouse model. METHODS: Mice (C57BL/6) were subjected to MCAO for various times (30 min to 24 h), and degrees of cerebral damage were assessed using total infarction volumes, brain edema severities and neurological deficit scores. Hematoxylin and eosin and cresyl violet staining were used to observe morphological changes in ischemic brains. Levels of equol monosulfate in plasma and the relationships between these and degree of brain injury were investigated. RESULTS: Infarction volumes, brain edema severity and neurological deficit scores were significantly correlated with ischemic time, and morphological deteriorations of brain neuronal cells also increased with ischemic duration. Equol monosulfate contents were ischemic-time dependently lower in MCAO treated animals than in sham-operated controls. CONCLUSION: Ischemic stroke may time-dependently reduce plasma levels of equol monosulfate by lowering the metabolic rate of equol in MCAO-induced mice. This study provides indirect support of the brain-gut axis hypothesis.

Mesenchymal Stem Cells: The Potential Therapeutic Cell Therapy to Reduce Brain Stroke Side Effects.

Tissue plasminogen activator (tPA) is the gold standard treatment for ischemic stroke in the time window of 3-4.5 hours after the onset of symptoms. However, tPA administration is associated with inflammation and neurotoxic effects. Mesenchymal stem cells (MSC)-based therapy is emerging as a promising therapeutic strategy to control different inflammatory conditions. This project was designed to examine the protective role of MSC administration alone or in combination with royal jelly (RJ) five hours after stroke onset. The mice model of middle cerebral artery occlusion (MCAO) was established and put to six groups, including intact (healthy mice without stroke), control (untreated stroke), treated with mouse MSC (mMSC), Sup (conditioned medium), RJ and combination of mMSC and RJ (mMSC/RJ). Thereafter, behavioral functions, serum and brain (in both infarcted and non-infarcted tissues) levels of interleukin (IL)-1ß, IL-4, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) the sizes of brain infarction have been determined in the groups. Administration of mMSC and mMSC/RJ significantly improved the behavioral functions when compared to the controls. mMSC, RJ and mMSC/RJ significantly decreased the infarcted volumes. RJ and mMSC/RJ, but not mMSC, significantly decreased the brain edema. The infarction increased the serum levels of the cytokines, except TNF-α, and treatment with mMSC, Sup and RJ reduced serum levels of the pro-inflammatory cytokines. mMSC reduced IL-1ß in the non-infarcted brain tissue. To conclude, data revealed that using mMSC/RJ combination significantly reduced stroke side effects, including brain edema and serum levels of pro-inflammatory cytokines, and suggested that combination therapy of MSCs with RJ may be considered as an effective stroke therapeutic strategy.

Early NT-ProBNP (N-Terminal Probrain Natriuretic Peptide) Elevation Predicts Malignant Edema and Death After Reperfusion Therapy in Acute Ischemic Stroke Patients.

BACKGROUND AND PURPOSE: We aimed to investigate the relationship between early NT-proBNP (N-terminal probrain natriuretic peptide) and all-cause death in patients receiving reperfusion therapy, including intravenous thrombolysis and endovascular thrombectomy (EVT). METHODS: This study included 1039 acute ischemic stroke patients with early NT-proBNP data at 2 hours after the beginning of alteplase infusion for those with intravenous thrombolysis only or immediately at the end of EVT for those with EVT. We performed natural log transformation for NT-proBNP (Ln(NT-proBNP)). Malignant brain edema was ascertained by using the SITS-MOST (Safe Implementation of Thrombolysis in Stroke-Monitoring Study) criteria. RESULTS: Median serum NT-proBNP level was 349 pg/mL (interquartile range, 89-1250 pg/mL). One hundred twenty-one (11.6%) patients died. Malignant edema was observed in 78 (7.5%) patients. Ln(NT-proBNP) was independently associated with 3-month mortality in patients with intravenous thrombolysis only (odds ratio, 1.465 [95% CI, 1.169-1.836]; P=0.001) and in those receiving EVT (odds ratio, 1.563 [95% CI, 1.139-2.145]; P=0.006). The elevation of Ln(NT-proBNP) was also independently associated with malignant edema in patients with intravenous thrombolysis only (odds ratio, 1.334 [95% CI, 1.020-1.745]; P=0.036), and in those with EVT (odds ratio, 1.455 [95% CI, 1.057-2.003]; P=0.022). CONCLUSIONS: An early increase in NT-proBNP levels was related to malignant edema and stroke mortality after reperfusion therapy.

Systemic inflammation status at admission affects the outcome of intracerebral hemorrhage by increasing perihematomal edema but not the hematoma growth.

Acute stress and inflammation responses are associated with worse outcomes in intracerebral hemorrhage (ICH) but the precise mechanisms involved are unclear. We evaluated the effect of neutrophil-to-lymphocyte ratio (NLR) in ICH outcome, with focus on hematoma expansion and early cerebral edema. In a retrospective study, we included all patients with primary ICH admitted to our center within 24-h from symptom onset from January 2014 to February 2015. We retrieved demographic and medical history data, Glasgow Coma Scale scores, blood cell counts, glucose, and C-reactive protein, and calculated NLR. We obtained hematoma volumes by computerized planimetry. Outcomes included independence at 90 days (modified Rankin scale 0-2), mortality at 30 days, significant hematoma expansion (> 33% or > 6 mL) and early cerebral edema causing significant midline shift (> 2.5 mm) at 24 h. We included 135 patients. NLR independently associated with independence at 90 days (adjusted odds ratio (aOR) 0.79, 95% CI 0.67-0.93, p = 0.006) significant cerebral edema (aOR 1.08, 95%CI 1.01-1.15, p = 0.016) but not hematoma expansion (aOR 0.99, 95%CI 0.94-1.04, p = 0.736). The severity of midline shift was positively correlated with NLR (adjusted beta = 0.08, 95% CI 0.05-0.11, p < 0.001). In ICH, an immediate and intense systemic inflammatory response reduces the likelihood of a better functional outcome at 90 days, which is more likely to be explained by perihematomal edema growth than due to a significant hematoma expansion. These findings could have implications in new treatment strategies and trial designs, which endpoints tend to target exclusively hematoma enlargement.

Correlation between cerebral biomarkers and optic nerve sheath diameter in patients with severe preeclampsia.

Objective: To examine the correlation between plasma cerebral biomarkers (S100B and neuron-specific enolase (NSE)) and ultrasonographic optic-nerve-sheath-diameter (ONSD) in preeclampsia. Methods: Thirty preeclampsia patients and 27 controls were included. Mann-Whitney-U test was used for comparison of S100B, NSE, and ONSD in preeclampsia vs. controls. Kendall's tau was used to assess the correlation between biomarkers and ONSD (p < 0.05 significant). Results: ONSD, S100B and NSE were significantly higher in preeclampsia (p < 0.001, p = 0.004, and p < 0.001, respectively). There was significant correlation between NSE levels and ONSD: Kendall's tau = 0.26; p = 0.01. Conclusions: S100B and NSE are elevated in severe preeclampsia. NSE correlates with increased ONSD suggesting cerebral edema.

Peripheral Blood Occludin Level as a Biomarker for Perioperative Cerebral Edema in Patients with Brain Tumors.

OBJECTIVE: Cerebral edema is a common complication of brain tumors in the perioperative period. However, there is currently no reliable and convenient method to evaluate the extent of brain edema. The objective is to explore the effectiveness of serum occludin on predicting the extent of perioperative brain edema and outcome in patients with brain tumors. METHODS: This prospective study enrolled 55 patients with brain tumors and 24 healthy controls in Sanbo Brain Hospital from June 2019 through November 2019. Serum occludin levels were measured preoperatively and on postoperative day 1. Peritumoral edema was assessed preoperatively using MRI. Pericavity brain edema on postoperative day 1 was evaluated using CT. RESULTS: Compared with healthy controls, the serum occludin level was higher in patients with brain tumors both preoperatively and postoperatively (P < 0.001). The serum occludin level correlated positively with the degree of brain edema preoperatively (r = 0.78, P < 0.001) and postoperatively (r = 0.59, P < 0.001). At an optimal cutoff of 3.015 ng/mL, the preoperative serum occludin level discriminated between mild and severe preoperative brain edema with a sensitivity of 90.48% and specificity of 84.62%. At an optimal cutoff value of 3.033 ng/mL, the postoperative serum occludin level distinguished between mild and severe postoperative brain edema with a sensitivity of 97.30% and specificity of 55.56%. CONCLUSIONS: The serum occludin level is associated with cerebral edema and could potentially be used as a biomarker for perioperative cerebral edema. This trial is registered with ChiCTR1900023742.

Association Between Neutrophil to Lymphocyte Ratio and Malignant Brain Edema in Patients With Large Hemispheric Infarction.

INTRODUCTION: Malignant brain edema (MBE) is a life-threatening complication for patients with large hemispheric infarction (LHI). Stroke-related inflammatory responses may cause secondary brain injury and lead to brain edema. The neutrophil to lymphocyte ratio (NLR) is a well-known systemic inflammatory biomarker. The aim of this study was to evaluate if NLR is associated with MBE in patients with LHI. METHODS: A retrospective analysis was performed of LHI patients within 24 h from stroke onset admitted to the Department of Neurology, West China Hospital from January 1, 2017 to December 31, 2018. Blood samples were collected upon admission. MBE was diagnosed by any neurological deterioration accompanied by brain edema in follow-up images. Patients were categorized according to NLR tertiles. Univariate analyses were performed to identify potential confounding variables and a multivariate logistic regression analysis was conducted to determine the correlation between NLR and MBE. RESULTS: A total of 257 patients with a mean age of 68.6 ± 14.0 years were identified. Among them, 83 (32.3%) patients developed MBE with a median time of one day (interquartile range [IQR] 0-2 days) from hospital admission. An elevated NLR was related to an increased risk of MBE when the lowest and highest tertiles were compared (odds ratio 2.27, 95% confidence interval 1.11-4.62, p = 0.024). The risk of MBE increased with the increase of NLR in a dosedependent manner (p for trend = 0.029). No interaction between potential modifiers and NLR on MBE was observed. CONCLUSIONS: Higher NLR was associated with an increased risk of MBE in patients with LHI.

The Changes of Brain Edema and Neurological Outcome, and the Probable Mechanisms in Diffuse Traumatic Brain Injury Induced in Rats with the History of Exercise.

Since no definitive treatment has been suggested for diffuse traumatic brain injury (TBI), and also as the effect of exercise has been proven to be beneficial in neurodegenerative diseases, the effect of endurance exercise on the complications of TBI along with its possible neuroprotective mechanism was investigated in this study. Our objective was to find out whether previous endurance exercise influences brain edema and neurological outcome in TBI. We also assessed the probable mechanism of endurance exercise effect in TBI. Rats were randomly assigned into four groups of sham, TBI, exercise + sham and exercise + TBI. Endurance exercise was carried out before TBI. Brain edema was assessed by calculating the percentage of brain water content 24 h after the surgery. Neurological outcome was evaluated by obtaining veterinary coma scale (VCS) at - 1, 1, 4 and 24 h after the surgery. Interleukin-1ß (IL-1ß), total antioxidant capacity (TAC), malondialdehyde (MDA), protein carbonyl and histopathological changes were evaluated 24 h after the surgery. Previous exercise prevented the increase in brain water content, MDA level, histopathological edema and apoptosis following TBI. The reduction in VCS in exercise + TBI group was lower than that of TBI group. In addition, a decrease in the level of serum IL-1ß and the content of brain protein carbonyl was reported in exercise + TBI group in comparison with the TBI group. We suggest that the previous endurance exercise prevents brain edema and improves neurological outcome following diffuse TBI, probably by reducing apoptosis, inflammation and oxidative stress.

Elevated blood glucose is associated with aggravated brain edema in acute stroke.

BACKGROUND AND PURPOSE: Clinical outcome after endovascular thrombectomy in patients with acute ischemic stroke still varies significantly. Higher blood glucose levels (BGL) have been associated with worse clinical outcome, but the pathophysiological causes are not yet understood. We hypothesized that higher levels of BGL are associated with more pronounced ischemic brain edema and worse clinical outcome mediated by cerebral collateral circulation. METHODS: 178 acute ischemic stroke patients who underwent mechanical thrombectomy were included. Early ischemic brain edema was determined using quantitative lesion water uptake on initial computed tomography (CT) and collateral status was assessed with an established 5-point scoring system in CT-angiography. Good clinical outcome was defined as functional independence (modified Rankin Scale [mRS] score 0-2). Multivariable logistic regression analysis was performed to predict functional independence and linear regression analyses to investigate the impact of BGL and collateral status on water uptake. RESULTS: The mean BGL at admission was significantly lower in patients with good outcome at 90 days (116.5 versus 138.5 mg/dl; p < 0.001) and early water uptake was lower (6.3% versus 9.6%; p < 0.001). The likelihood for good outcome declined with increasing BGL (odds ratio [OR] per 100 mg/dl BGL increase: 0.15; 95% CI 0.02-0.86; p = 0.039). Worse collaterals (1% water uptake per point, 95% CI 0.4-1.7%) and higher BGL (0.6% per 10 mg/dl BGL, 95% CI 0.3-0.8%) were significantly associated with increased water uptake. CONCLUSION: Elevated admission BGL were associated with increased early brain edema and poor clinical outcome mediated by collateral status. Patients with higher BGL might be targeted by adjuvant anti-edematous treatment.

Copeptin Kinetics in Acute Ischemic Stroke May Differ According to Revascularization Strategies: Pilot Data.

Background and Purpose- Prognostic value of copeptin in acute ischemic stroke has been widely reported. This study aimed to evaluate copeptin temporal profile according to revascularization strategies and the development of brain edema and hemorrhagic transformation. Methods- Plasma copeptin and brain edema and hemorrhagic transformation assessed by computed tomography/magnetic resonance imaging were evaluated upon admission (T0), at 24 hours (T1), and between the third and fifth day of hospitalization (T2) in 34 acute ischemic stroke patients. Results- Median copeptin concentration was 50.71 pmol/L at T0, 18.31 pmol/L at T1, and 10.92 pmol/L at T2. Copeptin at T1 was higher in patients with medium/severe brain edema at T2 (32.25 versus 13.67 pmol/L; P=0.038) and hemorrhagic transformation at T1 (93.10 versus 13.67 pmol/L; P<0.003) and T2 (85.70 versus 14.45 pmol/L; P=0.024). Copeptin level drop (CopΔT1-T0) was significantly steeper in patients receiving revascularization, particularly in those undergoing combined therapy (-129.34 versus -5.43 pmol/L; P=0.038). ΔT1-T0 also correlated with Thrombolysis in Cerebral Infarction score (P<0.001). Conclusions- Copeptin resulted associated with brain edema and hemorrhagic transformation in acute ischemic stroke, and its drop at 24 hours may mirror effective brain vessel recanalization.

Moderate Protein Restriction Protects Against Focal Cerebral Ischemia in Mice by Mechanisms Involving Anti-inflammatory and Anti-oxidant Responses.

Food composition influences stroke risk, but its effects on ischemic injury and neurological deficits are poorly examined. While severe reduction of protein content was found to aggravate neurological impairment and brain injury as a consequence of combined energy-protein malnutrition, moderate protein restriction not resulting in energy deprivation was recently suggested to protect against perinatal hypoxia-ischemia. Male C57BL6/j mice were exposed to moderate protein restriction by providing a normocaloric diet containing 8% protein (control: 20% protein) for 7, 14, or 30 days. Intraluminal middle cerebral artery occlusion was then induced. Mice were sacrificed 24 h later. Irrespective of the duration of food modification (that is, 7-30 days), protein restriction reduced neurological impairment of ischemic mice revealed by a global and focal deficit score. Prolonged protein restriction over 30 days also reduced infarct volume, brain edema, and blood-brain barrier permeability and increased the survival of NeuN+ neurons in the core of the stroke (i.e., striatum). Neuroprotection by prolonged protein restriction went along with reduced brain infiltration of CD45+ leukocytes and reduced expression of inducible NO synthase and interleukin-1ß. As potential mechanisms, increased levels of the NAD-dependent deacetylase sirtuin-1 and anti-oxidant glutathione peroxidase-3 were noted in ischemic brain tissue. Irrespective of the protein restriction duration, a shift from pro-oxidant oxidative stress markers (NADPH oxidase-4) to anti-oxidant markers (superoxide dismutase-1/2, glutathione peroxidase-3 and catalase) was found in the liver. Moderate protein restriction protects against ischemia in the adult brain. Accordingly, dietary modifications may be efficacious strategies promoting stroke outcome.

Modeling prognostic factors for poor neurological outcome in conservatively treated patients with intracerebral hemorrhage: A focus on TNF-α.

OBJECTIVE: Prognostic models for Intracerebral hemorrhage (ICH), mainly based on clinical evaluation, have remained inherently confounded by subjective scoring assessments and limited accuracy. In this study, we aimed at assessing the risk for poor outcome after ICH based on peripheral biochemical markers (TNF-α, glutamate and glucose) and radiological variables (both at admission and five days after patient's care), for modeling purposes of prognostication. PATIENTS AND METHODS: The defined initial variables of fifty non-comatose conservatively treated ICH patients without severe complications during the hospitalization process (as intraventricular bleeding, or hematoma expansion) were aligned with the evaluated parameters during re-evaluation (3 months later). A comprehensive statistical approach has been applied by using different modeling strategies for prediction of their functional status and outcome. RESULTS: Higher blood plasma glutamate, TNF-α and initial ICH volume at admission, as well as higher volumes of ICH and perihematomal edema after five days of care were significantly more likely associated with the poor outcome. Nevertheless, in all of the constructed models, TNF-α was estimated as the only significant predictive risk factor, thus outperforming the capacity of the initial ICH volume and the radiological variables after 5 days, both in terms of prognostication of the functional status and the 3-month neurological outcome. The constructed canonical variable that has fairly marked off the different outcomes was also mainly weighed by the admission TNF-α levels. For the first time, we have carefully developed probability functions for the neurological outcome as a response to the admission TNF-α levels; TNF-α levels >110.35 pg/mL were assessed as an optimal cutoff point fairly identifying patients who will fall into the group with poor outcome. CONCLUSIONS: TNF-α based models and admission TNF-α screening might be appropriate as a key component that assists more objective prognostication and management of patient's care in clinical decision making, as rapid initial diagnosis and concentrated management are crucial for secondary prevention of further devastating neurological impairments after ICH.

Therapeutic effects of JLX001 on cerebral ischemia through inhibiting platelet activation and thrombus formation in rats.

(3ß,5α,16α,20S)-4,4,14-trimethyl-3,20-bis(methylamino)-9,19-cyclopregnan-16-ol-dihydrochloride (JLX001), a derivative of cyclovirobuxine D (CVB-D), is a novel compound from synthesis. This study aims to confirm the therapeutic effect of JLX001 on cerebral ischemia and researchits antiplatelet and antithrombosis activities via thromboxane (TXA2)/phospholipase C-ß-3(PLCß3)/protein kinase C (PKC) pathway suppression. The therapeutic effects of JLX001 was evaluated by infarct sizes, brain edema and neurological scores in Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO). Brain TXA2 and prostacyclin (PGI2) were measured by enzyme-linked immunosorbentassay (ELISA). P-PLCß3and activated PKC were detected by immunohistochemical method. Adenosine diphosphate (ADP) or 9, 11-dieoxy-11α, 9α-epoxymethanoeprostaglandin F2α (U46619) was used as platelet agonist in the in vivo and in vitro platelet aggregation experiments. Clotting time and bleeding time were determined. Besides, two whole-animal experiments including arteriovenous shunt thrombosis and pulmonary thromboembolism model were conducted. Results showed that JLX001 treatment markedly alleviated cerebral infarcts, edema, and neurological scores in permanent middle cerebral artery occlusion (pMCAO) rats. Brain TXA2 level, p-PLCß3and activated PKC were decreased, while PGI2level had no significant change. Besides, JLX001 inhibited platelet aggregation induced by ADP or U46619 and exhibited anti-coagulation effects with a minor bleeding risk. In the two whole-animal experiments, JLX001 inhibited thrombus formation. In summary, JLX001 attenuates cerebral ischemia injury and the underlying mechanisms relate to inhibiting platelet activation and thrombus formation via TXA2/PLCß3/PKC pathway suppression.

Procalcitonin as a Biomarker for Malignant Cerebral Edema in Massive Cerebral Infarction.

The objective of this study is to explore whether procalcitonin (PCT) can serve as an early biomarker of malignant cerebral edema in patients with massive cerebral infarction (MCI). Ninety-three patients with acute MCI were divided into death or survival groups based on whether they died or survived within 1 week of cerebral herniation. Differences in laboratory parameters between these two groups were analyzed by univariate analysis, followed by multivariate logistic regression analyses if the influencing factors were significantly different. Compared with the survival group, the patients in the death group had a larger cerebral infarct area, higher body temperature, neutrophil counts, PCT level, and neuron-specific enolase (NSE) level within 48 h of onset. Multivariate logistic regression analyses revealed an odds ratio (OR) of 1.830 or 1.235 for PCT and neutrophil counts respectively, suggesting that PCT and neutrophil counts are two independent risk factors for death in MCI. The area under receiver operating characteristic (ROC) curve was 0.754 for PCT, larger than that for neutrophil counts. Thus, both serum PCT levels and neutrophil counts can be used as biomarkers to predict malignant cerebral edema at the early stages after MCI, but PCT levels are superior predictors of malignant cerebral edema.