Convolutional neural network-based magnetic resonance image differentiation of filum terminale ependymomas from schwannomas.

PURPOSE: Preoperative diagnosis of filum terminale ependymomas (FTEs) versus schwannomas is difficult but essential for surgical planning and prognostic assessment. With the advancement of deep-learning approaches based on convolutional neural networks (CNNs), the aim of this study was to determine whether CNN-based interpretation of magnetic resonance (MR) images of these two tumours could be achieved. METHODS: Contrast-enhanced MRI data from 50 patients with primary FTE and 50 schwannomas in the lumbosacral spinal canal were retrospectively collected and used as training and internal validation datasets. The diagnostic accuracy of MRI was determined by consistency with postoperative histopathological examination. T1-weighted (T1-WI), T2-weighted (T2-WI) and contrast-enhanced T1-weighted (CE-T1) MR images of the sagittal plane containing the tumour mass were selected for analysis. For each sequence, patient MRI data were randomly allocated to 5 groups that further underwent fivefold cross-validation to evaluate the diagnostic efficacy of the CNN models. An additional 34 pairs of cases were used as an external test dataset to validate the CNN classifiers. RESULTS: After comparing multiple backbone CNN models, we developed a diagnostic system using Inception-v3. In the external test dataset, the per-examination combined sensitivities were 0.78 (0.71-0.84, 95% CI) based on T1-weighted images, 0.79 (0.72-0.84, 95% CI) for T2-weighted images, 0.88 (0.83-0.92, 95% CI) for CE-T1 images, and 0.88 (0.83-0.92, 95% CI) for all weighted images. The combined specificities were 0.72 based on T1-WI (0.66-0.78, 95% CI), 0.84 (0.78-0.89, 95% CI) based on T2-WI, 0.74 (0.67-0.80, 95% CI) for CE-T1, and 0.81 (0.76-0.86, 95% CI) for all weighted images. After all three MRI modalities were merged, the receiver operating characteristic (ROC) curve was calculated, and the area under the curve (AUC) was 0.93, with an accuracy of 0.87. CONCLUSIONS: CNN based MRI analysis has the potential to accurately differentiate ependymomas from schwannomas in the lumbar segment.

Ly6C-high monocytes alleviate brain injury in experimental subarachnoid hemorrhage in mice.

BACKGROUND: Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the development of drugs for SAH. We aimed to investigate the pathophysiological mechanisms of SAH and to elucidate the cellular and molecular biological response to SAH-induced injury. METHODS: A cross-species (human and mouse) multiomics approach combining high-throughput data and bioinformatic analysis was used to explore the key pathophysiological processes and cells involved in SAH-induced brain injury. Patient data were collected from the hospital (n = 712). SAH was established in adult male mice via endovascular perforation, and flow cytometry, a bone marrow chimera model, qPCR, and microglial depletion experiments were conducted to explore the origin and chemotaxis mechanism of the immune cells. To investigate cell effects on SAH prognosis, murine neurological function was evaluated based on a modified Garcia score, pole test, and rotarod test. RESULTS: The bioinformatics analysis confirmed that inflammatory and immune responses were the key pathophysiological processes after SAH. Significant increases in the monocyte levels were observed in both the mouse brains and the peripheral blood of patients after SAH. Ly6C-high monocytes originated in the bone marrow, and the skull bone marrow contribute a higher proportion of these monocytes than neutrophils. The mRNA level of Ccl2 was significantly upregulated after SAH and was greater in CD11b-positive than CD11b-negative cells. Microglial depletion, microglial inhibition, and CCL2 blockade reduced the numbers of Ly6C-high monocytes after SAH. With CCR2 antagonization, the neurological function of the mice exhibited a slow recovery. Three days post-SAH, the monocyte-derived dendritic cell (moDC) population had a higher proportion of TNF-α-positive cells and a lower proportion of IL-10-positive cells than the macrophage population. The ratio of moDCs to macrophages was higher on day 3 than on day 5 post-SAH. CONCLUSIONS: Inflammatory and immune responses are significantly involved in SAH-induced brain injury. Ly6C-high monocytes derived from the bone marrow, including the skull bone marrow, infiltrated into mouse brains via CCL2 secreted from microglia. Moreover, Ly6C-high monocytes alleviated neurological dysfunction after SAH.

Abnormal brain functional and structural connectivity between the left supplementary motor area and inferior frontal gyrus in moyamoya disease.

BACKGROUND: Disruption of brain functional connectivity has been detected after stroke, but whether it also occurs in moyamoya disease (MMD) is unknown. Impaired functional connectivity is always correlated with abnormal white matter fibers. Herein, we used multimodal imaging techniques to explore the changes in brain functional and structural connectivity in MMD patients. METHODS: We collected structural images, resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging for each subject. Cognitive functions of MMD patients were evaluated using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Trail Making Test parts A and B (TMT-A/-B). We calculated the functional connectivity for every paired region using 90 regions of interest from the Anatomical Automatic Labeling Atlas and then determined the differences between MMD patients and HCs. We extracted the functional connectivity of paired brain regions with significant differences between the two groups. Correlation analyses were then performed between the functional connectivity and variable cognitive functions. To explore whether the impaired functional connectivity and cognitive performances were attributed to the destruction of white matter fibers, we further analyzed fiber integrity using tractography between paired regions that were correlated with cognition. RESULTS: There was lower functional connectivity in MMD patients as compared to HCs between the bilateral inferior frontal gyrus, between the bilateral supramarginal gyrus, between the left supplementary motor area (SMA) and the left orbital part of the inferior frontal gyrus (IFGorb), and between the left SMA and the left middle temporal gyrus (P < 0.01, FDR corrected). The decreased functional connectivity between the left SMA and the left IFGorb was significantly correlated with the MMSE (r = 0.52, P = 0.024), MoCA (r = 0.60, P = 0.006), and TMT-B (r = -0.54, P = 0.048) in MMD patients. White matter fibers were also injured between the SMA and IFGorb in the left hemisphere and were positively correlated with reduced functional connectivity. CONCLUSIONS: Brain functional and structural connectivity between the supplementary motor area and inferior frontal gyrus in the left hemisphere are damaged in MMD. These findings could be useful in the evaluation of disease progression and prognosis of MMD.

Comprehensive landscape of STEAP family functions and prognostic prediction value in glioblastoma.

Glioblastoma (GBM) is the most common, malignant, and deadly primary glioma. Six-transmembrane epithelial antigen of prostate (STEAP) family is involved in tumorigenesis; here, we have explored the biological function and the prognostic value of the STEAP family in GBM. Differentially expressed STEAP genes in tumor and normal samples were screened by using The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression identified the prognosis-related genes: STEAP2 and STEAP3, which were involved in the regulation of immune response and cell cycle. Finally, a prognostic nomogram combining age, gender, chemotherapy, radiotherapy, IDH1 status, and the risk score model based on STEAP2 and STEAP3 was built and further validated in TCGA and Chinese Glioma Genome Atlas (CGGA) cohorts via concordance index and calibration plot, which suggested a favorable value for prognosis prediction. In conclusion, our results provided a comprehensive analysis of the STEAP family and a model for the prognosis prediction of GBM.

Ultra-Early Cerebral Thrombosis Formation After Experimental Subarachnoid Hemorrhage Detected on T2* Magnetic Resonance Imaging.

BACKGROUND AND PURPOSE: The mechanisms of brain damage during ultra-early subarachnoid hemorrhage (SAH) have not been well studied. The current study examined the SAH-induced hyperacute brain damage at 4 hours using magnetic resonance imaging and brain histology in a mouse model. METHODS: SAH was induced by endovascular perforation in adult mice. First, adult male wild-type mice underwent magnetic resonance imaging T2 and T2* 4 hours after an endovascular perforation or a sham operation and were euthanized to assess brain histology. Second, male and female adult lipocalin-2 knockout mice had SAH. All animals underwent magnetic resonance imaging at 4 hours, and the brains were harvested for brain histology. RESULTS: T2* hypointensity vessels were observed in the brain 4 hours after SAH in male wild-type mice. The numbers of T2*-positive vessels were significantly higher in SAH brains than in sham-operated mice. Brain histology showed thrombosis and erythrocyte plugs in the T2*-positive cerebral vessels which may be venules. The number of T2*-positive vessels correlated with SAH grade and the presence of T2 lesions. Brain thrombosis was also accompanied by albumin leakage and neuronal injury. LCN2 deficient male mice had lower numbers of T2*-positive vessels after SAH compared with wild-type male mice. CONCLUSIONS: SAH causes ultra-early brain vessel thrombosis that can be detected by T2* gradient-echo sequence at 4 hours after SAH. LCN2 deficiency decreased the number of T2*-positive vessels.

Prx2 (Peroxiredoxin 2) as a Cause of Hydrocephalus After Intraventricular Hemorrhage.

Background and Purpose- Our recent study demonstrated that release of Prx2 (peroxiredoxin 2) from red blood cells (RBCs) is involved in the inflammatory response and brain injury after intracerebral hemorrhage. The current study investigated the role of extracellular Prx2 in hydrocephalus development after experimental intraventricular hemorrhage. Methods- There were 4 parts in this study. First, Sprague-Dawley rats received an intraventricular injection of lysed RBC or saline and were euthanized at 1 hour for Prx2 measurements. Second, rats received an intraventricular injection of Prx2, deactivated Prx2, or saline. Third, lysed RBC was coinjected with conoidin A, a Prx2 inhibitor, or vehicle. Fourth, rats received Prx2 injection and were treated with minocycline or saline (i.p.). The effects of Prx2 and the inhibitors were examined using magnetic resonance imaging assessing ventriculomegaly, histology assessing ventricular wall damage, and immunohistochemistry to assess inflammation, particularly at the choroid plexus. Results- Intraventricular injection of lysed RBC resulted in increased brain Prx2 and hydrocephalus. Intraventricular injection of Prx2 alone caused hydrocephalus, ventricular wall damage, activation of choroid plexus epiplexus cells (macrophages), and an accumulation of neutrophils. Conoidin A attenuated lysed RBC-induced injury. Systemic minocycline treatment reduced the epiplexus cell activation and hydrocephalus induced by Prx2. Conclusions- Prx2 contributed to the intraventricular hemorrhage-induced hydrocephalus, probably by inducing inflammatory responses in choroid plexus and ventricular wall damage.

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage.

BACKGROUND: Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. METHODS: A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. RESULTS: STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1ß, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro. CONCLUSION: Microglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH.

Fluoxetine-enhanced autophagy ameliorates early brain injury via inhibition of NLRP3 inflammasome activation following subrachnoid hemorrhage in rats.

BACKGROUND: The NLRP3 inflammasome is a multiprotein complex that regulates the innate immune inflammatory response by activating caspase-1 and subsequent IL-1ß and IL-18. Fluoxetine has been shown to have the anti-inflammatory properties in many disease models. However, the effects and mechanisms of these effects of fluoxetine in early brain injury after subarachnoid hemorrhage (SAH) have not been defined. METHODS: The SAH model was induced by an endovascular perforation in adult male Sprague-Dawley (SD) rats weighing 300-320 g. N-Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (AC-YVAD-CMK) was injected intraperitoneally (5 mg/kg) 1 h after SAH. Fluoxetine was administered via intravenous route 6 h after SAH. 3-Methyladenine (3-MA) was intracerebroventricularly injected 20 min before SAH. SAH grade, neurological function, brain water content, propidium iodide (PI) staining, western blot, double immunostaining, and transmission electron microscopy were performed. RESULTS: Expression of caspase-1 increased and peaked at 24 h after SAH. Caspase activation was along with the increased necrotic cells, which occurred mainly in neurons. Necrotic cell death of microglia and astrocyte were also found. Administration of AC-YVAD-CMK, a caspase-1 inhibitor, reduced the expression of IL-1ß and IL-18 and the number of PI-positive cells, attenuated brain edema, and improved neurological function, which was also observed in fluoxetine-treated rats. Furthermore, fluoxetine treatment significantly decreased the expression of NLRP3 and cleaved caspase-1 and upregulated the expression of beclin-1, a marker for autophagy. Finally, the effects of fluoxetine in NLRP3 inflammasome activation were reversed by additional 3-MA administration. CONCLUSIONS: Together, our present study indicated that NLRP3 inflammasome and caspase-1 activation play a deleterious role in early brain injury and fluoxetine mitigates NLRP3 inflammasome and caspase-1 activation through autophagy activation after SAH, providing a potential therapeutic agent for SAH treatment.

Methylene blue attenuates neuroinflammation after subarachnoid hemorrhage in rats through the Akt/GSK-3ß/MEF2D signaling pathway.

Subarachnoid hemorrhage (SAH) is a serious medical problem with few effective pharmacotherapies available, and neuroinflammation has been identified as an important pathological process in early brain injury (EBI) after SAH. Methylene blue (MB) is an older drug that has been recently proven to exert extraordinary neuroprotective effects in several brain insults. However, no study has reported the beneficial effects of MB in SAH. In the current investigation, we studied the neuroprotective effects of MB in EBI after SAH and focused on its anti-inflammatory role. A total of 303 rats were subjected to an endovascular perforation process to produce an SAH model. We found that MB could significantly ameliorate brain edema secondary to BBB disruption and alleviate neurological dysfunction after SAH. MB administration also promoted the phosphorylation of Akt and GSK-3ß, leading to an increased concentration of MEF2D in the nucleus. The cytokine IL-10 was up-regulated, and IL-1ß, IL-6 and TNF-α were down-regulated after MB administration. MB administration could also alleviate neutrophil infiltration and microglia activation after SAH. MK2206, a selective inhibitor of Akt, abolished the neuroprotective effects of MB, inhibited the phosphorylation of Akt and prevented the nuclear localization of MEF2D. MK2206 also reduced the expression of IL-10 and increased the expression of pro-inflammatory cytokines. In conclusion, these data suggested that MB could ameliorate neuroinflammatory responses after SAH, and its anti-inflammatory effects might be exerted via activation of the Akt/GSK-3ß/MEF2D pathway.

The Polarization States of Microglia in TBI: A New Paradigm for Pharmacological Intervention.

Traumatic brain injury (TBI) is a serious medical and social problem worldwide. Because of the complex pathophysiological mechanisms of TBI, effective pharmacotherapy is still lacking. The microglial cells are resident tissue macrophages located in the brain and have two major polarization states, M1 phenotype and M2 phenotype, when activated. The M1 phenotype is related to the release of proinflammatory cytokines and secondary brain injury, while the M2 phenotype has been proved to be responsible for the release of anti-inflammation cytokines and for central nervous system (CNS) repair. In animal models, pharmacological strategies inhibiting the M1 phenotype and promoting the M2 phenotype of microglial cells could alleviate cerebral damage and improve neurological function recovery after TBI. In this review, we aimed to summarize the current knowledge about the pathological significance of microglial M1/M2 polarization in the pathophysiology of TBI. In addition, we reviewed several drugs that have provided neuroprotective effects against brain injury following TBI by altering the polarization states of the microglia. We emphasized that future investigation of the regulation mechanisms of microglial M1/M2 polarization in TBI is anticipated, which could contribute to the development of new targets of pharmacological intervention in TBI.

Melatonin attenuates neurogenic pulmonary edema via the regulation of inflammation and apoptosis after subarachnoid hemorrhage in rats.

Neurogenic pulmonary edema (NPE) is a serious non-neurological complication that can occur after a subarachnoid hemorrhage (SAH) and is associated with decreased survival and a poor neurological outcome. Melatonin is a strong antioxidant that has beneficial effects against SAH in rats, including reduced mortality and reduced neurological deficits. The molecular mechanisms underlying these clinical effects in the SAH model, however, have not been clearly identified. This study was undertaken to determine the influence of melatonin on SAH-induced NPE and the potential mechanism of these effects using the filament perforation model of SAH in male Sprague Dawley rats. Either melatonin (150 mg/kg) or a vehicle was given via an intraperitoneal injection 2 hr after an SAH induction. Lung samples were extracted 24 hr after SAH. The results show that the melatonin treatment attenuated SAH-induced NPE by preventing alveolar-capillary barrier dysfunctions via inhibiting the disruption of tight junction proteins (ZO-1 and occludin). Moreover, the treatment downregulated the levels of mature interleukin (IL) -1ß, myeloperoxidase (MPO), and matrix metallopeptidase (MMP) 9 expression/activation, which were increased in the lung; also, melatonin treatment improved neurological deficits. Furthermore, the melatonin treatment markedly reduced caspase-3 activity and the number of TUNEL-positive cells in the lung. Taken together, these findings show that administration of melatonin attenuates NPE by preventing alveolar-capillary barrier dysfunctions via repressing the inflammatory response and by anti-apoptosis effects after SAH.

Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage.

Melatonin is a strong antioxidant that has beneficial effects against early brain injury (EBI) following a subarachnoid hemorrhage (SAH) in rats; protection includes reduced mortality and brain water content. The molecular mechanisms underlying these clinical effects in the SAH model, however, have not been clearly identified. This study was undertaken to determine the influence of melatonin on neural apoptosis and the potential mechanism of these effects in EBI following SAH using the filament perforation model of SAH in male Sprague Dawley rats. Melatonin (150 mg/kg) or vehicle was given via an intraperitoneal injection 2 hr after SAH induction. Brain samples were extracted 24 hr after SAH. The results show that melatonin treatment markedly reduced caspase-3 activity and the number of TUNEL-positive cells, while the treatment increased the LC3-II/LC3-I, an autophagy marker, which indicated that melatonin-enhanced autophagy ameliorated apoptotic cell death in rats subjected to SAH. To further identify the mechanism of autophagy protection, we demonstrated that melatonin administration reduced Bax translocation to the mitochondria and the release of cytochrome c into the cytosol. Taken together, this report demonstrates that melatonin improved the neurological outcome in rats by protecting against neural apoptosis after the induction of filament perforation SAH; moreover, the mechanism of these antiapoptosis effects was related to the enhancement of autophagy, which ameliorated cell apoptosis via a mitochondrial pathway.

Melatonin attenuates inflammatory response-induced brain edema in early brain injury following a subarachnoid hemorrhage: a possible role for the regulation of pro-inflammatory cytokines.

Melatonin is a strong anti-oxidant that has beneficial effects against early brain injury (EBI) following a subarachnoid hemorrhage (SAH) in rats; protection includes the reduction of both mortality and neurological deficits. The molecular mechanisms underlying these clinical effects in the SAH model have not been clearly identified. This study examined the influence of melatonin on brain edema secondary to disruption of the blood-brain barrier (BBB) and the relationship between these effects and pro-inflammatory cytokines in EBI following SAH using the filament perforation model of SAH in male Sprague-Dawley rats. Melatonin (150 mg/kg) or vehicle was given via an intraperitoneal injection 2 hr after SAH induction. Brain samples were extracted 24 hr after SAH. Melatonin treatment markedly attenuated brain edema secondary to BBB dysfunctions by preventing the disruption of tight junction protein expression (ZO-1, occludin, and claudin-5). Melatonin treatment also repressed cortical levels of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), which were increased in EBI 24 hr after SAH. To further identify the mechanism of this protection, we demonstrated that administration of melatonin attenuated matrix metallopeptidase 9 expression/activity and vascular endothelial growth factor expression, which are related to the inflammatory response and BBB disruption in EBI after SAH. Taken together, this report shows that melatonin prevents disruption of tight junction proteins which might play a role in attenuating brain edema secondary to BBB dysfunctions by repressing the inflammatory response in EBI after SAH, possibly associated with regulation of pro-inflammatory cytokines.

High density amorphous ice at room temperature.

The phase diagram of water is both unusual and complex, exhibiting a wide range of polymorphs including proton-ordered or disordered forms. In addition, a variety of stable and metastable forms are observed. The richness of H(2)O phases attests the versatility of hydrogen-bonded network structures that include kinetically stable amorphous ices. Information of the amorphous solids, however, is rarely available especially for the stability field and transformation dynamics--but all reported to exist below the crystallization temperature of approximately 150-170 K below 4-5 GPa. Here, we present the evidence of high density amorphous (HDA) ice formed well above the crystallization temperature at 1 GPa--well inside the so-called "no-man's land." It is formed from metastable ice VII in the stability field of ice VI under rapid compression using dynamic-diamond anvil cell (d-DAC) and results from structural similarities between HDA and ice VII. The formation follows an interfacial growth mechanism unlike the melting process. Nevertheless, the occurrence of HDA along the extrapolated melt line of ice VII resembles the ice Ih-to-HDA transition, indicating that structural instabilities of parent ice VII and Ih drive the pressure-induced amorphization.

[The relationship between hypoxia-inducible factor-1α expression and apoptosis in early brain injury after subarachnoid hemorrhage].

OBJECTIVE: To investigate the association of hypoxia-inducible factor-1α (HIF-1α) expression and apoptosis in the cerebral cortex following subarachnoid hemorrhage (SAH). METHODS: Subarachnoid hemorrhage was induced by modified monofilament puncture method in rats. Thirty-five adult male Sprague-Dawley rats were randomly assigned to five groups: sham-operated group, SAH 6 h, SAH 12 h, SAH 24 h and SAH 72 h groups. HIF-1α expression was assessed by immunofluorescence staining. TdT-mediated dUTP-biotin nick end-labeling (TUNEL) technique was adopted to detect apoptotic cells. Double immunolabeling was used to identify cell types with positive HIF-1α expression. RESULTS: The expression of HIF-1α was increased at 6 h (4.65%±1.01%), peaked at 24 h (18.55%±4.23%), and decreased at 72 h (6.31%±1.15%) after SAH (P<0.05). TUNEL-positive cells were up-regulated in the brain at 6 h (7.09%±2.34%), peaked at 24 h (25.54%±7.36%), and down-regulated at 72 h (14.11%±3.03%) after SAH (P<0.05). A significant positive correlation was noted between HIF-1α positive rates and TUNEL positive rates following SAH (r=0.738, P<0.05). Double immunolabeling indicated that HIF-1α was expressed predominantly in neurons and some nuclei with positive HIF-1α were co-stained with TUNEL. CONCLUSION: The data indicate that HIF-1α might participate in the pathological progression of early brain injury after SAH.

Inhibiting HIF-1α by 2ME2 ameliorates early brain injury after experimental subarachnoid hemorrhage in rats.

Although hypoxia-inducible factor-1α (HIF-1α) has been extensively studied in brain injury following hypoxia-ischemia, the role of HIF-1α in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The present study was under taken to investigate a potential role of HIF-1α in EBI after SAH. Rats (n=60) were randomly divided into sham+vehicle, SAH+2-methoxyestradiol (2ME2), and SAH+vehicle groups. The SAH model was induced by endovascular perforation and all the rats were subsequently sacrificed at 24h after SAH. We found that treatment with 2ME2 suppressed the expression of HIF-1α, BNIP3 and VEGF and reduced cell apoptosis, blood-brain barrier (BBB) permeability, brain edema, and neurologic scores. Double fluorescence labeling revealed that HIF-1α was expressed predominantly in the nuclei of neurons and TUNEL-positive cells. Our work demonstrated that HIF-1α may play a role in EBI after SAH, causing cell apoptosis, BBB disruption, and brain edema by up-regulating its downstream targets, BNIP3 and VEGF. These effects were blocked by the HIF-1α inhibitor, 2ME2.

Pressure-induced phase transition and polymerization of tetracyanoethylene (TCNE).

We have studied the pressure-induced physical and chemical transformations of tetracyanoethylene (TCNE or C6N4) in diamond anvil cells using micro-Raman spectroscopy, laser-heating, emission spectroscopy, and synchrotron x-ray diffraction. The results indicate that TCNE in a quasi-hydrostatic condition undergoes a shear-induced phase transition at 10 GPa and then a chemical change to two-dimensional (2D) C=N polymers above 14 GPa. These phase and chemical transformations depend strongly on the state of stress in the sample and occur sluggishly in non-hydrostatic conditions over a large pressure range between 7 and 14 GPa. The x-ray diffraction data indicate that the phase transition occurs isostructurally within the monoclinic structure (P21∕c) without any apparent volume discontinuity and the C=N polymer is highly disordered but remains stable to 60 GPa-the maximum pressure studied. On the other hand, laser-heating of the C=N polymer above 25 GPa further converts to a theoretically predicted 3D C-N network structure, evident from an emergence of new Raman νs(C-N) at 1404 cm(-1) at 25 GPa and the visual appearance of translucent solid. The C-N product is, however, unstable upon pressure unloading below 10 GPa, resulting in a grayish powder that can be considered as nano-diamonds with high-nitrogen content at ambient pressure. The C-N product shows a strong emission line centered at 640 nm at 30 GPa, which linearly shifts toward shorter wavelength at the rate of -1.38 nm∕GPa. We conjecture that the observed red shift upon unloading pressure is due to increase of defects in the C-N product and thereby weakening of C-N bonds.

Preoperative Brain Functional Connectivity Improve Predictive Accuracy of Outcomes After Revascularization in Moyamoya Disease.

BACKGROUND: In patients with moyamoya disease (MMD), focal impairments in cerebral hemodynamics are often inconsistent with patients' clinical prognoses. Evaluation of entire brain functional networks may enable predicting MMD outcomes after revascularization. OBJECTIVE: To investigate whether preoperative brain functional connectivity could predict outcomes after revascularization in MMD. METHODS: We included 34 patients with MMD who underwent preoperative MRI scanning and combined revascularization surgery. We used region of interest analyses to explore the differences in functional connectivity for 90 paired brain regions between patients who had favorable outcomes 1 year after surgery (no recurrent stroke, with improved preoperative symptoms, or modified Rankin Scale [mRS]) and those who had unimproved outcomes (recurrent stroke, persistent symptoms, or declined mRS). Variables, including age, body mass index, mRS at admission, Suzuki stage, posterior cerebral artery involvement, and functional connectivity with significant differences between the groups, were included in the discriminant function analysis to predict patient outcomes. RESULTS: Functional connectivity between posterior cingulate cortex and paracentral lobule within the right hemisphere, and interhemispheric connection between superior parietal gyrus and middle frontal gyrus, precuneus and middle cingulate cortex, cuneus and precuneus, differed significantly between the groups (P < .001, false discovery rate corrected) and had the greatest discriminant function in the prediction model. Although clinical characteristics of patients with MMD showed great accuracy in predicting outcomes (64.7%), adding information on functional connections improved accuracy to 91.2%. CONCLUSION: Preoperative functional connectivity derived from rs-fMRI may be an early hallmark for predicting patients' prognosis after revascularization surgery for MMD.

Formation and phase transitions of methane hydrates under dynamic loadings: compression rate dependent kinetics.

We describe high-pressure kinetic studies of the formation and phase transitions of methane hydrates (MH) under dynamic loading conditions, using a dynamic-diamond anvil cell (d-DAC) coupled with time-resolved confocal micro-Raman spectroscopy and high-speed microphotography. The time-resolved spectra and dynamic pressure responses exhibit profound compression-rate dependences associated with both the formation and the solid-solid phase transitions of MH-I to II and MH-II to III. Under dynamic loading conditions, MH forms only from super-compressed water and liquid methane in a narrow pressure range between 0.9 and 1.6 GPa at the one-dimensional (1D) growth rate of 42 µm/s. MH-I to II phase transition occurs at the onset of water solidification 0.9 GPa, following a diffusion controlled mechanism. We estimated the activation volume to be -109±29 Å(3), primarily associated with relatively slow methane diffusion which follows the rapid interfacial reconstruction, or martensitic displacements of atomic positions and hydrogen bonds, of 5(12)6(2) water cages in MH-I to 4(3)5(12)6(3) cages in MH-II. MH-II to III transition, on the other hand, occurs over a broad pressure range between 1.5 and 2.2 GPa, following a reconstructive mechanism from super-compressed MH-II clathrates to a broken ice-filled viscoelastic solid of MH-III. It is found that the profound dynamic effects observed in the MH formation and phase transitions are primarily governed by the stability of water and ice phases at the relevant pressures.

Moyamoya Disease With Initial Ischemic or Hemorrhagic Attack Shows Different Brain Structural and Functional Features: A Pilot Study.

Objective: Cerebral ischemia and intracranial hemorrhage are the two main phenotypes of moyamoya disease (MMD). However, the pathophysiological processes of these two MMD phenotypes are still largely unknown. Here, we aimed to use multimodal neuroimaging techniques to explore the brain structural and functional differences between the two MMD subtypes. Methods: We included 12 patients with ischemic MMD, 10 patients with hemorrhagic MMD, and 10 healthy controls (HCs). Each patient underwent MRI scans and cognitive assessment. The cortical thickness of two MMD subtypes and HC group were compared. Arterial spin labeling (ASL) and diffusion tensor imaging (DTI) were used to inspect the cerebral blood flow (CBF) of cortical regions and the integrity of related white matter fibers, respectively. Correlation analyses were then performed among the MRI metrics and cognitive function scores. Results: We found that only the cortical thickness in the right middle temporal gyrus (MTG) of hemorrhagic MMD was significantly greater than both ischemic MMD and HC (p < 0.05). In addition, the right MTG showed higher ASL-CBF, and its associated fiber tract (arcuate fasciculus, AF) exhibited higher fractional anisotropy (FA) values in hemorrhagic MMD. Furthermore, the cortical thickness of the right MTG was positively correlated with its ASL-CBF values (r = 0.37, p = 0.046) and the FA values of right AF (r = 0.67, p < 0.001). At last, the FA values of right AF were found to be significantly correlated with cognitive performances within patients with MMD. Conclusions: Hemorrhagic MMD shows increased cortical thickness on the right MTG in comparison with ischemic MMD and HCs. The increased cortical thickness is associated with the higher CBF values and the increased integrity of the right AF. These findings are important to understand the clinical symptoms and pathophysiology of MMD and further applied to clinical practice.