Endometriosis-targeted MRI imaging using bevacizumab-modified nanoparticles aimed at vascular endothelial growth factor.

Endometriosis is a tumor-like disease with high recurrence. In this case, the accurate imaging-based diagnosis of endometriosis can help clinicians eradicate it by improving their surgical plan. However, although contrast agents can improve the visibility of the tissue of interest in vivo via magnetic resonance imaging (MRI), the lack of biomarkers in endometriosis hinders the development of agents for its targeted imaging and diagnosis. Herein, aiming at the enriched vascular endothelial growth factor (VEGF) in endometriosis, we developed a targeting MRI contrast agent modified with bevacizumab, i.e., NaGdF4@PEG@bevacizumab-Cy5.5 nanoparticles (NPBCNs), to detect endometriosis. NPBCNs showed negligible cytotoxicity and high affinity towards VEGF in endometrial cells in vitro. Furthermore, NPBCNs generated a strong signal enhancement in vivo in endometriosis lesions in rats in T1-weighted images via MRI at 3 days post-injection, as confirmed by the histopathological staining results and fluorescence imaging on the same day. Our approach can enable NPBCNs to target endometriosis effectively, thus avoiding missed diagnoses.

Magnetic Resonance Imaging-guided Focused Ultrasound Surgery in a Swine Adenomyosis Model.

RATIONALE AND OBJECTIVES: The purpose of this study was to explore the feasibility of magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) for the treatment of an adenomyosis model of Bama pigs and the changes in the level of oxytocin receptor (OTR), vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) in the myometrium tissues of Bama pigs after MRgFUS. MATERIALS AND METHODS: Three Bama pig models of adenomyosis were established by autologous endometrial implantation and evaluated by magnetic resonance imaging, computed tomography, and hematoxylin-eosin (H&E) staining. After the successful construction of the model, the pigs underwent MRgFUS. Before the modeling surgery, three months after the modeling, and two months after ablation, the myometrium tissues were clipped, then embedded and H&E stained for immunohistochemical examination. The average optical density of OTR, VEGF, and COX-2 were semi-quantitatively analyzed. RESULTS: The adenomyosis models were established in all Bama pigs and confirmed by magnetic resonance imaging, computed tomography and H&E staining. Magnetic resonance imaging and computed tomography examination showed that the uterine wall at the modeling site was significantly thickened with uneven enhancement after contrast injection. All Bama pigs with adenomyosis lesions underwent MRgFUS without complications. The expression level of OTR and COX-2 in the myometrium increased three months after modeling surgery and decreased two months after MRgFUS. The expression level of VEGF decreased two months after MRgFUS. CONCLUSION: Autologous endometrial implantation is effective in establishing the adenomyosis model of Bama pigs. It is feasible to treat adenomyosis in the Bama pig model with MRgFUS. The levels of OTR, COX-2 and VEGF in the local myometrium decreased after MRgFUS, which may be associated with symptom relief after treatment.

Mid-term efficacy grading evaluation and predictive factors of magnetic resonance-guided focused ultrasound surgery for painful bone metastases: a multi-center study.

OBJECTIVES: MR imaging-guided focused ultrasound surgery (MRgFUS) is an emerging non-invasive treatment. It is helpful in investigating the mid-term grading efficacy and safety of MRgFUS, and possible risk factors in participants with painful bone metastases. METHODS: This four-center prospective study enrolled 96 participants between June 2016 and May 2019 with painful bone metastases. The Numerical Rating Scale (NRS), Brief Pain Inventory-Quality of Life (BPI-QoL) score, morphine equivalent daily dose (MEDD), and the adverse events (AEs) were recorded before and at 1 week, 1 month, 2 months, and 3 months after MRgFUS. The repeated ANOVA tests were used to analyze the change in NRS and BPI-QoL, and logistic regression analysis was used to analyze the possible risk factors. RESULTS: A total of 82 participants completed the 3-month follow-up period. And 16 (19.5%) participants were complete responders (CR), 46 (56.1%) participants were effective responders (ER), and the other 20 (24.4%) participants were non-responders (NR). The NRS (2.67 ± 2.47 at 3 months compared to 6.38 ± 1.70 before treatment) and BPI-QoL score (3.11 ± 2.51 at 3 months compared to 5.40 ± 1.85 before treatment) significantly decreased after the treatment at all time points (p < 0.001). Eleven adverse events were recorded and they were all cured within 1 to 52 days after treatment. The non-perfused volume (NPV) ratio (p = 0.001) and the bone metastases lesion type (p = 0.025) were the key risk factors. CONCLUSIONS: MRgFUS can be used as a non-invasive, effective, and safe modality to treat painful bone metastases. NPV ratio and the lesion type may be used as affecting factors to predict the mid-term efficacy of MRgFUS. KEY POINTS: • MRgFUS can be considered a non-invasive, effective, and safe modality to treat painful bone metastases. • The NRS and BPI-QoL score at 1 week, 1 month, 2 months, and 3 months all decreased significantly (p < 0.001) after receiving MRgFUS. Among 82 participants, 16 (19.5%) were complete responders, 46 (56.1%) were effective responders, and the other 20 (24.4%) were non-responders. • According to logistic regression analysis, non-perfused volume ratio and the bone metastases lesion type were the affecting factors to predict the mid-term efficacy of MRgFUS. The adjusted OR of non-perfused volume ratio was 0.86 (p = 0.001), and osteoblastic lesion type was 0.06 (p = 0.025).

Diffuse Tract Damage Correlates With Global Cognitive Impairment in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: A Tract-Based Spatial Statistics Study.

PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial arteriopathy characterized by recurrent lacunar stroke, migraine, and depression. The mechanism of cognitive dysfunction in CADASIL is still uncertain. The aim of this study was to use tract-based spatial statistics (TBSS) to map voxelwise the spatial distribution of brain microstructural change revealed by DTI-derived indices in patients with CADASIL to further study the underlying neuropsychopathological mechanism of CADASIL. METHOD: Twelve patients with CADASIL and 11 age-, sex-matched healthy controls underwent magnetic resonance imaging at 3 T. Then we evaluated DTI-derived indices (fractional anisotropy [FA], mode of anisotropy [MO], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]) of brain white matter (WM) between CADASIL patients and healthy subjects through TBSS. RESULTS: Compared with healthy controls, patients with CADASIL showed extensive decreased FA, MO and increased RD, AD, and MD throughout the entire brain (mainly the WM of the temporal poles, inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corpus callosum, uncinate fasciculus, internal capsule, external capsule, corona radiata, thalamic radiation, and cingulum). Furthermore, these WM microstructural alterations were significantly correlated with cognitive scores and Scheltens scores. Decreased FA values and MO values were positively correlated with Montreal Cognitive Assessment scores in CADASIL patients. Increased AD, RD, and MD values were significantly negatively correlated with Montreal Cognitive Assessment scores. CONCLUSIONS: Widespread WM abnormalities were clearly shown in CADASIL by using TBSS. Severity of microstructural changes correlates significantly with extension of T2 hyperintensity. Moreover, WM microstructural damage and cognitive impairment were significantly correlated. This study indicated that WM tract damage plays an important role in cognitive impairment in CADASIL.

Optimization of Contrast Agent Dosage on Contrast-Enhanced T2 Fluid-Attenuated Inversion Recovery: An In Vitro and In Vivo Study.

OBJECTIVE: This study aimed to ascertain the minimum gadolinium dosage on contrast-enhanced (CE) T2 fluid-attenuated inversion recovery (FLAIR) at appropriate imaging time. METHODS: Different dosages of gadodiamide were imaged with a 3.0-T magnetic resonance scanner for T2-FLAIR and T1WI. Twenty glioma-induced rat models were randomly assigned into 4 groups (1/2, 1/4, 1/6, 1/8 of routine dosage) and imaged for T2-FLAIR and T1WI preinjection and postinjection of gadodiamide. Contrast-enhanced T2-FLAIR was acquired for 8 repetitions postinjection. Enhancement effects were assessed by calculating contrast-noise ratio and contrast ratio using Kruskal-Wallis and Mann-Whitney rank sum test. RESULTS: The in vitro experiment showed that gadodiamide at 1/4 of the T1WI dosage presented the best contrast on CE-T2-FLAIR. For in vivo study, the best enhancement effect on CE-T2-FLAIR was achieved at 1/2 of the routine dosage at 8 to 12 minutes of delayed scanning. Compared with CE-T1WI at routine dosage, CE-T2-FLAIR at 1/2 gadodiamide dosage presented similar enhancement effects with no statistical difference (P = 0.244 and 0.090 for contrast-noise ratio and contrast ratio, respectively). CONCLUSIONS: Contrast-enhanced T2-FLAIR imaging with half of T1WI routine gadodiamide dosage can produce similar enhancement effects to CE-T1WI when characterizing brain gliomas. The cut-down of contrast agent dosage may help reduce gadolinium accumulation in certain tissues.

Improvement in cognitive dysfunction following blast induced traumatic brain injury by thymosin α1 in rats: Involvement of inhibition of tau phosphorylation at the Thr205 epitope.

Cognitive impairment is a significant sequela of traumatic brain injury (TBI) especially blast induced traumatic brain injury (bTBI), which is characterized by rapid impairments of learning and memory ability. Although several neuroprotective agents have been postulated as promising drugs for bTBI in animal studies, very few ideal therapeutic options exist to improve cognitive impairment following bTBI. Thymosin α1(Tα1), a 28-amino-acid protein that possesses immunomodulatory functions, has exhibited beneficial effects in the treatment of infectious diseases, immunodeficiency diseases and cancers. However, it remains unclear whether Tα1 has a therapeutic role in bTBI. Thus, we hypothesized that Tα1 administration could reverse the outcomes of bTBI. The blast induced TBI (bTBI) rat model was established with the compressed gas driven blast injury model system. A consecutive Tα1 therapy (in 1 ml saline, twice a day) at a dose of 200 µg/kg or normal saline (NS) (1 ml, twice a day) for 3 days or 2 weeks was performed. Utilizing our newly designed bTBI model, we investigated the beneficial effects of Tα1 therapy on rats exposed to bTBI including: cognitive functions, general histology, regulatory T (Treg) cells, edema, inflammation reactions and the expression and phosphorylation level of tau via Morris Water Maze test (MWM test), HE staining, flow cytometry, brain water content (BWC) calculation, IL-6 assay and Western blotting, respectively. Tα1 treatment seemed to reduce the 24-hour mortality, albeit with no statistical significance. Moreover, Tα1 treatment markedly improved cognitive dysfunction by decreasing the escape latency in the acquisition phase, and increasing the crossing numbers in the probe phase of MWM test. More interestingly, Tα1 significantly inhibited tau phosphorylation at the Thr205 epitope, but not at the Ser404 and Ser262 epitopes. Tα1 increased the percentage of Treg cells and inhibited plasma IL-6 production on 3d post bTBI. Moreover, Tα1 suppressed brain edema as demonstrated by decrease of BWC. However, there was a lack of obvious change in histopathology in the brain upon Tα1 treatment. This is the first study showing that Tα1 improves neurological deficits after bTBI in rats, which is potentially related to the inhibition of tau phosphorylation at the Thr205 epitope, increased Treg cells and decreased inflammatory reactions and brain edema.

Iron Sucrose as MRI Contrast Agent in Ischemic Stroke Model.

BACKGROUND: Despite the growing concern about the safety of gadolinium-based contrast agents (GBCAs), they are still the most commonly used. Ferumoxytol, as an off-label alternative MRI contrast agent, cannot be administered by a rapid bolus for dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI). PURPOSE: To assess the feasibility of iron sucrose (IS) as a contrast agent for MR angiography (MRA) and DSC-PWI. STUDY TYPE: Prospective animal model. ANIMAL MODEL: Thirty-six normal rats (16 for MRA, 20 for biocompability tests) and 36 occlusion of the middle cerebral artery (MCAO) model rats. FIELD STRENGTH/SEQUENCE: 3.0T; head and neck angiography, using a fast spoiled gradient-recalled-echo (FSPGR) sequence and DSC-MRI using echo planar imaging(EPI) sequence. ASSESSMENT: MRA was performed on normal rats to examine the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of different doses of IS. DSC-PWI was performed on MCAO rats at 0, 24, 48, and 72 hours postreperfusion to investigate the lesion detectability of IS. Arterial spin labeling (ASL) and DSC-PWI enhanced by GBCAs were conducted on MCAO rats as controls. STATISTICAL TESTS: Kruskal-Wallis test was used to compare qualitative assessment. One-way analysis of variance (ANOVA) was used to compare the parametric data. Pearson's r values were evaluated between relative cerebral blood flow(rCBF)-ASL, rCBF-DSCIS , and rCBF obtained from DSC-PWI enhanced by GBCA. RESULTS: The mean SNR and CNR of the common carotid artery at doses of 10 mg Fe/kg of IS were comparable with the standard dose of GBCAs (SNR: 68.04 ± 12.55 vs. 67.72 ± 14.66; CNR: 23.78 ± 7.21vs. 21.63 ± 6.83). In MCAO rat models, rCBF and relative cerebral blood volume (rCBV) of ipsilateral striatum declined (0.72 ± 0.14, 0.86 ± 0.11) with prolonged relative mean transit time (rMTT) and relative time-to-peak (rTTP) (1.27 ± 0.24, 1.07 ± 0.03) following occlusion. Hyperperfusion was observed in all rats at 48 and 72 hours postreperfusion, in 4/6 rats at 24 hours postreperfusion for IS-mediated DSC-PWI. DATA CONCLUSION: IS may be an effective contrast agent for both MRA and DSC-PWI in ischemic stroke models. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;52:836-849.

A novel model of blast induced traumatic brain injury caused by compressed gas produced sustained cognitive deficits in rats: involvement of phosphorylation of tau at the Thr205 epitope.

Improvised explosive devices (IEDs) represent the leading causes for casualties among civilians and soldiers in the present war (including counter-terrorism). Traumatic brain injury (TBI) caused by IEDs results in different degrees of impairment of cognition and behavior, but the exact brain pathophysiological mechanism following exposure to blast has not been clearly investigated. Here, we sought to establish a rat model of closed-head blast injury using compressed gas to deliver a single blast only to the brain without systemic injuries. The cognitive functions of these bTBI models were assessed by Morris Water Maze test (MWM test). The HE staining, flow cytometry, ELISA and Western Blotting were used to measure the effects of shock wave on general histology, regulatory T (Treg) cells percentage, inflammatory reactions, the expression and phosphorylation level of tau, respectively. In addition, the brain water content and 24 -h mortality were also assessed. As the distance from the blast source increased, the input pressure did not change, the overpressure decreased, and the mortality decreased. Receiver operating characteristic (ROC) curves for predicting 24 -h mortality using peak overpressure fits with the following areas under ROC curves: 0.833. In 2 weeks after blast injury, cognitive tests revealed significantly decreased performance at 20 cm distance from the blast (about 136.44 kPa) as demonstrated by increased escape latency in the acquisition phase, and decreased crossing numbers in the probe phase of MWM test. Interestingly, a single blast exposure (at 20 cm) lead to significantly increased tau phosphorylation at the Thr205 epitope but not at the Ser404 and Ser262 epitopes at 12 h, 24 h, 3d, and 7d after blast injury. Blast decreased the percentage of CD4+T cells, CD8+T cells, Treg cells and lymphocytes at different time points after blast injury, and blast increased the percentage of neutrophils at 12 h after blast injury and significantly increased IL-6 production at 12 h, 24 h and 3d after blast injury. In addition, blast lead to an increase of brain edema at 24 h and 3d after blast injury. However, no obvious alterations in brain gross pathology were found acutely in the blast-exposed rats. In conclusion, we established a rat model of simple craniocerebral blast injury characterized by impairment of cognitive function, Thr205 phosphorylation of tau, decreased Treg cells and increased inflammatory reactions and brain edema. We expect this model may help clarify the underlying mechanism after blast injury and possibly serve as a useful animal model in the development of novel therapeutic and diagnostic approaches.

Involvement of the microglial NLRP3 inflammasome in the anti-inflammatory effect of the antidepressant clomipramine.

BACKGROUND: Depression has recently been referred to as a neuroimmune disease because it is characterized by inflammatory changes in the cerebral cortex and hippocampus. Studies have demonstrated that microglial activation plays a crucial role in releasing inflammatory cytokines in the central nervous system (CNS), thereby contributing to depression, the mechanism underlying which remains unclear. METHODS: First, we examined microglial activation and inflammatory changes in C57BL/6 male mice injected with lipopolysaccharide (LPS; 1 mg/kg), which leads to depressive behaviors in mice that were attenuated by the antidepressant clomipramine. Second, we utilized a BV2 cell line and primary microglial cultures to determine the inflammatory response in vitro, and the effects of clomipramine exerted on the inflammatory response using real-time polymerase chain reaction and ELISA. Third, we utilized NLRP3 (NOD-like receptor protein 3) knock-out (KO) mice to prove that NLRP3 is involved in the effects of clomipramine. RESULTS: The results showed that LPS injection induced depressive-like behaviors in mice, as assessed using several behavioral tests including body weight, and forced swimming and tail suspension tests. The LPS-induced expression of interleukin-1beta (IL-1ß), IL-6, and tumor necrosis factor alpha could be downregulated by clomipramine pre-treatment both in vivo and in vitro. The inhibitory effect of clomipramine on the LPS-induced increase in cytokines was found at both the protein and gene levels. Clomipramine significantly reduced the LPS-induced increase in NLRP3 gene expression in BV2 cells. Furthermore, we utilized NLRP3 KO mice to explore whether NLPP3 was involved in this process and found that clomipramine treatment inhibits the LPS-induced increased expression of IL-1ß. CONCLUSION: These results imply that clomipramine could attenuate depressive behaviors and neuroinflammation induced by LPS via partial regulation of NLRP3.

MR textural analysis on contrast enhanced 3D-SPACE images in assessment of consistency of pituitary macroadenoma.

OBJECTIVES: To explore the value of magnetic resonance textural analysis (MRTA) in assessing consistency of pituitary macroadenoma (PMA) based on contrast enhanced (CE) three-dimensional sampling perfection with application-optimized contrasts by using different flip angle evolution (3D-SPACE) images. MATERIALS AND METHODS: Fifty-three patients with PMAs that underwent CE 3D-SPACE scanning by 3.0 T MRI and endoscopic trans-sphenoidal surgery were included in the present study. Consistency levels of PMAs were evaluated intraoperatively by two neurosurgeons. Each resection specimen was stained with H&E and anti-collagen IV. MRTA was conducted and texture features were calculated. An unpaired t-test was used to analyze the differences of texture features between soft and hard PMAs. ROC curves by individual and combined features were used to calculate the diagnostic accuracy of MRTA in predicting PMA consistency. RESULTS: First-order energy and second-order correlation negatively correlated with hard PMAs, while first-order entropy and second-order variance, sum variance, and sum entropy positively correlated with stiffness. All showed significant differences between soft and hard PMAs (P < 0.05). Diagnostic accuracy of combined negative features could achieve an AUC of 0.819, sensitivity of 88.9%, specificity of 61.5%, PPV of 70.6%, NPV of 84.2% and positive features could achieve an AUC of 0.836, sensitivity of 85.2%, specificity of 69.2%, PPV of 74.2%, NPV of 81.8% (P < 0.001). CONCLUSION: MRTA using CE 3D-SPACE images is helpful for assessing PMA consistency preoperatively and noninvasively.

3D-ASL perfusion correlates with VEGF expression and overall survival in glioma patients: Comparison of quantitative perfusion and pathology on accurate spatial location-matched basis.

BACKGROUND: There is a need for an imaging-based tool for measuring vascular endothelial growth factor (VEGF) expression and overall survival (OS) in patients with glioma. PURPOSE: To assess the correlation between cerebral blood flow (CBF), measured by 3D pseudo-continuous arterial spin-labeling (3D-ASL), and VEGF expression in gliomas on the basis of coregistered localized biopsy, and investigate whether CBF correlated with survival month (SM) in glioma patients. STUDY TYPE: Prospective cohort. SUBJECTS: Thirty-seven patients with gliomas from whom 63 biopsy specimens were obtained. SEQUENCE: 3D-ASL acquired with a 3.0T MR unit. ASSESSMENT: Biopsy specimens were grouped as high-grade (HGG) or low-grade glioma (LGG). CBF measurements were spatially matched with VEGF expression by coregistered localized biopsies, and the CBF value was correlated with quantitative VEGF expression for each specimen. Patients' survival information was derived and connected with CBF. STATISTICAL TESTS: Patients' OS was analyzed by Kaplan-Meier and Cox-regression methods. VEGF expression and CBF were compared in both LGG and HGG. The Spearman rank correlation was calculated for CBF and VEGF expression, SM. Significance level, P < 0.05. RESULTS: CBF-derived 3D-ASL positively correlated significantly with VEGF expression in both LGG (31 specimens) and HGG (32 specimens), r = 0.604 (P < 0.001) and r = 0.665 (P < 0.001), respectively. LGG and HGG together gave a correlation coefficient r = 0.728 (P < 0.001). Median survival for LGG and HGG patients was 34.19 and 17.17 months, respectively (P = 0.037); CBF value negatively correlated significantly with SM with r = -0.714 (P < 0.001) regardless of glioma grade. CBF was an independent risk factor for OS with HR = 1.027 (P = 0.044), 1.028 (P = 0.010) for univariate/multivariate regression analysis. DATA CONCLUSION: CBF determined by 3D-ASL correlates with VEGF expression in glioma and is an independent risk factor for OS in these patients. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:209-220.

Noninvasive Prediction of IDH1 Mutation and ATRX Expression Loss in Low-Grade Gliomas Using Multiparametric MR Radiomic Features.

BACKGROUND: Noninvasive detection of isocitrate dehydrogenase 1 mutation (IDH1(+)) and loss of nuclear alpha thalassemia/mental retardation syndrome X-linked expression ((ATRX(-)) are clinically meaningful for molecular stratification of low-grade gliomas (LGGs). PURPOSE: To study a radiomic approach based on multiparametric MR for noninvasively determining molecular status of IDH1(+) and ATRX(-) in patients with LGG. STUDY TYPE: Retrospective, radiomics. POPULATION: Fifty-seven LGG patients with IDH1(+) (n = 36 with 19 ATRX(-) and 17 ATRX(+) patients) and IDH1(-) (n = 21). FIELD STRENGTH/SEQUENCE: 3.0T MRI / 3D arterial spin labeling (3D-ASL), T2 /fluid-attenuated inversion recovery (T2 FLAIR), and diffusion-weighted imaging (DWI). ASSESSMENT: In all, 265 high-throughput radiomic features were extracted on each tumor volume of interest from T2 FLAIR and the other three parametric maps of ASL-derived cerebral blood flow (CBF), DWI-derived apparent diffusion coefficient (ADC), and exponential ADC (eADC). Optimal feature subsets were selected as using the support vector machine with a recursive feature elimination algorithm (SVM-RFE). Receiver operating characteristic curve (ROC) analysis was employed to assess the efficiency for identifying the IDH1(+) and ATRX(-) status. STATISTICAL TESTS: Student's t-test, chi-square test, and Fisher's exact test were applied to confirm whether intergroup significant differences exist between molecular subtypes decided by IDH1 and ATRX. RESULTS: Optimal SVM predictive models of IDH1(+) and ATRX(-) were established using 28 features from T2 Flair, ADC, eADC, and CBF and six features from T2 Flair, ADC, and CBF. The accuracies/AUCs/sensitivity/specifity/PPV/NPV of predicting IDH1(+) in LGG were 94.74%/0.931/100%/85.71%/92.31%/100%, and those of predicting ATRX(-) in LGG with IDH1(+) were 91.67%/0.926/94.74%/88.24%/90.00%/93.75%, respectively. DATA CONCLUSION: Using the optimal texture features extracted from multiple MR sequences or parametric maps, a promising stratifying strategy was acquired for predicting molecular subtypes of IDH1 and ATRX in LGGs. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;49:808-817.

Establishment of a novel rat model of blast-related diffuse axonal injury.

Although studies concerning blast-related traumatic brain injury (bTBI) have demonstrated the significance of diffuse axonal injury (DAI), no standard models for this type of injury have been widely accepted. The present study investigated a mechanism of inducing DAI through real blast injury, which was achieved by performing instantaneous high-speed swinging of the rat head, thus establishing a stable animal model of blast DAI. Adult Sprague-Dawley rats weighing 150±10 g were randomly divided into experimental (n=16), control (n=10) and sham control (n=6) groups. The frontal, parietal and occipital cortex of the rats in the experimental group were exposed, whereas those of the control group were unexposed; the sham control group rats were anesthetized and attached to the craniocerebral blast device without experiencing a blast. The rats were subjected to craniocerebral blast injury through a blast equivalent to 400 mg of trinitrotoluene using an electric detonator. Biomechanical parameters, and physical and behavioural changes of the sagittal head swing were measured using a high-speed camera. Magnetic resonance imaging (MRI) scans were conducted at 2, 12, 24 and 48 h after craniocerebral injury, only the experimental group indicated brain stem injury. The rats were sacrificed immediately following the MRI at 48 h for pathological examination of the brain stem using haematoxylin and eosin staining. The results indicated that 14 rats (87.5%) in the experimental group exhibited blast DAI, while no DAI was observed in the control and sham control groups, and the difference between the groups was significant (P<0.05). The present results indicated that this experimental design may serve to provide a stable model of blast DAI in rats.

Small-worldness of brain networks after brachial plexus injury: A resting-state functional magnetic resonance imaging study.

Research on brain function after brachial plexus injury focuses on local cortical functional reorganization, and few studies have focused on brain networks after brachial plexus injury. Changes in brain networks may help understanding of brain plasticity at the global level. We hypothesized that topology of the global cerebral resting-state functional network changes after unilateral brachial plexus injury. Thus, in this cross-sectional study, we recruited eight male patients with unilateral brachial plexus injury (right handedness, mean age of 27.9 ± 5.4 years old) and eight male healthy controls (right handedness, mean age of 28.6 ± 3.2). After acquiring and preprocessing resting-state magnetic resonance imaging data, the cerebrum was divided into 90 regions and Pearson's correlation coefficient calculated between regions. These correlation matrices were then converted into a binary matrix with affixed sparsity values of 0.1-0.46. Under sparsity conditions, both groups satisfied this small-world property. The clustering coefficient was markedly lower, while average shortest path remarkably higher in patients compared with healthy controls. These findings confirm that cerebral functional networks in patients still show small-world characteristics, which are highly effective in information transmission in the brain, as well as normal controls. Alternatively, varied small-worldness suggests that capacity of information transmission and integration in different brain regions in brachial plexus injury patients is damaged.

Surgical management of 142 cases of split cord malformations associated with osseous divide.

OBJECTIVES: To investigate the key surgical points in treating split cord malformations associated with osseous divide and scoliosis (SCM-OD-S). MATERIALS AND METHODS: The surgical options and methods of a total of 142 SCM-OD-S cases were retrospectively analyzed, and the surgical precautions and imaging diagnosis were also discussed. RESULTS: The 142 patients were performed osseous divide resection plus dural sac molding, which achieved good results and no serious complication such as spinal cord and nerve injury occurred; certain symptoms such as urination-defecation disorders, muscle strength subsidence, Pes Cavus, and toe movement disorder in partial patients achieved various degrees of relief, and it also created good conditions for next-step treatment against scoliosis. CONCLUSIONS: The diagnosis of SCM-OD mainly depended on imaging inspection, routine magnetic resonance imaging (MRI) combined with computed tomography (CT) 3D reconstruction, which can comprehensively evaluate the types and features of diastematomyelia as well as other concomitant diseases. SCM alone needed no treatment, but surgery will be the only means of treating SCM-OD. Intraoperatively removing osseous divide step-by-step, as well as carefully freeing the spinal cord and remodeling the dural sac, can lay good foundations for relieving tethered cord, improving neurological symptoms, and further scoliosis orthomorphia, thus particularly exhibiting importance for the growth and development of adolescents.

Emodin plays an interventional role in epileptic rats via multidrug resistance gene 1 (MDR1).

OBJECTIVE: To observe the interventional effects of emodin in epileptic rats and elucidate its possible mechanism of action. METHODS: Thirty-six female Wistar rats were randomly divided into normal control group, model group (intraperitoneal injection of kainic acid) and emodin group (intraperitoneal injection of kainic acid+emodin intervention). The rat epilepsy model was confirmed by behavioral tests and electroencephalography. The protein levels of P-glycoprotein and N-methyl-D-aspartate (NMDA) receptor in cerebral vascular tissue were analyzed by western blotting, and mRNA levels of multidrug resistance gene 1 (MDR1) and cyclooxygenase-2 (COX-2) were analyzed by real-time PCR. COX-2 and P-glycoprotein levels in the brains were detected by immunohistochemical assay. RESULTS: The seizures were relieved in emodin group. Laser scanning confocal microscopy showed P-glycoprotein fluorescence increased significantly after seizures, indicating that epilepsy can induce overexpression of P-glycoprotein. Compared with control group, protein levels of P-glycoprotein and NMDA receptor in cerebral vascular tissue were significantly higher in model group, and mRNA levels of MDR1 and COX-2 were also significantly increased. Compared with model group, P-glycoprotein and NMDA receptor levels in cerebral vascular tissue were significantly decreased in emodin group (P<0.05), and the levels of MDR1 and COX-2 were down-regulated (P<0.05). In the rat brain, seizures could significantly increase COX-2 and P-glycoprotein levels, while emodin intervention was able to significantly reduce the levels of both. DISCUSSION: These findings suggest that epileptic seizures are tightly associated with up-regulated MDR1 gene, and emodin shows good antagonistic effects on epileptic rats, possibly through inhibition of MDR1 gene and its associated genes.

A dorsally located giant posterior fossa neurenteric cyst in a Chinese woman.

Neurenteric cysts (NC) are rare, endodermal-derived intracranial lesions, commonly located anteriorly in the posterior cranial fossa. We describe a rare case of a giant posterior fossa NC (6.5 × 5.9 × 4.3cm) located dorsal to the brain stem in a Chinese woman with a 1 week history of cerebellar symptoms. To our knowledge, this is the largest documented cyst of this type and the third dorsally located NC in the posterior fossa.

Gene expression profiles of patients with cerebral hematoma following spontaneous intracerebral hemorrhage.

The present study aimed to investigate the gene functions and expression profiles in perihematomal (PH) brain regions following spontaneous intracerebral hemorrhage. The gene expression profiles were downloaded from the Gene Expression Omnibus database under accession number GSE24265, which includes 11 brain samples from different regions, including four samples from PH areas, four from contralateral grey matter (CG) and three from contralateral white matter (CW). The gene expression profiles were pre-processed and the differentially expressed genes (DEGs) between PH and CG tissue, and PH and CW tissue were identified using R packages. The expression of genes in different tissues was analyzed by hierarchical clustering. Then, the interaction network between the DEGs was constructed using String software. Finally, Gene Ontology was performed and pathway analysis was conducted using FuncAssociate and Expression Analysis Systematic Explorer to identify the gene function. As a result, 399 DEGs were obtained between PH and CG, and 756 DEGs were identified between PH and CW. There were 35 common DEGs between the two groups. These DEGs may be involved in PH edema by regulating the calcium signaling pathway [calcium channel, voltage­dependent, T-type, α1I subunit, Ca2+/calmodulin­dependent protein kinase II α (CAMK2A), ryanodine receptor 2 (RYR2) and inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1)], cell proliferation (sphingosine kinase 1), neuron differentiation (Ephrin-A5) or extracellular matrix-receptor interaction [collagen, type I, α 2, laminin B1 (LAMB1), syndecan 2, fibronectin 1 and integrin α5 (ITGA5)]. A number of genes may cooperate to participate in the same pathway, such as ITPR1-RYR2, CAMK2A-RYR2 and ITGA5-LAMB1 interaction pairs. The present study provides several potential targets to decrease hematoma expansion and alleviate neuronal cell death following spontaneous intracerebral hemorrhage.

Pharmacokinetics of dexamethasone and nefopam administered alone or in combination using a newly developed prefilled multi-drug injector in rats.

BACKGROUND/AIM: It is significant for patients with traumatic brain injury (TBI) to receive prehospital emergency treatment as early as possible to reduce mortality. Therefore, a new prefilled multi-drug injector was developed to improve the treatment of TBI. Here, we studied the pharmacokinetics of dexamethasone (DXM) and nefopam using the injector to investigate the significance of drug interactions and the necessity of dose adjustment. METHODS: Rats were administered DXM and nefopam intramuscularly alone or in combination using the injector. The concentrations of DXM and nefopam were measured by means of HPLC. The noncompartmental approach was used to calculate pharmacokinetic parameters. RESULTS: All animals appeared to tolerate the injection very well. The maximum concentration 90% confidence interval (CI) of nefopam was in the bioequivalence range when nefopam was co-administered with DXM. However, the AUC 90% CI of nefopam was out of the range. A statistically significant alteration was also observed in the clearance of nefopam. The co-administration exhibited no significant influence on the pharmacokinetic parameters of DXM. CONCLUSIONS: These results indicate that the co-administration of DXM and nefopam using the prefilled multi-drug injector significantly alters some pharmacokinetic parameters of nefopam and has a minor effect on DXM pharmacokinetics.