In vivo assessment of nodularin-induced hepatotoxicity in the rat using magnetic resonance techniques (MRI, MRS and EPR oximetry)

Acute nodularin-induced hepatotoxicity was assessed in vivo, in rats using magnetic resonance (MR) techniques, including MR imaging (MRI), MR spectroscopy (MRS), and electron paramagnetic resonance (EPR) oximetry. Nodularin is a cyclic hepatotoxin isolated from the cyanobacterium Nodularia spumigena. Three hours following the intraperitoneal (i.p.) administration of nodularin (LD50), a region of 'damage', characterized by an increase in signal intensity, was observed proximal to the porta hepatis (PH) region in T2-weighted MR images of rat liver. Image analysis of these regions of apparent 'damage' indicated a statistically significant increase in signal intensity around the PH region following nodularin administration, in comparison with controls and regions peripheral to the PH region. An increase in signal intensity was also observed proximal to the PH region in water chemical shift selective images (CSSI) of nodularin-treated rat livers, indicating that the increased signal observed by MRI is an oedematous response to the toxin. Microscopic assessment (histology and electron microscopy) and serum liver enzyme function tests (aminotransferase (ALT) and aspartate ALT (AST)) confirmed the nodularin-induced tissue injury observed by MRI. In vivo and in vitro MRS was used to detect alterations in metabolites, such as lipids, Glu+Gln, and choline, during the hepatotoxic response (2-3 h post-exposure). Biochemical assessment of perchloric acid extracts of nodularin-treated rat livers were used to confirm the MRS results. In vivo EPR oximetry was used to monitor decreasing hepatic pO2 (approximately 2-fold from controls) 2-3 h following nodularin exposure. In vivo MR techniques (MRI, MRS and EPR oximetry) are able to highlight effects that may not have been evident in single end point studies, and are ideal methods to follow tissue injury progression in longitudinally, increasing the power of a study through repeated measures, and decreasing the number of animals to perform a similar study using histological or biochemical techniques.     

Minocycline improves the functional recovery after traumatic brain injury via inhibition of aquaporin-4

Traumatic brain injury (TBI) is one of the main concerns worldwide as there is still no comprehensive therapeutic intervention. Astrocytic water channel aquaporin-4 (AQP-4) system is closely related to the brain edema, water transport at blood-brain barrier (BBB) and astrocyte function in the central nervous system (CNS). Minocycline, a broad-spectrum semisynthetic tetracycline antibiotic, has shown anti-inflammation, anti-apoptotic, vascular protection and neuroprotective effects on TBI models. Here, we tried to further explore the underlying mechanism of minocycline treatment for TBI, especially the relationship of minocycline and AQP4 during TBI treatment. In present study, we observed that minocycline efficaciously reduces the elevation of AQP4 in TBI mice. Furthermore, minocycline significantly reduced neuronal apoptosis, ameliorated brain edema and BBB disruption after TBI. In addition, the expressions of tight junction protein and astrocyte morphology alteration were optimized by minocycline administration. Similar results were found after treating with TGN-020 (an inhibitor of AQP4) in TBI mice. Moreover, these effects were reversed by cyanamide (CYA) treatment, which notably upregulated AQP4 expression level in vivo. In primary cultured astrocytes, small-interfering RNA (siRNA) AQP4 treatment prevented glutamate-induced astrocyte swelling. To sum up, our study suggests that minocycline improves the functional recovery of TBI through reducing AQP4 level to optimize BBB integrity and astrocyte function, and highlights that the AQP4 may be an important therapeutic target during minocycline treating for TBI.     

急性弥漫性轴索损伤CT与MRI对比的研究

目的:比较急性弥漫性轴索损伤患者CT及MRI表现的不同。方法:选取60例急性弥漫性轴索损伤患者,而CT无异常改变或改变轻微的病例行MRI检查。全部检查均在损伤后6天内完成。GCS评分＜8分44例,9—12分16例。结果:MRI显示具有DAI损伤表现的共41例,阳性率68．3%,其中单独具有DAIⅠ、Ⅱ和Ⅲ型损伤表现的分别为7例、12例和1例,同时具有DAIⅠ和Ⅱ型损伤表现的共12例,同时具有DAJⅠ和Ⅲ型损伤表现的共2例,同时具有DAJⅡ和Ⅲ型损伤表现的共2例,同时具有三型DAI损伤表现的共5例;CT显示具有DAI损伤表现的共3例,阳性率5．0%,其中具有DAIⅠ型损伤表现的2例,具有DAIⅡ型损伤表现的1例,具有DAIⅢ型损伤表现的0例。结论:CT缺乏异常表现或轻微异常表现的急性弥漫性轴索损伤,MRI常常能显示损伤,包括特殊的损伤部位和一些其他类型合并损伤。     

Neurodegeneration with brain iron accumulation — Clinical syndromes and neuroimaging

Iron participates in a wide array of cellular functions and is essential for normal neural development and physiology. However, if inappropriately managed, the transition metal is capable of generating neurotoxic reactive oxygen species. A number of hereditary conditions perturb body iron homeostasis and some, collectively referred to as neurodegeneration with brain iron accumulation (NBIA), promote pathological deposition of the metal predominantly or exclusively within the central nervous system (CNS). In this article, we discuss seven NBIA disorders with emphasis on the clinical syndromes and neuroimaging. The latter primarily entails magnetic resonance scanning using iron-sensitive sequences. The conditions considered are Friedreich ataxia (FA), pantothenate kinase 2-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), FA2H-associated neurodegeneration (FAHN), Kufor-Rakeb disease (KRD), aceruloplasminemia, and neuroferritinopathy. An approach to differential diagnosis and the status of iron chelation therapy for several of these entities are presented. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Potential biomarkers to detect traumatic brain injury by the profiling of salivary extracellular vesicles

Traumatic brain injury (TBI) is a common cause of death and acquired disability in adults and children. Identifying biomarkers for mild TBI (mTBI) that can predict functional impairments on neuropsychiatric and neurocognitive testing after head trauma is yet to be firmly established. Extracellular vesicles (EVs) are known to traffic from the brain to the oral cavity and can be detected in saliva. We hypothesize the genetic profile of salivary EVs in patients who have suffered head trauma will differ from normal healthy controls, thus constituting a unique expression signature for mTBI. We enrolled a total of 54 subjects including for saliva sampling, 23 controls with no history of head traumas, 16 patients enrolled from an outpatient concussion clinic, and 15 patients from the emergency department who had sustained a head trauma within 24 hr. We performed real-time PCR of the salivary EVs of the 54 subjects profiling 96 genes from the TaqMan Human Alzheimer's disease array. Real-time PCR analysis revealed 57 (15 genes, p < 0.05) upregulated genes in emergency department patients and 56 (14 genes, p < 0.05) upregulated genes in concussion clinic patients when compared with controls. Three genes were upregulated in both the emergency department patients and concussion clinic patients: CDC2, CSNK1A1, and CTSD ( p < 0.05). Our results demonstrate that salivary EVs gene expression can serve as a viable source of biomarkers for mTBI. This study shows multiple Alzheimer's disease genes present after an mTBI.     

PETER PHAN: An MRI phantom for the optimisation of radiomic studies of the female pelvis

PurposeTo develop a phantom for methodological radiomic investigation on Magnetic Resonance (MR) images of female patients affected by pelvic cancer.MethodsA pelvis-shaped container was filled with a MnCl₂ solution reproducing the relaxation times (T₁, T₂) of muscle surrounding pelvic malignancies. Inserts simulating multi-textured lesions were embedded in the phantom. The relaxation times of muscle and tumour were measured on an MR scanner on healthy volunteers and patients; T₁ and T₂ of MnCl₂ solutions were evaluated with a relaxometer to find the concentrations providing a match to in vivo relaxation times. Radiomic features were extracted from the phantom inserts and the patients’ lesions. Their repeatability was assessed by multiple measurements.ResultsMuscle T₁ and T₂ were 1128 (806–1378) and 51 (40–65) ms, respectively. The phantom reproduced in vivo values within 13% (T₁) and 12% (T₂). T₁ and T₂ of tumour tissue were 1637 (1396–2121) and 94 (79–101) ms, respectively. The phantom insert best mimicking the tumour agreed within 7% (T₁) and 24% (T₂) with in vivo values. Out of 1034 features, 75% (95%) had interclass correlation coefficient greater than 0.9 on T₁ (T₂)-weighted images, reducing to 33% (25%) if the phantom was repositioned. The most repeatable features on phantom showed values in agreement with the features extracted from patients’ lesions.ConclusionsWe developed an MR phantom with inserts mimicking both relaxation times and texture of pelvic tumours. As exemplified with repeatability assessment, such phantom is useful to investigate features robustness and optimise the radiomic workflow on pelvic MR images.     

三维MRI用于高度近视眼球形态定量测量和后巩膜葡萄肿分型

目的:研究运用三维磁共振成像(Three-Dimensional Magnetic Resonance Imaging,3D MRI)技术对高度近视的眼球形态进行定量测量以及后巩膜葡萄肿分型的可行性。方法:纳入我院129例共246个高度近视眼球(屈光度≥-600,眼轴长度≥26.0 mm)和50个正视眼(屈光度-100～100,正视眼组)。采用三维稳态进动快速采集成像序列(Three-Dimensional Fast Imaging Employing Steady-state Acquisition,3D-FIESTA)扫描,扫描整个眼眶后获得的三维图像进行容积再现(Volume Rendering,VR)重建。评估眼球形态、后巩膜葡萄肿的形态和范围、与视神经的关系;测量眼球前后(AP)、左右(RL)、上下(SI)径线和RL/AP、SI/AP比值;根据后巩膜葡萄肿的形态和范围进行宽型和窄型分型。结果:246个高度近视眼球中,共100个眼球只表现为眼轴增长(眼轴增长组),146个表现为后巩膜葡萄肿(后巩膜葡萄肿组)。正视眼组、后巩膜葡萄肿组和眼轴增长组在AP径线上的差异有统计学意义(P0.001);反映眼球形变的比值RL/AP和SI/AP三组间的差异有统计学意义(P0.001)。不同组间的年龄差异均有统计学意义(P0.001)。146个后巩膜葡萄肿中宽型葡萄肿111个和窄型葡萄肿35个。结论:3D MRI可定量测量评估高度近视眼球的形态,诊断后巩膜葡萄肿并对其进行分型。     

The human patellar tendon moment arm assessed in vivo using dual-energy X-ray absorptiometry

Accurate assessment of muscle–tendon forces in vivo requires knowledge of the muscle–tendon moment arm. Dual-energy X-ray absorptiometry (DXA) can produce 2D images suitable for visualising both tendon and bone, thereby potentially allowing the moment arm to be measured but there is currently no validated DXA method for this purpose. The aims of this study were (i) to compare in vivo measurements of the patellar tendon moment arm (d_PT) assessed from 2D DXA and magnetic resonance (MR) images and (ii) to compare the reliability of the two methods. Twelve healthy adults (mean±SD: 31.4±9.5 yr; 174.0±9.5 cm; 76.2±16.6 kg) underwent two DXA and two MR scans of the fully extended knee at rest. The tibiofemoral contact point (TFCP) was used as the centre of joint rotation in both techniques, and the d_PT was defined as the perpendicular distance from the patellar tendon axis to the TFCP. The d_PT was consistently longer when assessed via DXA compared to MRI (+3.79±1.25 mm or +9.78±3.31%; P<0.001). The test–retest reliability of the DXA [CV=2.13%; ICC=0.94; ratio limits of agreement (RLA)=1.01 (?/÷1.07)] and MR [(CV=2.27%; ICC=0.96; RLA=1.00 (?/÷1.07)] methods was very high and comparable between techniques. Moreover, the RLA between the mean DXA and MRI d_PT values [1.097 (?/÷1.061)] demonstrated very strong agreement between the two methods. In conclusion, highly reproducible d_PT measurements can be determined from DXA imaging with the knee fully extended at rest. This has implications for the calculation of patellar tendon forces in vivo where MR equipment is not available.     

Effects of over‐expression of HIF‐1alpha in bone marrow‐derived mesenchymal stem cells on traumatic brain injury

Mesenchymal stem cells (MSCs) have been shown to play therapeutic effect in traumatic brain injury (TBI). To augment the therapeutic effect, MSCs could be engineered to over‐express genes that are beneficial for treatment. In the present study, we over‐expressed hypoxia inducible factor (HIF)‐1alpha in bone marrow derived MSCs (BM‐MSCs) and sought to investigate whether HIF‐1alpha could enhance the therapeutic effect of MSCs in a mouse model of TBI. Balb/c mice were subjected to controlled cortical impact injury and MSCs were transplanted intravenously at 6 h after injury. The lesion volume and brain water content were measured and the neurological function was assessed by modified neurologic severity score tests. Double‐labeled immunofluorescence for BrdU and NeuU was performed to determine angiogenesis and neurogenesis. The expression of erythropoietin (EPO) and vascular endothelial growth factor (VEGF) was measured by quantitative RT‐PCR and western blotting. After TBI, mice received BM‐MSCs over‐expressing HIF‐1alpha showed significantly more functional recovery, reduced brain damage, increased angiogenesis and neurogenesis and increased expression of VEGF and EPO, compared with control mice or mice treated with non‐transduced BM‐MSCs. Over‐expression of HIF‐1alpha enhanced BM‐MSCs induced improvement of neurological recovery after TBI, by stimulating angiogenesis and neurogenesis.     

CT与MRI对肝硬化背景下小肝癌检出率的比较

目的:分析比较CT与MR对肝硬化背景下小肝癌检出情况,探究CT与MR在肝硬化背景下小肝癌的诊断价值。方法:选择2010年6月~2015年6月期间,我院收治确诊为肝硬化背景下小肝癌患者91例为研究对象,病理及临床相关方法确诊102个病灶,其中小肝癌69个和微小肝癌33个,患者均在不同时期或序列下行多排螺旋CT与MRI检查,分析比较两者对小肝癌和微小肝癌的检出率。结果:多排螺旋CT检查发现肝癌小病灶91个,其中66个小肝癌,25个微小肝癌;MRI检查发现95个病灶,小肝癌67个,微小肝癌28个;69个小肝癌病灶,检出率最高的为CT动脉期(92.75%)与LAVA动脉期(92.75%),检出率最低的为CT平扫(76.81%);33个微小肝癌病灶,检出率最高为LAVA动脉期(75.76%),检出率最低的为LAVA平衡期(36.36%);CT平扫、门静脉期、动脉期、平衡期、MRI-IN-PHASE、LAVA平衡期、LAVA平扫对小肝癌的检出率显著高于对微小肝癌的检出率(P0.05);CT对小肝癌的检出率显著高于微小肝癌的检出率(P0.05),MRI对小肝癌与微小肝癌的检出率无显著差异(P0.05);MRI与CT对小肝癌的检出率不存在差异(P0.05),但MRI对微小肝癌的检出率显著高于CT(P0.05)。结论:MRI-LAVA的动脉期序列对小肝癌病灶与微小肝癌病灶的检出率最高;CT与MRI在对小肝癌的检出率不存在差异,但MRI对微小肝癌的检出具有更明显的优势。     

MRI在甲状腺肿瘤的肿块定位和良恶性判断中的应用研究

目的:总结甲状腺肿瘤的核磁共振成像(MRI)影像学表现,评价MRI在甲状腺肿瘤的肿块定位及良恶性判断中的应用价值。方法:选取我院外科收治的经MRI诊断为甲状腺癌的患者60例,总结所有患者的影像学资料,并将其与诊断金标准(病理学检查结果)相比较,分析MRI检查诊断累及组织和鉴别良恶性甲状腺肿瘤的准确率等。结果:MRI影像学结果清晰可见甲状腺肿瘤的部位、形态、密度、边界及是否有钙化等重要征象;MRI对良恶性肿瘤诊断准确性为95.0%。MRI对肿瘤累积膜外脂肪、肿瘤的淋巴结以及肿瘤的食管转移均有较高的准确性、敏感性与特异性。结论:MRI影像学检查清晰可见甲状腺肿瘤的部位、形态、密度、边界及是否有钙化等重要征象,对临床上甲状腺肿瘤的肿块定位及良恶性鉴别诊断具有重要的参考意义。     

Robust algorithm for brain magnetic resonance image (MRI) classification based on GARCH variances series

In this paper, a robust algorithm for disease type determination in brain magnetic resonance image (MRI) is presented. The proposed method classifies MRI into normal or one of the seven different diseases. At first two-level two-dimensional discrete wavelet transform (2D DWT) of input image is calculated. Our analysis show that the wavelet coefficients of detail sub-bands can be modeled by generalized autoregressive conditional heteroscedasticity (GARCH) statistical model. The parameters of GARCH model are considered as the primary feature vector. After feature vector normalization, principal component analysis (PCA) and linear discriminant analysis (LDA) are used to extract the proper features and remove the redundancy from the primary feature vector. Finally, the extracted features are applied to the K-nearest neighbor (KNN) and support vector machine (SVM) classifiers separately to determine the normal image or disease type. Experimental results indicate that the proposed algorithm achieves high classification rate and outperforms recently introduced methods while it needs less number of features for classification.     

Development and validation of a subject-specific moving-axis tibiofemoral joint model using MRI and EOS imaging during a quasi-static lunge

The aims of this study were to introduce and validate a novel computationally-efficient subject-specific tibiofemoral joint model. Subjects performed a quasi-static lunge while micro-dose radiation bi-planar X-rays (EOS Imaging, Paris, France) were captured at roughly 0°, 20°, 45°, 60°, and 90° of tibiofemoral flexion. Joint translations and rotations were extracted from this experimental data through 2D-to-3D bone reconstructions, using an iterative closest point optimization technique, and employed during model calibration and validation. Subject-specific moving-axis and hinge models for comparisons were constructed in the AnyBody Modeling System (AMS) from Magnetic Resonance Imaging (MRI)-extracted anatomical surfaces and compared against the experimental data. The tibiofemoral axis of the hinge model was defined between the epicondyles while the moving-axis model was defined based on two tibiofemoral flexion angles (0° and 90°) and the articulation modeled such that the tibiofemoral joint axis moved linearly between these two positions as a function of the tibiofemoral flexion. Outside this range, the joint axis was assumed to remain stationary. Overall, the secondary joint kinematics (ML: medial–lateral, AP: anterior-posterior, SI: superior-inferior, IE: internal-external, AA: adduction-abduction) were better approximated by the moving-axis model with mean differences and standard errors of (ML: −1.98 ± 0.37 mm, AP: 6.50 ± 0.82 mm, SI: 0.05 ± 0.20 mm, IE: 0.59 ± 0.36°, AA: 1.90 ± 0.79°) and higher coefficients of determination (R²) for each clinical measure. While the hinge model achieved mean differences and standard errors of (ML: −0.84 ± 0.45 mm, AP: 10.11 ± 0.88 mm, SI: 0.66 ± 0.62 mm, IE: −3.17 ± 0.86°, AA: 11.60 ± 1.51°).     

Thiamine preserves mitochondrial function in a rat model of traumatic brain injury,preventing inactivation of the 2-oxoglutarate dehydrogenase complex

Background and purpose

Based on the fact that traumatic brain injury is associated with mitochondrial dysfunction we aimed at localization of mitochondrial defect and attempted to correct it by thiamine.

Lack of X-linked inhibitor of apoptosis protein leads to increased apoptosis and tissue loss following neonatal brain injury

Neurological deficits caused by H-I (hypoxia-ischaemia) to the perinatal brain are often severely debilitating and lead to motor impairment, intellectual disability and seizures. Perinatal brain injury is distinct from adult brain injury in that the developing brain is undergoing the normal process of neuronal elimination by apoptotic cell death and thus the apoptotic machinery is more easily engaged and activated in response to injury. Thus cell death in response to neonatal H-I brain injury is partially due to mitochondrial dysfunction and activation of the apoptosome and caspase 3. An important regulator of the apoptotic response following mitochondrial dysfunction is XIAP (X-linked inhibitor of apoptosis protein). XIAP inhibits apoptosis at the level of caspase 9 and caspase 3 activation, and lack of XIAP in vitro has been shown to lead to increased apoptotic cell death. In the present study we show that mice lacking the gene encoding the XIAP protein have an exacerbated response to neonatal H-I injury as measured by tissue loss at 7 days following the injury. In addition, when the XIAP-deficient mice were studied at 24 h post-H-I we found that the increase in injury correlates with an increased apoptotic response in the XIAP-deficient mice and also with brain imaging changes in T2-weighted magnetic resonance imaging and apparent diffusion coefficient that correspond to the location of apoptotic cell death. These results identify a critical role of XIAP in regulating neuronal apoptosis in vivo and demonstrate the enhanced vulnerability of neurons to injury in the absence of XIAP in the developing brain.     

Monitoring the formation of an Aureobasidium pullulans biofilm in a bead-packed reactor via flow-weighted magnetic resonance imaging

The biofilm-forming fungus, Aureobasidium pullulans DSM 2404, was grown in a bead-packed reactor. Alterations within the reactor were analysed in several cross-sectional slices by magnetic resonance imaging (MRI) with flow contrast. For the first time, biofilm accumulation could be continuously elucidated without using any contrast agents, and the non-stationary flow through the fixed-bed reactor could be visualized. The results indicate that the non-stationary flow through the biofilm reactor changes significantly due to the changing reactor morphology. Preferential flow lines arise during biofilm formation. The accumulation of the biomass was determined and compared to gravimetrical biomass data. The described technique can be used to monitor hydrodynamic transport, and to combine flow-field characteristics with morphological data for the prediction of undesirable reactor processes, e.g. clogging.     

Strategies for the covalent conjugation of a bifunctional chelating agent to albumin: synthesis and characterization of potential MRI contrast agents

With the purpose to develop macromolecular magnetic resonance imaging contrast agents, we herein report three different synthetic approaches to the covalent attachment of bifunctional chelating agents to human serum albumin followed by coordination to contrast enhancing gadolinium(III). Applied methods cover active ester-mediated conjugation, linkage through glutaryl spacer, as well as the connection by the employment of glutaraldehyde. The content of gadolinium(III) was evaluated by inductively-coupled-plasma mass-spectrometry (ICP-MS) measurements and indicated reproducible amounts of conjugated contrast enhancing material. Small angle X-ray scattering (SAXS) experiments provided the size and altered shape of the gadolinium loaded proteins in comparison to unmodified albumin. Finally, the magnetic resonance properties of the protein conjugates were evaluated. The results indicated suitability of the gadolinium(III) loaded protein conjugates for use as macromolecular contrast agents in magnetic resonance imaging (MRI).     

Array CGH analysis of a cohort of Russian patients with intellectual disability

The use of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated the identification of many new microdeletion/microduplication syndromes (MMSs). Furthermore, this method has allowed for the identification of copy number variations (CNVs) whose pathogenic role has yet to be uncovered. Here, we report on our application of array CGH for the identification of pathogenic CNVs in 79 Russian children with intellectual disability (ID). Twenty-six pathogenic or likely pathogenic changes in copy number were detected in 22 patients (28%): 8 CNVs corresponded to known MMSs, and 17 were not associated with previously described syndromes. In this report, we describe our findings and comment on genes potentially associated with ID that are located within the CNV regions.     

Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery

The epithelial and endothelial barriers of the human body are major obstacles for drug delivery to the systemic circulation and to organs with unique environment and homeostasis, like the central nervous system. Several transport routes exist in these barriers, which potentially can be exploited for enhancing drug permeability. Beside the transcellular pathways via transporters, adsorptive and receptor-mediated transcytosis, the paracellular flux for cells and molecules is very limited. While lipophilic molecules can diffuse across the cellular plasma membranes, the junctional complexes restrict or completely block the free passage of hydrophilic molecules through the paracellular clefts. Absorption or permeability enhancers developed in the last 40 years for modifying intercellular junctions and paracellular permeability have unspecific mode of action and the effective and toxic doses are very close. Recent advances in barrier research led to the discovery of an increasing number of integral membrane, adaptor, regulator and signalling proteins in tight and adherens junctions. New tight junction modulators are under development, which can directly target tight or adherens junction proteins, the signalling pathways regulating junctional function, or tight junction associated lipid raft microdomains. Modulators acting directly on tight junctions include peptides derived from zonula occludens toxin, or Clostridium perfringens enterotoxin, peptides selected by phage display that bind to integral membrane tight junction proteins, and lipid modulators. They can reversibly increase paracellular transport and drug delivery with less toxicity than previous absorption enhancers, and have a potential to be used as pharmaceutical excipients to improve drug delivery across epithelial barriers and the blood-brain barrier.