GPX4 deficiency-dependent phospholipid peroxidation drives motor deficits of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by oxidative stress that triggers motor neurons loss in the brain and spinal cord. However, the mechanisms underlying the exact role of oxidative stress in ALS-associated neural degeneration are not definitively established. Oxidative stress-generated phospholipid peroxides are known to have extensive physiological and pathological consequences to tissues. Here, we discovered that the deficiency of glutathione peroxidase 4 (GPX4), an essential antioxidant peroxidase, led to the accumulation of phospholipid peroxides and resulted in a loss of motor neurons in spinal cords of ALS mice. Mutant human SOD1G93A transgenic mice were intrathecally injected with neuron-targeted adeno-associated virus (AAV) expressing GPX4 (GPX4-AAV) or phospholipid peroxidation inhibitor, ferrostatin-1. The results showed that impaired motor performance and neural loss induced by SOD1G93A toxicity in the lumbar spine were substantially alleviated by ferrostatin-1 treatment and AAV-mediated GPX4 delivery. In addition, the denervation of neuron-muscle junction and spinal atrophy in ALS mice were rescued by neural GPX4 overexpression, suggesting that GPX4 is essential for the motor neural maintenance and function. In comparison, conditional knockdown of Gpx4 in the spinal cords of Gpx4fl/fl mice triggered an obvious increase of phospholipid peroxides and the occurrence of ALS-like motor phenotype. Altogether, our findings underscore the importance of GPX4 in maintaining phospholipid redox homeostasis in the spinal cord and presents GPX4 as an attractive therapeutic target for ALS treatment.

High-Degree Middle Cerebral Artery Stenosis : Can Advanced 3D DSA-MRI Fusion Imaging Better Illustrate Plaques and Perforators?

PURPOSE: Endovascular treatment in severe middle cerebral artery (MCA) stenosis is controversial owing to high rates of periprocedural complications, especially occlusion of the lenticulostriate arteries (LSA). The characteristics of LSAs and the spatial relationships between MCA plaques and LSAs using the fusion of three-dimensional (3D) digital subtraction angiography (DSA) and magnetic resonance imaging (3D DSA-MRI fusion) were investigated. METHODS: We retrospectively analyzed data from 32 ischemic stroke or transient ischemic attack patients with severe MCA stenosis, who underwent MRI and DSA within 2 weeks after symptom onset. The patients were divided into culprit and non-culprit MCA stenosis groups. The 3D DSA-MRI fusion was performed on dedicated workstations, which allowed automated overlays of the target vessels. The characteristics of LSAs, plaque distribution and lesion patterns, and their relationships were evaluated. RESULTS: The 3D DSA-MRI fusion image was able to illustrate the spatial relationships between MCA plaques and LSA orifices. Of 42 LSA stems in 32 patients, 10 had MCA plaque over the LSA orifice and were all found in the culprit MCA stenosis group. Over half (51.9%) of the LSA stems in patients with culprit MCA stenosis originated from the stenotic MCA segment. The MCA plaque-LSA orifice spatial relationships were classified into four types, which were significantly different between the two groups (p = 0.016). CONCLUSION: The 3D DSA-MRI fusion technique enables visualization of the LSA orifice and MCA plaque and their spatial relationships. This classification of the type of spatial relationships can provide insights into the pathogenesis of MCA stroke and useful guides for treatment strategies.

Structural and functional brain changes in early- and mid-stage primary open-angle glaucoma using voxel-based morphometry and functional magnetic resonance imaging.

To investigate structural and functional brain changes in patients with primary open-angle glaucoma (POAG) by using voxel-based morphometry based on diffeomorphic anatomical registration through exponentiated Lie algebra (VBM-DARTEL) and blood oxygenation level dependent functional magnetic resonance imaging (BOLD-fMRI), respectively.Thirteen patients diagnosed with POAG and 13 age- and sex-matched healthy controls were enrolled in the study. For each participant, high-resolution structural brain imaging and blood flow imaging were acquired on a 3.0-Tesla magnetic resonance imaging (MRI) scanner. Structural and functional changes between the POAG and control groups were analyzed. An analysis was carried out to identify correlations between structural and functional changes acquired in the previous analysis and the retinal nerve fiber layer (RNFL).Patients in the POAG group showed a significant (P < 0.001) volume increase in the midbrain, left brainstem, frontal gyrus, cerebellar vermis, left inferior parietal lobule, caudate nucleus, thalamus, precuneus, and Brodmann areas 7, 18, and 46. Moreover, significant (P < 0.001) BOLD signal changes were observed in the right supramarginal gyrus, frontal gyrus, superior frontal gyrus, left inferior parietal lobule, left cuneus, and left midcingulate area; many of these regions had high correlations with the RNFL.Patients with POAG undergo widespread and complex changes in cortical brain structure and blood flow. (ClinicalTrials.gov number: NCT02570867).

Role of the texture features of images in the diagnosis of solitary pulmonary nodules in different sizes.

OBJECTIVE: To explore the role of the texture features of images in the diagnosis of solitary pulmonary nodules (SPNs) in different sizes. MATERIALS AND METHODS: A total of 379 patients with pathologically confirmed SPNs were enrolled in this study. They were divided into three groups based on the SPN sizes: ≤10, 11-20, and >20 mm. Their texture features were segmented and extracted. The differences in the image features between benign and malignant SPNs were compared. The SPNs in these three groups were determined and analyzed with the texture features of images. RESULTS: These 379 SPNs were successfully segmented using the 2D Otsu threshold method and the self-adaptive threshold segmentation method. The texture features of these SPNs were obtained using the method of grey level co-occurrence matrix (GLCM). Of these 379 patients, 120 had benign SPNs and 259 had malignant SPNs. The entropy, contrast, energy, homogeneity, and correlation were 3.5597±0.6470, 0.5384±0.2561, 0.1921±0.1256, 0.8281±0.0604, and 0.8748±0.0740 in the benign SPNs and 3.8007±0.6235, 0.6088±0.2961, 0.1673±0.1070, 0.7980±0.0555, and 0.8550±0.0869 in the malignant SPNs (all P<0.05). The sensitivity, specificity, and accuracy of the texture features of images were 83.3%, 90.0%, and 86.8%, respectively, for SPNs sized ≤10 mm, and were 86.6%, 88.2%, and 87.1%, respectively, for SPNs sized 11-20 mm and 94.7%, 91.8%, and 93.9%, respectively, for SPNs sized >20 mm. CONCLUSIONS: The entropy and contrast of malignant pulmonary nodules have been demonstrated to be higher in comparison to those of benign pulmonary nodules, while the energy, homogeneity correlation of malignant pulmonary nodules are lower than those of benign pulmonary nodules. The texture features of images can reflect the tissue features and have high sensitivity, specificity, and accuracy in differentiating SPNs. The sensitivity and accuracy increase for larger SPNs.

Size of solitary pulmonary nodule was the risk factor of malignancy.

OBJECTIVE: The purpose of this study was to analyze the role of the sizes of solitary pulmonary nodules (SPNs) in predicting their potential malignancies. METHODS: A total of 379 patients with pathologically confirmed SPNs were enrolled in this study. They were divided into three groups based on the SPN sizes: ≤10, 11-20, and >20 mm. The computed tomography (CT) findings of these SPNs were analyzed in these three groups to identify the malignant and benign SPNs. The risk factors were analyzed using binary logistic regression analysis. RESULTS: Of these 379 patients, 120 had benign SPNs and 259 had malignant SPNs. In the ≤10 mm SPN group, air cavity density was the risk factor for malignancy, with the sensitivity, specificity, and accuracy being 77.8%, 75.0%, and 76.3%. In the 11-20 mm SPN group, age, glitches and vascular aggregation were the risk factors for malignancy, with the sensitivity, specificity, and accuracy being 91.3%, 56.9%, and 81.5%. In the >20 mm SPN group, age, lobulation, and vascular aggregation were the risk factors for malignancy, with the sensitivity, specificity, and accuracy being 88.6%, 57.1%, and 79.1%. CONCLUSIONS: According to CT findings of SPNs, age, glitches, lobulation, vascular aggregation, and air cavity density are the risk factors of malignancy, whereas calcification and satellite lesions are the protective factors. During the course of development from small to large nodules, air cavity density could be firstly detected in early stages, followed by glitches and vascular aggregation. Lobulation is associated with relatively large lesions.