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.

Assessment of renal function in patients with unilateral ureteral obstruction using whole-organ perfusion imaging with 320-detector row computed tomography.

BACKGROUND: Obstructed nephropathy is a common complication of several disease processes. Accurate evaluation of the functional status of the obstructed kidney is important to achieve a good outcome. The purpose of this study was to investigate renal cortical and medullary perfusion changes associated with unilateral ureteral obstruction (UUO) using whole-organ perfusion imaging with 320-detector row computed tomography (CT). METHODOLOGY/PRINCIPLE FINDINGS: Sixty-four patients with UUO underwent whole-organ CT perfusion imaging. Patients were divided into 3 groups, mild, moderate, and severe, based on hydronephrosis severity. Twenty sex- and age-matched patients without renal disease, who referred to abdominal CT, were chosen as control subjects. Mean cortical and medullary perfusion parameters of obstructed and contralateral kidneys were compared, and mean perfusion ratios between obstructed and contralateral kidneys were calculated and compared. Mean cortical or medullary blood flow (BF) and blood volume (BV) of the obstructed kidneys in the moderate UUO and BF, BV, and clearance (CL) in the severe UUO were significantly lower than those of the contralateral kidneys (p < 0.05). The mean cortical or medullary BF of the obstructed kidney in the moderate UUO, and BF, BV, and CL in the severe UUO were significantly lower than those of the kidneys in control subjects (p < 0.05). Mean cortical or medullary BF of the non-obstructed kidneys in the severe UUO were statistically greater than that of normal kidneys in control subjects (p < 0.05). An inverse correlation was observed between cortical and medullary perfusion ratios and grades of hydronephosis (p < 0.01). CONCLUSIONS/SIGNIFICANCE: Perfusion measurements of the whole kidney can be obtained with 320-detector row CT, and estimated perfusion ratios have potential for quantitatively evaluating UUO renal injury grades.

Iodine Distribution Map in Dual-Energy Computed Tomography Pulmonary Artery Imaging with Rapid kVp Switching for the Diagnostic Analysis and Quantitative Evaluation of Acute Pulmonary Embolism.

RATIONALE AND OBJECTIVES: To assess the diagnostic value of dual-energy (DE) computed tomography pulmonary angiography (CTPA) for acute pulmonary embolism (PE) using a helical DE scan mode with rapid kVp switching. MATERIALS AND METHODS: Seventy-six patients with suspected acute PE underwent DE CTPA. Two readers independently assessed and measured the iodine maps. CTPA images were assessed for the presence, location, and degree of PE as the standard of reference. Iodine maps were used to identify the perfusion defect (PD), and the diagnostic accuracy of iodine maps was calculated. The iodine concentrations of PDs and normal lung parenchyma were also measured and compared. RESULTS: A per-patient analysis showed the 84.6% sensitivity and 96.0% specificity of iodine map for PE, and on per-segment analysis, the sensitivity and specificity for PE were 82.9% and 99.6%, respectively. Intraobserver and interobserver variability correlations were excellent, with k values from 0.806 to 1.000. Quantitative analysis showed there was a significant difference for iodine concentration between circumscribed/patchy PDs or wedge-shaped PDs consistent with PE and normal lung parenchyma (P < .05). The intraobserver reliability of reader 1 was from 0.928 to 0.997, and reader 2 was from 0.912 to 0.995. And, the interobserver reliability between two readers was from 0.967 to 0.999. CONCLUSIONS: CTPA based on DE scanning with rapid kVp switching can provide both morphologic analysis and quantitative evaluation of PD related to acute PE in addition to standard CTPA data. Quantification of iodine concentration may be helpful for identifying the presence or absence of PE.