Efficient and harmless removal of insecticide diazinon via the stepwise combination of biodegradation and photodegradation.

Diazinon, an organophosphorus insecticide, is predominantly removed through photodegradation and biodegradation in the environment. However, photodegradation can generate diazoxon, a highly toxic oxidation byproduct, while biodegradation is hard to complete mineralize diazinon, showing limitations in both methods. In this study, we provided an efficient strategy for the complete and harmless removal of diazinon by synergistically employing biodegradation and photodegradation. The diazinon-degrading strain X1 was capable of completely degrading 200 µM of diazinon into 2-isopropyl-6-methyl-4-pyrimidinol (IMP) within 6 h without producing the highly toxic diazoxon. IMP was the only intermediate metabolite in biodegradation process, which cannot be further degraded by strain X1. Through RT-qPCR and prokaryotic expression analyses, the hydrolase OpdB was pinpointed as the key enzyme for diazinon degradation in strain X1. Photodegradation was further used to degrade IMP and a pyridazine ring-opening product of IMP was identified via high resolution mass spectrometry. The acute toxicity of this product to aquatic organisms were 123 times and 6630 times lower than that of diazinon and IMP, respectively. The stepwise application of biodegradation and photodegradation was proved to be a successful approach for the remediation of diazinon and its metabolite IMP. This integrated method ensures the harmless and complete elimination of diazinon and IMP within only 6 h. The research provides a theoretical basis for the efficient and harmless remediation of organophosphorus insecticide residuals in the environment.

Predictive visual field outcomes after optic chiasm decompressive surgery by retinal vessels parameters using optical coherence tomography angiography.

AIM: To evaluate the predictive value of superficial retinal capillary plexus (SRCP) and radial peripapillary capillary (RPC) for visual field recovery after optic cross decompression and compare them with peripapillary nerve fiber layer (pRNFL) and ganglion cell complex (GCC). METHODS: This prospective longitudinal observational study included patients with chiasmal compression due to sellar region mass scheduled for decompressive surgery. Generalized estimating equations were used to compare retinal vessel density and retinal layer thickness pre- and post-operatively and with healthy controls. Logistic regression models were used to assess the relationship between preoperative GCC, pRNFL, SRCP, and RPC parameters and visual field recovery after surgery. RESULTS: The study included 43 eyes of 24 patients and 48 eyes of 24 healthy controls. Preoperative RPC and SRCP vessel density and pRNFL and GCC thickness were lower than healthy controls and higher than postoperative values. The best predictive GCC and pRNFL models were based on the superior GCC [area under the curve (AUC)=0.866] and the tempo-inferior pRNFL (AUC=0.824), and the best predictive SRCP and RPC models were based on the nasal SRCP (AUC=0.718) and tempo-inferior RPC (AUC=0.825). There was no statistical difference in the predictive value of the superior GCC, tempo-inferior pRNFL, and tempo-inferior RPC (all P>0.05). CONCLUSION: Compression of the optic chiasm by tumors in the saddle area can reduce retinal thickness and blood perfusion. This reduction persists despite the recovery of the visual field after decompression surgery. GCC, pRNFL, and RPC can be used as sensitive predictors of visual field recovery after decompression surgery.

Efficient biodegradation characteristics and detoxification pathway of organophosphorus insecticide profenofos via Cupriavidus nantongensis X1T and enzyme OpdB.

Profenofos residues in the environment pose a high risk to mammals and non-target organisms. In this study, the biodegradation and detoxification of profenofos in an efficient degrading strain, Cupriavidus nantongensis X1T, was investigated. Strain X1T could degrade 88.82 % of 20 mg/L profenofos in 48 h. The optimum temperature and inoculation amount of strain X1T for the degradation of profenofos were 30-37 °C and 20 % (V/V), respectively. Metabolic pathway analysis showed that strain X1T could degrade both profenofos and its main metabolite 4-bromo-2-chlorophenol. Metabolite toxicity analysis results showed that dehalogenation was the main detoxification step in profenofos biodegradation. The key gene and enzyme for profenofos degradation in strain X1T were also explored. RT-qPCR shows that organophosphorus hydrolase (OpdB) was the key enzyme to control the hydrolysis process in strain X1T. The purified enzyme OpdB in vitro had the same degradation characteristics as strain X1T. Divalent metal cations could significantly enhance the hydrolysis activity of strain X1T and enzyme OpdB. Meanwhile, strain X1T could degrade 60.89 % of 20 mg/L profenofos in actual field soil within 72 h. This study provides an efficient biological resource for the remediation of profenofos residual pollution in the environment.

GDNF Promotes Astrocyte Abnormal Proliferation and Migration Through the GFRα1/RET/MAPK/pCREB/LOXL2 Signaling Axis.

Glial cell-line derived neurotrophic factor (GDNF) is a powerful astroglioma (AG) proliferation and migration factor that is highly expressed in AG cells derived from astrocytes. However, it is still unclear whether high levels of GDNF promote AG occurrence or if they are secondary to AG formation. We previously reported that high concentrations of GDNF (200 and 500 ng/mL) can inhibit DNA damage-induced rat primary astrocytes (RA) apoptosis, suggesting that high concentrations of GDNF may be involved in the malignant transformation of astrocytes to AG cells. Here we show that 200 ng/mL GDNF significantly increased the proliferation and migration ability of RA cells and human primary astrocytes (HA). This treatment also induced RA cells to highly express Pgf, Itgb2, Ibsp, Loxl2, Lif, Cxcl10, Serpine1, and other genes that enhance AG proliferation and migration. LOXL2 is an important AG occurrence and development promotion factor and was highly expressed in AG tissues and cells. High concentrations of GDNF promote LOXL2 expression and secretion in RA cells through GDNF family receptor alpha-1(GFRα1)/rearranged during transfection proto-oncogene (RET)/mitogen-activated protein kinase (MAPK)/phosphorylated cyclic AMP response element binding protein (pCREB) signaling. GDNF-induced LOXL2 significantly promotes RA and HA cell proliferation and migration, and increases the expression of Ccl2, Gbp5, MMP11, TNN, and other genes that regulate the extracellular microenvironment in RA cells. Our results demonstrate that high concentrations of GDNF activate LOXL2 expression and secretion via the GFRα1/RET/MAPK/pCREB signal axis, which leads to remodeling of the astrocyte extracellular microenvironment through molecules such as Ccl2, Gbp5, MMP11, TNN. This ultimately results in abnormal astrocyte proliferation and migration. Collectively, these findings suggest that high GDNF concentrations may promote the malignant transformation of astrocytes to AG cells.

Spatiotemporal variation of phosphorus in the Three Gorges Reservoir: impact of upstream cascade reservoirs.

The impoundment of the Three Gorges Reservoir (TGR) and upstream cascade reservoirs (UCRs) has altered the hydrologic regime, with inevitable effects on phosphorus transport processes in the TGR. In order to investigate the effects of impoundment, long-term monitoring data of flow rate, suspended sediment (SS), and phosphorus fractions of six stations in the TGR basin were collected and divided into three periods, period 1 (P1) (1985-2002), period 2 (P2) (2003-2012), and period 3 (P3) (2013-2017), based on the periodic impoundment time. The results indicated that the impoundment of the TGR and UCRs considerably decreased the SS concentration. Efficient sediment interception by the UCRs led to a dramatic decline in the concentrations of total phosphorus (TP) and particulate phosphorus (PP) in the mainstream, while the total dissolved phosphorus (TDP) showed a general increasing trend from 2004 to 2017. Different phosphorus fractions in the mainstream exhibited seasonal variations; among them, the concentrations of TP and PP were highest in the wet season, while the highest TDP concentration occurred in the dry season. Further analysis indicated that the seasonal distribution of TP was significantly homogenized in P3. Additionally, the SS concentration was positively correlated with the concentrations of TP and PP in the mainstream, while the correlations in P3 were significantly lower than that in P2. The findings can provide a scientific reference for future investigations dedicated to the long-term effects of the UCRs on the eco-environment in the TGR as well as the downstream.

Responses of cyprinid (Ancherythroculter nigrocauda) to flow with a semi-circular cylinder patch.

Flows in river habitats are characterized by unsteady turbulence due to the existence of woody debris, boulders and vegetation. As a representative aquatic species, fish is important for the riverine ecosystems, with its complex behavioural responses to turbulent flows. Previous studies investigated the fish-vortices interaction with vortex streets by placing objects with simplified geometries centred at the flow. Nonetheless, complex river morphology in natural rivers results in much more spatially heterogeneous flows due to randomly distributed obstructions. Thus, a semi-circular cylinder patch located on one side of the flume is used to mimic a vegetation patch at the riverbank. The patch varies in diameter (D0  = 16, 20 and 24 cm) and density (φ = 0.04 and 0.1), whereas the flow velocity is fixed at 25 cm s-1 . Fish are observed to swim in three typical patterns, which are "swim around" (pattern 1), "spill" (pattern 2) and "swim through" (pattern 3). For flow with a dense patch, all three patterns are recorded, but only patterns 1 and 2 are observed in sparse patches. It is noticed that in patterns 1 and 2, fish prefer to hold place in zones of low velocity and low turbulence. Moreover, variations in patch diameter have little influence on pattern selection. Results showed that tail beat amplitude (TBA*) in each zone displayed more variations compared with tail beat frequency (TBF). In addition, Spearman's rank tests revealed that TBA* is affected by none of the four hydrodynamic variables ( U , u std , τ xy , Ω z ), whereas flow velocity imposes the most influence on TBF. Both diameter and density of the patch displayed no significant influence on TBA* and TBF.

Ginsenoside 20(S)-Rh2 promotes cellular pharmacokinetics and intracellular antibacterial activity of levofloxacin against Staphylococcus aureus through drug efflux inhibition and subcellular stabilization.

Intracellular Staphylococcus aureus (S. aureus) often causes clinical failure and relapse after antibiotic treatment. We previously found that 20(S)-ginsenoside Rh2 [20(S)-Rh2] enhanced the therapeutic effect of quinolones in a mouse model of peritonitis, which we attributed to the increased concentrations of quinolones within bacteria. In this study, we investigated the enhancing effect of 20(S)-Rh2 on levofloxacin (LVF) from a perspective of intracellular bacteria. In S. aureus 25923-infected mice, coadministration of LVF (1.5 mg/kg, i.v.) and 20(S)-Rh2 (25, 50 mg/kg, i.g.) markedly increased the survival rate, and decreased intracellular bacteria counts accompanied by increased accumulation of LVF in peritoneal macrophages. In addition, 20(S)-Rh2 (1, 5, 10 µM) dose-dependently increased the uptake and accumulation of LVF in peritoneal macrophages from infected mice without drug treatment. In a model of S. aureus 25923-infected THP-1 macrophages, we showed that 20(S)-Rh2 (1, 5, 10 µM) dose-dependently enhanced the intracellular antibacterial activity of LVF. At the cellular level, 20(S)-Rh2 increased the intracellular accumulation of LVF by inhibiting P-gp and BCRP. PK-PD modeling revealed that 20(S)-Rh2 altered the properties of the cell but not LVF. At the subcellular level, 20(S)-Rh2 did not increase the distribution of LVF in lysosomes but exhibited a stronger sensitizing effect in acidic environments. Molecular dynamics (MD) simulations showed that 20(S)-Rh2 improved the stability of the DNA gyrase-LVF complex in lysosome-like acidic conditions. In conclusion, 20(S)-Rh2 promotes the cellular pharmacokinetics and intracellular antibacterial activities of LVF against S. aureus through efflux transporter inhibition and subcellular stabilization, which is beneficial for infection treatment.

Laboratory study on behavioral responses of hybrid sturgeon, Acipenseridae, to wake flows induced by cylindrical bluff bodies.

Interaction between flow and cylindrical-shaped structures generates coherent and periodic turbulent flow that is frequently experienced by fish in natural environments, influencing fish maneuvering and swimming stability. The current study evaluated the behavioral responses of hybrid sturgeon (Acipenser dabryanus ♀ × Acipenser baerii ♂) when interacting with the wake flows induced by a D-shaped cylinder, with diameter ranging from 2 to 6 cm. A two dimensional Particle Image Velocimetry (PIV) was used to measure the wake flows hydrodynamics induced by D-shaped cylinders, and the fish behavior was recorded by camera. Hydrodynamic space occupancy together with swimming behaviors were analyzed, and the result shows that due to the presence of lowest velocity and relatively low turbulence, the regions behind cylinder were characterized by the preferred station holding zone for fish. Sturgeon adopted distinctive swimming gaits (Kármán gaiting or spill) in response to the cylinder wake flow and the associated fish swimming kinematics differed from each other. Kármán gaiting and spill significantly depended on velocity, vorticity and Reynolds shear stress, and varied according to the ratio of turbulence length scale to standard fish length (Lu/Lfish), which highlights the importance of cylinder vortex structure in influencing fish holding station and swimming stability. It is envisioned that these results can provide insights into the positions where fish may prefer to occupy in natural habitats and recommendations for the design and optimization of fish-friendly projects.

Enhancer II-targeted dsRNA decreases GDNF expression via histone H3K9 trimethylation to inhibit glioblastoma progression.

BACKGROUND: Glial cell line-derived neurotrophic factor (GDNF) is expressed in both astrocytes and glioblastoma (GBM) cells. GDNF expression is significantly increased in GBM, and inhibiting its expression can retard GBM progression. However, there is no known method for specific inhibition of GDNF in GBM cells. METHODS: Promoter-targeted dsRNA-induced transcriptional gene silencing or activation was recently achieved in human cells. This approach has the potential to specifically regulate gene transcription via epigenetic modifications. In this study, we designed six candidate dsRNAs targeting the enhancer or silencer in GDNF gene promoter II to check their effects on GDNF transcription and GBM progression. RESULTS: Among these dsRNAs, enhancer II-targeted dsRNA significantly inhibited U251 GBM progression by downregulating GDNF (P < 0.05), while silencer II-targeted dsRNA exerted an opposite effect. Moreover, enhancer II-targeted dsRNA did not significantly change GDNF expression in human astrocytes (HA) and the proliferation and migration of HA cells (P > 0.05). Bisulfate PCR and chromatin immunoprecipitation analyses revealed that both DNA methylation and trimethylation of histone 3 at lysine 9 (H3K9me3) at silencer II-targeted region significantly increased, and H3K9me3 at enhancer II-targeted region significantly decreased, in U251 cells compared with HA cells in non-intervention condition (P < 0.05). Both enhancer II- and silencer II-targeted dsRNA significantly increased H3K9me3 methylation rather than DNA at the targeted site in U251 cells (P < 0.05). The expression and activity of histone methyltransferase SETDB1 increased dramatically in U251 cells compared with HA cells, and it was recruited to enhancer II targeting region after enhancer II-targeted dsRNA treatment in U251 cells (P < 0.05). CONCLUSIONS: Our results demonstrate that a promoter-targeted dsRNA can silence or promote gene transcription depending on its targeted site in different cis-acting elements in the gene promoter. Targeted inhibition of GDNF by enhancer II-targeted dsRNA may be explored as a novel treatment for GBM.

Repeatability of regional pulmonary functional metrics of Hyperpolarized 129 Xe dissolved-phase MRI.

BACKGROUND: MRI of hyperpolarized 129 Xenon (HP 129 Xe) is increasingly utilized for investigating pulmonary function. The solubility of HP 129 Xe in lung tissue, blood plasma (Barrier), and red blood cells (RBC), with unique chemical shifts, enables spectroscopic imaging of potential imaging biomarkers of gas exchange and microstructural pulmonary physiology. PURPOSE: To quantify global average and regional repeatability of Barrier:gas, RBC:gas, and RBC:Barrier ratios derived from dissolved-phase 129 Xe imaging and their dependence on intervisit changes in lung inflation volume. STUDY TYPE: Prospective. POPULATION: Fourteen healthy volunteers. One subject was unable to complete the study resulting in 13 subjects for analysis (eight female, five male, ages 24-69, 53.8 ± 13.9). FIELD STRENGTH: 1.5T. ASSESSMENT: Subjects were imaged using a 3D radial 1-point Dixon method to separate Barrier and RBC component signals, at two different timepoints, with ~1 month between visits. RBC:Gas, Barrier:Gas, and RBC:Barrier measures were compared across time and with pulmonary function tests (PFTs). STATISTICAL TESTS: Repeatablilty was quantified using Bland-Altman plots, coefficient of repeatability, coefficient of variation (CV), and intraclass correlation coefficients (ICCs). Dependence of imaging measures on PFTs and lung volume was evaluated using Spearman and Pearson correlation coefficients, respectively. Statistical significance was determined by F-test for intraclass correlations, and t-test for Spearman correlations and regression. RESULTS: Mean RBC:Gas, Barrier:Gas, and RBC:Barrier had CVs of 19.2%, 20.0%, and 11.5%, respectively, and had significant ICCs, equal to 0.78, 0.79, and 0.92, respectively. Intervisit differences in RBC:Barrier were significantly correlated with intervisit differences in DLCO (r = 0.93, P = 0.007). Significant correlations with intervisit lung volume differences and intervisit differences in mean RBC:Gas (r = -0.73, P = 0.005) and Barrier:Gas (r = -0.69, P = 0.009) were found. DATA CONCLUSION: Three commonly used 129 Xe MRI-based measures of gas-exchange show good repeatability, particularly the Barrier:RBC ratio, which did not depend on lung inflation volume and was strongly associated with intervisit changes in DLCO . LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1182-1190.

Deep convolutional neural networks with multiplane consensus labeling for lung function quantification using UTE proton MRI.

BACKGROUND: Ultrashort echo time (UTE) proton MRI has gained popularity for assessing lung structure and function in pulmonary imaging; however, the development of rapid biomarker extraction and regional quantification has lagged behind due to labor-intensive lung segmentation. PURPOSE: To evaluate a deep learning (DL) approach for automated lung segmentation to extract image-based biomarkers from functional lung imaging using 3D radial UTE oxygen-enhanced (OE) MRI. STUDY TYPE: Retrospective study aimed to evaluate a technical development. POPULATION: Forty-five human subjects, including 16 healthy volunteers, 5 asthma, and 24 patients with cystic fibrosis. FIELD STRENGTH/SEQUENCE: 1.5T MRI, 3D radial UTE (TE = 0.08 msec) sequence. ASSESSMENT: Two 3D radial UTE volumes were acquired sequentially under normoxic (21% O2 ) and hyperoxic (100% O2 ) conditions. Automated segmentation of the lungs using 2D convolutional encoder-decoder based DL method, and the subsequent functional quantification via adaptive K-means were compared with the results obtained from the reference method, supervised region growing. STATISTICAL TESTS: Relative to the reference method, the performance of DL on volumetric quantification was assessed using Dice coefficient with 95% confidence interval (CI) for accuracy, two-sided Wilcoxon signed-rank test for computation time, and Bland-Altman analysis on the functional measure derived from the OE images. RESULTS: The DL method produced strong agreement with supervised region growing for the right (Dice: 0.97; 95% CI = [0.96, 0.97]; P < 0.001) and left lungs (Dice: 0.96; 95% CI = [0.96, 0.97]; P < 0.001). The DL method averaged 46 seconds to generate the automatic segmentations in contrast to 1.93 hours using the reference method (P < 0.001). Bland-Altman analysis showed nonsignificant intermethod differences of volumetric (P ≥ 0.12) and functional measurements (P ≥ 0.34) in the left and right lungs. DATA CONCLUSION: DL provides rapid, automated, and robust lung segmentation for quantification of regional lung function using UTE proton MRI. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1169-1181.

"Structure-Function Imaging of Lung Disease Using Ultrashort Echo Time MRI".

RATIONALE AND OBJECTIVES: The purpose of this review is to acquaint the reader with recent advances in ultrashort echo time (UTE) magnetic resonance imaging (MRI) of the lung and its implications for pulmonary MRI when used in conjunction with functional MRI technique. MATERIALS AND METHODS: We provide an overview of recent technical advances of UTE and explore the advantages of combined structure-function pulmonary imaging in the context of restrictive and obstructive pulmonary diseases such as idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF). RESULTS: UTE MRI clearly shows the lung parenchymal changes due to IPF and CF. The use of UTE MRI, in conjunction with established functional lung MRI in chronic lung diseases, will serve to mitigate the need for computed tomography in children. CONCLUSION: Current limitations of UTE MRI include long scan times, poor delineation of thin-walled structures (e.g. cysts and reticulation) due to limited spatial resolution, low signal to noise ratio, and imperfect motion compensation. Despite these limitations, UTE MRI can now be considered as an alternative to multidetector computed tomography for the longitudinal follow-up of the morphological changes from lung diseases in neonates, children, and young adults, particularly as a complement to the unique functional capabilities of MRI.

A Comparison of Two Hyperpolarized 129Xe MRI Ventilation Quantification Pipelines: The Effect of Signal to Noise Ratio.

RATIONALE: Hyperpolarized 129Xe MRI enables quantitative evaluation of regional ventilation. To this end, multiple classifiers have been proposed to determine ventilation defect percentage (VDP) as well as other cluster populations. However, consensus has not yet been reached regarding which of these methods to deploy for multicenter clinical trials. Here, we compare two published classification techniques-linear-binning and adaptive K-means-to establish their limits of agreement and their robustness against reduced signal-to-noise ratio (SNR). METHODS: A total of 29 subjects (age: 38.4 ± 19.0 years) were retrospectively identified for inter-method comparison. For each 129Xe ventilation image, 7 images with reduced SNR were generated with equal decrements relative to the native SNR. All 8 sets of images were then analyzed using both methods independently to classify all lung voxels into four clusters: VDP, low-, medium-, and high-ventilation-percentage (LVP, MVP and HVP). For each cluster, the percentage of the lung it comprised was compared between the two methods, as well as how these values persisted as SNR was degraded. RESULTS: The limits of agreement for calculating VDP were [+0.2%, +4.0%] with a +1.5% bias for binning relative to K-means. However, the inter-method agreement for the other clusters was moderate, with biases of -5.7%, 8.1%, and -4.0% for LVP, MVP, and HVP, respectively. As SNR decreased below ∼4, both methods began reporting values that deviated substantially from the native image. By requiring VDP to remain within ≤1.8% of that calculated from the native image, the minimum tolerable SNR values were 2.4 ± 1.0 for the linear-binning, and 3.5 ± 1.5 for the K-means. CONCLUSIONS: Both methods agree well in quantifying VDP, but agreement for LVP and MVP remains variable. We suggest a required SNR threshold be two standard deviations above the minimum value of 3.5 ± 1.5 for robust determination of VDP, suggesting a minimum SNR of 6.6. However, robust quantification of the ventilated clusters required an SNR of 13.4.

Three-dimensional Isotropic Functional Imaging of Cystic Fibrosis Using Oxygen-enhanced MRI: Comparison with Hyperpolarized 3He MRI.

Purpose To compare the performance of three-dimensional radial ultrashort echo time (UTE) oxygen-enhanced (OE) MRI with that of hyperpolarized helium 3 (3He) MRI with respect to quantitative ventilation measurements in patients with cystic fibrosis (CF). Materials and Methods In this prospective study conducted from June 2013 to May 2015, 25 participants with CF aged 10-55 years (14 male; age range, 13-55 years; 11 female; age range, 10-37 years) successfully underwent pulmonary function tests, hyperpolarized 3He MRI, and OE MRI. OE MRI used two sequential 3.5-minute normoxic and hyperoxic steady-state free-breathing UTE acquisitions. Seven participants underwent imaging at two separate examinations 1-2 weeks apart to assess repeatability. Regional ventilation was quantified as ventilation defect percentage (VDP) individually from OE MRI and hyperpolarized 3He MRI by using the same automated quantification tool. Bland-Altman analysis, intraclass correlation coefficient (ICC), Spearman correlation coefficient, and Wilcoxon signed-rank test were used to evaluate repeatability. Results In all 24 participants, the global VDP measurements from either OE MRI (ρ = -0.66, P < .001) or hyperpolarized 3He MRI (ρ = -0.75, P < .001) were significantly correlated with the percentage predicted forced expiratory volume in 1 second. VDP reported at OE MRI was 5.0% smaller than (P = .014) but highly correlated with (ρ = 0.78, P < .001) VDP reported at hyperpolarized 3He MRI. Both OE MRI-based VDP and hyperpolarized 3He MRI-based VDP demonstrated good repeatability (ICC = 0.91 and 0.95, respectively; P ≤ .001). Conclusion In lungs with cystic fibrosis, ultrashort echo time oxygen-enhanced MRI showed similar performance compared with hyperpolarized 3He MRI for quantitative measures of ventilation defects and their repeatability. © RSNA, 2018 Online supplemental material is available for this article.

Patient-Specific Computational Simulations of Hyperpolarized 3He MRI Ventilation Defects in Healthy and Asthmatic Subjects.

Combined, medical imaging data and respiratory computer simulations may facilitate novel insight into pulmonary disease phenotypes, including the structure/function relationships within the airways. This integration may ultimately enable improved classification and treatment of asthma. Severe asthma (15% of asthmatics) is particularly challenging to treat, as these patients do not respond well to inhaled therapeutics. METHODS: This study combines medical image data with patient-specific computational models to predict gas distributions and airway mechanics in healthy and asthmatic subjects. We achieve this by integrating segmental volume defect percent (SVDP), measured from hyperpolarized 3He MRI and CT images, to create models of patient-specific gas flow within the conducting airways. Predicted and measured SVDP distributions are achieved when the prescribed resistances are increased systematically. RESULTS: Because of differences in airway morphology and regional function, airway resistances and flow structures varied between the asthmatic subjects. Specifically, while mean SVDP was similar between the severe asthmatics (4.30±5.22 versus 3.54±5.98%), one subject exhibited abnormal flow structures, high near wall flow gradients, and enhanced conducting airway resistances (17.3E-3versus 1.1E-3 cmH2O-s/mL) in comparison to the other severe asthmatic subject. CONCLUSION: By coupling medical imaging data with computer simulations, we provide detailed insight into pathological flow characteristics and airway mechanics in asthmatics, beyond what could be inferred independently.

Pulmonary ventilation imaging in asthma and cystic fibrosis using oxygen-enhanced 3D radial ultrashort echo time MRI.

BACKGROUND: A previous study demonstrated the feasibility of using 3D radial ultrashort echo time (UTE) oxygen-enhanced MRI (UTE OE-MRI) for functional imaging of healthy human lungs. The repeatability of quantitative measures from UTE OE-MRI needs to be established prior to its application in clinical research. PURPOSE: To evaluate repeatability of obstructive patterns in asthma and cystic fibrosis (CF) with UTE OE-MRI with isotropic spatial resolution and full chest coverage. STUDY TYPE: Volunteer and patient repeatability. POPULATION: Eighteen human subjects (five asthma, six CF, and seven normal subjects). FIELD STRENGTH/SEQUENCE: Respiratory-gated free-breathing 3D radial UTE (80 µs) sequence at 1.5T. ASSESSMENT: Two 3D radial UTE volumes were acquired sequentially under normoxic and hyperoxic conditions. A subset of subjects underwent repeat acquisitions on either the same day or ≤15 days apart. Asthma and CF subjects also underwent spirometry. A workflow including deformable registration and retrospective lung density correction was used to compute 3D isotropic percent signal enhancement (PSE) maps. Median PSE (MPSE) and ventilation defect percent (VDP) of the lung were measured from the PSE map. STATISTICAL TESTS: The relations between MPSE, VDP, and spirometric measures were assessed using Spearman correlations. The test-retest repeatability was evaluated using Bland-Altman analysis and intraclass correlation coefficients (ICC). RESULTS: Ventilation measures in normal subjects (MPSE = 8.0%, VDP = 3.3%) were significantly different from those in asthma (MPSE = 6.0%, P = 0.042; VDP = 21.7%, P = 0.018) and CF group (MPSE = 4.5%, P = 0.0006; VDP = 27.2%, P = 0.002). MPSE correlated significantly with forced expiratory lung volume in 1 second percent predicted (ρ = 0.72, P = 0.017). The ICC of the test-retest VDP and MPSE were both ≥0.90. In all subject groups, an anterior/posterior gradient was observed with higher MPSE and lower VDP in the posterior compared to anterior regions (P ≤ 0.0021 for all comparisons). DATA CONCLUSION: 3D radial UTE OE-MRI supports quantitative differentiation of diseased vs. healthy lungs using either whole lung VDP or MPSE with excellent test-retest repeatability. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1287-1297.

Regional Heterogeneity of Lobar Ventilation in Asthma Using Hyperpolarized Helium-3 MRI.

RATIONALE AND OBJECTIVES: To determine lobar ventilation patterns in asthmatic lungs with hyperpolarized 3He magnetic resonance imaging (HP 3He MRI). MATERIALS AND METHODS: Eighty-two subjects (14 normal, 48 mild-to-moderate asthma, and 20 severe asthma) underwent HP 3He MRI, computed tomography (CT), and pulmonary function testing. After registering proton to 3He images, we segmented the lungs from proton MRI and further segmented the five lung lobes (right upper lobe [RUL], right middle lobe [RML], and right lower lobe [RLL]; left upper lobe and left lower lobe [LLL]) by referring to the lobar segmentation from CT. We classified the gas volume into four signal intensity levels as follows: ventilation defect percent (VDP), low ventilation percent, medium ventilation percent, and high ventilation percent. The local signal intensity variations in the ventilated volume were estimated using heterogeneity score (Hs). We compared each ventilation level and Hs measured in the whole lung and lobar regions across the three subject groups. RESULTS: In mild-to-moderate asthma, the RML and RUL showed significantly greater VDP than the two lower lobes (RLL and LLL) (P ≤ .047). In severe asthma, the pattern was more variable with the VDP in the RUL significantly greater than in the RLL (P = .026). In both asthma groups, the lower lobes (RLL and LLL) showed significantly higher high ventilation percent and Hs compared to the three upper lobes (all P ≤ .015). CONCLUSIONS: In asthma, the RML and RUL showed greater ventilation abnormalities, and the RLL and LLL were more highly ventilated with greater local heterogeneity. These findings may facilitate guided bronchoscopic sampling and localized airway treatment in future studies.

Semiautomated Ventilation Defect Quantification in Exercise-induced Bronchoconstriction Using Hyperpolarized Helium-3 Magnetic Resonance Imaging: A Repeatability Study.

RATIONALE AND OBJECTIVES: This study aimed to compare the performance of a semiautomated ventilation defect segmentation approach, adaptive K-means, with manual segmentation of hyperpolarized helium-3 magnetic resonance imaging in subjects with exercise-induced bronchoconstriction (EIB). MATERIALS AND METHODS: Six subjects with EIB underwent hyperpolarized helium-3 magnetic resonance imaging and spirometry tests at baseline, post exercise, and recovery over two separate visits. Ventilation defects were analyzed by two methods. First, two independent readers manually segmented ventilation defects. Second, defects were quantified by an adaptive K-means method that corrected for coil sensitivity, applied a vesselness filter to estimate pulmonary vasculature, and segmented defects adaptively based on the overall low-intensity signals in the lungs. These two methods were then compared in four aspects: (1) ventilation defect percent (VDP) measurements, (2) correlation between spirometric measures and measured VDP, (3) regional VDP variations pre- and post exercise challenge, and (4) Dice coefficient for spatial agreement. RESULTS: The adaptive K-means method was ~5 times faster, and the measured VDP bias was under 2%. The correlation between predicted forced expiratory volume in 1 second over forced vital capacity and VDP measured by adaptive K-means (ρ = -0.64, P <0.0001) and by the manual method (ρ = -0.63, P <0.0001) yielded almost identical 95% confidence intervals. Neither method of measuring VDP indicated apical/basal or anterior dependence in this small study cohort. CONCLUSIONS: Compared to the manual method, the adaptive K-means method provided faster, reproducible, comparable measures of VDP in EIB and may be applied to a variety of lung diseases.

Nox2 and Cyclosporine-Induced Renal Hypoxia.

BACKGROUND: We hypothesized that nicotinamide adenosine diphosphate oxidase 2 (Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia. METHODS: We tested this hypothesis in Fisher 344 rats, C57BL/6 J wild type and Nox2-/- mice, and in liver transplant recipients with chronic CsA nephrotoxicity. We used noninvasive molecular imaging (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging) and molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and the molecular phenotype of CsA nephrotoxicity. RESULTS: We observed that chemical and genetic inhibition of Nox2 in rats and mice resulted in the prevention of CsA-induced hypoxia independent of regional perfusion (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging, pimonidazole, HIF-1α). Nicotinamide adenosine diphosphate oxidase 2 knockout was also associated with decreased oxidative stress (Nox2, HIF-1α, hydrogen peroxide, hydroxynonenal), and fibrogenesis (α-smooth muscle actin, picrosirius red, trichrome, vimentin). The molecular signature of chronic CsA nephrotoxicity using transcriptomic analyses demonstrated significant changes in 40 genes involved in injury repair, metabolism, and oxidative stress in Nox2-/- mice. Immunohistochemical analyses of kidney biopsies from liver transplant recipients with chronic CsA nephrotoxicity showed significantly greater Nox2, α-smooth muscle actin and picrosirius levels compared with controls. CONCLUSIONS: These studies suggest that Nox2 is a modulator of CsA-induced hypoxia upstream of HIF-1α and define the molecular characteristics that could be used for the diagnosis and monitoring of chronic calcineurin inhibitor nephrotoxicity.