Citations

Objectives The ability to determine the severity of renal fibrosis, which is involved in most chronic kidney diseases, may be beneficial for monitoring disease progression and management. The aim of this study was to assess a new method involving gold nanoparticles conjugated to an anti-collagen-I antibody (Co-I-AuNPs) as a computed tomography (CT) imaging contrast for the evaluation of renal fibrosis in situ. Materials and Methods Gold nanoparticles conjugated to an anti-collagen-I antibody were prepared using gold chloride reduction with sodium citrate and coated with polyethylene glycol (PEG), and their size was determined by electron microscopy and nanoparticle tracking analysis. Anti-collagen-I antibody was then conjugated to PEG-SH/COOH on the AuNP surface. The success of antibody conjugation was tested in vitro using collagen-coated plate and mouse stenotic kidney sections and in vivo using micro-CT and multidetector CT imaging. Results Bare AuNPs were 18.7 ± 0.6 nm and PEG-coated AuNPs were 45.3 ± 0.1 nm in size. In vitro, Co-I-AuNPs specifically bound to both a collagen-coated plate and mouse fibrotic kidneys. Furthermore, the stenotic mouse kidney showed increased Co-I-AuNPs retention compared with the contralateral kidney (59.3 ± 5.1 vs 45.1 ± 1.7 HU, P = 0.05), which correlated with its collagen deposition. Micro-CT also detected gold signals in situ in the Co-I-AuNP-injected kidney, which colocalized with histological trichrome staining. Conclusion Gold nanoparticles conjugated to an anti-collagen-I antibody are able to visualize kidney fibrosis in vitro and in situ and may be useful for nondestructive quantification of tissue fibrosis.

AbstractThree‐dimensional structural scaffolds have played an important role in tissue engineering, especially broad applications in areas such as regenerative medicine. We have developed novel biodegradable porous poly(propylene fumarate)‐co‐poly(lactic‐co‐glycolic acid) (PPF‐co‐PLGA) scaffolds using thermally induced phase separation, and determined the effects of critical parameters such as copolymer concentration (6, 8, and 10 wt %) and the binary solvent ratio of dioxane:water (78/22, 80/20, 82/18 wt/wt %) on the fabrication process. The cloud‐point temperatures of PPF‐co‐PLGA changed in parallel with increasing copolymer concentration, but inversely with increasing dioxane content. The compressive moduli of the scaffolds increased with greater weight composition and dioxane:water ratio. Scaffolds formed using high copolymer concentrations and solvent ratios exhibited preferable biomineralization. All samples showed biodegradation capability in both accelerated solution and phosphate‐buffered saline (PBS). Cell toxicity testing indicated that the scaffolds had good biocompatibility with bone and nerve cells, which adhered well to the scaffolds. Variations in the copolymer concentration and solvent ratio exercised a remarkable influence on morphology, mechanical properties, biomineralization, and biodegradation, but not on the cell viability and adhesion of the cross‐linked scaffolds. An 8 to 10 wt % solute concentration and 80/20 to 82/18 wt/wt dioxane:water ratio were the optimum parameters for scaffold fabrication. PPF‐co‐PLGA scaffolds thus possess several promising prospects for tissue engineering applications. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2507–2517, 2018.

Key PointsINCB040093 was active across lymphoma subtypes, and the addition of itacitinib provided substantial activity in classic Hodgkin lymphoma. INCB040093 ± itacitinib had a manageable safety and tolerability profile; severe hepatic adverse effects were less common with the combination.

Interstitial lung disease manifested as fibrotic and stiffened lung tissue, resulting in symptoms such as dyspnea and may lead to respiratory failure. We recently developed a lung ultrasound surface wave elastography for evaluating the elastic properties of superficial lung tissue. In this abstract, we present a finite element analysis to investigate the effects of pleural effusion on the shear wave propagation of superficial lung tissue. The muscle, pleural effusion, and lung tissue were simulated by a 2D planar model of an infinite elastic medium with densities for different materials. A nearly incompressible, linear elastic model was used to model muscle, pleural effusion and lung. The model was excited using a line source on the muscle surface. Harmonic excitations were performed at 100, 150 and 200 Hz with duration of 0.1 s. The boundaries of lung and muscle were attached to an infinite. The mesh of muscle, pleural effusion, and lung were constructed using linear quadrilateral elements. The infinite region was meshed by infinite elements (type CINPE4). The dynamic responses of the tissue model to the excitations were solved by the ABAQUS explicit dynamic solver with automatic step size control. Insignificant difference in shear wave speeds of lung tissue at different excitation frequencies was found in both simulations with and without taking into account the pleural effusion, indicating that pleural effusion does not affect the measurements of shear wave speeds in ultrasound elastography.

Lung ultrasound surface wave elastography (LUSWE) was developed as a non-invasive tool for assessing pulmonary fibrosis. In this research, the effect of the fleural fluid on surface wave speed measurement of the lung is studied. Low-cost sponges [J. Ultrasound Med. 2017; 36, 2133], as good lung phantoms, were used in this study. The ultrasound transmission gel was used to simulate the pleural fluid. A harmonic vibration was generated at sponge surfaces using a shaker at 100, 150, and 200 Hz. The sponge surface wave speeds were measured with a 6 MHz ultrasound probe for both with and without a thin layer gel. The ultrasound features of A and B-lines were clearly observed in every sponge model in our experiment. The surface wave speeds for the sponges with the gel were indistinguishable from those without the gel for each frequency. The surface wave speeds were faster at higher excitation frequencies which is consistent with our patient study results. It was conclude that the pleural fluid may not affect the lung surface wave speed measurement based upon our lung phantom sponge models.

Color flow imaging is an ultrasound imaging technique widely used to image the blood movement through arteries and veins. Quantification of velocity is urgently demanding. The objective of this study is to use ultrafast plane wave imaging to measure the flow in speed in vitro. For the flow phantom, the diagonal vessel (2-mm inner diameter at 40° angle) was studied with injection of blood mimic fluid via syringe pump at various volume rates (15, 20, 25, and 30 ml/min). Verasonics Vantage system (Verasonics Inc., Kirkland, WA, USA) and a linear array transducer L11-4v (Verasonics Inc., Kirkland, WA, USA) were used for ultrasound acquisition, a 8-angle (−7° to 7°) plane wave compounding with effective pulse-repetition frequency (PRF) of 1000 Hz was used (central frequency = 6.42 MHz, number of transmit cycles = 4). A total of 600 ensembles were acquired. The frame rate was 1000/s.[XZ1] [BZ2] The ultrasound in-phase quadrature data size was 195 × 156 × 600 (axial x lateral x temporal) with data type of complex double. Singular value decomposition (SVD)-based ultrasound blood flow clutter filters was used for ultrafast plane wave imaging.[XZ3] [BZ4] Randomized SVD was utilized to filter noise and tissue motion. Power Doppler image was generated. The color flow images were generated by using the 2-D autocorrelation method. Results showed that color flow measurement can quantitatively evaluate the flow speed in the tube of the flow phantom.

A lung ultrasound surface wave elastography (LUSWE) technique is developed for assessing interstitial lung disease (ILD). In LUSWE, a 0.1 second harmonic vibration is generated on the chest wall of a subject using a handheld vibrator. An ultrasound probe is aligned with the vibration indenter in the same intercostal region to measure the generated surface wave speed of the lung. A human subject is examined in a sitting position. The lung is tested at the total lung volume. The upper anterior lungs are tested through the second intercostal space in the mid-clavicular line. The lower lateral lungs are tested in the mid-axillary line and the lower posterior lungs are tested in the mid-scapular line. In a prospective clinical study, we measure both lungs through the six intercostal regions for patients and healthy controls. The surface wave speed is measured at 100 Hz, 150 Hz, and 200 Hz. Significant differences of wave speed between patients and controls were found in all lung regions at all frequencies. We also found positive correlation between LUSWE and CT analyses. LUSWE is a safe and noninvasive technique for generating and measuring surface wave propagation on the lung. LUSWE may be useful for assessing ILD.

Lung density is directly associated with lung pathology. Computed Tomography (CT) evaluates lung pathology using the Hounsfield unit (HU) but not directly the lung density. We recently developed a lung ultrasound surface wave elastography (LUSWE) technique for measuring the surface wave speed of superficial lung tissue. The objective of this study is to analyze lung density of superficial lung tissue using deep neural network (DNN) and wave speed measurements obtained from LUSWE. The synthetic training dataset (7,88,000 in total) in terms of wave speeds of superficial lung tissue at different excitation frequencies from LUSWE, viscoelasticity and density of lung tissue was used to train the DNN. DNN is composed of 3 hidden layers of 1024 neurons and trained for 10 epochs with a batch size of 4096 and a learning rate of 0.001 with Adam optimizer. Test dataset in terms of wave speeds at different excitation frequencies (100, 150, and 200 Hz) as well as elasticity was used to predict the lung density and evaluate its accuracy. The obtained results showed that predictions matched well with test dataset (validation accuracy is 0.997). This method may be useful to analyze lung density based on the LUSWE measurements.

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.