Shear wave elastography for liver fibrosis in chronic hepatitis B: Adapting the cut-offs to alanine aminotransferase levels improves accuracy.

OBJECTIVES: To determine and validate alanine aminotransferase (ALT)-adapted dual cut-offs of liver stiffness measurements (LSMs) for assessing liver fibrosis with two-dimensional shear wave elastography (2D-SWE) in patients with chronic hepatitis B (CHB) infection. METHODS: Patients with CHB infection who underwent liver biopsy to assess liver fibrosis were consecutively included. 2D-SWE confirmation thresholds with a positive likelihood ratio ≥10 and 2D-SWE exclusion thresholds with a negative likelihood ratio ≤0.1 were identified to rule in or rule out significant fibrosis and cirrhosis, respectively. RESULTS: The first 515 patients (index cohort) and the next 421 patients (validation cohort) were included in the final analysis. The low and high cut-offs to rule out and rule in patients with significant fibrosis (≥ F2) were 5.4 kPa and 9.0 kPa, respectively, in patients with ALT levels ≤ 2 × the upper limit of normal (ULN) and 7.1 kPa and 11.2 kPa in patients with ALT levels > 2 × ULN. For cirrhosis (F4), the corresponding values were 8.1 kPa and 12.3 kPa in patients with ALT levels ≤ 2 × ULN and 11.9 kPa and 24.7 kPa in patients with ALT levels > 2 × ULN. The dual cut-off values showed an overall accuracy of more than 90% for diagnosis of the presence or absence of significant fibrosis and cirrhosis in the index and validation cohorts. There were no significant differences in the accuracy values between the cohorts (all p>0.05). CONCLUSION: The ALT-adapted dual cut-offs of LSMs showed high accuracy for diagnosis of the presence or absence of significant fibrosis and cirrhosis in patients with CHB infection. KEY POINTS: • The ALT-adapted dual cut-off values of LSMs showed high accuracy for diagnosis of the presence or absence of significant fibrosis and cirrhosis. • ALT levels did not influence the overall diagnostic accuracy for predicting significant fibrosis and cirrhosis. • The ALT-adapted dual cut-offs in patients with ALT levels > 2 × ULN were markedly higher than those in patients with ALT levels ≤ 2 × ULN.

Supercontinuum generation in an Er-doped figure-eight passively mode-locked fiber laser.

A supercontinuum source based on a figure-eight Er-doped fiber ring cavity has been experimentally demonstrated with low repetition rate. The proposed configuration of the experiment is a figure-eight fiber laser grounded in Nonlinear Optical Loop Mirror (NOLM) technique. A broad spectrum of approximately 410 nm spanning the range 1315-1725 nm at the level of 30 dB can be obtained at a given average power of 2.6 mW and without any amplifier. Such wide spectrum can be directly achieved in the fiber resonator, which makes the structure compact and robust. By changing the pump power, the temporal pulse width can be adjusted accordingly. The pulse width is about 4 ns at the pump power of around 240 mW. The broadband spectrum was generated directly from the fiber resonator, which can be easily applied in numerous areas, such as the optical frequency metrology, optical spectroscopy, optical coherence tomography, optical communications, and medical sciences.

Tumor-penetrating Peptide-integrated Thermally Sensitive Liposomal Doxorubicin Enhances Efficacy of Radiofrequency Ablation in Liver Tumors.

Purpose To investigate the role of a tumor-penetrating peptide (internalizing CRGDRGPDC [iRGD])-integrated thermally sensitive liposomal (TSL) doxorubicin (DOX) in combination with radiofrequency (RF) ablation of liver tumors in an animal model. Materials and Methods Approval from the institutional animal care and use committee was obtained. Characterization of iRGD-TSL-DOX was performed in vitro. Next, H22 liver adenocarcinomas were implanted in 138 mice in vivo. The DOX accumulation and cell apoptosis of iRGD-TSL-DOX and TSL-DOX with or without RF were evaluated (n = 5) at different time points after treatment with quantitative analysis or pathologic staining. Mice bearing tumors were randomized into the following six groups (each group, eight mice): no treatment, iRGD-TSL-DOX, TSL-DOX, RF alone, RF ablation followed by TSL-DOX at 30 minutes (TSL-DOX combined with RF), and RF ablation followed by iRGD-TSL-DOX (iRGD-TSL-DOX combined with RF). Kaplan-Meier method was used to estimate the survival curves and log-rank test was used for comparison with statistical software. Results DOX encapsulation efficiency in iRGD-TSL-DOX was 97.5% ± 1.3 (standard deviation) with temperature-dependent drug release capability confirmed in vitro. In vivo, the iRGD-TSL-DOX group had overall higher DOX concentration in the tumor and had maximal difference at 24 hours compared with TSL-DOX group (2.7-fold). RF caused more intense cell apoptosis at 24 hours (median, 65% vs 21%, respectively; P < .001). For end-point survival, the iRGD-TSL-DOX combined with RF group had better survival (median, 32 days) than TSL-DOX combined with RF (median, 27 days; P = .035) or RF alone (median, 21 days; P < .001). Conclusion Conjugation to iRGD helped to improve intratumoral DOX accumulation and further enhanced the activity of TSL-DOX in RF ablation of liver tumors. © RSNA, 2017 Online supplemental material is available for this article.

Ultrasound Strain Elastography for Breast Lesions: Computer-Aided Evaluation With Quantifiable Elastographic Features.

OBJECTIVES: To develop and evaluate a set of quantifiable elastographic features based on ultrasound real-time strain elastography (SE) in differentiating between benign and malignant breast lesions. METHODS: The SE and conventional B-mode ultrasound images of 226 breast lesions (81 malignant, 145 benign) were obtained from 226 consecutive women. By using a computer-aided tool, four elastographic features (elasticity score, lesion stiffness degree, lesion-to-fat strain ratio, and elastography-to-B-mode lesion area ratio) were respectively calculated and evaluated. Histopathologic results were used as the reference standard. B-mode Breast Imaging Reporting and Data System categorization was used to compare the performances between B-mode ultrasound and SE. Sensitivity, specificity, positive and negative predictive values, and receiver operating characteristic curve analyses were performed to evaluate the diagnostic performances for three data sets (conventional B-mode ultrasound alone, SE features alone, combined SE features). RESULTS: Quantifiable SE features for malignant lesions all showed significantly higher values than those for benign lesions (all P < .001). The evaluation with any individual SE feature significantly improved the specificity in breast lesion differentiation compared with B-mode ultrasound (all P <.001). The logistic regression model combing SE features significantly improved the diagnostic performance compared with B-mode US, with significantly increased specificity (95.2% versus 54.5%; P < .001) and area under the receiver operating characteristic curve (0.988 versus 0.921, P < .001). CONCLUSIONS: Computer-aided tool with SE provided further elasticity information for breast characterization. Evaluation using quantifiable SE features showed better diagnostic performance than conventional B-mode ultrasound in breast lesion differentiation.

The relationship between HbA1c and ultrasound plaque textures in atherosclerotic patients.

OBJECTIVE: Diabetes mellitus (DM) is associated to the morphological and componential characteristics of atheromatous plaques. It has proven that plaque textures are related to plaque components and beneficial for atherosclerotic risk stratification. The aim of this study is to compare plaque textures in patients with and without DM, and examine the relationship between HbA1c levels and the ultrasound plaque textures in atherosclerotic patients. METHODS: A total of 136 participants (among them 66 are diabetic and 70 are non-diabetic) suffering from carotid plaques were included. About 300 texture features were extracted from the ultrasound images of plaques using the algorithms of histogram, absolute gradient, run-length matrix, gray-level co-occurrence matrix, autoregressive model and wavelet transform, respectively. Thirty optimal features were selected by the Fisher coefficient and the mutual information measure. The most discriminating feature (MDF) was obtained from the linear discriminant analysis for the optimal features. Linear regression model was performed to investigate the relationship between HbA1c and MDF. The receiver operating characteristics (ROC) curve was further developed to validate the relation between the estimated HbA1c (models output) and diabetes status. RESULTS: A total of 12 texture features showed statistical difference between patients with and without DM. The MDF was significant higher in non-diabetic patients (0.326 ± 0.049) than diabetic patients (-0.346 ± 0.052) (p < 0.001). The optimal regression model (r = 0.348, p < 0.001) for HbA1c included a constant (p < 0.001) and the MDF (p < 0.001). The areas under ROC curve used to estimate HbA1c was 0.828. CONCLUSIONS: The results indicate that there is a quantitative relationship between the HbA1c levels and plaque textures in ultrasonic images of atherosclerotic patients, which may suggest that texture analysis of the ultrasonic image of plaque is a promising method for evaluating the cardiovascular risk caused by DM in patients with plaques.

Design strategies of fluorescent probes for selective detection among biothiols.

Simple thiol derivatives, such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH), play key roles in biological processes, and the fluorescent probes to detect such thiols in vivo selectively with high sensitivity and fast response times are critical for understanding their numerous functions. However, the similar structures and reactivities of these thiols pose considerable challenges to the development of such probes. This review focuses on various strategies for the design of fluorescent probes for the selective detection of biothiols. We classify the fluorescent probes for discrimination among biothiols according to reaction types between the probes and thiols such as cyclization with aldehydes, conjugate addition-cyclization with acrylates, native chemical ligation, and aromatic substitution-rearrangement.

Fluorescent sensors for selective detection of thiols: expanding the intramolecular displacement based mechanism to new chromophores.

Biological thiols, including cysteine (Cys), homocystein (Hcy) and glutathione (GSH), play crucial roles in maintaining the appropriate redox status of biological systems. An abnormal level of biothiols is associated with different diseases, therefore, the discrimination between them is of great importance. Herein, we present two fluorescent sensors for selective detection of biothiols based on our recently reported intramolecular displacement mechanism. We expanded this mechanism to commercially available chromophores, 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) and heptamethine cyanine dye IR-780. The sensors operate by undergoing displacement of chloride by thiolate. The amino groups of Cys/Hcy further replace the thiolate to form amino-substituted products, which exhibit dramatically different photophysical properties compared to sulfur-substituted products from the reaction with GSH. NBD-Cl is highly selective towards Cys/Hcy and exhibits significant fluorescence enhancement. IR-780 showed a variation in its fluorescence ratio towards Cys over other thiols. Both of the sensors can be used for live-cell imaging of Cys. The wide applicability of the mechanism may provide a powerful tool for developing novel fluorescent sensors for selective detection of biothiols.

Real-time 3-dimensional contrast-enhanced ultrasound in detecting hemorrhage of blunt renal trauma.

OBJECTIVES: The objective of this study is to evaluate the diagnostic value of real-time 3-dimensional contrast-enhanced ultrasound in the hemorrhage of blunt renal trauma. METHODS: Eighteen healthy New Zealand white rabbits were randomly divided into 3 groups. Blunt renal trauma was performed on each group by using minitype striker. Ultrasonography, color Doppler flow imaging, and contrast-enhanced 2-dimensional and real-time 3-dimensional ultrasound were applied before and after the strike. The time to shock and blood pressure were subjected to statistical analysis. Then, a comparative study of ultrasound and pathology was carried out. RESULTS: All the struck kidneys were traumatic. In the ultrasonography, free fluid was found under the renal capsule. In the color Doppler flow imaging, active hemorrhage was not identified. In 2-dimensional contrast-enhanced ultrasound, active hemorrhage of the damaged kidney was characterized. Real-time 3-dimensional contrast-enhanced ultrasound showed a real-time and stereoscopic ongoing bleeding of the injured kidney. The wider the hemorrhage area in 4-dimensional contrast-enhanced ultrasound was, the faster the blood pressure decreased. CONCLUSIONS: Real-time 3-dimensional contrast-enhanced ultrasound is a promising noninvasive tool for stereoscopically and vividly detecting ongoing hemorrhage of blunt renal trauma in real time.

Mechanism of low-frequency, low-intensity ultrasound modulation of the mouse retina.

Objective.Ultrasound has been shown to modulate the activity of retinal ganglion cells (RGCs) in mice, but the mechanism remains poorly understood. This study aims to address this question.Approach.Multi-electrode recordings together with pharmacological methods were used to investigate the possible cellular/circuitry mechanism(s) underlying the neuronal modulation induced by low-frequency (1 MHz), low-intensity (ISPTA0.5 W cm-2) ultrasound stimulation.Main results.We found that ultrasound activated mechanosensitive channels (transient receptor potential vanilloid 4 (TRPV4) channels are involved) in Müller cells, causing the release of glutamate, which acts on the extrasynapticN-methyl-D-aspartate receptors of RGCs, thus leading to the modulation of neuronal activity.Significance.Our results reveal a novel mechanism of low-frequency, low-intensity ultrasound modulation, involving TRPV4 as a mechanosensitive target for ultrasound and glutamate as an essential mediator of neuron-glia communication. These findings also demonstrate that the mechanical-force-mediated pathway is important for retinal signal modulation during visual processes, such as visual accommodation.

Serratene triterpenoids from Lycopodium cernuum L. as α-glucosidase inhibitors: Identification, structure-activity relationship and molecular docking studies.

Phytochemical investigation of Lycopodium cernuum L. afforded seven undescribed serratene triterpenoids named 3ß, 21ß-dihydroxyserra-14-en-24-oic acid-3ß-(5'-hydroxybenzoate) (1), 3ß, 21ß, 24-trihydroxyserrat-14-en-3ß-(5'-hydroxyl benzoate) (2), 3ß, 14α, 15α, 21ß-tetrahydroxyserratane-24-methyl ester (3), 3ß, 14α, 21ß-trihydroxyserratane-15α-(4'-methoxy-5'-hydroxybenzoate)-24-methyl ester (4), 3ß, 14α, 21ß-trihydroxyserratane-15α-(4'-methoxy-5'-hydroxybenzoate) (5), 3ß-hydroxy-21ß-acetate-16-oxoserrat-14-en-24-oic acid (6), 3ß, 21ß-dihydroxy-16α, 29-epoxyserrat-14-en-24-methyl ester (7), together with eleven known compounds (8-18), whose chemical structures were elucidated through spectroscopic analysis of HRESIMS, 1D NMR, 2D NMR and comparison between the literature. All compounds were evaluated for their α-glucosidase inhibitory activity for the first time. The results showed that compounds 1, 2, 4, 5, 6, 10, 13, 15, and 16 were among the most potent α-glucosidase inhibitors, with IC50 values ranging from 23.22 ± 0.64 to 50.65 ± 0.82 µM. Structure-activity relationship (SAR) studies indicated that the combined properties of the 5-hydroxybenzoate moiety at C-3, ß-OH at C-21, COOH- at C-24, and Δ14,15 groups enabled an increase in the α-glucosidase inhibitory effect. In addition, molecular docking studies showed that the potential inhibitors mainly interact with key amino acid residues in the active site of α-glucosidase through hydrogen bonds and hydrophobic forces.

Low-frequency, low-intensity ultrasound modulates light responsiveness of mouse retinal ganglion cells.

Objective. Ultrasound modulates the firing activity of retinal ganglion cells (RGCs), but the effects of lower-frequency, lower-intensity ultrasound on RGCs and underlying mechanism(s) remain poorly understood. This study aims to address these questions.Approach. Multi-electrode recordings were used in this study to record the firing sequences of RGCs in isolated mouse retinas. RGCs' background firing activities as well as their light responses were recorded with or without ultrasound stimulation. Cross-correlation analyses were performed to investigate the possible cellular/circuitry mechanism(s) underlying ultrasound modulation.Main results. It was found that ultrasound stimulation of isolated mouse retina enhanced the background activity of ON-RGCs and OFF-RGCs. In addition, background ultrasound stimulation shortened the light response latency of both ON-RGCs and OFF-RGCs, while enhancing part of the RGCs' (both ON- and OFF-subtypes) light response and decreasing that of the others. In some ON-OFF RGCs, the ON- and OFF-responses of an individual cell were oppositely modulated by the ultrasound stimulation, which suggests that ultrasound stimulation does not necessarily exert its effect directly on RGCs, but rather via its influence on other type(s) of cells. By analyzing the cross-correlation between the firing sequences of RGC pairs, it was found that concerted activity occurred during ultrasound stimulation differed from that occurred during light stimulation, in both spatial and temporal aspects. These results suggest that the cellular circuits involved in ultrasound- and light-induced concerted activities are different and glial cells may be involved in the circuit in response to ultrasound.Significance. These findings demonstrate that ultrasound affects neuronal background activity and light responsiveness, which are critical for visual information processing. These results may also imply a hitherto unrecognized role of glial cell activation in the bidirectional modulation effects of RGCs and may be critical for the nervous system.

[Spectroscopic study on the energy transfer effect in Sm3+/Eu3+ codoped tetragonal LaOF nanocrystals system].

The powder samples of Sm3+/Eu3+ co-doped in LaOF nanocrystals were synthesized by using a hydrothermal-sintering technique. The characterization results of XRD and TE M suggests that t he structure of the nanocrystals is tetragonal,and its size is between 60-80 nm. Using 442 nm laser to pump the LaOF: Sm3+/Eu3+ nanocrystals samples, the energy transfer effect from Sm3+ ions to Eu3+ ions was completed, and the fluorescence emissions originating from the 5D0 level of Eu3+ were observed. The luminescence properties of the LaOF: Sm3+/Eu3+ nanocrystals system were analyzed with a spectroscopic method, and the mechanism and dynamic process of the energy transfer were explored. It was found that the efficiency of the energy transfer increase with the increase in the concentration of Eu3+ ions and the size of nanocrystals.

An Acoustic Meta-Skin Insulator.

Acoustic metamaterials with artificial microstructures are attractive to realize intriguing functions, including efficient waveguiding, which requires large impedance mismatches to realize total side reflection with negligible transmission and absorption. While large impedance mismatch can be readily realized in an air environment, acoustic waveguiding in an underwater environment remains elusive due to insufficient impedance mismatch of state-of-the-art metamaterials. Here, a superhydrophobic acoustic metasurface of microstructured poly(vinylidene fluoride) membrane, referred to as a "meta-skin" insulator, which is able to confine acoustic waves in an all-angle and wide spectrum range due to tremendous impedance mismatch at stable air/water interfaces, viz., the Cassie-Baxter state is demonstrated. By utilizing the meta-skin insulator with broadband and high throughput, orbital-angular-momentum multiplexing at a high spectral efficiency and binary coding along large-angle bending channels for bit-error-free acoustic data transmission in an underwater environment are demonstrated. Very different from optical and/or electrical cable communications, acoustic waves can be simply and effectively coupled into remote meta-skin acoustic fibers from free space, which is technologically significant for long-haul and anti-interference communication. This work can enlighten many fluidic applications based on efficient waveguiding, such as in vivo ultrasound medical treatment and imaging.

[Spectroscopic study on the interaction of glass matrixes and nanoparticles in Tm3+ doped oxyfluoride glass ceramics].

Fluorescence emission spectra from Tm3+ in crystal phase and glass phase were separated under selective excitation of 1D2 level in Tm3+ doped transparent oxyfluoride glass ceramics containing LaF3 nanocrystals. Emissions from the crystal phase and from the glass phase were detected. The influence of the interaction between glass matrix and nanocrystals on the optical characteristics of Tm3+ ions in the two different local environments was investigated. The results indicate that the increase in nanocrystal size results in a decrease in the impact of oxides glass on Tm3+ in the crystal phase, and an enhancement of the impact of nanocrystals on Tm3+ in the glass phase. For smaller nanoparticles, the emission efficiency of Tm3+ ions in the crystal phase was reduced, and the influence of nanocrystals on the ions in the glass phase was reduced too. The larger the nanocrystal size, the weaker the influence of oxide glass on the Tm3+ ions in the crystal phase, and the better performance of fluorescence emission. It was also found that the content of SiO2 in glass matrix could affect the emission efficiency of Tm3+ in both environments.

Polysubstituted Isoflavonoids from Spatholobus suberectus, Flemingia macrophylla, and Cudrania cochinchinensis.

Four hitherto unknown polysubstituted isoflavonoids, including three isoflavans: 7,4'-dihydroxy-8,2',3'-trimethoxyisoflavan (1), 7,2',4'-trihydroxy-8,3'-dimethoxyisoflavan (2), and 7,2',4'-trihydroxy-5-methoxyisoflavan (3), and one prenylated isoflavone cudraisoflavone M (4) were isolated from the ethanol extracts of Spatholobus suberectus (for 1 and 2), Flemingia macrophylla (for 3), and Cudrania cochinchinensis (for 4), respectively. Their structures were established on the basis of extensive spectroscopic analysis. Compounds 1 and 4 exhibited weak cytotoxic activity against five human cancer cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW-480).

Improved Anatomical Specificity of Non-invasive Neuro-stimulation by High Frequency (5 MHz) Ultrasound.

Low frequency ultrasound (<1 MHz) has been demonstrated to be a promising approach for non-invasive neuro-stimulation. However, the focal width is limited to be half centimeter scale. Minimizing the stimulation region with higher frequency ultrasound will provide a great opportunity to expand its application. This study first time examines the feasibility of using high frequency (5 MHz) ultrasound to achieve neuro-stimulation in brain, and verifies the anatomical specificity of neuro-stimulation in vivo. 1 MHz and 5 MHz ultrasound stimulation were evaluated in the same group of mice. Electromyography (EMG) collected from tail muscles together with the motion response videos were analyzed for evaluating the stimulation effects. Our results indicate that 5 MHz ultrasound can successfully achieve neuro-stimulation. The equivalent diameter (ED) of the stimulation region with 5 MHz ultrasound (0.29 ± 0.08 mm) is significantly smaller than that with 1 MHz (0.83 ± 0.11 mm). The response latency of 5 MHz ultrasound (45 ± 31 ms) is also shorter than that of 1 MHz ultrasound (208 ± 111 ms). Consequently, high frequency (5 MHz) ultrasound can successfully activate the brain circuits in mice. It provides a smaller stimulation region, which offers improved anatomical specificity for neuro-stimulation in a non-invasive manner.

Influence of measurement depth on the stiffness assessment of healthy liver with real-time shear wave elastography.

The purpose of this study was to determine the measurement depth range within which liver stiffness can be reliably assessed using real-time shear wave elastography (SWE) technology. Measurements were performed on phantoms and healthy volunteers. In the first group of patients, measurements were performed at depths of 2-8 cm from the probe surface. In the second group of patients, measurements were conducted 0-7 cm below the liver capsule. Success rate of measurements (SRoM), success rate of patients (SRoS) and coefficients of variation (CVs) of repeated measurements were compared. The SRoMs at 3-7 cm and the CVs at 2-5 cm from the probe surface were significantly higher and lower than those at other depths (p < 0.001), respectively. SRoS was zero 0-1 cm below the liver capsule. Furthermore, the features of 2-D stiffness mapping images were also found to change with depth. According to our results, the depth range for the most reliable liver stiffness assessment using SWE should be 3-5 cm from the probe surface and simultaneously 1-2 cm below the liver capsule.