Functional Characterization of YM928, a Novel Noncompetitive ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist

ABSTRACT The ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is thought to play an important role in the pathogenesis of several neurological disorders as well as normal brain function. The search for AMPA receptor antagonists as potential therapeutics is ongoing. Here, we describe the functional characterization of a novel noncompetitive AMPA receptor antagonist, 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (YM928). This compound inhibited AMPA receptor-mediated toxicity in primary rat hippocampal cultures with an IC 50 of 2 M. Its manner of inhibition was noncompetitive as the agonist concentration was increased. YM928 blocked AMPA-induced intracellular calcium influx with an IC 50 of 3 M and antagonized AMPA-induced inward currents with an IC 50 of 1 M in cultured cells. YM928 displaced neither [ 3 H]AMPA binding nor other existing glutamate receptor-related ligand binding in rat brain membranes. In terms of in vivo activity, YM928 had an anticonvulsant effect in sound-induced seizures in DBA/2 mice 45 min after oral administration at 3 mg/kg. Thus, YM928 has potential as an oral therapeutic drug for various types of neurological disorders

Efficacy of shear wave elastography for evaluating right ventricular myocardial fibrosis in monocrotaline-induced pulmonary hypertension rats

Background: Right ventricular (RV) function is important for outcomes in pulmonary hypertension. Evaluation of RV myocardial characteristics is useful to assess the disease severity. Shear wave elastography (SWE) provides information of shear wave (SW) elasticity, which is related to tissue hardness, and SW dispersion slope, which reflects tissue viscosity. This study aimed to test the hypothesis that SW elasticity is increased and SW dispersion slope is decreased in the right ventricle of monocrotaline (MCT)-induced pulmonary hypertension rats. Methods: Rats were divided into MCT-induced pulmonary hypertension group (n = 10) and control group (n = 10). SW elasticity and SW dispersion slope were measured on excised hearts. Myocardial fibrosis was evaluated histologically. Results: RV hypertrophy was observed in the MCT group. SW elasticity of right ventricle was higher in the MCT group than in the control group (3.5 ± 0.9 kPa vs. 2.5 ± 0.4 kPa, p Conclusions: Higher SW elasticity and lower SW dispersion slope were observed in the fibrotic myocardium of right ventricle in MCT-induced pulmonary hypertension rats. SWE may have the potential to evaluate RV function by assessing myocardial characteristics

Probable Noonan syndrome in a boy without PTPN11 mutation, manifesting unusual complications.

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Efficacy of shear wave elasticity for evaluating myocardial hypertrophy in hypertensive rats

Shear wave (SW) imaging is a novel ultrasound-based technique for assessing tissue characteristics. SW elasticity may be useful to assess the severity of hypertensive left ventricular (LV) hypertrophy. This study aimed to evaluate the efficacy of SW elasticity for assessing the degree of myocardial hypertrophy using hypertensive rats. Rats were divided into hypertension group and control group. SW elasticity was measured on the excised heart. Myocardial hypertrophy was assessed histologically. LV weight was greater in hypertension group. An increase in interventricular septum and LV free wall thicknesses was observed in hypertension group. SW elasticity was significantly higher in hypertension group than in control group (14.6 +/- 4.3 kPa vs. 6.5 +/- 1.1 kPa, P < 0.01). The cross-sectional area of cardiomyocytes was larger in hypertension group than in control group (397 +/- 50 mu m(2) vs. 243 +/- 14 mu m(2), P < 0.01), and SW elasticity was positively correlated with the cross-sectional area of cardiomyocytes (R = 0.96, P < 0.01). This study showed that SW elasticity was higher in hypertensive rats and was closely correlated with the degree of myocardial hypertrophy, suggesting the efficacy of SW elasticity for estimating the severity of hypertensive LV hypertrophy

Impact of shear wave dispersion slope analysis for assessing the severity of myocarditis

This study aimed to elucidate the utility of a novel ultrasound-based technique, shear wave dispersion slope (SWDS) analysis, which estimates tissue viscosity, for evaluating the severity of myocardial inflammation. Experimental autoimmune myocarditis (EAM) at different disease phases [3-week (acute phase): n = 10, 5-week (subacute phase): n = 9, and 7-week (late phase): n = 11] were developed in male Lewis rats. SWDS was measured in the right and the left ventricular free walls (RVFW and LVFW) under a retrograde perfusion condition. Histological myocardial inflammation was evaluated by CD68 staining. The accumulation of CD68-positive cells was severe in the myocardium of the EAM 3-week group. The median (interquartile range) SWDS of RVFW was significantly higher in the EAM 3-week group [9.9 (6.5-11.0) m/s/kHz] than in the control group [5.4 (4.5-6.8) m/s/kHz] (P = 0.034). The median SWDS of LVFW was also significantly higher in the EAM 3-week group [8.1 (6.4-11.0) m/s/kHz] than in the control group [4.4 (4.2-4.8) m/s/kHz] (P = 0.003). SWDS and the percentage of CD68-positive area showed a significant correlation in RVFW (R-2 = 0.64, P < 0.001) and LVFW (R-2 = 0.73, P < 0.001). This study showed that SWDS was elevated in ventricular walls with acute inflammation and also significantly correlated with the degree of myocardial inflammation. These results suggest the potential of SWDS in estimating the histological severity of acute myocarditis

Soft Gamma-ray Detector for the ASTRO-H Mission

ASTRO-H is the next generation JAXA X-ray satellite, intended to carry instruments with broad energy coverage and exquisite energy resolution. The Soft Gamma-ray Detector (SGD) is one of ASTRO-H instruments and will feature wide energy band (40-600 keV) at a background level 10 times better than the current instruments on orbit. SGD is complimentary to ASTRO-H's Hard X-ray Imager covering the energy range of 5-80 keV. The SGD achieves low background by combining a Compton camera scheme with a narrow field-of-view active shield where Compton kinematics is utilized to reject backgrounds. The Compton camera in the SGD is realized as a hybrid semiconductor detector system which consists of silicon and CdTe (cadmium telluride) sensors. Good energy resolution is afforded by semiconductor sensors, and it results in good background rejection capability due to better constraints on Compton kinematics. Utilization of Compton kinematics also makes the SGD sensitive to the gamma-ray polarization, opening up a new window to study properties of gamma-ray emission processes. The ASTRO-H mission is approved by ISAS/JAXA to proceed to a detailed design phase with an expected launch in 2014. In this paper, we present science drivers and concept of the SGD instrument followed by detailed description of the instrument and expected performance.Comment: 17 pages, 15 figures, Proceedings of the SPIE Astronomical Instrumentation "Space Telescopes and Instrumentation 2010: Ultraviolet to Gamma Ray

Label-free multiphoton excitation imaging as a promising diagnostic tool for breast cancer

Histopathological diagnosis is the ultimate method of attaining the final diagnosis; however, the observation range is limited to the two-dimensional plane, and it requires thin slicing of the tissue, which limits diagnostic information. To seek solutions for these problems, we proposed a novel imaging-based histopathological examination. We used the multiphoton excitation microscopy (MPM) technique to establish a method for visualizing unfixed/unstained human breast tissues. Under near-infrared ray excitation, fresh human breast tissues emitted fluorescent signals with three major peaks, which enabled visualizing the breast tissue morphology without any fixation or dye staining. Our study using human breast tissue samples from 32 patients indicated that experienced pathologists can estimate normal or cancerous lesions using only these MPM images with a kappa coefficient of 1.0. Moreover, we developed an image classification algorithm with artificial intelligence that enabled us to automatically define cancer cells in small areas with a high sensitivity of ≥0.942. Taken together, label-free MPM imaging is a promising method for the real-time automatic diagnosis of breast cancer.This is the pre-peer reviewed version of the following article:Matsui T., Iwasa A., Mimura M., et al. Label-free multiphoton excitation imaging as a promising diagnostic tool for breast cancer. Cancer Science 113, 2916 (2022), which has been published in final form at https://doi.org/10.1111/cas.15428. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving