Edoxaban Monotherapy in Nonvalvular Atrial Fibrillation Patients with Coronary Artery Disease.

Background: Current guidelines recommend an oral anticoagulant (OAC) monotherapy in patients with nonvalvular atrial fibrillation (NVAF) and stable coronary artery disease (CAD) 1 year postpercutaneous coronary intervention (PCI). It might be possible to shorten the time for de-escalation from a dual therapy to monotherapy, but data regarding de-escalation to an edoxaban monotherapy are lacking. This study aimed to assess the clinical safety of an edoxaban monotherapy in patients with NVAF and stable CAD. Methods: A multicenter, prospective, randomized, open-label, and parallel group study was established to investigate the safety of an edoxaban monotherapy in patients with NVAF and stable CAD including over 6 months postimplantation of a third-generation DES and 1 year postimplantation of other stents (PRAEDO AF study). Between March 2018 and June 2020, 147 patients from 8 institutions in Japan were randomized to receive either an edoxaban monotherapy (n = 74) or combination therapy (edoxaban plus clopidogrel, n = 73). The primary study endpoint was the composite incidence of major bleeding and clinically significant bleeding, defined according to the ISTH criteria. Results: Major or clinically significant bleeding occurred in 2 patients in the monotherapy group (1.67% per patient-year) and in 5 patients in the combination therapy group (4.28% per patient-year) (hazard ratio, 0.39; 95% confidence interval, 0.08-2.02). There was no incidence of a myocardial infarction, stent thrombosis, unstable angina requiring revascularization, ischemic stroke, systemic stroke, or hemorrhagic stroke in either of the groups. Conclusions: The edoxaban monotherapy was shown to have acceptable clinical safety in patients with NVAF and stable CAD. The study was registered with the Japan Registry of Clinical Trials (jRCTs031180119).

Clinical outcomes for intracoronary imaging strategies at different medical facilities in Japanese patients with coronary artery disease: the SAKURA imaging PCI Registry.

The relationships between intracoronary imaging modalities and outcomes among Japanese patients with coronary artery disease (CAD) based on the type of medical facility providing outpatient care remain unclear. In this multicenter prospective study (SAKURA PCI Registry), we aimed to investigate the clinical outcomes of patients with CAD who underwent percutaneous coronary intervention (PCI) between April 2015 and December 2018. In this registry, we investigated differences in patient characteristics, intracoronary imaging modalities, and clinical outcomes between two types of medical facilities. Of the 414 patients enrolled in this registry, 196 were treated at two university hospitals, and 218 were treated at five community hospitals (median follow-up 11.0 months). The primary endpoint was clinically relevant events (CREs), including a composite of all-cause death, non-fatal myocardial infarction, clinically driven target lesion revascularization, stent thrombosis, stroke, and major bleeding. Patients treated at university hospitals had higher rates of diabetes (50% vs. 38%, p = 0.015) and malignant tumors (12% vs. 6%, p = 0.015) and more frequent use of multiple intracoronary imaging modalities than patients treated at community hospitals (21% vs. 0.5%, p < 0.001). The Kaplan-Meier incidence of CREs at 1 year was comparable between university hospitals and community hospitals (8.8% vs. 7.3%, p = 0.527, log-rank test). Despite the relatively higher risk among patients in university hospitals with frequent use of multi-intracoronary imaging modalities, adverse clinical events appeared to be comparable between patients with CAD treated at university and community hospitals in Japan.

Zoledronate promotes inflammatory cytokine expression in human CD14-positive monocytes among peripheral mononuclear cells in the presence of γδ T cells.

Bisphosphonates distributed to bone exert toxic effects specifically towards osteoclasts. On the other hand, intravenous administration of a nitrogen-containing bisphosphonate (N-BP) such as zoledronate induces acute-phase reactions (APRs), including influenza-like fever 1 day later, indicating an interaction with immunocompetent cells circulating blood. Although it has been reported that activation of γδ T cells is pivotal to induce an APR following treatment with zoledronate, downstream events, including the production of inflammatory cytokines after activation of γδ T cells, remain obscure. We investigated the effects of zoledronate on inflammatory cytokine expression in human peripheral blood mononuclear cells (PBMCs) in vitro. While zoledronate induced mRNA expressions of tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6 and interferon-γ (IFN-γ) in PBMC, depletion of γδ T cells abolished that zoledronate-induced expression of those cytokines, indicating the necessity of γδ T cells for expression induction by zoledronate. However, which types of cells were responsible for the production of those cytokines in blood remained unclear. As it is generally accepted that monocytes and macrophages are primary sources of inflammatory cytokines, CD14+ cells from PBMC were exposed to zoledronate in the presence of PBMC, which resulted in induced expression of mRNAs for IL-1ß, IL-6 and IFN-γ, but not for TNF-α. These results indicate that CD14+ cells are responsible, at least in part, for the production of IL-1ß, IL-6 and IFN-γ in blood exposed to zoledronate. This suggests that CD14+ cells play an essential role in the occurrence of APRs following N-BP administration.

Enantioselectivity of 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks.

Nineteen ortho-substituted PCBs are chiral and found enantioselectively enriched in ecosystems. Their differential actions on biological targets are not understood. PCB 95 (2,2',3,5',6-pentachlorobiphenyl), a chiral PCB of current environmental relevance, is among the most potent toward modifying ryanodine receptors (RyR) function and Ca2+ signaling. PCB 95 enantiomers are separated and assigned aR- and aS-PCB 95 using three chiral-column HPLC and circular dichroism spectroscopy. Studies of RyR1-enriched microsomes show aR-PCB 95 with >4× greater potency (EC50 = 0.20 ± 0.05 µM), ∼ 1.3× higher efficacy (Bmax = 3.74 ± 0.07 µM) in [3H]Ryanodine-binding and >3× greater rates (R = 7.72 ± 0.31 nmol/sec/mg) of Ca2+ efflux compared with aS-PCB 95, whereas racemate has intermediate activity. aR-PCB 95 has modest selectivity for RyR2, and lower potency than racemate toward the RyR isoform mixture in brain membranes. Chronic exposure of hippocampal neuronal networks to nanomolar PCB 95 during a critical developmental period shows divergent influences on synchronous Ca2+ oscillation (SCO): rac-PCB 95 increasing and aR-PCB 95 decreasing SCO frequency at 50 nM, although the latter's effects are nonmonotonic at higher concentration. aS-PCB95 shows the greatest influence on inhibiting responses to 20 Hz electrical pulse trains. Considering persistence of PCB 95 in the environment, stereoselectivity toward RyRs and developing neuronal networks may clarify health risks associated with enantioisomeric enrichment of PCBs.

Motion Capture Depends Upon the Common Fate Factor Among Elements.

When observers move the head backwards and forwards while fixating on the center of the concentric circles that consist of oblique lines, they see illusory rotation of those circles. If several dots are superimposed on the proximity to the inner concentric circles, observers see the illusory rotation not only for the circles but also for the superimposed dots. This illusory rotation of the dots is based on motion capture. In this study, in order to understand the basis of the motion capture, we examined how motion signal with different directions (rotation, expansion/contraction, and horizontal translation) in terms of motion on a display, as well as illusory motion signal from the oblique components, affects the motion capture. If the stimulus presented rotation with expansion/contraction, or rotation with horizontal translation for the entire stimulus, then observers tended to perceive motion capture for the superimposed dots. However, if the stimulus presented only rotation of the circles, then observers tended to perceive induced motion for the superimposed dots. These results suggest that the existences of the common fate factor for the entire stimulus determine the means of allocating and integrating the motion signal in each element in the stimulus to generate motion capture.

Emotional response evoked by viewing facial expression pictures leads to higher temporal resolution.

We examined the effects of emotional response, with different levels of valence and arousal, on the temporal resolution of visual processing by using photos of various facial expressions. As an index of the temporal resolution of visual processing, we measured the minimum lengths of the noticeable durations for desaturated photographs using the method of constant stimuli by switching colorful facial expression photographs to desaturated versions of the same photographs. Experiments 1 and 2 used facial photographs that evoke various degrees of arousal and valence. Those photographs were prepared not only in an upright orientation but also in an inverted orientation to reduce emotional response without changing the photographs' image properties. Results showed that the minimum duration to notice monochrome photographs for anger, fear, and joy was shorter than that for a neutral face when viewing upright face photographs but not when viewing inverted face photographs. For Experiment 3, we used facial expression photographs to evoke various degrees of arousal. Results showed that the temporal resolution of visual processing increased with the degree of arousal. These results suggest that the arousal of emotional responses evoked by viewing facial expressions might increase the temporal resolution of visual processing.

Perceptual simultaneity range for two dichotically presented pure tones with frequency separation below 0.5 Bark.

The perceptual simultaneity range for two diotically presented tones increases with decreasing frequency separation of the two tones from approximately 0.5 Bark. As the present study of two frequency regions shows, this effect is not observed when the two tones are not presented to the same ear, i.e., presented dichotically. Since the increase in simultaneity is only observed when the tones are presented to the same ear, it is possible that it reflects the time-frequency uncertainty within a cochlear filter.

New Hybrid Spikelet Sterility Gene Found in Interspecific Cross between Oryza sativa and O. meridionalis.

Various kinds of reproductive barriers have been reported in intraspecific and interspecific crosses between the AA genome Oryza species, to which Asian rice (O. sativa) and African rice (O. glaberrima) belong. A hybrid seed sterility phenomenon was found in the progeny of the cross between O. sativa and O. meridionalis, which is found in Northern Australia and Indonesia and has diverged from the other AA genome species. This phenomenon could be explained by an egg-killer model. Linkage analysis using DNA markers showed that the causal gene was located on the distal end of chromosome 1. Because no known egg-killer gene was located in that chromosomal region, this gene was named HYBRID SPIKELET STERILITY 57 (abbreviated form, S57). In heterozygotes, the eggs carrying the sativa allele are killed, causing semi-sterility. This killer system works incompletely: some eggs carrying the sativa allele survive and can be fertilized. The distribution of alleles in wild populations of O. meridionalis was discussed from the perspective of genetic differentiation of populations.

Predicting individual emotion from perception-based non-contact sensor big data.

This study proposes a system for estimating individual emotions based on collected indoor environment data for human participants. At the first step, we develop wireless sensor nodes, which collect indoor environment data regarding human perception, for monitoring working environments. The developed system collects indoor environment data obtained from the developed sensor nodes and the emotions data obtained from pulse and skin temperatures as big data. Then, the proposed system estimates individual emotions from collected indoor environment data. This study also investigates whether sensory data are effective for estimating individual emotions. Indoor environmental data obtained by developed sensors and emotions data obtained from vital data were logged over a period of 60 days. Emotions were estimated from indoor environmental data by machine learning method. The experimental results show that the proposed system achieves about 80% or more estimation correspondence by using multiple types of sensors, thereby demonstrating the effectiveness of the proposed system. Our obtained result that emotions can be determined with high accuracy from environmental data is a useful finding for future research approaches.

Perceived Duration Depends Upon Target Detection in Rapid Serial Visual Presentation Sequence.

It is well known that the perceived duration for a given time period decreases with the reduction of the number of perceived events. We examined whether target detection failures in viewing Rapid Serial Visual Presentation (RSVP) sequence, caused by attentional blink, affect this reduction of perceived duration. In two experiments, trials consisted of displays of two series of RSVP sequences; in the first sequence (the comparison), two, one, or no numerals were presented as targets embedded within the string of letters, while in the second sequence (the standard), only alphabetic letters were presented. In each trial, participants judged whether the duration of the comparison is perceived as longer than that of the standard (Experiment 1), or whether the number of frames in the comparison is perceived as more than that in the standard (Experiment 2). Results showed that perceived duration was inflated with target detection, but not with the increment of presented frames although number of perceived frames was inflated with both target detection and increment of presented frames. These results suggest that perceived duration in viewing RSVP sequences is determined by the cognitive load necessary to accomplish target detection rather than by the number of perceived frames.

Preparative separation of the saponin lancemaside a from Codonopsis lanceolata by centrifugal partition chromatography.

INTRODUCTION: Lancemaside A is a saponin that inhibits decreases in blood testosterone level and thus prevents or ameliorates symptoms associated with male climacteric disorder. Our initial attempt to preparative isolation of lancemaside A from the saponin fraction of Codonopsis lanceolata roots by a preparative HPLC did not give a clear result. OBJECTIVE: To develop a simple and efficient method for the preparative isolation of lancemaside A from the hot water extract of C. lanceolata roots using centrifugal partition chromatography (CPC). METHODOLOGY: The saponin fraction obtained from the hot water extract of C. lanceolata roots was used as the sample for preparative-scale separation of lancemasides by CPC using n-hexane:n-butanol:methanol:0.1% aqueous formic acid (3:4:1:6, v/v) as the two-phase solvent system. The upper phase (organic phase) of the two-phase solvent system was used as the mobile phase, and 0.5 g of saponin fraction was applied for separation by CPC. Each fraction that was separated by CPC was analysed by HPLC, and the fractions containing each of the separated compounds were pooled together, and then were purified by simple preparative HPLC. RESULTS: The demonstrated separation sequence, hot water extraction, DIAION HP-20 column chromatography, CPC and preparative HPLC, yielded lancemaside A, foetidissimoside A and astersaponin Hb in their pure forms. CONCLUSION: The simple and efficient method for the preparative isolation of lancemaside A along with two other saponins, foetidissimoside A and astersaponin Hb, from the saponin fraction of C. lanceolata was established using CPC.

Effect of dehydration and urea on stability of homosulfamine in solid states.

In the presence of urea in solid states, the stability of unpulverized homosulfamine hydrate (phase I; UHH) is significantly decreased whereas that of unpulverized homosulfamine anhydrate (UHA) is not. The stability of UHH is decreased slightly more by pulverization (PHH). The major objective of this study was to investigate the effects of urea, dehydration, and pulverization on the stability of homosulfamine in solid states. Binary mixtures of UHH and urea, PHH and urea, and UHA and urea in a ratio of 1:1 (wt/wt) were prepared as physical mixtures and were analyzed by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and Fourier transform infrared (FTIR) spectroscopy to study their appearance and structural changes before and after storage. PXRD analysis revealed that physical mixtures comprising UHH and urea and PHH and urea have the same diffraction pattern as that of the mixture of UHA and urea after preparation. The dehydration rate of the crystal water of UHH was accelerated by the presence of urea in addition to pulverization. Moreover, the PXRD patterns of the physical mixtures of UHH/urea and PHH/urea were significantly altered during storage, whereas that of UHA/urea was not, which was consistent with the SEM and FTIR results. The particle shape and appearance of UHH varied significantly as a result of pulverization. The stability of homosulfamine was influenced not only by the presence of urea and dehydration but also by the surface state and particle size of the crystalline form.

Lepidepyrone, a new gamma-pyrone derivative, from Neolentinus lepideus, inhibits hyaluronidase.

In the course of screening for hyaluronidase (HAase) inhibitory agents, a new gamma-pyrone derivative, lepidepyrone, C(8)H(10)O(5), was isolated from the cultured mycelium of the mushroom Neolentinus lepideus TMC-1102 as a major HAase inhibitory compound (IC(50) 3.3 mM). The structure of lepidepyrone was established on the basis of spectroscopic investigation.

Multidetector row computed tomographic findings in a patient with anomalous origin of the right coronary artery from the left sinus of Valsalva.

Anomalous origin of the right coronary artery (RCA) is a rare congenital anomaly, which may cause myocardial ischemia and sudden death. However, the causes of myocardial ischemia remain uncertain. Multidetector row computed tomography (MDCT) was performed in a 22-year-old woman who had exercise-induced myocardial ischemia. MDCT revealed a small orifice of the RCA in the left sinus of Valsalva, separate from the left main coronary artery, an acute-angled takeoff from the aorta, an intramural course of the proximal portion within the aortic wall, and a course between the great vessels. Three-dimensional virtual angioscopy also depicted a small orifice.

Manual control of the visual stimulus reduces the flash-lag effect.

We investigated how observers' control of the stimulus change affects temporal aspects of visual perception. We compared the flash-lag effects for motion (Experiment 1) and for luminance (Experiment 2) under several conditions that differed in the degree of the observers' control of change in a stimulus. The flash-lag effect was salient if the observers passively viewed the automatic change in the stimulus. However, if the observers controlled the stimulus change by a computer-mouse, the flash-lag effect was significantly reduced. In Experiment 3, we examined how observers' control of the stimulus movement by a mouse affects the reaction time for the shape change in the moving stimulus and flash. Results showed that the control reduced the reaction time for both moving stimulus and flash. These results suggest that observers' manual control of the stimulus reduces the flash-lag effect in terms of facilitation in visual processing.

Changes in organosulfur compounds in garlic cloves during storage.

We determined the changes in the contents of three gamma-glutamyl peptides and four sulfoxides in garlic cloves during storage at -3, 4, and 23 degrees C for 150 days using a validated high-performance liquid chromatography method that we reported recently. When garlic was stored at 4 degrees C for 150 days, marked conversion of the gamma-glutamyl peptides, gamma-L-glutamyl-S-allyl-L-cysteine and gamma-L-glutamyl-S-(trans-1-propenyl)-L-cysteine (GSPC), to sulfoxides, alliin and isoalliin, was observed. Interestingly, however, when garlic was stored at 23 degrees C, a decrease in GSPC and a marked increase in cycloalliin, rather than isoalliin, occurred. To elucidate in detail the mechanism involved, the conversion of isoalliin to cycloalliin in both buffer solutions (pH 4.6, 5.5, and 6.5) and garlic cloves at 25 and 35 degrees C was examined. Decreases in the concentration of isoalliin in both the solutions and the garlic cloves during storage followed first-order kinetics and coincided with the conversion of cycloalliin. Our data indicated that isoalliin produced enzymatically from GSPC is chemically converted to cycloalliin and that the cycloalliin content of garlic cloves increases during storage at higher temperature. These data may be useful for controlling the quality and biological activities of garlic and its preparations.

Determination of seven organosulfur compounds in garlic by high-performance liquid chromatography.

The properties of garlic (Allium sativum L.) are attributed to organosulfur compounds. Although these compounds change during cultivation and storage, there is no report of their simultaneous analysis. Here, a newly developed analytical method with a rapid and simple sample preparation to determine four sulfoxides and three gamma-glutamyl peptides in garlic is reported. All garlic samples were simply extracted with 90% methanol solution containing 0.01 N hydrochloric acid and prepared for analysis. Alliin, isoalliin, methiin, cycloalliin, and gamma-l-glutamyl-S-methyl-l-cysteine were determined by normal-phase HPLC using an aminopropyl-bonded column. gamma-l-Glutamyl-S-(2-propenyl)-l-cysteine and gamma-l-glutamyl-S-(trans-1-propenyl)-l-cysteine were separated on an octadecylsilane column. The overall recoveries were 97.1-102.3%, and the relative standard deviation values of intra- and interday precision were lower than 2.6 and 4.6%, respectively. This newly developed method offers some advantages over the currently accepted techniques including specificity, speed, and ease of use and would be useful for chemical and biological studies of garlic and its preparations.

Pharmacokinetics of cycloalliin, an organosulfur compound found in garlic and onion, in rats.

Cycloalliin, an organosulfur compound found in garlic and onion, has been reported to exert several biological activities and also to remain stable during storage and processing. In this study, we investigated the pharmacokinetics of cycloalliin in rats after intravenous or oral administration. Cycloalliin and its metabolite, (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid, in plasma, urine, feces, and organs was determined by a validated liquid chromatography-mass spectrometry method. When administered intravenously at 50 mg/kg, cycloalliin was rapidly eliminated from blood and excreted into urine, and its total recovery in urine was 97.8% +/- 1.3% in 48 h. After oral administration, cycloalliin appeared rapidly in plasma, with a tmax of 0.47 +/- 0.03 h at 25 mg/kg and 0.67 +/- 0.14 h at 50 mg/kg. Orally administered cycloalliin was distributed in heart, lung, liver, spleen, and especially kidney. The Cmax and AUC0-inf values of cycloalliin at 50 mg/kg were approximately 5 times those at 25 mg/kg. When administered orally at 50 mg/kg, cycloalliin was excreted into urine (17.6% +/- 4.2%) but not feces. However, the total fecal excretion of (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid was 67.3% +/- 5.9% (value corrected for cycloalliin equivalents). In addition, no (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid was detected in plasma (<0.1 microg/mL), and negligible amounts (1.0% +/- 0.3%) were excreted into urine. In in vitro experiments, cycloalliin was reduced to (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid during anaerobic incubation with cecal contents of rats. These data indicated that the low bioavailability (3.73% and 9.65% at 25 and 50 mg/kg, respectively) of cycloalliin was due mainly to reduction to (3R,5S)-5-methyl-1,4-thiazane-3-carboxylic acid by the intestinal flora and also poor absorption in the upper gastrointestinal tract. These findings are helpful for understanding the biological effects of cycloalliin.

Visual Presentation Effects on Identification of Multiple Environmental Sounds.

This study examined how the contents and timing of a visual stimulus affect the identification of mixed sounds recorded in a daily life environment. For experiments, we presented four environment sounds as auditory stimuli for 5 s along with a picture or a written word as a visual stimulus that might or might not denote the source of one of the four sounds. Three conditions of temporal relations between the visual stimuli and sounds were used. The visual stimulus was presented either: (a) for 5 s simultaneously with the sound; (b) for 5 s, 1 s before the sound (SOA between the audio and visual stimuli was 6 s); or (c) for 33 ms, 1 s before the sound (SOA was 1033 ms). Participants reported all identifiable sounds for those audio-visual stimuli. To characterize the effects of visual stimuli on sound identification, the following were used: the identification rates of sounds for which the visual stimulus denoted its sound source, the rates of other sounds for which the visual stimulus did not denote the sound source, and the frequency of false hearing of a sound that was not presented for each sound set. Results of the four experiments demonstrated that a picture or a written word promoted identification of the sound when it was related to the sound, particularly when the visual stimulus was presented for 5 s simultaneously with the sounds. However, a visual stimulus preceding the sounds had a benefit only for the picture, not for the written word. Furthermore, presentation with a picture denoting a sound simultaneously with the sound reduced the frequency of false hearing. These results suggest three ways that presenting a visual stimulus affects identification of the auditory stimulus. First, activation of the visual representation extracted directly from the picture promotes identification of the denoted sound and suppresses the processing of sounds for which the visual stimulus did not denote the sound source. Second, effects based on processing of the conceptual information promote identification of the denoted sound and suppress the processing of sounds for which the visual stimulus did not denote the sound source. Third, processing of the concurrent visual representation suppresses false hearing.