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Background: The structural and functional characteristics of the heart in patients with diabetes mellitus (DM) and without myocardial infarction (MI) are not fully understood., Methods: We retrospectively analysed the data of patients with left ventricular ejection fraction (LVEF) ≥ 40% who underwent contrast-enhanced cardiac magnetic resonance imaging (CMR), which was also used to exclude MI, at two hospitals. Volumetric data and extracellular volume fraction (ECVf) of the myocardium evaluated using CMR were compared between patients with and without DM, and their association with diastolic function was evaluated., Results: Among 322 analysed patients, 53 had DM. CMR revealed that the left ventricular mass index (LVMi) and ECVf were increased while LVEF was decreased in patients with DM after adjusting for patient characteristics (all P < 0.05). A stronger positive correlation was observed between LVMi and the early diastolic transmitral flow velocity to early diastolic mitral annular velocity ratio (E/e') in patients with DM than in those without DM (correlation coefficient [R] = 0.46, p = 0.001; R = 0.15, p = 0.021, respectively; p for interaction = 0.011). ECVf correlated with E/e' only in patients with DM (R = 0.61, p = 0.004)., Conclusions: Patients with DM have increased LVMi and ECVf. Importantly, there was a difference between patients with and without DM in the relationship between these structural changes and E/e', with a stronger relationship in patients with DM. Furthermore, DM is associated with mildly reduced LVEF even in the absence of MI., Competing Interests: Declaration of competing interest M.K. received research grants from KOWA company, Ltd. and FUJIREBIO Inc. Y.A. received scholarship grants from Abbott Medical Japan and Terumo. T.F. received a research grant from General Electric. Y.S. received an honorarium from Astra-Zeneca, Nippon Boehringer-Ingelheim Co., Ltd., Daiichi-Sankyo Company, and Novartis., (Copyright © 2024. Published by Elsevier B.V.)

Background and Study Aims: The infliximab biosimilar CT-P13 was the first biosimilar drug targeting tumor necrosis factor-α. However, its efficacy and safety in real-world clinical situations have remained insufficient. Therefore, we aimed to verify the efficacy and safety of CT-P13 in bio-naïve patients with Crohn's disease., Patients and Methods: This retrospective multicenter study compared the remission rate at week 54 between patients with Crohn's disease who were treated with originator infliximab or CT-P13. Endoscopic and laboratory findings were assessed in both groups. A total of 184 (156 originator and 28 CT-P13) patients were analyzed. Of these, 138 originator users and 19 biosimilar users completed 54-week administration., Results: The clinical remission rates in patients taking originator infliximab of CT-P13 at week 54 were 92.5 % and 100 %, respectively. The endoscopic scores of each group significantly decreased from baseline at week 54 in both groups, and the mucosal healing rate at week 54 was 53 % and 64 %, respectively. Laboratory data including C-reactive protein, serum albumin, and hemoglobin significantly improved from baseline to week 14 and 54 in both groups. Adverse events were observed more frequently in the CT-P13 group (25 % vs. 4.5 %, p = 0.0015), but severe adverse events were rare in both groups., Conclusion: The efficacy and safety of CT-P13 were comparable with those of originator infliximab in bio-naïve patients with Crohn's disease evaluated by clinical, endoscopic, and laboratory findings. This study establishes the needed groundwork for the development of a strategy for treatment with biologics in patients with Crohn's disease., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Osteoporotic fragility fractures substantially impact aging societies, necessitating long-term care and increasing healthcare costs. Myokine irisin, secreted by skeletal muscle, influences bone metabolism; however, a comprehensive understanding of the mechanisms by which irisin affects bone metabolism is still lacking. Therefore, this study aimed to explore the effects of irisin on osteogenesis and osteoblast differentiation triggered by bone morphogenetic protein-2 (BMP-2). We used 4-week-old male ICR mice and implanted polyethylene glycol pellets containing recombinant human BMP-2 (rh-BMP-2) into the left dorsal muscle pouch. Mice received weekly intraperitoneal injections of either phosphate-buffered saline or recombinant irisin (re-irisin). Ectopic bone formation was evaluated 3 weeks post-surgery using micro-computed tomography (μ-CT) and histological analysis. In vitro experiments, C2C12 cells were treated with or without rh-BMP-2 and re-irisin, and we assessed osteoblast differentiation markers, e.g., runt-related transcription factor 2, alkaline phosphatase, osteocalcin, and osteopontin, using real-time reverse transcription-polymerase chain reaction. The μ-CT analyses showed that re-irisin significantly increased bone mineral content and bone volume of ectopic bones newly formed by rh-BMP-2. The gene expressions of the osteoblast markers were significantly increased by rh-BMP-2 and further upregulated by re-irisin. The treatment of cyclic AMP response element-binding protein (CREB) small interfering RNA attenuated these effects, suggesting that CREB signaling pathway was involved in rh-BMP-2/re-irisin-induced osteoblastic differentiation. This study demonstrates the potential of irisin to enhance osteogenesis through BMP signaling, offering insights for osteoporosis treatment and highlighting irisin as a promising therapeutic target for improving bone health and extending a healthy lifespan., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Stem anteversion plays a crucial role in mitigating postoperative complications in total hip arthroplasty (THA). The application of the combined-anteversion theory in THA necessitates the intraoperative measurement of the stem anteversion angle (SAA). However, estimating SAA intraoperatively poses challenges for surgeons lacking a computer-assisted navigation system. In this study, we assessed the precision of intraoperative SAA measurements using a recently developed device, comparing them with 3-dimensional measurements obtained from postoperative computed tomography., Methods: We examined 127 hips in 127 patients who underwent unilateral THA at our institution. Employing our newly constructed device, attachable to rasping broach handles, we measured the SAA intraoperatively. This process involved incorporating the correction angle derived from the preoperative epicondylar view. We then compared the postoperative SAA with the intraoperative measurements, both with and without the correction angle, to ascertain the device's utility., Results: The device yielded an intraoperative SAA measurement of 17.93 ± 7.53°. In contrast, the true SAA measured on postoperative computed tomography was 26.40 ± 9.73°. The discrepancy between intraoperative and true SAA was 8.94 ± 5.44° (without the correction angle) and 4.93 ± 3.85° (with the correction angle). Accuracy within a discrepancy of <5° was achieved in 77 cases (60.6%), and <10° was achieved in 113 cases (89.0%). The accuracy remained consistent regardless of the stem-placement angle (varus/valgus, or flexion/extension) or the presence of ipsilateral knee osteoarthritis., Conclusions: The SAA-measuring device, attachable to various rasping handles, proves useful for straightforward, cost-effective, and noninvasive intraoperative SAA measurement during THA., (© 2024 The Authors.)

Background: This study aimed to investigate the relationship between 3-dimensional (3D) alignment and postoperative bone mineral density (BMD) changes with Accolade II tapered wedge stems, which have a different proximal shape from other tapered wedge stems, up to 5 years after primary total hip arthroplasty., Methods: We retrospectively analyzed the hips of 89 patients who underwent total hip arthroplasty using the second-generation proximally coated cementless stem (Accolade II; Stryker Orthopedics, Mahwah, NJ) at our institution from 2014 to 2018 over a 5-year follow-up. We evaluated the relationship between stem alignment, measured using 3D-templating software, and BMD changes in the 7 Gruen zones and compared the data with those from a former study using other short taper-wedge stems., Results: BMDs in zones 1 and 7 continued to decrease gradually every year after surgery, and BMD in zone 7 showed the largest decrease (21%) from baseline over 5 years. No correlation was found between stem alignment (varus/valgus, flexion/extension, and anteversion/retroversion) and changes in BMD in each zone over 5 years., Conclusions: Our data showed no correlation between 3D stem alignment and changes in BMD in each Gruen zone over 5 years. This suggests that the Accolade II stem may fit better into any shape of the proximal medullary canal because of its unique characteristics., (© 2024 The Authors.)

Previous human and rodent studies indicated that nociceptive stimuli activate many brain regions that is involved in the somatosensory and emotional sensation. Although these studies have identified several important brain regions involved in pain perception, it has been a challenge to observe neural activity directly and simultaneously in these multiple brain regions during pain perception. Using a transgenic mouse expressing G-CaMP7 in majority of astrocytes and a subpopulation of excitatory neurons, we recorded the brain activity in the mouse cerebral cortex during acute pain stimulation. Both of hind paw pinch and intraplantar administration of formalin caused strong transient increase of the fluorescence in several cortical regions, including primary somatosensory, motor and retrosplenial cortex. This increase of the fluorescence intensity was attenuated by the pretreatment with morphine. The present study provides important insight into the cortico-cortical network during pain perception., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Computed tomography late enhancement (CT-LE) is emerging as a non-invasive technique for cardiac diagnosis with wider accessibility compared to MRI, despite its typically lower contrast-to-noise ratio. Optimizing CT-LE image quality necessitates a thorough methodology addressing contrast administration, timing, and radiation dose, alongside a robust understanding of extracellular volume (ECV) quantification methods. This review summarizes CT-LE protocols, clinical utility, and advances in ECV measurement through both single-energy and dual-energy CT. It also highlights photon-counting detector CT technology as an innovative means to potentially improve image quality and reduce radiation exposure., Competing Interests: Declaration of competing interest No author declared a conflict of interest with respect to this manuscript. Other potentially competing interests were provided in detail separately., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Successful bone regeneration on titanium (Ti) surfaces is a key process in dental implant treatment. Bone marrow mesenchymal stem cells (BMSCs) are fundamental cellular components of this process, and their early recruitment, proliferation, and differentiation into bone-forming osteoblasts are crucial. A proteoglycan (PG)-rich layer has been reported to exist between Ti surfaces and bones; however, the molecules that could potentially affect the formation of this layer remain unknown. Family with sequence similarity 20 member B (FAM20B) is a newly identified kinase that regulates the synthesis of glycosaminoglycans, an important component of the PG-rich layer. Because FAM20B is also closely associated with bone development, in this study, we examined the function of FAM20B in osteogenic differentiation of BMSCs on Ti surfaces. For this, BMSC cell lines with knocked down FAM20B (shBMSCs) were cultured on Ti surfaces. The results showed that the depletion of FAM20B reduced the formation of a PG-rich layer between the Ti surfaces and cells. The shBMSCs exhibited downregulated expression of osteogenic marker genes (ALP and OCN) and decreased mineral deposition. Moreover, shBMSCs reduced the molecular levels of p-ERK1/2, which plays an important role in MSC osteogenesis. The nuclear translocation of RUNX2, an important transcription factor for osteogenic differentiation, on the Ti surfaces is inhibited by the depletion of FAM20B in BMSCs. Moreover, the depletion of FAM20B reduced the transcriptional activity of RUNX2, which is important in regulating the expression of osteogenic genes. STATEMENT OF SIGNIFICANCE: Bone healing and regeneration on implanted titanium surfaces is a cell-material interaction. Such an interaction is enabled by bone marrow mesenchymal stem cells (BMSCs), and their early recruitment, proliferation, and differentiation into bone-forming osteoblasts are essential for bone healing and osseointegration. In this study, we found that the family with sequence similarity 20-B influenced the formation of a proteoglycan rich layer between BMSCs and the titanium surface and regulated the differentiation of BMSCs into bone-forming osteoblasts. We believe that our study contributes significantly to the further exploration of bone healing and osseointegration mechanisms on implanted titanium surfaces., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Gastrulation is the first dynamic cell movement during embryogenesis. Endoderm and mesoderm cells are internalized into embryos during this process. Ascidian embryos provide a simple system for studying gastrulation in chordates. Gastrulation starts in spherical late 64-cell embryos with 10 endoderm blastomeres. The mechanisms of gastrulation in ascidians have been investigated, and a two-step model has been proposed. The first step involves apical constriction of endoderm cells, followed by apicobasal shortening in the second step. In this study, isolated ascidian endoderm progenitor cells displayed dynamic blebbing activity at the gastrula stage, although such a dynamic cell-shape change was not recognized in toto. Blebbing is often observed in migrating animal cells. In ascidians, endoderm cells displayed blebbing activity, while mesoderm and ectoderm cells did not. The timing of blebbing of isolated endoderm cells coincided with that of cell invagination. The constriction rate of apical surfaces correlated with the intensity of blebbing activity in each endoderm-lineage cell. Fibroblast growth factor (FGF) signaling was both necessary and sufficient for inducing blebbing activity, independent of cell fate specification. In contrast, the timing of initiation of blebbing and intensity of blebbing response to FGF signaling were controlled by intrinsic cellular factors. It is likely that the difference in intensity of blebbing activity between the anterior A-line and posterior B-line cells could account for the anteroposterior difference in the steepness of the archenteron wall. Inhibition of zygotic transcription, FGF signaling, and Rho kinase, all of which suppressed blebbing activity, resulted in incomplete apical constriction and failure of the eventual formation of cup-shaped gastrulae. Blebbing activity was involved in the progression and maintenance of apical constriction, but not in apicobasal shortening in whole embryos. Apical constriction is mediated by distinct blebbing-dependent and blebbing-independent mechanisms. Surface tension and consequent membrane contraction may not be the sole mechanical force for apical constriction and formation of cup-shaped gastrulae. The present study reveals the hidden cellular potential of endodermal cells during gastrulation and discusses the possible roles of blebbing in the invagination process., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Protons (H + ) are essential for most physiological functions in organelles and cells. In this study, we have demonstrated a sulfonated polyaniline (SPA) biotransducer that can modulate the intracellular pH in C6 cells with an applied potential, which is directly coupled with H + to facilitate engineering interactions with physiological processes in the cells. To modulate the pH in the intracellular fluid, we improved the performance of SPA biotransducer by coating of a carbon nanotube (CNT) supportive layer that provides high H + selectivity in the solution and also high H + capacity in the hybrid SPA electrode. The intracellular pH modulation was succeeded by applying a potential difference of less than ±0.6 V. pH modulation in the cells is effected by using the biotransducer, which drives the activity of plasma membrane potential and the flow of molecules through the permeable membrane between cells and culture medium, whereas the poly (3,4-ethylenedioxythiophene) (PEDOT)-based biotransducer, which does not have H + selectivity, was insufficient for modulation. Furthermore, the protonic biotransducer can control the increase/decrease in mitochondria membrane potential, reactive oxygen species and intracellular Ca 2+ concentration. Therefore, the protonic biotransducer provides a new perspective to transfer a H + signal into the cells for modulating the functions., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Idiopathic normal pressure hydrocephalus (iNPH) is primarily characterized by cognitive impairment and gait disturbance. Our objective was to evaluate the clinical characteristics of iNPH and the association between cerebral blood flow (CBF), measured using single-photon emission computed tomography (SPECT), and both cognitive and gait disturbances in iNPH patients., Methods: We compared cognitive and motor functions and neuroimaging findings between 29 iNPH patients and 35 age-matched Parkinson's disease (PD) patients. We examined the associations between cognitive and motor dysfunctions and CBF in iNPH patients using 99m Tc-ECD SPECT subtraction imaging data from a database of healthy control subjects., Results: The cognitive function of iNPH patients, as measured by the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB), was significantly poorer than that of PD patients; however motor function of the legs based on the Unified PD Rating Scale (UPDRS) part III was similar across groups. Impairment in cognitive function based on the MMSE and FAB was significantly correlated with motor dysfunction of the legs on the UPDRS part III and the 3-m Timed Up and Go test. Furthermore, 99m Tc-ECD SPECT subtraction imaging revealed lower CBF in the bilateral lingual gyrus of iNPH patients with severely impaired cognitive and motor functions than healthy control subjects., Conclusion: Patients with iNPH have severely impaired cognitive function; however, motor dysfunction of the legs is similar to PD patients. The cognitive and gait disturbances of iNPH are significantly interrelated, which may be associated with an impaired brain network that includes the bilateral lingual gyrus., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: D-dimer levels can predict ischemic stroke in patients with acute heart failure (AHF). However, the effects of direct oral anticoagulants on D-dimer levels have not been investigated during admission for AHF in patients with atrial fibrillation (AF). This study examined D-dimer levels immediately after admission and following edoxaban initiation as a sub-analysis of a multi-center study that investigated the pharmacokinetics and pharmacodynamics of edoxaban in patients with nonvalvular AF (NVAF) and AHF., Methods: Hospitalized patients with NVAF and AHF received edoxaban according to the label. The primary measure was the change in D-dimer levels on 7 consecutive days after admission for AHF. We also investigated differences according to prior edoxaban use (de novo at the time of admission or continuation)., Results: In 10/13 (76.9%) de novo patients, D-dimer levels exceeded the reference value (1.0 µg/mL) at admission (mean, 2.12 µg/mL) and subsequently decreased in 9 patients (at final blood sampling: mean, 1.12 µg/mL); 1 patient did not fall below the reference value due to stasis dermatitis. In the continuation group, most patients had D-dimer levels below the reference value from Day 1 (mean, 0.93 µg/mL), and levels remained stable or decreased (at final blood sampling: mean, 0.49 µg/mL). No events of stroke were observed., Conclusions: D-dimer levels may be elevated in patients with NVAF and AHF, particularly in those without prior anticoagulant treatment. Edoxaban may be effective for lowering and keeping D-dimer levels, a biomarker for predicting ischemic stroke, below the reference value in patients with NVAF and AHF., (Copyright © 2022. Published by Elsevier Ltd.)

Mitochondria change their morphology and inner membrane structure depending on their activity. Since mitochondrial activity also depends on their structure, it is important to elucidate the interrelationship between the activity and structure of mitochondria. However, the mechanism by which mitochondrial activity affects the structure of cristae, the folded structure of the inner membrane, is not well understood. In this study, the effect of the mitochondrial activity on the cristae structure was investigated by examining the structural rigidity of cristae. Taking advantage of the fact that unfolding of cristae induces mitochondrial swelling, we investigated the relationship between mitochondrial activity and the susceptibility to swelling. The swelling of individual isolated mitochondria exposed to a hypotonic solution was observed with an optical microscope. The presence of respiratory substrates (malate and glutamate) increased the percentage of mitochondria that underwent swelling, and the further addition of rotenone or KCN (inhibitors of proton pumps) reversed the increase. In the absence of respiratory substrates, acidification of the buffer surrounding the mitochondria also increased the percentage of swollen mitochondria. These observations suggest that acidification of the outer surface of inner membranes, especially intracristal space, by proton translocation from the matrix to the intracristal space, decreases the structural rigidity of the cristae. This interpretation was verified by the observation that ADP or CCCP, which induces proton re-entry to the matrix, suppressed the mitochondrial swelling in the presence of respiratory substrates. The addition of CCCP to the cells induced a morphological change in mitochondria from an initial elongated structure to a largely curved structure at pH 7.4, but there were no morphological changes when the pH of the cytosol dropped to 6.2. These results suggest that a low pH in the intracristal space may be helpful in maintaining the elongated structure of mitochondria. The present study shows that proton pumping by the electron transfer chain is the mechanism underlying mitochondrial morphology and the flexibility of cristae structure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Vitamin D has been shown to reduce symptoms in patients with osteoarthritis (OA). In a previous study, local administration of eldecalcitol, an active vitamin D 3 analog, reduced degenerative changes in articular cartilage in the early phase of experimental OA. However, the target of vitamin D in OA remains unknown. Here, we investigated the effect of eldecalcitol treatment on chondrocytes, which were divided into superficial zone chondrocytes (SZC), deep zone chondrocytes (DZC), and differentiated chondrocytes. SZC and DZC were cultured in monolayer and 3D pellet cultures treated with eldecalcitol. The gene expressions of articular cartilage and chondrocyte differentiation markers were evaluated. Histological analysis of SZC and DZC 3D pellet cultures was performed. The results showed that the articular cartilage markers ETS-related gene (Erg) and lubricin/proteoglycan 4 (PRG4) were significantly increased in SZC, but not in DZC, in the monolayer culture treated with eldecalcitol. The chondrocyte differentiation markers type X collagen and alkaline phosphatase (ALP) were significantly decreased in the DZC pellet culture treated with eldecalcitol. Immunochemical analysis also showed that Erg and lubricin/PRG4 expressions were elevated in the SZC pellet culture treated with eldecalcitol, while type X collagen and ALP expressions were decreased in the DZC pellet culture treated with eldecalcitol. In conclusion, this study showed that eldecalcitol upregulated articular cartilage markers in SZC and suppressed differentiation markers in DZC. Such regulation of chondrocytes by eldecalcitol could be potentially effective against OA progression., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Use of a porous tantalum tibial component for total knee arthroplasty (TKA) was reported to have beneficial effects on periprosthetic bone mineral density (BMD). In some cases, hexagonal peg is placed close to or in contact with the tibial cortex, which may result in stress-shielding around the peg. However, no studies have analyzed the relationship between peg position and BMD. The aim of this study was to compare the peg position and BMD around the peg in a porous tantalum tibial component after TKA., Methods: Twenty-seven patients (27 knees) who underwent primary TKA with a cementless porous tantalum tibial component were investigated. BMD was measured by dual-energy X-ray absorptiometry for 2 years after the operation. The distance between the peg and the tibial cortex (peg distance) was measured on the medial and lateral sides., Results: BMD was decreased in the medial region after the operation (p < 0.01). Relative change in BMD was lower in the medial region than in the central and lateral regions (p < 0.01). Multiple regression analysis showed that medial peg distance was negatively correlated with relative change of BMD in the medial part of the tibia (p = 0.04, R = 0.402)., Conclusions: The medial peg position affected the postoperative relative change of BMD in the medial part of the tibia, but did not affect the longevity of the implant. As the tibial medial peg became closer to the medial tibial cortex, the BMD loss became larger in the medial part of the tibia at 2 years postoperatively., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Due to an increasing number of dementia patients, the development of a rapid and sensitive method for cognitive assessment is awaited. Here, we examined the usefulness of a novel and short (3 min) eye tracking device to evaluate the cognitive function of normal control (NC, n = 52), mild cognitive impairment (MCI, n = 52), and Alzheimer's disease (AD, n = 70) subjects. Eye tracking total score declined significantly in MCI (**p < 0.01 vs NC) and AD (**p < 0.01 vs NC, ## p < 0.01 vs MCI), and correlated well with the mini-mental state examination (MMSE) score (r = 0.57, *p < 0.05). Furthermore, the eye tracking test, especially memory and deductive reasoning tasks, effectively discriminated NC, MCI and AD. The present novel eye tracking test clearly discriminated cognitive functions among NC, MCI, and AD subjects, thereby providing an advantage for the early detection of MCI and AD in screening., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cu-diacetyl-bis (N4-methylthiosemicarbazone) (CuATSM) has both anti-oxidative and anti-inflammatory activities, but its therapeutic efficacy for oxidative stress has not been thoroughly investigated in acute ischemic stroke. Here, the present study was designed to assess the efficacies of CuATSM in acute ischemic stroke by comparing with the standard neuroprotective reagent edaravone. Mice were subjected to transient middle cerebral occlusion (tMCAO) for 60 min, and then intravenously administrated with CuATSM (1.5 mg/kg) or edaravone (3 mg/kg) just after the reperfusion, and examined at 1 and 3 d. Compared with the vehicle group, CuATSM treatment decreased infarct volumes and oxidative stress at 3d after tMCAO, which was further enhanced by combined CuATSM + edaravone treatment as compared with single CuATSM group, but not improve neurobehaviors. The present study demonstrated that CuATSM showed strong antioxidative and neuroprotective effects in acute ischemic stroke, which was enhanced by the combination with edaravone., Competing Interests: Declaration of Competing Interest The authors disclose no potential conflict of interests., (Copyright © 2020 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

The liver is the major organ maintaining metabolic homeostasis in animals during shifts between fed and fasted states. Circadian oscillations in peripheral tissues including the liver are connected with feeding-fasting cycles. We generated transgenic mice with hepatocyte specific E4BP4, D-box negative regulator, overexpression. Liver-specific E4BP4 overexpression was also achieved by adenoviral gene transfer. Interestingly, hepatic E4BP4 overexpression induced marked insulin resistance, that was rescued by DBP, a competing D-box positive regulator, overexpression. At basal conditions hepatocyte E4BP4 transgenic mice exhibited increased gluconeogenesis with reduced AKT phosphorylation in liver. In muscle, AKT phosphorylation was impaired after insulin stimulation. Such muscle insulin resistance was associated with elevated free fatty acid flux from the liver and reduced fatty acid utilization as an energy source during the inactive phase. E4BP4, one of the clock-controlled output genes, are key metabolic regulators in liver adjusting liver and muscle metabolism and insulin sensitivity in the feeding-fasting cycles. Its tuning is critical for preventing metabolic disorders., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Successful osseointegration is essential for dental implants. However, the complete molecular mechanism of osseointegration remains to be elucidated. In this study, we focused on the proteoglycan (PG)-rich layer between titanium oxides (TiOx) and bone, and chondroitin-4-sulfate transferase-1 (C4ST-1), which forms the sugar chain in PGs. Human bone marrow mesenchymal stem cells (hBMSCs) depleted of C4ST-1 were cultured on titanium (Ti) plates, and the interface between hBMSCs and TiOx was analyzed using transmission electron microscopy. Immunotolerance, proliferation, initial adhesion, and calcification of the cells were analyzed in vitro. At 14 days of cultivation, a PG-rich layer was observed between hBMSCs and TiOx. However, the PG-rich layer was reduced in C4ST-1-depleted hBMSCs on TiOx. Real-time RT-PCR showed that conditioned media increased the levels of expression of M1-macrophage markers in human macrophages. However, depletion of C4ST-1 did not affect calcification, cell proliferation, or initial cell adhesion on Ti plates. These results suggested that C4ST-1 in hBMSCs affects their immunotolerance and alters the formation of PG-rich layer formation on TiOx., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Background: The free radical scavenger edaravone is a proven neuroprotective drug for patients with amyotrophic lateral sclerosis (ALS). Our objective was to evaluate the therapeutic effects of edaravone for oxidative stress and anti-oxidative activity in ALS patients., Methods: Twenty-two ALS patients with a disease duration of 2 years, treated by edaravone, and 25 control participants were evaluated according to their clinical scores, including ALS functional rating scale-revised (ALSFRS-R), and serum and cerebrospinal fluid (CSF) markers of oxidative stress dROM and anti-oxidative activity OXY., Results: Serum and CSF markers of anti-oxidative activity OXY were significantly decreased in ALS patients at pre-treatment compared with controls ( ## p < .01), which was improved in the course of edaravone treatment. Both serum and CSF OXY were significantly correlated with ALS clinical scores including ALSFRS-R (*p < .05, **p < .01, ***p < .001). Furthermore, serum OXY at pre-treatment was significantly correlated with a change in the ALSFRS-R score in the sixth cycle of edaravone treatment (*p < .05)., Conclusions: The present study suggests significant correlations between anti-oxidative activity and ALS clinical severity, and the therapeutic efficacy of edaravone for decreased anti-oxidative activity in ALS., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To measure myocardial extracellular volume fraction (ECV) for each region or segment using iodine density image (IDI) with single-source dual-energy computed tomography (DECT) and compare the results with an MRI T1 mapping approach., Materials and Methods: For this prospective study, 79 consecutive heart failure patients referred for MRI were included and 23 patients (14 men, 63 ± 14 years) who underwent both MRI and late contrast enhancement DECT following coronary CT angiography were evaluated. CT-ECV was computed from IDI using late acquisition projection data. MR-ECV was computed from native and post-contrast T1 maps using non-rigid image registration for segments with evaluable image quality from 3.0-T MRI. Regional CT-ECV and MR-ECV were measured based on 16-segment models. CT-ECV and MR-ECV were compared using Pearson correlations. Agreement among methods was assessed using Bland-Altman comparisons., Results: In the 368 segments, although all segments were evaluable on IDI, 37 segments were rated as non-evaluable on T1 maps. Overall, 331 segments were analyzed. Mean CT-ECV and MR-ECV were 31.6 ± 9.1 and 33.2 ± 9.1, respectively. Strong correlations were seen between CT-ECV and MR-ECV for each region, as follows: all segments, r = 0.837; septal, r = 0.871; mid-septal, r = 0.895; anterior, r = 0.869; inferior, r = 0.793; and lateral, 0.864 (all p < 0.001). Differences between CT-ECV and MR-ECV were as follows: all segments, 1.13 ± 4.98; septal, -1.51 ± 4.37; mid-septal, -1.85 ± 4.22; anterior, 2.54 ± 4.89; inferior, 1.2 ± 5.78; and lateral, 2.65 ± 3.98., Conclusion: ECV using DECT and from cardiac MRI showed a strong correlation on regional and segmental evaluations. DECT is useful for characterizing myocardial ECV changes as well as MRI., (Copyright © 2020 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: Peri-prosthetic bone mineral density (BMD) decreases after total knee arthroplasty (TKA). We aimed to specifically compare peri-prosthetic BMD changes between mobile- and fixed-bearing prostheses in patients undergoing oral bisphosphonate therapy, hypothesizing that mobile-bearing components would have a favorable effect on postoperative peri-prosthetic BMD., Methods: This prospective cohort study investigated 30 patients who underwent simultaneous bilateral TKA for primary knee osteoarthritis between December 2007 and September 2012. All patients underwent mobile-bearing TKA in one knee and fixed-bearing TKA in the other and received oral alendronate therapy at a dosage of 35 mg/week. Peri-prosthetic and lumbar spine BMDs were measured using dual X-ray absorptiometry scans, with peri-prosthetic BMD changes being compared between the two prostheses in each patient at six months and one, two, three, and five years post-operation., Results: Clinical results did not significantly differ between two prostheses. Relative change of lumbar spine BMD was significantly greater at five years post-operation than at one year post-operation (p = 0.01), and was significantly correlated at five years post-operation with peri-prosthetic BMD in the central femur (r = 0.39, p = 0.002), posterior femur (r = 0.39, p = 0.002), and medial tibia (r = 0.42, p = 0.007)., Conclusions: There was no difference in peri-prosthetic BMD changes between two prostheses in patients undergoing oral bisphosphonate therapy. Our results suggest that the influence of oral bisphosphonate therapy might offset the influence of prosthetic design. Thus, oral bisphosphonate therapy may be more effective than prosthetic design selection in preventing post-TKA peri-prosthetic BMD loss., Level of Evidence: II., Competing Interests: Declaration of competing interest There were no direct conflicts of interest to report with regard to this study. The other potential conflicts of interests are declared below: Yukihide Minoda: Paid presenter or speaker of Aesculap, Biomet, DePuy, Kyocera, Smith & Nephew, Microport, and Stryker. Other authors: None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Plasmacytoid dendritic cells (pDCs) are characterized by an exclusive expression of nucleic acid sensing Toll-like receptor 7 (TLR7) and TLR9, and production of high amounts of type I interferon (IFN) in response to TLR7/9 signaling. This function is crucial for both antiviral immunity and the pathogenesis of autoimmune diseases. An Ets family transcription factor, i.e., Spi-B (which is highly expressed in pDCs) is required for TLR7/9 signal-induced type I IFN production and can transactivate IFN-α promoter in synergy with IFN regulatory factor-7 (IRF-7). Herein, we analyzed how Spi-B contributes to the transactivation of the Ifna4 promoter. We performed deletion and/or mutational analyses of the Ifna4 promoter and an electrophoretic mobility shift assay (EMSA) and observed an Spi-B binding site in close proximity to the IRF-7 binding site. The EMSA results also showed that the binding of Spi-B to the double-stranded DNA probe potentiated the recruitment of IRF-7 to its binding site. We also observed that the association of Spi-B with transcriptional coactivator p300 was required for the Spi-B-induced synergistic enhancement of the Ifna4 promoter activity by Spi-B. These results clarify the molecular mechanism of action of Spi-B in the transcriptional activation of the Ifna4 promoter., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We investigated differences in the feeding habits of the starspotted smooth-hound, Mustelus manazo, in Tokyo Bay between the mid-1990s (low stock size) and the late 2000s (high stock size). The frequency of M. manazo with empty stomachs increased from 5.9% in the mid-1990s to 16.1% in the late 2000s. A decrease in the relative weight of the stomach contents was evident from the mid-1990s to the late 2000s, especially in the small size classes, along with changes in the species composition in the stomach contents. Although crustaceans were the main constituents of the stomach contents, the proportion of crabs increased while those of shrimps and hermit crabs decreased. Changes in the feeding habits of M. manazo may be associated with shifts in the benthic community structure in Tokyo Bay., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: We aimed to assess the prevalence of myocardial delayed enhancement (MDE) in patients with suspected obstructive coronary artery disease (CAD), and to investigate factors related to the presence or absence of MDE., Methods: We retrospectively evaluated 191 consecutive patients who underwent coronary computed tomography angiography (CCTA) with MDE imaging for clinical suspicion of CAD from December 2014 to December 2016. The presence of MDE on iodine-density images using dual-energy CT was assessed by two independent readers. Multivariable logistic regression analyses were used to determine factors associated with the presence of MDE., Results: MDE was detected in 58 (30%) patients. Male gender, hypertension, prior heart failure (HF) hospitalization, and CCTA-detected CAD were independent factors related to the presence of MDE. When CCTA-detected CAD was excluded to narrow down the analysis to factors obtainable before CCTA, interventricular septum thickness (IVST) ≥12 mm was added as another independent factor. The combination of the following four factors: female gender, no history of hypertension, no history of prior HF hospitalization, and IVST < 12 mm demonstrated high specificity (98.3%) and positive predictive value (96.2%) for predicting the absence of MDE., Conclusions: Male gender, hypertension, prior HF hospitalization, and CAD were independently associated with the presence of MDE in patients with suspected CAD. The combination of female gender, no history of hypertension, no history of prior HF hospitalization, and IVST < 12 mm is likely to be a helpful predictor in discriminating patients without MDE before CCTA., (Copyright © 2019. Published by Elsevier Ltd.)

The Arf (ADP-ribosylation factor) GAPs (GTPase-activating proteins) regulate membrane trafficking and actin cytoskeleton. The molecular mechanism of how Arf GAPs regulate actin cytoskeleton remains to be elucidated. We identified AGAP1, a subtype of Arf GAP, as a binding protein of FilGAP, a Rac-specific GAP, in mammalian cells. AGAP1 binds to C-terminus of FilGAP whereas FilGAP binds to N-terminus of AGAP1 containing GLD domain. FilGAP co-localized with AGAP1 at intracellular vesicles and targeting of FilGAP at the vesicles requires its interaction with AGAP1. Consistently, depletion of endogenous AGAP1 induced the accumulation of endogenous FilGAP into paxillin-positive focal adhesions and actin cytoskeletal structures. Knockdown of endogenous AGAP1 suppressed cell spreading on collagen and the suppression was released by depletion of endogenous FilGAP. Moreover, depletion of AGAP1 in MDA-MB-231 cells promoted cell invasion in extracellular matrices and depletion of FilGAP blocked the invasion. Taken together, the present study suggests that AGAP1 may regulate subcellular localization of FilGAP and control cell migration and invasion through interaction with FilGAP., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Because endovascular abdominal aortic repair (EVAR) lowers the lumbar arterial blood flow, we hypothesized that the volume of the psoas muscle decreases after surgery. When internal iliac artery (IIA) embolization is performed, the lumbar arterial blood flow further decreases; therefore, we also hypothesized that the decrease in the volume of the psoas muscle becomes more significant. This study was performed to assess the volume change in the psoas muscle after EVAR., Methods: Fifty-three consecutive patients who underwent EVAR from January 2016 to December 2016 were included. The psoas muscle volume was measured by preoperative and postoperative computed tomography (CT). Postoperative CT scans were performed 6-12 months after EVAR. Axial CT images with a 2-mm slice thickness were used to measure the psoas muscle volume. Data were transferred to a 3-dimensional workstation, and the psoas muscle volume was measured., Results: In the EVAR group, the volume of the psoas muscle decreased by an average of 5.8 mL (4.6%) from 114.8 ± 32.0 mL preoperatively to 109.0 ± 30.3 mL postoperatively (P < 0.01). There was a significant difference in the change in the psoas muscle volume between patients with and without IIA embolization (embolization group: preoperative 118.1 ± 31.0 mL, postoperative 107.5 ± 29.2 mL, mean volume change rate -8.8%; nonembolization group: preoperative 114.0 ± 32.3 mL, postoperative 109.4 ± 30.7 mL, mean volume change rate -3.6%; P < 0.05)., Conclusions: The psoas muscle volume is reduced with EVAR. Moreover, when the IIA is embolized, the psoas muscle volume is further reduced., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study was conducted to evaluate the linear vestibulo-ocular reflex (lVOR) mediated by the saccule, and to investigate the relationship between the lVOR and the ability to distinguish the direction of centripetal acceleration during centric and eccentric rotation. Participants sat on a chair in darkness, with the right ear facing downwards, either directly above the center of rotation, or with their nose out, nose in, right shoulder out, or left shoulder out against the center of rotation (eccentric rotation). Participants were given no information about the chair position, and were rotated sinusoidally at 0.1-0.7 Hz. Three-dimensional eye movements during rotation were analyzed. Participants were asked to describe the position of the chair after rotation. Correctly reporting the five possible chair positions requires recognition of the direction of centripetal acceleration. We analyzed the rate of correct answers to assess participants' ability to identify the direction of centripetal acceleration. lVOR mediated by the saccule was observed only at high rotational frequencies. The rate of correct answers was higher at high rotational frequencies than that at low rotational frequencies. These results indicate that high rotational frequency is important for both lVOR mediated by the saccule and distinguishing the direction of centripetal acceleration., (Copyright © 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Epithelial cells form a globular organ-like multi-cellular structure called cyst when cultured in extracellular matrix. The cyst generates extension followed by cell chains and tubules in response to hepatocyte growth factor (HGF). The Rho family small GTPases play essential roles for tubulogenesis. FilGAP, a Rac specific Rho GTPase-activating protein, is highly expressed in kidney. In this study, we examined the role of FilGAP in the tubulogenesis of Madin-Darby Canine Kidney (MDCK) epithelial cells. HGF induces basolateral extensions from cysts. Depletion of FilGAP by siRNA increased the number of extensions in response to HGF, whereas forced expression of FilGAP decreased the number of the extensions. FilGAP is phosphorylated and activated downstream of Rho-ROCK-signaling. Overexpression of phospho-mimic FilGAP (ST/D) mutant blocked formation of the membrane extensions induced by HGF in the presence of ROCK inhibitor, Y-27632. On the other hand, treatment of the tubules with Y27632 induced scattering of the cells, but FilGAP (ST/D) blocked cell scattering and promoted lumen formation. Taken together, our study suggests that FilGAP may suppress formation of extensions whereas stabilize tubule formation downstream of Rho-ROCK-signaling., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cerebral neuroinflammation defines a novel pathway for progressing Alzheimer's disease (AD) pathology. We investigated immunohistological changes of neuroinflammation with nucleotide-binding domain and leucine-rich repeat (NLR)-protein 3 (NLRP3), activated caspase-1 and interleukin-1 beta (IL-1β) in a novel AD (APP23) mice with chronic cerebral hypoperfusion (CCH) model from 4 months (M) of age, moreover, examined protective effect of galantamine. CCH strongly enhanced NLRP3, activated caspase-1 and IL-1β expressions in hippocampus and thalamus at age 12 M of AD mice. CCH also exaggerated amyloid-beta (Aβ) 40 depositions in cerebral cortex. Furthermore, CCH exacerbated a marked dissociation of neurovascular unit (NVU). These pathological changes were ameliorated by galantamine treatment. The present study demonstrated that CCH strongly enhanced primary AD pathology including neuroinflammation, Aβ accumulations and NVU dissociation in AD mice, which was greatly protected by an allosterically potentiating ligand galantamine., (Copyright © 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Mitochondrial functions are closely related to the membrane structure. Mitochondrial swelling, which is accompanied with dissipation of the crista structure and rupture of the outer membrane, have been observed as mitochondrial damage when mitochondria are under Ca 2+ -overload or oxidative stress. Although these phenomena have been well studied, the detailed behaviors of individual mitochondria upon swelling remain unknown. The aim of this study was to investigate the detailed behavior of mitochondrial volume upon addition of Ca 2+ . Here, we report for the first time, time-lapse measurements of single mitochondrion swelling and permeability transition induced by Ca 2+ by optical microscopy. We added 220 μM Ca 2+ to mitochondria, and found that 1) the swelling rate depended on the mitochondrion, 2) a small number of mitochondria showed step-like swelling, 3) cyclosporin A decreased the percentage of mitochondria that underwent swelling induced by Ca 2+ , but did not affect the amplitude of swelling, 4) permeability transition is necessary but not sufficient for Ca 2+ -induced swelling, 5) permeability transition is more sensitive to Ca 2+ than swelling, 6) Ca 2+ stimulated mitochondrial swelling after permeability transition. These results suggest that single mitochondrion measurement of swelling is a powerful tool for examining the regulation of mitochondrial structure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate the feasibility of myocardial iodine density and extracellular volume fraction (ECV) from delayed iodine density images using dual-energy computed tomography (DECT) for differentiation between non-ischemic dilated cardiomyopathy (NIDCM) patients and normal subjects., Methods: Forty-six subjects were imaged, including 35 normal subjects and 11 patients with NIDCM. All subjects underwent myocardial delayed enhancement (MDE) imaging on rapid-kVp switching DECT. Global and segmental iodine density and ECV were calculated from MDE images. Histogram analysis was also performed. Receiver-operator characteristic (ROC) analysis was used to determine the cut-off value and diagnostic performances in differentiating NIDCM patients from normal subjects., Results: Global iodine density and ECV were significantly higher in NIDCM compared with normal controls (iodine: 14.19 ± 3.90 vs. 10.69 ± 1.88 in 100 μg/cm 3 , p = 0.015; ECV: 31.35 ± 2.53% vs. 26.62 ± 2.69%, p < 0.001). In histogram analyses, kurtosis was higher in NIDCM than in controls (0.47 ± 0.46 vs. 1.26 ± 0.88, p < 0.001). On segmental analysis, ECV showed higher values in NIDCM than in controls for all segments. ECV could differentiate between normal myocardium and NIDCM with 91.0% sensitivity and 86.0% specificity at a cut-off of 28.82% (area under the curve of ROC, 0.906). Iodine density could differentiate between normal myocardium and NIDCM with 91% sensitivity and 60% specificity at a cut-off of 11.18 (area under the curve of ROC, 0.812)., Conclusions: Iodine density and ECV values from DECT may provide indices offering high diagnostic accuracy for discriminating between NIDCM and normal myocardium., (Copyright © 2019 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)