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E7130 is a novel drug candidate with an exceedingly complex chemical structure of the halichondrin class, discovered by a total synthesis approach through joint research between the Kishi group at Harvard University and Eisai. Only 18 months after completion of the initial milligram-scale synthesis, ten-gram-scale synthesis of E7130 was achieved, providing the first good manufacturing practice (GMP) batch to supply clinical trials. This paper highlights the challenges in developing ten-gram-scale synthesis from the milligram-scale synthesis.

Aims: The present study aimed to clarify the relationships between novel and traditional anthropometric indices and insulin sensitivity (SI) in young and middle-aged Japanese persons with normal glucose tolerance (NGT), and middle-aged Japanese persons with NGT and glucose intolerance. Methods: Plasma glucose and insulin levels were measured in 1270 young (age <40 years) and 2153 middle-aged persons with NGT ( n  = 1531) and glucose intolerance ( n  = 622) during a 75-g oral glucose tolerance test. Height (Ht), weight, and waist circumference (WC) were measured. The body mass index (BMI), WC, and the WC/Ht ratio were used as traditional anthropometric indices. A body shape index (ABSI) and the body roundness index (BRI) were calculated as novel indices. Indices of SI (Matsuda index and 1/homeostasis model assessment of insulin resistance) were calculated and compared with anthropometric indices. Results: The ABSI showed a weak correlation with SI indices in all groups. The BRI showed almost the same correlation with SI indices as the BMI, WC, and WC/Ht in all groups. The inverse correlation between each of the anthropometric indices other than ABSI and SI indices was weak in young persons, at 0.16-0.27 (Spearman's ρ values), but strong in middle-aged persons, at 0.38-1.00. On receiver-operating characteristic (ROC) curve analysis for detection of insulin resistance, the ABSI had a lower area under the ROC curve (AUC) than the other anthropometric indices, and the BRI and the WC/Ht ratio showed similar AUCs. The AUCs for the BRI and WC/Ht ratio were the highest in middle-aged men with NGT and glucose intolerance. Conclusions: The BRI, not the ABSI, was better correlated with SI in young and middle-aged Japanese persons. The BRI and WC/Ht ratio were comparable in their correlations with SI and the detection of insulin resistance in the participants of the present study.

Introduction: Sensory disturbance due to injury of the superficial branch of the radial nerve (SBRN) is a donor-site morbidity of the radial forearm (RF) flap. The relationship between the SBRN preservation method and the post-operative sensation at the flap donor-site was retrospectively investigated., Methods: We included 39 patients who underwent head and neck reconstruction with a free RF flap at Hyogo Cancer Center between April 2014 and March 2018. The patients were classified into the following three groups according to the SBRN preservation method: group 1, zero preservation, excision of the entire SBRN; group 2, main trunk preservation, excision of all branches except the main trunk of the SBRN; and group 3, complete preservation, preservation of the entire SBRN. Objective sensations and subjective symptoms at the flap donor-site were analyzed., Results: The mean objective sensory scores were 3.18, 2.97, and 1.78 in groups 1, 2, and 3, respectively. Differences between groups 1 and 3 and between groups 2 and 3 were significant ( p  = 0.0035 and p  = 0.037, respectively). The mean subjective symptom scores were 2.40, 1.33, and 1.40 in groups 1, 2, and 3, respectively. Differences between groups 1 and 2, and between groups 1 and 3 were significant ( p  = 0.032 and p  = 0.019, respectively)., Conclusions: Zero preservation method had a higher risk of subjective symptoms and objective hypoesthesia development at the flap donor-site than the complete preservation method. Despite inevitable objective hypoesthesia, the main trunk preservation prevented the development of subjective symptoms. Complete preservation is optimal for RF flap harvest; however, in case of perforator crossing, main trunk preservation is another option., Competing Interests: None., (© 2023 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

For a long time, ex vivo-expanded peripheral-blood-derived γδT cell (PBγδT)-based immunotherapy has been attractive, and clinical trials have been undertaken. However, the difficulty in expanding cytotoxic γδT cells to an adequate number has been a major limitation to the efficacy of treatment in most cases. We successfully re-generated γδT cells from γδT cell-derived human induced pluripotent stem cells (iPSCs). The iPSC-derived γδT cells (iγδTs) killed several cancer types in a major histocompatibility complex (MHC)-unrestricted manner. Single-cell RNA sequencing (scRNA-seq) revealed that the iγδTs were identical to a minor subset of PBγδTs. Compared with a major subset of PBγδTs, the iγδTs showed a distinctive gene expression pattern: lower CD2, CD5, and antigen-presenting genes; higher CD7, KIT, and natural killer (NK) cell markers. The iγδTs expressed granzyme B and perforin but not interferon gamma (IFNγ). Our data provide a new source for γδT cell-based immunotherapy without quantitative limitation., Competing Interests: Conflict of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Innate and adaptive resistance to cancer therapies, such as chemotherapies, molecularly targeted therapies, and immune-modulating therapies, is a major issue in clinical practice. Subpopulations of tumor cells expressing the receptor tyrosine kinase AXL become enriched after treatment with antimitotic drugs, causing tumor relapse. Elevated AXL expression is closely associated with drug resistance in clinical samples, suggesting that AXL plays a pivotal role in drug resistance. Although several molecules with AXL inhibitory activity have been developed, none have sufficient activity and selectivity to be clinically effective when administered in combination with a cancer therapy. Here, we report a novel small molecule, ER-851, which is a potent and highly selective AXL inhibitor. To investigate resistance mechanisms and identify driving molecules, we conducted a comprehensive gene expression analysis of chemoresistant tumor cells in mouse xenograft models of genetically engineered human lung cancer and human triple-negative breast cancer. Consistent with the effect of AXL knockdown, cotreatment of ER-851 and antimitotic drugs produced an antitumor effect and prolonged relapse-free survival in the mouse xenograft model of human triple-negative breast cancer. Importantly, when orally administered to BALB/c mice, this compound did not induce retinal toxicity, a known side effect of chronic MER inhibition. Together, these data strongly suggest that AXL is a therapeutic target for overcoming drug resistance and that ER-851 is a promising candidate therapeutic agent for use against AXL-expressing antimitotic-resistant tumors., (©2022 American Association for Cancer Research.)

Context: The role of hepatic steatosis (HS) in the initial stages of developing type 2 diabetes remains unclear., Objective: We aimed to clarify the impact of HS indexed by Fatty Liver Index (FLI) and high-normal fasting plasma glucose (FPG) as risk factors for incident prediabetes in a nonobese cohort., Methods: Data from 1125 participants with ADA-defined normal glucose metabolism (median age 52 years; BMI 23.1 kg/m 2 ) were used for retrospective analysis. In the entire population, correlation between normal FPG and FLI was evaluated by multiple regression adjusted for age and sex. Follow-up data from 599 participants in whom 75-g OGTT was repeated 3.7 years later showed that 169 developed prediabetes. This was analyzed by the multivariate Cox proportional hazards model., Results: In the entire population, FLI was positively correlated with FPG ( P  < 0.01): mean FLI increased from 15.8 at FPG 4.2 mmol/L to 31.6 at FPG 5.5 mmol/L. Analysis of the 599 participants (2061 person-years) by Cox model, adjusted for sex, age, family history of diabetes, ISI MATSUDA , and Stumvoll-1, clarified an increased risk of prediabetes with high-normal FPG and FLI. Risk was increased 2.2 times with FLI ≥ 16.5 vs FLI < 16.5, P  < 0.001, and increased 2.1 times in participants with FPG ≥ 5.3 mmol/L, P  < 0.001. Cutoff values (unadjusted) were obtained by ROC at the point of the largest Youden's index using the entire range of the variables., Conclusion: Even among nonobese individuals, HS indexed by FLI and a high-normal FPG (≥ 5.3 mmol/L) are risk factors for prediabetes, independently from insulin., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Spin and lattice are two fundamental degrees of freedom in a solid, and their fluctuations about the equilibrium values in a magnetic ordered crystalline lattice form quasiparticles termed magnons (spin waves) and phonons (lattice waves), respectively. In most materials with strong spin-lattice coupling (SLC), the interaction of spin and lattice induces energy gaps in the spin wave dispersion at the nominal intersections of magnon and phonon modes. Here we use neutron scattering to show that in the two-dimensional (2D) van der Waals honeycomb lattice ferromagnetic CrGeTe 3 , spin waves propagating within the 2D plane exhibit an anomalous dispersion, damping, and breakdown of quasiparticle conservation, while magnons along the c axis behave as expected for a local moment ferromagnet. These results indicate the presence of dynamical SLC arising from the zero-temperature quantum fluctuations in CrGeTe 3 , suggesting that the observed in-plane spin waves are mixed spin and lattice quasiparticles fundamentally different from pure magnons and phonons., (© 2022. The Author(s).)

Background: Non-thrombotic skin paddle necrosis occasionally occurs during mandibular reconstructions with free fibula osteocutaneous flaps. The number of perforators, size of the skin paddle, and ischemia time of the flap are considered as causes of skin paddle necrosis. The importance of donor side selection has also been highlighted. This study aimed to investigate the leading cause of skin paddle necrosis and the optimal reconstructive procedure., Methods: A total of 66 patients who underwent mandibular reconstruction using a free fibula osteocutaneous flap were retrospectively analyzed. Skin paddle necrosis, number of cutaneous perforators, size of the skin paddle, and ischemia time of the flap were investigated. An incorrect "laterality" was defined as a skin paddle (septum) covering the reconstruction plate. Donor-site morbidity was recorded., Results: Skin paddle necrosis occurred in 15.2% of patients. An incorrect laterality was associated with a higher incidence of skin paddle necrosis (odds ratio, 22.0; 95% confidence interval, 2.5-195; p = .005). Donor-site morbidity was noted in 18.8% of the patients, without any significant difference in terms of the donor side with and without skin graft (p = .592). The postoperative activities of daily living were not affected., Conclusions: To prevent skin paddle necrosis, donor side selection is an important safety strategy during mandibular reconstruction with free fibula osteocutaneous flap. The postoperative activities of daily living were found to be little affected by differences in the donor side., (© 2022 Wiley Periodicals LLC.)

Aims: The present study aimed to clarify the relationships between diabetic family history (FH), and dysglycemic response to the oral glucose tolerance test (OGTT), insulin secretion, and insulin sensitivity in young Japanese persons with normal glucose tolerance (NGT)., Methods: We measured plasma glucose (PG) and immunoreactive insulin levels in 1,309 young Japanese persons (age <40 years) with NGT before and at 30, 60, and 120 min during a 75-g OGTT. Dysglycemia during OGTT was analyzed by k-means clustering analysis. Body mass index (BMI), blood pressure (BP), and lipids were measured. Insulin secretion and sensitivity indices were calculated., Results: PG levels during OGTT were classified by k-means clustering analysis into three groups with stepwise decreases in glucose tolerance even among individuals with NGT. In these clusters, proportion of males, BMI, BP and frequency of FH were higher, and lipid levels were worse, together with decreasing glucose tolerance. Subjects with a diabetic FH showed increases in PG after glucose loading and decreases in insulinogenic index and Matsuda index., Conclusions: Dysglycemic response to OGTT by k-means clustering analysis was associated with FH in young Japanese persons with NGT. FH was also associated with post-loading glucose, insulinogenic index, and Matsuda index., Competing Interests: None., (© 2022 The Authors.)

This study aims to test the hypothesis that the effect of excimer laser coronary angioplasty (ELCA) not only vaporizes thrombi and their underlying coronary plaque, it also changes their quality. We performed a series of cross-sectional analyses in 52 lesions in 51 patients before and after ELCA with integrated backscatter-intravascular ultrasound (IB-IVUS). The constituent parts of the plaque can be assessed by IB-IVUS (i.e., calcified, fibrous, lipid) according to integrated backscatter values. Minimum lumen diameter, lumen volume and vessel volume expanded after ELCA, while plaque volume did not significantly decrease. There was also a decrease of 'lipid' component (35.4-30.3%, P < 0.001) and an increase of IB-IVUS-derived 'fibrous' part (34.5-38.3%, P < 0.001). These results may help in understanding plaque change after ELCA. Excimer laser coronary angioplasty seems to contribute to the modification of coronary plaque composition in addition to debulking it., (© 2021. The Author(s).)

This article proposes a process to identify the standing stabilizer, namely, the controller in humans to keep upright posture stable against perturbations. We model the controller as a piecewise-linear feedback system, where the state of the center of mass (COM) is regulated by coordinating the whole body so as to locate the zero-moment point (ZMP) at the desired position. This was developed for humanoid robots and is possibly able to elaborate the fundamental control scheme used by humans to stabilize themselves. Difficulties lie on how to collect motion trajectories in a wide area of the state space for reliable identification and how to identify the piecewise-affine dynamical system. For the former problem, a motion measurement protocol is devised based on the theoretical phase portrait of the system. Regarding the latter problem, some clustering techniques including K -means method and EM (Expectation-and-Maximization) algorithm were examined. We found that a modified K -means method produced the most accurate result in this study. The method was applied to the identification of a lateral standing controller of a human subject. The result of the identification quantitatively supported a hypothesis that the COM-ZMP regulator reasonably models the human's controller when deviations of the angular momentum about the COM are limited., Competing Interests: Author TS is employed by OMRON Corporation. Authors DK and NM are employed by Kawada Robotics Corporation., (Copyright © 2022 Sugihara, Kaneta and Murai.)

We report thermodynamic and neutron scattering measurements of the triangular-lattice quantum Ising magnet TmMgGaO 4 in longitudinal magnetic fields. Our experiments reveal a quasi-plateau state induced by quantum fluctuations. This state exhibits an unconventional non-monotonic field and temperature dependence of the magnetic order and excitation gap. In the high field regime where the quantum fluctuations are largely suppressed, we observed a disordered state with coherent magnon-like excitations despite the suppression of the spin excitation intensity. Through detailed semi-classical calculations, we are able to understand these behaviors quantitatively from the subtle competition between quantum fluctuations and frustrated Ising interactions., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2021 Science China Press. Published by Elsevier B.V. All rights reserved.)

Drug repositioning has recently emerged as a strategy for developing new treatments at low cost. In this study, we used a library of approved drugs to screen for compounds that suppress cardiomyocyte hypertrophy. We identified the antiplatelet drug sarpogrelate, a selective serotonin-2A (5-HT 2A ) receptor antagonist, and investigated the drug's anti-hypertrophic effect in cultured cardiomyocytes and its effect on heart failure in vivo. Primary cultured cardiomyocytes pretreated with sarpogrelate were stimulated with angiotensin II, endothelin-1, or phenylephrine. Immunofluorescence staining showed that sarpogrelate suppressed the cardiomyocyte hypertrophy induced by each of the stimuli. Western blotting analysis revealed that 5-HT 2A receptor level was not changed by phenylephrine, and that sarpogrelate suppressed phenylephrine-induced phosphorylation of ERK1/2 and GATA4. C57BL/6J male mice were subjected to transverse aortic constriction (TAC) surgery followed by daily oral administration of sarpogrelate for 8 weeks. Echocardiography showed that 5 mg/kg of sarpogrelate suppressed TAC-induced cardiac hypertrophy and systolic dysfunction. Western blotting revealed that sarpogrelate suppressed TAC-induced phosphorylation of ERK1/2 and GATA4. These results indicate that sarpogrelate suppresses the development of heart failure and that it does so at least in part by inhibiting the ERK1/2-GATA4 signaling pathway.

Associations of arterial stiffness with glucose, insulin, and proinsulin dynamics during the oral glucose tolerance test (OGTT) remain under debate. The aim of this study was to investigate whether plasma glucose (PG), insulin, and proinsulin (Pro) contribute to arterial stiffness, measured by pulse wave velocity (PWV), in young Japanese persons. PG, immunoreactive insulin (IRI), and Pro levels were determined in 1193 young Japanese subjects (<40 years of age) with normal glucose tolerance or nondiabetic hyperglycemia before and at 30, 60, and 120 min during a 75-g OGTT. Participants were divided into two groups according to the median PWV. Background factors, PG, IRI, and Pro levels during the OGTT, and insulin sensitivity (SI) indices in each group were compared. Several multiple regression analysis models were used to evaluate factors contributing to PWV. All IRI and Pro levels before and after glucose loading and the area under the curve (AUC) values for IRI and Pro increased with higher PWV. 1/HOMA-IR and ISI-Matsuda as measures of SI decreased with higher PWV. The IRI AUC and Pro level before glucose loading (Pro0) were independently associated with PWV, in addition to male sex, heart rate, and mean blood pressure. The IRI AUC had a stronger relationship with PWV than Pro0. The IRI AUC had an independent relationship with PWV, whereas both SI indices did not. Postloading insulinemia, but not reduced SI, was independently associated with arterial stiffness in young Japanese persons., (© 2021. The Author(s).)

Axl and Mer are members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases. Previously, we reported that enzyme-mediated inhibition of Mer by an Axl/Mer dual inhibitor led to retinal toxicity in mice, whereas selective Axl inhibition by compound 1 did not. On the other hand, compound 1 showed low membrane permeability. Here, we designed and synthesized a novel series of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives and evaluated their Axl and Mer inhibitory activities, leading to identification of ER-001259851-000 as a potent and selective Axl inhibitor with drug-likeness and a promising pharmacokinetic profile in mice., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The aim of the study was to investigate the relationship between glucose effectiveness (Sg) and some metabolic parameters in male and female young Japanese. Methods: We measured plasma glucose and immunoreactive insulin levels in 1309 young Japanese persons (age <40 years) with normal glucose tolerance (NGT) before and at 30, 60, and 120 min during a 75 gram oral glucose tolerance test. We also measured serum adiponectin and high-sensitivity C-reactive protein (hsCRP) levels and oral glucose effectiveness (SgI O ), and investigated factors related to SgI O . Results: The results of Spearman correlation analysis revealed that high-density lipoprotein cholesterol (HDL) and adiponectin were positively correlated with SgI O , whereas the proportion of males, body mass index, waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure, triglycerides (TG), and hsCRP were inversely correlated with SgI O . The results of multiple regression analysis indicated negative correlations between SgI O and the proportion of males, WC, and SBP and a positive correlation with HDL. The results of multiple regression analysis excluding WC indicated negative correlations between SgI O and the proportion of males, SBP, and TG and positive correlations with HDL and adiponectin. Conclusions: Sg decreased with a subtle worsening of metabolic parameters, even in young persons with NGT. Decreased Sg may be involved in the development of glucose intolerance in individuals with worse metabolic parameters.

Axl and Mer are a members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases, which, when activated, can promote tumor cell survival, proliferation, migration, invasion, angiogenesis, and tumor-host interactions. Chronic inhibition of Mer leads to retinal toxicity in mice. Therefore, successful development of an Axl targeting agent requires ensuring that it is safe for prolonged treatment. Here, to clarify whether enzyme inhibition of Mer by a small molecule leads to retinal toxicity in mice, we designed and synthesized Axl/Mer inhibitors and Axl-selective inhibitors. We identified an Axl/Mer dual inhibitor 28a, which showed retinal toxicity at a dose of 100 mg/kg in mice. Subsequent derivatization of a pyridine derivative led to the discovery of a pyrimidine derivative, 33g, which selectively inhibited the activity of Axl over Mer without retinal toxicity at a dose of 100 mg/kg in mice. Additionally, the compound displayed in vivo anti-tumor effects without influencing body weight in a Ba/F3-Axl isogenic subcutaneous model., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: The epidemiology of infectious diseases in Japan remains undefined despite the increasing tourism. GeoSentinel, an epidemiological surveillance system for reporting imported infectious diseases, has only two participating facilities in Japan. Although the number of infectious diseases is reported by the National Institute of Infectious Diseases, there is no detailed clinical information about these cases. Therefore, we established J-RIDA (Japan Registry for Infectious Diseases from Abroad) to clarify the status of imported infectious diseases in Japan and provide detailed information., Methods: J-RIDA was started as a registry of imported infectious diseases. Case registration began in October 2017. Between October 2017 and September 2019, 15 medical institutions participated in this clinical study. The registry collected information about the patient's age, sex, nationality, chief complaint, consultation date, date of onset, whether visit was made to a travel clinic before travel, blood test results (if samples were collected), travel history, and final diagnosis., Results: Of the 3046 cases included in this study, 46.7% to Southeast Asia, 13.0% to Africa, 13.7% to East Asia, 11.5% to South Asia, 7.5% to Europe, 3.8% to Central and South America, 4.6% to North America, 3.9% to Oceania, and 2.8% to Central and west Asia. More than 85% of chief complaints were fever and general symptoms, gastrointestinal symptoms, respiratory symptoms, or dermatologic problems. The most common diseases were travelers' diarrhea, animal bite, upper respiratory infection, influenza, and dengue fever., Conclusions: We summarized two-year cases registered in Japan's imported infectious disease registry. These results will significantly contribute to the epidemiology in Japan., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Study Design: A retrospective study., Objective: The aim of this study was to explore the relationship between postoperative neurological disturbance of the upper extremities (NDUE) after cervical laminoplasty and intervertebral foraminal stenosis., Summary of Background Data: The relationship between foraminal stenosis and neurological disturbance in the C5 segment (C5 palsy) has been reported, but the relationship at other levels has not been examined before. We evaluated foraminal stenosis morphologically using three-dimensional computed tomography (3D-CT), alongside other risk factors for NDUE., Methods: We retrospectively reviewed patients treated by open-door laminoplasty at the authors' institution between January and June 2016. NDUE was defined as postoperative motor deterioration and/or newly emerged sensory disturbance within 2 weeks of surgery. Radiological measurements were performed in bilateral intervertebral foramina from C5 to C8, using 3D-CT. Investigation using magnetic resonance imaging (MRI) was also performed., Results: Thirty-one patients were reviewed, and 10 (32.3%) developed NDUE. Nineteen NDUE were observed: seven were in the C5 segment, five in the C6 segment, three in the C7 segment, and four in the C8 segment. Four patients (40%) had NDUE from multiple segments. The mean width of the foramen was 2.60 ± 1.26 mm and 3.66 ± 1.66 mm (P = 0.007), and cross-sectional area was 32.8 ± 10.8 mm and 41.6 ± 12.4 mm (P = 0.003), in symptomatic (n = 19) and nonsymptomatic (n = 187) foramina, respectively. The mean transverse diameter of bony spurs and the maximum shift of the spinal cord on MRI was significantly larger in the NDUE group. The odds ratio of having a foraminal cross-sectional area under 28.0 mm in combination with a maximum spinal shift over 3.10 mm was 14.6 (P < 0.001)., Conclusion: Stenosis of the intervertebral foramen could be a risk factor for NDUE after cervical laminoplasty, and could be aggravated by excessive posterior spinal cord shift., Level of Evidence: 3.

Background: Endocrine hormones are closely associated with homeostasis, so it is important to clarify hormone secretion dynamics in shock. Few reports, however, have examined the dynamics of endogenous hormone secretion relative to prognosis in cardiac arrest patients. Therefore, to clarify the roles of endocrine hormones in out-of-hospital cardiac arrest (OHCA) patients, the concentrations of anterior pituitary, thyroid, and adrenocortical hormones were measured, and their associations with return of spontaneous circulation (ROSC) were examined., Methods: The subjects were OHCA patients transported to our Emergency Department. In addition to conventional clinical laboratory tests, the following were measured: serum TSH, serum free T3, serum free T4 (F-T4), plasma ACTH, serum cortisol, serum GH, serum IGF-1, plasma aldosterone concentration (PAC), and plasma renin activity. The primary endpoint was the presence or absence of ROSC, and the secondary endpoint was 24-hour survival., Results: A total of 29 patients, 17 in the ROSC group and 12 in the non-ROSC group, were studied. There were associations between ROSC and low serum potassium, high F-T4, low cortisol, and low PAC on bivariate analyses. There were associations between ROSC and serum potassium, F-T4, and GH using the step-wise method. On multiple logistic regression analysis, a relationship between ROSC and high serum F-T4 level was identified by both methods. There were also associations between 24-hour survival and both low serum potassium and elevated blood glucose levels., Conclusions: The present findings suggest a possible relationship between the serum F-T4 level and ROSC in OHCA patients. A higher serum F-T4 level might cause an increase in the β -adrenergic response in cardiomyocytes and increased responsiveness to catecholamines and was possibly associated with ROSC., Competing Interests: The authors declare that there are no conflicts of interest in this paper., (Copyright © 2020 Go Koizumi et al.)

Microglia are the primary immune cells of the central nervous system and crucial to proper development and maintenance of the brain. Microglia have been recognized to be associated with neurodegenerative diseases and neuroinflammatory disorders. CX3C chemokine receptor 1 (CX3CR1), which is specifically expressed in microglia, regulates microglia homeostatic functions such as microglial activation and is downregulated in aged brain and disease-associated microglia in rodents, yet its role in human microglia is not fully understood. In this study, we investigated the function of CX3CR1 in human microglia using human induced pluripotent stem (iPS) cell-derived microglia-like cells. Human iPS cell-derived microglia-like cells expressed microglial markers and showed an activated state and phagocytic activity. Using CRISPR/Cas9 genome editing, we deleted CX3CR1 in human iPS cells and found increased inflammatory responses and phagocytic activity in mutant as compared to wild-type microglia-like cells. In addition, the CX3C chemokine ligand 1 (CX3CL1, a ligand for CX3CR1) significantly decreased the upregulation of IL-6 by lipopolysaccharide stimulation in human iPS cell-derived microglia-like cells. These results suggest that CX3CR1 in human microglia may contribute to microglial homeostasis by regulating inflammatory response and phagocytosis., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Purpose: To report the clinical and genetic features of a 9-year-old female Japanese patient with Bardet-Biedl syndrome (BBS)., Methods: Genetic analysis using whole-exome sequencing (WES) was performed for the patient and her parents to identify disease-causing variants. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to investigate the impact of splice-site variants. Comprehensive ophthalmic and systemic examinations, including electroretinography (ERG), were performed., Results: In the patient, WES identified novel compound heterozygous splice-site variants (c.124+2T>G and c.723+2T>G) in the BBS1 gene, and RT-PCR revealed skipping of exons 2 and 8 (p.N17AfsX56 and p.T198&#95;K241del). Each parent had one of the variants. Ophthalmologically, the patient's decimal best-corrected visual acuity was 0.6 in the right eye and 0.4 in the left eye. Funduscopy revealed no apparent retinal degeneration or narrowed blood vessels in the periphery, but macular abnormalities were found on fundus autofluorescence imaging and optical coherence tomography images. Unexpectedly, non-recordable responses in rod ERG were found, with a non-recordable response of the right eye and an extremely reduced and delayed a-wave of the left eye in standard ERG, non-recordable responses in cone ERG, and extremely decreased responses in 30 Hz flicker ERG. Finally, the patient fulfilled four primary features of BBS diagnostic criteria: rod-cone dystrophy, polydactyly, central obesity, and learning disabilities, being diagnosed with BBS., Conclusions: This is the first report of a BBS patient with biallelic splice-site BBS1 variants in the Japanese population. Disparity between funduscopic and ERG findings may be a feature of BBS1-associated rod-cone dystrophy.

Cell lines are powerful tools for research into liver function at the molecular level. However, they are generally unsuitable for rigorously assessing the effects of amino acid composition, because many lines require serum-containing medium for their maintenance. Here, we aimed to investigate the effects of ornithine and arginine, which are included in the characteristic metabolic process in hepatocyte, on a human hepatoma-derived cell line (FLC-4) that can be cultured in serum-free medium. FLC-4 cells were cultured under the following three conditions: + ornithine/ - arginine, - ornithine/ - arginine, and -ornithine/ + arginine. Albumin expression evaluated by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay and showed no obvious differences based on the presence of ornithine or arginine. However, the mRNA levels of two liver-enriched transcription factors (CEBPB and HNF1A), which are involved in regulating albumin expression, were significantly higher in cells grown in medium-containing arginine than that in cells grown in ornithine-containing medium. Western blotting showed that the levels both activating and inhibitory C/EBPβ isoforms were significantly increased in cells grown in arginine medium. Furthermore, we have found that depletion of both ornithine and arginine, the polyamine sources, in the medium did not cause polyamine deficiency. When ornithine and arginine were depleted, albumin production was significantly reduced at the mRNA level, CEBPB mRNA levels were increased, and the level of activating form of C/EBPβ was increased. The results of this study suggest that in hepatocyte, these two amino acids might have different functions, and because of which they elicit disparate cellular responses.

Context: Slight elevations in plasma glucose (PG) manifest in advance of diabetes onset, but abnormalities in immunoreactive insulin (IRI), proinsulin (Pro), and adiponectin dynamics during this stage remain poorly understood., Objective: The objective of this work is to investigate whether IRI and Pro dynamics become abnormal as glucose tolerance deteriorates from within the normal range toward impaired glucose tolerance (IGT), as well as the relationship between PG, and these dynamics and serum adiponectin levels., Design: A cross-sectional study was designed., Setting: This study took place at Jichi Medical University in Japan., Participants and Measurements: PG, IRI, and Pro levels were determined in 1311 young Japanese individuals (age < 40 years) with normal or IGT before and at 30, 60, and 120 minutes during a 75-g oral glucose tolerance test. Participants were assigned to 4 groups according to glucose tolerance, and then background factors, adiponectin levels, insulin sensitivity (SI), and insulin secretion (β) indexes were determined., Results: PG levels as well as IRI and Pro levels 60 and 120 minutes after glucose-loading increased incrementally with deteriorating glucose tolerance. All measures of β and the SI measure index of insulin sensitivity (ISI)-Matsuda decreased incrementally. Serum adiponectin levels were not significantly different among the glucose tolerance groups, but were independently and negatively correlated with fasting glucose., Conclusions: Early β decreased and postloading Pro levels became excessive in a progressive manner as glucose tolerance deteriorated from within the normal range toward IGT., (© Endocrine Society 2020.)

The gamma-aminobutyric acid type B (GABA B ) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABA B receptor agonists is limited by their undesirable side-effects. To clarify whether GABA B receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABA B receptor agonist in FM, we investigated the potential of a novel GABA B receptor PAM, ASP8062, for FM treatment. We examined the in vitro profiles of ASP8062, the effects of a GABA B receptor PAM and an agonist on pain in a rat model of FM, and the sleep/wake cycle, EEG during sleep stages and motor coordination in rats. ASP8062 showed PAM activity on human and rat GABA B receptors. Oral administration of ASP8062 significantly reversed the decrease in muscle pressure threshold in reserpine-induced myalgia rats. The analgesic effects of ASP8062 were significantly blocked by a GABA B receptor antagonist. ASP8062 had a significant effect on motor coordination at a 1000-fold higher dose than the analgesic dose in rats. ASP8062 significantly decreased total REM sleep time and frequency of sleep interruptions, and increased the power in delta waves frequency during non-REM sleep in rats. ASP8062, a novel GABA B receptor PAM, has therapeutic potential to exert analgesic effects with less side-effects compared to GABA B receptor agonists in patients with FM., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A 38-year-old woman who consulted a local doctor with chief complaints of sudden palpitations, headaches, and chest pain is herein presented. After admission, pheochromocytoma crisis was suspected. Since the patient had a history of acute heart failure and had once survived an episode of cardiac arrest, a rapid decrease in the catecholamine levels was needed. After resuscitation, pharmacological therapy with agents such as phentolamine and landiolol was administered, and continuous hemodiafiltration (CHDF) was performed to reduce the catecholamine levels. Elective surgery was then performed, and a positive outcome was achieved. This case suggests that the preoperative use of CHDF to control pheochromocytoma crisis may therefore be effective.

Background: Ghrelin is involved in feeding regulation and energy metabolism and is also known to inhibit insulin secretion (β). However, few clinical studies have demonstrated the relationship between β and ghrelin dynamics. This study tested the hypothesis that, in oral glucose tolerance tests (OGTT), ghrelin dynamics are associated with β., Methods: Subjects were 1145 healthy individuals <40 years old who tested normal on the 75-g OGTT. The following indicators and the ghrelin suppression ratio (GSR) during OGTT were calculated: insulin sensitivity (SI) [1/homoeostasis model assessment of insulin resistance, insulin sensitivity index-Matsuda and 1/fasting insulin (1/FIRI)]; and β [Stumvoll first-phase index (Stumvoll-1), Stumvoll second-phase index and insulinogenic index]. From nine combinations of SI and β, combinations that produce hyperbolic relationships were identified., Results: Stumvoll-1 and 1/FIRI showed a hyperbolic relationship in nonobese subjects, and the product of Stumvoll-1 and 1/FIRI was used as the disposition index (DI). When analyzed by BMI quartiles, post-loading glucose and insulin levels at each time point increased from Q1 (low BMI) through Q4 (high BMI), whereas the DI, ghrelin levels at each time point, and GSR decreased from Q1 to Q4. On multivariate and bivariate analysis, GSR and DI were positive and independent, and fasting ghrelin and FIRI were negatively and independently correlated., Conclusions: Ghrelin dynamics were associated with beta cell function in subjects with normal glucose tolerance. Glucose intolerance in obesity may be due not only to insulin resistance but also to impaired beta cell function associated with abnormalities of ghrelin dynamics., (© 2019 John Wiley & Sons Ltd.)

Background: Body weight loss in patients with obesity improves abnormal glucose tolerance, dyslipidemia and hypertension; however, it is difficult to maintain this loss of body weight. The objective of this study was to examine factors involved in body weight loss and its maintenance in morbidly obese inpatients., Method: The subjects were 31 patients (11 males and 20 females) who were admitted to hospital for obesity management. Factors involved in body weight changes during hospitalization and after discharge were examined retrospectively. The mean age was 58.1 ± 13.6 years and body mass index (BMI) was 40.2 ± 10.2 kg/m 2 . Twenty-four patients were complicated with type 2 diabetes mellitus. Diet therapy was 23.8 ± 3.9 kcal/kg ideal body weight/day., Results: Excess weight loss (EWL) during hospitalization varied from 4.2 to 61.7%. Since EWL was affected by duration of hospital stay, the subjects were divided by the median of EWL per day. The subjects with greater EWL per day had lower body weight, BMI and fat mass on admission in the entire ( n  = 31), diabetic ( n  = 24), and non-diabetic subjects ( n  = 7), respectively. EWL per day was not different between diabetic and non-diabetic subjects. Follow-up data revealed that BMI remained unchanged 3 months after discharge but modestly increased 1 year after discharge, irrespective of EWL per day during hospitalization. In diabetic subjects followed up 1 year after discharge ( n  = 15), the increase in body weight was smaller than that in non-diabetic subjects ( n  = 3)., Conclusion: These results suggest that EWL in morbidly obese inpatients is greater than those with lower baseline BMI and fat mass. The presence of diabetes had no effects on EWL during hospitalization. EWL during hospitalization was not correlated with its maintenance after discharge. Diabetic patients displayed lesser degree of body weight gain after discharge, possibly due to the effects of anti-diabetic medications., Competing Interests: Conflict of interestAll authors declare that they have no conflict of interest., (© The Japan Diabetes Society 2019.)

Changes in imaging findings and hormone levels before and after pheochromocytoma rupture, as well as detailed histopathology of resected tumors, have rarely been reported. A 52-year-old woman developed hypertension and diabetes mellitus in 2014, but despite treatment with antihypertensive and hypoglycemic drugs, good control was not achieved. On April 2, 2016, the patient started to have headaches and palpitations, and on April 6, she visited our hospital. Plain computed tomography (CT) of the abdomen showed a 4-cm, isodense mass in the left adrenal gland, and the patient was hospitalized for further examination. Because the patient had hypertension, tachycardia, and hyperglycemia on admission, therapies for those were started. Catecholamine levels were markedly elevated. However, after the patient developed left flank pain on Day 4, antihypertensive and insulin therapies were no longer required. Plain CT then showed heterogeneous high density areas in the left adrenal mass. On Day 7, 3 meta-iodobenzylguanidine scintigraphy showed no abnormal uptake. On Day 8, contrast CT showed low density areas within the left adrenal tumor and contrast enhancement of the tumor margins, and catecholamine levels were markedly decreased. Elective left adrenal tumor resection was performed on Day 49. The capsule of the resected tumor was ruptured. Histopathology showed widespread hemorrhagic necrosis and viable cell components in the tumor margins. Positive chromogranin A staining of the tumor cells confirmed a diagnosis of pheochromocytoma. This patient displayed remarkable changes in imaging findings and hormone levels before and after pheochromocytoma rupture. Pheochromocytoma rupture and hemorrhagic necrosis were confirmed histopathologically.

Cancer stem cells (CSCs) exhibit tumorigenic potential and can generate resistance to chemotherapy and radiotherapy. A labeled ornithine decarboxylase (ODC, a rate-limiting enzyme involved in polyamine [PA] biosynthesis) degradation motif (degron) system allows visualization of a fraction of CSC-like cells in heterogeneous tumor populations. A labeled ODC degradation motif system allowed visualization of a fraction of CSC-like cells in heterogeneous tumor populations. Using this system, analysis of polyamine flux indicated that polyamine metabolism is active in CSCs. The results showed that intracellular polyamines inhibited the activity of histone lysine 4 demethylase enzymes, including lysine-specific demethylase-1 (LSD1). Chromatin immunoprecipitation with Pol II antibody followed by massively parallel DNA sequencing, revealed the global enrichment of Pol II in transcription start sites in CSCs. Increase of polyamines within cells resulted in an enhancement of ID1 gene expression. The results of this study reveal details of metabolic pathways that drive epigenetic control of cancer cell stemness and determine effective therapeutic targets in CSCs., Competing Interests: Institutional endowments were received from Taiho Pharmaceutical Co., Ltd. (Tokyo, Japan), Evidence Based Medical Research Center Inc. (Osaka, Japan), UNITECH Co., Ltd. (Chiba, Japan), IDEA Consultants, Inc. (Tokyo, Japan), and Kinshu-kai Medical Corporation (Osaka, Japan).

Senior Løken syndrome (SLS) is a heterogeneous disorder characterized by severe retinal degenerations and juvenile-onset nephronophthisis. Genetic variants in ten different genes have been reported as the causes of SLS. Clinical evaluation of a patient with SLS and her unaffected parents revealed that the patient had infantile-onset retinal dystrophy and juvenile-onset nephronophthisis. Other systemic abnormalities included hepatic dysfunction, megacystis, mild learning disability, autism, obesity, and hyperinsulinemia. Whole-exome sequencing identified compound heterozygous SCLT1 variants (c.1218 + 3insT and c.1631A > G) in the patient. The unaffected parents were heterozygous for each variant. Transcript analysis using reverse transcription PCR demonstrated that the c.1218 + 3insT variant leads to exon 14 skipping (p.V383&#95;M406del), while the other variant (c.1631A > G) primarily leads to exon 17 skipping (p.D480EfsX11) as well as minor amounts of two transcripts (6 bps deletion in the last of exon 17 [p.V543&#95;K544del] and exons 17 and 18 skipping [p.D480E, S481&#95;K610del]). Immunohistochemical analysis demonstrated that the Sclt1 protein was localized to the distal appendage of the photoreceptor basal body, indicating a ciliary protein. In conclusion, we identified compound heterozygous splice site variants of SCLT1 in a patient with a new form of ciliopathies that exhibits clinical features of SLS.

Muscle injury accounts for about one-third of total sports-related injuries. The lower limb muscles have one of the highest predisposition for injury in high-level professional athletic sports, such as the National Football League. The commonest group of muscles injured among football players include the hamstrings, followed by the quadriceps. Muscle injuries lead to significant time, off the field and affect return to play. Sports physicians and teams have been keen on assessing such injuries and also relying on multiple tools to safely return the player back to the field. MRI plays a key role in evaluation, follow-up, and assessment for return to play (RTP). In this review, we will discuss details of muscle anatomy, incidence of muscle injuries, injury mechanisms, and use of MRI in assessment, grading, follow-up and in predicting the natural course of muscle injuries in the high-end athletic players. While the use of MRI is clear in diagnosis, and for follow up of muscle injuries, there is some limitation in its ability to predict RTP, based on current MRI classification systems. Footballers who have clinical injuries without MRI evidence of significant muscle injury (grade 0 and 1) have a shorter period of RTP. Injuries classified as high grade (3 and 4) on MRI do not correlate well with time to RTP. Further trials are required to improve the capability of MRI in its prediction of RTP., (Published by Elsevier B.V.)

The electron-doped SrTiO 3 exhibits good thermoelectric properties, which makes this material a promising candidate of an n-type oxide thermoelectric device. Recent studies indicated that only a few percent co-doping of La and Mn in SrTiO 3 substantially reduces the thermal conductivity, thereby greatly improving the thermoelectric figure of merit at room temperature. Our time-of-flight neutron scattering studies revealed that by doping both La and Mn into SrTiO 3 , the inelastic scattering spectrum shows a momentum-independent increase in the low-energy spectral weight approximately below 10 meV. The increase in the low-energy spectral weight exhibits a clear correlation with thermal conductivity. The correlation is attributed to dynamical and local structural fluctuations caused by the Jahn-Teller instability in Mn 3+ ions coupled with the incipient ferroelectric nature of SrTiO 3 , as the origin of the low thermal conductivity.

The aim of this study was to clarify the mechanism of disuse-induced muscle hyperalgesia through the evaluation of the pharmacological behaviour of muscle hyperalgesia profiles in chronic post-cast pain (CPCP) rats with acute and chronic-phase mirror-image muscle hyperalgesia treated with diclofenac (NSAID), pregabalin (an inhibitor of Ca 2+ channel α2δ), and duloxetine (SNRI). After 2 weeks of cast immobilization, the peak cross-sectional area and muscle wet weight of the ipsilateral soleus and gastrocnemius muscles decreased more significantly in CPCP rats than in untreated rats. Histological findings revealed disuse-induced muscle atrophy in CPCP rats. The blood biochemical parameters of CPCP rats in acute and chronic phases did not differ significantly from those of untreated rats. The diclofenac and pregabalin-treated groups exhibited no improvement in acute or chronic muscle hyperalgesia. In contrast, the duloxetine-treated group exhibited an improvement in acute muscle hyperalgesia, but showed no apparent effect on chronic muscle hyperalgesia on ipsilateral or contralateral sides. However, the chronic muscle hyperalgesia was reversed by intrathecal administration of DAMGO (a μ-opioid receptor agonist). The results suggest that chronic muscle hyperalgesia in CPCP rats did not result from an inflammatory mechanism, and there is only a low probability that it's caused by a neuropathic mechanism.

The proto-oncogene c-Myc encodes a short-lived protein c-Myc that regulates various cellular processes including cell growth, differentiation and apoptosis. Degradation of c-Myc is catalyzed by the proteasome and requires phosphorylation of Thr-58 for ubiquitination by E3 ubiquitin ligase, Fbxw7/ FBW7. Here we show that a polyamine regulatory protein, antizyme 2 (AZ2), interacts with c-Myc in the nucleus and nucleolus, to accelerate proteasome-mediated c-Myc degradation without ubiquitination or Thr-58 phosphorylation. Polyamines, the inducer of AZ2, also destabilize c-Myc in an AZ2-dependent manner. Knockdown of AZ2 by small interfering RNA (siRNA) increases nucleolar c-Myc and also cellular pre-rRNA whose synthesis is promoted by c-Myc. AZ2-dependent c-Myc degradation likely operates under specific conditions such as glucose deprivation or hypoxia. These findings reveal the targeting mechanism for nucleolar ubiquitin-independent c-Myc degradation.

Lysophosphatidic acid (LPA) plays an important role in a variety of cellular functions. In particular, LPA5 receptor is highly expressed in spinal cord and dorsal root ganglion, which are associated with pain. This fact prompted us to hypothesize that LPA5 antagonists show analgesic effects. To search for potent LPA5 antagonists with blood brain barrier (BBB) permeability, we conducted high throughput screening (HTS). In HTS campaign, we found a 2H-isoquinoline-1-one scaffold showing antagonistic activity against LPA5 and synthesized a series of 2H-isoquinoline-1-one derivatives and evaluated their LPA5 activities. Among these compounds, compound 7e showed potent LPA5 activity with an IC 50 value of 0.12 μM, and acceptable BBB permeability. Furthermore, it showed effective analgesic effect in a chronic constriction injury rat model. Therefore, 7e may have a potential as novel pain therapeutic approach., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7-dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin-1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE 2 -, PGF 2α -, and AMPA-induced allodynia, while both pregabalin and duloxetine alleviated only PGE 2 -induced allodynia in mice. Similarly, AS2717638 significantly ameliorated static mechanical allodynia and thermal hyperalgesia in rat models of chronic constriction injury (CCI)-induced neuropathic pain. AS2717638 also showed analgesic effects in a rat model of inflammatory pain. These findings suggest that LPA5 antagonists elicit broad analgesic effects against both neuropathic and inflammatory pain. Accordingly, pharmacological LPA5 antagonists are attractive development candidates for potential novel pain therapies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Type 1 diabetes mellitus is a progressive disease caused by the destruction of pancreatic β-cells, resulting in insulin dependency and hyperglycemia. While transplanted bone marrow-derived mesenchymal stem/stromal cells (BMMSCs) have been explored as an alternative therapeutic approach for diseases, the choice of delivery route may be a critical factor determining their sustainability. This study evaluated the effects of intrapancreatic and intravenous injection of human BMMSCs (hBMMSCs) in streptozotocin (STZ)-induced type 1 diabetic mouse model. C57/BL6 mice were intraperitoneally injected with 115 mg/kg STZ on day 0. hBMMSCs (1 × 106 cells) or vehicle were injected into the pancreas or jugular vein on day 7. Intrapancreatic, but not intravenous, hBMMSC injection significantly reduced blood glucose levels on day 28 compared with vehicle injection by the same route. This glucose-lowering effect was not induced by intrapancreatic injection of human fibroblasts as the xenograft control. Intrapancreatically injected fluorescence-labeled hBMMSCs were observed in the intra- and extra-lobular spaces of the pancreas, and intravenously injected cells were in the lung region, although the number of cells mostly decreased within 2 weeks of injection. For hBMMSCs injected twice into the pancreatic region on days 7 and 28, the injected mice had further reduced blood glucose to borderline diabetic levels on day 56. Animals injected with hBMMSCs twice exhibited increases in the plasma insulin level, number and size of islets, insulin-positive proportion of the total pancreas area, and intensity of insulin staining compared with vehicle-injected animals. We found a decrease of Iba1-positive cells in islets and an increase of CD206-positive cells in both the endocrine and exocrine pancreas. The hBMMSC injection also reduced the number of CD40-positive cells merged with glucagon immunoreactions in the islets. These results suggest that intrapancreatic injection may be a better delivery route of hBMMSCs for the treatment of type 1 diabetes mellitus.

KCNH3 (BEC1) is a member of the ether-à-go-go (KCNH) family of voltage-gated K + channels. The aim of this study was to determine the pharmacological profiles in vitro and in vivo of a KCNH3 inhibitor N-(4-fluorophenyl)-N'-phenyl-N''-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine (ASP2905). We analyzed the effects of ASP2905 on channel activity in vitro and its neuropharmacological properties in young and aged rats as well as in mice. ASP2905 potently inhibited potassium currents in CHO cells expressing KCNH3 (IC 50 = 9.0nM). In contrast, ASP2905 (≤ 10μM) minimally bound with low affinities to 55 transmembrane proteins. ASP2905 (0.1µM, 1µM) decreased the frequency of spontaneous inhibitory postsynaptic currents in cultured rat hippocampal neurons. In mice, ASP2905 reversed the disruption of spontaneous alternation behavior induced by MK-801 and scopolamine (minimum effective dose of ASP2905: 0.0625mg/kg, po). ASP2905 ameliorated the cognitive deficits of aged rats in step-through passive avoidance (0.0313 and 0.0625mg/kg, po) and Morris water-maze tasks (0.01mg/kg, po) and effectively penetrated the brain. The mean plasma and brain concentrations of ASP2905 reached their maxima (C max = 0.399ng/ml and 1.77ng/g, respectively) 1h after a single oral administration and then decreased (t 1/2 = 1.5-1.6h) (brain plasma ratio = 2.7-4.9). The present study suggests that ASP2905 is a selective, orally administered inhibitor of KCNH3, which can enhance cognitive performance., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Type 2 diabetes mellitus is a well-known risk factor for atherosclerosis. Intima media thickness (IMT) of the carotid arteries has been widely used for assessing atherosclerotic changes representing cerebro-cardiovascular disease risk. Previous studies have associated the presence of inactive aldehyde dehydrogenase with progression of atherosclerosis and alcohol flushing. However, reports conflict on whether alcohol flushing could potentially modify the degree of atherosclerosis in type 2 diabetic patients., Methods: We retrospectively assessed the relationships among alcohol flushing, IMT, and clinical characteristics in 123 consecutive Japanese type 2 diabetic patients. Alcohol flushing was assessed by standardized questionnaires., Results: Patients with alcohol flushing had lower mean IMT [0.7 (0.65-0.80) vs. 0.8 (0.73-0.90) mm, p  < 0.05], despite having higher triglycerides [132 (94-169) vs. 98 (70-139) mg/dL, p  < 0.01] and lower high-density lipoprotein cholesterol [52 (44-60) vs. 59 (49-67) mg/dL, p  < 0.05] concentration. Patients with alcohol flushing had lower frequency of alcohol intake (45 vs. 76%, p  < 0.0001). Mean IMT was positively associated with age and low-density lipoprotein cholesterol concentration, and negatively with alcohol flushing according to stepwise multiple regression analysis. Alcohol flushing was also independently associated with mean IMT by multivariate analysis., Conclusions: These findings suggest that alcohol flushing is independently associated with lesser degree of carotid atherosclerosis in Japanese type 2 diabetic patients., Competing Interests: Compliance with ethical standardsAll the authors declare that they have no conflict of interest.

Background: Sweat secretion is the major function of eccrine sweat glands; when this process is disturbed (paridrosis), serious skin problems can arise. To elucidate the causes of paridrosis, an improved understanding of the regulation, mechanisms and factors underlying sweat production is required. Pituitary adenylate cyclase-activating polypeptide (PACAP) exhibits pleiotropic functions that are mediated via its receptors [PACAP-specific receptor (PAC1R), vasoactive intestinal peptide (VIP) receptor type 1 (VPAC1R) and VPAC2R]. Although some studies have suggested a role for PACAP in the skin and several exocrine glands, the effects of PACAP on the process of eccrine sweat secretion have not been examined., Objectives: To investigate the effect of PACAP on eccrine sweat secretion., Methods: Reverse transcriptase-polymerase chain reaction and immunostaining were used to determine the expression and localization of PACAP and its receptors in mouse and human eccrine sweat glands. We injected PACAP subcutaneously into the footpads of mice and used the starch-iodine test to visualize sweat-secreting glands., Results: Immunostaining showed PACAP and PAC1R expression by secretory cells from mouse and human sweat glands. PACAP immunoreactivity was also localized in nerve fibres around eccrine sweat glands. PACAP significantly promoted sweat secretion at the injection site, and this could be blocked by the PAC1R-antagonist PACAP6-38. VIP, an agonist of VPAC1R and VPAC2R, failed to induce sweat secretion., Conclusions: This is the first report demonstrating that PACAP may play a crucial role in sweat secretion via its action on PAC1R located in eccrine sweat glands. The mechanisms underlying the role of PACAP in sweat secretion may provide new therapeutic options to combat sweating disorders., (© 2016 British Association of Dermatologists.)

In contrast to the general tendency that six coordinate iron(iii) porphyrin complexes with neutral oxygen ligands adopt a high-spin state in a wide range of temperature, some complexes with substituted pyridine N-oxides have exhibited spin-crossover from high-spin to low-spin states with decreasing temperature both in solution and in the solid state.

Background: The impact of lymphaticovenous anastomosis on lymphedema has yet to be defined. The authors investigated the clinical evidence regarding the effectiveness of lymphaticovenous anastomosis in lower limb lymphedema., Methods: Eighty-four patients (162 limbs; 73 female and 11 male patients) with lower limb lymphedema who underwent multisite lymphaticovenous anastomosis in the authors' clinic between August of 2010 and May of 2014 were included in this retrospective study. Lymphedema was diagnosed using lymphoscintigraphy and indocyanine green lymphography. All lymphaticovenous anastomoses were performed under local anesthesia. The lymphatic vessels that were identified were classified using the normal, ectasis, contraction, and sclerosis type (NECST) classification. Limb circumference, subjective symptoms, and frequency of cellulitis were evaluated., Results: The average patient age was 60 years (range, 24 to 94 years); mean postoperative follow-up period was 18.3 months (range, 6 to 51 months). The postoperative change rate in limb circumference indicated that 67 limbs (47.7 percent) were classified as improved, 35 (27.3 percent) were classified as stable, and 32 (25 percent) were classified as worse. Postoperative interview revealed improvement in subjective symptoms in 67 limbs (61.5 percent), no change in 38 (34.9 percent), and exacerbation in four (3.7 percent). The postoperative mean occurrence of cellulitis was decreased to 0.13 times per year compared with 0.89 preoperatively, which was statistically significant (p = 0.00084). Multiple regression analysis using the postanastomosis limb circumference and NECST classification confirmed the following results: change rate (percent) = -0.40 + (0.30 × N) + (-0.84 × E) + (0.22 × C) + (-0.61 × S)., Conclusion: Lymphaticovenous anastomosis is effective for lower limb lymphedema, in point of limb circumference, subjective symptoms, and the frequency of cellulitis., Clincal Question/level of Evidence: Therapeutic, IV.

In the subgranular zone (SGZ) of the hippocampus, neurogenesis persists throughout life and is upregulated following ischemia. Accumulating evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to recovery after stroke. However, the mechanisms underlying the upregulation of neurogenesis are unclear. We have demonstrated that a neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), exerts a wide range of effects on neural stem cells (NSCs) during neural development. Here, we examined the effects of endogenous and exogenous PACAP in adult NSCs of the SGZ. Immunostaining showed expression of the PACAP receptor PAC1R in nestin-positive NSCs of adult naive mice. PACAP injection into the lateral ventricle increased bromodeoxyuridine (BrdU)-positive proliferative cells in the SGZ. These data suggest that PACAP promoted the proliferation of NSCs. In global ischemia model mice, the number of BrdU-positive cells was increased in wild-type mice but not in PACAP heterozygous knockout mice. The BrdU-positive cells that increased in number after ischemia were immunopositive for SOX2, a marker of NSCs, and differentiated into NeuN-positive mature neurons at 4 weeks after ischemia. These findings suggest that PACAP contributes to the proliferation of NSCs and may be associated with recovery after brain injury.

Antizyme (AZ) regulates cellular polyamines (i.e., putrescine, spermidine, and spermine) through binding to ornithine decarboxylase and subsequent ubiquitin-independent degradation of the enzyme protein by the 26S proteasome. Screening for AZ-binding proteins using a yeast two-hybrid system identified ATP citrate lyase (ACLY), a cytosolic enzyme which catalyzes the production of acetyl-CoA that is used for lipid anabolism or acetylation of cellular components. We confirmed that both AZ1 and AZ2 bind to ACLY and AZ colocalizes with ACLY to the cytoplasm. Unexpectedly, neither AZ1 nor AZ2 accelerated ACLY degradation. Additionally, purified AZ, particularly AZ1, increased the activity of purified ACLY in a dose-dependent manner in vitro, suggesting that AZ activates ACLY through protein-protein interaction. Polyamines themselves had no effect on the ACLY activity in vitro. Knockdown of AZ1 and/or AZ2 in human cancer cells significantly decreased the ACLY activity as well as cellular levels of acetyl-CoA and cholesterol. Our results are the first to show the crosstalk between polyamine and acetyl-CoA metabolism. We hypothesize that AZ may promote acetyl-CoA synthesis to downregulate spermidine and spermine through acetylation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The most common histological diagnosis of bilateral parotid gland neoplasm is Warthin tumor. Bilateral malignant tumors of the parotid gland are extremely rare., Methods: A 60-year-old man presented with a painless mass in the right preauricular area and an MRI scan showed multiple masses in the parotid glands, bilaterally. A standard superficial parotidectomy was performed on the right parotid gland followed by subtotal parotidectomy on the left. The diagnosis was synchronous bilateral epithelial-myoepithelial carcinoma arising in the parotid glands., Results: Histopathology of the tumor on both sides indicated epithelial-myoepithelial carcinoma. There was no evidence of locoregional or remote disease during a 5-year follow-up period., Conclusion: Malignant tumors should be included in the differential diagnosis of bilateral parotid gland tumors. Management of unilateral malignant parotid tumors should involve careful observation of the contralateral parotid gland., (© 2015 Wiley Periodicals, Inc.)