Publications by authors named "Mitsuhiro Kawata"

157 Publications

Estrogens influence female itch sensitivity via the spinal gastrin-releasing peptide receptor neurons.

Proc Natl Acad Sci U S A 2021 Aug;118(31)

Ushimado Marine Institute, Graduate School of Natural Science and Technology, Okayama University, Setouchi 701-4303, Japan.

There are sex differences in somatosensory sensitivity. Circulating estrogens appear to have a pronociceptive effect that explains why females are reported to be more sensitive to pain than males. Although itch symptoms develop during pregnancy in many women, the underlying mechanism of female-specific pruritus is unknown. Here, we demonstrate that estradiol, but not progesterone, enhances histamine-evoked scratching behavior indicative of itch in female rats. Estradiol increased the expression of the spinal itch mediator, gastrin-releasing peptide (GRP), and increased the histamine-evoked activity of itch-processing neurons that express the GRP receptor (GRPR) in the spinal dorsal horn. The enhancement of itch behavior by estradiol was suppressed by intrathecal administration of a GRPR blocker. In vivo electrophysiological analysis showed that estradiol increased the histamine-evoked firing frequency and prolonged the response of spinal GRP-sensitive neurons in female rats. On the other hand, estradiol did not affect the threshold of noxious thermal pain and decreased touch sensitivity, indicating that estradiol separately affects itch, pain, and touch modalities. Thus, estrogens selectively enhance histamine-evoked itch in females via the spinal GRP/GRPR system. This may explain why itch sensation varies with estrogen levels and provides a basis for treating itch in females by targeting GRPR.
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http://dx.doi.org/10.1073/pnas.2103536118DOI Listing
August 2021

Subcellular dynamics of estrogen-related receptors involved in transrepression through interactions with scaffold attachment factor B1.

Histochem Cell Biol 2021 Jun 15. Epub 2021 Jun 15.

Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.

Estrogen-related receptor (ERR), a member of the nuclear receptor superfamily, consists of three subtypes (α, β, γ) and has strong homology with estrogen receptor. No endogenous ligands have been identified for ERRs, but they play key roles in metabolic, hormonal, and developmental processes as transcription factors without ligand binding. Although subnuclear dynamics are essential for nuclear events including nuclear receptor-mediated transcriptional regulation, the dynamics of ERRs are poorly understood. Here, we report that ERRs show subcellular kinetic changes in response to diethylstilbestrol (DES), a synthetic estrogen that represses the transactivity of all three ERR subtypes, using live-cell imaging with fluorescent protein labeling. Upon DES treatment, all ERR subtypes formed discrete clusters in the nucleus, with ERRγ also displaying nuclear export. Fluorescence recovery after photobleaching analyses revealed significant reductions in the intranuclear mobility of DES-bound ERRα and ERRβ, and a slight reduction in the intranuclear mobility of DES-bound ERRγ. After DES treatment, colocalization of all ERR subtypes with scaffold attachment factor B1 (SAFB1), a nuclear matrix-associated protein, was observed in dot-like subnuclear clusters, suggesting interactions of the ERRs with the nuclear matrix. Consistently, co-immunoprecipitation analyses confirmed enhanced interactions between ERRs and SAFB1 in the presence of DES. SAFB1 was clarified to repress the transactivity of all ERR subtypes through the ERR-response element. These results demonstrate ligand-dependent cluster formation of ERRs in the nucleus that is closely associated with SAFB1-mediated transrepression. Taken together, the present findings provide a new understanding of the pathophysiology regulated by ERR/SAFB1 signaling pathways and their subcellular dynamics.
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http://dx.doi.org/10.1007/s00418-021-01998-7DOI Listing
June 2021

Risk analysis for early mortality in emergency acute type A aortic dissection surgery: experience of Tokyo Acute Aortic Super-network.

Eur J Cardiothorac Surg 2021 Apr 8. Epub 2021 Apr 8.

Tokyo CCU Network Scientific Committee, Tokyo, Japan.

Objectives: We investigated the various pre- and postoperative complications related to early (30-day) mortality after open surgery for acute type A aortic dissection.

Methods: Data from the Tokyo Acute Aortic Super-network database spanning January 2015 to December 2017 were retrospectively reviewed. Pre- and postoperative factors related to early postoperative mortality were assessed in 1504 of 2058 (73.0%) consecutive patients [age: 66.6 (SD: 13.5) years, male: 52.9%] who underwent acute type A aortic dissection repair.

Results: The early mortality rate following surgical repair was 8.9%. According to multivariable analysis, male sex [odds ratio (OR) 1.670, 95% confidence interval (CI) 1.063-2.624, P = 0.026], use of percutaneous circulatory assist devices (n = 116, 7.7%) including extracorporeal membrane oxygenators or intra-aortic balloon pumps (OR 4.857, 95% CI 2.867-8.228, P < 0.001), shock (n = 162, 10.8%) (OR 3.06, 95% CI 1.741-5.387, P < 0.001), cardiopulmonary arrest (n = 41, 2.7%) (OR 7.534, 95% CI 3.407-16.661, P < 0.001), coronary ischaemia (n = 36, 2.3%) (OR 2.583, 95% CI 1.042-6.404, P = 0.041) and cerebral ischaemia (n = 59, 3.9%) (OR 2.904, 95% CI 1.347-6.261, P = 0.007) were independent preoperative risk factors for early mortality, while cardiac tamponade (n = 34, 2.3%) (OR 10.282, 95% CI 4.640-22.785, P < 0.001), cerebral ischaemia (n = 80, 5.3%) (OR 2.409, 95% CI 1.179-4.923, P = 0.016) and mesenteric ischaemia (n = 15, 1.0%) (OR 44.763, 95% CI 13.027-153.808, P < 0.001) were independent postoperative risk factors.

Conclusions: Not only critical preoperative conditions but also postoperative cardiac tamponade and vital organ ischaemia are risk factors for early mortality after acute type A aortic dissection repair.
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http://dx.doi.org/10.1093/ejcts/ezab146DOI Listing
April 2021

Dexmedetomidine for dyspnoea.

BMJ Support Palliat Care 2020 Jun 11. Epub 2020 Jun 11.

Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.

Dexmedetomidine is a selective α-adrenoreceptor agonist with a broad range of effects, including easily controllable sedation, analgesia and anxiolysis. Because of these favorable features, it has replaced traditional sedatives, such as benzodiazepines, and is becoming the first-line sedative for the patients in intensive care units. Terminally ill patients often need sedatives for symptom management, especially for dyspnoea. However, the use of dexmedetomidine in a palliative care setting has rarely been recognised to date. We experienced a patient nearing the end of life due to uncontrollable pulmonary haemorrhage on ventilator, whose dyspnoea was successfully managed by dexmedetomidine in addition to continuous intravenous infusion of oxycodone.
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http://dx.doi.org/10.1136/bmjspcare-2020-002334DOI Listing
June 2020

Scaffold attachment factor B: distribution and interaction with ERα in the rat brain.

Histochem Cell Biol 2020 May 21;153(5):323-338. Epub 2020 Feb 21.

Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.

Scaffold attachment factor (SAFB) 1 and its homologue SAFB2 are multifunctional proteins that are involved in various cellular mechanisms, including chromatin organization and transcriptional regulation, and are also corepressors of estrogen receptor alpha (ERα). Both SAFBs are expressed at high levels in the brain. However, the distributions of SAFB1 and SAFB2 have yet to be characterized in detail and it is unclear whether both proteins interact with ERα in the brain. In this study, we investigated the expression and distribution of both SAFBs and their interaction with ERα in adult male rat brain. Immunohistochemical staining showed that SAFB1 and SAFB2 have a similar distribution pattern and are widely expressed throughout the brain. Double-fluorescence immunohistochemical and immunocytochemical analyses in primary cultures showed that the two SAFB proteins are localized in nuclei of neurons, astrocytes, and oligodendrocytes. Of note, SAFB2 was also found in cytoplasmic regions in these cell lineages. Both SAFB proteins were also expressed in ERα-positive cells in the medial preoptic area (MPOA) and arcuate and ventromedial hypothalamic nuclei. Co-immunoprecipitation experiments revealed that both SAFB proteins from the MPOA reciprocally interact with endogenous ERα. These results indicate that, in addition to a role in basal cellular function in the brain, the SAFB proteins may serve as ERα corepressors in hormone-sensitive regions.
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http://dx.doi.org/10.1007/s00418-020-01853-1DOI Listing
May 2020

Abnormal Posture Relating to the Alignment of Spine and Lower Extremity.

Adv Orthop 2019 25;2019:8460364. Epub 2019 Jul 25.

School of Health Sciences, Bukkyo University, 7 Higashitoganoo-cho, Nakagyo-ku, Kyoto 604-8418, Japan.

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http://dx.doi.org/10.1155/2019/8460364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683802PMC
July 2019

Knee-Hip-Spine Syndrome: Improvement in Preoperative Abnormal Posture following Total Knee Arthroplasty.

Adv Orthop 2019 1;2019:8484938. Epub 2019 Jul 1.

Department of Orthopaedic Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.

An ergonomic upright body posture is maintained by the alignment of the spine, pelvis, and lower extremities, and the muscle strength of body trunk and lower extremities. The posture varies with age because of the degenerative changes in the involved structures and the weakening of the muscles. The compensatory mechanisms underlying these changes have recently been evaluated, and the loss of lumbar lordosis results in spinal kyphosis, pelvic retroversion, hip extension, knee flexion, and ankle dorsiflexion. These mechanisms are referred to as the hip-spine and knee-spine syndromes. The spine, hip, and knee are anatomically connected, and the pain and discomfort of the lower back, hip, and knee frequently arise due to degenerative changes of these structures. Thus, these mechanisms are considered as the knee-hip-spine syndrome. Spinal fusion, total hip arthroplasty, and total knee arthroplasty are the surgical procedures for severe degeneration, and their clinical outcomes for the affected sites are promising. However, despite surgeries, other structures may degenerate and result in complications, such as proximal junctional kyphosis and hip dislocation, following spinal fusion. Therefore, it is necessary to evaluate each patient under specific conditions and to treat each section while considering associations between the target structure and entire body. The purpose of this article is to introduce postural maintenance, variations with age, and improvements with surgical interventions of spine, hip, and knee as the knee-hip-spine syndrome.
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http://dx.doi.org/10.1155/2019/8484938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634073PMC
July 2019

Is systolic blood pressure high in patients with acute aortic dissection on first medical contact before hospital transfer?

Heart Vessels 2019 Nov 6;34(11):1748-1757. Epub 2019 May 6.

Tokyo CCU Network Scientific Committee, Tokyo, Japan.

Acute aortic dissection (AAD) cases are thought to have high blood pressure (BP) on admission; however, little data are available on BP prior to admission. The purpose of this study was to investigate systolic blood pressure (SBP) very early after symptom onset and before hospital transfer in patients with AAD to determine whether SBPs were high, and also whether SBPs were higher or lower compared with SBPs at hospital admission. We obtained results using three-year data derived from the Tokyo Acute Aortic Super Network Database. First, we selected 830 patients with AAD for which the "duration from symptom onset to first medical contact by ambulance crews" (SO-FMC) was within 60 min. We examined the SBPs of such patients. Next, we selected 222 patients with AAD whose SBPs were measured both at FMC, within 15 min after symptom onset, and at hospital admission, and compared SBPs at FMC with those at hospital admission. Among types A (n = 190) and B (n = 117), in patients with an SO-FMC ≤ 15 min, the median SBP was 100 mmHg and 178 mmHg (p < 0.001), respectively; 9% and 50% (p < 0.001) of such patients, respectively, exhibited an SBP ≥ 180 mmHg; and 43% and 10% (p < 0.001) of such patients, respectively, had an SBP < 90 mmHg. Of patients with types A (n = 124) and B (n = 98) AAD whose SBPs were measured both at FMC, within 15 min after symptom onset, and at hospital admission, SBPs at FMC were higher than those at hospital admission for the SBP ≥ 180 mmHg subgroups of both type A (194 mmHg vs. 159 mmHg, p < 0.001) and type B (199 mmHg vs. 186 mmHg, p < 0.001). Approximately 10 min after symptom onset and before hospital transfer, the measured SBPs of many patients with type A AAD were not necessarily high. However, the SBPs of cases with type B AAD were high as previously reported for SBP on admission. In addition, for the subgroup of SBP ≥ 180 mmHg at FMC within 15 min after symptom onset, SBPs at FMC were significantly higher than those at hospital admission for both types A and B; the higher SBP at symptom onset may have been partially associated with being a trigger of AD.
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http://dx.doi.org/10.1007/s00380-019-01419-9DOI Listing
November 2019

A case of HeartMate II implantation in non-dilated left ventricle.

J Artif Organs 2019 Jun 8;22(2):173-176. Epub 2019 Feb 8.

The Department of Cardiothoracic Surgery, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakae-Cho Itabashi-ku, Tokyo, 173-0015, Japan.

Left ventricular assist device is an established therapeutic option for the patient with end-stage heart failure. Recently, durable continuous-flow devices have replaced earlier generation of pulsatile devices and their desirable features are accelerating the utilization of these devices. However, their powerful performance could sometimes induce unfavorable complications such as sucking, especially in not so dilated left ventricle. Special maneuvers such as cannula position and lower pump speed may be reasonable for patients with non-dilated left ventricular, however, those managements have not been established yet to date. Right ventricular failure is also another concern in these devices. We experienced a patient who got a HeartMate II in spade-shaped, non-dilated left ventricle concomitant with right ventricular dysfunction, and successfully managed her.
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http://dx.doi.org/10.1007/s10047-019-01093-8DOI Listing
June 2019

Distribution of endogenous normal tau in the mouse brain.

J Comp Neurol 2019 04 5;527(5):985-998. Epub 2018 Dec 5.

Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.

Tau is a microtubule-associated protein (MAP) that is localized to the axon. In Alzheimer's disease (AD), the distribution of tau undergoes a remarkable alteration, leading to the formation of tau inclusions in the somatodendritic compartment. While the abnormal aggregated tau has been extensively studied in human patient tissues and animal models of AD, how normal tau localizes to the axon, which would be the foundation to understand how the mis-localization occurs, has not been well studied due to the poor detectability of normal unaggregated tau in vivo. Therefore, we developed immunohistochemical techniques that can detect normal mouse and human tau in brain tissues with high sensitivity. Using these techniques, we demonstrate the global distribution of tau in the mouse brain and confirmed that normal tau is exclusively localized to the axonal compartment in vivo. Interestingly, tau antibodies strongly labeled nonmyelinated axons such as hippocampal mossy fibers, while white matters generally exhibited low levels of immunoreactivity. Furthermore, mouse tau is highly expressed not only in neurons but also in oligodendrocytes. With super resolution imaging using the stimulated-depletion microscopy, axonal tau appeared punctate rather than fibrous, indicating that tau decorates microtubules sparsely. Co-labeling with presynaptic and postsynaptic markers revealed that normal tau is not localized to synapses but sparsely distributes in the axon. Taken together, this study reports novel antibodies to investigate the localization and mis-localization of tau in vivo and novel findings of normal tau localization in the mouse brain.
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http://dx.doi.org/10.1002/cne.24577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587864PMC
April 2019

Intranuclear Mobility of Estrogen Receptor: Implication for Transcriptional Regulation.

Acta Histochem Cytochem 2018 Aug 23;51(4):129-136. Epub 2018 Aug 23.

School of Health Sciences, Bukkyo University, Kyoto, Japan.

The estrogen receptor (ER) is a ligand-dependent transcription factor that has two subtypes: ERα and ERβ. ERs regulate transcription of estrogen-responsive genes through interactions with multiple intranuclear components, such as cofactors and the nuclear matrix. Live cell imaging using fluorescent protein-labeled ERs has revealed that ligand-activated ERs are highly mobile in the nucleus, with transient association with the DNA and nuclear matrix. Scaffold attachment factor B (SAFB) 1 and its paralogue, SAFB2, are nuclear matrix-binding proteins that negatively modulate ERα-mediated transcription. Expression of SAFB1 and SAFB2 reduces the mobility of ERα in the presence of ligand. This regulatory machinery is emerging as an epigenetic-like mechanism that alters transcriptional activity through control of intranuclear molecular mobility.
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http://dx.doi.org/10.1267/ahc.18023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160615PMC
August 2018

Combined operation for thymoma with myasthenia gravis and coronary artery disease in an octogenarian.

Geriatr Gerontol Int 2018 06;18(6):975-977

Department of Thoracic Surgery, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.

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http://dx.doi.org/10.1111/ggi.13296DOI Listing
June 2018

Effects of Sex Steroids on the Spinal Gastrin-Releasing Peptide System Controlling Male Sexual Function in Rats.

Endocrinology 2018 04;159(4):1886-1896

Ushimado Marine Institute, Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan.

The gastrin-releasing peptide (GRP) system in the lumbosacral spinal cord controls male sexual function in rats. In contrast, in female rats, GRP neurons could scarcely be detected around puberty when circulating ovarian steroid hormones such as estradiol and progesterone levels are increasing. However, little information is available on feminizing or demasculinizing effects of ovarian steroids on the central nervous system in female puberty and adulthood. In this study, to visualize the spinal GRP neurons in vivo, we generated a GRP-promoter-Venus transgenic (Tg) rat line and studied the effects of the sex steroid hormones on GRP expression in the rat lumbar cord by examining the Venus fluorescence. In these Tg rats, the sexually dimorphic spinal GRP neurons controlling male sexual function were clearly labeled with Venus fluorescence. As expected, Venus fluorescence in the male lumbar cord was markedly decreased after castration and restored by chronic androgen replacement. Furthermore, androgen-induced Venus expression in the spinal cord of adult Tg males was significantly attenuated by chronic treatment with progesterone but not with estradiol. A luciferase assay using a human GRP-promoter construct showed that androgens enhance the spinal GRP system, and more strikingly, that progesterone acts to inhibit the GRP system via an androgen receptor-mediated mechanism. These results demonstrate that circulating androgens may play an important role in the spinal GRP system controlling male sexual function not only in rats but also in humans and that progesterone could be an important feminizing factor in the spinal GRP system in females during pubertal development.
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http://dx.doi.org/10.1210/en.2018-00043DOI Listing
April 2018

Brain atrophy in the visual cortex and thalamus induced by severe stress in animal model.

Sci Rep 2017 10 6;7(1):12731. Epub 2017 Oct 6.

Health Care Center, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.

Psychological stress induces many diseases including post-traumatic stress disorder (PTSD); however, the causal relationship between stress and brain atrophy has not been clarified. Applying single-prolonged stress (SPS) to explore the global effect of severe stress, we performed brain magnetic resonance imaging (MRI) acquisition and Voxel-based morphometry (VBM). Significant atrophy was detected in the bilateral thalamus and right visual cortex. Fluorescent immunohistochemistry for Iba-1 as the marker of activated microglia indicates regional microglial activation as stress-reaction in these atrophic areas. These data certify the impact of severe psychological stress on the atrophy of the visual cortex and the thalamus. Unexpectedly, these results are similar to chronic neuropathic pain rather than PTSD clinical research. We believe that some sensitisation mechanism from severe stress-induced atrophy in the visual cortex and thalamus, and the functional defect of the visual system may be a potential therapeutic target for stress-related diseases.
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http://dx.doi.org/10.1038/s41598-017-12917-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630603PMC
October 2017

Effect of Footprint Preparation on Tendon-to-Bone Healing: A Histologic and Biomechanical Study in a Rat Rotator Cuff Repair Model.

Arthroscopy 2017 Aug 9;33(8):1482-1492. Epub 2017 Jun 9.

Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Purpose: To compare the histologic and biomechanical effects of 3 different footprint preparations for repair of tendon-to-bone insertions and to assess the behavior of bone marrow-derived cells in each method of insertion repair.

Methods: We randomized 81 male Sprague-Dawley rats and green fluorescent protein-bone marrow chimeric rats into 3 groups. In group A, we performed rotator cuff repair after separating the supraspinatus tendon from the greater tuberosity and removing the residual tendon tissue. In group B, we also drilled 3 holes into the footprint. The native fibrocartilage was preserved in groups A and B. In group C, we excavated the footprint until the cancellous bone was exposed. Histologic repair of the tendon-to-bone insertion, behavior of the bone marrow-derived cells, and ultimate force to failure were examined postoperatively.

Results: The areas of metachromasia in groups A, B, and C were 0.033 ± 0.019, 0.089 ± 0.022, and 0.002 ± 0.001 mm/mm, respectively, at 4 weeks and 0.029 ± 0.022, 0.090 ± 0.039, and 0.003 ± 0.001 mm/mm, respectively, at 8 weeks. At 4 and 8 weeks postoperatively, significantly higher cartilage matrix production was observed in group B than in group C (4 weeks, P = .002; 8 weeks, P < .001). In green fluorescent protein-bone marrow chimeric rats in group B, bone marrow-derived chondrogenic cells infiltrated the fibrocartilage layer. Ultimate force to failure was significantly higher in group B (19.7 ± 3.4 N) than in group C (16.7 ± 2.0 N) at 8 weeks (P = .031).

Conclusions: Drilling into the footprint and preserving the fibrocartilage improved the quality of repair tissue and biomechanical strength at the tendon-to-bone insertion after rotator cuff repair in an animal model.

Clinical Relevance: Drilling into the footprint and preserving the fibrocartilage can enhance repair of tendon-to-bone insertions. This method may be clinically useful in rotator cuff repair.
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http://dx.doi.org/10.1016/j.arthro.2017.03.031DOI Listing
August 2017

The Arcuate Nucleus: A Site of Fast Negative Feedback for Corticosterone Secretion in Male Rats.

eNeuro 2017 Jan-Feb;4(1). Epub 2017 Mar 2.

Departamento De Biología Celular y Fisiología, Instituto De Investigaciones Biomédicas, Universidad Nacional Autónoma De México , 04510 Mexico City, Mexico.

Variations in circulating corticosterone (Cort) are driven by the paraventricular nucleus of the hypothalamus (PVN), mainly via the sympathetic autonomic nervous system (ANS) directly stimulating Cort release from the adrenal gland and via corticotropin-releasing hormone targeting the adenohypophysis to release adrenocorticotropic hormone (ACTH). Cort feeds back through glucocorticoid receptors (GRs). Here we show in male Wistar rats that PVN neurons projecting to the adrenal gland do not express GRs, leaving the question of how the ANS in the PVN gets information about circulating Cort levels to control the adrenal. Since the arcuate nucleus (ARC) shows a less restrictive blood-brain barrier, expresses GRs, and projects to the PVN, we investigated whether the ARC can detect and produce fast adjustments of circulating Cort. In low Cort conditions (morning), local microdialysis in the ARC with type I GR antagonist produced a fast and sustained increase of Cort. This was not observed with a type II antagonist. At the circadian peak levels of Cort (afternoon), a type II GR antagonist, but not a type I antagonist, increased Cort levels but not ACTH levels. Antagonist infusions in the PVN did not modify circulating Cort levels, demonstrating the specificity of the ARC to give Cort negative feedback. Furthermore, type I and II GR agonists in the ARC prevented the increase of Cort after stress, demonstrating the role of the ARC as sensor to modulate Cort release. Our findings show that the ARC may be essential to sense blood levels of Cort and adapt Cort secretion depending on such conditions as stress or time of day.
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http://dx.doi.org/10.1523/ENEURO.0350-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334455PMC
October 2017

Fatal fungal endocarditis by Aspergillus udagawae: an emerging cause of invasive aspergillosis.

Cardiovasc Pathol 2017 May - Jun;28:14-17. Epub 2017 Feb 8.

Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.

Aspergillus udagawae has morphological similarities to Aspergillusfumigatus; however, it shows a low susceptibility to common antifungal drugs and poor in vitro sporulation. We present the first reported case of infectious endocarditis caused by A. udagawae. An awareness of this newly described Aspergillus species is vital for further clarification.
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http://dx.doi.org/10.1016/j.carpath.2017.02.002DOI Listing
December 2017

Comparative Anatomy of Gastrin-releasing Peptide Pathways in the Trigeminal Sensory System of Mouse and the Asian House Musk Shrew .

Acta Histochem Cytochem 2016 Dec 22;49(6):181-190. Epub 2016 Dec 22.

Ushimado Marine Institute (UMI), Graduate School of Natural Science and Technology, Okayama University , Ushimado, Setouchi, Okayama 701-4303, Japan.

Gastrin-releasing peptide (GRP) has recently been identified as an itch-signaling molecule in the primary afferents and spinal cord of rodents. However, little information exists on the expression and localization of GRP in the trigeminal somatosensory system other than in rats. We examined the generality of the trigeminal GRP system in mammals using two distinct species, suncus as a model of specialized placental mammals known to have a well-developed trigeminal sensory system and mice as a representative small laboratory animal. We first analyzed the gross morphology of the trigeminal somatosensory system in suncus to provide a brainstem atlas on which to map GRP distribution. Immunohistochemical analyses showed that 8% of trigeminal ganglion neurons in suncus and 6% in mice expressed GRP. Expression was restricted to cells with smaller somata. The GRP-containing fibers were densely distributed in the superficial layers of the caudal part of the trigeminal spinal nucleus (Vc) but rare in the rostral parts, both in suncus and mice. Expression of GRP receptor mRNA and protein was also detected in the Vc of suncus. Taken together, these results suggest that the trigeminal GRP system mediating itch sensation is conserved in mammals.
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http://dx.doi.org/10.1267/ahc.16030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5263228PMC
December 2016

Immunohistochemical profiling of estrogen-related receptor gamma in rat brain and colocalization with estrogen receptor alpha in the preoptic area.

Brain Res 2017 03 21;1659:71-80. Epub 2017 Jan 21.

Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.

Estrogen-related receptor (ERR) is a member of the nuclear receptor superfamily that has strong homology with estrogen receptor (ER) α. Despite the lack of endogenous ligands, ERR serves as transcription factors through their constitutively active structure with or without interaction with ERα. Among the three subtypes of ERR (α, β, and γ), ERRγ is highly expressed in brain, but the distribution of ERRγ is poorly characterized. Therefore, we investigated ERRγ immunoreactivity throughout the rostro-caudal axis in rat brain. Immunohistochemistry revealed localization of ERRγ protein in the cell nucleus, and a ubiquitous distribution of ERRγ in brain regions including the olfactory bulb, cerebrum, brain stem, and cerebellum. Selective intense immunoreactivity was observed in the reticular thalamic nucleus, zona incerta, circular nucleus, interpeduncular nucleus, pontine nucleus, and parasolitary nucleus. Most ERRγ-immunoreactive (ir) regions were also positive for ERα and/or ERβ, which suggests that ERRγ is involved in modulation of estrogen signaling in adult rat brain. Double immunofluorescence demonstrated colocalization of ERRγ with ERα within the anteroventral periventricular nucleus of the preoptic area (AVPV) and medial preoptic nucleus (MPO), which are major target sites for estrogen action. The results of this study suggest that ERRγ function in the brain is affected by estrogens through an interaction with ERα. The findings also provide basic information on brain region-specific ERRγ function.
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http://dx.doi.org/10.1016/j.brainres.2017.01.024DOI Listing
March 2017

Decrease in neuronal spine density in the postpartum period in the amygdala and bed nucleus of the stria terminalis in rat.

Neurosci Lett 2017 02 20;641:21-25. Epub 2017 Jan 20.

Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

In pregnancy and the postpartum period, many women have emotional instability and some suffer from depression. The ovarian steroid hormone milieu is markedly changed during these periods, and this hormonal change may be an important cause of peripartum emotional instability. The amygdala is a central region of emotion, and the bed nucleus of the stria terminalis (BNST), which is considered to be the extended amygdala, is also involved in the emotional response. The amygdala and BNST are well characterized as target brain regions for ovarian steroid hormones, and this suggests that the functional response of neurons in these regions to hormonal fluctuation is affected in the peripartum period. In this study, we investigated the neuronal morphology in the central (CeA) and basolateral (BLA) nucleus of the amygdala and BNST on gestational days 15 (G15) (mid-gestation) and 20 (G20) (late gestation) and 4days after delivery (P4) (early postpartum) in rat. Golgi staining showed that the dendritic spine density, and particularly the number of mature mushroom-type spines, in the CeA, BLA and BNST was significantly decreased at P4, compared with G15 and G20 and with virgin females in the estrous phase in the normal estrous cycle (Est). Interestingly, the presence of pups after delivery influenced the spine density in the BNST. The density was significantly decreased with pup presence compared with pup absence at P4, and compared with G15, G20 and Est. These results provide fundamental insights into the neuronal basis underlying emotional instability during pregnancy and postpartum.
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http://dx.doi.org/10.1016/j.neulet.2017.01.040DOI Listing
February 2017

Investigation of the Longitudinal Relaxation Time of Rat Tibial Cortical Bone Using SWIFT.

Magn Reson Med Sci 2017 Oct 12;16(4):351-356. Epub 2016 Dec 12.

Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.

Sweep imaging with Fourier transform (SWIFT) method has been developed to image tissues with very short T values, such as cortical bone. The purpose of this study was to measure the T value of the rat cortical bone. It was approximately 120 ms on 7.04T. This result could thus be useful for studying bony tissue according to the SWIFT method in the future.
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http://dx.doi.org/10.2463/mrms.tn.2016-0050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743527PMC
October 2017

A Sexually Dimorphic Area of the Dorsal Hypothalamus in Mice and Common Marmosets.

Endocrinology 2016 Dec 11;157(12):4817-4828. Epub 2016 Oct 11.

Division of Life Science (Y.M., C.K.-T.-T., T.T., H.I., I.S., T.S., S.T.), Graduate School of Science and Engineering, Saitama University, Sakura-ku, Saitama 338-8570, Japan; Drug Safety Research Laboratories (S.Y., F.I., A.A.), Shin Nippon Biomedical Laboratories, Ltd, Kagoshima 891-1394, Japan; Department of Anatomy and Neurobiology (K.-I.M., M.K.), Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; Department of Psychosomatic Internal Medicine (G.K., A.I.), Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; and Laboratory of Behavioral Neuroendocrinology (S.O.), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.

We found a novel sexually dimorphic area (SDA) in the dorsal hypothalamus (DH) of mice. The SDA-DH was sandwiched between 2 known male-biased sexually dimorphic nuclei, the principal nucleus of the bed nucleus of the stria terminalis and the calbindin-sexually dimorphic nucleus, and exhibited a female-biased sex difference in neuronal cell density. The density of neurons in the SDA-DH was increased in male mice by orchidectomy on the day of birth and decreased in female mice by treatment with testosterone, dihydrotestosterone, or estradiol within 5 days after birth. These findings indicate that the SDA-DH is defeminized under the influence of testicular testosterone, which acts via both directly by binding to the androgen receptor, and indirectly by binding to the estrogen receptor after aromatization. We measured the activity of SDA-DH neurons with c-Fos, a neuronal activity marker, in female mice during maternal and sexual behaviors. The number of c-Fos-expressing neurons in the SDA-DH of female mice was negatively correlated with maternal behavior performance. However, the number of c-Fos-expressing neurons did not change during female sexual behavior. These findings suggest that the SDA-DH contains a neuronal cell population, the activity of which decreases in females exhibiting higher performance of maternal behavior, but it may contribute less to female sexual behavior. Additionally, we examined the brain of common marmosets and found an area that appears to be homologous with the mouse SDA-DH. The sexually dimorphic structure identified in this study is not specific to mice and may be found in other species.
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http://dx.doi.org/10.1210/en.2016-1428DOI Listing
December 2016

Membrane-bound glucocorticoid receptors on distinct nociceptive neurons as potential targets for pain control through rapid non-genomic effects.

Neuropharmacology 2016 12 21;111:1-13. Epub 2016 Aug 21.

Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany. Electronic address:

Glucocorticoids were long believed to primarily function through cytosolic glucocorticoid receptor (GR) activation and subsequent classical genomic pathways. Recently, however, evidence has emerged that suggests the presence of rapid non-genomic GR-dependent signaling pathways within the brain, though their existence in spinal and peripheral nociceptive neurons remains elusive. In this paper, we aim to systemically identify GR within the spinal cord and periphery, to verify their putative membrane location and to characterize possible G protein coupling and pain modulating properties. Double immunofluorescence confocal microscopy revealed that GR predominantly localized in peripheral peptidergic and non-peptidergic nociceptive C- and Aδ-neurons and existed only marginally in myelinated mechanoreceptive and proprioreceptive neurons. Within the spinal cord, GR predominantly localized in incoming presynaptic nociceptive neurons, in pre- and postsynaptic structures of the dorsal horn, as well as in microglia. GR saturation binding revealed that these receptors are linked to the cell membrane of sensory neurons and, upon activation, they trigger membrane targeted [S]GTPγS binding, indicating G protein coupling to a putative receptor. Importantly, subcutaneous dexamethasone immediately and dose-dependently attenuated acute nociceptive behavior elicited in an animal model of formalin-induced pain hypersensitivity compared to naive rats. Overall, this study provides firm evidence for a novel neuronal mechanism of GR agonists that is rapid, non-genomic, dependent on membrane binding and G protein coupling, and acutely modulates nociceptive behavior, thus unraveling a yet unconsidered mechanism of pain relief.
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http://dx.doi.org/10.1016/j.neuropharm.2016.08.019DOI Listing
December 2016

Erdheim-Chester Disease With Cardiovascular Involvement and BRAF V600E Mutation.

Circ J 2016 Jun 9;80(7):1657-9. Epub 2016 Jun 9.

Department of Cardiovascular Surgery, Tsukuba Memorial Hospital.

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http://dx.doi.org/10.1253/circj.CJ-16-0109DOI Listing
June 2016

Expression of Sex Steroid Hormone Receptors in Vagal Motor Neurons Innervating the Trachea and Esophagus in Mouse.

Acta Histochem Cytochem 2016 Feb 24;49(1):37-46. Epub 2016 Feb 24.

Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine; School of Health Sciences, Bukkyo University, 7, Higashitoganoo-cho, Nishinokyo, Kyoto 604-8418, Japan.

The medullary vagal motor nuclei, the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMV), innervate the respiratory and gastrointestinal tracts. We conducted immunohistochemical analysis of expression of the androgen receptor (AR) and estrogen receptor α (ERα), in relation to innervation of the trachea and esophagus via vagal motor nuclei in mice. AR and ERα were expressed in the rostral NA and in part of the DMV. Tracing experiments using cholera toxin B subunit demonstrated that neurons of vagal motor nuclei that innervate the trachea and esophagus express AR and ERα. There was no difference in expression of sex steroid hormone receptors between trachea- and esophagus-innervating neurons. These results suggest that sex steroid hormones may act on vagal motor nuclei via their receptors, thereby regulating functions of the trachea and esophagus.
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http://dx.doi.org/10.1267/ahc.15037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794553PMC
February 2016

Critical role of androgen receptor in the postnatal period in male sexual behavior in rats.

Neurosci Lett 2015 Nov 19;609:189-93. Epub 2015 Oct 19.

Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Gonadal hormones have a developmental role in organization of the nervous system that regulates sexually dimorphic behavior. It is well known that androgen secreted from testes in the perinatal period is converted to estrogen by aromatase in rodent brain, and that estrogen and its receptor play a pivotal role in masculinization of brain structure and function. Treatment with flutamide, an androgen receptor (AR) antagonist, during the perinatal period inhibits development of malespecific brain structure and function, suggesting that androgen signaling via AR also influences brain masculinization. In this study, we investigated which stage during the postnatal period is critical for androgen signaling in brain masculinization. The postnatal period was designated as postnatal days (PD) 0-22, and divided into stages I (PD 0-7), II (PD 8-14), and III (PD 15-22). Newborn male rats were given flutamide subcutaneously in each stage. After adulthood, the effects of postnatal flutamide treatment on brain masculinization were evaluated byanalysis of male sexual behavior. Continuous inhibition of AR throughout stages I and II caused a robust reduction of the intromission ratio and ejaculation frequency compared with other groups. AR inhibition in stage I, II, or III did not cause any change. AR inhibition had no effect onmount behavior. These results show that stage-specific AR activation in the first two postnatal weeks may contribute to brain masculinization mediating male sexual behavior in adulthood.
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http://dx.doi.org/10.1016/j.neulet.2015.10.040DOI Listing
November 2015

Hepatocyte growth factor/c-met promotes proliferation, suppresses apoptosis, and improves matrix metabolism in rabbit nucleus pulposus cells in vitro.

J Orthop Res 2016 Apr 14;34(4):709-16. Epub 2015 Oct 14.

Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.

The etiology of intervertebral disc (IVD) degeneration is closely related to apoptosis and extracellular matrix degradation in nucleus pulposus (NP) cells. These defects in NP cells are induced by excessive external stressors such as reactive oxygen species (ROS) and inflammatory cytokines. Recently, hepatocyte growth factor (HGF) has been shown to repair damage in various diseases through anti-apoptotic and anti-inflammatory activity. In this study, we investigated the effects of HGF on NP cell abnormality caused by ROS and inflammatory cytokines by using primary NP cells isolated from rabbit IVD. HGF significantly enhanced the proliferation of NP cells. Apoptosis of NP cells induced by H2 O2 or TNF-α was significantly inhibited by HGF. Induction of mRNA expression of the inflammation mediators cyclooxygenase-2 and matrix metalloproteinase-3 and -9 by TNF-α was significantly suppressed by HGF treatment. Expression of c-Met, a specific receptor for HGF, was confirmed in NP cells and was increased by TNF-α, suggesting that inflammatory cytokines increase sensitivity to HGF. These findings demonstrate that activation of HGF/c-Met signaling suppresses damage caused by ROS and inflammation in NP cells through multiple pathways. We further suggest the clinical potential of HGF for counteracting IVD degradation involved in NP cell abnormalities.
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http://dx.doi.org/10.1002/jor.23063DOI Listing
April 2016

Three-dimensional visualization of multiple synapses in thick sections using high-voltage electron microscopy in the rat spinal cord.

Data Brief 2015 Sep 26;4:566-70. Epub 2015 Jul 26.

Ushimado Marine Institute, Graduate School of Natural Science and Technology, Okayama University, Ushimado, Setouchi, Okayama 701-4303, Japan.

This data article contains complementary figure and movies (Supplementary Movies 1-3) related to the research article entitled, "Effective synaptome analysis of itch-mediating neurons in the spinal cord: a novel immunohistochemical methodology using high-voltage electron microscopy" [7]. It is important to show the synaptic connections at the ultrastructural level to understand the neural circuit, which requires the three-dimensional (3-D) analyses in the electron microscopy. Here, we applied a new sample preparation method, a high-contrast en bloc staining according to the protocol of the National Center for Microscopy and Imaging Research (NCMIR), University of California, San Diego, CA, USA to high-voltage electron microscopy (HVEM) tomography in order to examine the 3-D chemical neuroanatomy of the rat spinal cord. Pre-embedding immunoelectron microscopy was used in this study. HVEM has an excellent potential to directly visualize the ultrastructures in semi-thin sections (~5 μm thick), and we have successfully visualized many itch-mediating synaptic connections and neural networks in the spinal cord using "HVEM tomography". Moreover, the methodology used in this study is simple and can be applied in multiple ways. This is an important contribution to ultrastructural investigations of the central nervous system in the present post-genomic age.
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http://dx.doi.org/10.1016/j.dib.2015.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539164PMC
September 2015

Sex differences in cells expressing green fluorescent protein under the control of the estrogen receptor-α promoter in the hypothalamus of mice.

Neurosci Res 2015 Dec 17;101:44-52. Epub 2015 Jul 17.

Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-Okubo, Sakura-ku, Saitama City, Saitama 338-8570, Japan. Electronic address:

Estradiol that originates from testicular testosterone and binds to estrogen receptor-α (ERα) during developing period acts to organize the male-type brain in mice. Here, we examined transgenic mice expressing green fluorescent protein (GFP) under the control of the ERα promoter, in which ERα-expressing cells in the brain can be visualized by GFP. Fluorescence microscopy revealed the existence of many GFP-expressing cells in the medial preoptic area, medial preoptic nucleus (MPN), bed nucleus of the stria terminalis (BNST), and striohypothalamic nucleus (StHy) of adult transgenic mice. Neuronal nuclear antigen, a neuron marker, but not glial fibrillary acidic protein, an astrocyte marker, was mostly expressed by GFP-expressing cells. Analysis of GFP expression area showed that adult females had higher GFP expression in a region including the ventral part of the BNST, StHy, and dorsal part of the MPN than in adult males. Such female-biased sex difference was also found in transgenic pups on postnatal day 5 and 8. The GFP expression area of adult females was decreased by postnatal treatment with testosterone or estradiol. These results indicate that GFP visualizes a sex difference of ERα-expressing neurons. The transgenic mice may be useful for the analysis of the sexual differentiation of the brain.
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http://dx.doi.org/10.1016/j.neures.2015.07.006DOI Listing
December 2015
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