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Gastrointestinal involvement is a rare manifestation of systemic amyloidosis, and few reports have been published on localized amyloidosis of the colon. Only one case report has been published on the long-term prognosis of localized colorectal amyloidosis, and there are no previous reports on localized colorectal ATTR amyloidosis. Here, we report an 80-year-old male with localized colorectal wild-type ATTR amyloidosis who presented with edematous mucosa with vascular changes throughout the colon. He did not exhibit any symptoms or endoscopic exacerbation for 8 years after diagnosis. However, after 8 years, he developed early stage colorectal cancer and cytomegalovirus-associated ulcer. He was treated with endoscopic submucosal dissection, which was relatively challenging due to his hemorrhagic condition and poor elevation of the submucosa caused by amyloid deposits. Since the tumor was completely resected, he will undergo regular follow-up. Our review of 20 previous cases of localized colorectal amyloidosis revealed its clinical features and long-term prognosis. Specifically, ours is the second case of a diffuse pan-colon type of colorectal localized amyloidosis, which may lead to various complications, such as colorectal cancer, over a long period of time, and thus, regular follow-up is necessary.

The strategy of identifying stigmata of recent hemorrhage (SRH) and treating the bleeding source is important for the prevention of rebleeding in colonic diverticular hemorrhage (CDH). However, there are few known reports on SRH identification thus far. This large multicenter study evaluated factors correlated with SRH identification, including observation time during colonoscopy. A total of 392 CDH cases were classified into presumptive CDH (n = 276) or definitive CDH with SRH (n = 116) on the basis of colonoscopy results. Multivariate Cox proportional hazards regression was employed to identify factors correlated with SRH identification. For the endoscopic treatment, endoscopic clips (EC), endoscopic band ligation (EBL) or endoscopic detachable snare ligation (EDSL) was performed. Longer observation time was significantly correlated with SRH identification in multivariate analysis (OR, 10.3 [95% CI: 3.84–27.9], pvs. 31.9%, p=.001), suggesting the importance of identifying SRH and treating the bleeding source for reducing the risk of recurrent bleeding. Long-observation time correlated with SRH identification in this study, in which bowel preparation and water-jet scope and cap attachment are commonly used. This is the first known study to highlight the significance of observation time in the SRH identification rates.

Ulcerative colitis (UC) is an inflammatory bowel disease that causes chronic inflammation in the colon. 5-aminosalicylic acid and immunosuppressive medications such as corticosteroids, immunomodulators, and biologic agents are used to treat these patients. However, patients with UC who receive immunosuppressive medications may be at risk for certain opportunistic infections. Epstein-Barr virus (EBV) is one of those opportunistic infections, and its pathogenic role has been implicated in refractory UC, but its pathogenicity should be further investigated. Here, we report a surgical case of refractory UC that demonstrated a serologically post-infected pattern of EBV at admission but that later had a high load of EBV in both the peripheral blood and colonic mucosa. These findings suggest that EBV may have been reactivated in the colon, after which it damaged the colonic mucosa and aggravated inflammation in this patient with UC. Thus, EBV might lead to severity and a refractory response against corticosteroids and anti-TNFα agents, necessitating emergency surgery. Viral surveillance for EBV in patients with refractory UC may facilitate understanding of the patient's pathophysiology and predicting response to medications, and the development of antiviral intervention for those patients may improve their prognosis.

Treatment of fibromyalgia is an unmet medical need; however, its pathogenesis is still poorly understood. In a series of studies, we have demonstrated that some pharmacological treatments reverse generalized chronic pain but do not affect the lack of morphine analgesia in the intermittent cold stress (ICS)-induced fibromyalgia-like pain model in mice. Here we report that repeated intraperitoneal treatments with mirtazapine, which is presumed to disinhibit 5-hydroxytriptamine (5-HT) release and activate 5-HT1 receptor through mechanisms of blocking presynaptic adrenergic α2 and postsynaptic 5-HT2 and 5-HT3 receptors, completely reversed the chronic pain for more than 4 to 5 days after the cessation of treatments. The repeated mirtazapine treatments also recovered the morphine analgesia after the return of nociceptive threshold to the normal level. The microinjection of small interfering RNA (siRNA) adrenergic α2a receptor (ADRA2A) into the habenula, which showed a selective upregulation of α2 receptor gene expression after ICS, reversed the hyperalgesia but did not recover the morphine analgesia. However, both reversal of hyperalgesia and recovery of morphine analgesia were observed when siRNA ADRA2A was administered intracerebroventricularly. As the habenular is reported to be involved in the emotion/reward-related pain and hypoalgesia, these results suggest that mirtazapine could attenuate pain and/or augment hypoalgesia by blocking the habenular α2 receptor after ICS. The recovery of morphine analgesia in the ICS model, on the other hand, seems to be mediated through a blockade of α2 receptor in unidentified brain regions. SIGNIFICANCE STATEMENT: This study reports possible mechanisms underlying the complete reversal of hyperalgesia and recovery of morphine analgesia by mirtazapine, a unique antidepressant with adrenergic α2 and serotonergic receptor antagonist properties, in a type of intermittently repeated stress (ICS)-induced fibromyalgia-like pain model. Habenula, a brain region which is related to the control of emotional pain, was found to play key roles in the antihyperalgesia, whereas other brain regions appeared to be involved in the recovery of morphine analgesia in the ICS model.

The maintenance of balanced oral homeostasis depends on saliva. A readily available and molecularly rich source of biological fluid, saliva fulfills many functions in the oral cavity, including lubrication, pH buffering, and tooth mineralization. Saliva composition and flow can be modulated by different factors, including circadian rhythm, diet, age, drugs, and disease. Recent events have revealed that saliva plays a central role in the dissemination and detection of the SARS-CoV-2 coronavirus. A working knowledge of saliva function and physiology is essential for dental health professionals.

本研究は，宮城県・岩手県において数百年以上の間，持続的なマネジメントによって維持されてきた屋敷林「居久根（いぐね）」の多面的機能性，特に居久根の植栽構成の工夫と生活文化的価値，防風効果の価値，および鳥類の生息環境としての価値を明らかにした。1）居久根の竹類を除いた樹木構成は針葉樹7割，常緑広葉樹2割，落葉広葉樹1割であった。居久根の北西側に枝葉の細かいスギやアスナロなど常緑針葉樹を多数植栽することで防風効果を高めると同時にこれらの樹種は建築材として活用され，スギ下に植えられたタケ類は防風用として，かつ農業・漁業の道具として活用されていた。潮風に強いヤブツバキやマサキ，湿地帯に適応したハンノキを植栽する工夫がみられた。2）居久根の内外の気象データの解析から，居久根は冬季の季節風を7-9割減速させ，居久根内の母屋に安定した居住環境をもたらしていることを明らかにした。さらに3次元GISとCFD（Computational Fluid Dynamics）による風況解析シミュレーションによって居久根の防風効果と風の流れを可視化することで，減速域が風下側に約100 m以上の距離にまで広がっていることがわかった。3）冬季鳥類の生息環境としての居久根の機能を明らかにするため，水田域内の農地，居久根が含まれる水田域内の農地，丘陵樹林地の異なる3つの環境を対象に調査した。その結果，居久根が含まれる農地で31種が確認され，地点当たりの確認種数は水田域内の農地よりも多く，居久根は樹林内や林縁を好む種の生息場所として機能していた。今日の大災害時代の我が国においてグリーンインフラとしての多面的機能性を有する居久根は，気候変動の緩和と適応や災害に対するレジリエンスをはじめ，屋敷林文化の価値，野生動物の生息場所の提供，故郷の風景の再生や愛郷心に大いに貢献できると考えられる。, Homestead trees and hedges, known as “Igune”, have been a feature of the traditional rural landscape in the Miyagi and Iwate prefectures for at least 400 years. We evaluated the green infrastructure value of the multiple benefits provided by Igune. In particular, we concentrated on the cultural and lifestyle values, windbreak effects, and habitat for forest and forest-edge living birds. Our findings show that 1) conifer trees account for about 70% of Igune trees, evergreen broadleaved trees for about 20% and deciduous broadleaved trees for about 10% of all Igune tree types, excluding bamboos. Fine foliaged conifer trees such as Cryptomeria japonica were found to be planted on the northwest side of the Igune to enhance windbreak effects and for use in building materials. Bamboos were also planted to serve as windbreaks under the Cryptomeria japonica and are used for making agricultural and fishery implements. Camellia japonica and Euonymus japonicus are particularly robust against onshore winds, and the wetland-adapted Alnus japonica is a common Igune tree in wetter areas and is planted to improve poor soils. We found that farmers’ wisdom and techniques combine to make the most of species characteristics whilst helping preserve and reinforce traditional lifestyles and cultural values. 2) Igune homestead trees, shrubs and hedgerows provide effective windbreaks : winter wind speeds were found to be reduced by 70-90%, creating a stable and habitable residential area within the bounds of the Igune. Wind dynamics were simulated by three-dimensional GIS and CFD analysis. We found that the reduced wind speed area extended more than 100 m on the leeward side of the Igune. 3) We compared bird species richness, individual abundance and species diversity index among three landscape habitats including open paddy fields, paddy fields where Igune trees and shrubs were present, and forest. These habitat types differed significantly with respect to bird species richness and diversity index. Forest and paddy fields having Igune both had higher species richness than the open paddy fields, but no significant differences in mean bird abundance were found between the habitats. These results suggets that Igune provide habitat for some forest-living birds. The green infrastructure of Igune homestead trees can clearly contribute to climate change mitigation and adaptation, and delivers simultaneous cultural, traditional, and biodiversity co-benefits, which together can support the regeneration of regional landscape identities.

Radiation therapy for head and neck cancers causes salivary gland dysfunction leading to permanent xerostomia. Limited progress in the discovery of new therapeutic strategies is attributed to the lack of in vitro models that mimic salivary gland function and allow high-throughput drug screening. We address this limitation by combining engineered extracellular matrices with microbubble (MB) array technology to develop functional tissue mimetics for mouse and human salivary glands. We demonstrate that mouse and human salivary tissues encapsulated within matrix metalloproteinase-degradable poly(ethylene glycol) hydrogels formed in MB arrays are viable, express key salivary gland markers, and exhibit polarized localization of functional proteins. The salivary gland mimetics (SGm) respond to calcium signaling agonists and secrete salivary proteins. SGm were then used to evaluate radiosensitivity and mitigation of radiation damage using a radioprotective compound. Altogether, SGm exhibit phenotypic and functional parameters of salivary glands, and provide an enabling technology for high-content/throughput drug testing., Song, Uchida, and Sharipol et al. develop functional tissue mimetics for mouse and human salivary glands by combining engineered extracellular matrices with microbubble array technology. The resulting tissue mimetics emulate phenotype and function of salivary glands and provide promise for high-content/throughput drug testing.

Treatment of fibromyalgia is an unmet medical need; however, its pathogenesis is still poorly understood. In a series of studies, we have demonstrated that some pharmacological treatments reverse generalized chronic pain but do not affect the lack of morphine analgesia in the intermittent cold stress (ICS)-induced fibromyalgia-like pain model in mice. Here we report that repeated intraperitoneal treatments with mirtazapine, which is presumed to disinhibit 5-hydroxytriptamine (5-HT) release and activate 5-HT1 receptor through mechanisms of blocking presynaptic adrenergic

Because of the ageing society, the number of elderly deaths in isolation is increasing and becoming a major problem in Japan. We conducted a quantitative survey in the neighborhood associations to see the likelihood of ICT service introduction in the context of neighborhood monitoring to support the elderly who is living alone. Two local communities in Kawasaki city were selected and the questionnaire was distributed in every household of the associations (250~400 households). The result illustrated that there is a great interest of neighborhood monitoring in urban area contrary to our expectations. Both associations showed that the communities are ageing, however certain amount of residents are using smartphones even if they are categorized as the elderly. Therefore, we concluded the introduction of ICT for neighborhood monitoring in the area is possible.

Progress in the development of salivary gland regenerative strategies is limited by poor maintenance of the secretory function of salivary gland cells (SGCs) in vitro. To reduce the precipitous loss of secretory function, a modified approach to isolate intact acinar cell clusters and intercalated ducts (AIDUCs), rather than commonly used single cell suspension, was investigated. This isolation approach yielded AIDUCs that maintain many of the cell-cell and cell-matrix interactions of intact glands. Encapsulation of AIDUCs in matrix metalloproteinase (MMP)-degradable PEG hydrogels promoted self-assembly into salivary gland mimetics (SGm) with acinar-like structure. Expression of Mist1, a transcription factor associated with secretory function, was detectable throughout the in vitro culture period up to 14 days. Immunohistochemistry also confirmed expression of acinar cell markers (NKCC1, PIP and AQP5), duct cell markers (K7 and K5), and myoepithelial cell markers (SMA). Robust carbachol and ATP-stimulated calcium flux was observed within the SGm for up to 14 days after encapsulation, indicating that secretory function is maintained. Though some acinar-to-ductal metaplasia was observed within SGm, it was reduced compared to previous reports. In conclusion, cell-cell interactions maintained within AIDUCs together with the hydrogel microenvironment may be a promising platform for salivary gland regenerative strategies.

Salivary secretion displays day-night variations that are controlled by the circadian clock. The central clock in the suprachiasmatic nucleus (SCN) regulates daily physiological rhythms by prompting peripheral oscillators to adjust to changing environments. Aquaporin 5 (Aqp5) is known to play a key role in salivary secretion, but the association between Aqp5 and the circadian rhythm is poorly understood. The aim of our study was to evaluate whether Aqp5 expression in submandibular glands (SMGs) is driven by the central clock in the SCN or by autonomous oscillations. We observed circadian oscillations in the activity of period circadian protein homolog 2 and luciferase fusion protein (PER2::LUC) in cultured SMGs with periodicity depending on core clock genes. A daily rhythm was detected in the expression profiles of Aqp5 in SMGs in vivo. In cultured SMGs ex vivo, clock genes showed distinct circadian rhythms, whereas Aqp5 expression did not. These data indicate that daily Aqp5 expression in the mouse SMG is driven by the central clock in the SCN.

Adenosine deaminase acting on RNA (ADAR) enzymes, ADAR1 and ADAR2, mediates adenosine-to-inosine RNA editing, and their mRNA expressions are altered during developmental, physiological, and pathophysiological processes in the nervous system. The present study attempted to investigate the involvement of epigenetic modifying enzymes, such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC), in the regulation of ADAR1 and ADAR2 mRNA expressions in neuronal cells. Using human neuronal SH-SY5Y cells, we found that the DNMT inhibitor 5-aza-2'-deoxycytidine led to an increase in ADAR2, but not ADAR1, mRNA expression in a concentration-dependent and time-dependent manner. However, treatment with HDAC inhibitor trichostatin A elicited an increase in ADAR2 mRNA expression and a decrease in ADAR1 mRNA expression, and these changes were blocked by actinomycin D, a transcription inhibitor. Taken together, these findings suggest that ADAR1 and ADAR2 expressions are subject to different regulations by DNMT and HDAC enzymes in neuronal SH-SY5Y cells.

Gastrin-releasing peptide (GRP) receptor-expressing (GRPR)(+) neurons have a central role in the spinal transmission of itch. Because their fundamental regulatory mechanisms are not yet understood, it is important to determine how such neurons are excited and integrate itch sensations. In this study, we investigated the mechanisms for the activation of itch-responsive GRPR(+) neurons in the spinal dorsal horn (SDH). GRPR(+) neurons expressed the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) containing the GluR2 subunit. In mice, peripherally elicited histaminergic and non-histaminergic itch was prevented by intrathecal (i.t.) administration of the AMPAR antagonist NBQX, which was consistent with the fact that firing of GRPR(+) neurons in SDH under histaminergic and non-histaminergic itch was completely blocked by NBQX, but not by the GRPR antagonist RC-3095. Because GRP(+) neurons in SDH contain glutamate, we investigated the role of GRP(+) (GRP(+)/Glu(+)) neurons in regulating itch. Chemogenetic inhibition of GRP(+) neurons suppressed both histaminergic and non-histaminergic itch without affecting the mechanical pain threshold. In nonhuman primates, i.t. administration of NBQX also attenuated peripherally elicited itch without affecting the thermal pain threshold. In a mouse model of diphenylcyclopropenone (DCP)-induced contact dermatitis, GRP, GRPR, and AMPAR subunits were upregulated in SDH. DCP-induced itch was prevented by either silencing GRP(+) neurons or ablation of GRPR(+) neurons. Altogether, these findings demonstrate that GRP and glutamate cooperatively regulate GRPR(+) AMPAR(+) neurons in SDH, mediating itch sensation. GRP–GRPR and the glutamate–AMPAR system may play pivotal roles in the spinal transmission of itch in rodents and nonhuman primates.

cGMP-dependent kinase-I (cGKI) is known to regulate spinal pain processing. This enzyme consists of two isoforms (cGKIα and cGKIβ) that show distinct substrate specificity and tissue distribution. It has long been believed that the α isoform is exclusively expressed in the adult dorsal root ganglion. The aim of the present study was to reexamine the expression of cGKI isoforms in the adult mouse dorsal root ganglion using isoform-specific cGKI antibodies whose specificities had been validated in the previous studies. Immunoblot and immunohistochemical analyses revealed the presence of both isoforms in the dorsal root ganglion. Moreover, cGKIα was found to be mainly expressed within the cytoplasm of small- to medium-sized peptidergic and nonpeptidegic C-fibers, whereas cGKIβ was located within the nuclei of a wide range of dorsal root ganglion neurons. In addition, glutamine synthetase-positive satellite glial cells expressed both isoforms to varying degrees. Finally, using an experimental model for neuropathic pain produced by L5 spinal nerve transection, we found that cGKIα expression was downregulated in the injured, but not in the uninjured, dorsal root ganglion. In contrast, cGKIβ expression was upregulated in both the injured and uninjured dorsal root ganglions. Also, injury-induced cGKIβ upregulation was found to occur in small-to-medium-diameter dorsal root ganglion neurons. These data thus demonstrate the existence of two differently distributed cGKI isoforms in the dorsal root ganglion, and may provide insight into the cellular and molecular mechanisms of pain.

Treatment of fibromyalgia is an unmet medical need. To develop novel therapies for the treatment of fibromyalgia, we explored pain therapeutic actions of existing pharmaceuticals, which inhibit the somatic symptoms frequently observed in fibromyalgia patients. This study first examined the therapeutic actions of pilocarpine, which inhibits dry-eye and dry-mouth symptoms, using an experimental fibromyalgia-like chronic pain model produced by intermittent cold stress (ICS) in mice. A single intraperitoneal and intracerebroventricular, but not intrathecal, pilocarpine administration attenuated ICS-induced thermal hyperalgesia and mechanical allodynia, and this action was abolished by muscarinic antagonist pirenzepine (i.c.v.). Treatment with 1-10 μg/kg donepezil (i.p.), which can easily penetrate into the brain, also showed similar therapeutic effects. Importantly, we found that both pilocarpine and donepezil produced antihyperalgesic effects via supraspinal action. Furthermore, repeated donepezil treatments completely cured the ICS-induced hyperalgesia and allodynia even after the cessation of drug treatments. Acute and chronic treatments of these cholinomimetics had no effects on the nociceptive threshold in control animals. By contrast, the lack of morphine (i.c.v.) analgesia initially observed in the ICS model remained in ICS model mice treated with long-term donepezil. Collectively, these findings suggest that stimulation of the muscarinic cholinergic system effectively inhibits some mechanisms underlying chronic pain in the ICS model, but does not inhibit the lack of descending pain-inhibitory mechanisms, which are driven by central morphine.

Amyloidosis is a protein conformational disorder with the distinctive feature of extracellular accumulation of amyloid fibrils that come from different proteins. In the ligamentum flavum of the lumbar spine, amyloid deposits were frequently found in elderly patients with lumbar spinal canal stenosis and were at least partially formed by wild-type transthyretin. However, how amyloid deposits in the ligamentum flavum affect lumbar spinal canal stenosis has remained unclear. In this study, we analyzed clinical, pathologic, and radiologic findings of patients with lumbar spinal canal stenosis who had amyloid deposits in the ligamentum flavum. We studied 95 ligamentum flavum specimens obtained from 56 patients with lumbar spinal canal stenosis and 21 ligamentum flavum specimens obtained from 19 patients with lumbar disk herniation. We evaluated histopathologic findings and clinicoradiologic manifestations, such as thickness of the ligamentum flavum and lumbar spinal segmental instability. We found that all 95 ligamentum flavum specimens resected from patients with lumbar spinal canal stenosis had amyloid deposits, which we classified into two types, transthyretin-positive and transthyretin-negative, and that transthyretin amyloid formation in the ligamentum flavum of patients with lumbar spinal canal stenosis was an age-associated phenomenon. The amount of amyloid in the ligamentum flavum was related to clinical manifestations of lumbar spinal canal stenosis, such as thickness of the ligamentum flavum and lumbar spinal segmental instability, in the patients with lumbar spinal canal stenosis with transthyretin-positive amyloid deposits. To our knowledge, this report is the first to show clinicopathologic correlations in transthyretin amyloid deposits of the ligamentum flavum. In conclusion, transthyretin amyloid deposits in the ligamentum flavum may be related to the pathogenesis of lumbar spinal canal stenosis in elderly patients.

Neuropathic pain is characterized by complicated combination of positive (e.g., hyperalgesia and allodynia) and negative (e.g., hypoesthesia and hypoalgesia) symptoms, and is often refractory to conventional pharmacological agents, including morphine. Although the molecular mechanisms for positive symptoms are extensively studied, those for negative symptoms are poorly understood. There is convincing evidence that altered gene expression within peripheral and central nervous systems is a key mechanism for neuropathic pain; however, its transcriptional mechanisms are poorly understood. Epigenetic modifications, such as DNA methylation and histone modifications (e.g., acetylation, methylation, and phosphorylation), are known to cause stable gene expression via chromatin remodeling. These mechanisms have a role not only in the determination of developmental cell fates, but also in the physiological and pathological processes in nervous system. Moreover, epigenetic therapies using epigenetic modifying compounds are progressively advanced in the treatments of diverse diseases, including cancer and neurological diseases. Importantly, there is emerging evidence that a variety of genes undergo epigenetic regulation via DNA methylation and histone modifications within peripheral and central nervous systems, thereby contributing to the alterations in both pain sensitivity and pharmacological efficacy in neuropathic pain. In this review, we will highlight the epigenetic gene regulation underlying neuropathic pain, especially focusing on the negative symptoms. Moreover, we will discuss whether epigenetic mechanisms can serve as a potential target to treat neuropathic pain.

The crack-healing behavior of SiN/SiC nanolaminated thin films in a high-temperature environment was investigated. Laminated films with a thickness of 1 μm were fabricated on a silicon substrate by ion-beam-assisted deposition. The number of layers was fixed to four, and the bilayer ratio of SiN to SiC was set to either 1 or 3. Cracked samples were heated in an air atmosphere at 600–1200 °C. In the case of the SiN/SiC nanolaminated film, the crack was perfectly filled with the oxide by heating at 1000 °C, whereas the crack of the SiN film was not healed. Moreover, the filled crack length of the SiN/SiC laminated film with a bilayer ratio of 1 was longer than that of the same type of film with a bilayer ratio of 3. These results suggest that inserting SiC layers in SiN films may confer crack-healing ability to SiN thin films. Moreover, the influence of heating on crack‐healing was investigated systematically. Crack‐healing was improved with increasing heating temperature and time.

The influence of functionally graded TiN coating on fretting fatigue behavior of titanium alloy was investigated. The coating was deposited using an ion beam assisted deposition technique. TiN film was fabricated by an electron beam evaporation of titanium and simultaneous nitrogen ion bombardment. An acceleration voltage of ion beam was set at 0.2 or 2.0 keV. The functionally graded layer was fabricated by varying the mixing ratio of nitrogen/argon ion beam. The mixed layer became thicker by an increase in acceleration voltage. The adhesive strength and wear resistance were improved with an increase in the acceleration voltage. Moreover, they were significantly improved by inserting the functionally graded layer. The fretting fatigue tests were conducted using a four-point bending fatigue testing machine. The fretting fatigue life of specimen coated with monolayer TiN film was longer than that of uncoated specimen. The TiN coating with functionally graded layer was the most effective to improve the fretting fatigue life.

The emergence of the circadian rhythm is a dramatic and physiologically essential event for mammals to adapt to daily environmental cycles. It has been demonstrated that circadian rhythms develop during the embryonic stage even when the maternal central pacemaker suprachiasmatic nucleus has been disrupted. However, the mechanisms controlling development of the circadian clock are not yet fully understood. Here, we show that the circadian molecular oscillation in primary dispersed embryonic cells and explanted salivary glands obtained from mPER2Luc mice embryos developed cell- or tissue-autonomously even in tissue culture conditions. Moreover, the circadian clock in the primary mPER2Luc fibroblasts could be reprogrammed by the expression of the reprogramming factors. These findings suggest that mammalian circadian clock development may interact with cellular differentiation mechanisms.

Transcriptional and post-translational regulations are important in peripheral nerve injury-induced neuropathic pain, but little is known about the role of post-transcriptional modification. Our objective was to determine the possible effect of adenosine deaminase acting on RNA (ADAR) enzymes, which catalyze post-transcriptional RNA editing, in tactile allodynia, a hallmark of neuropathic pain. Seven days after L5 spinal nerve transection (SNT) in adult mice, we found an increase in ADAR2 expression and a decrease in ADAR3 expression in the injured, but not in the uninjured, dorsal root ganglions (DRGs). These changes were accompanied by elevated levels of editing at the D site of the serotonin (5-hydroxytryptamine) 2C receptor (5-HT2CR), at the I/V site of coatomer protein complex subunit α (COPA), and at the R/G site of AMPA receptor subunit GluA2 in the injured DRG. Compared to Adar2+/+/Gria2R/R littermate controls, Adar2-/-/Gria2R/R mice completely lacked the increased editing of 5-HT2CR, COPA, and GluA2 transcripts in the injured DRG and showed attenuated tactile allodynia after SNT. Furthermore, the antidepressant fluoxetine inhibited neuropathic allodynia after injury and reduced the COPA I/V site editing in the injured DRG. These findings suggest that ADAR2 is a mediator of injury-induced tactile allodynia and thus a potential therapeutic target for the treatment of neuropathic pain.-Uchida, H., Matsumura, S., Okada, S., Suzuki, T., Minami, T., Ito, S. RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury.

Itch and pain are intimately related and may share similar peripheral and central mechanisms and pathways. However, it has been believed that synaptic glutamate release from a group of peripheral nociceptors is required to sense pain and suppress itch. Although we previously demonstrated that phosphorylation of GluN2B subunits of the NMDA receptor at Tyr1472 is important for central sensitization in a neuropathic pain model of mice with a knock-in mutation of the Tyr1472 site to phenylalanine of GluN2B (Y1472F-KI), the role of NMDA receptors in itch transmission remains unknown. Here, we demonstrated that the scratching behaviors elicited by various pruritogens applied to the cheek and c-fos expression in the region innervated by the trigeminal nerve were markedly attenuated in the Y1472F-KI mice. The c-fos immunoreactivity was co-localized with the receptor of gastrin-releasing peptide (GRP). Scratching behaviors evoked by chloroquine were inhibited by the NMDA receptor antagonists D-AP5 and CP101,606 and by the Src kinase inhibitor PP2. Direct activation of the trigeminal region by intracisternal administration of NMDA and GRP induced robust scratching behaviors, both of which were reduced by the GRP receptor antagonist RC-3095. Taken together, the data obtained in this present study are the first to demonstrate that phosphorylation of GluN2B subunit at Tyr1472 is important for trigeminal transmission of itch and suggest that the NMDA receptor activation occurs upstream of the GRP-GRP receptor pathway.

Background: Fibromyalgia (FM) is characterized by chronic widespread pain, which is often refractory to conventional painkillers. Numerous clinical studies have demonstrated that antidepressants are effective in treating FM pain. We previously established a mouse model of FM-like pain, induced by intermittent cold stress (ICS). Results: In this study, we find that ICS exposure causes a transient increase in plasma corticosterone concentration, but not in anxiety or depression-like behaviors. A single intrathecal injection of an antidepressant, such as milnacipran, amitriptyline, mianserin or paroxetine, had an acute analgesic effect on ICS-induced thermal hyperalgesia at post-stress day 1 in a dose-dependent manner. In addition, repeated daily antidepressant treatments during post-stress days 1-5 gradually reversed the reduction in thermal pain threshold, and this recovery was maintained for at least 7 days after the final treatment. In addition, relief from mechanical allodynia, induced by ICS exposure, was also observed at day 9 after the cessation of antidepressant treatment. In contrast, the intravenous administration of these antidepressants at conventional doses failed to provide relief. Conclusions: These results suggest that the repetitive intrathecal administration of antidepressants permanently cures ICS-induced FM pain in mice.

原発性骨粗鬆症の患者に非外傷性に発症した胸骨骨折の1症例を経験したので報告する．症例：80歳，女性．多発性胸椎腰椎圧迫骨折の既往あり．2010年1月，外傷の既往なく，前胸部の激しい疼痛を自覚したため当院を受診した．初診時，胸骨に強い圧痛を認め，胸骨単純X線像にて胸骨体の上1/3の部位に骨折を認めた．また病的骨折を疑わせる所見は見られなかった．躯幹骨二重X線吸収（DXA）法による骨量測定値は腰椎にて若年成人平均値(YAM)の58％，大腿骨にてYAMの38％とWHOの骨折リスクはHigh Riskであった．経過：非外傷性胸骨骨折と診断し，保存療法が可能と考えバストバンド固定のうえ入院加療を行った．その後疼痛は漸減した．考察：本症例の発症機序として原発性骨粗鬆症に起因する後弯変形を原因に胸骨に持続的なストレスがかかったことによって非外傷性に骨折が生じたものと考えられた．