The Anorexigenic Fatty Acid Synthase Inhibitor, C75, Is a Nonspecific Neuronal Activator

C75, a recently derived compound that potently suppresses feeding and induces weight loss, has been proposed to act mainly by inhibiting fatty acid synthase (FAS) in central neurons that control feeding. For example, normal, fasting- associated, hypothalamic increases in neuropeptide Y (NPY)/Agouti-related protein (AGRP) expression and decreases in proopiomelanocortin (POMC)/cocaine and amphetamine regulated transcript (CART) expression were reported to be blocked by C75. Using loose-patch extracellular recording in acute slices, we tested the effect of C75 on anorexigenic POMC neurons and orexigenic NPY neurons of the hypothalamic arcuate nucleus, which were identified by promoter-driven GFP expression, as well as on feeding-unrelated cerebellar Purkinje neurons. We expected C75 to activate POMC neurons, inhibit NPY neurons, and have no effect on Purkinje neurons. Instead, C75 activated all cell types, suggesting that it lacks target specificity. This activation was probably not caused by FAS inhibition, because the classical FAS inhibitor, cerulenin, did not have this effect when tested on POMC and NPY neurons. Nonspecific neuronal activation and resulting neurological effects might contribute to the decreased feeding reported to follow centrally administered C75. Injection, ip, of C75 induced severe loosening or liquefaction of stools, weight loss, and decreased food intake in both wild-type and melanocortin-4 receptor knockout mice. In contrast, cerulenin failed to loosen stools, even at a molar dose over 9-fold greater than C75, and had a much smaller effect on body weight. FAS inhibitory activity, by itself, seems to be insufficient to reproduce all of the effects of ip-injected C75

マウス破骨細胞形成における抗微生物ペプチド Cathelicidin-related antimicrobial peptide （CRAMP）の役割）

Cathelicidin-related antimicrobial peptide (CRAMP) not only kills bacteria but also binds to lipopolysaccharide (LPS) to neutralize its activity. CRAMP is highly expressed in bone marrow and its expression is reported to be up-regulated by inflammatory and infectious stimuli. Here, we examined the role of CRAMP in murine osteoclastogenesis. Osteoclasts were formed in co-cultures of osteoblasts and bone marrow cells in response to 1a,25-dihydroxyvitamin D3 [1a,25(OH)2D3], prostaglandin E2(PGE2), and Toll-like receptor (TLR) ligands such as LPS and flagellin through the induction of receptor activator of nuclear factor-jB ligand(RANKL) expression in osteoblasts. CRAMP inhibited the osteoclastogenesis in co-cultures treated with LPS and flagellin, but not in those treated with 1a,25(OH)2D3 or PGE2. Although bone marrow macrophages(BMMs) highly expressed formyl peptide receptor 2 (a receptor of CRAMP), CRAMP showed no inhibitory effect on osteoclastogenesis in BMM cultures treated with RANKL. CRAMP suppressed both LPS- and flagellin-induced RANKL expression in osteoblasts and tumour necrosis factor-a (TNF-a) expression in BMMs, suggesting that CRAMP neutralizes the actions of LPS and flagellin. LPS and flagellin enhanced the expression of CRAMP mRNA in osteoblasts. Extracellularly added CRAMP suppressed LPS- and flagellin-induced CRAMP expression. These results suggest that the production of CRAMP promoted by LPS and flagellin is inhibited by CRAMP released by osteoblasts through a feedback regulation. Even though CRAMP itself has no effect on osteoclastogenesis in mice, we propose that CRAMP is an osteoblast-derived protector in bacterial infection-induced osteoclastic bone resorption.2013博士（歯学）松本歯科大

microRNA-875-5p plays critical role for mesenchymal condensation in epithelial-mesenchymal interaction during tooth development

Epithelial-mesenchymal interaction has critical roles for organ development including teeth, during which epithelial thickening and mesenchymal condensation are initiated by precise regulation of the signaling pathway. In teeth, neural crest-derived mesenchymal cells expressed PDGF receptors migrate and become condensed toward invaginated epithelium. To identify the molecular mechanism of this interaction, we explored the specific transcriptional start sites (TSSs) of tooth organs using cap analysis of gene expression (CAGE). We identified a tooth specific TSS detected in the chromosome 15qD1 region, which codes microRNA-875 (mir875). MiR875-5p is specifically expressed in dental mesenchyme during the early stage of tooth development. Furthermore, PRRX1/2 binds to the mir875 promoter region and enhances the expression of mir875. To assess the role of miR875-5p in dental mesenchyme, we transfected mimic miR875-5p into mouse dental pulp (mDP) cells, which showed that cell migration toward dental epithelial cells was significantly induced by miR875-5p via the PDGF signaling pathway. Those results also demonstrated that miR875-5p induces cell migration by inhibiting PTEN and STAT1, which are regulated by miR875-5p as part of post-transcriptional regulation. Together, our findings indicate that tooth specific miR875-5p has important roles in cell condensation of mesenchymal cells around invaginated dental epithelium and induction of epithelial-mesenchymal interaction

Relationship between retinal fluid and visual acuity in patients with exudative age-related macular degeneration treated with intravitreal aflibercept using a treat-and-extend regimen: subgroup and post-hoc analyses from the ALTAIR study.

Purpose:To explore the relationship between retinal fluid status and best-corrected visual acuity (BCVA) in patients treated with intravitreal aflibercept (IVT-AFL) treat-and-extend (T&E) in the ALTAIR study.Methods:Outcomes were investigated according to overall fluid status at week 16 (predefined) and the relationship between any fluid, intraretinal fluid (IRF), subretinal fluid (SRF), or pigment epithelial detachment with BCVA at baseline, and weeks 16, 52, and 96 (post-hoc). The analyses involved treatment-naïve patients (N = 246) with exudative age-related macular degeneration (AMD), aged ≥ 50 years with BCVA of 73-25 Early Treatment Diabetic Retinopathy Study letters, who participated in the ALTAIR study.Results:The mean (standard deviation) change in BCVA from baseline to week 52 was + 10.6 (10.9) and + 6.5 (16.0) letters in patients without and with fluid at week 16, respectively; and to week 96 was + 9.1 (14.3) and + 4.3 (16.1) letters in patients without and with fluid at week 16, respectively. The last injection interval was 16 weeks in 33.6% and 2.0% (week 52), and 62.9% and 17.6% (week 96) of patients without or with fluid at week 16, respectively. At baseline, 35.7% of patients had IRF and 85.2% of patients had SRF, which decreased to 11.8% (IRF) and 31.7% (SRF) of patients, 8.5% (IRF) and 18.7% (SRF), and 6.5% (IRF) and 20.7% (SRF) at weeks 16, 52, and 96, respectively. Presence of IRF at all timepoints was associated with poorer BCVA than if IRF was absent, while the presence of SRF was not associated with poorer BCVA compared with the absence of SRF.Conclusion:IVT-AFL T&E dosing was effective at clearing fluid regardless of fluid type in ~ 80% of patients with exudative AMD. Patients without fluid at week 16 had numerically better BCVA than those with fluid at week 16. Over 60% of patients without fluid at week 16 achieved the maximum treatment interval of 16 weeks by study end, compared with < 20% of patients with fluid at week 16. IRF (weeks 16, 52, 96), although evident in a small number of patients, was associated with poorer BCVA, whereas SRF was not.Trial registration: ClinicalTrials.gov Identifier: NCT02305238. (http://clinicaltrials.gov/show/NCT02305238

Case report: Remission of chronic low back pain and oral dysesthesia comorbid with attention deficit/hyperactivity disorder by treatment with atomoxetine and pramipexole

IntroductionOral dysesthesia is a disease characterized by pain and/or abnormal sensations in the oral region, without any organic abnormality. Its symptoms include pain, and it is considered to be a disorder associated with idiopathic oral-facial pain. It is also known that idiopathic oral-facial pain tends to coexist with chronic musculoskeletal pain, including low back pain, even before its onset. Such coexisting idiopathic pain conditions are also called chronic overlapping pain conditions (COPCs). In general, COPCs are often refractory to treatment. Recently, it has been reported that attention deficit hyperactivity disorder (ADHD) is associated with many COPCs, such as pain in the facial and lower back regions and so on. However, there are no reports of (1) ADHD as a comorbidity with oral dysesthesia (OD) or (2) of the therapeutic effects of ADHD medications or dopamine agonists on low back pain and OD or an (3) evaluation of cerebral blood flow over time after treatment with these medications for OD and low back pain.Case PresentationIn this study, we report the case of an 80-year-old man with OD and chronic low back pain that persisted for more than 25 years. His OD and chronic back pain were refractory to standard treatment, prevented him from continuing work, and tended to be exacerbated by conflicts in his relationship with his son. In recent years, ADHD has often been found to be comorbid with chronic pain, and ADHD medications have been reported to improve chronic pain as well. The patient was confirmed to have undiagnosed ADHD and was treated with the ADHD medication atomoxetine and dopamine agonist pramipexole, which dramatically improved his OD, chronic back pain, and cognitive function. Furthermore, along the course of treatment, there was improvement in cerebral blood flow in his prefrontal cortex, which was thought to reflect improved function in the region. Consequently, he was able to resume work and improve his family relationships.ConclusionTherefore, in the cases of ODs and COPCs, screening for ADHD and, if ADHD is diagnosed, ADHD medications or dopamine agonists may be considered

骨芽細胞系列細胞のビタミンD受容体は、in vivo において1α,25(OH)2D3の骨吸収促進活性に必須である

要旨我々は以前、活性型ビタミンD3 [1α,25(OH)2D3]製剤であるエルデカルシトールの薬用量の投与は、骨吸収を抑制することで、骨量を増加させることを報告した。この骨吸収抑制効果は、骨芽細胞系列細胞のビタミンD受容体（VDR）を介することを明らかにした。本研究において我々は、骨芽細胞系列細胞特異的VDR欠損（Ob-VDR-cKO）マウスを用いて、1α,25(OH)2D3の大量投与によって誘導される骨吸収促進が骨芽細胞系列細胞のVDRを介するか否かを調べた。4日間の野生型マウスへの1α,25(OH)2D3（5 µg/kg体重/日）投与は、骨における破骨細胞数を増加させ、骨吸収マーカーであるI型コラーゲンC末端テロペプチド（C-terminal crosslinked telopeptide of type I collagen, CTX-I）の血清濃度を上昇させた。骨吸収促進は、血清カルシウム（Ca）値、線維芽細胞増殖因子23（Fibroblast Growth Factor, FGF-23）値の上昇と、体重の減少を伴っていた。このことは、中毒量の1α,25(OH)2D3は、骨吸収促進と高Ca血症を誘導することを示している。対照的に、野生型マウスへの抗Receptor Activator of NF-κB Ligand（RANKL）中和抗体前投与は、1α,25(OH)2D3が誘導する血清CTX-I, CaおよびFGF23値の上昇を抑制した。また、抗RANKL中和抗体前投与は、1α,25(OH)2D3が誘導する体重減少を抑制した。抗RANKL中和抗体前投与マウスの所見と一致して、1α,25(OH)2D3をOb-VDR-cKOマウスに大量投与しても、破骨細胞数、血清CTX-I値、血清Ca値、血清FGF-23値は、有意に上昇せず、また体重も減少しなかった。以上、本研究において、1α,25(OH)2D3の大量投与による骨吸収促進、血清Ca値上昇および毒性作用は、骨芽細胞系列細胞のVDRを介して発揮されることを明らかにした。2020博士（歯学）松本歯科大

21セイキ ノ カンドウミャク インターベンション

Coronary intervention has come to achieve good results with the use of new devices, such as Rotablator (ROTA), new directional coronary atherectomy (DCA), and a special guide wire, even for lesions in which good results were not obtained with plain old balloon angioplasty. In the present study, we evaluated the initial results in patients who underwent ROTA procedures, coronary intervention for chronic total occlusion (CTO), and new DCA procedures in our hospital between January and December 2001. (1) There were 99 patients who underwent ROTA, with an average age of 68±12 years, a lesion length of 15.9±9.9 mm, a reference vessel diameter of 2.7±0.6 mm, and a success rate of 98%. Among these 99 patients, there were 82 patients (83%) with B2 or C type lesion, which is difficult to treat. (2) There were 61 patients with CTO who underwent coronary intervention, with an average age of 63±9 years, an occlusion length of 22.8±13.3 mm, a reference vessel diameter of 2.6±0.7 mm, and a success rate of 82%. (3) There were 5 patients who underwent DCA for ostial lesion of left anterior desending artery and the target lesion was successfully dilated in all these patients. These results indicated that new devices for coronary intervention have made it possible to treat a wider range of lesions, but restenosis still remains to be solved. In Europe and the U.S.A., restenosis is reported to have been drastically reduced by drug eluting stents, which are expected to be introduced in Japan in the future