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Background: Insomnia is associated with psychiatric illnesses such as bipolar disorder or schizophrenia. Treating insomnia improves psychotic symptoms severity, quality of life, and functional outcomes. Patients with psychiatric disorders are often dissatisfied with the available therapeutic options for their insomnia. In contrast, positive allosteric modulation of adenosine A2A receptors (A2ARs) leads to slow-wave sleep without cardiovascular side effects in contrast to A2AR agonists.Methods: We investigated the hypnotic effects of A2AR positive allosteric modulators (PAMs) in mice with mania-like behavior produced by ablating GABAergic neurons in the ventral medial midbrain/pons area and in a mouse model of schizophrenia by knocking out of microtubule-associated protein 6. We also compared the properties of sleep induced by A2AR PAMs in mice with mania-like behavior with those induced by DORA-22, a dual orexin receptor antagonist that improves sleep in pre-clinical models, and the benzodiazepine diazepam.Results: A2AR PAMs suppress insomnia associated with mania- or schizophrenia-like behaviors in mice. A2AR PAM-mediated suppression of insomnia in mice with mania-like behavior was similar to that mediated by DORA-22, and, unlike diazepam, did not result in abnormal sleep.Conclusion: A2AR allosteric modulation may represent a new therapeutic avenue for sleep disruption associated with bipolar disorder or psychosis.

Behçet’s-like disease, which incompletely fulfils the criteria of Behçet’s disease, is often associated with trisomy 8–positive myelodysplastic syndrome (MDS). We report a case of an 82-year-old man with these conditions carrying the E148Q variant of MEFV gene who presented with periodic fever. The patient presented with joint pain, muscle pain, and episodes of periodic fever every 2 weeks for the past 3 months. On admission, painful erythema and fever were observed. Colonoscopy revealed erosion in the caecum and ascending colon. The patient had bicytopenia, and a bone marrow biopsy showed findings compatible with trisomy 8–positive unclassifiable MDS. Because the patient incompletely fulfilled the criteria for Behçet’s disease, he was diagnosed with Behçet’s-like disease associated with trisomy 8–positive MDS. Positron emission tomography–computed tomography performed during the fever revealed multiple muscle lesions consistent with the sites of pain. To examine the cause of the periodic fever attacks, MEFV gene was analysed, and the results revealed an E148Q variant. Steroids were ineffective against periodic fever attacks. A daily dose of 0.5 mg colchicine was prescribed, but the effect was minimal, probably, because of the insufficient dose due to renal dysfunction. Based on the diagnosis of atypical familial Mediterranean fever, canakinumab was added, which partially mitigated the periodic fever. This case suggests the importance of ruling out MDS when physicians see an elderly patient who present with Behçet’s-like disease. Although the significance of the E148Q variant in the pathogenesis of periodic fever remains controversial, it may act as a disease modifier in accordance with trisomy 8–positive MDS.

Orexins are a family of neuropeptides that regulate various physiological events such as sleep/wakefulness as well as emotional and feeding behavior, and that act on two G-protein-coupled receptors, i.e., the orexin 1 (OX1R) and orexin 2 receptors (OX2R). Since the discovery that dysfunction of the orexin/OX2R system causes the sleep disorder narcolepsy, several OX2R-selective and OX1/2R dual agonists have been disclosed. However, an OX1R-selective agonist has not yet been reported, despite the importance of the biological function of OX1R. Herein, we report the discovery of a potent OX1R-selective agonist, (R,E)-3-(4-methoxy-3-(N-(8-(2-(3-methoxyphenyl)-N-methylacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)phenyl)-N-(pyridin-4-yl)acrylamide ((R)-YNT-3708; EC50 = 7.48 nM for OX1R; OX2R/OX1R EC50 ratio = 22.5). Unlike the OX2R-selective agonist, the OX1R-selective agonist (R)-YNT-3708 exhibited antinociceptive and reinforcing effects in mice more potently than the dual agonist.

Background Cervical lymphadenopathy is commonly seen in general practice, and its etiology is diverse. Establishing the diagnostic strategy for lymphadenopathy would be desirable to avoid overlooking neoplasms or other critical conditions. This study aims to identify the useful laboratory parameters for cervical lymphadenopathy that require clinical observation or intervention. Methods The participants were outpatients presenting cervical swelling or cervical lymph node (LN) pain who consulted the General Internal Medicine department from 2010 to 2016. We evaluated the characteristics, physical findings, and laboratory parameters with final diagnoses by multivariate logistic regression analysis. We categorized the final diagnoses as “Clinical Intervention Required Group (CIRG)” including necrotizing lymphadenitis, hematologic neoplasms, metastatic lymphadenopathy, tuberculous lymphadenitis, bacterial infectious diseases, infectious mononucleosis, autoimmune diseases, and other abnormal conditions or “No‐CIRG” not requiring further clinical observation or intervention. Results We evaluated 409 participants, with 130 (31.8%) diagnosed as belonging to the CIRG. There was an association between CIRG and various parameters: age ≥60 years old (adjusted odds ratio [AOR], 2.70; 95% confidence interval [CI], 1.48‐4.90), having a referral (AOR, 1.83; 95% CI, 1.12‐3.00), diameter of LN ≥ 2 cm (AOR, 1.91; 95% CI, 1.05‐3.48), fixed LNs (AOR, 2.74; 95% CI, 1.02‐7.37), and lactate dehydrogenase (LD) ≥400 U/L (AOR, 3.78; 95% CI, 1.46‐9.77). Eighty‐two percent of LD ≥ 400 cases in the CIRG were infectious mononucleosis or necrotizing lymphadenitis. Conclusions Besides the clinical indicators reported previously, we may apply an elevated LD level as a useful indicator of cervical lymphadenopathy that requires further clinical observation or intervention., We evaluated 409 participants presenting cervical swelling or cervical lymph node pain to identify useful physical findings or laboratory parameters for cervical lymphadenopathy that require clinical observation or intervention. The risk factors associated with that by multivariate analysis were age ≥60 years, having a referral, diameter of cervical LN ≥2 cm, fixed cervical LNs, and LD ≥400 U/L.

In addition to the well-known motor control, the cerebellum has recently been implicated in memory, cognition, addiction, and social behavior. Given that the cerebellum contains more neurons than the cerebral cortex and has tight connections to the thalamus and brainstem nuclei, it is possible that the cerebellum also regulates sleep/wakefulness. However, the role of the cerebellum in sleep was unclear, since cerebellar lesion studies inevitably involved massive inflammation in the adjacent brainstem, and sleep changes in lesion studies were not consistent with each other. Here, we examine the role of the cerebellum in sleep and wakefulness using mesencephalon- and rhombomere 1-specific Ptf1a conditional knockout (Ptf1a cKO) mice, which lack the cerebellar cortex and its related structures, and exhibit ataxic gait. Ptf1a cKO mice had similar wake and non-rapid eye movement sleep (NREMS) time as control mice and showed reduced slow wave activity during wakefulness, NREMS and REMS. Ptf1a cKO mice showed a decrease in REMS time during the light phase and had increased NREMS delta power in response to 6 h of sleep deprivation, as did control mice. Ptf1a cKO mice also had similar numbers of sleep spindles and fear memories as control mice. Thus, the cerebellum does not appear to play a major role in sleep-wake control, but may be involved in the generation of slow waves.

A novel series of 1-amino-tetralin derivatives were designed and synthesized based on the putative binding mode of the naphthalene-type orexin receptor agonist 5 and their agonist activities against orexin receptors were evaluated. The introduction of N-methyl-(3-methoxyphenyl)acetamide unit onto the 1-amino-tetralin skeleton remarkably enhanced the potency of the agonist. The asymmetric synthesis of 6 revealed that (-)-6 having a (S)-1-amino-tetralin skeleton showed a OX

A novel series of naphthalene derivatives were designed and synthesized based on the strategy focusing on the restriction of the flexible bond rotation of OX2R selective agonist YNT-185 (1) and their agonist activities against orexin receptors were evaluated. The 1,7-naphthalene derivatives showed superior agonist activity than 2,7-naphthalene derivatives, suggesting that the bent form of 1 would be favorable for the agonist activity. The conformational analysis of 1,7-naphthalene derivatives indicated that the twisting of the amide unit out from the naphthalene plane is important for the enhancement of activity. The introduction of a methyl group on the 2-position of 1,7-naphthalene ring effectively increased the activity, which led to the discovery of the potent OX2R agonist 28c (EC50 = 9.21 nM for OX2R, 148 nM for OX1R). The structure-activity relationship results were well supported by a comparison of the docking simulation results of the most potent derivative 28c with an active state of agonist-bound OX2R cryo-EM SPA structure. These results suggested important information for understanding the active conformation and orientation of pharmacophores in the orexin receptor agonists, which is expected as a chemotherapeutic agent for the treatment of narcolepsy.

Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a high degree of three-dimensional properties, leading to a novel small-scale focused library based on 1,3,5- trioxazatriquinane. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (–)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) could serve as a privileged structure for G-protein coupled receptors (GPCRs) and the TriMER library approach might be useful for the hit discovery process targeting other GPCRs not only opioid and orexin receptors.

Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a high degree of three-dimensional properties, leading to a novel small-scale focused library based on 1,3,5- trioxazatriquinane. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (–)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) could serve as a privileged structure for G-protein coupled receptors (GPCRs) and the TriMER library approach might be useful for the hit discovery process targeting other GPCRs not only opioid and orexin receptors.

Retinal stem cell differentiation is orchestrated by transcription cascades, and is prone to be influenced by stress factors. While threshold radiation dose for human mental retardation is reported, the effects on retinal transcription factors are unknown. To elucidate the effects of low-dose radiation on retinal differentiation, stem cells were irradiated. Genome-wide gene expression and histone modification were observed. After a month, the expression of PAX6, an essential transcription factor for retinal ganglion cell, was increased by 30 mGy but decreased by 180 mGy. POU5F1, POU2F1, SOX2, and PAX6 were predicted to be involved in regulation of PAX6. Further, upstream of POU5F1/POU2F1/ SOX2 was detected. Altered Rho family could be responsible for activity of SRF/STAT3/RELA, which were upstream of POU2F1/SOX2. These cascades could contribute to the regulation of PAX6 and unstable retinal development under stressful environment. Identification of the hierarchical regulations in the differentiation will help elucidate the retinal cell maintenance.

Bovine spongiform encephalopathy (BSE) prion is more resistant to heat inactivation compared to other prions, but the effect of heat inactivation has been reported to differ depending on the BSE-contaminated tissue state or heating type. We aimed to evaluate the secure level of inactivation of original BSE transmissibility by dry-heating. Cattle tissues affected with BSE were subjected to dry-heat treatment for 20 min at various temperatures ranging from 150 to 1000 °C. To assess the inactivation effect, we conducted protein misfolding cyclic amplification (PMCA) and follicular dendritic cell (FDC) assays in transgenic mice expressing bovine prion protein genes. Under dry-heating at 600 °C or higher, BSE cattle tissues lost their transmissibility in transgenic mice. In contrast, transmissibility was detected in the cattle tissues treated at temperatures of 400 °C or lower through the FDC assay combined with PMCA. In this study, we confirmed that transmissibility was eliminated in BSE-affected cattle tissues by dry-heating at 600 °C or higher.

Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX1R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX1R. In the 6β-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX1R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6β-derivatives.

Background: Strategies to prevent the development and progression of chronic kidney disease (CKD) are important in clinical practice due to increased life expectancy. The present study investigated the prevalence of CKD as well as lipid profiles affecting CKD, especially triglyceride (TG) levels.Methods: In total, 5,169 subjects were eligible for a cross-sectional analysis of baseline data from the Jichi Medical School Cohort Study. We examined CKD subjects with an estimated glomerular filtration rate (eGFR) of 59 mL/min/1.73m2 or lower and independent factors associated with reductions in eGFR.Results: The prevalence of CKD was 17.7%. Age, systolic blood pressure, and hyperlipidemia were defined as related factors for CKD. The lowest, second, third, and highest quartile ranges of total cholesterol (TC) and TG were 0-166, 167-188, 189-212, and 213 mg/dL or higher and 0-71, 72-100, 101-148, and 149 mg/dL or higher, respectively. The odds ratio (OR) of Q2 to Q4 of TC relative to that of Q1 for CKD increased linearly (OR [95%CI]: Q2, 1.3 [1.0-1.7]; Q3, 1.38 [1.1-1.8]; Q4, 1.5 [1.4-2.4]). The ORs of Q2 and Q3 of TG for CKD did not increase, whereas that of Q4 did (OR [95% CI]: Q2, 0.95 [0.7-1.2]; Q3, 0.98 [0.8-1.2]; Q4, 1.21 [1.0-1.5]). Conclusion: Increases in TC and TG levels were both independently associated with CKD. The relationship with CKD became stronger as TC increased, and the TG had threshold was 149 mg/dL.

Acquired loss of hypothalamic orexin (hypocretin)-producing neurons causes the chronic sleep disorder narcolepsy-cataplexy. Orexin replacement therapy using orexin receptor agonists is expected as a mechanistic treatment for narcolepsy. Orexins act on two receptor subtypes, OX1R and OX2R, the latter being more strongly implicated in sleep/wake regulation. However, it has been unclear whether the activation of only OX2R, or both OX1R and OX2R, is required to replace the endogenous orexin functions in the brain. In the present study, we examined whether the selective activation of OX2R is sufficient to rescue the phenotype of cataplexy and sleep/wake fragmentation in orexin knockout mice. Intracerebroventricular [Ala11, D-Leu15]-orexin-B, a peptidic OX2R-selective agonist, selectively activated OX2R-expressing histaminergic neurons in vivo, whereas intracerebroventricular orexin-A, an OX1R/OX2R non-selective agonist, additionally activated OX1R-positive noradrenergic neurons in vivo. Administration of [Ala11, D-Leu15]-orexin-B extended wake time, reduced state transition frequency between wake and NREM sleep, and reduced the number of cataplexy-like episodes, to the same degree as compared with orexin-A. Furthermore, intracerebroventricular orexin-A but not [Ala11, D-Leu15]-orexin-B induced drug-seeking behaviors in a dose-dependent manner in wild-type mice, suggesting that OX2R-selective agonism has a lower propensity for reinforcing/drug-seeking effects. Collectively, these findings provide a proof-of-concept for safer mechanistic treatment of narcolepsy-cataplexy through OX2R-selective agonism.

Guillain–Barré syndrome (GBS) usually has a good prognosis; however, patients may develop sequelae without prompt treatment. We herein describe an 81-year-old woman who developed acute-onset excruciating thigh pain and weakness in her lower extremities after spinal surgery. We diagnosed acute inflammatory demyelinating polyradiculoneuropathy by a nerve conduction study, which showed findings of demyelination without cerebrospinal fluid analysis because of a spinal prosthesis. Although anti-GM1 and anti-GalNAc-GD1a antibodies were positive, the patient was clinically diagnosed with acute inflammatory demyelinating polyradiculoneuropathy (a subtype of GBS), not acute motor axonal neuropathy. She recovered well with immunoglobulin therapy. A literature review of 18 cases revealed that unexplained weakness, areflexia, and numbness of the extremities after spinal surgery, a shorter time from spinal surgery to symptom onset to general GBS, abnormal nerve conduction study results, normal spinal imaging findings, and the development of atypical symptoms such as cranial and autonomic nerve syndrome and respiratory failure are useful for diagnosing GBS when cerebrospinal fluid examination cannot be performed after spinal surgery.

Contrast-enhanced computed tomography angiography reveals "railroad track-like" calcifications bilaterally from the femoral to the popliteal arteries.

To investigate the contribution of hydrogen bonding between the 14-hydroxy group and the 6-amide chain on the binding affinity of nalfurafine toward KOR and OX

The five-membered D-ring nalfurafine (d-nor-nalfurafine) derivatives with a 16-sulfonamide group were synthesized. Conversion of the 16-cyclopropylmethyl group to the 16-benzenesulfonamide group in the d-nor-nalfurafine derivatives drastically improved the orexin 1 receptor (OX

Summary: The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain. : Fujiyama et al. find that forebrain-specific Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sexually dimorphic behaviors, reproductive organs, and severely altered expression of sex-biased genes, including Kiss1, in the hypothalamus in both sexes, which suggests that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain. Keywords: sexual differentiation, sexual behavior, hypothalamus, Ptf1a, kisspeptin, central nervous system

The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.

Antineutrophil cytoplasmic antibody‐associated vasculitis (AAV) presents a variety of manifestations. Two patients with a history of intractable otitis media were diagnosed as having AAV. One was an 87‐year‐old woman who presented with cough, anorexia, and fever with a one‐year and four‐month history of otitis media, and the other was a 65‐year‐old woman with arthritis that appeared after the diagnosis of otitis media. The history of otitis media was a diagnostic clue to AAV in both patients. Diagnosis at the early localized stage is crucial to prevent irreversible status of AAV. Primary care physicians should be aware of the otological manifestation of AAV.

The D-nor-nalfurafine derivatives, which were synthesized by contraction of the six-membered D-ring in nalfurafine (1), had no affinity for orexin 1 receptors (OX1Rs). The 17N-lone electron pair in 1 oriented toward the axial direction, while that of D-nor-derivatives was directed in the equatorial configuration. The axial lone electron pair can form a hydrogen bond with the 14-hydroxy group, which could push the 6-amide side chain toward the downward direction with respect to the C-ring. The resulting conformation would be an active conformation for binding with OX1R. The dual affinities of 1 for OX1R and κ opioid receptor (KOR) led us to elucidate the mechanism by which only 1 showed no aversion but U-50488H. Actually, 1 selectively induced severe aversion in OX1R knockout mice, but not in wild-type mice. These results well support that OX1R suppresses the aversion of 1. This is the elucidation of long period puzzle which 1 showed no aversion in KOR.

Cortical neurons fire intermittently and synchronously during non-rapid eye movement sleep (NREMS), in which active and silent periods are referred to as ON and OFF periods, respectively. Neuronal firing rates during ON periods (NREMS-ON-activity) are similar to those of wakefulness (W-activity), raising the possibility that NREMS-ON neuronal-activity is fragmented W-activity. To test this, we investigated the patterning and organization of cortical spike trains and of spike ensembles in neuronal networks using extracellular recordings in mice. Firing rates of neurons during NREMS-ON and W were similar, but showed enhanced bursting in NREMS with no apparent preference in occurrence, relative to the beginning or end of the on-state. Additionally, there was an overall increase in the randomness of occurrence of sequences comprised of multi-neuron ensembles in NREMS recorded from tetrodes. In association with increased burst firing, somatic calcium transients were increased in NREMS. The increased calcium transients associated with bursting during NREM may activate calcium-dependent, cell-signaling pathways for sleep related cellular processes.

We investigated the effectiveness of epinephrine auto‐injector (EpiPen®) skill training for Yogo teachers in the community medicine. The auto‐injector skill training might be effective for establishing a caring system for anaphylaxis at schools in the context of community medicine.

The essential structure of the orexin 1 receptor (OX 1 R) antagonist YNT-707 ( 2 ) was clarified, particularly the roles to OX 1 R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX 1 R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX 1 R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX 1 R ligands.

Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexin-deficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists.

β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependent reductase that converts cortisone to cortisol in adipose tissue. We previously reported that GH and IGF-I decrease 11β-HSD1 activity and mRNA levels in adipocytes. Hexose-6-phosphate dehydrogenase (H6PDH) is involved in the production of NADPH, which is a coenzyme for 11β-HSD1. The aim of the present study was to clarify further the mechanism of repression of 11β-HSD1 activity by GH using linsitinib, an IGF-I receptor inhibitor. The suppression of 11β-HSD1 mRNA by IGF-I was attenuated in the presence of 1 μM linsitinib (17.2% vs. 53.3% of basal level, P

Nalfurafine, a κ-selective opioid receptor agonist, unexpectedly showed a selective antagonist activity toward the orexin 1 receptor (OX1R) (Ki = 250 nM). Modification of the 17-amino side chain of the opioid ligand to an arylsulfonyl group and the 6-furan acrylamide chain to 2-pyridyl acrylamide led to compound 71 with improvement of the antagonist activity (OX1R, Ki = 1.36 nM; OX2R, not active) without any detectable affinity for the opioid receptor. The dihydrosulfate salt of 71, freely soluble in water, attenuated the physical dependence of morphine. Furthermore, all of the active nalfurafine derivatives in this study had almost no activity for OX2R, which led to high OX1R selectivity. These results suggest that nalfurafine derivatives could be a useful series of lead compounds to develop highly selective OX1R antagonists.

Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of therapeutic options for postprandial hyperglycemia. Previously, we reported potent and selective SGLT1 inhibitors 1 and 2 showing efficacy in oral carbohydrate tolerance tests in diabetic rat models. In a pharmacokinetic (PK) study of 2, excessive systemic exposure to metabolites of 2 was observed, presumably due to the high permeability of its aglycone (2a). To further improve SGLT1 inhibitory activity and reduce aglycone permeability, a series of 4-benzyl-5-isopropyl-1H-pyrazol-3-yl β-D-glycopyranoside derivatives bearing novel hydrophilic substitution groups on the phenyl ring were synthesized and their inhibitory activity toward SGLTs was evaluated. Optimized compound 14c showed an improved profile satisfying both higher activity and lower permeability of its aglycone (22f) compared with initial leads 1 and 2. Moreover, the superior efficacy of 14c in various carbohydrate tolerance tests in diabetic rat models was confirmed compared with acarbose, an α-glucosidase inhibitor (α-GI) widely used in the clinic.

The rapid detection of infectivity of several agents that cause Creutzfeldt-Jakob disease has previously been achieved by assaying for deposits of abnormal prion protein (PrPSc) in follicular dendritic cells in the spleens of transgenic mice carrying the human prion protein gene. In this study, transgenic mice expressing the bovine prion protein were inoculated intraperitoneally with classical (C-type) or atypical L-type bovine spongiform encephalopathies (BSE). Proteinase-resistant PrPSc were detected in the spleens of all transgenic mice at 75 days after inoculation with both types of BSE. Infectivity in PrPSc-positive spleens of the transgenic mice revealed that prions of C- and L-type BSE replicated. These results suggest that bioassay system by the transgenic mice could be useful for the rapid detection of BSE infectivity with discriminating between C- and L-type BSEs.

The high-affinity sodium glucose cotransporter (SGLT1) plays a critical role in glucose absorption from the gastrointestinal tract. We have developed 3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)propionamide (KGA-2727), which has a pyrazole-O-glucoside structure, as the first selective SGLT1 inhibitor. KGA-2727 inhibited SGLT1 potently and highly selectively in an in vitro assay using cells transiently expressing recombinant SGLTs. In a small intestine closed loop absorption test with normal rats, KGA-2727 inhibited the absorption of glucose but not that of fructose. After oral intake of starch along with KGA-2727 in normal rats, the residual content of glucose in the gastrointestinal tract increased. In the oral glucose tolerance test with streptozotocin-induced diabetic rats, KGA-2727 attenuated the elevation of plasma glucose after glucose loading, indicating that KGA-2727 improved postprandial hyperglycemia. In Zucker diabetic fatty (ZDF) rats, chronic treatments with KGA-2727 reduced the levels of plasma glucose and glycated hemoglobin. Furthermore, KGA-2727 preserved glucose-stimulated insulin secretion and reduced urinary glucose excretion with improved morphological changes of pancreatic islets and renal distal tubules in ZDF rats. In addition, the chronic treatment with KGA-2727 increased the level of glucagon-like peptide-1 in the portal vein. Taken together, our data indicate that the selective SGLT1 inhibitor KGA-2727 had antidiabetic efficacy and allow us to propose KGA-2727 as a candidate for a novel and useful antidiabetic agent.

本論文では,1980年代から現在までに大阪・神戸エリアで司会者として携わったウェディング・セレモニーから,その変遷を様々な観点からまとめることを目的とする。そこでは,「家」を重視する思考から,「個」を重視する思考への変化とともに,初婚年齢の上昇に伴う新郎新婦のこだわりを見出すことができる。そして,こだわりやもてなしを実現するための経費が,親や身内への依存から新郎新婦本人達の負担に徐々に移り変わったことも見出せた。また婚姻儀式における親世代の関わりの後退と,婚姻の当事者である新郎新婦の「新しい家族」としての意識の萌芽を背景として,「絆」の演出が重要視されていることが指摘できる。, The purpose of this paper is to summarize the changes in wedding ceremonies throughthe experiences of the author who has acted as a master of ceremonies since 1980s.Thisresearch has clarified some changes. The first is the change of values from"family" to "individuals". Second, the average age for the first marriage has gone up, and bridal pairs have paid more attention to the reception. The expenses paid by parents have decreased gradually. Finally, the portion of the involvement of parents in the wedding ceremonies hasdecreased, and the bridal pairs have emphasized the staging to show "ties" of new family.

This qualitative study was conducted in order to explore interaction between advisors and advisees in peer-advising sessions conducted with a view of promoting independent language study. The data was collected through observation, documentation, and interviews with a newly-trained and relatively inexperienced student peer-advisor. The data was transcribed and coded for closer analysis. The study revealed that the advice which the student advisor gave to peers was very much influenced by her own language study experience and beliefs, especially with regard to grammar-focused study and time-management methods. Moreover, the data offered a number of interesting observations, such as a feeling of relatedness between peers, and a conflict between being strict and being generous. In this article, the author will discuss the areas in which the student advisor’s own beliefs were most reflected in her advising. Other observations from the data will also be highlighted.

Background Ambulatory blood pressure (BP) (ABP) is a better predictor of adverse cardiovascular events than office BP (OBP). Owing to the extensive literature on the 'white coat effect', it is widely believed that ABP tends to be lower than OBP, with statements to this effect in Joint National Committee VII. However, recent evidence suggests that the difference varies systematically with age. Methods We searched PubMed to identify population studies, published before April 2009, which assessed OBP and either ABP or home BP (HBP). On account of significant heterogeneity in the outcomes, random effect models were used for the meta-analyses. Results OBP increased with age more steeply than awake ABP. OBP became higher than awake systolic/diastolic ABP at the age of 51.3/42.7 years in men (13 studies, N=3562) and 51.9/42.3 years in women (11 studies, N=2585). In the data in which OBP and HBP were measured (eight studies, N=4916), OBP was higher than HBP at all ages. In the data in which OBP, awake ABP, and HBP were all measured (two studies, N=895), awake ABP was higher than HBP at younger ages, becoming similar at the older age. Conclusion OBP tends to be higher than awake ABP only after the age of 50 years for systolic and after the age of 45 years for diastolic BP, but is lower than ABP at younger ages; in contrast OBP tends to exceed HBP at all ages.

Using a hybrid baculovirus system, we compared the expression of 45 recombinant proteins from six categories using two models: silkworm (larvae and pupae) and an Sf9 cell line. A total of 45 proteins were successfully expressed; preparation of hybrid baculovirus was unsuccessful for one protein, and two proteins were not expressed. A similar pattern of expression was seen in both silkworm and Sf9 cells, with double and multiple bands found in immunoblotting of the precipitate of both hosts. Degraded proteins were seen only in the silkworm system (particularly in the larvae). Production was more efficient in silkworms; a single silkworm produced about 70 times more protein than 10(6) Sf9 cells in 2 ml of culture medium.

It has been reported that subjects with prehypertension (pre-HT) (systolic blood pressure [SBP] 120-139 mmHg and/or diastolic blood pressure [DBP] 80-89 mmHg) have an increased risk of cardiovascular disease (CVD). We evaluated the prevalence and determinants of pre-HT in a Japanese general population. We enrolled 4,706 males and 7,342 females aged 18 to 90 years whose BPs were measured at baseline. The subjects' BPs were classified as follows: normotension (NT: SPB/DBP120/80 mmHg), pre-HT (120/80-139/89 mmHg), and hypertension (HT:or = 140/90 mmHg or treated hypertension). The prevalence of pre-HT was 34.8% (males), and 31.8% (females). Body mass index (BMI) of more than 23.0 kg/m2 was the strongest determinant of pre-HT (Males--BMI: 23.0-24.9 kg/m2, odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.21-1.79; BMI: 25.0-26.9 kg/m2, OR = 2.20, 95% CI =1.68-2.87; BMI: 27.0-29.9 kg/m2, OR = 2.75, 95% CI = 1.80-4.19; BMI:or = 30.0 kg/m2, OR = 3.39, 95% CI = 1.21-9.46. Females--BMI: 23.0-24.9 kg/m2, OR = 1.67, 95% CI = 1.42-1.95; BMI: 25.0-26.9 kg/m2, OR = 1.79, 95% CI = 1.46-2.19; BMI: 27.0-29.9 kg/m2, OR = 3.65, 95% CI = 2.73-4.89; BMI:or = 30.0 kg/m2, OR = 4.23, 95% CI = 2.33-7.70). The other determinants of pre-HT were hyperlipidemia (Males: OR = 1.25; Females: OR = 1.43), and aging (by 10 years; Males: OR = 1.12; Females: OR = 1.48). Determinants of pre-HT in females were impaired glucose tolerance (OR = 1.41, 95% CI = 1.03-1.94), diabetes (OR = 2.01, 95% CI = 1.16-3.47) and a family history of HT in both parents (OR = 1.90, 95% CI = 1.38-2.62), whereas in males the only other predictor was alcohol drinking (OR = 1.45, 95% CI = 1.23-1.70). In conclusion, even subjects with a mild increase of BMI (23.0-24.9 kg/m2) had an increased risk of pre-HT in a Japanese population, and the level of BMI associated with pre-HT was lower than that in Western countries. Additionally, there were gender differences in the determinants of pre-HT.

Yukiko Ishikawa,1 Taro Takeshima,1,2 Junichi Mise,1 Shizukiyo Ishikawa,1 Masami Matsumura1 1Division of General Medicine, 2Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan Purpose: General practitioners have an important role in diagnosing a variety of patients, including psychiatric patients with complicated symptoms. We evaluated the relationship between physical symptoms and psychiatric disorders in general internal medicine (GIM) outpatients in a Japanese university hospital. Materials and methods: We coded the symptoms and diagnoses of outpatients from medical documents using the International Classification of Primary Care, second edition (ICPC-2). The participants were new outpatients who consulted the GIM outpatient division at Jichi Medical University Hospital in Tochigi, Japan from January–June, 2012. We reviewed all medical documents and noted symptoms and diagnoses. These were coded using ICPC-2. Results: A total of 1,194 participants were evaluated, 148 (12.4%) of whom were diagnosed as having psychiatric disorders. The prevalence of depression, anxiety disorder, and somatization was 19.6% (number [n] =29), 14.9% (n=22), and 14.2% (n=21), respectively, among the participants with psychiatric disorders. The presence of several particular symptoms was associated with having a psychiatric disorder as compared with the absence of these symptoms after adjusting for sex, age, and the presence of multiple symptoms (odds ratio [OR] =4.98 [95% confidence interval {CI}: 1.66–14.89] for palpitation; OR =4.36 [95% CI: 2.05–9.39] for dyspnea; OR =3.46 [95% CI: 1.43–8.36] for tiredness; and OR =2.99 [95% CI: 1.75–5.13] for headache). Conclusion: Not only the psychiatric symptoms, but also some physical symptoms, were associated with psychiatric disorders in GIM outpatients at our university hospital. These results may be of help to general practitioners in appropriately approaching and managing patients with psychiatric disorders. Keywords: physical symptoms, psychiatric disorders, university hospital, International Classification of Primary Care 2nd edition

In some patients with non-islet-cell tumor hypoglycemia (NICTH), a high molecular weight form of IGF-II (big IGF-II) derived from tumors is present in the circulation and might be associated with recurrent hypoglycemia. In this study, in order to survey the clinical characteristics of patients with IGF-II producing NICTH, we analyzed the medical records of 78 patients with NICTH (M/F 44/34, age 62+/-1.8, range; 9-86 years.) whose serum contained a large amount of big IGF-II. Hepatocellular carcinoma and gastric carcinoma were the most common causes of NICTH. The diameters of the tumors were more than 10 cm in 70% of the patients. Basal immunoreactive insulin (IRI) levels were less than 3 microU/dl in 79% of the patients. Hypoglycemic attack was the onset of disease in 31 of 65 cases (48%), but the tumor was revealed prior to the occurrence of hypoglycemia in 34 cases (52%). Twenty-five of 47 (53%) patients had decreased serum potassium levels. These data suggested that hypoinsulinemic hypoglycemia associated with the presence of a large tumor supports the diagnosis of IGF-II producing NICTH. Hypokalemia was associated with hypoglycemia in some patients. The BMI (21.4+/-0.6 kg/m2) and serum total protein levels (6.6+/-0.1g/dl) were preserved at the occurrence of first hypoglycemic attack suggesting that malnutrition might not be the main cause of hypoglycemia in most patients.