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Aims/Introduction: The association between diabetes and periodontal disease is considered to be bidirectional. However, there is still controversy surrounding the relationship between periodontal disease and type 1 diabetes. We investigated whether insulin improves periodontitis without any local treatments for periodontitis under type 1 diabetes conditions using the ligature‐induced experimental periodontitis model. Materials and Methods: Type 1 diabetic rats were induced by streptozotocin injection. Experimental periodontitis was induced by ligature in normal and diabetic rats. Half of the diabetic rats were treated with insulin. Two weeks after the ligature, periodontitis was evaluated. Results: Insulin treatment significantly improved inflammatory cell infiltration and inflammatory cytokine gene expression, leading to suppression of alveolar bone loss, in the periodontitis of diabetic rats. Insulin also suppressed the periodontitis‐increased nitric oxide synthase‐positive cells in periodontal tissue of the diabetic rats. Even without induction of periodontitis, diabetic rats showed decreased gingival blood flow and an increased number of nitric oxide synthase‐positive cells in the gingiva and alveolar bone loss compared with normal rats, all of which were ameliorated by insulin treatment. We further confirmed that insulin directly suppressed lipopolysaccharide‐induced inflammatory cytokine expressions in THP‐1 cells. Conclusions: There were abnormalities of periodontal tissue even without the induction of periodontitis in streptozotocin‐induced diabetic rats. Insulin treatment significantly ameliorated periodontitis without local periodontitis treatment in diabetic rats. These data suggest the therapeutic impacts of insulin on periodontitis in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Objectives: The siderophore cephalosporin cefiderocol possesses in vitro activity against MDR Gram-negative bacteria. The stability of cefiderocol against serine- and metallo-type carbapenemases has been reported previously, but little is known about how cefiderocol interacts with chromosomal AmpC β-lactamases. We investigated a number of features of cefiderocol, namely antibacterial activity against AmpC overproducers, stability against AmpC β-lactamases and propensity for AmpC induction using Pseudomonas aeruginosa and Enterobacter cloacae.Methods: MICs were determined by broth microdilution according to CLSI guidelines. The MIC of cefiderocol was determined in iron-depleted CAMHB. Hydrolysis of the antibiotics was determined by monitoring the changes in the absorbance in the presence of AmpC β-lactamase, and AmpC induction was evaluated by double disc diffusion and nitrocefin degradation assays.Results: The MICs of ceftazidime and cefepime for PAO1 increased 4- to 16-fold with inactivation of either ampD or dacB, whereas cefiderocol MICs were little affected by these inactivations (<2-fold increase). Cefiderocol has 17- and 740-fold lower affinity (higher Ki) to AmpCs of P. aeruginosa SR24-12 and E. cloacae P99, respectively, compared with ceftazidime. Both disc diffusion and nitrocefin degradation assays indicated that cefiderocol did not induce AmpC β-lactamases of P. aeruginosa PAO1 and ATCC 27853 and E. cloacae ATCC 13047, whereas imipenem did.Conclusions: Cefiderocol showed in vitro activity against the AmpC-overproducing strains, low affinity for chromosomal AmpC β-lactamases, and a low propensity of temporal induction of AmpC β-lactamases of P. aeruginosa and E. cloacae. These features relating to chromosomal AmpC could explain the potent antibacterial activity of cefiderocol against drug-resistant strains producing AmpC β-lactamases. [ABSTRACT FROM AUTHOR]

Aim Periodontal disease is highly prevalent and severe in diabetic patients, and is considered one of the diabetic complications. To elucidate how periodontitis progresses in diabetes, we examined an animal model of periodontitis in diabetic rats. Materials and Methods Two weeks after the induction of diabetes by streptozotocin, surgical nylon thread was ligated around the cervical portion of the unilateral maxillary second molar to induce periodontitis. Periodontitis was evaluated 2 weeks after the ligation by gingival blood flow, m RNA expressions, Western blot analysis, histological examination and micro CT. Results Ligation-induced severe periodontitis in the diabetic rats, which was apparently shown by the increase of TNF-α and i NOS m RNA expressions and inflammatory cell infiltration in the gingiva and alveolar bone loss. The number of nitrotyrosine, a footprint of nitrosative stress, -positive cells was significantly higher in the periodontitis of the diabetic rats compared with that in the normal rats. Western blot analysis confirmed that the nitrotyrosine was increased in the periodontitis of the diabetic rats. Conclusions This is the first study to confirm increased nitrosative stress due to periodontitis in diabetic rats. Nitrosative stress may play a crucial role in the exacerbation of periodontitis in diabetic patients. [ABSTRACT FROM AUTHOR]

Abstract: d-Serine is a unique endogenous substance enriched in the brain at the exceptionally high concentrations as a free d-amino acid in mammals throughout their life. Peripheral tissues and blood contain low or trace levels of the d-amino acid. In the nervous systems, d-serine appears to act as an intrinsic coagonist for the N-methyl-d-aspartate type glutamate receptor (NMDA receptor) based upon the following characteristics: (i) d-serine stereoselectively binds to and stimulates the glycine-regulatory site of the NMDA receptor consisting of GRIN1/GRIN2 subunits more potently than glycine with an affinity and ED50 at high nanomolar ranges, (ii) the selective elimination of d-serine in brain tissues attenuates the NMDA receptor functions, indicating an indispensable role in physiological activation of the glutamate receptor, and (iii) the distribution of d-serine is uneven and closely correlated with that of the binding densities of the various NMDA receptor sites, and especially of the GRIN2B subunit in the brain. Moreover, d-serine exerts substantial influence on the GRIN1/GRIN3-NMDA and δ2 glutamate receptor. In the brain and retina, metabolic processes of d-serine, such as biosynthesis, extracellular release, uptake, and degradation, are observed and some candidate molecules that mediate these processes have been isolated. The fact that the mode of extracellular release of d-serine in the brain differs from that of classical neurotransmitters is likely to be related to the detection of d-serine in both glial cells and neurons, suggesting that d-serine signals could be required for the glia–synapse interaction. Moreover, the findings from the basic experiments and clinical observations support the views that the signaling system of endogenous free d-serine plays important roles, at least, through the action on the NMDA receptors in the brain wiring development and the regulation of higher brain functions, including cognitive, emotional and sensorimotor function. Based upon these data, aberrant d-serine–NMDA receptor interactions have been considered to be involved in the pathophysiology of a variety of neuropsychiatric disorders including schizophrenia and ischemic neuronal cell death. The molecular and cellular mechanisms for regulating the d-serine signals in the nervous system are, therefore, suitable targets for studies aiming to elucidate the causes of neuropsychiatric disorders and for the development of new treatments for intractable neuropsychiatric symptoms. [Copyright &y& Elsevier]

Objectives: To study the antitumor effects of fleroxacin against bladder tumor cell lines and the synergistic effect with 5-fluorouracil (5-FU) both in vitro and in vivo. Methods: In vitro, the MBT-2 and T-24 urothelial carcinoma cell lines were exposed to fleroxacin in concentrations of 0-800 μg/mL for 12, 24, and 48 hours. Cytotoxicity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Synergism of fleroxacin with 5-FU was evaluated using the normalized isobologram and combination index by CalcuSyn for Windows computer program. In vivo, 4-week-old female C57BL/6 mice were orally administered fleroxacin and/or 5-FU 1 week before starting administration of a carcinogenic agent (0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine) for 12 weeks. The mice were killed 8 weeks after the end of administration for histologic evaluation of the urinary bladder. Results: Fleroxacin significantly inhibited cell proliferation in a dose- and time-dependent manner at concentrations of 50-800 μg/mL for 12, 24, and 48 hours. The inhibitory effects of fleroxacin combined with 5-FU appeared synergistic using normalized isobologram and combination index analysis. In vivo, no significant changes in bladder tumor frequency were noted between the control and fleroxacin and 5-FU groups. Significant inhibition of tumor frequency was observed only when fleroxacin was administered with 5-FU. Conclusions: Fleroxacin combined with 5-FU inhibited the proliferation of bladder tumor cell lines both in vitro and in vivo. This combination therapy might be applicable in clinical settings. [Copyright &y& Elsevier]

The article presents a study which investigates the growth-promoting effect of an alginate oligosaccharide mixture (AOM) in a normal and Cu 2+ -induced stress condition in a unicellular marine microalga Nannochloropsis oculata. Through the process of gel-filtration and cultivation, AOM was found to promote the growth of N. oculata and overcome alga's Cu 2+ -induced growth suppression. It suggests that AOM is an agent for the establishment of mass culture of N. oculata.

The article discusses the study on liquid chromatography/tandem mass spectrometry (LC-MS/MS) for the detection of alginate oligosaccharides (AOs) in mouse plasma and urine. It mentions that on a calibration curve with an AO trimer peak area, the maximum plasma and urine concentrations were estimated to be 24.5µg/ml at 5 minutes and 425.5µg/ml at 30 minutes. The results suggest that the LC-MS/MS best suited to pharmacokinetic analysis of AOs in an in vivo system.

A three-dimensional radiative heat transfer analysis of an arbitrary-shaped modeled cloud subjected to solar and sky irradiation has been performed. The Radiation Element Method by Ray Emission Model (REM2) was used for numerical simulation. Nongray, anisotropic scattering, absorbing, and emitting are taken into account in calculating the three-dimensional cloud. The modeled cloud is considered to be a low-level fair-weather cumulus in a tropical atmosphere. The cloud is modeled by unstructured mesh elements in order to investigate the curvature of cloud shape. Radiative cooling occurs in the thin layer below the cloud surface, and the thickness is approximately 20–40 m. Radiative cooling is enhanced at the swelled top of the cloud with a convex shape, which can cause a downward forcing and enhance the entrainment instability. On the other hand, radiative cooling close to the root of the swelled top is relatively weak. The solar heating does not affect the temperature change in the cloud compared with radiative heat transfer by longwave infrared radiation. [ABSTRACT FROM AUTHOR]

We have performed a one-dimensional and transient radiative heat transfer analysis in order to investigate interaction between atmospheric radiation and convective instability within a nocturnal fog. The radiation element method using the Ray Emission Model (REM2), which is a generalized numerical method, in conjunction with a line-by-line (LBL) method, is employed to attain high spectral resolution calculations for anisotropically scattering fog. The results show that the convective instability has a strong dependence on radiative properties of the fog. For the condition of a 20-μm droplet diameter and liquid water content of 0.1 × 10-3 kg m-3;, the temperature profile within the fog becomes “S” shaped, and a convective instability layer forms in the middle or lower level of the fog. However, for the same water content and a 40-μm diameter droplet, no strong convective instability layer forms, whereas for a 10-μm diameter droplet a strong convective instability is observed. [ABSTRACT FROM AUTHOR]

Background: The fistula tract angle formed by percutaneous endoscopic gastrostomy (PEG) was examined. Also, the previous literature on fistula tract disruption is reviewed and the possible influence of the fistula tract angle on fistula tract disruption by non-endoscopic catheter change is discussed. Methods: A total of 15 patients aged 24–80 years were examined.The fistula tract angle was measured as the angle of elevation between the tangent line at the orifice of the PEG stoma and the longitudinal axis of the catheter. Results: Values of the angle ranged from 56 to 90° (mean 77.6°), with four cases (27%) having angles below 70°.With one case of pan-peritonitis after catheter insertion at 90°, laparotomy revealed that the angle of the fistula tract was low at 62° and that the catheter had broken through the tract just below the abdominal wall. Conclusion: This study suggests that the fistula tract angle might be a potential risk factor for fistula tract disruption by non-endoscopic catheter change. [ABSTRACT FROM AUTHOR]

Investigates development of high-frequency depositional sequences in a middle and upper Pleistocene succession. Analysis of shallow-marine and coastal deposits developed in paleo-Tokyo Bay, Japan; Importance of local basin tectonics to depositional sequences.

We recently reported fleroxacin significantly affected cell proliferation in a dose-dependent manner in transitional cell carcinoma cell lines. In this study, we investigated the effect of fleroxacin on mouse bladder carcinogenesis with N-butyl-N-(4-hydroxybutyl) nitrosamine (BHBN). Five-week-old C57BL/6 female mice were divided into three groups. The forced oral administrations of fleroxacin (10 or 50 mg/kg/day) were done for 1 week, then the 0.05% BHBN was given for 8 or 12 weeks. Fleroxacin treatments were continued until sacrifice. The mice were sacrificed at 4 weeks or 8 weeks latent period after BHBN administration, and the histological changes in the bladder were examined. Our study suggested that fleroxacin tended to suppress the development of bladder carcinoma or the malignant changes induced by a shorter period of BHBN administration (8 weeks) in mice. However, in the group of the BHBN administration for 12 weeks, there were no significant effects on the prevention of bladder carcinoma in both of the treatment groups with fleroxacin (10 or 50 mg/kg/day). This study did not make it clear that oral administration of fleroxacin suppressed the development of bladder carcinoma induced by BHBN in mice. However, it is very preliminary data and further experiments need to be done with a much higher dose of the fleroxacin or with other kinds of fluoroquinolone antibiotics. [ABSTRACT FROM AUTHOR]

The article presents case studies of patients treated with paroxetine after diagnosed with whole-body allodynia. Topics discussed include the medical history of the patients, the diagnosis of their illness, their symptoms, and the effects of paroxetine on their body as they were treated by this medicine.

A correction is presented to the article "Stability and low induction propensity of cefiderocol against chromosomal AmpC beta-lactamases of Pseudomonas aeruginosa and Enterobacter cloacae" in the jornal's 2018 issue.

A correction is presented to the article "Stability and low induction propensity of cefiderocol against chromosomal AmpC b-lactamases of Pseudomonas aeruginosa and Enterobacter cloacae" includes modification of abstract and discussion.

Background: Robotic rehabilitation has been attracting attention as a means to carry out "intensive", "repetitive", "task-specific", gait training. The newly developed robotic device, the Hybrid Assistive Limb (HAL), is thought to have the possibility of having an excellent effect on gait speed improvement over the conventional automatic programed assist robot. The purpose of this study was to investigate the spatiotemporal characteristics related to gait speed improvement using the HAL in chronic stroke patients.Research Question: To investigate the effects of robotic gait training on gait speed and gait parameters.Methods: An observational study with an intervention for single group was used. Intervention was conducted in University Hospital. Eleven chronic stroke patients were enrolled in this study. The patients performed 8 gait training sessions using the HAL, 2-5 sessions/week for 3 weeks. Gait speed, stride length, cadence, time of gait cycle (double-limb stance phases and single-limb stance phases) and time asymmetry index were measured before and after intervention.Results: After intervention, gait speed, stride length, and cadence were significantly improved (Effect size = 0.39, 0.29, and 0.29), the affected initial double-limb stance phase was significantly shortened (from 15.8 ± 3.46%-13.3 ± 4.20%, p =  .01), and the affected single-limb stance phase was significantly lengthened (from 21.8±7.02%-24.5±7.95%, p <  .01). The time asymmetry index showed a tendency to improve after intervention (from 22.9±11.8-17.6±9.62, p =  .06). There was a significant correlation between gait speed and the stride length increase rate (r = .72, p =  .01).Significance: This study showed that increasing stride length with lengthening of the affected single-stance phase by gait training using the HAL improved gait speed in chronic stroke patients. However, the actual contributions on HAL cannot be separated from gait training because this study is an observational research without a control group. [ABSTRACT FROM AUTHOR]

It has been well accepted that d -serine may be an exclusive endogenous coagonist for the N -methyl- d -aspartate (NMDA)-type glutamate receptor in mammalian forebrain regions. We have recently found by using an in vivo dialysis method that an intra-medial prefrontal cortex infusion of S-α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (S-AMPA), a selective AMPA-type glutamate receptor agonist, causes a reduction in the extracellular levels of d -serine in a calcium-permeable AMPA receptor antagonist-sensitive manner. The inhibitory influence by the AMPA receptor on the extracellular d -serine, however, contradicts the data obtained from in vitro experiments that the AMPA receptor stimulation leads to facilitation of the d -serine liberation. This discrepancy appears to be due to the different cell setups between the in vivo and in vitro preparations. From the viewpoints of the previous reports indicating (1) the neuronal presence of d -serine synthesizing enzyme, serine racemase, and d -serine-like immunoreactivity and (2) the same high tissue concentrations of d -serine in the glia-enriched white matter and in the neuron-enriched gray matter of the mammalian neocortex, we have now investigated in the mouse medial prefrontal cortex, the effects of attenuation of neuronal and glial activities, by tetrodotoxin or fluorocitrate, respectively, on the S-AMPA-induced downregulation of the extracellular d -serine contents. In vivo dialysis studies revealed that a local infusion of tetrodotoxin or fluorocitrate eliminated the ability of S-AMPA given intra-cortically to cause a significant decrease in the dialysate concentrations of d -serine without affecting the elevating effects of S-AMPA on those of glycine, another intrinsic coagonist for the NMDA receptor. These findings suggest that the control by the AMPA receptor of the extracellular d -serine levels could be modulated by the neuronal and glial activities in the prefrontal cortex. It cannot be excluded that fluorocitrate would indirectly alter the modulation by changing synaptic neurotransmission via glial activity attenuation as previously reported. [ABSTRACT FROM AUTHOR]

Diminished glutamate neurotransmission via the N-methyl-d-aspartate type glutamate receptor (NMDAR) has been considered to be involved in the pathophysiology of schizophrenia based upon the observation that the antagonists and autoantibodies of NMDAR cause positive, negative and cognitive symptomatologies similar to those of schizophrenia. The possible reduced extracellular levels of d-serine by overstimulation of the calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor (CP-AMPAR) following the NMDAR hypofunction-induced compensatory increase in the glutamate release could aggravate the NMDAR hypofunction in the brain of the drug- or antibody-associated psychoses and schizophrenia, because d-serine is an intrinsic coagonist for the NMDAR. To obtain an insight into the therapeutic approach to such a glutamate-linked psychotic state, we have studied the effects of the systemic administration of the CP-AMPAR-selective antagonist, IEM 1460 (N,N,N-trimethyl-5- [(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]-1-pentanaminium bromide hydrobromide), on the hyperactivity following an injection of a schizophrenomimetic NMDAR antagonist, phencyclidine, in the mouse. The subcutaneous IEM 1460 application produced a dose-dependent inhibition of the increased movement counts after the subcutaneous injection of phencyclidine. This inhibiting influence was also seen on the hyperactivity elicited by another NMDAR antagonist, dizocilpine. Moreover, the IEM 1460 administration attenuated the ability of a schizophrenomimetic dopamine agonist, methamphetamine, to increase spontaneous movements. These findings indicate that dysregulation of the CP-AMPAR could, at least in part, be implicated in the glutamate pathology of schizophrenia and/or related psychotic symptoms and be a potential target for the development of their novel treatment. [ABSTRACT FROM AUTHOR]

11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C−C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu4N][Ph3SnF2], which directly constructs the crucial C−C bond at the C11 position in SEA. The NaVCh-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC50 value of (47±12) n m, which is approximately twice as potent as decarbamoyl-STX (dcSTX). [ABSTRACT FROM AUTHOR]

11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C−C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu4N][Ph3SnF2], which directly constructs the crucial C−C bond at the C11 position in SEA. The NaVCh-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC50 value of (47±12) n m, which is approximately twice as potent as decarbamoyl-STX (dcSTX). [ABSTRACT FROM AUTHOR]

d-Serine has been shown to play an important role in the expression and control of a variety of brain functions by acting as the endogenous coagonist for the N-methyl-d-aspartate type glutamate receptor (NMDAR), at least, in the forebrain. To obtain further insight into the still debatable cellular localization of the d-amino acid, we have examined the effects of the selective destruction of the neuronal cell bodies by quinolinate on the tissue or extracellular d-serine concentrations in the medial prefrontal cortex of the rat. A local quinolinate infusion into the bilateral medial prefrontal cortex produced a cortical lesion with a marked (− 65%) and non-significant alteration (− 5%) in the cortical and striatal tissue d-serine concentrations, respectively, 7 days post-infusion. In vivo microdialysis experiments in the right prefrontal lesion site 9 days after the quinolinate application revealed that the basal extracellular d-serine levels were also dramatically reduced (− 64%). A prominent reduction in the tissue levels of GABA in the interneurons of the prefrontal cortex (− 78%) without significant changes in those in the striatum (+ 12%) verified that a major lesion part was confined to the cortical portion. The lack of a significant influence of the prefrontal quinolinate lesion on its dopamine concentrations in the mesocortical dopamine projections suggests that the nerve terminals and axons in the lesion site may be spared. These findings are consistent with the perikarya-selective nature of the present quinolinate-induced lesion and further support the view that neuronal cell bodies of intrinsic neurons in the prefrontal cortical region contain substantial amounts of d-serine, which may sustain the basal extracellular concentrations of d-serine. [ABSTRACT FROM AUTHOR]

Lithium's inhibitory effect on enzymes involved in sulfation process, such as inhibition of 3'(2')-phosphoadenosine 5'-phosphate (PAP) phosphatase, is a possible mechanism of its therapeutic effect for bipolar disorder (BD). 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is translocated from cytosol to Golgi lumen by PAPS transporter 1 (PAPST1/SLC35B2), where it acts as a sulfa donor. Since SLC35B2 was previously recognized as a molecule that facilitates the release of D-serine, a co-agonist of N-methyl-D-aspartate type glutamate receptor, altered function of SLC35B2 might be associated with the pathophysiology of BD and schizophrenia (SCZ). We performed genetic association analyses of the SLC35B2 gene using Japanese cohorts with 366 BD cases and 370 controls and 2012 SCZ cases and 2170 controls. We then investigated expression of SLC35B2 mRNA in postmortem brains by QPCR using a Caucasian cohort with 33 BD and 34 SCZ cases and 34 controls and by in situ hybridization using a Caucasian cohort with 37 SCZ and 29 controls. We found significant associations between three SNPs (rs575034, rs1875324, and rs3832441) and BD, and significantly reduced SLC35B2 mRNA expression in postmortem dorsolateral prefrontal cortex (DLPFC) of BD. Moreover, we observed normalized SLC35B2 mRNA expression in BD subgroups who were medicated with lithium. While there was a significant association of SLC35B2 with SCZ (SNP rs2233437), its expression was not changed in SCZ. These findings indicate that SLC35B2 might be differentially involved in the pathophysiology of BD and SCZ by influencing the sulfation process and/or glutamate system in the central nervous system. [ABSTRACT FROM AUTHOR]

Abstract: Alginate is a natural acidic linear polysaccharide that is produced by brown seaweeds. It is currently used in a broad range of commercial enterprises, such as the food and medical products industries. Recent evidence has demonstrated that alginate oligosaccharides may function as growth promoting agents for certain plant cells, including those of some green algae. Chlamydomonas reinhardtii is a green alga that is used as a model organism in fundamental molecular biology studies; it is also a producer of biohydrogen. In the present study, we examined effects of two types of alginate oligosaccharide mixtures (AOMs), which were prepared by either enzymatic degradation (ED) or acid hydrolysis (AH), on the growth of C. reinhardtii. Growth was significantly promoted by AOM (ED) in a concentration-dependent manner. The maximum effect was observed on day 4 of treatment. The fatty acid composition of C. reinhardtii was also influenced by AOM (ED); the levels of C16:0, C18:2 cis and C18:3 n−3 increased in treated cells. AOM (AH) and the other saccharides that we tested did not affect the growth of C. reinhardtii. The effects that we identified could promote efficient biomass production by reducing culture times and by changing cellular fatty acid levels. [Copyright &y& Elsevier]

Background: Liver stiffness (LS) has been reported to correlate with fibrosis stage (F). The correlation between LS and fibrosis stage and the reduction of LS by antiviral therapy were examined in patients with hepatitis B infection. Methods: LS was measured by FibroScan in 212 patients infected with hepatitis B virus. Liver biopsies were done in 51 patients. Changes of LS were assessed in 29 patients treated with nucleotide or nucleoside analogs and 52 patients without antiviral therapy. Results: LS was significantly correlated with fibrosis stage ( ρ = 0.686, P < 0.0001). The optimal cut-off values of LS were 7.1 kPa for F ≥ 2, 10.7 kPa for F ≥ 3, and 16.0 kPa for F4. LS was significantly reduced by antiviral therapy, from 12.9 (range 6.2-17.9) kPa to 6.6 (4.4-10.3) kPa measured at an interval of 512 (range 366-728) days ( P < 0.0001). Eleven of 19 (58%) patients with baseline fibrosis stages of F3-4 deduced from LS had 2-point or greater reductions of deduced stage at the last LS measurement. The change ratio of hyaluronic acid ( P = 0.0390) was associated with a 2-point or greater reduction of deduced fibrosis stage. Without antiviral therapy, LS tended to increase, increasing from 6.1 (range 3.9-8.5) kPa to 6.3 (range 4.4-9.7) kPa at an interval of 422 (range 358-709) days ( P = 0.0682). Conclusions: LS was significantly correlated with fibrosis stage in patients with chronic hepatitis B. The reduction of LS by antiviral therapy was significantly correlated with the reduction of hyaluronic acid. Thus, we conclude that LS can be useful to assess the progression and regression of liver fibrosis stage noninvasively. [ABSTRACT FROM AUTHOR]

Abstract: Exposure to novelty, a mild psychological stressor, induces neuronal activations in the hippocampus of rodents, which may play an important role in the adaptation to stress. We examined the changes in three parameters, i.e., gene expression in the hippocampus using a RT-PCR method, corticosterone and motor activity, in mice exposed to a new environment for 120min. A sharp and short-lasting increase in the gene expression of a set of stress-related genes previously reported, e.g., Fos and Nr4a1, was observed during the stress, with a similar pattern of changes in corticosterone. The motor activity gradually decreased during the novelty stress, indicating a process of adaptation to the new environment. In addition, in order to minimize the effects of elevated adrenal hormones by the stress, we carried out experiments on adrenalectomized (ADX) mice. However, the adrenalectomy produced minimal changes in the pattern and the magnitude of the gene response after the stress, while the motor activity showed a relatively slower pattern of adaptation in the ADX mice. Hence, the present study suggests that there was a coordinated adaptation process to the new environment in mice, and that the transcriptional response was mediated by neuronal networks rather than by adrenal hormones. [Copyright &y& Elsevier]

The mammalian cerebral neocortex occupies the largest area of the cerebral cortex and is cytoarchitectually composed of six layers (I–VI). Recent molecular analysis has begun to reveal the existence of various developmental programs, including the genetic regulation of arealization of the neocortex. Although an increasing number of molecular determinants of the developmental stages of the neocortex have been identified, no genes specifically expressed in the adult neocortex have been identified to date. By global screening using microarrays, combined with systematicin situhybridization, we identified a zinc-finger type transcription factor, Fez1, which is expressed predominantly in the mouse adult neocortex. No other genes in the neocortex have been shown to date to have their expression with such high specificity. Using two-colorin situhybridization, we show that Fez1 is mainly expressed in cortical layers V and VI, not inγ-aminobutyric acid neurons but in pyramidal neurons, the projection neurons of the cerebral cortex. Immunohistochemistry also shows that Fez1 is expressed in deep layers of the neocortex. Fez1 will be invaluable not only for the molecular understanding of corticogenesis but also for understanding the physiological functions of the adult neocortex, as well as for the use of its promoter in gene-manipulated animals and in conditional expression systems. [ABSTRACT FROM AUTHOR]

• An isogenic hES cell line with 16p11.2 deletion was generated using CRISPR/Cas9. • Transcriptome analysis was performed using neural cells derived from isogenic hESCs. • 16p11.2 deletion cells enhanced neurogenesis and neuronal maturation. • Transcriptome analysis identified dysregulation of FMRP targets including GRM5. • Pathway analyses identified upregulation of GPCR and RAF/MAPK signaling. 16p11.2 deletion is one of the most influential copy number variations (CNVs) associated with autism spectrum disorder (ASD). Previous studies have investigated the pathophysiology of 16p11.2 deletion both in vitro and in vivo , and have identified features such as NMDAR dysfunction, excitation-inhibition imbalance, transcriptional dysregulation, and impaired cortical development. However, little is known about the transcriptional profiles of human neural cells. Here, we constructed an isogenic human embryonic stem (hES) cell model with 16p11.2 deletion using a CRISPR/Cas9 system and performed transcriptome analyses of hES-derived 2-dimensional neural cells. We identified several characteristics which may correlate with the neuropathology of 16p11.2 deletion: predisposition to differentiate into neural lineages, enhanced neurogenesis, and dysregulation of G protein-coupled receptor signaling and RAF/MAPK pathway. We also found upregulation of fragile X mental retardation protein (FMRP) target genes including GRM5, which is implicated as a common trait between 16p11.2 deletion and fragile X syndrome. Extending our knowledge into other ASD models would help us to understand the molecular pathology of this disorder. [ABSTRACT FROM AUTHOR]

Excessive accumulation of amyloid β-protein (Aβ) is one of the primary mechanisms that leads to neuronal death with phosphorylated tau in the pathogenesis of Alzheimer's disease (AD). Protofibrils, one of the high-molecular-weight Aβ oligomers (HMW-Aβo), are implicated to be important targets of disease modifying therapy of AD. We previously reported that phenolic compounds such as myricetin inhibit Aβ1-40, Aβ1-42, and α-synuclein aggregations, including their oligomerizations, which may exert protective effects against AD and Parkinson's disease. The purpose of this study was to clarify the detailed mechanism of the protective effect of myricetin against the neurotoxicity of HMW-Aβo in SH-SY5Y cells. To assess the effect of myricetin on HMW-Aβo-induced oxidative stress, we systematically examined the level of membrane oxidative damage by measuring cell membrane lipid peroxidation, membrane fluidity, and cell membrane potential, and the mitochondrial oxidative damage was evaluated by mitochondrial permeability transition (MPT), mitochondrial reactive oxygen species (ROS), and manganese-superoxide dismutase (Mn-SOD), and adenosine triphosphate (ATP) assay in SH-SY5Y cells. Myricetin has been found to increased cell viability by suppression of HMW-Aβo-induced membrane disruption in SH-SY5Y cells, as shown in reducing membrane phospholipid peroxidation and increasing membrane fluidity and membrane resistance. Myricetin has also been found to suppress HMW-Aβo-induced mitochondria dysfunction, as demonstrated in decreasing MPT, Mn-SOD, and ATP generation, raising mitochondrial membrane potential, and increasing mitochondrial-ROS generation. These results suggest that myricetin preventing HMW-Aβo-induced neurotoxicity through multiple antioxidant functions may be developed as a disease-modifying agent against AD. [Display omitted] • Myricetin suppresses neurotoxicity by high molecular weight amyloid β oligomers. • The therapeutic target is oxidative stress at the cell membrane and mitochondria. • It not only works as an antioxidant but boosts the antioxidant function of neurons. • Myricetin may be developed as a disease-modifying agent for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

In this study, we described developmental changes in an event-related magnetic source of P300 activity during a visual oddball paradigm using magnetoencephalography. The maximum and minimum points of each peak of target P300 activity were scattered in a more anterior temporal area in children than in adults. The single dipole source analysis successfully estimated a dipole in the vicinity of the thalamus and the cingulate gyrus in adults. The location differed in children, although the dipole had overall greater moment in children than in adults. Our findings suggest that the thalamus plays an important role in generating P300 activity specific to color discrimination processing, and that in children the source is not consistent during development. [Copyright &y& Elsevier]

AbstractWe have studied in the rat the effects of acute subcutaneous injection of psychotomimetics including methamphetamine (MAP), cocaine and phencyclidine (PCP) on the expression of a brain plasticity‐related molecule, tissue plasminogen activator (tPA) mRNA, using non‐radioactive in situ hybridization histochemistry. In addition to the constitutive expression of tPA mRNA in cerebellar Purkinje cells, ventricular ependymal cells and meningeal blood vessel‐associated cells, MAP (1–4 mg/kg), cocaine (30 mg/kg) and PCP (1.25–5 mg/kg) caused a transient and dose‐dependent induction of the transcript with its peak at 3 h postinjection in a group of neurons of the medial and insular prefrontal cortices, and the piriform cortex. Another indirect dopamine agonist nomifensine (20–40 mg/kg) mimicked the tPA mRNA induction in the prefrontal cortical areas. Moreover, MAP induction of tPA mRNA was markedly inhibited by pretreatment with a D1 (R(+)‐SCH23390: R(+)‐7‐chloro‐8‐hydroxy‐3‐methyl‐1‐phenyl‐2,3,4,5‐tetra‐hydro‐1H‐3‐benzazepine hydrochloride) or a D2 (haloperidol) dopamine receptor‐preferring antagonist. Intramedial striatum, but not intrathalamic, application of a fluorescent tracer, fluorogold, retrogradely labelled the cortical cells expressing tPA mRNA. The present results suggest that acute injections of the above psychotomimetic drugs may induce tPA mRNA in a group of the prefrontal cortical neurons that project to the medial striatum. This tPA mRNA expression may be due to the activation of the dopamine neurotransmission. Because it is well documented that single or repeated administration of methamphetamine, cocaine and PCP produces enduring changes in responses to these drugs in humans and experimental animals (e.g. behavioural sensitization), the psychotomimetic‐induction of tPA mRNA could be implicated in an initial step in the plastic rearrangements in the neuronal circuits underlying long‐lasting changes in behavioural expression. [ABSTRACT FROM AUTHOR]

Oral dysesthesia denotes a condition characterized by abnormal sensations in oral regions without a somatic basis, and is often seen in people with autistic traits, including those with autism spectrum disorder. This study aimed to examine the association between the symptoms of oral dysesthesia and the degree of autistic traits. A retrospective chart review was performed on 44 patients with oral dysesthesia, and associations among the subscales of the Oral Dysesthesia Rating Scale (Oral DRS), Autism Spectrum Quotient (AQ), and Glasgow Sensory Questionnaire (GSQ) were investigated. A Pearson correlation analysis revealed a significant, positive correlation between AQ scores and the A3 (squeezing or pulling) subscale of the Oral DRS (r = 0.37), but there were no significant correlations between the AQ and other subscale scores. There was a significant correlation between the AQ and GSQ score, but no correlation was detected between the GSQ and A3 scores or any other Oral DRS subscale scores. In conclusion, an abnormal squeezing or pulling sensation in oral regions without a somatic basis was associated with autistic traits and could be highlighted as a specific abnormality in sensory processing in autism spectrum disorder. [ABSTRACT FROM AUTHOR]

Objective: Oral cenesthopathy is characterized by foreign body sensations without medical and dental evidence for them. It is thought to be a rare disease in psychiatry, but many patients are visiting dental clinics seeking treatment to remove a foreign body. Even though the features of oral cenesthopathy might be different between a psychiatric clinic and a dental clinic, there has been no clinicostatistical study from dentists. In this study, we report a clinicostatistical study of patients with oral cenesthopathy in dentistry. Methods: This is a retrospective chart review of 606 outpatients with oral cenesthopathy in Tokyo Medical and Dental University from April 2010 through to March 2015. Results: A total of 159 male and 447 female patients were included in this study. The mean age was 62.08 years, and female patients were older than male patients. The trigger of the dental treatment and the acute phase of depression at the onset were significantly related (p=0.037). Only 128 patients (36%) had clinically significant improvement after 6 months of pharmacotherapy. No history of psychiatric disorders (odds ratio [OR] 0.479 [95% confidence interval {CI}: 0.262–0.875], p=0.017) and longer duration of illness (.18 months) (OR 2.626 [95% CI: 1.437–4.799], p=0.002) were significant factors for clinical outcomes. Conclusion: Patients with oral cenesthopathy in our clinic were predominantly elderly female patients. Dental treatment in the acute phase of depression might be a risk factor for oral cenestopathy. Therefore, comprehending the situation of psychiatric disorder and obtaining adequate informed consent might be required to prevent the trouble concerning oral cenesthopathy. [ABSTRACT FROM AUTHOR]

The structure-activity relationship (SAR) for a novel series of catechol conjugated siderophore cephalosporins is described with their in vitro activities against multi-drug resistant Gram-negative pathogens including Pseudomonas aeruginosa , Acinetobacter baumannii , Stenotrophomonas maltophilia and Enterobacteriaceae . Cefiderocol ( 3 ) was one of the best molecules which displayed well-balanced and potent activities against multi-drug resistant Gram-negative pathogens including carbapenem resistant bacteria among the prepared compounds with the modified C-7 side chain and the modified C-3 side chain. Cefiderocol ( 3 ) is a highly promising parenteral cephalosporin for the treatment of multi-drug resistant Gram-negative infection. [ABSTRACT FROM AUTHOR]

Aim: While electroconvulsive therapy (ECT) is a well‐established, safe, and effective treatment for mental illnesses, the potential for adverse effects on cognitive functions remains controversial. We aimed to evaluate multiple cognitive functions in different time periods before and after ECT in a Japanese population. Methods: A battery of five neurocognitive tests was administered to patients who underwent a course of ECT treatment at three time points: before, immediately after, and 4 weeks after ECT. Results: A transient but significant decline in letter fluency function was observed immediately after ECT, but had recovered well by 4 weeks. We also observed a significant improvement in the trail‐making task at 4 weeks after ECT. Conclusion: In a Japanese population, adverse effects of ECT on verbal fluency function‐related and other cognitive impairments were transient. Over the longer term, we detected significant improvements in the performance of tasks that presumably reflected information processing speed and executive functions. [ABSTRACT FROM AUTHOR]

Background: D-serine is an endogenous co-agonist of N-methyl-D-aspartate receptor (NMDAR) and plays an important role in glutamate neurotransmission. Several studies suggested the possible involvement of D-serine related in the pathophysiology of psychiatric disorders including major depression disorders (MDD). We tried to examine whether cerebrospinal fluid (CSF) or plasma D-serine concentrations are altered in MDD and whether D-serine concentrations correlated with disease severity.Methods: 26 MDD patients and 27 healthy controls matched for age, sex and ethnicity were enrolled. We measured amino acids in these samples using by high-performance liquid chromatography with fluorometric detection.Results: D-serine and L-serine, precursor of D-serine, levels in CSF or plasma were not significantly different in patients of MDD compared to controls. Furthermore, a significant correlation between D-serine levels in CSF and Hamilton Depression Rating Scale (HAMD)-17 score was observed (r = -0.65, p = 0.006). Furthermore, we found a positive correlation between CSF D-serine and HVA concentrations in MDD patients (r = 0.54, p = 0.007). CSF D-serine concentrations were correlated with those of plasma in MDD (r = 0.61, p = 0.01) but not in controls. In CSF, we also confirmed a significant correlation between D-serine and L-serine levels in MDD (r = 0.72, p < 0.0001) and controls (r = 0.70, p < 0.0001).Conclusions: The study has some limitations; sample size was relatively small and most patients were medicated. We revealed that CSF D-serine concentrations were correlated with depression severity and HVA concentrations and further investigation were required to reveal the effect of medication and disease heterogeneity. [ABSTRACT FROM AUTHOR]

Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and N-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein N-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of WDR3 and ALG1 in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic P = 0.003, genotypic P = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)–W5 (rs379058) also displayed a significant association in the female schizophrenics (P = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the WDR3 gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia. [ABSTRACT FROM AUTHOR]

Significant roles of the primary cilia in the central nervous system have been reported in neural generation and cognitive functions. However, little is known about the possible pathological changes in brain primary cilia in neuropsychiatric disorders. To obtain an insight into the relationship between cilial dysregulation and schizophrenia, we presently investigated the effects of psychotomimetics, phencyclidine, MK-801 (dizocilpine), and methamphetamine, on morphological and molecular indices in the rodent brain. Using an immunohistochemical technique, we found that a subcutaneous injection of phencyclidine, an NMDA type glutamate receptor (NMDAR) antagonist, caused a reduction in the long axis length of a primary cilium in the CA1 region of the hippocampus without affecting that in the dentate gyrus and medial prefrontal cortex of rats and mice. The region-selective modulation of primary cilia was mimicked by another NMDAR antagonist, MK-801, but not by the indirect dopamine agonist methamphetamine. Furthermore, systemic administration of phencyclidine, but not methamphetamine, down-regulated mRNA expression of primary cilium morphology-related genes, including kif3a , 5-HTR6 , RPGRIP1L , and TMEM67 , and of genes composing the cilial Wnt/β-catenin signaling pathway, β-catenin , syn2 and Bcl-2 , in the hippocampus, but not in the cerebral cortex of rats. These findings suggest that NMDAR hypofunction-induced dysregulation of CA1 primary cilia could be involved in the pathophysiology of dopamine transmission-independent symptoms of schizophrenia. [ABSTRACT FROM AUTHOR]

Aim The aetiology of progressive periodontitis in diabetes has not yet been elucidated. We previously demonstrated that nitrosative stress is increased in diabetic rats with periodontitis. Nitrosative stress induces poly( ADP-ribose) polymerase ( PARP) activation. Here, we demonstrated the involvement of PARP activation in diabetic periodontitis and detailed the therapeutic effects of PARP inhibitor. Materials and Methods Experimental periodontitis was induced by placing a nylon thread ligature. Half of the normal and diabetic rats received the PARP inhibitor, 1,5-isoquinolinediol, for 2 weeks. Gingival PARP activation was detected by immunostaining for poly( ADP-ribose). Periodontitis was evaluated by gingival inflammatory cell infiltration, inflammatory gene expressions and micro- CT analyses. Results Although both periodontitis and the presence of diabetes increased PARP activation in the gingiva, diabetic rats with periodontitis had the highest activation of PARP. Diabetic rats with periodontitis also showed significant increases in monocyte/macrophage invasion into the gingiva, inflammatory gene expressions, nitrotyrosine-positive cells in the gingiva and alveolar bone loss, all of which were suppressed by treatment with the PARP inhibitor. Conclusions These results indicate the involvement of PARP activation in the pathogenesis and aggravation of periodontal disease in diabetes and suggest the therapeutic potential of PARP inhibition for treating periodontal disease, especially in patients with diabetes. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) studies have revealed a changed integrity in the white matter of bipolar disorder. However, only a few investigations have examined bipolar II disorder (BP-II). A cross-sectional study was conducted to compare thirty-eight patients with BP-II (mean age = 38.26 years, F/M = 19/19) with thirty-eight age- and gender-matched healthy controls (mean age = 34.45 years, F/M = 18/20). Tract Based Spatial Statistics (TBSS) analysis of the fractional anisotropy (FA) was done with age, gender and education years as covariates, then a complementary atlas-based region-of-interest (ROI) analysis including the axial diffusivity (AD) and radial diffusivity (RD) was conducted to obtain further information. The patients with BP-II showed a significant decrease in FA in the corpus callosum (commissure fibers), fornix (association fibers) and right anterior corona radiata (projection fibers) compared to the controls. Moreover, a significant increase in the RD was observed in all of the fibers of the BP-II patients, while the AD significantly increased only in the fornix of the patients. Thus, in addition to the abnormal integrity of the commissure and projection fibers, the present study suggested an involvement of the limbic association fibers in the pathophysiology of BP-II induced by a distinctive neuropathology. [ABSTRACT FROM AUTHOR]

G72 is a modulator of D-amino acid oxidase, the enzyme that degrades D -serine, an amino acid that plays a critical role in glutamate neurotransmission, and has been implicated in psychiatric disorders. The aim of this study was to examine whether plasma or cerebrospinal fluid (CSF) G72 protein levels were altered in either schizophrenia or major depressive disorder (MDD) and whether any correlation between G72 levels and disease severity existed. Initially, 27 schizophrenic patients, 26 MDD patients, and 27 healthy controls matched for age, sex, and ethnicity were enrolled. Compared to those of controls, plasma or CSF G72 levels were not significantly different in patients with schizophrenia or MDD. Although we found a significant positive correlation between plasma G72 levels and a positive symptoms score on the positive and negative syndrome scale (PANSS), this was not replicated in the second study (40 schizophrenic patients). CSF G72 levels showed no significant correlation with PANSS scores. In MDD, neither plasma nor CSF G72 levels correlated significantly with depression severity. Since severity of our patients were relatively mild, further investigations in a large number of subjects including drug-free patients, younger patients, and more severely affected patients are warranted. [ABSTRACT FROM AUTHOR]

Aim Genome-wide association studies have revealed that single nucleotide polymorphism (SNP) of human leukocyte antigen ( HLA)-DQ is associated with the clearance of hepatitis B surface antigen (HBsAg) in acute hepatitis B virus (HBV) infection. We examined the effects of SNPs on the development of hepatocellular carcinoma (HCC) and markers of HBV in chronic HBV infection. Methods The SNPs of HLA-DQ (rs2856718 and rs7453920) were determined in 299 patients with chronic HBV infection. Results In 224 hepatitis B e antigen (HBeAg)-negative patients, those with rs2856718 genotype AG + GG had significantly lower hepatitis B core-related antigen levels ( P = 0.0184), less frequent treatment with nucleotide/nucleoside analogs (NAs) ( P = 0.0433), and less frequent HCC development ( P = 0.0256) than those with genotype AA. Multivariate analysis selected age ( P = 0.0460), platelet count ( P = 0.0481), γ-glutamyl transpeptidase ( P = 0.0030), and nucleotide/nucleoside analog treatment ( P = 0.0003) as factors independently associated with HCC development. HBeAg-negative patients with rs7453920 genotype GG had significantly lower HBsAg levels ( P < 0.0001), a higher prevalence of HBV genotype C ( P = 0.0063), and a lower prevalence of the wild-type basal core promoter region ( P = 0.0045) than those with genotype AA + AG. Multivariate analysis selected age ( P < 0.0001), platelet count ( P = 0.0021), HBV DNA levels ( P = 0.0314), wild type of precore region ( P = 0.0015), and rs7453920 ( P < 0.0001) as factors independently associated with HBsAg levels. Conclusion This study revealed an association between rs2856718 and HCC development and an association between rs7453920 and HBsAg levels. [ABSTRACT FROM AUTHOR]

Aims/Introduction The involvement of glucose-dependent insulinotropic polypeptide ( GIP) on inflammation was explored in atherosclerosis and adipose tissue. Periodontal disease is a chronic inflammatory disease, and is considered one of the diabetic complications. In the present study, to examine the effect of GIP on periodontitis, we induced experimental periodontitis in glucose-dependent insulinotropic polypeptide receptor-knockout mice ( GIPRKO). We also investigated the anti-inflammatory effect of GIP in a culture system. Materials and Methods Experimental periodontitis was induced by ligature wire in GIPRKO and C57 BL/C mice. Two weeks after the ligature, immunohistological evaluation and inflammatory messenger ribonucleic acid expression in the gingiva was examined. To elucidate the role of GIP in inflammation, the effects of GIP on lipopolysaccharide-induced gene expressions in THP-1 cells were evaluated. Results Periodontitis increased inflammatory cell infiltration, macrophage accumulation and tumor necrosis factor-α and nitric oxide synthase gene expressions in the gingiva. Periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue. Mac-1-positive macrophages and the inflammatory gene expressions were significantly increased in periodontitis in GIPRKO compared with C57 BL/C mice periodontitis. Immunohistochemical staining confirmed that GIP receptors were expressed in residual and infiltrated Mac-1-positive macrophages. The in vitro study showed that GIP suppressed lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide synthase gene expression in a dose-dependent manner. Furthermore, the inhibitory effect of GIP on lipopolysaccharide-induced inflammatory gene expressions was at least partially through cyclic adenosine monophosphate/protein kinase A pathway. Conclusions These results suggest the beneficial effects of GIP on periodontal disease. In diabetic patients, GIP is expected to have a direct anti-inflammatory effect on periodontitis in addition to its glucose-lowering effect. [ABSTRACT FROM AUTHOR]

Cenesthopathy is characterized by abnormal and strange bodily sensations and is classified as a 'delusional disorder, somatic type' or 'somatoform disorder' according to the DSM 5. The oral cavity is one of the frequent sites of cenesthopathy, thus the term 'oral cenesthopathy.' Patients with oral cenesthopathy complain of unusual sensations without corresponding abnormal findings in the oral area, such as excessive mucus secretion, a slimy sensation, or a feeling of coils or wires being present within the oral region. They usually visit multiple dentists rather than psychiatrists. Without a proper diagnosis, they repeatedly pursue unnecessary surgical procedures to remove their 'foreign body'. This sometimes creates a dilemma between the dentists and patients. The nosography of oral cenesthopathy has been discussed in some case reports and reviews but is overlooked in mainstream medicine. This review focuses on the various aspects of oral cenesthopathy. The estimated prevalence of cenesthopathy was 0.2 to 1.9 % in a study done at a Japanese university psychiatry clinic and 27 % in a study done at a Japanese psychosomatic dentistry clinic. Oral cenesthopathy do not have clear disposition, while some studies reported that elderly women were most commonly affected. Its pathophysiology has not been fully elucidated. However, recent studies have suggested a right > left asymmetrical pattern of the cerebral blood flow of patients with oral cenesthopathy. Antidepressants, antipsychotic drugs, electroconvulsive therapy, and psychotherapy might be effective in some cases, though it is known to be intractable. To date, the epidemiology, pathophysiology, etiology, classification and treatment of oral cenesthopathy are unknown due to the few reports on the disorder, though there are a few case reports. To overcome this difficult medical condition, clinico-statistical and case--control studies done under rigorous criteria and with a large sample size are required. [ABSTRACT FROM AUTHOR]

In the hippocampus of mice lacking the gene for serine racemase (SR), a d-serine synthesizing enzyme, in the CaMKIIα-expressing neurons, we observed a significant decrease in the extracellular concentration of d-serine, a coagonist for the N-methyl- d-aspartate type glutamate receptor (NMDAR), and NMDAR hypofunction as revealed by diminished extracellular taurine concentrations after an intra-hippocampal NMDA infusion when compared to the wild type controls. Therefore, the neuronal SR could regulate the extracellular d-serine signaling responsible for NMDAR activation in the hippocampus. [ABSTRACT FROM AUTHOR]

It is widely accepted that malfunction of the N-methyl- d-aspartate (NMDA)-type glutamate receptor may be involved in the pathophysiology of schizophrenia. Several recent microRNA (miRNA) studies have demonstrated that the expression of the glutamate system-related miR-132 and miR-212 is changed in postmortem schizophrenic brains. Here we attempted to obtain further insight into the relationships among schizophrenia, the NMDA receptor, the molecular cascades controlled by these miRNAs and commonly predicted target genes of the two miRNAs. We focused on the H2AFZ (encoding H2A histone family, member Z) gene, whose expression was shown in our screening study to be modified by a schizophrenomimetic NMDA antagonist, phencyclidine. By performing polymerase chain reaction with fluorescent signal detention using the TaqMan system, we examined four tag single nucleotide polymorphisms (SNPs; SNP01-04) located around and within the H2AFZ gene for their genetic association with schizophrenia. The subjects were a Japanese cohort (2,012 patients with schizophrenia and 2,170 control subjects). We did not detect any significant genetic association of these SNPs with schizophrenia in this cohort. However, we observed a significant association of SNP02 (rs2276939) in the male patients with schizophrenia (allelic P = 0.003, genotypic P = 0.008). A haplotype analysis revealed that haplotypes consisting of SNP02-SNP03 (rs10014424)-SNP04 (rs6854536) also showed a significant association in the male patients with schizophrenia ( P = 0.018). These associations remained significant even after correction for multiple testing. The present findings suggest that the H2AFZ gene may be a susceptibility factor in male subjects with schizophrenia, and that modification of the H2AFZ signaling pathway warrants further study in terms of the pathophysiology of schizophrenia. [ABSTRACT FROM AUTHOR]

The psychotomimetic effects of stimulant drugs including amphetamines and cocaine are known to change during the postnatal development in humans and experimental animals. To obtain an insight into the molecular basis of the onset of stimulant-induced psychosis, we have explored the gene transcripts that differentially respond to methamphetamine (MAP) in the developing rat brains using a differential cloning technique, the RNA arbitrarily-primed PCR. We identified from the rat neocortex a novel and developmentally regulated MAP-inducible gene mrt3 (MAP responsive transcript 3) that is transcribed to a presumable non-coding RNA of 3.8 kb and is located on the reverse strand of the F-box/LRR-repeat protein 17-like gene mapped on the rat chromosome Xq12. The mrt3 mRNAs are predominantly expressed in the brain and lung. Acute MAP injection upregulated the mrt3 expression in the neocortex at postnatal day 50, but not days 8, 15 and 23, in a D1 receptor antagonist-sensitive manner. This upregulation was mimicked by another stimulant, cocaine, whereas pentobarbital and D1 antagonist failed to alter the mrt3 expression. Moreover, repeated treatment with MAP for 5 days inhibited the ability of the challenge dose of MAP or cocaine to increase the neocortical mrt3 expression without affecting the basal mrt3 mRNA levels on day 14 of withdrawal. These late-developing, cocaine-cross reactive, D1 antagonist-sensitive and long-term regulations of mrt3 by MAP are similar to those of stimulant-induced behavioral sensitization, a model of the onset and relapse of stimulant-induced psychosis and schizophrenia, and therefore may be associated with the pathophysiology of the model. [ABSTRACT FROM AUTHOR]

A relationship between periodontal disease and atherosclerosis has been suggested by epidemiological studies. Ligature-induced experimental periodontitis is an adequate model for clinical periodontitis, which starts from plaque accumulation, followed by inflammation in the periodontal tissue. Here we have demonstrated using a ligature-induced periodontitis model that periodontitis activates monocytes/ macrophages, which subsequently circulate in the blood and adhere to vascular endothelial cells without altering the serum TNF-α concentration. Adherent monocytes/macrophages induced NF-κB activation and VCAM-1 expression in the endothelium and increased the expression of the TNF-α signaling cascade in the aorta. Peripheral blood-derived mononuclear cells from rats with experimental periodontitis showed enhanced adhesion and increased NF-κB/VCAM-1 in cultured vascular endothelial cells. Our results suggest that periodontitis triggers the initial pathogenesis of atherosclerosis, inflammation of the vasculature, through activating monocytes/macrophages. [ABSTRACT FROM AUTHOR]

Schizophrenia and similar psychoses induced by NMDA-type glutamate receptor antagonists, such as phencyclidine (PCP) and ketamine, usually develop after adolescence. Moreover, adult-type behavioral disturbance following NMDA receptor antagonist application in rodents is observed after a critical period at around 3 postnatal weeks. These observations suggest that the schizophrenic symptoms caused by and psychotomimetic effects of NMDA antagonists require the maturation of certain brain neuron circuits and molecular networks, which differentially respond to NMDA receptor antagonists across adolescence and the critical period. From this viewpoint, we have identified a novel developmentally regulated phencyclidine-responsive transcript from the rat thalamus, designated as prt6, as a candidate molecule involved in the above schizophrenia-related systems using a DNA microarray technique. The transcript is a non-coding RNA that includes sequences of at least two microRNAs, miR132 and miR212, and is expressed strongly in the brain and testis, with trace or non-detectable levels in the spleen, heart, liver, kidney, lung and skeletal muscle, as revealed by Northern blot analysis. The systemic administration of PCP (7.5 mg/kg, subcutaneously (s.c.)) significantly elevated the expression of prt6 mRNA in the thalamus at postnatal days (PD) 32 and 50, but not at PD 8, 13, 20, or 24 as compared to saline-treated controls. At PD 50, another NMDA receptor antagonist, dizocilpine (0.5 mg/kg, s.c.), and a schizophrenomimetic dopamine agonist, methamphetamine (4.8 mg/kg, s.c.), mimicked a significant increase in the levels of thalamic prt6 mRNAs, while a D2 dopmamine receptor antagonist, haloperidol, partly inhibited the increasing influence of PCP on thalamic prt6 expression without its own effects. These data indicate that prt6 may be involved in the pathophysiology of the onset of drug-induced schizophrenia-like symptoms and schizophrenia through the possible dysregulation of target genes of the long non-coding RNA or microRNAs in the transcript. [ABSTRACT FROM AUTHOR]