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BACKGROUND: Basic fibroblast growth factor (bFGF) has been applied for periodontal regeneration. However, the application depends on bone defect morphology because bFGF diffuses rapidly from defect sites. In a previous study, collagen-binding bFGF (CB-bFGF) has been shown to enhance bone formation by collagen-anchoring in the orthopedic field. The aim of this study is to demonstrate the efficacy of CB-bFGF with collagen scaffolds in bone regeneration of horizontal bone defect. METHODS: Cell proliferation activity and collagen binding activity of CB-bFGF was confirmed by WST-8 assay and collagen binding assay, respectively. The retention of CB-bFGF in the collagen sheet (CS) was measured by fluorescence imaging. The rat horizontal alveolar bone defect model was employed to investigate the efficacy of CB-bFGF with collagen powder (CP). After 4 and 8 weeks, the regenerative efficacy was evaluated by microcomputed tomography, histological, and immunohistochemical analyses. RESULTS: CB-bFGF had a comparable proliferation activity to bFGF and a collagen binding activity. CB-bFGF was retained in CS longer than bFGF. At 8 weeks postoperation, bone volume, bone mineral content, and new bone area in CB-bFGF/CP group were significantly increased compared with those in other groups. Furthermore, epithelial downgrowth was significantly suppressed in CB-bFGF/CP group. At 4 weeks, the numbers of osteocalcin, proliferating cell nuclear antigen, and osteopontin-positive cells at the regeneration site in CB-bFGF/CP group were greater than those in other groups. CONCLUSIONS: CB-bFGF/CP effectively promoted bone regeneration of horizontal bone defect possibly by sustained release of bFGF. The potential of CB-bFGF composite material for improved periodontal regeneration in vertical axis was shown.

DOI： 10.1002/JPER.18-0674

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Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

DOI： 10.3389/fimmu.2019.00307

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer New York LLC  

Oral bacteria initiate biofilm formation by attaching to tooth surfaces via an interaction of a lectin-like bacterial protein with carbohydrate chains on the pellicle. This study aimed to find naturally derived lectins that inhibit the initial attachment of a cariogenic bacterial species, Streptococcus mutans (S. mutans), to carbohydrate chains in saliva in vitro. Seventy kinds of lectins were screened for candidate motifs that inhibit the attachment of S. mutans ATCC 25175 to a saliva-coated culture plate. The inhibitory effect of the lectins on attachment of the S. mutans to the plates was quantified by crystal violet staining, and the biofilm was observed under a scanning electron microscope (SEM). Surface plasmon resonance (SPR) analysis was performed to examine the binding of S. mutans to carbohydrate chains and the binding of candidate lectins to carbohydrate chains, respectively. Moreover, binding assay between the biotinylated-lectins and the saliva components was conducted to measure the lectin binding. Lectins recognizing a salivary carbohydrate chain, Galβ1-3GalNAc, inhibited the binding of S. mutans to the plate. In particular, Agaricus bisporus agglutinin (ABA) markedly inhibited the binding. This inhibition was confirmed by SEM observation. SPR analysis indicated that S. mutans strongly binds to Galβ1-3GalNAc, and ABA binds to Galβ1-3GalNAc. Finally, the biotinylated Galβ1-3GalNAc-binding lectins including ABA demonstrated marked binding to the saliva components. These results suggest that ABA lectin inhibited the attachment of S. mutans to Galβ1-3GalNAc in saliva and ABA can be useful as a potent inhibitor for initial attachment of oral bacteria and biofilm formation.

DOI： 10.1007/s10719-017-9795-2

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Chronic periodontitis is a silent infectious disease prevalent worldwide and affects lifestyle-related diseases. Therefore, efficient screening of patients is essential for general health. This study was performed to evaluate prospectively the diagnostic utility of a blood IgG antibody titer test against periodontal pathogens. Oral examination was performed, and IgG titers against periodontal pathogens were measured by ELISA in 1,387 individuals. The cut-off value of the IgG titer was determined in receiver operating characteristic curve analysis, and changes in periodontal clinical parameters and IgG titers by periodontal treatment were evaluated. The relationships between IgG titers and severity of periodontitis were analyzed. The best cut-off value of IgG titer against Porphyromonas gingivalis for screening periodontitis was 1.682. Both clinical parameters and IgG titers decreased significantly under periodontal treatment. IgG titers of periodontitis patients were significantly higher than those of healthy controls, especially in those with sites of probing pocket depth over 4 mm. Multiplied cut-off values were useful to select patients with severe periodontitis. A blood IgG antibody titer test for Porphyromonas gingivalis is useful to screen hitherto chronic periodontitis patients (ClinicalTrials.gov number NCT01658475).

DOI： 10.1177/0022034512461796

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/0022034512461796

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/j.1600-0757.2005.00142.x

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1016/j.femsim.2004.08.005

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1016/S0928-8244(03)00224-4

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1902/jop.2003.74.1.103

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Microbiology  

<title>ABSTRACT</title>
During infection, circulating blood monocytes migrate from the vasculature to the extravascular compartments where they mature into tissue macrophages. The maturation process prepares the cell to actively participate in the inflammatory and the immune responses, and many transcription factors have been found to be involved. Here we report on a novel role for nuclear factor κB (NF-κB) in this process. Its accumulation in the cytoplasm of differentiated macrophages is responsible for the enhanced ability of the cell to respond to lipopolysaccharide (LPS) stimulation, as determined by tumor necrosis factor alpha (TNF-α) secretion. Differentiation of the human monocytic cell line THP-1 into macrophage-like cells was induced by exposure of the cells to phorbol myristate acetate. DNA-bindable NF-κB was not detected in the cytoplasm of undifferentiated THP-1 cells but accumulated in the cytoplasm of the cells following differentiation. No TNF-α was detected in the media of resting differentiated and nondifferentiated THP-1 cells. Stimulation with LPS of differentiated cells induced the production of higher levels of TNF-α than stimulation of nondifferentiated cells. This hyperresponsiveness to LPS was found in the mRNA and secreted TNF-α levels. Furthermore, stimulation with LPS induced the translocation of NF-κB from the cytoplasm into the nucleus. This translocation process was more rapid in the differentiated cells than in the nondifferentiated cells, and the resultant accumulated levels of NF-κB in the nucleus were higher. The DNA-bindable NF-κB was identified as a heterodimer of p65 and p50. The results suggest that NF-κB accumulation in the cytoplasm during maturation of monocytes to macrophages primes the cells for enhanced responsiveness to LPS and results in the rapid secretion of inflammatory mediators, such as TNF-α, by mature macrophages following LPS challenge.

DOI： 10.1128/iai.67.11.5573-5578.1999

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Human leukocyte antigens (HLA) are essential in the recognition of foreign antigens in humoral immune response, which is genetically predetermined. Susceptibility to certain diseases that involve the immune response has been studied in relation to distinct HLA types. Although some diseases have been found Co correlate to specific HLA loci positively, it has been difficult to isolate HLA types that predispose patients to periodontal destruction. Here. we review the current knowledge and recent advances in HLA genetics and its biology, which determine susceptibility to early-onset periodontitis (EOP). The HLA-DRB1*1501-DQB1*0602 genotype has been found with increasing frequency in EOP patients. This HLA genotype expresses aspartic acid at position 57 and glycine at position 70 on the DQ beta chain, suggesting a capability to bind certain bacterial antigens. The T cell response against the outer membrane protein (Ag53) of Porphyromonas against gingivalis was examined via this HLA genotype. Strong T cell response against Ag53 p141-161 was inhibited partially by anti-DR antibody, but not by anti-DQ antibody, possible host and bacterial peptides capable of binding DRB1*1501 were elucidated when the peptide sequence was compared to gene and protein databases. These results suggest that patients who have the HLA-DRB1*1501-DQB1*0602 genotype may have an accelerated T cell response to certain periodontapathic bacteria such as P. gingivalis in hyperimmune reactions and thus increased susceptibility to EOP.

DOI： 10.1111/j.1600-0765.1999.tb02269.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Proceedings of the National Academy of Sciences  

DOI： 10.1073/pnas.96.8.4518

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DNA TYPING WAS PERFORMED on 24 Japanese patients with early-onset periodontitis (EOP) using the PCR-RFLP method to investigate an association of the susceptibility to EOP with the particular HLA class II alleles (HLA-DRB1, -DQA1, and -DQB1), DRB1*1401, DRB1*1501, DQB1*0503, and DQB1*0602 were found more frequently (''susceptible'') in the EOP patients than in healthy controls. In contrast, DRB1*0405 and DQB1*0401 were found less frequently (''resistant'') in EOP patients, All patients carrying DQB1*0602 had an atypical BamHI site in the intron upstream of the third exon of the DQB1 gene, which in our previous studies appeared to be a susceptible marker for EOP. A comparative analysis of the amino acid sequences of these susceptible and resistant HLA-DRB1 and DQB1 alleles elucidated some differences in antigen-derived peptide binding sites related to the susceptible or resistant alleles. Especially, DQB1*0503 and DQB1*0602 alleles carrying aspartic acid at position 57 and glycine at position 70 are increased significantly in EOP. Since amino acid residues at positions 57 and 70 on the DQB1 molecule are supposed to be involved in antigen binding, amino acid substitutions at these positions may affect the immune responsiveness to the periodontopathic antigen. Our results suggest that the DQB1 molecule plays a crucial role in the pathogenesis of EOP and that the susceptibility to EOP may be determined by the binding ability between the peptide and HLA-DQ antigens.

DOI： 10.1902/jop.1996.67.9.888

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Lipopolysaccharide (LPS) is one of the most potent trigger substances for monocytes and macrophages causing secretion of tumor necrosis factor alpha (TNF-alpha) and other inflammatory mediators. The nature of the nuclear factors involved in human TNF-alpha gene regulation is still unknown. Nuclear factor kappa B (NF-kappa B) proteins have been suggested to play an important role in gene transcription of inflammatory mediators when monocytes are stimulated with LPS. However, it remains unclear whether these nuclear factors are the only ones involved in human TNF-alpha gene regulation. In this report, to further the identification of nuclear factor(s) involved in TNF-alpha gene regulation, human monocytic THP-1 cells were transfected with a series of truncated versions of human TNF-alpha promoter. A 98-bp region located from nucleotides -584 to -487 demonstrated strong promoter activity. Electrophoretic mobility shift assays demonstrated that a 64-bp fragment located within the 98-bp region and lacking any potential NF-kappa B-binding sites avidly bound LPS-challenged THP-1 nuclear protein. Although this binding was inhibited in salicylate-treated cells, as was binding of NF-kappa B, the pattern of binding was found to differ from that noted for NF-kappa B. Analysis of this 64-bp fragment disclosed the absence of an NF-kappa B consensus sequence, suggesting a novel nuclear DNA-binding protein necessary for the initiation of human TNF-alpha transcription other than, or in addition to, NF-kappa B.

DOI： 10.1128/iai.63.4.1529-1534.1995

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Bacterial LPS stimulates human monocytes to secrete inflammatory cytokines, which are involved in several disease processes. However, the mechanism of LPS activation of cytokine expression and secretion is not completely understood. In this study, we investigated the signal transduction pathways involved in LPS-stimulated TNF-alpha and IL-1 beta secretion. TNF-alpha and IL-1 beta secretion were completely blocked by protein kinase C (PKC) and cyclic nucleotide-dependent protein kinase inhibitor, H-7, but were not affected by H-89, a specific cyclic nucleotide-dependent protein kinase inhibitor. In addition, LPS was found to induce activation of PKC, reaching maximal activity at 30 min and returning to unstimulated levels after 60 min. LPS stimulation only slightly increased intracellular levels of diacylglycerol, the natural activator of PKC, and pretreatment of monocytes with the diacylglycerol-kinase inhibitor, R59022, did not affect LPS-stimulated TNF-alpha secretion. LPS-induced PKC activation was found not to be affected by blocking of the LPS receptor, CD14, with mAb or by inhibition of protein tyrosine kinase with herbimycin A. However, these agents suppressed LPS-induced TNF-alpha secretion and TNF-alpha mRNA accumulation. The results suggest that TNF-alpha and IL-1 beta secretion after LPS stimulation of human monocytes requires the activation of protein tyrosine kinase and PKC, upstream to the activation of gene transcription. The activation of PKC by LPS is probably mediated by a diacylglycerol-independent pathway.

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HUMAN LEUKOCYTE ANTIGEN (HLA) class II beta chain plays an important role in the recognition of foreign antigens in immune reactions. Different forms of immune reaction may be concerned with initiation and progression of infectious diseases such as periodontitis. In this study we examined the frequency of HLA class II serotype and the variation of HLA class II beta gene in periodontitis patients. HLA serotypic frequencies in 70 Japanese patients with periodontitis and 26 individuals with periodontal health were examined. No HLA serotype specific to any type of periodontitis was observed. In order to detect differences among some HLA serotypes, restriction fragment length polymorphism (RFLP) analysis was undertaken with cDNA probes for HLA-DR beta and HLA-DQ beta genes in 20 subjects (15 patients and 5 healthy individuals). Atypical BamHI and EcoRI restriction sites were found in the HLA-DQ beta gene from 3 patients with early-onset periodontitis. In addition to these 20 subjects, an additional 80 subjects (40 patients and 40 healthy individuals) were screened for the atypical BamHI restriction site using the polymerase chain reaction method. It was detected in 7 patients with early-onset periodontitis, 1 patient with adult periodontitis, and 3 healthy subjects. No clinical differences except age were found between patients with this gene variation and other patients. Interestingly, all 3 healthy subjects with this gene variation were from subjects whose family members developed early-onset periodontitis with the gene variation. Atypical BamHI and EcoRI restriction sites and 41-nt repeated sequence were found in the intron before the third exon of HLA-DQB gene. These results suggest that these intronic gene variations may be useful as gene markers for a subpopulation of early-onset periodontitis and might affect immune reactions such as antigen recognition.

DOI： 10.1902/jop.1994.65.5.379

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We report the sequence of a 1.2-kb human tumor necrosis factor alpha (TNFalpha) promoter region, which was cloned using PCR. The sequence has several variations from two previous reports and exhibits many potential DNA-binding sites specific to mammalian gene regulatory proteins inducible by lipopolysaccharides.

DOI： 10.1016/0378-1119(93)90314-s

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Inflammatory mediators produced by cells in the gingiva have been implicated in the initiation and progression of periodontal disease, a common infectious disease. In this study, we examined the biological activity of neutrophil chemotactic factors and the kinetics of expression of interleukin-8 (IL-8) mRNA derived from normal gingival fibroblasts in response to inflammatory mediators in an in vitro model. Gingival fibroblasts stimulated by either recombinant human interleukin-1 beta or recombinant human tumor necrosis factor alpha produced neutrophil chemotactic factors after 4 h, whereas expression of cell-derived IL-8 mRNA was detected within 1 h after stimulation. Furthermore, in a neutralization assay, rabbit anti-recombinant human IL-8 antiserum inhibited neutrophil chemotactic activity to basal levels. These results provide evidence that gingival fibroblasts synthesize potent chemotactic factors such as IL-8 in the presence of the inflammatory mediators interleukin-1 beta and tumor necrosis factor alpha. The activity of these factors may contribute to neutrophil-mediated processes in the pathogenesis of periodontal disease.

DOI： 10.1128/iai.60.12.5253-5258.1992

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.heliyon.2024.e34206

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.heliyon.2024.e31872

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BACKGROUND/AIM: Malignant melanoma is a tumor with a poor prognosis that can metastasize distally at an early stage. Terrein, a metabolite produced by Aspergillus terreus, suppresses the expression of angiogenin, an angiogenic factor. However, the pharmacological effects of natural terrein have not been elucidated, because only a small amount of terrein can be extracted from large fungal cultures. In this study, we investigated the antineoplastic effects of terrein on human malignant melanoma cells and its underlying mechanisms. MATERIALS AND METHODS: Human malignant melanoma cell lines were cultured in the presence of terrein and analyzed. Angiogenin production was evaluated using ELISA. Ribosome biosynthesis was evaluated using silver staining of the nucleolar organizer region. Intracellular signaling pathways were analyzed using western blotting. Malignant melanoma cells were transplanted subcutaneously into the backs of nude mice. The tumors were removed at 5 weeks and analyzed histopathologically. RESULTS: Terrein inhibited angiogenin expression, proliferation, migration, invasion, and ribosome biosynthesis in malignant melanoma cells. Terrein was shown to inhibit tumor growth and angiogenesis in animal models. CONCLUSION: This study demonstrated that terrein has anti-tumor effects against malignant melanoma. Furthermore, chemically synthesized non-natural terrein can be mass-produced and serve as a novel potential anti-tumor drug candidate.

DOI： 10.21873/cgp.20464

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BACKGROUND: We determined the effects and an accurate marker of periodontal treatment on serum interleukin (IL)-6 and high-sensitivity C-reactive protein (HsCRP) levels in systemically healthy individuals with periodontal disease. METHODS: This multicenter study included systemically healthy individuals with periodontal disease who received initial periodontal treatment and had no periodontal treatment history. Periodontal parameters, including periodontal inflamed surface area, masticatory efficiency, and periodontal disease classification; serum IL-6 and HsCRP levels; and serum immunoglobulin (Ig)G titers against periodontal pathogens were evaluated at baseline and after treatment. Subjects were classified as low or high responders (group) based on periodontal inflamed surface area changes. RESULTS: There were 153 participants. Only periodontal inflamed surface area changes were markedly different between low and high responders. Periodontal treatment (time point) decreased both serum IL-6 and HsCRP levels. The interaction between group and time point was remarkable only for serum IL-6 levels. Changes in serum immunoglobulin (Ig)G titers against periodontal pathogens were not associated with IL-6 changes in high responders. We analyzed the indirect effect of serum anti-Porphyromonas gingivalis type 2 IgG titer changes using mediation analysis and found no significance. However, the direct effect of group (low or high responder) on IL-6 changes was considerable. CONCLUSIONS: Periodontal treatment effectively decreased serum IL-6 levels, independent of periodontal pathogen infection, in systemically healthy individuals with periodontal disease.

DOI： 10.1016/j.amjmed.2023.11.001

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BACKGROUND: Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity. CASE PRESENTATION: This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated. CONCLUSIONS: Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

DOI： 10.1186/s12903-023-03586-8

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Dental caries are an oral infectious disease that can affect human health both orally and systemically. It remains an urgent issue to establish a novel antibacterial method to prevent oral infection for a healthy life expectancy. The aim of this study was to evaluate the inhibitory effects of novel iron chelators, super-polyphenols (SPs), on the cariogenic bacterium Streptococcus mutans, in vitro. SPs were developed to reduce the side effects of iron chelation therapy and were either water-soluble or insoluble depending on their isoforms. We found that SP6 and SP10 inhibited bacterial growth equivalent to povidone-iodine, and viability tests indicated that their effects were bacteriostatic. These results suggest that SP6 and SP10 have the potential to control oral bacterial infections such as Streptococcus mutans.

DOI： 10.3390/antibiotics12111562

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We herein elucidate the function of SARS-CoV-2derived 5'UTR in the human cells. 5'UTR bound host cellular RNAs were immunoprecipitated by gRNA-dCas13 (targeting luciferase RNA fused to SARS-CoV-2 5'UTR) in HEK293T and A549 cells. The 5'UTR bound RNA extractions were predominantly enriched for regulating lipid metabolism. Overexpression of SARS-CoV-2 5'UTR RNA altered the expression of factors involved in the process of the human Mevalonate pathway. In addition, we found that HMG-CoA reductase inhibitors were shown to suppress SARS-CoV-2 5'UTR-mediated translation activities. In conclusion, we deduce the array of host RNAs interacting with SARS-CoV-2 5'UTR that drives SARS-CoV-2 translation and influences host metabolic pathways.

DOI： 10.1038/s41598-023-36680-6

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Apical periodontitis is an inflammatory response caused by pulp infection. It induces bone resorption in the apical and periapical regions of the tooth. The most conservative approach to treat this condition is nonsurgical endodontic treatment. However, clinical failure has been reported with this approach; thus, alternative procedures are required. This review highlights recent literature regarding advanced approaches for the treatment of apical periodontitis. Various therapies, including biological medications, antioxidants, specialized pro-resolving lipid mediators, and stem cell therapy, have been tested to increase the success rate of treatment for apical periodontitis. Some of these approaches remain in the in vivo phase of research, while others have just entered the translational research phase to validate clinical application. However, a detailed understanding of the molecular mechanisms that occur during development of the immunoinflammatory reaction in apical periodontitis remains unclear. The aim of this review was to summarize advanced approaches for the treatment of apical periodontitis. Further research can confirm the potential of these alternative nonsurgical endodontic treatment approaches.

DOI： 10.3390/bioengineering10040488

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The curriculum at the Department of Pathophysiology in the Periodontal Sciences program at Okayama University includes normative preclinical training (NPT) using phantoms. NPT is given to the whole class of 5 th year students divided in groups of 8 students/instructor. In 2019, an innovative personalized preclinical training (PPT) pilot study was implemented for this group of students whereby two students, each with their own dental unit, were coached by one instructor. The main topics covered were dental ergonomics and endodontics. We aimed to evaluate the effectiveness of PPT in dental ergonomics and endodontics toward increasing the knowledge and future clinical skills of students who had already undergone NPT. A test on endodontics was taken before and after PPT. A questionnaire was completed to assess their perception of improvement regarding the above-mentioned topics. Test scores and questionnaire results both showed that the students' level of knowledge and awareness of future clinical skills was significantly higher after PPT. This pilot study demonstrated that PPT increased the students' knowledge and future clinical skills. As preclinical training forms the foundation for clinical practice, investment in future research regarding this personalized approach is likely to enhance students' understanding and clinical performance.

DOI： 10.18926/AMO/65144

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Current periodontal treatment focuses on the mechanical removal of the source of infection, such as bacteria and their products, and there is no approach to control the host inflammatory response that leads to tissue destruction. In order to control periodontal inflammation, we have previously reported the optimization of (+)-terrein synthesis methods and the inhibitory effect of (+)-terrein on osteoclast differentiation in vitro. However, the pharmacological effect of (+)-terrein in vivo in the periodontitis model is still unknown. In this study, we investigated the effect of synthetic (+)-terrein on inflammatory bone resorption using a ligature-induced periodontitis mouse model. Synthetic (+)-terrein (30 mg/kg) was administered intraperitoneally twice a week to the mouse periodontitis model. The control group was treated with phosphate buffer. One to two weeks after the induction of periodontitis, the periodontal tissues were harvested for radiological evaluation (micro-CT), histological evaluation (HE staining and TRAP staining), and the evaluation of inflammatory cytokine production in the periodontal tissues and serum (quantitative reverse-transcription PCR, ELISA). The synthetic (+)-terrein-treated group suppressed alveolar bone resorption and the number of osteoclasts in the periodontal tissues compared to the control group (p &lt; 0.05). In addition, synthetic (+)-terrein significantly suppressed both mRNA expression of TNF-α in the periodontal tissues and the serum concentration of TNF-α (both p &lt; 0.05). In conclusion, we have demonstrated that synthetic (+)-terrein abrogates alveolar bone resorption via the suppression of TNF-α production and osteoclast differentiation in vivo. Therefore, we could expect potential clinical effects when using (+)-terrein on inflammatory bone resorption, including periodontitis.

DOI： 10.3390/jof9030314

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The major active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), is known for its wide bioactivity in periodontal tissues. Although the exact mechanisms underlying its protective action against periodontitis remain unclear, recent studies have shown that 1,25D3 regulates autophagy. Autophagy is vital for intracellular pathogen invasion control, inflammation regulation, and bone metabolic balance in periodontal tissue homeostasis, and its regulation could be an interesting pathway for future periodontal studies. Since vitamin D deficiency is a worldwide health problem, its role as a potential regulator of autophagy provides new insights into periodontal diseases. Based on this premise, this narrative literature review aimed to investigate the possible connection between 1,25D3 and autophagy in periodontitis. A comprehensive literature search was conducted on PubMed using the following keywords (e.g., vitamin D, autophagy, periodontitis, pathogens, epithelial cells, immunity, inflammation, and bone loss). In this review, the latest studies on the protective action of 1,25D3 against periodontitis and the regulation of autophagy by 1,25D3 are summarized, and the potential role of 1,25D3-activated autophagy in the pathogenesis of periodontitis is analyzed. 1,25D3 can exert a protective effect against periodontitis through different signaling pathways in the pathogenesis of periodontitis, and at least part of this regulatory effect is achieved through the activation of the autophagic response. This review will help clarify the relationship between 1,25D3 and autophagy in the homeostasis of periodontal tissues and provide perspectives for researchers to optimize prevention and treatment strategies in the future.

DOI： 10.1186/s12903-023-02802-9

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DOI： 10.34376/jsachd.C-2022-0002

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UNLABELLED: Periodontal disease often develops in patients with diabetes, and further exacerbated with diabetic complications. It would be clinically important to clarify the relationship between diabetic microvascular diseases and periodontal disease. This study aimed to evaluate the association between periodontal disease and diabetic complications in patients with type 2 diabetes with poor glycemic control. A total of 447 patients with type 2 diabetes hospitalized at Rakuwakai Otowa Hospital, Japan, were initially recruited in this study. After excluding 134 patients who lacked clinical data or were edentulous, 312 were included in our study. The severity of periodontal disease was evaluated based on the average bone resorption rate. Patients with diabetic nephropathy developed severe periodontal disease (multivariate-adjusted odds ratio, 3.00 [95% CI 1.41-5.19]). Diabetic neuropathy was positively associated with the severity of periodontal disease; the multivariate-adjusted odds ratio (95% CI) was 1.62 (0.87‒2.99) for moderate and 4.26 (2.21‒8.20) for severe periodontal disease. In contrast, diabetic retinopathy was linked with moderate periodontal disease (multivariate-adjusted odds ratio 2.23 [95% CI 1.10-4.10]), but not with severe conditions (multivariate-adjusted odds ratio 0.92 [95% CI 0.67-3.07]). In conclusion, periodontal disease, evaluated by average bone resorption rate, was associated with diabetic nephropathy and neuropathy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-022-00591-0.

DOI： 10.1007/s13340-022-00591-0

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Tokyo Dental College  

DOI： 10.2209/tdcpublication.2022-0019

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The failure of endodontic treatment is directly associated with microbial infection in the root canal or periapical areas. An endodontic sealer that is both bactericidal and biocompatible is essential for the success of root canal treatments. This is one of the vital issues yet to be solved in clinical dental practice. This in vitro study assessed the effectiveness of graphene oxide (GO) composites GO-CaF2 and GO-Ag-CaF2 as endodontic sealer materials. Dentin slices were coated with either the GO-based composites or commonly used root canal sealers (non-eugenol zinc oxide sealer). The coated slices were treated in 0.9% NaCl, phosphate-buffered saline (PBS), and simulated body fluid (SBF) at 37˚C for 24 hours to compare their sealing effect on the dentin surface. In addition, the radiopacity of these composites was examined to assess whether they complied with the requirements of a sealer for good radiographic visualization. Scanning electron microscopy showed the significant sealing capability of the composites as coating materials. Radiographic images confirmed their radiopacity. Mineral deposition indicated their bioactivity, especially of GO-Ag-CaF2, and thus it is potential for regenerative application. They were both previously shown to be bactericidal to oral microbes and cytocompatible with host cells. With such a unique assemblage of critical properties, these GO-based composites show promise as endodontic sealers for protection against reinfection in root canal treatment and enhanced success in endodontic treatment overall.

DOI： 10.18926/AMO/64122

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BACKGROUND: Periodontal disease is associated with non-alcoholic fatty liver disease (NAFLD). We evaluated periodontal treatment efficacy in patients with NAFLD and periodontal disease. METHODS: This multicenter, 2-arm, randomized study recruited adult patients with NAFLD and periodontitis, alanine aminotransferase levels ≥40 U/L, and equivalent steatosis grade ≥1. Forty eligible patients (18 men and 22 women) were randomly assigned to 2 groups (scaling and root planning [SRP; n = 20] and tooth-brushing [n = 20] groups) stratified by age and sex. The primary and secondary endpoints were changes in alanine aminotransferase levels and serum Porphyromonas gingivalis IgG-antibody titers from baseline to 12 weeks, respectively. Efficacy analysis was performed using an intention-to-treat approach (t-test). This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMINXXXXXXX). RESULTS: We observed a significantly higher decrease in absolute alanine aminotransferase levels and P. gingivalis IgG-antibody titers in the SRP group than in the tooth-brushing group (-12 vs 1 U/L; mean difference [δ], -12; 95% confidence interval [CI], -20 to -5; P = 0.002). The decrease in P. gingivalis IgG-antibody titer was significantly higher in the SRP group than in the tooth-brushing group (FDC381, -1.6 [2.5]; δ, -1.6; 95% CI, -2.7 to -0.4; P = 0.0092; SU63, -1.7 [2.0]; δ, -1.7; 95% CI, -2.7 to -0.7). No life-threatening events or treatment-related deaths occurred. CONCLUSION: Periodontal treatment induced significant short- and mid-term reductions in liver enzyme levels and antibody titers. Further research is warranted to clearly define SRP efficacy and tolerability in patients with NAFLD and periodontitis.

DOI： 10.14309/ctg.0000000000000520

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

The risk factors for non-alcoholic fatty liver disease (NAFLD) progression are not completely known. Porphyromonasgingivalis infection is a risk factor for systemic diseases. We investigated the association of P.gingivalis infection with the risk of non-alcoholic steatohepatitis progression. Here, hematological tests, periodontal examination, and saliva collection were performed for 164 patients with NAFLD. P.gingivalis was identified in saliva using polymerase chain reaction. Hepatic steatosis and stiffness were evaluated using vibration-controlled transient elastography (VCTE) and magnetic resonance imaging. In patients with NAFLD, P.gingivalis positivity (P.gingivalis ratio ≥ 0.01%) in saliva correlated with liver stiffness determined using magnetic resonance elastography (MRE; p &lt; 0.0001). A P.gingivalis ratio of 0.01% corresponds to 100,000 cells/mL and indicates the proportion of P.gingivalis in the total number of bacteria in the oral cavity. Patients with NAFLD and advanced fibrosis on MRE showed significantly elevated endotoxin activity; those who had &gt; 10 periodontal pockets with depths ≥ 4 mm had significantly increased hepatic stiffness on both VCTE and MRE.

DOI： 10.1038/s41598-022-17917-2

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Other Link： https://www.nature.com/articles/s41598-022-17917-2

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Recent studies have shown that periodontitis is associated with rheumatoid arthritis (RA) and periodontal bacteria, such as Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg) are involved in the pathogenesis of RA via citrullinated proteins. Smoking has also been shown to be involved in the pathogenesis of RA; however, the extent of this involvement is still poorly understood. In addition, RA and polymyalgia rheumatica (PMR) are sometimes difficult to differentiate; however, the relationship between PMR and the factors from smoking and periodontal bacteria is unclear. The aim of this study was to clarify the relationship between periodontal pathogenic bacterial infections and smoking in patients with RA or PMR. This case-control study included 142 patients with untreated RA or PMR. This study evaluated the serum antibody titers against periodontal pathogenic bacterial antigens and an anti-citrullinated peptide antibody (ACPA). In patients with RA, the relationship between antibody titers and disease activity of RA and response after 3 months of treatment was also investigated. Additionally, the effects of smoking were evaluated. Although there was no significant difference in serum antibody titer against periodontal pathogenic bacteria between the ACPA-positive RA group and the ACPA-negative PMR group, we found an association between the elevated antibody titer against Pg and the degree of ACPA value, especially between negative group and high-value positive group (≥ 100 U/mL). The antibody titers against Aa and Pg did not differ depending on disease activity score 28 (DAS28) at baseline; however, patients with high antibody titers had poor RA therapeutic response as judged by DAS28 after 3 months. We could not find any association between smoking and any of these parameters. Periodontal pathogenic bacteria, especially Pg, are associated with elevated ACPA levels. Our findings suggest that Pg and Aa infections interfere with the therapeutic response of RA.

DOI： 10.1038/s41598-022-16279-z

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The study aims to reveal the composition of subgingival bacteria in monozygotic twins with discordant in severity and progression risk of periodontitis. Microbiome analysis indicated that most bacteria were heritable but differed in their abundance and immune response. The dysbiotic bacteria can be considered as risk markers for periodontitis progression.

DOI： 10.1002/ccr3.5725

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BACKGROUND: Periodontal disease is the most common dental disease in dogs. Although the systemic effects of periodontal disease have not been clarified in veterinary science, it is necessary to evaluate the effects of periodontal disease in clinical trials in the future. There have been a few clinical attempts made, however, to assess the severity of periodontal inflammation and its impact on the systemic health of dogs. Meanwhile, in the field of dentistry for humans, the periodontal inflamed surface area (PISA) and periodontal epithelial surface area (PESA) have been used to quantitatively assess the degree of periodontal disease affecting a single tooth as well as the overall extent of periodontitis. Recent studies have also suggested the use of these assessments to examine the relationship between periodontal inflammation and systemic health. RESULTS: The estimation formula for a dog's periodontal pocket surface area (PPSA), an alternative to PISA and PESA in humans, was established using body weight and periodontal pocket depth. Actual values were measured using extracted teeth from various dog breeds and sizes (2.3-25.0 kg of body weight) to obtain universal regression equations for PPSA. Altogether, 625 teeth from 73 dogs of 16 breeds were extracted and subsequently analyzed for morphological information. PPSA was measured in 61 dogs of 10 breeds with periodontal disease using the established estimation formulas, and the correlation between PPSA and preoperative blood chemistry data was analyzed accordingly. A strong correlation was found between PPSA and serum globulin (r = 0.71) while moderate correlations were found for C-reactive protein (r = 0.54) and serum albumin (r = -0.51). CONCLUSIONS: Estimation formulas using body weight and the 6-point probing depth were established for determining PPSA. Direct correlations between PPSA and several blood test results were observed in the study sample. Taken together, these results suggest that PPSA could be useful for evaluating the effects of periodontitis on systemic conditions in dogs.

DOI： 10.1186/s12917-021-03116-0

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Periodontal disease is a chronic inflammatory condition caused by periodontal pathogens in the gingival sulcus. Short-chain fatty acids (SCFAs) produced by causal bacteria are closely related to the onset and progression of periodontal disease and have been reported to proliferate in the periodontal sulcus of patients experiencing this pathology. In such patients, propionic acid (C3), butyric acid (C4), isobutyric acid (IC4), valeric acid (C5), isovaleric acid (IC5), and caproic acid (C6), henceforth referred to as [C3-C6], has been reported to have a detrimental effect, while acetic acid (C2) exhibits no detrimental effect. In this study, we established an inexpensive and simple enzymatic assay that can fractionate and measure these acids. The possibility of applying this technique to determine the severity of periodontal disease by adapting it to specimens collected from humans has been explored. We established an enzyme system using acetate kinase and butyrate kinase capable of measuring SCFAs in two fractions, C2 and [C3-C6]. The gingival crevicular fluid (GCF) and saliva of 10 healthy participants and 10 participants with mild and severe periodontal disease were measured using the established enzymatic method and conventional gas chromatography-mass spectrometry (GC-MS). The quantification of C2 and [C3-C6] in human GCF and saliva was well correlated when using the GC-MS method. Furthermore, both C2 and [C3-C6] in the GCF increased with disease severity. However, while no significant difference was observed between healthy participants and periodontal patients when using saliva, [C3-C6] significantly differed between mild and severe periodontal disease. The enzymatic method was able to measure C2 and [C3-C6] separately as well as using the GC-MS method. Furthermore, the C2 and [C3-C6] fractions of GCF correlated with disease severity, suggesting that this method can be applied clinically. In contrast, the quantification of C2 and [C3-C6] in saliva did not differ significantly between healthy participants and patients with periodontal disease. Future studies should focus on inflammation rather than on tissue destruction.

DOI： 10.1371/journal.pone.0268671

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This case report highlights the importance of using a dental operating microscope (DOM) and ultrasonic endodontic tips (UETs) to locate all root canals in the lower first premolar. A 53-year-old woman presented to our clinic with pain in the lower right first premolar. After a detailed search using a DOM and UETs, three root canals were found, prepared with rotary HyFlex endodontic files, and obturated using the lateral condensation technique. At the five-year follow-up after treatment, the tooth was completely restored and fulfilling its function, with no signs or symptoms of any post-treatment flare-up.

DOI： 10.18926/AMO/62778

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Malnutrition causes prolonged inflammation, resulting in delayed wound healing. High mobility group box-1 (HMGB1) is a damage-associated molecular pattern that is present in the nuclei of macrophages and is secreted into the extracellular milieu in response to stimuli. It stimulates the production of interleukin-1β (IL-1β) through the receptors for advanced glycation end products (RAGE), inducing an inflammatory response, which is an essential response to initiate wound healing. We hypothesized that malnutrition may interfere with this cascade, causing abnormal inflammation and ultimately delaying wound healing. We used tooth-extracted mice with malnutrition fed with low-casein diet for two weeks. On days 3 and 7 after tooth extraction, the wound tissue was histologically observed and analyzed for several factors in the inflammation-regeneration lineage, including IL-1β, mesenchymal stem cells, myeloperoxidase activity, HMGB1, macrophage polarization, and adenosine 5-triphosphate (ATP). On day 7, delayed wound healing was observed with the following findings under malnutrition conditions: decreased mRNA expression of genes for regeneration and mesenchymal stem cell (MSC) accumulation, an obvious increase in myeloperoxidase and IL-1β mRNA expression, an increase in HMGB1 levels, and an increase in ATP concentration in tissues with elevated proportion of M2 macrophages. These results suggest that the significantly increased secretion of HMGB1 associated with the upregulated production of ATP and IL-1β secretion via the RAGE pathway may interfere with the resolution of inflammation and wound healing under the state of malnutrition.

DOI： 10.1016/j.intimp.2021.107772

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Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKCα/βII, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.

DOI： 10.3389/fphar.2021.674366

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Oral health is closely related to subjective general health and systemic diseases. This cross-sectional study aimed to identify the factors related to oral symptoms and their worsening in relation to psychosocial factors after the Great East Japan Earthquake. In this study, 64,186 residents aged 15-101 years old, who experienced the earthquake on 11 March 2011, were surveyed regarding their oral symptoms; psychological factors, such as post-traumatic reactions and psychological distress; and social factors such as evacuation, work change, and loss of a close person; history of systemic diseases; and lifestyle. Binomial logistic regression analysis was used to calculate odds ratios, and 95% confidence intervals were established for each factor associated with prevalent and exacerbated oral symptoms. The proportions of participants with prevalent and exacerbated oral symptoms were 10.3% and 1.6%, respectively. The multivariate odds ratios and 95% CI of psychosocial factors associated with exacerbated oral symptoms were as follows: post-traumatic stress disorder symptoms, 2.24 (1.64-3.06); work changes, 1.88 (1.34-2.65); history of dyslipidemia, 1.74 (1.27-2.39); and subjective current poor health condition, 2.73 (2.00-3.75). Psychological factors, social factors, and physical factors were associated with both prevalent and exacerbated oral symptoms.

DOI： 10.3390/ijerph18116054

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Language：English   Publishing type：Research paper (scientific journal)  

Periodontal disease is a chronic inflammatory disease of the periodontal tissue. The periodontal inflamed surface area (PISA) is a proposed index for quantifying the inflammatory burden resulting from periodontitis lesions. This study aimed to investigate longitudinal changes in the periodontal status as evaluated by the PISA following the active periodontal treatment. To elucidate the prognostic factors of PISA, mixed-effect modeling was performed for clinical parameters, tooth-type, and levels of periodontal pathogens as independent variables. One-hundred-twenty-five patients with chronic periodontitis who completed the active periodontal treatment were followed-up for 24 months, with evaluations conducted at 6-month intervals. Five-times repeated measures of mean PISA values were 130+/-173, 161+/-276, 184+/-320, 175+/-417, and 209+/-469 mm2. Changes in clinical parameters and salivary and subgingival periodontal pathogens were analyzed by mixed-effect modeling. Plaque index, clinical attachment level, and salivary levels of Porphyromonas gingivalis were associated with changes in PISA at the patient- and tooth-level. Subgingival levels of P. gingivalis and Prevotella intermedia were associated with changes in PISA at the sample site. For most patients, changes in PISA were within 10% of baseline during the 24-month follow-up. However, an increase in the number of bleeding sites in a tooth with a deep periodontal pocket increased the PISA value exponentially.

DOI： 10.3390/jcm10061165

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The periodontal inflamed surface area (PISA) is a useful index for clinical and epidemiological assessments, since it can represent the inflammation status of patients in one contentious variable. However, calculation of the PISA is difficult, requiring six point probing depth measurements with or without bleeding on probing on 28 teeth, followed by data input in a calculation program. More simple methods are essential for screening periodontal disease or in epidemiological studies. In this study, we tried to establish a convenient partial examination method to estimate PISA. Cross-sectional data of 254 subjects who completed active periodontal therapy were analyzed. Teeth that represent the PISA value were selected by an item response theory approach. The maxillary second molar, first premolar, and lateral incisor and the mandibular second molar and lateral incisor were selected. The sum of the PISAs of these teeth was significantly correlated with the patient's PISA (R2 = 0.938). More simply, the sum of the maximum values of probing pocket depth with bleeding for these teeth were also significantly correlated with the patient's PISA (R2 = 0.6457). The simple model presented in this study may be useful to estimate PISA.

DOI： 10.3390/jcm10040723

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There is no conclusive evidence regarding a causal relationship between periodontitis and atherosclerosis. In this study, we examined the microbiome in the oral cavity and atheromatous plaques from atherosclerosis patients with or without periodontitis to investigate the role of oral bacteria in the formation of atheromatous plaques. We chose four patients with and without periodontitis, who had undergone carotid endarterectomy. Bacterial samples were extracted from the tongue surface, from periodontal pocket (during the oral examination), and from the atheromatous plaques (APs). We investigated the general and oral conditions from each patient and performed next-generation sequencing (NGS) analysis for all bacterial samples. There were no significant differences between both groups concerning general conditions. However, the microbiome patterns of the gingival pocket showed differences depending on the absence or presence of periodontitis, while those of the tongue surface were relatively similar. The microbiome pattern of the atheromatous plaques was entirely different from that on the tongue surface and gingival pocket, and oral bacteria were seldom detected. However, the microbiome pattern in atheromatous plaques was different in the presence or absence of periodontitis. These results suggested that oral bacteria did not affect the formation of atheromatous plaques directly.

DOI： 10.1007/s10266-020-00524-w

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s42399-020-00671-9

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Other Link： http://link.springer.com/article/10.1007/s42399-020-00671-9/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

Periodontal examination data have a complex structure. For epidemiological studies, mass screenings, and public health use, a simple index that represents the periodontal condition is necessary. Periodontal indices for partial examination of selected teeth have been developed. However, the selected teeth vary between indices, and a justification for the selection of examination teeth has not been presented. We applied a graded response model based on the item response theory to select optimal examination teeth and sites that represent periodontal conditions. Data were obtained from 254 patients who participated in a multicenter follow-up study. Baseline data were obtained from initial follow-up. Optimal examination sites were selected using item information calculated by graded response modeling. Twelve sites-maxillary 2nd premolar (palatal-medial), 1st premolar (palatal-distal), canine (palatal-medial), lateral incisor (palatal-central), central incisor (palatal-distal) and mandibular 1st premolar (lingual, medial)-were selected. Mean values for clinical attachment level, probing pocket depth, and bleeding on probing by full mouth examinations were used for objective variables. Measuring the clinical parameters of these sites can predict the results of full mouth examination. For calculating the periodontal index by partial oral examination, a justification for the selection of examination sites is essential. This study presents an evidence-based partial examination methodology and its modeling.

DOI： 10.3390/jcm9113754

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Salivary glands (SGs) are very important for maintaining the physiological functions of the mouth. When SGs regenerate and repair from various damages, including mechanical, radiological, and immune diseases, acinar and granular duct cells originate from intercalated duct cells. However, the recovery is often insufficient because of SGs' limited self-repair function. Furthermore, the precise repair mechanism has been unclear. Here, we focused on CD49f, one of the putative stem cell markers, and characterized CD49f positive cells (CD49f+ cells) isolated from male murine SGs. CD49f+ cells possess self-renewal ability and express epithelial and pluripotent markers. Compared to CD49f negative cells, freshly isolated CD49f+ cells highly expressed inhibin beta A and beta B, which are components of activin that has anti-proliferative effects. Notably, an inhibitor of activin, follistatin was expressed in mechanically-damaged SGs, meanwhile no follistatin was expressed in normal SGs in vivo. Moreover, sub-cultured CD49f+ cells highly expressed both Follistatin and a series of proliferative genes, expressions of which were decreased by Follistatin siRNA. These findings indicated that the molecular interaction between activin and follistatin may induce CD49f+ cells proliferation in the regeneration and repair of mouse SGs.

DOI： 10.1038/s41598-020-77004-2

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Authorship：Last author   Language：Japanese   Publisher：(NPO)日本歯科保存学会  

緒言:歯周病原細菌の感染と歯周組織の炎症が,妊娠に影響を与える可能性が報告されている.今回,不妊治療の経過が思わしくない侵襲性歯周炎患者に感染源除去の観点から専門的歯周治療を行い,自然妊娠から正常出産にいたった症例の経過をふまえ病態を考察する.症例:33歳,女性,既婚(不妊治療中).2016年9月,26の動揺および同部の自発痛を自覚し,かかりつけ歯科医院を受診した.同院でエックス線検査を受けて,重度の歯槽骨吸収があると説明された.早期の専門的歯周治療を勧められ,当科を紹介された.既往歴の特記事項はなく,不妊検査においても患者本人および夫ともに異常所見はなかった.歯周組織検査において,probing pocket depthが4mm以上の部位の割合は49.5%,bleeding on probingは47.9%,plaque control recordは3.1%,歯周炎症表面積(PISA)は2,392mm2であった.エックス線検査所見では,主訴部の26部を中心に根尖に及ぶ骨吸収像が多数存在した.歯周病原細菌に対する血清抗体価検査および歯周ポケット内細菌DNA検査ともに,Porphyromonas gingivalisの感染が強く疑われた.診断は広汎型侵襲性歯周炎(ステージIV,グレードC),二次性咬合性外傷とした.治療方針として,患者の妊娠希望に配慮して,できるかぎり早期(1年以内)の歯周環境の改善を目指すこととした.また,歯周外科治療が終了するまでの不妊治療を含めた妊娠活動を控える必要性について説明し,同意を得た.治療計画は,(1)歯周基本治療(患者教育,抜歯,局所抗菌療法を併用したスケーリング・ルートプレーニング,暫間固定),(2)歯周組織再生療法,(3)口腔機能回復治療,(4)歯周病安定期治療(SPT)とした.治療経過として,歯周治療に対する宿主反応性は非常に良く,炎症改善と歯槽骨の再生を確認した(歯周外科治療後PISA:43mm2).口腔機能回復治療中に自然妊娠し,35歳時に男児を正常出産(経腟分娩,3,240g,出産週数:38週+5日)した.考察および結論:重度のP. gingivalis感染および歯周炎症を伴う侵襲性歯周炎の罹患が,妊娠成立に影響を及ぼす可能性が示唆された.本症例のように不妊治療の経過が思わしくない場合には,歯周組織を含めた口腔状態を一度精査することが望まれる.(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01092&link_issn=&doc_id=20201110310013&doc_link_id=%2Fdo1conde%2F2020%2F006305%2F013%2F0451-0460%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdo1conde%2F2020%2F006305%2F013%2F0451-0460%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(NPO)日本歯周病学会  

超高齢社会の日本において医療界、特に歯科医療界がどこに向かうのか考察した。大学を含む病院が主な勤務先である医師とは異なり、歯科医師はほとんどが歯科診療所に勤務している。また、厚労省の統計によると歯科医師は医師よりも平均年齢が7歳若く、これは高齢者の割合が増加している患者への対応方法に若干の違いをもたらしている可能性がある。一方で医師と歯科医師の分布の地域差が顕著であり、来たるべき歯科医師の高齢化についても配慮が必要となる。こうした社会の変化の中で、日本歯周病学会の歯周病専門医は厚生労働省の「医療に関する広告が可能となった医師等の専門性に関する資格名」として周知されている。今後は、(一社)日本歯科専門医機構の承認も得ることには違いない。また、高度で広範囲な歯周病専門医による治療を日本国内の各地に均平化することも必要である。

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Publishing type：Research paper (scientific journal)   Publisher：The Society for Chromatographic Sciences  

DOI： 10.15583/jpchrom.2019.025

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Pathophysiological bone resorption is commonly associated with periodontal disease and involves the excessive resorption of bone matrix by activated osteoclasts. Receptor activator of nuclear factor (NF)-κB ligand (RANKL) signaling pathways have been proposed as targets for inhibiting osteoclast differentiation and bone resorption. The fungal secondary metabolite (+)-terrein is a natural compound derived from Aspergillus terreus that has previously shown anti-interleukin-6 properties related to inflammatory bone resorption. However, its effects and molecular mechanism of action on osteoclastogenesis and bone resorption remain unclear. In the present study, we showed that 10 µM synthetic (+)-terrein inhibited RANKL-induced osteoclast formation and bone resorption in a dose-dependent manner and without cytotoxicity. RANKL-induced messenger RNA expression of osteoclast-specific markers including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), the master regulator of osteoclastogenesis, cathepsin K, tartrate-resistant acid phosphatase (Trap) was completely inhibited by synthetic (+)-terrein treatment. Furthermore, synthetic (+)-terrein decreased RANKL-induced NFATc1 protein expression. This study revealed that synthetic (+)-terrein attenuated osteoclast formation and bone resorption by mediating RANKL signaling pathways, especially NFATc1, and indicated the potential effect of (+)-terrein on inflammatory bone resorption including periodontal disease.

DOI： 10.1016/j.intimp.2020.106429

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The prevention of nosocomial infections is an imperative task. The dental chair unit (DCU) is an indispensable device used in dental treatment. However, it is known that the dental unit water line (DUWL) can become contaminated with biofilm, consisting mainly of heterotrophic bacteria (HB). Recently, the International Organization for Standardization specified the methods for testing DUWL contamination management. On these grounds, a simulator reproducing DUWL was prepared to standardize the examination method of the DUWL contamination. Objectives: To evaluate the reproducibility of the DUWL simulator, monitor the DUWL contamination states, and test the efficacy of a commercial decontaminant for DUWL. Methods: The DUWL simulator was assembled by a DCU manufacturing company. The simulator's DUWL was filled with tap water (TW), and left for approximately one year. Neutral electrolyzed water (NEW) was used as a decontaminant for DUWL. Both TW and NEW were passed through DUWL in a timely manner simulating daily dental treatment. Water was sampled from the air turbine hand piece weekly for 4 weeks and used for HB culture. Contamination status was evaluated by measuring bacterial adenosine triphosphate release and by culturing on Reasoner's 2A medium. Results: The DUWL released contaminated water had a bacterial count of over 6 × 104 cfu/mL. After passing NEW through DUWL for 1 week, the count drastically decreased to its basal level and remained steady for 4 weeks. However, TW showed no effect on DUWL decontamination throughout the examination periods. Conclusions: The DUWL simulator could be useful to examine the efficacy of the decontaminant for DUWL and development of new methods in DUWL contamination management.

DOI： 10.1016/j.heliyon.2020.e04132

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This inclusive review summarizes the recent advances in the application of graphene oxide (GO) and functionalized GO in oral and dental research. GO possesses several extraordinary physical, chemical, optical, electrical, and mechanical properties. Because of its high surface area and oxygenated functional groups, GO exhibits excellent interaction ability with metals and ions as well as organic species. The current review reveals that GO has been used to produce a variety of functionalized nanocomposites, scaffolds, and advanced nanoparticle carriers. Accordingly, GO shows potential in a variety of research fields, such as tissue engineering, materials engineering, biomaterials, and drug delivery, indicating that the application of GO to biomedicine is particularly promising. More specifically, the recent application of GO in dentistry has provided outstanding results in antimicrobial action, regenerative dentistry, bone tissue engineering, drug delivery, physicomechanical property enhancement of dental biomaterials, and oral cancer treatment. The biocompatibilities of GO and its nanocomposites make them potential units in bone regeneration, osseointegration, and cell proliferation. Furthermore, its antibiofilm and antiadhesion properties have inspired researchers to develop GO for biofilm and caries prevention, as well as implant surface modification and as a quorum sensing inhibitor. This updated review is wide-ranging and provides a useful source for additional information on GO and its composites in dental research and applications.

DOI： 10.1016/j.apmt.2020.100576

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BACKGROUND: We report the first protocol for a multicenter, randomized comparison study to compare the efficacies of periodontal scaling and root-planing treatment against that of tooth-brushing treatment for nonalcoholic fatty liver disease (NAFLD) (PERION: PERIOdontal treatment for NAFLD). Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD, which can progress to cirrhosis and hepatocellular carcinoma. Increased endotoxemia is associated with the progression of NAFLD. Periodontal bacteria possess endotoxins; Porphyromonas gingivalis is well-known as a major pathogenic bacterium in periodontitis, and serum antibody levels for P. gingivalis are high in patients with periodontitis. Several reports have indicated that P. gingivalis is related to NAFLD. This study aims to investigate the effect of periodontal treatment for liver damage, P. gingivalis infection, and endotoxemia on patients with NAFLD. METHODS: We will include adult patients (20-85 years old) with NAFLD, alanine aminotransferase (ALT) ≥ 40 IU/L, and equivalent steatosis grade ≥ 1 (target sample size, n = 40 patients; planned number of patients with outcome data, n = 32). Participants will be randomly assigned to one of two groups: a scaling and root-planing group or tooth-brushing as the usual group. The primary outcome will be the change in ALT levels from baseline to 12 weeks; the key secondary outcome will be the change in the serum immunoglobulin G (IgG) antibody titer for P. gingivalis at 12 weeks. DISCUSSION: This study should determine whether periodontal treatment decreases liver damage, P. gingivalis infection, and endotoxemia in patients with NAFLD. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, ID: UMIN000022079.

DOI： 10.1186/s13063-020-4201-y

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Dental caries is a type of oral microbiome dysbiosis and biofilm infection that affects oral and systemic conditions. For healthy life expectancy, natural bacteriostatic products are ideal for daily and lifetime use as anti-oral infection agents. This study aimed to evaluate the inhibitory effects of abietic acid, a diterpene derived from pine rosin, on the in vitro growth of cariogenic bacterial species, Streptococcus mutans. The effective minimum inhibitory concentration of abietic acid was determined through observation of S. mutans growth, acidification, and biofilm formation. The inhibitory effects of abietic acid on the bacterial membrane were investigated through the use of in situ viability analysis and scanning electron microscopic analysis. Cytotoxicity of abietic acid was also examined in the context of several human cell lines using tetrazolium reduction assay. Abietic acid was found to inhibit key bacterial growth hallmarks such as colony forming ability, adenosine triphosphate activity (both planktonic and biofilm), acid production, and biofilm formation. Abietic acid was identified as bacteriostatic, and this compound caused minimal damage to the bacterial membrane. This action was different from that of povidone-iodine or cetylpyridinium chloride. Additionally, abietic acid was significantly less cytotoxic compared to povidone-iodine, and it exerted lower toxicity towards epithelial cells and fibroblasts compared to that against monocytic cells. These data suggest that abietic acid may prove useful as an antibacterial and antibiofilm agent for controlling S. mutans infection.

DOI： 10.1007/s10266-019-00456-0

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High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein of about 30 kDa. It is released from a variety of cells into the extracellular milieu in response to inflammatory stimuli and acts on specific cell-surface receptors, such as receptors for advanced glycation end-products (RAGE), Toll-like receptor (TLR)2, TLR4, with or without forming a complex with other molecules. HMGB1 mediates various mechanisms such as inflammation, cell migration, proliferation, and differentiation. On the other hand, HMGB1 enhances chemotaxis acting through the C-X-C motif chemokine ligand (CXCL)12/C-X-C chemokine receptor (CXCR)4 axis and is involved in regeneration. In the oral cavity, high levels of HMGB1 have been detected in the gingival tissue from periodontitis and peri-implantitis patients, and it has been shown that secreted HMGB1 induces pro-inflammatory cytokine expression, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, which prolong inflammation. In contrast, wound healing after tooth extraction or titanium dental implant osseointegration requires an initial acute inflammation, which is regulated by secreted HMGB1. This indicates that secreted HMGB1 regulates angiogenesis and bone remodeling by osteoclast and osteoblast activation and promotes bone healing in oral tissue repair. Therefore, HMGB1 can prolong inflammation in the periodontal tissue and, conversely, can regenerate or repair damaged tissues in the oral cavity. In this review, we highlight the role of HMGB1 in the oral cavity by comparing its function and regulation with its function in other diseases. We also discuss the necessity for further studies in this field to provide more specific scientific evidence for dentistry.

DOI： 10.3389/fimmu.2020.01461

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We report a case of acute prevertebral abscess caused by traumatic tooth fractures in a 77-year-old Japanese man. After being transferred to our hospital the patient was initially diagnosed with a neck hematoma; however, blood culture showed Streptococcus parasanguinis, an oral bacterium, and an MRI examination suggested prevertebral abscesses. Tooth fractures, severe periodontitis, and peri-implantitis with Streptococcus parasanguinis were observed. Antibiotics were administered and fractured teeth were extracted. The patient's condition then gradually improved. We concluded that bacteremia caused by traumatic tooth fractures induced the acute prevertebral abscesses.

DOI： 10.18926/AMO/57376

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The periodontal pathogen Porphyromonas gingivalis shows colonial pigmentation on blood agar and produces gingipains (Kgp, RgpA, and RgpB), cysteine proteases involved in an organism's virulence and pigmentation. We showed previously that deletion of the PGN_0300 gene abolished the pigmentation activity and reduced the proteolytic activity of gingipains. The role of the PGN_0297 gene, which consists of an operon with the PGN_0300 gene, is unclear. Herein we examined the effect of PGN_0297 gene deletion on the pigmentation and proteolytic activities and transcriptional levels of gingipains. A PGN_0297 gene deletion mutant (ΔPGN_0297) did not exhibit the pigmentation. The proteolytic activity of the gingipains was decreased in the culture supernatant and on the cell surface of ΔPGN_0297. The mutant ΔPGN_0297 failed to attenuate Akt phosphorylation at Thr308 and Ser473, but both phosphorylations were attenuated in the wild-type and its complementation strain. The deletion of PGN_0297 gene did not substantially affect the transcriptional levels of the gingipain genes kgp, rgpA, and rgpB. Taken together, these results indicate that PGN_0297 is closely involved in the secretion and maturation of gingipains.

DOI： 10.18926/AMO/56933

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Contamination of dental unit waterlines (DUWL) with heterotrophic bacteria can cause problems in immune compromised patients (aged, tumor and organ transplantation-patients). We focused on the use of low-concentrated ozonized water (OZW) as the biofilm formation restraint system for DUWL. Here, we examined the effects of low-concentrated OZW on the growth of bacteria and related biofilm formation and harmfulness to dental unit components (DUCs) in vitro. Objectives: To evaluate the bactericidal effects of OZW on biofilms in DUWL and DUC in vitro. Methods: Low-concentrated OZW (0.4 mg/L) was generated using an OZS-PTDX generator. Heterotrophic bacterial biofilms in old DUWL tubes and Candia albicans solution (control microbe) were treated with OZW for 1 h with gentle agitation before static culturing for 96 h in Reasoner's 2A liquid media. The control solutions were 0.1% cetylpyridinium chloride (CPC), chlorinated tap water (TW), and phosphate-buffered saline (PBS). Adenosine triphosphate (ATP) amounts of the microbes were measured and the biofilms of these microbes were observed using scanning electron microscopy (SEM). Moreover, surfaces of DUC soaked in OZW and TW were observed by SEM. Results: The OZW reduced ATP levels in microbes to 50% compared to TW and PBS treatment, although CPC reduced it below detection limits. SEM observation revealed deformation of microbes cultured with OZW, whereas no changes were seen on DUC surfaces. Conclusions: Low-concentrated OZW is bactericidal against heterotrophic bacteria biofilms and it is not harmful to DUC, suggesting that it might be useful in preventing DUWL contamination.

DOI： 10.1016/j.heliyon.2019.e02306

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Taste alteration is one of the complications of severe diabetes. It is important in diabetes treatment to assess taste alteration and perform dietary counseling, therapeutic exercise, and oral care. In this case, multidisciplinary clinical approach by medical staff was successful for a severely diabetic patient with dysgeusia.

DOI： 10.1002/ccr3.2111

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Authorship：Lead author   Language：Japanese   Publisher：日本歯科医学会  

医科歯科連携に深く関連する歯周病関連部分を、医療全般から理解される検査として再構築することによって、プロジェクト研究テーマB「歯科診療における臨床検査の新規開発」の一部へ対応させる。これによって、21世紀の医療において、歯科医療のみならず医療全般に変革をもたらす検査法と診断体系の開発に繋がる。ペリオドンタルメディシンの考え方が普及して、口腔と全身の疾患との関連(平成28年3月に日本歯周病学会が『歯周病と全身の健康』を刊行)の中から特に糖尿病治療体系に歯周病治療が取り入れられ、さらには抗菌剤のポケット内への投与が保険収載されるようにもなった。こうした展開を歯周病が関連する他の疾患へも広げることが、歯科医療のみならず医療全般の充実をもたらす。そこで、歯周病の発症と進行、口腔機能の喪失、全身への影響という観点から、(1)感染、(2)炎症、(3)咬合力・咀嚼率、といった3つの因子を包括的に把握する。これらの3分野の組み合せで歯周病の病状を捉えるように解析方法を開発するとともに、歯周病が関連する疾患への影響度の指標となるように解析方法を検討した。(著者抄録)

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Objective: We aimed to evaluate molecular imaging as a novel diagnostic tool for mice periodontitis model induced by ligature and Porphyromonas gingivalis (Pg) inoculation. Materials and methods: Twelve female mice were assigned to the following groups: no treatment as control group (n = 4)
periodontitis group induced by ligature and Pg as Pg group (n = 4)
and Pg group treated with glycyrrhizinic acid (GA) as Pg + GA group (n = 4). All mice were administered a myeloperoxidase (MPO) activity-specific luminescent probe and observed using a charge-coupled device camera on day 14. Image analysis on all mice was conducted using software to determine the signal intensity of inflammation. Additionally, histological and radiographic evaluation for periodontal inflammation and bone resorption at the site of periodontitis, and quantitative enzyme-linked immunosorbent assay (ELISA) were conducted on three mice for each group. Each experiment was performed three times. Results: Levels of serum IgG antibody against P. gingivalis were significantly higher in the Pg than in the Pg + GA group. Histological analyses indicated that the number of osteoclasts and neutrophils were significantly lower in the Pg + GA than in the Pg group. Micro-CT image analysis indicated no difference in bone resorption between the Pg and Pg + GA groups. The signal intensity of MPO activity was detected on the complete craniofacial image
moreover, strong signal intensity was localized specifically at the periodontitis site in the ex vivo palate, with group-wise differences. Conclusions: Molecular imaging analysis based on MPO activity showed high sensitivity of detection of periodontal inflammation in mice. Clinical relevance: Molecular imaging analysis based on MPO activity has potential as a diagnostic tool for periodontitis.

DOI： 10.1007/s00784-018-2510-2

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The recruitment of tissue-resident stem cells is important for wound regeneration. Periodontal ligament cells (PDL cells) are heterogeneous cell populations with stemness features that migrate into wound sites to regenerate periodontal fibres and neighbouring hard tissues. Cell migration is regulated by the local microenvironment, coordinated by growth factors and the extracellular matrix (ECM). Integrin-mediated cell adhesion to the ECM provides essential signals for migration. We hypothesized that PDL cell migration could be enhanced by selective expression of integrins. The migration of primary cultured PDL cells was induced by platelet-derived growth factor-BB (PDGF-BB). The effects of blocking specific integrins on migration and ECM adhesion were investigated based on the integrin expression profiles observed during migration. Up-regulation of integrins α3, α5, and fibronectin was identified at distinct localizations in migrating PDL cells. Treatment with anti-integrin α5 antibodies inhibited PDL cell migration. Treatment with anti-integrin α3, α3-blocking peptide, and α3 siRNA significantly enhanced cell migration, comparable to treatment with PDGF-BB. Furthermore, integrin α3 inhibition preferentially enhanced adhesion to fibronectin via integrin α5. These findings indicate that PDL cell migration is reciprocally regulated by integrin α3-mediated inhibition and α5-mediated promotion. Thus, targeting integrin expression is a possible therapeutic strategy for periodontal regeneration.

DOI： 10.1111/jcmm.14023

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(NPO)日本臨床歯周病学会  

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Background: The aim of this study was to investigate the protein and trace element components of PM2.5 and their contribution to the allergic airway inflammation in BALB/c mice. Methods: PM2.5, treated at high temperature and with a strong acid to hydrolyze any protein content and remove trace elements, was administered to BALB/c mice. Allergic airway inflammation was compared between the three groups (saline, pure PM2.5 and treated PM2.5) by evaluating airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF) cells, serum IgE, the mRNA of various cytokine (IL-4, IL-5, IL-13, eotaxin-1 and CXCL3), mucus protein mRNA (MUC5ac and MUC5b) and the filtration of inflammatory cells in the lung. Results: The treatment of PM2.5 with a strong acid at a high temperature attenuated AHR, eosinophil percentage in BALF, mRNA levels of IL-13 and CXCL3 and peribronchial inflammation. On the contrary, the percentage of neutrophils in BALF, mRNA expression of MIP2α, EGFR, Nrf2, and TLR4 and 4-OH-2-nonenal levels in the lung was increased. Moreover, the treatment of the PM2.5 reduced PM2.5-bound proteins as well as the percentages of the trace elements in PM2.5 in the order Zn > Cu > Pb > P > S > Mn > Fe > Ca > Ni, whereas the percentage of C, Si and Cl increased. Conclusions: PM2.5 collected by of the cyclone system induced allergic airway inflammation in mice. PM2.5-bound proteins and acid-soluble metals may be involved in the pathogenesis of PM2.5-induced allergic airway inflammation.

DOI： 10.1080/08958378.2018.1561769

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Control of bacterial infection-induced inflammatory responses is one of the effective therapeutic approaches of periodontal diseases. Natural products such as lipid mediators and metabolites from microorganisms have been used for decreasing inflammation. We previously reported that (+)-terrein inhibited activation of STAT3 and ERK1/2 in interleukin-6 (IL-6) signaling cascade, leading to prevent vascular endothelial growth factor (VEGF) secretion in human gingival fibroblasts (HGFs). However, little is still known about the role of (+)-terrein on inflammatory responses. In this study, we provided the possibility of novel action that (+)-terrein inhibits activation of Janus-activated kinase 1 (JAK1), which has a central function in IL-6 signaling cascade, and alters expression of mRNAs and proteins induced by IL-6/soluble IL-6 receptor (sIL-6R) stimulation in HGFs. First, we performed PCR array to examine IL-6/sIL-6R-induced mRNA expression, and then expression of mRNA and protein of colony stimulating factor-1 (CSF1) and VEGF were clearly determined by quantitative RT-PCR and ELISA, respectively. Treatment with (+)-terrein suppressed expression of mRNA and protein of CSF1 and VEGF by IL-6/sIL-6R stimulation. Next, to test the effect of (+)-terrein on IL-6/sIL-6R signaling cascade, we demonstrated whether (+)-terrein affects phosphorylation of JAK1 and its downstream proteins, Akt and SHP-2. Western blotting revealed that (+)-terrein inhibited IL-6/sIL-6R-induced phosphorylation of JAK1, Akt, and SHP-2. Therefore, (+)-terrein suppresses IL-6/sIL-6R-induced expression of CSF1 and VEGF via inhibition of JAK1, Akt, and SHP-2. Based on our results, we suggest that (+)-terrein is a candidate compound for anti-inflammatory effect associated with IL-6 signaling.

DOI： 10.1016/j.heliyon.2018.e00979

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley-Liss Inc.  

High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein that is secreted into the extracellular milieu in response to inflammatory stimuli. The secreted HMGB1 has been suggested to mediate various inflammatory diseases. However, it is still unknown whether HMGB1 is involved in a healing process in the tooth extraction socket, the tissue containing gingival epithelium, and alveolar bone that is exposed to oral bacteria. In this study, we constructed a murine tooth extraction model with anti-HMGB1 neutralization antibody administration and observed the inflammatory response and bone healing process in tooth extraction sockets by molecular imaging of myeloperoxidase (MPO) activity, histological analysis, and quantitative RT-PCR. The translocation of HMGB1 from the nucleus to the cytoplasm in gingival epithelial cells and inflammatory cells was inhibited by anti-HMGB1 antibody administration. The MPO activity around the tooth extraction socket was significantly reduced, and the numbers of CD31- and CD68-positive cells were significantly lower in the anti-HMGB1 antibody treatment samples than in the control samples. The TRAP-positive cells, osteocalcin positive cells, and the neoplastic bone area were significantly lower in anti-HMGB1 antibody treatment samples than in control samples. The expression levels of IL-1β and VEGF-A were also decreased in anti-HMGB1 antibody treatment samples compared to that in control samples. Secreted HMGB1 induced initial acute inflammation and inflammatory cells recruitment after tooth extraction. HMGB1 was associated with angiogenesis and bone remodeling by osteoclast and osteoblast activation and promoted bone healing in the tooth extraction socket.

DOI： 10.1002/jcb.26710

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

Unfortunately, in Table-5 of the original article, the parameter in the 5th row was published incorrectly as “LDL-C (mg/dL)”. The correct parameter should read as “HDL-C (mg/dL)”.

DOI： 10.1007/s10266-018-0346-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

Unfortunately, in Table-5 of the original article, the parameter in the 5th row was published incorrectly as “LDL-C (mg/dL)”. The correct parameter should read as “HDL-C (mg/dL)”.

DOI： 10.1007/s10266-018-0346-5

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Microbiology  

High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein that is secreted into the extracellular milieu in response to inflammatory stimuli. The secreted HMGB1 mediates various inflammatory diseases, including periodontitis
however, the underlying mechanisms of HMGB1-induced periodontal inflammation are not completely understood. Here, we examined whether anti-HMGB1 neutralizing antibody inhibits periodontal progression and investigated the molecular pathology of HMGB1 in vitro and in vivo. In vitro analysis indicated that HMGB1, granulocytemacrophage colony-stimulating factor (GM-CSF), and interleukin-1β (IL-1β) were secreted in response to tumor necrosis factor-α (TNF-α) stimuli in human gingival epithelial cells (HGECs) and human monocytic leukemia cells (THP-1) treated with phorbol myristate acetate. Increased levels of GM-CSF and IL-1β were observed in the conditioned media from TNF-α-stimulated HGECs and THP-1 in vitro. Simultaneous stimulation with TNF-α and anti-HMGB1 antibody significantly decreased TNF-α- induced inflammatory cytokine secretion. Experimental periodontitis was induced in mice using Porphyromonas gingivalis-soaked ligatures. The extracellular translocation was confirmed in gingival epithelia in the periodontitis model mice by immunofluorescence analysis. Systemic administration of anti-HMGB1 neutralizing antibody significantly inhibited translocation of HMGB1. The anti-HMGB1 antibody inhibited periodontal inflammation, expression of IL-1β and C-X-C motif chemokine ligand 1 (CXCL1), migration of neutrophils, and bone resorption, shown by bioluminescence imaging of myeloperoxidase activity, quantitative reverse transcription-PCR (RT-PCR), and micro-computed tomography analysis. These findings indicate that HMGB1 is secreted in response to inflammatory stimuli caused by periodontal infection, which is crucial for the initiation of periodontitis, and the anti-HMGB1 antibody attenuates the secretion of a series of inflammatory cytokines, consequently suppressing the progression of periodontitis.

DOI： 10.1128/IAI.00111-18

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

In the original publication of the article, one of the author name was published incorrectly as “Keisuke Yamashairo” and correct name should be “Keisuke Yamashiro”.

DOI： 10.1007/s10266-017-0334-1

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We previously isolated rat 14.7K-interacting protein-2 (rFIP-2) from the rat-wounded pulp. The protein, homologous to human FIP-2, is known as optineurin and was initially identified as a novel tumor necrosis factor-α (TNF-α)-inducible protein, and more recently, as an autophagy receptor. However, the biological role of optineurin in dental pulp remains elusive. We hypothesized that optineurin has a crucial role in regulating molecular processes during pulp inflammatory responses induced by TNF-α. We examined the kinetics of optineurin expression in pulp inflammation. Optineurin localization and expression were examined using rat pulp fibroblasts. The cells were treated with pharmacological inhibitors for TNF-α-induced inflammatory signals or with hydrogen peroxide as apoptotic stimuli. Stable optineurin-knockdown cells (OPTN-KD cells) were established by transfecting normal rat kidney cells with a vector expressing optineurin-specific small interfering RNA. Cell proliferation and the profiles of cytokines and intracellular signaling molecules were examined using OPTN-KD cells stimulated by TNF-α. Optineurin was localized in the cytoplasm and then translocated into the nucleus upon apoptotic stimuli. Optineurin expression was increased by TNF-α and decreased by a specific inhibitor of c-Jun N-terminal kinase. The OPTN-KD cells secreted smaller amounts of monocyte chemotactic protein-1 (MCP-1) and intracellular MCP-1 mRNA, and cell proliferation was significantly increased. Apoptosis-related signaling molecules were downregulated in OPTN-KD cells. These results demonstrated that optineurin is a crucial molecule mediated by TNF-α, which induces the production of inflammatory factors and apoptosis signaling, suggesting the presence of signaling interactions between optineurin and a transcription factor for MCP-1.

DOI： 10.1007/s10266-017-0314-5

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Netherlands  

Cells behave in a variety of ways when they perceive changes in their microenvironment
the behavior of cells is guided by their coordinated interactions with growth factors, niche cells, and extracellular matrix (ECM). Modulation of the microenvironment affects the cell morphology and multiple gene expressions. Rho/Rho-associated coiled-coil-containing protein kinase (ROCK) signaling is one of the key regulators of cytoskeletal dynamics and actively and/or passively determines the cell fate, such as proliferation, migration, differentiation, and apoptosis, by reciprocal communication with the microenvironment. During periodontal wound healing, it is important to recruit the residential stem cells into the defect site for regeneration and homeostasis of the periodontal tissue. Periodontal ligament (PDL) cells contain a heterogeneous fibroblast population, including mesenchymal stem cells, and contribute to the reconstruction of tooth-supporting tissues. Therefore, bio-regeneration of PDL cells has been the ultimate goal of periodontal therapy for decades. Recent stem cell researches have shed light on intrinsic ECM properties, providing paradigm shifts in cell fate determination. This review focuses on the role of ROCK activity and the effects of Y-27632, a specific inhibitor of ROCK, in the modulation of ECM-microenvironment. Further, it presents the current understanding of how Rho/ROCK signaling affects the fate determination of stem cells, especially PDL cells. In addition, we have also discussed in detail the underlying mechanisms behind the reciprocal response to the microenvironment.

DOI： 10.1007/s12079-017-0425-3

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BACKGROUND: A number of studies have suggested a bidirectional relationship of periodontitis with rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). However, the genetic factors that underlie these relationships have not been elucidated. METHODS: We conducted a multicenter case-control study that included 185 patients with RA and chronic periodontitis (CP), 149 patients with T2DM and CP, 251 patients with CP, and 130 systemically and periodontally healthy controls from a cohort of Japanese adults to assess the shared genetic risk factors for RA and CP as well as for T2DM and CP. A total of 17 candidate single nucleotide polymorphisms (SNPs) associated with RA, T2DM, and CP were genotyped. RESULTS: Multiple logistic regression analyses revealed that the KCNQ1 rs2237892 was significantly associated with comorbidity of RA and CP (P = 0.005) after adjustment for age, sex, and smoking status. The carriers of the T allele among patients with RA and CP showed significantly higher disease activity scores including 28 joints using C-reactive protein values than the non-carriers (P = 0.02), although the age, female percentage, and smoking status were comparable. Other SNPs were not associated with comorbidity of RA and CP, T2DM and CP, or susceptibility to CP. CONCLUSION: The results of the present pilot study suggest for the first time that the KCNQ1 rs2237892 may constitute a shared genetic risk factor for RA and CP, but not for T2DM and CP in Japanese adults.

DOI： 10.1002/JPER.17-0412

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Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：(一社)日本口腔検査学会  

目的:歯周病治療の効果を「感染」、「炎症」、そして「機能」の3つの観点から評価して、治療効果を示す指標を探った。方法:歯周病治療を終えて安定期治療に至った7症例において、歯周局所の歯周病原細菌数と9菌種の血清IgG抗体価、歯周ポケット深さとプロービング時の出血から算出する歯周炎症表面積(PISA)、そして咀嚼機能の簡易指標として残存歯の動揺度を測定した。これら4つの指標の変動を治療時期の一定ポイントで調べ、それらの相互関係を検討した。結果:歯周治療が進むにしたがって、PISA、歯の動揺度およびPorphyromonas gingivalis(Pg)に対する抗体価の数値は低下し、7症例の各時期における平均値をとると、経時的な有意差が認められた(P<0.05)。しかしながら、他の菌種に対する抗体価や歯周局所の細菌数には増加するものもみられた。結論:「感染」、「炎症」、「機能」の3つの観点から歯周病治療の効果を評価する指標として、抗Pg抗体価、PISA、そして歯の動揺度を用いることは有用であった。(著者抄録)

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Luigi Ponzio e figlio Editori  

An insertion sequence, IS1598 (IsPg4) has been found in virulent strains of Porphyromonas gingivalis in a murine abscess model. The present study was performed to investigate the effects of genetic rearrangements by IS1598 on the phenotypic characteristics of the virulent strains. For this purpose, we searched for a common insertion site of IS1598 among the virulent strains. Through cloning and database search, a common insertion site was identified beside an nrdD-like gene in the virulent FDC 381, W83 and W50 strains. In this region, predicted promoters of the nrdD-like gene and IS1598 are located in tandem, and accumulation of nrdD-like gene mRNA was 5-fold higher in virulent strains (W83, W50, FDC 381) than avirulent strains (ATCC33277, SU63, SUNY1021, ESO59 without IS1598). The role of the nrdD-like gene in virulence of P. gingivalis was investigated by constructing a nrdD-deficient mutant. In the murine abscess model, the parental W83 strain produced necrotic abscesses, while the nrdD-deficient mutant had almost lost this ability. Insertion of IS1598 into the nrdD-like gene promoter region may be related to the phenotypic differences in virulence among P. gingivalis strains through upregulation of the expression of this gene.

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Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science (PLoS)  

DOI： 10.1371/journal.pone.0188014

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/ccr3.751

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The diagnosis of the progression of periodontitis presently depends on the use of clinical symptoms (such as attachment loss) and radiographic imaging. The aim of the multicenter study described here was to evaluate the diagnostic use of the bacterial content of subgingival plaque recovered from the deepest pockets in assessing disease progression in chronic periodontitis patients. METHODS: This study consisted of a 24-month investigation of a total of 163 patients with chronic periodontitis who received trimonthly follow-up care. Subgingival plaque from the deepest pockets was recovered and assessed for bacterial content of Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans using the modified Invader PLUS assay. The corresponding serum IgG titers were measured using ELISA. Changes in clinical parameters were evaluated over the course of 24 months. The sensitivity, specificity, and prediction values were calculated and used to determine cutoff points for prediction of the progression of chronic periodontitis. RESULTS: Of the 124 individuals who completed the 24-month monitoring phase, 62 exhibited progression of periodontitis, whereas 62 demonstrated stable disease. The P. gingivalis counts of subgingival plaque from the deepest pockets was significantly associated with the progression of periodontitis (p < 0.001, positive predictive value = 0.708). CONCLUSIONS: The P. gingivalis counts of subgingival plaque from the deepest pockets may be associated with the progression of periodontitis.

DOI： 10.1186/s12903-017-0337-x

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：(NPO)日本歯周病学会  

歯周病対策の基本である口腔細菌バイオフィルムの制御について概説した。バイオフィルムの形成は、細菌の初期付着、不可逆性付着、バイオフィルムの形成、増大と成熟、バイオフィルムからの細菌の分散、といった5段階であるとされる。バイオフィルムを形成すると、細菌間での情報交換であるquorum sensingが活発になり、浮遊状態である細菌の代謝活性とは異なるものになる。口腔に棲息する常在細菌叢を、質的に各細菌種の構成割合を維持し、一方で量的には各細菌種の細菌数を減少させることが,細菌と生体のバランスを考えると望ましいと考えられ、相利共生(symbiosis)の概念が普及してきた。また、細菌叢内でのquorum sensingを理解することで、細菌間での連携を攪乱する方法でバイオフィルムを阻止することも考えられている。

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s11010-017-3076-z

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0188670

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/cbin.10769

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/jre.12353

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Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.archoralbio.2016.06.025

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Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.oooo.2016.04.006

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Authorship：Last author   Language：Japanese   Publisher：(一社)日本糖尿病合併症学会  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

This OTC medication is biochemically effective for steady chronic periodontitis in the supportive periodontal therapy phase.

DOI： 10.1111/jre.12311

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Publishing type：Research paper (scientific journal)  

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/jbmr.2738

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jbmr.2738

Authorship：Last author   Language：Japanese   Publisher：(NPO)日本歯科保存学会  

目的:近年,口腔インプラント治療の増加に伴い,歯周病原細菌をはじめとする口腔細菌の感染症であるインプラント周囲炎が急増している.インプラント周囲炎は,口腔インプラントの予後を左右する主な因子の一つであり,細菌学的評価に基づいたインプラントを含む口腔内の感染管理の充実が求められる.そこでこのたび,歯周病原細菌関連検査におけるインプラント周囲炎の予測因子の有用性について検討した.方法:歯周病安定期治療あるいはインプラントリコール目的で受診中である,20歳以上の口腔インプラント治療歴があるメインテナンス患者5名(メインテナンス群)と,supportive periodontal therapy患者(SPT患者)10名(SPT群)を対象とした.対象の歯周ポケットとインプラント周囲ポケットの深さを測定し,パノラマX線写真から骨吸収がスクリューに及ぶインプラント(bone resoption in implant screw:BRIS)の有無を調査した.さらに,歯周病原細菌に対する血漿IgG抗体価検査と歯周病原細菌量の唾液検査(定量PCR法)を行った.得られたデータについて,メインテナンス群とSPT群間,BRIS非保有群とBRIS保有群間において統計学的に評価した.結果:BRIS保有患者数が,メインテナンス群よりもSPT群に有意に多かった.Porphyromonas. gingivalisに対する血漿IgG抗体価のcut-off値1.68を用いて陽性者と陰性者間で比較すると,抗体価の陽性者数がメインテナンス群よりSPT群に有意に多かった.また,唾液中の歯周病原細菌検出者数をメインテナンス群とSPT群間で比較したところ,唾液中のTannerella forsythiaの保菌者がメインテナンス群よりSPT群に有意に多かった.さらに,歯周病原細菌に対する血漿IgG抗体価と唾液中の歯周病原細菌検出者数をBRIS非保有群とBRIS保有群間で比較した.その結果,P.gingivalisに対する血漿IgG抗体価の陽性者数と唾液中のT.forsythiaの保菌者が,BRIS非保有群よりBRIS保有群に有意に多かった.結論:血液と唾液を用いた歯周病原細菌関連検査が,インプラント周囲炎の予測因子として有用である可能性が示唆された.(著者抄録)

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Authorship：Last author   Language：Japanese   Publisher：(NPO)日本歯科保存学会  

目的:放射線が照射された顎骨では,骨の細胞活性能が低下し,細菌感染により骨髄炎を発症しやすい.今回,下咽頭癌に対する放射線治療の既往がある患者に発症した46の根尖性歯周炎に起因する放射線性下顎骨骨髄炎に対して,抗菌薬投与と感染根管治療の併用によって保存的治療を行い,良好な経過を得た症例について報告し,その対処法を考察する.症例の概要:患者は58歳男性.下咽頭癌に対して,岡山大学病院耳鼻咽喉科と放射線科にて2006年11月から2007年1月まで化学放射線療法を受けた.2010年5月初旬に右側下顎部に疼痛を自覚していたところ,定期検査時の18F-fluoro-deoxyglucose positron emission tomography-computed tomography(FDG-PET/CT)検査にて,下顎右側にFDG異常集積が認められた.当院歯周科および口腔外科にて,46の根尖性歯周炎に起因する放射線性下顎骨骨髄炎と診断された.口腔外科にて抗菌薬および鎮痛剤の投与が継続され,同科からの依頼により当科にて46の根管治療を継続した.治療経過:46に対して感染根管治療を継続するも,右側下顎部の自発痛が続き,弓倉症状による強い打診痛の範囲が46から前方へと波及した.下顎骨に放射線治療の既往があるため,下顎骨骨髄の減圧を目的とした外科処置を行うことができなかった.そこで,外科処置に代わる減圧手段として,MR画像上における浮腫性変化を示す範囲内の全歯に対して根管開放を行い,並行して耳鼻咽喉科での抗癌剤中止に加えて口腔外科での抗菌薬投与を継続した.さらに,これらの歯を咬合させないよう安静に維持することで,急性症状が軽快して骨髄炎を沈静化させることができた.その後から現在まで,下顎部は良好に経過している.考察および結論:46の根尖性歯周炎に起因する放射線性下顎骨骨髄炎に対して,抗菌薬投与と感染根管治療の併用によって良好な経過を得ることができた.顎骨への放射線照射を行う患者において,放射線治療前に医科歯科連携下による歯性感染巣除去を行い,顎骨骨髄炎を予防することが重要である.(著者抄録)

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It has been revealed that atherosclerosis and periodontal disease may have a common mechanism of "chronic inflammation". Several reports have indicated that periodontal infection is related to atherosclerosis, but none have yet reported such an investigation through the cooperation of local clinics. This study was performed in local Japanese clinics to examine the relationship between periodontal disease and atherosclerosis under collaborative medical and dental care. A pilot multicenter cross-sectional study was conducted on 37 medical patients with lifestyle-related diseases under consultation in participating medical clinics, and 79 periodontal patients not undergoing medical treatment but who were seen by participating dental clinics. Systemic examination and periodontal examination were performed at baseline, and the relationships between periodontal and atherosclerosis-related clinical markers were analyzed. There was a positive correlation between LDL-C level and plasma IgG antibody titer to Porphyromonas gingivalis. According to the analysis under adjusted age, at a cut-off value of 5.04 for plasma IgG titer to Porphyromonas gingivalis, the IgG titer was significantly correlated with the level of low-density lipoprotein cholesterol (LDL-C). This study suggested that infection with periodontal bacteria (Porphyromonas gingivalis) is associated with the progression of atherosclerosis. Plasma IgG titer to Porphyromonas gingivalis may be useful as the clinical risk marker for atherosclerosis related to periodontal disease. Moreover, the application of the blood examination as a medical check may lead to the development of collaborative medical and dental care within the local medical clinical system for the purpose of preventing the lifestyle-related disease.

DOI： 10.1007/s10266-014-0172-3

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BACKGROUND AND OBJECTIVE: Tumor necrosis factor alpha (TNF-α) is a major cytokine implicated in various inflammatory diseases. The nature of the nuclear factors associated with human TNF-α gene regulation is not well elucidated. We previously identified a novel region located from -550 to -487 in human TNF-α promoter that did not contain the reported binding sites for nuclear factor kappa B (NF-κB) but showed lipopolysaccharide (LPS)-induced transcriptional activity. The purpose of this study is to identify novel factors that bind to the promoter region and regulate TNF-α expression. MATERIAL AND METHODS: To identify DNA-binding proteins that bound to the target region of TNF-α promoter, a cDNA library from LPS-stimulated human monocytic cell line THP-1 was screened using a yeast one-hybrid system. Cellular localizations of the DNA-binding protein in the cells were examined by subcellular immunocytochemistry. Nuclear amounts of the protein in LPS-stimulated THP-1 cells were identified by western blot analysis. Expression of mRNA of the protein in the cells was quantified by real-time polymerase chain reaction. Electrophoretic mobility shift assays were performed to confirm the DNA-binding profile. Overexpression of the protein and knockdown of the gene were also performed to investigate the role for TNF-α expression. RESULTS: Several candidates were identified from the cDNA library and transactivation-responsive DNA-binding protein 43 (TARDBP43; TDP-43) was focused on. Western blot analysis revealed that nuclear TDP-43 protein was increased in the LPS-stimulated THP-1 cells. Expression of TDP-43 mRNA was already enhanced before TNF-α induction by LPS. Electrophoretic mobility shift assay analysis showed that nuclear extracts obtained by overexpressing FLAG-tagged TDP-43 bound to the -550 to -487 TNF-α promoter fragments. Overexpression of TDP-43 in THP-1 cells resulted in an increase of TNF-α expression. Knockdown of TDP-43 in THP-1 cells downregulated TNF-α expression. CONCLUSION: We identified TDP-43 as one of the novel TNF-α factors and found that it bound to the LPS-responsive element in the TNF-α promoter to increase TNF-α expression.

DOI： 10.1111/jre.12227

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/ggi.12430

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Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：日本歯科医学会  

歯周組織再生治療を成功に導くには、歯周炎による歯槽骨欠損の幅、深さ、角度、そして残存する骨壁数を術前に正確に把握することによる適応症診断が重要である。歯科用Cone beam computed tomography(CBCT)は、従来の診査方法では困難であった口腔内の3次元的形態を描出できるという点で、歯科領域で頻繁に使用されているものの、歯周組織再生治療の評価に有効であるかの十分なコンセンサスは得られてない。そこで本研究では、ブタ歯槽骨に規格化した骨欠損を人工的に作製し、評価項目毎の実測値とCBCT画像上の長さ(画像値)の誤差を比較し、歯周組織再生治療の評価への有用性を検討した。骨欠損の規格化は、デジタルノギスでの測定下でブタ下顎骨を技工用バーで削合することによって行った。各条件の骨欠損(n=3)の実測値とCBCTによる画像値を比較した結果、評価項目全体の誤差の平均は0.32mmで、骨欠損実測値の大小に関わらず一定の傾向はなかった。また、頬側骨の厚さが1mmあれば、CBCTで描出することは可能だった。さらに、骨欠損の体積は、頬側骨の厚さが2mmに近づくにつれ、その誤差は減少した。以上の結果から、CBCTは、骨欠損の大きさを正確に計測することは難しいが、骨欠損の位置や骨欠損の壁数を把握できることが明らかになった。すなわち、CBCTは歯周組織再生治療を行う際の骨欠損を診断するための一つの診査方法として有効であると考える。(著者抄録)

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Authorship：Last author,　Corresponding author   Language：Japanese   Publisher：(一社)日本口腔検査学会  

目的:岡山県におけるベーチェット病患者の口腔内状態に対する医師の把握状況を調査することを目的とした。方法:岡山県から岡山大学病院腎臓・糖尿病・内分泌内科へ提供された「ベーチェット病登録医療機関」(特定疾患申請時に「受診予定」として患者が登録した医療機関)から抽出した262施設に対して,無記名アンケートを実施した。結果:回答のあった123施設中,「ベーチェット病と口腔内感染巣の関連性」に関心のある施設は約6割の73施設であった。また,ベーチェット病患者が通院中の施設は63施設で,通院患者総数は191人であった。そのうち,歯科医療施設へ通院中のベーチェット病患者は21人であった。「口腔衛生状態不良と思われるベーチェット病患者はいますか?」との質問に対して,「はい」との回答は63施設中8施設,「いいえ」は34施設,そして「不明」が21施設であった。さらに,歯科治療によってベーチェット病の症状に変化を生じた患者を経験した施設は5施設のみで,それらの症状は,悪化したものが眼症状,口内炎,皮膚症状,そして発熱であり,改善したものが口内炎であった。結論:本アンケート調査から,医科におけるベーチェット病患者の口腔内状態の把握度が低い可能性が推察される。また,歯科治療によってベーチェット病の症状に変化が生じる可能性がある。これらから,口腔領域の簡易検査を充実させた医科歯科連携による口腔内感染管理システムが重要であることを認識した。(著者抄録)

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Publishing type：Research paper (scientific journal)   Publisher：American Society for Microbiology  

<title>ABSTRACT</title>

The oral Gram-negative anaerobic bacterium
<named-content content-type="genus-species">Porphyromonas gingivalis</named-content>
is an important pathogen involved in chronic periodontitis. Among its virulence factors, the major extracellular proteinases, Arg-gingipain and Lys-gingipain, are of interest given their abilities to degrade host proteins and process other virulence factors. Gingipains possess C-terminal domains (CTDs) and are translocated to the cell surface or into the extracellular milieu by the type IX secretion system (T9SS). Gingipains contribute to the colonial pigmentation of the bacterium on blood agar. In this study, Omp17, the PGN_0300 gene product, was found in the outer membrane fraction. A mutant lacking Omp17 did not show pigmentation on blood agar and showed reduced proteolytic activity of the gingipains. CTD-containing proteins were released from bacterial cells without cleavage of the CTDs in the
<italic>omp17</italic>
mutant. Although synthesis of the anionic polysaccharide (A-LPS) was not affected in the
<italic>omp17</italic>
mutant, the processing of and A-LPS modification of CTD-containing proteins was defective. PorU, a C-terminal signal peptidase that cleaves the CTDs of other CTD-containing proteins, was not detected in any membrane fraction of the
<italic>omp17</italic>
mutant, suggesting that the defective maturation of CTD-containing proteins by impairment of Omp17 is partly due to loss of function of PorU. In the mouse subcutaneous infection experiment, the
<italic>omp17</italic>
mutant was less virulent than the wild type. These results suggested that Omp17 is involved in
<named-content content-type="genus-species">P. gingivalis</named-content>
virulence.

DOI： 10.1128/IAI.01308-15

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DOI： 10.1016/j.ajodo.2014.09.022

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DOI： 10.1007/s00520-014-2432-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.2147/cia.s73388

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DOI： 10.1002/ccr3.112

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DOI： 10.1002/ccr3.114

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.bmc.2014.07.047

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DOI： 10.1007/s00520-014-2151-1

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BACKGROUND AND OBJECTIVE: Spatiotemporal inhibition of apical migration and proliferation of gingival epithelium are significant factors involved in periodontal regeneration. Transforming growth factor β (TGF-β) is important in multiple aspects of wound healing, and Smad2, a downstream transcription factor of TGF-β, has an inhibitory effect on re-epithelialization during gingival wound healing. Therefore, we investigated the effects on migration and proliferation status, and intra/extracellular signaling regulated by Smad2 overexpression in gingival epithelial cells. MATERIAL AND METHODS: Gingival epithelial cells were isolated from the palatal gingival tissue of transgenic mice overexpressing Smad2 driven by the Keratin14 promoter. Smad2 expression was identified by western blotting and immunofluorescence analysis. Scratch assay and 5-bromo-2'-deoxyuridine staining were performed to assess cell migration and proliferation. To inactivate TGF-β type I receptor, the cultures were supplemented with SB431542. Secreted TGF-β was quantified by ELISA. Smad2 target gene expression was examined by real-time RT-PCR and in vivo immunofluorescence analysis of gingival junctional epithelium. RESULTS: Smad2-overexpressing cells were confirmed to have significant phosphorylated Smad2 in the nucleus. Scratch assay and 5-bromo-2'-deoxyuridine staining indicated that Smad2-overexpressing cells showed no significant differences in migration, but had reduced proliferation rates compared to wild-type controls. SB431542 significantly inhibited Smad2 phosphorylation, which coincided with restoration of the proliferation rate in Smad2-overexpressing cells. ELISA of TGF-β release did not show any differences between genotypes. The cell cycle inhibitors, p15 and p21, showed significant upregulation in Smad2-overexpressing cells compared to wild-type controls. Moreover, junctional epithelium of the transgenic mice showed increased expression of P-Smad2, p15 and p21. CONCLUSION: The signaling activation triggered by overexpression of Smad2 was dependent on TGF-β type I receptor, and the activated Smad2 increased p15 and p21 expression, responsible for inhibiting cell cycle entry, resulting in antiproliferative effects on gingival epithelial cells. Understanding of Smad2-induced signaling would be useful for possible clinical application to regulate gingival epithelial downgrowth.

DOI： 10.1111/jre.12106

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ある広汎型侵襲性歯周炎患者(女性)の24歳時からの26年間に及ぶ歯周治療経過を、臨床的観点と細菌学的・免疫学的な観点から追った。その間、患者には結婚、転居、出産、そして育児といったライフステージの変化があった。そこで、このライフステージによる生活習慣の変化が歯周病の病態に影響を与える可能性を考えて、動的治療期からSupportive Periodontal Therapy(SPT)期に渡って臨床症状が出現する前に病態変化を捉えようと、歯周病原細菌感染度を歯周病原細菌に対する血清IgG抗体価を用いてモニタした。この治療経過における患者の病態とSPT期における継続的な受診支援に関して考察し、10代後半から20代前半に発症する侵襲性歯周炎患者の長期管理法を提案する。この方法は、細菌の持続感染による疾患の活動性を把握するために用いた血清IgG抗体価検査による、口腔内の感染管理に注目するものである。(著者抄録)

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DNA normalizationを応用した高感度な細菌叢解析法(T-RFLP)について検討した。A.actinomycetemcomitans(Aa)、P.gingivalis(Pg)、P.intermedia(Pi)のDNA濃度比を、試料1で100:10:1、試料2で10:0:1、試料3で1:1:1に設定した。Nsp IによるT-RFLP法パターンでは、Normalization前において、試料1および試料2ではDNA濃度が最も高いAaのみが検出された。Normalization後は、試料1ではAa、Pg、Piの3菌種、試料2ではAaおよびPiの2菌種を検出した。試料3では、Normalization前後で3菌種全ての検出を確認した。また、Normalization後の検出率は、いずれも陽性コントロールの結果と一致した。

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.micinf.2013.10.005

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DOI： 10.1016/j.diff.2014.09.002

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歯周病に対する感受性が高い侵襲性歯周炎患者の治療においては、徹底した感染のコントロールによる疾患活動性の抑制が必要である。とりわけ、歯列不正を伴う歯周炎患者に矯正治療を行うことは、長期に渡る感染のコントロールを行う上で非常に有効である。しかし、歯周炎患者に矯正治療を行う場合に、感染がコントロールされている歯周状態かどうかを決定する基準は未だ明確でない。今回報告するのは、Agregatibacter actinomycetemcomitans(Aa)の感染が主な病態形成因子と考えられる、初診時22歳の広汎型侵襲性歯周炎患者に対して、矯正治療を含めた包括的歯周治療を行った症例である。初診以降、臨床計測値の変化に加えて、細菌DNA検査と歯周病原細菌に対する血清IgG抗体価検査を用いて、歯周病原細菌の感染度を評価した。その結果、歯周外科治療を含む感染源除去によって、細菌DNA検査でAaが検出されず、Aaに対する血清IgG抗体価が健常者レベルに推移したことを矯正治療移行前に確認した。すなわち、歯周病原細菌感染度が低下したと判断した後に、矯正治療を行うことで、現在まで良好なSPTを維持している。本症例においては、Aaの感染度の低下を細菌DNA検査と血清IgG抗体価を用いて評価することによって、客観的な根拠をもって矯正治療に移行できたと考える。(著者抄録)

DOI： 10.2329/perio.55.340

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本老年歯科医学会  

近年、病院や高齢者施設における医療職種の適切な人材配置が、医療の質や安全性の向上につながることが明らかになってきた。一方、歯科医療職の人材配置による入院患者の健康状態への影響については十分に検証されていない。そこで、今回われわれは、基礎的調査として、高齢者対象の病棟および施設こおける職種ごとの人材配置の現状を把握し、歯科医療職と他職種との相違を比較した。岡山県および広島県内の1施設および4病院に勤務する医療職274名を対象に、就業時間と業務内容に関する無記名自記式アンケート調査を実施した。入院患者に関わる業務は、直接業務、書類業務、環境業務の3業務に分類した。また、各々の業務に関わる時間を算出し、入院患者に関わる合計時間から入院病床数100床あたりの医療職の人数を算出し、スタッフ/病床比と定義した。平均スタッフ/病床比は、介護職と看護師において12.3および9.3と高値を示した一方で、歯科医師と歯科衛生士では、0.3および0.6と低かった。さらに、歯科衛生士では入院患者に接する直接業務時間も有意に短かった。本結果より、歯科医療職は、他職種と比して病棟への人材配置が少ないことが明らかになり、介入が不足している可能性が示唆された。「口腔環境と全身疾患との関連性について多くの報告がなされるなか、病院、施設において、歯科医療職の入院患者への業務時間を増やす取り組みが必要であると考える。(著者抄録)

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DOI： 10.1111/2049-632X.12041

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Allergy, Asthma, and Immunology Association of Thailand  

DOI： 10.12932/AP0287.31.4.2013

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本歯科医学会  

高齢者の歯科医療現場においては、歯周病の進行に伴い露出した根面や義歯表面に多量のプラークが付着していることが多く見受けられる。このことが原因となって、口腔内のトラブルを来していることがある。そこで、露出根面と義歯表面をターゲットとした抗菌性物質を開発し、高齢者医療での口腔細菌の感染対策を主体とした保存的治療を確立しようとした。まず、歯質接着性を有するリン酸化プルランを抗菌剤である塩化セチルピリジニウム(CPC)と混合することによって、歯面への細菌の付着を持続的に抑制することが明らかになった。実際の口腔内を想定した試験や動物における安全性試験などから実用性を確認し、大学発のベンチャー設立につながった。また、CPC配合の薬剤をタフトブラシと一体化した容器に封入した製剤を開発し、その臨床的および細菌学的効果をサンスター株式会社との産学連携の共同研究にて明らかにした。その成果から、第3類医薬品「G・U・mメディカルマージナルポイントケアA」が上市された。一方、義歯床用レジンにシリカをコーティングすることによって、細菌の付着を抑制することを試みた。低温でのシリカ添加の方法を樹立し、床用レジン上での安定性を確保することができたので、臨床応用に向けて取り組んでいるところである。以上から、高齢者医療における歯科保存治療技術・素材として、歯科診療への応用を臨学産連携で図ることができるようになってきた。今後は、学会主導でこれらの製品や技術を用いて、細菌感染対策の面から高齢者医療における歯科保存治療を行う指針を策定する段階が近づいていると思われる。(著者抄録)

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag  

DOI： 10.1007/s00520-012-1602-9

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During periodontal regeneration, inhibition of gingival downgrowth is necessary to promote migration of mesenchymal cells into the defects. Transforming growth factor (TGF)-β is a pleiotropic cytokine that has numerous cell functions, including regulation of epithelial growth. Recent studies have shown that Smad2, a downstream transcription factor of TGF-β, plays crucial roles in wound healing in the epithelia. Therefore, we investigated the effects of Smad2 overexpression on re-epithelialization of gingival wounds. Transgenic mice overexpressing smad2 driven by the keratin 14 promoter ( k14-smad2) were confirmed to have significant Smad2 phosphorylation in gingival basal epithelia. Punch wounds were made in the palatal gingiva, and wound healing was assessed histologically for 7 days. Re-epithelialization was significantly retarded on day 2, while collagen deposition was enhanced on day 7 in k14-smad2 compared with wild-type mice. Moreover, expression of keratin 16 (K16), an indicator of keratinocyte migration, was significantly inhibited in wound-edge keratinocytes in k14-smad2. The inhibition of K16 coincided with the induction of Smad2 in the corresponding epithelia, while BrdU incorporation was unaffected. These results indicated that Smad2 has inhibitory effects in regulating keratinocyte migration during gingival wound healing. TGF-β/Smad2 signaling mediating alteration of K16 expression must be tightly regulated during periodontal regeneration.

DOI： 10.1177/0022034512451449

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DOI： 10.1371/journal.pone.0040570

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DOI： 10.1007/s10266-011-0051-0

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For the treatment of patients with aggressive periodontitis, a thorough control of the infection is required to reduce the disease activity. Detection of periodontal pathogens by a polymerase chain reaction-based method or measurement of the serum IgG antibody titers by enzyme-linked immunosorbent assay are now widely used for microbiological diagnosis and assessment of the disease activity. We report the case of a 25-year-old woman with impaired neutrophil phagocytosis ability who suffered from generalized aggressive periodontitis . After the initial periodontal treatment and periodontal regenerative surgery, she received the final prosthodontics, and supportive periodontal treatment (SPT) was initiated. For over a decade, from the beginning of the treatments, the clinical parameters and serum titers of IgG periodontal pathogens have been monitored, and the relationships between the twoanalyzed. During the SPT, recurrence and progression of periodontitis was seen around site 26, despite maintenance of a stable periodontal condition at other sites. The serum IgG antibody titers against periodontal pathogens were elevated in parallel with the progression of periodontitis at site 26. In the present case of generalized aggressive periodontitis, the serum IgG antibody titers reflected the disease activity of periodontitis even around a single tooth, suggesting the usefulness of the examination for assessment of the disease activity. Nihon Shishubyo Gakkai Kaishi(J Jpn Soc Periodontol)54(2):193-202, 2012

DOI： 10.2329/perio.54.193

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塩基性線維芽細胞増殖因子(FGF-2:basic fibroblast growth factor)は、歯周組織再生誘導薬の有力な候補の一つと期待されており、動物実験および臨床治験によって、その有効性と安全性が明らかにされている。本研究では、KCB-1D(歯周病を対象とした遺伝子組み換えヒト型FGF-2の治験薬コード)を用いた探索的第II相臨床治験に参加した79名の被験者を対象として、フラップ手術時にプラセボ(0%)あるいは0.03%、0.1%、0.3%の何れか濃度のFGF-2を投与した被験歯の長期経過を調査した。すなわち、診療録などの診療情報から、臨床治験最終観察日から本研究調査実施日までの間(約8年間)に、各種濃度のFGF-2あるいはプラセボを投与された被験歯に対して行なわれた治療や、被験歯に出現した症状の内容と年月日を調査した。そして、これらのうち、治験薬投与部位における歯周炎の悪化に起因すると判定された治療や症状をイベント、それ以外を打ち切りとして、生存時間解析を行った。その結果、発生した全イベントは14例で、生存時間解析の結果、0.3%FGF-2投与群はフラップ手術を単独で施行したプラセボ群に比べてイベント発生までの期間の有意な延長が認められた(一般化Wilcoxon検定:p=0.0345)。また、本研究の観察期間を含めてFGF-2投与の安全性に関する問題は認めなかった。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for Dental Materials and Devices  

DOI： 10.4012/dmj.2011-164

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DOI： 10.1371/journal.pone.0026163

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DOI： 10.1007/s00520-010-0923-9

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OBJECTIVE: Multiple risk factor syndrome is a clustering of cardiovascular risk factors, such as diabetes, dyslipidemia, hypertension, and obesity associated epidemiologically with insulin resistance. This report describes the clinical course of a patient suffering from severe periodontitis with multiple risk factor syndrome, and discusses the association between periodontal infection and systemic health. METHODS: The patient had a history of type 2 diabetes, dyslipidemia, and hypertension for over 10 years. At baseline, her hemoglobin A1 c was 8.1%. However, she had no diabetic complications except periodontitis. The IgG antibody titers against Porphyromonas gingivalis FDC 381 and SU63 were elevated above the mean of healthy subjects +2 standard deviations. Intensive periodontal treatment, including periodontal surgery, was performed to reduce periodontal infection and bacteremia. Her systemic and periodontal conditions were evaluated longitudinally for 10 years. RESULTS: Following periodontal treatment, antibody titers against Porphyromonas gingivalis and hemoglobin A1c values were significantly improved. The other clinical data and medication for her systemic condition also remained stable during supportive periodontal therapy. However, she developed myocardial infarction, and showed continuous deterioration of hemoglobin A1 c level and periodontitis. CONCLUSION: The long-term clustering of risk factors, such as diabetes, dyslipidemia, hypertension, and periodontitis, are associated with the development of myocardial infarction. Treatment of systemic conditions in combination with comprehensive periodontal treatment is important in management of patients with multiple risk factor syndrome.

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The enzyme-labeled antigen method was applied to visualize plasma cells producing antibodies to Porphyromonas gingivalis, flora of the human oral cavity. Antibodies to P. gingivalis have reportedly been detected in sera of patients with periodontitis. Biotinylated bacterial antigens, Ag53, and four gingipain domains (Arg-pro, Arg-hgp, Lys-pro, and Lys-hgp) were prepared by the cell-free protein synthesis system using the wheat germ extract. In paraformaldehyde-fixed frozen sections of rat lymph nodes experimentally immunized with Ag53-positive and Ag53-negative P. gingivalis, plasma cells were labeled with biotinylated Arg-hgp and Lys-hgp. Antibodies to Ag53 were detected only in the nodes immunized with Ag53-positive bacteria. In two of eight lesions of gingival radicular cyst with inflammatory infiltration, CD138-positive plasma cells in frozen sections were signalized for Arg-hgp and Lys-hgp. An absorption study using unlabeled antigens confirmed the specificity of staining. The AlphaScreen method identified the same-type antibodies in tissue extracts but not in sera. Antibodies to Ag53, Arg-pro, and Lys-pro were undetectable. In two cases, serum antibodies to Arg-hgp and Lys-hgp were AlphaScreen positive, whereas plasma cells were scarcely observed within the lesions. These findings indicate the validity of the enzyme-labeled antigen method. This is the very first application of this novel histochemical technique to human clinical samples.

DOI： 10.1369/0022155411408906

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DOI： 10.1111/j.1601-5037.2010.00448.x

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Periodontitis is localized infectious disease caused by periodontopathic bacteria such as Porphyromonas gingivalis (T: gingivalis), and the severity correlates to significance of immune responses. Recently, it has been reported that periodontitis is associated with the development of systemic disease such as diabetes and atherosclerosis because of increasing invasion of oral pathogens to the circulation. However, the association between local and systemic infectious responses is still unclear. In the present study, we examined the differences of biological responses in animals with or without bacterial infection. After Balb/c mice were infected subcutaneously with live P gingivalis W83, serum, skin and liver were collected according to experimental protocol. The skin and liver tissues were observed pathologically by haematoxylin-eosin staining, and serum IL-6 levels were measured using ELISA method. Throughout the experimental period, conditions of the mice were observed continuously. As expected, severe infiltration of leukocytes were observed at inflamed skin corresponding to the number of bacterial challenges. Although no inflammatory appearance of skin was observed, serum IL-6 levels were increased dramatically (P &lt; 0.01, Student&apos;s t-test) and liver tissues were injured in the mice without bacterial challenge. Interestingly, although severe inflammatory appearance of the skin was observed, serum IL-6 levels were not increased and no inflammatory responses were observed in the liver of the 3-times bacterially challenged group. Importantly, immunoglobulin G against P gingivalis W83 was detected in the blood of mice with 3-times bacterial challenge corresponding to improvement of weight loss and survival. In conclusion, although multiple infections develop severe localized inflammation, the immune system should be sufficient to protect the systemic inflammatory responses.

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本歯科医学会  

新しい検査法の歯科臨床導入に関するプロジェクト研究として、これまでのチェアーサイドの歯周組織検査と、日本歯周病学会の研究委員会を中心として実施していた学会主導型研究である細菌検査を集約して歯周病臨床データベースを構築・運営し、歯周支援治療(SPT)や抗菌療法の効果判定指標とする展開を図った。日本歯周病学会が管理していたこれまでの研究資産を用いて、Web口腔感染データ管理システム(http://61.194.59.38/dentweb/、2010年8月末現在)を活用した。研究の全体像は、データを蓄積していき、さらには診断補助となる基準的な抗体価を示すようにした。その際に、細菌DNA検査の結果を加えて、抗原側と抗体側からの応用方法を検討した。その結果、抗体価検査の利用法が分かり、歯周組織検査の取り込みシステムの必要性が分かった。さらに、それらを歯周病抗菌療法へも反映しつつある。(著者抄録)

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DOI： 10.1007/s00520-010-1002-y

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The efficacy of the local application of recombinant human fibroblast growth factor-2 (FGF-2) in periodontal regeneration has been investigated. In this study, a randomized, double-blind, placebo-controlled clinical trial was conducted in 253 adult patients with periodontitis. Modified Widman periodontal surgery was performed, during which 200 µL of the investigational formulation containing 0% (vehicle alone), 0.2%, 0.3%, or 0.4% FGF-2 was administered to 2- or 3-walled vertical bone defects. Each dose of FGF-2 showed significant superiority over vehicle alone (p &lt; 0.01) for the percentage of bone fill at 36 wks after administration, and the percentage peaked in the 0.3% FGF-2 group. No significant differences among groups were observed in clinical attachment regained, scoring approximately 2 mm. No clinical safety problems, including an abnormal increase in alveolar bone or ankylosis, were identified. These results strongly suggest that topical application of FGF-2 can be efficacious in the regeneration of human periodontal tissue that has been destroyed by periodontitis.

DOI： 10.1177/0022034510384616

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DOI： 10.1002/jcla.20381

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Periodontitis is a chronic inflammatory disease caused by the infection of periodontopathic bacteria in dental plaque However, an individual's susceptibility to this disease appears to be associated with multiple genetic factors, as seen in the case of leprosy In order to gain a better understanding of the pathophysiology of periodontal disease in subjects with leprosy, we investigated the clinical features of periodontitis and the immunological responses against periodontopathic bacteria in 382 subjects with a history of leprosy and 451 age-matched control subjects The prevalence of periodontitis and the degree of periodontal pocket depth were found to be significantly higher in leprosy patients than in age-matched controls Furthermore, a comparison of the clinical parameters of lepromatous leprosy (L-lep) and tuberculoid leprosy (T-lep) patients showed that the probing pocket depth of L-lep patients with periodontal disease was significantly higher than that for T-lep patients In contrast, serum IgG titers against Porphyromonas gingivalis in L-lep patients were significantly lower than in T-lep patients These results imply that L-lep patients show more severe periodontal disease than T-lep patients or age-matched control subjects, and that low humoral immunity against P gingivalis might be one of the genetic factors determining periodontal disease susceptibility in leprosy patients

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Authorship：Last author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本歯周病学会  

サポーティブペリオドンタルセラピー(SPT)期における歯周組織の安定には、定期的な専門的管理に加え、患者自身の日々のプラークコントロールが重要である。今回我々は、患者によるプラークコントロールを強化する目的で、殺菌作用のある塩化セチルピリジニウム、抗炎症効果のあるグリチルリチン酸二カリウムおよび組織創傷治癒効果をもつアラントインの3種の薬効成分を配合した薬剤をタフトブラシと一体化した塗布用ブラシ一体型歯周病薬(MC1)を開発した。本研究では、SPT期の歯周組織の維持・改善に対するMC1の有効性を臨床的および細菌学的指標を用いて評価した。本研究は、SPT期の慢性歯周炎患者を対象とした二重盲検法にて実施した。被験者として61名が参加し(試験群:27名、プラセボ群:28名、脱落:6名)、4mm以上の歯周ポケットを残す臼歯2歯の辺縁歯肉に、1日2回12週間、MC1を塗布した。MC1の効果は、ベースライン時、6および12週間目の3時点について、臨床指標(PPD、BOP、PCR、GIおよびGCF量)、および細菌学的指標(GCF中の総菌数、Porphyromonas gingivalis、Tannerella forsythiaおよびTreponema denticola)を算出し、統計学的に群間比較して検討した。PCRを除く全ての臨床指標は2群ともに経時的に有意に改善した。特に試験群では、GIおよびGCF量が早期に改善する傾向にあった。一方、5mm以上の歯周ポケットを有する部位において、試験群では調べた3菌種すべての菌数が、プラセボ群よりも有意に減少した。以上のことから、MC1はSPT期の慢性歯周炎患者の病状安定において、臨床的および細菌学的に有効であることが示唆された。(著者抄録)

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DOI： 10.1111/j.1600-0765.1998.tb02289.x

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：岡山歯学会  

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21世紀の歯科医療は、開業医が主体となって行うprimary care dentistryと、大学病院などにおいて専門医同士がチームを組んで行うinterdisciplinary approach(以下IA)に二極化していくことが予想されている。また、最近では患者の訴えやニーズが多種多様であるため、患者個々に応じたオーダーメード治療が求められている。岡山大学病院の歯科系各診療科は、様々な学会の認定研修施設に認定されており、各科にはそれぞれの学会の認定医や専門医、さらにはそれらの指導医が名を連ねている。すなわち、当院は専門医同士のIAによるオーダーメード治療が容易に実践できる環境にある。今回、重度の歯周炎により咬合が崩壊している63歳男性患者に対し、歯周科、矯正科、補綴科の専門医が十分な連携の下でIAを行い、患者の高い満足度が得られたので報告した。

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DOI： 10.1111/j.2041-1014.2009.00548.x

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Aim:
To develop a detection assay for staphylococcal mecA and spa by using loop-mediated isothermal amplification (LAMP) method.
Methods and Results:
Staphylococcus aureus and other related species were subjected to the detection of mecA and spa by both PCR and LAMP methods. The LAMP successfully amplified the genes under isothermal conditions at 64 degrees C within 60 min, and demonstrated identical results with the conventional PCR methods. The detection limits of the LAMP for mecA and spa, by gel electrophoresis, were 102 and 10 cells per tube, respectively. The naked-eye inspections were possible with 103 and 10 cells for detection of mecA and spa, respectively. The LAMP method was then applied to sputum and dental plaque samples. The LAMP and PCR demonstrated identical results for the plaque samples, although frequency in detection of mecA and spa by the LAMP was relatively lower for the sputum samples when compared to the PCR methods.
Conclusion:
Application of the LAMP enabled a rapid detection assay for mecA and spa. The assay may be applicable to clinical plaque samples.
Significance and Impact of the Study:
The LAMP offers an alternative detection assay for mecA and spa with a great advantage of the rapidity.

DOI： 10.1111/j.1472-765x.2010.02806.x

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DOI： 10.1111/j.1574-695X.2009.00624.x

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DOI： 10.1007/s00520-009-0789-x

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DOI： 10.1007/s00520-009-0637-z

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DOI： 10.1541/ieejeiss.130.807

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Genetic variants at multiple loci have been shown to be associated with susceptibility to periodontitis. To better assess the genetic risk factors for periodontitis, we performed a case-control study in 319 Japanese individuals with periodontitis (172 aggressive and 147 chronic disease) and 303 race-matched healthy control individuals. Thirty-five functional gene polymorphisms that had been previously associated with immune responses were genotyped. For all gene polymorphisms tested, no significant differences were observed in the allele frequencies of persons with aggressive, chronic, and combined (aggressive and chronic) periodontitis, compared with control individuals. Multiple logistic regression analysis revealed a significant association of the vitamin D receptor +1056 T/C polymorphism with susceptibility to chronic periodontitis, after adjustment for age, gender, and smoking status (P = 0.002). These results suggest that none of the polymorphisms tested was strongly associated with periodontitis in a Japanese population. However, the vitamin D receptor +1056 polymorphism may be related to chronic periodontitis.

DOI： 10.1177/0022034509350037

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(公社)日本補綴歯科学会  

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DOI： 10.1111/j.1600-0765.2008.01150.x

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Language：Japanese   Publisher：(NPO)日本歯周病学会  

歯周病は中年期以降の日本人の約8割が罹患する炎症性疾患であり、口腔内の健康のみにとどまらず、全身の健康状態にもさまざまな影響を及ぼすことが知られている。歯周治療の基本は炎症のコントロールであり、この目的で、歯と歯周組織に付着した細菌性プラークと細菌由来物質を徹底して機械的に除去することが必要である。歯科医師・歯科衛生士が行うスケーリング・ルートプレーニングと、患者自らが行うブラッシングなどの日々の口腔ケアがこれに相当する。中等度以上に進行した歯周病患者の治療においては、炎症のコントロールのみならず外傷力のコントロールが重要となる。これは支持組織の破壊によって歯の動揺や欠損が生じるため、通常の咬合力であっても歯周組織に対して外傷力として働き、二次性咬合性外傷を惹起する。外傷力が存在すると、炎症・感染のコントロールのみを進めても歯周組織の修復がうまく行われない。したがって、歯周病患者の治療においては、治療の初期段階から咬合力の軽減と分散をはかる必要がある。歯周基本治療の段階から、咬合調整、暫間固定、暫間補綴などを行って外傷力をコントロールし、歯周組織へのダメージを最小限に抑える。暫間補綴装置は大きく暫間被覆冠と暫間義歯とに分けられ、ともに顎位を確保し咬合力を分散するのに役立つ。また暫間補綴装置の装着は、最終補綴装置を審美的・機能的に満足のいく形態とするためにも重要である。しかし暫間補綴装置にはいくつかの問題点が存在する。長期間にわたって暫間被覆冠を装着すると、材質の劣化あるいはプラークの蓄積を引き起こす。さらにセメントの溶解に伴うカリエス、脱離や破損による顎位の不安定化や頻繁な修理・再製作など、患者・歯科医師の双方にとって望ましくない状況を生じることがある。さらに、暫間補綴装置の強度不足によって、歯周病変の進行抑制に困難が生じることがある。暫間補綴装置では歯周病変の進行抑制に限界を生じる例としては、(1)義歯の前処置としての支台歯の補綴症例、(2)多数歯に対する固定が必要な症例、(3)支台歯に側方運動のガイドを付与したい症例などをあげることができる。義歯の支台歯の場合には、レジン製の暫間被覆冠ではなく、レスト座とガイドプレーンを付与した金属冠を装着する必要がある。多数歯に対する固定においても、一定期間安定した咬合を得るためには、レジンではなく金属かセラミックなどの耐摩耗性の高い材料の使用が求められる。いずれの症例においても早期に最終補綴装置を装着して咬合の確保を得ることが好ましい。この歯周病患者における早期補綴の提言は、あくまでも咬合性外傷のコントロールによって歯周治療を効果的に進めることを目指しており、患者の希望に沿ってのみ行われるわけではない。咬合性外傷の関与が強く疑われる歯周病患者においてのみ、治療の選択肢の一つとして早期補綴治療を提示する。また早期補綴治療を行う場合には、当該歯の歯周基本治療は終了していることを必要条件とする。患者には、なぜ補綴歯科治療を先行するのかを十分に説明するとともに、歯周治療を完了しないまま来院しなくなると、歯周病の進行を招く結果となってしまうことを理解してもらう。さらに歯周病と全身疾患との関連が注目されるなか、歯周病の治療が口腔内の健康状態を保つことのみでなく、全身の健康に寄与することの重要性を認識してもらうことが必要である。(著者抄録)

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現在までの介入患者数を調べ、歯科に期待されている周術期医療のニーズを明らかにした。すなわち、プラークフリーの実施状況およびマウスプロテクターの作製状況を調べ、超急性期病院である大学病院における医科・歯科連携のニーズを明らかにした。5ヵ月間に、岡山大学病院周術期管理センターを受診した65例を対象とした。周術期管理センター(歯科部門)受診者数は62例、周術期管理センター本部受診者数65例の95.4%であった。プラークフリー受診者数は月毎に増加し、延べ66例となった。延べ人数となっているのは、複数回手術を受けた患者の場合、その都度プラークフリーを受けているためである。マウスプロテクターを必要とした患者は合計7例であり、その理由は、動揺歯の固定の他、高額私費補綴物の保護、充填物や歯質の破損の防止等、様々であった。

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DOI： 10.1007/s00520-008-0532-z

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DOI： 10.1016/j.dental.2008.08.012

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DOI： 10.1902/jop.2009.080516

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Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本口腔検査学会  

歯周病患者血清を用いて、歯周病の臨床症状と歯周病菌に対する血清IgG抗体価の統計学的な関連を調べた。次に、将来の郵送検診への応用を念頭において、血漿試料を用いた場合でも、歯周病原細菌に対する血漿中IgG抗体価検査が可能かどうかについても検討した。4mm以上の歯周ポケット深さの割合が「10%以上30%未満」群においてA.actinomycetemcomitans ATCC29523に対する血清IgG抗体価は、「10%未満」群よりも有意に高値を示した。次に、ボランティア10例の指尖血漿試料を用いてP.gingivalis FDC381に対する血漿IgG抗体価の経日的変化を調べた。抗体価は採取後10日目まで安定して推移し、指尖血漿を用いた歯周病原細菌に対する血漿IgG抗体価検査は、歯周病病態の指標になる検査として郵送検診システムに体系化できる可能性が示唆された。

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DOI： 10.1111/j.1600-0765.2008.01097.x

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1997年11月〜2006年11月にサポーティブペリオドンタルセラピー(SPT)およびメインテナンスを専門に実施するSPT外来を受診した180名中、継続して受診した26名(男8名、女18名、年齢66.0±8.4歳)をSPT継続群、一度中断し再受診した11名(男7名、女4名、年齢57.2±10.4歳)をSPT中断群として比較検討した。その結果、残存歯数、プロービング時の出血(BOP)程度では2群間に有意差は認めなかった。歯周組織の臨床変化を比較では、4mm以上の歯周ポケット保有率の変化はSPT継続群では有意に減少し、SPT中断群では有意差はないが増加傾向を認めた。BOPを認めた部位の割合は両群とも有意な変化は認めなかった。平均歯槽骨吸収率の変化はSPT中断群ではSPT継続群に比べて増加率が有意に高かった。以上よりSPT移行時に深い歯周ポケットが残存している場合はSPTを中断すると歯周病が悪化しやすく、歯周組織を安定させるためにはSPTの長期継続が重要でありことが示唆された。

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DOI： 10.1002/jcp.21517

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DOI： 10.1007/s00520-008-0470-9

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DOI： 10.1111/j.1574-6968.2008.01304.x

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タデ藍は染料用植物としてよく知られている一方で、そのエキスが抗炎症作用および歯周病原因菌に対する抗菌作用を有することも明らかにされている。本研究の目的は、このタデ藍水抽出エキスを用いて、歯肉の炎症に対する効果を調べることとした。本研究は、病状安定期(SPT期)にある慢性歯周炎患者30名を対象とした二重盲検法にて実施した。被験者は、10週間にわたって、1日3回食後の口腔清掃後に、タデ藍エキス含有ジェル1gを歯肉に塗布した。開始前、5週目および10週目に、被験歯4歯のプラーク指数(PlI)。プロービングポケット深さ(PPD)、およびプロービング時出血(BOP)を評価した。また、同時期に歯肉溝滲出液(GCF)を採取し、その重量とTNF-α濃度を測定した。被験者全体でみると、タデ藍水抽出エキス含有濃度に関わらず経時的にPlIおよびBOPが減少する傾向にあった。一方、開始時の平均PlIが1.5以上の被験者に絞ってみると、含有濃度依存的に経時的にBOPが減少する傾向にあり、また、GCFの重量は、高濃度群で経時的に有意に減少し、かつ10週目において対照群および低濃度群と比較して有意に低値を示した。なお、いずれにおいてもPPDおよびGCF中のTNF-α濃度には変化が見られなかった。以上の結果から、タデ藍水抽出エキスは自身での清掃が十分でない人への応用が有益であり、歯肉の炎症を抑制する可能性が示唆された。(著者抄録)

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DOI： 10.1111/j.1574-695X.2008.00417.x

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本歯科保存学会  

薬物誘発性歯肉増殖症は,カルシウム拮抗剤,抗てんかん剤あるいは免疫抑制剤の服用者の一部に認められる副作用である.歯肉増殖症の発症機構についてこれまでにさまざまな報告がなされてきたが,近年,歯肉増殖症は歯肉線維芽細胞におけるα2インテグリン発現の抑制とコラーゲンファゴサイトーシスの抑制を介したコラーゲン線維の蓄積により発症することが示された.しかしながら,歯肉増殖症の発症率が報告により異なっている原因については不明である.いくつかの疾患において,その発症に関与する遺伝的素因として一塩基多型が知られている.筆者らは,α2インテグリン+807C/T遺伝子多型が歯肉増殖症の発症と関連することを示したが,この遺伝子多型はアミノ酸変異を生じないため発症との直接の関与は考えられず,+807の近傍のほかの一塩基多型との協調関与の可能性が考えられた.そこで本研究では,歯肉増殖症の発症と+807遺伝子多型と連鎖不平衡の関係にあるα2インテグリン+1648G/A遺伝子多型との関連について検討を行った.被験者は,徳島大学病院および新潟大学病院に通院するカルシウム拮抗剤,フェニトイン,あるいはサイクロスポリン服用患者98名を対象とした.歯肉増殖はMcGawらの基準に基づき判定した.末梢血サンプルは増殖症患者45名(増殖症群)と非増殖症患者53名(非増殖症群)から採取した.血液からゲノムDNAを抽出し,α2インテグリン+1648遺伝子部位についてシークエンス分析を行った.その結果,α2インテグリン+1648G/Aの遺伝子型分布は,GGが増殖症群と非増殖症群でそれぞれ95.6%と88.7%と著しく高く,GAはそれぞれ4.4%と9.4%,そしてAAは非増殖症群の1例のみであった.また,アレル頻度については+1646Gアレルが増殖症群と非増殖症群でそれぞれ97.8%と94.7%で,+1648Aアレルがそれぞれ2.2%と5.3%であり,両群間には有意な差は認められなかった.これらの結果は,薬物誘発性歯肉増殖症の発症はヒトα2インテグリン+1648G/A遺伝子多型と相関しないことを示している.しかしながら,歯肉増殖症はα2インテグリン+807C/T遺伝子多型と+1648G/A以外のその他の遺伝子多型との協調を介して発症することも考えられる.(著者抄録)

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DOI： 10.1371/journal.pone.0002611

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DOI： 10.1111/j.1601-0825.1999.tb00100.x

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DOI： 10.1007/s00520-007-0391-z

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DOI： 10.1111/j.1600-051X.2008.01208.x

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DOI： 10.1902/jop.2008.070205

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Ningen Dock  

Background Periodontal disease is a multiple infection caused by bacteria represented by Porphyromonas gingivalis (Pg). The prevalence of periodontal disease is high, as it predominantly affects the people in the same age range as diabetes mellitus, but it is often overlooked because of the lack of subjective symptoms. There has been a need for the introduction of self-sampled device-treated plasma using fingertip capillary blood in routine tests.<br>Methods Based on the report by Kudo et al. (Beppu Conference 2006, p.46, 2006) on enzyme-linked immunosorbent assay (ELISA) as a blood test for periodontal disease bacteria, the precision and disease specificity were examined towards the establishment of a methodology for routine tests.<br>Results The intra-assay reproducibility of the measurements using Pg and 3 other types of antigens, Prevotella intermedia (Pi), Eikenella corroders (Ec), and Actinobacillus actinomycetemcomitans (Aa), was coefficient of variation (CV) 4-7%, and the results from capillary blood and those from venous blood were closely analogous to each other with a correlation (r) of 0.900 or more. The difference between the non-periodontal control subjects group and the periodontal disease group in the distribution of data on histograms using the Pg antigen was approximately 7-fold. In addition, the correlation with mean periodontal pocket depth was significant (r=0.597, p<0.001) in the group showing the test results (SD index; SDI) of 20 or more. These results substantiated the specificity of this method.<br>Conclusion The ability to detect periodontal disease in the setting of "Human Dry Dock" screening examinations using the sampling and test methods proposed by us would be an important means to improve services. This study established the practical feasibility of this approach.

DOI： 10.11320/ningendock2005.22.6_35

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DOI： 10.1111/j.1600-0765.2007.00985.x

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本歯科保存学会  

岡山大学医学部・歯学部附属病院卒後臨床研修センター歯科研修部門(研修センター)では,平成18年から,定員65名の研修歯科医を受け入れ,電子ポートフォリオシステムを用いた卒後研修を行っている.今回,研修歯科医の歯科保存分野研修状況を把握し,岡山大学医学部・歯学部附属病院での研修教育システムを充実することを目的として,平成18年度に研修センターにおいて1年間研修を行った研修歯科医42名を対象に,担当した患者数や歯科保存分野の診療研修の状況を,本院で使用している電子ポートフォリオシステムを用いて集計・分析を行った.研修歯科医が1年間の研修期間において担当する患者数の平均は,17.0±4.9人であった.また,電子ポートフォリオから抽出した処置項目の合計数は,23,911項目であった.これらの項目を,歯科保存,補綴,口腔外科・歯科麻酔,小児歯科,矯正歯科,およびその他の診療分野の6分野に分類したところ,歯科保存分野が11,316項目(47.3%)と最も多かった.さらに,歯科保存分野を保存修復,歯内療法,および歯周治療の3分野に分類したところ,全体に占める割合は,保存修復分野が2,239項目(9.4%),歯内療法分野が2,335項目(9.8%),および歯周治療分野が6,742項目(28.2%)で,歯周治療分野が最も多かった.そのなかで,根管充てんとSRP(Scaling and Root Planing)の研修歯科医1人当たりの平均経験数は10回を超えており,レジン充てん,根管拡大・貼薬,歯周組織検査,ブラッシング指導,超音波スケーリング,そして,SPT(Supportive Periodontal Therapy)の研修歯科医1人当たりの平均経験数は20回を超えていた.以上から,岡山大学医学部・歯学部附属病院における臨床研修は,歯科保存分野の研修が約半数を占めており,基本的な歯科保存分野の治療に関しては,10回以上経験している項目が多いことがわかった.(著者抄録)

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DOI： 10.1038/oby.2007.305

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DOI： 10.1007/s00441-007-0457-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Diabetic subjects are susceptible to atherosclerosis. It has been postulated that inflammation plays a crucial role in atherogenesis. Since previous studies suggested persistent low-grade infection by Gram-negative bacteria such as Chlamydia spp. and/or periodontal infection is associated with increased atherogenesis among diabetic subjects, we hypothesized that macrophages under hyperglycemia respond to lipopolysaccharide (LPS) challenge in a more exaggerated manner than under normal glucose conditions. Therefore, we examined cytokine productivity and associated signal transduction molecules in LPS-stimulated the monocytic cell line THP-1, under conditions of hyperglycemia. Differentiated THP-1 cells were cultured under normal and high glucose conditions without fetal bovine serum, and were stimulated with Escherichia coli LPS in the presence of LPS binding protein. Following stimulation, activated signal transduction molecules were detected by protein microarray and confirmed thereafter. Results indicated that c-jun N-terminal kinase (JNK) was highly-phosphorylated at high glucose concentrations, and this was confirmed by Western-immunoblotting. Tumor necrosis factor-α and monocyte chemo-attractant protein-1 production were significantly enhanced under these conditions. SP600125, a selective inhibitor of JNK, dose-dependently suppressed the production of these cytokine. Therefore, we suggest that this may be one of the mechanisms by which sub-clinical infection by Gram-negative bacteria promotes atherosclerosis in diabetic subjects.

DOI： 10.1177/0968051907082608

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DOI： 10.1016/j.joen.2007.04.016

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DOI： 10.1111/j.1365-2249.2007.03450.x

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Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：岡山歯学会  

慢性歯周病患者で、上下顎第一・第二大臼歯部にII度或いはIII度の根分岐部病変を有し、歯周基本治療後に歯根切除療法を施行し、以降、Supportive Periodontal Treatment(SPT)を継続した141名の患歯186歯について後ろ向き調査を行った。歯根切除療法後の累積生存率は5年後が93.8%、7年後が87.6%、10年後が76.9%、15年後が54.3%であった。治療法別の累積生存率に有意差はなかった。抜歯に至った原因は、歯周病変が62.2%(23歯)を占め最も頻度が高かった。歯根切除療法を施行した歯の各治療法別における割合は、セパレーションが40歯(21.5%)、ヘミセクションが76歯(40.8%)、トリセクションが70歯(37.7%)であった。各々の治療法における補綴形態は、セパレーションで単独補綴/連結固定比が5/35(14%)、ヘミセクションで7/69(10%)、トリセクションで15/55(27%)であった。Cox比例ハザードモデルから「連結固定」のみがエンドポイントに関わる臨床因子として抽出され、歯根切除療法後に連結固定を行うことでエンドポイントに関わるリスクが43%低減した。

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本歯周病学会  

臨床歯学では、知識だけでなく技能および患者対応を含めた総合的な習得が求められている。そこで今回、今後の歯周病学実習の内容を検討するために各大学の歯周病学実習で行っているOSCEや臨床実地試験問題の実態を把握することを目的とし、全国29歯学部・歯科大学から、臨床前の歯周病学の臨床基礎実習内容と実習運営の現状に関してアンケート調査を行った。調査対象者は、歯周病学を担当する日本歯周病学会理事29名で、歯周病学実習の実態把握のための無記名式の質問票を、平成15年12月に郵送し、平成16年3月10日までに回収を行った。その結果、29校のうち、4年次に実習を開始するところが最も多く、次いで5年次に開始していた。実習の回数は、2回〜23回まで幅広い分布を示していた。また、1回の実習時間は、90分から360分の間に分布しており、総実習時間の平均は34.5時間であった。実習の内容としては、過半数の大学が実施しているのは、歯周診査、ペリオチャート・レントゲン診断、ブラッシング指導、スケーリング、歯周外科、咬合調整、暫間固定であった。OSCE形式の課題としては、ブラッシング指導が最も多く、次いで、スケーリング・ルートプレーニングであった。最近の傾向としては、歯周病の病状説明かブラッシング指導に重点が置かれている。OSCEにおける歯周病学の課題は、今後の歯周病学教育の方向性を示すものであり、非常に重要性が高いと考えられる。(著者抄録)

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Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本歯周病学会  

糖尿病・高血圧・高脂血症・肥満といったインスリン抵抗性を基盤に持つマルチプルリスクファクターシンドローム(MRFS)を有する患者は、心筋梗塞に代表される虚血性心疾患を高頻度に発症することが知られている。今回、歯周治療に伴い血糖コントロールは改善したものの、SPT中に心筋梗塞・脳梗塞を発症、さらに、心不全を合併したMRFSを基盤にもつ慢性歯周炎患者の治療経過から、歯周炎が全身に及ぼす影響について考察する。患者は、62歳・女性。全身疾患として、2型糖尿病・高脂血症・高血圧症・重度慢性歯周炎を有していた。初診時、ヘモグロビンA1c(HbA1c)値は8.1%と血糖コントロールは不良で、歯周病原性細菌に対する血清IgG抗体価は健常者の2SDを超えて高値を示していた。肥満度を内すBody Mass Index(BMI)は21.3kg/m2であり、糖尿病性合併症は有していなかった。したがって、これらのことより本患者をインスリン抵抗性を背景に有している歯周炎患者と捉え、感染源を徹底的に除去することを目的に歯周治療を行った。長期的にみると、歯周治療に伴い歯周組織の臨床症状および、歯周病原性細菌に対する血清IgG抗体価は改善し、血糖コントロールの指標であるHbA1c値は6%台後半を推移していた。しかしながら、本患者はSPT中に心筋梗塞を発症した。2型糖尿病患者では冠状動脈疾患の発症リスクは健常者の2-3倍と報告されている。本患者の場合、重度慢性歯周炎を含め高血圧症、高脂血症といった危険因子の蓄積が結果的に心筋梗塞の発症につながったと考えられる。MRFSを有する患者は、生活習慣病予防の一環として、より積極的に歯周疾患の予防、治療を行うべきであると考える。(著者抄録)

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近年、多血小板血漿(PRP)に骨移植材を併用した歯周組織再生療法の有効性が示唆されている。骨移植材には、自家骨、他家骨、異種骨、人工骨があるが、骨伝導能、骨誘導能、骨増殖能すべてを有する自家骨をPRPに併用した歯周組織再生療法に関する臨床報告はない。本研究は、歯周疾患によって生じた垂直性骨欠損部を対象として、PRPと自家骨を併用した歯周組織再生療法の治療効果を評価することを目的とした。歯周基本治療が終了した垂直性骨欠損を有する非喫煙者で、慢性歯周炎患者17名22部位に対してPRPと自家骨を併用した歯周組織再生療法を施行し、術前および術後6ヵ月における臨床所見およびレントゲン線写真を評価した。その結果、プロービング深さ(PD)減少量とクリニカルアタッチメントレベル(CAL)獲得量は、それぞれ3.20±1.28mm,2.52±1.08mmであった。レントゲン写真における評価では、術前の骨欠損程度を100%と規定すると、術後の骨欠損程度は54.4±8.9%であった。すなわち、45.3±9.3%骨が改善していることがわかった。これらのことから、PRPに自家骨を併用した方法は、歯周組織再生に有効な術式であることが示唆された。(著者抄録)

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本歯周病学会  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.biocel.2007.01.015

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DOI： 10.1111/j.1365-4632.2006.02900.x

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血液疾患患者122名を対象に、歯周病原性細菌として代表的なP.gingivalisに対する血清IgG抗体価と歯周病の程度との間に関連がみられるか検討した。結果、多様な血液像(白血球減少など)を呈する血液疾患患者においても健常者と同様に歯周病の程度が重いほどIgG抗体価は高値であった。

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：岡山歯学会  

岡山大学における歯学部の将来と日本の歯科界の将来を素晴らしいものにすることを期待して、歯学部に設置された「将来を考えるワーキンググループ」(ワーキンググループ)が種々の観点から将来像の検討を行い、岡山大学歯科系の全教員・職員に対して、提案を行った。その提案に対して集まった意見をまとめ、岡山大学歯学部の将来像を設定するための対策を検討した。今回は教育関連項目をまとめた。岡山大学歯学部学生の動機付けを行い、就学中に、歯学へ興味を持つような授業カリキュラムを作成、調整することが望まれた。教育カリキュラムの一つとしてチュートリアル教育が様々な大学に広まりつつあり、自ら考え、成長して行く歯科医師を作ることが期待された。学生評価の厳格化、評価方法の見直し、さらには教育・教員に対する評価も求められていた。

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本歯科保存学会  

ビタミンC(VC)とビタミンE(VE)補充の歯周病に対する予防的効果を無作為化比較対照試験で検討した。歯周病メインテナンス管理下にある非喫煙者39名(平均年齢60.4歳)にVCとVEを含有する試験製剤(試験群)もしくはプラセボ製剤を24週間投与した。その結果、試験群では歯周ポケットの深さは減少し、歯肉炎指数(GI)は維持され、bleeding on probingは改善していた。また、試験群では血清中のVC、VEの濃度、歯肉溝滲出液(GCF)中のVC、還元グルタチオンの濃度・総量が有意に上昇し、GCF中のVEレベルは維持された。製剤摂取開始時に炎症がなかった部位の試験期間中のGIの増悪は有意に抑制された。歯周病予防にVC、VE摂取は有用であり、この作用は歯周組織局所の抗酸化物の増大による可能性が示唆された。

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1111/j.1574-695X.2006.00094.x

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DOI： 10.1111/j.1574-6968.1997.tb10187.x

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DOI： 10.1007/s10103-005-0350-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

α2 integrin on fibroblasts is reported to play an important role in the induction of drug-induced gingival overgrowth, which is characterized by excessive accumulation of type I collagen in gingival connective tissue. Silent polymorphism 807 T/C within the α2 integrin gene is associated with high/low α2 integrin expression. The aim of this study was to test the hypothesis that expression of α2 integrin 807 T/C polymorphism correlates with drug-induced gingival overgrowth. A case-control study comparing 136 subjects taking calcium channel blockers (72 with vs. 64 without drug-induced gingival overgrowth) demonstrated that the frequency of the +807 C allele was significantly higher in the case group than in the controls (odds ratio, 3.61; 95% confidence interval, 2.14 – 6.10; P &lt; 0.05). The present findings suggest that the α2 +807 C allele is one of the genetic risk factors for drug-induced gingival overgrowth.

DOI： 10.1177/154405910508401217

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Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本歯科保存学会  

浸透圧の上昇に応答して発現上昇するとされるsgk遺伝子が培養ヒト歯根膜線維芽細胞(HPLF)においてどのような発現動態を示すか調べるとともに,sgk発現におけるアクチン細胞骨格の関与について検討した.HPLFにおいても浸透圧の上昇に伴ってsgk発現は上昇することが明らかになり,この発現変化はアクチン細胞骨格に関係する刺激伝達系によって制御されていることが示唆された

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Pulpal wound healing followed by cavity preparation may involve reactionary or reparative dentinogenesis in relation to the cavity position; however, little is known about the molecular responses. We aimed to isolate and analyze genes induced or suppressed in the wounded pulp to identify molecular processes involved in the pulp responses to injury. Twenty-three cDNAs were isolated by cDNA subtraction between healthy and wounded pulp of rats. By library screening, we identified rat 14.7K-interacting protein (rFIP)-2A and B genes homologous to human FIP-2, being involved in regulating membrane trafficking and cellular morphogenesis. RT-PCR analysis showed induction for only rFIP-2B in the wounded pulp. In situ hybridization analysis revealed that both rFIP-2s were expressed strongly in condensing mesenchymal cells of the palatal process and surrounding Meckel’s cartilage, but not in intramembranous chondrogenic cells. Thus, up-regulated rFIP-2B expression may play a role in regulating membrane trafficking or cellular morphogenesis of these embryonic and wounded pulpal cells.

DOI： 10.1177/154405910508400912

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1016/j.femsim.2005.01.008

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Background: Aplastic anemia (AA) is a rare hematologic disease characterized by hypo-cellular bone marrow. The clinical features include fatigue, increased bruising, and gingival bleeding caused by anemia, leukopenia, and thrombocytopenia. A patient with AA is at high risk for infection because of leukopenia. The risk of systemic infection is especially high in AA patients with severe local infections, including periodontitis. Accordingly, periodontal treatment should include antibiotic prophylaxis to reduce the risk of systemic infection. However, treatment of periodontitis in the AA patient is significantly complicated by the bleeding disorder. We present a case report of the successful periodontal treatment of an AA patient with spontaneous gingival bleeding.
Methods: The patient was closely monitored for platelet and neutrophil counts before every treatment. The patient's platelet count was always under 10,000/mu l. Therefore, it was necessary to increase platelet counts to over 25,000/mu l by transfusion, after which subgingival scaling with anesthesia was performed. When the neutrophil count was less than 2,000/mu l, local minocycline chemotherapy was applied to the pockets. Periodontal infection was monitored by detection of bacterial DNA and measurement of serum immunoglobulin (Ig) G titer against periodontal bacteria.
Results: Following the physical and chemical treatment, the gingival appearance improved dramatically and the spontaneous gingival bleeding disappeared. Moreover, the IgG titer against periodontal bacteria decreased to normal range and specific periodontal pathogens were no longer detectable in the tested pockets.
Conclusion: We believe that the treatment strategy in the present report provides new sight into treatment planning for severely medically compromised patients.

DOI： 10.1902/jop.2005.76.7.1211

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DOI： 10.1111/j.1399-302x.2004.00203.x

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An elevated level of C-reactive protein (CRP) predicts the future development of coronary heart disease. Periodontitis appears to up-regulate CRP. CRP is produced by hepatocytes in response to interleukin-6 (IL-6). A major source of IL-6 in obese subjects is adipocytes. We hypothesized that lipopolysaccharide (LPS) from periodontal pathogens stimulated adipocytes to produce IL-6, and that the production was suppressed by the drugs targeted against insulin resistance, thiazolidinedione (pioglitazone), since this agent potentially showed an anti-inflammatory effect. Mouse 3T3-L1 adipocytes were stimulated with E. coli, P. gingivalis, and F. nucleatum LPS. The IL-6 concentration in culture supernatants was measured. All LPS stimulated adipocytes to produce IL-6. Although pioglitazone changed adipocyte appearance from large to small, and completely suppressed P. gingivalis and F. nucleatum LPS-induced IL-6 production, E. coli LPS-induced IL-6 production was not efficiently blocked. Thus, pioglitazone completely blocked periodontal-bacteria-derived LPS-induced IL-6 production in adipocytes, a major inducer of CRP.

DOI： 10.1177/154405910508400306

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BACKGROUND: Gingival overgrowth is a common side-effect following administration of cyclosporin A. We reported previously that lysosomal protease cathepsin-L activity, but not cathepsin-B, was significantly suppressed by short-term cyclosporin A exposure in human gingival fibroblasts. Although this suppression may lead to decreased degradation of gingival connective tissue, a net increase in matrix proteins, and gingival overgrowth, the effects of cyclosporin A need to be more elucidated, considering the long-term use for patients following organ transplantation. OBJECTIVE: The aim of the present study was to evaluate the effects of clinically relevant doses of cyclosporin A on cultured human gingival fibroblasts. We evaluated the effects of long-term cyclosporin A exposure on cell proliferation, mRNA expression of various proteases and both cathepsin-B and -L activity in human gingival fibroblasts. MATERIALS AND METHODS: Human gingival fibroblasts were isolated from three donors' healthy gingiva and cultured from five to eight passages with or without 200 ng/ml of cyclosporin A. Proliferative activity of cyclosporin A-treated cells was examined using MTT assay. Total RNA and cellular proteins were collected for semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis and for measurement of the cathepsin-B and -L activity. RESULTS: Long-term cyclosporin A exposure had no effects on cell proliferation. Accumulation of cathepsin-B, -H and -L mRNA was markedly suppressed by long-term cyclosporin A exposure, whereas accumulation of another lysosomal enzyme N-acetyl-beta-D-glucosaminidase mRNA, which is involved in remodeling of gingival epithelium, was not apparently impaired in cyclosporin A-treated cells. Accumulation of matrix metalloprotease-1 (MMP-1) and tissue inhibitor of matrix metalloprotease-1 (TIMP-1) mRNA, which are involved in remodeling of extracellular matrix, also was not impaired. In addition, we demonstrated that long-term cyclosporin A exposure significantly suppressed not only the activity of the active form of cathepsin-(B + L) compared to the activity in non-treated cells (p = 0.0458), but also the activity of the active form of cathepsin-B (p < 0.0001) in human gingival fibroblasts. CONCLUSION: The decreased ability of protein degradation by not only cathepsin-L but also cathepsin-B is, at least, one of the several factors developing the cyclosporin A-induced gingival overgrowth.

DOI： 10.1111/j.1600-0765.2004.00746.x

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Periodontal healing requires the participation of regulatory molecules, cells, and scaffold or matrix. Here, we hypothesized that a certain set of genes is expressed in alveolar bone wound healing. Reciprocal subtraction gave 400 clones from the injured alveolar bone of Wistar rats. Identification of 34 genes and analysis of their expression in injured tissue revealed several clusters of unique gene regulation patterns, including the up-regulation at 1 wk of cytochrome c oxidase regulating electron transfer and energy metabolism, presumably occurring at the site of inflammation; up-regulation at 2.5 wks of pro-α-2 type I collagen involving the formation of a connective tissue structure; and up-regulation at 1 and 2 wks and down-regulation at 2.5 and 4 wks of ubiquitin carboxyl-terminal hydrolase l3 involving cell cycle, DNA repair, and stress response. The differential expression of genes may be associated with the processes of inflammation, wound contraction, and formation of a connective tissue structure.

DOI： 10.1177/154405910408300707

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DOI： 10.1074/jbc.M311688200

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DOI： 10.1016/j.yexmp.2003.09.002

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Authorship：Last author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本歯科保存学会  

16歳(再植施行時)女.歯科矯正治療に際して発見された下顎左側第一大臼歯根尖周囲のX線透過病変の精査加療で受診した.X線写真から,近心根および遠心根根尖付近の穿孔部は,再封鎖された状態であった.根管充填によっていったんは治癒傾向を示したものの,根尖部が嚢胞腔内に長期問さらされることによって生じた感染セメント質を原因とする下顎左側第一大臼歯歯根嚢胞と診断した.感染セメント質の除去と,根尖部の再封鎖を目的とした意図的再植を計画した.自覚的および他覚的症状はなく,機能的にも問題なく経過した

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2004&ichushi_jid=J01092&link_issn=&doc_id=20040305120005&doc_link_id=%2Fdo1conde%2F2004%2F004701%2F005%2F0031-0036%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdo1conde%2F2004%2F004701%2F005%2F0031-0036%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.lfs.2003.07.018

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Authorship：Last author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(NPO)日本歯周病学会  

歯周病は顕著なグラム陰性菌によって引き起こされる細菌感染性の疾患であるが,その病態は局所の宿主反応によって規定されている.したがって,歯根面のバイオフィルムだけでなく歯周炎局所の炎症反応を修飾・調整している仲介分子が,糖尿病,心臓冠動脈疾患,低体重児出産,呼吸器疾患などの全身疾患症状のマイナス要因とみなされるのである.このように歯周病は健康と福祉の必須要因として認識されつつある.そこで,生活習慣病の観点に立って,1)歯周病の病態・病因,2)歯周炎と全身疾患の関わり,3)歯周病における保健の意義について述べた

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2003&ichushi_jid=J01095&link_issn=&doc_id=20040113440001&doc_link_id=%2Fcp9perlo%2F2003%2F004504%2F001%2F0325-0348%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcp9perlo%2F2003%2F004504%2F001%2F0325-0348%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：岡山歯学会  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/01.TP.0000085661.52980.95

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1034/j.1600-0765.2003.02607.x

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Genes expressed by human periodontal ligament fibroblasts (HPFs) are likely to be associated with specific functions of the ligament. The aim of this study is to profile genes expressed highly by HPFs. A library (6 × 10³pfu) was constructed, followed by subtraction of HPF cDNAs with human gingival fibroblast (HGF) cDNAs. Reverse-dot hybridization revealed that 33 clones expressed higher levels of specific mRNAs in HPFs than in HGFs. These were mRNAs for known genes, including several associated with maturation and differentiation of cells. None had been reported in PFs. One clone, PDL-29, identified as a COX assembly factor, showed much stronger mRNA expression in HPFs than in HGFs in culture. In rat periodontium, however, PDL-29 mRNA expression was similar in PFs and GFs. These results suggest that HPFs express many previously unreported genes associated with maturation and differentiation, but expression can differ in vitro and in vivo.

DOI： 10.1177/154405910308200814

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/154405910308200814

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1902/jop.2003.74.8.1231

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley