Language：Japanese   Publisher：新潟歯学会  

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：Japanese   Publisher：(公社)日本顎顔面インプラント学会  

新潟大学医歯学総合病院では2006年4月インプラント治療部が開設された。今回、開設後10年間(2006年4月から2016年3月)における外来患者、入院患者、インプラント手術を総括し、今後の当治療部の運営に資することを目的に臨床的検討を行った。10年間の外来患者の総数は1,606人(男性598人、女性1,008人)であった。年齢は50〜60歳代が多くを占め、平均55.1歳(最低16歳、最高87歳)であり、また院外からの紹介患者は43%と多くを占めた。インプラント埋入手術件数(本数)は年間90〜150件(150〜260本)、平均114件(198本)であった。10年間に顎堤形成術や上顎洞底挙上術を含めた骨増生術は入院下に計183件に施行された。10年間のインプラント埋入総数1,986本のうち、インプラント脱落本数(率)は54本(2.7%)であった。外来患者数は一時的な増減がみられたが、最近、一定の患者数があり、インプラント埋入手術および骨増生術件数は安定して推移していた。今後も特定機能病院としてインプラント治療成績向上に貢献すべく、入院治療を含めた総合的な医療提供を務めることが肝要である。(著者抄録)

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Language：Japanese   Publisher：(一社)日本形成外科学会  

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DOI： 10.1016/j.alit.2019.05.015

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

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

Adult Cebpb KO mice incisors present amelogenin-positive epithelium pearls, enamel and dentin allopathic hyperplasia, fewer Sox2-positive cells in labial cervical loop epitheliums, and reduced Sox2 expression in enamel epithelial stem cells. Thus, Cebpb acts upstream of Sox2 to regulate stemness. In this study, Cebpb KO mice demonstrated cementum-like hard tissue in dental pulp, loss of polarity by ameloblasts, enamel matrix in ameloblastic layer, and increased expression of epithelial-mesenchymal transition (EMT) markers in a Cebpb knockdown mouse enamel epithelial stem cell line. Runx2 knockdown in the cell line presented a similar expression pattern. Therefore, the EMT enabled disengaged odontogenic epithelial stem cells to develop supernumerary teeth. Cebpb and Runx2 knockdown in the cell line revealed higher Biglycan and Decorin expression, and Decorin-positive staining in the periapical region, indicating their involvement in supernumerary tooth formation. Cebpb and Runx2 acted synergistically and played an important role in the formation of supernumerary teeth in adult incisors.

DOI： 10.1038/s41598-018-23515-y

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Language：Japanese   Publisher：新潟歯学会  

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Language：Japanese   Publisher：新潟歯学会  

新潟大学顎顔面口腔外科では1983年より二段階口蓋形成手術法を施行しており、顎発育による分析から、2010年より硬口蓋閉鎖時期を5歳半から4歳へ早期移行した。これまで、硬口蓋閉鎖時期の早期移行が4歳時から6歳時における言語機能獲得に与える影響について、音声言語の聴覚判定による分析から検討しており、硬口蓋閉鎖術を5歳半に施行した群(晩期群)に比較して4歳に施行した群(早期群)は、5歳時の鼻咽腔閉鎖機能において、良好例の有意な増加がみられ、言語機能獲得に肯定的な結果が示された。本研究では、この聴覚的な臨床データを裏付けるために、ナゾメーターによる分析から再検討した。その結果、5歳時の文章および高圧文のnasalance scoreにおいて、早期群と晩期群の硬口蓋閉鎖床撤去時の間に有意差を認め、音声言語の聴覚判定と整合する結果が示された。顎発育および音声言語の聴覚判定ならびにナゾメーターによる分析を統合すると、当科の二段階口蓋形成手術法における硬口蓋閉鎖時期の妥当性が再確認された。(著者抄録)

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Language：Japanese   Publisher：新潟歯学会  

新潟大学顎顔面口腔外科では1983年より二段階口蓋形成手術法を施行しており、顎発育による分析から、2010年より硬口蓋閉鎖時期を5歳半から4歳へ早期移行した。これまで、硬口蓋閉鎖時期の早期移行が4歳時から6歳時における言語機能獲得に与える影響について、音声言語の聴覚判定による分析から検討しており、硬口蓋閉鎖術を5歳半に施行した群(晩期群)に比較して4歳に施行した群(早期群)は、5歳時の鼻咽腔閉鎖機能において、良好例の有意な増加がみられ、言語機能獲得に肯定的な結果が示された。本研究では、この聴覚的な臨床データを裏付けるために、ナゾメーターによる分析から再検討した。その結果、5歳時の文章および高圧文のnasalance scoreにおいて、早期群と晩期群の硬口蓋閉鎖床撤去時の間に有意差を認め、音声言語の聴覚判定と整合する結果が示された。顎発育および音声言語の聴覚判定ならびにナゾメーターによる分析を統合すると、当科の二段階口蓋形成手術法における硬口蓋閉鎖時期の妥当性が再確認された。(著者抄録)

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

Objective: To elucidate the mechanism underlying secretion of human immunodeficiency virus type 1 (HIV-1) into the oral cavity, by examining the relationships between various oral and systemic factors and the viral load in saliva. Methods: Plasma and saliva samples from HIV-1 infected patients were assayed using the COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, version 1.0 and a Poisson distribution-based polymerase chain reaction (PCR) method for quantifying HIV-1 RNA and DNA. Results: Forty-four pairs of samples were obtained from 18 patients. Salivary viral load was approximately 10% of the plasma viral load, but higher than the plasma load in two patients. The salivary viral DNA load was &lt
1% of the total HIV-1 nucleic acid load except in one patient who had more viral DNA than RNA. Multiple regression analysis showed that salivary viral load was significantly correlated with plasma viral load (partial correlation coefficient, 0.90) and the community periodontal index (–0.63). Conclusions: The present results suggest that excretion through salivary glands, but not occult bleeding, may be a major pathway of HIV-1 into the oral cavity.

DOI： 10.1177/0300060517728652

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

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Language：Japanese   Publisher：一般社団法人 日本口蓋裂学会  

We have performed two-stage palatoplasty for patients with cleft lips and palates in the Oral and Maxillofacial Surgery Clinic of Niigata University Medical and Dental Hospital since 1983. As a result of evaluating maxillary growth, we have changed the timing of hard palate closure from 5.5 years of age to 4 years of age since 2010. To validate the earlier hard palate closure in our two-stage procedure, we evaluated speech outcome at 4, 5, and 6 years of age. At 5 years of age, the cases with good velopharyngeal function increased significantly and the palatalized articulation was significantly reduced due to the earlier hard palate closure. Based on an evaluation of maxillary growth and speech outcome together, we conclude that earlier hard palate closure is reasonable for our two-stage procedure.

DOI： 10.11224/cleftpalate.42.201

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

A human-cultured alveolar bone-derived periosteal (hCP) sheet is an osteogenic grafting material used clinically in periodontal regenerative therapy, while platelet-rich fibrin (PRF), a platelet concentrate with fibrin clot, is considered to augment the wound healing process. Therefore, whether the combined use of hCP-PRF complex could facilitate bone regeneration synergistically was evaluated in animal models. Human periosteal segments (1 × 1 mm) were cultured initially on plastic dishes and formed an hCP sheet. The hCP sheet was implanted with freshly prepared human PRF into subcutaneous tissue (hCP: n = 4, hCP + PRF: n = 4) and 4 mm diameter calvarial bone defect models (hCP: n = 4, hCP + PRF: n = 4, control [defect-only]: n = 4) that prepared in nude mice. At 4 weeks postimplantation, new bone formation was evaluated by using μCT. Cell growth and neovascularization were evaluated by histochemical and immunohistological methods. In the subcutaneous tissue, mineral deposit formation, collagen deposition, and number of vessels were higher in the hCP + PRF group than in the hCP alone group. In the calvarial defect models, new bone formation was significantly higher in the hCP + PRF group than in the hCP alone group and defect-only control group. The numbers of vessels and PCNA-positive cells in calvarial defects were also increased in the hCP + PRF group more than in the hCP alone group. Platelet-rich fibrin preparations support the proliferation and the growth of periosteal cells to form well-combined active biological materials. Platelet-rich fibrin also stimulates the local angiogenesis in the implantation site. Therefore, the combined use of hCP and PRF could be clinically applicable in bone regeneration therapy.

DOI： 10.1002/cre2.71

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Language：Japanese   Publisher：一般社団法人 日本口蓋裂学会  

We investigated speech outcomes in 80 patients with submucous cleft palate assessed by the Oral and Maxillofacial Surgery Clinic and the Speech Clinic in Dentistry at the Niigata University Medical and Dental Hospital from 1982 to 2012. Of the 80 patients, there were 60 patients in the surgically treated group and 20 patients in the non-surgically treated group.<br>The results were as follows:<br>1) In the surgically treated group, the velopharyngeal function evaluated after palatoplasty (an average of 2 years postoperatively) was good (good＋fairly good) in 36 patients (63.4%). When we examined the association between age at palatoplasty and velopharyngeal function, the velopharyngeal function evaluated postoperatively was good in almost all of the 1-year-old children, but poor (fairly poor＋poor) in more than half of the children over 5 years of age. When we examined the association between mental retardation (MR) and velopharyngeal function, the MR group tended not to have better outcomes than the non-MR group.<br>2) In the non-surgically treated group, there was no clear change before and after treatment.

DOI： 10.11224/cleftpalate.41.173

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background and Purpose: Sinus lift (SL) using cultured autogenous periosteal cells (CAPCs) combined with autogenous bone and platelet-rich plasma (PRP) was performed to evaluate the effect of cell administration on bone regeneration, by using high-resolution three-dimensional computed tomography (CT).
Materials and Methods: SL with autogenous bone and PRP plus CAPC [CAPC(+)SL] was performed in 23 patients. A piece of periosteum taken from the mandible was cultured in M199 medium with 10% fetal bovine serum (FBS) for 6 weeks. As control, 16 patients received SL with autogenous bone and PRP [CAPC(-)SL]. Three-dimensional CT imaging was performed before and 4 months and 1 year after SL, and stratification was performed based on CT numbers (HUs) corresponding to soft tissue and cancellous or cortical bone.
Results: The augmented bone in CAPC(+)SL revealed an increase in HUs corresponding to cancellous bone as well as a decrease in HUs corresponding to grafted cortical bone. In addition, HUs corresponding to cancellous bone in the graft bed were increased in CAPC(+)SL but were decreased in CAPC(-)SL. Insertion torque during implant placement was significantly higher in CAPC(+)SL.
Conclusion: By promoting bone anabolic activity both in augmented bone and graft bed, CAPCs are expected to aid primary fixation and osseointegration of implants in clinical applications.

DOI： 10.1111/cid.12356

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

In preparing cell-based products for regenerative therapy, cell quality should be strictly controlled. Methodologies for evaluating cell viability, identity, and purity are established and used routinely, whereas current methodologies for evaluating cell safety, particularly genetic integrity or tumorigenicity, are time-consuming and relatively insensitive. As part of developing a more practical screening system, the authors previously demonstrated that gamma-H2AX and p53 were useful markers for evaluating the history of DNA damage. To validate these markers further and develop a more quantitative methodology, single cell-based expression of these markers and two additional candidates have now been examined using flow cytometry (FCM). FCM analysis and immunofluorescent staining demonstrated that gamma-ray-irradiation suppressed proliferation, enlarged cells, and cell nuclei, and immediately upregulated gamma-H2AX and p21(waf1) in large numbers of cells for up to 12 days. Gamma-H2AX foci were formed in the nuclei of many affected cells. An initial sharp increase in p53 expression declined slowly over 12 days, while Rb expression increased linearly. The present findings suggest that this high-throughput, cell-based, combinational evaluation of protein markers and cell size enables a small number of cells with a history of DNA damage to be detected quickly and routinely from within a very large cell population. Using this screening methodology will improve the ability to verify the quality of cell-based products used in regenerative therapy.

DOI： 10.1089/bio.2015.0072

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Language：Japanese   Publisher：(一社)日本口蓋裂学会  

新潟大学医歯学総合病院顎顔面口腔外科において1982年から2012年の31年間に粘膜下口蓋裂と診断した84例を対象に、性別、出生時体重、初診時年齢、主訴、来院経路、合併症、Calnanの3徴候、治療内容および母親の出産時年齢について回顧的に検討した。なお、当科の粘膜下口蓋裂の診断基準は軟口蓋の筋層離開とした。その結果、以下の知見を得た。1)性別は男性42例(50.0%)、女性42例(50.0%)であり、性差はみられなかった。2)初診時年齢は生後9日から49歳にわたり、平均4.6歳であった。3)主訴は構音や言語発達などの言語の異常に関する訴えが最も多く、59例(70.2%)であった。4)当科への来院は小児科からの紹介が26例(31.0%)、他院歯科が21例(25.0%)であり、両者で半数以上を占めていた。5)精神発達遅滞の合併は28例(33.3%)にみられた。6)Calnanの3徴候がすべて確認された症例は62例(73.8%)であった。7)当科の初回手術は口蓋形成術とし、口蓋形成術を施行した症例は60例(71.4%)、施行しなかった症例は24例(28.6%)であった。(著者抄録)

DOI： 10.11224/cleftpalate.41.24

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Purpose: To assure the quality of cells to be used in cell therapy, we examined the applicability of digital holographic microscopy (DHM) for non-invasive, quantitative assessment of changes in cell morphology.
Materials and methods: Mesenchymal stem cells derived from adipose tissue (MSC-AT) and bone marrow (MSC-BM), in addition to human alveolar periosteal cells (PC) as a reference, were c-ray irradiated (1 and 4 Gy), and their morphological changes were quantified without fixation using holographic microscopy. After detachment and fixation with ethanol, cell number and surface antigen expression were determined using an automated cell counter kit and flow-cytometry, respectively.
Results: Among various indexes, only indexes related to cell size were significantly changed after c-irradiation. Both BMC-AT and BMC-BM were enlarged and more sensitive to a low dose of gamma-irradiation than PC. In contrast to PC, proteins related to DNA damage repair (gamma-H2AX, p21(waf1), p53 and Rb) were not substantially upregulated or sustained for a week in either MSC-AT or MSC-BM.
Conclusion: Instead of DNA damage markers, we suggest that cell morphological parameters (e.g. cell volume) that are monitored by DHM could be a useful and more stable marker of MSC quality.

DOI： 10.1080/09553002.2016.1230242

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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DOI： 10.3892/mco.2015.578

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Background aims. For successful cell transplantation therapy, the quality of cells must be strictly controlled. Unfortunately, to exclude inappropriate cells that possess structurally abnormal chromosomes, currently only karyotyping functions as an assessment. Unfortunately, this methodology is time-consuming and only effective for metaphasic cells. To develop a more efficient, inclusive and sensitive methodology, we examined the phosphorylation of histone H2AX and the p53 levels in normal human periosteal cells exposed to x-rays or other oxidative stressors. Methods. Periosteal cells were obtained from human alveolar bone before being exposed to x-rays, ultraviolet C or hydrogen peroxide. The cell cycle, electric nuclear volume and CD44 expression were evaluated using flow cytometry, and the phosphorylated H2AX (gamma-H2AX), p53, p21 and proliferating cell nuclear antigen (PCNA) levels were evaluated by Western blot analyses. Results. Each oxidative stress dose-dependently arrested cell growth and partially induced premature cellular senescence. In parallel, each oxidative stress rapidly phosphorylated H2AX and stabilized p53, and intense stress sustained these high levels for at least 8 days. Conclusions. Intensive oxidative stress induces sustained high levels of gamma-H2AX and p53, which force cells toward senescence or non-apoptotic cell death. Lower doses of oxidative stress induced more modest and transient increases in gamma-H2AX and p53, and these cells eventually survive. However, because DNA is repaired without a template in the majority of these cells, G1 mutations accumulate. Therefore, we recommend that any cell population expressing elevated gamma-H2AX and p53 levels be excluded from cell transplantation therapy.

DOI： 10.1016/j.jcyt.2014.08.005

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Background aims. Cultured human periosteal sheets more effectively function as an osteogenic grafting material at implantation sites than do dispersed periosteal cells. Because adherent cell growth and differentiation are regulated by cell-cell and cell extracellular matrix contacts, we hypothesized that this advantage is a result of the unique cell adhesion pattern formed by their multiple cell layers and abundant extracellular matrix. To test this hypothesis, we prepared three distinct forms of periosteal cell cultures: three-dimensional cell-multilayered periosteal sheets, two-dimensional dispersed cell cultures, and three-dimensional hybrid mock-ups of cells dispersed onto collagen sponges. Methods. Periosteal cells were obtained from human alveolar bone. Cell adhesion and extracellular matrix molecules were quantitatively determined at the messenger RNA and protein levels by means of real-time quantitative polymerase chain reaction and flow cytometry, respectively. Results. Real-time quantitative polymerase chain reaction analysis demonstrated that regardless of culture media al integrin, vascular cell adhesion molecule-1, fibronectin and collagen type 1 were substantially upregulated, whereas CD44 was strongly downregulated in periosteal sheets compared with dispersed cell monolayers. With increased thickness, stem cell medium upregulated several integrins (beta 1, alpha 1 and alpha 4), CD146, vascular cell adhesion molecule-1, fibronectin and collagen type 1 in the periosteal sheets. Flow cytomeftic analysis revealed that the active configuration of beta 1 integrin was substantially downregulated in the stem cell medium expanded cell cultures. The cell adhesion pattern found in the mockup cultures was almost identical to that of genuine periosteal sheets. Conclusions. Integrin alpha 1 beta 1 and CD44 function as the main cell adhesion molecule in highly cell-multilayered periosteal sheets and dispersed cells, respectively. This difference may account for the more potent osteogenic activity shown by the thicker periosteal sheets.

DOI： 10.1016/j.jcyt.2013.11.003

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Language：Japanese   Publisher：(一社)日本形成外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI PUBLISHING CORPORATION  

Background. Local recurrence remains a challenging clinical issue for the treatment of oral squamous cell carcinoma (SCC). We analyzed retrospectively how effective the frozen section technique (FS) was against recurrences of oral SCC. Methods. We screened 343 surgical samples from 236 patients who had oral SCC, carcinoma in situ (CIS), or epithelial dysplasia, and we followed up their clinical outcomes for at least 5 years. Histopathological states of surgical margins were compared between FS and surgical materials in relapse and relapse-free groups, respectively. Results. Among the 236 patients, 191 were classified into the relapse-free group, and 45 into the relapse group. FS was more frequently performed in the relapse-free group (128/191) than in the relapse group (83/152). Histopathologically, moderate dysplasia or CIS (borderline malignancies) and SCC were recognized in 55 samples of the relapse-free group and in 57 of the relapse group. For those surgical margins with borderline malignancies, additional incisions were performed in 38 of the 55 relapse-free cases, which reduced to 20 from the 38 margins with borderline malignancies (47.4% reduction), and in 39 of the 57 relapse cases, which reduced to only 3 of 39 (7.7% reduction). Conclusions. The intraoperative assessment of surgical margins by FS is essential in preventing recurrences of oral mucosal malignancies.

DOI： 10.1155/2014/823968

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Background: Molecular biomarkers are essential for monitoring treatment effects, predicting prognosis, and improving survival rate in oral squamous cell carcinoma. This study sought to verify the effectiveness of two integrin gene expression ratios as biomarkers.Methods: Gene expression analyses of integrin α3 (ITGA3), integrin β4 (ITGB4), CD9 antigen (CD9), and plakoglobin (JUP) by quantitative real-time PCR were conducted on total RNA from 270 OSCC cases. The logrank test, Cox proportional hazards model, and Kaplan-Meier estimates were performed on the gene expression ratios of ITGA3/CD9 and ITGB4/JUP and on the clinicopathological parameters for major clinical events.Results: A high rate (around 80%) of lymph node metastasis was found in cases with a high ITGA3/CD9 ratio (high-ITGA3/CD9) and invasive histopathology (YK4). Primary site recurrence (PSR) was associated with high-ITGA3/CD9, T3-4 (TNM class), and positive margin, indicating that PSR is synergistically influenced by treatment failure and biological malignancy. A high ITGB4/JUP ratio (high-ITGB4/JUP) was revealed to be a primary contributor to distant metastasis without the involvement of clinicopathological factors, suggesting intervention of a critical step dependent on the function of the integrin β4 subunit. Kaplan-Meier curves revealed positive margin as a lethal treatment consequence in high-ITGA3/CD9 and YK4 double-positive cases.Conclusion: Two types of metastatic trait were found in OSCC: locoregional dissemination, which was reflected by high-ITGA3/CD9, and distant metastasis through hematogenous dissemination, uniquely distinguished by high-ITGB4/JUP. The clinical significance of the integrin biomarkers implies that biological mechanisms such as cancer cell motility and anchorage-independent survival are vital for OSCC recurrence and metastasis. © 2013 Nagata et al.
licensee BioMed Central Ltd.

DOI： 10.1186/1471-2407-13-410

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We previously published an investigation indicating freeze-dried platelet-rich plasma (PRP)-coated polyglactin mesh was a promising wound-dressing material. However, one of its disadvantages was the inflammatory nature due to degradation of the polyglactin. Therefore, in this study, we investigated the use of a collagen sponge as the carrier for PRP. When implanted subcutaneously in nude mice, the PRP-coated sponge alone rapidly induced angiogenesis and infiltration of surrounding connective tissue without inducing appreciable inflammation. Moreover, addition of periosteal fibroblastic cells substantially augmented the angiogenic response. With in vitro studies, the PRP-coated sponge provided various major growth factors at high levels to stimulate the proliferation of cells cultured on plastic dishes, but did not stimulate the proliferation of cells inoculated into the PRP-coated sponge. Cells were embedded in the fibrin mesh and maintained their spherical shape without stretching. The atomic force microscopic analysis demonstrated that the fibrin gel formed on the PRP-coated sponge was much softer (approx. 22. kPa) than the cross-linked collagen that formed the sponge base (appox. 1.9. MPa). Because insoluble matrices have recently and increasingly been considered important regulatory factors of cellular behavior, as are soluble growth factors, it is suggested that this soft fibrin mesh possibly suppresses cell survival. Overall, our investigation has successfully demonstrated improved wound-healing and regenerative potential of the PRP-coated mesh by combining it with the collagen sponge. In the clinical setting, this PRP-coated collagen sponge is a promising material for connective tissue regenerative therapy, such as periodontal therapy, burn victim treatment and in cosmetic or plastic surgery. © 2013 Elsevier Inc.

DOI： 10.1016/j.cryobiol.2013.01.006

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We previously demonstrated that thicker periosteal sheets with enhanced cell layering maintain their component cells at relatively immature stages of differentiation but express a high in vivo osteogenic potential. As it has been recently proposed that stiff scaffolds provide a mechanical cue to various cell types that promotes differentiation, we postulated that the maintenance of immature cells in our periosteal sheets is due to the mechanical stiffness of the multilayered-cell architecture. To demonstrate the biomechanical characteristics of our periosteal sheets, we have determined their stiffnesses with atomic force microscopy (AFM) and evaluated the expression of extracellular matrix (ECM) components specifically by both immunocytochemistry and a complementary DNA microarray technology. Compared to osteoblastic Saos2 cells, the cytoskeletal fibers were developed more in the periosteal cells, but the periosteal cells in monolayer culture developed before either the cells in the peripheral or central regions of the periosteal sheets developed. However, the nanoindentation by AFM distinguished the central region from the peripheral region. The peak stiffness values of cells were ordered as follows: tissue culture polystyrene (1.66. GPa). ⋙. dispersed (9.99. kPa). &gt
. central region (5.20. kPa). &gt
. peripheral regions (3.67. kPa). Similarly, the degree of development of α-smooth muscle actin (αSMA) filaments within cells was dispersed. &gt
. central region. &gt
. peripheral region. In conjunction with the abundantly deposited ECM in the periosteal sheets, these findings suggest that the order of cell stiffness may depend on the integration of the stiffness of individual ECM components and the extent of cytoskeletal fiber formation. Because recently published data have demonstrated that the optimal stiffness for osteogenic differentiation is 25-40. kPa, it is plausible that the periosteal cells residing in the less-stiff multilayer regions could be maintained at relatively immature stages under the control of the stem-cell medium in vitro but start differentiating when exposed to the proper stiffness upon release from the culture conditions at the implantation site. © 2013 Elsevier Ltd.

DOI： 10.1016/j.micron.2013.02.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：QUINTESSENCE PUBLISHING CO INC  

One-year data after autologous grafting of infrabony periodontal defects with human cultured periosteum sheets in combination with platelet-rich plasma and hydroxyapatite granules have shown favorable clinical and radiographic results. A 5-year follow-up evaluation of 22 selected patients indicated that treated infrabony defects remained stable. Radiographically, there was an increase in osseous radiopacity and bone trabeculation suggesting further bone maturation. This novel tissue-engineered periodontal treatment approach has resulted in significant clinical improvement, and defects remained stable after 5 years.

DOI： 10.11607/prd.1545

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

It has been well demonstrated that excessive blood glucose level could be detrimental to the myocardial function through the variety of mechanisms, of which endoplasmic reticulum stress (ERS) could play an unprecedented role through the activation of unfolded protein response (UPR). Recently, reports are coming out with the evidences that UPR signaling proteins are regulated differentially depend on the experimental conditions and cell types. In addition, ERS has been proposed to be closely associated with the regulation of lipogenesis. Therefore, in this study we tried to find out the expressions of myocardial UPR signaling proteins as well as proteins involved in lipid and glucose metabolism in non-obese type 2 diabetic mellitus (DM) condition using Spontaneous Diabetic Toni (SDT) rat. We have found the significant up-regulation of oxidative, nitrosative and ERS marker proteins in the myocardium of the SDT rats, in comparison to its normal (Sprague-Dawley - SD) rats. In addition, the sub-arm-of UPR signaling proteins, such as p-PERK, p-eIF2 alpha, ATF6, CHOP/GADD153, TRAF2, apoptotic signaling proteins, such as BAD, cytochrome C, cleaved caspase-7 and -12, were significantly up-regulated in the SDT rats, in comparison to the SD rats. Interestingly, there were no significant changes in the phosphorylation of IRE-1 alpha, and XBP-1 protein expression. In addition, the proteins involved in lipid and glucose metabolisms, such as PPAR alpha, PPAR gamma, CPT1, PGC-1 alpha except GLUT4, and the proteins involved in insulin signaling, such as p-Akt and p-PI3K were shown significant attenuation in its expressions in the SDT rats, when compared with the SD rats. Taken together, it is suggested that the activation of PERK and ATF6 pathway are the major determinant rather than the IRE-1 alpha-XBP1 pathway for the ERS-mediated metabolic dysfunction, which might eventually leads to diabetic cardiomyopathy in non-obese type 2 DM. (c) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.biocel.2012.09.017

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

We have previously demonstrated that nnultilayered periosteal sheets prepared from the explant culture of alveolar periosteum serve as a promising osteogenic grafting material in periodontal tissue regeneration. For the preparation of more potent periosteal sheets, we examined the applicability of stem-cell culture media. Compared to the control medium (Medium 199+10% FBS), periosteal sheets expanded with MesenPRO-RS (TM) medium exhibited these features: Cells grew three-dimensionally and deposited collagen in the extracellular spaces to form thicker multilayers of cells. Chondrocytic markers were not significantly upregulated. Contractile force was generated in proportion with the increased thickness of the periosteal sheets and the formation of cytoplasmic alpha-smooth muscle actin fibers. However, myofibroblastic markers were not significantly upregulated. The surface marker CD146 was substantially upregulated, while both CD73 and CD105 were downregulated. Alkaline phosphatase, a representative osteoblastic marker, was not upregulated by osteogenic induction. However, these expanded periosteal sheets exhibited substantially stronger osteogenic differentiation when implanted in nude mice. Therefore, despite our reservations, MesenPRO medium effectively expanded the cells contained in periosteal sheets to promote the formation of thicker multilayers of cells in vitro, and these enhanced periosteal sheets expressed increased osteogenic potential at implantation sites in vivo. In conjunction with data indicating that CD146-positive cells were notably expanded and the recently proposed concept that CD146 is a marker for osteogenic progenitor cells found in the bone marrow stroma, our findings suggest that MesenPRO medium improves the preparation of highly osteogenic periosteal sheets suitable for clinical application largely through the induction of CD146-positive cells. (C) 2012 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.scr.2012.08.006

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

As part of our clinical tests on bone regeneration using cultured periosteal sheets, here, we prepared cultured periosteal sheets in two types of stem-cell culture media, STK1 and STK3. Human periosteum was expanded either in 1% human serum-supplemented STK1 for 28 days, in 1% human serum-supplemented STK1 for 14 days followed by 1% human serum-supplemented STK3 for 14 days (1% human serum-supplemented STK1+3), or in 10% fetal bovine serum-supplemented Medium 199 for 28 days (control). Cultured periosteal sheet diameter and DNA content were significantly higher, and the multilayer structure was prominent in 1% human serum-supplemented STK1 and 1% human serum-supplemented STK1+3. The messenger RNA of osteoblastic markers was significantly upregulated in 1% human serum-supplemented STK1+3. Osteopontin-immunopositive staining and mineralization were evident across a wide area of the cultured periosteal sheet in 1% human serum-supplemented STK1+3. Subcutaneous implantation in nude mice following expansion in 1% human serum-supplemented STK1+3 produced the highest cultured periosteal sheet osteogenic activity. Expansion in 1% human serum-supplemented STK1+3 successfully induced cultured periosteal sheet growth while retaining osteogenic potential, and subsequent osteoblastic induction promoted the production of homogeneous cell material. © The Author(s) 2013.

DOI： 10.1177/2041731413509646

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

The development of diabetic cardiomyopathy is accompanied with a high membrane-bound protein kinase C (PKC) levels. Curcumin is a naturally occurring compound which is known to inhibit PKC activity. However, the effects of curcumin on ameliorating diabetic cardiomyopathy are still undefined. We evaluated whether curcumin treatment is associated with the modulation of PKC-alpha and -beta(2)-mitogen-activated protein kinase (MAPK) pathway in experimental diabetic cardiomyopathy. Diabetes was induced in male Sprague-Dawley rats by streptozotocin (STZ). Curcumin (100 mg/kg/day) was started three weeks after STZ injection and was given for 8 weeks. We demonstrate that curcumin significantly prevented diabetes-induced translocation of PKC-alpha and -beta 2 to membranous fraction and diabetes-induced increased phosphorylation of p38MAPK and extracellular regulated-signal kinase (ERK)1/2 in left ventricular tissues of diabetic rats. Curcumin treatment also markedly decreased NAD(P)H oxidase subunits (p67phox, p22phox, gp91phox), growth factors (transforming growth factor-beta, osteopontin) and myocyte enhancer factor-2 protein expression as well as inhibited NF-kappa B activity at nuclear level. Furthermore, curcumin decreased the mRNA expression of transcriptional coactivator p300 and atrial natriuretic peptide, decreased accumulation of ECM protein and reversed the increment of superoxide production in left ventricular tissues, as evidenced by dihydroethidium staining. It is also significantly lowered plasma glucose and attenuated oxidative stress, as determined by lipid peroxidation and activity of anti-oxidant enzyme, and as a result attenuated cardiomyocyte hypertrophy, myocardial fibrosis and left ventricular dysfunction. Taken together, it is suggested that curcumin by inhibiting PKC-alpha and -beta(2)-MAPK pathway may be useful as an adjuvant therapy for the prevention of diabetic cardiomyopathy. (C) 2012 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejps.2012.04.018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

There are various reports suggesting the role of angiotensin (Ang) receptor blockers, Ang converting enzyme inhibitors, calcium channel blockers, diuretics and antioxidants against the progression of experimental autoimmune myocarditis (EAM) to dilated cardiomyopathy (DCM). Most of them were reported to be effective during this adverse cardiac remodeling. Recently much attention has been paid to studying the involvement of AMP-activated protein kinase (AMPK) and mitogen activated protein kinase (MAPK) in various cardiovascular ailments. AMPK acts as a master sensor of cellular energy balance via maintenance of lipid and glucose metabolism. Evidences also suggest the relation between AMPK and oxidative stress during physiological and pathological myocardial cellular function. Since, it is of interest to identify the roles of AMPK and MAPK during the progression of EAM to DCM and also the effect of edaravone, a novel free radical scavenger, against its progression. For this, we have carried out western blotting, histopathological staining and immunohistochemical analyses to measure the myocardial expressions of AMPK signaling and oxidative stress related parameters in normal and vehicle or edaravone-treated EAM rats, respectively. We identified the myocardial levels of phospho Akt and phosphoinositide 3-kinase, which are the upstream proteins of AMPK and MAPK activation and both were up-regulated in the vehicle-treated rats, whereas candesartan treatment significantly reversed these changes. We have also measured the myocardial levels of p-AMPK alpha, different isoforms of protein kinase C and MAPK signaling proteins. All of these protein levels were significantly elevated in the hearts of DCM rats whereas edaravone treatment significantly reversed these changes. In viewing these results, we can suggest that along with MAPK, AMPK signaling also plays a crucial role in the progression of EAM and it can be effectively blocked by the treatment with a novel antioxidant, edaravone. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yexmp.2012.04.012

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Intestinal fibrosis is a common and severe complication of inflammatory bowel disease (IBD), especially Crohn's disease (CD). To investigate the therapeutic approach to intestinal fibrosis, we have developed a mouse model of intestinal fibrosis by administering dextran sulfate sodium (DSS) and examining the effects of irsogladine maleate (IM) [2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate], which has been widely used as an antiulcer drug for gastric mucosa in Japan, on DDS-induced chronic colitis. In this experimental colitis lesion, several pathognomonic changes were found: increased deposition of collagen, increased number of profibrogenic mesenchymal cells such as fibroblasts (vimentin(+), alpha-SMA(-)) and myofibroblasts (vimentin(+), alpha-SMA(+)) in both mucosa and submucosa of the colon with infiltrating inflammatory cells, and increased mRNA expressions of collagen type I, transforming growth factor (TGF)-beta, matrix metalloproteinase (MMP)-2, and tissue inhibitor of matrix metalloproteinase (TIMP)-1. When IM was administered intrarectally to this colitis, all these pathological changes were significantly decreased or suppressed, suggesting a potential adjunctive therapy for intestinal fibrosis. IM could consequently reduce fibrosis in DSS colitis by direct or indirect effect on profibrogenic factors or fibroblasts. Therefore, the precise effect of IM on intestinal fibrosis should be investigated further.

DOI： 10.1007/s00795-011-0550-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Edaravone, a novel antioxidant, acts by trapping hydroxyl radicals, quenching active oxygen and so on. Its cardioprotective activity against experimental autoimmune myocarditis (EAM) was reported. Nevertheless, it remains to be determined whether edaravone protects against cardiac remodelling in dilated cardiomyopathy (DCM). The present study was undertaken to assess whether edaravone attenuates myocardial fibrosis, and examine the effect of edaravone on cardiac function in rats with DCM after EAM. Rat model of EAM was prepared by injection with porcine cardiac myosin 28 days after immunization, we administered edaravone intraperitoneally at 3 and 10 mg/kg/day to rats for 28 days. The results were compared with vehicle-treated rats with DCM. Cardiac function, by haemodynamic and echocardiographic study and histopathology were performed. Left ventricular (LV) expression of NADPH oxidase subunits (p47phox, p67phox, gp91phox and Nox4), fibrosis markers (TGF-beta 1 and OPN), endoplasmic reticulum (ER) stress markers (GRP78 and GADD 153) and apoptosis markers (cytochrome C and caspase-3) were measured by Western blotting. Edaravone-treated DCM rats showed better cardiac function compared with those of the vehicle-treated rats. In addition, LV expressions of NADPH oxidase subunits levels were significantly down-regulated in edaravone-treated rats. Furthermore, the number of collagen-III positive cells in the myocardium of edaravone-treated rats was lower compared with those of the vehicle-treated rats. Our results suggest that edaravone ameliorated the progression of DCM by modulating oxidative and ER stress-mediated myocardial apoptosis and fibrosis.

DOI： 10.1111/j.1582-4934.2012.01526.x

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Intestinal fi brosis is a common and severe complication of infl ammatory bowel disease (IBD), especially Crohn's disease (CD). To investigate the therapeutic approach to intestinal fi brosis, we have developed a mouse model of intestinal fi brosis by administering dextran sulfate sodium (DSS) and examining the effects of irsogladine maleate (IM) [2,4-diamino-6-(2,5- dichlorophenyl)-s-triazine maleate], which has been widely used as an antiulcer drug for gastric mucosa in Japan, on DDS-induced chronic colitis. In this experimental colitis lesion, several pathognomonic changes were found: increased deposition of collagen, increased number of profi brogenic mesenchymal cells such as fi broblasts (vimentin+, 〈-SMA) and myofi broblasts (vimentin+, 〈-SMA+) in both mucosa and submucosa of the colon with infi ltrating infl ammatory cells, and increased mRNA expressions of collagen type I, transforming growth factor (TGF)-®, matrix metalloproteinase (MMP)-2, and tissue inhibitor of matrix metalloproteinase (TIMP)-1. When IM was administered intrarectally to this colitis, all these pathological changes were signifi cantly decreased or suppressed, suggesting a potential adjunctive therapy for intestinal fi brosis. IM could consequently reduce fi brosis in DSS colitis by direct or indirect effect on profi brogenic factors or fi broblasts. Therefore, the precise effect of IM on intestinal fi brosis should be investigated further. © 2012 The Japanese Society for Clinical Molecular Morphology.

DOI： 10.1007/s00795-011-0550-7

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Language：English   Publisher：新潟歯学会  

この研究の目的は頭頸部癌患者対する温熱化学放射線療法の成績向上のための重要な予後因子について検討することである。対象および方法:15名の切除不能頸部リンパ節転移20病巣に対して温熱化学放射線療法を行なった。温熱療法はマイクロ波またはRF波加温装置を用いて平均で8.8回実施した。化学療法はシスプラチンにペプレオマイシンまたは5Fuを併用し、さらに、外照射を加えた。結果:20病巣中8例(40%)は著効、8例(40%)は有効であったが、残りの4例(20%)では変化がなかった。奏効率は80%であった。全例の5年累積病巣制御率は64.2%を示し、放射線量別では、50Gy以上の照射例では5年病巣制御率は80.2%に対し、30Gy以下の照射例では3ヵ月で0%であった。統計学的解析により放射線療法の総線量は累積病巣制御率との間に有意差が認められた(P<0.05)。他の治療に関する因子(温熱療法の方法、回数、シスプラチン投与量、併用薬)および腫瘍に関する因子(再発巣か否か、腫瘍の大きさ、WHO分類、癌浸潤様式)では、病巣制御との間に有意差は認められなかった。結論:50Gy以上を併用した温熱化学放射線療法は頭頸部癌の切除不能な頸部リンパ節転移巣に対する効果的な治療方法であることが示された。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J00999&link_issn=&doc_id=20120725420004&doc_link_id=%2Fdj2ngtdt%2F2012%2F004201%2F004%2F0027-0036%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdj2ngtdt%2F2012%2F004201%2F004%2F0027-0036%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 SCIENCE INC  

In ongoing clinical research into the use of cultured autogenous periosteal cells (CAPCs) in alveolar bone regeneration, CAPCs were grafted into 33 sites (15 for alveolar ridge augmentation and 18 for maxillary sinus lift) in 25 cases. CAPCs were cultured for 6 weeks, mixed with particulate autogenous bone and platelet-rich plasma, and then grafted into the sites. Clinical outcomes were determined from high-resolution three-dimensional computed tomography (3D-CT) images and histological findings. No serious adverse events were attributable to the use of grafted CAPCs. Bone regeneration was satisfactory even in cases of advanced atrophy of the alveolar process. Bone biopsy after bone grafting with CAPCs revealed prominent recruitment of osteoblasts and osteoclasts accompanied by angiogenesis around the regenerated bone. 3D-CT imaging suggested that remodeling of the grafted autogenous cortical bone particles was faster in bone grafting with CAPCs than in conventional bone grafting. The use of CAPCs offers cell-based bone regeneration therapy, affording complex bone regeneration across a wide area, and thus expanding the indications for dental implants. Also, it enables the content of particulate autogenous bone in the graft material to be reduced to as low as 40%, making the procedure less invasive, or enabling larger amounts of graft materials to be prepared. It may also be possible to dispense with the use of autogenous bone altogether in the future. The results suggest that CAPC grafting induces bone remodeling, thereby enhancing osseointegration and consequently reducing postoperative waiting time after dental implant placement. (C) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2012.02.631

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Angiotensin-converting enzyme 2 (ACE-2) is a membrane-associated carboxy-peptidase catalyzes the conversion of the vasoconstrictor angiotensin (ANG)-II to the vasodilatory peptide ANG 1-7. In view of the expanding axis of the renin angiotensin system, we have investigated the cardioprotective effects of olmesartan (10 mg/kg/day) in experimental autoimmune myocarditis. Olmesartan treatment effectively suppressed the myocardial protein expressions of inflammatory markers in comparison to the vehicle-treated rats. However, the protein and mRNA levels of ACE-2 and ANG 1-7, and its receptor Mas were upregulated in olmesartan treated group compared to vehicle-treated rats. Olmesartan medoxomil treatment significantly decreased the expression levels of phospho-p38 mitogen-activated protein kinase (MAPK), phospho-JNK, phospho-ERK and phospho-(MAPK) activated protein kinase-2 than with those of vehicle-treated rats. Moreover, vehicle-treated rats were shown to be up-regulated protein expressions of NADPH oxidase subunits (p47phox, p67phox and Nox-4), myocardial apoptotic markers and endoplasmic reticulum stress markers in comparison to those of normal and all these effects are expectedly down-regulated by an olmesartan. In addition, attenuated protein levels of phosphatidylinositol-3-kinase (PI3K) and phospho-Akt in the vehicle-treated EAM rats were prevented by olmesartan treatment. Our results suggest that beneficial effects of olmesartan treatment was more effective therapy in combating the inflammation, oxidative stress, apoptosis and signaling pathways associated with heart failure at least in part via the modulation of ANG 1-7 mas receptor. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mce.2011.12.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

There are evidences that the activation of AMPK is playing pivotal role in the lipid and glucose metabolism. It has been reported that both the AMPK and angiotensin-II acts as a negative regulator for each protein. It has been well proven that the MAPK cascade could be modulated by the presence of angiotensin-II. Moreover, studies were shown that p38 MAPK stimulates glucose uptake through the AMPK activation. Therefore, we speculate and tried to demonstrate that the modulation of AT-R/MAPK pathway through AMPK might play crucial roles for the pathogenesis of diabetic cardiomyopathy, using the transgenic (Spontaneous Diabetic Torii - SDT) rats. We performed Western blot analysis for the measurement of myocardial AT-R, AMPK and MAPK cascades-related protein expressions, p67-phox and caspase-12. In addition, we employed dihydroethidium (DHE), Azan Mallory and hemotoxylin eosin (HE) staining methods to demonstrate the superoxide radical production, fibrosis and hypertrophy, respectively. The protein expressions, such as AT-1R, p-ERK1/2, p67-phox and caspase-12 were found to be significantly increased and conversely, the Ang-(1-7) mas R. Tak1, LKB1 and p-AMPK alpha 1, p-p38 MARK and p-p1K protein expressions were found to be considerably decreased in the SOT rats, in comparison to the normal rats. The DHE, Azan Mallory and HE stainings also revealed that the SDT rats have more superoxide radical production, fibrosis and hypertrophy, respectively than the normal rats. Taken together, it is suggested that the modulation of AT-1R/AMPK-MAPK pathway might play crucial roles for the pathogenesis of diabetic cardiomyopathy and it could become an important therapeutic target to ameliorate the diabetic cardiomyopathy. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bcp.2011.11.018

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In this in vitro study, novel porous poly(l-lactic acid) membranes were developed to improve periosteal sheets by promoting initial adhesion of periosteal tissue segments and stimulating the formation of a viable multilayered cellular sheet. The biocompatibility, biodegradability, and osteogenicity were evaluated using human periosteal tissue segments cultured on porous poly(l-lactic acid) membranes
the periosteal sheets were osteogen induced and were then implanted in the dorsal subcutaneous tissue of nude mice. In vivo, the membrane degraded into clusters of membrane particles separated by wide cracks
fibroblastic cells invaded along with small blood vessels from the surrounding mouse connective tissue. In osteoinduced periosteal sheets, the membrane clusters were surrounded by numerous capillaries and a number of tartrate-resistant acid phosphatase-positive, multinucleated cells. Neither severe inflammation nor fibrous encapsulation was observed throughout the implantation (∼12 weeks). These porous poly(l-lactic acid) membranes were highly biocompatible and functioned well as biodegradable scaffolds that could enhance the use of osteogenic periosteal sheets in therapy. © The Author(s) 2012.

DOI： 10.1177/0883911512438306

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

In order to test the hypothesis that treatment with quercetin at a dose of 10 mg/kg protects from the progression of experimental autoimmune myocarditis (EAM) to dilated cardiomyopathy (DCM), we have used the rat model of EAM induced by porcine cardiac myosin. Our results identified that the post-myocarditis rats suffered from elevated endoplasmic reticulum (ER) stress and adverse cardiac remodelling in the form of myocardial fibrosis, whereas the rats treated with quercetin have been protected from these changes as evidenced by the decreased myocardial levels of ER stress and fibrosis markers when compared with the vehicle-treated DCM rats. In addition, the myocardial dimensions and cardiac function were preserved significantly in the quercetin-treated rats in comparison with the DCM rats treated with vehicle alone. Interestingly, the rats treated with quercetin showed significant suppression of the myocardial endothelin-1 and also the mitogen activated protein kinases (MAPK) suggesting that the protection offered by quercetin treatment against progression of EAM involves the modulation of MAPK signalling cascade. Collectively, the present study provides data to support the role of quercetin in protecting the hearts of the rats with post myocarditis DCM.

DOI： 10.3109/10715762.2011.647010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT INC  

In the past decade, it has increasingly been reported that epigallocatechin-3-gallate (EGCG), a major catechin derivative extracted from Green tea, has various bioactivities, including a cell-protective action on mammalian cells and tissues. In this study, we have tested a commercial preservation solution containing EGCG (Theliokeep (R)) in both two- and three-dimensional cultures of human periosteal sheets, which have been used as an osteogenic grafting material for periodontal regenerative therapy. When periosteal sheets were 3D-cultured on collagen mesh, cell viability was maintained for 2 days using the hypothermic EGCG preservation solution. Replenishment of EGCG solution with 2-day intervals prevented the time-dependent decline in cell viability at 3 days and later. As observed in nonpreserved control cultures, most cells were positive for proliferating cell-nuclear antigen (PCNA) in the cultures preserved at 4 degrees C in the EGCG solution, whereas PCNA-negative cells were increased in the cultures preserved at 4 degrees C in the MesenPRO medium. In periosteal sheets 2D-cultured in plastic dishes, the EGCG solution occasionally was associated with vacuole formation in the cytoplasm, but cells could again expand in the culture medium at 37 degrees C. As observed in the nonpreserved periosteal sheets control, the osteogenic induction upregulated alkaline phosphatase in those cells and tissues preserved in the EGCG solution. The EGCG solution protected cells from the cold shock-induced membrane phospholipid peroxidation. Our data suggest that the EGCG solution acts as an antioxidant to protect periosteal cells from cold shock and preserves cells under chilled conditions. The limited period of preservation time could be expanded by repeating replenishment of the EGCG solution or by optimizing the formula to be more favorable for human periosteal sheets without sacrificing cell viability. This methodology of preserving human cultured periosteal sheets with EGCG would be expected to support and spread the clinical use of regenerative therapy with autologous periosteal sheets.

DOI： 10.1089/bio.2011.0051

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Human cultured periosteal sheets, which are developed from small excised periosteum tissue segments (PTSs) in culture dishes by simple expansion culture, have been applied as a promising autologous osteogenic grafting material for periodontal regenerative therapy. However, the weak initial adhesion of PTSs to dish surfaces often hampers cellular outgrowth and limits the number of preparations. To correct this weakness and still avoid the use of animal-derived adhesion biomolecules, we have developed a novel, biodegradable, porous poly(L-lactic acid) (pPLLA) membrane. Freshly excised PTSs bound well to the highly porous pPLLA membrane, possibly due to the presence of semihemispheric 20-30 mu m diameter openings on the upper surface. Global gene expression analysis demonstrated that periosteal sheets cultured on pPLLA membranes upregulated expression of many adhesion molecules. Osteogenic induction stimulated the production of proteoglycans by these cells and concomitantly enhanced their expansion and penetration into the deep pore regions of the membrane in parallel with the progression of in vitro mineralization. These findings suggest that our pPLLA membranes not only facilitate initial adhesion, primarily mediated by adsorbed proteins, but also enhance biological adhesion by inducing endogenous adhesion molecules in periosteal sheet cultures. Therefore, the efficacy of periosteal sheets in therapy should be greatly enhanced by using this new pPLLA membrane. (C) 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 98A: 100-113, 2011.

DOI： 10.1002/jbm.a.33074

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Cultured human periosteal sheets constitute a promising grafting material for periodontal tissue regenerative therapy. However, preparation of these sheets usually requires six weeks or longer, and this lengthy commitment and delay limits both clinical applicability and availability. The aim of this study is to develop an efficient, practical, cost-effective cryopreservation method for periosteal tissue segments (PTSs). Human PTSs were aseptically excised from alveolar bone and pre-cultured in Medium 199 + 10% fetal bovine serum (FBS) for the indicated number of days before they were slowly frozen down to -75 degrees C in a commercial freezing vessel using medium containing 10% dimethyl sulfoxide (Me(2)SO) and various concentrations of FBS. After fast-thawing at 37 degrees C, PTSs were again cultured, and their growth and responses to standard osteogenic induction were evaluated (vs. freshly excised PTSs). Proliferating cells were obtained at the highest levels from cryopreserved FTSs that were pre-cultured for 14 days before freezing. When a concentration of 50% or more FBS was included in the cryopreservation solution, cells migrated out more actively and grew faster. Importantly, osteoinduction up-regulated alkaline phosphatase (ALP) activity and osteoblastic marker mRNAs in cryopreserved PTS-derived sheets just as effectively as it did in native PTS-derived ones. These data suggest that pre-conditioned PTSs can be efficiently cryopreserved in a freezing solution containing high FBS by traditional manual cryopreservation methods without aid of a program freezer or more elaborate equipment. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cryobiol.2011.03.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Activation of osteoblastic bone anabolism in the calvarial sutures is considered to be the essential pathologic condition underlying mutant FGFR2-related craniofacial dysostosis. However, early clinical investigations indicated that abnormal cartilage development in the cranial base was rather a primary site of abnormal feature in Apert Syndrome (AS). To examine the significance of cartilaginous growth of the cranial base in AS, we generated a transgenic mouse bearing AS-type mutant Fgfr2IIIc under the control of the Col2a1 promoter-enhancer (Fgfr2IIIc(P253R) mouse). Despite the lacking expression of Fgfr2IIIc(P253R) in osteoblasts, exclusive disruption of chondrocytic differentiation and growth reproduced AS-like acrocephaly accompanied by short anterior cranial base with fusion of the cranial base synchondroses, maxillary hypoplasia and synostosis of the calvarial sutures with no significant abnormalities in the trunk and extremities. Gene expression analyses demonstrated upregulation of p21, Ihh and Mmp-13 accompanied by modest increase in expression of Sox9 and Runx2, indicating acceleration of chondrocytic maturation and hypertrophy in the cranial base of the Fgfr2IIIc(P253R) mice. Furthermore, an acquired affinity and specificity of mutant FGFR2IIIc(P253R) receptor with FGF2 and FGF10 is suggested as a mechanism of activation of FGFR2 signaling selectively in the cranial base. In this report, we strongly suggest that the acrocephalic feature of AS is not alone a result of the coronal suture synostosis, but is a result of the primary disturbance in growth of the cranial base with precocious endochondral ossification. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2010.11.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Fibrogenic mesenchymal cells including fibroblasts and myofibroblasts play a key role in intestinal fibrosis, however, their precise role is largely unknown. To investigate their role in intestinal fibrosis, we analyzed the lesions of chronic colitis in C57BL/6 (B6) mice induced by dextran sulfate sodium (DSS). B6 mice exposed to single cycle administration of DSS for 5 days developed acute colitis that progressed to severe chronic inflammation with dense infiltrates of mononuclear cells, irregular epithelial structure, thickening of colonic wall, and persistent deposits of collagen. Increased mRNA expressions of proinflammatory cytokines are correlated with extensive cellular infiltration, and the mRNA expressions of collagen 1, transforming growth factor (TGF)-beta, and matrix metalloproteinases were also enhanced in the colon. In the colon of chronic DSS colitis, fibroblasts (vimentin+, alpha-smooth muscle actin (alpha-SMA)-) were increased in both mucosal and submucosal layers, while myofibroblasts (vimentin+, alpha-SMA+) were increased in mucosal but not in submucosal layers. Primary mouse subcutaneous fibroblast cultures experiments revealed that exogenously added TGF-beta 1 substantially augmented the expressions of both vimentin and alpha-SMA proteins with increased production of collagen. In conclusion, profibrogenic mesenchymal cells play an important role in the development of intestinal fibrosis in this chronic DSS-induced colitis model.

DOI： 10.1111/j.1440-1827.2011.02647.x

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Fibrogenic mesenchymal cells including fibroblasts and myofibroblasts play a key role in intestinal fibrosis, however, their precise role is largely unknown. To investigate their role in intestinal fibrosis, we analyzed the lesions of chronic colitis in C57BL/6 (B6) mice induced by dextran sulfate sodium (DSS). B6 mice exposed to single cycle administration of DSS for 5days developed acute colitis that progressed to severe chronic inflammation with dense infiltrates of mononuclear cells, irregular epithelial structure, thickening of colonic wall, and persistent deposits of collagen. Increased mRNA expressions of proinflammatory cytokines are correlated with extensive cellular infiltration, and the mRNA expressions of collagen 1, transforming growth factor (TGF)-β, and matrix metalloproteinases were also enhanced in the colon. In the colon of chronic DSS colitis, fibroblasts (vimentin +, α-smooth muscle actin (α-SMA) -) were increased in both mucosal and submucosal layers, while myofibroblasts (vimentin +, α-SMA +) were increased in mucosal but not in submucosal layers. Primary mouse subcutaneous fibroblast cultures experiments revealed that exogenously added TGF-β 1 substantially augmented the expressions of both vimentin and α-SMA proteins with increased production of collagen. In conclusion, profibrogenic mesenchymal cells play an important role in the development of intestinal fibrosis in this chronic DSS-induced colitis model. © 2011 The Authors. Pathology International © 2011 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.

DOI： 10.1111/j.1440-1827.2011.02647.x

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DOI： 10.14833/amjsp.2011s.0.14.0

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Language：Japanese   Publisher：新潟歯学会  

昨今、抗血栓療法患者における歯科観血処置前の慣習的な休薬が見直されるようになり、当科でも2006年1月以降、原則非休薬の治療方針をマニュアル化して診療にあたっている。今回、当科のマニュアルの妥当性を検証し、術後出血リスクを効果的に軽減させる具体的方策を探ることを目的として、回顧的検討を行った。また、休薬せざるを得なかった症例についても、その周術期管理を考察した。対象は、2006年1月〜2007年12月までに口腔外科処置を行った抗血栓療法患者で、非休薬下で施術した症例103名(のベ137回)、休薬下で施術した症例9名(のベ9回)、合計112名(のベ146回)である。術後出血の程度と時期、血栓塞栓性合併症の有無と時期を評価するとともに、各種止血処置と術後出血の関連を検討した。その結見、非休薬群では137例中22例(16.1%)に術後出血を認め、出血時期は全て術直後であった。特徴的な結果として、抗凝固療法患者に術後出血が有意に多かったが、PT-INRと出血頻度に相関はなかった。また、術野が広範囲になるに従い術後出血が増加し、抜歯症例に限ると、抜歯数の増加にともない術後出血も増加した。止血処置に関して、止血材料使用と縫合を単独もしくは併用した症例で術後出血が減少した。術後出血した症例は、いずれも直視直達による通常の後出血処置により止血可能で再出血はなかった。休薬群では9例中2例(22.2%)に術後出血があり、抗血栓療法再開時期を調整して出血管理を行い再出血はなかった。休薬群、非休薬群のいずれでも周術期に血栓塞栓症の徴候はなかった。当科の「抗血栓療法患者周術期管理マニュアル」に従い、全身的な要件として「病状照会(抗凝固療法患者ではPT-INRの把握)にて抗血栓療法を行うに至った基礎疾患を含む既往疾患が良好にコントロールされていること」、および局所的な要件として「予期せぬ術野からの出血に対し直視直達にて容易に止血可能と判断されること」が遵守され、「抗血栓療法の詳細、術野の常態、症例に応じた止血処置を勘案した周術期管理体制が整備」がなされていれば、安心で安全な口腔外科処置が抗血栓療法患者においても可能と考えられた。(著者抄録)

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Background: We previously demonstrated that human periosteal sheets prepared on culture dishes function as an osteogenic "graft material" applicable to periodontal regenerative therapy. However, a lower level of initial adhesion of the excised periosteum tissue segments to culture dishes was a critical point that compromised the successful preparation of functional periosteal sheets. To improve on this weakness, we developed a transparent, biodegradable poly(L-lactide-co-epsilon-caprolactone) (LCL) film and tested its function as a scaffold and carrier of periosteal sheets.
Methods: Human periosteum tissue segments excised from alveolar bone of healthy donors were cultured on type I atelocollagen-coated LCL films. Initial adhesion was examined by simple agitation. Cell outgrowth and in vitro mineralization were cytohistochemically examined. Osteogenic activity was histochemically examined in an animal implantation model using nude mice.
Results: Surface collagen-coating modified the hydrophobic nature of LCL and substantially improved the initial adhesion. Compared to cultures in plastic dishes, the growth rate was delayed in non-coated films, but not in collagen-coated films. In the trimming process for animal implantation, periosteal sheets were frequently detached from non-coated films, but not from collagen-coated films. Regardless of collagen-coating, LCL films did not cause any significant infiltration of inflammatory cells, or negatively impact mineralized tissue formation.
Conclusions: Collagen-coating improved the initial adhesion of periosteum segments, which facilitated cell outgrowth and also handling efficiency on implantation. Therefore, we believe that once evaluated in human studies, our collagen-coated LCL film will contribute to improving the periodontal regenerative methodology with the application of cultured autologous periosteal sheets. J Periodontol 2010;81:1653-1662.

DOI： 10.1902/jop.2010.100194

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The signaling axis comprising the parathyroid hormone (PTH)-related peptide (PTHrP), the PTH/PTHrP receptor and the fibroblast growth factor receptor 3 (FGFR3) plays a central role in chondrocyte proliferation. The Indian hedgehog (IHH) gene is normally expressed in early hypertrophic chondrocytes, and its negative feedback loop was shown to regulate PTH/PTHrP receptor signaling. In this study, we examined the regulation of PTH/PTHrP receptor gene expression in a FGFR3-transfected chondrocytic cell line, CFK2. Expression of IHH could not be verified on these cells, with consequent absence of hypertrophic differentiation. Also, expression of the PTH/PTHrP receptor (75% reduction of total mRNA) and the PTHrP (50% reduction) genes was reduced in CFK2 cells transfected with FGFR3 cDNA. Interestingly, we verified significant reduction in cell growth and increased apoptosis in the transfected cells. STAT1 was detected in the nuclei of the CFK2 cells transfected with FGFR3 cDNA, indicating predominance of the JAK/STAT signaling pathway. The reduction in PTH/PTHrP receptor gene in CFK2 cells overexpressing FGFR3 was partially blocked by treatment with an inhibitor of JAK3 (WHI-P131), but not with an inhibitor of MAPK (SB203580) or JAK2 (AG490). Altogether, these findings suggest that FGFR3 down-regulates PTH/PTHrP receptor gene expression via the JAK/STAT signaling in chondrocytic cells. The Author 2010. Published by Oxford University Press on behalf of Japanese Society of Microscopy. All rights reserved.

DOI： 10.1093/jmicro/dfq002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

The signaling axis comprising the parathyroid hormone (PTH)-related peptide (PTHrP), the PTH/PTHrP receptor and the fibroblast growth factor receptor 3 (FGFR3) plays a central role in chondrocyte proliferation. The Indian hedgehog (IHH) gene is normally expressed in early hypertrophic chondrocytes, and its negative feedback loop was shown to regulate PTH/PTHrP receptor signaling. In this study, we examined the regulation of PTH/PTHrP receptor gene expression in a FGFR3-transfected chondrocytic cell line, CFK2. Expression of IHH could not be verified on these cells, with consequent absence of hypertrophic differentiation. Also, expression of the PTH/PTHrP receptor (75% reduction of total mRNA) and the PTHrP (50% reduction) genes was reduced in CFK2 cells transfected with FGFR3 cDNA. Interestingly, we verified significant reduction in cell growth and increased apoptosis in the transfected cells. STAT1 was detected in the nuclei of the CFK2 cells transfected with FGFR3 cDNA, indicating predominance of the JAK/STAT signaling pathway. The reduction in PTH/PTHrP receptor gene in CFK2 cells overexpressing FGFR3 was partially blocked by treatment with an inhibitor of JAK3 (WHI-P131), but not with an inhibitor of MAPK (SB203580) or JAK2 (AG490). Altogether, these findings suggest that FGFR3 down-regulates PTH/PTHrP receptor gene expression via the JAK/STAT signaling in chondrocytic cells.

DOI： 10.1093/jmicro/dfq002

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Background: A superporous (85%) hydroxyapatite (HA) block was recently developed to improve osteoconductivity, but it was often not clinically successful when used to treat periodontal osseous defects. The primary purpose of this study is to develop a clinically applicable tissue-engineered bone substitute using this HA block and human alveolar periosteum-derived cells.
Methods: Commercially available superporous HA blocks were acid treated and subjected to a three-dimensional (3D) culture for periosteal cell cultivation. Cells in the pore regions of the treated HA block were observed on the fracture surface by scanning electron microscopy. After osteogenic induction, the cell HA complexes were implanted subcutaneously in nude mice. Osteoid formation was histologically evaluated.
Results: Acid treatment enlarged the interconnections among pores, resulting in the deep penetration of periosteal cells. Under these conditions, cells were maintained for >2 weeks without appreciable cell death in the deep pore regions of the HA block. The cell HA complexes that received in vitro osteogenic induction formed osteoids in pore regions of the treated HA blocks in vivo. In contrast, most pore regions in the non-pretreated, cell-free HA blocks that were evaluated in vivo remained cell free.
Conclusions: Our findings suggest that an acid-treated HA block could function as a better scaffold for the 3D high-density culture of human periosteal cells in vitro, and this cell HA complex had significant osteogenic potential at the site of implantation in vivo. Compared with the cell-free HA block, our cell HA complex using periosteal cells, which are the most accessible for clinical periodontists, showed promising results as a bone substitute in periodontal regenerative therapy. J Periodontal 2010;81:420-427.

DOI： 10.1902/jop.2009.090523

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Mast cells play a key role in the pathophysiology of inflammatory bowel disease (IBD). Tranilast, a mast cell stabilizer, has been empirically used for IBD in Japan, but its precise role in the treatment of IBD is largely unknown. To investigate the role of tranilast for the treatment of IBD, tranilast was administered intrarectally to mice with dextran sulfate sodium (DSS)-induced colitis. Tranilast ameliorated DSS colitis clinically and pathologically, as demonstrated by decreased number and degranulation of mast cells in the colon. mRNA expression was increased for tumor necrosis factor-α, interferon-γ and interleukin (IL)-6, and decreased for IL-10 in the colon of DSS colitis mice. In contrast, tranilast markedly decreased expression of mRNAs for the pro-inflammatory cytokines, and increased that of the anti-inflammatory cytokines. Moreover, tranilast increased heme oxygenase (HO)-1 expression on colonic epithelial cells as well as on colon-infiltrating cells of DSS colitis. In conclusion, tranilast ameliorated DSS colitis by regulating mast cell degranulation, decreasing inflammatory cytokines and increasing anti-inflammatory cytokines. Tranilast might exert these effects partly through enhanced HO-1 expression in the colon, suggesting a potential adjunctive therapy for IBD. © 2009 Japanese Society of Pathology.

DOI： 10.1111/j.1440-1827.2009.02490.x

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

Our animal implantation studies have demonstrated that, after osteogenic processing, cultured human periosteal sheets form osteoid tissue ectopically without the aid of conventional scaffolding materials. To improve the osteogenic activity of these periosteal sheets, we have tested the effects of including a scaffold made of salmon collagen-coated ePTFE mesh. Periosteal sheets were produced with minimal manipulation without enzymatic digestion. Outgrown cells penetrated into the coated mesh fiber networks to form complex multicellular layers and increased expression of alkaline phosphatase activity in response to the osteoinduction. In vitro mineralization was notably enhanced in the original tissue segment regions, but numerous micro-mineral deposits were also formed on the coated-fiber networks. When implanted subcutaneously into nude mice, periosteal sheets efficiently form osteoid around the mineral deposits. These findings suggest that the intricate three-dimensional mesh composed of collagen-coated fibers substantially augmented the osteogenic activity of human periosteal sheets both in vitro and in vivo.

DOI： 10.1007/s10856-009-3896-9

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Mast cells play a key role in the pathophysiology of inflammatory bowel disease (IBD). Tranilast, a mast cell stabilizer, has been empirically used for IBD in Japan, but its precise role in the treatment of IBD is largely unknown. To investigate the role of tranilast for the treatment of IBD, tranilast was administered intrarectally to mice with dextran sulfate sodium (DSS)-induced colitis. Tranilast ameliorated DSS colitis clinically and pathologically, as demonstrated by decreased number and degranulation of mast cells in the colon. mRNA expression was increased for tumor necrosis factor-a, interferon-g and interleukin (IL)-6, and decreased for IL-10 in the colon of DSS colitis mice. In contrast, tranilast markedly decreased expression of mRNAs for the pro-inflammatory cytokines, and increased that of the anti-inflammatory cytokines. Moreover, tranilast increased heme oxygenase (HO)-1 expression on colonic epithelial cells as well as on colon-infiltrating cells of DSS colitis. In conclusion, tranilast ameliorated DSS colitis by regulating mast cell degranulation, decreasing inflammatory cytokines and increasing anti-inflammatory cytokines. Tranilast might exert these effects partly through enhanced HO-1 expression in the colon, suggesting a potential adjunctive therapy for IBD.

DOI： 10.1111/j.1440-1827.2009.02490.x

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

Oral lichen planus (OLP) is a refractory mucosal disease. Its pathogenesis is thought to involve immunologic and genetic alterations. To gain a better understanding of the genetic risk factors, the authors evaluated associations between 14 functional gene polymorphisms and OLP. 32 Japanese patients with OLP and 99 unrelated healthy Japanese controls were genotyped for 14 single nucleotide polymorphisms (SNPs) of genes that regulate host immune responses. Genotyping was performed with a modified version of the serial invasive signal amplification reaction. A trend towards over-representation of turner necrosis factor receptor 2 (TNFR2) +587 G allele was found in the patients compared with the controls (allele frequency: P = 0.049). The other 13 SNPs were unassociated with OLP. These results suggest that TNFR2 +587 gene polymorphism may be associated with susceptibility to OLP.

DOI： 10.1016/j.ijom.2009.05.001

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Accurate assessment of malignancy in oral squamous cell carcinoma is essential to optimize treatment planning. To detect a biomarker related to malignant propensity in gingival squamous cell carcinoma (GSCC), quantitative gene expression analysis of tetraspanin family genes was conducted. In 73 cases of GSCC, total RNA was extracted from carcinoma tissues, and gene expression was analyzed by quantitative real time-PCR. Six tetraspanin family genes (CD9, CD63, CD81, CD82, CD151, NAG-2) were investigated. Housekeeping genes (ACTB and GAPDH), anchor protein genes (JUP and PXN) and an integrin gene (ITGA3) were used as reference genes. Forty-five gene expression ratios were calculated from these It gene expression levels and were analyzed with clinical parameters using multivariate statistical methods. According to the results of the logistic regression analysis subjecting cervical lymph node metastasis as a target variable, CD9/ACTB (p = 0.0.13) or CD9/CD82 (p = 0.013) in addition to tumor size (p = 0.028) were detected as significant factors. In Cox proportional hazards regression analysis, delayed cervical lymph node metastasis (p = 0.039) and tumor cell positive surgical margin (p = 0.032) in addition to CD151/GAPDH (p = 0.024) were detected as significant factors for death outcome. A Kaplan-Meier survival curve presented a significantly lower survival rate of the group with a CD151/GAPDH value of 10 or more (log rank and generalized Wilcoxon tests: p = 0.0003). Results of this study present the usefulness of CD9 and CD151 expression levels as biomarkers for assessment of malignancy in GSCC. They also indicate that detection of residual tumor cells at the surgical margin and the biological malignancy of a tumor interdependently affects prognosis. (C) 2009 UICC

DOI： 10.1002/ijc.24297

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT INST ANTICANCER RESEARCH  

Background: A giant cell tumor (GCT) of bone is a locally aggressive tumor with a propensity for local recurrence. A characteristic pattern of peripheral bone formation has been described in GCT recurrence in soft tissue, and in some pulmonary metastases from benign GCT. Although the bone formation in GCT in supposedly due to bone morphogenetic proteins (BMPs), the expression pattern of BMPs in GCT has not been well investigated. Materials and Methods: The expression of BMPs in GCT tissues, cultured stromal cells from GCT and osteoclast-like giant cells harvested by laser microdissection (LM), as well as from control osteosarcoma (NOS-1) cells was analyzed using reverse transcriptional-semiquantitative PCR. Results: BMP 2, 3, 4, 5 and 6 were expressed in the GCT tissue. The cultured GCT cells expressed BMP 2, 4, 5 and 6. The osteoclast-like giant cells expressed BMP 2, 3, 5 and 6 and BMP 5 was expressed at the highest level. Conclusion: Both stromal cells and osteoclast-like cells in GCT expressed several kinds of BMPs.

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The bone anabolic effect of rhFGF2 is attributed to activation of proliferation and differentiation of osteoblasts. Concomitant up-regulation of Runx2 and Bmp2 implies a coordinative function of FGF/FGFR signaling on osteoblast differentiation.
Introduction: Duration and tissue concentration of growth factor exposure are important in tissue regeneration. This Study analyzed the availability of rhFGF2. using a sustained release gelatin hydrogel system. To examine biological aspects of the bone anabolic effect, we carried Out morphological and cell proliferation assays together with gene expression analyses of osteoblast related genes induced by rhFGF2 using localizing and quantifying procedures in vivo.
Materials and methods: Bone formation induced by implantation of gelatin hydrogel impregnated with 20 mu g rhFGF2 (rhFGF2(+)) onto mice maxillae was analyzed by micro Computed tomography, proliferating cell nuclear antigen (PCNA) immunohistochemistry, in situ hybridization and quantitative real time polymerase chain reaction combined with laser microdissection (LMD-QPCR).
Results: The bony maxilla was augmented to 1.58 times its original Volume (p = 0.002) by the implantation of rhFGF2(+) gelatin hydrogel. An increased number of PCNA-positive nuclei were observed among differentiated osteoblasts as well as undifferentiated mesenchymal cells. Fgfr1, Fgfr2 and Runx2 were shown to be co-expressed mainly in differentiated osteoblasts but also in osteoblast marker negative spindle-shaped cells that were scattered within the Outer layer of hyperplastic periosteum. LMD-QPCR revealed up-regulation of Bmp2 expression accompanied by increased transcription of Fgfr1, Fgfr2 and Runx2 by rhFGF2 controlled release.
Conclusions: rhFGF2 sustained release results in bone formation oil the maxilla by positively regulating the expansion and differentiation of osteoblastic cells. It is suggested that FGF/FGFR signaling coordinates a bone anabolic effect by Simultaneously activating RUNX2 and BMP2 pathways. The gelatin hydrogel system, which enables a sustained slow rate of release of rhFGF2 ill tissue has advantages of optimizing bone regeneration. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2008.12.017

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Our recent clinical studies have demonstrated that autologous implantation of human cultured periosteal (hCP) sheets in combination with porous hydroxylapatite (HAp) particles at the site of periodontal bone defects strikingly facilitates tissue regeneration. To better understand how the hCP sheet functions at the implantation site, we have now examined its biochemical and morphological characteristics in vitro and its ectopic osteoinductivity in nude mice. Cultured human periosteal tissue segments produced periosteal cells that migrated out from the central region within 4-8 days and grew more rapidly with longer culture times. Alkaline phosphatase activity increased in parallel with actual osteoblastic induction. Cytokine array assays demonstrated that osteoblastic induction downregulated IL-6 and thrombopoietin, but upregulated IL-8, IL-13, IGF-I and IGFBP-2 in hCP sheets. When differentiated hCP sheets were implanted alone, areas of osteoid and mineralized tissue were formed within 2 weeks, but non-induced, immature hCP sheets did not produce much mineralization. These findings suggest that mature hCP sheets potentially function not only as seeds of ectopic bone formation without the need of synthetic tissue scaffolds, but also as living drug-delivery systems, to influence cells near implantation sites by producing several important cytokines. These two major characteristics indicate that a mature hCP sheet is a promising osteoinductive biomaterial, even without conventional scaffolds for periodontal regenerative therapy. Copyright (c) 2009 John Wiley & Sons, Ltd.

DOI： 10.1002/term.156

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DOI： 10.14833/amjsp.2009f.0.88.0

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今回われわれは、内側に転位していた左側関節円板が復位する際に生じる閉口障害(臼歯部の離開)を経験したので報告する。症例:35歳、女性。主訴:ときどき口が閉じにくいことがある。現病歴:以前に左側顎関節に雑音があったかどうかはっきり覚えていない。また、明らかな開口障害の記憶はない。1998年10月末、大開口時に大きな音がして、その直後から上下顎の歯が接触しない程度の閉口障害が生じた。この時点では下顎を左右に動かすことで閉口可能であった。症状に改善がないため、1998年11月9日当科初診した。MR所見にて関節円板の内側転位および円板が復位することによる閉口末期の閉口障害が疑われたが、患者の希望により経過観察となった。しかし、症状に改善はなく、逆に閉口障害の頻度が増し、日常生活に支障をきたすようになったため、5年後に再評価を行った。処置および経過:全身麻酔下に関節円板切除術を施行した。術後3日目より開口練習を開始した。現在、開閉口運動はスムーズで、開口量は49mm、閉口障害(左側臼歯部の離開)の出現はなく経過は良好である。本症例は、転位していた関節円板の復位に起因する臼歯部の離開という稀な症例であり、間欠的に長期に継続し、日常生活に支障をきたす場合の処置として外科的治療が選択肢の一つとなると思われた。(著者抄録)

DOI： 10.11246/gakukansetsu1989.20.16

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BACKGROUND. The objective of the current study was to identify biomarkers that reflect the clinical course of squamous cell carcinoma of the tongue (TSCC).
METHODS. TSCC tissue samples from 66 patients were subjected to gene expression analysis by real-time polymerase chain reaction. Eleven integrin family genes and 14 genes used for normalization, including housekeeping genes and genes that encode desmosomal, cytoskeletal, and extracellular matrix molecules, were considered. Multivariate statistical analysis was performed on 154 expression ratios of integrin genes with clinical parameters.
RESULTS. in principal-component analysis, the first principal component was related to the outcome of death, and the second principal component mainly reflected the tendency for cervical lymph node (LN) metastasis. The former axis consisted of the variance of the integrin beta 4 gene (ITGB4) and ITGB5 expression levels, and the latter axis agreed with the expression level of the integrin alpha 3 gene (ITGA3). Multivariate logistic regression analysis with cervical LN metastasis as the response variable concordantly identified ITGA3/junction plakoglobin gene (JUP) expression (P =.02) and ITGB5/paxillin gene (PXN) expression (P = .04) as significant factors. Only ITGB4/JUP expression was identified as a significant factor in terms of the outcome of death (P <.00049) by a Cox proportional hazards model. The group with high ITGB4/JUP levels exhibited a significantly high death rate on a Kaplan-Meier curve (P <.0001; Wilcoxon and log-rank tests).
CONCLUSIONS. The expression levels of ITGA3, ITGB4, and ITGB5 with functional normalization by desmosomal or cytoskeletal molecule genes were selected as candidate biomarkers for cervical LN metastasis or for the outcome of death in TSCC.

DOI： 10.1002/cncr23295

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Background: The balance between the degradation and synthesis of extracellular matrix determines periodontal attachment levels and alveolar bone matrix concentration in periodontal diseases. Matrix metalloproteinases (MMPs) are known to degrade periodontal ligamental attachment and bone matrix proteins. The purpose of this study was to examine the effect of different expression levels of MMPs and their inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs), in periodontitis.
Methods: Sixteen inflamed gingival tissue samples from subjects with generalized chronic periodontitis and 14 control tissue samples from systemically and periodontally healthy subjects were evaluated. The total RNA was extracted, and the transcript levels for MMP-1, -3, -9, and -13 and TIMP-1, -2, -3, and -4 relative to P-actin were determined by quantitative real-time reverse transcription - polymerase chain reaction.
Results: Gene transcript levels for MMP-1 and TIMP-4 were significantly higher in periodontitis-affected gingival tissues (P <0.05). MMP-3, -9, and - 13 and TIMP-1 mRNAs also were elevated in periodontitis; however, the difference was not statistically significant. TIMP-2 and -3 mRNA levels were similar in healthy and diseased gingivae. The ratios of MMP-1 /TIMP-2 (P <0.01), MMP-3/TlMP-2 (P<0.05), MMP-9/TIMP-2 (P<0.05), and MMP-1/TIMP-3 (P<0.01) from periodontitis lesions were significantly higher than those in the control tissues.
Conclusions: Upregulated MMP expression and an increased MMP/TIMP ratio indicate that a potential imbalance between degradation and synthesis of extracellular matrix persists in periodontitis-affected gingival tissues. This process may be responsible for increased tissue breakdown in periodontitis.

DOI： 10.1902/jop.2008.070159

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Background: Matrix metalloproteinase (MMP) is known to be involved in the initial and progressive stages of cancer development, and in the aggressive phenotypes of cancer. This study examines the association of single nucleotide polymorphisms in promoter regions of MMP-1 and MMP-3 with susceptibility to oral squamous cell carcinoma (OSCC).
Methods: We compared 170 Japanese OSCC cases and 164 healthy controls for genotypes of MMP-1 and MMP-3.
Results: The frequency of the MMP-1 2G allele was higher and that of the 1G homozygote was lower in the OSCC cases ( p = 0.034). A multivariate logistic regression analysis revealed that subjects who were 45 years old or older had a significantly increased (2.47-fold) risk of OSCC (95% CI 1.47-4.14, p = 0.0006), and those carrying the MMP-1 2G allele had a 2.30-fold risk (95% CI 1.15-4.58, p = 0.018), indicating independent involvement of these factors in OSCC. One of the key discoveries of this research is the apparent reduction of the MMP-1 1G/1G and 1G/2G genotype distributions among the early onset OSCC cases under the ages of 45 years. It should be noted that the tongue was the primary site in 86.2% of these early onset cases. This could suggest the specific carcinogenic mechanisms, i.e. specific carcinogenic stimulations and/or genetic factors in the tongue.
Conclusion: Since the 2G allele is a majority of the MMP-1 genotype in the general population, it seems to act as a genetic pre-condition in OSCC development. However this report suggests a crucial impact of the MMP-1 2G allele in the early onset OSCC.

DOI： 10.1186/1471-2407-7-187

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ドセタキセル(TXT)を用いた温熱化学療法の抗腫瘍効果および頸部リンパ節転移抑制効果について検討した。実験材料および方法:頬粘膜癌転移モデル(O-1N、扁平上皮癌)を用い、温熱群、化学(TXT)群、温熱化学群、無処置群の4群を設定した。加温はRF誘電型加温装置を用い、頬粘膜腫瘍に対し43℃、40分加温を3日間隔で2回施行した。TXTは10mg/kgを各加温直前に腹腔内投与した。実験後腫瘍の大きさを計測し、21日、28日に原発巣および頸部リンパ節を摘出、病理組織学的に検討し、転移リンパ節における腫瘍進展度を分類した。結果 腫瘍増大曲線では、無処置群で指数関数的に増大したのに比し、化学群では腫瘍増大抑制、温熱群、温熱化学群では腫瘍縮小効果が認められた。原発腫瘍消失率は、化学群0%、温熱群36.8%、温熱化学群は84.2%であり、温熱化学群において著明な抗腫瘍効果が認められた。リンパ節転移率は、無処置群が75.0%に対し、化学群は50.0%、温熱群では15.8%、温熱化学群では21.1%と低値を示した。無処置群に比し、温熱群と温熱化学群では有意に転移抑制効果が認められた。転移リンパ節における病理組織学的所見では無処置群は節外型が半数を超えていたのに対し、化学群、温熱群、温熱化学群では節内型が多くを占めた。以上、TXTによる温熱化学併用療法による抗腫瘍効果の増強が示唆された。(著者抄録)

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Apert症候群は頭蓋冠縫合早期異常癒合や合指症など特徴的な病態を呈し,Fibroblast growth factor receptor 2(FGFR2)遺伝子のセリン252トリプトファンあるいはプロリン253アルギニンなどのレセプター活性化型ミスセンスが頭蓋冠縫合部の骨芽細胞の分化を亢進することが原因とされている.一方でApert症候群において軟骨縫合の早期異常閉鎖がもう一つの主要な骨格異常であるにも関わらず,軟骨内における変異型FGFR2シグナリングの役割は定義されていない.この研究では,FGFR2の活性化が頭蓋顔面の軟骨性成長におよぼす影響について分子機構の一端を解明することを目的とした.実験動物にはApert症候群型変異Fgfr2遺伝子(Fgfr2IIIcP253R)を2型コラゲンのプロモーターによって軟骨組織特異的に発現するトランスジェニックマウス(Tgマウス)を用いた.変異Fgfr2IIICP253R遺伝子導入に伴いRunx2/Cbfa1,Indian hedgehog(Ihh),Matrix metalloproteinase 13(Mpm-13)遺伝子の検出レベル上昇が軟骨組織に観察され,FGFR2シグナリング活性化が軟骨分化に変化をもたらしたことが示唆された.組織所見における頭蓋底軟骨縫合の縮小と骨化亢進を考え合わせると,FGFR2シグナリングが軟骨性成長の抑制を通じて頭蓋底の成長を抑制的に調節すると考えられた.総じて,FGFR2シグナリングは骨芽細胞系と軟骨細胞系の細胞分化に対する統合的な調節作用を通じて頭蓋顔面の形態形成と発育に重要な役割を果たすことが示唆された(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2006232455

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Language：Japanese   Publisher：新潟歯学会  

1984年1月〜2002年に治療した口腔領域扁平上皮癌181症例中,原発巣再発がないのにも関わらず頸部リンパ節に後発転移をきたした17症例(男性9例,女性8例,60〜84歳)を対象に臨床病理学的に検討した.その結果,後発転移の発生時期は一次治療終了後平均5ヵ月(1〜12.5ヵ月)で,6ヵ月以内の発生が64.7%を占めており,N0症例の13.1%に後発転移が認められた.後発転移の予測因子として原発部位・T分類・組織学的分化度・浸潤様式・一次治療について検討したが,特徴的な所見は認められなかった.17例中15例(88.2%)に節外リンパ節転移を認め,頸部制御率は82.4%,累積生存率は3年70.6%・5年64.2%であり,初診時転移症例より良好であった.定期的に診査可能な症例では予防的頸部郭清術ではなく治療的頸部郭清術が望ましいものと考えられた

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

OBJECTIVE: To investigate the linkage between candidate genes on chromosome 19 and cleft lip with or without cleft palate in Japanese using a parametric method.
MATERIALS AND METHODS: After informed consent was obtained, blood samples were drawn from 90 individuals in 14 families, 30 of whom were affected, and genomic DNAs were extracted. PCR-amplified products using four microsatellite markers, D19S178, BCL3, APOC2[007/008] and APOC2[AC1/AC2] located in 19q13.2, were separated by 8% polyacrylamide gel electrophoresis. Linkage analysis was carried out using the MLINK and LINKMAP programs, and logarithm of odds (LOD) scores were calculated for each family.
RESULTS: Before undertaking linkage analysis, we analyzed 74 healthy Japanese subjects and found racial differences in that the observed number of alleles and their heterozygosity were lower in Japanese than in Caucasians, and that both populations tended to show a different allele distribution. In 14 families, two-point maximum LOD score (Z(max)) for BCL3 was 0.341 and multi-point Z(max) was less than -2 excluding linkage. But in 9 families with left and bilateral CL/P, two-point Z(max) for APOC2[AC1/AC2] was 1.701 and multi-point Z(max) at APOC2 locus was 1.909.
CONCLUSION: The LOD score was relatively high but provided no evidence of linkage for CL/P to BCL3 and nearby genes in Japanese subjects.

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これまで下顎骨原発の悪性腫瘍に対して温熱化学放射線療法を行ったとする報告はほとんどみられない.そこで,温熱化学放射線療法を施行した進行・再発下顎歯肉癌6例の治療結果について検討した.一次効果はComplete response(CR)が2例,Partial response(PR)が3例,No change(NC)1例で,奏効率は83.3%であった.全例除痛効果を認めた.後続治療としてPRとなった3例中2例は切除可能となった.切除物の病理組織学的所見では生存癌細胞なしと一部の生存癌細胞ありが各1例であった.5年累積局所制御率および生存率は66.7%であった.温熱化学放射線療法は進行・再発下顎歯肉癌に対する有力なtreatment strategyであることが示唆された

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Other Link： http://search.jamas.or.jp/link/ui/2005098920

Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY, INC  

Objective. To evaluate the occurrence and prognostic significance of perineural invasion (PNI) in squamous cell carcinomas (SCC) of the oral cavity and oropharynx.
Study design. A retrospective study of 101 patients with previously untreated SCC of the oral cavity and oropharynx was undertaken to evaluate the occurrence and prognostic significance of PNI in relation to local recurrence, regional recurrence, distant metastasis and survival. The logistic regression test was used for univariate and multivariate analyses. Actuarial survival curves were determined using the Kaplan-Meier method.
Results. PNI was present in 26 (25.7%) of 101 patients and was significantly associated with tumor differentiation, lymph node metastasis, and depth of invasion. Univariate analyses showed PNI was associated with local recurrence (P = .005), regional recurrence (P = .007), and distant metastasis (P = .013). In multivariate analysis, PNI was significantly associated with regional recurrence (P = .033) and distant metastasis (P = .021), but not with local recurrence (P = .109). The 5-year disease-specific survival for patients with and without PNI was 56.6% and 94.6%, respectively (P < .0001).
Conclusion. PNI is an important predictor for outcome of patients with SCC of the oral cavity and oropharynx.

DOI： 10.1016/j.tripleo.2003.10.014

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The purpose of this study was to evaluate the effects of maxillary growth of patients with complete bilateral cleft lip and palate (BCLP) treated by twostage palatal repair combined with a Hotz's plate.<BR>The subjects were 26 BCLP patients from 5 to 12 years of age who had received two-stage palatal repair combined with a Hotz's plate (TSPR). Serial maxillary casts were used to analyze and compare with those of 34 BCLP treated by one-stage palatal repair (OSPR), and 24 normal children without any clefts (NC).<BR>The results were as follows:<BR>1. The length and width of the maxillary arch in the TSPR group were the same as for the NC group in patients from 5 to 6 years of age (before hard palate closure).<BR>2. From 7 to 12 years of age (after hard palate closure), the length of the maxillary arch grew gradually in the TSPR group, just like in the NC group. The maxillary width tended to be slightly smaller in the TSPR group than in the NC group. On the other hand, the incidence of cross bite in lateral dentition was lower in the TSPR group than in the OSPR group.<BR>It was concluded that two-stage palatal repair combined with a Hotz's plate was effective for maxillary growth in bilateral cleft lip and palate patients.

DOI： 10.11277/stomatology1952.52.6

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

安静時の側方頭部X線規格写真をもとに口蓋裂症例の術前後の鼻咽腔形態の変化について,非口蓋裂症例を対照群として比較検討した.上顎の前方移動術により,口蓋裂群,対照群ともに咽頭の深さが増加した一方で,軟口蓋長の伸展,軟口蓋傾斜角の増加がみられ,軟口蓋-咽頭後壁間最短距離の変化は殆ど認められなかった.両群比較では口蓋裂群で軟口蓋長の伸長,咽頭の深さの増大が少なかった.瘢痕の強い症例では,前方移動量が5mm程度の場合,咽頭部の軟組織の変化が6割程度となることが示された

DOI： 10.5794/jjoms.48.501

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Language：Japanese   Publisher：新潟歯学会  

Hotz床併用二段階口蓋形成術を施行した唇顎口蓋裂73例86顎裂(男児46例・女児27例,平均10.2歳;二段階群)と他院にて2歳以前に一期的に口蓋形成術が行われ,二次的顎裂部骨移植術を施行した唇顎口蓋裂20例22顎裂(男児12例・女児8例,平均11.9歳;一段階群)における術後早期成績について検討した.その結果,骨架橋形成は片側性唇口蓋裂では96.6%,両側性では全例に認められ,垂直的骨架橋が上顎中切歯および側切歯で平均歯根長が11mm以上のものが二段階群では片側性で84.7%,両側性で66.7%,一段階群では片側性62.6%,両側性33.3%で,片側性が有意に高かった.又,歯槽頂の高さは上顎中切歯歯根の3/4以上あるものが二段階群片側性88.1%,両側性77.8%,一段階群片側性56.3%,両側性なしと二段階群で有意に高かった.以上により二段階群は上顎切歯の歯軸の改善や側切歯・犬歯の萠出誘導に有利であると考えられた

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DOI： 10.11277/stomatology1952.51.15

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入院患者の動向と今後の改善点を把握することを目的に,10年間の入院患者について,臨床統計学的に検討した.その結果,入院患者総数は,3481人で,男女比は1:1であり,疾患別では,唇顎口蓋裂を中心とした奇形が1216人と最も多く,30歳未満が過半数であった.居住地別では,市内・佐渡を除く下越地方の患者が6割以上を占めていた.今後の展望として,入院施設を有効に利用するには,集学的な治療を活かすことを考慮し対象疾患を選択し,専門的な治療体制作りが必要である.治療体制整備の一環として,新潟県各地に入院施設を持つ病院歯科・口腔外科が新設されつつある中,広い範囲で各病院歯科との役割分担の確立も重要である

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Language：Japanese   Publisher：(株)癌と化学療法社  

頭頸部癌の切除不能な進行例や再発例18例25病巣に対し,放射線療法に温熱化学(CDDP)療法を併用してきた.温熱群の治療成績について検討し,併せて温熱化学療法を導入前の放射線化学療法群(22例27病巣)を対照群とし比較検討した.温熱化学療法は週2回,平均8.8回行い,腫瘍内温度は延べ219回の内,185回(84.5%)は42℃以上に加温されていた.3種の加温システム(ラジオ波(RF)誘導型システム,マイクロ波システム,RF組織内システム)を用いた.温熱群ではcomplete response(CR)が11病巣(44.0%),partial response(PR)が12病巣(48.8%),no change(NC)が2病巣(8.0%)で,奏効率は92.0%であった.一方,対照群では,CRが5病巣(18.5%),PRが12病巣(44.5%),NCが10病巣(37.0%)で,奏効率は63.0%であった.CRT率と奏効率は両群間に有意差が認められた.更に5年累積局所制御率および生存率は温熱群ではそれぞれ68.2%,44.4%を示したのに対し,対照群ではそれぞれ22.2%,18.2%であった.局所制御率は両群間に有意差が認められた.以上,温熱化学放射線療法は進行頭頸部癌に有力な治療法であると考えられた

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Language：Japanese   Publisher：Japanese Stomatological Society  

To clarify the mechanisms of the developmental anomaly of the tooth adjacent to the alveolar cleft, the maxillary incisor close to the cleft, the form of the alveolar cleft and the maxillofacial malformation combined with the cleft in CL/ Fr strain mouse with spontaneous cleft lip and/or alveolus (CL / A) were observed.<BR>Among 2340 offspring, a total of 515 mice (22.0%) with cleft lip and/or palate (CL/P) were observed. In this study, 11 mice with CL/P survived till weaning (3 weeks). The cleft patterns of survived mice were CL/A.<BR>In the dry skull observation, the alveolar clefts existed outside of the piriform apertura to the anterior part of the anterior palatine foramen. There were various types of cleft such as the wedge-shaped bone defect outside of the piriform apertura, the narrow cleft like bone suture, and the cleft separating the premaxilla into two parts.<BR>The side shift of the maxilla and/or premaxilla were observed in all cases. They tended to bend to the non-cleft side (6 out of 7 cases). Incisor anomalies on the cleft side were also observed, for example, tooth width reduction, rough enamel surface, and/or root shortening.<BR>As a result, the degree of tooth anomaly depended on the type of alveolar cleft.<BR>In conclusion, it was suggested that the developmental anomaly of maxillary incisor in CL/P mice was related to the cause of the cleft.

DOI： 10.11277/stomatology1952.48.454

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Language：Japanese   Publisher：JAPANESE SOCIETY OF PEDIATRIC ORAL AND MAXILLOFACIAL SURGERY  

A case of regional odontodysplasia with osteomyelitis in the left mandilble was reported.<BR>A 3-year-old boy was referred to our clinic complaining of spontaneous pain of the left mandibular molar region.<BR>At first visit, severe swelling and redness were observed at the left buccal and submandibular region extraorally and from the lower left primary canine to retromolar region intraorally.<BR>The lower left primary second molar had not erupted completely. The enamel surface of this tooth was rough.<BR>The radiograph of the left mandible showed ghost-like appearances of the lower left primary canine and second molar. A radiolucent area was observed at the apical region of the lower left primary second molar. The germs of the lower left permanent canine and first molar were hypop-lastic and the germs of the lower left first and second premolar were not formed.<BR>The lower left primary second molar was extracted, after the inflammatory symptoms disappeared.<BR>Histological examination of the lower left primary first molar revealed that the enamel and dentin were thin, hypoplastic and hypocalcified. The dystrophic calcification was observed along the enamel surface.

DOI： 10.11265/poms1991.8.2_8

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口唇裂又は口唇口蓋裂児の母親75名(口唇裂群),口蓋裂児の母親32名(口蓋裂群),及び,対照として1993年に出生した健常児の母親201名(以下,健常群)に作成した質問票を用いて,聞き取り方式で行い,それぞれの調査項目において各群を比較し検討した.その結果,口唇裂群では妊娠初期の感冒罹患の有無で健常群との間で有意差が認められ,口唇裂口蓋裂発生との関連が示唆された

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Language：English   Publisher：AMER SOC CELL BIOLOGY  

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Language：Japanese   Publisher：日口蓋誌  

Cleft lip and/or palate is a malformation of relatively high incidence in Japan. Many studies have reported its incidence, however, there were little of recent surveys based on a large size of population. Since it is expected to have some changes of social environmental factors such as maternal aging, present study is aimed to investigate current rate of incidence using a questionnaire at the maternity hospitals in Niigata Prefecture from November,1994 to October,1995.&lt;BR&gt;A total of 20566 new born infants were examined, and 36 had cleft lip and /or palate (0.175 %). Among those 36 infants with cleft lip and/or palate,13 had cleft lip,15 had cleft lip and palate, and 8 had cleft palate. Of the 13 infants with cleft lip,11 were unilateral and 2 were bilateral type of cleft. Of the 15 infants with cleft lip and palate,11 were unilateral and 4 were bilateral.&lt;BR&gt;As for the sex,6 males and 7 females were in infants with cleft lip,10 males an d 5 females in infants with cleft lip and palate, and 1 male and 7 females in infants with cleft palate only.&lt;BR&gt;Association of malformations were recognized in 9 out of the 36 infants (25.0 %) includi ng syndromes of Pierre-Robin, Opitz, Down,18 trisomy, and defects of the brain, skull, heart, limbs, and auricle.

DOI： 10.11224/cleftpalate1976.22.3_138

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Language：Japanese   Publisher：日口蓋誌  

In patients who undergo two-stage palatoplasty of cleft lip and palate, the residual hard palate cleft gradually narrows after velar closure. Depending on the type, the cleft borders may come close together or remain slightly apart. In this study, the residual hard palate cleft after veloplasty, performed according to the modified Widmaier technique described by Perko, was examined for changes by using serial maxillary casts obtained from 53 patients one year and six months to six years of age. The results were as follows:&lt;BR&gt;1. The residual cleft spontaneously narrowed until four years of age and showed no statistically significant changes there after.&lt;BR&gt;2. The anterior cleft width was reduced to 15% and 55% of that at the velar closure in unilateral and bilateral cleft alveolus and palate, respectively. On the other hand, the posterior cleft width was reduced to 50% in both cleft types.&lt;BR&gt;3. In two patients with unil ateral cleft alveolus and palate, the cleft borders came into contact and apparently disappeared.&lt;BR&gt;4. As the maxillary alveolar width was not reduced, the narrowing of the hard palate cleft was thought to be due to growth of the palatal shelves in the medial direction.&lt;BR&gt;5. A difference in attachment of the nasal septum to the maxil lary segments had no influence on the narrowing of the hard palate cleft.

DOI： 10.11224/cleftpalate1976.21.3_126

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：Japanese   Publisher：(公社)日本口腔インプラント学会  

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Language：Japanese   Publisher：(一社)日本口蓋裂学会  

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Language：Japanese   Publisher：(一社)日本母乳の会  

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本小児口腔外科学会  

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Language：Japanese   Publisher：(一社)日本小児口腔外科学会  

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Objective: Although the pathogeneses of Alzheimer's disease (AD) and periodontal diseases have overlapping features, including ageing and chronic inflammation, the association between AD and periodontitis remains unclear. To explore the pathogenesis of periodontitis, a comprehensive gene expression/transcriptome analysis in periodontitis-affected gingival tissues found that the AD pathway was significantly up-regulated in periodontitis-affected gingival tissues. AD-related genes, amyloid beta precursor protein (APP), interleukin-1 beta and compliment 1QA, were significantly elevated in periodontitis. In the present study, balance between mRNA expression of APP and a potent amyloid degradation enzyme, neprilysin (NEP), as well as protein localisation of APP and NEP were analysed.
Design: Eighteen periodontitis-affected and 18 clinically healthy control gingival tissues were taken from patients with severe chronic periodontitis or undergoing tooth extraction. Total RNA was purified and used for quantitative reverse transcription real-time polymerase chain reaction (qRT-PCR). The localisation of APP and NEP was analysed by immunohistochemistry (IHC).
Results: Both APP and NEP genes were up-regulated in periodontitis-affected gingival tissues. APP expressing macrophages and NEP-expressing neutrophils and fibroblasts, reflecting inflammatory stages, were detected in inflamed gingival tissues by IHC.
Conclusion: The up-regulation of APP and NEP mRNA levels in periodontitis-affected gingival tissues compared with healthy controls was confirmed by qRT-PCR analyses. Since NEP is one of the primary enzymes that degrades amyloid beta, increased NEP mRNA levels in periodontitis may act as an inhibitor of amyloid beta accumulation in gingival tissues, balancing increased APP mRNA expression. However, NEP has several effects including degradation of vasoactive substances; therefore, further sresearch is needed. (C) 2017 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.archoralbio.2017.03.003

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マレイン酸イルソグラジン(IM;商品名 ガスロンN)は広く臨床で使用されている胃炎・胃潰瘍治療剤であり、ギャップ結合細胞間コミュニケーション活性化作用や抗炎症作用などが明らかにされている。我々はC57BL/6Jマウスに3%Dextran sulfate sodium(DSS)を自由飲水させて腸炎を惹起し、IMを注腸投与し、その効果を検討した。病態コントロール群に比べ、IM治療群ではDSS腸炎の臨床所見・病理組織学的所見が改善した。このメカニズムとして、IMは、DSSによる粘液分泌減少を抑制し、タイトジャンクションやギャップ結合の機能を改善させている可能性が示唆された。(著者抄録)

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DOI： 10.14833/amjsp.2011f.0.49.0

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

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DOI： 10.14833/amjsp.2011f.0.93.0

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

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Language：Japanese   Publisher：日本消化器免疫学会  

近年、angiotensin II(Ang II)は炎症誘発メディエーターと考えられ、Ang IIの作用を阻害することによる抗炎症効果が様々な臓器で報告されている。我々はC57BL/6Jマウスに3% Dextran sulfate sodium(DSS)を自由飲水させて腸炎を惹起し、angiotensin II type 1 receptor blocker(ARB)であるTelmisartan(TELM)を注腸投与し、その効果を検討した。対照群に対し、TELM投与群では、ほぼ用量依存的にDSS腸炎の臨床所見・病理組織学的所見が悪化した。一方で、PCNA陽性細胞数が増加し残存陰窩が伸長するなどの組織修復へ向かう所見も認められた。今後、実験モデルや投与量・投与経路の検討を行う必要があると考えられた。(著者抄録)

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DOI： 10.14833/amjsp.2009f.0.88.0

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2009&ichushi_jid=J00990&link_issn=&doc_id=20090728040006&doc_link_id=%2Fdg3nigta%2F2009%2F012304%2F006%2F0193-0193%26dl%3D2&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2009%2F012304%2F006%2F0193-0193%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

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口腔扁平上皮癌(OSCC)170名を対象とし,罹患状況とMatrix Metalloproteinase(MMP)-1遺伝子多型との関連について検討した.遺伝子型分布を健常者188人と比較したところ,2G/2G,又は1g/2Gの遺伝子型はOSCC群において有意に高く,1G/1G型は有意に少なかった.年齢分布を比較したところ,OSCC群は1G/1G型の頻度が低く,特に若年層では分布の消失がみられた.多重ロジスティック回帰分析では,OCSSの有無は「年齢」「2G+」の因子が各々独立してOSCC発症と強い因果関係を有していた.MMP-1遺伝子一塩基多形がOSCC易罹病性に関与する可能性が示唆され,特に若年発症例において強い影響力を持つことがわかった

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Other Link： http://search.jamas.or.jp/link/ui/2006232460

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Other Link： http://search.jamas.or.jp/link/ui/2006109724

Language：English   Publisher：CHURCHILL LIVINGSTONE  

We quantified telomerase activity (TA) in patients with oral and maxillofacial malignant and nonmalignant lesions, and compared it with their clinical status and grade of malignancy.
Fifty-two malignant and 52 nonmalignant lesions were analyzed. All malignant lesions were pathologically diagnosed as oral squamous cell carcinoma (OSCC). Normal gingival tissue served as a control. These specimens were obtained by biopsy or surgical resection, and stored at -80 degreesC until use. TA was quantified by a fluorescence-based TRAP method.
TA levels ranged from 0.00 to 95.24 (average 33.24) U/mugP in 52 malignant lesions, and from 0.00 to 79.35 (average 11.91) U/mugP in 52 nonmalignant lesions (P &lt; 0.0001). TA was detected in 96.2% of malignant and 65.4% of nonmalignant lesions. There was no relationship between TA levels and clinical stages or YK classification. However, under WHO classification, there were significant differences (P &lt; 0.05) between Grades I and III or II + III.
Among nonmalignant lesions, epithelial dysplasia showed a significantly higher TA level than that of oral lichen planus (P &lt; 0.05) and other benign lesions (P &lt; 0.0001). Oral lichen planus also significantly differed from other benign lesions (P &lt; 0.05).
These results suggest that TA is related to the histological grade of malignancy, and is also useful as a prognostic predictor for precancerous lesions and conditions.

DOI： 10.1016/j.ijom.2004.01.016

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Other Link： http://search.jamas.or.jp/link/ui/2004181239

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We surveyed the expression of 557 cancer-related genes in 15 cases of well-differentiated OSCC by cDNA microarray analysis. To identify potential biomarkers for lymph node metastasis, all microarray data were compared by the Mann-Whitney test and the significance analysis of microarrays between OSCCs with and those without lymph node metastasis. The tissues of OSCCs with lymph node metastasis exhibited increased expression levels of MMP-1, MMP-3, uPA, integrin-alpha3, paxillin, tenascin C and IL-6 transcripts. All of these genes were included in common clusters on the Cluster/TreeView analysis, implying that functional gene, groups of proteolytic enzymes and integrin-related molecules are involved in cervical lymph node metastasis. The results of RTQ-PCR for differentially expressed genes were in accord with those of cDNA microarray analyses, suggesting that the data obtained by microarray gene expression analyses were valid. Consistent with cooperative expression patterns, immunohistochemical analyses demonstrated that products of MMP-1, MMP-3 and uPA were colocalized to components of the neoplastic stroma, particularly mononuclear inflammatory cells with well-developed eosinophilic cytoplasm. Our results suggest that expression levels of molecules involved in tissue remodeling and cell-ECM adhesion, especially MMP-1 and integrin-alpha3, can provide an accurate biomarker system for predicting the risk of cervical lymph node metastasis in OSCC. (C) 2003 Wiley-Liss, Inc.

DOI： 10.1002/ijc.11283

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Language：English   Publisher：WILEY-LISS  

We surveyed the expression of 557 cancer-related genes in 15 cases of well-differentiated OSCC by cDNA microarray analysis. To identify potential biomarkers for lymph node metastasis, all microarray data were compared by the Mann-Whitney test and the significance analysis of microarrays between OSCCs with and those without lymph node metastasis. The tissues of OSCCs with lymph node metastasis exhibited increased expression levels of MMP-1, MMP-3, uPA, integrin-alpha3, paxillin, tenascin C and IL-6 transcripts. All of these genes were included in common clusters on the Cluster/TreeView analysis, implying that functional gene, groups of proteolytic enzymes and integrin-related molecules are involved in cervical lymph node metastasis. The results of RTQ-PCR for differentially expressed genes were in accord with those of cDNA microarray analyses, suggesting that the data obtained by microarray gene expression analyses were valid. Consistent with cooperative expression patterns, immunohistochemical analyses demonstrated that products of MMP-1, MMP-3 and uPA were colocalized to components of the neoplastic stroma, particularly mononuclear inflammatory cells with well-developed eosinophilic cytoplasm. Our results suggest that expression levels of molecules involved in tissue remodeling and cell-ECM adhesion, especially MMP-1 and integrin-alpha3, can provide an accurate biomarker system for predicting the risk of cervical lymph node metastasis in OSCC. (C) 2003 Wiley-Liss, Inc.

DOI： 10.1002/ijc.11283

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新潟大学歯学部附属病院口腔外科顎顔面外科診療室において,1976〜2001年に,有茎及び遊離皮弁による一次再建手術を施行した舌癌13例,口底癌17例,計30例を対象とした.5年累積生存率は舌癌69.2%,口底癌81.4%であった.又,皮弁の生着は,完全生着26例,部分壊死4例で,全部壊死はなかった.術後機能は,舌部分切除例,口底側方切除例,舌口底半側切除例共に,比較的良好に温存されていたが,口底前方切除例では機能の低下がみられ,舌亜全摘例においては,重度の機能障害が遺残していた.咀嚼機能では歯の欠損もともなうため,補綴処置が不可能な場合には十分な機能回復が得られていなかった

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publisher：SPRINGER-VERLAG  

The localization and biosynthesis of basement membrane-type heparan sulfate proteoglycan (HSPG), known as perlecan, were studied in ameloblastomas using surgical tissue sections and cells in primary culture to demonstrate the existence of extracellular matrix (ECM) molecules in the intercellular space of epithelial tissue. HSPG was immunolocalized in the intercellular spaces of stellate reticulum-like cells and small vacuolar structures between basal cells in tumor cell nests as well as in myxofibrous stroma. By means of in-situ hybridization, mRNA signals for the HSPG core were intensely demonstrated in the cytoplasm of basal and parabasal cells of parenchyma. Furthermore, the in-vitro biosynthesis of HSPG core protein by ameloblastoma cells was confirmed using immunofluorescence, immunoprecipitation, and reverse-transcriptase polymerase chain reaction (RT-PCR). The results indicated that ameloblastoma cells synthesize HSPG and deposit it in their intercellular space. The intercellular HSPG might act as a carrier for transport of nutrients to tumor cells within ameloblastomatous foci.

DOI： 10.1007/s00428-001-0556-y

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Language：English   Publisher：SPRINGER-VERLAG  

The localization and biosynthesis of basement membrane-type heparan sulfate proteoglycan (HSPG), known as perlecan, were studied in ameloblastomas using surgical tissue sections and cells in primary culture to demonstrate the existence of extracellular matrix (ECM) molecules in the intercellular space of epithelial tissue. HSPG was immunolocalized in the intercellular spaces of stellate reticulum-like cells and small vacuolar structures between basal cells in tumor cell nests as well as in myxofibrous stroma. By means of in-situ hybridization, mRNA signals for the HSPG core were intensely demonstrated in the cytoplasm of basal and parabasal cells of parenchyma. Furthermore, the in-vitro biosynthesis of HSPG core protein by ameloblastoma cells was confirmed using immunofluorescence, immunoprecipitation, and reverse-transcriptase polymerase chain reaction (RT-PCR). The results indicated that ameloblastoma cells synthesize HSPG and deposit it in their intercellular space. The intercellular HSPG might act as a carrier for transport of nutrients to tumor cells within ameloblastomatous foci.

DOI： 10.1007/s00428-001-0556-y

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Language：English   Publisher：WILEY-LISS  

During early mouse embryogenesis, cranial neural crest cells (CNCC) emigrate from the posterior midbrain and rhombomeres I and 2 of the anterior hindbrain into the first branchial arch-derived maxillary and mandibular processes and there provide cell lineages for several phenotypes, including cartilage, bone, and tooth. Here, we report that Sox9 and Msx2 were coexpressed in a subpopulation of CNCC during their migration. Because Sox9 is a transactivator of chondrogenesis, and Msx genes can act as transcriptional repressors, we hypothesized that Sox9 expression indicates the determination of CNCC-derived chondrogenic cell lineage and that Msx2. represses chondrogenic differentiation until CNCC migration is completed within the mandibular processes. To test whether Msx2 represses chondrogenesis,, we designed experiments to inhibit Msx2 function in migratory CNCC in primary cultures through the expression of loss-of-function Msx2 mutants. We showed that infection of migratory CNCC with adenovirus Msx2 mutants accelerated the rate and extent of chondrogenesis, as indicated by the expression level of type II collagen and aggrecan, and the amount of alcian blue staining. Adenovirus infections did not apparently interfere with CNCC proliferation or migration. These findings suggest that an important early event in craniofacial morphogenesis is a transient expression of both Sox9 and Msx2 during emigration into the forming mandibular processes followed by restricted expression of Sox9 within CNCC-derived chondroprogenitor cells. We conclude that Msx2 serves as a repressor of chondrogenic differentiation during CNCC migration. Published 2001 Wiley-Liss, Inc.

DOI： 10.1002/dvdy.1185

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Language：Japanese   Publisher：(一社)日本形成外科学会  

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Language：Japanese   Publisher：(一社)日本口蓋裂学会  

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Language：Japanese   Publisher：Japan Society for Head and Neck Cancer  

Eighteen patients with 25 unresectable advanced or recurrent head and neck cancers (squamous cell carcinomas) received thermochemotherapy in combination with radiotherapy. The total radiation dose ranged from 50 to 82 Gy (mean, 65.6Gy). Patients received thermochemotherapy twice a week, for a total number of 8.8 sessions, on average. The temperature in the tumor, as a result of the hyperthermia, was over 42°C in 185 (84.5%) of the 219 treatments. Three kinds of heating systems were used: a 13.56-MHz radiofrequency system, a 2450-MHz microwave system, and a radiofrequency interstitial system. The total amount of administered CDDP ranged from 40 to 300mg (mean, 110mg), combined with PEP and/or 5FU. Background factors (tumor factors and treatment factors) were investigated in detail, and the clinical results (tumor response and the 5-year cumulative focal control rate) were evaluated. The relationship between these two results was then analyzed using univariate and multivariate statistics.<br>The clinical results of patients with a WHO histological classification of grade 3 were poor compared with patients with a classification of grade 1 or 2. The difference between these two results was significant when analyzed using univariate statistics, but not significant when analyzed using multivariate statistics. The clinical results of patients with primary lesions surrounded by bony tissues were slightly poor compared with those of patients whose lesions were surrounded by soft tissues, but the difference between these two results was not significant. Successful treatment of refractory recurrent tumors, large tumor masses, and diffuse invasive carcinomas was not affected by the treatment factors (heating systems, heating sessions, radiation dose, and CDDP dose and drug combination).<br>These results suggest that refractory recurrence, proximity to bony tissues, tumor size, and histological malignancy might not be prognostic variables for thermochemoradiotherapy strategy in patients with advanced or recurrent head and neck cancers.

DOI： 10.5981/jjhnc1974.27.181

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Other Link： http://search.jamas.or.jp/link/ui/2004063199

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

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Language：Japanese   Publisher：新潟歯学会  

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Language：Japanese   Publisher：(一社)日本小児口腔外科学会  

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Language：Japanese   Publisher：Japanese Society of Oral and Maxillofacial Surgeons  

We retrospectively investigated the clinical findings and treatment of cleft lip, cleft palate, or both associated with chromosomal karyotype aberration. The patients were examined at the Second Department of Oral and Maxillofacial Surgery, Niigata University Dental Hospital between April 1982 and March 1998.<BR>The findings obtained were as follows:<BR>1. Twelve of 806 patients with cleft lip, cleft palate, or both (1.5%) had chromosomal aberrations. Four of these patients had bilateral cleft lip, alveolus, and palate, and 8 had cleft palate. In 10 primary cases, the incidence of chromosomal aberrations was 4.4%(3/68) in patients with bilateral cleft lip, alveolus, and palate and 5.1%(7/138) in patients with cleft palate.<BR>2. Various types of chromosomal aberrations (No.13, 15, 21 numerical abnormalities and No.1, 2, 4, 5, 6, 7, 9, 13, 18, 21 structural abnormalities) were found, but there was no evidence of an association between the type of chromosomal aberration and the type of cleft lip or palate.<BR>3. A history of spontaneous abortion was confirmed in the mothers of five patients, and similar chromosomal aberrations in blood relatives were confirmed in two patients.<BR>4. Eight patients had major anomalies, and all 12 had minor anomalies. Mental retardation was confirmed in all patients.<BR>5. Among 10 patients with primary cleft lip, cleft palate, or both, 1 underwent cheiloplasty and 5 underwent palatoplasty under general anesthesia. After the physical condition of the patient had stabilized, cheiloplasty was carried out at about 1 year of age and palatoplasty at 2 to 3 years of age in close cooperation with pediatricians and anesthesiologists. To minimize trauma, surgery should be done in one step.

DOI： 10.5794/jjoms.46.519

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Other Link： http://search.jamas.or.jp/link/ui/2001055931