Kazuo Shimozato

Aichi Gakuin University, Nagoya, Aichi, Japan

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Publications (93)126.18 Total impact

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    ABSTRACT: Management of oral leukoplakia - a potentially malignant disorder - is currently not evidence-based. Of the few randomized trials that have been reported, most have negative data. Therefore, a multi-centre, randomized, double-blind controlled trial (RCT) was undertaken to evaluate the use of low-dose beta-carotene combined with vitamin C supplements for the treatment and to prevent malignant transformation of oral leukoplakia.46 Japanese participants with oral leukoplakia were allocated randomly either to an experimental arm (10mg/day of beta-carotene and 500mg/day of vitamin C) or placebo arm (50mg/day of vitamin C). Current or ex-smokers within 3 months of cessation were excluded. The supplements were continued over a period of 1 year. The primary endpoint was clinical remission at 1-year and the likelihood of malignant transformation during a 5-year follow-up period as a secondary endpoint.The overall clinical response rate in the experimental arm was 17.4% (4/23) and 4.3% (1/23) in the placebo arm (P=0.346). During the median 60-month follow-up period, two subjects in the experimental arm and three in the control arm developed oral cancer. Under the intention-to-treat principle, relative risk by supplementing with beta-carotene and vitamin C was 0.77 (95%CI: 0.28-1.89) (P=0.580) by the Cox proportional hazards model. No unfavourable side-effects were noted.Beta-carotene (10mg/day) and vitamin C were neither effective for clinical remission, nor for protection against the development of cancer. Data from this RCT does not support the hypothesis that chemoprevention with this treatment is effective for oral leukoplakia. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 04/2015; 136(7). DOI:10.1002/ijc.29156 · 5.01 Impact Factor
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    ABSTRACT: Mammary analogue secretory carcinoma (MASC) is a recently described low-grade carcinoma with morphologic and genetic similarity, including ETV6-NTRK3 fusion, to secretory carcinoma of the breast. ETV6 is frequently involved in other epithelial and nonepithelial tumors, and many fusion partners of ETV6 have been reported. In the present study, 14 Japanese MASC cases were clinicopathologically and molecularly analyzed. The median age of the patients was 39 years, and the male:female ratio was 6:8. All cases showed histopathologic findings compatible with those previously described for MASC and harbored an ETV6 split as visualized by fluorescence in situ hybridization. Two cases showed thick fibrous septa and invasive features including vascular or perineural tumor involvement, findings that are rare in MASC. In addition, in these 2 cases, non-NTRK3 genes appeared to fuse with ETV6 (ETV6-X fusion). NTRK1 and NTRK2, both members of the NTRK family, were not involved. Of the 14 MASC cases, the ETV6-NTRK3 fusion transcript was positive in 6 cases, and the relative expression level of the ETV6-NTRK3 fusion transcript was variable, ranging from 1 to 5.8. Results of the present study of MASC suggest that (1) ETV6 occasionally fuses with unknown non-NTRK3 genes, (2) ETV6-X cases might have an invasive histology, (3) for molecular diagnosis of MASC, fluorescence in situ hybridization to detect ETV6 splits is the method of choice, and (4) the expression level of the ETV6-NTRK3 fusion transcript is considerably variable. These findings provide a novel insight into the oncogenesis, histopathology, diagnosis, treatment, and prognosis of this newly recognized carcinoma.
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    ABSTRACT: Androgen receptor (AR) is usually expressed in salivary duct carcinoma (SDC), but only infrequently in other carcinoma types including mucoepidermoid carcinoma (MEC). The clinicopathological characteristics of AR-positive MEC remain to be clarified. Here we report a case of AR-positive MEC. A 76-year-old man presented with a growing painless tumor of the right parotid. The resected tumor was a high-grade tumor with necroses. Since the tumor was positive for AR, GCDFP-15, and HER2, SDC was first suspected, but it was also positive for CK5/6 and P63, and negative for S-100 protein and α-smooth muscle actin. In addition, scattered mucous secreting tumor cells were found in the tumor nests, and they were positive for Alcian blue. A diagnosis of AR-positive MEC was finally made. The patient died of the tumor 5 years after the surgery. The present case may expand the histopathological spectrum of high-grade MEC. © The Author(s) 2015.
    International Journal of Surgical Pathology 01/2015; DOI:10.1177/1066896914565024 · 0.96 Impact Factor
  • Journal of Oral and Maxillofacial Surgery 09/2014; 72(9):e141-e142. DOI:10.1016/j.joms.2014.06.255 · 1.28 Impact Factor
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    ABSTRACT: Since MSX1 and PAX9 are linked to the pathogenesis of nonsyndromic tooth agenesis, we performed detailed mutational analysis of these two genes sampled from Japanese patients. We identified two novel MSX1 variants with an amino acid substitution within the homeodomain; Thr174Ile (T174I) from a sporadic hypodontia case and Leu205Arg (L205R) from a familial oligodontia case. Both the Thr174 and Leu205 residues in the MSX1 homeodomain are highly conserved among different species. To define possible roles of mutations at these amino acids in the pathogenesis of nonsyndromic tooth agenesis, we performed several functional analyses. It has been demonstrated that MSX1 plays a pivotal role in hard tissue development as a suppressor for mesenchymal cell differentiation. To evaluate the suppression activity of the variants in mesenchymal cells, we used the myoD-promoter, which is one of convenient reporter assay system for MSX1. Although the gene products of these MSX1 variants are stable and capable of normal nuclear localization, they do not suppress myoD-promoter activity in differentiated C2C12 cells. To clarify the molecular mechanisms underlying our results, we performed further analyses including electrophoretic mobility shift assays, and co-immunoprecipitation assays to survey the molecular interactions between the mutant MSX1 proteins and the oligonucleotide DNA with MSX1 consensus binding motif or EZH2 methyltransferase. Since EZH2 is reported to interact with MSX1 and regulate MSX1 mediated gene suppression, we hypothesized that the T174I and L205R substitutions would impair this interaction. We conclude from the results of our experiments that the DNA binding ability of MSX1 is abolished by these two amino acid substitutions. This illustrates a causative role of the T174I and L205R MSX1 homeodomain mutations in tooth agenesis, and suggests that they may influence cell proliferation and differentiation resulting in lesser tooth germ formation in vivo.
    PLoS ONE 08/2014; 9(8):e102944. DOI:10.1371/journal.pone.0102944 · 3.53 Impact Factor
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    ABSTRACT: Tooth agenesis is one of the most common congenital anomalies in humans. However, the etiology of tooth agenesis remains largely unclear, as well as evidence base useful for genetic counseling. Therefore, we estimated the prevalence and sibling recurrence risk, and investigated agenetic patterns systematically. Tooth agenesis was classified into two subtypes: hypodontia (one to five missing teeth) and oligodontia (six or more missing teeth). The prevalence of these two subtypes were 6.8% (95% CI: 6.1 to 7.7%) and 0.1% (95% CI: 0.04 to 0.3%), respectively, and sibling recurrence risk of these were 24.5 (95% CI: 13.8 to 38.3%) and 43.8% (95% CI: 26.4 to 62.3%), respectively. This result suggests that the severe phenotype, oligodontia, might be mostly transmitted in a dominant fashion. Using a simple statistical modeling approach, our data were found to be consistent with a bilateral symmetry model, meaning that there was equal probability of missing teeth from the right and left sides.
    Clinical Genetics 07/2014; DOI:10.1111/cge.12456 · 3.65 Impact Factor
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    ABSTRACT: Iris hypoplasia (IH) is rare autosomal dominant disorder characterized by a poorly developed iris stroma and malformations of the eyes and umbilicus. This disorder is caused by mutation of the paired-like homeodomain 2 (PITX2) gene. Here, we describe a novel PITX2 mutation (c.205C4T) in an IH family presenting with very mild eye features but with tooth agenesis as the most obvious clinical feature. Human Genome Variation (2014) 1, 14005; doi:10.1038/hgv.2014.5; published online 31 July 2014 Mutations in the PITX2 (paired-like homeodomain 2) gene are associated with three allelic disorders: iris hypoplasia (IH), iridogoniodysgenesis syndrome (IGDS; OMIM 137600) and Axenfeld-Rieger syndrome (ARS; OMIM 180500). 1–3 Various dental abnormalities including tooth agenesis are also found in IH, IGDS and ARS, which are characterized by abnormal development of the anterior segment of the eyes and umbilicus anomalies. 1–4 IH shows the mildest phenotype among the three, characterized by only iris hypoplasia and glaucoma. 1,5 IGDS presents with goniodysgenesis in addition to iris hypoplasia and glaucoma. 2
    06/2014; 1. DOI:10.1038/hgv.2014.5
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    ABSTRACT: Mucous membrane pemphigoid (MMP) is a rare autoimmune bullous disease caused by various autoantibodies. This study aimed to evaluate the diagnostic value of MMP-specific autoantibodies in patient sera. We analyzed sera from 30 MMP-suspected patients with intractable oral mucosal lesions using a combination of indirect immunofluorescence with 1M NaCl-split skin, immunoblot analysis, and ELISAs. We also analyzed clinical features among different types of MMP. Seventeen, 4, and 3 patients were diagnosed with anti-BP180-type MMP, anti-laminin-332-type MMP, and combined anti-BP180/anti-laminin-332-type MMP, respectively. Our results indicated that a combination of immunologic testing for circulating autoantibodies is useful for the diagnosis of MMP.
    12/2013; 117(4). DOI:10.1016/j.oooo.2013.12.402
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    ABSTRACT: Nonsyndromic tooth agenesis is one of the most common anomalies in human development. Part of the malformation is inherited and is associated with paired box 9 (PAX9), msh homeobox 1 (MSX1), and axin 2 (AXIN2) mutations. To obtain a comprehensive understanding of the genetic and molecular mechanisms that underlie this genetic disease, we investigated six familial and seven sporadic Japanese cases of nonsyndromic tooth agenesis. Searches for mutations in these candidate genes detected a novel nonsense mutation (c.416G>A) in exon 1 of MSX1 from a family with oligodontia. This mutation co-segregated in the affected family members. Moreover, this mutation produced a termination codon in the first exon and therefore the gene product (W139X) was truncated at the C terminus, hence, the entire homeodomain/MH4, which has many functions, such as DNA binding, protein-protein interaction, and nuclear localization, was absent. We characterized the properties of this truncated MSX1 by investigating the subcellular localization of the mutant gene product in transfected cells. The wild-type MSX1 localized exclusively at the nuclear periphery of transfected cells, whereas the mutant MSX1 was stable but localized diffusely throughout the whole cell. These results indicate that W139X MSX1 is responsible for tooth agenesis.
    European Journal Of Oral Sciences 12/2013; DOI:10.1111/eos.12105 · 1.73 Impact Factor
  • International Journal of Oral and Maxillofacial Surgery 10/2013; 42(10):1315. DOI:10.1016/j.ijom.2013.07.493 · 1.36 Impact Factor
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    ABSTRACT: For the study of Candida albicans genotypes involved in development of candidiasis, Candida albicans isolates were collected from healthy volunteers and patients with oral candidiasis and genotyped on the basis of 25S rDNA and microsatellite polymorphisms. In the microsatellite analysis using two microsatellite markers (CDC3 and CAI), 63 healthy volunteer isolates were classified into 35 genotypes (allelic relations to CDC3 alleles 1:2/CAI alleles 1:2), among which genotypes II (115:119/23:23), III (115:123/18:27), and V (123:127/32:41) were found at frequencies of 12.7 %, 7.9 %, and 7.9 %, respectively. In 68 oral candidiasis isolates classified into 39 genotypes, genotypes II and III were identified in 4.4 % and 20.6 % of the isolates, respectively. The frequency of genotype III was higher in the candidiasis isolates than in the healthy isolates (p < 0.05). These results suggest that genotype III C. albicans assigned by CDC3/CAI is related to the development of oral candidiasis.
    Journal of Infection and Chemotherapy 06/2013; 19(6). DOI:10.1007/s10156-013-0626-5 · 1.38 Impact Factor
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    ABSTRACT: N-methyl-D-aspartate (NMDA) has been demonstrated to induce rhythmic activity in various neurons, including hypoglossal motoneurons (XIIms) and converts them to conditional pacemakers. Using whole-cell patch clamp recording in a slice preparation from neonatal rats, we confirmed that some XIIms act as conditional pacemakers, with TTX-insensitivity and a burst period that is voltage-dependent during NMDA application. Other XIIms in this study only fired tonically with NMDA application. Effects of medullary structures on conditional pacemaker XIIms were assessed using lesioned preparations. As a result, NMDA-induced rhythm (NIR) in the XIIm was observed with ventral lesions (excluding inspiratory neurons) and with dorsal lesions (excluding the swallowing center located in the nucleus of the solitary tract). The NIR was also observed with lateral lesions, but with a significantly decreased burst period. These data suggest that NMDA receptor activation selects a subset of XIIms and changes them to pacemakers whose properties can be altered by their excitability. The data also demonstrate that structures fundamental to the NIR are located within the area near the XII nucleus, indicating that the NIR is distinct from inspiratory and swallowing activities. The lateral medulla is considered to be a source of modulation of the excitability of XIIms.
    Neuroscience Research 03/2013; 76(1-2). DOI:10.1016/j.neures.2013.03.007 · 2.15 Impact Factor
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    ABSTRACT: Background Studies have investigated factors related to aspiration pneumonia (AP) onset in stroke patients. However, no study has examined the influence of swallowing function assessment-based strategies. Purpose The purpose of this study is to investigate factors related to the onset of AP that differ before and after swallowing function assessment. Methods and subjects Subjects consisted of 143 patients admitted to acute-stage hospitals within 7 days of stroke onset. We examined the association between AP onset within 1 year after stroke and several parameters. Results AP incidence was 24.5% overall, 20.3% before swallowing function assessment, and 7.7% after assessment. In patients who developed AP prior to swallowing function assessment, the onset was associated with male gender [odds ratio (OR): 6.206, 95% confidence interval (CI): 1.871–28.937], dysarthria (OR: 5.683, CI: 1.432–38.713), and denture usage (OR: 2.843, CI: 1.011–8.048). In those who developed AP after swallowing function assessment, AP was associated with cerebral atrophy (OR: 4.225, CI: 1.071–16.705), infracted foci in the basal ganglia (OR: 8.914, CI: 1.489–77.776), and Barthel Index (BI) <100 points before admission (OR: 5.404, CI: 1.418–21.482). Conclusions Onset of AP after stroke was associated with gender, dysarthria, denture usage at before swallowing function assessment and cerebral atrophy, infarcted foci in the basal ganglia, and BI before admission at after swallowing function assessment. It is necessary to pay attention to the fact that factors related to AP differ before and after swallowing function assessment to identify patients at high risk of developing AP after stroke.
    International Journal of Oral Science 01/2013; DOI:10.1016/S1348-8643(13)00009-8 · 2.03 Impact Factor
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    ABSTRACT: Endoscopic-assisted surgery has gained widespread popularity as a minimally invasive procedure, particularly in the field of maxillofacial surgery. Because the surgical field around the mandibular angle is extremely narrow, the surrounding tissues may get caught in sharp rotary cutting instruments. In piezosurgery, bone tissues are selectively cut. This technique has various applications because minimal damage is caused by the rotary cutting instruments when they briefly come in contact with soft tissues. We report the case of a 33-year-old man who underwent resection of an osteoma in the region of the mandibular angle region via an intraoral approach. During surgery, the complete surgical field was within the view of the endoscope, thereby enabling the surgeon to easily resection the osteoma with the piezosurgery device. Considering that piezosurgery limits the extent of surgical invasion, this is an excellent low-risk technique that can be used in the field of maxillofacial surgery.
    01/2013; 115(1):e16-e20. DOI:10.1016/j.oooo.2011.09.032
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    ABSTRACT: To determine whether specific morphologic features of the mandibular ramus can predict increased surgical time and blood loss in sagittal split-ramus osteotomy (SSRO). The clinical and morphologic features of the mandibular ramus, obtained from computed tomographic images (n = 50), were analyzed to predict the surgical time, the time required for ablation of the medial mandibular ramus, and the time required for sectioning of the mandible in performing a modified Obwegeser SSRO. Significant factors associated with surgical time were an anterior border of the ramus at least 10.5 mm wide, a maximal length of the thickened ramus of at least 8.5 mm, and a distance from the mandibular incisor to the posterior border of the mandible of at least 97.5 mm. There were significant differences in blood loss between the 2 axial aspects of the medial ramus. The greater protrusion of the medial oblique ridge, thickened ramus, and longer distance from the mandibular incisors to the posterior border of the mandible may increase the surgical time and blood loss in patients undergoing classic SSRO. When planning or performing an SSRO, the morphologic features obtained from computed tomographic images may help surgeons gain a better understanding of the potential difficulties when the surgical site involves the medial aspect of the ascending ramus of the mandible.
    Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons 01/2013; 71(1):e31-41. DOI:10.1016/j.joms.2012.09.001 · 1.28 Impact Factor
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    ABSTRACT: Prediction of neurosensory deficit in the lower lip and chin after sagittal split ramus osteotomy (SSRO) is challenging. This study aimed to elucidate factors related to the development and improvement of neurosensory disturbance (NSD) after SSRO with respect to surgical procedure and the anatomical and structural characteristics of the craniomaxillofacial skeleton. Subjects comprised 50 patients treated by a single experienced surgeon. Anatomical data and landmarks were obtained by computed tomography (CT) imaging. There was a significant difference between patients with or without NSD for the surgical space on the medial side of mandibular ramus 1 week after SSRO (P=0.006). Less than 15.0mm between the lingula and mandibular notch (relative risk, 6.7; 95% CI, 1.7-33.8) and 195.0mm(2) or more space on the medial side of the mandibular ramus (relative risk, 17.2; 95% CI, 3.9-100.4) indicated a significant risk of NSD development at 6 months postoperatively. These results suggested that the development of NSD is related to the surgical space on the medial side of the mandibular ramus and subsequent manipulation of the inferior alveolar nerve (IAN) in that region. Limited periosteal degloving prevents excessive stretching of the IAN during SSRO, thus lowering NSD incidence.
    International Journal of Oral and Maxillofacial Surgery 12/2012; DOI:10.1016/j.ijom.2012.11.016 · 1.36 Impact Factor
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    ABSTRACT: CRTC1-MAML2 and CRTC3-MAML2 fusions have been associated with favorable clinicopathological features of mucoepidermoid carcinoma. However, significance of MAML2 gene split has not been fully clarified. Ninety-five mucoepidermoid carcinomas (paraffin-embedded materials) were analyzed for CRTC1-MAML2 and CRTC3-MAML2 fusions by the reverse transcription polymerase chain reaction (RT-PCR) and for the MAML2 gene split by fluorescence in situ hybridization (FISH). Quantitative RT-PCR for the CRTC1-MAML2 transcript was performed in selected cases. MLL gene involvement, which has been reported in some leukemia cases, was examined by FISH in fusion partner-unknown cases. CRTC1-MAML2 and CRTC3-MAML2 fusions were detected in 37 and six cases, respectively. The MAML2 gene split was detected in 62 cases, which included all CRTC1/3-MAML2 fusion-positive cases. The level of CRTC1-MAML2 transcript expression was highly variable, and its clinicopathological impact was unclear. The MLL gene split was not detected. Mucoepidermoid carcinomas negative for CRTC1/3-MAML2 and positive for the MAML2 gene split (n=19) showed favorable clinicopathological tumor features similar to those positive for CRTC1/3-MAML2 fusions. As compared with negative cases (n=33), mucoepidermoid carcinomas positive for the MAML2 split (n=62) showed a lower patients' age, a mild female predilection, a smaller tumor size, less frequent nodal metastasis, a lower clinical stage, a lower histological grade, and a longer overall and disease-free survival. The MAML2 gene split emerged as an independent prognostic factor for both overall and disease-free survival in multivariate prognostic analysis. The presence of the MAML2 gene split defines a distinct mucoepidermoid carcinoma subset that is associated clinicopathologically with favorable tumor features.
    Cancer Science 10/2012; DOI:10.1111/cas.12039 · 3.53 Impact Factor
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    ABSTRACT: For the doctors and other medical staff treating oral cancers, it is necessary to standardize basic concepts and rules on oral cancers to progress in the treatment, research and diagnosis. Oral cancers are integrated in head and neck cancers and are applied to the general rules on head and neck cancer, but it is considered that more detailed rules based on the characteristics of oral cancers are essential. The objectives of this 'General Rules for Clinical and Pathological Studies on Oral Cancer' are to contribute to the development of the diagnosis, treatment and research of oral cancers based on the correct and useful medical information of clinical, surgical, pathological and image findings accumulated from individual patients at various institutions.
    Japanese Journal of Clinical Oncology 09/2012; 42(11):1099-109. DOI:10.1093/jjco/hys141 · 1.75 Impact Factor
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    ABSTRACT: OBJECTIVE: This study demonstrated pterygomaxillary disjunction patterns and elucidated factors related to unfavorable pterygomaxillary junction fractures in Le Fort I osteotomy without using an osteotome. STUDY DESIGN: Clinical and anatomical data obtained from computed tomography images (100 sides) were analyzed for their ability to predict patterns of pterygomaxillary disjunction. RESULTS: Separation of the pterygomaxillary junction was most frequently performed at the maxillary tuberosity (48.0%). Twenty-eight pterygoid plates were fractured. Male gender, increased age, thickness of the pterygomaxillary junction, and length of the maxillary tuberosity were significant risk factors for pterygoid process fractures. We also identified that a pterygomaxillary junction thickness less than 2.6 mm and a maxillary tuberosity length of more than 11.5 mm indicated a statistically significant risk of pterygoid process fractures. CONCLUSIONS: Prediction of frangible pterygoid plates by preoperative quantitative evaluation of morphometric values provides useful information for selecting safe procedures.
    08/2012; 115(3). DOI:10.1016/j.oooo.2012.04.020
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the degeneration of both upper and lower motor neurons. Moreover, dysphagia and respiratory failure almost invariably develop in ALS patients. Dysarthria and dysphagia sometimes occur early ALS patients, and the understanding and management of such patients are important. We report the case of an ALS patient with dysphagia/dysarthria in whom we used various types of palatal augmentation prostheses (PAPs) and serially observed the course of dysphagia/dysarthria. We fabricated 3 types of PAPs (2 for dysphagia/dysarthria and 1 obturator-type PAP) for the patient, and their effectiveness in improving dysphagia was evaluated by videofluoroscopic swallowing studies and fibreoptic endoscopic examination of swallowing, whereas their effectiveness in improving dysarthria was evaluated by the standard Japanese speech intelligibility test comprising 100 syllables.We believe that the obturator-type PAP was useful for improving dysphagia in the long term, while the other PAPs were useful for improving dysphagia/dysarthria only in the initial stages. PAPs are an adjunctive therapy for treating dysphagia/dysarthria and for maintaining patient function and improving quality of life in ALS patients.
    05/2012; 24(2):119–123. DOI:10.1016/j.ajoms.2011.11.006

Publication Stats

627 Citations
126.18 Total Impact Points


  • 2003–2015
    • Aichi Gakuin University
      • • Department of Oral and Maxillofacial Surgery
      • • Department of Dentistry
      Nagoya, Aichi, Japan
  • 2012
    • Nara Medical University
      • Department of Oral and Maxillofacial Surgery
      Kashihara, Nara, Japan
  • 2006
    • Nagasaki University
      • Graduate School of Biomedical Sciences
      Nagasaki, Nagasaki, Japan