Kazuyuki Tobe

University of Toyama, Тояма, Toyama, Japan

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Publications (266)1439.5 Total impact

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    ABSTRACT: The usefulness of the Palliative Prognostic Index (PPI) has been successfully validated in a variety of clinical settings. However, while lung cancer is the leading cause of death worldwide, patients with lung cancer accounted for only 6.9-25.8 % of the study populations in these previous studies. We conducted a retrospective study to evaluate the usefulness of the PPI for survival prediction in patients with lung cancer. Patients with lung cancer who were admitted to our hospital between 2009 and 2013 to receive palliative care were enrolled. The association between the Palliative Prognostic Index, determined based on the data recorded in the clinical charts at the last admission to our hospital, and survival was evaluated. The patient group with a PPI of >6 showed a significantly shorter survival time than the patient group with a PPI of ≤6 (P < 0.0001, log-rank test). The sensitivity and specificity of the PPI determined using the cutoff value of 6 for predicting less than 3 weeks of survival were 61.3 and 86.8 %, respectively. However, the sensitivity decreased to 50.0 % when the assessment was carried out in only patients with small cell lung carcinoma. Our findings suggest the existence of a close association between the PPI and survival in patients with lung cancer receiving palliative care. However, the sensitivity of the index for predicting less than 3 weeks of survival was relatively low in patients with small cell lung carcinoma.
    Medical oncology (Northwood, London, England). 09/2014; 31(9):154.
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    ABSTRACT: Central venous catheterization at the femoral site is associated with higher complication rates of infections and thrombosis than at the jugular or subclavian sites. However, the procedure of insertion at the femoral site is considered safer. We present a unique but dangerous positioning of a left femoral central venous catheter into the iliolumbar vein. We were aware of this accidental cannulation by chance when our patient underwent bone scintigraphy. Although a few cases were reported about accidental cannulation into the ascending lumbar vein, this is the first case where a femoral central venous catheter was misplaced into the iliolumbar vein.
    Clinical nuclear medicine. 08/2014;
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    ABSTRACT: The efficacy of docetaxel, vinorelbine, or gemcitabine monotherapy in previously untreated elderly patients with non-small cell lung cancer has been reported.Pemetrexed monotherapy has shown clinically equivalent efficacy to docetaxel, a standard therapeutic option, in patients with previously treated non-small cell lung cancer and in those with a lower incidence of toxicity such as febrile neutropenia.
    Gan to kagaku ryoho. Cancer & chemotherapy 07/2014; 41(7):849-52.
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    ABSTRACT: NAD biosynthesis is of substantial interest owing to its important roles in regulating various biological processes. Nicotinamide mononucleotide adenylyltransferase 3 (Nmnat3) is considered a mitochondria- localized NAD synthesis enzyme involved in de novo and salvage pathways. Although the biochemical properties of Nmnat3 are well documented, its physiological function in vivo remains unclear. In this study, we demonstrated that Nmnat3 was localized in the cytoplasm of mature erythrocytes and critically regulated their NAD pool. Deficiency of Nmnat3 in mice caused splenomegaly and hemolytic anemia, which was associated with the findings that Nmnat3-deficient erythrocytes had markedly lower ATP levels and shortened lifespans. However, NAD level in other tissues were not apparently affected by the deficiency of Nmnat3. LC-MS/MS based metabolomics revealed that the glycolysis pathway in Nmnat3-deficient erythrocytes was blocked at glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step because of the shortage of co-enzyme NAD. Stable isotope tracer analysis further demonstrated that deficiency of Nmnat3 resulted in glycolysis stall and a shift to pentose phosphate pathway. Our findings indicate the critical roles of Nmnat3 in maintenance of the NAD pool in mature erythrocytes and the physiological impacts at its absence in mice.
    Journal of Biological Chemistry 04/2014; · 4.65 Impact Factor
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    ABSTRACT: Orogenital ulcer is one of the clinical manifestations of Behçet's disease (BD). However, orogenital ulcer may be observed in various conditions, such as complex aphthous dermatitis and herpes simplex virus infections. Therefore, orogenital ulcer along with skin lesions, including acne or erythema nodosum, may be misdiagnosed as BD, but is actually pseudo-BD instead. We report here a case of pseudo-BD due to Mycobacterium tuberculosis infection in which anti-tuberculous treatment resulted in complete resolution. Furthermore, we review the literature regarding the association of BD and M. tuberculosis infection.
    Rheumatology International 03/2014; · 2.21 Impact Factor
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    ABSTRACT: In recent years, several oral antidiabetic drugs with new mechanisms of action have become available, expanding the number of treatment options. Sodium/glucose cotransporter-2 (SGLT2) inhibitors are a new class of oral antidiabetic drugs with an insulin-independent mechanism promoting urinary glucose excretion. We report the results of a combined Phase 2 and 3 clinical study (Japic CTI-101349) of the SGLT2 inhibitor tofogliflozin (CSG452, RG7201) in Japanese patients with type 2 diabetes mellitus. The efficacy and safety of tofogliflozin were assessed in this multicenter, placebo-controlled, randomized, double-blind parallel-group study involving 230 patients with type 2 diabetes mellitus with inadequate glycemic control on diet/exercise therapy. Between 30 October 2010 and 28 February 2012, patients at 33 centers were randomized to either placebo (n = 56) or tofogliflozin (10, 20, or 40 mg; n = 58 each) orally, once daily for 24 weeks. The primary efficacy endpoint was the change from baseline in HbA1c at week 24. Overall, 229 patients were included in the full analysis set (placebo: n = 56; tofogliflozin 10 mg: n = 57; tofogliflozin 20 and 40 mg: n = 58 each). The least squares (LS) mean change (95% confidence interval) from baseline in HbA1c at week 24 was -0.028% (-0.192 to 0.137) in the placebo group, compared with -0.797% (-0.960 to -0.634) in the tofogliflozin 10 mg group, -1.017% (-1.178 to -0.856) in the tofogliflozin 20 mg group, and -0.870% (-1.031 to -0.709) in the tofogliflozin 40 mg group (p < 0.0001 for the LS mean differences in all tofogliflozin groups vs placebo). There were also prominent decreases in fasting blood glucose, 2-h postprandial glucose, and body weight in all tofogliflozin groups compared with the placebo group. The main adverse events were hyperketonemia, ketonuria, and pollakiuria. The incidence of hypoglycemia was low. Furthermore, most adverse events were classified as mild or moderate in severity. Tofogliflozin 10, 20, or 40 mg administered once daily as monotherapy significantly decreased HbA1c and body weight, and was generally well tolerated in Japanese patients with type 2 diabetes mellitus. Phase 3 studies were recently completed and support the findings of this combined Phase 2 and 3 study.Trial registration: This study was registered in the JAPIC clinical trials registry (ID: Japic CTI-101349).
    Cardiovascular Diabetology 03/2014; 13(1):65. · 4.21 Impact Factor
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    ABSTRACT: Objective: To evaluate long-term safety and efficacy of tofogliflozin in Japanese patients with type 2 diabetes as monotherapy or in combination with other oral antidiabetic agents, we conducted 52-week, open-label, randomized controlled trials. Research design and methods: The single-agent trial included patients with inadequate glycemic control on diet and exercise, whereas the add-on trial included those uncontrolled with any of the oral antidiabetic agents. In both trials, patients were randomly assigned to receive tofogliflozin 20 or 40 mg once daily orally for 52 weeks. Main outcome measures: Safety assessments. Results: A total of 194 patients (65, 20-mg group; 129, 40-mg group) were enrolled into the single-agent trial, whereas 602 (178 and 424, respectively) were enrolled into the add-on trial. Tofogliflozin was well tolerated for 52 weeks in both trials with < 6% of treatment discontinuation because of adverse events in each treatment group. It also reduced hemoglobin A1c. In the single-agent trial, mean reductions at 52 weeks were 0.67 and 0.66% in the 20- and 40-mg groups, respectively. In the add-on trial, mean reductions ranged from 0.71 to 0.93% across the subgroups by dose and background therapy. Conclusion: Tofogliflozin was well tolerated and showed sustained efficacy in both trials.
    Expert Opinion on Pharmacotherapy 03/2014; 15(6). · 2.86 Impact Factor
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    ABSTRACT: Diabetes mellitus is the leading cause of blindness and end-stage renal disease. To understand the pathogenesis of diabetic complications, suitable animal models for this disease have been needed. The activation of Ca2+/ calmodulin-dependent protein kinase II (CaMKII) in pancreatic β-cells has been thought to play a central role in Ca2+-mediated insulin secretion. We generated transgenic mice over expressing the constitutively active-type CaMKIIα (Thr286Asp) in β-cells, which showed very high plasma glucose levels and exhibited the features of diabetic nephropathy and retinopathy. In cDNA microarray analysis osteopontin mRNA increased in CaMKIIα transgenic mice. In quantitative real-time RT-PCR analyses, not only M1 macrophage marker genes but also M2 macrophage marker genes were over expressed in renal cortex of CaMKIIα transgenic mice. The mice were crossed with conditional knockout mice in which platelet-derived growth factor receptor-β gene (Pdgfr-β) was deleted postnatal. The increased oxidative stress in the kidneys of the CaMKII α transgenic mice, which was shown by the increased urinary 8-hydroxydeoxyguanosine excretion and the increased expression of NAD (P) H oxidase 4, was decreased by Pdgfr-β deletion. The CaMKIIα (Thr286Asp) transgenic mice will be valuable as a novel model of severe insulin-dependent diabetes accompanied by an early progression of diabetic micro vascular complications.
    Austin Journal of Endocrinology and Diabetes. 01/2014; 1(1):9.
  • Revue du Rhumatisme. 01/2014;
  • Joint Bone Spine. 01/2014;
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    ABSTRACT: Aims/IntroductionThe objective of the present study was to clarify the validity of β-cell function-related parameters for predicting the insulin requirement of Japanese type 2 diabetic patients. Materials and Methods In 188 patients with type 2 diabetes who had been admitted to the University of Toyama Hospital (Toyama, Japan) without receiving insulin therapy, we carried out a cross-sectional study examining the relationship between the homeostasis model assessment of β-cell function (HOMA-β) and C-peptide-based indices, and also carried out a retrospective study to examine the utility for predicting insulin requirement of several β -cell function-related indices using a receiver operating characteristic (ROC) curve analysis. ResultsThe secretory units of islets in transplantation index (SUIT) had the strongest correlation with HOMA-β, followed by the fasting serum C-peptide immunoreactivity index (CPI); the fasting serum C-peptide immunoreactivity itself (F-CPR) had the least correlation. The CPI, HOMA-β and SUIT were significantly lower in the insulin-requiring group than in the non-insulin-requiring group, even after adjustments for confounding factors (P < 0.01). The areas under the ROC curve for insulin requirement were 0.622, 0.774, 0.808, and 0.759 for F-CPR, CPI, SUIT, and HOMA-β, respectively. The cut-off values of SUIT, CPI, and HOMA-β for an over 80% specificity for the prediction of insulin therapy were 23.5, 1.00, and 14.9, respectively. Conclusions The present study shows that SUIT is the best predictor of insulin requirement among these β-cell function-related markers.
    Journal of Diabetes Investigation. 12/2013;
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    ABSTRACT: East Asian genome-wide association studies (GWAS) for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population. We genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls) for each of the 9 single nucleotide polymorphisms (SNPs), rs7041847 in GLIS3, rs6017317 in FITM2-R3HDML-HNF4A, rs6467136 near GCCI-PAX4, rs831571 near PSMD6, rs9470794 in ZFAND3, rs3786897 in PEPD, rs1535500 in KCNK16, rs16955379 in CMIP, and rs17797882 near WWOX. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS) by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis. With the exception of rs1535500 in KCNK16, all SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (p = 4.0 × 10(-4), OR = 1.05, 95% confidence interval: 1.02-1.09). In quantitative trait analyses, rs16955379 in CMIP was nominally associated with a decreased homeostasis model assessment of β-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits. These results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population.
    PLoS ONE 09/2013; 8(9):e76317. · 3.53 Impact Factor
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    ABSTRACT: ContextGenome-wide association studies (GWAS) have identified over 60 susceptibility loci for type 2 diabetes (T2D). Although the ability of previous genetic information (∼40 loci) to discriminate between susceptible and non-susceptible individuals is limited, the added benefit of updated genetic information has not been evaluated.Objective We assessed the clinical utility of GWAS-derived T2D susceptibility variants in a Japanese population.Design and settingA cross-sectional case-control study.ParticipantsT2D cases (n = 2,613) and controls (n = 1,786) with complete genotype data for 49 SNPs were selected for analyses.Outcome MeasuresWe constructed genetic risk scores (GRSs) by summing the susceptibility alleles of 49 SNP loci for T2D (GRS-49) or 10 SNP loci with genome-wide significant association in previous Japanese studies (GRS-10), and examined the association of the GRSs with the disease by receiver operating characteristic (ROC) analyses using a logistic regression model.ResultsThe GRS-49 was significantly associated with T2D (p = 8.75 × 10(-45)). The area under the curve (AUC) for GRS-49 alone (model-1) and for age, sex, and BMI (model-2) was 0.624 and 0.743, respectively. Addition of the GRS-49 to model-2 resulted in a small but significant increase in the AUC (ΔAUC = 0.03, p = 7.99 × 10(-15)). ROC-AUC was greater for GRS-49 than for GRS-10 (0.624 vs. 0.603, p = 0.019), whereas the odds ratio per risk allele was smaller for GRS-49 than for GRS-10 (GRS-49; 1.13, 95% confidence interval (CI) 1.11-1.15, GRS-10; 1.26, 95% CI 1.22-1.31, p = 7.31 × 10(-10)). The GRS-49 was significantly associated with age at diagnosis in 1,591 cases (β = -0.199, p = 0.0069) and with fasting plasma glucose in 804 controls (β = 0.009, p = 0.021).Conclusions Updated genetic information slightly improves disease prediction ability, but is not sufficiently robust for translation into clinical practice.
    The Journal of Clinical Endocrinology and Metabolism 08/2013; · 6.31 Impact Factor
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    Journal of the American Geriatrics Society 06/2013; 61(6):1043-4. · 4.22 Impact Factor
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    ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP) has been known as a neuroprotectant agent in several retinal injury models. However, a detailed mechanism of this effect is still not well understood. In this study, we examined the retinoprotective effects and associated underlying mechanisms of action of PACAP in the mouse N-methyl-D-aspartic acid (NMDA)-induced retinal injury model, focusing on the relationship between PACAP and retinal microglia/macrophage (MG/MΦ) status. Adult male C57BL/6 mice received an intravitreal injection of NMDA to induce retinal injury. Three days after NMDA injection, the number of MG/MΦ increased significantly in the retinas. The concomitant intravitreal injection of PACAP suppressed NMDA-induced cell loss in the ganglion cell layer (GCL) and significantly increased the number of MG/MΦ. These outcomes associated with PACAP were attenuated by cotreatment with PACAP6-38, while the beneficial effects of PACAP were not seen in interleukin-10 (IL-10) knockout mice. PACAP significantly elevated the messenger RNA levels of anti-inflammatory cytokines such as transforming growth factor beta 1 and IL-10 in the injured retina, with the immunoreactivities seen to overlap with markers of MG/MΦ. These results suggest that PACAP enhances the proliferation and/or infiltration of retinal MG/MΦ and modulates their status into an acquired deactivation subtype to favor conditions for neuroprotection.
    Journal of Molecular Neuroscience 05/2013; · 2.89 Impact Factor
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    ABSTRACT: Since oxidative stress promotes insulin resistance in obesity and type 2 diabetes, it is crucial to find effective antioxidant for the purpose of decreasing this threat. In this study, we explored the effect of astaxanthin, a carotenoid antioxidant, on insulin signaling and investigated whether astaxanthin improves cytokine- and free fatty acid-induced insulin resistance in vitro. We examined the effect of astaxanthin on insulin-stimulated GLUT4 translocation, glucose uptake and insulin signaling in cultured rat L6 muscle cells using plasma membrane lawn assay, 2-Deoxyglucose uptake and Western blot analysis. Next, we examined the effect of astaxanthin on TNFα- and palmitate-induced insulin resistance. The amount of reactive oxygen species (ROS) generated by TNFα or palmitate with or without astaxanthin was evaluated by DCF staining. We also compared the effect of astaxanthin on insulin signaling with that of other antioxidants, α-lipoic acid and α-tocopherol. We observed astaxanthin enhanced insulin-stimulated GLUT4 translocation and glucose uptake, which was associated with an increase in IRS-1 tyrosine and Akt phosphorylation and a decrease in JNK and IRS-1 serine 307 phosphorylation. Furthermore, astaxanthin restored TNFα- and palmitate-induced decreases in insulin-stimulated GLUT4 translocation or glucose uptake with a concomitant decrease in ROS generation. α-Lipoic acid enhanced Akt phosphorylation and decreased ERK and JNK phosphorylation, whereas α-tocopherol enhanced ERK and JNK phosphorylation but had little effect on Akt phosphorylation. Collectively, these findings indicate astaxanthin is a very effective antioxidant for ameliorating insulin resistance by protecting cells from oxidative stress generated by various stimuli including TNFα and palmitate.
    Endocrinology 05/2013; · 4.72 Impact Factor
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    ABSTRACT: By an association mapping for the candidate locus in chromosome 21q, rs3746876 within KCNJ15 was shown to be associated with type 2 diabetes in Japanese populations. However, the association of rs3746876 with type 2 diabetes has not been validated in an independent cohort. The aim of the present study was to ascertain the association of rs3746876 with type 2 diabetes in an independent larger Japanese sample. We genotyped 7885 Japanese participants (4967 individuals with type 2 diabetes and 2918 control individuals) for rs3746876 with polymerase-chain reaction-invader assay. The association of rs3746876 with type 2 diabetes was examined by using logistic regression analysis. Quantitative traits analyses for homeostasis model assessment (HOMA) of β-cell function, HOMA of insulin resistance, fasting plasma glucose, fasting immunoreactive insulin and body mass index (BMI) were performed in control individuals by using multiple-linear regression analysis. We observed a significant association of rs3746876-T with type 2 diabetes (P=0.0281, odds ratio (OR)=0.82, 95% confidence interval (CI, 0.68-0.98)), but the direction of effect was opposite to that in the original report. The association of rs3746876 with type 2 diabetes was more significant in obese patients (BMI25 kg m(-2), P=0.0025, OR=0.62, 95% CI, 0.45-0.84). We did not observe significant association of rs3746876 with any of the quantitative traits in the control individuals. We could not replicate the original finding for the association of rs3746876 with type 2 diabetes, although rs3746876 was significantly associated with obese type 2 diabetes in the present Japanese population.Journal of Human Genetics advance online publication, 18 April 2013; doi:10.1038/jhg.2013.28.
    Journal of Human Genetics 04/2013; · 2.37 Impact Factor
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    ABSTRACT: Genetic risk variants for type 2 diabetes; rs391300-G in SRR and rs17584499-T in PTPRD, have been identified by a genome-wide association study using Han Chinese individuals living in Taiwan. In an attempt to know the effects of these two variants in conferring susceptibility to type 2 diabetes in the Japanese, we carried out a replication study for the association of the two single nucleotide polymorphisms (SNPs) with type 2 diabetes in a Japanese population.
    Journal of diabetes investigation. 03/2013; 4(2):168-73.
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    ABSTRACT: Cytophagic histiocytic panniculitis is a chronic histiocytic disease of the subcutaneous adipose tissue characterised by lobular panniculitis with histiocytes containing blood cell fragments. It is also associated with marked systemic features such as fever, pancytopenia, hepatosplenomegaly, liver abnormalities and coagulopathy. We report a case of cytophagic histiocytic panniculitis in a 74-year-old man successfully treated using combination therapy with prednisolone and cyclosporine A.
    Age and Ageing 03/2013; · 3.82 Impact Factor
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    ABSTRACT: AIMS/HYPOTHESIS: As obesity progresses, adipose tissue exhibits a hypoxic and inflammatory phenotype characterised by the infiltration of adipose tissue macrophages (ATMs). In this study, we examined how adipose tissue hypoxia is involved in the induction of the inflammatory M1 and anti-inflammatory M2 polarities of ATMs. METHODS: The hypoxic characteristics of ATMs were evaluated using flow cytometry after the injection of pimonidazole, a hypoxia probe, in normal-chow-fed or high-fat-fed mice. The expression of hypoxia-related and inflammation-related genes was then examined in M1/M2 ATMs and cultured macrophages. RESULTS: Pimonidazole uptake was greater in M1 ATMs than in M2 ATMs. This uptake was paralleled by the levels of inflammatory cytokines, such as TNF-α, IL-6 and IL-1β. The expression level of hypoxia-related genes, as well as inflammation-related genes, was also higher in M1 ATMs than in M2 ATMs. The expression of Il6, Il1β and Nos2 in cultured macrophages was increased by exposure to hypoxia in vitro but was markedly decreased by the gene deletion of Hif1a. In contrast, the expression of Tnf, another inflammatory cytokine gene, was neither increased by exposure to hypoxia nor affected by Hif1a deficiency. These results suggest that hypoxia induces the inflammatory phenotypes of macrophages via Hif1a-dependent and -independent mechanisms. On the other hand, the expression of inflammatory genes in cultured M2 macrophages treated with IL-4 responded poorly to hypoxia. CONCLUSIONS/INTERPRETATION: Adipose tissue hypoxia induces an inflammatory phenotype via Hif1a-dependent and Hif1a-independent mechanisms in M1 ATMs but not in M2 ATMs.
    Diabetologia 03/2013; · 6.49 Impact Factor

Publication Stats

15k Citations
1,439.50 Total Impact Points


  • 2011–2014
    • University of Toyama
      • Department of Internal Medicine 3
      Тояма, Toyama, Japan
  • 2012–2013
    • St. Marianna University School of Medicine
      • Department of Internal Medicine
      Kawasaki, Kanagawa-ken, Japan
  • 1987–2013
    • The University of Tokyo
      • • Department of Diabetes and Metabolic Diseases
      • • Faculty & Graduate School of Medicine
      • • Department of Internal Medicine
      • • Division of Internal Medicine
      Edo, Tōkyō, Japan
  • 2009–2012
    • Toyama University
      Тояма, Toyama, Japan
  • 2010
    • Asahi General Hospital
      Asahi, Chiba, Japan
  • 2006–2008
    • Central Institute for Experimental Animals
      Kawasaki Si, Kanagawa, Japan
  • 2001
    • Tokyo Medical University
      • Animal Research Center
      Edo, Tōkyō, Japan
  • 1999–2001
    • Okayama University
      Okayama, Okayama, Japan
    • Osaka City University
      • Graduate School of Medicine
      Ōsaka-shi, Osaka-fu, Japan
  • 2000
    • Chiba University
      Tiba, Chiba, Japan
  • 1996
    • Kyoto University
      • Institute for Virus Research
      Kyoto, Kyoto-fu, Japan
  • 1992
    • Gifu Pharmaceutical University
      • Department of Biology
      Gihu, Gifu, Japan