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Articles by M Tanaka
Total Records ( 16 ) for M Tanaka
  M Nakasuji , M Nakamura , N Imanaka , M Tanaka , M Nomura and S. H. Suh

Remifentanil is associated with increased incidence of post-anaesthetic shivering (PAS). The aim of this study was to compare the effects of intraoperative high and low doses of remifentanil on PAS.


We investigated 50 consecutive patients, aged <60 yr, who underwent gynaecological laparotomy. Patients who underwent prolonged surgery (>4 h) were excluded from the study. Anaesthesia throughout surgery was maintained with i.v. propofol and remifentanil, and epidural ropivacaine, and no nitrous oxide was used. Fifty patients were randomly assigned to receive intraoperative remifentanil at 0.1 µg kg–1 min–1 (low-dose group, n=25) or 0.25 µg kg–1 min–1 (high-dose group, n=25) until the end of surgery. Intraoperative analgesia was achieved by a fixed infusion rate of remifentanil and titrated epidural ropivacaine. PAS was evaluated by nursing stuff over the first hour after surgery.


PAS occurred more frequently in the high-dose group than in the low-dose group (60% vs 20%, P=0.009). None of the patients complained of pain during the observation period due to epidural analgesia. There were no significant differences in rectal or palm skin temperature after extubation between the two dose groups.


Remifentanil-induced PAS is not a phenomenon of intraoperative hypothermia. The higher incidence of PAS with higher doses of remifentanil probably reflects acute opioid tolerance and stimulation of N-methyl-d-aspartate receptors, similar to hyperalgesia. We conclude that patients administered high doses of remifentanil are sensitive to shivering after sudden drug withdrawal.

  M Toyofuku , T Kimura , T Morimoto , Y Hayashi , H Ueda , K Kawai , Y Nozaki , S Hiramatsu , A Miura , Y Yokoi , S Toyoshima , H Nakashima , K Haze , M Tanaka , S Take , S Saito , T Isshiki , K Mitsudo and on Behalf of the j Cypher Registry Investigators

Background— Long-term outcomes after stenting of an unprotected left main coronary artery (ULMCA) with drug-eluting stents have not been addressed adequately despite the growing popularity of this procedure.

Methods and Results— j-Cypher is a multicenter prospective registry of consecutive patients undergoing sirolimus-eluting stent implantation in Japan. Among 12 824 patients enrolled in the j-Cypher registry, the unadjusted mortality rate at 3 years was significantly higher in patients with ULMCA stenting (n=582) than in patients without ULMCA stenting (n=12 242; 14.6% versus 9.2%, respectively; P<0.0001); however, there was no significant difference between the 2 groups in the adjusted risk of death (hazard ratio 1.23, 95% confidence interval 0.95 to 1.60, P=0.12). Among 476 patients whose ULMCA lesions were treated exclusively with a sirolimus-eluting stent, patients with ostial/shaft lesions (n=96) compared with those with bifurcation lesions (n=380) had a significantly lower rate of target-lesion revascularization for the ULMCA lesions (3.6% versus 17.1%, P=0.005), with similar cardiac death rates at 3 years (9.8% versus 7.6%, P=0.41). Among patients with bifurcation lesions, patients with stenting of both the main and side branches (n=119) had significantly higher rates of cardiac death (12.2% versus 5.5%; P=0.02) and target-lesion revascularization (30.9% versus 11.1%; P<0.0001) than those with main-branch stenting alone (n=261).

Conclusions— The higher unadjusted mortality rate of patients undergoing ULMCA stenting with a sirolimus-eluting stent did not appear to be related to ULMCA treatment itself but rather to the patients’ high-risk profile. Although long-term outcomes in patients with ostial/shaft ULMCA lesions were favorable, outcomes in patients with bifurcation lesions treated with stenting of both the main and side branches appeared unacceptable.

  H Ishii , T Toriyama , T Aoyama , H Takahashi , T Amano , M Hayashi , M Tanaka , Y Kawamura , Y Yasuda , Y Yuzawa , S Maruyama , S Matsuo , T Matsubara and T. Murohara

Background— Percutaneous coronary intervention (PCI) using drug-eluting stents significantly reduces the risk of restenosis in the general population. However, in patients on hemodialysis, adverse cardiac events are frequently seen even if treated with drug-eluting stents. Recent studies suggest that C-reactive protein (CRP) reflects vascular wall inflammation and can predict adverse cardiac events. We evaluated possible prognostic values of CRP on outcomes in patients on hemodialysis undergoing PCI with drug-eluting stents.

Methods and Results— A total of 167 patients undergoing PCI with sirolimus-eluting stents for stable angina (322 lesions) were enrolled. They were divided into tertiles according to serum CRP levels. We analyzed the incidence of major adverse cardiovascular events including cardiovascular death, nonfatal myocardial infarction, and target lesion revascularization after PCI as well as quantitative coronary angiographic data. The mean follow-up was 31 months (SD, 14). Major adverse cardiac events occurred in 11 patients (19.6%) of the lowest tertile, in 22 patients (39.3%) of the middle tertile, and in 28 patients (50.9%) of the highest tertile during follow-up period (P=0.0009). There was a progressive increase in neointimal growth after sirolimus-eluting stent implantation during follow-up because preprocedural CRP levels were higher, despite similar angiographic data just after PCI. Angiographic restenosis at 6 to 8 months after PCI was seen in 10.6% in the lowest tertile, 17.9% in the middle tertile, and 32.0% in the highest tertile (P=0.0007).

Conclusions— Increased preprocedural serum CRP levels would predict higher major adverse cardiac events and restenosis rates after sirolimus-eluting stents implantation in patients on hemodialysis.

  M Fukui , M Tanaka , M Hamaguchi , T Senmaru , K Sakabe , E Shiraishi , I Harusato , M Yamazaki , G Hasegawa and N. Nakamura

Background and objectives: Patients with allergic disorders such as allergic rhinitis or asthma have been reported to be at increased risk for atherosclerosis. In this study, we evaluated the relationships between peripheral eosinophil count and degree of albumin excretion rate, which is a useful marker of cardiovascular mortality as well as diabetic nephropathy in patients with type 2 diabetes.

Design, setting, participants, & measurements: We evaluated relationships of peripheral eosinophil count to degree of albumin excretion rate as well as to major cardiovascular risk factors, including age, BP, serum lipid concentration, and glycemic control (glycosylated hemoglobin); body mass index; current treatment for diabetes; smoking status; and presence of cardiovascular disease in 783 patients (416 men and 367 women) with type 2 diabetes.

Results: Log(eosinophil count) was positively associated with systolic BP (r = 0.124, P = 0.0108), serum triglyceride concentration (r = 0.108, P = 0.0284), and log(albumin excretion rate) (r = 0.301, P < 0.0001) in men; however, no association was found between log(eosinophil count) and log(albumin excretion rate) (r = 0.085, P = 0.1050) in women. Multivariate linear regression analysis demonstrated that log(eosinophil count) (β = 0.260, P < 0.0001), duration of diabetes (β = 0.203, P = 0.0003), glycosylated hemoglobin (β = 0.117, P = 0.0238), systolic BP (β = 0.205, P = 0.0001), and serum triglyceride concentration (β = 0.162, P = 0.0038) were independent determinants of log(albumin excretion rate) in men.

Conclusions: Allergic disorders may be associated with microalbuminuria in men with type 2 diabetes.

  H Komaba , S Nakanishi , A Fujimori , M Tanaka , J Shin , K Shibuya , M Nishioka , H Hasegawa , T Kurosawa and M. Fukagawa

Background and objectives: Cinacalcet is effective in reducing serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. However, it has not been proven whether parathyroid gland size predicts response to therapy and whether cinacalcet is capable of inducing a reduction in parathyroid volume.

Design, setting, participants, & measurements: This 52-week, multicenter, open-label study enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism (intact PTH >300 pg/ml). Doses of cinacalcet were adjusted between 25 and 100 mg to achieve intact PTH <180 pg/ml. Ultrasonography was performed to measure the parathyroid gland size at baseline, week 26, and week 52. Findings were also compared with those of historical controls.

Results: Of the 81 subjects enrolled, 56 had parathyroid glands smaller than 500 mm3 (group S) and 25 had at least one enlarged gland larger than 500 mm3 (group L). Treatment with cinacalcet effectively decreased intact PTH by 55% from baseline in group S and by 58% in group L. A slightly greater proportion of patients in group S versus group L achieved an intact PTH <180 pg/ml (46 versus 32%) and a >30% reduction from baseline (88 versus 78%), but this was not statistically significant. Cinacalcet therapy also resulted in a significant reduction in parathyroid gland volume regardless of pretreatment size, which was in sharp contrast to historical controls (n = 87) where parathyroid gland volume progressively increased with traditional therapy alone.

Conclusions: Cinacalcet effectively decreases serum PTH levels and concomitantly reduces parathyroid gland volume, even in patients with marked parathyroid hyperplasia.

  T Matsumoto , K Minegishi , H Ishimoto , M Tanaka , J. D Hennebold , T Teranishi , Y Hattori , M Furuya , T Higuchi , S Asai , S. H Kim , K Miyakoshi and Y. Yoshimura

Ovary-specific acidic protein (OSAP) is a novel molecule discovered from a genomic project designed to identify ovary-selective genes in mice. Whereas public databases suggest extraovarian expression of OSAP, its tissue distribution has not yet been well documented. Thus, the expression profile of mouse and human OSAP was determined by quantitative real-time RT-PCR using RNAs isolated from various tissues. The results demonstrate that the human and mouse OSAP expression profiles are similar; OSAP is prominently expressed in steroidogenic tissues with the highest level of expression observed in the adrenal gland. Placenta served as an exception and possessed minimal level of OSAP mRNA. Immunohistochemical studies show that mouse OSAP localizes almost exclusively to the steroid-producing cells of the ovary, adrenal gland, and testis. Consistent with predictions made by several subcellular localization algorithms, dual labeling studies in Y-1 mouse adrenocortical cells indicate OSAP resides in the mitochondria. Because of its abundant expression in steroidogenic cells and mitochondrial localization, a role for OSAP in steroidogenesis was determined. OSAP silencing by specific small interfering RNAs significantly inhibits 8-bromoadenosine-cAMP-induced progesterone production in Y-1 cells. Reduction in OSAP levels results in mitochondrial fragmentation and a decrease in the cellular content of mitochondrial DNA, indicative of decreased mitochondrial abundance. Lastly, 8-bromoadenosine-cAMP does not regulate OSAP protein expression in Y-1 cells as is the case for other steroidogenic components known to be induced by cAMP. Collectively these results suggest that OSAP is involved in steroidogenesis, potentially through its ability to maintain mitochondrial abundance and morphology.

  M Tomura , Y. S Mori , R Watanabe , M Tanaka , A Miyawaki and O. Kanagawa

Fluorescent protein that detects caspase-3 activation was used for the time-lapse observation of CTL–target cell interaction. In the target cells transfected with SCAT3.1 (caspase-3-sensitive fusion protein) complementary DNA, caspase-3 activation can be detected significantly earlier than the commonly used annexin-V binding that detects membrane change in apoptotic cells. Moreover, during the cytolytic interaction between OE4 CTL and W3 tumor target cells, detachment of CTL from the target cells occurred prior to caspase-3 activation and death of the target cells, indicating very early sensing of apoptotic target cells by CTL. This early detachment of OE4 CTL from W3 target cells was inhibited by the expression of CD80 co-stimulatory molecule on the target cells. Taken together, time-lapse observation of cellular interaction with functional probe, SCAT3.1 provides new kinetic information and demonstrates that co-stimulatory molecules regulate the kinetics of CTL–target cell interaction.

  M. O Butler , S Ansen , M Tanaka , O Imataki , A Berezovskaya , M. M Mooney , G Metzler , M. I Milstein , L. M Nadler and N. Hirano

Many preclinical experiments have attested to the critical role of CD4+ T cell help in CD8+ cytotoxic T lymphocyte (CTL)-mediated immunity. Recent clinical trials have demonstrated that reinfusion of CD4+ T cells can induce responses in infectious diseases and cancer. However, few standardized and versatile systems exist to expand antigen-specific CD4+ Th for clinical use. K562 is a human erythroleukemic cell line, which lacks expression of HLA class I and class II, invariant chain and HLA-DM but expresses adhesion molecules such as intercellular adhesion molecule-1 and leukocyte function-associated antigen-3. With this unique immunologic phenotype, K562 has been tested in clinical trials of cancer immunotherapy. Previously, we created a K562-based artificial antigen-presenting cell (aAPC) that generates ex vivo long-lived HLA-A2-restricted CD8+ CTL with a central/effector memory phenotype armed with potent effector function. We successfully generated a clinical version of this aAPC and conducted a clinical trial where large numbers of anti-tumor CTL are reinfused to cancer patients. In this article, we shifted focus to CD4+ T cells and developed a panel of novel K562-derived aAPC, where each expresses a different single HLA-DR allele, invariant chain, HLA-DM, CD80, CD83 and CD64; takes up soluble protein by endocytosis and processes and presents CD4+ T-cell peptides. Using this aAPC, we were able to determine novel DR-restricted CD4+ T-cell epitopes and expand long-lived CD4+ T-cells specific for multiple antigens without growing bystander Foxp3+ regulatory T cells. Our results suggest that K562-based aAPC may serve as a translatable platform to generate both antigen-specific CD8+ CTL and CD4+ Th.

  N Sato , Y Ito , A Ioka , M Tanaka and H. Tsukuma

Relative 5-year survival for stomach cancer has increased gradually in Osaka for more than two decades, while women show a small but consistently lower survival for it. We analyzed gender differences in stomach cancer survival, using relative survival model proposed by Dickman et al. Study subjects were reported stomach cancer cases diagnosed in 1975–99. We estimated the excess hazard ratios (EHRs) of death using Poisson's regression model. The crude EHR for women was 1.12 [95% confidence interval (CI): 1.09–1.14] in comparison with men. After adjustments for year and age at diagnosis, the EHR for women decreased to 1.07 (95% CI: 1.05–1.09), and furthermore, it reached to an insignificant level of 1.02 (95% CI: 0.99–1.04) after an additional adjustment for the extent of disease (localized, regional, distant and unknown). With further adjustments by histological type (intestinal, diffuse and others/unknown), method of detection (screening or not) and treatment (surgery or not), the EHR decreased to 0.97 (95% CI: 0.94–0.99), significantly lower than the unity. These results indicate that the lower stomach cancer survival among women was attributable mainly to more advanced stages among women. The survival for women would have been a little better than for men if prognostic factors for stomach cancer had been comparable between the sexes. Inequality by the gender in taking screening, medical examination or treatment for stomach cancer was suggested to exist in Osaka, Japan.

  R Yamaguchi , M Tanaka , K Kondo , T Yokoyama , Y Kaneko , M Yamaguchi , Y Ogata , O Nakashima , M Kage and H. Yano

Invasive micropapillary carcinoma of the breast is a distinct variant of breast cancer. In the present study, we analyzed potential immunophenotypic changes in invasive micropapillary carcinoma.


Specimens from 15 patients with invasive micropapillary carcinoma were analyzed using clinicopathological and immunohistochemical methods. We also examined the relationship between clinicopathological factors using the Ki-67 labeling index.


Immunohistochemical staining for cytoplasmic p63 expression was seen in four (27%) tumors, and p63 nuclear expression was also observed in four (27%) tumors. Involucrin and 34betaE12 were expressed in the invasive micropapillary carcinoma component of nine (60%) and four (27%) tumors, respectively. Cytokeratin 5/6 was expressed in three (20%) tumors and cytokeratin 14 staining was negative in all tumors. In one tumor (case 3), vimentin, epithelial membrane antigen and cytokeratin 8/18 were co-expressed. Four tumors (27%) were negative for the estrogen receptor/progesterone receptor/HER2. However, 11 out of 15 (73%) tumors were positive for the estrogen receptor. The Ki-67 labeling index was significantly higher in cases with p63 tumor expression than in those without (P < 0.0001), and also higher in cases with lymph node metastasis than in cases without (P = 0.0029).


Nuclear expression of p63, involucrin and 34betaE12 were detected indicating squamous differentiation. Cytoplasmic p63 expression was also identified. The fact that the Ki-67 labeling index was significantly higher in such cases may have been associated with the aggressive behavior of these tumors. Our findings suggest that the characteristic morphology of invasive micropapillary carcinomas may be due to immunophenotypical and oncogenic changes.

  E. T Alexander , M Tanaka , M Kono , H Saito , D. J Rader and M. C. Phillips

Carriers of the apolipoprotein A-IMilano (apoA-IM) variant, R173C, have reduced levels of plasma HDL but no increase in cardiovascular disease. Despite intensive study, it is not clear whether the removal of the arginine or the introduction of the cysteine is responsible for this altered functionality. We investigated this question using two engineered variations of the apoA-IM mutation: R173S apoA-I, similar to apoA-IM but incapable of forming a disulfide bond, and R173K apoA-I, a conservative mutation. Characterization of the lipid-free proteins showed that the order of stability was wild typeR173K>R173S>R173C. Compared with wild-type apoA-I, apoA-IM had a lower affinity for lipids, while R173S apoA-I displayed intermediate affinity. The in vivo effects of the apoA-I variants were measured by injecting apoA-I-expressing adeno-associated virus into apoA-I-null mice. Mice that expressed the R173S variant again showed an intermediate phenotype. Thus, both the loss of the arginine and its replacement by a cysteine contribute to the altered properties of apoA-IM. The arginine is potentially involved in an intrahelical salt bridge with E169 that is disrupted by the loss of the positively charged arginine and repelled by the cysteine, destabilizing the helix bundle domain in the apoA-I molecule and modifying its lipid binding characteristics.

  K Hanai , T Babazono , I Nyumura , K Toya , N Tanaka , M Tanaka , A Ishii and Y. Iwamoto

Background. Nitric oxide (NO) is thought to play an important role in the pathogenesis of diabetic nephropathy. We conducted a prospective, observational cohort study to explore the relationship between plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, and the development and progression of nephropathy in patients with type 2 diabetes.

Methods. This was a hospital-based observational cohort study in Japanese type 2 diabetic patients with normoalbuminuria [urinary albumin-to-creatinine ratio (ACR) <30 mg/g creatinine] or microalbuminuria (30 ≤ ACR <300 mg/g creatinine). The primary endpoint was the development or progression of diabetic nephropathy, based on transition from any given stage to a more advanced stage of albuminuria.

Results. We studied 225 diabetic patients, 81 women and 144 men, with a mean (±SD) age of 64 ± 10 years. The majority (183) of patients were normoalbuminuric, with the remainder microalbuminuric (42). During the median follow-up period of 5.2 years, 27 normoalbuminuric and 10 microalbuminuric patients reached the primary endpoint. When patients were separated according to the median ADMA level (0.46 µmol/l), patients with higher ADMA levels had a greater incidence of reaching the endpoint (P = 0.014 by the log-rank test). In the multivariate Cox proportional hazard model, the hazard ratio for reaching the endpoint for patients with higher versus lower ADMA levels was 2.72 (95% confidence interval 1.25–5.95; P = 0.012).

Conclusions. Higher plasma levels of ADMA may be a novel and potent predictor of the progression of nephropathy in adult Japanese type 2 diabetic patients.

  T Igawa , H Tsunoda , Y Kikuchi , M Yoshida , M Tanaka , A Koga , Y Sekimori , T Orita , Y Aso , K Hattori and M. Tsuchiya

Thrombopoietin receptor agonist humanized VB22B single-chain diabody (hVB22B (scFv)2) was found to be expressed as a mixture of two conformational isomers, a single-chain diabody form and a bivalent scFv form, which had different VH/VL (variable region of the heavy chain/light chain) association patterns. The single-chain diabody form showed significantly higher biological activity than the bivalent scFv form and, when incubated at elevated temperatures, exhibited novel isomerization to the inactive bivalent scFv form. Therefore, therapeutic development of hVB22B (scFv)2 would require separation of the purified single-chain diabody form from the mixture of the two conformational isomers and also inhibition of isomerization into an inactive bivalent scFv form during storage. Novel VH/VL interface engineering in hVB22 (scFv)2, in which hydrogen bonding between H39 and L38 was substituted with electrostatic interaction to enhance the desired VH/VL association and inhibit the undesired VH/VL association, enabled selective expression of the desired conformational isomer without any reduction in biological activity or thermal stability. Moreover, VH/VL interface-engineered hVB22 (scFv)2 was completely resistant to isomerization. Because the hydrogen bonding interaction between H39 and L38 and the surrounding residues are highly conserved in human antibody sequences, VH/VL interface engineering could be generally applied to various (scFv)2 molecules for selective expression and inhibition of the isomerization of conformational isomers.

  T Endo , K Kano , R Motoki , K Hama , S Okudaira , M Ishida , H Ogiso , M Tanaka , N Matsuki , R Taguchi , M Kanai , M Shibasaki , H Arai and J. Aoki

Lysophosphatidic acid (LPA) is a simple phospholipid but has numerous biological effects through a series of G-protein-coupled receptors specific to LPA. In general, LPA is short-lived when applied in vivo, which hinders most pharmacological experiments. In our continuing study to identify stable LPA analogues capable of in vivo applications, we identified here lysophosphatidylmethanol (LPM) as a stable and pan-LPA receptor agonist. A synthetic LPM activated all five LPA receptors (LPA1–5), and stimulates both cell proliferation and LPA-receptor-dependent cell motility. In addition, LPM showed a hypertensive effect in rodent when applied in vivo. We found that, when fetal calf serum was incubated in the presence of methanol, formation of LPM occurred rapidly, whereas it was completely blocked by depletion of autotaxin (ATX), a plasma enzyme that converts lysophosphatidylcholine (LPC) to LPA. When recombinant ATX was incubated with LPC in the presence of methanol, both LPM and LPA were produced with a ratio of 1:10, showing that ATX has transphosphatidylation activity in addition to its lysophospholipase D activity. Administration of methanol in mice resulted in the formation of several micromoles of LPM in plasma, which is much higher than that of LPA. The present study identified LPM as a novel and stable lysophospholipid mediator with LPA-like activities and ATX as a potential synthetic enzyme for LPM.

  K Wada , M Niida , M Tanaka and T. Kamitani

Upon activation, NF-B translocates into the nucleus and initiates biological events. This NF-B signalling is mainly regulated by the protein kinase IKKβ. Early in this signalling pathway, IKKβ is phosphorylated for activation by several factors, such as pro-inflammatory cytokines and the Tax oncoprotein of HTLV-1. In cells infected by HTLV-1, IKKβ is persistently phosphorylated and conjugated with monoubiquitin due to Tax expression. Although this Tax-induced monoubiquitination appears to be an important regulation system for IKKβ, how the monoubiquitination occurs is unknown and its role in NF-B signalling is still unclear. Here, we show that an E3-ubiquitin ligase Ro52 interacts weakly with wild-type IKKβ but strongly with a phosphomimetic mutant IKKβ to conjugate monoubiquitin in cooperation with an E2-ubiquitin-conjugating enzyme UbcH5B. These results suggest that the Tax-induced phosphorylation of IKKβ causes an interaction with Ro52 for the subsequent monoubiquitination. NF-B reporter assays have shown that the IKKβ activity is suppressed by wild-type Ro52, but not by its inactive mutant. In addition, monoubiquitin fusion of IKKβ reduced its activity for NF-B signalling. We also found that Ro52 dramatically reduces the level of Tax. These results suggest that Ro52 down-regulates Tax-induced NF-B signalling by monoubiquitinating IKKβ and by reducing the level of Tax.

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