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Articles by Y Watanabe
Total Records ( 12 ) for Y Watanabe
  H Yamanaka , Y Hayashi , Y Watanabe , H Uematu and T. Mashimo

Hoarseness is a common complication after tracheal intubation and prolonged hoarseness may be very limiting for a patient. This study was designed to examine the duration of hoarseness after tracheal intubation and to identify risk factors that may increase the duration of hoarseness.


We prospectively studied 3093 adult patients (aged 18–77 yr), over a 3 yr period who required tracheal intubation. Postoperative hoarseness was assessed on the day of operation and on postoperative days 1, 3, and 7 by standardized interview by the resident anaesthetist managing the patient. If postoperative hoarseness was still present on postoperative day 7, the patient was followed up until complete resolution. We evaluated age, gender, weight, Cormack grades, duration of intubation, and the anaesthetic agents used as factors affecting the duration of hoarseness after tracheal intubation.


Hoarseness was observed in 49% of patients on the day of surgery and in 29%, 11%, and 0.8% on 1, 3, and 7 postoperative days, respectively. Multiple regression analysis showed that patient age and duration of intubation, but not gender, weight, Cormack grades, or the agents used, were significant predictors of increased duration of hoarseness after tracheal intubation. We found three patients with arytenoid cartilage dislocation (0.097%) in our study population.


The age of the patient and duration of intubation were significant factors in the duration of hoarseness after tracheal intubation. In addition, the incidence of arytenoid cartilage dislocation was 0.097%.

  K Konishi , L Shen , J Jelinek , Y Watanabe , S Ahmed , K Kaneko , M Kogo , T Takano , M Imawari , S. R Hamilton and J. P. J. Issa

Epigenetic changes have been proposed as mediators of the field defect in colorectal carcinogenesis, which has implications for risk assessment and cancer prevention. As a test of this hypothesis, we evaluated the methylation status of eight genes (MINT1, 2, 31, MLH1, p16, p14, MGMT, and ESR1), as well as BRAF and KRAS mutations, in 57 multiple colorectal neoplasias (M-CRN) and compared these to 69 solitary colorectal cancers (S-CRC). There were no significant differences in methylation between M-CRNs and S-CRCs except for p14 and MGMT that was significantly higher in M-CRNs than S-CRCs (16.1% versus 9.3%; 26.5% versus 17.3%, respectively; P < 0.05). We found significant (P < 0.05) correlations for MINT1 (r = 0.8), p16 (r = 0.8), MLH1 (r = 0.9), and MGMT (r = 0.6) methylation between tumors pairs of the same site (proximal/proximal and distal/distal). KRAS showed no concordance in mutations. BRAF mutation showed concordance in proximal site pairs but was discordant in different site pairs. Histologically, eight of 10 paired cancers with similar locations were concordant for a cribriform glandular configuration. We conclude that synchronous colorectal tumors of the same site are highly concordant for methylation of multiple genes, BRAF mutations, and a cribriform glandular configuration, all consistent with a patient-specific predisposition to particular subtypes of colorectal cancers. Screening for and secondary prevention of colon cancer should take this fact into account.

  H Suzuki , S Igarashi , M Nojima , R Maruyama , E Yamamoto , M Kai , H Akashi , Y Watanabe , H Yamamoto , Y Sasaki , F Itoh , K Imai , T Sugai , L Shen , J. P. J Issa , Y Shinomura , T Tokino and M. Toyota

A subset of colorectal cancers (CRCs) show simultaneous methylation of multiple genes; these tumors have the CpG island methylator phenotype (CIMP). CRCs with CIMP show a specific pattern of genetic alterations, including a high frequency of BRAF mutations and a low frequency of p53 mutations. We therefore hypothesized that genes inactivated by DNA methylation are involved in the BRAF- and p53-signaling pathways. Among those, we examined the epigenetic inactivation of insulin-like growth factor-binding protein 7 (IGFBP7) expression in CRCs. We found that in CRC cell lines, the silencing of IGFBP7 expression was correlated with high levels of DNA methylation and low levels of histone H3K4 methylation. Luciferase and chromatin immunoprecipitation assays in unmethylated cells revealed that p53 induces expression of IGFBP7 upon binding to a p53 response element within intron 1 of the gene. Treating methylated CRC cell lines with 5-aza-2'-deoxycytidine restored p53-induced IGFBP7 expression. Levels of IGFBP7 methylation were also significantly higher in primary CRC specimens than in normal colonic tissue (P < 0.001). Methylation of IGFBP7 was correlated with BRAF mutations, an absence of p53 mutations and the presence of CIMP. Thus, epigenetic inactivation of IGFBP7 appears to play a key role in tumorigenesis of CRCs with CIMP by enabling escape from p53-induced senescence.

  Y Watanabe , K Takeda and S. Funahashi

To understand functional roles of the thalamic mediodorsal nucleus (MD) in sensory-to-motor information transformation during spatial working memory performance and compare with those of the dorsolateral prefrontal cortex (DLPFC), we calculated population vectors using a population of MD activities recorded during 2 tasks. In the oculomotor delayed-response (ODR) task, monkeys needed to make a memory-guided saccade to the cue location, whereas in the rotatory oculomotor delayed-response (R-ODR) task, they needed to make a memory-guided saccade 90o clockwise from the cue direction. The directions of population vectors calculated from populations of cue- and response-period activities were similar to the cue and saccade target directions, respectively, which confirmed that population vectors represent information regarding the directions of the visual cue and the saccade target. We then calculated population vectors of delay-period activity using a sliding 250-ms time window. In the ODR task, population vectors were directed toward the cue direction throughout the delay. However, in the R-ODR task, they gradually rotated from the cue direction to the saccade target direction. Based on a comparison with the results obtained from DLPFC neurons, the rotation of population vectors started earlier in the MD than in the DLPFC, suggesting that the motor information regarding forthcoming saccade is provided from the MD.

  Y Watanabe , S Miyagawa Tomita , S. D Vincent , R. G Kelly , A. M Moon and M. E. Buckingham

Rationale: The genes encoding fibroblast growth factor (FGF) 8 and 10 are expressed in the anterior part of the second heart field that constitutes a population of cardiac progenitor cells contributing to the arterial pole of the heart. Previous studies of hypomorphic and conditional Fgf8 mutants show disrupted outflow tract (OFT) and right ventricle (RV) development, whereas Fgf10 mutants do not have detectable OFT defects.

Objectives: Our aim was to investigate functional overlap between Fgf8 and Fgf10 during formation of the arterial pole.

Methods and Results: We generated mesodermal Fgf8; Fgf10 compound mutants with MesP1Cre. The OFT/RV morphology in these mutants was affected with variable penetrance; however, the incidence of embryos with severely affected OFT/RV morphology was significantly increased in response to decreasing Fgf8 and Fgf10 gene dosage. Fgf8 expression in the pharyngeal arch ectoderm is important for development of the pharyngeal arch arteries and their derivatives. We now show that Fgf8 deletion in the mesoderm alone leads to pharyngeal arch artery phenotypes and that these vascular phenotypes are exacerbated by loss of Fgf10 function in the mesodermal core of the arches.

Conclusions: These results show functional overlap of FGF8 and FGF10 signaling from second heart field mesoderm during development of the OFT/RV, and from pharyngeal arch mesoderm during pharyngeal arch artery formation, highlighting the sensitivity of these key aspects of cardiovascular development to FGF dosage.

  J. e Obata , T Nakamura , Y Kitta , Y Kodama , K Sano , K. I Kawabata , Y Saitoh , D Fujioka , T Kobayashi , T Yano , Y Watanabe , K Watanabe and K. Kugiyama

Background— Sirolimus-eluting stent (SES) implantation aggravated endothelial vasomotor dysfunction in infarct-related coronary arteries.

Methods and Results— This study examined the effect of SES implantation on the duration of reperfusion-induced endothelial vasomotor dysfunction in infarct-related coronary arteries and on postinfarct left ventricular dysfunction in acute myocardial infarction (AMI). Patients with a first AMI due to occlusion of the left anterior descending coronary artery and successful reperfusion using SES (n=15) or bare metal stents (BMS; n=18) were examined. The vasomotor response of the left anterior descending coronary artery to acetylcholine and left ventriculography were examined 2 weeks and 6 months after AMI. At 6 months after AMI, the impairment of epicardial coronary artery dilation and coronary blood flow increase in response to acetylcholine was recovered from 2 weeks after AMI in BMS-treated patients, whereas the responses of SES-treated patients improved but remained impaired compared with BMS-treated patients (% increase in blood flow, 77±12% in SES versus 116±15% in BMS at 10 µg/min of acetylcholine, P<0.01). Left ventricular regional wall dysfunction in the left anterior descending coronary artery territory improved from 2 weeks to 6 months after AMI in BMS-treated patients but not in SES-treated patients (% improvement of average SD/chord, 6% in SES versus 19% in BMS, P<0.05), although left ventricular global ejection fraction was similar between the groups at any time points.

Conclusions— SES implantation may delay recovery of reperfusion-induced endothelial vasomotor dysfunction in infarct-related coronary arteries and left ventricular regional dysfunction for at least 6 months after AMI.

  H Koyama , S Fukuda , T Shoji , M Inaba , Y Tsujimoto , T Tabata , S Okuno , T Yamakawa , S Okada , M Okamura , H Kuratsune , H Fujii , Y Hirayama , Y Watanabe and Y. Nishizawa

Background and objectives: Despite potential significance of fatigue and its underlying components in the occurrence of cardiovascular diseases, epidemiologic data showing the link are virtually limited. This study was designed to examine whether fatigue symptoms or fatigue's underlying components are a predictor for cardiovascular diseases in high-risk subjects with ESRD.

Design, setting, participants, & measurements: 788 volunteer patients under hemodialysis therapy (506 male, 282 female) completed the survey between October and November 2005, with the follow-up period up to 26 months to monitor occurrence of fatal or nonfatal cardiovascular events. The questionnaire consisted of 64 questions, and promax rotation analysis of the principal component method conceptualized eight fatigue-related factors: fatigue itself, anxiety and depression, loss of attention and memory, pain, overwork, autonomic imbalance, sleep problems, and infection.

Results: 14.7% of the patients showed fatigue scores higher than twice the SD of the mean for healthy volunteers. These highly fatigued patients exhibited a significantly higher risk for cardiovascular events (hazard ratio: 2.17; P < 0.01), with the relationship independent of the well-known risk factors, including age, diabetes, cardiovascular disease history, and inflammation and malnutrition markers. Moreover, comparisons of the risk in key subgroups showed that the risk of high fatigue score for cardiovascular events was more prominent in well-nourished patients, including lower age, absence of past cardiovascular diseases, higher serum albumin, and high non-HDL cholesterol.

Conclusions: Fatigue can be an important predictor for cardiovascular events in patients with ESRD, with the relationship independent of the nutritional or inflammatory status.

  Y Watanabe , T Takahashi , A Okajima , M Shiokawa , N Ishii , I Katano , R Ito , M Ito , M Minegishi , N Minegishi , S Tsuchiya and K. Sugamura

‘Humanized mice’ are anticipated to be a valuable tool for studying the human immune system, but the reconstituted human immune cells have not yet been well characterized. Here, we extensively investigated the differentiation and functions of human B and T cells in a supra-immunodeficient mouse strain, NOD/shi-scid/cnull (NOG) reconstituted with CD34+ hematopoietic stem cells obtained from umbilical cord blood. In these hu-HSC NOG mice, the development of human B cells was partially blocked, and a significant number of B-cell progenitors accumulated in the spleen. The mature CD19+IgM+IgD+ human B cells of the hu-HSC NOG mice could produce IgG in vivo and in vitro by antigenic stimulation. In contrast, although human T cells with an apparently normal phenotype developed, most of them could neither proliferate nor produce IL-2 in response to antigenic stimulation by anti-CD3 and anti-CD28 antibodies in vitro. The positive selection of human T cells in the thymus was sufficiently functional, if not complete, and mainly mediated by mouse class II, suggesting that the human T cells lost their function in the periphery. We found that multiple mechanisms were involved in the T-cell abnormalities. Collectively, our results demonstrate that further improvements are necessary before humanized mice with a functional human immune system are achieved.

  H Ishida , Y Miyake , M Fukunaga , Y Watanabe , T Kato , H Takemoto and H. Furukawa

This is a feasibility trial of oral uracil/tegafur (UFT)/oral leucovorin (LV) and irinotecan (TEGAFIRI) with maximum dose confirmed in Japan. To document the toxicity and define the objective response rate (RR); and determine progression-free and overall survival.


Patients with advanced or metastatic colorectal cancer (CRC) received: UFT 300 mg/m2, LV 75 mg/body and CPT-11 150 mg/m2 (UFT and LV given on days 1–14, and CPT-11 on day 1, every 3 weeks). Eligibility: ECOG performance status (PS) 0–1, adequate bone marrow/liver function and serum creatinine level less than institutional normal value.


Eighteen patients enrolled, 17 evaluable for toxicity and response and 1 patients recalled chemotherapy upon registration. Characteristics: 61% male, median age 63.5 years (51–71). Seventy-two per cent PS 0, 50% first line. One hundred and eighty-six cycles have been delivered. The common Grade 3–4 toxicities were neutropenia (35.3%), leukopenia (29.4%), diarrhea (5.9%), anorexia (5.9%), vomiting (5.9%) and dizziness (5.9%). There was no episode of febrile neutropenia. No death occurred on treatment: Overall RR was 41.2% [7/17: 1 complete response (CR) + 6 partial response (PR)]. Progression-free survival (PFS) is 6.9 months, median survival time (MST) is 25.1 months and 1-year survival rate is 70.6%, whereas PFS 15.0 months, MST 43.6+ months and 1-year survival rate 100% in cases with CR or PR.


Approved dose of CPT-11 is 150 mg/m2 in Japan. As is lower dose with CPT-11, TEGAFIRI for patients with advanced or metastatic CRC in Japan seems to have the similar effect with that reported abroad and indicates prolonged PFS and MST in cases with CR or PR.

  K Yamasaki , K Omori , E. I Takaoka , N Sekido , M Shigai , K Mori , M Minami , Y Watanabe , T Shimazui and H. Akaza

We present the clinical course of a ureteroiliac arterial fistula in a patient who had been managed by ureteral stenting for 8 years for severe ureteral stricture after abdominoperineal resection with pelvic irradiation for advanced rectal cancer. A multidisciplinary team approach including provocative angiography and an endovascular stent saved the life of the patient. Ureteroarterial fistula is a rare complication of a long-term indwelling ureteral stent that is potentially fatal unless a prompt diagnosis and adequate therapy are provided. Heightened awareness and a high index of suspicion for this condition are required to make an early diagnosis.

  A Kamei , Y Watanabe , T Ishijima , M Uehara , S Arai , H Kato , Y Nakai and K. Abe

Anemia can be induced by dietary iron deficiency, as well as by hemorrhagia. It may also be associated with changes in lipid metabolism. However, no global analysis detailing the consequences of iron deficiency in the liver has yet been conducted. Since the liver is a metabolically important organ and also a major iron-storing organ, we performed a comprehensive transcriptome analysis to determine the effects of iron deficiency on hepatic gene expression. Four-week-old rats were fed an iron-deficient diet, ~3 ppm iron, ad libitum for 16 days. These rats were compared with similar rats pair-fed a control diet with a normal iron level, 48 ppm iron. The 16-day iron-deficient diet apparently induced anemia. On day 17, the rats were killed under anesthesia, and their livers were dissected for DNA microarray analysis. We identified 600 upregulated and 500 downregulated probe sets that characterized the iron-deficient diet group. In the upregulated probe sets, genes involved in cholesterol, amino acid, and glucose metabolism were significantly enriched, while genes related to lipid metabolism were significantly enriched in the downregulated probe sets. We also found that genes for caspases 3 and 12, which mediate endoplasmic reticulum (ER)-specific apoptosis, were upregulated in the iron-deficient group. Combined, these results suggest that iron deficiency exerts various influences, not only on nutrient metabolism but also on apoptosis, as a consequence of ER stress in the liver.

  T Kubo , Y Uchida , Y Watanabe , M Abe , A Nakamura , M Ono , S Akira and T. Takai

Pathogens are sensed by Toll-like receptors (TLRs) expressed in leukocytes in the innate immune system. However, excess stimulation of TLR pathways is supposed to be connected with provocation of autoimmunity. We show that paired immunoglobulin (Ig)-like receptor B (PIR-B), an immunoreceptor tyrosine-based inhibitory motif–harboring receptor for major histocompatibility class I molecules, on relatively primitive B cells, B-1 cells, suppresses TLR9 signaling via Bruton's tyrosine kinase (Btk) dephosphorylation, which leads to attenuated activation of nuclear factor B p65RelA but not p38 or Erk, and blocks the production of natural IgM antibodies, including anti-IgG Fc autoantibodies, particularly rheumatoid factor. The autoantibody production in PIR-B–deficient (Pirb–/–) mice was further augmented in combination with the Faslpr mutation, which might be linked to the development of autoimmune glomerulonephritis. These results show the critical link between TLR9-mediated sensing and a simultaneously evoked, PIR-B–mediated inhibitory circuit with a Btk intersection in B-1 cells, and suggest a novel way toward preventing pathogenic natural autoantibody production.

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