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Articles by M Yamamoto
Total Records ( 14 ) for M Yamamoto
  M Yamamoto , M. S Hayashi , N. T Nguyen , T. D Nguyen , S McCloud and D. K. Imagawa

Objective  To investigate the use of Seamguard, a bioabsorbable staple line–reinforcement product, to prevent pancreatic leak after distal pancreatectomy.

Design, Setting, and Participants  A retrospective study examined 85 consecutive patients undergoing distal pancreatectomy at an academic institution from September 5, 1997, to September 30, 2007.

Main Outcome Measures  Pancreatic fistula and overall mortality and morbidity.

Results  In February 2004, the use of Seamguard in distal pancreas resections was introduced at our institution. Indications for resection included trauma (11 patients), neoplasms (62 patients), and chronic pancreatitis (12 patients). Pancreatic leak was defined as drain output of 25 mL/d or more 7 days postoperatively with a drain amylase level of 1000 U/L or more. Pancreatic leak occurred in 10 of 38 patients (26%) undergoing conventional resection with suture ligation of the pancreatic duct or nonreinforced stapled resection vs 2 of 47 patients (4%) undergoing staple resection using Seamguard reinforcement. Multivariate analysis showed that use of Seamguard with the stapler independently decreased the risk for pancreatic fistula after distal pancreatectomy (odds ratio, 0.07; 95% confidence interval, 0.01-0.43; P = .01).

Conclusions  The use of Seamguard is quickly becoming a common adjunct in distal pancreas resections. Our study shows a lower incidence of pancreatic leak after distal pancreatectomy with the use of this staple line–reinforcing product.

  M. S Yates , Q. T Tran , P. M Dolan , W. O Osburn , S Shin , C. C McCulloch , J. B Silkworth , K Taguchi , M Yamamoto , C. R Williams , K. T Liby , M. B Sporn , T. R Sutter and T. W. Kensler

Loss of NF-E2-related factor 2 (Nrf2) signaling increases susceptibility to acute toxicity, inflammation and carcinogenesis in mice due to the inability to mount adaptive responses. In contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice, although inactivating mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. Liver-targeted conditional Keap1-null, Albumin-Cre:Keap1(flox/–) (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared with hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. The results show that genetic and pharmacologic activation of Nrf2 signaling modulates pathways beyond detoxication and cytoprotection, with the largest cluster of genes associated with lipid metabolism. Genetic activation of Nrf2 results in much larger numbers of detoxication and lipid metabolism gene changes. Additionally, analysis of pharmacologic activation suggests that Nrf2 is the primary mediator of CDDO-Im activity, though other cell-signaling targets are also modulated following an oral dose of 30 µmol/kg.

  M. O Kelleher , M McMahon , I. M Eggleston , M. J Dixon , K Taguchi , M Yamamoto and J. D. Hayes

Epithionitriles represent a previously unrecognized class of cancer chemopreventive phytochemical generated from alkenyl glucosinolates in cruciferous vegetables. In rat liver RL-34 epithelial cells, 1-cyano-2,3-epithiopropane (CETP), 1-cyano-3,4-epithiobutane (CETB) and 1-cyano-4,5-epithiopentane (CETPent) were shown to induce cytoprotective enzymes including NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione (GSH) S-transferase A3 and the glutamate–cysteine ligase modifier subunit; CETP was more potent in this regard than were either CETB or CETPent, with 50 µM CETP eliciting a remarkable ~10-fold induction of NQO1. Furthermore, 50 µM CETP stimulated a 2.0-fold overproduction of GSH in RL-34 cells. Transfection experiments demonstrated that epithionitriles induced gene expression through an antioxidant response element (ARE) and that transactivation of an Nqo1-luciferase reporter plasmid was dependent on NF-E2 p45-related factor 2 (Nrf2), a cap'n'collar basic region leucine zipper transcription factor. Evidence is presented that CETP affected Nrf2-mediated induction of ARE-driven transcription by inhibiting Kelch-like ECH-associated protein 1 (Keap1), a ubiquitin ligase substrate adaptor that negatively regulates Nrf2. We found that Nqo1 was expressed constitutively at high levels in Keap1–/– mouse embryonic fibroblasts (MEFs) and it was not further induced by CETP. However, knock-in of mouse Keap1 or zebrafish Keap1a into Keap1–/– MEFs repressed Nqo1-luciferase reporter gene activity, but repression by the murine or zebrafish proteins was antagonized by CETP. Pre-treatment of Nrf2+/+ MEFs, but not Nrf2–/– MEFs, with 15 µM CETP for 24 h conferred 2.4-fold resistance against subsequent exposure to the ,β-unsaturated aldehyde acrolein, indicating that the phytochemical exerts chemopreventive properties against genotoxic xenobiotics.

  I. D Greener , J. O Tellez , H Dobrzynski , M Yamamoto , G. M Graham , R Billeter and M. R. Boyett

Background— Little is known about the distribution of gap junctions and ion channels in the atrioventricular node, even though the physiology and pathology of the atrioventricular node is ultimately dependent on them.

Methods and Results— The abundance of 30 transcripts for markers, gap junctions, ion channels, and Ca2+-handling proteins in different regions of the rabbit atrioventricular node (nodal extension and proximal and distal penetrating bundle of His as well as atrial and ventricular muscle) was measured using a novel quantitative polymerase chain reaction technique and in situ hybridization. The expression profile of the nodal extension (slow pathway into penetrating bundle) was similar to that of the sinoatrial node. For example, in the nodal extension, in contrast to the atrial muscle and as expected for a slowly conducting tissue with pacemaker activity, there was no or reduced expression of Cx43, Nav1.5, Cav1.2, Kv1.4, KChIP2, and RYR3 and high expression of Cav1.3 and HCN4. The expression profile of the penetrating bundle was less specialized. In situ hybridization revealed a transitional zone with reduced expression of Cx43, Nav1.5, and KChIP2 that may form the fast pathway into the penetrating bundle.

Conclusions— At the atrioventricular node, the expression of gap junctions and ion channels in the nodal extension (slow pathway) and a transitional zone (putative fast pathway) as well as the penetrating bundle (output pathway) is specialized and heterogeneous and roughly matches the electrophysiology of the different regions.

  Y Seo , T Ishizu , Y Enomoto , H Sugimori , M Yamamoto , T Machino , R Kawamura and K. Aonuma

Background— Three-dimensional speckle tracking imaging (3D-STI) has been introduced to assess regional left ventricular (LV) myocardial function. This study was designed to validate LV strain measurements by 3D-STI against data obtained by sonomicrometry.

Methods and Results— In each of 10 anesthetized sheep, sonomicrometry crystals were implanted on the endocardium and epicardium at the LV basal, mid, and apical anterior and lateral walls. LV 3D-STI data sets were obtained from the apical approach at a frame rate of approximately 30 frames/s. Segmental longitudinal (LS), radial (RS), and circumferential strain (CS) measurements by 3D-STI were compared with those by sonomicrometry at baseline and during pharmacological stress tests (dobutamine and propranolol infusion) and acute myocardial ischemia induced by coronary artery occlusion. Data were available from 136 LS, 108 CS, and 175 RS measurements. Good correlations were observed between strain measurements by 3D-STI and those by sonomicrometry (LS: r=0.89, P<0.001; RS: r=0.84, P<0.001; CS: r=0.90, P<0.001). In each segmental study, significant correlations of the 3 strain components were observed (LS: r=0.65 to 0.68, P<0.001; RS: r=0.59 to 0.70, P<0.001; CS: r=0.71 to 0.78, P<0.001).

Conclusions— The newly developed 3D-STI technique can estimate LV regional circumferential, longitudinal, and radial strain components with reasonable correlation to sonomicrometry data. This methodology could be applied clinically to assess alteration of myocardial function by accurately measuring strain in basal, mid, and apical LV segments, even during pharmacological and ischemic interventions. Therefore, 3D-STI appears to be a reliable tool to assess LV regional wall function.

  S Yokoyama , M Takano , M Yamamoto , S Inami , S Sakai , K Okamatsu , S Okuni , K Seimiya , D Murakami , T Ohba , R Uemura , Y Seino , N Hata and K. Mizuno

Background— Although coronary angiograms after bare-metal stent (BMS) implantation show late luminal narrowing beyond 4 years, the detailed changes inside the BMS have not yet been fully elucidated.

Methods and Results— Serial angiographic and angioscopic examinations were performed immediately (baseline), 6 to 12 months (first follow-up), and ≥4 years (second follow-up) after stenting without target lesion revascularization in 26 segments of 26 patients who received BMS deployment for their native coronary arteries. Angioscopic observation showed atherosclerotic yellow plaque crushed out by stent struts in 22 patients (85%) and mural thrombus in 21 patients (81%) at baseline. At first follow-up, white neointimal hyperplasia was almost completely buried inside the struts, and both yellow plaque and thrombus had decreased in comparison with baseline (12% and 4%, respectively; P<0.001). The frequencies of yellow plaque and thrombus increased from the first to second follow-ups (58% and 31%, respectively; P<0.05). All of the yellow plaques in the second follow-up were located not exterior to the struts but protruding from the vessel wall into the lumen. Late luminal narrowing, defined as an increasing of percent diameter stenosis between the first and second follow-ups, was greater in segments with yellow plaque than in those without yellow plaque (18.4±17.3% versus 3.6±4.2%, respectively; P=0.011).

Conclusions— This angiographic and angioscopic study suggests that white neointima of the BMS may often change into yellow plaque over an extended period of time, and atherosclerotic progression inside the BMS may contribute to late luminal narrowing.

  M Takano , M Yamamoto , M Mizuno , D Murakami , T Inami , N Kimata , K Murai , N Kobayashi , K Okamatsu , T Ohba , Y Seino and K. Mizuno

Late vascular responses after implantation of drug-eluting stents may play a key role in steadily increasing occurrence of very late stent thrombosis have not yet been fully investigated in human beings.

Methods and Results—

Serial optical coherence tomography observations at 2 and 4 years were collected for 17 patients treated with 21 sirolimus-eluting stents. Corresponding 376 cross sections within single-stent segments at intervals of 1 mm were selected for analyses, and neointimal thickness on each strut was measured. Extrastent lumen (ESL) was defined as an external lumen of the stent. Area and angle of ESL were measured. A total of 3369 and 3221 struts were identified at 2 and 4 years, respectively. From 2 to 4 years, mean neointimal thickness increased (76.8±75.6 µm versus 123.0±102.5 µm; P<0.0001), whereas frequency of patients with uncovered struts decreased (88% versus 29%; P=0.002). Although prevalence of patients that had ESL was similar (59% of 2 years versus 65% of 4 years; P=1.0), the cross sections with ESL increased (9.6% versus 15.2%; P=0.02). Moreover, area and angle of ESL increased from 2 to 4 years (0.28±0.27 mm2 versus 0.62±0.68 mm2 and 16.6±5.4° versus 65.1±38.4°; P<0.01, respectively). The incidence of subclinical thrombus did not decrease (24% at 2 years versus 29% at 4 years; P=1.0). All thrombi were identified in patients who had cross sections with ESL.


The current serial optical coherence tomography study showed an augmentation of neointimal growth at the late phase of sirolimus-eluting stent implantation. ESL may contribute to thrombus formation and ESL of sirolimus-eluting stents expanded from 2 to 4 years.

  H Ogata , C Kumata Maeta , K Shishido , M Mizobuchi , M Yamamoto , F Koiwa , E Kinugasa and T. Akizawa

Background and objectives: Peripheral arterial disease (PAD) is a known predictor of cardiovascular morbidity and mortality among hemodialysis patients. Although ankle-brachial BP index (ABI) is a simple and reliable test for PAD screening, its sensitivity has been suggested to decrease among dialysis patients.

Design, setting, participants, & measurements: We performed a cross-sectional outpatient cohort study to examine prevalence of PAD among hemodialysis patients using duplex ultrasonography of the lower extremity artery. We also evaluate the influence of increased arterial stiffness on impaired accuracy of ABI for PAD screening.

Results: Of 315 total patients, 23.8% had PAD. PAD was associated with younger age, diabetes, current smoking, atherosclerotic comorbidities, increased total cholesterol levels, increased triglyceride levels, and lower Kt/V. The receiver operating characteristic analysis (area under the receiver operating characteristic curve = 0.846) showed that sensitivity and specificity of ABI values for PAD were 49.0 and 94.8%, respectively. An ABI cut-off value of 1.05 resulted in the best sensitivity (74.5%) and specificity (84.4%). There was a significant difference in sensitivity of ABI levels <0.9 for detecting PAD among patients in different brachial-ankle pulse wave velocity quartiles. In patients with the highest brachial-ankle pulse wave velocity quartile, PAD was most prevalent (46.5%), and ABI had the highest accuracy in detecting PAD (area under the curve, 0.933).

Conclusions: These results suggest that duplex ultrasonography was a useful tool for screening asymptomatic PAD among hemodialysis patients and that the diagnostic value of ABI for PAD was affected by various factors.

  M Uehara , K Yashiro , K Takaoka , M Yamamoto and H. Hamada

The abundance of retinoic acid (RA) is determined by the balance between its synthesis by retinaldehyde dehydrogenase (RALDH) and its degradation by CYP26. In particular, the dynamic expression of three CYP26 genes controls the regional level of RA within the body. Pregastrulation mouse embryos express CYP26 but not RALDH. We now show that mice lacking all three CYP26 genes manifest duplication of the body axis as a result of expansion of the Nodal expression domain throughout the epiblast. Mouse Nodal was found to contain an RA-responsive element in intron 1 that is highly conserved among mammals. In the absence of CYP26, maternally derived RA activates Nodal expression in the entire epiblast of pregastrulation embryos via this element. These observations suggest that maternal RA must be removed by embryonic CYP26 for correct Nodal expression during embryonic patterning.

  K Nohara , T Suzuki , K Ao , H Murai , Y Miyamoto , K Inouye , X Pan , H Motohashi , Y Fujii Kuriyama , M Yamamoto and C. Tohyama

The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) has been implicated in various immune functions. Our previous studies have shown that AhR activation by exposure of ovalbumin (OVA)-immunized mice to the potent ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases immunization-induced IFN- production in the spleen and suppresses the production of Th2 cytokines and OVA-specific antibodies. In the present study, we used transgenic (Tg) mice that express a constitutively active mutant of aryl hydrocarbon receptor (CA-AhR) specifically in T-lineage cells to clarify the role of AhR activation in T cells in these reactions. The results of this study clearly demonstrated that AhR activation only in the T cells augments IFN- production upon OVA immunization. By contrast, production of Th2 cytokines and antibodies were not significantly suppressed by CA-AhR in the T cells. These results suggest that suppression of Th2 cytokines and antibodies production require AhR activation not only in T cells but also in other cell types as caused by TCDD exposure. Alternatively, these results may indicate that IFN- augmentation and Th2 cytokines and antibodies suppression depend on different ways of functions of AhR in the T cells and that CA-AhR does not replicate the suppressive effect of TCDD-activated AhR on Th2 cytokines and antibodies. Expression of CA-AhR in the T cells was also shown to increase the percentage of CD25+ cells among CD4+ cells in the thymus and spleen. Thus, studies using T-cell-specific CA-AhR Tg mice provide a way to dissect the role of AhR in individual cell types and how the AhR functions.

  Y Hayashi , M Yamamoto , H Mizoguchi , C Watanabe , R Ito , S Yamamoto , X. y Sun and Y. Murata

Multiple bioactive peptides, including glucagon, glucagon-like peptide-1 (GLP-1), and GLP-2, are derived from the glucagon gene (Gcg). In the present study, we disrupted Gcg by introduction of GFP cDNA and established a knock-in mouse line. Gcggfp/gfp mice that lack most, if not all, of Gcg-derived peptides were born in an expected Mendelian ratio without gross abnormalities. Gcggfp/gfp mice showed lower blood glucose levels at 2 wk of age, but those in adult Gcggfp/gfp mice were not significantly different from those in Gcg+/+ and Gcggfp/+ mice, even after starvation for 16 h. Serum insulin levels in Gcggfp/gfp mice were lower than in Gcg+/+ and Gcggfp/+ on ad libitum feeding, but no significant differences were observed on starvation. Islet -cells and intestinal L-cells were readily visualized in Gcggfp/gfp and Gcggfp/+ mice under fluorescence. The Gcggfp/gfp postnatally developed hyperplasia of islet -cells, whereas the population of intestinal L-cells was not increased. In the Gcggfp/gfp, expression of Aristaless-related homeobox (Arx) was markedly increased in pancreas but not in intestine and suggested involvement of Arx in differential regulation of proliferation of Gcg-expressing cells. These results illustrated that Gcg-derived peptides are dispensable for survival and maintaining normoglycemia in adult mice and that Gcg-derived peptides differentially regulate proliferation/differentiation of -cells and L-cells. The present model is useful for analyzing glucose/energy metabolism in the absence of Gcg-derived peptides. It is useful also for analysis of the development, differentiation, and function of Gcg-expressing cells, because such cells are readily visualized by fluorescence in this model.

  K Kosaka , J Mimura , K Itoh , T Satoh , Y Shimojo , C Kitajima , A Maruyama , M Yamamoto and T. Shirasawa

Neurotrophins such as NGF promote neuronal survival and differentiation via the cell surface TrkA neurotrophin receptor. Compounds with neurotrophic actions that are low in molecular weight and can permeate the blood–brain barrier are promising therapeutic agents against neurodegenerative diseases such as Alzheimer’s disease. Carnosic acid (CA), an electrophilic compound in rosemary, activates antioxidant responsive element (ARE)-mediated transcription via activation of Nrf2. In the present study, we discovered that CA strongly promotes neurite outgrowth of PC12h cells. NGF as well as CA activated Nrf2, whereas CA and NGF-mediated neuronal differentiation was suppressed by Nrf2 knockdown. On the other hand, CA activated TrkA-downstream kinase Erk1/2 independently of Nrf2. CA-induced p62/ZIP expression in an Nrf2-dependent manner, while the CA-induced neural differentiation was suppressed by p62/ZIP knockdown. Furthermore, CA-induced ARE activation was attenuated both by p62/ZIP knockdown and a Trk signal inhibitor. These results suggest that the CA induction of p62/ZIP by Nrf2 enhances TrkA signaling which subsequently potentiates Nrf2 pathway. This is the first demonstration that activation of the Nrf2-p62/ZIP pathway by a low-molecular natural electrophilic compound plays important roles in TrkA-mediated neural differentiation and may represent the common molecular mechanism for neurotrophic activities of electrophilic compounds.

  T Moriguchi , K Ida , T Hikima , G Ueno , M Yamamoto and H. Suzuki

We characterized the crystal structures of heterotetrameric sarcosine oxidase (SO) from Corynebacterium sp. U-96 complexed with methylthioacetate (MTA), pyrrole 2-carboxylate (PCA) and sulphite, and of sarcosine-reduced SO. SO comprises -, β-, - and -subunits; FAD and FMN cofactors; and a large internal cavity. MTA and PCA are sandwiched between the re-face of the FAD isoalloxazine ring and the β-subunit C-terminal residues. Reduction of flavin cofactors shifts the β-subunit Ala1 towards the -subunit Met55, forming a surface cavity at the oxygen-channel vestibule and rendering the β-subunit C-terminal residues mobile. We identified three channels connecting the cavity and the enzyme surface. Two of them exist in the inter-subunit space between and β-subunits, and the substrate sarcosine seems to enter the active site through either of these channels and reaches the re-side of the FAD isoalloxazine ring by traversing the mobile β-subunit C-terminal residues. The third channel goes through the -subunit and has a folinic acid-binding site, where the iminium intermediate is converted to Gly and either formaldehyde or, 5,10-methylenetetrahydrofolate. Oxygen molecules are probably located on the surface cavity and diffuse to the FMN isoalloxazine ring; the H2O2 formed exits via the oxygen channel.

  M Yamamoto , D. M Standley , S Takashima , H Saiga , M Okuyama , H Kayama , E Kubo , H Ito , M Takaura , T Matsuda , D Soldati Favre and K. Takeda

Infection by Toxoplasma gondii down-regulates the host innate immune responses, such as proinflammatory cytokine production, in a Stat3-dependent manner. A forward genetic approach recently demonstrated that the type II strain fails to suppress immune responses because of a potential defect in a highly polymorphic parasite-derived kinase, ROP16. We generated ROP16-deficient type I parasites by reverse genetics and found a severe defect in parasite-induced Stat3 activation, culminating in enhanced production of interleukin (IL) 6 and IL-12 p40 in the infected macrophages. Furthermore, overexpression of ROP16 but not ROP18 in mammalian cells resulted in Stat3 phosphorylation and strong activation of Stat3-dependent promoters. In addition, kinase-inactive ROP16 failed to activate Stat3. Comparison of type I and type II ROP16 revealed that a single amino acid substitution in the kinase domain determined the strain difference in terms of Stat3 activation. Moreover, ROP16 bound Stat3 and directly induced phosphorylation of this transcription factor. These results formally establish an essential and direct requirement of ROP16 in parasite-induced Stat3 activation and the significance of a single amino acid replacement in the function of type II ROP16.

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