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Articles by T Usui
Total Records ( 6 ) for T Usui
  N Honda , T Mimura , T Usui and S. Amano
 

Objective  To investigate the feasibility of Descemet stripping automated endothelial keratoplasty (DSAEK) using cultured human corneal endothelial cells (HCECs) in an animal model.

Methods  Descemet stripping automated endothelial keratoplasty grafts were produced by seeding cultured HCEC suspensions onto human corneal stromal discs. Three insertion techniques were assessed in an ex vivo model. The feasibility of DSAEK grafts with cultured HCECs was examined in a rabbit model. Rabbits received stromal disc transplants with cultured HCECs (c-DSAEK) or without HCECs (controls).

Results  The HCECs on the DSAEK grafts had a consistent size and polygonal shape. Mean (SD) percentage of cell loss in the taco-folding group (38.7% [5.2%]) was significantly greater than that in the Busin glide (11.6% [1.5%]; P = .001) and lens glide (18.0% [5.4%]; P = .007) groups. Corneal transparency gradually recovered in the c-DSAEK group, whereas edema persisted for up to 28 days in controls. Histologic examination after surgery revealed donor HCECs covering the posterior surface of the graft in the c-DSAEK group.

Conclusions  Further enhancements of the efficacy and safety of DSAEK using cultured HCECs will make this a clinically feasible alternative therapy for corneal endothelial dysfunction.

Clinical Relevance  Descemet stripping automated endothelial keratoplasty using cultured HCECs may be a novel therapeutic approach to treat corneal endothelial dysfunction.

  N Honda , T Miyai , R Nejima , K Miyata , T Mimura , T Usui , M Aihara , M Araie and S. Amano
 

Objective  To investigate the effect of topical latanoprost on the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase 1 (TIMP-1) on the ocular surface.

Methods  Tears were collected from 39 patients with glaucoma who used latanoprost, 0.005%, eyedrops (Xalatan) and 28 healthy volunteers. The MMP-9 concentration was measured. Conjunctival epithelial cells were collected from 10 eyes of 10 patients before and 1 to 3 months after starting to take topical latanoprost, 0.005%, and MMP-1, MMP-9, and TIMP-1 messenger RNA (mRNA) expression was analyzed. Both eyes of 48 mice were treated once a day with latanoprost, 0.005%, timolol gel, 0.5%, eyedrops, vehicle of Xalatan, or phosphate-buffered saline, and MMP-9 and TIMP-1 mRNA expression was analyzed.

Results  The median MMP-9 concentration in latanoprost-treated cases was 91.2 ng/mL (in controls, 19.7 ng/mL; P < .001). In latanoprost-treated cases, the relative ratio of MMP-9 to glyceraldehyde 3-phosphate dehydrogenase mRNA was significantly increased from 6.42 to 21.3 (P = .04, paired t test) and the relative amount of TIMP-1 was significantly decreased from 154 to 105 (P = .009). The relative amount of MMP-1 to GAPDH mRNA before and after latanoprost use was not significantly different (P = .16). In mice, MMP-9 expression was increased and TIMP-1 expression was decreased on the ocular surface at 8 weeks after latanoprost use.

Conclusion  The topical use of latanoprost increases MMP-1 and MMP-9 and decreases TIMP-1 on the ocular surface.

Clinical Relevance  The use of topical latanoprost might not be recommended in patients with keratoconus or after laser-assisted in situ keratomileusis.

  N Sasaki , T Yamashita , M Takeda , M Shinohara , K Nakajima , H Tawa , T Usui and K. i. Hirata
 

Background— Accumulating evidence suggests that several subsets of regulatory T cells that actively mediate immunologic tolerance play crucial roles in atherogenesis. Recently, orally administered anti-CD3 monoclonal antibody has been shown as an inducer of novel regulatory T cells expressing latency-associated peptide (LAP) on their surface, which potently prevents systemic autoimmunity. In the present study, we hypothesized that oral anti-CD3 antibody treatment may inhibit atherosclerosis in mice.

Methods and Results— Six-week-old apolipoprotein E–deficient mice on a standard diet were orally given anti-CD3 antibody or control immunoglobulin G on 5 consecutive days, and atherosclerosis was assessed at age 16 weeks. Oral administration of anti-CD3 antibody significantly reduced atherosclerotic lesion formation and accumulations of macrophages and CD4+ T cells in the plaques compared with controls. We observed a significant increase in LAP+ cells and CD25+Foxp3+ cells in the CD4+ T-cell population in anti-CD3–treated mice, in association with increased production of the antiinflammatory cytokine transforming growth factor-β and suppressed T-helper type 1 and type 2 immune responses. Neutralization of transforming growth factor-β in vivo abrogated the preventive effect of oral anti-CD3 antibody.

Conclusions— Our findings indicate the atheroprotective role of oral anti-CD3 antibody treatment in mice via induction of a regulatory T-cell response. These findings suggest that oral immune modulation may represent an attractive therapeutic approach to atherosclerosis.

  K. i Umehara , K Wada , K Noguchi , T Iwatsubo , T Usui and H. Kamimura
 

(–)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel "funny" If current channel (If channel) inhibitor, is developed as a treatment for stable angina and atrial fibrillation. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) relationship after intravenous administration of YM758 to tachycardia-induced dogs was investigated and described based on the simplified compartment model. The PK of YM758 in dogs did not differ between the nontreated and tachycardia-induced groups. A drug-induced reduction in heart rate (HR) was clearly observed, and the half-life of the duration of the effect (approximately 4.0 h) was longer than that of the plasma concentration of the unchanged drug. The fitting and simulation procedure from the PK/PD relationship between the time profiles for YM758 plasma concentration and HR reduction had an ECe50 value (YM758 concentration in the effective compartment resulting in a 50% decrease of the maximum effect) of 6.0 ng/ml, which did not agree with the results of the in vitro experiment using right atria isolated from guinea pigs (EC30, 70.4 ng/ml). In addition, in the in vitro experiments, YM758 metabolites had a weak inhibitory effect, if any, on the spontaneous beat rate of the right atria from guinea pigs. These data, along with the previous finding that YM758 and its metabolites are eliminated rapidly from rat hearts, indicate that the duration of the pharmacological effect of YM758 (compared with the rapid elimination of the plasma drug concentration) may be the result of strong binding and/or slower dissociation of YM758 in the If channel. Such PK/PD analyses allow the pharmacological profiles of many drugs, especially cardiovascular drugs, to be more readily understood and better predicted during the clinical stages.

  K. i Umehara , K Wada , K Noguchi , T Iwatsubo , T Usui and H. Kamimura
 

(–)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel "funny" If current channel (If channel) inhibitor, is developed as a treatment for stable angina and atrial fibrillation. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) relationship after intravenous administration of YM758 to tachycardia-induced dogs was investigated and described based on the simplified compartment model. The PK of YM758 in dogs did not differ between the nontreated and tachycardia-induced groups. A drug-induced reduction in heart rate (HR) was clearly observed, and the half-life of the duration of the effect (approximately 4.0 h) was longer than that of the plasma concentration of the unchanged drug. The fitting and simulation procedure from the PK/PD relationship between the time profiles for YM758 plasma concentration and HR reduction had an ECe50 value (YM758 concentration in the effective compartment resulting in a 50% decrease of the maximum effect) of 6.0 ng/ml, which did not agree with the results of the in vitro experiment using right atria isolated from guinea pigs (EC30, 70.4 ng/ml). In addition, in the in vitro experiments, YM758 metabolites had a weak inhibitory effect, if any, on the spontaneous beat rate of the right atria from guinea pigs. These data, along with the previous finding that YM758 and its metabolites are eliminated rapidly from rat hearts, indicate that the duration of the pharmacological effect of YM758 (compared with the rapid elimination of the plasma drug concentration) may be the result of strong binding and/or slower dissociation of YM758 in the If channel. Such PK/PD analyses allow the pharmacological profiles of many drugs, especially cardiovascular drugs, to be more readily understood and better predicted during the clinical stages.

  S Kouda , M Ohara , M Onodera , Y Fujiue , M Sasaki , T Kohara , S Kashiyama , S Hayashida , T Harino , T Tsuji , H Itaha , N Gotoh , A Matsubara , T Usui and M. Sugai
  Objectives

The aim of this study was to evaluate the dissemination of metallo-β-lactamase (MBL)-encoding genes among multidrug-resistant (MDR) Pseudomonas aeruginosa isolates recovered from major hospitals in the Hiroshima region.

Methods

During July to December from 2004 to 2006, a surveillance of eight major hospitals in the Hiroshima region identified 387 non-duplicate isolates resistant to imipenem (MIC ≥ 16 mg/L). They were screened for resistance to amikacin (MIC ≥ 64 mg/L) and ciprofloxacin (MIC ≥ 4 mg/L) and MBL-encoding genes. The structure of the variable regions of the integrons was determined using PCR mapping. Clonality was assessed using PFGE and multilocus sequence typing (MLST).

Results

The frequency of MBL-positive isolates in MDR P. aeruginosa isolates significantly increased from 42.3% in 2004 to 81.4% in 2006. Most of the MBL-positive isolates produced IMP-1 followed by VIM-2. The blaIMP-1 and blaVIM-2 genes were present in class 1 integrons. Characterization of the variable regions of the integron showed the presence of six different gene cassette arrays in blaIMP-1 cassettes and a single array in blaVIM-2 cassettes. The IMP-1 producers belonged to two clonal lineages using PFGE and MLST analyses and the integron variations correlated well with the clonal complexes. Among them, strains positive for a newly identified In113-derived blaIMP-1 gene cassette array were most widely distributed in Hiroshima.

Conclusions

This study shows a dramatic increase in MBL genes, primarily blaIMP-1, in MDR P. aeruginosa isolates in Hiroshima during these 3 years. In addition, MDR P. aeruginosa with the newly discovered In113-derived blaIMP-1 gene cassette array appears to be clonally expanding.

 
 
 
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