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Biomedical subjects

T Ikeda

Publications and source records attributed to T Ikeda.

At least 19 recordsLinked to original sources
PubMed2007

Prediction of pharmacokinetics of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in humans using animal data.

The pharmacokinetics of CS-023 (RO4908463, formerly R-115685), a novel parenteral carbapenem antibiotic, in humans was successfully predicted using the data collected from mice, rats, rabbits, and dogs; while inclusion of the monkey data led to a significant underestimation of the total plasma clearance (CL). Double logarithmic plots of CL and distribution volume at the steady-state (Vss) vs. body weight in four animal species were linear with high correlation coefficients; and the predicted CL and Vss values in humans agreed well with the observed values after administration of CS-023 by an intravenous drip infusion for 30 min. The plasma concentration-time profile in humans, which was predicted using a bi-exponential equation fitted to a complex Dedrick plot of the animal data, approximated the observed profile. An underestimation of CL caused by including the monkey data in a prediction is quite likely due to the net tubular reabsorption in monkeys, but not at least in rabbits, dogs, and humans.

Animals↗
PubMed2006

Spin correlations of strongly interacting massive fermion pairs as a test of Bell's inequality.

We report the results of the first-time test of the local hidden variable theories (Bell-Clauser-Horne-Shimony-Holt) involving strongly interacting pairs of massive spin 1/2 hadrons from the decay of short-lived (tau<10;-21sec) 2He spin-singlet state, populated in the nuclear reaction 2H+;1H-->;2He+n. The novel features of this experiment are (a) the use of an 'event-ready' [corrected] detector of nearly 100% efficiency to prepare an unbiased sample and (b) a focal-plane polarimeter of full 2pi sr acceptance with a random "post selection" of the reference axes. The spin-correlation function is deduced to be S[exp](pi/4)=2.83+/-0.24stat+/-0.07sys. This result is in agreement with nonlocal quantum mechanical prediction and it violates the Bell-CHSH inequality of |S|<or=2 at a confidence level of 99.3%.

Journal Article↗
PubMed2006

Bonding effectiveness of adhesive luting agents to enamel and dentin.

OBJECTIVES: The bonding effectiveness of five adhesive luting agents to enamel and dentin using different application procedures was determined using a micro-tensile bond strength protocol (microTBS). METHODS: Enamel/dentin surfaces of human third molars were flattened using a high-speed diamond bur. Composite resin blocks (Paradigm, 3M ESPE) were luted using either Linkmax (LM; GC), Nexus 2 (NX; Kerr), Panavia F (PN; Kuraray), RelyX Unicem (UN; 3M ESPE) or Variolink II (VL; Ivoclar-Vivadent), strictly following manufacturers' instructions. For some luting agents, modified application procedures were also tested, resulting in four other experimental groups: Prompt L-Pop+RelyX Unicem (PLP+UN; 3M ESPE), Scotchbond Etchant+RelyX Unicem (SE+UN; 3M ESPE), Optibond Solo Plus Activator+Nexus 2 (ACT+NX; Kerr) and K-Etchant gel+Panavia-F (KE+P; Kuraray). The experimental groups were classified according to the adhesive approach in self-adhesive (UN), etch-and-rinse (ACT+NX, NX, KE+P, SE+UN and VL when bonded to enamel) and self-etch adhesive luting agents (LM, PLP+UN, PN and VL when bonded to dentin). The specimens were stored for 24h in distilled water at 37 degrees C prior to microTBS testing. The Kruskal-Wallis test was used to determine pairwise statistical differences (p<0.05) in microTBS between the experimental groups. RESULTS: When bonded to enamel, ACT+NX (15 MPa) and UN (19.6 MPa) scored significantly lower than VL (49.3 MPa), LM (49.2 MPa), PN (35.4 MPa) and SE+UN (35.2 MPa), while PLP+UN (23.5 MPa) showed a significantly lower microTBS than VL (49.3 MPa) and LM (49.2 MPa). No significant differences were noticed between VL (49.3 MPa), LM (49.2 MPa), NX (37.9 MPa), KE+PN (38.8 MPa), PN (35.4 MPa) and SE+UN (35.2 MPa). Regarding the bonding effectiveness to dentin, all luting agents bonded equally effectively (UN: 15.9 MPa; LM: 15.4 MPa; PN: 17.5 MPa; NX: 22.3 MPa), except VL (1.1 MPa), SE+UN (5.9 MPa) and ACT+NX (13.2 MPa). VL revealed an exceptionally high number of pre-testing failures, most likely due to a combined effect of not having cured the adhesive separately and an insufficiently light-cured luting agent. SIGNIFICANCE: Following a correct application procedure, the etch-and-rinse, self-etch and self-adhesive luting agents are equally effective in bonding to enamel and dentin. Several factors negatively influenced bond strength such as bonding RelyX Unicem to enamel without prior phosphoric acid etching; no separate light-curing of a light-polymerizable adhesive prior to cementation, use of a light-polymerizing adhesive converted into a dual-polymerizing adhesive, and use of a dual-cure luting agent with a low auto-polymerizable potential.

Acid Etching, Dental↗
PubMed2006

Effect of FTY720 in rat small bowel transplantation: apoptosis of crypt cells and lymphocytes in gut-associated lymphoid tissues.

AIM: We investigated the extent of apoptosis in crypt cells and Peyer's patches (PPs) during small bowel allograft rejection in rats to examine the effect of FTY720 during rejection. METHODS: Orthotopic small bowel transplantations (SBTs) were performed from BN to LEW rats. Isografted animals served as controls. Three groups of SBT animals were studied on days 3, 5, and 7 after operation: isograft, untreated allograft, allograft with FTY720. FTY720 was orally administered by gavage (1 mg/kg/d) to allograft recipients on 7 consecutive days. Cryostat sections were prepared from grafts, including PPs. An in situ end-labeling (ISEL) technique was used to detect apoptotic cells. Indirect immunoperoxidase staining was also performed using monoclonal antibodies against rat Fas/Fas-L. RESULTS: Graft survival was prolonged in the FTY720-treated group. The number of ISEL-positive enterocytes in the allografts increased significantly on days 3, 5, and 7 compared with the isograft group. In the FTY720-treated group, the number of ISEL-positive enterocytes in the allografts was down-regulated significantly on days 3, 5, and 7 compared with untreated allograft group. In the PPs, the number of ISEL-positive mononuclear cells increased significantly in the allografts compared with the isograft group. In the FTY720-treated groups, the number of ISEL-positive mononuclear cells were down-regulated significantly in the allografts compared with the untreated allograft group. The number of Fas/FasL-positive enterocytes were increased significantly in allografts compared with isograft group. In FTY720-treated groups, the number of Fas/FasL-positive enterocytes were down-regulated significantly on day 7 compared with the untreated allograft group. In the PPs, Fas/FasL-positive mononuclear cells also increased significantly on day 7 in the allografts compared with isografts. In the FTY720-treated groups, Fas/FasL-positive mononuclear cells were down-regulated significantly in the allografts compared with the untreated allograft group. CONCLUSIONS: The number of apoptotic enterocytes, lymphocytes, and Fas/FasL-positive lymphocytes increased during small bowel graft rejection. FTY720 prevented up-regulation of the number of apoptotic enterocytes, lymphocytes, and Fas/FasL-positive lymphocytes while also prolonging small bowel allograft survival.

Animals↗
PubMed2006

Renal handling of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in rabbits in comparison with meropenem.

The plasma half-life of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, is longer than that of meropenem in animals and humans. To address this issue, renal clearance studies were conducted in rabbits. A constant rate infusion of CS-023 and meropenem was conducted in male Japanese White rabbits. Concentrations in the plasma, urine and renal cortex were measured to evaluate renal clearance and renal tissue uptake. CS-023 showed a clearance ratio (renal clearance/glomerular filtration rate) of around 1, which was not affected by co-administration of probenecid or p-aminohippurate. On the other hand, meropenem exhibited a clearance ratio of around 3, which was significantly decreased to 1 by co-administration of probenecid. p-Aminohippurate, in contrast, had no effect. The renal cortex/plasma concentration ratio of CS-023 was around 0.6 with or without probenecid co-administration. This ratio of meropenem was around 3, which was decreased significantly by co-administration of probenecid to around 0.6. These data suggest that meropenem is secreted in the renal tubules via organic anion transporters, but CS-023 is not. The present findings in rabbits would indicate that a lack of renal tubular secretion of CS-023 is a reason for the long plasma half-life compared with meropenem.

Animals↗
PubMed2006

Nestin expression in odontoblasts and odontogenic ectomesenchymal tissue of odontogenic tumours.

BACKGROUND: Nestin, one of the intermediate filaments constituting the cytoskeleton, is a marker of neural stem cells or progenitor cells. Its expression is also related to tooth development and repair of dentine. AIMS: The aim of this study was to investigate nestin expression in various odontogenic tumours and evaluate its usefulness for histopathological diagnosis. METHODS: We studied formalin fixed, paraffin embedded specimens from 129 cases of odontogenic tumours and 9 of mandibular intraosseous myxoma. After characterisation of odontogenic ectomesenchymal tissues in these tumours using antibodies to vimentin, desmin, neurofilament, and glial fibrillary acidic protein, we immunohistochemically examined nestin expression. RESULTS: No differentiation towards muscle and nervous tissues was found in the odontogenic ectomesenchymal tissues. Although almost all the ameloblastomas and malignant ameloblastomas were negative for nestin, odontogenic ectomesenchyme in the odontogenic mixed tumours demonstrated nestin immunolocalisation, particularly in the region adjacent to the odontogenic epithelium. Odontoblasts and their processes, pulp cells near the positive odontoblasts, and flat cells adhering to the dentine showed immunoreaction with nestin in the odontomas and odontoma-like component in the ameloblastic fibro-odontomas. Neoplastic cells in almost half cases of jaw myxoma and one case of odontogenic fibroma expressed nestin. CONCLUSIONS: The distribution of nestin in the odontogenic mixed tumours suggests that nestin expression in the odontogenic ectomesenchyme is upregulated by stimulation from odontogenic epithelium. In addition, nestin may also be involved in the differentiation from pulp cells to odontoblasts in odontogenic tumours. Therefore, nestin is a useful marker for the odontogenic ectomesenchyme and odontoblasts in odontogenic tumours. Nestin, one of the intermediate filaments constituting the cytoskeleton, is a marker of neural stem cells or progenitor cells. Its expression is also related to tooth development and repair of dentine.

Adolescent↗
PubMed2005

Neuroradiologic and clinicopathologic features of oculoleptomeningeal type amyloidosis.

OBJECTIVE: To clarify the pathogenesis of leptomeningeal amyloidosis in familial amyloidotic polyneuropathy amyloidogenic transthyretin Y114C (FAP ATTR Y114C). METHODS: The authors analyzed eight FAP ATTR Y114C patients. Six patients showed CNS symptoms associated with leptomeningeal amyloidosis. To examine the function of the blood-CSF barrier and blood-brain barrier (BBB), the authors performed CSF and MRI studies. The authors also performed a histopathologic study of autopsy specimens to examine the distribution of amyloid deposition in the CNS. RESULTS: CSF study showed high total protein concentrations and increased albumin CSF/serum concentration quotients (Qalb; an indication of blood-CSF barrier function). MRI with gadolinium (Gd) revealed enhancement from brainstem to spinal cord. Serial brain MRI studies with FLAIR images after Gd administration showed Gd leakage into the subarachnoid space (two patients). These findings suggested the blood-CSF barrier and BBB dysfunctions. Constructive interference in steady state (CISS) three-dimensional Fourier transformation (CISS-3DFT) sequence analysis demonstrated amyloid-induced funiculus structures joining the spinal cord and dura mater (one patient). Histopathologic study revealed intense amyloid deposition in leptomeninges, vessel walls, and parenchyma in spinal cord and the brain. These distributions of amyloid deposition are unique compared to other TTR related leptomeningeal amyloidosis. CONCLUSIONS: Patients with familial amyloidotic polyneuropathy amyloidogenic transthyretin Y114C had CNS disorders related to amyloid deposition in leptomeninges, vessel walls, and parenchyma in spinal cord and the brain. The pathogenesis of CNS disorders may reflect disruption of the blood-CSF barrier and blood-brain barrier by amyloid deposition.

Adult↗
PubMed2005

Jet formation and shock wave emission during collapse of ultrasound-induced cavitation bubbles and their role in the therapeutic applications of high-intensity focused ultrasound.

The dynamics of inertial cavitation bubbles produced by short pulses of high-intensity focused ultrasound near a rigid boundary are studied to get a better understanding of the role of jet formation and shock wave emission during bubble collapse in the therapeutic applications of ultrasound. The bubble dynamics are investigated by high-speed photography with up to 2 million frames/s and acoustic measurements, as well as by numerical calculations. The significant parameter of this study is the dimensionless stand-off, gamma, which is defined as the distance of the bubble centre at its maximum expansion scaled by the maximum bubble radius. High-speed photography is applied to observe the bubble motion and the velocity of the liquid jet formed during bubble collapse. Hydrophone measurements are used to determine the pressure and the duration of the shock wave emitted during bubble rebound. Calculations yield the variation with time of the bubble wall, the maximum velocity and the kinetic energy of the re-entrant jet. The comparisons between experimental and numerical data are favourable with regard to both shape history and translational motion of the bubble. The acoustic energy constitutes the largest individual amount in the energy balance of bubble collapse. The ratio of the shock wave energy, measured at 10 mm from the emission centre, to the cavitation bubble energy was 1:2.4 at gamma = 1.55 and 1:3.5 at gamma = 1. At this distance, the shock wave pressure ranges from 0.122 MPa, at gamma = 1, to 0.162 MPa, at gamma = 1.55, and the temporal duration at the half maximum level is 87 ns. The maximum jet velocity ranges from 27 m s(-1), at gamma = 1, to 36 m s(-1), at gamma = 1.55. For gamma < 1.2, the re-entrant jet can generate an impact pressure on the nearby boundary larger than 50 MPa. We discuss the implications of the results for the therapeutic applications of high-intensity focused ultrasound.

Computer Simulation↗
PubMed2005

Suppressor of cytokine signalling 1 in lymphocytes regulates the development of intestinal inflammation in mice.

BACKGROUND AND AIMS: Imbalance between pro- and anti-inflammatory cytokines produced by intestinal T cells induces inflammatory bowel diseases (IBD). However, the importance of regulation of cytokine signalling in IBD has not been fully clarified. We have demonstrated that suppressor of cytokine signalling 1 (SOCS1) is expressed in inflamed tissues in an experimental colitis model. In the present study, we investigated the role of SOCS1 in colitis models to clarify the mechanism of IBD development. METHODS: Intestinal T cells in transgenic mice expressing high levels of SOCS1 in lymphocytes (SOCS1Tg mice) were characterised by flow cytometric analysis and cytokine production from intestinal T cells was determined by ELISA. 2,4,6-Trinitrobenzene sulphonic acid (TNBS) induced colitis was induced in SOCS1Tg mice and severity was compared with control littermates by measurement of survival rates. Intracellular signalling was assessed by western blotting analysis. RESULTS: SOCS1Tg mice developed colitis spontaneously with age. Young SOCS1Tg mice less than 15 weeks of age, before the onset of colitis, were susceptible to TNBS induced colitis. Intestinal T cells of SOCS1Tg mice showed increased interferon gamma and tumour necrosis factor alpha production and decreased transforming growth factor beta production. Expression of cytotoxic T lymphocyte associated antigen 4 (CTLA-4), a negative regulator of T cell activation, in SOCS1Tg mice was severely impaired at the protein level although mRNA levels of CTLA-4 in SOCS1Tg mice were comparable with those in control mice. CONCLUSIONS: Our data suggest that SOCS1 plays an important role in the regulation of colitis by controlling intestinal T cell activation mediated through CTLA-4 expression.

Animals↗
PubMed2005

Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome.

Absence of functional FMRP causes Fragile X syndrome. Abnormalities in synaptic processes in the cerebral cortex and hippocampus contribute to cognitive deficits in Fragile X patients. So far, the potential roles of cerebellar deficits have not been investigated. Here, we demonstrate that both global and Purkinje cell-specific knockouts of Fmr1 show deficits in classical delay eye-blink conditioning in that the percentage of conditioned responses as well as their peak amplitude and peak velocity are reduced. Purkinje cells of these mice show elongated spines and enhanced LTD induction at the parallel fiber synapses that innervate these spines. Moreover, Fragile X patients display the same cerebellar deficits in eye-blink conditioning as the mutant mice. These data indicate that a lack of FMRP leads to cerebellar deficits at both the cellular and behavioral levels and raise the possibility that cerebellar dysfunctions can contribute to motor learning deficits in Fragile X patients.

Animals↗
PubMed2005

Ocular blood flow changes after dynamic exercise in humans.

PURPOSE: To investigate control mechanisms for ocular blood flow changes after dynamic exercise using two different methods. METHODS: Changes over time in the tissue blood flow in the retina and choroid-retina of healthy volunteers were determined after dynamic exercise (Master's double two-step test), using scanning laser Doppler flowmetry (SLDF) and laser speckle flowgraphy (LSFG). Changes in intraocular pressure (IOP), blood pressure, plasma CO(2) gas concentration (pCO(2)), and levels of nitric oxide (NO) metabolites were examined. RESULTS: Retinal blood flow measured by SLDF increased significantly only at 15 min after exercise. In contrast, normalized blur (NB) values in the choroid-retina, obtained by LSFG, increased significantly up to 60 min after exercise. Ocular perfusion pressure (OPP), calculated from IOP and blood pressure, increased significantly immediately and 15 min after exercise. The plasma NO metabolite levels increased significantly, although pCO(2) levels were unchanged. CONCLUSIONS: Dynamic exercise changes OPP and produces increased tissue blood flow in the retina in the immediate postexercise period, while blood flow increases more persistently in the choroid-retina. Difference in control of blood flow in these two regions may be related to stronger autoregulatory mechanism of blood flow in the retina. Nitric oxide may play a role in the regulation of blood flow.

Adult↗
PubMed2005

Effect of FTY720 in rat small bowel transplantation: expression of mucosal addressin cell adhesion molecule-1.

AIM: Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) mediates the homing of lymphocytes to gut-associated tissues (GALT). We performed a semiquantitative analysis of MAdCAM-1 expression during small bowel graft rejection in rat treated with FTY720. METHODS: Orthotopic small bowel transplantations (SBT) were performed from BN rats to LEW rats. Isografted animals served as controls. Three groups of SBT animals were studied on days 3, 5, 7 after operations (Isograft, untreated allograft, allograft with FTY720). FTY720 was orally administered by gavage (1 mg/kg/d) to allograft models on 7 consecutive days. Cryostat sections were prepared from grafts, including Peyer's patches (PPs). Indirect immunoperoxidase staining was performed using mAbs against MAdCAM-1. The degree of vascular endothelial staining on high endothelial venules (HEV) in the PPs was graded from 1 (low levels) to 5 (high levels), and in the vessels of the lamina propia from 1 (faint), to 2 (low at the base of villi), 3 (low to the middle of villi), 4 (high to the middle of villi), to 5 (high to villi tip). RESULTS: The graft survival was prolonged in the FTY720-treated group. MAdCAM-1 expression on HEVs in PPs was down-regulated during rejection. In contrast its expression on endothelial cells of vessels in the lamina propria was up-regulated during rejection. In the FTY720-treated groups, MAdCAM-1 expression on HEVs in PPs was up-regulated and its expression on endothelial cells of vessels in the lamina propria was down-regulated compared with untreated allograft group. CONCLUSIONS: Alteration in MAdCAM-1 expression may be associated with the development of SB graft rejection. The vessels at the base of villi, which are associated with lymphocyte recruitment, may become sites of intestine immune reactivity during the early phase of small bowel allograft rejection. FTY720 was found to prevent the down-regulation of MAdCAM-1 expression on HEVs in PPs and the up-regulation of its expression on endothelial cells of vessels in the lamina propria while also prolonging small bowel allograft survival.

Animals↗
PubMed2005

Triterpenoid CDDO-Im downregulates PML/RARalpha expression in acute promyelocytic leukemia cells.

The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces differentiation and apoptosis of diverse human tumor cells. In the present study, we examined the effects of the CDDO imidazolide imide (CDDO-Im) on the NB4 acute promyelocytic leukemia (APL) cell line and primary APL cells. The results show that CDDO-Im selectively downregulates expression of the PML/retinoic receptor alpha fusion protein by a caspase-dependent mechanism and sensitizes APL cells to the differentiating effects of all-trans retinoic acid (ATRA). CDDO-Im treatment of APL cells was also associated with disruption of redox balance and activation of the extrinsic apoptotic pathway. In concert with these results, CDDO-Im sensitizes APL cells to arsenic trioxide (ATO)-induced apoptosis. Our findings indicate that CDDO-Im may be effective in the treatment of APL by: (i) downregulation of PML/RARalpha; (ii) enhancement of ATRA-induced differentiation; and (iii) sensitization of ATO-induced APL cell death.

Apoptosis↗
PubMed2005

Acute interstitial pneumonitis during chemotherapy for haematological malignancy.

Fourteen adult patients with haematological malignancies (eight non-Hodgkin's lymphoma, one multiple myeloma, one chronic lymphocytic leukaemia, two acute lymphoblastic leukaemia and two acute myeloid leukaemia) developed acute interstitial pneumonitis (IP) during the course of chemotherapy. All patients manifested high fever over 38 degrees C, bilateral diffuse pulmonary interstitial infiltrates in the chest radiograph and severe hypoxia without hypercapnia in the arterial blood gas analysis. Pathogenic microorganisms were not detected in repeated examinations in any patient. Chemotherapy given included various anti-neoplastic drugs. Five patients had received granulocyte colony-stimulating factor (G-CSF) for chemotherapy-induced leucopenia. The onset was associated with an increase of leucocytes in 10 patients. All patients were treated with high dose steroid hormone and broad spectrum antibiotics with or without anti-fungal agents, and three required mechanical ventilation. Eleven patients quickly recovered from these situations, whereas three died. Autopsies were done in two patients and disclosed pneumocystis carinii (PC) pneumonitis in one and non-specific pulmonary congestive oedema and fibrosis in the other. In conclusion, IP of unknown cause could develop in patients with various haematological malignancies especially at the recovery phase of chemotherapy-induced leucopenia irrespective of the previous G-CSF administration. High dose steroid hormone should be used as therapy for such patients as soon as possible after exclusion of an infective aetiology.

Acute Disease↗
PubMed2005

The effects of vitamin A derivative etretinate on the skin of MRL mice.

MRL/Mp-lpr/lpr (MRL/lpr) mice are characterized by the disorder of apoptosis due to defects in Fas antigens and autoimmune symptoms including spontaneous lupus erythematosus (LE)-like skin lesions. MRL/Mp- + / + (MRL/n) mice do not carry the defect of lpr mutation nor do they exhibit skin disorders during the first six months of life. Retinoids are known to inhibit the proliferation of skin fibroblasts, collagen synthesis, modulate immune responses, and apoptosis by Fas ligand upregulation in skin fibroblasts. We examined changes in dermal thickness and appearance of skin disorders in five months old MRL/lpr mice by oral treatment with etretinate, a retinoic acid derivative. Etretinate treated MRL/lpr mice did not have skin lesions or dermatopathological characteristics including an increase in cells infiltrating the dermis. The mean dermal thickness of MRL/lpr and MRL/n mice treated with etretinate decreased significantly and apoptotic cells density in the dermis of MRL/lpr mice with etretinate was significantly higher compared with the control group (P < 0.05) although MRL/lpr mice have a defect within the Fas antigen. We assumed that etretinate reduced dermal thickness, and suppressed the appearance of skin lesions by inducting apoptosis and perhaps regulation of cytokine expression.

Administration, Oral↗