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Biomedical subjects

Y Yazawa

Publications and source records attributed to Y Yazawa.

At least 19 recordsLinked to original sources

XAFS study of the additive cation effect on the oxidation-resistance of platinum catalyst.

The additive cation effect on the oxidation-resistance of platinum supported on alumina was investigated by Pt L(III) and L(II)-edge XAFS. The white line intensity at Pt L(III)-edge of oxidized catalysts decreased with an increase in the electronegativity of the additive cation in the same way as the support effect previously reported: The addition of electrophilic cations make the supported platinum less oxidized state compared with the original Pt/Al2O3 and vice versa. Thus, it was revealed that the addition of more electrophilic cations provides the higher oxidation-resistance to platinum catalyst, even when platinum is supported on basic oxides.

Journal Article↗

Cortical and subcortical vestibular response to caloric stimulation detected by functional magnetic resonance imaging.

The posterior insula, central sulcus, and inferior parietal lobule including the intraparietal sulcus have been considered the vestibular cortex based on functional brain mapping in humans as well as experiments in lower primates. The same regions receive optokinetic, visual, and proprioceptive projections. We examined the cortical and subcortical projection of vestibular activity with visual and proprioceptive input eliminated during caloric stimulation (CS), using functional magnetic resonance imaging (fMRI). Single-shot gradient-echo echoplanar image (EPI) volumes were sensitive to BOLD contrast in oblique orientation. We adopted a pharmacokinetic model for analysis of imaging data from 10 subjects as a group. The insular gyrus, intraparietal sulcus, superior temporal gyrus, hippocampus, cingulate gyrus, and thalamus showed activation by CS. Cortical and subcortical activation during CS in the present study was observed within regions less precisely delineated by other methods. As intraparietal sulcus activation showed right hemispheric dominance, this region may have an oculomotor projection as well as the vestibular input.

Adult↗

Schedule-dependent synergism and antagonism between raltitrexed ("Tomudex") and methotrexate in human colon cancer cell lines in vitro.

The folate-dependent enzymes are attractive targets for cancer chemotherapy. Methotrexate (MTX), which inhibits dihydrofolate reductase, has been widely used for the treatment of solid tumors and hematological cancers. Raltitrexed ("Tomudex") ), which inhibits thymidylate synthase, is a novel anticancer agent active against colorectal cancer and some other solid tumors. We studied the optimal schedule of raltitrexed and MTX in combination against four human colon cancer cell lines Colo201, Colo320, LoVo, and WiDr. These cells were simultaneously exposed to raltitrexed and MTX for 24 h, or sequentially exposed to raltitrexed for 24 h followed by MTX for 24 h, or vice versa. Cell growth inhibition after 5 days was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of drug combinations at the concentrations of drug that produced 80% and 50% cell growth inhibition (IC(80) and IC(50)) were analyzed by the isobologram method (Steel and Peckham, 1979). Cytotoxic interactions between raltitrexed and MTX were schedule-dependent. The simultaneous exposure to raltitrexed and MTX showed additive effects in Colo201, LoVo and WiDr cells and antagonistic effects in Colo320 cells. The sequential exposure to raltitrexed followed by MTX produced additive effects in all four cell lines. The sequential exposure to MTX followed by raltitrexed produced synergistic effects in Colo201, LoVo and WiDr cells and additive effects in Colo320 cells. These findings suggest that the sequential administration of MTX followed by raltitrexed produces more than the expected cytotoxicity and may be the optimal schedule at the cellular level. Further in vivo and clinical studies will be necessary to determine the toxicity and to test the antitumor effects of sequential administration of MTX followed by raltitrexed proposed on the basis of the in vitro synergism.

Antineoplastic Combined Chemotherapy Protocols↗

Presence of autoantibodies in the sera of Meniere's disease.

We examined the sera of patients with Meniere's disease for the presence of antibodies against 8 inner ear antigens by enzyme-linked immunosorbent assay (ELISA). One hundred eight patients with Meniere's disease and 28 control subjects were studied. The antibodies against chicken type II collagen, bovine type II collagen, the cyanogen bromide cleaved peptide 11 (CB11) of each, type IX and XI collagens, C-Raf, and tubulin were measured by ELISA. The sensitivity of each antigen was between 37% and 60% individually, and was 91% when all 8 inner ear antigens were combined. These results showed that 91% of Meniere's disease sera have antibody activities to 1 or more of these inner ear antigens. The results suggest that performing ELISA for these 8 inner ear antigens was useful as a diagnostic tool for Meniere's disease. Further study is required for elucidating the role of these antigens in the pathogenesis of Meniere's disease, which might eventually result in better therapy.

Autoantibodies↗

Effects of endolymphatic-perilymphatic fistula on endolymphatic hydrops in guinea pig.

The endolymphatic-perilymphatic shunt operation between the scala media and scala tympani was performed in 22 guinea pigs with endolymphatic hydrops induced by the silver nitrate injection method 2 months before the operation. Two (n = 10), 7 (n = 6), and 28 (n = 6) days after the operation, the condition of the fistula and the inner ear pathology were studied histopathologically. In half of the animals, the fistula was open, whereas in the other half, the fistula was closed. In the group examined after 2 postoperative days, the animals with open fistulas showed a slight collapse of Reissner's membrane, which might indicate that excess endolymph escaped through the fistula into the scala tympani. In the groups examined later, especially in the group examined after 28 postoperative days, the animals showed distention of hydrops despite preservation of the fistula. Moderate-to-severe degenerative changes of the organ of Corti, macula sacculi, and stria vascularis were observed in the vicinity of the fistula. We conclude from this study that the endolymphatic-perilymphatic fistula created inside the cochlea apparently was not sufficient to reduce the hydrops. Rather, it caused degenerative changes of the inner ear structure. This type of surgery is not suitable for Meniere's disease.

Animals↗

C-type natriuretic peptide-like immunoreactivity in the rat inner ear.

C-type natriuretic peptide (CNP) is a member of the atrial natriuretic peptide family (ANP family). The family also includes ANP and brain natriuretic peptide (BNP). These peptides regulate the homeostasis of body fluid and blood pressure as a neuropeptide in the central nervous system as well as a cardiac hormone in the periphery. We have recently reported the expression of CNP mRNA in the inner ear. To assess the possible physiological role of CNP in the inner ear, we investigated the localization of CNP peptide in the rat inner ear by immunohistochemistry at the light and electron microscopic level. CNP-like immunoreactivity was widely distributed in the secretory and the neuronal portion of the inner ear, i.e. the spiral ligament, the dark cell region of the utriculus, the epithelium of the endolymphatic sac, the spiral ganglion cells and the vestibular ganglion cells. The results suggest that CNP may play a role in the homeostasis of the perilymph and endolymph and may also influence nerve activities in the inner ear.

Animals↗

Schedule-dependent interactions between raltitrexed and cisplatin in human carcinoma cell lines in vitro.

Raltitrexed ('Tomudex') is a new anticancer agent which inhibits thymidylate synthase. To provide a rational basis for clinical trial design of the combination of raltitrexed and cisplatin, we studied the cytotoxic effects of this combination using various schedules in vitro and four human colon cancer cell lines, Colo201, Colo320, LoVo, and WiDr. Cell growth inhibition after 5 days was determined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. The effects of drug combinations at the concentration producing 80% cell growth inhibition (IC(80)) level were analyzed by the isobologram method. Simultaneous exposure to raltitrexed and cisplatin for 24 h, and sequential exposure to raltitrexed followed by cisplatin produced additive effects in the Colo201, Colo320, and LoVo cells, and additive and synergistic effects in WiDr cells. Sequential exposure to cisplatin followed by raltitrexed produced additive effects in the Colo201 cells and antagonistic effects in other three cell lines. Simultaneous and continuous exposure to both agents for 5 days produced additive effects in all four cell lines. These findings suggest that the simultaneous administration of raltitrexed and cisplatin, or the sequential administration of raltitrexed followed by cisplatin, generally produce the expected cytotoxicity at the cellular level and are optimal schedules, while the sequential administration of cisplatin followed by raltitrexed produces antagonistic effects and is inappropriate for this combination. Further in vivo and clinical studies will be necessary to determine the toxicity and antitumor effects of this schedule.

Antineoplastic Combined Chemotherapy Protocols↗

Antitumor promoting effect of an active component of Polyporus, ergosterol and related compounds on rat urinary bladder carcinogenesis in a short-term test with concanavalin A.

The effect of fractions from a water extract of Polyporus on bladder tumor promotion was examined using 5% sodium saccharin (SS) in a short-term test with concanavalin A (Con A) in Wistar rats. Rats were given N-butyl-N-(4-hydroxybutyl) nitrosamine (BHBN) in drinking water for one week, and then promoter alone or test samples (given orally) plus promoter was administered for 3 weeks. Treatment with the BuOH fraction isolated from the water extract showed a strong inhibitory effect against the promoter. It was found that the inhibitory effect of the BuOH fraction is due to the effect of ergosterol contained in the fraction. Treatment with ergosterol showed a strong inhibitory effect against 5% SS, 0.01% BHBN, 3% DL-tryptophan (Trp) or 2% butylated hydroxyanisole (BHA); ID50 was 1.4 microg/kg/d, 2.9 microg/kg/d, 11.6 microg/kg/d, and 11.7 microg/kg/d against SS, BHBN, Trp and BHA, respectively. We also examined the effect of steroids and related compounds. Squalene and vitamin D2 showed strong inhibitory effect against 5% SS-induced bladder tumor promotion. These results strongly suggest that ergosterol could provide significant protection against the promotion of bladder tumor induced by many types of promoters in the environment.

Agglutination Tests↗

Schedule-dependent interaction between raltitrexed and 5-fluorouracil in human colon cancer cell lines in vitro.

Raltitrexed (Tomudex) is a novel thymidylate synthase inhibitor with significant activity against advanced colorectal cancer. We studied the cytotoxic interactions of raltitrexed and 5-fluorouracil (5-FU) in four human colon cancer cell lines on various schedules. The cell growth inhibition after 5 days was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cytotoxic interactions at the IC80 level were evaluated by the isobologram method. Simultaneous exposure to raltitrexed and 5-FU for 5 days produced additive to synergistic effects in Colo201 cells, and produced additive effects in Colo321, LoVo, and WiDr cells. Simultaneous exposure to raltitrexed and 5-FU for 24 h produced additive effects in Colo201, LoVo, and WiDr cells, and produced antagonistic effects in Colo320 cells. Sequential exposure to raltitrexed for 24 h followed by 5-FU for 24 h produced additive effects in Colo201, Colo320, and LoVo cells, and produced antagonistic effects in WiDr cells. The reverse sequence produced additive effects in Colo201 cells, and produced antagonistic effects in Colo320, LoVo, and WiDr cells. Simultaneous exposure to raltitrexed and 5-FU for 4 h and sequential exposure to raltitrexed for 4 h followed by 5-FU for 4 h with a 20-h interval produced additive effects, while the reverse sequence produced antagonistic effects in LoVo and WiDr cells. These findings suggest that the simultaneous administration of raltitrexed and 5-FU or the sequential administration of raltitrexed followed by 5-FU may be the optimal sequence, while the reverse sequence may be inappropriate. Preclinical and clinical studies of the simultaneous administration of raltitrexed and 5-FU and the sequential administration of raltitrexed followed by 5-FU are required to better understand the antitumor, toxic, and pharmacokinetic interactions of this combination in order to develop the combination chemotherapy of raltitrexed and 5-FU.

Antineoplastic Combined Chemotherapy Protocols↗

[Auditory cortical response to monaural stimulation as detected by functional magnetic resonance imaging].

In order to confirm the crossed-innervation between auditory cortex and the ear that receives monosyllabic sound, the auditory cortical response to monaural monosyllabic stimulation as detected by functional magnetic resonance imaging (fMRI) was investigated in six normal hearing subjects. Stimulus amplitude averaged 95 dBSPL at the distal end of the audio system. A series of 440 echo planar images was acquired during the acoustic stimulation within the four OFF-ON cycle paradigm. Five image series with 10 slices were collected within each OFF or On period. Each scanning session began with four baseline images before the OFF-ON paradigm. Monosyllabic sounds were presented monaurally during the ON period at a rate of one monosyllable/sec. Functional MRI data were analyzed with SPM99b software (Statistical Parametric Mapping). The background scanner noise averaged 97dBSPL. The selicon ear plug and headphone as acoustic shields attenuated the noise as much as 17 dB. A broad and intense auditory cortical response was observed bilaterally in response to monaural monosyllable stimulation. Sound presentation to the right ear was followed by a larger response in the left auditory cortex than in the right, and left ear stimulation evoked a larger response in the right auditory cortex than in the left. This pattern was consistent in all subjects examined. The primary auditory cortex responded to monosyllabic words presented to the contralateral ear. The results confirmed the crossed-innervation between the auditory cortex and ear for listening to monosyllables. Functional MRI is a useful tool for investigating auditory cortex function, if the scanner noise is adequated controlled.

Acoustic Stimulation↗

Arginine kinase evolved twice: evidence that echinoderm arginine kinase originated from creatine kinase.

Arginine kinase (AK) was isolated from the longitudinal muscle of the sea cucumber Stichopus japonicus. Unlike the monomeric 40 kDa AKs from molluscs and arthropods, but like the cytoplasmic isoenzymes of vertebrate creatine kinase (CK), the Stichopus enzyme was dimeric. To explore the evolutionary origin of the dimeric AK, we determined its cDNA-derived amino acid sequence of 370 residues. A comparison of the sequence with those of other enzymes belonging to the phosphagen kinase family indicated that the entire amino acid sequence of Stichopus AK is apparently much more similar to vertebrate CKs than to all other AKs. A phylogenetic tree also strongly suggests that the Stichopus AK has evolved from CK. These results support the conclusion that AK evolved at least twice during the evolution of phosphagen kinases: first at an early stage of phosphagen kinase evolution (its descendants are molluscan and arthropod AKs) and secondly from CK later in metazoan evolution. A comparison of the amino acid sequence around the guanidino specificity (GS) region (which is a possible candidate for the guanidine substrate recognition site in the phosphagen kinase family) of the Stichopus enzyme with those of other phosphagen kinases showed that the GS region of the Stichopus enzyme was of the AK type: five amino acid deletions in the flexible loop region that might help to accommodate larger guanidine substrates in the active site. The presence of the AK-type deletions in the Stichopus AK, even though it seems that the enzyme's most immediate ancestor was probably CK, strongly suggests that the GS region has a role in substrate specificity. Stichopus AK and presumably other echinoderm AKs seem to have evolved from the CK gene; the sequence of GS region might have been replaced by the AK type via exon shuffling. The presence of an intron near the GS region in the Stichopus AK gene supports this hypothesis.

Amino Acid Sequence↗

Regulation of inner ear fluid in the rat by vasopressin.

The anti-diuretic hormone vasopressin has been shown to be important in regulating inner ear fluid. The diuretic hormone, CNP, and its receptor, ANP-B receptor, may also function in the regulation of inner ear fluid. To determine whether vasopressin directly affects the fluid level, we infused this hormone to rat and assay of V2-AVP receptor mRNA by semiquantitative RT-PCR demonstrated a significantly lower level of this transcript in vasopressin-infused animals than in saline-infused animals. The levels of CNP and ANP-B receptors mRNA, however, were the same in both groups of rats. Results suggest that high plasma levels of vasopressin may be a principal causal factor of endolymphatic hydrops in Meniere's disease, perhaps by down-regulating the number of vasopressin receptors.

Animals↗

Schedule-dependent interactions between paclitaxel and etoposide in human carcinoma cell lines in vitro.

Clinical studies of paclitaxel in combination with etoposide against solid tumors have been carried out. The combination schedules used in these studies are different. We studied the cytotoxic effects of paclitaxel with etoposide against four human cancer cell lines in vitro to determine the optimal schedule of this combination at the cellular level. Cells were exposed simultaneously to paclitaxel and to etoposide for 24 h or sequentially to one drug for 24 h followed by the other for 24 h, after which they were incubated in drug-free medium for 4 and 3 days, respectively. Cell growth inhibition was determined by an MTT reduction assay. The effects of drug combinations at concentrations producing 80% inhibition (IC(80)) were analyzed by the isobologram method of Steel and Peckham. The cytotoxic effect of paclitaxel and etoposide was cell line- and schedule-dependent. Simultaneous exposure to paclitaxel and etoposide for 24 h produced additive effects in the lung cancer cell line A549 and ovarian cancer PA1 cells, and antagonistic effects in the breast cancer cell line MCF7 and colon cancer WIDr cells. Sequential exposures to paclitaxel followed by etoposide and vice versa produced additive effects in all four cell lines. These results suggest that maximum cytotoxic effects can be obtained with sequential administration, but not simultaneous administration, of paclitaxel and etoposide. These findings may have important clinical implications for this combination.

Breast Neoplasms↗

Effects of 4-hydroperoxy ifosfamide in combination with other anticancer agents on human cancer cell lines.

Ifosfamide is one of the currently available anticancer agents with a broad spectrum of clinical activity against a variety of tumors. To investigate its optimal combinations, we studied the effect of 4-hydroperoxy ifosfamide (the active form of ifosfamide) in combination with other anticancer agents against two human cancer cell lines, MG-63 (an osteosarcoma cell line) and MOLT-3 cells (a T-cell leukemia cell line). The cells were incubated for 4 days and 3 days, respectively, in the presence of 4-hydroperoxy ifosfamide and the other agent. Cell growth inhibition was determined by MTT assay. The effects of these drug combinations at the concentration producing 50% inhibition (IC50) were analyzed by the isobologram method. 4-Hydroperoxy ifosfamide showed additive effects with bleomycin, cisplatin, cytarabine, doxorubicin, etoposide, 5-fluorouracil, and mitomycin C, while it showed a protective effect with methotrexate in both cell lines. 4-Hydroperoxy ifosfamide showed an additive effect with vincristine in the MG-63 cell line, while it showed a sub-additive effect in the MOLT-3 cell line. No anticancer agents tested showed a supra-additive effect with 4-hydroperoxy ifosfamide. These data suggest that ifosfamide is advantageous for simultaneous administration with a majority of the anticancer agents we studied. Methotrexate is an inappropriate drug for simultaneous administration with ifosfamide.

Antineoplastic Agents, Alkylating↗

Expression of inducible nitric oxide synthase in human thyroid papillary carcinomas.

To evaluate the relationship between nitric oxide (NO) and carcinogenesis, we assayed 4 human thyroid papillary carcinomas (TPC) and 3 normal thyroid glands for the presence of inducible nitric oxide synthase (iNOS). Using an antibody against iNOS, we observed immunohistochemical staining if iNOS in the TPC samples, but not in normal thyroid. When we incubated TPC samples with antibodies against both iNOS and human leukocyte antigen (LCA), a macrophage marker, we found that while most TPC cells were stained with anti-iNOS antibody, only a few were stained with both. Reverse transcription polymerase chain reaction (RT-PCR) showed that iNOS mRNA was expressed in the samples of TPC, but not in normal thyroid. The sequence of iNOS message in the TPC samples was identical to that previously detected in a human colon cancer cell line. These results suggest that iNOS in human TPC is mostly derived from tumor cells, rather than macrophages, and that it may play a direct role in carcinogenesis.

Base Sequence↗

Murine model of autoimmune hearing loss induced by myelin protein P0.

Myelin protein P0 has been identified as an autoantigen in inner ear diseases. In order to study autoimmune hearing loss, we performed brain stem auditory-evoked potential (BAEP) studies on P0-sensitized mice. Two P0-sensitized mice showed hunched posture, poor coat, loss of body weight, and abnormal walking with a waddling gait. About 25% of the P0-sensitized mice developed hearing loss. In the BAEP study, peak latencies of waves I, III, and V and the interpeak latency I-III were prolonged in the P0-sensitized hearing loss group of mice. Hearing thresholds were elevated in this group of mice in comparison with the control mice. Inflammatory cell infiltration was observed in the cochlear nerve region, and a reduced number of spiral ganglion cells was also detected. These results suggest that P0-sensitized mice are a useful model for studying autoimmune inflammation of the peripheral portion of the auditory system.

Animals↗