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Biomedical subjects

M Yasuda

Publications and source records attributed to M Yasuda.

At least 649 records · Page 36Linked to original sources
PubMedDate not supplied

All-trans-retinoic acid-induced variant patterns of palatal rugae in Crj:SD rat fetuses and their potential as indicators for teratogenicity.

We determined the critical period for cleft palate formation in the presence of all-trans-retinoic acid (RA) and defined anomalous patterns within the variants of palatal rugae. The total incidence of variant patterns of palatal rugae in rat fetuses treated with RA at 40 mg/kg on gestation days 13 and 14 dramatically increased with concurrent induction of cleft palate. Correspondence analysis connected the variant patterns of palatal rugae, such as median discontinuity, extra peaks, supernumerary ruga (extra type), shortness, fusion, and bifurcation, with cleft palate. Therefore, these variants were concluded to be anomalous. The incidence of the anomalous patterns of palatal rugae was about 10 times that of cleft palate, and consequently, these anomalies might be sensitive indicators of the teratogenicity of a chemical.

Animals↗
PubMedDate not supplied

Neurotoxicity of phenytoin administered to newborn mice on developing cerebellum.

To examine the neurotoxic effects of phenytoin (PHT) on cerebellar development, we administered 50 mg/kg PHT suspended in sesame oil orally to newborn Jcl:ICR mice once a day during postnatal days 2-14 and determined plasma PHT concentrations at designated intervals during the administration period. In the treated group, walking reflex and negative geotaxis were poorly developed on postnatal day 14. Pyknotic cells in the external granular layer (EGL) significantly increased and were prominent in the vermis area compared with controls on postnatal day 14. Plasma PHT levels were 34-36 micrograms/ml on the 3rd day of PHT treatment and approached a steady-state situation. Total brain weight, size of the cerebellum, and cerebellar weight were significantly reduced in the treated group on postnatal day 56. Accordingly, oral administration of PHT in the neonatal period induced neurotoxic damage on the developing cerebellum.

Animals↗
PubMedDate not supplied

Model simulation of environmental profile transformation and fate of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans by the multimedia environmental fate model.

Environmental profile transformation and fate of polychlorinated dibenzo-p-dioxins (PCDD) and polychlorinated dibenzofurans (PCDF) were studied using the fugacity-based multimedia environmental fate model. Mass fluxes between compartments were estimated by the steady-state modeling. From the model estimates, major mass fluxes coming from emission source were shown to go to the soil and water through wet/dry deposition, then go to degradation mainly in the soil and sediment. Simulation of homologue profile transformation was also performed and some controlling parameters were pointed out. Part of profile transformation phenomenon was simulated well at least qualitatively, which was the result of the difference in the physical/chemical properties of homologues. Long-term environmental fate of PCDD/PCDF was also studied using the non steady-state multimedia fate model.

Air Pollution↗
PubMedDate not supplied

Simulation of long-term environmental dynamics of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans using the dynamic multimedia environmental fate model and its implication to the time trend analysis of dioxins.

Long term environmental fate of polychlorinated dibenzo-p-dioxins (PCDD) and polychlorinated dibenzofurans (PCDF) were studied using the fugacity-based dynamic multimedia environmental fate model. New formulation about soil wind erosion into air was included into the model. Effect of process assumption, sensitivity analysis for parameters, and tentative validation against the measured sediment core analysis was performed. Mass fluxes between compartments were estimated by the dynamic modeling. From the model estimates, major mass fluxes coming from emission source were shown to go to the soil and water through wet/dry deposition, then go to degradation mainly in the soil and sediment. Major mass fluxes of TCDD and OCDD come from the impurities in CNP (Chlornitrofen) and PCP (Pentachlorophenol) directly into the soil. Consideration about multimedia environmental dynamics using the modeled mass fluxes was shown in the discussion.

Benzofurans↗
PubMedDate not supplied

Palatal ruga anomaly induced by all-trans-retinoic acid in the Crj:SD rat: possible warning sign of teratogenicity.

We have reported that the critical period for cleft palate formation by all-trans-retinoic acid (RA) is on gestation day 14 in rats, and classified abnormal patterns of palatal rugae into minor variations and anomalous patterns. In this study, we examined the dose-response relationship for cleft palate and an anomalous pattern of palatal rugae formation and discussed the toxicologic significance of the palatal ruga anomaly as an indicator of teratogenicity. The ED(50) values for cleft palate and anomalous pattern were calculated to be 43.6 and 4.95 mg/kg, respectively. The results clearly show that anomalous rugal patterns occur in the fetuses from litters receiving RA at a lower dose than cleft palate induction; the anomalous ruga pattern is thus more sensitive than cleft palate induction. The anomalies of palatal rugae could be taken as a warning sign or an indicator of teratogenicity of a drug.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Harmonisation of rat fetal skeletal terminology and classification. Report of the Third Workshop on the Terminology in Developmental Toxicology. Berlin, 14-16 September 2000.

The initial efforts of the Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV) and the Free University of Berlin to standardise terminology in the field of developmental toxicology began in 1995. Procedures were undertaken to harmonise the terminology used by the International Federation of Teratology Societies (IFTS) and the International Programme on Chemical Safety (IPCS). This article reflects these activities and is a report on the Third Workshop on the Terminology in Developmental Toxicology held in September 2000. This Workshop served as a forum to discuss the results of a survey on the classification of skeletal anomalies that had been previously sent to scientists active in the field. Although high agreement was reached among the evaluators for several terms, the use of a number of terms was rather variable. Therefore, the discussions at the workshop among the experts from research institutions, regulatory agencies, and industry were mainly focussed on those terms for which there was disagreement and/or uncertainties and the possible reasons. Pictures provided by the participants for the illustration of "grey zone" anomalies constituted the basis for detailed discussions. In many of the cases with lower agreement, decisions were facilitated by the provision of the corresponding picture. The main reasons for lower agreement were imprecise terms, insufficient knowledge on postnatal consequences, theoretical terms that are unlikely to occur in isolation, and the possibility of observing a range of severity that might be decisive for the classification of either a malformation or variation. The attendees concluded that "grey-zone" anomalies will never disappear completely and that for the assessment, the grade of severity and/or the frequency of the observation can be decisive for the terminology chosen. A Joint IPCS/IFTS Project was proposed to further consensus of terminology and classification and to link these anomalies to pictures at different skeletal sites. In order to support the harmonisation of regulatory decisions, it was proposed to establish a "Clearinghouse" System under the umbrella of the IPCS. The Clearinghouse could be contacted either by the regulatory authorities or by any company to clarify their queries, particularly with regard to registration or authorisation processes. Finally, it was recommended to also carry out a similar survey on "soft tissue anomalies" and "external findings." The results of this survey will be discussed at a Joint IPCS/IFTS Workshop in Berlin in 2002.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Effects of low-dose phenytoin administered to newborn mice on developing cerebellum.

To examine correlations between dose levels of phenytoin (PHT) and neurotoxic effects on cerebellar development, we administered 10, 17.5, 25, and 35 mg/kg PHT suspended in sesame oil orally to newborn Jcl:ICR mice once a day during postnatal days 2-4 and determined plasma PHT concentrations during the administration period. Mortality rates were 12.5% and 35.2% in males and 15.3% and 33.3% in females for the 25 and 35 mg/kg PHT-treated groups during the PHT treatment, respectively. In the 25 and 35 mg/kg PHT-treated groups, total brain weight, the size of the cerebellum, and cerebellar weight were significantly reduced on postnatal day 21. However, in the 10 and 17.5 mg/kg PHT-treated groups, total brain weight and the size and weight of the cerebellum did not differ from those of the control group. Histologically, the number of pyknotic cells in the external granular layer (EGL) in the 25 and 35 mg/kg PHT-treated groups was increased on postnatal day 5, and the EGL was thicker than in the control group on postnatal day 14. Some of the Purkinje cells in the 35 mg/kg PHT-treated group showed degeneration. Plasma PHT levels were 10.7 +/- 2.2 and 24.6 +/- 2.6 micrograms/ml in the 25 and 35 mg/kg PHT groups on the third day of PHT treatment, respectively. In the 25 mg/kg PHT group, plasma PHT level was found to be in the therapeutic range for humans, 10-20 micrograms/ml. Accordingly, during pregnancy, epileptic women should be carefully given PHT at the lowest effective dose while plasma PHT levels are monitored properly. These findings emphasize the importance of pharmacokinetics in evaluating of phenytoin-induced developmental neurotoxicity.

Animals↗
PubMedDate not supplied

Neurotoxic effects of phenytoin on postnatal mouse brain development following neonatal administration.

Phenytoin (PHT) is a commonly used anticonvulsant drug. It has been reported that children exposed prenatally to PHT have brain malformations and psychomotor dysfunction. The neonatal development of the central nervous system (CNS) in mice corresponds to the last trimester in humans. To examine the neurotoxic effects of PHT on postnatal brain development, we administered PHT at doses of 10, 17.5, 25, or 35 mg/kg to newborn mice once a day during postnatal days (PD) 2-4. These dose levels result in plasma levels corresponding to the therapeutic ranges in humans. We measured the weight of total brain, cerebrum, cerebellum, and brain stem on PD 5 through 21, and examined early motor functions including head elevation, elevation of pelvis, pivoting, crawling, and righting reflex . Total brain weight, cerebral weight, and cerebellar weight in the group treated with 25 or 35 mg/kg were significantly reduced compared to controls from PD 5 to 21. Mice treated with PHT at 25 or 35 mg/kg showed decreased locomotor abilities and righting reflex on PD 5. In all phenytoin treatment groups, phenytoin levels in the brain were higher than those in the plasma on the third day of PHT treatment. We thus observed neurotoxic effects of PHT on postnatal brain development in mice. Our present data may provide useful implications for the management of PHT-induced developmental neurotoxicity and evaluation of psychomotor development in children exposed to PHT during the late fetal period.

Aging↗
PubMedDate not supplied

Effect of additives on refolding of a denatured protein.

Denatured lysozyme was refolded by a dilution method. The refolding yield depended greatly on the lysozyme concentration in the refolding mixture. When the concentration of denatured lysozyme was 0.02 g/L, the refolding yield was as high as 60%. However, when the concentration of denatured lysozyme was 0.2 g/L, the refolding yield was as low as 10% due to the formation of aggregates. To prevent the formation of aggregates and to increase the refolding yield at a low cost, inexpensive additives were screened. The addition of acetone, acetoamide, or urea derivatives was very effective for improving the refolding yield. To clarify why the addition of acetoamide in the refolding mixture improved the refolding yield at the high lysozyme concentration, the time courses of the concentration and the average diameter of the aggregates in the refolding mixture were monitored by the dynamic light scattering method. The experimental results showed that acetoamide played a role in preventing the formation and growth of aggregates and secondary aggregation between the lysozyme aggregates.

Acetamides↗
PubMedDate not supplied

Asbestos fiber analysis in seven asbestosis cases.

Asbestos bodies and fibers deposited in the lungs of seven asbestosis cases were counted after tissue digestion. The types and sizes of 100 asbestos fibers for each case were also analyzed. Asbestos bodies were counted with an optical microscope at 100x magnification, and asbestos fibers were counted with a transmission electron microscope (TEM) at 2000x magnification. Most asbestos fibers detected with TEM were longer than 3 microns (92.5%) and thicker than 0.1 microns (92.3%). Short fibers less than 2 microns--both chrysotile and amphiboles, as well as long, thin fibers less than 0.06 microns--would be missed at 2000x (TEM). An average of 1.37 (0.081-5.5) x 10(6) asbestos bodies and 164.8 (0.55-610) x 10(6) asbestos fibers per 5 g wet (0.88 g dry) lung tissue were found, and these values are higher than what was reported in mesothelioma cases without asbestosis that were reported previously. More than 13 (average = 266.2) asbestos bodies were found in a 4-micron-thick tissue section (average area = 3.24 cm2). One asbestos body in a section equaled approximately 5,000 per 5 g wet lung tissue. The intensity of fibrosis was minimal in one case, mild in four, moderate and severe in one each, and the intensity was correlated with the number of asbestos bodies and fibers. The fibrosis in the severe case may have been intensified by repeated infection. Crocidolite fibers were found most frequently (84.7%), were thin, and had a high aspect ratio by our counting rules. Crocidolite with a high aspect ratio may be most fibrogenic in the lung.

Adult↗
PubMedDate not supplied

Loss of heterozygosity alterations associated with progesterone therapy in endometrial hyperplasia and adenocarcinoma.

Loss of heterozygosity (LOH) was analyzed in four patients with endometrial hyperplasia (EH) with atypia (two patients) and without atypia (two patients) and in five patients with endometrial adenocarcinoma (EAC) to clarify the clinicopathologic relationship between genetic alterations and hormone therapy. Each patient was initially administered high-dose medroxyprogesterone acetate (MPA) as a uterine-sparing treatment. The five microsatellite markers used to analyze LOH were at chromosomal loci 8p22.1, 8p21, 8p21.3, 8p22, and 8p22. DNA was extracted from paraffin-embedded sections before, during, and after MPA therapy using laser capture microdissection. As a result, LOH was more frequently detected after MPA therapy (overall ratios were 16, 17, and 29% before, during, and after MPA therapy, respectively). LOH is more easily detected in EH loci than in EAC loci before MPA. For EAC, initial LOH detection on chromosome 8 may be related to an incomplete response to MPA, but negative LOH does not guarantee a favorable treatment outcome. For EH or atypical endometrial hyperplasia, it is unknown whether LOH alteration associated with MPA therapy is related to atypia of the disease.

Adenocarcinoma↗
PubMedDate not supplied

Whole-body positron emission tomography and tumor marker CA125 for detection of recurrence in epithelial ovarian cancer.

We evaluated the clinical role of the combination of positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) and tumor marker CA125, in the detection of recurrence after initial therapy for epithelial ovarian cancer. The indication is the cases that cannot be confirmed the recurrence by conventional imaging modalities. Ninety patients underwent PET and computed tomography, including the measurement of specific tumor markers. FDG-PET confirmed recurrence in 46 patients (51%), and the recurrent site was confirmed by PET alone in 17 (37%). PET had high sensitivity for detecting both intraperitoneal and retroperitoneal metastases (93.9 and 92.9%, respectively). PET imaging was able to detect normal-sized metastases in the lymph nodes in 14 (50%) of the 28 patients with retroperitoneal metastasis. PET could show 87.5% positive rate of recurrent patients with asymptomatic rise of CA125 who had no sign of recurrence by conventional imaging methods. Of the 46 recurrent patients, 41 (89%) had specific elevated titers of CA125 at the first treatment. PET imaging was able to detect recurrence at relatively low titers (a median 68 U/mL) of CA125. In 8 (19.5%) of these 41 patients, recurrence with normal CA125 levels could be confirmed only by PET. The sensitivity of the combination of PET and CA125 was 97.8% with only one false-negative case. The combination of FDG-PET and CA125 titer is useful for the accurate detection of recurrence.

Adenocarcinoma↗
PubMedDate not supplied

Fas gene promoter -670 polymorphism in gynecological cancer.

Single-nucleotide polymorphism at -670 of Fas gene promoter (A/G) was examined in a total of 354 blood samples from normal healthy women and gynecological cancer patients. They consisted of 95 normal, 83 cervical, 108 endometrial, and 68 ovarian cancer cases. Eighty-three patients with cervical cancer had statistically higher frequency of GG genotype and G allele than 95 controls (P= 0.0353 and 0.0278, respectively). There was no significant difference in the genotype or allele prevalence between control subjects and endometrial or ovarian cancer patients. The Fas -670 GG genotype was associated with an increased risk for the development of cervical cancer (OR = 2.56, 95% CI = 1.08-6.10) compared with the AA genotype. The G allele also increased the risk of cervical cancer (OR = 1.60, 95% CI = 1.05-2.43) compared with the A allele. Germ-line polymorphism of Fas gene promoter -670 may be associated with the risk of cervical cancer in a Japanese population.

Adult↗
PubMedDate not supplied

Whole-body positron emission tomography with F-18 fluorodeoxyglucose for the detection of recurrence in uterine sarcomas.

We evaluated the usefulness of whole-body positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG-PET) for the detection of recurrence in follow-up patients after primary treatment of uterine sarcoma. Eight patients with pathologically proven uterine sarcoma underwent FDG-PET, computed tomography (CT), and ultrasonography (US). Final diagnoses of recurrence were established in five cases (three carcinosarcomas and two leiomyosarcomas). PET revealed recurrent sites in the intraperitoneum, liver, lung, bone, and retroperitoneal lymph nodes. However, the minimum size of the tumor detected by PET depended on the sites of recurrence. CT and US images showed two false-negative cases of intraperitoneal tumors. PET was able to detect a solitary small intraperitoneal tumor, which was very difficult to detect by CT and US. Positive PET findings did not affect the prognosis in three of the five recurrent patients; however, the remaining two patients consequently underwent the combination therapy consisting of surgery and chemotherapy and survived for more than 1 year after the positive FDG-PET results. Application of PET imaging for the early detection of recurrent sites was useful for the decision of treatment strategy for patients with recurrent uterine sarcoma.

Adult↗
PubMedDate not supplied

Increased intestinal permeability correlates with gastrointestinal toxicity among formulations of the fluorouracil analogue tegafur in rats.

BACKGROUND: S-1 is a new antitumor agent which was developed based on biochemical modulation of fluorouracil. S-1 consists of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. S-1 has been reported to enhance therapeutic effects and to reduce the gastrointestinal toxicity as compared with 5-fluorouracil. In this study performed in rats, S-1 was used to assess the relationship between gastrointestinal mucosal toxicity and changes in intestinal barrier function. METHODS: Fifteen rats were equally divided into three groups: group A (untreated controls), group B (FT and CDHP mixture), and group C (FT and CDHP in combination with Oxo). The animals in groups B and C received equitoxic doses of the drugs in their food for 14 consecutive days. The intestinal permeability was determined on the basis of the urinary recovery of orally administered lactulose and mannitol (L/M). Injury to the small intestines was evaluated by light microscopy. The cell surface expression of CD44 was evaluated immunohistochemically. RESULTS: Recovery of L/M in urine (expressed as a fraction of the dose administered) was 0.15 +/- (SE) 0.08, 0.23 +/- 0.13, and 0.09 +/- 0.04 in groups A, B, and C, respectively. The intestinal permeability in group B was significantly higher than that in group C (p < 0.05). Treatment with FT and CDHP (groups B and C) induced injury to the small intestine and decreased expression of CD44 within the intestinal mucosa, but the extent of damage was reduced by coadministration of Oxo (group C). CONCLUSION: This experimental study suggested that the gastrointestinal toxicity resulting from administration of anticancer drugs is accompanied by an impaired gut barrier function measurable as an increase in intestinal permeability to L/M.

Animals↗
PubMedDate not supplied

Assessment of the intestinal permeability following postoperative chemotherapy for human malignant disease.

PURPOSE: Administration of anticancer drugs may damage gastrointestinal epithelium, thereby increasing the permeability of the gastrointestinal mucosa. We estimated the usefulness of oral lactulose and mannitol (L/M) test for assessment the extent of mucosal damage following postoperative chemotherapy for human malignant disease. METHODS: The permeability index (PI): the urinary recovery ratio of excreted L to M was measured before and after chemotherapy in 31 patients with gastrointestinal cancers who underwent surgical resection. These findings were compared with data on 12 patients with breast cancer. The effect of chemotherapy was evaluated by the ratio of increase in PI, which was designed as post-chemotherapy value on day 7 divided by pre-chemotherapy value. RESULTS: The mean PIs before chemotherapy in patients who underwent gastrectomy or colectomy were significantly higher than the value in those treated with mastectomy (p < 0.05). In the gastrointestinal cancer patients, the mean PIs significantly increased after chemotherapy compared with the pre-chemotherapeutic value (p < 0.01), however no significant difference was seen in breast cancer patients. When the ratios of increase in PI were calculated among gastric cancer patients, the total gastrectomy group showed a significantly higher increase in PI compared with the partial gastrectomy group (p < 0.05). CONCLUSIONS: Since the oral L/M absorption test is useful for assessing the degree of mucosal damage and measurement of intestinal permeability, this analysis should be recommended to determine the optimum timing and the adequate dosage of the anticancer drug administration.

Antineoplastic Agents, Phytogenic↗