Biomedical subjects
K Shiota
Publications and source records attributed to K Shiota.
[Symposium on asthama. Infection and asthma].
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[Symposium. I. Asthma].
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[Infectious diseases and chemotherapy].
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Effects of prenatal alcohol exposure in mice: influence of an ADH inhibitor and a chronic inhalation study.
In order to examine the effects of an alcohol dehydrogenase inhibitor on the embryotoxic effects of ethanol, pregnant ICR mice were treated with 100 mg/kg pyrazole prior to ethanol injection. I.p. treatment with 2 or 4 g/kg ethanol on day 7 of gestation increased the prenatal mortality rate and produced external and skeletal malformations in the offspring, and the embryotoxic effects were potentiated by pyrazole pretreatment, suggesting that ethanol rather than its metabolites is mainly responsible for the embryotoxicity. In the second experiment, we housed pregnant mice in an ethanol-vapor box for 3 or 6 days in order to examine the effects of prolonged low level exposure to alcohol. The maternal blood alcohol concentration was maintained approximately 0.03 mg/mL during inhalation. The inhalation treatment with ethanol increased the prenatal mortality rate, although teratogenicity was not shown.
Effects of anticonvulsant drugs on fetal mouse palates cultured in vitro.
Maxillary regions of day-12.5 ICR mouse fetuses were dissected and cultured in a chemically defined serumless medium, and the effects of anticonvulsant drugs on in vitro palatogenesis were studied. The explants were treated for 72 h in vitro with 50 to 200 micrograms/mL diphenylhydantoin (DPH), 200 to 800 micrograms/mL sodium phenobarbital (PB), 12.5 to 400 micrograms/mL sodium valproate (VPA), and 3 to 100 micrograms/mL diazepam (DAZ). During the culture, the secondary palatal shelves of control explants elevated, grew medially, and fused after 72-h culture in a manner similar to the palatogenetic process in vivo. The fusion of palatal shelves was inhibited dose-dependently by treatments with DPH, VPA, and DAZ. PB showed no significant inhibitory effects on palatal fusion at concentrations up to 800 micrograms/mL. The in vitro toxicity of the anticonvulsants tested appeared to correlate with the relative in vivo teratogenic potential of the drugs. The present study demonstrated that the in vitro organ culture system should be useful for screening teratogenic agents, especially those causing cleft palate, and for exploring the mechanisms of cleft palate formation.
Hyperthermia and birth defects.
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Heat shock-induced homeotic transformations of the axial skeleton and associated shifts of Hox gene expression domains in mouse embryos.
Pregnant ICR mice were immersed in water at 42 degrees C for up to 15 min on Day 8.5 of gestation (plug day = Day 0), and their term fetuses were double stained with alcian blue and alizarin red S for skeletal examination. Heat exposure for 15 min induced homeotic vertebral transformations in more than one-third of the living fetuses, in which the morphologic identity of vertebrae (T6-S1) was shifted anteriorly by one or two segmental levels. The frequency of fetuses with vertebral transformations and the degree of the shift of vertebral identity were dependent on the length of heat exposure. The expression domains of Hoxa-7, Hoxc-8, and Hoxc-9 genes as examined by whole mount in situ hybridization were found to be shifted anteriorly in heated embryos. The heat-induced shifts of Hox gene expression domains were consistent with the observed vertebral transformations and suggested correlation or colinearity with the clustered organization of the Hox genes. The result of the present study indicates that a brief heat shock at a critical stage of differentiation can interfere with the normal establishment of Hox codes and subsequently, perturb the specification of vertebral identity.
Effects of amphetamine on rat embryos developing in vitro.
Wistar rat embryos were explanted on Day 10.5 of gestation and exposed in vitro to amphetamine (AMP) at concentrations of 0.1, 0.4, 0.8, 1.2, or 1.6 mM for 24 h, and the direct dysmorphogenic effects of the drug on the embryos were examined by comparisons with a control group. The viability of the cultured embryos was not affected by the AMP treatment. The yolk sac diameter was reduced at AMP concentrations of 1.2 and 1.6 mM. The crown-rump length, the somite number, and the protein content of the embryos were decreased significantly at these two doses, as was the developmental score. The frequency of malformed embryos was increased significantly at the two highest concentrations. The malformations induced in treated embryos included microcephaly, neural tube defects, incomplete rotation of the body axis, and tortuous spinal cord. Abnormal histologic changes, such as derangement and necrosis of the neuroepithelial tissue, were observed in the embryos exposed to the two highest concentrations of the drug. The observed embryotoxic effects appeared to depend on the AMP concentration. Our results demonstrated the direct embryotoxic effects of AMP on rats. The direct dysmorphogenic effect of AMP might be weaker than that of methamphetamine.
Effects of heat on embryos and foetuses.
OBJECTIVES: This paper reviews the effects of elevated maternal temperature on embryo and foetal development in experimental animals and in humans. CONCLUSIONS: Hyperthermia during pregnancy can cause embryonic death, abortion, growth retardation and developmental defects. Processes critical to embryonic development, such as cell proliferation, migration, differentiation and programmed cell death (apoptosis) are adversely affected by elevated maternal temperatures, showing some similarity to the effects of ionizing radiation. The development of the central nervous system is especially susceptible: a 2.5 degrees C elevation for 1 h during early neural tube closure in rats resulted in an increased incidence of cranio-facial defects, and a 'spike' temperature elevation of 2-2.5 degrees C in an exposure of 1 h during early neurogenesis in guinea pigs caused an increase in the incidence of microencephaly. However, in general, thresholds and dose-response relationships vary between species and even between different strains of the same species, depending on genotype. This precludes rigorous quantitative extrapolation to humans, although some general principles can be inferred. In humans, epidemiological studies suggest that an elevation of maternal body temperature by 2 degrees C for at least 24 h during fever can cause a range of developmental defects, but there is little information on thresholds for shorter exposures. Further experimental and epidemiological studies are recommended, focusing on stage-specific developmental effects in the central nervous system using a variety of sensitive assays.
Altered expression of retinoic acid (RA) receptor mRNAs in the fetal mouse secondary palate by all-trans and 13-cis RAs: implications for RA-induced teratogenesis.
Retinoic acid (RA) is mandatory for various biological processes and normal embryonic development but is teratogenic at high concentrations. In rodents, one of the major malformations induced by RA is cleft palate (CP). RA mediates its effects by RA receptors (RARs), but the expression patterns of RARs in the developing palate are still unclear. We investigated the normal expression of RAR alpha, beta, and gamma messenger RNAs (mRNAs) in the fetal mouse secondary palate and the effects of all-trans and 13-cis RAs on the expression of RAR mRNAs by Northern blot analysis. RAR alpha (2.8, 3.8 kb), RAR beta (3.3 kb), and RAR gamma (3.7 kb) mRNAs were detected in the fetal palate on gestational days (GD) 12.5-14.5. The expression of RAR alpha and gamma mRNAs did not show apparent sequential changes, but that of RAR beta mRNA increased at GD 13.5. Treatment of pregnant mice with 100 mg/kg all-trans RA induced CP in 94% of the fetuses and elevated the levels of RAR beta and gamma mRNAs in the fetal palate. The up-regulation of RAR beta mRNA by all-trans RA was more marked than that of RAR gamma mRNA. Treatment with 100 mg/kg 13-cis RA induced CP in only 19% of the fetuses. Although 13-cis RA elevated the RAR beta and gamma mRNA levels in fetal palates, its up-regulation was slower and less marked than that induced by all-trans RA. These findings indicate that the induction of RAR beta mRNA in the fetal palate correlates well with the tissue concentration of all-trans RA after RA treatment, and RAR beta may be one of the most influential candidate molecules for RA-induced teratogenesis.
Clinicopathologic study on cholangiolocellular carcinoma.
We clinicopathologically studied 6 resected cases of cholangiolocarcinoma (CLC) including 2 referred cases from other hospitals. The frequency of CLC was 0.56% of the 708 consecutively resected cases of primary liver cancer and the mean age of CLC cases was 66 years. Three of the 6 cases (50%) were hepatitis C virus antibody (HCVab) positive, one (17%) was hepatitis B virus surface antigen (HBsAg) positive, and 2 (33%) were negative to both HCVAb and HBsAg. Serum levels of alpha-fetoprotein were slightly elavated only in 1 case. Clinically, 4 cases were diagnosed as hepatocellular carcinoma (HCC) and 2 cases as cholangiocellular carcinoma (CCC). Grossly, CLCs were whitish in color and solid, not encapsulated, and resembled CCC. Histologically, the tumor cells had eosinophilic cytoplasm with ovoid nuclei, and mild atypia. The tumor proliferated in an anastomosing pattern of Hering's canal-like small glands with an abundant fibrous stroma. Four of the 6 tumors (83%) consisted of only CLC and other 2 tumors contained CCC-like area and HCC-like area in a part of the nodules, respectively. Immunohistochemically, all tumors were positive to cytokeratin (CK) 7. CK8 were also positive in all of 6 cases. These results revealed that CLC had the clinical features resembling HCC but the morphologic features resembling CCC. It is suggested that CLC cells might be derived from Hering's canal or stem cells which have the intermediate features between hepatocytes and bile duct epithelium.
Mechanism of apoptosis induced by cisplatin and VP-16 in PANC-1 cells.
Cisplatin and VP-16 were used to study the induction of apoptosis in Panc-1 cells. Cisplatin and VP-16 inhibited the growth of Panc-1 cells. After 2 hours exposure to cisplatin or VP-16, attached and detached cells were subjected to TUNEL staining to calculate the ratio of apoptosis. In detached cells TUNEL positive ratios increased in a time- and dose-dependent manner. In Western blotting, Bax expression was obviously up-regulated, but Bcl-2 remained almost constant. The results suggested that in Panc-1 cells cisplatin and VP-16 induced apoptotic cell death which was mediated through the interaction of Bax expression in the presence of mutated p53.
Intra-operative detection of lymph node involvement in carcinoma of the colon.
BACKGROUND/AIMS: We studied the accuracy rate of intra-operative lymph node assessment compared with pathological examination to determine whether surgeons could modify the extent of lymphadenectomy during the operation. METHODOLOGY: Intra-operative and pathological lymph node assessments were compared in 360 patients with carcinoma of the colon. RESULTS: A total of 6,431 lymph nodes were examined, mean number per patient was 17.9. The overall accuracy rate of intra-operative diagnosis was 56.1%, sensitivity was 93.2%, and specificity was 41.7%. The accuracy rate of the diagnosis of N1 and N2 was 43.7% and that of N3 and N4 was 78.3% (p=0.001). There was no significant difference in the diagnosis rates in the colonic region. These results indicated that diagnosis in < or = N3 was more accurate than that in > or = N2. There were 5 false-negative cases. All of the false-negative lymph nodes were located adjacent to the colonic wall. CONCLUSIONS: Intra-operative diagnosis of the positivity of < or = N2 lymph nodes was too poor to decide the extent of lymph node dissection of < D2. It is adequate to dissect according to at least the D2 criteria in all cases. If the surgeon observes N3 involvement, he should add the D3 dissection.