Biomedical subjects
I Nagata
Publications and source records attributed to I Nagata.
A synthetic peptide deduced from the sequence in the cross-region of laminin A chain mediates neurite outgrowth, cell attachment and heparin binding.
Synthetic peptides from the cross-region of the laminin A chain were prepared and tested for their biological activities, especially for neurite outgrowth. A synthetic 8-mer peptide (designated LMA-5) in the cross-region of the laminin A chain was found to promote neurite outgrowth in PC12 cells and cerebellar microexplant cultures. Furthermore, this peptide mediated cell attachment and heparin binding. In addition, an antibody against peptide LMA-5 inhibited laminin- and LMA-5-mediated cell attachment. This antibody also inhibited more than half of the LMA-5-promoted neurite outgrowth in cerebellar microexplant cultures. These data suggest that peptide LMA-5 is one of the active sites in laminin that regulate cell behaviour including neurite outgrowth, cell attachment and heparin binding.
Insulin sensitivity, insulin secretion, and glucose effectiveness in subjects with impaired glucose tolerance: a minimal model analysis.
The aim of the present study was to estimate insulin secretion, insulin sensitivity (SI), and glucose effectiveness (SG) in non-obese Japanese subjects with impaired glucose tolerance (IGT). Ten IGT subjects (five men, five women) and 15 normal-tolerance subjects (seven men, eight women) without a family history of diabetes were studied. They underwent a modified frequently sampled intravenous glucose tolerance test (FSIGT); glucose (300 mg/kg body weight) was administered, and insulin (20 mU/kg over 5 minutes) was infused from 20 to 25 minutes after the administration of glucose. SI and SG were estimated by Bergman's minimal model method. No significant difference was observed in body mass index ([BMI] 22.1 +/- 0.8 v 21.1 +/- 0.5 kg/m2), fasting plasma glucose (5.19 +/- 0.18 v 5.07 +/- 0.11 mmol/L), and insulin levels (50.7 +/- 7.3 v 45.2 +/- 4.5 pmol/L) of subjects with IGT and normal controls. The glucose disappearance rate (KG) was significantly lower in subjects with IGT than in normal-tolerance subjects (1.57 +/- 0.20 v 2.09 +/- 0.15%/min, P < .05). Pancreatic insulin secretion expressed as the integrated area of plasma insulin above the basal level during the first 20 minutes was lower in IGT subjects (2,556 +/- 572 pmol/L x min) than in normal-tolerance subjects (4,957 +/- 800 pmol/L x min, P < .05). SI was not statistically different between the two groups (0.84 +/- 0.13 x 10(-4) v 1.14 +/- 0.15 x 10(-4).min-1.pmol/L-1). However, SG was significantly lower in subjects with IGT than in normal controls (0.013 +/- 0.002 v 0.023 +/- 0.002 min-1, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
Migration behavior of granule cells on laminin in cerebellar microexplant cultures from early postnatal reeler mutant mice.
The behaviors of neuroblasts of granule cell neurons and their precursor cells on a poly-L-lysine/laminin substratum were examined in cerebellar microexplant cultures from early postnatal reeler mutant and normal mice. The total numbers of migrating neuroblasts and their precursor cells or blast cells derived from the mutant cerebellum were markedly reduced in comparison with their normal counterparts. However, no difference was shown between these two strains in either the numbers of blast cells or neuroblasts that migrated from single explants. In addition, all behaviors examined, such as migration of neuroblasts and the proliferation of blast cells in culture were identical between both genotypes. Thus, behaviors of both granule cells and their precursors in the cerebellar cortex of reeler mutant mouse may be qualitatively identical to those of normal counterparts, but precursors of granule cells in the external germinal layer of the cerebellar cortex may be reduced in the reeler mouse.
A novel biological aspect of ovarian oxytocin: oxytocin gene expression in cumulus/luteal cells and the effect of oxytocin on embryogenesis in fertilized oocytes.
Recently, several reports have demonstrated the presence of oxytocin (OT) in the corpus luteum of mammalian species. However, the biological role of ovarian OT remains obscure. This study was performed to examine OT gene expression in cumulus cells of mice and humans, and in human corpus luteum, and the role of OT in early embryogenesis. OT gene and OT mRNA were analyzed by reverse transcription-polymerase chain reaction, with single-strand-conformation polymorphism and heteroduplex procedures. OT-treated in-vitro-fertilized mouse oocytes were cultured and the rate of blastocyst development estimated. An immunohistochemical study was also carried out to detect OT on the surface of the mouse oocytes.
An infant with pseudohypoaldosteronism accompanied by cholelithiasis.
A case of an infant with very rare concurrence of pseudohypoaldosteronism and cholelithiasis is described. Aldosterone concentration was extremely high (64.6 nmol/l; normal 0.03-4.4 nmol/l) and fludrocortisone did not have favorable effects on hyperkalemia (7.4 mEq/l) and hyponatremia (124 mEq/l). A gallstone was found using ultrasonography at age 6 months, and it was extirpated surgically. The combination has not been reported previously. The study supports the previous hypothesis that cholelithiasis is found more often in infants with dehydration or electrolyte derangement.
Endometriotic tissues produce immunosuppressive factors.
In order to study the possible role of the immune functions in the pathogenesis of endometriosis, effects of supernatants from endometrial and endometriotic tissue cultures on the natural killer (NK) activity were examined by determining the lymphocyte cytotoxicity toward an erythroleukemic cell line (K562). Endometrial and endometriotic tissues were obtained at the time of operation from patients with ectopic endometriosis or uterine myoma. The normal peritoneum and myoma tissues were used as controls. The supernatants obtained by culturing the ectopic endometriotic tissues for 24-48 h had significant (p < 0.01) suppressive effects on NK activity of peripheral blood lymphocytes (PBL) from a healthy woman, compared to the supernatants from the normal peritoneum and the myoma tissues. There was no significant difference between NK activities of PBL from patients with ectopic endometriosis and age-matched healthy women. However, the NK activity in patients with low NK status before surgery was significantly elevated after surgery while that in patients with normal NK status before surgery was not changed. Although PBL from the same healthy women could significantly lyse the endometrial cells, the ability was about-one-third the level at which they could lyse K562 cells. These results suggest that the immunosuppressive factors secreted by endometriotic tissues may be involved in the local implantation and development of ectopic endometriosis.
Parathyroid hormone-related protein during pregnancy and the perinatal period.
To evaluate whether parathyroid hormone-related protein (PTHrP) plays any role in calcium metabolism during pregnancy and the perinatal period, we measured parathyroid hormone (PTH), immunoreactive PTHrP and calcium in maternal serum of women during pregnancy and puerperium, and in maternal and cord serum at delivery. Serum PTH levels in pregnant women were lower than those in nonpregnant women (p < 0.01). However, serum PTHrP levels were similar in the two groups of women. Cord serum total and ionic calcium levels were higher, and cord serum PTH levels were lower compared to maternal values (p < 0.01). Cord serum PTHrP levels were higher than maternal values, and umbilical arterial levels were higher than umbilical venous levels (p < 0.01). Higher levels of PTHrP in umbilical arterial blood than in umbilical venous blood suggest that the main source of cord blood PTHrP may be the fetus. PTHrP is reported to stimulate placental calcium transfer from mother to fetus in animals. The elevated cord blood PTHrP level in association with the decreased PTH level suggests that stimulation of placental calcium transfer by PTHrP may also be operative in humans.
Cord blood levels of calcium-regulating hormones and osteocalcin in premature infants.
We measured cord blood levels of calcium-regulating hormones and osteocalcin in 34 premature infants of various gestational ages. 1,25(OH)2D levels were low in mid-gestation and increased with advancing gestation. Parathyroid hormone levels were low, and calcitonin levels were high in mid-gestation. Both of them declined with advancing gestation. Osteocalcin levels were high in mid-gestation. They increased from 22 weeks through 27 weeks of gestational age, and decreased thereafter. Circulating osteocalcin is considered as a clinical marker of bone turnover. However, cord blood osteocalcin decreased between 27 and 36 weeks of gestation during which period calcium accumulation by the fetus increases. Therefore, cord blood osteocalcin does not appear to reflect fetal bone formation.
Glucose effectiveness in two subtypes within impaired glucose tolerance. A minimal model analysis.
To clarify the event that is involved in the pathogenesis of impaired glucose tolerance (IGT), we studied 15 individuals with IGT and 15 subjects with normal tolerance using the minimal model approach. Our IGT subjects were characterized by normal insulin secretory responses to oral glucose and mild impairments in insulin sensitivity (SI) and glucose effectiveness (SG) at basal and zero insulin. Next, we classified our IGT subjects into two subpopulations: one with normal insulin sensitivity (SI: 0.92 +/- 0.11 x 10(-4) min-1.pmol/l-1 and the other with insulin resistance (SI:0.31 +/- 0.06 x 10(-4)min-1.pmol/l-1, P < 0.05). The populations did not differ with respect to body mass index and fasting plasma glucose level. Basal plasma insulin level was higher in the insulin-resistant group (84.8 +/- 23.3 pmol/l) than in the insulin-sensitive group (48.7 +/- 6.8 pmol/l), but the difference was not statistically significant. The absolute insulin secretory responses to oral glucose were significantly higher in the resistant group (83,205 +/- 17,787 pmol/l x min) than in the sensitive group (24,727 +/- 3,591 pmol/l x min, P < 0.01), whose absolute responses were similar to those of normal control subjects (24,576 +/- 2,767 pmol/l x min). No significant difference was observed in SG between the resistant (0.016 +/- 0.002 min-1) and sensitive (0.013 +/- 0.002 min-1, P > 0.05) type of IGT, but SG was significantly type of IGT, but SG was significantly decreased in both groups compared with normal control subjects (0.023 +/- 0.002 min-1, P < 0.05-0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
[Potentiation of cisplatin sensitivity of cisplatin-resistant human ovarian cancer cell lines by L-buthionine-S,R-sulfoximine].
We established two human ovarian cancer cell lines (KK and MH) from the ascites of patients who did not respond to cisplatin (CDDP)-based combination chemotherapy. These cell lines showed higher resistance to CDDP in vitro than HRA cells which were established previously in our laboratory, and also have cross resistance with its analogues. The amount of intracellular glutathione (GSH) in these cells correlated with the degree of resistance to CDDP and was high, but the intracellular platinum (Pt) uptake was unchanged. Preincubation with L-buthionine-S,R-sulfoximine (BSO) reduced cellular GSH in these cells to 9-25%, while the Pt uptake remained unchanged. When the CDDP-resistant KK and MH cells were incubated in the presence of 10 microM BSO, they were sensitized to CDDP and its analogues showing a decrease to 79-38% in the IC50 values. On the basis of these results, we conclude that GSH may be involved in the mechanisms of resistance to CDDP and its analogues in the KK and MH cells.
[A case of dumbbell-shaped hypoglossal neurinoma].
The authors report a case of dumbbell-shaped hypoglossal neurinoma. A 46-year-old female was admitted to our clinic with a history of right hemiatrophy of the tongue for more than 10 years and bilateral paresthesia on the face and legs for half a year. Neurological findings on admission were right hypoglossal palsy, attenuation of right gag and palatal reflex, mild truncal ataxia, right Bruns nystagmus, bilateral paresthesia on the face and legs (left > right), bilateral hyper-reflexia on the extremities. No sign of increased intracranial pressure was noted. Conventional computed tomography demonstrated the bone destruction around the right hypoglossal canal, and three-demensional computed tomography clearly revealed the extent of the bone destruction. Magnetic resonance imaging showed a large dumbbell-shaped mass extending both intra-and extra-cranially through the right hypoglossal canal, which severely compressed the brainstem postero-medially. Right suboccipital craniotomy with C1 laminectomy was performed in the prone position, and the occipital bone was drilled far-laterally around the Foramen Magnum with right occipital condyle rongeured to expose the intracanallicular mass. The mass was totally removed except around the IX Xth cranial nerves near the jugular foramen. Hypoglossal neurinoma is rare, and our case is the 62nd case, and the 15th dumbbell-shaped case in the literature. Hypoglossal nerve palsy is characteristic in dumbbell-shaped hypoglossal neurinoma. Enlargement of the hypoglossal canal can be detected by conventional and three-dimensional CT. MRI is more effective than CT in revealing the mass. Total removal of the dumbbell-shaped tumor requires that the hypoglossal canal can be exposed sufficiently.(ABSTRACT TRUNCATED AT 250 WORDS)
[Surgical indication for the cerebral aneurysms].
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Modulation of sensitivity of human ovarian cancer cells to cis-diamminedichloroplatinum(II) by 12-O-tetradecanoylphorbol-13-acetate and D,L-buthionine-S,R-sulphoximine.
The ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) and D,L-buthionine-S,R-sulphoximine (BSO) to modulate cis-diamminedichloroplatinum(II) (CDDP) sensitivity was investigated in human ovarian cancer cell lines sensitive (KF) or with intrinsic resistance (KK and MH) to CDDP. The KK and MH cell lines were derived from ascites of patients with clear-cell carcinoma and serous cystadenocarcinoma of the ovary who both showed clinical resistance to CDDP. The CDDP IC50 value of KK and MH cells was about 4.6- and 10.2-fold higher than that of KF cells. PKC activities in the cytosol and membrane of KK and MH cells were also about 4- to 5-fold higher than those of KF cells. Proliferation of KF, KK and MH cells was inhibited in a dose-dependent manner by TPA. The membrane PKC activities in the KF cells were rapidly activated and down-regulated 24 hr after exposure to TPA, while those in the KK and MH cells were not down-regulated even after exposure to TPA for 24 hr, suggesting that the membrane form of PKC may be involved in the intrinsic resistance. Continuous exposure to 10 nM TPA for 5 days significantly reduced the CDDP sensitivity of KF and KK cells, while exposure to 10 nM TPA for 1 hr significantly elevated that of KK and MH cells. Interestingly, 1-hr exposure to 1 microM TPA induced CDDP-resistance in KK cells. Such changes in CDDP sensitivity by TPA seemed to be linked with those of cellular PKC activity, i.e., when the CDDP sensitivity was reduced by TPA, the cellular PKC rose.(ABSTRACT TRUNCATED AT 250 WORDS)
C-type natriuretic peptide (CNP) is the major natriuretic peptide in human cerebrospinal fluid.
In order to investigate whether C-type natriuretic peptide (CNP) is present in human cerebrospinal fluid (CSF), we measured CNP-like immunoreactivity (-LI) in human CSF by specific radioimmunoassay (RIA) for CNP. We also measured atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations in human CSF. ANP-LI, BNP-LI, and CNP-LI concentrations of CSF collected from fifteen patients without neurological disorders were 0.20 +/- 0.13, 0.27 +/- 0.10, and 2.13 +/- 0.27 fmol/ml (mean +/- S.D.), respectively. In fifteen patients with neurological disorders, ANP-LI, BNP-LI, and CNP-LI concentrations in CSF were 0.21 +/- 0.18, 0.33 +/- 0.19, and 2.09 +/- 0.82 fmol/ml, respectively. Although ANP-LI and BNP-LI concentrations in plasma were much higher than those in CSF, CNP-LI was undetectable in plasma (less than 0.2 fmol/ml). These results demonstrate that three natriuretic peptides are present in CSF and that CNP is the major natriuretic peptide in human CSF. These results suggest that CNP in CSF is originated from and play important roles in the central nervous system.
[Revascularization of extracranial cerebral arteries].
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Enhancement of antiproliferative effect of cis-diamminedichloroplatinum(II) by clomiphene and tamoxifen in human ovarian cancer cells.
In this study, we examined antiproliferative effect of clomiphene and tamoxifen alone and their combined effect on cis-diamminedichloroplatinum(II) (CDDP) by using human ovarian cancer cells (KF, KK, and MH cells) with different sensitivity to CDDP and MCF-7 cells derived from human breast cancer. KF, KK, and MH cells did not have estrogen receptor while MCF-7 cells had it. The KF cells were most sensitive to CDDP followed by KK, MCF-7, and MH cells. Similarly, the KF cells among three human ovarian cancer cell lines were most sensitive to clomiphene and tamoxifen alone. The MCF-7 cells had similar high sensitivity to both clomiphene and tamoxifen. When effects of clomiphene and tamoxifen on the protein kinase C (PKC) activity in the cancer cells were examined, the degree of inhibition of the PKC activity in the KF cells by clomiphene and tamoxifen was most marked and that by clomiphene was followed by those by KK, MH, and MCF-7 cells, while that by tamoxifen was, in increasing order, MH, MCF-7, and KK cells. Analyses of effects of clomiphene or tamoxifen on concentrations of CDDP required for 50% inhibition of cell proliferation (IC50) revealed that although the combined effects, in the KF and KK cells were only marginal, marked enhancement of antiproliferative effects of CDDP on the MH cells resistant to CDDP was obtained. When 5 x 10(6) cells were incubated with 100 microM CDDP for 3 hr, uptake of CDDP by MCF-7 cells was lowest, followed by MH, KK, and KF cells. The CDDP uptake by KF and KK cells was increased about 30-40% in the presence of clomiphene or tamoxifen. The CDDP uptake by the MH cells in which most marked enhancement of antiproliferative effect of CDDP was observed by a combination with clomiphene or tamoxifen was increased about 80-90% in the presence of clomiphene or tamoxifen. These results suggest that not only tamoxifen but also clomiphene can potentiate antiproliferative effect of CDDP in the ER-negative CDDP-resistant cancer cells by enhancing the CDDP uptake.
Inhibitory effects by oral administration of ginsenoside Rh2 on the growth of human ovarian cancer cells in nude mice.
Recently two new compounds, ginsenosides Rh1 and Rh2, have been isolated from an ethanol extract of the processed root of Panax ginseng CA Meyer, and Rh2 (but not Rh1) has been found to cause growth inhibition of cultured B16 melanoma cells. We have also demonstrated that Rh2 caused inhibition of cultured human ovarian cancer cell (HRA) proliferation. The effect of oral administration of Rh2 on tumor growth and survival of nude mice bearing HRA cells was examined. Nude mice were inoculated subcutaneously in the right flank with 10(6) HRA cells. After 7 days of tumor inoculation 2 mg/kg cis-diamminedichloroplatinum(II) (cisplatin) was administered intraperitoneally once a week for 5 weeks. In Rh2-treated groups. Rh2 was dissolved in absolute ethanol, adjusted with distilled water to 1, 15, and 120 microM, and 0.4 ml of each concentration was administered orally by canula every day for 90 days, from the next day of tumor inoculation. The tumor volume, hematocrit and body weight were measured every week. On days 56 and 63 after tumor inoculation, the tumor volumes in all groups treated with Rh2 were significantly less than those in an ethanol-treated control group and also in cisplatin treated group. After 70 days, the tumor growth in nude mice treated with 15 microM and 120 microM Rh2 was significantly inhibited compared to that in a cisplatin treated group as well as a control group. Consequently, the survival of nude mice treated with 15 microM and 120 microM Rh2 was also significantly prolonged, compared to that of cisplatin treated mice. No toxic effects were observed in any of the mice.