Esophageal stenosis and Graves disease in brittle type 1 diabetes mellitus.
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Blood Glucose↗
Biomedical subjects
K Yoshioka
Publications and source records attributed to K Yoshioka.
Establishment and characterization of a murine osteosarcoma cell line (LM8) with high metastatic potential to the lung.
We established a murine osteosarcoma cell line (LM8) with high metastatic potential to the lung from murine Dunn osteosarcoma using 8 repeated Fidler's procedures. We performed the biological characterization of the LM8 and the maternal Dunn cell lines in vitro and in vivo. Morphologically, LM8 possesses many fillopodial protrusions, lamellipodial structures surrounding the cell surface and membrane ruffles suggesting enhanced cell motility. The increased matrix metalloproteinase (MMP) 2 activity of this cell line might help cell invasion after penetration of the endothelial (mesothelial) cell layer. This cell line exhibited high in vitro invasive activity when seeded onto the mesothelial cell monolayer. Higher expression of VEGF mRNA in this cell line might facilitate neovascularization at the site of metastasis, resulting in extremely high metastatic potency after i.v. injection. LM8 also showed a high metastatic incidence (7/7) to the lung even after s.c. transplantation into the back space of mice. This cell line can provide an excellent tool for studying inhibitory agents against pulmonary metastasis as well as the various important factors involved in metastasis of osteosarcoma.
Alkaline Phosphatase↗
Small GTP-binding protein Rho stimulates the actomyosin system, leading to invasion of tumor cells.
We have shown previously that Rho plays a pivotal role in 1-oleoyl-lysophosphatidic acid (LPA)-dependent invasion of rat hepatoma cells (MM1). Herein we made stable transfectants of MM1 expressing active and Botulinum exoenzyme C3 (C3)-sensitive (Val14), or active and C3-insensitive (Val14/Ile41) forms of human RhoA. Both transfectants showed greatly promoted invasive ability in vitro in the absence of LPA as well as in vivo, adherence to the dish with scattered shape, and enhanced phosphorylation level of 20-kDa myosin light chain (MLC20). A specific MLC kinase inhibitor (KT5926) could inhibit their invasion and the phosphorylation level of MLC20. Stable active RhoA transfectants of W1 cells (low invasive counterpart of MM1) also demonstrated promoted invasive ability in vitro and in vivo, and enhanced phosphorylation level of MLC20. C3 treatment inhibited the invasiveness of the Val14 RhoA transfectant but not that of the Val14/Ile41 RhoA transfectant. LPA enhanced the invasiveness of both transfectants, and this enhancement was abolished by the C3 treatment. These results suggested that 1) the Rho signaling pathway and actomyosin system were linked in the transmigration of tumor cells, and 2) expressed active RhoA enhanced LPA-induced tumor cell invasion via the activation of endogenous RhoA pathway, indicating a positive feedback mechanism in the activation of RhoA.
ADP Ribose Transferases↗
Pharmacological profiles of new orally active nonpeptide tachykinin NK1 receptor antagonists.
Pharmacological profiles of new orally active amide-based tachykinin NK1 receptor antagonists, N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-fluorophenyl)-7,8-dihydro-N,7-di methyl-8-oxo-1,7-naphthyridine-6-carboxamide (referred to as compound I) and two related compounds (compounds II and III), were compared with that of (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), another nonpeptide tachykinin NK1 receptor antagonist. Compounds I, II, III and CP-99,994 caused parallel rightward shifts of the concentration-response curve of substance P in the guinea-pig ileum pretreated with atropine, mepyramine and indomethacin, with the pA2 values of 8.70, 7.56, 8.41 and 8.27, respectively. These antagonists did not alter the concentration-response curve of acetylcholine in the guinea-pig ileum nor that of neurokinin A in the rat vas deferens. Furthermore, contractile responses to senktide of the rat portal vein were not affected by these antagonists. In the isolated neonatal gerbil spinal cord pretreated with tetrodotoxin, substance P produced a dose-dependent depolarization of ventral roots. Compounds I, II, III and CP-99,994 caused parallel rightward shifts of the concentration-response curve of substance P in the spinal cord with the pA2 values of 7.07, 5.93, 6.40 and 7.26, respectively. In contrast, these antagonists did not affect the concentration-response curve of L-glutamate. These results suggest that compounds I, II and III are selective antagonists for tachykinin NK1 receptor both in peripheral tissues and the central nervous system.
Administration, Oral↗
Bone marrow mast cell disease associated with Felty's syndrome and liver cirrhosis.
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Bone Marrow Cells↗
Muscle fiber immaturity and inactivity reduce myonecrosis in Duchenne muscular dystrophy.
We report on the first case of X-linked recessive myotubular myopathy (MTM1) coinciding with Duchenne muscular dystrophy (DMD). The muscle biopsy specimens of the patient show only the characteristic findings of MTM1, without the findings of DMD. We theorize that this was caused by the muscle fiber immaturity and inactivity.
Child, Preschool↗
Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Osaka Liver Disease Study Group.
To elucidate the risk factors for liver carcinogenesis and to examine the incidence of hepatocellular carcinoma (HCC) after interferon therapy, 1,022 chronic hepatitis C patients treated with interferon were followed by ultrasonography for 13 to 97 months (median 36 months). Sustained response with prolonged alanine aminotransferase normalization was found in 313 patients, transient response with alanine aminotransferase relapse after therapy in 304, and no response in 405. Forty-six developed HCC, of whom 5 were sustained responders, 9 were transient responders, and 32 were nonresponders. The cumulative incidence of HCC in transient responders was almost equal to that in sustained responders, and it was significantly higher in nonresponders than in sustained and transient responders (P=.0009). The seventh-year cumulative incidence rates of HCC in sustained responders, transient responders, and nonresponders were estimated to be 4.3%, 4.7%, and 26.1%, respectively. However, there was no significant difference in the cumulative incidence of HCC between patients with HCV subtype 1 and 2 (P=.14). Cox regression analysis showed that the risk of HCC development was not elevated in transient responders compared with sustained responders, but that the risk was 7.90-fold higher in nonresponders than in sustained responders (P=.008). Patients > or =55 years of age had a significantly higher risk ratio (4.65) than did those under 55 years of age (P=.006). The risk of HCC development in men was 4.35 times higher than the risk in women (P=.02). However, the degree of fibrosis was not a significant risk factor for the development of HCC (risk ratio, 3.16; P=.052). These results suggest that patients in the high-risk group of HCC after interferon therapy were those who showed no response, those who were older, and those who were male, and that such patients should be carefully followed using ultrasonography.
Adult↗
Broadly reactive antibodies to hypervariable region 1 in hepatitis C virus-infected patient sera: relation to viral loads and response to interferon.
To clarify the nature of serum anti-hypervariable region 1 (HVR1) antibodies in patients infected with hepatitis C virus (HCV), we assessed the reactivity of 21 patients' sera with 42 HVR1 proteins by Western blot. HVR1 was expressed as fusion proteins with glutathione S-transferase (GST). The patients' sera reacted with variable percentages of the HVR1 proteins, and always reacted with HVR1 proteins of the different genotype. In the genotype-1b-infected patients, the percentage of genotype-1b HVR1 proteins reactive with serum correlated significantly with viral loads; the sera reactive with the higher percentages of HVR1 proteins contained the larger viral loads. In addition, it was significantly lower in the responders of interferon (IFN) therapy than in nonresponders. The competition assays indicated that multiple fractions of anti-HVR1 antibodies with different specificity in a serum reacted with different HVR1 proteins, and that, additionally, a single fraction of antibodies often reacted with more than one HVR1 protein through a similar amino acid sequence. In conclusion, serum anti-HVR1 antibodies were broadly reactive by the mechanism of both the cross-reactivity of a single fraction of anti-HVR1 antibodies with more than one HVR1 protein and the presence of multiple fractions of anti-HVR1 antibodies with different specificity in a serum. In genotype-1b-infected patients, the broad reactivity of serum anti-HVR1 antibodies correlated with viral loads and response to IFN. Further studies are necessary to elucidate the correlation among the broad reactivity of sera with multiple HVR1 proteins and clinical features of chronic hepatitis C patients.
Adult↗
Trp64Arg mutation of beta3-adrenoceptor gene is associated with diabetic nephropathy in Type II diabetes mellitus.
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Aged↗
Activation of protein kinase C in human hepatocellular carcinoma (HEP3B) cells increases erythropoietin production.
Some investigators have reported previously that phorbol esters inhibit in vitro erythropoietin production stimulated by hypoxia; whereas others have reported that phorbol esters enhanced Epo production during exposure to hypoxia. We have demonstrated in the present experiments that hypoxia significantly increased diacylglycerol levels in cultured human hepatocellular carcinoma (Hep3B) cells. 1-oleoyl-2-acetyl-ras-glycerol (OAG) and N-(6-phenylhexyl)-5-chloro-1-naphthalenesulfonamide (SC-9), two well-known protein kinase C activators, significantly increased medium levels of erythropoietin as well as erythropoietin messenger RNA levels in normoxic Hep3B cells. A potent protein kinase C inhibitor, chelerythrine chloride, significantly decreased hypoxia-induced increases in medium levels of erythropoietin as well as erythropoietin messenger RNA levels in Hep3B cells. A cis-unsaturated free fatty acid, oleic acid, significantly enhanced OAG-induced medium levels of erythropoietin in normoxic Hep3B cells, whereas a phospholipase A2 inhibitor, mepacrine, significantly decreased hypoxia-induced erythropoietin production in Hep3B cells. These results provide strong support for a positive role for protein kinase C in the hypoxic regulation of erythropoietin production.
Alkaloids↗
Effects of a tachykinin NK3 receptor antagonist, SR 142801, studied in isolated neonatal rat spinal cord.
Effects of a nonpeptide tachykinin NK3 receptor antagonist, SR 142801, were studied in the isolated spinal cord preparation of the neonatal rat. Potential changes were recorded extracellularly from a lumbar ventral root. Bath-application of neurokinin B induced a dose-dependent depolarization of the ventral root. SR 142801 caused rightward shifts of the concentration-response curve for neurokinin B with pA2 of 6.57, but did not affect the depolarizing responses to other agonists. Stimulation of a dorsal root evoked in the ipsilateral ventral root of the same segment monosynaptic and polysynaptic reflexes of fast time course which were followed by a slow depolarization (ipsilateral slow ventral root potential). SR 142801 depressed the ipsilateral slow ventral root potential. The present results indicate that SR 142801 is a specific antagonist for tachykinin NK3 receptors in the spinal cord and suggest that NK3 receptors are involved in primary afferent-evoked nociceptive responses of spinal neurones.
Animals↗
Post-transplant diabetes with anti-glutamic acid decarboxylase antibody during tacrolimus therapy.
A 54-year-old man undergoing hemodialysis because of end-stage renal failure was transplanted with a cadaver kidney in November 1997. He had no history of diabetes. Tacrolimus was used as the primary immunosuppressant. Three weeks after transplantation, he developed insulin-requiring diabetes mellitus. Anti-glutamic acid decarboxylase antibody was not detected on the third post-operative day, but appeared 4 weeks after transplantation. The recipient had DNA haplotypes that indicated susceptibility to Type 1 diabetes in Japanese subjects. Immunosuppressive therapy was changed from tacrolimus to cyclosporin. Thereafter, titer of anti-glutamic acid decarboxylase antibody disappeared and the patient's insulin requirement was notably reduced. The mechanism underlying the development of diabetes in this case appears to be, in part, direct beta-cell toxicity due to tacrolimus therapy, resulting in secondary beta-cell autoimmunity. This case suggests that tacrolimus therapy after transplantation should be used with caution in patients with genetic susceptibility to Type 1 diabetes.
Antibodies↗
Troglitazone ameliorates insulin resistance in a diabetic patient with Prader-Willi syndrome.
We report a patient with Prader-Willi syndrome (PWS) complicated by diabetes mellitus. PWS is a genetic disorder characterized by obesity, mental retardation and hypogonadism. Glucose intolerance in this syndrome is thought to be secondary to insulin resistance associated with morbid obesity. Therapy was directed primarily at decreasing insulin resistance and thereby improving glucose intolerance by the administration of troglitazone, which increases insulin sensitivity. Changes in glucose disposal rate assessed by euglycemic hyperinsulinemic clamp test were measured, as well as glucose and insulin responses to a 75 g-OGTT before and after troglitazone therapy. Glucose disposal rate increased by 36% and plasma glucose responses to 75 g-OGTT decreased by about 50% during 12 weeks of troglitazone therapy despite slight weight gain. Thus, troglitazone has beneficial effects on glycemic control by improving insulin sensitivity in patients with PWS complicated by diabetes mellitus.
Adolescent↗
Different constitution of hepatitis C virus population in peripheral blood mononuclear cells and plasma in patients with type C chronic liver disease.
We searched for the presence of the plus or minus strand of hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMCs) from three patients with chronic HCV infection using the strand-specific reverse transcription and polymerase chain reaction (RT-PCR) method. To examine whether the HCV population of PBMCs differs from that of plasma, a sequence of the hypervariable region (HVR) in the E2/NS1 region was analyzed. All three patients had both plus and minus strands of HCV RNA in their PBMCs. Sequence study revealed that the HCV population in PBMCs was homogeneous in all patients, while that in plasma was composed of two main clones. One of these had the same sequence as the clones seen in PBMCs, except for one patient. Our results suggest that PBMCs represent one of the extrahepatic replication sites of HCV and that tissue tropism is expressed by some of the HCV population.
Amino Acid Sequence↗
Differential effects of wortmannin on the release of substance P and amino acids from the isolated spinal cord of the neonatal rat.
1. Effects of wortmannin, an inhibitor of myosin light chain kinase, on the release of substance P and amino acids, GABA and glutamate, were investigated in the isolated spinal cord preparation of the neonatal rat. 2. Wortmannin at 0.5 - 10 microM depressed the release of substance P evoked by high-K+ (90 mM) medium from the spinal cord (IC50 = 1.1 microM). Wortmannin also depressed the high-K+ (70 mM)-evoked release of substance P from cultured dorsal root ganglion neurons of neonatal rats. In contrast, the high-K+ (90 mM)-evoked release of GABA and glutamate from the spinal cord was not affected by wortmannin (0.1 - 10 microM). 3. Upon stimulation of a dorsal root, a monosynaptic reflex and a subsequent slow ventral root depolarization were evoked in the ipsilateral ventral root of the same segment in the isolated spinal cord preparation. The magnitude of the slow ventral root depolarization was depressed gradually to about 70% of the control during the course of 30 min under wortmannin (1 microM). In contrast, the monosynaptic reflex was unaffected by wortmannin. 4. Immunofluorescent staining revealed that immunoreactivities of substance P and myosin II were colocalized at presynaptic terminals in the dorsal horn of the neonatal rat spinal cord. 5. The present results suggest that myosin phosphorylation by myosin light chain kinase may play a crucial role in the release of substance P, but not in the release of GABA and glutamate in the neonatal rat spinal cord. This may reflect a difference in the exocytic mechanisms of substance P-containing large dense core vesicles and amino acid-containing small clear vesicles.
Amino Acids↗
Pouch perineal rectosigmoidectomy gives better functional results than conventional rectosigmoidectomy in elderly patients with rectal prolapse.
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Aged↗
Follow-up study of children with nephrotic syndrome treated with a long-term moderate dose of cyclosporine.
Because of its potential for chronic nephrotoxicity, the long-term use of cyclosporine A (CsA) as treatment for nephrotic syndrome (NS) is controversial. The clinical outcome of patients with NS treated with CsA is unclear. We retrospectively evaluated 35 children with idiopathic NS, 24 with steroid-dependent NS (SDNS), and 11 with steroid-resistant NS (SRNS), who received CsA therapy for more than 12 months (median, 23 months) at the dosage maintaining 50 to 120 ng/mL in trough level. For SDNS patients, CsA was added to prednisolone after complete remission was achieved. For SRNS patients, CsA was used in combination with alternate-day prednisolone. Initial renal histology showed minimal changes (MC) in 28 patients (including all of the patients with SDNS) and focal segmental glomerulosclerosis (FSGS) in seven patients. The patients were followed up for 2 to 10.5 years (median, 6.5 years) after the termination of the CsA therapy. In SDNS patients, the relapse rate, dosage of prednisolone, standard deviation score for height, and body mass index significantly improved during CsA treatment. The follow-up study showed the proportion of SDNS decreased to 13 of 24 (54%) patients. In SRNS patients, CsA therapy induced remission in 8 of 11 patients (73%) (complete remission in seven and incomplete remission in one). Six of 11 patients (55%) then became steroid sensitive. Post-therapy biopsies, performed in 13 patients (10 with SDNS and three with SRNS), showed mild stripped interstitial fibrosis in two SDNS patients (15%). Long-term CsA therapy in moderate doses was effective to the patients with SDNS and SRNS and low in incidence of nephrotoxicity. The long-term use of CsA appears to result in a decrease in the proportion of SDNS and acquisition of subsequent steroid responsiveness in SRNS.
Adolescent↗
Differential expression of activin subunits, activin receptors and follistatin genes in bovine oocytes and preimplantation embryos.
The presence of inhibin subunits (alpha, betaA and betaB), activin binding protein follistatin and activin receptors (ActR-I, ActR-IB, ActR-II and ActR-IIB) mRNA transcripts in bovine oocytes and preimplantation embryos was examined by reverse transcription-polymerase chain reaction. Immature and matured oocytes, zygotes, 2-cell, 3-4-cell, 5-8-cell, 9-16-cell embryos, morulae, blastocysts and hatched blastocysts were produced by in vitro maturation, fertilization and culture for this study. Activin betaA subunit and follistatin transcripts were detected in all of the stages tested. However, alpha subunit transcripts were detected only in oocytes (immature and matured), blastocysts and hatched blastocysts, and no betaB subunit transcripts were found in any of the stages. Whereas ActR-I transcripts were detectable in all stages, ActR-IB transcripts were not detectable in oocytes or embryos except in matured oocytes. Activin type II receptors (ActR-II and ActR-IIB) transcripts were detectable in oocytes and embryos except for ActR-IIB, which was not found in the 5-8-cell stage embryos. The results suggest that bovine embryos may produce activin A (homodimer of the betaA subunits) at least from zygotes to morulae. Furthermore, bovine oocytes and embryos express the activin receptors mainly by the combination of ActR-I and either ActR-II or ActR-IIB.
Activin Receptors↗