Search PubMed⌕ Search

Biomedical subjects

K Tamura

Publications and source records attributed to K Tamura.

At least 595 records · Page 33Linked to original sources
PubMed1995

Transcriptional inhibition of insulin by FK506 and possible involvement of FK506 binding protein-12 in pancreatic beta-cell.

FK506 (tacrolimus) is a strong immunosuppressant: it has been approved as a drug for liver transplantation in Japan, the United States, and the United Kingdom. One of its main adverse effects is hyperglycemia. Thus, in this study, we investigated the mechanism and the reversibility of the hyperglycemia caused by FK506. FK506 did not affect the glucose uptake by insulin into rat strio-muscle cell line, but suppressed insulin production in rat insulinoma cells. Two-week oral administration of FK506 at 10 mg/kg/day suppressed insulin production time-dependently at the transcriptional step in pancreatic beta-cells, while glucagon content in pancreatic alpha-cells was not affected. When FK506 administration was stopped in these rats, insulin mRNA transcription and insulin production returned to normal. This recovery indicates that the adverse effect of FK506 on the pancreas is reversible. A high content of FK506 binding protein-12 (FKBP-12) in the pancreatic beta-cells was confirmed by immunostaining with anti-human FKBP-12 mAb, but the content was less in the pancreatic alpha-cells and almost negligible in the acinar cells. In contrast, a high content of calcineurin in the pancreatic alpha-cells was confirmed by using anti-calcineurin polyclonal antibody, but this content was less in the pancreatic beta-cells and not found in the acinar cells. Thus, as in the case with NF-AT in T cells, these findings point to the reduction of unidentified nuclear factors for insulin mRNA transcription caused by the binding of FK506 to FKBP-12 and a subsequent inhibition of calcineurin in the beta-cells.

Animals↗
PubMed1995

Molecular variant of angiotensinogen gene is associated with coronary atherosclerosis.

BACKGROUND: A positive association was previously reported between angiotensin-converting enzyme (ACE) gene polymorphism and several cardiovascular diseases, such as myocardial infarction, left ventricular hypertrophy, and restenosis after percutaneous transluminal coronary angioplasty. Plasma ACE activity and carotid-wall thickening measured by ultrasonography were related, and it was postulated that long-term exposure to high levels of plasma ACE could be involved in structural changes of the arterial wall. In addition, angiotensinogen gene mutation was recently reported to be associated with essential hypertension and preeclampsia. There exists a possibility that the renin-angiotensin system plays an important role in the progress of cardiovascular diseases in humans. Therefore, we examined the association between the molecular variant of the angiotensin gene and coronary atherosclerosis. METHODS AND RESULTS: This study included 82 patients who had coronary atherosclerosis and 160 control subjects; all study participants were Japanese. All patients with coronary atherosclerosis had at least one coronary artery with > 25% luminal diameter obstruction on average according to multiple coronary angiographic views. Angiotensinogen gene molecular variants were designated AA, Aa, and aa. The a allele indicated thymine-cytosine transition at nucleotide 704 in exon 2. Genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction was performed to amplify the concerned region of the angiotensinogen gene. After restriction enzyme digestion, it was possible to distinguish the molecular variant of the angiotensinogen gene. The frequencies of these genotypes were 7.3%, 26.8%, and 65.9% in the patients and 18.8%, 31.9%, and 49.3% in the control subjects for the AA, Aa, and aa alleles, respectively. There was an excess in the a allele among patients (P < .01). CONCLUSIONS: We found a significant association between coronary atherosclerosis and a molecular variant of the angiotensin gene. The results suggested that the molecular variant of the angiotensinogen gene could be a new risk factor for coronary atherosclerosis.

Angiotensinogen↗
PubMed1995

MRC-5 cells induce the AER prior to the duplicated pattern formation in chick limb bud.

We have previously shown that MRC-5 cells induce the duplication of the chick limb bud following the implantation into the anterior limb bud only during pre-limb-bud stages. We now report the process of duplicated pattern formation caused by MRC-5 cells. The duplicated patterns are also formed following the implantation into the center of the limb bud and an excess apical ectodermal ridge (AER) with Msx2 expression is induced prior to these duplicated pattern formulations. Only after the implantation into the anterior leg bud, the shh gene is expressed additionally in the anterior leg bud and the mirror-symmetric duplication along the anteroposterior (A-P) axis is formed. The map of the polarizing activity in stage 21 embryo suggests that the high polarizing activity of the normal flank region is responsible for the changes in the A-P polarity when MRC-5 cells are grafted into the anterior leg bud. These results indicate that MRC-5 cells induce the AER and that the excess AER produces the duplicated cartilage pattern of the limb bud.

Animals↗
PubMed1995

Histocytochemical and immunohistochemical studies related to the role of glycogen in human developing digestive organs.

To elucidate the role of glycogen in the epithelium of developing digestive organs, we investigated the appearance of glycogen and glycogen phosphorylase (GP) in these organs. We studied 64 externally normal human embryos at Carnegie stages 13-23 (5.1-28.0 mm in crown-rump length, 4-8 weeks of gestation) by histocytochemical staining for glycogen and immunohistochemical staining with antibodies against two isoenzymes of GP: brain-type (BGP) and muscle-brain-type (MBGP) GP. At stage 13, glycogen appeared in the epithelium of the digestive tract and the parenchyma of the pancreas. As development advanced, glycogen granules increased in number and size in these tissues, and they became evenly distributed in the epithelium of the digestive tract as either single particles or aggregates, as deduced by electron microscopy at late embryonic stages. Immunoreactivity specific both for BGP and for MBGP was detected in the digestive tract and the pancreas from stage 13. As development advanced, both BGP- and MBGP-immunoreactive cells increased in number and in immunoreactivity, and the number of MBGP-immunoreactive cells became larger than that of BGP-immunoreactive cells. By contrast, in hepatic cells, which serve as a major storage site for glycogen in adults, glycogen was detected only from stage 20, in smaller amounts, without formation of aggregates, and no immunoreactivity specific for BGP or MBGP was apparent throughout the embryonic stages examined. Thus, in the epithelium of the digestive tract and the parenchyma of the pancreas, but not in hepatic cells, the appearance and localization of GP coincided almost exactly with that of glycogen. These observations suggest that glycogen in the epithelium of the digestive tract and the parenchyma of the pancreas has not only been synthesized but also degraded from an early embryonic period and may, thus, be related to active cellular metabolism that is specific for embryonic development, including proliferation of the epithelium and interactions between epithelium and mesenchyme.

Digestive System↗
PubMed1995

Origins of nerve fibers containing nitric oxide synthase in the rat celiac-superior mesenteric ganglion.

The origin of nitric oxide synthase-containing nerve fibers in rat celiac-superior mesenteric ganglion was examined using retrograde tracing techniques combined with the immunofluorescence method. Fluoro-Gold was injected into the celiac-superior mesenteric ganglion. Neuronal cell bodies retrogradely labeled with Fluoro-Gold in the thoracic spinal cord, the dorsal root ganglia at the thoracic level, the nodose ganglion, and the intestine from the duodenum to the proximal colon were examined for nitric oxide synthase immunoreactivity. About 60% of sympathetic preganglionic neurons in the intermediolateral nucleus projecting to the celiac-superior mesenteric ganglion were immunoreactive for nitric oxide synthase, as were approximately 27% of nodose ganglion neurons and about 65% of dorsal root ganglion neurons projecting to the celiac-superior mesenteric ganglion. Neurons projecting to the celiac-superior mesenteric ganglion were found in the myenteric plexus of the small and large intestine. In the proximal colon, about 23% of such neurons were immunoreactive for nitric oxide synthase. However, in the small intestine, no immunoreactivity was found in these neurons.

Amino Acid Oxidoreductases↗
PubMed1995

Phase I study of NKT-01.

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.

Adult↗
PubMed1995

Abnormalities in elastic fibers and other connective-tissue components of floppy mitral valve.

Histologic, immunohistochemical, and ultrastructural studies were performed on 12 floppy mitral valves, 4 mitral valves showing focal myxomatous changes without prolapse, and 3 normal mitral valves. All floppy mitral valves were thickened by deposits of proteoglycans and also showed diverse structural abnormalities in collagen and elastic fibers. From these observations we conclude that (1) the structure of all major components of connective tissue in floppy mitral valves is abnormal; (2) alterations in collagen and accumulations of proteoglycans are nonspecific changes that may be caused by the abnormal mechanical forces to which floppy mitral valves are subjected because of their excessively large surface area; (3) the presence of excessive amounts of proteoglycans may interfere with the normal assembly of collagen and elastic fibers; (4) abnormalities of elastic fibers resemble those in other conditions characterized by structural dilatation or tissue expansion; and (5) alterations in elastin could result from defective formation, increased degradation, or both.

Actin Cytoskeleton↗
PubMed1995

Hirschsprung's disease associated with Ondine's curse: a special subgroup?

The authors report a case of the rare occurrence of congenital central hypoventilation syndrome (Ondine's curse) and long segmental colonic aganglionosis (Hirschsprung's disease). A review of 24 reported cases showed that the proportion of females having this concurrence is higher than for ordinary Hirschsprung's disease. It also appears that the aganglionic segment is much longer in these cases than in ordinary Hirschsprung's disease.

Female↗
PubMed1995

Beta-cell function and replication in spontaneously hypertensive rats.

We examined beta-cell function and replication in spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). Rats were subjected to 90% pancreatectomy (Px) or sham operation at the age of 8 weeks, and islet function and regeneration were examined 4 weeks after surgery. Plasma glucose levels were higher in SHR than in WKY (509 +/- 38 v 325 +/- 109 mg/dL, P < .0001) 1 week after Px and throughout the experimental period. Plasma glucose responses to intravenous injection of glucose (0.5 g/kg body weight) were not different in the sham-operated animals of the two strains, whereas plasma insulin responses were greater in SHR than in WKY. No insulin responses to glucose were observed in either strain of Px rats. The insulin content of the remnant equivalent (6.7 +/- 2.1 v 4.2 +/- 0.4 micrograms, P < .05) and whole pancreas (156.7 +/- 10.7 v 123.8 +/- 23.5 micrograms, P < .01) in sham-operated rats was greater in SHR than in WKY. However, insulin content was lower (P < .05) in Px-SHR (1.0 +/- 0.2 microgram) than in Px-WKY (3.9 +/- 1.7 micrograms). Histological examination showed that fibrotic degeneration of islets was much greater in Px-SHR than in Px-WKY. These data strongly suggest that the beta cells of SHR were more vulnerable to reduction of islet mass than those of WKY. Our data also suggest that hyperinsulinemia and/or insulin resistance in SHR has a deleterious effect on beta-cell replication.

Animals↗
PubMed1995

Angiographic extravasation of contrast medium in acute "spontaneous" subdural hematoma.

Acute spontaneous subdural hematoma is very rare. We have encountered four such cases and verified the arterial origin of the bleeding at operation. None of the patients had a history of head trauma, and each had developed sudden onset of headache and other neurologic deficits, which simulate other cerebrovascular diseases. CT directly revealed subdural hematoma but gave no indication as to the source of the bleeding. Cerebral angiography was performed in all cases, with three of them showing localized extravasation of the contrast material into the subdural space. The extravasation was noted usually in the late arterial phase. This is a useful finding for diagnosing this disease and localizing the bleeding point. It is expected that with more routine use of cerebral angiography in cases of acute spontaneous subdural hematoma, extravasation of the contrast medium will be seen more frequently.

Acute Disease↗
PubMed1995

Effect of chronic vanadate administration in partially depancreatized rats.

The effects of vanadate on B-cell function and replication in rats after 90% partial pancreatectomy (Px) were compared with insulin therapy. At the age of 4 weeks, male Wistar rats were subjected to sham operation or Px. Vanadate (0.2 mg/ml) was given in drinking water for 3 weeks starting at 2 weeks after surgery. Regular insulin (2.4 units/day) was administered as a continuous subcutaneous infusion through an osmotic pump. Plasma glucose levels were significantly higher in the Px rats than in the sham rats from 1 week after surgery. Vanadate lowered plasma glucose levels to near normal values in the Px rats as early as 2 days. The effect was sustained throughout the experiment. The hypoglycemic effect of insulin was less than that of vanadate. During an i.p. glucose tolerance test, plasma glucose levels were decreased in the Px rats treated with vanadate or insulin, while plasma insulin levels were not affected. The insulin content in the Px rats treated with vanadate was significantly (P < 0.01) greater than in the insulin-treated Px rats. Histological examination showed fibrotic degeneration in the enlarged islets of Px rats, whereas the normal structure was retained in most islets of the Px rats treated with vanadate and insulin. In addition, B-cell areas within the islet were restored to normal levels not only in the insulin-treated Px rats but in the vanadate-treated Px rats. However, both vanadate and insulin failed to stimulate proliferative activity of the B-cells. These data suggest that vanadate is a new therapeutic option to ameliorate the diabetic state after Px.

Analysis of Variance↗
PubMed1995

Lack of effect of CS-045, a new antidiabetic agent, on insulin secretion in the remnant pancreas after 90% pancreatectomy in rats.

We assessed the effect of CS-045, a new hypoglycemic agent, on B-cell function in partially pancreatectomized rats. At the age of 4 weeks, male Wistar rats were subjected to 90% pancreatectomy (Px). For 2 weeks starting at 6 weeks after surgery the Px rats were treated with CS-045 (CS rats) mixed with chow pellets in a proportion of 0.2% (w/w). To compare the efficacy of CS-045 with that of insulin therapy, an osmotic pump was implanted to release insulin (1.2 units/day) into the intraperitoneal cavity of the Px rats (Is rats). Plasma glucose levels in the CS and Is rats were significantly lower than in the control Px rats; however, no marked improvement in plasma glucose or insulin levels was observed in glucose tolerance test (2 g/kg, i.p.) in the CS rats. Insulin secretion by the isolated perfused pancreas in response to 16.7 mM glucose showed a biphasic pattern, but was slightly reduced in the Px and CS rats compared with the Is rats. Insulin secretion induced by 19 mM arginine was unaffected by the treatment. The insulin content of the CS rats was significantly greater than in the Px and Is rats. Histological observations suggested regranulation of the pancreatic islets of the CS rats. B-cell areas within the islet were restored to normal levels in the Cs and Is rats. These findings indicate that the hypoglycemic effect of CS-045, which is not mediated by insulin secretion from the residual pancreas, prevents destruction of the islet.

Animals↗
PubMed1995

Angiotensin I converting enzyme (ACE) gene polymorphism and essential hypertension in Japan. Ethnic difference of ACE genotype.

A polymorphism of the angiotensin I converting enzyme (ACE) gene has recently been reported and analysis of this polymorphism has indicated that it is associated with several cardiovascular diseases. However, the results are still controversial and such association has not yet been established conclusively. To determine whether the ACE gene may be responsible for essential hypertension in a Japanese population, we also compared the distribution of genotypes and the allele frequency of this polymorphism in our findings of a Japanese population with these features in other countries. Eighty-seven hypertensive patients with a family history of essential hypertension and 95 normotensive patients whose parents had no such history were enrolled in the study. Polymorphism of the ACE gene was determined by using the polymerase chain reaction. Homozygotes for this polymorphism had either a 490-bp band (II) or a 190-bp band (DD) and heterozygotes had both bands (ID). In hypertensive subjects, the numbers and frequency of the ACE genotypes were: II, 44 (0.51); ID, 26 (0.30); DD, 17 (0.19). In normotensive subjects these were: II, 35 (0.37); ID, 43 (0.45); DD, 17 (0.18). There were no significant differences between the two groups in derived allele frequencies (chi 2 = 1.41). The difference between the overall allelic frequency in Japan and that reported in several other countries was significant. We did not find any association between ACE gene polymorphism and essential hypertension in Japan. However, there were significant differences in derived allele frequencies between our findings in a Japanese population and those reported from Europe and Australia.

Alleles↗
PubMed1995

A comparison of failure modes of glutaraldehyde-treated versus antibiotic-preserved mitral valve allografts implanted in sheep.

Morphologic studies and calcium analyses were made on mitral valve allografts from 12 juvenile sheep surviving 12 to 24 weeks after mitral valve replacement. Before implantation, the allografts were treated with 0.625% glutaraldehyde (group I, n = 4) or with cold antibiotic solution (group II, n = 8). Three group I animals died 12 to 19 weeks after implantation because of dysfunction of calcified valves; the surviving animal also had extensive allograft calcification. One group II animal died of mitral regurgitation; the valves of the other seven (including five with regurgitation shown by Doppler and ventriculographic studies) were explanted at 19 to 24 weeks. Chordal rupture related to calcific deposits was found in all group I valves. Leaflet perforations (n = 4) and ruptured chordae (n = 4), each caused by connective tissue deterioration, were found in group II valves. Inflammatory reaction was absent or minimal in group I valves but moderate or severe in group II valves. Fibrous sheaths were thicker in group II than in group I valves. Calcium levels were much higher in group I than in group II valves. Calcification in group I valves was diffuse and involved collagen, elastic fibers, and connective tissue cells and matrix; in group II valves, it was localized in connective tissue cells. Thus glutaraldehyde-treated allografts failed because of extensive calcification, whereas antibiotic-preserved allografts underwent deterioration of connective tissue and infiltration by inflammatory cells.

Animals↗
PubMed1995

Effect of dietary protein concentration on responses to Escherichia coli endotoxin in broiler chickens.

The effect of dietary protein concentration on stress responses against injection of Escherichia coli lipopolysaccharide (LPS) was studied in male broiler chickens. Chickens (7 d of age) were fed on a 100 (low-protein; LP) or 300 g protein/kg (high-protein; HP) diet for 2 weeks. LPS was injected intraperitoneally every 2 d during the final 6 d, or once 16 h before the end of the experiment, at a concentration of 900 micrograms/chick. The LPS injection did not affect body-weight gain, feed intake, gain:intake ratio, or plasma Fe concentration. The single injection of LPS reduced plasma Zn concentration, but the repeated injections did not. Feeding the HP diet increased the response of plasma Zn concentration to the single injection of LPS. Plasma albumin concentration was reduced by LPS injection. Feeding the HP diet resulted in a higher plasma alpha 1-acid glycoprotein (AGP) concentration than feeding the LP diet, in chicks untreated with LPS. An increase in plasma AGP concentration observed after LPS injection in chicks fed on the LP diet was greater than that seen in chicks fed on the HP diet. No significant changes in plasma AGP concentration in response to repeated injections of LPS were observed in chicks fed on the HP diet. Plasma interleukin-1 (IL-1)-like activity was greater in chicks fed on the LP diet than in those fed on the HP diet, when LPS was injected. The response of plasma IL-1-like activity to the single injection of LPS in chicks fed on the LP diet was the greatest among the treatment groups. These results suggest that acute-phase responses to LPS injection are much greater in chicks fed on a LP diet than in those fed on a HP diet, and multiple injection of LPS weakens the responses.

Acute-Phase Reaction↗
PubMed1995

Inhibitory effects of sulfation inhibitors on initiation of pancreatic ductal carcinogenesis by N-nitrosobis(2-oxopropyl)amine in hamsters.

The effects of dehydroepiandrosterone sulfate (DHAS), a typical hydroxysteroid sulfotransferase (HSTase) inhibitor, and of 3'-phosphoadenosine 5'-phosphate (PAP), a nonspecific sulfation inhibitor on N-nitrosobis(2-oxopropyl)-amine (BOP)-induced initiation were examined in a rapid production model for pancreatic carcinomas in hamsters in order to elucidate the involvement of sulfotransferase in the metabolic activation of beta-oxypropylnitrosamines. While neither low nor high doses of DHAS and PAP exerted any significant influence on the incidence of ductal lesions including carcinomas, the high dose of DHAS (350 mg/kg body wt) and a both low (90 mg/kg) and high (180 mg/kg) doses of PAP reduced the mean numbers of pancreatic ductal adenocarcinomas. The high dose of PAP also reduced the number of all ductal lesions combined. The results thus suggest that metabolic activation with STase is involved in BOP-induced pancreatic ductal carcinogenesis in hamsters, and support the hypothesis that BOP is metabolized to beta-hydroxyalkylnitrosamines followed by activation to proximate sulfuric acid esters by HSTase.

Animals↗
PubMed1995

Mechanism for ammonia-induced promotion of gastric carcinogenesis in rats.

Although an association is suggested between gastric cancer and prior infection with Helicobacter pylori (HP), the role of HP in gastric carcinogenesis remains obscure. HP has potent urease activity and produces ammonia, a factor causing HP-related gastroduodenal mucosal lesions. In this study, rats were examined in an effort to determine effects of ammonia on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). After pretreatment with MNNG (83 mg/l) for 24 weeks, a solution of either 0.01% ammonia or plain tap water was administered to the animals as drinking water for an additional 24 weeks. The administration of the 0.01% ammonia solution significantly increased the incidence and number of cancers in the glandular stomach. The numbers of cases in which these cancers penetrated the muscle layer or deeper and of low-grade differentiated adenocarcinomas were significantly higher in rats receiving the ammonia solution. Continuing administration of ammonia accelerated cell proliferation in the gastric mucosa, but had no effect on the serum gastrin level. Therefore, gastric ammonia, which stimulates mucosal cell proliferation, appears to be an important promoter in carcinogenesis in rats and possibly in the HP-related gastric carcinogenesis in humans.

Ammonia↗