Biomedical subjects

N Takeichi

Publications and source records attributed to N Takeichi.

At least 91 records · Page 5Linked to original sources

PubMed1992

Genetic linkage between copper accumulation and hepatitis/hepatoma development in LEC rats.

The concentration of copper in the livers of Long-Evans rats with cinnamon-like coat color (LEC), in which hepatitis and then hepatomas develop spontaneously, was recently found to be abnormally high. Therefore, we examined the copper concentrations in the livers of LEC F1 backcrosses (LEC F1 x LEC) to determine the linkage of copper accumulation with development of hepatitis. Consistent with a previously reported ratio of rats with hepatitis to rats without hepatitis of about 1:1, hepatitis developed in 14 of 30 F1 backcrosses. The copper concentrations in the livers of all LEC F1 backcrosses with hepatitis were abnormally high and comparable to those of LEC rats. In contrast, the concentrations in all backcrosses without hepatitis were similar to those in normal Long-Evans with agouti coat color or Brown-Norway rats. Copper accumulation was shown to be closely linked with the development of hepatitis in LEC rats and appeared to be a possible cause of hepatitis. The concentrations of copper in the livers of Fischer 344 rats after carbon tetrachloride treatment were in the range for normal liver, indicating that a high copper concentration in the liver is specific to LEC rats and not a specific characteristic of hepatitis. Furthermore, we found that the size and level of ceruloplasmin mRNA in the livers of LEC rats were the same as those in LEA rats and that the size and level of ceruloplasmin polypeptide in their livers and plasma were almost the same as those in LEA rats. Therefore, these results suggest that the copper accumulation is not due to alteration of expression or to gross alteration of the ceruloplasmin gene.

Animals↗

PubMed1992

Decreased numbers of cholecystokinin-immunoreactive nerve cells in the cerebral cortex of LEC rats with a hereditary hepatitis.

The distribution of CCK-immunoreactive cells was investigated by the indirect fluorescence method in the cerebral cortex of LEC (Long-Evans Cinnamon) rats which have recently been introduced as a model of jaundice and hepatic encephalopathy. Reduction of CCK-immunoreactive nerve cells was observed in the brains of LEC rats with stage III to V hepatic encephalopathy in comparison with the rats without hepatic encephalopathy. These observations were confirmed by counting the CCK-positive nerve cells at magnification x 125. 3 microscopic fields per animal were immunostained and CCK-immunoreactive nerve cells counted. The number of CCK-immunoreactive cells per field was 28.5 +/- 0.7 (mean +/- SEM, n = 5) in rats without hepatic encephalopathy, and 14.1 +/- 2.0 (n = 3) in rats with stage III to V hepatic encephalopathy. Thus, the number of CCK-immunoreactive nerve cells was significantly less in rats with stage III to V hepatic encephalopathy (p less than 0.05). A decrease in CCK-immunoreactive nerve cells was not observed in the rats with stage I or II hepatic encephalopathy. This study shows that there is a relationship between the severity of hepatic encephalopathy and the number of CCK-immunoreactive nerve cells in the cerebral cortex.

Animals↗

PubMed1992

Malignant progression of a mouse fibrosarcoma by host cells reactive to a foreign body (gelatin sponge).

The QR regressor tumour (QR-32), a fibrosarcoma which is unable to grow progressively in normal syngeneic C57BL/6 mice, was able to grow progressively in 13 out of 22 mice (59%) when it was subcutaneously coimplanted with gelatin sponge. We established four culture tumour lines from the resultant tumours (QRsP tumour lines). These QRsP tumour lines were able to grow progressively in mice even in the absence of gelatin sponge. The ability of QRsP tumour cells to colonise the lungs after intravenous injection and to produce high amounts of prostaglandin E2 (PGE2) during in vitro cell culture was much greater than that of parent QR-32 cells. These biological characteristics of QR-32 cells and QRsP tumour cells were found to be stable for at least 6 months when they were maintained in culture. We also observed that QR-32 cells were able to grow progressively in five out of 12 (42%) mice after coimplantation with plastic non-adherent peritoneal cells obtained from mice which had been intraperitoneally implanted with gelatin sponge. These host cells reactive to gelatin sponge increased the production of high amounts of PGE2 by QR-32 cells during 48 h coculture. Preliminary in vitro studies implicated the involvement of hydrogen peroxide and hydroxyl radical as some of the factors necessary to induce QR-32 cells to produce high amounts of PGE2 and to accelerate tumour progression.

Animals↗

PubMed1992

Progression of weakly malignant clone cells derived from rat mammary carcinoma by host cells reactive to plastic plates.

Tumor progression is the process by which tumor cells acquire more malignant properties, such as invasiveness and metastasis, during tumor development. To elucidate mechanisms of tumor progression, we examined the role of interactions between the tumor and its host by using a cloned cell line, ER-1, which was derived from a rat mammary carcinoma. ER-1 is weakly tumorigenic and non-metastatic when s.c. injected into syngeneic hosts in single cell suspension. However, ER-1 cells show a high incidence of lethal growth when s.c. implanted (5 x 10(2) cells), being attached to a 10 x 5 x 1 mm polystyrene plate. Tumor cell lines (PLT) obtained from tumors which had arisen from the plate-attached ER-1 cells no longer required plates for their growth in normal hosts, and had acquired metastatic ability to the lungs. The malignant phenotypes of PLT were stable under a usual culture condition for at least 6 months. Furthermore, the incidence of tumor development increased when small numbers of ER-1 cells were injected onto plates (or at their periphery) which had previously been implanted s.c. without tumor cells. The tumorigenicity of ER-1 cells increased after they were cocultivated for more than 30 days with host reactive cells obtained from the tissues surrounding the plates. These results suggest that host cells reactive to the foreign body (plastic plate) may not only promote the local growth of ER-1 cells but also convert them into much more malignant tumors.

Animals↗

PubMed1992

Inherited copper toxicity in Long-Evans cinnamon rats exhibiting spontaneous hepatitis: a model of Wilson's disease.

The copper concentrations in organs of developing Long-Evans Cinnamon (LEC) rats (2 d to 13 mo) were measured to elucidate the pathogenesis of their hereditary hepatitis. Hepatic copper contents of LEC rats were significantly higher than those of control rats (26 to 92 times higher). The subcellular distribution of hepatic copper indicated that the nuclear and large granular fractions had been saturated and the cytosol fraction contained about 70% of all the hepatic copper in LEC rats. The serum concentrations of copper and ceruloplasmin were significantly lower than those of control rats from the 4th wk (10-12% and 5-19%, respectively). Copper contents in kidney of LEC rats did not exhibit an increase over those of control rats until 12 wk, but then increased to nearly 40 times higher during fulminant hepatic failure. Accumulation of copper was not detected in the brain or small intestines of LEC rats until 13 mo. The hepatic copper concentration, its subcellular distribution, and serum copper concentration of F1 rats (LEC x Long-Evans Agouti) exhibited the same levels as those of Long-Evans Agouti rats. In addition to their similarity concerning inheritance of autosomal recessive means and clinical course, we found causality relating copper accumulation to the pathogenesis of the disease. We propose that LEC rats will be the most promising animal model for the study of Wilson's disease.

Age Factors↗

PubMed1991

Reduced somatostatin-like immunoreactivity in the brain of LEC rats with hepatic encephalopathy.

Somatostatin-14-like immunoreactivity (S14LI) and somatostatin-28(1-12)-like immunoreactivity (S28(1-12)LI) in the brain of LEC (Long Evans Cinnamon) rats with hepatic encephalopathy were measured. Significant reduction of both S14LI and S28(1-12)LI was observed in the hypothalamus, medulla oblongata, striatum and spinal cord. Both of the immunoreactivities in the hypothalamus of these rats were approx. 50% of those in LEC rats without hepatic encephalopathy. The amounts of reduction of S14LI significantly correlated with those of reduction of S28(1-12)LI. No significant difference in gel chromatographic profiles of S14LI and S28(1-12)LI was observed between LEC rats with and without hepatic encephalopathy. These results suggest that the reduction of somatostatin-like immunoreactivity in LEC rats with hepatic encephalopathy may be caused by a decrease in production of prosomatostatin rather than altered degradation.

Animals↗

PubMed1991

Occurrence of autoimmune antibodies to liver microsomal proteins in association with fulminant hepatitis in the LEC strain of rats.

The Long Evans Cinnamon (LEC) rat, which has been established as a strain showing hereditary hepatitis and hepatic carcinoma, was found to possess autoimmune antibodies to liver microsomal proteins, particularly to a protein with the molecular weight of 56kD. The antibodies also recognized a protein(s) in liver microsomes from Long Evans Agouti and Sprague-Dawley rats. About 42 and 15 percent of respective female and male LEC rats died within a week after acute hepatitis; sera from all of the animals contained the antibodies. About 43 and 0 percent of the surviving female and male LEC rats possessed the antibodies, respectively. These results suggest that the autoantibodies occur in association with acute lethal hepatitis in the LEC rats.

Animals↗

PubMed1991

Reduced cholecystokinin in the brain of LEC rats with hepatic encephalopathy.

Levels of cholecystokinin (CCK) immunoreactivity and distribution of CCK immunoreactive cells were studied in the cerebral cortex of LEC (Long Evans Cinnamon) rats with hepatic encephalopathy. CCK immunoreactivity in water extract of cerebral cortex of LEC rats with hepatic encephalopathy (n = 7) was 41.5 +/- 2.6 (mean +/- S.E.M. pmol/g wet wt.) and that of LEC rats without encephalopathy (n = 8) was 67.1 +/- 6.9, the difference being significant (P less than 0.01). CCK immunoreactive cells assessed by immunohistochemistry were also markedly decreased in the cortex of LEC rats with hepatic encephalopathy of stage IV. Thus, CCK reduction was observed in the cerebral cortex of LEC rats with hepatic encephalopathy which are provided as a model for analysis of the pathogenesis of acute hepatic encephalopathy.

Amino Acids↗

PubMed1991

Kinetic changes of liver regeneration and hepatocellular carcinoma cells after partial hepatectomy in rats.

We investigated, using rats, the effect of partial hepatectomy (PH) on hepatocellular carcinoma (HCC, KDH-8 and AH-66) cells, and the effect of HCC cells on the regeneration of remaining hepatocytes after PH. Our results showed that PH significantly enhanced the growth of HCC cells in rats. Tumor volume increased more significantly in the partially hepatectomized group (H-group) than in the control group, and the tumor wet weights on the 14th postoperative day were significantly higher in the H-group than in the control group. Such an enhanced growth effect of PH on the injected (s.c.) HCC cells was related to an abrupt increase of tumor volume within 24 hours after operation, which was supported by the mitotic indices (MI) of the KDH-8 cells. These phenomena of the enhanced growth of the HCC cells following PH were not observed at all in rats injected with estrogen receptor (ER)-negative mammary carcinoma (SST-2) or nonepithelial fibrosarcoma (KMT-75) cells. The MIs of the remaining hepatocytes after PH increased abruptly at the 30th postoperative hour and reached a maximum at the 36th postoperative hour, and the MIs were significantly higher in the H-group with the KDH-8 cells than in the H-group without them from the 42th to the 60th postoperative hour. In the control group, the MIs of hepatocytes were not regardless of the presence of KDH-8 cells. From these results, we speculate that some growth factor(s) induced by PH may act on injected (s.c.) HCC cells, and that the other growth factor(s) secreted by HCC cells may act on the regenerating hepatocytes after PH.

Animals↗

PubMed1991

Relation between estrogen receptor and malignancy of thyroid cancer.

The relationship between the histological grade of dedifferentiation of thyroid cancer and estrogen receptors (ER) was examined immunohistochemically. Thyroid cancers were from postmenopausal females of almost the same mean age (69-73 years old) and within the same period of time (1974-1983). ER immunoreactivity located in the nucleus of the epithelium was found in all 6 well differentiated papillary cancers, and 5 of them (83.3%) showed ER-immunoreactive (ER-IR) cells amounting to 20 or more per visual field (x 100) under a light microscope. Of the 6 cases of poorly differentiated papillary cancer, 5 (83.3%) had 1-19 ER-IR cells per visual field. ER-IR cells were negative in 5 out of 6 cases (83.3%) of anaplastic cancers. Thus, the number of ER-IR cells tended to decrease with the degree of atypism of thyroid cancer (P less than 0.001).

Aged↗

PubMed1991

Abnormal copper accumulation in non-cancerous and cancerous liver tissues of LEC rats developing hereditary hepatitis and spontaneous hepatoma.

We studied the copper concentrations in the non-cancerous and cancerous liver tissues of LEC rats with hereditary hepatitis and spontaneous hepatoma by atomic absorption spectrophotometry. Copper concentration in the non-cancerous livers of 29-month-old male LEC rats was comparable to that in the livers of LEC rats aged 2, 3 and 8 months whose hepatic copper concentrations were more than 40 times those of normal LEA rats. Copper concentration in spontaneously developed hepatocellular carcinomas of the 29-month-old male LEC rats was lower than that in the surrounding non-cancerous liver tissues, but was still more than 39 times that of 8-month-old male LEA rats. These findings suggest that in LEC rats an abnormal copper metabolism may be maintained during the process of hepatic carcinogenesis.

Age Factors↗

PubMed1991

Parathyroid tumors in atomic bomb survivors in Hiroshima: epidemiological study from registered cases at Hiroshima Prefecture Tumor Tissue Registry, 1974-1987.

An examination of registered cases of parathyroid tumor in Hiroshima Prefecture between 1974 and 1987 revealed 23 cases. An epidemiological study showed that the incidence of parathyroid tumors in Hiroshima Prefecture was significantly higher in the total exposed, especially among the proximally exposed (within 2,000 m from the hypocenter), than in the control nonexposed group (P less than 0.001). A similar trend was seen for parathyroid tumor associated with primary hyperparathyroidism.

Humans↗

PubMed1991

Spontaneous hepatic copper accumulation in Long-Evans Cinnamon rats with hereditary hepatitis. A model of Wilson's disease.

Long-Evans Cinnamon (LEC) rats, an inbred strain of a mutant rat isolated from Long-Evans rats, develop hereditary hepatitis. To elucidate the role of copper metabolism in the development of the hepatitis in LEC rats, we examined the copper concentration in the tissues and serum levels of copper and ceruloplasmin. Copper concentration in the liver of LEC rats was over 40 times that of normal Long-Evans Agouti (LEA) rats, while the serum ceruloplasmin and copper concentrations in LEC rats decreased significantly. The hepatocytes of LEC rats show steatosis in cytoplasm and pleomorphism of mitochondria, resembling the histologic features of the liver in Wilson's disease. These findings suggest that the hereditary hepatitis in LEC rats is closely associated with copper toxicity, and may be dealing with a rat form of Wilson's disease. Thus the LEC rats will provide a unique and useful animal model for clarifying the mechanism and for developing treatment strategies for Wilson's disease and other abnormal copper metabolism in humans.

Animals↗

PubMed1991

A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Thyroid cancer: reports up to date and a review.

Evidence to date from a number of studies, indicates that there is an increased incidence of thyroid cancer among A-bomb survivors, and that the incidence rises with increase of dose and is especially predominant in females exposed at younger ages. Although 45 years have elapsed since A-bomb exposure, there are still some questions about the development of thyroid cancer: 1) Is the incidence now decreasing? 2) What factors, other than radiation exposure, are involved? 3) What is the incidence of multiple cancer, including thyroid cancer? With these questions in mind, it is apparent that studies in this field must continue for some time to come.

Female↗

PubMed1991

Parathyroid tumors in atomic bomb survivors in Hiroshima: a review.

Parathyroid tumors in A-bomb survivors in Hiroshima have been studied. Thirteen cases of parathyroid tumor were confirmed from 4,136 autopsy cases between 1961 to 1977, and an elevated incidence of tumor with increase of dose (T65D) was demonstrated (P less than 0.01). A high proportion of 42.9%, 6 out of 14 parathyroid tumors extirpated at Hiroshima University Hospital between 1956 and 1988, were atomic bomb survivors exposed within 4.1 km from the hypocenter. From an epidemiological study using 23 parathyroid tumor cases detected in Hiroshima Prefecture between 1974 and 1987, an elevated incidence of parathyroid tumors with increase of dose (proximally exposed, other exposed and control nonexposed) was demonstrated (P less than 0.001).

Humans↗

PubMed1991

Thyroid cancer: epidemiological study of thyroid cancer in A-bomb survivors from extended life span study cohort in Hiroshima.

We analysed thyroid cancers which were diagnosed clinically or detected at autopsy during 22 years (1958 to 1979) in a sample of 75,493 study subjects exposed in Hiroshima belonging to the extended LSS sample of the Radiation Effects Research Foundation. One hundred and twenty-five cases of clinical thyroid cancer (15 in males and 110 in females) were confirmed, giving a crude incidence rate per 100,000 person-years of 2.7 for males, 12.4 for females and 8.6 for both sexes combined. There was a significant increase of thyroid cancer with increase of atomic bomb radiation dose (thyroid tissue dose based on T65D) in females and in the sexes combined. This tendency was predominant in those exposed at less than 19 years of age. Compared to the control group, the relative risk in the greater than or equal to 0.50 Gy group was higher at 4.0 for males (not significant) and at 4.3 for females (p less than 0.01). Latent thyroid cancer was detected in 155 cases or 3.5% (2.5% for males and 4.5% for females) of the 4,425 cases that came to autopsy during the same period. Compared to the control group, the relative risk in the 50+ rad group was 1.7 for males (not significant), 2.0 for females (p less than 0.05) and 1.9 for both sexes combined (p less than 0.05). New data obtained from autopsy cases between 1950 and 1985 have been added.

Female↗

PubMed1991

[A high serum level of interleukin-6 in a patient with aggressive multiple myeloma].

A 58-year-old female was admitted to our hospital because of anemia in March 1987. Monoclonal protein (IgA, kappa) was detected and a diagnosis of multiple myeloma was made. Partial remission was obtained after VAD therapy with alpha-interferon. In December 1989, she was readmitted because of a pathological fracture of the left humerus. A white blood cell count was 4400/microliters with 30% myeloma cells and the urine protein (Bence Jones protein) was 26 g/day. Systemic chemotherapy was not effective. She developed pleural and pericardial effusions, bone mass, disturbance of consciousness and died of respiratory failure only 3 months after readmission. The pleural and pericardial fluids contained many myeloma cells. c-myc gene rearrangement was detected in myeloma cells obtained from the pleural fluid using c-myc exon1 and exon2 probes. The levels of interleukin-6 (IL-6) measured by ELISA was 107.4 pg/ml in serum, 56.2 pg/ml in pleural fluid and 780.0 pg/ml in pericardial fluid. Because of the lack of any overt infectious focus, the level of IL-6 appears to have been related to aggressive proliferation of myeloma cells. It was of interest that C-reactive protein, induced by IL-6, was a good marker reflecting disease activity.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

Hepatocarcinogenesis in the LEC rat with hereditary hepatitis.

A new mutant developing spontaneous hepatitis and hepatocellular carcinoma has been discovered among Long Evans rats. Hepatitis appears suddenly in the mutant, Long Evans Cinnamon (LEC) rats, three to four months after birth. Characteristic clinical signs of the hepatitis are jaundice, bilirubinuria, subcutaneous bleeding and loss of body weight. The affected rats showed a high mortality and histological changes with focal necrosis of hepatocytes and infiltration of a few inflammatory cells. Genetic studies indicate that a single autosomal recessive gene is responsible for the hepatitis. Long-surviving rats show chronic hepatitis, and subsequently develop hepatocellular carcinoma at one and a half years of age. We recently found an abnormal copper accumulation in the liver of LEC rats prior to development of the hepatitis. Copper concentration in the liver is over 40 times more than that of normal Long Evans Agouti (LEA) rats, whereas the serum ceruloplasmin and copper levels are lower. An excess of toxic-form copper, free copper, will cause DNA damage in the presence of free radicals and oxygen radicals. Such DNA damage by the radicals is considered to be responsible for hepatic necrosis and hepatocellular carcinoma in LEC rats.

Animals↗