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Biomedical subjects

M Shimada

Publications and source records attributed to M Shimada.

At least 451 records · Page 25Linked to original sources
PubMed1995

Spontaneous generation of human CD8+ TCR alpha beta+ cells derived from precursors within the double negative compartment.

Flow cytometric analysis demonstrated that fresh human thymocytes contain only a low level of mature CD8+ TCR alpha beta + or CD8+ TCR gamma delta + cells and they consist consist of approximately 70% double positive (DP) and approximately 10% double negative (DN) cells. These unfractionated thymocytes could be selectively expanded in vitro by stimulation with 12-O-tetradecanoylphorbol 13-acetate (TPA) and PHA in the presence of IL-2. The majority of the cells expanded from unfractionated thymocytes expressed CD3, TCR alpha beta and CD8 molecules after long-term culture (18 days). When highly purified DN thymocytes were expanded over a period of 18 days in the presence of DP cells, they also co-expressed CD3, TCR alpha beta and CD8 molecules on their surface. However, when purified DN thymocytes were expanded alone, that is, in the absence of DP cells for 18 days, they expressed CD3-associated TCR gamma delta, but not CD8 or TCR alpha beta. Despite the expression of measurable levels of IL-2 alpha and beta receptors, as well as a significant level of TCR alpha beta, purified DP cells failed to proliferate. These findings provide the first evidence, in humans, that the progression of precursor cells in the DN compartment to a later stage of differentiation can be induced outside the thymus and that DP cells can affect the development of TCR expression in proliferating DN thymocytes.

CD8-Positive T-Lymphocytes↗
PubMed1995

Distribution of immunoreactive 2',5'-oligoadenylate synthetase in mouse digestive tract.

2',5'-Oligoadenylate synthetase (2-5OAS), an enzyme induced by interferon (IFN), has also been found in various "normal" animals that had not been treated with IFN. The distribution of this enzyme in the digestive tracts of normal healthy mice was studied by western blotting and by an immunohistochemical method using a specific monoclonal antibody. On western blotting, the antibody to 42 kD 2-5OA synthetase reacted with extracts from the stomach and intestines (small and large intestine), but not with extracts from the esophagus. Immunohistochemically, the 42 kD 2-5OAS was localized on the following cells: surface mucous and parietal cells of fundic glands in the stomach; surface epithelial cells in the intestines; and some enteric nervous cells in the esophagus, stomach, and intestines. Treatment with IFN- alpha/beta did not essentially change the distribution of the enzyme in the tissues, although a small amount of the enzyme was detected in the esophagus by western blotting. Expression of the 42 kD 2-5OAS in the digestive tract may be responsible for the prevention of viral infections.

2',5'-Oligoadenylate Synthetase↗
PubMed1995

A case of CREST syndrome associated with sick sinus syndrome.

Cardiac manifestations of the CREST syndrome or limited systemic sclerosis (ISSc) are very rare. We report a case of CREST syndrome associated with sick sinus syndrome. Histopathology of cardiac muscle revealed fibrotic changes, suggesting that such changes may be pathogenetically related to CREST syndrome.

CREST Syndrome↗
PubMed1995

Infrequent replication errors at microsatellite loci in tumors of patients with multiple primary cancers of the esophagus and various other tissues.

Patients with esophageal cancer are at high risk of developing other primary tumors, especially squamous cell carcinoma in the head and neck. Heavy smoking and excessive consumption of alcohol are considered to be crucial environmental risk-factors for development of these multiple primary cancers. To investigate whether any genetic background, such as defects in the DNA-mismatch repair system, may influence the development of these multiple primary tumors, we examined replication errors (RER) at six microsatellite loci in DNAs of 46 tumors from 33 patients who had developed primary cancers in various tissues in addition to the esophagus. RER(+) (RER-positive) phenotype was observed in three tumors in two patients of the 33 patients examined. Our results suggested that development of multiple primary tumors in these patients would not be affected by an abnormality in the DNA repair system(s) detected as the RER phenotype. However, it is noteworthy that a single patient who developed multiple cancers revealed RER(+) phenotypes at multiple microsatellite loci in both tumors, indicating that a defect in the DNA repair gene(s) may have played an important role in the development of the tumors in this patient.

Adenocarcinoma↗
PubMed1995

Expression of CA15-3 in renal cell carcinoma.

CA15-3 expression was analyzed in renal cell carcinoma (RCC) from the standpoint of the histogenesis of RCC. Tissue sections from surgical specimens of 12 cases of clear cell type RCC and from autopsy specimens of eight fetal kidneys were stained by an indirect immunoperoxidase method using DF-3. All the RCC cases stained positively for CA15-3, with 10 of the 12 cases showing strong, diffuse immunoreactivity on the cell membrane. Expression of CA15-3, as well as other markers such as epithelial membrane antigen, neuron-specific enolase, glandular cytokeratin and other lectins, suggest a more complicated histogenesis of RCC, rather than a simple proximal tubular origin.

Carcinoma, Renal Cell↗
PubMed1995

The role of ribonuclease H in multicopy single-stranded DNA synthesis in retron-Ec73 and retron-Ec107 of Escherichia coli.

Bacterial reverse transcriptase is responsible for the synthesis of multicopy single-stranded DNA (msDNA). Reverse transcriptases from retron-Ec73 and retron-Ec107 do not contain an RNase H domain. Cellular RNase H is therefore considered to be required to make the mature form of msDNA. We found that RNase HI, but not RNase HII, is required for the production of the mature form of both msDNAs.

Base Sequence↗
PubMed1995

Spastic tetraplegia as an initial manifestation of familial Alzheimer's disease.

Two sisters with familial Alzheimer's disease developed spastic gait disturbance as an initial manifestation. Their gait disturbance progressed gradually, followed by dementia a few years later. Post-mortem examination of one of the patients disclosed degeneration of the thalamus and corticospinal tract in addition to numerous senile plaques and neurofibrillary tangles in the neocortex, both of which were confirmed by immunohistochemistry. This is the first report in which clinicopathological evaluation is sufficient to establish a new variant of Alzheimer's disease presenting initially as spastic tetraplegia.

Alzheimer Disease↗
PubMed1995

Determination of salivary cortisol by ELISA and its application to the assessment of the circadian rhythm in children.

In 35 young children, circadian rhythms of salivary cortisol levels were determined by ELISA using a commercially available kit with a minor modification. The concentration of labeled cortisol in the serum kit was reduced in order to measure cortisol in 10 microliters of saliva. Intra- and interassay coefficients of variation for salivary cortisol ranged from 2.4 to 9.9 and 3.2 to 8.9%, respectively. Recovery of salivary cortisol was 82.9-107.0%. There was a highly significant correlation between cortisol levels in saliva and serum in adults (r = 0.857). Salivary cortisol levels ranged from 0.01 to 2.252 micrograms/100 ml and showed significant diurnal variation in the children. Our ELISA is a precise, simple, noninvasive and useful method for clinical practice and study in infants and children.

Adult↗
PubMed1995

Overexpression of human lipoprotein lipase protects diabetic transgenic mice from diabetic hypertriglyceridemia and hypercholesterolemia.

We investigated the role of the overexpression of lipoprotein lipase (LPL) in lipoprotein abnormalities in transgenic mice with streptozotocin-induced diabetes mellitus. Before the induction of diabetes, LPL activity was 4.6-fold in skeletal muscle and 2.0-fold higher in the heart in transgenic mice than in their nontransgenic littermates. LPL activity in skeletal muscles in diabetic nontransgenic mice and cardiac LPL activity in diabetic nontransgenic and transgenic mice were decreased. Body weights were similarly reduced, and no appreciable amount of adipose tissue was observed in diabetes in both groups. The plasma triglyceride level was lower in diabetic transgenic mice than in diabetic nontransgenic mice (33.2 +/- 22.5 versus 185.3 +/- 57.4 mg/dL). Induction of diabetes was associated with a significant increase in the plasma cholesterol level in nontransgenic mice (90.0 +/- 11.1 versus 163.9 +/- 39.3 mg/dL) but much less in transgenic mice. Our results indicate that overexpression of LPL in transgenic mice inhibited diabetes-associated hypertriglyceridemia and hypercholesterolemia but did not affect the loss of body weight induced by diabetes.

Animals↗
PubMed1995

Effects of platelet-derived growth factor on the synthesis of lipoprotein lipase in human monocyte-derived macrophages.

Lipoprotein lipase (LPL), which is secreted by the two predominant cell types in atherosclerotic plaque, macrophages and smooth muscle cells, may be involved in atherosclerosis by generating atherogenic remnant lipoproteins. We investigated the effects of platelet-derived growth factor (PDGF)-BB on the synthesis of LPL by human monocyte-derived macrophages. These cells were cultured in the presence of PDGF-BB for 8 days, after which the enzyme activity, mass, and mRNA levels of LPL were determined. The effect of PDGF-BB was time-dependent and dose-dependent at concentrations of 1 to 10 ng/mL. At 10 ng/mL PDGF-BB enhanced twofold to 2.3-fold the secretion of LPL, and a pulse-labeling study with [35S]methionine revealed that 10 ng/mL PDGF-BB significantly increased the synthesis of LPL. Northern blotting analysis showed that the LPL mRNA level increased dose dependently in macrophages treated with PDGF-BB, and 10 ng/mL PDGF-BB enhanced twofold the expression of LPL mRNA. The protein kinase C inhibitor staurosporine suppressed the effect of PDGF-BB on LPL activity. These results indicate that PDGF-BB stimulated transcription of the LPL gene in human monocyte-derived macrophages through protein kinase C activation and resulted in an increased synthesis of LPL. Therefore, we hypothesize that the augmented synthesis of LPL by PDGF-BB modulates atherosclerosis by influencing lipoprotein metabolism in the vascular wall.

Becaplermin↗
PubMed1995

Inhibition of diet-induced atheroma formation in transgenic mice expressing apolipoprotein E in the arterial wall.

Apolipoprotein E (apoE) plays a crucial role in lipoprotein metabolism both in plasma and in peripheral tissues. To test whether apoE in the vascular wall has a direct and local effect on atherogenesis, we established transgenic mice expressing human apoE under control of H2 Ld promoter. Studies on mRNA levels and immunohistochemistry demonstrated that this line was characterized by high expression of human apoE in the arterial wall while its expression was relatively low in other tissues as compared with the respective endogenous expression of mouse apoE. They showed no difference in plasma cholesterol levels and lipoprotein profile from controls when fed both normal and atherogenic diets. However, after 24 wk of an atherogenic diet, the formation of fatty streak lesions in proximal aorta was markedly inhibited in transgenic mice as compared with controls. Both lesion area and esterified cholesterol content were < 30% of those in controls. In a tissue cholesterol labeling study with 3H-cholesterol, the specific activity of aorta cholesterol was much less in transgenic mice, suggesting that apoE enhances cholesterol efflux from the aortic wall into plasma. Thus, apoE has anti-atherogenic action which is mediated via enhancing reverse cholesterol transport from arterial wall.

Animals↗
PubMed1995

Induction of sustained expression of proto-oncogene c-fms by platelet-derived growth factor, epidermal growth factor, and basic fibroblast growth factor, and its suppression by interferon-gamma and macrophage colony-stimulating factor in human aortic medial smooth muscle cells.

Vascular medial smooth muscle cells migrate, proliferate and transform to foam cells in the process of atherosclerosis. We have reported that the intimal smooth muscle cells express proto-oncogene c-fms, a characteristic gene of monocyte-macrophages, which is not normally expressed in medial smooth muscle cells. In the present study, we demonstrated that combinations of platelet-derived growth factor (PDGF)-BB and either epidermal growth factor (EGF) or fibroblast growth factor (FGF) induced high expression of c-fms in normal human medial smooth muscle cells to the level of intimal smooth muscle cells or monocyte-derived macrophages, whereas c-fms expression by PDGF-BB alone was 1/10 and both EGF and FGF had no independent effect on c-fms expression. By contrast, interferon (IFN)-gamma and macrophage colony-stimulating factor (M-CSF) suppressed the induction of c-fms expression. These results indicate that multiple growth factors and cytokines may play a role in the phenotypic transformation of medial smooth muscle cells to intimal smooth muscle cells in atherosclerotic lesions by altering c-fms expression.

Aorta↗
PubMed1995

Male reproductive toxicity study of nefiracetam in rats.

Sprague-Dawley male rats were administered nefiracetam orally at daily doses of 500 and 1500 mg/kg/day for 4 or 9 weeks. Although the copulation index was not affected by nefiracetam treatment, the fertility index was extremely low in the 1500 mg/kg/day group for both treatment periods. This high dose group consistently exhibited decreased testicular weights. Epididymal and prostate weights were also reduced in the 1500 mg/kg/day group after both 4- and 9-week treatments and in the 500 mg/kg/day group after the 9-week treatment. Severe degenerative changes such as degeneration of germ cells, loss of germ cells and atrophy of seminiferous tubules were observed in all rats of the 1500 mg/kg/day groups after both 4 and 9 weeks of treatment. Retention of spermatids in stage IX, X and XI seminiferous tubules was also noted after the 4- and 9-week treatments at 500 mg/kg/day. The testicular sperm head counts were markedly decreased following the 4- and 9-week treatments at 1500 mg/kg/day, and mildly reduced after the 4-weeks treatment at 500 mg/kg/day. From these results it is concluded that histopathological examination and the testicular sperm head count method are highly useful for detecting testicular toxicity and that testicular lesions caused by nefiracetam can be detected after 4 weeks of exposure.

Animals↗
PubMed1995

Overexpression of apolipoprotein E prevents development of diabetic hyperlipidemia in transgenic mice.

To determine the role of apolipoprotein E (apoE) in diabetic hyperlipidemia, we induced diabetes in transgenic mice overexpressing apoE by intravenous injection of streptozotocin (STZ) and examined plasma lipoprotein metabolism in these mice. In STZ-induced diabetic mice, blood glucose levels were > 19 mmol/l (350 mg/dl) and plasma insulin levels were reduced to < 5 pmol/l (1 microU/ml). The diabetic nontransgenic mice developed hypercholesterolemia (plasma total cholesterol level: 4.55 +/- 1.32 vs. 1.97 +/- 0.13 mmol/l [176 +/- 51 vs. 76 +/- 5 mg/dl]) and hypertriglyceridemia (plasma triglyceride level: 0.82 +/- 0.29 vx. 0.42 +/- 0.11 mmol/l [73 +/- 26 vs. 37 +/- 10 mg/dl]) compared with values before induction of diabetes. In the diabetic nontransgenic mice, enhanced intestinal acylCoA:cholesterol acyltransferase activity was demonstrated, a factor that may contribute to the development of diabetic hyperlipidemia. Induction of apoE remarkably reduced the development of hyperlipidemia in diabetic transgenic mice compared with diabetic nontransgenic mice (plasma cholesterol level: 4.55 +/- 1.32 vs. 3.31 +/- 0.47 mmol/l [176 +/- 51 vs. 128 +/- 18 mg/dl], P < 0.01, and plasma triglyceride level: 0.82 +/- 0.29 vs. 0.17 +/- 0.11 mmol/l [73 +/- 26 vs. 15 +/- 10 mg/dl], P < 0.01). Plasma lipoprotein analysis by gel filtration chromatography showed that the reduction of plasma cholesterol and triglyceride levels was due to the disappearance of lipoproteins containing apoB. In these studies, we demonstrated the usefulness of STZ-induced diabetes in mice as an animal model for diabetic hyperlipidemia and demonstrated that endogenous induction of apoE in transgenic mice improved diabetic hyperlipidemia.

Animals↗
PubMed1995

Thy1(+) lymphocytes with LAK-like activity are present in rat liver sinusoids.

Lymphocytes with cytotoxic activity have been identified in sinusoids of rat liver. We investigated the effects of aging on the cytotoxicity of liver sinusoidal lymphocytes in the rat and attempted to identify the cells responsible for cytotoxicity using a Thy1 monoclonal antibody. Natural Killer (NK) activity against YAC1 peaked at the age of 8 weeks, while cytotoxicity against NK-resistant Lymphokine Activated Killer (LAK)-sensitive P815 increased gradually with age. A cold target inhibition assay showed that lymphocytes cytotoxic for P815 and AH109 were also present in the liver sinusoids of aged rats. When these cells were fractionated by the Percoll discontinuous density gradient method, cytotoxic cells were found to comprise large granular lymphocytes (LGLs) rich in low- and middle-density fractions. Cytotoxicity against various targets increased when CD5(+) cells were removed using CD5-conjugated beads. Cytotoxicity against P815, AH109 and AH130 was decreased as compared with control lymphocytes when CD5(-) Thy1(+) lymphocytes were removed using CD5, Thy1-conjugated beads. Immunohistologic examination revealed Thy1(+) LGLs with rod-cored vesicles and electron-dense granules in the liver sinusoids. We consider that LAK-like cells with a Thy1 phenotype are present in the liver sinusoids and suggest that they have a broad range of cytotoxicity.

Aging↗
PubMed1995

Age- and sex-related alterations of microsomal drug- and testosterone-oxidizing cytochrome P450 in Sprague-Dawley strain-derived dwarf rats.

Effect of growth hormone (GH) on the age-related changes in hepatic cytochrome P450 (P450) was studied using GH-deficient dwarf and parental Sprague-Dawley rats. Microsomal testosterone (T) T2 alpha- and T2 beta-hydroxylations were lower in livers of mature male dwarf rats than the normals, whereas T16 beta-hydroxylation was rather higher in male dwarf rats. Although T2 alpha-, T2 beta-, T6 beta-, T16 alpha- and T16 beta-hydroxylations were barely detectable in senescence normal rats (24 months old), considerable levels of T6 beta-, T16 alpha- and T16 beta-hydroxylations were maintained in senescence dwarf rats (after 22 months old). These results are caused by the alteration of specific P450 forms including CYP2B1, CYP2B2, CYP2C11 and CYP3A2 in dwarf rats. Appearance of male-specific CYP2C11 and CYP3A2 and high levels of CYP2B1 and CYP2B2 in female dwarf rats indicate the role of pituitary GH on liver of normal rats. However, the additional role of a factor other than GH was suggested on the sex-related differences and age-associated alterations of specific P450 contents in dwarf rats. CYP2C11 appears in dwarf female rats with the same developmental profile as observed in normal male rats. This form appears apparently with the development of GH receptor in livers, suggesting the possibility that a factor independent from androgen and GH governs the ontogeny of this P450 in the liver. A female-specific protein, CYP2C12, in normal rat livers, also appeared in both sexes of senescence dwarf rats, suggesting the role of non-GH factor on the expression of this P450 in liver.

Age Factors↗