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Biomedical subjects

S Saito

Publications and source records attributed to S Saito.

At least 19 recordsLinked to original sources
PubMed1992

[Pathophysiology and gene abnormalities of endocrine tumors].

Various functioning and non-functioning tumors arise from endocrine glands in both the sporadic and familial forms and pathophysiology of the tumors is variable due to differences in the sort of tumor-bearing endocrine organs and in the amount of hormones released. In this paper, gene abnormalities in growth hormone (GH)-secreting pituitary adenoma, ectopic GHRH-producing tumor, multiple endocrine neoplasia (MEN) and ectopic parathyroid hormone (PTH)-producing tumor are documented in relation to etiology and pathophysiology. GH-secreting pituitary adenoma is heterogeneous in clinical features, pathological findings and GH responses to various secretagogues. A point mutation of codon 201 of Gs alpha gene was observed in 2 out of 45 GH-secreting pituitary adenomas (4.4%), but no point mutation of Gi2 alpha gene was found. Pituitary tumors may occur at any stage of differentiation from the totipotent cells to mature anterior pituitary cells, and the mutations of Gs alpha and H-ras genes as well as loss of heterozygosity (LOH) found on chromosome 11 in some adenomas must be involved in their tumorigeneses. Since 1959, 34 patients with ectopic GHRH-producing tumor associated with acromegaly have been reported. In our case of MEN type 1, the paradoxical rise of plasma GH after TRH or glucose administration disappeared after resection of the tumor. The tumor cells showed neither rearrangement nor amplification of GHRH gene and 20 oncogenes including ras, myc, and erb. Only LOHs of HRAS1 and D11S151 were detected in this tumor, but no point mutation was found in HRAS1 gene. Therefore, a kind of tumor suppressor gene may be involved in the tumorigenesis of the tumor in addition to inactivation of MEN-1 locus. In MEN-1 patients, we reported LOH on chromosomes 1, 9, 11 and 16, while we reported point mutation as being present only in Gs alpha gene on chromosome 20. This point mutation was found specifically in GH-secreting pituitary adenoma but not in hyperplastic parathyroid and pancreas adenoma. These data suggest that in MEN-1 patients tumorigenesis occurs and advances from hyperplasia and adenoma to cancer during multistep changes of genes such as inactivation of MEN-1 gene and other tumor suppressor genes and activation of oncogenes. Ectopic PTH-producing tumor was first reported by us in 1989, and this was followed by 2 papers. These patients showed a disturbance of consciousness and high levels of serum calcium and plasma PTH.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1992

Mouse dopamine beta-hydroxylase: primary structure deduced from the cDNA sequence and exon/intron organization of the gene.

Genomic clones for mouse dopamine beta-hydroxylase (DBH) were isolated from two genomic libraries derived from DBA/2J and 129/SV mouse strains, by plaque hybridization with the human DBH cDNA probe. Subsequently, cDNA encoding mouse DBH was amplified with reverse transcription-polymerase chain reaction (RT-PCR) method using primers corresponding to 5'- and 3'-portions of the mouse DBH mRNA, subcloned into a plasmid vector, and subjected to nucleotide sequence analysis. The clone encoded a protein of 621 amino acids with a calculated molecular mass of 70,186 daltons. The predicted amino acid sequence of mouse DBH showed 87%, 80% and 79% identities with the rat, bovine and human enzymes, respectively. Several potential amino acid sequences that are involved in the posttranslational modification and catalytic function of DBH were identified in mouse DBH protein. Nucleotide sequence analysis of the overlapping genomic clones showed that the mouse DBH gene was composed of 12 exons about 17 kb in length. Typical TATA and CCAAT boxes were observed in the 5'-upstream region of the gene. Northern blot analysis of adrenal gland RNA detected a single size species of the mouse DBH mRNA.

Adrenal Glands↗
PubMed1992

Measurement of plasma membrane potential in isolated rat hepatocytes using the lipophilic cation, tetraphenylphosphonium: correction of probe intracellular binding and mitochondrial accumulation.

The lipophilic cation tetraphenylphosphonium (TPP+) has been extensively utilized as the probe for the membrane potential (Vm) in various cells. For application to mammalian cells, however, two serious problems require resolution: (1), correction of TPP+ binding to intracellular constituents and (2), estimation of the considerable TPP+ accumulation in mitochondria. We propose here a simple corrective method for the TPP+ binding and its accumulation. TPP+ distribution is assumed as: (1), two compartments (a cytosolic and a mitochondrial space); (2), a proportional relationship between TPP+ bound amount and its unbound concentration in each compartment. We theoretically derived the simple equation: Vm = - RT/F ln(C/Mphys ratio/C/Mabol ratio) where R, T and F have their usual thermodynamic significance. Here, the C/M ratio is defined as the ratio of TPP+ concentration of apparent intracellular to extracellular space. The suffixes phys and abol, respectively, mean the physiological and solely Vm-abolished conditions. This equation was checked with hepatocytes, because estimating hepatocytes Vm with TPP+ distribution is not considered possible because of the relatively high mitochondrial content. The selective Vm abolition was achieved by permeabilization with 20 microM of amphotericin B. The Vm value was, thus, estimated to be -38.6 +/- 0.3 mV, compatible with those obtained with microelectrodes in other laboratories. Vm in hepatocytes is composed of transmembrane K+ diffusion potential (-20.6 +/- 0.3 mV) and electrogenic Na+/K(+)-ATPase (-19.6 +/- 0.4 mV). Addition of rheogenic L-alanine caused a transient but significant depolarization (from control to -34 +/- 0.3 mV). These results taken together indicate that hepatocyte Vm can be accurately determined with the present simple method, so that it may possibly be applicable to the evaluation of Vm in other mammalian cells.

Amphotericin B↗
PubMed1992

Fine-scale deletion mapping of the distal long arm of chromosome 6 in 70 human ovarian cancers.

To define a small region on chromosome 6q containing a putative tumor suppressor gene for ovarian cancer, we examined loss of heterozygosity in 70 ovarian tumors of three histological types with nine restriction fragment length polymorphism markers located at 6q24-27. Among 33 cancers of serous type that were informative at one or more loci, 17 showed allelic loss at a few or all loci examined, whereas only 1 of 15 mucinous-type tumors and 2 of 12 clear-cell tumors revealed loss of heterozygosity. This result supported our earlier suggestion that alteration of a gene on chromosome 6q may play an important role during development of serous ovarian tumors (Sato et al., Cancer Res., 51: 5118-5122, 1991). Frequent losses were observed between loci defined by CI6-119 (D6S195) at 6q26 and CI6-49 (D6S161) at 6q27. A detailed deletion map indicated a commonly deleted region between loci defined by CI6-111 (D6S193) and CI6-24 (D6S149); these two markers are estimated to be 1.9 cM apart on the basis of linkage analysis. Our results further define a region containing a tumor suppressor gene involved in ovarian carcinoma within an approximately 2-megabase-long segment of chromosome 6q.

Blotting, Southern↗
PubMed1992

Two new nonsense mutations in type Ia antithrombin III deficiency at Leu 140 and Arg 197.

Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing, the molecular basis of hereditary type Ia antithrombin III (AT III) deficiency was disclosed in two families. One mutation was a change from T to A in the codon of TTA for Leu 140 forming a stop codon of TAA, which was confirmed by mutated primer-mediated PCR-HindIII digestion. The application of this method demonstrated that all four affected members had the mutant allele in a heterozygous state and that none of unaffected subjects had this mutation. Another mutation in the second family was a change from C to T in the codon of CGA for Arg 197 also forming a stop codon of TGA, which was confirmed by PCR-HaeIII digestion. Based on these, it was concluded that the two new nonsense mutations in the AT III gene in a heterozygous state are the molecular basis of hereditary type Ia AT III deficiency.

Antithrombin III↗
PubMed1992

Role of p53 mutations in endocrine tumorigenesis: mutation detection by polymerase chain reaction-single strand conformation polymorphism.

To elucidate the molecular basis for endocrine tumorigenesis, p53 mutations in human endocrine tumors were analyzed by using polymerase chain reaction-single strand conformation polymorphism. Exons 5 through 10 of the p53 gene were studied in genomic DNAs from 134 primary endocrine tumors and 6 human endocrine cancer-derived cell lines. Mutations were detected and identified in 4 endocrine tumors, including one parathyroid adenoma and three thyroid carcinoma cell lines. The sites of these mutations were in exons 5 (codon 151 and 152) and 7 (codon 248 and 255). In all of three tumor cell lines, but not in a parathyroid adenoma, the normal allele encoding the p53 gene was lost. However, p53 mutations were not found in any other endocrine tumors or cell lines. Based upon these results, we concluded that the p53 gene may play a role in the tumorigenesis of a limited number of parathyroid adenoma and thyroid cancers, and that the p53 mutation with an allelic loss of the p53 gene is an important factor in malignant tumorigenesis of the thyroid gland.

Base Sequence↗
PubMed1992

Generation of a small cell lung cancer variant resistant to lymphokine-activated killer (LAK) cells: association with resistance to a LAK cell-derived, cytostatic factor.

Cells of OS2-RA, a human small cell lung cancer line sensitive to lymphokine-activated killer (LAK) cells, were repeatedly cocultured with human LAK cells. Fourteen cycles of the coculture produced a variant, termed OS2-RA-R, capable of growing successfully in the presence of LAK cells. OS2-RA-R showed a moderate resistance to lysis by LAK cells in 4-h 51Cr release assays. OS2-RA-R acted positively as a cold target for lysis of OS2-RA by LAK cells, suggesting no loss of the binding site for LAK cells on the cell surface of the variant. On the other hand, LAK cells were shown to produce a factor capable of suppressing the proliferation of OS2-RA and certain other cell lines but not lymphocytes. Interestingly, OS2-RA-R exhibited a substantial resistance to the cytostatic activity of LAK cell supernatants. The cytostatic factor, eluted at the 57-kDa fraction in gel filtration, showed no activity of interleukin 1, gamma-interferon, transforming growth factor beta, or tumor necrosis factor. These results suggest that LAK cells exhibit antitumor activity through not only rapid cytolysis but also slow-acting cytokine production, and the successful growth of OS2-RA-R in a coculture with LAK cells is the result of acquiring resistance to these two different LAK cell phenomena.

Animals↗
PubMed1992

The existence of activin A/erythroid differentiation factor and its inhibitor in human serum: comparison of normal and chronic renal failure sera.

Activin A/EDF, initially found as a differentiation inducer of murine Friend erythroleukemia, also has a stimulatory effect on erythropoiesis in vitro and in vivo. Here we proved activin A/EDF activity in human serum. The activin A/EDF level in 18 normal human serum samples was measured by a specific bioassay and was found to be 8.3 +/- 4.6 ng/ml, indicating that there exists sufficient activity to affect erythropoiesis in normal serum. In contrast, activin A/EDF activity was reduced in the chronic renal failure patients and 23/26 serum samples examined showed levels below 1.2 ng/ml. Further analysis using HPLC revealed that chronic renal failure serum actually contained as much activin A/EDF as normal serum, and that the difference between normal and patient serum existed in the content of a specific inhibitor of activin A/EDF. This observation suggests the possibility that the inhibitor is participating in the regulation of activin A/EDF activity in vivo in chronic renal failure patients and also the possibility of activin A/EDF could be utilized in the therapy of the anemia of such patients.

Activins↗
PubMed1992

Biochemical characterization of nerve growth cones isolated from both fetal and neonatal rat forebrains: the growth cone particle fraction mainly consists of axonal growth cones in both stages.

Nerve growth cones are responsible for the exact pathway finding, and for the establishment of neurocytoarchitecture. To elucidate the developmental changes of biochemical characteristics of nerve growth cones, growth cone particle (GCP) fractions were isolated biochemically from embryonal day 17 (E17) rat forebrain and from postnatal day 5 (P5). There were no significant differences in protein phosphorylation pattern in a Ca(2+)-dependent manner between E17-GCP fraction and that of P5. As for the membrane lipid composition, molar ratios of cholesterol to total phospholipids were well conserved during these ages. The immunoreactivity to anti-synaptophysin monoclonal antibody as a marker of mature synaptic elements could not be detected either in E17-GCP or P5-GCP fractions. To exclude the possibility of the contamination of dendritic elements, RNA contents and immunoreactivity to anti-high molecular weight microtubule-associated protein 2 (MAP2) monoclonal antibody were examined. RNA contents of the GCP fractions were extremely low compared to those of other subcellular fractions both in E17 and P5. No immunoreactivities to anti-MAP2 antibody were observed in either GCP fraction. Our results suggest that the GCP fractions, isolated from forebrains of E17 to P5 rat, are free from the contamination of the synaptic elements, and that the GCP fractions are mainly composed of axonal growth cones.

Aging↗
PubMed1992

[Long-term treatment of acromegaly and gigantism with octreotide (SMS 201-995)].

Twenty-one patients with active acromegaly and two patients with pituitary gigantism were treated with the long-acting somatostatin analogue octreotide (100-600 micrograms/day, sc, two or three times daily or 300-1500 micrograms daily by intermittent sc infusion) for 9-63 months. There was rapid clinical improvement. The fasting plasma GH levels were significantly suppressed (less than 50% of the values before treatment) in 17 patients and were normalized (less than 5 ng/ml) in 6 patients (27.3%). Plasma IGF-I levels were lowered by 50% and were normalized in 7 out of 18 cases. The effect of octreotide on pituitary tumor size was evaluated in 13 patients. In 4 cases, the shrinkage of the pituitary tumor was detected by computed tomographic scans and/or magnetic resonance imaging studies. The drug was generally well tolerated. However, there were probably newly formed gallstones in two patients during the therapy. Our study suggests that octreotide is an effective and relatively safe new approach for treating active acromegaly and gigantism.

Acromegaly↗
PubMed1992

Circadian variation of tumor blood flow in rat subcutaneous tumors and its alteration by angiotensin II-induced hypertension.

Circadian fluctuation in tumor blood flow of the rat subcutaneous tumor was investigated. Tumor tissue blood flows in the daytime zone (10 a.m. to 4 p.m.) and in the nighttime zone (10 p.m. to 4 a.m.) in both the first phase (doubling time of tumor volume = 1.7 days) and the second phase (doubling time of tumor volume = 5.7 days) of growth of the LY80 tumor in rats were measured using the hydrogen gas clearance technique. In the first phase of tumor growth, the tumor blood flow was 20.3 +/- 12.2 ml/min/100 g in the daytime zone (n = 22) and 46.6 +/- 19.3 ml/min/100 g in the nighttime zone (n = 22). In the second phase, tumor blood flow was 9.6 +/- 5.7 ml/min/100 g in the daytime zone (n = 45) and 19.4 +/- 8.2 ml/min/100 g in the nighttime zone (n = 38). Tumor blood flow in the nighttime zone was significantly higher than that in the daytime zone (first phase, P less than 0.001; second phase, P less than 0.001). However, there were no significant differences in the mean arterial blood pressure, tumor size, and body weight of rats between the daytime zone and the nighttime zone. There was also a marked difference in the effect of angiotensin II-induced hypertension on tumor blood flow between the daytime zone and the nighttime zone. These results suggest that circadian fluctuations in tumor blood flow should be carefully considered when developing strategies to maximize the effectiveness of cancer therapy in relation to the flow rate of circulating blood.

Angiotensin II↗
PubMed1992

Type I congenital plasminogen deficiency is not a risk factor for thrombosis.

The risk of thrombosis in type I congenital plasminogen (PLG) deficiency has been suggested, but is still not confirmed. We studied 40 members of two unrelated families with this disease, and found that 21 were heterozygotes of type I congenital PLG deficiency. Three of them had thrombosis, but the other 18 had no thrombosis. The percentages of family members with no history of thrombosis up to a given age among subjects with type I congenital PLG deficiency and healthy controls were analyzed by the Kaplan-Meier method. No significant difference between the two groups was observed by the generalized Wilcoxon test (p = 0.23). These results suggest that there is no significant correlation between type I congenital PLG deficiency and thrombosis.

Adult↗
PubMed1992

Expression of the signal transducing regions of CD4-like and lck genes in murine egg.

We previously demonstrated that the MHC class II molecule on murine sperm and CD4-like molecule on the egg vitelline membrane are involved in fertilization. In this study, the RNA transcripts in murine eggs corresponding to parts of the CD4 gene and lck gene in thymocytes were demonstrated by means of the reverse transcriptase (RT)/polymerase chain reaction (PCR) followed by the sequencing of the PCR products. The deduced sequences potentially encode the amino acid sequence of the transmembrane to the cytoplasmic domain of CD4 and that of the N-terminal domain of p56lck respectively. These findings indicate that a signal transducing complex similar to that in immune T cells is expressed at the transcriptional level in murine eggs.

Amino Acid Sequence↗
PubMed1992

Percutaneous fenestration of dissecting intima with a transseptal needle. A new therapeutic technique for visceral ischemia complicating acute aortic dissection.

Noncardiac visceral ischemia is a major complication with acute aortic dissection and is caused by obstruction of the major visceral arteries by dissecting intima. Two patients with this condition underwent emergency percutaneous fenestration of dissecting intima, and the blood flow to the lower extremity and kidney was restored. A transseptal needle and peripheral angioplasty balloon catheter were used for fenestration. There were no associated complications in either patient. One patient was treated medically and another had ascending aortic replacement surgery the day after percutaneous fenestration. Clinical follow-up of 10 and 5 months, respectively, revealed good clinical outcomes. Percutaneous fenestration should be considered the treatment of choice for visceral ischemia due to acute aortic dissection.

Aortic Dissection↗
PubMed1992

HTLV-I infection in patients with autoimmune thyroiditis (Hashimoto's thyroiditis).

To investigate the possible relationship of HTLV-I virus infection to autoimmune thyroid disease, we examined, firstly, the frequency of HTLV-I seropositivity among patients with Hashimoto's thyroiditis and, secondly, the frequency of Hashimoto's thyroiditis in patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Of 144 patients with Hashimoto's thyroiditis in the Tokushima and Kochi Prefectures, Japan, 9 (6.3%) were positive for serum HTLV-I virus antibody 2 of whom were confirmed histologically to have Hashimoto's thyroiditis. This percentage is significantly higher (P < 0.01) than the estimated prevalence (2.2%) of HTLV-I carriers among the general population in this region. Of 9 patients with HAM/TSP, 3 (33.3%), including 2 biopsy-proven cases, had evidence of Hashimoto's thyroiditis. This proportion is apparently much higher than the prevalence (1.7%) of Hashimoto's thyroiditis in the general population. These findings suggest that HTLV-I virus may be related to the development of Hashimoto's thyroiditis.

Adult↗