Biomedical subjects
Publications and source records attributed to T Sano.
1. Clozapine caused dose-dependent inhibition of the release of [14C]serotonin and 45Ca uptake by purified rat peritoneal mast cells activated by concanavalin A, which is similar to the effect of benzodiazepines. 2. However, it had little ability to displace [3H]diazepam binding to mast cells.
A histologic and immunocytochemical study of 69 autopsy-obtained pituitaries from women who died during pregnancy, after abortion, or in the postpartum period revealed an accumulation of large chromophobic to slightly acidophilic and periodic acid-Schiff-negative pregnancy cells that were immunoreactive for prolactin but not for other pituitary hormones. This increase in the number of prolactin cells was confirmed by cell counts. Thus, pregnancy cells are capable of prolactin production. The finding of mitotic figures in such cells supports the view that they arise by multiplication from preexisting prolactin cells. With use of "mirror section" techniques, no mammosomatotrophs (cells immunoreactive for growth hormone and prolactin) were identified. Hyperplasia of prolactin cells was evident at 1 month of pregnancy and gradually disappeared within several months after delivery or abortion; the process of involution seemed to be retarded in the one lactating patient investigated. In some pituitaries, the accumulation of prolactin cells was so extensive that the hyperplastic foci resembled microadenomas. Another striking change in the pituitaries of pregnant women was appreciable reduction of immunostaining of gonadotropic cells, a process that was reversible as soon as 1 month after delivery. Among the 69 pituitaries studied, 8 noninvasive microadenomas (12%) were encountered (7 contained prolactin only and 1 was plurihormonal). Prolactin-producing adenomas were no more numerous or larger than were similar tumors encountered in nonpregnant women or normal men; thus, pregnancy neither initiates formation of pituitary adenomas nor accelerates their growth. In the pituitaries that harbored prolactin-producing adenomas, massive pregnancy cell hyperplasia was evident outside the tumor; thus, prolactin production by adenoma cells did not seem to suppress the proliferation of prolactin-containing pregnancy cells.
We describe the construction of systems for expressing the cloned streptavidin gene in Escherichia coli. Although the streptavidin gene is extremely lethal to the host cells, because of the strong biotin binding of the gene product, the gene was expressed efficiently in E. coli by using T7 RNA polymerase/T7 promoter expression systems. The expressed streptavidin accumulated to more than 35% of the total cell protein. The expressed streptavidin was insoluble in the cell. However, after solubilization by dialysis against 6 M guanidine hydrochloride (pH 1.5) and removal of guanidine hydrochloride by dialysis, the protein became soluble and renatured. This simple procedure yielded streptavidin purified almost to homogeneity. The purified streptavidin bound 3.5-3.9 molecules of biotin per molecule, indicating that it had almost full biotin-binding ability. Some of the purified streptavidin molecules aggregated into oligomers, suggesting that the C-terminal region of the molecule, present in our material but absent in typical preparations, may be responsible for the aggregation.
STUDY OBJECTIVE - The aim of the study was to examine the effects of antihypertensive drugs on heart and resistance vessels to see whether regression of peripheral vascular hypertrophy accompanies reduction in cardiac mass. DESIGN - Matched groups of spontaneously hypertensive and control rats were treated for 12 weeks with captopril (average dose 65 mg.kg-1.d-1) or hydrochlorothiazide (73 mg.kg-1.d-1) and compared to untreated groups. Perfusion pressure, which has been validated as an index of hypertrophy of resistance vessels, was determined in hind limbs of pithed rats at constant blood flow and maximum vasodilatation. SUBJECTS - Experimental animals were 14 week old male spontaneously hypertensive (SHR) rats (n = 41) and strictly age matched Wistar Kyoto rats (n = 12). SHR rats were assigned at random to three groups: (a) captopril treated (n = 15), (b) hydrochlorothiazide treated (n = 15), (c) control (n = 11). MEASUREMENTS and RESULTS - Mean perfusion pressure was 29.5(SEM 0.4) mm Hg in untreated Wistar Kyoto rats and 37.4(0.5) mm Hg in untreated SHR rats. In comparison with untreated SHR rats, treatment with captopril lowered blood pressure, perfusion pressure [35.2(0.3) v 37.4(0.5) mm Hg, p less than 0.01)], and left ventricular to body weight ratio [2.28(0.03) v 2.63(0.05) mg.g-1, p less than 0.01)]. Treatment with hydrochlorothiazide also lowered blood pressure but had no significant effect on left ventricular weight to body weight ratio [2.54(0.04)]. However, perfusion pressure was reduced to 35.3(0.5) mm Hg, p less than 0.01. CONCLUSIONS - For equal regression of vascular hypertrophy, captopril and hydrochlorothiazide had different effects on regression of left ventricular hypertrophy. Thus left ventricular and vascular structural changes may respond differently to the same drug in the same animal.
The expressions of mRNA for epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and EGF receptor (EGFR) genes were examined in 7 human gastric carcinoma cell lines and 15 gastric carcinoma tissues and the corresponding normal mucosas. All of the gastric carcinoma cell lines expressed mRNA for EGFR and TGF-alpha genes. TMK-1 and MKN-28 cells also expressed EGF mRNA. Production of EGF, TGF-alpha and EGFR protein by gastric carcinoma cell lines was also confirmed by EGF and TGF-alpha specific monoclonal antibody binding. As for surgical specimens, EGFR and TGF-alpha mRNA were detected at high levels in all the tumor tissues. Interestingly, EGF mRNA was detected in 5 (33.3%) of the 15 gastric carcinomas but it was not detected in normal tissues. Moreover, anti-EGF and anti-TGF-alpha monoclonal antibodies inhibited the spontaneous 3H-TdR uptake by gastric carcinoma cells. These results suggest that EGF and/or TGF-alpha produced by tumor cells act as autocrine growth factors for gastric carcinomas.
We examined the effects of epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) on EGF receptor (EGFR) phosphorylation and the expression of mRNAs for oncogenes, growth factors, their receptors and metalloproteinase genes by MKN-28 gastric carcinoma cells which express EGF, TGF-alpha and EGFR genes. Both EGF and TGF-alpha stimulated EGFR phosphorylation, EGF and TGF-alpha induced FOS, MYC and ERBB-2 oncogene expression. Interestingly, EGF increased the expression of mRNAs for TGF-alpha and EGFR. On the other hand, TGF-alpha increased TGF-alpha mRNA but decreased the expression of mRNAs for EGFR and TGF-beta. Furthermore, mRNAs for interstitial collagenase, stromelysin and procollagen type I genes were also enhanced after treatment with EGF and TGF-alpha. These results indicate that EGF and TGF-alpha successively evoke cascade phenomena which favor tumor progression, invasion and extracellular matrix formation, acting as autocrine growth regulators for gastric carcinomas.
We investigated whether two representative 1,4-dihydropyridine derivatives, NK-250 and NK-252, could potentiate the antitumor activity of multiple anticancer agents including vincristine (VCR), vinblastine, vindesine and actinomycin D in drug-resistant tumor cells and their parental drug-sensitive tumor cells. NK-250 and NK-252 at 5-10 microM almost completely reversed VCR resistance in cultured VCR-resistant P388/VCR cells derived from the mouse drug-sensitive P388/S leukemia cell line and also potentiated the cytocidal activity of VCR in drug-sensitive P388/S cells. NK-250 and NK-252 at 1-10 microM inhibited the photoaffinity labeling by [3H]azidopine of the cell-surface 170,000-molecular-weight P-glycoprotein. In chemotherapeutic experiments with leukemia-bearing mice, NK-250 or NK-252 was orally administered in combination with different drugs of the MDR phenotype administered intraperitoneally. The antitumor activity of the various combinations was found to be augmented in mice bearing P388/S- and P388/VCR-leukemia. Among the combinations examined, the combination of NK-250 and VCR was the most effective. These two 1,4-dihydropyridines, NK-250 and NK-252, are unique compounds because they were effective not only in circumventing the drug resistance, but also in potentiating the action of antitumor drugs against drug-sensitive tumors.
A case of giant cell fibroblastoma occurring in the knee of a 16-month-old girl is reported. The ill-defined subcutaneous tumor measuring 2 x 2 cm was composed of diffusely proliferating spindle-shaped tumor cells with scattered, atypical multinucleated giant cells in a myxoid or collagenous background and irregularly branching sinusoid-like tissue spaces. In addition to floret-type giant cells, a few osteoclast-like giant cells were present in a cellular area where tumor cells were focally arranged in a storiform pattern. Immunohistochemically, the tumor cells gave positive reactions for only vimentin and actin. In spite of the high recurrence rate of this type of tumor, the course of the patient after excision of the tumor has been uneventful. It is important to distinguish this rare, peculiar fibrous tumor from other soft tissue tumors including some sarcomas.
1. The cardioprotective effects of antiarrhythmic agents classified as class III, amiodarone, sotalol and E-4031, were investigated in anaesthetized dogs. 2. The left anterior descending coronary artery was occluded for 2 h. 3. Heart mitochondria were prepared from both the ischaemic and non-ischaemic areas, and their function was estimated polarographically. 4. Activities of the lysosomal enzymes, N-acetyl-beta-glucosaminidase and beta-glucuronidase, were measured in each fraction. 5. Two hour occlusion induced ventricular arrhythmias, and amiodarone, sotalol and E-4031 greatly suppressed the development of arrhythmias. 6. Amiodarone, sotalol and E-4031 significantly protected mitochondria against ischaemia, and prevented ischaemia-induced leakage of lysosomal enzymes. 7. Antiarrhythmic agents classified as class III show cardioprotective effects, which might participate in their antiarrhythmic effect.
Galanin is a 29-amino acid neuropeptide widely distributed in the central nervous system. Galanin-like immunoreactivity (galanin-LI) was investigated in 23 nontumorous human adenohypophyses and 27 pituitary adenomas. Galanin-LI was demonstrated by immunohistochemistry on formalin-fixed paraffin-embedded sections, using the avidin-biotin-peroxidase complex method. All 23 nontumorous pituitaries showed the presence of galanin-positive cells which were similar to the corticotrophs in shape, size, histological features, and distribution. Immunoreactivity based on the study of mirror sections was found to be present in the cytoplasm of corticotrophs, indicating that galanin-LI colocalizes with ACTH. Crooke's cells and basophilic cells spreading to the posterior lobe (basophil invasion) were also positive for galanin. No galanin-LI was seen in lactotrophs of the human pituitaries, including 4 estrogen-treated men and 4 pregnant women. Varying numbers of tumor cells in 13 of 18 corticotroph adenomas were positive for galanin. Galanin-LI and ACTH were coexpressed in the cytoplasm of the same adenoma cells. In 19 pituitary adenomas composed of cells other than corticotrophs, no galanin-LI was noted. This study is the first report providing evidence of the presence of galanin-LI in corticotrophs of the human pituitary.
Two cases of dilated cardiomyopathy with incessant supraventricular tachycardia were treated with beta-blockade. Propranolol at a dose of 30 mg per day in combination with diuretics and digitalis decreased atrial rate of tachycardia and the cardiac size in both cases. The careful administration of beta-blockade seems to be one of the choices for the treatment for atrial tachycardia associated with dilated cardiomyopathy.
A 59-year-old man with a gastric cancer underwent a laparotomy and was found to have an unresectable tumor that formed a large mass with metastatic lymph nodes around the aorta. He therefore was treated by a combined administration of Mitomycin C, FT-207, and Lentinan for 3 months. Remarkable tumor reduction was observed endoscopically, and a subtotal gastrectomy was performed. The immunochemotherapy then was resumed, and the patient has survived for 16 months despite the remnant lymph node metastases. A histological examination of the resected stomach revealed a marked degeneration of the tumor.
A 48-year-old male was admitted for further examination of a coin lesion with a diameter of 8 mm seen on chest X-ray. The patient was a heavy smoker and his serum level of CEA was elevated to 29.8 ng/ml. Since the broncho-fiberscopic examination was not able to yield a definitive diagnosis, an operation was performed as lung cancer was suspected. According to the histological examination, the small nodule was diagnosed as an intrapulmonary lymph node with anthracosis and silicotic nodules. A review of the limited number of case reports shows that men are more prone to intrapulmonary lymph nodes, and that the patients were all smokers but not necessarily with occupational experience of exposure to silica.
We studied four patients (a mother, her two daughters, and her son) with bullous mastocytosis, or diffuse cutaneous mastocytosis, whose genetic inheritance suggested an autosomal dominant pattern. The clinical characteristics included extensive bullae, numerous urticaria, pruritus, flushing, and pseudolichenified skin over all body surfaces without systemic organ involvement. The histopathologic findings disclosed a pronounced accumulation of mast cells in the dermis. Electron microscopic studies of lesional skin obtained in infancy showed round or spindle-shaped mast cells with numerous fingerlike villous protrusions. The cytoplasmic granules varied in size and shape, and the appearance of degranulation was markedly noted. In the adult, most mast cells had markedly decreased numbers of granules and cytoplasmic villi. Some cells displayed degenerative or necrotic appearances. These findings correlated well with the clinical course of these cases, which improved spontaneously over time.
The influence of right ventricular (RV) volume overload by pulmonary regurgitation (PR) on left ventricular (LV) function was evaluated postoperatively in 23 patients with tetralogy of Fallot (TF). The age at operation was 3.1 +/- 1.7 (mean +/- SD) years. The age at postoperative study was 5.9 +/- 2.0 years. We determined RV end-diastolic volume (%RVEDV), RV ejection fraction (EF), %LVEDV, LV end-systolic volume (%LVESV), LVEF, and LV end-systolic stress (ESS)/%LVESV. Patients were divided into 2 groups on the basis of presence or absence of RV volume overload by PR as follows: The %RVEDV (175 +/- 23%) of group 1 (n = 10) was 150% greater than normal RVEDV. Group 2 (n = 13) had normal %RVEDV (108 +/- 23%). Preoperatively, there had been no differences in hemoglobin, %RVEDV, RVEF, %LVEDV, LVEF, and in the ratio of average cross-sectional area of the left and right pulmonary arteries to cross-sectional area of the normal right pulmonary artery between the 2 groups. Moreover, there were no differences in age at repair, or during postoperative study, nor in the postoperative ratio of RV to LV systolic pressure between the 2 groups. RVEF was significantly less in group 1 than in group 2 (0.53 +/- 0.05 vs 0.58 +/- 0.05, p less than 0.05). %LVEDV and %LVESV in group 1, 138 +/- 10% and 171 +/- 30% respectively, were significantly greater than those in group 2, 116 +/- 11% and 133 +/- 20% respectively (p less than 0.001 in %LVEDV and p less than 0.01 in %LVESV).(ABSTRACT TRUNCATED AT 250 WORDS)
During the period 1962-1986, 43 lung cancer patients, 2.3% of the 1,832 patients who underwent pulmonary resections at the National Cancer Center Hospital, Tokyo, had tumors greater than 10 cm in diameter. These 43 cancers were classified postsurgically according to the 1987 guidelines for TNM classification of malignant tumors established by Union Internationale Contre le Cancer (UICC), and included 35 cases (81.0%) in stages IIIA, IIIB and IV. The histological tumor types were adenocarcinoma in 18 cases (41.9%), squamous cell carcinoma in 13 (30.2%), large cell carcinoma in 11 (25.6%) and adenosquamous cell carcinoma in one (2.3%). Twenty-two patients underwent pneumonectomy and 21, lobectomy. In terms of the radical extent of surgery, 16 patients underwent a curative operation (37.2%) and 27 received non-curative surgery (62.8%). Excluding one patient who died of an unknown postoperative cause, the overall cumulative five-year survival rate was 19.7%. There was, however, no significant difference in five-year survival rates between the patients who underwent a curative operation (21.5%) and those who received non-curative surgery (18.8%). There was no significant difference in five-year survival rates between patients with adenocarcinoma (21.2%), those with squamous cell carcinoma (15.4%) and those with large cell carcinoma (27.3%). There was little difference in five-year survival rates between patients with postoperative stage I or stage II tumors (25.0%), patients with stage IIIA tumors (9.5%), patients with stage IIIB tumors (30.0%) and patients with stage IV tumors (20.0%), while the five-year survival rates for patients with postoperative N0 disease were 33.3%, N1 disease 28.9% and N2 disease 0%. Among the 42 patients the survival study, there were eight long-term survivors (greater than 5 yr), all of whom had been in N0 or N1 stage and four of whom had undergone curative surgery. Two were classified as being in stage T4 with malignant pleural effusions, and the other two as being in stage M1 with intrapulmonary metastasis. Patients with N2 disease have an unfavorable prognosis and may be considered suitable for studies on adjuvant therapy, although the relative influence of other prognostic factors must be considered. Classifying the tumors according to whether or not they had reached 10 cm in diameter was of no importance.
From 1962 through 1988, a total of 29 consecutive patients had completion pneumonectomy (CP). Indications for initial pulmonary resection were primary lung cancer in 27 patients, metastatic lung tumor in 1, and mediastinal tumor with pulmonary invasion in 1. Indications for CP were lung cancer (including local recurrence, pulmonary metastasis from the first lung cancer, and second primary lung cancer) in 21 patients, complications after initial operations in 7, and pulmonary arterial injury during second operation in 1. Severe adhesion of the residual lung and the hilar structures made operative procedures extremely difficult. Injury of pulmonary arteries occurred in 6 patients. Especially, in cases the left upper lobe had been resected previously, deviation of the lower lobe and hilar adhesion lead to operative difficulty. Post-CP bronchial fistula occurred more frequently in what the bronchi had been dissected at more peripheral level than main bronchus, because of some severe hilar adhesions. Operative mortality was 13.8% (9.5% for second lung cancer, 28.5% for post-operative complication). Five-year survival for patients with lung cancer was 32.9% according to the Kaplan-Meier method. We conclude that the indications for CP are clinically resectable lung cancer and bronchial stenosis with residual pulmonary organic changes following bronhoplastic procedure. Postoperative bronchofistulae should be managed by other operative procedure.
We evaluated right and left atrial (RA and LA) volumes after modified Fontan operation in 6 patients, in 1 with mitral atresia and 5 with single ventricle. The age at operation was 10.2 +/- 2.5 (mean +/- SD) years. The interval between operation and study was 4.1 +/- 4.8 months. RA and LA maximum volume indexes (VImax) (ml/m2) were measured by angiography. One patient died 72 days after operation due to low output syndrome. In survived patients (n = 5), postoperative pulmonary arterial wedge pressure was 6 +/- 3 mmHg, right atrial pressure 13 +/- 5 mmHg, and end-diastolic pressure in the systemic ventricle 6 +/- 3 mmHg, and one who died had 18 mmHg, 25 mmHg, and 9 mmHg in each parameter, respectively. LAVImax in the survivors (53 +/- 18 ml/m2) were in the range of normal or above normal value. The nonsurvivor had extremely small LAVImax (13 ml/m2). RAVImax in the alive patients (25 +/- 11 ml/m2) was smaller than normal (data was not available in a non-survived patient). These results may indicate that a normal LA volume appears to be as important factor for the prognosis after modified Fontan operations with intraatrial routing for complex lesions regardless of the postoperative RA volume.