Biomedical subjects
Publications and source records attributed to H Fujii.
The present study examined an 11-year-old girl with Down syndrome who suffered from acute myeloblastic leukemia (AML) preceded by preleukemic pancytopenia. Chromosomal analysis of leukemic cells revealed a chromosome change at t(8;21) and trisomy 8 associated with constitutional trisomy 21. Treatment with antineoplastic agents led to complete remission.
OBJECTIVES: We examined whether there is a gender difference in the improvement of endothelium-dependent vasodilation after estrogen supplementation. BACKGROUND: Estrogen therapy reduces the risk of cardiovascular events in postmenopausal women, and the augmented release of endothelium-derived nitric oxide (NO) by estrogens has been suggested to be one of the mechanisms for the cardioprotective effects of estrogen. METHODS: With ultrasound technique, we measured the diameter and blood flow of the brachial artery at rest, during reactive hyperemia after transient occlusion and after nitroglycerin administration before and after estradiol supplementation in 15 postmenopausal women (mean 63 years) and in 15 men matched for age and risk factors for atherosclerosis. RESULTS: Estradiol supplementation augmented the flow-mediated vasodilation and serum level of nitrite/nitrate (metabolites of NO) in women (respectively, from mean +/- SEM of 8.0 +/- 0.6% to 12.9 +/- 0.6% [p < 0.01 by analysis of variance (ANOVA)] and from 64.9 +/- 8.7 to 93.7 +/- 9.4 mumol/liter [p < 0.05 by ANOVA]) but not in men (respectively, from 8.1 +/- 0.6% to 8.3 +/- 0.7% and from 57.8 +/- 6.7 to 60.8 +/- 5.4 mumol/liter). The increases in blood flow during reactive hyperemia and in diameter after nitroglycerin administration were not affected by estradiol supplementation in either men or women. CONCLUSIONS: Estradiol supplementation improves endothelium-dependent vasodilation in women, probably because of augmented NO production/release, but not in men. Thus, there may be gender differences in the effects of estrogen therapy on endothelial functions and NO production/release.
Cutaneous fatty acid-binding protein (C-FABP) has been newly discovered from rat skin. The immunohistochemical study revealed that C-FABP is strongly expressed in rat epidermis. Recently, a highly homologous protein to rat C-FABP was found in psoriatic epidermis, which is termed psoriasis-associated fatty acid-binding protein (PA-FABP). In the present study, we investigated the expression of PA-FABP in normal and pathological human skin using immunohistochemical techniques. In normal skin, PA-FABP was expressed in basal and prickle cell layers, and more strongly in the granular cell layer. The expression pattern of PA-FABP was similar to that of C-FABP in rat skin. In psoriatic skin, PA-FABP was expressed in suprabasal layers and more strongly in more differentiated keratinocytes. In squamous cell carcinoma, PA-FABP showed very strong expression in squamous nests. These results indicate that PA-FABP is a human homologue of C-FABP. Moreover, it is suggested that C-FABP has important roles in the transport and metabolism of fatty acids in epidermis and that altered lipid metabolism may affect the proliferation and/or differentiation of keratinocyte.
Osteoclasts are multinuclear bone-resorbing cells which contain abundant mitochondria. Morphological studies have suggested that a correlation may exist between mitochondrial concentration and bone resorption by osteoclasts. However, investigation of mitochondrial transmembrane potential (delta psi) and volume has been hampered by the difficulty in obtaining a sufficient number of osteoclasts for assessing these characteristics by flow cytometric analysis. In this study, we have used confocal laser scanning microscopy after loading the cells with Rhodamine 123 and 10-nonyl Acridine Orange to record mitochondrial delta psi and volume, respectively, in isolated rat osteoclasts cultured on bovine bone slices. Optimal staining conditions were found to be 10 micrograms ml-1 for 40 min for Rhodamine, and 1 microM for 10 min for the 10-nonyl Acridine Orange derivative. Two osteoclast populations, whose shape seemed to reflect bone resorption and migratory functions, were identified depending on their shape and on the distribution of the two dye probes. 'Round-shaped' osteoclasts had significantly higher mitochondrial delta psi and volume in the apical regions than in the basolateral portions (p < 0.00001). In contrast, mitochondrial delta psi and volume in 'irregular-shaped' osteoclasts were rather evenly distributed in both these regions (p > 0.05). Our results indicate that there is an apical polarization of mitochondria in osteoclasts corresponding to the energy demands associated with bone resorption.
We attempted to characterize the motivation, comprehension and expectations of patients who had given informed consent to participate in phase I trials of anti-cancer agents at the National Cancer Center of Japan. Thirty-three patients were given a simple multiple-choice questionnaire and asked to return it at a later date. The completed survey was returned by 32 patients. The patients were surveyed before they had received any investigational phase I agents. Nineteen per cent of patients were motivated to participate in the phase I trials by the possibility of therapeutic benefit, 9% because participation seemed a better choice than no treatment and only 6% for altruistic reasons. Most patients comprehended the major features of a phase I trial, namely its investigational nature, the unknown effects of the agent investigated and the unclear benefit to the patients themselves. Fifty-nine per cent of the patients anticipated that they might suffer severe or life-threatening side-effects if they participated in the phase I trial, and 43% were able to indicate accurately the purpose of the phase I trial as a dose determination study. Although only a minority of the patients indicated that their motivation to participate was possible treatment benefit to themselves, when answering questions regarding expectations, more than half indicated that there might be personal benefits of varying degrees by participation.
Explore the source record for details and available documents.
We recently reported an internal tandem duplication of the human flt3 receptor gene (FLT3) as a somatic mutation in 17% of acute myelogenous leukemia (AML). The present study revealed the duplication at the juxtamembrane and the first tyrosine kinase domains of FLT3 in seven of 92 (8%) patients with myelodysplastic syndrome (MDS) and AML with trilineage myelodysplasia (AML/TMDS), the diseases which may represent neoplastic changes of pluripotent stem cells. A tandem duplication of exon 11 of FLT3 was harbored by two of 58 (3%) patients with MDS and five of 34 (15%) with overt leukemia, including MDS-derived leukemia, AML/TMDS and therapy-related leukemia. Although the duplicated regions varied within exon 11 in each case, they occurred in-frame, and altered mRNA expressions were demonstrated by reverse-transcription polymerase chain reaction. Two cases of MDS with a FLT3 duplication transformed to overt leukemia within a few months. Longitudinal analyses in two other patients with leukemia revealed that the duplication was a late genetic event during the disease course; one of whom showed two independent duplications of FLT3 at the terminal therapy-resistant phase. Of seven patients with the FLT3 duplication, six had abnormal karyotypes, and four harbored a point mutation of the N-RAS and/or TP53 genes. Patients with FLT3 mutations have poor prognoses. This study uncovered the fact that the accumulation of genetic events, including FLT3 duplication, correlates with leukemic transformation from antecedent myelodysplasia and with subsequent disease progression.
This study was conducted to assess the merit of lecithinization of recombinant human interleukin-6 (IL-6) as a drug delivery system. IL-6 was lecithinized by covalently binding it with a phosphatidylcholine (lecithin, PC) derivative. The in-vivo thrombopoietic potency of lecithinized IL-6 (PC-IL-6) was greater than that of native IL-6 when administered subcutaneously, although the in-vitro bioactivity of PC-IL-6 was markedly reduced by lecithinization. When PC-IL-6 and native IL-6 were given in doses that produced the same level of thrombopoietic activity, the former stimulated less production of IgG1, a marker of the adverse effects of IL-6, than did the latter. Furthermore, PC-IL-6 persisted in the blood longer than native IL-6. Based on the above, PC-IL-6 appears to be useful as a drug delivery system and may also be useful in the treatment of drug-induced thrombocytopenia.
We investigated the function of splenic macrophages (M phi s) with respect to changes in plasma tumor necrosis factor (TNF) in lethally endotoxemic rats treated with gadolinium chloride (GdCl3), which blocks the phagocytosis of large liver M phi s. We also carried out an immunohistochemical study to investigate the change of populations of liver and splenic M phi s under the condition of dysfunction of liver M phi s with or without splenectomy. Twenty-four-hour survival rates were 100% in the GdCl3-treated group (n = 6) and 0% in the nontreated group (n = 6). These rates did not change with splenectomy. Immunohistochemical examination with the primary monoclonal antibodies ED1, ED2 and ED3 revealed that large liver M phi s were eliminated after GdCl3 injection, and that this was not related to splenectomy. The splenic M phi s were not affected by GdCl3 treatment. Plasma TNF levels did not differ between the GdCl3-treated and the nontreated groups, irrespective of whether splenectomy was performed. It was suggested that plasma TNF levels are not affected by the splenic M phi s and that they do not compensate for dysfunction of liver M phi s after GdCl3 treatment.
Tumor necrosis factor-alpha (TNF alpha) is an important mediator of endotoxic and septic shock. We previously reported that the survival rate in a rat sepsis model was improved by the administration of gadolinium chloride (GdCl3), whereas the level of TNF alpha in the blood was not affected. In the present study, we examined the effect of GdCl3 on endothelial permeability in vitro. Endothelial permeability was monitored by measuring the amount of fluorescein isothiocyanate-labeled dextran (FITC-Dx) passing through the calf pulmonary arterial endothelial (CPAE) cell monolayer. The incubation of the CPAE cell monolayer with TNF alpha (10-500 JUR/ml for 6-24 h) caused a dose- and time-dependent increase in the permeation of FITC-Dx passing through the monolayer. Whereas the integrity of the monolayer was not affected after preincubation with GdCl3 at concentrations from 10(-7) to 10(-4) M, the increased endothelial permeability induced by TNF alpha was inhibited by a pretreatment of the CPAE cell monolayer with GdCl3 in a dose-dependent manner. Our results suggest that GdCl3 has a protective effect on the endothelial cell monolayer exposed to TNF alpha.
Intraportal vein injection of highly metastatic L5 cells consistently resulted in liver metastases (increases in the number of tumor colonies in the liver), whereas inoculation of P cells rarely did. L5 cells invaded the basement membrane Matrigel in greater numbers than did P cells, suggesting that the metastatic potential of L5 cells is partly related to enhanced invasive properties. The enhanced adhesion of L5 cells to fibronectin-, laminin- and Matrigel-coated substrates, as well as their haptotactic migration to fribronectin, may be associated with the preferential expression of VLA-2 and VLA-4 integrins on the surface of these cells detected by flow cytometry. Gelatin zymograms showed that the degradative activity of 72-kD gelatinases was greater in L5 cells than P cells. These results indicate that, in addition to adhesiveness and motility, the invasive ability of L5 cells may also be attributed to enhanced gelatinolytic activity. L5 cells grew more rapidly than P cells in vitro. Thus, an experimental model using highly metastatic colon 26 L5 cells would be useful for analyzing the molecular mechanism of liver metastasis and for evaluating the efficacy of treatment of occult micrometastases which may already have been disseminated at the time of surgery.
Tumor metastasis into distinct organs and tissues, of which many patients with malignancies die, is regulated in multiple steps. Using a murine metastasis model, in which highly metastatic B16-BL6 melanoma cells were inoculated i.v. into syngeneic C57BL/6 mice, the administration of a recombinant human tissue inhibitor of metalloproteinases-2 (r-hTIMP-2) once a day on days -1 to 3 after the implantation significantly inhibited the formation of metastatic foci in the lungs. The antimetastatic effect of r-hTIMP-2 was detected irrespective of administration route [i.v., i.p., s.c., and i.m. routes] and in a dose-dependent manner. The i.m.-injection of r-hTIMP-2 during the early phase after tumor inoculation is suggested to be essential for antimetastasis. In another model using spontaneously metastasing B16-BL6 cells, multiple i.m.-injections of r-hTIMP-2 also resulted in a reduced but not statistically significant number of pulmonary metastases. In addition to these antimetastatic effects, a slight inhibitory effect on tumor cell growth was observed in vitro and in vivo. In conclusion, the antimetastasis by r-hTIMP-2 may be due to inhibition of the degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and, in part, to the suppression of the tumor cell growth.
A 73-year-old woman suffering from hypertension and asthma had chest radiography, which showed the shadow of a lump on the inner side of the right lung apex. From a chest CT scan, it was diagnosed as an upper mediastinal tumor (circular in shape with a diameter of 19 x 23 mm) adjacent to the right rib and showing a low-absorption range. Histopathology confirmed the diagnosis as an Antoni B-type melanotic schwannoma. On suspicion of secondary hypertension, the amount of urinary catecholamine was measured before surgery and this revealed high levels of total catecholamine (184.4 micrograms/day), dopamine (1134.6 micrograms/day) and noradrenaline (169.7 micrograms/day). A normal value of 14.7 micrograms/day of adrenalin was obtained. These measurements were conducted again after surgery, and normal values of 127.8 micrograms/day of total catecholamine, 388.6 micrograms/day of dopamine, 117.9 micrograms/day of noradrenalin and 9.9 micrograms/day of adrenalin were obtained. In view of these findings, the tumor was thought to be a neurogenic tumor of the sympathetic nervous system and capable of generating melanin. Incidentally, after removal of the tumor, the patient's hypertension became less severe and there was improvement in her asthma attacks.
Extended calcification of the total aorta and arch vessels may make coronary revascularization with cardiopulmonary bypass impossible. We report the left thoracotomy approach for a case of a 70-years diabetic man who was revascularized without cardiopulmonary bypass because of porcelain aorta extended into abdominal aorta, the arch vessels and femoral arteries. He had had prior anterior wall infarction. Cardiac catheterization showed poor ventricular function with an EF of 25% and there was a 60% occlusion of left main trunk, 90% occlusion of circumflex coronary. Through a left thoracotomy, saphenous vein grafting was performed without cardiopulmonary bypass from the noncalcified left subclavian artery to the circumflex coronary artery. During distal anastomosis, distal perfusion of coronary artery was carried out to support the heart up. Intraoperatively, hemodynamic remained stable with no electrocardiographic change. This technique may offer a practical solution to this problem.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
We measured the blood flow velocity in human retinal veins using a laser speckle flowgraphy system. This system consists of a fundus camera, a diode laser, an image sensor and a personal computer system. The fundus is illuminated with a diode laser through a fundus camera and the laser speckle pattern is imaged onto the area sensor. From the time change of contrast of speckle pattern, normalized blur (NB) value, a quantitative index of tissue blood velocity, was calculated by means of a logistic board, and two-dimensional distribution of NB in the measurement field was displayed in a color display. In the in vitro experiment, the NB obtained from the blood flow in a glass capillary tube was correlated with the diameter of the tube, background NB value and the blood flow rate actually measured. In the in vivo experiment, the blood velocity in human retinal veins of approximately 50 microns in diameter was estimated in 16 normal eyes using nomograms based on the results of the in vitro experiment. Velocity averaged 11.1 +/- 0.6 mm/ sec (mean +/- standard deviation, n = 16) in retinal veins of 53 +/- 6 microns in diameter and the reproducibility index of the in vivo measurements was 2.5 +/- 0.9%.
There is considerable variation in the assays used to evaluate the expression of mdr1 in various human malignancies. Current methodology includes reverse transcriptase polymerase chain reaction (RT-PCR) for assay of mdr1 mRNA, and immunohistochemistry or flow cytometry for detection of the multidrug transporter, P-glycoprotein(P-gp). Normal tissues, such as gastrointestinal mucosa, biliary tract and kidney, express high levels of P-gp, which suggests physiologic functions for this transporter. The some evidence suggests that mdr1 expression is a prognostic factor for response to chemotherapy, as well as for subsequent survival in various kind of tumors. We have developed a novel method using flow cytometry for detection of P-gp in gastric carcinomas. A strong correlation was noted between the flow cytometric data and the degree of drug resistance assessed by thymidine incorporation assay (TIA). We believe that this technique may have a significant potential to be utilized in prediction of P-gp related drug resistance in clinical cancer chemotherapy.