Biomedical subjects
H Fujii
Publications and source records attributed to H Fujii.
[Farnesoid X receptor(FXR)].
Explore the source record for details and available documents.
[Effect of fluticasone propionate at half dose of beclomethasone dipropionate divided twice daily and once daily in asthmatics inhaling beclomethasone dipropionate 800 micrograms daily or more].
We conducted a 12 weeks' single-arm prospective study comparing beclomethasone dipropionate (BDP), 1/2 doses of fluticasone propionate (FP) twice daily and the same dose of FP once daily in 47 asthmatics who had been inhaling BDP 800 mcg daily or more. Peak expiratory flow (PEF), FEV1, a symptom score and a frequency of beta 2 agonist were all significantly better in FP twice daily phase than BDP phase (329 vs. 306 L/min, 1.87 vs. 1.76 L, 3.6 vs. 6.0/week and 2.7 vs. 4.5 puffs/day, respectively). There was no significant difference in these endpoints between FP twice daily phase and FP once daily phase. FP twice daily produced better plumonary function and symptom relief than the double doses of BDP. Furthermore, FP twice daily could, at least in a short-term basis, safely be changed into the same doses of FP once daily.
18F-FDG PET detection of colonic adenomas.
UNLABELLED: The adenomatous polyp of the colon is clinically important as a precursor of colonic cancer. The aim of this preliminary study was to evaluate the potential usefulness of (18)F-FDG PET for detecting adenomatous polyps of the colon. METHODS: We performed a retrospective study of 110 subjects who underwent both PET study and total colonoscopy. On nonattenuation-corrected PET images, focal distinct FDG accumulation along the large intestine was considered a positive finding, and the PET results were compared with colonoscopic findings. Histology and adenoma size were determined by polypectomy. RESULTS: Fifty-nine adenomatous polyps, 5-30 mm in size, were found in 30 subjects by total colonoscopy. PET findings were positive for 14 of the 59 adenomas (24%). The positivity rate for PET images rose with the increase in size of the adenomas; it was 90% in adenomas (9/10) that were > or =13 mm. The overall false-positive rate was 5.5% (6/110 subjects). CONCLUSION: Increased glucose metabolism is observed in colonic adenomas, and detectability with PET increases with the increase in adenoma size. Adenomas are premalignant lesions, and it is important to realize that colonic adenomas may be found incidentally during an FDG PET study.
Optimal duration of oral adjuvant chemotherapy with Carmofur in the colorectal cancer patients: the Kansai Carmofur Study Group trial III.
A multi-institutional study was performed to evaluate the appropriate duration of oral administration of Carmofur (1-hexylcarbamoyl-5-fluorouracil, HCFU), a 5-fluorouracil (5-FU) derivative, for postoperative adjuvant chemotherapy in patients with colorectal cancer undergoing curative operation. Patients were divided into two: i) short duration group receiving 6 months of HCFU administration and ii) long duration group receiving 1 year of the administration, using a centralized registration system. Among 364 patients entered in this study, 293 evaluable cases were analyzed to investigate the appropriate duration of adjuvant oral chemotherapy. No statistical differences were found in the cumulative 5-year disease-free or survival rates between the groups. However, the actual duration of oral HCFU administration differed in the patients of short and long duration groups from the protocol. Namely, more than 70% of the patients received a different duration of oral adjuvant chemotherapy in each of the groups. Therefore, apart from this division of two groups, correlation between the actual duration of oral HCFU administration and the prognosis was examined in these patients. As a result, it was suggested that oral adjuvant chemotherapy with HCFU would be effective in colon cancer patients when the duration of administration exceeded 330 days. In rectal cancer patients, however, adjuvant chemotherapy with HCFU alone was considered to be not sufficient to affect the prognosis.
[Contrast enhancement for sentinel lymph node imaging].
The paper proposes a new contrast enhancement method for sentinel lymph node imaging. The sentinel lymph node image acquired by a conventional gamma camera system has a wide dynamic range, so that the contrast of sentinel lymph nodes relatively decreases. The proposed method, which is named an annular background subtraction (ABS) method, first found the center of the distribution of activity. Then we calculated the mean value in each annular area centered at the injection point of radiopharmaceuticals with one pixel width. The original image was subtracted by the mean value at each annular area. The performance of the proposed method was confirmed by clinical data.
Preliminary study for sentinel lymph node identification with Tc-99m tin colloid in patients with esophageal or gastric cancer.
The purpose of this study is to determine whether a lymph node identified with high radioisotope (RI) activity is a sentinel node. We studied 26 patients with either esophageal or gastric cancer whose preoperative imaging studies showed no lymph node metastasis. Before surgery, Tc-99m tin colloid was injected via endoscopy into the submucosa. In lymph nodes dissected at surgery, RI activity was measured by a scintillation counter, and metastatic status was examined by hematoxylin-eosin staining. The number of dissected nodes was 45 +/- 15 (mean +/- SD) per patient, and the number of nodes with high RI activity was 4 +/- 1. Nodal metastasis occurred in 11 of 26 patients. In 9 of these 11 patients, metastatic foci were found in one or more nodes with high RI activity. In one of the 2 remaining patients, endoscopic clipping was applied just above the injection sites, and in the other patient, the tumor invasion was beyond the muscle layer. For further analysis, the case with clipping was excluded, and only those in which the tumor invasion was confined within the muscle layer were evaluated. Six of 18 patients in this analysis showed nodal metastasis. Each of the 6 patients had at least one node that showed high RI activity and that was positive for metastasis. We conclude that when tumor invasion remains within the muscle layer, lymph nodes with high RI activity can be regarded as sentinel nodes.
Phase I and pharmacological study of a new camptothecin derivative, exatecan mesylate (DX-8951f), infused over 30 minutes every three weeks.
PURPOSE: A Phase I study of exatecan, a new water-soluble camptothecin derivative, was conducted to determine the maximum tolerated dose and a recommended dose, according to an internationally standardized core protocol. Pharmacological profiles of lactone and total (lactone + carboxylate) exatecan were also investigated. PATIENTS AND METHODS: Fifteen patients with advanced solid malignancies were treated with 3, 5, and 6.65 mg/m(2) of exatecan infused over 30 min every 3 weeks. Concentrations of lactone, total drug, and a metabolite in plasma and urine were determined during the first course. RESULTS: Dose-limiting neutropenia and liver dysfunction were observed in two of six patients at 6.65 mg/m(2), but no grade 3 or worse diarrhea was observed. Emesis was moderate, and no grade 3 or worse nausea and vomiting were observed at a recommended dose of 5 mg/m(2), with prophylactic use of granisetron. Pharmacokinetics were linear and had moderate variability; clearances of lactone and total drug were 6.8 +/- 2.8 and 2.1 +/- 1.1 (mean +/- SD) l/h/m(2), respectively. The ratio of lactone concentration to total drug concentration in plasma decreased from 0.81 +/- 0.06 at the end of infusion to 0.15 +/- 0.06 10 h after the infusion. The lactone:total ratio of drug exposure was 0.30 +/- 0.08, ranging from 0.16 to 0.43. Neutropenia was related to the drug exposure of both lactone and total drug. CONCLUSIONS: The recommended dose of exatecan infused over 30 min every 3 weeks is 5 mg/m(2), with a favorable toxicity profile of mild and infrequent diarrhea. Interpatient variability of pharmacokinetics was similar to or smaller than that with other camptothecin derivatives.
Laparoscopic detection of sentinel lymph nodes in gastrointestinal cancer: a novel and minimally invasive approach.
Although the sentinel node (SN) concept has been validated in malignant melanoma and breast cancer, the application of this concept for other solid tumors, including gastrointestinal (GI) cancer, is still controversial. We have demonstrated the feasibility of radioguided SN mapping during laparotomy in patients with esophageal, gastric, and colorectal cancers. In 188 patients, the SNs identified by this technique had an overall diagnostic accuracy of 96% for regional lymph node metastasis. Aberrant drainage sites that have been called skip metastasis from the primary lesion were detectable using this method. More recently, we have undertaken SN mapping during laparoscopic surgery. A combination of radiotracer and blue dye optimized the identification of SNs that drained GI cancers. Our preliminary data indicate that laparoscopic mapping of the SN is a sensitive intraoperative technique for identifying lymph node micrometastasis, and we believe that it will become an important component of a minimally invasive approach to early-stage GI cancers.
[Clinical significance of sentinel node navigation surgery in the treatment of early gastric cancer].
Radical lymphadenectomy is the standard surgical approach even for early-stage gastric cancer with a relatively low incidence of lymph node metastasis because of the limited sensitivity of diagnostic imaging to detect micrometastasis in regional lymph nodes. The sentinel node (SN) concept is one topic among novel diagnostic procedures for micrometastasis. The SN is defined as the first draining node from the primary lesion and it would be the first site of micrometastasis. SN biopsy has been clinically validated and applied for the surgical treatment of malignant melanoma and breast cancer. Although the feasibility of this technique in other solid tumors including gastric cancer is still controversial, there are several reports demonstrating the diagnostic significance of SN mapping in early gastric cancer. We have established radio-guided SN mapping for early gastric cancer, and the diagnostic accuracy using this procedure in cT1N0 cases reached 98%. The radio-guided method allows us to detect the SN in endoscopic surgery quantitatively and reproducibly. Validation of the SN concept in gastric cancer in a multi-centric clinical trial is essential for clinical application of this procedure, including the establishment of a novel, minimally invasive approach for early-stage gastric cancer.
Synthesis of optically active TAN-67, a highly selective delta opioid receptor agonist, and investigation of its pharmacological properties.
We have synthesized the nonpeptidic highly selective delta opioid receptor agonist, (+/-)-TAN-67, (4aS*, 12aR*)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydropyrido [3,4-b] acridine. In spite of high potent agonist activity for the delta opioid receptor in in vitro assay, (+/-)-TAN-67 afforded no analgesic activity in the mouse warm-plate test. This result led us to separate (+/-)-TAN-67 into optically pure compounds. Each enantiomer of racemic TAN-67 was synthesized from the corresponding optically active 6-oxodecahydroisoquinoline which was obtained by fractional recrystallization of its optically pure di-p-toluoyl tartaric acid salt. In bioassay using mouse vas deferens, (-)-TAN-67 showed full agonist activity (IC50 = 3.65 nM). On the other hand, (+)-TAN-67 showed almost no agonist activity, but interestingly afforded hyperalgesic activity in vivo (i.t. injection).
[Clinical significance and interpretation of red cell enzyme analyses].
Red cells have a life span of approximately 120 days and disturbances at biochemical pathways such as glycolysis, pentose phosphate shunt, nucleotide metabolism or glutathione synthesis/reduction systems lead to premature cell death, i.e. hemolysis. Red cell enzyme analysis is useful for screening for an enzyme defect which is responsible for hereditary nonspherocytic hemolytic anemia (HNSHA). Further clinical significance of red cell enzyme assay includes the diagnosis of paroxysmal nocturnal hemoglobinuria, methemoglobinemia, Diamond-Blackfan anemia, severe combined immune deficiency, glycogen storage disease, etc. Since several age-dependent enzymes are known, careful evaluation of enzyme activities is required if reticulocyte counts are elevated. It should be noted that deficiency of an isozyme may be masked by activity derived from another isozyme. Recent progress in the molecular genetics of red cell enzymopathies and protein structure-function mechanisms enable us to diagnose "enzyme deficiency" at DNA level.
[A case of Sertoli cell tumor of the testis].
A 24-year-old man was admitted to our hospital with the complaint of a painless mass in the left testis. Gynecomastia was not present. The serum levels of alpha fetoprotein and human chorionic gonadotropin-beta were not elevated. Ultrasound sonography showed a hypoechoic lesion in the left testis. There was no evidence of retroperitoneal lymph node enlargement or distant metastasis on computerized tomography. With a diagnosis of left testicular tumor, left high orchiectomy was done. The tumor measured 10 x 11 mm in size within the testis and was histologically diagnosed as benign Sertoli cell tumor. Immunohistochemcal analysis revealed negative findings with the tumor markers inhibin, CAM 5.2, pancytokeratin, EMA, and PLAP. No adjuvant therapy was performed. Twenty-six cases of Sertoli cell tumor of the testis in the Japanese literature are reviewed.
Embryonic development in the eggs of the silkworm, Bombyx mori, exposed to the space environment.
To investigate the effects of cosmic radiation and microgravity on embryogenesis and organogenesis in Bombyx eggs, two different stages of eggs, the early stage after oviposition and the diapause-terminated eggs, were loaded on the US Space Shuttle/Atlantis (STS-84) for a 9 day flight. More than 85% of the early stage eggs hatched in the flight sample and the ground control. In the diapause-terminated eggs, the percentage of unhatched eggs were 43% in the ground control and 56% in the flight sample. In these eggs, uncompleted embryonic reversal was observed two-fold higher percentage in the flight sample than in the ground control. The incidence of abnormality such as the larvae with segmental fusion and the appearance of abnormal crescent marking in the flight sample was significantly higher than that in the ground control. This was also observed in the 1st and 2nd filial generation of the flight sample. From these results, unsuccessful blastokinesis and the abnormal appearance was discussed in relation to cosmic radiation and microgravity.
Attenuation of hypothermia-induced platelet activation and platelet adhesion to artificial surfaces in vitro by modification of hemoglobin to carry S-nitric oxide and polyethylene glycol.
Hypothermic cardiopulmonary bypass alters platelet function and hypothermia is associated with postoperative myocardial ischemia. Thrombogenic surfaces such as extracorporeal circuits, vascular graft materials, and components of atherosclerotic plaque induce activation of platelets. The effects of human hemoglobin (Hb) covalently modified to carry S-nitric oxide (NO) functional groups (SNO-Hb), polyethylene glycol (PEG-Hb), and SNO-PEG-Hb on platelet activation were studied. Platelet activation was assessed by cytometric analysis of GPIIb-IIIa activation and P-selectin expression at hypothermic condition (22 degrees C) after stimulation with Hb derivatives. Platelet adhesion and aggregation were measured in a parallel glass plate chamber coated with unmodified Hb, SNO-Hb, PEG-Hb, SNO-PEG-Hb, and collagen. Platelet binding of antibodies to GPIIb-IIIa and P-selectin was significantly enhanced by hypothermic condition and by unmodified Hb. There was significantly less platelet binding of antibodies to GPIIb-IIIa and P-selectin with SNO-Hb, PEG-Hb, and SNO-PEG-Hb compared with unmodified Hb. There was significantly less platelet attachment, adhesion, and aggregation on the SNO-Hb, PEG-Hb and SNO-PEG-Hb coated surfaces compared with unmodified Hb-coated and -uncoated surfaces. SNO-Hb, PEG-Hb, and SNO-PEG-Hb induced less platelet activation at hypothermic temperature, and induced less platelet adhesion and aggregation on thrombogenic surfaces compared with unmodified Hb. The inhibitory effect may be derived from antiadhesive properties of Hb, antiplatelet actions of NO, and molecular barrier action of PEG.
Vacuolar H(+)-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts in cultured human saphenous vein.
BACKGROUND: The molecular mechanism of neointimal hyperplasia after vein graft surgery remains elusive. Vacuolar H(+)-ATPase (V-ATPase) is involved in intracellular trafficking and may play a crucial role in neointimal cell growth. METHODS AND RESULTS: Cultured human saphenous vein segments developed neointimal formation within 10 days. Neointimal cells were positive for vimentin and alpha-smooth muscle actin but negative for desmin, which is indicative of myofibroblasts. Those myofibroblasts were found to have originated from periadventitial fibroblasts, which upregulated the expression of 16-kDa proteolipid of V-ATPase before proliferation and phenotypic modulation. Neointimal myofibroblast growth and survival were highly sensitive to inhibition of V-ATPase by bafilomycin A(1) (BA(1)), because the incorporation of [(3)H]thymidine into the myofibroblasts was significantly inhibited by nanomolar concentrations of BA(1) and apoptotic cell death was induced by a similar concentration range of BA(1). In contrast, endothelial cells and differentiated smooth muscle cells were resistant to apoptosis by BA(1). CONCLUSIONS: These results suggest that V-ATPase plays a crucial role in growth and phenotypic modulation of myofibroblasts that contributes to neointimal formation in cultured human saphenous vein.
The effect of heparin on tissue factor and tissue factor pathway inhibitor in patients with acute myocardial infarction.
We examined plasma TF and free TFPI levels in 26 consecutive patients with AMI, 26 patients with stable exertional angina, and 25 patients with chest pain syndrome. In patients with AMI, blood samples were obtained immediately after admission and at 4, 8, 16, 24, and 48 h, and the third, fifth, seventh, and fourteenth day after initiation of reperfusion therapy. Plasma TF levels in patients with AMI on admission were significantly higher than in the chest pain syndrome and stable exertional angina groups (248.0+/-117. 4 vs. 179.5+/-29.2 vs. 189.5+/-29.6 pg/ml, P<0.01). In patients with AMI, the level subsequently decreased after heparin administration and was maintained at significantly lower levels compared to those on admission. Plasma free TFPI levels in patients with AMI on admission were significantly higher than in the chest pain syndrome and stable exertional angina groups [33.5+/-12.4 vs. 26.0+/-7.6 ng/ml (P<0.01) vs. 27.5+/-6.3 ng/ml, P<0.05]. In patients with AMI, it reached the maximum level at 4 h after the administration of heparin, and gradually decreased over the time course. These data indicated that continuous administration of a low dose of heparin was effective in decreasing TF levels without affecting TFPI levels. Our results elucidate one of the mechanisms by which the administration of heparin is beneficial in AMI patients undergoing percutaneous revascularization.
Differential requirement of the cytoplasmic subregions of gamma c chain in T cell development and function.
The common cytokine receptor gamma chain (gammac), a shared component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is critical for the development and function of lymphocytes. The cytoplasmic domain of gammac consists of 85 aa, in which the carboxyl-terminal 48 aa are essential for its interaction with and activation of the Janus kinase, Jak3. Evidence has been provided that Jak3-independent signals might be transmitted via the residual membrane-proximal region; however, its role in vivo remains totally unknown. In the present study, we expressed mutant forms of gammac, which lack either most of the cytoplasmic domain or only the membrane-distal Jak3-binding region, on a gammac null background. We demonstrate that, unlike gammac or Jak3 null mice, expression of the latter, but not the former mutant, restores T lymphopoiesis in vivo, accompanied by strong expression of Bcl-2. On the other hand, the in vitro functions of the restored T cells still remained impaired. These results not only reveal the hitherto unknown role of the gammac membrane-proximal region, but also suggest the differential requirement of the cytoplasmic subregions of gammac in T cell development and function.