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A non-invasive method for measuring portal blood flow by magnetic resonance (MR) phase contrast was evaluated in a flow phantom and 20 healthy volunteers. In a flow phantom study, the flow volumes and mean flow velocities measured by MR phase contrast showed close correlations with those measured by electromagnetic flowmetry. In 20 healthy volunteers, the cross-sectional areas, flow volumes and mean flow velocities measured by MR phase contrast correlated well with those measured by the Doppler ultrasound method. Portal blood flow averaged during the imaging time could be measured under natural breathing conditions by using a large number of acquisitions without the limitations imposed on the Doppler ultrasound method. MR phase contrast is considered to be useful for the non-invasive measurement of portal blood flow.

The purpose of this study was to investigate the effects of topical treatment with zinc oxide (2.5%, 10%, 25% and 50%) and intraperitoneal treatment with diethyldithiocarbamate (DEDTC) (50 mg/kg, 500 mg/kg and 1,000 mg/kg) on the mitotic index of epidermal basal cells in incised and non-incised mouse skin. The present results showed that topical application of zinc oxide (25% and 50%) increased the mitotic index of epidermal basal cells in incised skin and non-incised skin. Conversely, intraperitoneal administration of DEDTC (500 mg/kg and 1,000 mg/kg) decreased the mitotic index, but only in the incised skin. These results suggest that mitosis of epidermal basal cells may be stimulated by the topical application of zinc oxide both in incised and non-incised mouse skin, and that it also may be inhibited by the intraperitoneal administration of DEDTC in incised mouse skin.

P-glycoprotein is a transmembrane protein which acts as an energy-dependent drug efflux pump for a variety of anti-cancer drugs. The mdr-1 gene which encodes P-glycoprotein was successfully cloned in 1986. To investigate P-glycoprotein expression in diverse ovarian tumors, including benign, low malignant potential and malignant, immunohistochemical study was done using a monoclonal antibody (C 219). Overall, 8 out of the 59 epithelial ovarian tumors (13.6%) expressed P-glycoprotein. It was noted that 5 of the 12 mucinous tumors were found to express P-glycoprotein, while none of the 31 serous tumors were immunohistochemically positive. In 10 malignant ovarian tumors, P-glycoprotein immunostaining was examined both prior to and after chemotherapy. Nine of them did not express any P-glycoprotein before or after chemotherapy. However, one tumor expressed P-glycoprotein after six courses of multidrug resistance-related drug administration. These findings indicate that P-glycoprotein expression is not so common in ovarian tumors, regardless of their malignant potential. Nevertheless, the results suggest a strong association between P-glycoprotein expression and certain histological cell types in epithelial ovarian tumors. It is also possible that P-glycoprotein appears as a result of chemotherapy, but such a phenomenon can not occur unless chemotherapy is administered at high doses for a long period of time.

To identify diffuse mucosal changes which may precede the development of colorectal cancer and a possible indicator for detecting high-risk populations, we immunohistochemically studied cell-cycle events in crypts of normal-appearing rectal mucosa of patients with colorectal adenoma and cancer using an in vitro labeling method with bromodeoxyuridine (BrdU). Biopsy specimens of endoscopically normal-appearing rectal mucosa were obtained during colonoscopy from 20 patients with colorectal adenocarcinoma, 20 with adenoma, and 15 without apparent colorectal diseases. The specimens were incubated with BrdU in vitro, and labeled S-phase cells were identified immunohistochemically using a monoclonal antibody to BrdU. Modification of the BrdU-labeling pattern in the normal appearing rectal mucosa, such as the presence of BrdU-labeled cells at the mucosal surface or in the upper one-fifth of the crypt column, was observed in 15 of the 20 patients with adenocarcinoma, 17 of the 20 patients with adenoma and 6 of the 15 controls. This upward shift in the frequency of proliferating cells in the crypt was significantly higher in the patients with colorectal adenoma and cancer than in the controls, and may be used to identify subjects at high risk for colorectal cancer.

To determine the allergens of mite allergic rhinitis, we studied 31 patients with mite allergic rhinitis by skin tests and nasal provocation tests (15 for skin and 16 for nasal tests) using 6 fractions of Dermatophagoides pteronyssinus (Dp) extract differing in molecular weights (15, 25, 32, 53, 95 and 190 kDMW). In skin testing, patients showed intense positive reactions to the fractions of 15, 25, 32, 95 and 190 kDMW, among which the most patients showed positive reactions to the fractions of 15 and 25 kDMW. Significant differences were found in patients' positive reactivity among each fraction and between low (15 and 25 kD) and high (95 and 190 kD) molecular weight fractions as well. In nasal provocation tests, patients showed intense positive reactions to the fractions of 15, 32, 53 and 95 kDMW, especially to the fractions of 15 and 95 kDMW. Furthermore, the insidence of positive reactions to the 15 kDMW fraction was significantly higher than that to any other fraction in the skin tests (P < 0.05). From these results, the low molecular weight fraction, 15 kDMW, is considered to be the main allergen of this mite and the high molecular weight fractions, 95 and 190 kDMW, may also be considered to be allergens of this mite.

PSK (Krestin) is a protein-bound polysaccharide with antitumor and immunomodulatory activity. In this study, the effects of the oral administration of PSK were investigated on the natural killer (NK) activity of liver-associated lymphocytes and their subfractions separated by density gradient centrifugation, in WKAH rats with liver metastasis of KDA hepatoma. PSK was administered orally, at a dose of 500 mg/kg once a day for 3 weeks. The NK activity of nonparenchymal liver cells (NPLC) and their subfractions, including large granular lymphocytes (LGL), was markedly augmented by this treatment. The effects of oral PSK were also examined in CDF1 mice with liver metastases of Colon 26 adenocarcinoma; the survival of tumor-bearing mice was prolonged and both metastatic foci and liver weight were decreased. These results suggest that PSK may be effective for the suppression of liver metastasis through activation of liver-associated NK cells.

To clarify the events related to complement-mediated immune responses in human colorectal cancers, we immunohistochemically examined the distribution of decay-accelerating factor (DAF), CD59/homologous restriction factor 20 (HRF20), membrane cofactor protein (MCP) and terminal complement complex (TCC) in human colorectal adenomas and cancers, and then compared the findings with their distribution in normal colonic mucosa. In the normal mucosa, TCC was not present on epithelial cells. Whereas DAF and CD59/HRF20 were present only occasionally on the apical surfaces of normal epithelial cells, MCP was diffusely distributed on the basolateral surfaces of most epithelial cells of the colon. These findings suggest that MCP has a primary role in the regulation of complement activation on these cells. In adenoma cells, the expression of both DAF and CD59/HRF20 was enhanced. In cancer cells, the expression of CD59/HRF20 and MCP was diminished, whereas DAF expression was markedly enhanced. Since DAF was frequently stained in the lumen of the cancer glands, it was suggested that DAF was released into the colonic lumen in patients with colorectal cancer.

Stress is a proximal interphalangeal (PIP) joint model was analyzed by the two-dimensional and three-dimensional finite element methods (FEM) to study the onset mechanisms of the middle phalangeal base fracture. The structural shapes were obtained from sagittally sectioned specimens of the PIP joint for making FEM models. In those models, four different material properties were given corresponding to cortical bone, subchondral bone, cancellous bone and cartilage. Loading conditions were determined by estimating the amount and position of axial pressure added to the middle phalanx. A general finite element program (MARC) was used for computer simulation analysis. The results of the fracture experiments compared with the clinical manifestation of the fractures justify the applicability of the computer simulation models using FEM analysis. The stress distribution changed as the angle of the PIP joint changed. Concentrated stress was found on the volar side of the middle phalangeal base in the hyperextension position, and was found on the dorsal side in the flexion position. In the neutral position, the stress was found on both sides. Axial stress on the middle phalanx causes three different types of fractures (volar, dorsal and both) depending upon the angle of the PIP joint. These results demonstrate that the type of PIP joint fracture dislocation depends on the angle of the joint at the time of injury. The finite element method is one of the most useful methods for analyzing the onset mechanism of fractures.

Effects of acute (15h) and chronic (15h x 7 days) immobilization (IM) stress on plasma levels of nicorandil [N-(2-hydroxyethyl) nicotinamide nitrate (ester)] administered orally were examined in rats. The maximum plasma level was reached 30 min after administration. Acute IM stress significantly reduced plasma nicorandil levels both in the absorption and elimination phases (15 min and 2-6h after administration, respectively). Chronic IM stress further intensified the reduction of nicorandil levels in the absorption phase, but attenuated the influence of acute stress in the elimination phase. No significant difference was observed one day after removal of chronic IM stress. These results suggest that chronic IM stress markedly inhibits the absorption of nicorandil, but the distribution, metabolism and excretion were influenced more by acute IM stress.

Previously, we reported that interleukin-2 (IL-2)-stimulated helper T cells produced an unknown soluble factor which induced dendritic cell-like differentiation in primary cultures of monocytic leukemia cells and we referred to this factor as dendritic cell differentiation factor (DCDF). In this study, we attempted to purify and characterize DCDF and investigated its biological effect on normal human monocytes. Gel filtration chromatography indicated that the molecular weight of DCDF is approximately 30-35 kDa. Chromatofocusing indicated that the isoelectric point of DCDF is approximately 5.0. DCDF, partially purified by subsequent gel filtration, chromatofocusing, and hydrophobic chromatography, significantly enhanced the HLA-DR expression of normal human monocytes and a human monocytic leukemia cell line, THP-1. This biological activity was not neutralized by any known antibodies to human cytokines. DCDF significantly amplified the T-cell stimulatory activity of monocytes in the allogeneic mixed leukocyte reaction (MLR). Moreover, DCDF significantly enhanced IL-1 beta and IL-6 production by monocytes in a dose-dependent manner. These results suggest that DCDF is a novel human cytokine which stimulates the accessory cell function of monocytes.

Nipradilol is a newly synthesized beta-blocker which has a propranolol-like structure and contains a nitrate moiety. To examine the effect of nipradilol on venous blood flow, a single oral dose of nipradilol (6 mg) and propranolol (20 mg) was administered in the same 15 normal volunteers on separate days. Peak flow velocities, flow velocity integrals, and the diameter of the right brachiocephalic vein were measured before and 2 h after drug administration using Doppler echocardiography. These two beta-blockers significantly decreased systolic blood pressure to the same extent as they did heart rate. Nipradilol dilated the venous diameter by 8% and decreased peak flow velocity by 8% during systole and 9% during diastole. The flow velocity integral in one cardiac cycle also decreased significantly by 14%. Propranolol, however, failed to modify these parameters. These results suggest that nipradilol decreased venous return through its nitroglycerin-like direct vasodilating action.

Anodal direct currents at intensities ranging from 0.3 to 30.0 microA were unilaterally applied for 30 min once a day to the premotor area of the rabbit cerebral cortex. The anodal polarization was repeated 10 times at intervals of 2-3 days, and the effect on the motor activity of the forelimbs during and after each polarization trial was compared with that before polarization. Peripheral motor activity was classified as either gentle flexion of forelimbs or struggle with violent movement of forelimbs. A current of 0.3 microA caused no change in motor behavior. Flexion of the forelimb contralateral to the polarized cortex was clearly increased when a polarizing current of 1.0 or 3.0 microA was applied, and peak flexion was observed between the third and seventh polarization trials. A current of 10 or 30 microA had no effect on forelimb flexion. Conversely, forelimb struggle on both sides was decreased when 10.0 or 30.0 microA, but not 1.0 or 3.0 microA, was applied. These results show that anodal polarization of the cerebral cortex exerts dual effects on peripheral motor activity, probably through changes in cortical excitability associated with the current intensity.

Cytotoxic lymphocytes, including natural killer cells, lymphokine-activated killer cells, and cytotoxic T lymphocytes, adhere to and lyse cancer cells by recognizing cell surface antigens. Among the cell surface antigens, intercellular adhesion molecule-1 (ICAM-1) and HLA class I antigen are important for the cytotoxic activity of lymphocytes. The ICAM-1 and HLA class I antigen were examined in gastric cancer cell lines MKN-28 and MKN-45 by flow cytometry to determine whether their expression on the cell surface is enhanced by interferon gamma (IFN-gamma). The cell expression rate [stained cells/10(4) cells x 100(%)] was only 10% in ICAM-1 and about 20% in HLA class I antigen without IFN-gamma, but reached 70% in ICAM-1 and up to 60% in HLA class I antigen after incubation with IFN-gamma for 24-96 h. This enhanced expression of cell surface ICAM-1 and HLA class I antigen by IFN-gamma might increase sensitivity for cytotoxic lymphocytes.

Pulmonary metastatic tumors in two patients with locally well controlled uterine cancer were treated with bronchial arterial infusion chemotherapy. The first patient underwent a radical hysterectomy and pelvic lymphadenectomy for stage IIb cervical cancer. Fifteen months after the operation, pulmonary metastasis was identified. Clinical evidence of tumor was negative after bronchial arterial infusion chemotherapy, systemic chemotherapy and radiotherapy. The patient continues to be healthy without recurrent signs six years after bronchial arterial infusion chemotherapy. The second patient underwent a radical hysterectomy and pelvic lymphadenectomy for stage II endometrial cancer. Fifteen months after the operation, pulmonary metastasis was identified. After bronchial arterial infusion chemotherapy and systemic chemotherapy, regression of the tumors was observed. This patient has also survived for two years since the lung metastases. These results indicate that bronchial arterial infusion chemotherapy is a potent treatment for pulmonary metastases of uterine cancer.

The functional roles of the three-dimensional fibrillar ultrastructure of the proximal interphalangeal joint volar plates of human fingers were studied by light microscopy and scanning electron microscopy. The results revealed that the volar plate consists of three layers of fibers. The first layer forms an intracavity wall with two parts, the proximal "membranous portion", and the distal "meniscoid protrusion" that is separated from the middle phalangeal base by a "recess". The second layer contains the "check ligament", which lies parallel to the fibers of the tendon, anchors tightly into the middle phalangeal base, and protects the joint from hyperextension. The third layer connects to the fibers from the accessory ligament and ligamentous tendon sheath of the A3 pulley, perpendicularly crosses the fibers of the tendon, becomes the periosteum of the middle phalangeal base, and functions as a hanging support for the volar plate and as a gliding floor for the flexor tendon.

Serotonin (5-HT) is thought to play an important role in the seizures of El mice because the seizure threshold of El mice correlates with the 5-HT concentration in the central nervous system. In this study, the anticonvulsant effect of a 5-HT reuptake blocker, citalopram, was evaluated behaviorally and biochemically. El mouse convulsions were inhibited by chronic administration of citalopram (80 mg/kg/day, p.o. for 2 weeks), but were not inhibited by acute administration of citalopram (80 mg/kg, i.p., 2 h after single injection). Both chronic and acute administration of citalopram decreased the concentration of 5-hydroxyindolacetic acid in the brain, whereas the concentration of 5-HT was not changed by treatment with citalopram. Tryptophan hydroxylase activity was not different between the citalopram and control groups, although the monoamine oxydase-A activity was lowered by chronic administration of citalopram. These findings suggest that both acute and chronic administration of citalopram depresses the 5-HT turnover rate, however chronic administration is necessary to inhibit El mouse convulsions.

A study was conducted to compare the urinary iodine concentrations in populations from Pahang, Central Malaysia, with those in the capital city Kuala Lumpur, and to compare those of Malays from villages at Batu Talam, Batu Malim, FELDA Sungai Koyan and Hulu Sungai with neighboring aboriginal settlements at Lanai and Buntu. Two hundred and forty urine samples were collected randomly among the population (male 1 1 1 and female 129). The urinary iodine concentrations, measured by the ashing method, among Malays were as follows: Batu Talam 1.1-7.6 micrograms/dl, Batu Malim 1.4-6.6 micrograms/dl, FELDA Sungai Koyan 0.5-6.9 micrograms/dl and Hulu Sungai 0.6-9.9 micrograms/dl. Among aborigines, the urinary iodine levels were 0.1-2.9 micrograms/dl in Lanai and 1.7-6.5 micrograms/dl in Buntu. There was a significant difference in the levels of urinary iodine with regard to gender, but not regarding age. The aborigines had significantly lower iodine levels than Malays (P < 0.001). This difference was also significant with regard to location. The urinary iodine content in Kuala Lumpur was the highest and that in the aboriginal Lanai village was the lowest. Thus, the study showed that the levels of iodine in the urine were influenced by ethnicity and geographic location.

Immunotoxins composed of monoclonal antibodies (mAbs) and various toxins have been developed for the treatment of malignancies. We investigated the efficacy of three ricin toxin A-chain (RTA)-containing immunotoxins (ITs) conjugated from mAbs which recognize glycolipid asialo-GM2 and glycoprotein H-2d. These ITs retained the same immunoreactivity with mAbs. We evaluated the cytotoxicity of these ITs against mouse lymphoma cells L5178Y variants showing high (AA12,CC9) and low (27AV) expression of asialo-GM2. Anti-H-2d-RTA IT had the strongest cytotoxicity for all cell lines. Anti-asialo-GM2 (IgM)-RTA IT had stronger cytotoxicity than anti-asialo-GM2 (IgG3)-RTA IT. Anti-asialo-GM2-RTA ITs had different cytotoxicity against AA12 and CC9 cells. The establishment of appropriate anti-glycolipid mAbs may lead to effective immunotargeting therapy.

We have already developed the liposome immune lysis assay (LILA) for the determination of C-reactive protein (CRP) by employing an inhibition method and a sandwich method. We herein report a new LILA system involving the use of monoclonal antibodies-bearing liposomes. We established five monoclonal antibodies to CRP antigen, AC-1, -2, -3, -4, -5 which had the capacity to activate complement and form antigen-antibody complex. Each of these antibodies was covalently coupled to carboxyfluorescein-entrapped multilamellar liposomes. When the liposomes were incubated with CRP antigen in the presence of guinea pig complement, CRP antigen-dependent liposome lysis was observed but the sensitivity was not great enough for practical use. On the other hand, when liposomes coupling two monoclonal antibodies (AC-1, AC-2) which recognized distinct CRP antigenic determinants were employed in the assay, the sensitivity increased compared with that using only one monoclonal antibody, and the detectable concentration range was 5-300 ng/ml. These results indicated that the combination of two or more monoclonal antibodies which recognize distinct CRP antigenic determinants is effective for increasing the sensitivity of the assay.