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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.

Hepatitis C virus (HCV)-RNA in the blood was measured by polymerase chain reaction (PCR) in 37 subjects from eight families in which 2 or more persons tested seropositive for antibodies against C100-3 or CP9. HCV-RNA was positive in 17 of 37 subjects. Two or more HCV-RNA-positive subjects were observed in six of the families. Intrafamilial HCV infection was studied by determining the HCV-RNA type (I, II, III or IV) by PCR using type-specific primers. In two families, all of the subjects showed type III infection, and in three other families, all of the subjects showed type II infection, with different types of HCV infections being observed in only one family. The HCV type was uniform in all but one. These findings suggest a possibility of intrafamilial infection between husbands and wives and between members of the same household.

A unilateral 30-min application of anodal direct current to the promotor cortex of rabbits was repeated 10 times, and cyclic AMP accumulation in response to histamine was investigated in slices of different cortical areas. Polarization with 1.0 microA decreased the cyclic AMP accumulation in the cortical area contralateral to the polarization, by which regional dominance in cyclic AMP accumulation was produced in the polarized cortex. In contrast, the regional difference in cyclic AMP accumulation was reversed when 10.0 or 30.0 microA was applied. The histamine-elicited accumulation of cyclic AMP was almost completely inhibited by the selective H2-receptor antagonist cimetidine. These results suggest that repeated anodal polarization regionally alters H2-receptor-mediated cyclic AMP generation in the cortex depending on the intensity of the polarizing currents and this pattern of cyclic AMP accumulation is responsible for the characteristic motor behavior induced by anodal polarization.

We studied the distribution of class 1 and class 2 major histocompatibility complex (MHC) antigens on bile duct epithelial cells in liver from patients with primary biliary cirrhosis (PBC) by an immunohistochemical method using monoclonal antibodies to HLA-ABC products and HLA-D subregion products (HLA-DR, -DP, -DQ). By light microscopy, the expression of MHC class 1 antigens (HLA-ABC antigens) was enhanced in PBC compared with controls. While negligible staining of MHC class 2 antigens was detected on the bile duct in controls, de novo expression of MHC class 2 antigens, as well as the coexpression of HLA-DR, HLA-DQ, and HLA-DP antigens on the bile duct epithelial cells, was observed in PBC. By electron microscopy, HLA-ABC and HLA-DR antigens were present preferentially along the basolateral domain of the cell surface of the bile duct epithelial cells and on the membrane of the endoplasmic reticulum in the cytoplasm, suggesting that these MHC antigens are synthesized by the bile duct epithelial cells in PBC. The distribution of these MHC antigens on the basolateral surface of the bile duct epithelial cells, where they are easily accessible to immunocytes, supports the idea that MHC-restricted cytotoxic T lymphocytes are involved in the bile duct injury in PBC.

The aim of this study was to investigate the usefulness of magnetic resonance (MR) imaging in the evaluation of renal function, with particular attention to the effects of water load. Ten healthy volunteers underwent dynamic MR imaging after an injection of gadolinium diethylene-triaminepenta-acetic acid (Gd-DTPA) as a contrast agent to evaluate renal function by the following four methods: the positive method [longitudinal relaxation time (T1) shortening is the dominant effect], the negative method [transverse relaxation time (T2) shortening is the dominant effect] and two intermediate methods by switching the Gd-DTPA concentrations used in the positive and negative methods. A prolonged cortical peak time and a reduced medullary peak level were observed by the positive method under a dehydrated condition, suggesting that these variables were slightly influenced by Gd-DTPA concentrated in the medulla. By the negative method, low signals due to T2* (T2* is the effective transverse relaxation time, typically shorter than T2) shortening appeared in the medulla under normal conditions, but these signals were unclear when the subject was under an overhydrated condition. These results indicate that water metabolism, in addition to imaging parameters and Gd-DTPA dose levels, should be considered when renal function is evaluated by dynamic MR imaging. Analysis of both the pattern of MR images and the time-signal intensity curves may be useful in the evaluation of renal function. The results also indicate that the positive method is preferred when the patient is overhydrated as it allows the evaluation of the local renal kinetic function by recording changes in the regional contrast agent levels.

In this study, we investigated serum-soluble interleukin-2 receptor (sIL-2r) and neopterin (NPT) levels in five patients with severe postoperative infections. A total of 25 synchronous determinations of sIL-2r and NPT were performed. A marked increase in sIL-2r and NPT levels was observed, and the increase in sIL-2r was significantly correlated to that of NPT which is a marker of macrophage activity. These results suggest that macrophages are involved in the stimulation of sIL-2r release, representing a potentially negative biological effect. The results indicate that sIL-2r may be a useful indicator of the efficacy of antibiotics and of prognosis.

Both prolidase and prolinase from the human prostate were separated into two peaks by TSK DEAE-5PW chromatography. These peaks of prolidase isozymes I and II differed from each other in their responses to preincubation with Mn2+, their substrate specificity, optimal pH, and heat stability. The molecular weights of prolidases I and II were estimated to be 110,000 and 165,000, respectively, by gel filtration. Substrate specificity of prolinase peaks I and II was almost the same, but they differed in optimal pH and heat stability. The molecular weights of prolinases I and II were about 85,000 and 63,000, respectively. These results indicate that two isozymes of prolidase and of prolinase, which differ in various characteristics, are present in the human prostate.

Neurons with strongly negatively charged surface coats were recognized in mammalian, avian, reptilian, amphibian and piscine brains. Many large-sized neurons had strongly negatively charged surface coats in the visual cortex and brain stem of the cow, cat, guinea pig, mouse, quail and parakeet. Such neurons were also seen in the brain stem of the lower vertebrates such as the house lizard, Japanese terrapin, bullfrog, newt, carp and sweetfish.

The sensitivity and specificity of single cell polymerase chain reaction (PCR) were studied. Its high sensitivity enabled detection of a single-copy gene, such as human T-lymphotropic virus type I genome in paraffin sections. The rate of obtaining positive signals with this method was affected by the number of copies of the gene in the target cell. Specificity was satisfactory if the procedure was properly and carefully followed. Since the single cell PCR is a time-consuming method which requires skill and experience to pick up the target cells accurately, the applicability of this method is limited. It works best when it is used to analyze a single or a few copy genes in histologically identified cells.

Familial adenomatous polyposis (FAP) is a well-known autosomal dominant disorder characterized by the formation of multiple adenomatous polyps of the colon. Gardner's syndrome is a variant of familial polyposis coli, and both can be associated with colonic or extracolonic benign and/or malignant tumors. It has been widely recognized that an adenocarcinoma of the colon develops in virtually all cases, usually at an earlier age, if polyps are left untreated. Families of four individuals diagnosed of FAP were surveyed and 56 relatives of the families were examined. Of these 56, 21 had multiple colon polyps, 3 of whom had early-stage adenocarcinomas. We consider that familial survey of FAP individuals can be of considerable benefit for this high-risk population due to the autosomal nature of the disease, allowing diagnosis of an associated cancer at an earlier stage.