Biomedical subjects
Publications and source records attributed to A Horiuchi.
Urinary human epidermal growth factor levels were assayed in diabetic patients and controls before and after surgery. The preoperative levels in the diabetic patients were decreased and postoperatively, did not show the trough and peak pattern which was seen in the controls.
We evaluated the treatment of varicella-zoster infection with BV-araU in immuno-compromised patients with haematological malignancies in a randomized controlled study. Comparison was made between doses of 150 and 30 mg/day. For ethical reasons there was no placebo group. The percentage of patients given a 'very effective' rating by both attending physicians and the Evaluation Committee was significantly higher in the 150 mg/day group (56.0%) compared to the 30 mg/day group (15.0%). There was no significant difference in efficacy rate ('very effective' plus 'effective') between the two groups. The incidence of side effects was low (7.8%), all were mild and disappeared on stopping treatment. These results suggest that BV-araU is clinically useful, especially at a dose of 150 mg/day in immunocompromised patients. Further comparative studies between BV-araU and acyclovir or vidarabine are indicated.
A membrane-associated lymphotoxin (LT)-related molecule was detected on human lymphokine-activated killer (LAK) cells by flow cytometric analysis. Kinetic analysis revealed that the LT antigenicity on LAK cells appeared at 9 h after the beginning of culture and was maintained thereafter. By autoradiography, the molecular weight of membrane LT was estimated to be 31 kD and/or 62 kD.
1. The effects of neurotensin on pancreatic exocrine secretion were investigated both in the intact whole pancreas and in the isolated, blood-perfused pancreas ex vivo in anaesthetized dogs. 2. Intravenous (i.v.) injections of neurotensin (0.01-1 nmol/kg) elicited dose-dependent increases in the secretory rate of pancreatic juice without changes in plasma levels of cholecystokinin (CCK). The concentration of bicarbonate in the pancreatic juice induced by neurotensin was increased, but the protein concentration was scarcely changed. 3. The neurotensin-induced secretion was inhibited by SCH23390, a dopamine D-1 antagonist, but not by domperidone, phentolamine, propranolol, atropine, cimetidine, or L-364,718, a CCK antagonist. 4. Intra-arterial (i.a.) injections of neurotensin (0.1-3 nmol/kg) also elicited dose-dependent increases in the secretory rate of pancreatic juice flow, but did not change bicarbonate or protein concentration. The secretory activities were less effective and 1 nmol/kg of neurotensin i.a. was approximately equal to that of 0.03 nmol/kg of neurotensin i.v. 5. These results suggest that neurotensin mainly stimulates pancreatic secretion by acting indirectly. Neurotensin-induced secretion is, at least in part, mediated by endogenously released dopamine which activates dopamine D-1 receptors on the pancreas. In addition to its indirect action, neurotensin has a weak direct action to stimulate pancreatic secretion.
Interferon-gamma is one of the cytokines which have various immunoregulatory functions. In the present study, the serum interferon-gamma level was determined in autoimmune diseases. It was increased in the active cases of systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Since there was a positive correlation between the serum interferon-gamma level and the rate of peripheral mononuclear cells positive for HLA-DR antigen in systemic lupus erythematosus, circulating interferon-gamma might have a biological functions as suggested by many in vitro studies. In rheumatoid arthritis and Sjögren's syndrome, there was no correlation between the serum interferon-gamma level and the clinical findings. These data suggest that interferon-gamma might be associated with the pathogenesis of autoimmune diseases such as SLE and MCTD, and it can be one of the indices for their disease activity.
To characterize B cell hyperactivity in autoimmune NZB/NZW (B/W) F1 mice, we studied the effects of murine recombinant interferon gamma (IFN-gamma) on interleukin 4 (IL-4) induced resting B cell growth and differentiation. The number of resting B cells of B/W F1 mice were decreased, with more sensitivity to IL-4 than normal mice. Thus, resting B cell hyperresponsiveness to IL-4 was in a dose-dependent manner suppressed by IFN-gamma. This action was most noticeable when IFN-gamma was added to the culture system simultaneously with IL-4. As well, IFN-gamma did not exhibit cytotoxicity. These results suggest that IFN-gamma may have regulatory effects on IL-4 mediated B cell triggering.
The role of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) in the pathogenesis of the collagen vascular diseases was studied. The serum level of IL-4 was decreased in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), and was variable in patients with rheumatoid arthritis (RA). The serum level of IFN-gamma was increased in patients with SLE, MCTD and RA. In patients with SLE, there was an inverse correlation between the levels of IL-4 and IFN-gamma. The proliferation and immunoglobulin production of the high-density-B cells in response to IL-4 was suppressed in normal controls, although the degree of suppression was less in patients with SLE. Cell cycle analysis using ethidium bromide demonstrated the similar findings. These data suggest that IL-4 and IFN-gamma might participate in regulating both of growth and differentiation of B cells in vivo. However, immunoglobulin production by whole B cells in response to IL-2 or PHA-induced T-cell factor was extensively facilitated by IFN-gamma in patients with SLE. It is possible that IFN-gamma enhances the differentiation of already-activated B cells, and that polyclonal B cell activation is promoted. Therefore, the failure of the regulatory mechanism by these cytokines might be related to the pathogenesis of these diseases.
The object of this study was to establish the most effective regimen of cefodizime (CDZM) for patients with chronic renal failure undergoing hemodialysis (HD). T 1/2 beta of CDZM upon 1 g intravenous administration was 3.50 +/- 0.72 hours in an on-HD group, and it was 11.26 +/- 3.89 hours in an off-HD group. When CDZM was administered consecutively at a dose of 1 g or 2 g only after HD, the serum concentration of CDZM was maintained at levels sufficient to exert antibacterial activity, and no tendency for accumulation was observed. The most effective regimen of CDZM to HD patients, therefore, has been that in which concluded to administration was done only after completion of HD, in a dose of 1 g for mild infections and that of 2 g for severe infections.
We found that the sera obtained from patients with acute leukemia (AL) in complete remission or malignant lymphoma (ML) during the recovery phase after chemotherapy completely inhibited the GCT-CM-stimulated growth of allogenic and autologous bone marrow colonies in vitro. We investigated 5 AL patients and 6 ML patients from whom blood samples were taken either every day or every 6 h during the recovery phase after chemotherapy. Colony-inhibitory sera, were detected in all patients, more frequently when the peripheral leukocyte count recovered to about 2,500 x 10(6)/l, but then transiently and at intervals. The colony-inhibitory factor purified from the inhibitory sera inhibited the growth of G-CSF-responsive colonies in a dose-dependent manner, but no effect on the growth of GM-CSF-responsive colonies, CFU-E, or BFU-E, was observed. These results suggest that this factor may play a role in regulating granulopoiesis by inhibiting the differentiation of G-CSF-responsive precursor cells.
We studied the effect of interferon-gamma (IFN-gamma) on B cells in systemic lupus erythematosus (SLE). Low density B cells, which were fractionated on density gradients of Percoll, increased, and high density B cells decreased in number in SLE. Proliferative response of the high density B cells to interleukin 4 was reduced by IFN-gamma in normal controls, but not in SLE. IgG production of whole B cells induced by interleukin 2 or phytohemagglutinin induced T cell factors was enhanced by IFN-gamma in both normal controls and SLE in which activated B cells were thought to be increased in number. Therefore, IFN-gamma may be one of the factors which promote polyclonal B cell activation in SLE.
ARPP-16 (cAMP-regulated phosphoprotein of Mr = 16,000) is a substrate for cAMP-dependent protein kinase and is enriched in the basal ganglia. ARPP-16 has been purified to homogeneity from the soluble fraction of bovine caudate nuclei. An additional substrate for cAMP-dependent protein kinase of Mr = 19,000 (ARPP-19) was found to cross-react with rabbit anti-serum prepared against purified ARPP-16. Immunological analysis indicated that ARPP-16 was enriched in the basal ganglia while ARPP-19 was present in similar levels in all brain regions studied and was also present in non-neuronal tissues. ARPP-19 was also purified to homogeneity from bovine caudate nucleus cytosol. Using oligonucleotide probes based on the partial amino acid sequence of purified ARPP-16, cDNA clones for ARPP-16 and ARPP-19 were isolated from a bovine caudate nucleus cDNA library and sequenced. The predicted amino acid sequences of the two proteins were identical except that ARPP-19 had an additional 16 amino acids at the NH2-terminal. The two cDNA clones share an identical 3'-untranslated region of 756 nucleotides. The cDNA clone for ARPP-16 contained 806 additional nucleotides located 3' to this common sequence. The 5'-untranslated regions of the two clones were entirely different. The results suggest the possibility that ARPP-16 and ARPP-19 are produced by alternative transcription and splicing.
The endogenous induction of tumor necrosis factor serum (TNS) for cancer immunotherapy was undertaken in the immediate postoperative period using Lentinan as the primer and OK-432 as the inducer. The changes in several immunological markers of the blood were assayed and compared with a control group to clarify the effects of this treatment. Plasma TNF-alpha levels were elevated two to three hours after eliciting treatment. The neutrophil count was elevated on the 7th postoperative day (POD) and the natural killer (NK) cell activity was transiently suppressed on the 1st POD, but NK cells possessing a high activity (Leu7-CD16+) were preserved until the 7th POD. Helper/inducer (CD4+) and killer cells (CD8+ CD11-) tended to increase, and suppressor (CD8 bright+ CD11+) cells tended to decrease in the induction group. There was no difference in the levels of prostaglandin E2 (PGE2) between the groups, but a marked elevation of interferon-gamma was evident on the 1st POD in the induction group. This treatment may be useful as postoperative adjuvant immunotherapy for cancer due to its ability to induce cytokines and activate host immune mechanisms.
Endogenous pancreatic prostaglandin production in control and obstructive jaundice was investigated using isolated and perfused dog pancreas. In both groups, spontaneous production of prostaglandin E2 and prostaglandin I2 was recorded, and the levels did not change in both groups. The production of both prostaglandins in jaundice, however, was higher than that in the control on stimulation by 8 x 10(-11) mol of cholecystokinin-octapeptide. Amylase release with cholecystokinin-octapeptide at an amount of 8 x 10(-11) mol in jaundice was higher than in the control. The amylase release in both groups, however, showed further elevation on indomethacin pretreatment. On incubation of pancreatic dispersed cells in both groups, prostaglandin production in jaundiced cells was higher than that in control cells. These data showed that enhanced endogenous prostaglandin in obstructive jaundice might be caused by the characteristic change of pancreatic cells, which increased susceptibility to cholecystokinin-octapeptide because of long-term exposure to abnormal blood components, and enhanced prostaglandins might act as a cytoprotector of acinar cells in the pancreas damaged by cholecystokinin-octapeptide administration.
We have investigated the capacity of our established thymic stromal cell clone (MRL104.8a) or its derived factor(s) to induce the differentiation of immature thymocytes. Culture of purified adult murine double-negative (CD4-CD8-, indicated here as CD4-8-) thymocytes on the MRL104.8a thymic stromal cell monolayer for 1 day resulted in the induction of an appreciable percentage of CD4-8+ thymocytes. A bone marrow-derived stromal cell monolayer or a L929 fibroblast monolayer failed to generate CD4-8+ cells. This differentiation could also be induced by a semipurified sample of the MRL104.8a culture supernatant, which contained a thymic stroma-derived T-cell growth factor capable of contributing to the growth of double-negative immature thymocytes. CD4-8+ thymocytes generated 1 day after coculture with the MRL104.8a cells or the sample containing thymic stroma-derived T-cell growth factor were found to be CD3- and J11d+, excluding the possibility of expansion of mature (CD3+4-8+) thymocytes present in the thymus. More importantly, when the culture period was extended to 2 or 3 days, an appreciable number of CD4+8+ and single-positive (CD4+) cells were generated on the MRL104.8a monolayer. Thus, these results provide the direct demonstration that CD3-4-8- immature thymocytes are promoted to differentiate through a rapidly cycling intermediate (CD3-4-8+) into double- and single-positive cells by a specialized thymic stromal component.
Nicorandil, a compound containing a nitrate moiety, can act as a K+ channel opener. Previously we reported stimulatory effects of an intraarterial injection of nicorandil on pancreatic exocrine secretion in the isolated, blood-perfused pancreas under a constant perfusion pressure. To clarify this mechanism in relation to the chemical structure we studied the effects of nicorandil and its derivatives [nitrate containing structure, N-(3-hydroxy-propyl)nicotinamide nitrate (SG-89); nitrate lacking structure, N-(2-acetoxyethyl)nicotinamide (SG-209)], in addition to nitroglycerin (TNG) and pinacidil (a potent K+ channel opener) under a constant perfusion flow rate to the pancreas. Nicorandil, SG-89, and TNG elicited a dose-dependent increase in pancreatic fluid secretion, showing increases in bicarbonate and amylase concentrations. In contrast, SG-209 and pinacidil did not stimulate pancreatic secretion. Furthermore, stimulatory action of nicorandil was not inhibited by treatment with an intraarterial infusion of tetraethylammonium (TEA). These results suggest that nicorandil has direct secretory properties on pancreatic exocrine glands and its nitrate moiety has an important role in the stimulation of pancreatic exocrine secretion, but increasing flow rate and K+ channel opening action do not participate in the secretion.
This study showed several accumulated data through ten years from our experience in hematopoietic disorders and associated infections, which has been analyzed by the Hanshin Study Group of Hematopoietic Disorders and Infections. Since 1979 to 1988, our group had evaluated the sorts of causative organisms and the efficacy of various antibiotics therapy in 2119 cases of infectious diseases associated with hematopoietic disorders. On behalf of evaluating the changes of disease profile for ten years, we divided the accumulated data into three phases; former phase the first three years, middle phase the second three years and late phase the last four years. There was no significant difference in the frequency of various hematopoietic disorders among the three phases. Each leukemia patients occupied 77% of all cases. Sepsis suspected is the most frequent infectious disease accounting for 68.8%. The other infectious diseases were 8.4% of the sepsis, 14.8% of the respiratory infections and 3.1% of the urinary tract infections. Comparing the frequency of infections among the three phases, the respiratory and urinary tract infections inclined to decrease. Of the 532 strains isolated from 2119 cases and identified as causative organisms, gram-negative bacilli occupied 62.8% and gram-positive bacteria 36.5%. In comparing the percentage of gram-negative bacilli among the three phases, it showed a decreasing tendency in order former phase 63.6%, middle phase 76.4% and late phase 43.8%. Pseudomonas, however, had been isolated at almost constant ratio through ten years. On the other hand, the ratio of gram-positive bacteria isolated were 34.5% in former phase, 23.6% in middle phase and 56.3% in late phase, showing increasing a tendency through the period. Twenty-three kinds of antibiotics were administered by intravenous drip infusion. The efficacy rate was 43.9% to 67.2%. In particular, effectiveness of antibiotic therapy often depends on the change of peripheral neutrophil counts from the onset and during the therapy. The efficacy rate, however, was 36% even neutrophil counts have not shown the tendency of increase from less than 100/microliters.
The effects of proteinase inhibitors on the secretion of pancreatic juice were investigated in preparations of the isolated and blood-perfused dog pancreas as compared with those of secretin. Each drug tested was administered i.a. Graded doses of gabexate (1-10 mg) elicited dose-dependent biphasic responses for the secretory rates, bicarbonate concentrations and outputs of pancreatic juice, with maximum effects at approximately 5 mg, but had little effect on the protein concentrations. Camostat, at a high dose of 10 mg, caused significant increases in the secretory rate, bicarbonate concentration and output of pancreatic juice over their basal levels, but had little influence on the protein concentration. Secretin (0.03-0.3 U) usually produced similar to gabexate-induced results (1-5 mg). Both bicarbonate and protein concentrations of the juice obtained with gabexate or camostat were almost the same as those obtained with secretin at a similar secretory rate of pancreatic juice, suggesting the secretory action of gabexate or camostat might be similar to that of secretin. In addition, gabexate (3 mg) and camostat (10 mg) elicited more than the respective additive secretory responses in the presence of i.a. infusion of a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (12 micrograms/min) as well as secretin (0.1 U). These results indicate that gabexate and camostat induce water and bicarbonate secretion by acting directly on ductular cells of the dog pancreas, which might be mediated at least partially through cyclic AMP.
ARPP-16 and ARPP-19 are 2 cAMP-regulated phosphoproteins of Mr = 16,000 and 19,000, respectively, which are identical except for the presence of 15 additional amino acids on the NH2-terminus of ARPP-19. The phosphorylation of these 2 proteins is regulated by cAMP and vasoactive intestinal peptide in reaggregate striatal cultures (Girault et al., 1988). Using immunoblots and immunocytochemistry, we have compared the regional, subcellular, phylogenetic, and ontogenetic distributions of these 2 proteins. ARPP-19 was found in all vertebrate species studied and, at various levels, in all tissues of adult rat. ARPP-19 was also present at high levels in malignant cell lines. During development ARPP-19 concentrations were highest in the embryo and decreased during the pre- and postnatal periods. In contrast, ARPP-16 was detected only in some specific neurons of the dopamine-innervated regions of the basal ganglia and the cerebral cortex, which are known to possess D1 dopamine receptors, in particular the striatonigral neurons. ARPP-16 is phylogenetically recent, being found only in birds and mammals, and appears late in ontogenesis, increasing during the postnatal period. These 2 proteins provide a unique model for studying the specificity of signal transduction and gene expression in dopaminoceptive neurons.