Biomedical subjects
Publications and source records attributed to M Oka.
Terpestacin, a new antibiotic which inhibits syncytium formation, was isolated from Arthrinium sp. FA1744 (ATCC 74132). The structure of terpestacin was elucidated as a bicyclic sesterterpene on the basis of spectroscopic data and chemical derivatization.
Sequence of reactions in the process of ternary complex formation of BMY-28864 with D-mannopyranoside and calcium was spectrophotometrically determined under more strict analytical conditions using metal-free preparations of sugars and the pradimicin derivative at a bandpass slit width of 1 nm. In the first phase of ternary complex formation, BMY-28864 stereospecifically recognized and bound to D-mannopyranoside in the absence of calcium, which was revealed by a visible absorption maximum shift of ca. 8 nm. Subsequently, the BMY-28864-D-mannopyranoside conjugate reacted with calcium to yield the ternary complex, which was detected by an additional visible absorption maximum shift of ca. 8 nm. When the three components were mixed at the same time, both phases simultaneously occurred to produce the ternary complex which was accompanied by a visible absorption maximum shift of 16 nm in total. Based on this two-phased reaction sequence, the mechanism of ternary complex formation of BMY-28864 with D-mannopyranoside and calcium was reexamined in details. Terminal D-mannopyranoside was confirmed to be essential as BMY-28864-specific sugar receptor by in vitro analysis and animal cell experiments. While calcium, strontium and cadmium behaved similar in the in vitro ternary complex formation, the yeast and animal cell experiments showed that only calcium played a dual role as a base in the ternary complex formation and as an effector in physiological disturbances leading to cell death.
A novel neuritogenetic compound BU-4514N was isolated from the fermentation broth of Microtetraspora sp. T689-92. It showed significant NGF-mimic activity and antibacterial activity against Gram-positive bacteria. Structural studies revealed that BU-4514N was a new chemotype antibiotic related to lydicamycin.
One hundred and twenty three children with difficult to control epilepsy (DCE) were studied. Etiological factors which predominated included an age of onset less than 2 years (71.5%), male sex (69%), mixed, secondarily generalized, or complex partial seizures (77%), mental retardation (64%) and neurological abnormalities (52%). Static neurological disease was seen in 63%, with only 17% having idiopathic disease. Identifiable epileptic syndromes were noted in less than half the children. The surface EEG was abnormal in 84%, and correlated with the clinical seizure type in 81%. CT and MRI were helpful in diagnosis in only 38 and 48%, respectively, and even less so in therapy decisions, 7 and 16%, respectively. Prior therapy revealed the use of polytherapy in 61% and suboptimal dosages in 78%. In the 100 patients with adequate follow up, 67% showed a good response, i.e., 35% complete and 32% more than 50% reduction in seizures. Only 11% were total nonresponders, and most were severely retarded. Major treatment strategies employed included switching to monotherapy, supranormal dosages and avoidance of sedative anticonvulsants. Side effects were noted in 41% with 8 cases being life threatening. Overall mortality was 4%. We concluded that risk factors for DCE included early age of onset, mental retardation and certain seizure types. EEG was more helpful than neuroimaging. Treatment responses were favorable, especially in those with normal intellect and the use of normal or high dose monotherapy.
The pharmacological properties of AD-5423 [2-(4-ethyl-1-piper-azinyl)-4- (4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine] were studied in biochemical and behavioral tests. In vitro, AD-5423 bound preferentially to dopamine (DA)-D2 (Ki, 14.8 nM; cf. haloperidol, 8.79 nM; and clozapine, 149 nM) and serotonin (5-HT)-S2 (Ki, 3.98 nM; cf. haloperidol, 26.8 nM; and clozapine, 8.66 nM) receptors. It displayed low affinity for adrenaline (Ad)-alpha-1 (Ki, 56.3 nM) receptors and was virtually devoid of binding to DA-D1 (Ki, 2870 nM), 5-HT-S3, Ad-alpha-2, Ad-beta, muscarine, tau-aminobutyric acid and benzodiazepine receptors. In addition, AD-5423 was only a weak inhibitor of DA, 5-HT and noradrenaline uptake systems. When administered p.o., AD-5423 (0.3-10 mg/kg) increased brain contents of the DA metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in mice and rats and the 5-HT metabolite 5-hydroxyindoleacetic acid in mice. Behaviorally, AD-5423 (0.2-2 mg/kg p.o.) decreased exploratory activity in mice, suppressed conditioned avoidance responding and methamphetamine-induced hyperactivity in mice and rats, antagonized apomorphine-induced gnawing in rats and vomiting in dogs and reduced hostile responses in monkeys. In these effects, AD-5423 was more or less equi-potent to haloperidol. However, AD-5423 (10 mg/kg p.o.), unlike haloperidol, did not antagonize SKF38393-induced vacuous oral movements in rats. Head twitches induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane in mice and by para-chloroamphetamine in rats were antagonized by AD-5423 at much lower doses (0.5-2 mg/kg p.o.) than those of haloperidol and clozapine.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacological effects of the novel antipsychotic, 2-(4-ethyl-1-piperazinyl)-4-(fluorophenyl)-5,6,7,8,9,10-hexahydrocycl oocta [b]pyridine (AD-5423), were compared with those of haloperidol in rats. AD-5423 suppressed hyperactivity induced by microinjecting dopamine into the nucleus accumbens (0.3-3 mg/kg p.o.), and also antagonized both apomorphine- and methamphetamine-induced decreases in firing rate of neurons in the medial prefrontal cortex (1 mg/kg i.v.), indicating antidopaminergic effects of the compound in the possible brain areas involved in pathophysiology of schizophrenia. During repeated treatment with AD-5423 (0.5 and 1 mg/kg/day p.o.), the antiavoidance effect (predictive of antipsychotic efficacy) persisted at least for 14 days, whereas tolerance developed as rapidly as within 10 days to the antagonistic effect on apomorphine-induced gnawing (predictive of acute extrapyramidal side-effects). In these tests, AD-5423 was quite similar to haloperidol in potencies and time-course patterns of the effects. However, different results were obtained between the effects of AD-5423 and haloperidol in possible animal models of tardive dyskinesia and malignant syndrome. In rats treated for 21 days with haloperidol (3 mg/kg, once a day p.o.) and (+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine [(+)SCH23390] (0.05 mg/kg, twice a day s.c.), but not with AD-5423 (10 mg/kg, once a day p.o.), 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF38393) induced a greater number of vacuous oral movements than in nontreated rats. Unlike haloperidol (3 mg/kg p.o.), AD-5423 (10 mg/kg p.o.) did not cause hyperthermia in combined treatment with veratrine (into the preoptic anterior hypothalamus).(ABSTRACT TRUNCATED AT 250 WORDS)
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In this study, we discussed the influence of recombinant interleukin-2 (rIL-2) on nonparenchymal cell of the liver. Donryu rats (8-10 weeks, male) were continuously administered rIL-2 (IL-2 group) or saline (control group) for 6 days via the portal vein. On day 0 or 7 after administration, rats were sacrificed to obtain the blood and liver. Blood mononuclear cell (BMC) and nonparenchymal cell (NPC) of the liver were collected, and their cytotoxicity (NK activity and LAK activity) was measured by 51Cr release-assay. NK activity and LAK activity of BMC in IL-2 group were increased on day 0 and day 7 compared to those in the control group. NK activity and LAK activity of NPC in IL-2 group were augmented on day 0, and NK activity in IL-2 group was still high on day 7. These results suggest that preoperative IL-2 administration may be effective for prevention of formation and/or proliferation of liver metastasis, that are provoked by surgical intervention in cancer of the digestive organs.
Retinoic acid (RA) has been shown to inhibit melanogenesis in B16 mouse melanoma cells (B16 cells). On the other hand, it has been reported that RA increases protein kinase C (PKC) activity in these cells. Further investigation was carried out to identify the PKC subspecies expressed in B16 cells and to examine the changes in the level of each PKC subspecies by RA treatment. Hydroxyapatite column chromatography, immunoblot analysis, and kinetic analysis have shown that B16 cells express the alpha subspecies of PKC. Northern blot analysis has indicated that these cells normally express mRNA for the alpha, delta, epsilon, and zeta subspecies. Upon treatment of B16 cells with 1 microM RA for 48 h, both the activity of the alpha-subspecies and the level of mRNA for the alpha subspecies were increased, resulting in the decrease of melanin polymer formation and tyrosinase activity. Neither the enzyme activities nor mRNA for the beta and gamma subspecies were detected in either the RA-treated or untreated cells. The levels of mRNA for the delta, epsilon, and zeta subspecies were not altered by RA treatment. The demonstration of a selective increase of the alpha subspecies of PKC is a unique finding.
To clarify the possibility that sulfoconjugated dopamine (DA) may play a physiological role by being converted to active free DA, we examined the deconjugating activity in homogenates of organs from dogs. Each tissue homogenate was incubated with sulfoconjugated DA, and the deconjugating activity of the organs was compared. The kidney and liver exhibited the highest deconjugating activities. In contrast, the intestine and heart showed lower arylsulfatase activities, and almost no activity was found in the brain or skeletal muscle. Moreover, in the heart, the deconjugating activity for sulfoconjugated DA was higher in the atrium than the ventricle. These results indicate that sulfoconjugated DA is converted to active free DA in homogenates of organs from dogs and that the deconjugating activity varies between different parts of an organ. Sulfoconjugated DA must be looked upon as a possible precursor or reservoir for the production of active free DA.
Two cases of foreign bodies of the antrum are reported. One was a turbine bur which presumably entered through an oro-antral fistula after a tooth extraction. The other was also a turbine bur where the mode of entry was not clear (lack of oro-antral fistula), but it presumably entered through the socket of the extracted tooth. The mucosa of the antrum appeared normal in spite of the lengthy presence of the foreign body.
2-Lysophosphatidylcholine (lysoPtdCho), a product of the hydrolysis of phosphatidylcholine catalyzed by phospholipase A2, greatly potentiates the activation of human resting T lymphocytes that is induced by a membrane-permeant diacylglycerol plus a calcium ionophore, as determined by the expression of the alpha subunit of the interleukin 2 receptor and thymidine incorporation into DNA. LysoPtdCho per se is inactive unless both diacylglycerol and a calcium ionophore are present. This effect of lysoPtdCho is also observed when diacylglycerol is replaced by a tumor-promoting phorbol ester. Other lysophosphatides including lysophosphatidylserine, lysophosphatidylinositol, and lysophosphatidic acid are inert except for lysophosphatidylethanolamine, which is far less effective than lysoPtdCho. Tracer experiments with radioactive choline indicate that, when T lymphocytes are stimulated with an antigenic signal, lysoPtdCho is indeed produced in a time-dependent fashion, although the concentration of this lysophospholipid accumulated remains to be quantitated. It suggests that phospholipase A2 is directly involved in the signal transduction pathway through protein kinase C to induce long-term cellular responses.
Heat shock proteins (HSPs) are evolutionarily highly conserved polypeptides that appear to be produced by many cells to preserve cellular functions under a variety of conditions of stress, including infections. We report that a 65-kDa HSP is present in mouse peritoneal cells that have been infected with a low-virulence (Beverley) strain of Toxoplasma gondii, as determined by electroblot assay using a monoclonal antibody specific for microbial HSP65. This HSP is, however, not expressed when infection occurs with the high-virulence RH strain of T. gondii. Furthermore, HSP was demonstrable in mice that acquired resistance against infection with a lethal dose of bradyzoites of the Beverley strain or even of an inoculum of a highly virulent strain of T. gondii (RH). From these results, it can be suggested that HSPs play an important role in developing effective defenses that include effective immune responses against infection with Toxoplasma parasites in vivo.
Acting in synergy with diacylglycerol, unsaturated free fatty acids such as arachidonic, oleic, linoleic, linolenic and docosahexaenoic acids dramatically activate some members of the protein kinase C family at the basal level of Ca2+ concentration. It is plausible that phospholipase C and phospholipase A2, and possibly phospholipase D as well, are involved in the activation of protein kinase C. Presumably, this enzyme activation is integrated into the signal-induced membrane phospholipid degradation cascade, prolonging the activation of protein kinase C. The sustained activity of this enzyme appears to be of importance for long-term cellular responses such as development of neuronal plasticity and gene activation.
The prognosis of patients with advanced gastric cancer who undergo curative resection is still unsatisfactory. The relationship between prognosis and various factors such as stage, lymph node metastasis, serosal invasion and regional lymph node reaction (follicular hyperplasia and sinus histiocytosis) was evaluated. Of the factors studied, the only one that correlated well with survival was sinus histiocytosis. Lymph node metastasis was related weakly to prognosis. No correlation between prognosis and stage, serosal invasion or follicular hyperplasia was observed. Sinus histiocytosis may represent the morphological tumour-host immune reaction. Lymph node metastases or histological types were not related to regional lymph node reaction. These results suggest that sinus histiocytosis could be a useful prognostic factor for gastric cancer. Intensive postoperative follow-up for recurrence may be necessary even for patients with low-grade sinus histiocytosis in whom curative surgery is attempted.
Extensive acetabular defects produced surgically in 25 dogs were repaired using A-W glass-ceramic blocks. No dislocation of the femoral head, and no displacement or breakdown of the blocks was seen 1 year after surgery. All dogs were able to run normally shortly after surgery, except for one that limped for a short time. The failure load between the blocks and the bone had increased markedly 2 months after implantation. The failure load/unit area was 33.2 kgw/cm 2 1 year after implantation. We conclude that glass-ceramic supplementation of the acetabulum is successful experimentally, and that this may be a promising method for repair of large acetabular bone defects.
Ultra-high-strength poly(L-lactide) (PLLA) rods were fabricated using a drawing technique. Rods with a diameter of 3.2 mm and a draw ratio of 2.5:1 showed initial bending strength and modulus values of 240 MPa and 13 GPa, respectively. The purpose of this study was to investigate the in vitro and in vivo degradation of PLLA rods with a draw ratio of 2.5:1. The greater the rod diameter, the longer the bending strength was maintained in phosphate buffered saline at 37 degrees C. The bending strength retention of rods (diam. 3.2 mm) implanted in the subcutis of rabbits was almost equal to that of rods in the in vitro study, while those rods implanted in the medullary cavity of rabbit femora showed a slightly lower bending strength retention. Molecular weight was reduced to the greatest extent in the medullary cavity, followed by in the subcutis and in vitro. The weight of PLLA rods in the medullary cavity was reduced by 22% at 52 weeks and by 70% at 78 weeks after implantation. Histologically, no inflammatory or foreign body reaction was observed in the medullary cavity for 52 weeks. The drawn PLLA rods maintained a bending strength exceeding that of human cortical bone in the medullary canal for a period of 8 weeks, suggesting that the drawn PLLA rods may be useful in the repair of fractured human bones.
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