Biomedical subjects
H Hara
Publications and source records attributed to H Hara.
[CA 19-9 producing lung tumors].
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Characterization of specific (+)-[3H]N-allylnormetazocine and [3H]1,3-di(2-tolyl)guanidine binding sites in porcine gastric fundic mucosa.
We have identified and characterized sigma receptor sites in porcine gastric fundic mucosa by receptor binding assay techniques using two highly selective radioligands of sigma receptor, (+)-[3H]N-allylnormetazocine (SKF 10,047) and [3H]1,3-di(2-tolyl)guanidine (DTG). Specific binding of (+)-[3H]SKF 10,047 and [3H]DTG in porcine gastric fundic mucosa were saturable, reversible and of high affinity and capacity with Kd: 90.5 nM, Bmax: 1058 fmol/mg of protein and Kd: 53.6 nM, Bmax: 3573.3 fmol/mg of protein, respectively. The inhibitory effects of sigma receptor ligands on specific (+)-[3H]SKF 10,047 binding decreased in the following order: haloperidol > DTG > or = (+)-3-(3-hydroxyphenol)-N- (1-propyl)piperidine (3-PPP) > (+)-SKF 10,047 > (-)-3-PPP > or = dextromethorphan > rimcazole > (-)-SKF 10,047. Specific (+)-[3H]SKF 10,047 binding sites showed stereoselectivity for stereoisomers of SKF 10,047 and 3-PPP and were highly correlated with the profile of sigma-1 sites. On the other hand, the inhibitory effects on specific [3H]DTG binding decreased in the following order: DTG > haloperidol > rimcazole > (+)-3-PPP > or = (-)-3-PPP > dextromethorphan > (+)-SKF 10,047 = (-)-SKF 10,047. Specific [3H]DTG binding sites did not show stereoselectivity and were highly correlated with the profile of sigma-2 sites. These findings indicate that porcine gastric fundic mucosa contains sigma receptor sites with the characteristic of sigma-1 sites and sigma-like sites showing several of the characteristics of sigma-2 sites (putative sigma-2 sites).
[Diagnosis and drug treatment in hyperactive children].
A critical review was given to the diagnostic transition of hyperactive children, i.e., from attention deficit disorder to attention deficit-hyperactivity disorder, in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders. Based on the new diagnostic criteria for hyperactive children, or hyperkinetic disorders in ICD-10, 12 of 122 (9.8%) children with a birthweight less than 1,500 grams have found to show hyperkinetic disorders during ordinary follow-up examinations at 4 to 6 years of age. Discontinuation of stimulants during school holidays, or the "drug holidays" procedure, was recommended not only because a child's response to stimulants could be reconfirmed but also because the side effect of growth retardation could be avoided. Three typical drug responders with hyperactivity were presented. Case 1 was a 19-year-old male with some autistic features and tics. He had been taking pemoline from 10 to 13 years of age, but showed no side effects. Case 2 was a 15-year-old boy with epileptic EEG abnormalities, and had been also taking pemoline from 6 to 10. He was attacked by a partial seizure with secondary generalization just 2 months after the drug administration. Recurrence of epileptic seizures was prevented by additional medication of an anticonvalsant , carbamazepine. Case 3 was a 13-year-old boy with enuresis nocturna and with several febrile seizures, and had been taking clomipramine, a tricyclic antidepressant, from 4 to 6. The antidepressant proved very effective to his hyperactivity and temper tantrum, but not to his enuresis.
Acute hepatic failure with swollen mitochondria and microvesicular fatty degeneration of hepatocytes triggered by free radical initiator.
BACKGROUND: Reye syndrome and acute fatty liver of pregnancy are characterized by acute hepatic failure associated with characteristic pathologic changes of hepatocytes, i.e., microvesicular fatty degeneration with severe mitochondrial swelling. Several animal models of these conditions have been proposed, although none has demonstrated sufficiently similar laboratory and pathologic features. EXPERIMENTAL DESIGN: A single dose of 2,2'-azobis-(2-amidinopropane) dihydrochloride, a free radical initiator, 100 mg/kg of body weight, injected intraperitoneally to BALB/c mice induced a transient decrease in hepatic energy charge, liver mitochondrial respiratory activity, and succinate dehydrogenase activity and a transient increase in blood ammonia level, suggesting hepatic failure. RESULTS: The hepatocytes displayed microvesicular fatty degeneration with severely swollen mitochondria. CONCLUSIONS: This is the first model of acute hepatic failure with microvesicular fatty degeneration of hepatocytes. It suggests a role of free radicals in the pathogenesis of certain types of acute hepatic failure.
Sigma receptor-mediated effects of a new antiulcer agent, KB-5492, on experimental gastric mucosal lesions and gastric alkaline secretion in rats.
Using in vitro receptor autoradiography, we found specific [3H] 1,3-di(2-tolyl)guanidine (DTG) binding to be highly localized in the mucosa of the stomach and duodenum in rats. 4-Methoxyphenyl 4-(3,4,5-trimethoxybenzyl)-1-piperazine acetate monofumarate monohydrate (KB-5492), a novel antiulcer agent and a specific sigma receptor ligand, at 1 and 10 microM inhibited this specific [3H] DTG binding in rat stomach. The effects of KB-5492 and sigma receptor ligands such as DTG and rimcazole on the gastric lesions and alkaline secretion in rats were examined. KB-5492 (25-100 mg/kg, p.o.), DTG (3-30 mg/kg, p.o.) and rimcazole (30-100 mg/kg, p.o.) inhibited ethanol-induced and water-immersion stress-induced gastric mucosal lesions in rats. KB-5492 (30 mg/kg, i.g.) and DTG (30 mg/kg, i.g.) increased the gastric alkaline secretion in rats. These protective and alkaline-stimulated effects of KB-5492 and DTG were attenuated by haloperidol, a sigma receptor antagonist. These findings suggest that KB-5492 and DTG exert ulceroprotective effects through interaction with sigma receptors in the gastric mucosa.
[Long-term results of the surgical treatment for thymoma].
Long-term results of the surgical treatment for 27 cases of thymoma were studied. The clinical stages according to Masaoka's classification were: 7 cases of stage I, 9 cases of stage II, 8 cases of stage III, 1 case of stage IVa and 2 cases of stage IVb. The histological classifications were: epithelial cell type in 10 cases, lymphocytic type in 9 cases and mixed type in 8 cases. Complications consisted of 18 cases of myasthenia gravis (MG). The long-term survival at 5 and 10 years were as follows: 90.6%, 74.8% in all cases; 100.0%, 50.0% in the non-invasive type; 88.2%, 80.2% in the invasive type; 72.0%, 72.0% in the epithelial cell type; 100.0%, 75.0% in the lymphocytic type; 100.0%, 80.0% in the mixed type; 88.9%, 44.4% in cases not complicated with MG; 92.9%, 84.4% in cases complicated with MG. Complete resection and adjuvant therapy improved prognosis even in cases of invasive thymoma, but one case died due to local recurrence of thymoma at 10 years after operation, so we emphasize it is important to follow up for the long time period more than 10 years.
Deletion (X)(p11): another case of renal adenocarcinoma with involvement of Xp11.
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Internalization and degradation of hepatocyte growth factor in hepatocytes with down-regulation of the receptor/c-Met.
Hepatocyte growth factor (HGF) promotes proliferation of cultured hepatocytes by its interaction with cell surface receptors. In this paper, we examined the metabolic fate of HGF using hepatocytes. Kinetic analysis using [125I]HGF showed that 40% of surface-bound HGF was rapidly internalized in hepatocytes within 30 min at 37 degrees C. Under these conditions, the amount of HGF-bound c-Met, the high-affinity receptor, decreased from the cell surface. Furthermore, the internalized HGF was degraded and released from the cells. These results indicate that cell surface-bound HGF is internalized and degraded by the receptors, including c-Met, on hepatocytes.
Nicotinic acetylcholine receptor mRNAs in myasthenic thymuses: association with intrathymic pathogenesis of myasthenia gravis.
Reverse transcription and the polymerase chain reaction showed that the alpha-, beta- and gamma-subunit genes of nicotinic acetylcholine receptor (AChR) in human skeletal muscle were expressed in myasthenia gravis (MG) thymuses (3 thymomas and 7 hyperplastic thymuses). A study of the expression of these subunit mRNAs in a variety of human tissues showed that alpha-subunit mRNA was expressed in human thymus and cerebral cortex, and that all three subunits were expressed only in human child thymus. Our results suggest that a complete AChR similar to extrajunctional (embryonic) muscle AChR is expressed in MG thymuses and that intrathymic AChR might be the primary antigen which induces autoimmune responses to muscle AChR.
Effect of KB-2796, a new diphenylpiperazine Ca2+ antagonist, on voltage-dependent Ca2+ currents and oxidative metabolism in dissociated mammalian CNS neurons.
The effects of KB-2796, 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4- trimethoxybenzyl)piperazine-2HCl, on the low- and high-voltage activated Ca2+ currents (LVA and HVA ICa, respectively) and on oxidative metabolism were studied in neurons freshly dissociated from rat brain. KB-2796 reduced the peak amplitude of LVA ICa in a concentration-dependent manner with a threshold concentration of 10(-7) M when the LVA ICa was elicited every 30 s in the external solution with 10 mM Ca2+. The concentration for half-maximum inhibition (IC50) was 1.9 x 10(-6) M. At 10(-5) M or more of KB-2796, a complete suppression of the LVA ICa was observed in the majority of neurons tested. There was no apparent effect on the current-voltage (I-V) relationship and the current kinetics. KB-2796 delayed the reactivation and enhanced the inactivation of the Ca2+ channel for LVA ICa voltage- and time-dependently, suggesting that KB-2796 preferentially binds to the inactivated Ca2+ channel. KB-2796 at a concentration of 3.0 x 10(-6) M also decreased the peak amplitude of the HVA ICa without shifting the I-V relationship. In addition, KB-2796 reduced the oxidative metabolism (the formation of reactive oxygen species) of the neuron in a concentration-dependent manner with a threshold concentration of 3 x 10(-6) M. It is suggested that the inhibitory action of KB-2796 on the neuronal Ca2+ influx and the oxidative metabolism, in combination with a cerebral vasodilatory action, may reduce ischemic brain damage.
Chronological atrophy after transient middle cerebral artery occlusion in rats.
We studied the development of brain atrophy after transient focal ischemia in rats. The animals were subjected to cerebral ischemia induced by embolization of the right middle cerebral artery (MCA) for 60 min. The brains were studied morphologically 7 days, 1 month, 3 months and 9 months after recirculation. In addition, the effects of a new calcium antagonist, KB-2796, and a glutamate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX); were evaluated in this model 1 month after ischemia. The hemispheric volume of the ipsilateral ischemic side, expressed as a percentage of that on the contralateral non-ischemic side, was 99% in the sham operation group, 94% at 7 days, 87% at 1 month, 68% at 3 months and 65% at 9 months. Atrophy of the striatum and cortex, but not the hippocampus, was observed 1 month after ischemia. Atrophy of the ipsilateral substantia nigra and the thalamus, which are remote from the ischemic region, was observed 7 days and 1 month, respectively, after ischemia. Correlations between the extent of the atrophy in the striatum and that in the substantia nigra and between the extent of the atrophy in the cortex and in the thalamus were statistically significant. Treatment with KB-2796 or DNQX administered intraperitoneally at a dose of 10 mg/kg twice 30 min before ischemia and immediately after ischemia was effective in reducing the extent of atrophy in both the ipsilateral ischemic and non-ischemic regions. These results suggest that brain atrophy on the ipsilateral ischemic side develops time-sequentially after transient focal ischemia and that ischemia affects not only the primary ischemic focus but also remote regions through transsynaptic connections, and that KB-2796 and DNQX have beneficial effects on atrophy in the chronic phase after ischemia.
[Serum superoxide dismutase in patients with Graves' disease].
We studied serum superoxide dismutase (SOD) in patients with Graves' disease. Measurements of immunoreactive Cu, Zn-SOD and SOD-like activities were made by enzyme-linked immunosorbent assay (Ube Industries Ltd) and Nitroblue Tetrazolium method (Wako Ltd), respectively. Serum from patients with untreated Graves' disease had a significantly higher concentration of Cu, Zn-SOD and higher SOD-like activity than those from normal subjects, patients with Graves' disease under treatment over one year, patients with Graves' disease in remission, and patients with untreated Hashimoto's disease. Methimazole treatment produced no significant change in SOD-like activity and Cu, Zn-SOD concentration when patients with Graves' disease had normal thyroid function. These results indicated that oxidative tissue injury existed in patients with Graves' disease with normal thyroid function under treatment; however, we could not clearly establish that thyroid function had a direct connection with oxidative tissue injury.
Absence of bcr/abl gene in single hemopoietic progenitors in some patients with chronic myelogenous leukemia.
CD34+DR- and CD34+DR+ cells were isolated from the marrow mononuclear cells of five patients with chronic myelogenous leukemia (CML) carrying the Philadelphia (Ph) chromosome. Analysis of bcr/abl hybrid mRNA in individual colonies from a single cell using reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated the presence or absence of the hybrid mRNA. For patient 1 in the chronic phase of CML, the hybrid mRNA was detected in all colonies derived from CD34+DR+ and CD34+DR- hemopoietic progenitors. In contrast, for patient 2 in the chronic phase of CML, the mRNA was detected in all individual colonies from CD34+DR+ progenitors but not in any from CD34+DR- progenitors. For patient 3 in the chronic phase of CML, the mRNA was detected in all individual colonies from CD34+DR+ but in only some of the colonies from CD34+DR- progenitors. For patients 4 and 5 in the acute crisis of CML, the mRNA was found in a portion of colonies from CD34+DR+ and CD34+DR- progenitors. These results indicated that normal clones can persist in CD34+DR- progenitors in some patients with CML, even when chromosome analysis detects the Ph chromosome in all metaphases of bone marrow cells.
Multilineage response in aplastic anemia patients following long-term administration of filgrastim (recombinant human granulocyte colony stimulating factor).
The present multicenter study was undertaken to confirm whether filgrastim/recombinant human granulocyte colony stimulating factor (rhG-CSF) could mobilize residual multipotential stem cells by its G0-shortening effect in patients with aplastic anemia (AA) and induce a multilineage response. Twenty-seven patients with acquired severe or moderate AA received long-term administration (2 to 12+ months) of rhG-CSF in doses from 100 to 400 micrograms/body/day by s.c. injection or 250 to 1,500 micrograms/body/day by i.v. infusion. Twenty-six out of the 27 evaluable patients showed a substantial increase in neutrophils associated with a recovery of myeloid precursors in bone marrow within one month of therapy. Interestingly, 10 out of the 27 patients showed a dramatic improvement in severe anemia after two to ten months of therapy. Moreover, severe thrombocytopenia improved after two to four months of therapy in three out of these ten patients accompanied by a significant increase in megakaryocytes in bone marrow. Clonal cultures of bone marrow cells revealed a recovery in myeloid as well as erythroid precursors in most of these ten patients. In two patients who showed a trilineage response, mixed and megakaryocyte colony formations also recovered. These results suggest that long-term administration of rhG-CSF mobilizes myeloid, erythroid, megakaryocyte and multipotential progenitor cells and induces a multilineage response in some patients with AA.
Stimulation of DNA synthesis in skin fibroblasts by human hepatocyte growth factor/scatter factor.
The effect of hepatocyte growth factor/scatter factor (HGF/SF) on the proliferation of human skin fibroblasts was examined. At concentrations above 1.0 ng/ml, both native and recombinant human HGF/SF stimulated the DNA synthesis determined by [3H]thymidine incorporation, which was completely inhibited by an anti-human HGF/SF monoclonal antibody. The maximal DNA synthesis in the treated cells was nearly twice that in untreated cells. HGF/SF also caused an increase in the labelling index, DNA content and cell number. The effect of HGF/SF was more than additive to the maximal effect of insulin and epidermal growth factor, other mitogens for the fibroblasts. These results indicate that human skin fibroblasts are sensitive to the mitogenic action of HGF/SF.
Heparin modulates the receptor-binding and mitogenic activity of hepatocyte growth factor on hepatocytes.
Hepatocyte growth factor (HGF) is a mitogen for hepatocytes, having high affinity for heparin. In this study, we examined the function of cell surface heparin-like molecules in HGF/receptor interaction and HGF-induced mitogenic activity using hepatocytes. Binding studies using 125I-HGF showed that more than 85% of bound HGF was released from the cell surface by washing with heparin. This procedure also released HGF from the c-Met protein, which is a component of the high-affinity receptor. In addition, heparitinase digestion of hepatocytes reduced the HGF bound to c-Met protein. Furthermore, excess heparin added during the binding of 125I-HGF to hepatocytes, significantly diminished HGF bound to c-Met protein. Moreover, when DNA synthesis of hepatocytes was repressed and retarded by excess HGF, exogenous heparin restored it. These results suggest that HGF is bound to c-Met protein and that its mitogenic activity is regulated by heparin-like molecules on hepatocytes.
Effect of rat subarachnoid hemorrhage on serotonin innervation of the cerebral ventricular wall and serotonin neurons of the ventral surface of the brain stem: an immunohistochemical study.
The effect of subarachnoid hemorrhage on serotonin (5-HT) innervation of the cerebral ventricles and on 5-HT neurons in the ventral surface of the brain stem was studied immunohistochemically in the rat. Subarachnoid hemorrhage (SAH) was induced by injection of autologous arterial blood into the cisterna magna. In normal and sham-operated animals, the entire ependyma of the ventricles was supplied with 5-HT-immunoreactive supraependymal nerves. The ependyma in the dorsal third ventricle received the most dense innervation. 5-HT neurons on the surface of the brain stem were found in the median fissure and on the ventral surface of the pyramidal tract. A marked reduction in supraependymal 5-HT immunostaining was observed in animals sacrificed as early as 6 h post-SAH and this change continued until 14 days and recovered by 28 days following SAH. 5-HT neurons on the ventral surface of the brain stem were visible even in the rat with SAH. The results suggest that SAH caused a transient depletion of 5-HT immunoreactivity in the supraependymal nerves but 5-HT neurons on the ventral surface of the brain stem were unchanged. Depletion of 5-HT immunoreactive nerves on the cerebral ventricular wall might be involved in the pathophysiology after SAH.