CP violation and leptogenesis.
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Journal Article↗
Biomedical subjects
H Kikuchi
Publications and source records attributed to H Kikuchi.
Ischemic tolerance due to the induction of HSP70 in a rat ischemic recirculation model.
Various studies have demonstrated an increase in heat shock protein 70 (HSP70) synthesis in the brain following transiently induced ischemia, suggesting a protective role for HSP70 against ischemic insult. In this study, we determined the time course of HSP70 mRNA and protein induction in rat hippocampus following ischemia using Pulsinelli's four-vessel occlusion model, and suggested a protective role for HSP70 induction in limiting ischemic damage to neurons and delayed neuronal death. In Northern blotting analysis using human HSP70 DNA as a probe, the accumulation of HSP70 mRNA after 5 min ischemia became evident at 4 h, and continued until 16 h, while after 30 min ischemia, HSP70 mRNA appeared at 2 h, and continued above control level until 24 h after treatment. In immunoblot analysis using anti-HSP70 antibody, induction of HSP70 protein appeared 24 h and reached a maximum 48 h after 5 min ischemia. In immunohistochemical analysis using anti-HSP70 antibody, staining was not detected in CA1 neurons until 16 h after 5 min ischemia, but staining in CA1 gradually increased 1 day after ischemia and reached a maximum level 2 days after ischemia. Similar time profiles in the staining pattern of HSP70 protein were observed in CA3 and CA4 neuronal cells following 30 min ischemia. When rats pretreated with 5 min ischemia (non-lethal for CA1 pyramidal neurons) were exposed to a 30 min, lethal period of ischemia, 2 days after pretreatment, considerable staining of HSP70 was observed. Pretreated rats had much less neuronal damage in the CA1 sector than did rats subjected to lethal, 30 min ischemia alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Adaptation, Physiological↗
Supratentorial low-grade astrocytoma. Correlation of computed tomography findings with effect of radiation therapy and prognostic variables.
BACKGROUND: In supratentorial low-grade astrocytoma, radiation therapy effects and prognostic factors, especially with respect to computed tomography (CT) findings, are not yet well established. A retrospective analysis of 119 patients with this disease (histologically confirmed ordinary astrocytoma) therefore was conducted. METHODS: Between 1965 and 1989, 101 patients received postoperative radiation therapy, whereas 18 patients received surgery alone. Radiation was directed to the tumor plus a 1- to 3-cm margin in almost all cases; the dose range was 41 to 66 Gy (mean, 57 Gy). CT scan was performed before treatment on 74 patients. Postoperative survival rates were compared by both univariate and multivariate analyses. RESULTS: The 5- and 10-year survival rates for the irradiated group were 60% and 41%, respectively, which were significantly better than those for the surgery-alone group (37% and 11%, P = 0.048). Among various potential prognostic factors for the irradiated patients, only a lower age was associated with a better prognosis. Sex, tumor site (deep-seated or not), extent of surgery, radiation dose and field, and adjuvant chemotherapy did not influence the prognosis significantly. Among various CT findings, a clear tumor margin, a maximum tumor area less than 25 cm2, presence of a cyst, and lack of mass effect were associated with a better prognosis on univariate analysis (P = 0.02-0.12), but contrast enhancement was not related to prognosis. On multivariate analysis, however, mass effect was the only significant factor. CONCLUSIONS: Radiation therapy appears definitely to be effective in improving the prognosis for low-grade astrocytoma. Younger age, and the absence of mass effect determined by CT, were associated significantly with a better prognosis.
Adolescent↗
Developmental expression of trkB and low-affinity NGF receptor in the rat retina.
Brain-derived neurotrophic factor (BDNF) promotes the survival of retinal ganglion cells, but these effects are dependent on the developmental stages, and a number of retinal ganglion cells are eliminated during pre- and neonatal stages. We have examined the expression of BDNF receptors, trkB and low-affinity nerve growth factor receptor (LNGFR), in the rat retina during these period using Northern blot analysis. The expression of trkB and LNGFR displayed two peaks during embryonic day 17 (E17) through postnatal day 1 (P1), and during P14-P17, indicating that it may play an important role in neuronal development and neuronal cell death.
Animals↗
Novel antibodies specific for proteolyzed forms of protein kinase C: production of anti-peptide antibodies available for in situ analysis of intracellular limited proteolysis.
We show here a novel method for the in situ analysis of proteolyzed proteins in a cell. As a model, we focused on protein kinase C (PKC) beta, which is cleaved at a specific site between the catalytic and regulatory domains by calpain, the intracellular calcium-activated neutral proteinase. To detect proteolyzed PKC beta 'cleavage-site-directed antibodies', which specifically recognize the amino-terminal region of the catalytic fragment but do not cross-react with the unproteolyzed enzymes, were raised using synthetic peptide. The synthetic peptide used in this study was QGTKVPEEKTT, corresponding to the amino-terminal region of the catalytic fragment from human PKC beta generated by calpain. Rabbits were immunized with the synthetic peptide after conjugation with a carrier protein. Antibodies obtained reacted with the 46-kDa catalytic fragment of PKC beta, whereas they did not cross-react with unproteolyzed enzyme nor other fragments with different amino-termini. Thus, our antibody is specific to the amino-terminal sequence QGTKVPEEKTT, but does not recognize the same sequence located internally in native PKC beta. When human monoblast U937 cells were treated with calcium ionophore, the catalytic fragment of PKC beta was detected in the cytosol by immunoblotting with the antibody. However, this antibody did not bind unproteolyzed 80-kDa PKC beta, although this form was dominant in the cytosol of the calcium ionophore-treated cells. We could also detect comparable amounts of catalytic fragment in the calcium ionophore-treated cells by immunocytochemical staining with the same antibody. Our method was applied to examine the proteolysis of PKC beta in neutrophils stimulated with various reagents.
Amino Acid Sequence↗
A point mutation found in the WT1 gene in a sporadic Wilms' tumor without genitourinary abnormalities is identical with the most frequent point mutation in Denys-Drash syndrome.
We have analyzed exon 9 of the WT1 gene of 18 non-familial/sporadic unilateral Wilms' tumors (WTs) from Japanese patients, by the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method. After screening these WTs, a nucleotide alternation, which was present on both alleles, was found in only one case. Furthermore, PCR-SSCP analysis of the constitutional DNA revealed that this patient carried the mutation on only one allele in the germline. Sequence analysis showed that the tumor carried a point mutation (C-1180 to T-1180) in WT1 exon 9 of both alleles, resulting in an Arg-394 to Trp-394 amino acid substitution within the third zinc finger domain of the WT1 product. Interestingly, this mutation is identical with the most frequent point mutation associated with the Denys-Drash syndrome. However, the classical triad of Denys-Drash syndrome does not apply to this patient. This is in the first report of the point mutation in the zinc finger domain of both WT1 alleles in a sporadic unilateral WT without genitourinary abnormalities, and the mutation suggests that some sporadic WTs carry the Denys-Drash WT1 mutations.
Base Sequence↗
Extension of optic nerve fibers on genetically modified cells producing brain-derived neurotrophic factor.
Since brain-derived neurotrophic factor (BDNF) promotes the survival of retinal ganglion cells (RGCs), we transfected a rat BDNF cDNA into rat fibroblasts, and retinal fragments of rat embryos were cultured on cell monolayers of these cells. Retinal fragments showed enhanced neurite extension on BDNF-transfected cells compared with that on control cells. The degree of the neurite extension, however, decreased depending upon the embryonic stages. These results suggest that fibroblasts genetically modified to produce BDNF might be a promoter of neurite extension by RGCs, but this does not apply to the RGCs of late embryonic stages.
Animals↗
Kinetic analysis of tissue distribution of doxorubicin incorporated in liposomes in rats (II).
The objective of this study is to perform kinetic modelling of the tissue distribution of doxorubicin encapsulated into liposomes (L-DXR), especially to the heart and liver. The release process of doxorubicin (DXR) from liposomes in blood was quantified by a release clearance. This parameter defines a release rate of DXR based on the concentration of L-DXR in blood and was estimated from kinetic modelling of DXR distribution to the heart after L-DXR administration. The distribution of free DXR to the heart was modelled separately. The experimental data for this modelling were reported previously (Harashima et al., Biopharm. Drug. Disposit., 13, 155-170 (1992)). This analysis provided a free DXR concentration profile as well as a release clearance of DXR after L-DXR administration. There was a remarkable difference in the free DXR concentration in blood between free and liposomal administration. The area under the DXR curve in the heart was reduced by approximately one third from that for the first two hours after DXR administration by liposomal encapsulation, which could be the reason for reduced cardiac toxicity. In our previous report, the distribution of L-DXR to the liver was shown to be explained by a sequentially linked two-compartment model with efflux process. The validity of this efflux model was examined in this study by a repeated dose study. The apparent uptake clearance decreased with time and showed a second peak after the repeated dose, which justified the efflux model. These kinetic analyses give quantitative understanding of the effect of liposomal encapsulation on the tissue distribution of DXR.
Animals↗
Familial genetic defect in a case of leukocyte adhesion deficiency.
Leukocyte adhesion deficiency (LAD) is an inherited immunodeficiency disorder caused by CD18 subunit abnormality dependent defective expression of beta 2 integrins on the surface of leukocytes. On analysis of the CD18 molecular defect in a female Japanese patient with a severe deficiency LAD phenotype, neither CD11a nor CD18 molecules could be detected on the patient's EBV-transformed B lymphoblastoid cell line. The mRNA of the patient's B cells was normal in size, but was diminished in quantity, to approximately half normal levels. Sequencing of the CD18 cDNA of the patient revealed a C605 to T transition, resulting in a Pro178-->Leu substitution. This was heterozygous in the genomic DNA, and shown to be of maternal origin by family study. Only a few transcripts from the other allele without the Pro178-->Leu mutation were detectable. Northern blot analysis revealed reduced CD18 mRNA levels, not only in the patient, but also in the father and brother. These results indicate that our case is a compound heterozygote with two different mutant alleles: one causing a single amino acid substitution and the other causing defective expression of mRNA.
Amino Acid Sequence↗
Porous polyurethane tubes as vascular graft.
A vascular graft with the inner diameter of about 3 mm was prepared from segmented poly (ether urethane) with an extrusion technique. To make the wall of the vascular grafts porous, NaCl salts were added to the polyurethane solution to be extruded and removed with water extraction after evaporating the solvent in the extruded tube. The wall was reinforced with elastic fiber to prevent dilation. The compliance of the vascular graft measured with the method of Hayashi et al. ranged from 0.2 to 0.3% mmHg -1. The initial Young's modulus was close to that of canine carotic artery, to which the porous polyurethane graft 4-cm long was anastomosed. Vascular grafts were occluded within 2 weeks after implantation, when their pore size was 0, 1.7, or 4.4 mum, whereas those with the pore size of 5.5, 7.4, and 30 mum were patent for longer than 4 weeks. When the vascular graft with the pore size of 30 mum was implanted for 6 months, the luminal surface was covered with neointima, but the endothelium-like cells appearing in the middle of the intima of the vascular graft were immature and sometimes had a very big nucleus. In addition, spindle-shaped, modified smooth muscle cells were noticed in the deep layer of the neointima, especially in the tissue where anastomotic intimal hyperplasia occurred.
Animals↗
Transvenous embolization of dural caroticocavernous fistulae: technical considerations.
Sixteen patients with symptomatic dural caroticocavernous fistulae were treated by transvenous embolization, via the jugular vein and inferior petrosal sinus. The fistula was occluded by thrombogenic coils. Complete resolution of symptoms and signs was achieved in 14 patients, and complete angiographic resolution was also obtained in 14 patients. Failures to achieve angiographic cure were attributed to failure to reach the fistula within the cavernous sinus precisely. Factors which make placement of the catheter at the fistula difficult are trabeculae within the cavernous sinus, a specific configuration of the superior ophthalmic vein and venous thrombosis. To improve the efficacy of transvenous embolization, every possible venous route to the cavernous sinus therefore should be tried, to facilitate reaching the fistula and the possibility of transvenous embolization should not be thwarted by venous thrombosis.
Adult↗
Degenerative changes in the internal elastic lamina relating to the development of saccular cerebral aneurysms in rats.
In order to investigate the developmental mechanism of saccular cerebral aneurysms, changes in the internal elastic lamina at the junction of the anterior cerebral artery and the olfactory artery were electronmicroscopically studied in 6 control and 6 experimental rats undergoing ligation of the left carotid artery and branches of both renal arteries. In the control group, spontaneous destructive changes occurred on the luminal side of the internal elastic lamina and progressed from the luminal towards the abluminal side as the elastic lamina advanced to the apex. Close to the apex, these changes invaded and disrupted the whole elastic lamina. The elastic lamina was replaced by sparsely lined up lumps of elastic tissue in the walls of early aneurysmal alterations, and was atrophied and disappeared totally in the walls of aneurysmal alterations that had reached an advanced stage. These spontaneous changes were in agreement with reports in the literature and our own previous investigations. From the findings in the experimental rats it becomes likely that the aneurysmal changes in the elastic lamina are exaggerated forms of the normal catabolic metabolism. Therefore its synthesis on the abluminal side no longer balances with the catabolism on the luminal side. It is strongly suggested that aneurysmal alterations progress from the luminal towards the abluminal side of arterial walls and that the lytic process of elastase might play a role in the degenerative changes in aneurysmal development.
Animals↗
In vivo flow visualization of induced saccular cerebral aneurysms in rats.
A surgical procedure to expose the arterial bifurcation at the base of the rat brain was developed without sacrificing the animal. Using this technique, visualization of flow in and around the induced cerebral aneurysm was achieved by detecting and following fluorescent particles in the blood stream. Cerebral aneurysms were produced by ligating one common carotid artery, inducing experimental hypertension and feeding them with beta-aminopropionitrile. Flow studies of the arterial bifurcation with an early aneurysmal formation showed that there were spiral flows proximal and distal to the bifurcation. This was the first direct visualization of the actual flow in and around cerebral aneurysms in a vital state. This technology can add further information on the development, growth and rupture of cerebral aneurysms.
Animals↗
Scintigraphic detection of xenografted tumors producing human basic fibroblast growth factor.
A murine monoclonal antibody 3H3 recognizes the basic fibroblast growth factor (FGF) and inhibits the growth of human glioblastoma cells both in vitro and in vivo. We studied the potential of a scintigraphic technique using the 3H3 antibody to detect tumors that produce basic FGF. 125I- and 111In-labeled 3H3 bound to U87MG human glioblastoma cells in vitro. U87MG cells were inoculated subcutaneously into nude mice. After development of the tumor, radiolabeled 3H3 was injected into the subcutaneous space surrounding the tumor. A high level of radioactivity from 3H3 was retained at the tumor, whereas an irrelevant antibody cleared rapidly from the injected site. Radiolabeled 3H3 was not retained in tumors that did not produce basic FGF. Scintigraphic detection of tumors expressing basic FGF would be valuable for the therapeutic application of the antibody.
Animals↗
Chemotherapeutic effects of intra-arterial administration of ACNU in primary intracerebral non-Hodgkin's lymphoma.
The authors report five patients with primary intracerebral non-Hodgkin's lymphoma who were treated with several cycles of intra-arterial injection of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) at doses of 80 to 100 mg/m2/injection at several monthly intervals. There was no simultaneous use of steroids, and no patients had concomitant immunosuppression; no patient was human immunodeficiency virus positive. This therapy was initially used in four patients with advanced recurrent lymphoma. These patients experienced tumor progression despite our institutional standard therapy comprising cranial irradiation followed by repeated courses of systemic multi-agent chemotherapy (cyclophosphamide, vincristine, adriamycin, and prednisolone) more than 3 months previously. Based upon brain computed tomography scans and clinical neurologic examinations, three of the four cases showed partial responses ranging from 10 to 12 months in duration, whereas the other patient remained stable without worsening for 8 months. A fifth case was particularly noteworthy; this patient had no prior therapy and intra-arterial chemotherapy alone induced an 18-month, disease-free remission. No significant therapy-related complications nor neurotoxicity were seen. These results suggest that intra-arterial administration of ACNU may be a potential candidate for intracerebral lymphoma therapy.
Adult↗
Enhancement of systemic and mucosal immune responses following oral administration of liposomes.
The effects of liposomes on the systemic and mucosal immune response were investigated using bovine serum albumin (BSA) in BALB/c mice. Following three oral administrations of varied formulations at 1-week intervals, serum BSA-specific IgG levels were increased significantly by BSA encapsulated in liposomes and moderately by a mixture of liposomes and BSA. Serum and salivary BSA-specific IgA levels were elevated by BSA-encapsulating liposomes only. Liposomes thus activate not only the systemic immune response but also the mucosal immune response following their oral administration. However, no increase in salivary IgA levels was observed by intraperitoneal or subcutaneous injection of BSA-encapsulating liposomes. The production of IgA is closely related to the oral administration of liposomes encapsulating antigens. Liposomes thus function as carriers of oral vaccines against various infections of the mucosal surface.
Administration, Oral↗
Stability of liposomes in vitro and their uptake by rat Peyer's patches following oral administration.
To evaluate the usefulness of liposomes as a carrier for the targeted delivery of antigens to gut-associated lymphoid tissue, liposomal stability and uptake by rat Peyer's patches were investigated. Liposomes composed of distearoylphosphatidylcholine, phosphatidylserine, and cholesterol (DSPC-liposome), or dipalmitoylphosphatidylcholine, phosphatidylserine, and cholesterol were stable in acidic solution (pH 2.0), diluted bile, and pancreatin solution. Following the oral administration of liposomes to rats, rhodamine B-PE incorporated in the lipid phase of DSPC-liposomes was preferentially taken up by Peyer's patches in the lower ileum. The uptake of rhodamine B-PE from DSPC-liposomes larger than 374 nm in mean diameter was high. Orally administered DSPC-liposomes of a large diameter thus appear to serve effectively as a vehicle for delivering antigens to Peyer's patches.
Administration, Oral↗
Uptake of phosphatidylserine liposomes by rat Peyer's patches following intraluminal administration.
Uptake of the nonabsorbable marker 6-carboxyfluorescein was investigated both free and encapsulated in liposomes as a function of their surface charge and hydrodynamic diameter in rat Peyer's patch and nonpatch tissue. Significant uptake of the marker occurred only when encapsulated in liposomes consisting of at least 25 mol% phosphatidylserine and was highest in Peyer's patches. 6-Carboxyfluorescein encapsulated in liposomes equal to or greater than 374 nm was preferentially taken up by Peyer's patches. There was a trend to higher uptake in lower intestinal segments. These findings were supported by fluorescence microscopic observations. Uptake by Peyer's patches was specific for negatively charged liposomes as judged from competition studies.
Analysis of Variance↗