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Biomedical subjects

H Okamura

Publications and source records attributed to H Okamura.

At least 271 records · Page 15Linked to original sources
PubMed1998

Respiratory Difficulty Necessitated Early Delivery in a Woman with Spondyloepiphyseal Dysplasia.

> Spondyloepiphyseal dysplasia is a skeletal disorder in which the vertebrae are flattened, thus making the spine shorter and greatly deformed, with marked thoracic kyphoscoliosis, lumbar lordosis, and a shortened trunk. The pelvis is also severely deformed and contracted. The patient was a 40-year-old nulligravida. At the 33rd week of pregnancy, respiratory distress gradually worsened, and cesarean section under spinal anesthesia had to be done. In women with spondyloepiphyseal dysplasia, uterine expansion is limited. As respiratory difficulties increase, an early delivery may have to be done.

Journal Article↗
PubMed1997

Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript.

To understand how light might entrain a mammalian circadian clock, we examined the effects of light on mPer1, a sequence homolog of Drosophila per, that exhibits robust rhythmic expression in the SCN. mPer1 is rapidly induced by short duration exposure to light at levels sufficient to reset the clock, and dose-response curves reveal that mPer1 induction shows both reciprocity and a strong correlation with phase shifting of the overt rhythm. Thus, in both the phasing of dark expression and the response to light mPer1 is most similar to the Neurospora clock gene frq. Within the SCN there appears to be localization of the induction phenomenon, consistent with the localization of both light-sensitive and light-insensitive oscillators in this circadian center.

Animals↗
PubMed1997

Postnatal development and sex difference in neurons containing estrogen receptor-alpha immunoreactivity in the preoptic brain, the diencephalon, and the amygdala in the rat.

Estrogen has been considered as a key substance that induces sexual differentiation of the brain during fetal and neonatal life in the rat. Thus, to define the brain regions involved in the brain sexual differentiation, we examined the regions where the estrogen receptor (ER) is located in the developing rat brain. We examined immunohistochemical distribution of the cells containing estrogen receptor-alpha (ER-alpha) in the preoptic region, the diencephalon, and the amygdala in male and female rats on postnatal days 1-35 (PD1-PD35). The antibody used recognizes ER-alpha equally well for both occupied and unoccupied forms. ER-alpha immunostaining was restricted to the cell nuclei of specific cell groups. In PD1 rats, ER-alpha-immunoreactive (ER-IR) signals were detected in the lateral septum, the organum vasculosum lamina terminalis, the medial preoptic nucleus (MPN), the median preoptic nucleus, the bed nucleus of the stria terminalis, the hypothalamic periventricular nucleus, the lateral habenula, the posterodorsal part of the medial amygdala nucleus, the posterior part of the cortical amygdala nucleus, the hypothalamic ventromedial nucleus (VMH), the hypothalamic arcuate nucleus, and the posterior hypothalamic periventricular nucleus. The distribution pattern of ER-IR cells in the newborn rat was much the same as that in the adult in the preoptic-hypothalamic and amygdala regions. Moreover, the signals in the MPN and the VMH were stronger in the female than in the male, perhaps reflecting the ability ofestrogen generated by aromatization of testosterone in the male to down-regulate the ER signal. Thus, the brain regions showing sex differences may be sites of sexual differentiation of the brain by aromatizable androgen during the neonatal period.

Amygdala↗
PubMed1997

IL-18 protects mice against pulmonary and disseminated infection with Cryptococcus neoformans by inducing IFN-gamma production.

We examined the effects of a newly identified cytokine, IL-18, originally designated as IFN-gamma-inducing factor, in a mouse model of pulmonary and disseminated infection with a highly virulent strain of Cryptococcus neoformans. Administration of murine rIL-18 enhanced elimination of live micro-organisms from the lungs, prevented fungal dissemination to the brain, reduced the level of serum cryptococcal capsular polysaccharide Ags, and increased the survival rate of infected mice. Histologic examination of lung sections of infected and PBS-treated mice showed a poor cellular inflammatory reaction and a large number of multiplying C. neoformans yeast cells in alveolar spaces. In contrast, massive infiltration of inflammatory cells, consisting mainly of mononuclear cells, characterized sections of lungs of infected animals treated with IL-18. Treatment with IL-18 also increased the level of serum IFN-gamma. In addition, the protective effect of IL-18 on cryptococcal infection was abrogated by administration of neutralizing anti-IFN-gamma mAb. Finally, we examined the effect of neutralizing anti-IL-18 Ab on cryptococcal infection to define the physiologic role of this cytokine in host defense using another weakly virulent strain of C. neoformans, which induced the expression of IL-18 mRNA in the infected lungs. Administration of this Ab exacerbated the infection, as shown by the increased lung burden. Our results indicate that IL-18 plays an important role in host defense against infection with C. neoformans.

Animals↗
PubMed1997

IL-18 accounts for both TNF-alpha- and Fas ligand-mediated hepatotoxic pathways in endotoxin-induced liver injury in mice.

When LPS is administered to heat-killed Propionibacterium acnes-primed BALB/c nude mice, they develop endotoxin-induced liver injury. As previously reported, this liver injury can be prevented by treatment with an Ab against IL-18, a novel cytokine with the ability to induce IFN-gamma production and up-regulate functional Fas ligand (FasL) expression. To identify the pathologic role of IL-18 in this liver injury, we investigated the hepatic cytokine network and FasL induction after LPS challenge. After LPS challenge to BALB/c nude mice, their livers expressed IL-12 mRNA, followed by the induction of IFN-gamma and FasL mRNA and then by the late elevation of TNF-alpha mRNA, but stably expressed IL-18 mRNA. The TNF-alpha induction curve had two peaks. The first peak was the result of the direct reaction to LPS, and the late peak might have been induced, since P. acnes-elicited Kupffer cells showed one-peak TNF-alpha kinetics in response to LPS stimulation in vitro. LPS-activated P. acnes-elicited Kupffer cells secreted both IL-12 and IL-18, as determined by ELISA and bioassay, respectively. The in vivo administration of anti-IL-18 just before an LPS challenge suppressed not only the induction of IFN-gamma and the late TNF-alpha elevation, but also the FasL induction, resulting in the total prevention of liver injury, whereas such an anti-IL-12 treatment did not. Anti-IFN-gamma treatment reduced the late increase in TNF-alpha, but not FasL, resulting in a partial prevention of the liver injury. The administration of anti-TNF-alpha just before elevation of the late TNF-alpha peak also markedly, but incompletely, suppressed the LPS-induced liver injury. These data suggested that IL-18 activates both TNF-alpha- and FasL-mediated hepatocytotoxic pathways in endotoxin-induced liver injury.

Animals↗
PubMed1997

Circadian oscillation of a mammalian homologue of the Drosophila period gene.

Many biochemical, physiological and behavioural processes in organisms ranging from microorganisms to vertebrates exhibit circadian rhythms. In Drosophila, the gene period (per) is required for the circadian rhythms of locomotor activity and eclosion behaviour. Oscillation in the levels of per mRNA and Period (dPer) protein in the fly brain is thought to be responsible for the rhythmicity. However, no per homologues in animals other than insects have been identified. Here we identify the human and mouse genes (hPER and mPer, respectively) encoding PAS-domain (PAS, a dimerization domain present in Per, Amt and Sim)-containing polypeptides that are highly homologous to dPer. Besides this structural resemblance, mPer shows autonomous circadian oscillation in its expression in the suprachiasmaticnucleus, which is the primary circadian pacemaker in the mammalian brain. Clock, a mammalian clock gene encoding a PAS-containing polypeptide, has now been cloned: it is likely that the Per homologues dimerize with other molecule(s) such as Clock through PAS-PAS interaction in the circadian clock system.

Amino Acid Sequence↗
PubMed1997

A mechanism underlying synergy between IL-12 and IFN-gamma-inducing factor in enhanced production of IFN-gamma.

IL-12 and IFN-gamma-inducing factor (IGIF) have the capacity to stimulate IFN-gamma production by T cells. Using an IL-12-responsive T cell clone, 2D6, we investigated how these two cytokines collaborate for IFN-gamma production. 2D6 obtained from cultures containing rIL-12 produced IFN-gamma in response to rIGIF. 2D6 from cultures deprived of IL-12 for 24 h produced only marginal levels of IFN-gamma production following stimulation with either rIL-12 or rIGIF alone. However, simultaneous stimulation of these 2D6 cells with both cytokines resulted in strikingly enhanced levels of IFN-gamma production. 2D6 could also be maintained in the presence of rIL-2 instead of rIL-12. 2D6 lines maintained with rIL-12 (2D6(IL-12)) or rIL-2 (2D6(IL-2)) exhibited differential IGIF responsiveness: both lines responded similarly to rIL-2 or rIL-12, whereas the 2D6(IL-12) or 2D6(IL-2) exhibited high or marginal IGIF responsiveness, respectively. The 2D6(IL-12) line expressed IGIF receptor (IGIFR), whereas the 2D6(IL-2) did not. Overnight exposure of the 2D6(IL-12) to rIL-2 reduced IGIFR expression and conversely, exposure of the 2D6(IL-2) to rIL-12 restored IGIFR expression. IGIFR expression by these 2D6 lines correlated with the capacity to produce IFN-gamma in response to rIGIF. Purified naive T cells stimulated with anti-CD3 plus anti-CD28 mAb and subsequently cultured with rIL-12 were also found to express IGIFR and induce enhanced IFN-gamma production following IGIF stimulation. These results indicate that the induction of IGIFR by IL-12 represents one of the mechanisms underlying the synergy between IL-12 and IGIF in IFN-gamma production.

Animals↗
PubMed1997

Heat shock induces transient p53-dependent cell cycle arrest at G1/S.

Heat shock (43 degrees C, 45 min) induced transient nuclear accumulation of p53 in primary human fibroblasts without any clonogenically toxic effects. The accumulation of p53 reached a maximal level 3 approximately 5 h after heat shock, and returned to the basal level within 12 h. Following the increase in p53 level, cell cycle arrest at G1/S was observed in normal fibroblasts, whereas neither nuclear accumulation of p53 nor cell cycle arrest were observed in HeLa cells. By comparing cell cycle patterns of heat-treated mouse cells with different genotypes at the p53 locus (+/+, +/-, -/-), the observed cell cycle arrest at G1/S was demonstrated to be p53-dependent. Cell cycle arrest in normal human fibroblasts continued for nearly 24 h, resulting in a one day delay of cell growth compared with non-treated cells. Following enhancement of the p53 level, the amount of p21/WAF1/ CIP1 increased, and the high level of p21 was sustained for almost one day in a cell cycle-independent manner, suggesting the involvement of p21 in the inhibition of cell cycle progression by heat shock.

Animals↗
PubMed1997

Propionibacterium acnes treatment diminishes CD4+ NK1.1+ T cells but induces type I T cells in the liver by induction of IL-12 and IL-18 production from Kupffer cells.

LPS injection into normal mice does not induce liver injury, while the same treatment of Propionibacterium acnes-primed mice induces severe liver injury, indicating that P. acnes treatment renders the mice susceptible to LPS. Since IFN-gamma sensitizes macrophages to LPS, we investigated the mechanism of induction and activation of IFN-gamma-producing (type 1) T cells by P. acnes. Twenty percent of liver lymphocytes of C57BL/6 mice are CD4+ NK1.1+ T cells that promptly produce IL-4 in response to anti-CD3 in vitro. However, P. acnes treatment diminished these lymphocytes. Therefore, liver lymphocytes from P. acnes-primed mice showed reduced IL-4 production. Furthermore, P. acnes treatment induced CD4- type 1 T cells in the liver. Isolated P. acnes-elicited Kupffer cells produced IL-12 and to a lesser degree IL-18 in vitro. Injection of anti-IL-12 Ab totally abrogated these actions of P. acnes, while injection of anti-IL-18 Ab caused only partial abrogation. Thus, administration of P. acnes diminished CD4+ NK1.1+ T cells, but induced type 1 T cells in the liver by induction of IL-12 and IL-18 production. Injection of IL-12 (approximately 1,000 ng) dose dependently diminished CD4+ NK1.1+ T cells, but induced type 1 T cells. In contrast, injection of IL-18 (approximately 1,000 ng) failed, although injection of a much larger dose of IL-18 (10,000 ng) or IL-18 (approximately 1,000 ng) with suboptimal doses of IL-12 (1-100 ng) diminished CD4+ NK1.1+ T cells in a dose-dependent manner. Thus, P. acnes treatment renders the mice highly susceptible to LPS by induction and activation of type 1 T cells.

Animals↗
PubMed1997

Production of IL-18 (IFN-gamma-inducing factor) messenger RNA and functional protein by murine keratinocytes.

Recently, the novel cytokine IL-18 (IFN-gamma-inducing factor) has been described as a growth and differentiation factor for Th1 cells. Epidermal keratinocytes (KC) are known to direct T cell education by production of cytokines. Therefore, expression of IL-18 was sought in KC. Epidermal RNA was analyzed following stimulation with contact sensitizers or controls for IL-18 mRNA expression by semiquantitative reverse transcription-PCR. Constitutive expression of IL-18 mRNA was low in untreated epidermal cells (EC), but early up-regulation of IL-18 mRNA signals was detected following application of a contact allergen in vivo. The peak strength of IL-18 signals was observed within 4 to 6 h following stimulation with an allergen. Application of an irritant (benzalconiumchloride) or solvents did not result in increased signal strength. To determine the cellular origin of IL-18 mRNA in EC, depletion experiments were performed. IL-18 signals were not affected by depletion with anti-CD3 (T cells) or anti-MHC class II mAb-coupled beads identifying KC as a major source of IL-18. These results were confirmed by analysis of mRNA derived from the KC cell line PAM 212. Strong IL-18 signals could be detected by reverse transcription-PCR. To delineate whether IL-18 protein was produced by EC/KC, a sandwich ELISA was used to assay for IL-18 production. Supernatants from allergen-stimulated EC and KC showed production of IL-18 protein. To confirm that IL-18 protein was functional, EC or KC supernatants were tested for their ability to induce IFN-gamma production. Significant amounts of IFN-gamma were detected in supernatants of allergen-treated cells. In aggregate, our data indicate that murine KC are a source of both IL-18 mRNA and functional protein.

Animals↗
PubMed1997

Association of an acute reduction in lipoprotein(a) with coronary artery restenosis after percutaneous transluminal coronary angioplasty.

BACKGROUND: Lipoprotein(a) [Lp(a)], which structurally resembles-tissue-type plasminogen, is reported to be associated with coronary atherosclerosis. We examined whether the acute change in Lp(a) by percutaneous transluminal coronary angioplasty (PTCA) is related to restenosis after PTCA. METHODS AND RESULTS: We measured serum Lp(a) and other lipid parameters (triglycerides and total, LDL, and HDL cholesterol) before and 1 day after PTCA in 143 procedures and 3 days after and 4 months after PTCA in 62 procedures. Quantitative coronary angiography was performed, and restenosis was defined according to three criteria: (1) clinical recurrence of ischemic symptoms, (2) a final stenosis > 50%, and (3) an absolute decrease in minimal lumen diameter > 1/2 of the acute gain in the dilated segment. Restenosis was recognized in 25.9%, 35.7%, and 38.5% of the cases 4 months after PTCA for each criterion, respectively. Although triglyceride and LDL, HDL, and total cholesterol levels were similar in the restenosis and no-restenosis groups before PTCA, Lp(a) was significantly higher in the restenosis group. We found a significant reduction in Lp(a) in the restenosis but not the no-restenosis group 1 day after PTCA. At 3 days after and 4 months after PTCA, Lp(a) was similar in the two groups. A multivariate-analysis revealed that the absolute change in Lp(a) (before versus 1 day after PTCA) to be the sole significant predictor of restenosis among the clinical, angiographic, and plasma lipid parameters examined. CONCLUSIONS: Lp(a) levels were significantly higher in the restenosis group, and they fell significantly after PTCA in the restenosis group.

Aged↗
PubMed1997

Coexistence of calcitonin gene-related peptide and NADPH-diaphorase in the canine superior cervical ganglion.

By means of double staining technique of NADPH-diaphorase (NADPH-d) histochemistry and calcitonin gene-related peptide (CGRP) immunohistochemistry, we investigated the coexistence of NADPH-d reactivity and CGRP immunoreactivity in the canine superior cervical ganglion (SCG). Most of NADPH-d reactivity and CGRP immunoreactivity were coexisted in the principal postganglionic neurons. These neurons were distributed throughout the ganglion without specific localization. The present findings suggest the intimate role of CGRP and nitric oxide in postganglionic neurons of the canine SCG.

Animals↗
PubMed1997

Development of vasoactive intestinal peptide mRNA rhythm in the rat suprachiasmatic nucleus.

Development of the daily rhythm of vasoactive intestinal peptide (VIP) mRNA in the rat suprachiasmatic nucleus (SCN), a main locus of circadian oscillation, was investigated by in situ hybridization. The phenotypic expression of VIP neurons occurred in two developmental stages in the ventrolateral portion of the SCN (VLSCN): the first was found before birth in the rostral part, and the second occurred in the main part between postnatal day (P) 10 and P20. The latter period coincided with the time that the massive VIP-efferent fibers project to the subparaventricular zone. In the adult and P20, the VIP mRNA signals of the SCN showed a clear diurnal rhythm with a trough in the light phase and a peak in the dark phase under light/dark (LD) conditions, but under constant dark (DD) conditions, no VIP mRNA fluctuations were observed. At P10, however, it was found that SCN VIP mRNA showed a peak at the transition from night to day and a trough at early dark period in LD conditions, in sharp contrast to the night peak in the adult rhythm. In DD conditions, a light-phase peak and a dark-phase trough were also observed at P10, contrasting the arrhythmic feature at adult stage. The present findings suggest that daily VIP rhythm was first generated in the early developed clock-controlled rostral SCN neurons, and later regulated by light-dependent main VLSCN neurons.

Age Factors↗
PubMed1997

Induction of NGFI-A gene expression in the rat suprachiasmatic nucleus by photic stimulation.

Photic induction of NGFI-A gene expression was investigated in the rat suprachiasmatic nucleus (SCN) using in situ hybridization histochemistry. Following light exposure for 30 min, NGFI-A mRNA appeared in the ventral portion of the rostral SCN, in the ventrolateral and in part of the dorsomedial portion at the middle level, and in the lateral portion of the caudal SCN. The distribution of NGFI-A mRNA was wider than that of c-fos mRNA which was confined to the ventrolateral portion at the middle level of the SCN. By double labeling in situ hybridization, approximately half of NGFI-A mRNA-positive cells in the SCN were shown to coexpress vasoactive intestinal peptide (VIP) mRNA, while 16% of cells positive for c-fos mRNA coexpressed VIP mRNA. These findings indicate that the broadness of NGFI-A mRNA and c-fos mRNA expression after photic stimulation are different. NGFI-A gene induced in these cells of the SCN including VIP neurons may be involved in circadian entrainment by light.

Animals↗
PubMed1997

Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-gamma production from activated B cells.

Interleukin 18 (IL-18), originally called interferon (IFN)-gamma-inducing factor, is a recently cloned cytokine of approximately 18 kDa synthesized by Kupffer cells and activated macrophages. The major activity associated with this molecule is the induction of IFN-gamma production from anti-CD3-activated T helper 1 cells in the presence of IL-12. B cells produce IgG1 and IgE when stimulated with anti-CD40 and IL-4. Here we show that a combination of IL-12 and IL-18 induces anti-CD40-activated B cells to produce IFN-gamma, which inhibits IL-4-dependent IgE and IgG1 production and enhances IgG2a production without inhibiting the B cell proliferative response. We also show that 24.3% of B cells became positive for cytoplasmic IFN-gamma after being stimulated with IL-12 and IL-18. Furthermore, we show that, like splenic T cells stimulated with anti-CD3, IL-12, and IL-18, B cells produced high level of IFN-gamma in response to anti-CD40, IL-12, and IL-18. Injection of a mixture of IL-12 and IL-18 into mice inoculated with Nippostrongylus brasiliensis or injected with anti-IgD induced IFN-gamma-producing cells that inhibit IgE production in them. Furthermore, B cells obtained from normal mice could develop into IFN-gamma-producing cells in IFN-gamma(-/-) host mice in response to in vivo treatment with IL-12 and IL-18. These results indicate that IFN-gamma from activated B cells differentially regulates IgG1/IgE and IgG2a responses in vitro and in vivo, indicating that B cells act as regulatory cells in the immune response. Present results suggested that injection of IL-12 and IL-18 could present a unique approach for the treatment of allergic disorders.

Animals↗
PubMed1997

Stepwise requirement of c-kit tyrosine kinase in mouse ovarian follicle development.

Ovarian follicle development is controlled by the cycling variation of gonadotrophins derived from the central nervous system. Intragonadal signals are also required, especially in the autonomous development of small follicles. Receptor tyrosine kinase c-kit and its ligand SLF (Steel factor) are expressed on the surface of specific populations of follicle-forming cells in a contiguous manner and are thought to have important roles in follicular development. We blocked the interaction of c-kit and its ligand by administering the function-blocking antibody ACK2 to developing mice at various times after birth and monitored ovarian follicle development. A blockade of c-kit function disturbed the onset of primordial follicle development, primary follicle growth, follicular fluid formation of preantral follicles, and penultimate-stage ovarian follicle maturation before ovulation. Ovarian follicle growth was dependent on c-kit during the first 5 days after birth when the functional FSH receptor is not yet expressed in mouse ovary. In contrast, primordial follicle formation and survival, small preantral or antral follicle development, ovulation, and luteinization of the ovulated follicle were not affected by this antibody. These findings indicate the stepwise requirement of c-kit and its ligand interaction system in the developing ovarian follicle and that c-kit with its ligand supports the autonomous development of ovarian follicle independent of gonadotrophins.

Animals↗
PubMed1997

Interleukin-18 (interferon-gamma-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-gamma to inhibit osteoclast formation.

We have established by differential display polymerase chain reaction of mRNA that interleukin (IL)-18 is expressed by osteoblastic stromal cells. The stromal cell populations used for comparison differed in their ability to promote osteoclast-like multinucleated cell (OCL) formation. mRNA for IL-18 was found to be expressed in greater abundance in lines that were unable to support OCL formation than in supportive cells. Recombinant IL-18 was found to inhibit OCL formation in cocultures of osteoblasts and hemopoietic cells of spleen or bone marrow origin. IL-18 inhibited OCL formation in the presence of osteoclastogenic agents including 1alpha,25-dihydroxyvitamin D3, prostaglandin E2, parathyroid hormone, IL-1, and IL-11. The inhibitory effect of IL-18 was limited to the early phase of the cocultures, which coincides with proliferation of hemopoietic precursors. IL-18 has been reported to induce interferon-gamma (IFN-gamma) and granulocyte/macrophage colony-stimulating factor (GM-CSF) production in T cells, and both agents also inhibit OCL formation in vitro. Neutralizing antibodies to GM-CSF were able to rescue IL-18 inhibition of OCL formation, whereas neutralizing antibodies to IFN-gamma did not. In cocultures with osteoblasts and spleen cells from IFN-gamma receptor type II-deficient mice, IL-18 was found to inhibit OCL formation, indicating that IL-18 acted independently of IFN-gamma production: IFN-gamma had no effect in these cocultures. Additionally, in cocultures in which spleen cells were derived from receptor-deficient mice and osteoblasts were from wild-type mice and vice versa, we identified that the target cells for IFN-gamma inhibition of OCL formation were the hemopoietic cells. The work provides evidence that IL-18 is expressed by osteoblasts and inhibits OCL formation via GM-CSF production and not via IFN-gamma production.

Animals↗