Biomedical subjects

H Okamura

Publications and source records attributed to H Okamura.

At least 181 records · Page 10Linked to original sources

PubMed1999

Application of short-term bioassay guided chemical analysis for water quality of agricultural land run-off.

The effect of agricultural land run-off on the water quality of Lake Kojima, Japan, was investigated using a short-term bioassay-guided chemical analysis. Water samples were collected for 1 year starting from June 1995 to June 1996. Toxicity of the dissolved and adsorbed extracts in the water samples was evaluated using the Daphnia immobilization test and the concentrations of pesticides and putative toxic substance in the extracts were determined by high performance liquid chromatography. Most of the dissolved extracts caused immobilization of the test Daphnia magna at low concentrations during the period of paddy pesticide application. Some extracts were found to contain pesticides such as dymron, mefenacet and flutolanil, but their concentrations were too low to have a toxic effect on the daphnia. An unknown toxic compound, Peak C, was isolated from some river water samples, but it produced only a relatively weak toxicity to Daphnia. To better understand the impact of agricultural run-off on a receiving water body, the relationship between the observed toxicity and the concentrations of pesticides and Peak C in the water samples was studied both temporally and spatially.

Agriculture↗

PubMed1999

Expression and function of TNF-related apoptosis-inducing ligand on murine activated NK cells.

TNF-related apoptosis-inducing ligand (TRAIL), a new member of TNF family, induces apoptotic cell death of various tumor cells. We recently showed that TRAIL mediates perforin- and Fas ligand (FasL)-independent cytotoxic activity of human CD4+ T cell clones. In the present study, we investigated the expression and function of TRAIL on murine lymphocytes by using newly generated anti-murine TRAIL mAbs. Although freshly isolated T, B, or NK cells did not express a detectable level of TRAIL on their surface, a remarkable level of TRAIL expression was induced preferentially on CD3- NK1.1+ NK cells after stimulation with IL-2 or IL-15. In contrast, TRAIL expression was not induced by IL-18, whereas it efficiently potentiated lymphokine-activated killer activity of NK cells. In addition to perforin inactivation and neutralization of FasL by anti-FasL mAb, neutralization of TRAIL by anti-TRAIL mAb was needed for the complete inhibition of IL-2- or IL-15-activated NK cell cytotoxicity against mouse fibrosarcoma L929 target cells, which were susceptible to both FasL and TRAIL. These results indicated preferential expression of TRAIL on IL-2- or IL-15-activated NK cells and its potential involvement in lymphokine-activated killer activity.

Animals↗

PubMed1999

IL-18 inhibits diabetes development in nonobese diabetic mice by counterregulation of Th1-dependent destructive insulitis.

The development of type 1 diabetes in animal models is T cell and macrophage dependent. Islet inflammation begins as peripheral benign Th2 type insulitis and progresses to destructive Th1 type insulitis, which is driven by the innate immune system via secretion of IL-12 and IL-18. We now report that daily application of IL-18 to diabetes-prone female nonobese diabetic mice, starting at 10 wk of age, suppresses diabetes development (p < 0.001, 65% in sham-treated animals vs 33% in IL-18-treated animals by 140 days of age). In IL-18-treated animals, we detected significantly lower intraislet infiltration (p < 0.05) and concomitantly an impaired progression from Th2 insulitis to Th1-dependent insulitis, as evidenced from IFN-gamma and IL-10 mRNA levels in tissue. The deficient progression was probably due to lesser mRNA expression of the Th1 driving cytokines IL-12 and IL-18 by the innate immune system (p < 0.05). Furthermore, the mRNA expression of inducible NO synthase, a marker of destructive insulitis, was also not up-regulated in the IL-18-treated group. IL-18 did not exert its effect at the levels of islet cells. Cultivation of islets with IL-18 affected NO production or mitochondrial activity and did not protect from the toxicity mediated by IL-1beta, TNF-alpha, and IFN-gamma. In conclusion, we show for the first time that administration of IL-18, a mediator of the innate immune system, suppresses autoimmune diabetes in nonobese diabetic mice by targeting the Th1/Th2 balance of inflammatory immune reactivity in the pancreas.

Animals↗

PubMed1999

Differential antitumor effects of administration of recombinant IL-18 or recombinant IL-12 are mediated primarily by Fas-Fas ligand- and perforin-induced tumor apoptosis, respectively.

Systemic administration of rIL-18 protein to mice significantly suppresses the growth of murine tumor cell lines. The antitumor effect of IL-18 appears to be primarily mediated by asialo GM1+ cells. Since IL-18 enhances Fas ligand (FasL) expression on NK cell lines, the IL-18 antitumor effects could be mediated by FasL-induced cross-linking of Fas and subsequent tumor apoptosis. To address this question, rIL-18 or rIL-12 was administered to animals bearing the CL8-1 melanoma inoculated intradermally into wild type (wt), lymphoproliferation gene (lpr) (Fas deficient), or generalized lymphoproliferative disease gene (gld) (FasL deficient) mice. Although rIL-12 treatment retained significant antitumor effects in gld and lpr mice, those of rIL-18 administration were completely abrogated in gld but not lpr or wt mice. In vitro cytotoxicity was significantly enhanced against NK-sensitive YAC-1 cells and CL8-1 cells by rIL-18 administration to wt mice, but not to gld mice. Furthermore, rIL-18 administration augmented the cytotoxicity of liver lymphocytes harvested from perforin-deficient mice, whereas rIL-12 administration did not. Consistent with the role of this pathway, rIL-18 administration also up-regulates the expression of FasL mRNA in splenocytes. Lysis of CL8-1 cells induced by anti-Fas agonistic Ab was enhanced about 1.4-fold by IFN-gamma, a cytokine that is induced by IL-18 in vitro and in vivo. We conclude that the antitumor effect of IL-18 is exerted predominantly through a Fas-dependent pathway. The perforin pathway, however, appears to be the predominant cytolytic pathway mediating IL-12 antitumor effects.

Adjuvants, Immunologic↗

PubMed1999

IL-18 promotes type 1 cytokine production from NK cells and T cells in human intracellular infection.

We investigated the role of IL-18 in leprosy, a disease characterized by polar cytokine responses that correlate with clinical disease. In vivo, IL-18 mRNA expression was higher in lesions from resistant tuberculoid as compared with susceptible lepromatous patients, and, in vitro, monocytes produced IL-18 in response to Mycobacterium leprae. rIL-18 augmented M. leprae-induced IFN-gamma in tuberculoid patients, but not lepromatous patients, while IL-4 production was not induced by IL-18. Anti-IL-12 partially inhibited M. leprae-induced release of IFN-gamma in the presence of IL-18, suggesting a combined effect of IL-12 and IL-18 in promoting M. leprae-specific type 1 responses. IL-18 enhanced M. leprae-induced IFN-gamma production rapidly (24 h) by NK cells and in a more sustained manner (5 days) by T cells. Finally, IL-18 directly induced IFN-gamma production from mycobacteria-reactive T cell clones. These results suggest that IL-18 induces type 1 cytokine responses in the host defense against intracellular infection.

Cytokines↗

PubMed1999

Role of TNF-alpha in the induction of fungicidal activity of mouse peritoneal exudate cells against Cryptococcus neoformans by IL-12 and IL-18.

We have recently demonstrated that two IFN-gamma-inducing cytokines, interleukin (IL)-12 and IL-18, synergistically induced the fungicidal activity of mouse peritoneal exudate cells (PEC) against Cryptococcus neoformans through NK cell production of interferon (IFN)-gamma and nitric oxide (NO) synthesis. In the present study, we further dissected these effects by examining the involvement of tumor necrosis factor (TNF)-alpha in the induction of IL-12/IL-18-stimulated PEC fungicidal activity. The addition of neutralizing anti-TNF-alpha mAb significantly suppressed IL-12/IL-18-stimulated PEC anticryptococcal activity. This effect was ascribed to the inhibition of macrophage NO synthesis, but not of IFN-gamma production by NK cells, because the same treatment inhibited the former response, but not the latter one. On the other hand, combined treatment with IL-12 and IL-18 synergistically induced the production of TNF-alpha by PEC and this effect was almost completely abrogated by neutralizing anti-IFN-gamma mAb. The cell type producing TNF-alpha among PEC was mostly macrophage. TNF-alpha significantly promoted macrophage NO production and anticryptococcal activity induced by IFN-gamma, and furthermore anti-TNF-alpha mAb partially inhibited these responses. Considered together, our results indicated that TNF-alpha contributed to the potentiation of IL-12/IL-18-induced PEC fungicidal activity against C. neoformans through enhancement of IFN-gamma-induced production of NO by macrophages, but not through increased production of IFN-gamma by NK cells.

Animals↗

PubMed1999

Estrogen replacement therapy decreases platelet-activating factor-acetylhydrolase activity in post-menopausal women.

OBJECTIVE: To examine the effects of estrogen replacement therapy on plasma platelet-activating factor-acetylhydrolase (PAF-AH) activity and the lipoprotein profile in post-menopausal women. METHOD: Eight post-menopausal women received conjugated equine estrogen (0.625 mg/day) orally for a period of 10 weeks. PAF-AH activity and lipid levels were measured in plasma samples obtained from each subject prior to treatment and after 2, 6, and 10 weeks of estrogen therapy. RESULTS: Within 2 weeks of initiating estrogen treatment, a significant reduction in PAF-AH activity (-26%) was observed. Estrogen also caused significant decreases in total cholesterol (-8%), low-density lipoprotein-cholesterol (-24%), and the ratio of apolipoprotein B to A-II (-19%). On the other hand, levels of both high-density lipoprotein-cholesterol (18%) and triglyceride (31%) were elevated. CONCLUSION: Estrogen exerts a favorable effect on the lipoprotein profile, but decreased plasma PAF-AH activity may facilitate platelet aggregation thereby opposing protective effect of estrogen-replacement therapy with respect to thrombotic complications.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1999

IL-18 up-regulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor.

IL-18 is a powerful inducer of IFN-gamma production, particularly in collaboration with IL-12. IL-18, like IL-12, also augments NK activity. Here we investigated the molecular mechanism underlying the up-regulation of killing activity of NK cells by IL-18. IL-18, like IL-12, dose dependently enhanced NK activity of splenocytes. This action was further enhanced by costimulation with IL-12. Treatment with anti-IL-2R Ab did not affect IL-18- and/or IL-12-augmented NK activity, and splenocytes from IFN-gamma-deficient mice showed enhanced NK activity following stimulation with IL-12 and/or IL-18. Splenocytes from the mice deficient in both IL-12 and IL-18 normally responded to IL-18 and/or IL-12 with facilitated NK activity, suggesting that functional NK cells develop in the absence of IL-12 and IL-18. IL-18R, as well as IL-12R mRNA, was constitutively expressed in splenocytes from SCID mice, which lack T cells and B cells but have intact NK cells, and in those from IL-12 and IL-18 double knockout mice. NK cells isolated from SCID splenocytes expressed IL-18R on their surface. IL-18, in contrast to IL-12, did not enhance mRNA expression of perforin, a key molecule for exocytosis-mediated cytotoxicity. However, pretreatment with concanamycin A completely inhibited this IL-18- and/or IL-12-augmented NK activity. Furthermore, IL-18, like IL-12, failed to enhance NK activity of splenocytes from perforin-deficient mice. These data suggested that NK cells develop and express IL-12R and IL-18R in the absence of IL-12 or IL-18, and that both IL-18 and IL-12 directly and independently augment perforin-mediated cytotoxic activity of NK cells.

Animals↗

PubMed1999

Alleviation of lipopolysaccharide-induced acute liver injury in Propionibacterium acnes-primed IFN-gamma-deficient mice by a concomitant reduction of TNF-alpha, IL-12, and IL-18 production.

The present study was designed to investigate the role of IFN-gamma in LPS-induced liver injury following priming with Propionibacterium acnes. At 1 week after priming BALB/c mice with P. acnes, a large number of macrophages (Mphi) and lymphocytes predominantly infiltrated the portal area, resulting in the intrahepatic formation of granulomas consisting of epithelioid and lymphoid cells. In comparison, in IFN-gamma gene-disrupted BALB/c mice (IFN-gamma knockout mice), the number of infiltrated Mphi was decreased, with a significant reduction in the number and size of granulomas. Subsequent elicitation with a low dose of LPS induced massive hepatic necrosis in wild-type BALB/c mice, with a marked increase in the serum levels of TNF-alpha, IL-12, and IL-18 and subsequently of alanine transferase. In contrast, IFN-gamma knockout mice developed scattered focal necrosis of the liver with significantly lower levels of serum alanine transferase as well as drastic decreases in TNF-alpha, IL-12, and IL-18 production. The administration of an anti-IFN-gamma neutralizing mAb at the eliciting phase significantly alleviated liver injury and reduced serum IL-12 and IL-18 levels. Thus, endogenously produced IFN-gamma is involved in the pathogenesis of this liver injury model by regulating Mphi infiltration and granuloma formation in the priming phase as well as cytokine production in the eliciting phase.

Acute Disease↗

PubMed1999

Combined effects of IL-12 and IL-18 on the clinical course and local cytokine production in murine pulmonary infection with Cryptococcus neoformans.

We reported recently that interleukin (IL)-12 and IL-18 synergistically increased the fungicidal activity of mouse peritoneal exudate cells against Cryptococcus neoformans by inducing the production of interferon (IFN)-gamma by natural killer (NK) cells. To confirm these findings in vivo, we examined the effect of combined treatment using these two cytokines on the course of experimentally induced pulmonary and disseminated cryptococcosis in mice. IL-12 and IL-18 were used at subtherapeutic doses (0.005 and 2 microg/mouse/day, respectively). A single administration of either cytokine was not effective in protecting mice against the infection, while combined treatment significantly prolonged survival time of infected mice and reduced the lung and brain loads of organisms. These protective effects were associated with elevated IFN-gamma and reduced IL-4 levels in bronchoalveolar lavage fluid. Finally, depletion of NK and gammadelta T cells, but not of CD4+ T cells, by administration of specific antibodies, significantly reduced the production of IFN-gamma in lungs by IL-12/IL-18 treatment during the 7 days of infection. Our results demonstrated that IL-12 and IL-18 protected mice against cryptococcal infection in a synergistic manner by enhancing the local production of IFN-gamma by NK and gammadelta T cells in the early phase of infection and by suppressing the production of IL-4 in lungs.

Animals↗

PubMed1999

Functional morphology of the suprachiasmatic nucleus.

In mammals, the biological clock (circadian oscillator) is situated in the suprachiasmatic nucleus (SCN), a small bilaterally paired structure just above the optic chiasm. Circadian rhythms of sleep-wakefulness and hormone release disappear when the SCN is destroyed, and transplantation of fetal or neonatal SCN into an arrhythmic host restores rhythmicity. There are several kinds of peptide-synthesizing neurons in the SCN, with vasoactive intestinal peptide, arginine vasopressin, and somatostatine neurons being most prominent. Those peptides and their mRNA show diurnal rhythmicity and may or may not be affected by light stimuli. Major neuronal inputs from retinal ganglion cells as well as other inputs such as those from the lateral geniculate nucleus and raphe nucleus are very important for entrainment and shift of circadian rhythms. In this review, we describe morphological and functional interactions between neurons and glial elements and their development. We also consider the expression of immediate-early genes in the SCN after light stimulation during subjective night and their role in the mechanism of signal transduction. The reciprocal interaction between the SCN and melatonin, which is synthesized in the pineal body under the influence of polysynaptic inputs from the SCN, is also considered. Finally, morphological and functional characteristics of clock genes, particularly mPers, which are considered to promote circadian rhythm, are reviewed.

Animals↗

PubMed1999

Increased serum levels of 5-S-cysteinyldopa and intercellular adhesion molecule-1 in a patient with a uterine amelanotic metastasis from a primary vaginal malignant melanoma.

A 75-year-old Japanese woman, who had an enlarged uterus and two nodules on the anterior vaginal wall, underwent wide excision of the anterior vaginal wall, bilateral inguinal lymphadenectomy, modified radical hysterectomy, and pelvic lymph node dissection. Her serum level of 5-S-cysteinyldopa (5-S-CD) was elevated, but her serum intercellular adhesion molecule-1 (ICAM-1) level was within normal limits. Histologic examination of the vaginal wall revealed atypical melanocytes at the dermoepidermal junction and numerous melanin-containing granules in the cytoplasm of the tumor cells. The tumor in the uterus consisted of sheets of anaplastic cells with evidence of diminished melanization. Five months after her initial presentation, she developed a recurrence and expired. The serum level of ICAM-1 was beyond the normal limit at the time of recurrence. Both the serum 5-S-CD and the ICAM-1 levels became elevated after recurrence and appeared to be correlated with disease progression.

Aged↗

PubMed1999

Slow evolutionary rate of GB virus C/hepatitis G virus.

With the aim of elucidating evolutionary features of GB virus C/hepatitis G virus (GBV-C/HGV), molecular evolutionary analyses were conducted using the entire coding region of this virus. In particular, the rate of nucleotide substitution for this virus was estimated to be less than 9.0 x 10(-6) per site per year, which was much slower than those for other RNA viruses. The phylogenetic tree reconstructed for GBV-C/HGV, by using GB virus A (GBV-A) as outgroup, indicated that there were three major clusters (the HG, GB, and Asian types) in GBV-C/HGV, and the divergence between the ancestor of GB- and Asian-type strains and that of HG-type strains first took place more than 7000-10,000 years ago. The slow evolutionary rate for GBV-C/HGV suggested that this virus cannot escape from the immune response of the host by means of producing escape mutants, implying that it may have evolved other systems for persistent infection.

Evolution, Molecular↗

PubMed1999

Successful antidepressant treatment for five terminally ill cancer patients with major depression, suicidal ideation and a desire for death.

In the debate on euthanasia and physician-assisted suicide, we have to exclude terminally ill patients in whom the desire for death is caused by major depression. However, it is still not clear to what degree major depression can be treated by psychiatric intervention in this setting. We evaluated the effect of antidepressant treatment in terminally ill cancer patients. Six cancer patients with suicidal ideas thought to be due to major depression were treated with tricyclic antidepressants. Three had requested terminal sedation to relieve them from their suffering. The median survival of five of these patients was 4 weeks after diagnosis; one was lost to follow-up. The efficacy of the antidepressant treatment was assessed using the Hamilton Rating Scale for Depression (HRSD). One week after the start of treatment with antidepressants, five of the six patients showed a marked improvement in their mood and showed no further suicidal thoughts or requests for terminal sedation. The average reduction in the HRSD score was 23.4 points (14-38; SD = 9. 9). Antidepressant treatment can be effective in alleviating the desire for death due to major depression, even in terminally ill cancer patients.

Affect↗

PubMed1999

A novel in vitro experimental model for ovarian endometriosis: the three-dimensional culture of human ovarian surface epithelial cells in collagen gels.

OBJECTIVE: To develop an in vitro experimental model of ovarian endometriosis using human cells and to investigate the pathogenesis of endometriosis. DESIGN: Controlled in vitro coculture study. SETTING: A department of obstetrics and gynecology at a university hospital. PATIENT(S): Ovaries and endometrium were obtained from patients who underwent a hysterectomy because of gynecologic disease. INTERVENTION(S): Human ovarian surface epithelial (OSE) cells were cultured alone and OSE cells and endometrial stromal (ES) cells were cultured together in a three-dimensional collagen gel culture system with or without the addition of E2. MAIN OUTCOME MEASURE(S): The aggregated collagen gels containing the cultured cells were examined morphologically. RESULT(S): The OSE cells in single culture with E2 formed circular arrangements. These cells were immunohistochemically positive for cytokeratin but negative for epithelial membrane antigen. In the cocultures of OSE and ES cells with E2, the OSE cells formed a lumen structure surrounded by ES cells. Immunoreactivity for cytokeratin and epithelial membrane antigen was detected in the glandular cells and cilia were identified on the cell surface by electron microscopy. Without the addition of E2, no structures were detected. CONCLUSION(S): A new in vitro experimental model was established with the aid of human OSE cells. Endometriotic lesions can arise through a process of metaplasia from OSE cells in the presence of E2 and ES cells.

Adult↗

PubMed1999

A follicle-stimulating hormone-secreting gonadotroph adenoma with ovarian enlargement in a 10-year-old girl.

OBJECTIVE: To report a rare case of gonadotroph adenoma accompanied by ovarian enlargement in a child. DESIGN: Case report. SETTING: A university hospital. PATIENT(S): A 10-year-old Japanese girl with multiple cysts of both ovaries. INTERVENTION(S): Endocrinologic assays, immunohistochemical staining, ultrastructural observations, and in vitro analysis. MAIN OUTCOME MEASURE(S): The endocrinologic assays showed an elevated serum FSH level. The tumor cells excised from the gonadotroph adenoma were immunohistochemically positive for antihuman FSH monoclonal antibody. When cultured in vitro, the tumor cells secreted FSH in the primary culture. RESULT(S): The gonadotroph adenoma produced FSH. After transsphenoidal surgery, both ovaries decreased in size. CONCLUSION(S): The ovarian enlargement was induced by endogenous FSH from the gonadotroph adenoma. To our knowledge, this is the first reported case of gonadotroph adenoma accompanied by ovarian enlargement in childhood or adolescence.

Adenoma↗

PubMed1999

Increased platelet-activating factor-acetylhydrolase activity in the umbilical venous plasma of growth-restricted fetuses.

OBJECTIVE: To determine whether platelet-activating factor-acetylhydrolase activity in fetal plasma obtained at birth from umbilical vessels is different from that in maternal plasma, and (2) to compare platelet-activating factor-acetylhydrolase activity in cord plasma from fetuses with fetal growth restriction (FGR) and those with appropriate growth for gestational age (AGA). METHODS: Platelet-activating factor-acetylhydrolase activity was measured in the plasma of 22 nonpregnant healthy women, 16 pregnant women at term during labor, 28 fetuses exhibiting AGA, and seven fetuses with FGR. RESULTS: Plasma platelet-activating factor-acetylhydrolase activity in normotensive pregnant women at 37-41 weeks' gestation was 28.1+/-16.6 nmol/mL per minute, which was not statistically different from the activity in nonpregnant women (30.8+/-11.1 nmol/mL per minute). Platelet-activating factor-acetylhydrolase activity in venous cord plasma from AGA fetuses was significantly (P < .01) lower than that in maternal plasma (6.3+/-2.6 nmol/mL per minute), and there was no difference between the activities found in arterial and venous cord samples. In FGR fetuses, venous cord platelet-activating factor-acetylhydrolase activity was significantly (P < .01) higher (12.1+/-1.4 nmol/mL per minute), than the activity seen in AGA fetuses, and when the data from AGA and FGR fetuses were considered together, there was a negative correlation between cord plasma platelet-activating factor-acetylhydrolase activity and neonatal body weight (r = .46, P = .006). CONCLUSION: Platelet-activating factor hydrolysis is significantly lower in fetuses than adults. Further, the comparatively high platelet-activating factor-acetylhydrolase activity in FGR fetuses suggests the existence of a compensatory mechanism to maintain microcirculation within the placenta.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1999

Unsuspected extra-adrenal pheochromocytoma simulating ovarian tumor.

We report on a case of an extraadrenal pheochromocytoma simulating an ovarian tumor. Before intervention, the patient exhibited no symptoms suggestive of pheochromocytoma. Nevertheless, during surgery she experienced marked blood pressure fluctuations, and an unsuspected extraadrenal pheochromocytoma was diagnosed. Thus, although rare, when preparing to remove a pelvic mass, the gynecologist should consider the possibility of an extraadrenal pheochromocytoma.

Blood Pressure↗