Biomedical subjects
Publications and source records attributed to K Miyata.
Symptoms of early onset sarcoidosis characterized by skin eruptions, arthritis, and uveitis mimic those of systemic type juvenile rheumatoid arthritis (JRA). We report 2 Japanese patients with early onset sarcoidosis, both of whom were initially diagnosed and treated as having JRA. Intermittent fever and synovial swelling may mask sarcoidosis in children less than 4 years old.
To investigate the clinical manifestations of human T-lymphotropic virus type-1 uveitis (HU), 112 HU patients who were followed up periodically for more than one year were retrospectively analyzed with respect to their ophthalmological and systemic complications. The gender ratio (female/male ratio) of the HU patients was 2.0 and the initial complications were foggy vision in 34.5%, ocular floaters in 33.3%, and blurred vision in 15.5%. As for the ocular symptoms, the majority (78.6%) of patients were classified as intermediate uveitis with vitreous inflammation. Recurrence of uveitis episodes was seen in one half of the patients (51.8%); 12 patients had more than six uveitis episodes. The interval of uveitis episodes varied from two weeks to 10 years. Nearly one half of the patients (43.8%) had ocular complications: e.g., cataract in 22 patients, persistent vitreous opacities in 17 patients, and glaucoma in 16 patients. Although the visual prognosis was essentially good, 11 patients had poor visual prognosis (<0.1). The causes of poor vision in these patients were cataract, cystoid macular edema, epiretinal membrane, and optic nerve atrophy. Of the 112 HU patients, two developed HTLV-I-associated myelopathy (TSP/HAM) after the onset of HU, while none developed adult T-cell leukemia. Sixteen HU patients had a previous history of Graves' disease and a past history of methimazole therapy, while Graves' disease was found in another HU patient only after HU onset and methimazole was not administered before the onset of HU. The present data of long-term follow-up indicate that (1) HU causes various ocular complications and its visual prognosis can be poor, (2) TSP/HAM can be induced even after the onset of HU, and (3) methimazole is not a risk factor of HU after Graves' disease.
The effect of recombinant human interleukin-11 (rHuIL-11) on myelosuppressive nimustine (ACNU)-induced thrombocytopenia was assessed in nonhuman primates. A single intravenous (i.v.) injection of ACNU (15 mg/kg) was administered to cynomolgus monkeys on day 0. rHuIL-11 (100 microg/kg/day) or the vehicle was given subcutaneously (s.c.) from day 1 to day 21. In monkeys receiving ACNU, the circulating platelet count decreased to a low of 42 +/- 6 x 10(9)/L by day 21 but returned to pretreatment levels (375 +/- 48 x 10(9)/L) on day 30. Administration of rHuIL-11 prevented severe thrombocytopenia; the platelet count fell only to 138 +/- 23 x 10(9)/L on day 18, and platelet recovery was faster (458 +/- 91 x 10(9)/L by day 27) compared with that of the control animals. The size of bone marrow megakaryocytes from rHuIL-11-treated animals was larger than that of the controls, indicating that rHuIL-11 stimulated megakaryopoiesis in a myelosuppressive condition. Treatment with ACNU also caused leukopenia and moderate anemia. rHuIL-11 transiently and slightly decreased the white blood cell (WBC) and red blood cell (RBC) counts. Conversely, rHuIL-11 accelerated recovery of RBC count in the late administration period. These results support the assertion that rHuIL-11 may be an important therapeutic agent for reducing the severity and duration of thrombocytopenia following cancer chemotherapy.
Serotonin is one of the most important vasoactive substances and has been implicated in the pathogenesis of coronary artery spasm and of acute coronary syndrome. We have recently demonstrated that local and long-term treatment with interleukin-1beta(IL-1beta) causes coronary arteriosclerotic changes and hyperconstrictive responses to serotonin in pigs in vivo. However, it remains to be examined which serotonergic (5-HT) receptor subtype mediates coronary spasm and whether alterations in serotonergic receptors are involved in the abnormality. In this study, we examined the inhibitory effect of sarpogrelate, a selective 5-HT2A serotonergic receptor antagonist, on the serotonin-induced coronary spasm as well as the possible alterations of serotonergic receptors in our porcine model. A segment of the porcine coronary artery was carefully dissected and aseptically wrapped with cotton mesh absorbing IL-1beta-bound microbeads from the adventitia. Two weeks after the procedure, angiographic study was performed, followed by binding assay for 5-HT1B and 5-HT2A serotonergic receptors and reverse transcription-polymerase chain reaction (RT-PCR) analysis for mRNA of those receptors. Angiographic study showed coronary vasospastic responses to serotonin at the IL-1beta-treated site. Sarpogrelate dose-dependently inhibited the serotonin-induced coronary spasm, but it did not affect the prostaglandin F2alpha-induced vasoconstriction. Radiolabeled receptor-binding assay showed that receptor affinity or receptor number of the 5-HT1B, or 5-HT2A receptors did not differ significantly between the spastic and the control sites. Furthermore, RT-PCR analysis showed that the expression of neither 5-HT2A nor 5-HT1B receptor mRNA was significantly altered at the spastic site. These results indicate that serotonin-induced coronary spasm is mediated primarily by 5-HT2A receptor in our porcine model, although the 5-HT2A receptor was not up-regulated, suggesting that alteration in the signal-transduction pathway for vascular smooth muscle contraction beyond the 5-HT2A receptor plays a primary role in the pathogenesis of coronary spasm in our porcine model.
Tumor-derived endothelial-like cells (tEC) were prepared by culturing human umbilical vein endothelial cells (HUVEC) in the presence of HT1080 human fibrosarcoma-conditioned medium. tEC showed higher permeability and less cell-adhesion activity than normal HUVEC (nEC). Tumor necrosis factor-alpha (TNF) is known to have tumor-vasculature disrupting activity. tEC showed higher cytotoxicity to recombinant human TNF (rhTNF) than nEC, and was not observed using HUVEC cultured with WI38 human diploid cell-conditioned medium as a medium-control. These results demonstrate that tEC acquire physiological properties of tumor-associated vasculature, and may be a useful model system for the study of the mechanisms of TNF antitumor action. The TNF-mutant RGD-V29 (code No. F4614), which has an inserted 4Arg-Gly-Asp sequence and an 29Arg-->Val replacement, was found to induce greater preferential destruction of tEC compared to rhTNF. When the preferential activities were evaluated in terms of 30% cytotoxicity (IC30) ratio (nEC/tEC), the ratio was 460 for RGD-V29 compared to 4.2 for rhTNF. RGD-V29 also exhibited cell-adhesive function and bound preferentially to the p55 TNF-receptor. Both these properties of RGD-V29 contributed to the tEC selective cytotoxicity, indicating that the RGD ligands and selective p55 receptor binding on the cells, although uncharacterized, are involved in tEC targeting. Therefore, the TNF mutant RGD-V29 may show greater selectivity toward tumor vasculature than wild-type TNF.
We have previously shown that long-term treatment with an inflammatory cytokine from the adventitia causes the development of coronary vascular lesions, with the accumulation of macrophages. Recent studies in vitro have suggested that small G-protein Rho and its effector, Rho-kinase/ROK/ROCK, may be the key molecules for various cellular functions, including cell adhesion and movement. In this study, we examined whether adventitia-derived macrophages cause the formation of coronary vascular lesions in vivo and, if so, whether Rho-kinase is involved in the process. Porcine coronary segments from the adventitia were chronically treated with monocyte chemoattractant protein-1 alone, oxidized low density lipoprotein alone, or both. Vascular lesion formation (neointimal formation and development of vascular remodeling) was mostly enhanced at the coronary segment cotreated with monocyte chemoattractant protein-1 and oxidized low density lipoprotein, where the phosphorylation of myosin binding subunit of myosin phosphatase was increased, indicating an increased activity of Rho-kinase in vivo. Histological examination demonstrated that macrophages were accumulated at the adventitia and thereafter migrated into the vascular wall. Long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor (hydroxyfasudil) after oral absorption, markedly inhibited the myosin binding subunit phosphorylation, the macrophage accumulation and migration, and the coronary lesion formation in vivo. These results indicate that Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in our porcine model in vivo.
NO is known to have several important vasculoprotective actions. Although NO is synthesized by 3 different NO synthase (NOS) isoforms, the vasculoprotective action of individual NOS isoforms remains to be clarified. Permanent ligation of the left common carotid artery was performed in control, endothelial NOS (eNOS) knockout (eNOS-KO), and inducible NOS (iNOS) knockout (iNOS-KO) mice. Four weeks after the procedure, neointimal formation and reduction of cross-sectional vascular area (constrictive remodeling) were noted in the left carotid artery. In the eNOS-KO mice, the extent of neointimal formation was significantly larger than in the control or iNOS-KO mice, whereas the extent of vascular remodeling was the highest in the iNOS-KO mice compared with other 2 strains. Antiplatelet therapy with aspirin or antihypertensive treatment with bunazosin failed to inhibit the accelerated neointimal formation in the eNOS-KO mice. These results indicate that eNOS and iNOS have different vasculoprotective actions against the vascular lesion formation caused by blood flow disruption in vivo: NO derived from eNOS inhibits neointimal formation, whereas NO derived from iNOS suppresses the development of constrictive remodeling.
The spectrum of viruses inhibited by a genetically engineered consensus interferon (IFN) YM643 (interferon alfacon-1) was evaluated using a cytopathic effect inhibition assay or plaque inhibition assay for five DNA viruses and 12 RNA viruses. This activity was compared to that of natural IFN-alpha derived from Namalwa lymphoblastoid cell line [IFN-alpha (Namalwa)]. The viruses inhibited by both IFNs were herpesvirus types 1 and 2, human cytomegalovirus, varicella-zoster virus, vesicular stomatitis virus, yellow fever virus, bovine viral diarrhoea virus, Semliki Forest virus, western equine encephalitis virus, encephalomyocarditis virus, rhinovirus type A, respiratory syncytial virus, Newcastle disease virus and influenza virus type A (H1N1). Neither IFN inhibited coxsackie virus B1, reovirus type 3 or vaccinia virus in the experimental conditions used. The specific activity of YM643 in human cells generally ranged from 3.6x10(7) to 2.1x10(9) IU/mg, which was greater than that of IFN-alpha (Namalwa), which ranged from 3.1x10(6) to 4.6x10(8) IU/mg against all sensitive viruses, except human cytomegalovirus and rhinovirus type 1A, which displayed approximately equal sensitivity to both IFNs. Significantly, the potency of YM643 against bovine viral diarrhoea virus and yellow fever virus, which were selected to serve as surrogates of hepatitis C virus, equalled or exceeded that of IFN-alpha (Namalwa). These results suggest that the genetically engineered YM643 is more potent than natural IFN-alpha.
The effects of the surfactant secretagogue YM-40461 on the mucociliary transport (MCT) velocity were examined in guinea pigs with induced bronchitis. Guinea pigs were exposed to SO2 gas (900 ppm, 3 h/d) for 5 d. MCT velocity was measured by the movement of a 30% gelatin solution containing Evans blue dye placed on the tracheal mucosal surface. Repeated doses of YM-40461 improved the MCT guinea pigs with bronchitis within 5 d after the completion of SO2 exposure, with an ED50 value of 3.1 mg/kg p.o. At a dose of 10 mg/kg p.o., YM-40461 restored MCT to the control level (98.0% recovery). Ambroxol, bromhexine and salbutamol also improved MCT, but were far less effective than YM-40461. Airway fluid collected from bronchitic animals revealed increased disaturated phosphatidylcholine (DSPC, a major component of surfactants)-to-protein ratio and decreased surface tension produced by YM-40461 treatment (10 mg/kg). These results suggest that YM-40461 ameliorates MCT dysfunction in animals with SO2 gas-induced bronchitis by increasing the DSPC-to-protein ratio in the airway.
A rare case of a child with Noonan syndrome who had huge bilateral coronary artery dilatation is presented. Noonan syndrome is one of the most common nonchromosomal syndromes seen in children with cardiovascular abnormalities. Coronary artery abnormality should be considered in Noonan syndrome, because this syndrome may be associated with a higher incidence of coronary anomalies than previously thought.
The effects of lipid mediator antagonists: the LTD4-receptor antagonist pranlukast, the TXA2-receptor antagonist seratrodast, and the novel dual LTD4- and TXA2-receptor antagonist YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl) propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) were investigated in animals exhibiting immediate asthmatic response (IAR), late asthmatic response (LAR) and airway hyper-responsiveness (AHR). Antigen-induced LAR and AfR are inhibited by orally administered pranlukast (30, 100 mg/kg) and seratrodast (3, 10 mg/kg). YM158 (30 mg/kg), orally administered before or after IAR induction, also inhibited both LAR and AHR. However, while the inhibitory effects of pranlukast and seratrodast on IAR were marginal, the effects of YM158 (3, 10, 30 mg/kg) were dose-dependent, probably due to its multiple sites of action. Additionally, orally administered YM158 (30 mg/kg) inhibited ozone-induced AHR in guinea pigs. Thus, an antagonist that inhibits several lipid mediators might exhibit greater efficacy in treating asthmatic responses than antagonists with a single site of action. Therefore, YM158 shows great promise as a drug that will be able to treat bronchial asthma and related disorders more potently than currently used single-pathway inhibitors.
The effects of the new pulmonary surfactant secretagogue YM-40461, 1-(2-dimethylaminoethyl)-1-(3,4,5-trimethoxyphenyl) urea, on tracheal mucociliary transport (MCT) were assessed using guinea pigs with acute bronchitis. Acute bronchitis was induced by SO2 gas exposure (400 ppm for 3 h). MCT velocity was measured by means of the dye gelatin technique. YM-40461 at doses of 1-10 mg/kg, p.o. induced recovery of MCT function, with an ED50 value of 2.4 mg/kg. Maximal recovery (78.0+/-12.5%) was observed 2 h in the animals treated with 10 mg/kg of YM-40461. Ambroxol and bromhexine showed less effect on the MCT dysfunction than YM-40461. An artificial surfactant (Surfacten) also aided recovery. YM-40461 at a dose of 10 mg/kg, p.o. significantly improved surfactant production without affecting mucus secretion. These results show that YM-40461 ameliorates MCT dysfunction caused by SO2 exposure by activation of pulmonary surfactant secretion.
The antagonistic activity of oral YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl)propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene (LT) D4 and thromboxane (TX) A2 receptors, was investigated. Oral YM158 caused dose-dependent inhibition of LTD4-induced increases in plasma leakage and LTD4- or U46619-induced increases in airway resistance, with ED50 values of 6.6, 8.6 and 14 mg/kg, respectively. The dose-range of YM158's inhibitions was almost the same for both LTD4 and TXA2 receptors, and repeated oral doses did not affect its efficacy. Furthermore, oral YM158 inhibited antigen-induced bronchoconstriction. Although the potency of pranlukast for LTD4 receptor antagonism (ED50 = 0.34 mg/kg) is greater than that of YM158 (ED50 = 8.6 mg/kg), the doses of both pranlukast and YM158 for significant inhibition of the antigen-evoked airway response were the same, indicating that the TXA2 receptor antagonism of YM158 plays an important role in its anti-asthmatic effects. In conclusion, YM158 promises to be a novel agent for treating bronchial asthma.
A 5-day Hershberger assay using young mature male rats to detect compounds interfering with androgen receptor (AR)-mediated mechanisms was evaluated for ability to identify p,p'-DDE (a weak AR antagonist) and methyltestosterone (MT, an AR agonist). Fenitrothion, an organophosphate pesticide, was also evaluated in this validated assay. Castrated male Crj:CD(SD)IGS rats (1 week after castration, 11 weeks of age) were subjected to experiments. To determine a suitable value of testosterone propionate (TP) as a reference androgen for detection of antiandrogenic chemicals, castrated male rats were treated daily with TP (0, 0.06, 0.25, 1, 4, or 16 mg/kg/day, s.c.). TP produced increases in weights of ventral prostate, seminal vesicles and levator ani plus bulbocavernosus muscles. Serum androgen level measured by RIA kit (mostly TP) were elevated in a dose-related manner, while the weights of organs with 1 mg/kg/day of TP were nearly equivalent to the maximum responses (i.e., sub-maximal). One hundred mg/kg/day of p,p'-DDE significantly attenuated TP 0.1 mg/kg-induced increases in weights of seminal vesicles and muscles, and TP 1 mg/kg-induced increases in weights of ventral prostate, seminal vesicles and muscles, but did not affect the weight of these organs in either TP 16 mg/kg-treated or intact rats, demonstrating that the dose range of 0.1-1 mg/kg TP is suitable for reference androgen. Oral treatment with 100 mg/kg of MT increased the weights of ventral prostate, seminal vesicles and muscles as strongly as did subcutaneous injection of 1 mg/kg of TP. These findings demonstrate that the 5-day Hershberger assay using young mature as well as immature male rats is a sensitive and valid short-term screening method for the detection of chemicals interfering with AR-mediated mechanisms. To determine whether fenitrothion interferes with AR-mediated mechanisms in vivo, fenitrothion (0, 0.75, 1.5 or 3 mg/kg/day) was administered by gavage for 5 days to castrated rats for androgenicity, or to castrated rats treated with 1 mg/kg TP for antiandrogenicity. Treatment with fenitrothion had no adverse effects on clinical signs, body weight, or liver or kidney weights, but cholinesterase activities in the brain and erythrocytes were significantly suppressed by fenitrothion to, respectively, 77-81% and 66-67% of control levels. In the antiandrogenicity experiment, serum androgen levels of TP-treated, castrated rats did not differ among groups. Treatment with 100 mg/kg of p,p'-DDE as a positive control again significantly attenuated TP-induced increases in weights of the ventral prostate and seminal vesicles, while fenitrothion had no effect on the weights of any organs. In the androgenicity experiment, treatment with 100 mg/kg of MT significantly increased weights of ventral prostate, seminal vesicles and muscles, but fenitrothion had no effects on the weights of any of these organs. These findings yield no evidence that fenitrothion interferes with AR-mediated mechanisms in vivo, consistent with the result of several toxicological bioassays.
A follow-up study was conducted to elucidate the factors influencing continuation of home life after returning home from geriatric intermediate care facilities (GICFs). The subjects were 237 elderly persons (56 men, 181 women, average age of 84 years) who were admitted to three GICFs located in the suburbs of Osaka, and their family caregivers. A follow-up study was performed from 1997 to 1998. Seventy percent of the elderly were bedridden persons with grade B or C of activities of daily living (ADL) according to the criteria of disabled elderly of the Japanese government. Dementia was observed in 82.3% of them. Family caregivers were sons (30.7%), daughters (27.4%), daughters-in-law (27.8%) and spouses (9.7%). The percentage of families spending all day long with the elderly person was 57.5%. Although the rate of having their own detached house was high, that of a private room for the elderly individuals was only about 60%. Most of the families cared for the elderly before admission to the GICFs. The families desired them to stay in the GICFs for as long as possible. Therefore, the families did not want to take the elderly into their home after discharge and only 45% of the families desired home care after the discharge. Concerning the flow of the 237 elderly subjects, the rate of admission from hospitals was high (60.8%), and that of discharge to hospitals was also high (44.3%). The place of residence at the end of follow-up was the GICF (35.4%), the elderly subject's home (19.0%), and hospital (16.0%). Of the 96 elderly who had returned home from GICFs, 40.6% were re-admitted to GICFs. According to multiple logistic analysis, the factors related to continuation of home life were "the elderly with family caregivers who can always supervise him/her", and "the elderly without problem behavior". From the results obtained, it is important that in order for disabled elderly individuals to continue their home life, the GICFs must be the function as the center of a comprehensive service system in the community.
To clarify whether acute medial necrosis of the aorta induces aneurysms and intimal thickening at a later stage, we first attempted to induce acute aortic medial necrosis in 47 normal rabbits by the administration of Russell's viper venom intraperitoneally and of angiotensin II intravenously as used in a previous study and then followed the rabbits for 1 and 2 months respectively. As a control, 18 adult normal rabbits were used. Six control and 20 treated rabbits were sacrificed after aortagraphy at the end of one month, while the remaining 12 control and 27 treated rabbits were sacrificed at the end of 2 months. We evaluated the aortic lesions by gross observations and both light and electron microscopic examinations. In addition, at the end of one month, aortagraphy was performed to measure the luminal diameter of the aorta of the 6 control and 20 treated rabbits. We macroscopically found the saccular lesions to be surrounded by small crater like lesions mainly at the thoracic aortas in 18 out of 47 treated rabbits. These lesions consisted of the necrosis and calcification of the aortic media and the destruction of the elastic fiber along with intimal thickening. However, no aneurysmal dilatation was found in the aortagraphy findings. We thus conclude that acute medial necrosis produced saccular and crater like lesions but these lesions were not confirmed by aortagraphy.
Depression-like behavior induced by YM643, a consensus interferon-alpha (IFN-alpha), was evaluated with the tail-suspension test in mice and compared with depression-like behavior induced by sumiferon, a natural IFN-alpha. To investigate the mechanism of IFN-alpha-induced depression-like behavior, the effects of the tricyclic antidepressant imipramine, the cyclooxygenase inhibitor indomethacin, the opioid receptor antagonist naloxone, and the selective corticotropin-releasing hormone receptor antagonist CP-154, 526 on IFN-alpha-induced depression-like behavior were evaluated. Intravenously injected YM643 (2 x 10(8)-2 x 10(9) U/kg) and sumiferon (2 x 10(6)-2 x 10(7) I.U./kg) dose-dependently increased immobility time. Repeated s.c. injection of either YM643 (6 x 10(6)-6 x 10(8) U/kg) or sumiferon (6 x 10(4)-6 x 10(6) I.U./kg) for 7 days also dose-dependently increased immobility time. After i.c.v. injection of either YM643 (2 x 10(6) U/mouse) or sumiferon (6 x 10(4) I.U./mouse), significant prolongation of immobility time also was observed. Pretreatment with imipramine (30 mg/kg s.c.) significantly reduced the YM643- or sumiferon-induced increases in immobility time. CP-154,526 (0.3-3 mg/kg s.c.) dose-dependently reduced YM643- or sumiferon-induced increases in immobility time with ID(50) values of 0.6 mg/kg against YM643 and 1.3 mg/kg against sumiferon. However, neither indomethacin (10 mg/kg s.c.) nor naloxone (3 mg/kg s.c.) had any effect on YM643- or sumiferon-induced increases in immobility time. These results suggest that IFN-alpha centrally induces depression-like behavior in mice that can be alleviated with imipramine. The results also suggest that activation of corticotropin-releasing hormone receptors is involved in IFN-alpha-induced depression-like behavior, but the prostaglandin and opioid systems do not participate in this process.
We synthesized a novel phosphodiesterase type 4 (PDE4) inhibitor, YM976, that is structurally different from the other PDE4 inhibitors like rolipram. In the present study, the pharmacological profile of YM976 was investigated. YM976 exhibited a strong and competitive inhibition against PDE4 purified from human peripheral leukocytes with an IC(50) of 2.2 nM. IC(50) values of rolipram and RP73401 were 820 and 0.43 nM, respectively. Test compounds had no effects on the other PDE isozymes, PDE1, -2, -3, and -5. YM976 potentiated prostaglandin E(2)-induced cAMP accumulation in a human mononuclear cell line, U937, and inhibited tumor necrosis factor-alpha production from human peripheral blood mononuclear cells stimulated by lipopolysaccharide. Anti-inflammatory activities of PDE4 inhibitors were compared in rat carrageenan-induced pleurisy models. YM976, rolipram, and RP73401 inhibited the cell infiltration into the pleural cavity with oral ED(30) values of 9.1, 10, and 7.4 mg/kg, respectively. YM976 produced no emesis up to 10 mg/kg, whereas rolipram and RP73401 induced emesis at oral doses of 3 mg/kg. To evidence the dissociation of anti-inflammatory activity from emesis, the anti-inflammatory effect of YM976 was examined in ferrets. YM976 dose dependently reduced carrageenan-induced leukocyte infiltration at the doses of 1, 3, and 10 mg/kg, p.o. On the other hand, rolipram failed to show obvious inhibition at doses that do not induce emesis. In conclusion, YM976 is a novel and orally active PDE4 inhibitor and possesses a good separation of emetogenicity from anti-inflammatory activity.