Biomedical subjects

I Azuma

Publications and source records attributed to I Azuma.

At least 55 records · Page 3Linked to original sources

PubMed1997

[Effect of topically applied isopropyl unoprostone on microcirculation in the human ocular fundus evaluated with a laser speckle microcirculation analyser].

The effect of topically applied 0.12% isopropyl unoprostone (unoprostone, Rescula) on the circulation of optic nerve head (ONH) and choroid-retina was studied using a laser speckle tissue circulation analyser in 9 normal human eyes. Normalized blur (NB), a quantitative index of blood flow velocity, was measured every 0.125 sec and averaged over 5 pulses in the temporal site of ONH free of surface vessels and in the middle site of the choroid-retina between ONH and macula. Intraocular pressure (IOP), blood pressure (BP), and pulse rate (PR) were also measured. On the first day, NB, IOP, BP, and PR were measured before and every 90 minutes for 6 hours after a 30 microliters instillation of placebo in both eyes (control eyes). The measured values were used as controls. On the other day one week later, a 30 microliters instillation of unoprostone was performed in one randomly chosen eye and the placebo in the other eye (treated and untreated eye). The above parameters were measured as the first day in a double masked manner. In the control experiment, no significant change occurred in any parameter. After topical application of unoprostone, NB in ONH showed no significant change. NB in the choroid-retina significantly increased at 3 (8%) and 4.5 (11%) hours in the treated eyes compared with the control eyes. After topical application of unoprostone, the IOP significantly decreased at 1.5 and 4.5 hours in the treated eyes compared with the control eyes. BP and PR showed no significant change. These results suggest that instillation of unoprostone can increase blood flow in the choroidretna in human eyes.

Adult↗

PubMed1997

Modulation by neurogenic acetylcholine of nitroxidergic nerve function in porcine ciliary arteries.

PURPOSE: To determine whether nitroxidergic, cholinergic, and vasoactive intestinal polypeptide (VIP)-mediated nerves participate in the regulation of porcine ciliary arterial tone and to analyze the mechanisms underlying the neuronal interaction. METHODS: Changes in isometric tension were recorded in helical strips of the arteries, which were stimulated by transmurally applied electrical pulses or nicotine. The presence of perivascular nerve fibers containing reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase, acetylcholinesterase, and VIP immunoreactivity were determined histologically. RESULTS: Transmural electrical stimulation (2, 5, and 20 Hz) and nicotine produced a relaxation of the arterial strips denuded of the endothelium and contracted with prostaglandin F2alpha. The response was not influenced by timolol but was abolished by oxyhemoglobin and methylene blue. N(G)-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished the neurogenic relaxation, and L-arginine restored the response. Physostigmine inhibited, but atropine potentiated, the neurogenic response. The relaxation was attenuated by acetylcholine but was not influenced by VIP. There were nerve fibers and bundles containing NADPH diaphorase, acetylcholinesterase, and VIP immunoreactivity in the adventitia of ciliary arteries. CONCLUSIONS: Porcine ciliary arteries are innervated by NO synthase-containing nerves that liberate NO, possibly as a neurotransmitter on excitation to produce muscular relaxation. Nitroxidergic nerve function is inhibited by acetylcholine released from cholinergic nerve, possibly because of impaired production or release of NO. VIP does not seem to function as a neurotransmitter or a modulator.

Acetylcholine↗

PubMed1997

Retinal toxicity of nitric oxide released by administration of a nitric oxide donor in the albino rabbit.

PURPOSE: Nitric oxide (NO), which has been identified as an endothelium-derived relaxing factor, might be involved in regulation of retinal circulation and intraocular pressure. Recently, it was suggested that NO might also be related to neuronal excitotoxicity mediated by the N-methyl-D-aspartate receptor and to the pathologic changes induced by some kinds of uveitis. However, ocular toxicity of NO released by an NO donor has not been clearly demonstrated. In the current study, NO neurotoxicity in the retina was investigated. METHODS: S-nitroso-N-acetyl-DL-penicillamine (SNAP, 200 nmol) was injected into the vitreous of albino rabbits as an NO donor. The changes of retinal function were evaluated at 1, 2, and 3 hours and 1 and 4 weeks after SNAP injection, using electroretinogram and visual-evoked potentials. Histologic changes of the retina were also examined. RESULTS: Injection of SNAP reduced the a-wave amplitude. In contrast, the amplitudes of the oscillatory potentials were increased during the 3-hour observation period. Histologic examination showed vacuolar degeneration and loss of the nuclei of the photoreceptors. In the inner retina, some ganglion cells were lost, and cell density in the internal nuclear layer was decreased. CONCLUSION: Retinal toxicity of NO was demonstrated functionally and histologically, suggesting that NO may play a pathophysiologic role in retinal ischemia or in degenerative retinal diseases.

Animals↗

PubMed1996

Vaccination of tumor cells transfected with the B7-1 (CD80) gene induces the anti-metastatic effect and tumor immunity in mice.

The present study demonstrates that the transfection of B7-1 or its variant MB7-2 genes into MHC class I+ tumor cells (B16-BL6 or K1735-M2 melanoma) resulted in the remarkable reduction of lung metastasis caused by i.v. injection into immunocompetent syngeneic mice. However, i.v. injection of the transfectants into T cell-deficient nude mice did not affect reduction of lung tumor colonies as compared with parental wild-type tumors, suggesting that such an inhibitory effect was closely associated with T cell-mediated responses. The reduced metastasis of B7+ tumor cells consequently led to the significant prolongation of survival. Expression of B7 on tumor cells did not influence the tumorigenicity in vivo and tumor cell invasion into basement membrane Matrigel in vitro. We also found that immunization of X-irradiated B7 transfectants was effective as a tumor vaccine for preventing lung metastasis caused by i.v. injection of B7- parental B16-BL6 cells but not against other syngeneic 3LL tumors. Thus, the B7-mediated anti-metastatic effect was tumor-specific. Vaccinations of irradiated B7+ tumor cells before and after surgical excision of the s.c. inoculated primary B7- tumors on day 21 achieved effectively the prevention of spontaneous lung metastasis. Our report that vaccination of irradiated B7+ tumor cells led to a therapeutic effect in an established tumor metastasis model clearly expands and confirms previous related observations.

Animals↗

PubMed1996

Tolerance to the anti-metastatic effect of lipopolysaccharide against liver metastasis in mice.

We describe the involvement of endotoxin tolerance in the refractoriness of its anti-metastatic effect against murine syngeneic tumors. Three i.v. administrations of LPS at intervals of 4 days after tumor inoculation inhibited liver metastasis of L5178Y-ML25 cells, whereas 3 consecutive i.v. administrations of LPS showed only a slight suppressive effect. Multiple i.v. administrations of LPS, synthetic lipid A, its synthetic derivative DT-5461, Staphylococcus aureus (S. aureus) BioParticles or Staphylococcal enterotoxin B (SEB) on days 1, 5 and 9 after tumor inoculation inhibited liver metastasis of T-lymphoma cells in normal mice. The anti-metastatic effects of LPS, synthetic lipid A or DT-5461 but not S. aureus BioParticles or SEB were diminished in mice injected with LPS at daily intervals for 7 days before tumor inoculation. Mice receiving 3 consecutive i.v. administrations of LPS at daily intervals exhibited suppression of LPS-induced production of endogenous tumor necrosis factor-alpha (TNF-alpha), tumoricidal activity of macrophages, and natural-killer (NK) activity of splenocytes when compared with those of normal mice. Macrophages from mice receiving consecutive daily i.v. administrations of LPS for 3 days showed reduction of LPS-induced tyrosine phosphorylation of several intracellular proteins, including p42(mapk) /ERK2 when compared with that of the cells obtained from normal mice. These data suggest that the LPS-induced anergic state of monocytes/macrophages plays a crucial role in endotoxin tolerance with respect to the metastasis of T lymphoma in the liver.

Animals↗

PubMed1996

Functional role of sialyl Lewis X and fibronectin-derived RGDS peptide analogue on tumor-cell arrest in lungs followed by extravasation.

Our study demonstrates that synthetic sialyl Lewis X (SLex) as a ligand for selectins and fibronectin-derived RGDS peptide analogue [Ar(DRGDS)3] inhibits lung metastases produced by i.v. co-injection of B16-BL6 melanoma cells. To investigate the inhibitory mechanisms in a living animal, we performed positron-emission tomography (PET) analysis after i.v. injection of [2-18F]2-fluoro-2v-deoxy-D-glucose-labeled tumor cells with or without liposomal SLex or Ar(DRGDS)3. The real-time PET measurement for the first 120 min, started immediately after injection, showed that tumor-cell arrest, i.e., accumulation in the target organ (lung) was remarkably inhibited by liposomal SLex, but not inhibited by Ar(DRGDS)3 or liposomal Me-SLex, which is not recognized by selectins. In contrast, Ar(DRGDS)3 inhibited the invasion of B16-BL6 cells into reconstituted basement membrane (Matrigel) following tumor arrest, whereas SLex- or Me-SLex-entrapped liposomes did not affect tumor invasion. In the metastatic processes containing tumor-cell lodgement and arrest in the target organ followed by extravasation (invasion), SLex resulted in the inhibition of initial arrest of tumor cells, presumably tumor-endothelium interaction, while Ar(DRGDS)3 achieved inhibition of tumor invasion into basement membrane at later steps of the cascade, consequently leading to inhibition of metastasis. Thus, tumor-cell arrest in lungs in the metastatic processes must be precisely and properly controlled by different adhesion molecules at different stages, which are similar to those observed in leukocyte-endothelium interaction.

Amino Acid Sequence↗

PubMed1996

A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension. A 12-week study.

OBJECTIVE: To evaluate the intraocular pressure (IOP)-reducing effect and the side effects of latanoprost (PhXA41), a new phenyl-substituted prostaglandin F2 alpha-isopropyl ester analogue, in patients with elevated IOP, using timolol maleate as the reference drug. METHODS: A total of 184 patients with primary open-angle glaucoma or ocular hypertension at 35 medical centers participated in this randomized double-masked study. The patients were randomized to receive either 0.005% latanoprost once daily or 0.5% timolol maleate twice daily, for a period of 12 weeks. Intraocular pressure was measured 24 hours after the administration of timolol, at 2, 4, 8, and 12 weeks of treatment. RESULTS: Latanoprost reduced IOP at the end of 12 weeks by 6.2 +/- 2.7 mm Hg (mean +/- SD) (26.8%), while timolol reduced IOP by 4.4 +/- 2.3 mm Hg (19.9%). At all visits latanoprost reduced IOP significantly more than timolol did. The main ocular side effects observed in both groups were conjunctival hyperemia and smarting. The main systemic side effect was a reduced pulse rate, which occurred in patients treated with timolol. CONCLUSIONS: The results of this study demonstrated that 0.005% latanoprost taken once daily is well tolerated and more effective in reducing IOP than 0.5% timolol taken twice daily. Thus, latanoprost may become an important choice for the medical treatment of glaucoma.

Adrenergic beta-Antagonists↗

PubMed1996

Effect of MDP-Lys(L18) as a mucosal immunoadjuvant on protection of mucosal infections by Sendai virus and rotavirus.

To examine the effect of MDP-Lys(L18), a derivative of muramyl dipeptide (MDP), as a mucosal immunoadjuvant, we investigated its activity to augment host resistance against mucosal infections by Sendai virus and rotavirus in mice. In an experimental infection model using suckling mice (10-day-old) inoculated perorally (p.o.) with 1.5 x 10(6) p.f.u. mouse-1 of rotavirus strain SA11, intrarectal (i.r.) as well as p.o. administration of MDP-Lys(L18) (50 micrograms mouse-1) prior to virus infection markedly reduced rotavirus-induced diarrhea. Furthermore, when MDP-Lys(L18) was administered p.o. (1 mg mouse-1), i.r. (300 micrograms mouse-1) or intranasally (i.n., 100 micrograms mouse-1) various days before Sendai virus infection (2.6 x 10(4) HAD mouse-1), all the mucosal administration of MDP-Lys(L18) significantly protected a lethal infection of Sendai virus, showing a dose-dependent manner. However, the efficacy of MDP-Lys(L18) to induce the prophylactic activity against the viruses somewhat varied according to the administration route and timing. In time course analysis of virus isolation in vivo, the mice administered with MDP-Lys(L18) exhibited a significant reduction of both viruses in the lungs for Sendai virus and in the bowels for rotavirus. These results suggest that MDP-Lys(L18) is a potent mucosal immunoadjuvant to enhance nonspecific host resistance against two mucosal infectious viruses, Sendai virus and rotavirus.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1996

Oral application of romurtide, a synthetic muramyl dipeptide derivative, stimulates nonspecific resistance to microbial infections and hematopoiesis in mice.

Romurtide given orally enhanced the nonspecific resistance against microbial infections and hematopoiesis up to the levels achieved by subcutaneous (s.c.) injection of the compound in mice. Oral romurtide conferred protection and, in consequence, enhanced therapeutic efficacy of antibiotics against systemic infections in mice. The leukocytosis followed by the elevations of colony stimulating activity in serum and the colony forming unit of granulocyte-macrophage (c.f.u.-GM) in femoral bone marrow was observed as successive event in mice treated orally with romurtide. To obtain a comparable potency to s.c. injection of the compound at a dose of 0.1 mg per mouse, oral application required doses of 3 and 10 mg per mouse for stimulating the nonspecific resistance to infection and hematopoiesis, respectively.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1996

Serial passage of human immunodeficiency virus type 1 generates misalignment deletions in non-essential accessory genes.

Human immunodeficiency virus type 1 (HIV-1) derived from an infectious molecular clone pNL432 was extensively passaged in tissue culture by repeated rounds of acute infection. We previously showed the natural occurrence of a nonsense mutation in the vpr gene during continued passage of this virus. In this report, we show that two forms of large deletions (561 and 518 base pairs containing short direct repeats at the deletion junctions) occur after passage 50 in the region that spans the vif and vpr open reading frames. One model to explain the occurrence of these deletion regions is that such mutations result from misalignment of the growing point at a limited number of nucleotide positions. Infection of CD4+ T-cells with a recombinant HIV-1 construct containing the same vif to vpr deletion showed virtually no cytopathogenic phenotype. Thus, misalignment deletions at non-essential accessory genes of HIV-1 might be induced during replication, which result in the generation of virus with a low cytopathogenic potential.

Base Sequence↗

PubMed1996

Romurtide, a synthetic muramyl dipeptide derivative, accelerates peripheral platelet recovery in nonhuman primate chemotherapy model.

We investigated the therapeutic effects of romurtide, a synthetic muramyl dipeptide derivative, on experimental thrombocytopenia induced by carboplatin in cynomolgus monkeys. A prolonged thrombocytopenia due to a severe myelosuppression was induced by carboplatin. Romurtide given subcutaneously elevated significantly the peripheral platelet counts during both early initiation and later recovery phase of thrombocytopenia, thereby shortening the time required for recovery to a normal platelet level and the duration of thrombocytopenia. An oral administration of romurtide was also found to have a similar therapeutic efficacy to subcutaneous administration. These results demonstrated a possible therapeutic potential of romurtide in the management of thrombocytopenia associated with myelosuppression.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1996

Characterization of the nucleocapsid protein of Hantaan virus strain 76-118 using monoclonal antibodies.

We characterized the antigenic sites on the nucleocapsid protein (NP) of Hantaan virus (HTN) using 10 monoclonal antibodies (MAbs). At least seven antigenic sites were revealed by a competitive binding assay and divided into three partially overlapping antigenic regions (I, II and III). Regions I [amino acids (aa) 1-103], II (aa 104-204) and III (aa 205-402) were mapped on NP by examining the reactivity of truncated gene products. Those that corresponded to region I reacted with immune mouse serum, indicating that the region contained major linear epitopes as reported with Four corners virus (FCV) and Puumala virus (PUU) NP. At least one MAb to each region inhibited viral growth when they were introduced into cells by scrape-loading. In addition, they conferred protection from a lethal HTN challenge to newborn mice. A PEPSCAN assay localized the epitope of MAb E5/G6 between aa 166-175. Since E5/G6, which had the highest inhibitory effect both in cells and in mice, showed no virus neutralization activity by ordinary neutralization test, this region is suggested to be important for the virus growth after entry into the cells.

Amino Acid Sequence↗

PubMed1996

[Effect of a nitric oxide donor on optic nerve head circulation].

Recently the endothelium-derived relaxing factor was proved to be nitric oxide (NO) and it has been found to play an important role in the regulation of local blood flow. In this paper, we studied the effect of S-nitroso-N-acetyl-DL-penicillamine (SNAP), a NO donor, on the optic nerve head (ONH) circulation in rabbits, using a hydrogen gas clearance flowmeter etc. Intravitreal application of SNAP (20 nmol) increased the caliber of the retinal artery at the edge of the ONH 60 to 120 minutes later and capillary blood flow in the ONH 90 to 135 minutes later. A dose-response relation was found between 2 and 20 nmol. These changes were thought to be caused by NO produced from SNAP because they were inhibited by pretreatment with a NO trapping agent. Blood pressure and IOP were reduced 30 to 45 minutes later and 60 to 120 minutes later, respectively. It was considered that intravitreal injection of SNAP first reduced both the resistance of the ONH blood vessels and the perfusion pressure in the ONH and that the latter then rose, followed by an increase of the capillary blood flow in the ONH.

Animals↗

PubMed1996

[Comparative measurement of optic nerve head circulation using laser speckle circulation analyser of ocular fundus and a hydrogen clearance method].

The microcirculation in the optic nerve head (ONH) was measured using the recently developed laser speckle circulation analyser for the ocular fundus. The measurements were compared to those of the capillary blood flow (CBF) obtained by the hydrogen clearance method. The ONH blood flow was measured using both methods simultaneously in six normal albino rabbits. The blood flow was increased by inhalation of carbon dioxide (CO2) and reduced by systemic administration of endothelin-1 (ET-1). 10%CO2 inhalation showed a CBF increase of about 22% in the ONH in the hydrogen clearance method, and intravenous injection of ET-1 at 10(-10) mol/kg decreased the reading by about 19%. A significant correlation (r = 0.92, p < 0.01) was found between the relative values of NB (Normalized blur, by laser speckle method) and CBF in the ONH. This result indicates that the change of NB in the ONH shares the same accuracy as hydrogen clearance method within the range of our present experiment. This study provides a fundamental basis for the clinical application of the laser speckle method in measuring ONH circulation.

Animals↗

PubMed1996

[Basic studies on tuberculosis and tubercle bacilli in U.S.-Japan medical cooperative program tuberculosis panel].

The U.S.-Japan Medical Cooperative Program has been started in 1965 and Tuberculosis Panel is one of the most important field of the programs. In this lecture, the recent advances in the basic studies on tuberculosis researches which were reported in Tuberculosis panel of the program were summarized. The host defence mechanisms against M. tuberculosis infection were the most important subject. The role of Th1-mediated cytokins such as IL-2, IFN gamma and TNF beta in the host-defence mechanism against mycobacterial infection was extensively discussed. Bcg gene of the mice is the example case for the genetic background of host against mycobacterial infection. The virulence factor, however of M. tuberculosis is still unknown. The technique of molecular biology was applied to the diagnosis of tuberculosis. The PCR and RFLP methods are the useful strategies for the rapid diagnosis and analysis of the mode of infection with M. tuberculosis. The development of detection techniques of drug-resistant tubercle bacilli is also urgently required. Another approach by molecular biology to tuberculosis research is the cloning of gene of tuberculin protein and the production recombinant protein of M. tuberculosis. The amino acid sequences of several proteins have been determined and their immunological properties of recombinant proteins were investigated. The immunological functions of lipid fractions of tubercle bacilli such as cord factor (TDM) and lipoarabinomannan (LAM) have been described. Especially the immunomodulating activities and the role of TDM as diagnostic antigen in the tuberculosis patients were described. The adjuvant activity of mycobacterial cell wall was well established and the minimum structural requirement was reported to be N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP). The several MDP derivatives were selected as the cytokine inducers. Especially MDP-Lys (L18) was widely used as drug for the increasing the number of white blood cells and platelets in cancer patients. The effectiveness of MDP derivatives on the stimulating of mucosal immunity was also recently reported. The preventing activities of virus infection and cancer metastasis of MDP derivatives were shown in mice models.

Humans↗

PubMed1996

[Effect of a nitric oxide donor on intraocular pressure].

We examined the effect of nitric oxide (NO) on intraocular pressure (IOP) and aqueous humor dynamics by using a NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP) in rabbits. Intravitreal injection of 20 microliters of SNAP solution (10(-4) to 10(-2)M) reduced IOP from 60 to 120 min after injection. The magnitude of IOP reduction was dose-dependent within 10(-4) and 10(-3)M. The IOP reduction was inhibited by pretreatment with a NO trapping agent, carboxy-PTIO, indicating that IOP reduction was induced by NO released from SNAP. The aqueous flare as assessed with a laser cell flare meter was not accompanied with the IOP reduction indicating that no inflammatory response occurred. Neither tonographic outflow facility nor aqueous flow rate was affected by the treatment with SNAP. We conclude that NO reduces IOP through a mechanism which is not directly involved with the change of conventional outflow or aqueous formation in rabbits.

Animals↗

PubMed1996

Inhibition of tumor invasion and metastasis by peptidic mimetics of Arg-Gly Asp (RGD) derived from the cell recognition site of fibronectin.

The partially modified retro- and retro-inverso peptides of the Arg-Gly Asp (RGD) sequence of fibronectin, in which the direction of the Arg residue is reversed and/or the chirality of the amino acid residue is inverted, i.e., mainly R(rev)-COCH2CO-D and DR(rev)-COCH2CO-D, have been synthesized to examine their antimetastatic effects in murine lung or liver metastasis models, as well as their inhibitory effect on tumor cell invasion in vitro. R(rev)-COCH2CO-D inhibited lung metastasis produced by i.v. coinjection with B16-BL6 melanoma more potently than did other pseudo-peptides or the original RGDS peptide. Rrev-COCH2CO-D also showed antimetastatic effects against several different types of tumor cells such as B16-BL6 melanoma, Colon26 M3.1 carcinoma, and L5178Y-ML25 lymphoma cells, in a dose-dependent manner, and multiple administrations had a therapeutic effect on spontaneous lung metastasis. The invasion of melanoma cells into reconstituted basement membrane Matrigel in vitro was suppressed by R(rev)-COCH2CO-D more effectively than by RGDS. These results indicate that the antimetastatic effect by R(rev)-COCH2CO-D was in part due to the inhibition of tumor invasion. The RGDS peptide decomposed when incubated with fresh plasma in vitro, whereas R(rev)-COCH2CO-D was not affected by this treatment. Thus, the reversion of the Arg-Gly linkage in the RGD sequence resulted in protease resistance leading to the retardation of the clearance of the peptide in vivo, and consequently augmented its antimetastatic and antiinvasive properties. Designed peptide analogues may provide various advantages and be useful for preventing cancer metastasis.

Animals↗

PubMed1996

Measurement of optic nerve head circulation: comparison of laser speckle and hydrogen clearance methods.

Microcirculation in the optic nerve head (ONH) in the ocular fundus was measured noninvasively using the recently developed laser speckle circulation analyzer. Results were compared with capillary blood flow (CBF) measurements made by the hydrogen clearance method. The ONH blood flow of six normal rabbits was measured simultaneously by both methods. Inhalation of 10% carbon dioxide (CO2) increased the CBF by 22% (hydrogen clearance method). Intravenous injection of endothelin-1 (ET-1) (10(-10) mol/kg) decreased the CBF by 19%. Significant correlations were found between the NB (normalized blur) value by the laser speckle method and CBF (r = 0.38, P < 0.05, n = 30) and also between the relative change of NB and CBF (r = 0.92, P < 0.01, n = 30) in the ONH. This indicates that evaluation of the NB change in the ONH is as accurate with the laser speckle method as with the hydrogen clearance method, giving a basis for the clinical application of the laser speckle method of measuring ONH circulation.

Administration, Inhalation↗