Cost evaluation of basiliximab treatment for renal transplant patients in Japan.
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Antibodies, Monoclonal↗
Biomedical subjects
S Miki
Publications and source records attributed to S Miki.
The role of the hypothalamic nitric oxide in the pressor responses elicited by acute environmental stress in awake rats.
We quantitatively investigated the change in nitric oxide (NO) in the hypothalamic paraventricular nucleus (PVN) and its effect on cardiovascular regulation during shaker stress (SS) using brain microdialysis in awake rats. Male Wistar rats were fed either N(G)-nitro-L-arginine methyl ester (L-NAME, 0.7 g/L) or tap water for 2 weeks. Two days after implantation of an arterial catheter and guide shaft, a microdialysis probe was placed to perfuse the PVN with degassed Ringer solution at 2 microl/min in awake normotensive Wistar (CONTROL) and chronic L-NAME-treated hypertensive rats. After the rat was placed in a plastic cage set on a shaker, the blood pressure and heart rate was monitored and 10-min SS was loaded at a frequency of 200 cycles/min. Dialysate samples were analyzed by NO analyzer (based on the Griess reaction) every 10 min, and NOx (NO(2)(-) + NO(3)(-)) was measured. Plasma NOx was also measured before and after SS. Pressor responses elicited by SS were significantly greater in L-NAME-treated rats than in the CONTROL. Although NOx in the PVN dialysate were increased by SS in the CONTROL, these responses were attenuated in chronic L-NAME-treated rats. Resting plasma NOx were higher in the CONTROL than in L-NAME-treated rats. SS elicited no difference between two groups in plasma NOx. These results indicated that NO within the PVN, but not in systemic circulation, may play a role on the attenuation of the pressor responses elicited by SS. The dysfunction of NO release within the PVN may, in part, play a role in the exaggerated pressor responses in acute environmental stress.
Acute Disease↗
Role of the mitochondrial permeability transition and cytochrome C release in hydrogen peroxide-induced apoptosis.
We investigated the role of the mitochondrial inner membrane permeability transition and subsequent release of cytochrome c into the cytosol during oxidative stress-evoked apoptosis. Sublethal oxidative stress was applied by treating L929 cells with 0.5 mM H2O2 for 90 min. Then the cellular localization of cytochrome c was examined by immunofluorescent staining and Western blotting. H2O2 treatment caused the permeability transition and pore formation, resulting in membrane depolarization and translocation of cytochrome c from the mitochondria into the cytosol. Pretreatment with cyclosporin A and aristolochic acid (to inhibit pore formation) significantly attenuated a reduction of the mitochondrial membrane potential, as well as signs of apoptosis such as DNA fragmentation, increased plasma membrane permeability, and chromatin condensation. Therefore, exposure to H2O2 caused the opening of permeability transition pores in the inner mitochondrial membrane. An essential role of cytosolic cytochrome c in the execution of apoptosis was demonstrated by its direct microinjection into the cytosol, thus bypassing the need for cytochrome c release from the mitochondrial intermembrane space. Microinjection of cytochrome c caused caspase-dependent apoptosis.
Animals↗
In situ polymerization into porous ceramics: a novel route to tough biomimetic materials.
A hydroxyapatite-based biomimetic composite, which is henceforth referred to as a synthetic bony material with high toughness characteristics, was prepared. It was obtained from a hydroxyapatite (HAp) skeleton with a relative porosity fraction of approximately 32 vol %, prepared by cold-isostatic-press compaction, followed by a sintering process, leading to a hydroxyapatite structure containing percolated submicrometer porosity channels. The percolated pores were infiltrated with a liquid mixture of epsilon-caprolactam monomer and an initiator, before homogeneous in situ polymerization to 6-nylon within the fully percolated pore structure was induced thermally. The final composite consisted of a dense interpenetrated hydroxyapatite/6-nylon network in a fraction approximately 68/30 vol %. The work of fracture value of the hybrid composite was found to be comparable with those found in two natural materials (bovine femur and nacre), which were also investigated under the same testing conditions.
Journal Article↗
Antinociceptive effect of the novel compound OT-7100 in a diabetic neuropathy model.
We previously reported that OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-alpha]pyrimidine) had antinociceptive potency in various animal models. To further characterize this compound, the present study examined the effects of OT-7100 on mechanical hyperalgesia and motor nerve conduction velocity in streptozotocin-induced diabetic rats. OT-7100 significantly increased the nociceptive threshold in the diabetic rat in a dose-dependent manner. Gabapentin (anticonvulsant agent) and insulin strongly increased the nociceptive threshold but gabapentin increased it above normal levels. An aldose reductase inhibitor slightly increased the nociceptive threshold at a high dose. We also measured glucose levels and motor nerve conduction velocity in OT-7100-treated rats. Insulin decreased glucose levels but OT-7100 had no effect on glucose levels or on motor nerve conduction velocity. These results suggest that OT-7100 alleviates hyperalgesia in a diabetic neuropathy model in a different manner from gabapentin or aldose reductase inhibitor and may be a new treatment for the pain associated with peripheral nerve injury.
Acetates↗
Immunoassay for human serum albumin using capillary electrophoresis-semiconductor laser-induced fluorometry.
Capillary electrophoresis combined with semiconductor laser-induced fluorometry was applied to an immunoassay of human serum albumin. Human serum albumin was labeled with a fluorescent molecule (Cy5), which has an absorption maximum at 649 nm. The labeled albumin was purified by ultrafiltration in order to reduce signals, which are unreacted labeling reagent, product, and fragment products derived there from. After the purification, no signal for unreacted labeling reagent and fragment products was detectable in the electropherogram of the labeled albumin. The labeled albumin was then reacted with anti-albumin to form an immunocomplex, which was separated from the excess free albumin. The competitive immunoassay was used in the determination of human serum albumin in a controlled serum sample, using the labeled albumin. The obtained value was found to be 0.21 +/- 0.02 mg/ml, which is in good agreement with other known values.
Electrophoresis, Capillary↗
A single amino acid change at Leu-188 in the reverse transcriptase of HIV-2 and SIV renders them sensitive to non-nucleoside reverse transcriptase inhibitors.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are selective for human immunodeficiency virus type 1 (HIV-1) and generally not effective on HIV-2 or simian immunodeficiency virus (SIV). Only SIVagm was found to be sensitive to NNRTIs. When the amino acid differences in RT between SIVmac and SIVagm were compared with the known amino acid substitutions of NNRTI-resistance variants of HIV-1, we came to consider that the amino acid residue Leu-188 of HIV-2 and SIVmac might be related to their resistance to NNRTIs. To test this hypothesis, we substituted Leu-188 to Cys or Tyr in HIV-2 and SIVmac, and examined sensitivity of the mutant molecular clones to NNRTIs. The L188Y mutant of HIV-2 became completely sensitive to delavirdine and efavirenz, while that of SIVmac was also significantly sensitive to these NNRTIs. We further isolated NNRTI-resistant variants from these mutant viruses and determined amino acid substitutions in RT. The roles of the observed substitutions in NNRTI-resistance were further confirmed by site-directed mutagenesis. Our study reveals the crucial role of L188 in the natural resistance of HIV-2 and SIVmac to NNRTIs. Furthermore, the observed substitutions in RT of HIV-2 and SIVmac support the common mechanism of action of NNRTIs against HIV-1, HIV-2 and SIV.
Alkynes↗
Reduction of atherosclerosis despite hypercholesterolemia in lyn-deficient mice fed a high-fat diet.
Oxidation and other modifications of serum low-density lipoprotein (LDL) are associated with the development of atherosclerosis, and a scavenger receptor and CD40 signalling are also known to play important roles in the process. We previously showed that the Src family protein-tyrosine kinase Lyn is physically and/or functionally associated with macrophage type-I and type-II class-A scavenger receptors (MSR-A) and CD40. In this study, we addressed whether Lyn is involved in the build-up of serum lipid levels and in atherosclerotic changes. When fed a normal diet, lyn-deficient mice had serum lipid levels that were no different from those of wild-type mice. By contrast, lyn-deficient mice fed a high-fat diet showed serum lipid levels that were much higher than those seen in wild-type mice. Curiously, however, the lyn-deficient mice fed either diet showed no increase in incidence of atherosclerotic lesions compared with wild-type mice. This may be partly explained by our data showing suppression of proliferation of peritoneal macrophages in response to oxidized LDL in the absence of Lyn, and failure of stimulation of the CD40 pathway in lyn-deficient macrophages to induce expression of monocytic chemoattractant protein-1 (MCP-1), which is related to atherosclerosis. These results suggest that Lyn plays an important role in the metabolism of serum lipids and in the development of atherosclerotic lesions on high-fat diets.
Animals↗
Significantly rapid relief from steroid-resistant nephrotic syndrome by LDL apheresis compared with steroid monotherapy.
Rapid amelioration of hypercholesterolemia by LDL apheresis (LDL-A) was performed for long-standing nephrotic syndrome (NS) with hyperlipidemia due to focal segmental glomerulosclerosis (FGS) and the clinical data and prognosis were compared between LDL-A-treated and nontreated groups. Seventeen steroid-resistant NS patients treated with LDL-A (LDL-A group) and 10 NS patients treated with steroids only (steroid-monotherapy (SM) group) were compared. Serum cholesterol and phospholipid levels were significantly lowered only in the LDL-A group (p < 0.01, respectively). The LDL-A group showed a significant decrease of urinary protein (UP, p < 0.01) and increase of serum albumin (p < 0.05). Average time needed to achieve a decrease of UP to less than nephrotic range (< 3.5 g/day) was significantly shorter in the LDL-A group than in the SM group (p < 0.01). Although this is not a prospective study, it is highly expected that a rapid improvement of hypercholesterolemia by LDL-A in steroid-resistant NS will provide more rapid relief from NS than steroid therapy alone.
Adolescent↗
A novel analgesic compound OT-7100 attenuates nociceptive responses in animal models of inflammatory and neuropathic hyperalgesia: a possible involvement of adenosinergic anti-nociception.
We studied the effects of OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo [1,5-a]pyrimidine), a novel analgesic compound, on the inhibitory action of adenosine on the contraction of guinea pig ileum and investigated the effects of OT-7100 on the nociceptive responses in animal models of inflammatory and peripheral neuropathic hyperalgesia and decreases spinal c-Fos expression. OT-7100 at 0.3 - 3 microM significantly enhanced the inhibitory effect of adenosine on the contraction of guinea pig ileum. The efficacy of OT-7100 (1, 3 or 10 mg/kg, p.o.) on hyperalgesia induced by yeast or substance P and in the Bennett model was significantly suppressed by coadministration of the adenosine A1 antagonist DPCPX (0.01 or 0.1 pmol/animal, i.t.), while OT-7100 without DPCPX significantly increased the nociceptive threshold in each rat model. OT-7100 (3, 10 and 30 mg/kg per day, p.o.) significantly inhibited the mechanical nociceptive threshold in the injured paw in the Chung model. OT-7100 (30 mg/kg, p.o.) significantly decreased the number of Fos-LI neurons in the spinal dorsal horn in the Bennett model. These finding suggest that OT-7100 inhibits hyperalgesia in these animal models possibly by enhancing adenosinergic neurotransmission in the dorsal horn, although we still lack direct evidence for it.
Adenosine↗
Specific labeling of the bovine heart mitochondrial phosphate carrier with fluorescein 5-isothiocyanate: roles of Lys185 and putative adenine nucleotide recognition site in phosphate transport.
The amine/SH-modifying fluorescein 5-isothiocyanate (FITC) specifically labeled Lys(185) in the putative membrane-spanning region of the phosphate carrier from both the cytosolic and matrix sides of bovine heart mitochondria at 0 degrees C and pH 7.2, and the labeling inhibited the phosphate transport. Nonmodifying fluorescein derivatives having similar structural features to those of ADP and ATP (Majima, E., Yamaguchi, N., Chuman, H., Shinohara, Y., Ishida, M., Goto, S., and Terada, H. (1998) Biochemistry 37, 424-432) inhibited the specific FITC labeling and phosphate transport, but the nonfluorescein phenylisothiocyanate did not inhibit FITC labeling, suggesting that there is a region recognizing the adenine nucleotides in the phosphate carrier and that this region is closely associated with the transport activity. The phosphate transport inhibitor pyridoxal 5'-phosphate inhibited the specific FITC labeling, possibly due to competitive modification of Lys(185). In addition, FITC inhibited the ADP transport and specific labeling of the ADP/ATP carrier with the fluorescein SH reagent eosin 5-maleimide. Based on these results, we discuss the structural features of the phosphate carrier in relation to its transport activity.
Adenosine Diphosphate↗
Isolation and characterization of simian immunodeficiency virus variants that are resistant to nonnucleoside reverse transcriptase inhibitors.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) act quite specifically on human immunodeficiency virus type 1 (HIV-1). In general, they are not effective on human immunodeficiency virus type 2 (HIV-2) or simian immunodeficiency virus (SIV). Only SIV strains from African green monkeys are sensitive to several NNRTIs. Here we isolated NNRTI- and 3TC-resistant SIVagm variants. Viruses resistant to delavirdine contained V112I and M231I substitutions, while those resistant to 3TC contained a M 185I substitution. These amino acids are highly conserved in HIV-1, HIV-2, SIVmac and SIVagm, and the M184I (M185I in SIVagm) substitution was observed in 3TC-resistant HIV-1 and SIVmac. The roles of the observed mutations in NNRTI-resistance of SIVagm and HIV-1 were further confirmed by site-directed mutagenesis. The present results have provided a new insight into the common mechanism of sensitivity of HIV- 1 and SIVagm to NNRTIs.
Amino Acid Sequence↗
Nitric oxide is an excitatory modulator in the rostral ventrolateral medulla in rats.
Nitric oxide is a messenger molecule having various functions in the brain. Previous studies have reported conflicting results for the roles of nitric oxide in the rostral ventrolateral medulla, a major center that regulates sympathetic and cardiovascular activities. We hypothesized that in this region, nitric oxide may have a biphasic effect on cardiovascular activity. Microinjection of a low dose (1 nmol) of a nitric oxide donor sodium nitroprusside or a cyclic GMP agonist 8-bromocyclic GMP into this area increased arterial pressure, whereas injection of a nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester or a soluble guanylate cyclase inhibitor methylene blue decreased arterial pressure. Microinjection of a high dose (100 nmol) of sodium nitroprusside decreased arterial pressure and inhibited spontaneous respiration with concomitant production of peroxynitrite, a strong cytotoxic oxidant. Increases in arterial pressure caused by microinjection of L-glutamate were inhibited after preinjection of Nomega-nitro-L-arginine methyl ester or methylene blue. Increases in arterial pressure caused by microinjection of sodium nitroprusside (1 nmol) were inhibited after preinjection of a glutamate receptor antagonist kynurenate. These results suggest that low doses of nitric oxide may increase arterial pressure, whereas high doses of nitric oxide may decrease arterial pressure through cytotoxic effects in the rostral ventrolateral medulla. They also indicate that nitric oxide may stimulate neurons both through activation of the nitric oxide cyclic GMP pathway and through modulation of glutamate receptor stimulation, and therefore, increase arterial pressure in rats.
Animals↗
Modulation of endothelin-1 coronary vasoconstriction in spontaneously hypertensive rats by the nitric oxide system.
To determine whether nitric oxide contributes to the augmented vasoconstrictive response to endothelin-1 (ET-1) in coronary vessels of hypertensive hearts, and also whether L-arginine administration can inhibit the augmented response to ET-1, we designed experiments to measure coronary perfusion resistance in isolated hearts of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with or without L-arginine administration (0.5 g/L) for 2 weeks. The hearts were paced at a constant rate and perfused by the Langendorff technique at constant pressure (75 mm Hg). Perfusion flow and pressure were monitored, and coronary vascular resistance (CVR) was calculated. ET-1 infusion elicited dose-dependent increases in CVR in both WKY and SHR. At an ET-1 concentration of 1.5 x 10(-9) mol/L, the response was significantly greater in SHR. In L-NAME-treated WKY and SHR, responses to ET-1 were augmented, compared with those of nontreated rats, and this augmentation was greater in WKY. L-arginine administration reduced the CVR response to ET-1 in SHR, whereas it did not change responses to ET-1 in WKY. These findings suggest that the augmented vasoconstriction of the coronary artery induced by ET-1 in hypertensive hearts was due to a reduction in nitric oxide release in coronary vessels and that L-arginine can partially inhibit the vasoconstrictive response of the coronary artery.
Animals↗
Pressor response to pulsatile compression of the rostral ventrolateral medulla mediated by nitric oxide and c-fos expression.
It has been reported that neurovascular compression of the rostral ventrolateral medulla might be causally related to essential hypertension. Recently, we found that pulsatile compression of the rostral ventrolateral medulla increases sympathetic nerve activity and elevates arterial pressure via activation of glutamate receptors in rats. We also found that increases in sympathetic and cardiovascular activities by microinjection of L-glutamate into the rostral ventrolateral medulla are mediated by c-fos expression-related substance(s) following activation of the nitric oxide-cyclic GMP pathway. Herein, we investigated whether responses to pulsatile compression are mediated by local activation of the nitric oxide-cyclic GMP pathway and/or c-fos expression-related substance(s) in rats. Increases in arterial pressure (15+/-1 mmHg), heart rate (9+/-1 b.p.m.), and sympathetic nerve activity (% change: 8.5+/-1.1%) induced by pulsatile compression were partially but significantly inhibited after local microinjection of a nitric oxide synthase inhibitor, L-N(G)-nitroarginine methyl ester (8+/-2 mmHg, 1+/-1 b.p.m., 4.0+/-1.3%; P<0.05 vs compression without pretreatment) or 7-nitroindazole (7+/-2 mmHg, 2+/-1 b.p.m., 4.0+/-1. 5%; P<0.05), or a soluble guanylate cyclase inhibitor, methylene blue (9+/-1 mmHg, 4+/-1 b.p.m., 4.1+/-1.4%; P<0.05). In addition, increases in arterial pressure, heart rate, and sympathetic nerve activity by pulsatile compression were significantly reduced 6 h after microinjection of antisense oligodeoxynucleotide to c-fos mRNA (2+/-2 mmHg, 2+/-1 b.p.m., 1.0+/-1.0%; P<0.05 vs sense oligodeoxynucleotide). These results suggest that increases in sympathetic and cardiovascular activities induced by pulsatile compression of the rostral ventrolateral medulla are mediated, at least in part, by local activation of the nitric oxide-cyclic GMP pathway and c-fos expression-related substance(s) in rats.
Animals↗
Sensitive detection of myocardial contraction abnormality in chronic hemodialysis patients by ultrasonic tissue characterization with integrated backscatter.
Since acoustic properties of the myocardium are sensitive to the myocardial structure and the contractile conditions of myocyte, the authors evaluated cardiac dysfunction based on the integrated ultrasonic backscatter in 18 hemodialysis (HD) patients (duration: 102 +/- 84 months, mean age: 57.6 +/- 9.7 years) and 11 age-matched normals. The cyclic variation of integrated backscatter (CV-IB) at interventricular septum (IVS) and left ventricular posterior wall (PW) was measured and compared with percent fractional shortening (%FS) and percent wall thickening (%Th). The CV-IB of HD patients was smaller than that of control subjects (IVS: 6.2 +/- 1.1 dB vs 8.2 +/- 1.1 dB, p = 0.0003 and PW: 8.4 +/- 2.2 vs 10.3 +/- 1.3, p= 0.025). No significant difference was observed in %FS and %Th between HD patients and control subjects. In HD, the ratio of velocities of early diastolic inflow (E) to late atrial inflow was decreased (0.7 +/- 0.2 vs 1.1 +/- 0.7, p = 0.049) and deceleration time of E was prolonged significantly (200 +/- 28 msec vs 159 +/- 30 msec, p = 0.0082). In the absence of overt cardiac systolic dysfunction, myocardial damage indicated as a decrease in CV-IB and diastolic dysfunction identified on transmitral velocity waveform were detected, which may reflect from the myocardial fibrosis. As a mechanism, pressure overload, hyperparathyroidism, and anemia were neglected, and the other humoral factors may contribute to the myocardial damage in chronic renal failure.
Aged↗
Effect of long-term cholesterol-lowering treatment with HMG-CoA reductase inhibitor (simvastatin) on myocardial perfusion evaluated by thallium-201 single photon emission computed tomography.
Fifteen patients with either angina pectoris or old myocardial infarction, who had positive 201Tl single photon emission computed tomography (SPECT) imaging and coronary sclerosis of more than 50%, were treated with an HMG-CoA reductase inhibitor (simvastatin) for more than 1 year. They were compared with an untreated control group (n = 25). Total cholesterol decreased 22% and high-density lipoprotein (HDL) increased 9% with simvastatin; both changes were significantly different from those in controls. Long-term simvastatin induced improvement of myocardial perfusion on 201Tl SPECT images both during exercise and at rest, which was also significantly different from controls. In addition, the improvement of myocardial perfusion on 201Tl SPECT images was clearly related to the improvements in cholesterol values, especially nonHDL cholesterol. Thus, the greater the decrease in nonHDL cholesterol, the greater the improvement in myocardial perfusion at rest or during exercise with long-term treatment using an HMG-CoA reductase inhibitor. These findings indicate that the improvements in cholesterol values caused by HMG-CoA reductase inhibitor therapy are related to improvements of myocardial perfusion seen on 201Tl SPECT images.
Angina Pectoris↗
Enhanced HIV-1 replication by chemokines constitutively expressed in secondary lymphoid tissues.
Persistent infection of human immunodeficiency virus (HIV) takes place in the secondary lymphoid tissues even during clinically latent stages. The CC chemokines secondary lymphoid tissue chemokine (SLC) and EBI1-ligand chemokine (ELC) are constitutively expressed in the secondary lymphoid tissues. They share CCR7 expressed on lymphocytes and mature dendritic cells and play key roles in the trafficking of these types of cells into the secondary lymphoid tissues. Here we report that growth of both X4 and R5 strains of HIV-1 in activated peripheral blood T cells was enhanced by SLC. The enhancing effect of SLC was abrogated by pretreatment of cells with pertussis toxin, indicating the involvement of signaling via a receptor coupled with a Galphai class of G-protein. Furthermore, SLC was found to enhance the promoter activity of HIV-1 LTR. These results suggest that signaling via CCR7 has a strong positive effect on HIV growth. Thus, SLC and ELC may contribute to persistent infection of HIV in the secondary lymphoid tissues by promoting viral replication in activated T cells.
Adult↗