Biomedical subjects
Y Kitano
Publications and source records attributed to Y Kitano.
Evaluation of an extracorporeal membrane oxygenation system using a nonporous membrane oxygenator and a new method for heparin coating.
A new heparin binding method was applied to a miniature extracorporeal membrane oxygenation (ECMO) system with a nonporous membrane oxygenator (the priming volume, 45 mL; the membrane surface area, 0.4 m2; maximal flow rate, 2 L/min) that is resistant to plasma leakage. The authors evaluated the stability of the immobilized heparin in vitro and the feasibility of this system in animals. Samples of hollow fibers and tubing were rinsed at 40 degrees C for 4 days in normal saline, Ringer's lactate, and 1 mol/L NaCl solution. Heparin activities on hollow fibers after rinsing were 99 +/- 2.3% (mean +/- SD), 96 +/- 3.9%, and 93 +/- 2.0% of the control in each solution, while those of the tubing were 87 +/- 4.1%, 86 +/- 3.1%, and 76 +/- 8.6%, respectively. Veno-arterial ECMO using this heparin-coated system was performed on five beagles (8 to 12 kg) for 10 hours. Neither major thrombus formation nor plasma leakage was detected during the procedure in spite of a low flow rate (300 mL/min) and a reduced activated clotting time (mean, 128 seconds). Platelets decreased to 52% of the control (P < .01) at 1 hour, but no progressive decrease was seen thereafter. Antithrombin-III decreased (P < .01) and thrombin/antithrombin III complex increased (P < .05 at 4 hours and P < .01 at 6, 8, and 10 hours) during bypass, but the changes of fibrinogen and fibrinopeptide A were not significant. Fibrinogen/fibrin degeneration products, fibrinopeptide B beta 15-42, and plasma-free hemoglobin levels did not rise significantly. O2 transfer of the oxygenators at a flow rate of 300 mL/min were 12.3 +/- 0.4 mL/min at 30 minutes, 14.3 +/- 1.2 mL/min at 5 hours, and 14.7 +/- 1.7 mL/min at 10 hours (no statistical difference). Histological examination of the brains and the kidneys showed no evidence of thromboembolic sequela in any of the animals. These results suggest that this new system is a promising device for long-term ECMO in which the amount of systemic heparinization can be reduced with the minimal possibility of plasma leakage.
The role of subfractionation of alpha-fetoprotein in the treatment of pediatric surgical patients.
Subfractionation of serum alpha-fetoprotein (AFP) is a useful method to discriminate between yolk sac tumors, hepatic malignancies, and benign liver diseases in adults but has not been validated in infants and children. AFP subfractionation was performed on AFP-positive sera from 73 infants and children. AFP subfraction profiles were classified into three common types: (1) yolk sac type, (2) hepatoblastoma type, and (3) benign hepatic type, according to the reactivity of individual AFP samples to lectins. In 68 of 73 samples (93.2%), AFP subfraction profiles were accurately classified into these three types, and an atypical AFP subfraction profile resembling the hepatoblastoma type was found in sera from five infants (6.8%). Differentiation between hepatoblastoma and hepatitis when patients are very young can be difficult. Subfractionation is more accurate when patients are older. This technique was found to be useful in the diagnosis of neonatal ovarian tumors, in recurrent hepatoblastoma/ yolk sac tumor with low serum AFP, and in the differential diagnosis of hepatic mass (malignancy versus hyperplastic nodule) in the liver with long-standing cholestasis. Estimation of serum AFP subfraction profiles facilitates the differential diagnosis of various AFP-positive pediatric diseases, such as hepatoblastoma, hepatoma, hepatitis or germ cell tumors. This test is inexpensive, can be carried out within 48 hours, and should be performed for the differential diagnosis of pediatric liver disease.
The role of low density lipoprotein apheresis in the treatment of familial hypercholesterolemia.
The chief indication for low density lipoprotein (LDL) apheresis is the treatment of homozygous familial hypercholesterolemia (FH), a potentially fatal condition that responds poorly to conventional therapy. Dextran sulfate/cellulose adsorption columns (Kaneka) and on-line heparin precipitation (HELP) are the most popular systems used in LDL apheresis. Weekly or biweekly procedures plus concomitant drug therapy enable LDL cholesterol to be maintained at 30-50% of its untreated level, with regression of xanthomas, arrest of progression of coronary atherosclerosis, and improved life expectancy. However, aortic stenosis may progress despite apheresis and necessitate valve replacement. Better control of hypercholesterolemia results from combining apheresis with a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, atorvastatin. LDL apheresis can also be useful in treating drug-resistant FH heterozygotes with coronary disease. However, the FH Regression Study showed no evidence that reduction by apheresis of both LDL and lipoprotein(a), was more advantageous than reduction by combination drug therapy of LDL alone.
The familial hypercholesterolemia regression study: a randomized comparison of therapeutic reduction of both low-density lipoprotein and lipoprotein(a) versus low-density lipoprotein alone.
Lipoprotein (a) [Lp (a)] is a risk factor for coronary heart disease (CHD), especially in the presence of a raised low-density lipoprotein (LDL)-cholesterol (LDL-C). To ascertain whether reduction of both LDL and Lp(a) is more advantageous than reduction of LDL alone, patients with heterozygous FH and CHD were selected randomly to receive either LDL apheresis fortnightly plus simvastatin 40 mg/day or colestipol 20 g plus simvastatin 40 mg/day. Quantitative coronary angiography was undertaken before and after 2.1 years. Changes in serum lipids were similar in both groups except for the greater reduction of LDL-C and Lp(a) by apheresis. There were no significant differences in primary angiographic endpoints, and none of the angiographic changes correlated with Lp(a). Although LDL apheresis plus simvastatin was more effective than colestipol plus simvastatin in reducing LDL-C and Lp(a), it was not more beneficial in influencing coronary atherosclerosis. Decreasing Lp(a) seems unnecessary if LDL-C is reduced below 130 mg/dl.
Intraalveolar expression of tumor necrosis factor-alpha gene during conventional and high-frequency ventilation.
The effects of conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation (HFO) on intraalveolar expression of the tumor necrosis factor-alpha (TNF-alpha) gene were studied in surfactant-depleted rabbits. After lung lavage with saline, 13 rabbits were administered either CMV (n = 6) or HFO (n = 7) for 1 h at an FiO2 of 1.0 and a mean airway pressure of 13 cm H2O. Lung lavage was then repeated. The rabbits' RNA was extracted from the lavage cells, and mRNA for TNF-alpha was quantitated by reverse-transcription polymerase chain reaction using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an internal standard. At 1 h of ventilation, PaO2 was slightly lower with CMV than HFO, while lavage cell counts and cytology were similar between the two groups. The ratio of TNF-alpha mRNA to GAPDH mRNA increased with CMV (control, 0.48 +/- 0.04 [SE] versus 1 h, 1.02 +/- 0.14, p < 0.01) but did not change with HFO (0.55 +/- 0.07 versus 0.73 +/- 0.09). In a separate series of experiments, ten surfactant-depleted rabbits continued to be ventilated for 4 h either by CMV (n = 5) or HFO (n = 5). Conventional mechanical ventilation resulted in a progressive hypoxemia, decreased lung compliance, increased number of neutrophils in lung lavage fluid, and substantial morphological changes including hyaline membrane formation and neutrophil accumulation, whereas HFO was associated with minimal changes in such physiological and pathological abnormalities. These results suggest that activation of alveolar macrophages and production of proinflammatory cytokines may play a pivotal role in the early stage of ventilator-induced lung injury, and that ventilator mode (CMV or HFO) substantially modulates macrophage activation and hence the degree of lung injury.
[CAPD peritonitis, CAPD sclerosing peritonitis].
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[Infectious disease in hemodialysis patients].
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ICAM-1 expression on cardiac myocytes and aortic endothelial cells via their specific endothelin receptor subtype.
Endothelin-1 (ET-1) and Endothelin-3 (ET-3) increased the expression of intercellular adhesion molecule-1 (ICAM-1) on rat neonatal cultured cardiac myocytes and rat aortic endothelial cells. ET-1-induced ICAM-1 expression on cardiac myocytes was inhibited by a selective ETA receptor antagonist, S-0139, but not by a selective ETB receptor antagonist, BQ788. ET-3-induced ICAM-1 expression on endothelial cells was inhibited by BQ788 but not by S-0139. Protein kinase C (PKC) inhibitor staurosporine inhibited ETs-induced ICAM-1 expression on both cell types. Treatment of the cells with ETs increased neutrophil adhesion, which was inhibited by S-0139 and staurosporine on cardiac myocytes and by BQ788 and staurosporine on endothelial cells. These results suggest that ETs induce neutrophil adhesion to cardiac myocytes and aortic endothelial cells by increasing ICAM-1 expression, which mediate via ETA receptor on cardiac myocytes and via ETB receptor on aortic endothelial cells. ICAM-1 expression induced by activation of ETA and ETB receptors appears to be mediated through the PKC pathway.
Regulation of BiP gene expression by cyclopentenone prostaglandins through unfolded protein response element.
Delta12-Prostaglandin (PG) J2, a cyclopentenone prostaglandin, plays a role in various stress responses. BiP, a stress-inducible chaperone protein, is implicated in protein folding and translocation in endoplasmic reticulum and induced in the condition of accumulation of unfolded proteins. Here, we examined the effect of Delta12-PGJ2 on the expression of the BiP gene. Delta12-PGJ2 markedly stimulated the expression of the BiP gene in a time- and concentration-dependent manner in HeLa cells. This stimulation was specific for cyclopentenone PGs among various PGs. Cycloheximide pretreatment completely inhibited the Delta12-PGJ2-induced expression of the BiP gene, suggesting that the effects on nascent protein synthesis are involved in the signaling mechanism. Delta12-PGJ2 markedly stimulated the promoter activity of the 5'-flanking region of the BiP gene through the unfolded protein response element. Furthermore, Delta12-PGJ2 stimulated the enhancer activity of the 3'-half of the unfolded protein response element, and this stimulation required three nucleotides within this region. Gel mobility shift assay demonstrated that this region was occupied with two specific nuclear protein factors with different mobilities in the control cells, and Delta12-PGJ2 induced the dissociation of the protein-DNA complex with lower mobility. These findings indicate that Delta12-PGJ2 stimulates the expression of BiP gene through the 3'-half of the unfolded protein response element.
Dual role of tropomyosin on chemically modified actin filaments from skeletal muscle.
Actin filaments copolymerized with both intact and chemically modified actin monomers restored their sliding activity when they were supplemented with tropomyosin extracted from skeletal muscle. In contrast, the ATPase activation of the copolymers was decreased when supplemented with tropomyosin. The results indicate that tropomyosin along with actin monomers may facilitate sliding activity of the entire actin filament but suppress ATPase activation of intact actin monomers themselves. Accordingly, tropomyosin molecules could be viewed as playing a dual role of both mechanical and chemical regulation of actin monomers.
Suppressive effect of staphylococcal enterotoxin B on murine contact hypersensitivity.
Superantigens (SAg) possess the capacity to interact with particular V beta regions of T cell receptor (TCR) and major histocompatibility complex (MHC) class II molecules, and activate a large number of T cells and accessory cells. staphylococcal enterotoxins (SEs) are recently well known as SAg and anticipate to modulate immunological reactions. In this study, we investigated the effect of staphylococcal enterotoxin B (SEB) on contact hypersensitivity reaction (CHR) to 2,4-dinitrofluorobenzene (DNFB) in BALB/c mice. SEB-injection inhibited the induction of sensitization on CHR. Suppressor cells were not found in the spleen or lymph node cells from mice treated with SEB. Normal spleen cells cultured with SEB showed significant proliferation and tumor necrosis factor-alpha (TNF-alpha) production. CHR was suppressed by intravenous injection of the culture supernatant. In addition, anti-TNF-alpha antibodies inhibited the suppressive effect induced by the supernatant. These findings indicate that TNF-alpha produced by SEB-responding cells inhibits the induction of sensitization on CHR. Therefore, SAg may play important roles in the modulation of immune system through the stimulation of TNF-alpha production.
Studies on transient graft-versus-host disease in BALB/c nude mice injected with allogeneic C57BL/6 splenocytes.
Graft-versus-host disease (GVHD) is known to cause profound dysregulation of the immune system, although its effector mechanisms are not fully understood. In this study, we investigated what factors influenced the development of GVHD. BALB/c nude mice (H-2d) injected with MHC-disparate B6(H-2b) spleen cells exhibited transient GVHD such as hunched back, diarrhea, loss of body weight and splenomegaly. No animals died during the period of observation. BALB/c nude mice produced alloantibodies to the donor cells. The injection of the serum from GVHD nude mice into naive nude mice can protect from GVHD. Donor derived H-2b+ cells were recognized in the recipient lymph nodes and skin. Prevention of GVHD was achieved by the pretreatment of spleen cells with anti-Thy-1.2 antibody or anti-CD4 antibody and complement, while it was not done by the pretreatment of spleen cells with anti-CD8 antibody and complement. These data demonstrate that Thy-1.2+ CD4+ CD8- lymphocytes are important effector cells and alloantibodies to the donor cells prevent GVHD in this model.
Increasing-current electroshock seizure test: a new method for assessment of anti- and pro-convulsant activities of drugs in mice.
We developed the increasing-current electroshock seizure (ICES) test, a new method for assessment of anti- and pro-convulsant activities of drugs in mice. In this method, a single train of pulses (square wave, 5 msec, 20 Hz) of linearly increasing intensity from 5 to 30 mA (increment of 0.1 mA/0.1 sec, i.e., 5-30 mA in 25 sec) was applied via ear electrodes. The current at which tonic hindlimb extension occurred was recorded as the seizure threshold. Thus, this method allows determination of the seizure threshold current for individual animals. Carbamazepine, phenytoin, valproate, phenobarbital, diazepam, and morphine all increased the seizure threshold current in a dose-dependent manner, whereas ethosuximide was not effective. The seizure threshold current decreased after treatment with reserpine, chlorpromazine, aminophylline, strychnine, pentylenetetrazol, bicuculline, picrotoxin, and ethyl-beta-carboline-3-carboxylate (beta-CCE). These results indicate that the ICES test, like the maximal electroshock seizure test, is a model of grand mal-type seizure and is useful for evaluation of both the anti- and pro-convulsant activities of drugs.
Modulation of picryl chloride-induced contact hypersensitivity reaction in mice by nitric oxide.
We have studied the possible involvement of nitric oxide (NO) in the contact hypersensitivity reaction. A biphasic response of ear swelling was observed at 2 h (early phase) and 24 h (late phase) after application of the antigen to picryl chloride (PC1)-sensitized CBA/J mice. Intravenous injection of NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), at the time of PC1 challenge, inhibited in a concentration-dependent fashion the antigen-induced contact hypersensitivity reaction. Low-dose (1 mg/kg) L-NAME inhibited the early-phase reaction but not the late-phase reaction. High-dose (250 mg/kg) L-NAME inhibited both early- and late-phase reactions. D-NAME (enantiomer of L-NAME) did not inhibit the antigen-induced ear swelling. High-dose (250 mg/kg) L-arginine increased both early and late phase reactions. D-Arginine (enantiomer of L-arginine) did no increase the antigen-induced ear swelling. L-NAME injection, however, did not suppress phenol-induce irritant inflammation. Treatment of mice undergoing PC1-induced contact hypersensitivity reaction with L-NAME reduced the production of interleukin-2 and interferon-gamma by draining lymph node cells. Treatment with L-arginine, on the other hand increased the production of interleukin-2 and interferon-gamma. These results suggest that NO plays a modulating role in contact hypersensitivity reaction.
Proliferation and teratogenicity of Aino virus in chick embryos.
Aino virus (AIV; JaNAr 28 strain) 10(3) TCID50/0.2 ml was inoculated in the yolk sac of 8-day-old chick embryos. Recovery and titration of the virus from various organs including the central nervous system (CNS) and skeletal muscle were performed at 2, 4, 7, 10 and 13 days after inoculation (PI). AIV was systematically disseminated and proliferated even 2 days PI. The titers of the recovered virus from the CNS and from skeletal muscle was the highest at 4 days PI and declined with time, whereas hydranencephaly, arthrogryposis and cerebellar hypoplasia developed at 7 days PI and gradually progressed until 13 days PI.
Selective reduction in alpha-hydroxypalmitic acid-containing sphingomyelin and concurrent increase in hydroxylated ceramides in murine skin tumors induced by an initiation-promotion regimen.
The sphingomyelin cycle is activated to accumulate ceramides in the process of epidermal differentiation. We found that sphingomyelin in the epidermis of 4 different murine strains gave three bands on TLC, the lower band containing alpha-hydroxypalmitic acid (C16h:0(alpha)). However, in the papillomas induced in the skin of SENCAR and SSIN mice by initiation with 7,12-dimethylbenz[a]anthracene followed by promotion with 12-O-tetradecanoylphorbol acetate, the concentration of C16h:0(alpha)-containing sphingomyelin was selectively diminished with a concomitant increase in the concentrations of the ceramides containing alpha-hydroxy fatty acids. These findings indicate a possible involvement of the selective hydrolysis of alpha-hydroxy fatty acid-containing sphingomyelin in the process of tumorigenesis in mouse skin.
Allergic granulomatosis and angiitis of Churg-Strauss syndrome.
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