Biomedical subjects
Publications and source records attributed to S Kitagawa.
An unusual case of right anterior hepatic artery arising from the superior mesenteric artery is presented in a patient with hepatocellular carcinoma. This variation was demonstrated by angiography and computed tomography after transcatheter arterial embolization (TAE). It has not previously been identified in the medical literature.
99mTc-galactosyl serum albumin (GSA), a specific radiolabeled synthetic ligand for asialoglycoprotein receptors on hepatocytes, was used for functional liver imaging in 18 patients. Six patients had chronic hepatitis, and 12 had liver cirrhosis. Serial scintigraphic images were obtained for 60 minutes after intravenous administration of 1 mg of the ligand. High-quality images of the liver was obtained in all the patients. Dispersed accumulation in the liver in association with delayed clearance of the ligand from the heart was noted in cirrhotic patients. The activity of the entire liver (L) and that of the heart (H) were measured. The capacity of the liver in terms of elimination of the ligand was estimated by calculating [L/H+L] 15 and 30 minutes after the administration. [L/H+L] showed significant differences between patients with chronic hepatitis and those with liver cirrhosis, and also showed significant correlations with laboratory values such as indocyanine green clearance, prothrombin time, hepaplastin test, serum albumin level, and the Child-Turcotte classification score. 99mTc-GSA might be a useful radiopharmaceutical for obtaining hepatic functional images.
The effects of three short-chain alkyl alcohols and benzyl alcohol on the membrane fluidity of bovine blood platelets were investigated by studies on the fluorescence anisotropies of diphenylhexatriene (DPH), its cationic trimethylammonium derivative (TMA-DPH) and its anionic propionic acid derivative (DPH-PA). These alcohols decreased the fluorescence anisotropy of DPH, which is thought to be located within the hydrophobic core of the membrane, in concentration ranges that inhibited platelet aggregation. On the other hand, they had little or no effects on the fluorescence anisotropy of DPH-PA which is thought to be located in the interfacial region of the lipid bilayer. Likewise, they had little or no effects on the fluorescence anisotropy of TMA-DPH, which is also thought to be located in the interfacial region of the lipid bilayer, either when the probe was located in the outer layer of the plasma membrane or when the probe was located in the inner membrane compartment. These results suggest that alcohols mainly increase the fluidity in the central region of the lipid bilayer. Consistent with their effects on the fluorescence anisotropy of DPH, these alcohols increased the intracellular cyclic AMP concentration. Thus alcohols may inhibit platelet function due to stimulation of adenylate cyclase, which is mediated by perturbation of the central region of the membrane lipid bilayer.
The binding of cationic butyltrimethylammonium derivative of pyrene to bovine platelets was initially rapid and then increased gradually, unlike the bindings of other anionic and neutral derivatives of pyrene tested. The rate of increase in binding of the cationic probe depended on temperature and was due to its incorporation into the cytoplasmic side of the platelet membranes, as shown quantitatively by monitoring decrease in its extractability with albumin. The penetration into the inner membrane compartment did not reach equilibrium even after 4 h at 37 degrees C. Slow penetration of a fluorescent probe such as this is useful in studies on the physico-chemical properties of the outer layer and cytoplasmic side of the platelet membranes and their changes. Initial rapid binding of the cationic probe to platelets, representing the binding of the probe to the outer layer of the plasma membrane, was increased by ionomycin-induced platelet activation. Fluorescence spectra in the presence of a relatively high concentration of the cationic probe showed increase of the excimer of the cationic probe accompanied with the incorporation of the probe to the cytoplasmic side. On ionomycin-induced activation, the excimer-to-monomer intensity ratio of the probe in the cytoplasmic side of the platelet membranes decreased, possibly due to decrease in fluidity of the lipid layer near the probe or change in distribution of the probe.
The effects of hematopoietic growth factors on human monocyte superoxide (O2-) release were investigated by using purified human monocytes in suspension. Among growth factors studied, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage-CSF (M-CSF), and interleukin-3 (IL-3) primed human monocytes and enhanced O2- release stimulated by the receptor-mediated agonists, N-formyl-methionyl-leucyl-phenylalanine (FMLP) and concanavalin A (Con A), but not by phorbol myristate acetate, which bypasses the receptors to stimulate the cells. The optimal priming was obtained by pretreatment of cells with 1 to 5 ng/mL (0.07 to 0.34 nmol/L) GM-CSF, 50 to 100 ng/mL (0.5 to 1.1 nmol/L) M-CSF, or 10 to 20 ng/mL (0.6 to 1.3 nmol/L) IL-3 for 10 minutes at 37 degrees C. Potency of the maximal priming effects on FMLP- or Con A-induced O2- release was GM-CSF greater than M-CSF = IL-3. The combination of the optimal concentrations of any two CSFs resulted in the effect of more potent priming agent alone. Enhancement of O2- release by GM-CSF was observed over the complete range of effective concentrations of FMLP (10(-8) to 10(-6) mol/L). The pretreatment of monocytes with granulocyte-CSF (50 ng/mL), interferon-gamma (1,000 U/mL), or IL-4 (20 ng/mL) for 10 minutes at 37 degrees C had no effect on O2- release stimulated by FMLP or Con A. These findings show that GM-CSF, M-CSF, and IL-3 selectively enhance O2- release in human monocytes triggered by receptor-mediated agonists after short-term preincubation.
The intravenous sensitization of C57BL/6 (B6) mice with class I H-2-disparate B6-C-H-2bm1 (bm1) spleen cells results in almost complete abrogation of anti-bm1 CD8+ helper (proliferative and interleukin 2-producing) T cell (Th) activities. Although an appreciable portion of CD8+ cytotoxic T lymphocyte (CTL) precursors themselves remained after this regimen, such a residual CTL activity was eliminated after the engrafting of bm1 grafts, and these grafts exhibited prolonged survival. In contrast, the intravenous sensitization with (bm1 x B6-C-H-2bm12 [bm12])F1 cells instead of bm1 cells failed to induce the prolongation of bm1 graft survival as well as bm12 and (bm1 x bm12)F1 graft survival. In the (bm1 x bm12)F1-presensitized B6 mice before as well as after the engrafting of bm1 grafts, anti-bm1 CTL responses that were comparable to or slightly stronger than those observed in unpresensitized mice were induced in the absence of anti-bm1 Th activities. bm1 graft survival was also prolonged by intravenous presensitization with a mixture of bm1 and bm12 cells but not with a mixture of bm1 and (bm1 x bm12)F1 cells. The capacity of CD4+ T cells to reject bm12 grafts was eliminated by intravenous presensitization with antigen-presenting cell (APC)-depleted bm12 spleen cells. However, intravenous presensitization with APC-depleted (bm1 x bm12)F1 cells failed to induce the prolongation of bm1 graft survival under conditions in which appreciably prolonged bm12 graft survival was induced. More surprisingly, bm1 graft survival was not prolonged even when the (bm1 x bm12)F1 cell presensitization was performed in CD4+ T cell-depleted B6 mice. This contrasted with the fact that conventional class I-disparate grafts capable of activating self Ia-restricted CD4+ as well as allo-class I-reactive CD8+ Th exhibited prolonged survival in CD4+ T cell-depleted, class I-disparate cell-presensitized mice. These results indicate that: (a) intravenous presensitization with class I- and II-disparate cells fails to reduce anti-allo-class I rejection responses that would otherwise be eliminated using only class I-disparate cells; (b) such failure is generated according to the coexpression of both classes of alloantigens on a single cell as tolerogen; and (c) allo-class II antigens coexpressed on tolerogen function to activate CD4+ as well as non-CD4+ Th leading to the generation of anti-class I effector T cell responses.
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A method of 24-hour storage of asphyxiated canine hearts for orthotopic cardiac transplantation was studied to expand the geographical size of the donor pool. Left ventricular function of asphyxiated hearts preserved for 24 hours (group 1, n = 8) was compared with that of hearts donated on-site (group 2, n = 5). Group 1 donors were pretreated with verapamil hydrochloride, propranolol hydrochloride, and prostacyclin. The donor hearts were perfused with warm blood cardioplegia in situ after 10 minutes of asphyxiation and then perfused with cold crystalloid cardioplegia for 2 hours. The hearts were excised and stored in ice-cold University of Wisconsin solution for 22 hours. At orthotopic transplantation, coronary perfusion with warm blood cardioplegia was performed before the graft aorta was unclamped. Conventional cardiac variables (eg, cardiac output and maximum rate of rise of left ventricular pressure), myocardial performance, and diastolic compliance of grafted hearts were assessed 1 hour after weaning from bypass. All recipients in both groups were easily weaned from cardiopulmonary bypass without inotropic agents, and there were no significant differences in cardiac variables between the two groups. These results strongly suggest that cadaver hearts can be preserved for 24 hours with satisfactory cardiac function.
A child with trisomy 21 had altered mental status and hyperammonemia at presentation and was found to have a congenital portosystemic shunt as a result of a congenital abnormality of the portal venous system. Anomalies of the portal venous system leading to portosystemic shunting, although they are infrequent, should be considered in the differential diagnosis of hyperammonemia.
Myocardial energy metabolism in asphyxiated cadaver hearts preserved in UW solution (UWS; group 1, n = 6) or modified Collins' solution (MCS; group 2, n = 6) was compared with that in cardioplegic arrested hearts immersed in ice-cold MCS with (group 3, n = 6) or without myoprotective drugs (group 4, n = 5). All hearts were stored for 24 hr. The hearts in groups 1 and 2 were pretreated with prostacyclin, verapamil, and propranolol; asphyxiated for 10 min, reversed by coronary perfusion with warm blood cardioplegia (WBCP); perfused with ice-cold crystalloid cardioplegia for 2 hr; excised and immersed in cold storage solution for 22 hr; and perfused again with WBCP before reperfusion. ATP contents were measured in biopsy specimens by HPLC. Myocardial ATP level decreased significantly from 23.7 +/- 1.7 to 15.9 +/- 2.5 mumol/g dry wt. (P less than 0.0001) by asphyxia, but recovered to within normal limits by WBCP in group 1. The ATP level again decreased to 15.8 +/- 2.4 mumol/g dry wt. during 24-hr storage, but finally rose to 22.4 +/- 3.5 mumol/g dry wt. by terminal WBCP. The ATP metabolism in group 2 was similar to that in group 1. The ATP content in group 4 was significantly lower than that in other groups (P less than 0.01) after 24-hr preservation. The study shows that damage to cadaver hearts can be reversed and the hearts maintained satisfactorily viable for 24 hr.
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered (1.5 micrograms/kg body weight) subcutaneously once daily for 5 to 9 days to 5 patients with malignant lymphoma. In all patients, initial administration of rhG-CSF induced a rapid fall in the neutrophil count within 30 minutes, followed by a recovery and an increase in the neutrophil count within 150 min. A rapid fall in the neutrophil count was accompanied by increased expression of neutrophil C3bi-receptors, and neutrophils left in the circulation had lower activity of neutrophil alkaline phosphatase (NAP) and phagocytosis. A decrease in the NAP scores observed at 30 min reflected a preferential decrease of neutrophils with high NAP activity. A recovery and an increase in the neutrophil count were accompanied by a further decrease of NAP scores, which was caused by a preferential increase of neutrophils with lower NAP activity. The NAP scores of mature neutrophils from peripheral blood were not affected by in vitro treatment of cells with rhG-CSF for up to 150 min at 37 degrees C. These findings and the previous observations that neutrophils in the circulating and marginal pools have high NAP activity and neutrophils in the bone marrow pool have low NAP activity taken together suggest that, following initial administration of rhG-CSF, functionally active neutrophils leave the bloodstream preferentially, which is primarily followed by an influx of neutrophils from the bone marrow, but not by demargination of sequestered neutrophils.
A method was developed for semi-preparative scale enantioseparation of racemic homochlorcyclizine (HCZ) by high performance liquid chromatography (HPLC) on Chiralcel OD column. The best resolution was achieved using an eluent composed of n-hexane plus 0.2 M isopropylamine. By this method, about 5.0 mg of racemic HCZ could be resolved completely in one run. The optical purity of the enantiomers were both greater than 99.9%. The studies of antihistamine activity on guinea pig ileum demonstrated that l-HCZ is significantly more potent than d- and racemic HCZ. The pharmacokinetics of d- and l-HCZ after oral administration to rats also differed. The successful resolution of racemic HCZ permits comparison of the pharmacokinetics and antihistamine activity of the enantiomers.
The present study was designed to delineate changes in serum lipid levels following various kinds of tissue injury or inflammation such as contact sensitivity to picryl chloride, thermal burn, carrageenin-induced edema, the administration of turpentine oil, Freund's complete adjuvant (FCA), killed Bordetella pertussis (BP) or lipopolysaccharide (LPS). A uniform change in the serum lipid metabolism was observed in mice that received these inflammatory stimuli; that is, increases in total cholesterol, free cholesterol and phospholipid levels, a decrease in the ester ratio and a decline in lecithin: cholesterol acyltransferase activity as well as a decrease in albumin levels, which is an index of the acute-phase response. However, serum triglyceride levels were increased by treatment with the bacterial stimuli (FCA, BP and LPS) but decreased by treatment with the other stimuli. The serum free cholesterol and phospholipid levels were significantly correlated with the intensity of contact sensitivity, which was modified by treatment with cyclophosphamide. Indomethacin or dexamethasone suppressed carrageenin-induced edema and inhibited some of the alterations in lipid metabolism that developed during inflammation because each affected a part of the lipid metabolism. These findings suggest that, like the appearance of acute-phase proteins, the uniform change in serum lipid metabolism may be another sensitive index of the acute inflammatory response.
The present investigation was undertaken to characterize the relaxing responsiveness in aortic strips from rats with arteriosclerosis, which was produced by excess vitamin D2 (VD) administration followed by treatment with or without a high-cholesterol diet for 6 weeks (VD + CHOL and VD group, respectively). This arteriosclerotic aorta was characterized by medial calcification and intimal cell proliferation. Helical strips of thoracic aorta were suspended in oxygenated Krebs-Henseleit solution. Under precontraction with noradrenaline, endothelium-dependent relaxations to acetylcholine were significantly attenuated in the VD and VD + CHOL as compared with the control. Relaxation to calcium ionophore A23187 was also significantly attenuated in the VD + CHOL. However, the relaxing responses to acetylcholine and A23187 in aortas from rats fed a high-cholesterol diet alone remained unaffected. Nitroglycerin caused an equal degree of relaxation in aortas from control and arteriosclerotic rats. There was a significant negative correlation between the relaxing response to acetylcholine and the calcium content in the aorta. These results indicate that in arteriosclerotic rat aortas, the endothelium-dependent relaxation to acetylcholine is impaired in proportion to the degree of calcification, and such impairment is facilitated by cholesterol feeding but can not be attributed to hypercholesterolemia or vascular cholesterol deposition.
The role of platelet-activating factor (PAF) as a mediator of gastric damage associated with burn injury was examined in the rat. Gastric mucosal hemodynamics was recorded continuously by means of laser-Doppler flowmetry and reflectance spectrophotometry. Burn injury induced prolonged hypotension and rapid-onset and long-lasting gastric mucosal hemodynamic derangement-that is, ischemia with congestion. This hemodynamic disturbance was significantly inhibited by CV-6209, a specific PAF antagonist. Elevated tissue levels of thiobarbituric acid reactants and pathologic changes in the gastric mucosa subsequent to burn injury were also significantly alleviated by the preadministration of CV-6209. These results strongly suggest a role of PAF as an important mediator of gastric damage after burn injury through its potent vasoactive effect on gastric microcirculation.
Generation of active oxygen species by bovine blood platelets was examined by the electron spin resonance (ESR) spin trapping technique with 5,5-dimethyl-1-pyroline-1-oxide (DMPO). The hydroxyl spin-trapped adduct 5,5-dimethyl-2-hydroxyl-1-pyrolidinyloxy (DMPO-OH) was formed in the presence of platelets, indicating the generation of hydroxyl radicals (.OH) by the platelets. Generation of .OH was observed even with platelets in the resting state, but was markedly enhanced when the platelets were activated with stimulants. Stronger stimulants such as the calcium ionophore ionomycin, induced greater radical generation than the weaker stimulant ADP. When the platelets were stimulated by thrombin, generation of .OH was greatest after 1.5 min, and depended on the dose of the stimulant. It was inhibited by inhibitors of platelet activation such as forskolin and phenolic antioxidants.
The superoxide (O2-)-releasing capacity in response to N-formyl-methionyl-leucyl-phenylalanine (FMLP) and the priming effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on FMLP-induced O2-release were investigated in neutrophils from 13 patients with aplastic anemia (AA). The O2(-)-releasing capacity of AA neutrophils (0.85 +/- 0.36 nmol/5 min/1 x 10(5) cells, n = 13) was significantly (p < 0.01) increased as compared with that of normal neutrophils (0.24 +/- 0.12 nmol/5 min/1 x 10(5) cells, n = 17). There was no close relationship between the O2(-)-releasing capacity and the peripheral blood neutrophil count or the plasma concentration of C-reactive protein. The plasma concentrations of G-CSF and GM-CSF were not elevated to the detectable levels (< 0.1 ng/ml and < 0.2 ng/ml, respectively) in all patients tested. FMLP-induced O2(-)-release was further enhanced by pretreatment of cells with rhG-CSF or rhGM-CSF for 10 min at 37 degrees C, except that no significant priming by rhG-CSF was observed in five patients. The priming effect of rhGM-CSF was consistently greater than that of rhG-CSF in all patients. The i.v. administration of rhGM-CSF (6 micrograms/kg body weight/day) to one patient resulted in an increase in neutrophil O2(-)-release stimulated by FMLP. These findings indicate that neutrophils from AA patients are already primed in vivo for enhanced release of O2- and that these neutrophil functions are further potentiated by rhG-CSF or rhGM-CSF.
Despite many studies on percutaneous transhepatic biliary drainage (PTBD), there are no satisfactory reports of PTBD for malignant obstruction of the hepatic confluence. In this study, the results of PTBD using the direct anterior approach under fluoroscopic guidance are described in 16 patients with malignant biliary obstruction of the hepatic confluence. A total of forty-two drainage catheters were placed in the 16 patients: one catheter was placed in three patients; two catheters in six; three catheters in four; four catheters in two; seven catheters in one. PTBD was successful in 100% of the cases with no mortality or critical complications, and the biliary decompression effect of PTBD was highly satisfactory. Nine patients underwent histologically curative hepatectomies. Two of the nine resected cases died of postoperative hepatic failure, but the postoperative course in the others was satisfactory. The authors stress that selective biliary drainage for each isolated segmental duct is mandatory for advanced malignant obstruction of the hepatic confluence.