Biomedical subjects
Publications and source records attributed to A Abe.
Intracoronary acetylcholine prolonged the QT interval in 5 patients with congenital long QT syndrome but not in subjects with normal QT intervals. Prolongation was not due to bradycardia or adrenergic drive, and atropine was suggested to attenuate the response.
A homogenate of rat brain, rat liver or human colonic well differentiated adenocarcinoma was prepared in 250 mM sucrose isoosmolaric buffer (pH 7.6) and fractionated by differential centrifugation at 10(3), 10(4) and 10(5) g. Each precipitate or supernatant was incubated with NADPH and docosahexaenoic acid or arachidonic acid as a substrate for 30 min at 37 degrees c under aerobic conditions. omega-Hydroxydocosahexaenoic acid or omega-hydroxyeicosatetraenoic acid from an incubation mixture was detected by reversed-phase high-performance liquid chromatography-thermospray mass spectrometry with selected-ion monitoring. omega-Hydroxy polyunsaturated fatty acids were characterized by high intensity of the molecular ion (MH+) although common hydroxy polyunsaturated fatty acids were characterized by high intensity of the MH+ -H2O ion. For the rat brain, omega-hydroxylation activity (the amount of omega-hydroxy product produced in 30 min) was concentrated to a 10(3) g precipitate although the specific activity (the activity per 1 mg of protein) in the 10(3) g precipitate did not indicate superiority over other fractions. However, the specific activity of the rat brain increased on addition of a 10(4) or 10(5) g precipitate. For the rat liver, although omega-hydroxylation activity was concentrated to a 10(3) g precipitate, the specific activity was concentrated to a 10(5) g precipitate and the subcellular localization differed from that of rat brain. In the human colonic well differentiated adenocarcinoma, although omega-hydroxylation activity was relatively high in the 10(3) g supernatant, the specific activity was relatively high in the 10(3) g precipitates. These results suggest that there is a difference regarding subcellular localization of the omega-hydroxylation activity depending on the species of the organs.
We have developed a method for the analysis of 5,6-dihydroxyeicosatrienoate-1,5-lactone (5,6-DiHETriE-delta-lactone) in tissue homogenates, supplemented with NADPH and arachidonic acid [20:4(n-6)] as a substrate. During the incubation and the extraction, most of the 5,6-epoxyeicosatrienoic acid (5,6-EpETriE) was converted to 5,6-dihydroxyeicosatrienoic acid (5,6-DiHETriE), and most of the 5,6-DiHETriE was converted to 5,6-DiHETriE-delta-lactone. Consequently, the chief degradation product of 5,6-EpETriE and 5,6-DiHETriE in the incubation mixture was 5,6-DiHETriE-delta-lactone. 5,6-DiHETriE-delta-lactone, corresponding to [20:4(n-6)], was shown to be characterized by a high intensity of quasimolecular ions (MH+ and MNH4+), using ion analysis obtained by reversed-phase HPLC-thermospray MS. On selected-ion monitoring (SIM) chromatograms of 5,6-DiHETriE-delta-lactone and with deuterium-labeled 15(S)-hydroxyeicosatetraenoic acid as the internal standard, the regression equation of the peak-area ratio and the amount of 5,6-DiHETriE-delta-lactone was y = 12.2x + 0.7 (r = 0.9996). 5,6-Epoxygenase activity was represented as the sum of the amount of 5,6-DiHETriE-delta-lactone, 5,6-EpETriE and 5,6-DiHETriE per mg protein, after 30 min in an incubation mixture. The activity from rat brain homogenate decreased considerably with growth of the rat.
The lethal action and the effect from the removal of molecular sulfur by copper treatment were investigated in the Salmonella mutagenicity test for river sediments. Survival ratios of Ames Salmonella strains for five different sediment extracts were tested, and it was found that many of the river sediments showed the lethal action on TA98 and TA100, and the lethal action was stronger in the sample from which larger amount of extracts per unit weight were obtained. It was also found that the lethal action was reduced with the addition of the metabolizer S9 mix, and TA98 was more resistant than TA100 against the lethal substances in sediment extracts. Further, removal of molecular sulfur, one of the lethal substances, by copper treatment raised survival ratios of the tester strains. On high-pressure liquid chromatographic fractionation, the lethal substances, including molecular sulfur distributed in non-polar and slightly polar fractions, and medium or high polar fractions did not reveal lethal action. Consequently, the removal procedure of molecular sulfur was proper for applying on the fraction contained non-polar and slightly polar compounds.
Glucosylceramide (GlcCer) synthase acts on the sphingolipid, ceramide, to transer a glucose moiety from UDP-glc, thus forming the first member of a large family of glucosphingolipids. Two inhibitors of the enzyme, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) and N-butyldeoxynojirimycin (NBDN), have been found to induce an elevated level of the synthase in MDCK cells. In cells treated with 20 muM PDMP, then assayed for synthase activity under conditions in which the absorbed PDMP was partially diluted out, the assay showed that the enzyme's specific activity had risen considerably in only 1 h and reached a maximum of about three times the control activity within 6 h. Both cycloheximide and actinomycin D, inhibitors of translational and transcriptional protein synthesis, caused much of the synthase activity to disappear in 6 h, presumably because of normal catabolic destruction. However, simultaneous inclusion of PDMP or NBDN in the cell medium slowed the rate of synthase disappearance. L-Cycloserine, which blocked the synthesis of ceramide, nevertheless allowed PDMP to elevate the synthase activity. Thus the inductive effect appears to be due, in part at least, to resistance of the enzyme-inhibitor complex to the normal process of enzyme degradation. Two other inhibitors of GlcCer synthase, more active than PDMP, did not produce detectable induction because they could not be dissociated from the enzyme during the cell washing and diluting steps. Agents that produced a large increase in endogenous cell ceramide level (DL-erythro-PDMP,N-acetylsphingosine, and bacterial sphingomyelinase) also induced an elevated level of GlcCer synthase. The latter two agents did not protect the synthase from catabolism in the presence of cycloheximide. These findings suggest the existence of a second mechanism of enzyme induction, enhanced synthesis of the enzyme due to the increased availability of the enzyme's lipoidal substrate. The possibility is raised that events involving ceramide in cell signalling may be mediated in part by changes in glucosphingolipid levels.
In this paper, we report that an archaebacterium, Haloferax volcanii, cultured in medium containing a large excess of amino acids showed very low levels of rhodamine 123 (RH123), which is a potent substrate for P-glycoprotein and the bacterial multidrug efflux transporter. This low level involved the active efflux of RH123 from the cells. The level of intracellular RH123 was increased and the efflux inhibited by the Ca2+-channel antagonist verapamil and also by various anti-cancer drugs. The efflux transporter was suggested to be ATP-driven. We have previously selected a mutant of H. volcanii with resistance to doxorubicin, by repeatedly culturing cells in 1.5 microM doxorubicin [Miyauchi, Komatsubara and Kamo (1992) Biochim. Biophys. Acta 1110, 144-150]. The acquisition of resistance to doxorubicin involves the active expulsion of lipophilic drugs such as RH123 and doxorubicin. It is notable that the drug spectrum and ATP-dependency of the amino acid-induced efflux transporter resemble those of the efflux transporter induced by doxorubicin.
We describe a patient with acute myeloblastic leukemia (AML) who developed nephrotic syndrome after receiving several courses of chemotherapy, including macrophage-colony-stimulating factor (M-CSF). At the onset of nephrotic syndrome, the patient remained in a hematological remission. A renal biopsy showed diffuse mesangial proliferation with marked glomerular infiltration of macrophages and massive subendothelial and mesangial deposits. After the institution of the combined therapy with corticosteroid, anticoagulant, and dipyridamole, urinary protein excretion was attenuated to less than 1.0 g/day. It should be emphasized that the recurrence of nephrotic syndrome was observed after the following chemotherapy, including M-CSF, whereas the bone marrow still remained completely remitted. In contrast, after the last course of chemotherapy, which did not include M-CSF, urinary protein excretion was not enhanced. Of note is that the renal histology at autopsy showed a remarkable improvement of mesangial hypercellularity with concomitant reduction in the number of glomerular macrophages. These evolutional changes in both proteinuria and glomerular histology suggest a close linkage between the M-CSF treatment and macrophage-related glomerular injury. The possibility can be raised that M-CSF accelerated the underlying renal disease in this case through enhancing macrophage accumulation into the glomerulus, leading to the development of nephrotic syndrome.
OBJECTIVES: The action of mexiletine on diseased myocardium was assessed in reentrant ventricular tachycardia (VT). BACKGROUND: Whether class Ib antiarrhythmic agents exert a preferential action on the central common pathway of reentrant ventricular tachycardia has not yet been studied in humans. METHODS: In 10 consecutive patients (7 with a previous myocardial infarction, 3 with nonischemic disease), VT was induced and entrained with rapid pacing. The orthodromic conduction time was measured from stimulus to the entrained electrogram at the exit from the presumed central common pathway (i.e., the earliest site of activation). Mexiletine at 125 to 250 mg was administered intravenously, and when VT with the same configuration was induced, the study was repeated. The action of mexiletine on the central common pathway was assessed from the changes in VT cycle length and orthodromic conduction time. The effects on QRS complex duration, local conduction time between the exit and the pacing site and duration of the local electrogram were compared between normal and diseased myocardium. RESULTS: Mexiletine prolonged the VT cycle length in all patients, from (mean +/- SD) 316 +/- 30 to 360 +/- 64 ms (mean change 20 +/- 7%, p < 0.001); during entrainment of VT, the orthodromic conduction time was prolonged, from 306 +/- 58 to 367 +/- 89 ms (mean change 18 +/- 9%, p < 0.001). These changes were highly correlated (r = 0.95, p < 0.001). QRS duration changed little (4 +/- 3%), and local conduction time showed no change. The duration of the fragmented electrogram width was prolonged by mexiletine: from 146 +/- 50 to 176 +/- 56 ms (mean change 23 +/- 8% during VT, p < 0.001). Only a slight change occurred in the effective refractory period, both at the pacing site and at the exit. CONCLUSIONS: Mexiletine caused little change in conduction time in normal myocardium but prolonged VT cycle length, orthodromic conduction time and duration of the local electrogram at the earliest site of activation of VT. From these findings, a preferential action of mexiletine on diseased myocardium was suggested but seemed to occur only at higher frequencies during tachycardia.
Jak3 is a member of the Janus kinase family which plays an important role in cytokine signal transduction. Jak3 associates the gamma(c) chain of receptors for IL-2, IL-4, IL-7, IL-9 and IL-15, and is essential for the signal transduction of these cytokines. We have isolated Jak3 kinase from renal mesangial cells and demonstrated the constitutive expression of Jak3 in glomeruli in vivo. To investigate the physiological and pathological role of Jak3 in glomeruli, we prepared anti-Jak3 antibody and analysed the localization of Jak3 in glomeruli of renal biopsy samples from various nephritis patients and normal subjects. Among 61 nephritis patients and four normal subjects investigated in the present study, Jak3 was selectively localized to glomerular epithelia of IgA-N patients (14/34 cases) and focal glomerulosclerosis patients (1/5 cases), but not detected in minimal changes (n = 6), membranous glomerulonephropathy (n = 7), crescentic glomerulonephritis (n = 4), lupus nephritis patients (n = 5), and normal subjects (n = 4). The intense immunoreactivity for Jak3 is significantly associated with the decrease in creatinine clearance (81.5 +/- 10.4 ml/min versus 104.3 +/- 29.6 ml/min; P < 0.05, Student's t-test) and the increase in level of serum creatinine (1.13 +/- 0.33 mg/dl versus 0.75 +/- 0.23 mg/dl; P < 0.01, Student's t-test) in IgA-N patients. Furthermore, gamma(c) chain was concomitantly expressed with Jak3 in glomerular epithelia in vivo and in vitro, suggesting that signal transduction via gamma(c)-Jak3 cascade may be involved in the pathogenesis of glomerular injury of IgA-N. Taken together with the recent findings that IL-4-secreting T lymphocytes in affected glomeruli injure glomerular epithelium, the responsiveness of glomerular epithelium for IL-4 may be pathologically enhanced in IgA-N.
In this study, we examined the effects of macrophage-colony stimulating factor (M-CSF) on glomerular macrophages in lipopolysaccharide (LPS)-induced murine nephritis. Mice injected intraperitoneally with either M-CSF plus LPS, LPS alone, M-CSF alone or saline every day for 8 days were examined for the degree of urine albumin excretion and lymphocyte-function associated antigen-1-positive (LFA-1+) cells in peripheral blood as well as renal pathology. From our results, LPS or M-CSF combined with LPS emphasized the degree of proteinuria, glomerular deposition of immunoglobulins and mesangial proliferation, associated with accumulation of macrophages in the glomeruli. However, in immunohistological examination of kidneys from these nephritic mice, neither intercellular adhesion molecule-1 (ICAM-1), which may play an important role in the recruitment of macrophages into glomeruli, M-CSF receptor nor the number of LFA-1+ cells in peripheral blood was enhanced by M-CSF. On the other hand, M-CSF alone induced neither proteinuria nor any pathological changes and did not increase the number of glomerular Mac-1+ cells above that in saline-treated controls. These results indicate that M-CSF does not directly cause glomerulonephritis but might participate in accelerating the glomerular inflammatory process by stimulating a potent chemoattractant to recruit monocytes-macrophages into the glomeruli.
OBJECTIVE: Monomorphic sustained ventricular tachycardia (VT) can often be entrained and interrupted at a critical paced cycle length. The aim was to evaluate a possible determinant of this phenomenon by observing the action of mexiletine on the critical paced cycle length and other variables. METHODS: Nine consecutive patients with symptomatic VT were studied. After induction of VT, the area of slow conduction was mapped as the earliest site of the activation or the site with mid-diastolic potential during the tachycardia. Rapid pacing was performed at a site distant from the tachycardia circuit to entrain the tachycardia, starting at a cycle length 10-20 ms shorter than the VT cycle length, and repeated after a decrement of the cycle length in steps of 10 ms to obtain the longest paced cycle length that interrupted the tachycardia: the block cycle length. The effective refractory period (ERP) was measured at the pacing site at which the myocardium was presumed to be normal and also in the area of slow conduction. The effects of mexiletine on the cycle length of VT, the block cycle length, and the ERP at two sites were obtained before and after mexiletine administration. The relation between the cycle length of VT and block cycle length and their changes were also analysed. RESULTS: 11 VTs with the same morphology were induced before and after mexiletine administration. The VT cycle length was prolonged by mexiletine from 309 (SD 53) to 361 (47) ms, and it was interrupted at block cycle lengths of 247 (37) and 307 (41) ms, respectively, the changes being 18 (12)% and 23 (8)% (both P < 0.001). All VTs were entrained, and during pacing at the block cycle length there was abrupt loss of fusion and change in the presystolic electrogram, always associated with interruption of VT on cessation of rapid pacing. A good correlation was observed between the VT cycle length and the block cycle length (r = 0.77 to 0.80). The ERP at the pacing site (normal myocardium) and in the area of slow conduction showed no significant change: 241 (21) v 240 (22) ms and 262 (9) v 252 (9) ms, respectively. The block cycle length was longer than the ERP after mexiletine administration: 362 (55) v 252 (9) ms (P < 0.02). CONCLUSIONS: Mexiletine prolonged the cycle length of VT and the VT-interrupting critical cycle length but not the ERP. The prolongation of the VT cycle length and the block cycle length by mexiletine seemed to be unrelated to the action potential duration, but related to depressed intercellular conduction.
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A high plasma concentration of lipoprotein(a) [Lp(a)] has been suggested as a risk factor for coronary heart disease (CHD), but some recent prospective studies have questioned the significance of Lp(a). Lp(a) concentrations are determined to a large extent by the hypervariable apo(a) gene locus on chromosome 6q2.7, which contains a variable number of identical tandemly arranged transcribed kringle IV type 2 repeats. The number of these repeats correlates inversely with plasma Lp(a) concentration. We analyzed whether apo(a) gene variation (kringle IV repeat number) is associated with CHD. Apo(a) genotypes were determined by pulsed-field gel electrophoresis/genomic blotting in CHD patients who had undergone angiography (n = 69) and control subjects matched for age, sex, and ethnicity (n = 69) and were related to Lp(a) concentration, apo(a) isoform in plasma, and disease status. Apo(a) alleles with a low kringle IV copy number ( < 22) and high Lp(a) concentration were significantly more frequent in the CHD group (P < .001), whereas large nonexpressed alleles were more frequent in control subjects. The odds ratio for CHD increased continuously with a decreasing number of kringle IV repeats and ranged from 0.3 in individuals with > 25 kringle IV repeats on both alleles to 4.6 in those with < 20 repeats on at least one allele. This provides direct genetic evidence that variation at the apo(a) gene locus, which determines Lp(a) levels, is also a determinant of CHD risk.
In the isolated guinea pig aorta, the prostaglandin I2 analog iloprost (0.01-10 microM) inhibited the contractions induced by the thromboxane A2 analog U46619 (9,11-dideoxy-11 alpha,9 alpha-epoxymethanoprostaglandin F2 alpha; 30 nM) and prostaglandin F2 alpha (PGF2 alpha, 1 microM) in a concentration-dependent manner. In contrast, iloprost only partially inhibited the high K+ (65.4 mM)-induced contraction. In the muscle stimulated with high K+, verapamil (0.3 and 10 microM) inhibited [Ca2+]i and muscle tension in parallel, whereas iloprost (1 microM) inhibited muscle tension with only a small decrease in [Ca2+]i. In the muscle stimulated with U46619 (30 nM), verapamil and iloprost decreased both [Ca2+]i and muscle tension. However, as compared with the effect of verapamil, iloprost more strongly inhibited muscle tension than [Ca2+]i. The iloprost (0.1-1 microM)-induced relaxation was accompanied by a concentration-dependent increase in cAMP content. It was further demonstrated that inhibition of the U46619-contractions was augmented in the presence of cycloxygenase inhibitors, such as indomethacin (10 microM), ibuprofen (10 microM) and aspirin (10 microM). In contrast, the inhibition of PGF2 alpha-induced contraction was not affected by indomethacin. Similarly, the inhibitory effect of forskolin on U46619-induced contractions, but not on PGF2 alpha-induced contraction, was enhanced by indomethacin. These results suggest that iloprost inhibits vascular smooth muscle contraction by decreasing [Ca2+]i and the Ca2+ sensitivity of contractile elements through a cAMP-dependent mechanism. The results also suggest that in U46619-stimulated muscle, vasoactive prostaglandins that counterbalance the relaxing action of cAMP may be generated.
This study examined 12 VTs in 8 patients who underwent radiofrequency (RF) catheter ablation for ventricular tachycardia (VT) associated with non-ischemic underlying heart diseases, and who were followed-up for more than 24 months after ablation. The site of VT origin was determined to be within a narrow site (within 1.0 x 1.0 cm) in 5 VTs (4 patients), but VT originated from a wide origin (more than 1.0 x 1.0 cm) in the other 5 VTs (3 patients). The remaining patient had two macroreentrant VTs revolving around an anatomical obstacle in both the clockwise and counterclockwise directions. Two of 5 VTs originating from a narrow site were successfully ablated by 2-3 RF applications. In VT associated with a wide origin, two perpendicular linear RF lesions with 6.0 +/- 1.8 RF applications were required to ablate the VT. Eight of the 12 VTs (66.7%) were finally ablated by RF current (30-50 watts), and they did not recur during the follow-up period of 31.2 +/- 6.5 months. An excellent long-term outcome is expected, even in VT associated with non-ischemic underlying heart disease, if VT is successfully treated by RF ablation.
The most common mechanism of monomorphic sustained ventricular tachycardia (VT) is reentry with an excitable gap, but the electrophysiological properties and response to antiarrhythmic agents in the area of slow conduction are not yet fully known. The conduction time through the area of slow conduction may show a frequency-dependent delay in some VT but in others, constant conduction time was observed as the paced cycle length was decreased while VT was entrained. VT with a so-called decremental property could be terminated more often with rapid pacing with less risk of acceleration of the VT rate. When the excitable gap was estimated by the width of the zone of entrainment: defined as the difference between the cycle length of VT and the longest VT-interrupting paced cycle length during transient entrainment, there was no difference in the width of the zone of entrainment between the responders (VT induction was prevented with drugs) and the non-responders (VT remained inducible). The cycle length of VT was not a predictor of drug-efficacy. However, when the drug-effect was assessed at the intermediate doses, VT of those with a significantly narrowed width of the zone of entrainment were subsequently suppressed when the same drug was added. In conclusion, the electrophysiological properties of the area is diverse and it might affect pacing-induced terminability. Whether an antiarrhythmic agent is able to prevent VT-induction or not can not be predicted from the basal electrophysiologic parameters, but a significant narrowing of the width of the zone of entrainment, and hence the excitable gap, can be a hallmark for drug-efficacy.
We report here a rare case of 47 XXY/46 XY mosaic Klinefelter's syndrome associated with multiple endocrine disorders. A 35-year-old male admitted for the evaluation of renal dysfunction and recurrent bone fractures was diagnosed as having Klinefelter's syndrome by endocrinological examinations and sex chromosome analysis. He has suffered from diabetes mellitus for more than ten years. The serum FSH and LH levels were high together with low free testosterone and estradiol levels. There was a discrepancy between basal serum GH and somatomedin-C levels. On admission, thyroid function revealed thyrotoxicosis with low radioactive iodine uptake and negative thyroid autoantibodies. During hospitalization, serum FT3 and FT4 levels were gradually decreased and serum TSH levels became elevated, leading to the diagnosis of subacute thyroiditis. Serum ACTH levels showed high basal levels with delayed, exaggerated responses to insulin-induced hypoglycemia. Rapid ACTH test (1-24ACTH 0.25 mg) showed low cortisol responses and many of the adrenocortical steroids in plasma and urine were low or low normal. Furthermore, bone mineral density (BMD) by DEXA showed marked osteoporosis. Possible mechanisms underlying these varied endocrine disorders remain to be elucidated.
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