Effect of manidipine on balloon catheter-induced arterial smooth muscle cell proliferation in spontaneously diabetic GK rats.

The inhibitory effect of manidipine, a long acting calcium channel blocker, on vascular smooth muscle cell proliferation was investigated in spontaneously diabetic GK rats with balloon catheter-induced denudation of the carotid artery. Treatment with manidipine at doses of 4.6 and 15.1 mg/kg/day inhibited thickening of the neo-intima in the balloon catheter-injured artery without any effect on blood pressure and lowered the ratio of intima to wall areas and wall to total vascular areas in a dose-dependent fashion. These results suggest that manidipine inhibits an abnormal proliferation of the intima in the carotid artery of spontaneously diabetic rats.


Neurotrophic effects of epidermal growth factor on cultured brain neurons are blocked by protein kinase inhibitors.

The influences of protein kinase inhibitors, K-252a and staurosporine, on the neurotrophic effects of epidermal growth factor (EGF) were investigated in dissociated cell cultures of the hippocampus and cerebellum of fetal rats. Addition of 1 ng/ml EGF enhanced the survival of cultured neurons of both brain regions. Both K-252a (10-200 nM) and staurosporine (1-100 nM) blocked the survival-promoting effects of EGF in a concentration-dependent manner. These results suggest that activation of protein kinase(s) is involved in the neurotrophic effects of EGF.


Preventive actions of N-(3-aminopropionyl)-L-histidinato zinc (Z-103) through increases in the activities of oxygen-derived free radical scavenging enzymes in the gastric mucosa on ethanol-induced gastric mucosal damage in rats.

Z-103 at 1 to 25 mg/kg, p.o. prevented 100% ethanol-induced gastric mucosal lesions in a dose-dependent manner. Z-103 at 3 to 25 mg/kg, p.o. significantly elevated gastric mucosal superoxide dismutase (SOD)-like activity 1 hr after its administration to normal rats. In addition, Z-103 at doses (10 and 25 mg/kg, p.o.) which prevented 100% ethanol-induced gastric lesion further increased gastric mucosal SOD-like and glutathione peroxidase (GSH-px) activities elevated by 60% ethanol. Z-103 (10 and 25 mg/kg) significantly inhibited the increase in thiobarbituric acid-reactive substances in gastric mucosa injured by 60% ethanol. The combination with cycloheximide, a protein synthesis inhibitor, completely abolished the prevention of 60% ethanol-induced gastric mucosal lesions and the elevation of both free radical scavenging enzyme activities in the mucosa by Z-103 (10 mg/kg, p.o.). These results suggest that Z-103 may partly protect rat gastric mucosa against ethanol-induced damage by scavenging oxygen-derived free radicals via increases in the synthesis of SOD-like and GSH-px enzymes in the mucosa.


Ca2+ influx induced by the agonist U46619 is inhibited by hyperpolarization induced by the K+ channel opener cromakalim in canine coronary artery.

The fura-2 microscopic fluorimetric method was used to examine the effects of the thromboxane A2 analogue, U46619, on the force of contraction and intracellular calcium concentrations ([Ca2+]i) in canine coronary arteries. Upon cumulative application, U46619 increased [Ca2+]i and force. Depolarization by 20 mM KCl potentiated the increase in [Ca2+]i and increased the maximum force induced by U46619. In 5 mM KCl-PSS, the reduction of resting [Ca2+]i by cromakalim (3 x 10(-6) M) was greater than that by verapamil (3 x 10(-6) M). Cromakalim and verapamil inhibited the increases in [Ca2+]i and force induced by U46619 in 5 mM KCl-PSS. In 90 mM KCl-PSS in the presence of U46619, verapamil inhibited the increases in [Ca2+]i and force, whereas cromakalim did not inhibit them at all. The inhibitory effect of cromakalim was counteracted by depolarization by 20 or 25 mM KCl. Curves in the presence of U46619 which related force to [Ca2+]i were shifted to the left compared with that in the absence of U46619, suggesting that U46619 increases the Ca(2+)-sensitivity of the contractile proteins. Thus, U46619 produces Ca2+ influx through L-type Ca2+ channels, which are deactivated by hyperpolarization induced by cromakalim.


Hypolipidemic effect of ethyl all-cis-5,8,11,14,17-eicosapentaenoate (EPA-E) in rats.

We examined the effect of ethyl all-cis-5,8,11,14,17-eicosapentaenoate (EPA-E) with high purity on circulating lipids in rats under several experimental conditions. In normolipidemic rats, EPA-E decreased the lipids in a dose-dependent manner. Clofibrate (100 mg/kg/day) was more potent in lowering the lipids than EPA-E (1000 mg/kg/day). In high cholesterol diet-fed rats, EPA-E (300 mg/kg/day) decreased the total cholesterol. However, clofibrate (300 mg/kg/day) had little effect on the total cholesterol. In hypertriglycemic rats induced by corn oil, EPA-E (300 mg/kg/day) or clofibrate (100 mg/kg/day) reduced the rise of triglycerides. EPA-E (300 mg/kg/day), clinofibrate (100 mg/kg/day) or clofibrate (300 mg/kg/day) caused a significant reduction in the lipids induced by the injection of Triton WR-1339. Furthermore, EPA-E (300 mg/kg/day) or clinofibrate (100 mg/kg/day) decreased the elevation of lipids produced by feeding the rats a casein-rich diet. These results show that EPA-E possesses potent inhibitory activity on experimental hyperlipidemia induced either exogenously or endogenously.


Impairment of endothelium-dependent relaxation in aorta from rats with arteriosclerosis induced by excess vitamin D and a high-cholesterol diet.

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.


Protective effects of arbaprostil against indomethacin-induced gastric lesions in rats: significance of maintained gastric blood flow.

The purpose of the present study was to investigate the relationship between the effects of 15(R)-15-methylprostaglandin E2 (arbaprostil) on gastric blood flow (GBF) and its protective effects on gastric lesions in rats. The GBF of anesthetized rats was measured by two different methods: Total blood flow into the stomach (total GBF) was determined by means of an ultrasonic pulsed Doppler flow meter; and gastric mucosal blood flow (mucosal GBF) was measured by nonradioactive microspheres. Systemic blood pressure (SBP), heart rate (HR) and gastric vascular resistance (GVR) were recorded simultaneously. Arbaprostil (10-100 micrograms/kg) given i.v. did not affect resting total or mucosal GBF even though it decreased SBP and GVR. Significant improvement of the total and mucosal GBF decreased by indomethacin pretreatment (10 mg/kg, i.v.) was observed by administration of arbaprostil (10-100 micrograms/kg, i.v.) in a dose-dependent manner. Furthermore, i.v.-administration of this agent, in the same dose-range, prevented the formation of gastric lesions induced by indomethacin. The present result suggests that mitigation for the ischemic state of the gastric mucosa may be one of the important mechanisms for the prophylactic and curative effect of arbaprostil on gastric lesions induced by indomethacin.


Effects of KW-3635, a novel dibenzoxepin derivative of a selective thromboxane A2 antagonist, on human, guinea pig and rat platelets.

We examined the binding of [3H]U-46619, a thromboxane A2 agonist, to human and guinea pig platelets and the binding of [3H]SQ 29,548, a thromboxane A2 antagonist, to human, rat and guinea pig platelets. KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1- benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-c arboxylate monohydrate) concentration-dependently inhibited the [3H]U-46619 binding to human and guinea pig platelets with inhibition constants of 1.2 nM and 2.7 nM, respectively. KW-3635 also potently inhibited the [3H]SQ 29,548 binding to human and guinea pig platelets with inhibition constants of 1.9 nM and 3.2 nM, respectively. In contrast, KW-3635 was less active against thromboxane A2/prostaglandin H2 receptors in rat platelets with an inhibition constant of 97 nM. KW-3635 at 10(-5) M did not antagonize various receptors including prostaglandin E2, prostaglandin I2 and neurotransmitters. In addition, 10(-5) M KW-3635 did not alter the prostaglandin D2-induced cAMP accumulation in EBTr cells. KW-3635 was inactive towards thromboxane synthase, cyclooxygenase and prostaglandin I2 synthase up to 10(-5) M. KW-3635 slightly inhibited 5-lipoxygenase with an IC50 value of 71 microM. These data indicate that KW-3635 is a potent and selective non-prostanoic thromboxane A2 antagonist, and it can recognize the species differences in thromboxane A2/prostaglandin H2 receptors.


Basic fibroblast growth factor ameliorates rotational behavior of substantia nigral-transplanted rats with lesions of the dopaminergic nigrostriatal neurons.

Basic fibroblast growth factor (bFGF) was injected with dissociated substantia nigral cells into the striatum of rats prepared by unilateral lesion of the nigrostriatal pathway with 6-hydroxydopamine. The transplanted cells with 5 and 50 ng bFGF reduced the apomorphine-induced rotations by 40 and 30%, respectively, while the decrement of rotations was only 15% in the grafted control without bFGF. Immunohistochemical staining with anti-tyrosine hydroxylase antibody showed that bFGF also tended to increase the number of grafted catecholaminergic neurons along the tracts. In the case of 50 ng bFGF treatment but not 0 or 5 ng bFGF treatment, however, severe gliosis was detected along the grafted region by staining of anti-glial fibrillary acidic protein antibody. These immunohistochemical studies suggested that high-dose bFGF induced extensive gliosis, which might affect the survival of the grafted neurons.


Regulatory effect of neurotropin on nasal mucosal hypersensitivity in guinea pigs caused by SART (intermittent exposure to cold) stress.

We stated that SART-stressed guinea pigs showing nasal mucosal hypersensitivity would serve as an animal model for the in vivo evaluation of antiallergic drugs. In the present study, the mode of action of Neurotropin on nasal allergy compared with those of antiallergic drugs was studied by using SART-stressed guinea pigs. Daily administrations of Neurotropin improved the methacholine-induced hypersecretion and histamine-evoked sneeze response, which are parameters of nasal mucosal hypersensitivity, and increased the density of muscarinic ACh receptors located on the nasal mucosa caused by SART stress. In addition, the inhibitory action on nasal secretion in a passively sensitized model was more intense in SART-stressed guinea pigs than in normal ones. Ketotifen and tranilast were also found to have marked effects on nasal secretion in the passively sensitized SART-stressed model, but only had weak effects on nasal mucosal hypersensitivity. Neurotropin significantly potentiated the action of ketotifen or tranilast. Thus, at least part of the inhibitory effect of Neurotropin on nasal symptoms such as watery secretion and sneezing is thought to have been brought forth through the regulatory action on nasal mucosal hypersensitivity, and its combined use with antiallergic drugs would be a very effective therapeutic regimen for nasal allergy.


Caffeine does not effectively ameliorate, but rather may worsen the ethanol intoxication when assessed by discrete avoidance in mice.

Ethanol disrupted the discrete lever-press and shuttle avoidances in mice at doses over 1.6 and 2.4 g/kg, p.o., respectively, eliciting a dose-dependent decrease in the % of avoidance with no significant change or slight increase in the response rate. Caffeine increased the response rate of both the avoidances at the doses of 1-30 mg/kg, p.o., but disrupted the avoidance at 100 mg/kg. Caffeine (10 mg/kg) reduced the decreased % of avoidance by ethanol (1.6 and 2.4 g/kg) with a significant increase in the response rate. In contrast, the % of avoidance was significantly lower after the combined administration of ethanol (3.2 g/kg) with caffeine than after ethanol (3.2 g/kg) alone. Unlike ethanol, diazepam (2 mg/kg, s.c.) and pentobarbital (10 mg/kg, s.c.) significantly decreased both the response rate and the % of avoidance. Caffeine (10 mg/kg) ameliorated the decreased response rate and the % of avoidance produced by diazepam and pentobarbital. The present results suggest that caffeine does not effectively ameliorate, but rather may worsen the ethanol intoxication.


Anti-stress effect of ginseng on the inhibition of the development of morphine tolerance in stressed mice.

We examined how the ginseng extract (GE) acts on the antinociceptive effect induced by footshock (FS)-, psychological (PSY)- and forced swimming (SW)-stress (stress-induced analgesia, SIA), and also on the suppression by FS- and PSY-stress of the development of tolerance to morphine in mice. Neither an acute treatment nor 5 daily pretreatments with GE at 100 mg/kg, p.o. affected each SIA. Pretreatment with GE at 100 mg/kg, p.o. for 5 days followed by the treatment in combination with the exposure to stresses for another 5 days caused no appreciable changes in the development of tolerance to FS- and SW-SIA, but suppressed the development of tolerance to PSY-SIA. When mice were pretreated with GE for 5 days and given GE daily prior to morphine at 10 mg/kg/day, with stress exposure for another 5 days, the inhibitory effect of FS-stress on the development of tolerance to morphine was completely eliminated. The present results suggest that GE, by improving the general metabolism in the body, directs toward normalization of the adaptability which is impaired by stress exposure, while not compromising morphine antinociceptive activity or the SIA, another adaptability produced in confrontation to abnormal environmental stimuli. In addition, the differences in the mechanism underlying the FS- and PSY-stress effect which we have previously demonstrated are also reconfirmed.


The acyl-CoA synthetase inhibitor triacsin C enhanced eicosanoid release in leukocytes.

Triacsin C was previously reported to inhibit long-chain acyl-CoA synthetase and to reduce the production of acyl-CoA in rat neutrophils dose- and time-dependently. We found that preincubation with triacsin C inhibited the incorporation of labeled arachidonic acid into rat neutrophils. Furthermore, when triacsin C-treated neutrophils were stimulated with the Ca-ionophore A23187, they released an increased amount of eicosanoids into the culture medium. These results indicate that triacsin C suppressed acylation of arachidonic acid, which resulted in an increase in its metabolites.


Nootropic candidates inhibit head-twitches induced by mescaline in mice.

The effects of various nootropic candidates on mescaline-induced head-twitches were studied in mice. The number of head-twitches induced by mescaline (100 mg/kg, s.c.) was significantly reduced by idebenone (32 and 100 mg/kg, i.p.), minaprine (0.32-10 mg/kg, p.o.) and nebracetam (100 mg/kg, p.o.). Cholinesterase inhibitors such as tetrahydroaminoacridine (1 and 10 mg/kg, p.o.), NIK-247 (10 and 18 mg/kg, p.o.) and physostigmine (0.32 mg/kg, i.p.) also suppressed the head-twitch response to mescaline. These results suggest that the direct or indirect cholinergic-activating effects of these drugs may be involved in inhibiting mescaline-induced head-twitches.


Blockade by ginseng extract of the development of reverse tolerance to the ambulation-accelerating effect of methamphetamine in mice.

Daily repeated administration of methamphetamine (MAP) developed reverse tolerance to its ambulation-accelerating effect. After pretreatment of mice daily with ginseng extract (GE) for 5 days, concomitant injections of MAP and GE suppressed the development of reverse tolerance to the effect of MAP, although GE itself did not affect the spontaneous motor activity of the naive mice. These results provide evidence that GE may be useful for prevention and therapy of the adverse action of MAP.


Relationship between density of muscarinic receptors and nasal hypersecretion in a nasal allergic model.

In guinea pigs actively sensitized with ovalbumin, we have observed that nasal hyperreactivity and hypersensitivity to methacholine causes nasal secretion accompanied by an increase in the density of muscarinic acetylcholine receptor (m-ACh.R) following the appearance of nasal symptoms induced by the ovalbumin challenge. Therefore in the present investigation, we studied the relationship between the density of m-ACh.R and nasal hypersecretion in actively sensitized guinea pigs. There was no relationship between the quantity of nasal secretion and serum Ig G1 or Ig E levels. On the other hand, the sensitivity to methacholine and nasal secretion induced by methacholine were significantly related to the density of m-ACh.R located on the nasal mucosa. The quantity of nasal secretion induced by allergen was also correlated significantly to the density of m-ACh.R. These results suggest that the nasal hypersecretion observed in the nasal allergic model may be closely associated with an increase in the density of m-ACh.R located on the nasal mucosa.


Effects of naloxone and levallorphan on the spinal cord reflex potentials under the spinal ischemic condition in cats.

The spinal reflex potentials elicited by electrical stimulation of the tibial nerve were recorded from the lumbo-sacral ventral root in spinal cats. When the thoracic aorta and the bilateral internal mammary arteries were occluded for 10 min, the potentials were completely depressed. Reappearance of these potentials could be observed at about 10 min after removal of the occlusion and they gradually recovered. Intravenous injection of naloxone (1 or 10 mg/kg) or levallorphan (0.1 mg/kg) together with removal of occlusion significantly promoted the recovery of the polysynaptic reflex potential. Morphine (5 mg/kg) showed no particular effect on the recovery of potentials. Furthermore, pretreatment with morphine (5 mg/kg) did not influence the effects of these opioid antagonists. These results suggest that naloxone and levallorphan may preserve or potentiate the interneuronal activities of the lumbo-sacral spinal cord under the ischemic condition and that the effects may not be mediated through morphine-like opioid receptors.


Tolerance to the convulsions induced by daily nicotine treatment in rats.

Development of tolerance to the nicotine-induced convulsions in rats was examined. Acute intraperitoneal (i.p.) administration of nicotine (2.5, 3.75 and 5 mg/kg) produced convulsions in a dose-dependent manner. Mecamylamine (1 mg/kg, i.p.) antagonized the convulsions, but hexamethonium (5 mg/kg, i.p.) did not modify them. Daily nicotine administration (2.5, 3.75 and 5 mg/kg, i.p.) once a day for 6 days developed tolerance to the convulsions induced by nicotine. After the daily administrations of nicotine for 6 days, the effects of a challenge administration of nicotine (2 mg/kg) on the nicotine-induced convulsions were tested on the 7th-day. Further tolerances were also developed by the 7th-day challenge administration. After the 7th-day test, nicotine levels of the brain and blood 15 min after the challenge injection were measured. With nicotine (5 mg/kg once a day)-treatment, nicotine levels of all the brain regions were increased. In contrast, a similar challenge injection had no effect on blood nicotine level. These results indicate that the development of tolerance to the nicotine-induced convulsions is produced relatively earlier and day by day by daily administrations to rats, which is closely related with the increase in brain nicotine level.


Protective effect of benidipine against the development of glomerular sclerosis in experimental nephrotic syndrome.

An experimental focal segmental glomerular sclerosis (FSGS) was induced by the combined administration of puromycin aminonucleoside (PAN) and protamine sulfate (PS). Blood collections were made on days 0, 37, 70 and 94. Urine collections were made on days 0, 24, 80 and 94. Vehicle-treated rats showed severe proteinuria and an increase in serum total cholesterol (sTC). Benidipine (1 or 3 mg/kg, p.o.)-treated rats exhibited less proteinuria and lower sTC than the vehicle-treated rats. On days 70 and 94, both blood urea nitrogen (BUN) and serum creatinine (sCR) values in the vehicle-treated rats were significantly higher than those in normal rats (without treatment with PAN and PS). On the other hand, the treatment with benidipine (1 or 3 mg/kg, p.o.) attenuated the increases in BUN and sCR. On day 94, vehicle-treated rats showed a significant decrease in creatinine clearance as compared with normal rats, but benidipine (1 or 3 mg/kg, p.o.)-treated rats did not. The histology was examined on day 94. Vehicle-treated rats demonstrated a significantly greater percentage of glomeruli with segmental areas of glomerulosclerosis/hyalinosis, mesangial cell proliferation, and mesangial foam cell. Benidipine (3 mg/kg, p.o.) ameliorated the development of renal regeneration as estimated by histological examination. These results suggest that the Ca-channel blocker benidipine is a favorable drug for preventing the progression of glomerular sclerosis.


Antitumor activity of two novel low immunosuppressive fluoropyrimidines UK-21 and UK-25.

We have previously reported that 2',3',5'-tris-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (UK-21), a derivative of 5-fluorouridine (5-FUR), and 1-(6-[N-(2-n-propyl-n-pentanoyl)-glycyl]amino-n-hexylcarbamoyl)-5- fluorouracil (UK-25), a derivative of 5-fluorouracil (5-FU), exert their antitumor activity in mice bearing Meth A or EL4 tumor, while their immunosuppressive effects are mild. In the present study, we examined the effects of these compounds on Sarcoma-180 (S-180), P388, L1210, and Lewis lung carcinoma (LLC) in mice by p.o. administration and i.p.-administration. UK-21 given p.o. showed an antitumor effect against S-180, but it showed virtually no antitumor effects against P388, L1210 and LLC. UK-21 given i.p., on the other hand, strongly inhibited the growth of Meth A tumor at a far lower dose than that for oral administration. The bioavailability of UK-21 given p.o. was suspected to be poor. UK-25 given p.o., in contrast, showed the antitumor effect on all of the tumors employed. The bioavailability of UK-25 given p.o. seemed to be comparable to those of other drugs. These results suggest that UK-21 has the potential for development as a parenterally applicable anticancer drug, and UK-25 has the potential as an oral one.


Protective effects of antioxidants on paraquat-induced acute renal failure in mice.

The protective effects of antioxidants against elevated blood urea nitrogen (BUN) were studied in newly developed acute renal failure in mice induced by paraquat. The administration of paraquat caused marked azotemia accompanied by a decreased glomerular filtration rate. In contrast, elevated BUN was significantly reduced by the preadministration of either dimethylthiourea, deferoxamine or alpha-tocopherol. These data suggest that acute renal failure induced by paraquat is mainly related to the hydroxyl radicals produced via the iron-catalyzed Haber-Weiss reaction.


Characterization of subtype of propylbenzilylcholine mustard (PrBCM)-sensitive and -resistant muscarinic cholinoceptors in guinea pig ileal muscle.

The subtype of propylbenzilylcholine mustard (PrBCM)-sensitive and -resistant muscarinic cholinoceptors in guinea pig ileal muscle was examined using four selective muscarinic antagonists, pirenzepine, AF-DX 116, himbacine and 4-DAMP. The pA2 values of the four antagonists against pilocarpine were not different from their values against carbachol after the treatment with PrBCM and was identified with the values for the m3 subtype. These results suggest that the subtype of PrBCM-sensitive and -resistant muscarinic cholinoceptors in guinea pig ileal muscle is the m3 subtype only and not other subtypes.


Effects of nitric oxide-related compounds and carperitide on hemodynamics and hematocrit in anesthetized rats.

Sodium nitroprusside, nitroglycerin and carperitide (alpha-human ANP) all reduced mean blood pressure, but only carperitide increased the hematocrit in rats with bilateral renal artery- and ureter-ligation. NG-Monomethyl-L-arginine, a selective inhibitor of nitric oxide synthesis, elevated the mean blood pressure but did not change the hematocrit significantly. These findings suggest that ANP has a physiological role in regulating circulatory blood volume distinct from that of NO, although both increase intracellular cyclic GMP in the vasculature.


Inhibitory effect of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (SA3443), a novel cyclic disulfide, on the production of TNF-like factor from Propionibacterium acnes-primed rat liver macrophages/Kupffer cells.

The effect of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-dithiazocine-4-carboxylic acid (SA3443), a novel cyclic disulfide, on tumor necrosis factor (TNF)-like factor production from Propionibacterium acnes (P. acnes)-primed rat liver macrophages/Kupffer cells was investigated. A remarkable increase in TNF-like activity was detected in the culture supernatants of the liver macrophages/Kupffer cells from P. acnes-treated rats. At concentrations of 1 x 10(-6) to 1 x 10(-4) M, SA3443 significantly inhibited the production/release of TNF-like factor from these P. acnes-primed/activated liver macrophages/Kupffer cells.


The seizure prognosis of juvenile myoclonic epilepsy.

Thirty-two patients with juvenile myoclonic epilepsy (JME) were studied to evaluate the seizure prognosis. The response to antiepileptic drugs was excellent in 68%, but the patients, who had much more focal discharges on EEG and were sensitive to neuropsychological EEG activations at the beginning of treatment, had an unfavorable outcome. A combination of absence seizure alone resulted in the excellent prognosis for both absence and myoclonic seizures, and a combination of generalized tonic-clonic seizure on awakening related to rare myoclonic seizures. These findings suggest that the outcome of JME would be predicted by the EEG abnormality and the combination of the other types of seizures, which are probably determined by the pathophysiology at the beginning of treatment.


Long-term course of childhood epilepsy with intractable grand mal seizures.

Twenty-nine children with childhood epilepsy characterized by frequent grand mal (generalized tonic-clonic) seizures in spite of maximal doses of antiepileptic drugs and by an early onset of seizures (before 1 year of age) were followed up for more than 5 years. The children were divided into 3 groups: severe myoclonic epilepsy in infancy (SME), no SME, and intractable childhood epilepsy with generalized tonic-clonic seizures (GTC). In all the 3 groups, the grand mal seizures persisted, whereas the other types of seizures tended to disappear as the patients aged, and the prognosis for mental development was poor. In the majority of cases in all the 3 groups, the waking grand mal seizures altered to sleep grand mal seizures with aging. Two pairs of monozygotic twins with SME suggested that genetic factors play a role in this epileptic syndrome. Intractable childhood epilepsy with GTC is distinguished by the absence of other types of generalized seizures. It cannot be regarded as an epileptic syndrome, but its pathogenesis and treatment require further studies.


A long-term follow-up study of first episodes of idiopathic status convulsivus in childhood: in relation to subsequent epilepsy (second report).

Fifty-four idiopathic status convulsivus (SC) cases were followed prospectively for a period between 5 and 21 years, the average being 13 years. Three-fourths of the cases had no residuals. There were two patterns of subsequent epilepsy; 1) complex partial seizures (CPS) with or without secondarily generalization (GTS) developed 4.3 +/- 3.5 years after febrile SC, 2) unilateral seizures or CPS +/- GTS developed 1.2 +/- 1.0 years after afebrile SC. The seizure prognosis of these cases was good except for some cases in the former group. There have been two kinds of theories regarding SC and epilepsy until now. One was derived from retrospective studies: SC and/or complex febrile convulsion (FC) were considered the main causes of temporal lobe epilepsy (TLE) producing mesial temporal sclerosis (MTS). Another was derived from prospective studies, in which the relation between FC and TLE was considered weak. Our results revealed that 6 cases (15%) out of 30 febrile SC developed epilepsy, and that five of those six cases were diagnosed as CPS. Three of 5 CPS cases were diagnosed as TLE. Recently the seizure prognosis of operative therapy for TLE--especially the MTS type--has been very favorable. Furthermore, it has become easy to find MTS by Magnetic Resonance Imaging (MRI). So, we emphasize that a precise follow-up study of SC using MRI, EEG, etc., is important in deciding the appropriate therapy for TLE, as well as in the study of the pathogenesis of TLE.


Conditions for omitting invasive long-term monitoring before surgical resection in patients with temporal lobe epilepsy.

The omission of invasive long-term monitoring before surgical resection in patients with epilepsy should be permitted only for those in whom the epileptogenic focus is presumed to localize unilaterally in the mesial aspect of the temporal lobe. The localization may well be confirmed through noninvasive measures. Retrospective analyses of data obtained from noninvasive investigations (scalp-recorded and sphenoidal EEGs, neuroimages, and electroclinical seizure manifestations) were carried out in 58 patients. The localization of their epileptogenic focus was subsequently confirmed by the implantation of both intracerebral and subdural electrodes; the focus had an amygdalohippocampal origin in 41 patients and a lateral temporal origin in 17 patients. From the comparison of noninvasive findings between these two groups, we propose the following indispensable conditions for omitting an invasive evaluation: 1. Appearance of focal epileptic discharges unilaterally in the sphenoidal lead observed during the simple phase of partial seizures, or unilateral discharges with predominancy in the sphenoidal lead during the early phase of complex partial seizures. 2. Interictal spikes on scalp-recorded EEGs localizing unilaterally in the anterior region of the temporal lobe, and if bilaterally independent, presenting with unilateral predominancy in a ratio of greater than 4:1. 3. Presence of autonomic signs in the initial phase of signal symptoms. 4. Neuroimaging findings in the mesial temporal region: elongated T2 on MRI and hippocampal atrophy, or a tumorous lesion. The lateralization conforms to interictal and ictal paroxysmal EEG findings. There were 8 patients with seizure of amygdalohippocampal origin who satisfied all the indispensable condition, but not a single patient with seizures of lateral temporal origin.(ABSTRACT TRUNCATED AT 250 WORDS)


Surgical treatment for convexity focal epilepsy.

Fifty-four cases with intractable convexity focal epilepsy were analyzed with regard to surgical treatment. To acquire satisfactory results, preoperative precise localization of focus and selection of relevant operative methods are indicated.


Neuropsychological evaluation before and after surgical treatment of temporal lobe epilepsy.

We present the results of pre- and postoperative neuropsychological evaluations of 58 patients with temporal lobe epilepsy who underwent a chronic intracranial EEG monitoring and a subsequent standard anterior temporal lobectomy. Wada's test provided valuable information on the speech dominant side and on the focus localization. Some warning signs as well as verbal automatisms indicated the effect for focus localization and lateralization. The results of interictal neuropsychological tests suggested that each subgroup of TLE performed differently. A postoperative neuropsychological performance has improved in many tests that may be explained by the diminished epileptic bombardment resulting from the resection.


The effect of hypoxia on the epileptiform activities induced by magnesium-free medium in rat brain slices.

In order to understand the mechanisms underlying the seizure generation, the present study has investigated the effect of hypoxia on the transition between seizure and interictal bursting. Bathing rat brain slices of the hippocampus and entorhinal cortex in magnesium-free medium elicits electrographic seizures. However, they are eventually replaced by the interictal bursts. It has previously been shown that the interictal bursts, arising in the hippocampal area CA3, are propagated to and disrupt the seizure generation in the entorhinal cortex. In this report we demonstrate that hypoxia promotes the seizure reappearance in the entorhinal cortex by suppressing the interictal bursts in CA3.


Temporal lobe CO2 vasoreactivity in patients with complex partial seizures.

The topography of CO2 vasoreactivity during hyperventilation in 8 patients with complex partial seizure (CPS) was visualized using the regional cerebral blood flow (rCBF) as measured by H(2)15O-PET (positron emission tomography) and compared with that of 10 normal volunteers. In the normal volunteers, the vascular response to CO2 (VrCO2 = delta CBF%/delta PaCO2) in the temporal lobe was 2.46 +/- 0.56 (%/mmHg). In the patients with CPS, VrCO2 in the temporal lobe of the affected side was 2.08 +/- 0.40 (%/mmHg), while VrCO2 on the contralateral side was 2.30 +/- 0.46 (%/mmHg). There was a significant difference in VrCO2 between the affected side of the temporal lobes and the temporal lobes of the normal volunteers. Furthermore, there was a tendency for VrCO2 to be lower in the affected than in the contralateral side of the temporal lobe in patients with CPS. As CO2 is the main regulator of CBF, this impaired vasoreactivity may reflect the brain dysfunction in the seizure focus and adjacent areas.


Can we predict carbamazepine responsiveness in partial epilepsy?

We studied 153 patients with partial epilepsy who were placed on a carbamazepine monotherapy plan in order to evaluate the clinical factors that may determine drug responsiveness to carbamazepine. The subjects were divided into 3 groups based on their therapeutic outcome--complete seizure control (44%), significant seizure reduction (32%) and unsatisfactory control (24%). Fifteen tentative clinical factors were examined in relation to the therapeutic outcomes. Factors such as seizure type, number of generalized tonic-clonic seizures, age of onset, duration of illness, seizure frequency, previous treatment and EEG finding were relevant to drug responsiveness. However, other variables including mental retardation, etiology, febrile convulsion, positive family history and abnormal neurologic examination showed no significant correlation. Our data suggest that a potential success of carbamazepine treatment should not be underestimated even in patients with complicated clinical features.


Sleep grand mal--all-night polygraphic EEG recordings in 20 cases.

All-night polygraphic EEG recordings were carried out in 20 epileptic patients who are characterized as follows; 1) clinical attacks took the form of generalized tonic-clonic seizure (GTCS), which occurred only or at least 90% during sleep without other seizure types in awakening, 2) no epileptic discharges were revealed in routine EEG examinations, also including sphenoidal electrode deriving during daytime, 3) recognizable organic brain damage in these patients had been excluded by neurological examinations and CT-scan. Interictal records showed epileptiform abnormalities in 5 of the 20 patients, which were all related with NREM sleep. Four patients exhibited bilateral synchronous paroxysms of 3-3.5 Hz spike-wave short burst and only one patient had temporal-localized discharges. The results of this study demonstrated that although there was a difference compared with other reports, the most characteristic features seen in our patients diagnosed as idiopathic generalized epilepsy (IGE) were as follows: 1) less frequent SGM seizures within a year, 2) SZ onset around teen age, 3) seizures were easily evoked by some precipitating factors and 4) no recognizable organic lesions. As a conclusion, patients with an uncertain or unknown type of epilepsy should always be examined with sleep recordings and all-night sleep recordings if necessary.


A preliminary observation on auto-cholinergic synapse dysfunction in patients with different types of epilepsy.

Serum anti-acetylcholine receptor antibodies (A AchR Ab) and anti-synaptic premembrane antibodies (A PrM Ab) were measured in 21 patients with absence epilepsy, 21 cases with benign childhood epilepsy with centro-temporal spikes (BCECTs) and 13 cases with atypical epilepsy. Respectively, in five (23.8%), eleven (51.2%) and eight (66.7%) of the above mentioned groups of patients both A AchR Ab and A PrM Ab were found.


Status of follow-up among patients with epilepsy in epilepsy clinic.

Out of 238 consecutive patients entering our epilepsy clinic from October 1988 till March 1990, the status of follow-up was evaluated in October 1990. One hundred patients (42%) could adhere to the follow-up appointment and 33 patients (14%) visited the clinic irregularly. A total of 105 patients (44%) failed to return for the follow-up at least for 2 months dated backward from October 1990. Seventy-five percent of the patients lost the follow-up within 6 months. The main reasons of the dropout were poor seizure control, seizure free, denial of epilepsy, receiving operation in other hospitals. The appropriate strategies to aid in adherence to medical care among patients with epilepsy should be formulated through the analysis of factors contributing to the dropout, which might be strongly influenced by different medical and sociocultural backgrounds all over the world.


Forceps delivery as a risk factor in epilepsy: some further observations.

A total of 381 children born with forceps delivery and 372 with normal delivery were followed up for 4-7 years. More children in the forceps group developed seizures than in the normal group, i.e. 22:10. This was statistically significant (P < 0.05). There was no neurological deficit in any child who had seizures. Both partial and generalized seizures were seen but partial seizures were more frequent.


Long-term effectiveness of antiepileptic drug treatment and seizure recurrence in patients with epilepsy.

We studied the rate of seizure recurrence in 334 patients with epilepsy who had received antiepileptic drug (AED) therapy for at least eight years. During the three-year "observation period" (April 1985-March 1988), 163 or 48.8% of the 334 patients were considered to be seizure-free. Seizures were absent in 53 or 81.5% of 65 patients with idiopathic generalized epilepsy, 48 or 40% of 120 with temporal lobe epilepsy, 39 or 39.4% of 99 with partial epilepsy other than those involving the temporal lobe, 2 or 8.3% of 24 with symptomatic generalized epilepsy and 21 or 80.8% of 26 with other epilepsies. Of the 163 patients, 15 or 9.2% suffered seizure(s) during the three-year "follow-up period" (April 1988-March 1991). There was no difference among the different types of epilepsy with respect to seizure recurrence rates. Compared with the 15 patients whose seizures recurred, more of the 148 patients with nonrecurring seizures received AED monotherapy (p < 0.05). However, no significant differences were seen between the two groups for other background factors.


Behavior and EEG changes of unanesthetized cats after kainic acid injection into unilateral caudate nucleus.

1. The microinjection of KA into the unilateral caudate nucleus induces secondarily generalized seizure. 2. The caudate nucleus considered to be one of the important relay structures in the generalization of epilepsy. 3. In this model of caudate nucleus epilepsy, cats did not show spontaneous seizure or choreic movement in the chronic stage.


[The mechanism and specificity of IL-1 inhibitory factor released from human alveolar macrophages].

We have previously reported the presence of interleukin 1 (IL-1) inhibitory factor in the culture supernatants of alveolar macrophages. The activity is decreased in healthy smokers and patients with interstitial lung diseases (sarcoidosis, idiopathic pulmonary fibrosis), compared with healthy non-smokers. In this study, we further examined the mechanism and specificity of IL-1 inhibitory factor. The inhibitory factor exhibited specific inhibition of augmentation by IL-1 of PHA induced murine thymocyte proliferation, whereas there was no inhibition of the augmentation by IL-2, IL-4, IL-6 or TNF. This IL-1 inhibitory factor competitively blocked the binding of IL-1 to the IL-1 receptor on PHA-stimulated murine thymocytes. These results indicate that alveolar macrophages produce a specific IL-1 inhibitory factor which functions as a IL-1 receptor antagonist.


[Cytokine gene expression in interstitial lung diseases].

We studied the role of macrophages in the process of pulmonary fibrosis, focusing on gene expressions of cytokines. TGF-alpha is a factor which stimulates fibroblasts or endothelial cells to proliferate, by combining to receptors of EGF competitively with EGF in vitro. Total RNA was extracted from alveolar macrophages recovered by bronchoalveolar lavage from patients with idiopathic pulmonary fibrosis or normal healthy volunteers, and the expression of TGF-alpha mRNA was evaluated by Northern analysis. There was no detectable TGF-alpha mRNA in alveolar macrophages from normal healthy volunteers; however, in patients with idiopathic pulmonary fibrosis, a considerable level of mRNA of TGF-alpha could be detected. Using an experimental rat model of alveolitis induced by bleomycin, the expression of TNF-alpha mRNA in alveolar macrophages recovered by BAL was evaluated by Northern analysis. Alveolar macrophages from bleomycin-treated rats expressed a significant level of TNF-alpha mRNA. Both TGF-alpha and TNF-alpha have proliferative activity on fibroblasts, and may have an important role in the process of fibrosis of the lung.


[Alpha 1-antitrypsin genes in patients with alpha 1AT deficiency in Japan: mutational analysis and allelic background].

Deficiency of alpha 1-antitrypsin (alpha 1AT), a plasma serine protease inhibitor, increases the risk of precocious pulmonary emphysema. Patients with alpha 1AT deficiency in Japan are extremely rare and no Z type alpha 1AT deficiency, which is one of the most frequent genetic disorders among Caucasians, are reported in Japan at the level of gene analysis. It is not yet clear why Z type alpha 1AT is rare among Japanese. When Ala213(GCG)-Val213(GTG) mutation in the alpha 1AT gene was examined by restriction endonuclease BstPI, all of 156 Japanese samples were Val213(GTG) in contrast to the finding that 30% of U.S. Caucasians are Ala213(GCG), indicating that alpha 1AT genes among Japanese were diverted from M1(Val213) variant and are different from M1(Ala213) variant, from which Z variant was likely diverted. This may explain why Z type alpha 1AT deficiency is not found among Japanese. A new alpha 1AT deficient variant, Siiyama (Ser53(TCC)-Phe53(TTC)), was found in a 39-year-old male with pulmonary emphysema (Seyama K, et al, J Biol Chem, 266, 12627, 1991). Interestingly, 6 out of 10 families with alpha 1AT deficiency in Japan shared the identical substitution as Siiyama. This indicates that although Caucasian type Z alpha 1AT deficiency is not found, Siiyama variant may be relatively common in Japan and even in other oriental countries because of the historical migration of people.


[IgE-mediated allergy and Fc epsilon receptor II].

Two types of IgE receptors, Fc epsilon receptor I (Fc epsilon RI) and Fc epsilon receptor II (Fc epsilon RII), are known to be involved in IgE-mediated allergy. Fc epsilon RI is expressed on mast cells and basophils, and cross-linkage of Fc epsilon RI leads to the release of chemical mediators from these cells. Fc epsilon RI consists of alpha, beta and gamma chains, and cDNAs encoding these chains were recently cloned. Fc epsilon RII is expressed on various cells such as mature mu+delta+ B cells and activated monocytes and eosinophils. The cDNA encoding B cell Fc epsilon RII was cloned by several groups including ours, and Fc epsilon RII was found to be a single chain receptor expressed with its N-terminal inside the cells, homologous to C-type animal lectins. Subsequently, we identified two species of Fc epsilon RII, Fc epsilon RIIb, whose structures differ only at the N-terminal cytoplasmic region but share the same C-terminal extracellular region. These two receptors are generated utilizing different transcriptional initiation sites and 5' exons. Fc epsilon RIIa is constitutively expressed only on B cells. While Fc epsilon RIIb is inducible by IL-4 on B cells, monocytes and eosinophils. By employing transformants expressing Fc epsilon RIIa or Fc epsilon RIIb, it was demonstrated that Fc epsilon RIIa is involved in IgE-mediated endocytosis, whereas Fc epsilon RIIb functions in IgE-dependent phagocytosis.(ABSTRACT TRUNCATED AT 250 WORDS)


[Induction by local injections of IL-2 of antitumor effector cells and secondary production of cytokines in malignant pleural effusion].

The present study was undertaken to examine the effects of intrapleural administration of IL-2 on induction of cytotoxic killer cells and on secondary production of cytokines in malignant pleural effusions. During daily local administration of IL-2, significant in vivo induction of cytotoxic activity was observed after 3-7 days, followed by a decrease in this activity in pleural mononuclear cells (MNC) to almost zero by day 15. IL-4 suppressed induction of IL-2-inducible killer cells from MNC in blood and pleural effusion, but significantly augmented the killer induction from pleural effusion MNC obtained after local 7-day administration of IL-2. Before therapy, malignant pleural effusions contained various levels of IL-6 and M-CSF, but no IL-4 or IFN-gamma. Daily intrapleural instillation of IL-2 resulted in significant augmentation of the levels of IL-4, IL-6, IFN-gamma and M-CSF. Chromatographical fractionation of the pleural effusion showed only one major peak with a MW of 24 kD, which had IL-6 activity. The level of the latent form of TGF-beta also increased during local IL-2 therapy. In contrast, significant levels of TNF (alpha, beta), IL-1 beta or IFN-alpha were not detectable in pleural effusions before or during therapy. These data suggest that IL-2 is an important inducer of secondary production of various cytokines in vivo, responsible for up- or down-regulation of induction of IL-2-inducible killer activity.


[Evaluation of physical fitness and exercise performance in patients with chronic pulmonary emphysema].

Physical fitness was studied in patients with chronic pulmonary emphysema using Kraus-Weber methods in addition to pulmonary function and exercise tolerance. In Kraus-Weber tests, explosive strength of abdominal muscles in these patients were within the normal range, but both abdominal and back muscle endurance were significantly diminished compared to age-matched controls. On the other hand, flexibility was not different between the patients and the controls, although large variation was present. Exercise performance as assessed by 6 minutes' walk distance in patients was significantly correlated with FEV1.0, DLco and maximal inspiratory mouth pressure, as well as explosive strength of abdominal muscles and abdominal and back muscle endurance capacity. Treadmill walking training for 20 minutes with a load greater than 80% VO2max, twice a week for 2 months was performed in 11 patients with mild to moderate pulmonary emphysema. Six minutes' walk distance (6MD) was significantly prolonged with improvement of back muscle endurance and flexibility. Another walking training consisting of five repetitions of two minutes' near maximal walking and a two minute interval of rest was performed in 6 patients with severe pulmonary emphysema. 6MD tended to increase with improvement of both back and abdominal muscle endurance. However, pulmonary function tests and VO2max showed no significant changes after both types of training. Improved walked distance after the training was significantly correlated with improved VO2 at AT. Furthermore VO2, VE, HR and lactate production during exercise at the same load were significantly decreased compared to pre-training. Dyspnea sensation measured by modified Borg scale during exercise was improved after the training. It is concluded that a physical training program adapted to the condition of the individual patients could improve exercise performance, and should be prescribed in addition to medication.


[Clinical study on respiratory muscle training for chronic respiratory failure].

The purpose of respiratory muscle training for patients with chronic respiratory failure is to improve exercise performance during daily life. Firstly, to confirm the clinical effect on respiratory muscle training, the abdominal pad method for inspiratory muscle training and abdominal pad method with expiratory resistor for both inspiratory and expiratory muscle training were simultaneously performed. Both methods were clinically useful to increase respiratory muscle power and to subjectively decrease dyspnea. Ventilatory pattern analyzed by the Konno-Mead (K-M) diagram during exercise also showed their effectiveness. Secondly, the influence of hypoxemia and hypophosphatemia, which are important factors producing respiratory muscle fatigue, was investigated in a patient with respiratory failure. (1) O2 inhalation in patients receiving home oxygen therapy was effective in terms of the endurance time and ventilatory pattern analyzed by the K-M diagram during exercise. (2) A case of hypercapnea due to hypoventilation caused by respiratory muscle fatigue developed reduced PaCO2 following correction of serum phosphate level, suggesting that hypophosphatemia is an important clinical factor producing respiratory muscle fatigue.


[Recent technical advances in portable oxygen delivery systems].

According to a Japanese national survey (June 30, 1990), the number of patients receiving home oxygen therapy (HOT) has been greater than 18,000 since March 1985, when HOT was first covered by health insurance. The oxygen concentrator, especially the molecular sieve type, is the most common method of delivery (more than 90%). In April 1988, the portable oxygen cylinder was acknowledged by health insurance, and the liquid oxygen supply system in April 1990. Three types of portable oxygen delivery systems are available; oxygen cyclinder, liquid oxygen system, and oxygen concentrator (membrane type), of which the oxygen cylinder is most commonly used. In our hospital, portable oxygen supply systems were used in 80% of 168 HOT cases in 1990, and the use of 400 L aluminum oxygen cylinders at a flow rate of 1-2 L/min has been most popular. There is an strong desire from patients for lighter portable oxygen supply system of longer duration. In 19 patients with chronic respiratory failure, we evaluated a newly designed demand oxygen delivery system (DODS), which weighs 2.4 kg including the DOD device (TER-20 Teijin), 1.1 L oxygen cylinder made of ultressor, nasal cannula, and carrier. Arterial blood gases at rest (room air) were PaO2 61.9 +/- 6.3 torr, PaCO2 63.8 +/- 9.4 torr and pH 7.40 +/- 0.04. A crossover trial was performed under three conditions; breathing room air with no weight, and pulse oxygen flow and continuous oxygen flow each carrying 2.4 kg of weight. Both 6 minute walking (E1) and walking on a slow speed treadmill (E2) were studied.(ABSTRACT TRUNCATED AT 250 WORDS)


[Psychological approach to chronic respiratory failure].

Patients with chronic respiratory diseases, particularly chronic respiratory failure, are seriously handicapped mentally and physically as compared with those with diseases of other medical fields. This is because their disorders relate to breathing, which is the basic physical function directly associated with sustaining life. The authors have attempted a psychosomatic approach for patients with chronic respiratory disorders. Clinical science in this field of medicine in Japan is far behind that of other advanced nations. In the Comprehensive Emphysema Inventory, it was clearly reported that in many cases, psychological stress is involved in the onset of dyspnea. In SRQ-D or MAS, moreover, decreased motivation for treatment, anxiety regarding prognosis, and conflict were notable in psychosomatic tests. Patients on home oxygen therapy (HOT) appear to have problems in family relations and in the daily-living environment, even though HOT provides both mental and physical benefits. It was also noted that holistic or comprehensive care designed for improvement of not only physical condition, but also psychosocial aspects and quality of life, is essential to achieve good results in the respiratory rehabilitation of patients affected by chronic respiratory failure.


[Nutritional assessment and the effect of supplementary oral nutrition in patients with pulmonary emphysema].

Nutritional status and its relation to respiratory function and respiratory muscle strength were assessed in patients with pulmonary emphysema. Energy metabolism was also examined in order to elucidate the mechanism of their malnutrition. BCAA/AAA ratio of plasma amino acid was positively correlated with FEV1.0%. Resting energy expenditure (REE) was negatively correlated with FEV1.0%, and REE/REEpred ratio was also negatively correlated with BCAA/AAA and PImax. These findings suggest that increased mechanical work load, associated with airway obstruction and reduced respiratory muscle efficiency, contribute to the increased energy expenditure and amino acid imbalance. Oral nutritional supplementation using BCAA enriched-elemental diet was found to be effective, as assessed by nutritional parameters, PImax, D.O.E., and QOL index, in malnourished emphysema patients.


[Effect of potassium channel openers on hypoxic pulmonary vasoconstriction].

The ATP-sensitive potassium channel (K+ATP) has been suggested as an important mechanism for the reactivity of vascular smooth muscle. We investigated the effects of K+ channel openers (lemakalim, pinacidil) on hypoxic pulmonary vasoconstriction (HPV) and angiotensin II (Ag II) induced vasoconstriction in isolated rat lungs (Sprague-Dawley rats: 300-450 g). Ventilation with hypoxic gas (2% O2, 5% CO2) was performed for 6 min after the injection of Ag II (0.1 microgram). Isolated lungs were perfused under constant flow (0.04 ml/g/min) using 20 ml of blood from donor rat. The perfusion pressure was used as the pulmonary artery pressure. Lemakalim or pinacidil was pre-administered through the reservoir. Pretreatment with pinacidil (10(-4) M) or lemakalim (10(-5) M) inhibited the pressor response to hypoxia, but did not inhibit the response to angiotensin II. Although the effect of lemakalim on HPV was reversed by administration of glibenclamide (10(-5) M) or tolbutamide (10(-3) M), the effect of pinacidil on HPV was not influenced by either drug. These results suggest that 1) K+ channel openers (lemakalim and pinacidil) inhibit the pressor response to hypoxia, and 2) lemakalim seems to act through K+ATP, whereas pinacidil may have other mechanisms of inhibition of vascular smooth muscle contraction. K+ATP may play an important role in the regulation of pulmonary vascular reactivity to hypoxia.


[Relationship between signal intensity of blood flow in the pulmonary artery obtained by magnetic resonance imaging and results of right cardiac catheterization in patients with pulmonary disease].

Electrocardiogram-gated spin-echo magnetic resonance (MR) images of the chest were obtained in five normal controls and 35 patients with pulmonary disease (11 chronic obstructive pulmonary disease, 6 pulmonary thromboembolism, 5 primary pulmonary hypertension, 4 interstitial pulmonary disease, 4 pulmonary hypertension with disturbance of portal circulation, and 5 other diseases) who underwent right cardiac catheterization. In transverse images at the level of the right main pulmonary artery (rPA) and sagittal images at the level through the midsternal line and the spinal chord, the signal intensity of blood flow in the rPA was quantitatively evaluated, and the correlations with the MR signal intensity of intravascular flow and the parameters of hemodynamics were studied. In diastole MR images of both normal controls and patients mostly showed a significant signal intensity of flowing blood, but in systole some patients demonstrated significant signals and visible flow images. In systolic MR images, the mean values of hemodynamic parameters (mean pulmonary arterial pressure (mPAP), pulmonary arteriolar resistance (PAR), and cardiac index (CI)) were abnormal in patients with significant signal intensity of flow compared with those in patients without sufficient MR signal. The signal intensity was not correlated with mPAP; however, it significantly increased as PAR increased, and it increased as CI decreased both in diastole and in systole. Especially in systole, there was good correlation between the signal intensity in transverse MR images and CI (r = -0.85, P less than 0.01) and between signal intensity in sagittal MR images and PAR (r = 0.90, P less than 0.01). These results suggest that significant flow signal in the rPA in systole has pathophysiological significance, and signal intensity is considered to be significantly affected by changes of PAR and CI. The signal intensity of blood flow in the rPA on MR images can be used as an index of the severity of right heart failure associated with pulmonary disease. MR imaging is a useful modality to evaluate pulmonary circulation disturbance because of its ability to assess blood flow in the pulmonary artery noninvasively without interference from other structures such as bone and normal lung.


[Activity of the respiratory muscles during natural defecation: a study on experimental animals].

Activity of the respiratory muscles during natural defecation was studied in two anesthetized and two decerebrate dogs. In anesthetized dogs, excitation of the abdominal muscles and an increase in gastric pressure were observed during defecation. However, pleural pressure was little influenced by such increase in abdominal pressure, maintaining the same rhythmic changes as observed during spontaneous respiration. The rhythmic changes in pleural pressure were associated with rhythmic activity of the diaphragm. When gastric pressure increased during defecation, the diaphragmatic activity also increased during both the inspiratory and expiratory phases. In a decerebrate dog, airflow and airway pressure changed similarly to during defecation. The diaphragm was continuously active, with superimposed rhythmic augmentation. In a paralyzed and artificially ventilated dog with open-chest, the phrenic nerve similarly developed discharges. We conclude that the non-respiratory activity and rhythmic augmentation of phrenic nerve discharge during defecation is pre-programmed in the command for defecation. The activity of phrenic motoneurons may be further modulated by changes in thoracic and abdominal pressure. These mechanisms may act together to coordinate respiration and defecation.


[Production of reactive oxygen species by rat alveolar macrophages. Dissociation between the intracellular and extracellular release of hydrogen peroxide].

In order to clarify the features of reactive oxygen species produced by rat alveolar macrophages (AMs), the concentrations of intracellular and extracellular hydrogen peroxide were measured under various experimental conditions. Intracellular hydrogen peroxide was measured by DCFH method using a flow cytometer, while the extracellularly released fraction was measured by scopoletin method using a spectrophotometer. The concentration of intracellular hydrogen peroxide after stimulation with opsonized zymosan (10 micrograms/ml) was significantly higher than that after stimulation with phorbol myristate acetate (PMA; 100 ng/ml). On the other hand, hydrogen peroxide released extracellularly after stimulation with PMA was significantly greater that that after stimulation with opsonized zymosan. These results indicate that the soluble membrane stimulant and the phagocytic particles have different mechanisms in activating the production of hydrogen peroxide in AMs. That is, hydrogen peroxide induced by PMA was mainly released extracellularly, while that induced by zymosan was mainly released into the intracellular environment. At rest, the concentration of intracellular hydrogen peroxide in rat AMs was high. Potassium cyanate, a known mitochondrial inhibitor, suppressed the intracellular hydrogen peroxide in AMs not only at rest but also after stimulations, indicating that most of the reactive oxygen species released into the intracellular environment in AM are produced by mitochondria. From these results, in order to gain a closer insight into the function of AMs, it is very important to distinguish the oxidative metabolites produced intracellularly which are related to bactericidal function from those of the extracellularly released fraction which give rise to lung damage.


[A 14-year-old with pulmonary hamartomatous lymphangiomyomatosis associated with bilateral pneumothoraces].

A 14-year-old girl was admitted because of cough, chest pain and hemosputum. Chest roentgenogram on admission showed a pneumothorax and a cavitary lesion with niveau formation in the right lung and cystic lesions in the bilateral lung fields. After bed rest and intravenous administration of antibiotics for two weeks, the right lung inflated well and the niveau formation disappeared, and the patient was discharged. One week later, she was readmitted with sudden-onset severe dyspnea, caused by bilateral pneumothoraces. Emergency tube thoracostomy and wedge resection of the bullous lesion was performed. Macroscopically, multiple small cystic changes were seen on the surface of the right lung. Histological examination revealed nodular proliferations of smooth muscle cells in the interstitium and vessel walls in the lung, which contained slit-like lymphatic channels. The diagnosis of pulmonary lymphangiomyomatosis was made. In this case, we could not measure receptors for estrogen and progesterone. Recently, hormonal therapy and oophorectomy have been reported as being useful. Tamoxifen (Norvadex) was therefore initiated, and the patient has remained well with slight dyspnea on exertion. There has been no recurrence of pneumothorax. Lymphangiomyomatosis is a rare disease of unknown etiology which occurs exclusively in women, mostly in those of reproductive age. We report a 14-year-old female patient with lymphangiomyomatosis associated with repeated pneumothorax, who had been under treatment for epilepsy. We believe this case to be of importance because of the long discussed relation between pulmonary lymphangiomyomatosis and tuberous sclerosis.


[A case of bronchocentric granulomatosis associated with uveitis].

A 32-year-old female was admitted to our hospital because of abnormal pulmonary shadows and a decrease in visual acuity. Analysis of peripheral blood revealed eosinophilia, and chest roentgenogram demonstrated multiple infiltrates in the right upper lung field. Pathological examination of transbronchial lung biopsy specimens revealed necrotizing granulomatous lesions in the walls of bronchioles, and a definitive diagnosis of bronchocentric granulomatosis was made. The cause of bronchocentric granulomatosis in this patient was suggested to be an allergic reaction to Aspergillus because of positive response to skin test for Aspergillus. Although it is reported that extrapulmonary involvement is rare in bronchocentric granulomatosis, the present case was associated with uveitis, and to our knowledge is the first reported case.


[A case of pulmonary fibrosis in which inhibition of pulmonary vasoconstriction was detected using DSA pulmonary wedge angiography].

A 65-year-old man was admitted to our hospital complaining of productive cough and dyspnea on exertion. X-ray films and CT scan of the chest disclosed diffuse reticular shadows, especially in the bilateral lower lung fields. Blood gas analysis showed severe hypoxemia. Pulmonary function test disclosed severe restrictive pattern. From these findings, the patient was thought to have pulmonary fibrosis. Right heart catheterization showed pulmonary hypertension. To evaluate the pulmonary vascular bed, we performed DSA pulmonary wedge angiography. The pulmonary capillary phase stained homogeneously in normal subjects. However, in the present case, filling of the right pulmonary A9 was incomplete and capillary bed staining was decreased under room air condition. After breathing 5 L/min oxygen for 20 min., the A9 was filled well and capillary bed staining was increased. We consider that this change was induced by inhibition of hypoxic pulmonary vasoconstriction (HPV) by oxygen. DSA pulmonary wedge angiography was useful for visual evaluation of HPV.


[A case of early mucoepidermoid carcinoma arising from the left upper bronchus and presenting the flow-volume curve as a manner of extra-thoracic airway obstruction].

A 23-year-old female was admitted with dyspnea, dry cough, and rhonchi. No abnormalities were detected on chest roentgenogram. Fiber-bronchoscopy revealed a polypoid lesion with necrotic material occluding the left main bronchus. The pathological diagnosis of the biopsied material was low grade mucoepidermoid carcinoma. Following tumor reduction by Nd-YAG laser, it was clear that the primary lesion originated from the left upper bronchus. Sleeve lobectomy was performed, and the tumor was proved to be early lung cancer of hilar type with extension limited to the bronchial wall.


[An autopsy case of massive pulmonary hemorrhage in systemic lupus erythematosus].

A 60-year-old female was admitted to our hospital because of respiratory failure. She was diagnosed as having systemic lupus erythematosus (SLE) in 1971 and had been treated with low-dose oral corticosteroids for 13 years. She developed cough, fever and anemia several days after oral corticosteroids were tapered. Initially, she had no complications such as congestive heart failure, renal failure or bleeding tendency. Respiratory failure progressed without any response to antibiotic therapy. Chest roentgenogram showed bilateral diffuse infiltrates and air bronchograms. There was no improvement even with steroid pulse therapy, and she died of multiple organ failure. Autopsy revealed massive intra-alveolar hemorrhage and interstitial pneumonitis. Deposition of immunoglobulins in the lung was not seen. To our knowledge, this is the 11th reported case of SLE associated with pulmonary hemorrhage in Japan.


[A case of isoniazid (INH)-induced pneumonitis].

A 58-year-old man was referred for the evaluation of a lung nodule on chest X-ray. On admission, chest X-ray showed a solitary nodule with cavitation in the left lung field. Histological examination revealed epithelioid cell granulomas and the diagnosis of pulmonary tuberculosis was made. He was treated with INH, ethambutol (EB), and rifampicin (RFP). On the 16th day of treatment, he developed dry cough and high fever. On the 20th day, dyspnea developed and PaO2 was decreased to 38.2 Torr. Chest X-ray showed new widespread infiltrates in both lung fields and bilateral pleural effusions. The size of the cavitary lesion was decreased. Transbronchial biopsy specimen showed slight interstitial thickening, lymphocyte infiltration, and multiple granulomas. Drug lymphocyte stimulation test was positive only with INH (230%). INH-induced pneumonitis was highly suspected. All drugs was discontinued and hydrocortisone 2400 mg daily was started. He soon became afebrile, and dyspnea and dry cough resolved. Chest X-ray film showed resolution of infiltrative shadows. He was subsequently successfully treated with streptomycin, EB, and RFP without any adverse effects. To our knowledge, this is the sixth reported case of INH-induced pneumonitis.


[Case of adult primary varicella pneumonia].

We report a case of adult primary varicella pneumonia. A 34-year-old man was admitted to our hospital with fever, dry cough and eruptions. He had no history of chicken pox and his sons had contracted varicella 2 weeks before the onset of his symptoms. Chest X-ray showed diffuse nodular shadows in both lungs. The diagnosis of primary varicella pneumonia was made based on family history, typical eruptions and high titer of antibody against Varicella zoster virus. An electron micrograph indicated this case to be primary varicella pneumonia with fibrosis and edema of interstitial spaces and the presence of virus-like particles in cells. The patient was treated with antibiotics, an antiviral agent and immunoglobulin. The clinical symptoms and diffuse nodular shadows resolved with this treatment.


[Two cases of Churg-Strauss syndrome with bilateral wide-spread pulmonary infiltrates].

We report two cases of Churg-Strauss syndrome. The first case was a 25-year-old woman with a one year history of bronchial asthma, who developed fever, skin eruptions, abdominal pain and mononeuritis multiplex. During treatment with prednisolone 40 mg per day, chest X-ray films showed bilateral wide-spread infiltrates. When the dosage of prednisolone was increased to 80 mg per day, these infiltrates disappeared. Skin and lung biopsy specimens demonstrated allergic vasculitis and eosinophilic pneumonia. There was no response to high-dose methylprednisolone pulse therapy for persistent severe abdominal pain and mononeuritis multiplex. Pericardial and pleural effusions with eosinophilia recurred eight months later. The second case was a 31-year-old man with a six year history of bronchial asthma, who developed fever, skin eruptions, myalgia and mononeuritis multiplex. One year later, during treatment with prednisolone 15 mg per day, bronchial asthma with eosinophilia relapsed and chest X-ray films showed bilateral patchy infiltrates. Skin biopsy specimens demonstrated eosinophilic infiltrates and necrotizing vasculitis, while lung biopsy specimens demonstrated eosinophilic infiltrates and small granulomas. With additional administration of cyclophosphamide, he has had no evidence of active disease for six years. In both cases, the neurological symptoms persisted despite treatment with high doses of steroids, and during tapering of prednisolone, vasculitis syndrome relapsed. Therefore, long-term careful surveillance is necessary in this disease.


[A case of bronchial asthma whose disease activity was associated with changes in serum alkaline phosphatase linked-immunoglobulins levels].

A 67-year-old female was admitted to our hospital with status asthmaticus. Serum alkaline phosphatase (ALP) level was elevated and ALP-linked immunoglobulins (ALP-Igs) were detected by ALP isozyme analysis. Treatment with prednisolone resulted in improvement of her asthmatic symptoms and serum ALP level. Thereafter, elevations of serum ALP and ALP-Igs levels were seen whenever she had an asthmatic attack. She had no manifestations of autoimmune diseases. Changes in ALP-Igs levels in association with asthmatic activity suggested that ALP-Igs were related to the pathogenesis of bronchial asthma in this case.


[A case of pneumonitis and hepatic injury caused by a herbal drug (sho-saiko-to)].

We report a case of pneumonitis and hepatic injury caused by Sho-saiko-to. A 56-year-old man was admitted to our hospital because of hepatic disorder. The levels of serum transaminases returned to normal within two months without specific treatment and he was discharged. Four weeks later, he was readmitted because of severe pneumonitis and mild hepatic disorder. Under the suspicion of drug-induced pneumonitis, all medications were discontinued and high-dose glucocorticoid including "pulse therapy" was given. Consequently, pneumonitis and hepatic function markedly improved. Careful history taking revealed the ingestion of Sho-saiko-to before both admissions. Lymphocyte stimulation test against Sho-saiko-to was positive. Challenge test using Sho-saiko-to resulted in decrease of PaO2 and elevation of serum transaminases. Based on these findings, the diagnosis of pneumonitis and hepatic injury induced by Sho-saiko-to was established.


[Case report: chronic aggressive pulmonary sarcoidosis with bilateral cavitation].

A 34-year-old male patient was admitted to our hospital because of progressive exertional dyspnea and weight loss (8 kg in one year). Twelve years previously, he had had an episode of uveitis accompanied with bilateral hilar lymphadenopathy. Scalene node biopsy at that time revealed non-caseating epithelioid granulomas. Four years later, a follow-up chest radiograph showed bilateral fine nodular lesions. The bilateral parenchymal lesions gradually increased in density, and eventually, formed a confluent air-space consolidation containing multi-ocular cavities. On physical examination, the patient was emaciated (Ht 165 cm, Wt 40 kg). Nodular cutaneous lesions were present on his face and elbows. Hypoxemia with hypercapnea (PaO2 56 Torr, PaCO2 51 Torr) was noted. Repeated sputum cultures yielded negative results for acid-fast bacilli, fungi, and other pathological organisms. A transbronchial lung biopsy specimen obtained from near the cavitary lesion revealed non-caseating granulomas compatible with sarcoidosis. Skin lesion biopsy showed similar findings. The cavitation, was therefore considered to be due to ischemic necrosis of confluent sarcoid granulomas. Prednisolone (40 mg daily) was given with a prompt improvement of symptoms including dyspnea, as well as the radiographic abnormalities. We conclude that uncomplicated pulmonary sarcoidosis may rarely develop into an aggressive parenchymal disease with cavitation. It is of importance to differentiate such cases from infectious diseases (tuberculosis, mycosis etc.) because of the need for corticosteroid treatment.


[A case of bronchoplasty for endobronchial chondroid hamartoma].

A 62-year-old male was admitted to our hospital to investigate his obstructive pneumonia-like symptoms. A chest roentgenography, computed tomography revealed the tumor to be located in the left lower bronchus. Bronchoscopy showed endobronchial tumor at the level of the left lower lobe bronchus. Preoperative pathological confirmation was possible by transbronchial biopsy, pathological diagnosis of the tumor was endobronchial chondroid hamartoma. And then, bronchoplasty was performed. He was discharged from our hospital after operation, showing no evidence.


[Active infective endocarditis with idiopathic thrombocytopenic purpura: a case report].

This is a case report of infective endocarditis with idiopathic thrombocytopenic purpura (ITP). Open heart surgery to the patient with ITP has a problem of perioperative hemorrhage. Usually, treatment for ITP is performed before operation, and platelet transfusion is provided for hemorrhage. However, in our patient, we had to perform emergency operation because of progressive heart failure without treatment of ITP. Emergency operation should be performed without treatment of ITP, not to delay operative timing in such a case of progressive heart failure from active infective endocarditis.


[Bilocular pericardial cyst diagnosed by magnetic resonance imaging: a case report].

A 47-year-old female who had removal of pericardial cyst is reported. Preoperative examination including echocardiography, computed tomography and magnetic resonance imaging (MRI) demonstrated the cystic nature of the mass attaching to the right pericardial surface. MRI clearly revealed that the cyst was bilocular. MRI brings a more detailed information of pericardial cyst for surgery.


[A successful removal of the left ventricular lipoma].

We reported a rare case of left ventricular lipoma, which arose nearby the papillary muscle in the left ventricular wall. It was disclosed by echocardiography and nearly diagnosed by computed tomography and magnetic resonance images. We successfully removed the tumor. It measured 3.8 x 1.5 x 1.3 cm and 3.6 g. Microscopically, it was not encapsulated and consisted of mature adipose tissue. But, it did not invaded the cardiac muscles. In conclusion, the tumor detected lipoma. Postoperative course is uneventful, and the patient has been followed by serial echocardiography.


[A case of hydropneumothorax].

A 19-year-old girl was admitted because of fever, cough and suddenly occurred chest pain. One month earlier she had experienced a fever and cough, then she had felt sudden chest pain 2 weeks prior to the admission. A chest X-ray showed left pneumothorax and massive pleural effusion. A diagnosis of hydropneumothorax was made. In spite of the chest tube drainage, reexpansion of the lung was unsatisfactory. Thoracotomy and decortication of the lung resulted in good reexpansion. Histological finding revealed pleuritis due to bacterial peribronchial infection, which resulted in hydropneumothorax, namely an abscess ruptured to the pleural cavity.


[Cryosurgery for left atrial myxoma with coronary artery bypass grafting].

This is the first report of cryoblasion of atrial myxoma which was performed in conjunction with coronary artery bypass grafting. A 63-year-old man was admitted for left atrial tumor and ischemic heart disease. Following coronary artery bypass grafting and resection of left atrial myxoma, cryosurgery was carried out for the residual tumor on atrial septum and left atrial posterior wall. Ultrasonic cardiogram after 1 year revealed no signs of recurrence. Cryoablasion was effective in preventing the recurrence of atrial myxoma.


[Mitral valve replacement in a patient with hereditary hemorrhagic telangiectasia].

A 46-year-old female with mitral insufficiency complicated by hereditary hemorrhagic telangiectasia (Osler's disease) underwent successfully mitral valve replacement. The patient had a history of repeated large-volume nasal bleeding. Mitral valve replacement using a xenograft was safely performed with various attempts for preventing abnormal postoperative hemorrhage.


[Bilateral pneumothorax and rupture of dissecting aortic aneurysm following a mitral valve replacement in Marfan syndrome: a case report].

A 12-year-old girl with Marfan syndrome was referred to our department because of severe mitral regurgitation. The patient was pale and in a pre-shock condition. The echocardiogram revealed a chordae rupture of the posteromedial papillary muscle at the posterior leaflet. A moderate dilatation of the aortic annulus (30 mm) and the ascending aorta (45 mm) without aortic regurgitation was also observed. Emergent mitral valve replacement was performed without replacement of the aortic valve or the ascending aorta. After two months, the patient developed bilateral pneumothorax, which was resistant to continuous suction therapy and finally required surgical treatments. Despite the relatively uneventful recovery, a lethal rupture of dissecting aortic aneurysm into the pericardial cavity, developed four months after the initial operation. We discussed the desired surgical approaches and respiratory problems in patients with connective tissue disorder.


[Mitral valve replacement with concomitant coronary bypass for the papillary muscle rupture after acute myocardial infarction in situs inversus].

A 53-year-old man, who was known to have situs inversus totalis all of his life, had acute myocardial infarction complicated by partial rupture of the posterior papillary muscle causing mitral regurgitation and pulmonary edema. The patient underwent mitral valve replacement (Omnicarbon 27 mm) with concomitant aortocoronary saphenous vein bypass, and he is now doing well 9 months following the operation. To our knowledge, this is the first case of the successful mitral valve replacement and concomitant aortocoronary saphenous vein bypass on a patient with situs inversus totalis (mirror-image dextrocardia) in Japan.


[Cervical esophago-gastrostomy via the posterior mediastinal route for carcinoma of the thoracic esophagus].

From 1981 to 1990, 297 cases of carcinoma of the thoracic esophagus were resected in our department. Among these cases, 225 cases (84.3%) were reconstructed cervical esophagogastrostomy via the posterior mediastinal route. In this paper, these 225 cases were analysed to evaluate the usefulness of this procedure which was developed by S. Abo in 1975. Operative mortality was 4.4% Anastomotic leakage occurred in 24.4% of the cases, but the majority of the cases were treated successfully without any drainage and 83.3% of the cases could start their diet within one month after operation. The volume of oral intake by the patients after discharge increased satisfactorily (1,500-1,800 kcal/day), but the body weight decreased gradually. So the ambulatory enteral nutritional support was started and proved useful for maintaining their body weight. Alkaline reflux evaluated using 24-hour pH-monitoring system was observed in about half of the cases but the degree of the alkaline shift was not strong. Some complaints (heart burn in 6.3%, regurgitation in 21.9%, feeling of fullness after eating in 40.6%, stenotic sensation in 20.7%) were present but not serious.


[Brain dysfunction after operation of aortic arch aneurysm].

Postoperative brain dysfunction was studied for 18 patients who survived more than 30 days after operations of aortic arch aneurysms. The operative procedures were graft replacement in 12 patients, resection with direct or patch closure in 3, and thromboexclusion in 3. Except for thromboexclusion, adjuncts were used: temporary bypass in 1, partial EPC (extracorporeal circulation) in 2, and selective cerebral perfusion during EPC in 12. As for intra-operative monitoring, the temporal artery blood pressures were more than 50 mmHg in all, but the electroencephalogram changed to flat wave just after clamping the aorta in one patient. Postoperative brain dysfunction occurred in 5 patients, including temporary loss of consciousness in 2, lasting loss of consciousness in 1, and paralysis with loss of consciousness in 2. Postoperative brain dysfunction occurred more often in old aged men with atherosclerotic aneurysms. Patients with temporary brain dysfunction had no remarkable change in CT scan, but patients with lasting brain dysfunction had low density areas. It is recommended to prevent this complication as follows: 1) pre-operative evaluation of cerebral vascular disorders, 2) gentle maneuver of atherosclerotic lesions, 3) bilateral cerebral perfusions and intra-operative monitorings, 4) intensive perioperative care of circulation and respiration.


[Surgical treatment of coarctation of the aorta].

Repair of coarctation of the aorta was performed in 37 cases (31 patients, 6 patients of reoperation) ranging from 4 days old to 15 years old. Subclavian flap repair were performed in 15, resection and end-to-end anastomosis in 14, patch aortoplasty in 6, and interposition graft in 2. Subclavian flap angioplasty or end-to-end anastomosis is considered the procedure of choice in infants. However, the incidence of reoperation significantly increased in patients younger than age one month at initial subclavian flap repair. Mechanism of recurrent coarctation may be possibly related to retention of abnormal tissue, which is possibly ductal and/or intimal shelf, with the potential for proliferation and luminal narrowing. We suggest that in applicable case end-to-end anastomosis rather than subclavian flap angioplasty may be the surgical technique of choice in infants less than one month of age, and the most common reoperation technique was patch aortoplasty in re-stenosed cases.


[Cardiac valve replacement in the elderly].

From January 1980 through December 1990, seventy one consecutive patients over 60 years of age (mean age 64 +/- 4 years) and 231 patients younger than 60 years underwent cardiac valve replacement procedures. In the elderly group, aortic valve replacement was performed in nineteen patients, mitral valve replacement in thirty-three patients both aortic and mitral valve replacement in sixteen patients, and both mitral and tricuspid valve replacement in three patients. Aortocoronary bypass was performed in four and tricuspid annuloplasty in 19 patients simultaneously. Two patients were operated on emergency. As for preoperative status, 63 patients (88.7%) were in New York Heart Association (NYHA) Functional Class III or IV. Mechanical valves were implanted in all aortic position and 16 mitral position. Bioprosthetic valves were placed in 34 mitral position and 3 tricuspid position. Mean follow-up period was 42 +/- 33 months. The early mortality rate was 11% (8 patients) and the actuarial survival rate was 88 +/- 5% at five years and 74 +/- 10% at ten years. Postoperative functional improvement was excellent in 85.7% of the survivors. In the younger age group, 77.9% belonged to NYHA class III or IV preoperatively. The early mortality was 3.0% (7 patients) and the actuarial survival rate was 95 +/- 2% at five years and 86 +/- 2% at ten years. And postoperatively 91.3% were in NYHA class I or II. In conclusion, cardiac valve replacement in the elderly can be performed with an acceptable mortality and excellent functional improvement.


[Effects of blood-diltiazem-nitroglycerin-cardioplegia in coronary artery bypass grafting].

Forty-seven patients who underwent coronary artery bypass grafting using blood cardioplegia (BCP) were studied clinically. They were divided into 3 groups based on concentration of diltiazem (DTZ) and nitroglycerin (NTG). Group I (n = 12); DTZ 5 mg plus NTG 5 mg in BCP 1,000 ml, Group II (n = 10); NTG 25 mg in BCP 1,000 ml, Group III (n = 25); DTZ 5 mg plus NTG 25 mg in BCP 1,000 ml. From the standpoint of serum enzyme analysis, there was no significant difference between 3 groups, however, the incidence of perioperative myocardial infarction (PMI) and perioperative coronary spasm (PCS) were significantly higher in Group I than that in other groups. The present data suggests that intramyocardial concentration of NTG in Group II and III were 5 times higher than Group I. Increased dose of NTG in BCP would be benefit for myocardial protection in CABG.


[Left heart bypass using a centrifugal pump as an adjunct measure for surgery of thoracic descending aorta].

We have employed left heart bypass (LHB) using a centrifugal pump with heparin coated tubes as an adjunct measure for surgery of thoracic descending aortic aneurysm in 8 cases. During aortic cross-clamping, LHB was controlled to maintain the distal pressure above 50 mmHg. In 7 cases, hemodynamics were stable and no complication occurred in relation with this method. However, acute heart failure due to coronary insufficiency occurred in one patient, and subsequent cardiopulmonary bypass was required to maintain systemic circulation. LHB provides adequate distal perfusion and proximal decompression in most cases, and it has also contributed to diminution of intraoperative bleeding. However, LHB can not maintain distal perfusion when acute heart failure occurs, which indicates that we have to select another adjunct measures, such as femorofemoral bypass to avoid distal hypoperfusion in cases with heart diseases.


[A case report on the sliding commissuroplasty for mitral regurgitation due to posterior commissural chordal rupture].

We have performed a mitral valve reconstruction on a 31-year-old man who suffered from infective endocarditis four years ago. Severe mitral regurgitation and posterior commissural chordal rupture were noted. The mitral valve was repaired by Carpentier's sliding commissuroplasty and ring annuloplasty. The postoperative course was uneventful, and mitral regurgitation completely disappeared. It appears that Carpentier's sliding commissuroplasty is a superior new reconstructive technique for mitral regurgitation due to commissural chordal rupture.


[Indication of pulmonary embolectomy for acute pulmonary embolism].

During the past 7 years, 15 patients with acute pulmonary embolism (APE) were treated at Kagawa Medical School and 10 patients were survived. Nine patients had an embolus in a right or left pulmonary trunk (group A) and 6 patients were peripheral APE (group B). In group A abnormal findings in a chest x-ray film and an electrocardiogram were observed in many patients, but in group B these findings were slight. In group A a shock was observed in 89% and cardiac arrest in 4 patients, although in group B neither shock nor death were observed. Marked hypoxia with hypocapnia was observed in 8 patients in group A and only in 2 in group B. All patients in group B were recovered by medical therapy. In group A, however, only 3 patients were recovered by medical therapy. Two patients in group A were performed pulmonary embolectomy (PER), but one of them, who had been in nonreversible shock, died. We conclude that the patient who had marked hypoxia (PO2 less than or equal to 50 mmHg) with hypocapnia (PCO2 less than or equal to 35 mmHg) early at an attack should be taken a pulmonary angiography, and when a large embolus is found out in the proximal pulmonary artery, the PER should be performed as soon as possible.


[Treatment of postoperative mediastinitis using an omental pedicle flap].

Four patients with postoperative mediastinitis who were treated by omentopexy at the Fukuoka University Hospital between 1989 and 1990. Three of the 4 patients healed successfully, another one died of multiple organ failure 83 days after surgery. All patients were received coronary artery bypass surgery harvesting a left internal thoracic artery for ischemic heart disease. Three patients had diabetes mellitus, one patient had renal failure preoperatively. Recognition of mediastinitis was made by sternal wound purulent discharge and sternal dehiscence. Culture of the discharge fluid yielded methicillin-resistant Staphylococcus aureus in three, and Enterococcus cloacae in one. Irrigation with popidone-iodine or blonopol were ineffective. Thus, the wound was treated with debridement and omentopexy with an omental pedicle flap, respectively. Postoperative course after omentopexy were excellent, had no complications. We conclude that the omentopexy is useful in the treatment of postoperative refractory anterior mediastinitis.


[Advantage of internal thoracic artery for coronary arterial bypass surgery in patients over 70 years of age].

Between April 1988 and September 1991, 16 among 23 patients over 70 years of age underwent coronary bypass grafting (CABG) with at least one arterial graft. The age ranged from 70 to 77 years (mean, 72.1 years) and involved coronary lesions were two vessels in two patients and three vessels in 14 patients. Seven patients with unstable angina received emergency CABG. The number of distal anastomosis with arterial graft was mean of 1.3 per patient and left internal thoracic artery (ITA) was used as a pedicled graft in all patients. Sequential grafting with left ITA arterial graft was performed in two and right gastroepiploic artery was concomitantly used in three patients. No atherosclerosis was seen in left ITA, however, poor quality saphenous vein graft (SVG) was in five and atherosclerosis of ascending aorta was in five patients. After operation deep vein thrombosis of leg after harvesting SVG occurred in one patient. The angiogram performed within one month of operation in nine patients showed that the patency rate of arterial graft was 100% and that of SVG was 94.4%. The longest follow-up period was 42 months and New York Heart Association Functional Class improved to Class I or II in all patients. The use of pedicled ITA in elderly patient showed advantage for diseased ascending aorta and it seemed to prevent the postoperative complication due to the use of SVG.


[Concomitant cardiac and pulmonary operation in a case of lung tumor with unstable angina].

The patient, a 55-year-old male, suffered from malignant lung tumor with complaints of bloody sputum and anterior chest pain. Angina pectoris was detected during neoadjuvant chemotherapy, because of total obstruction at #7 and 99% stenosis at #12, as disclosed by CAG. As he complained frequently anginal chest pain in the course of time, the concomitant cardiac and pulmonary operation was decided via median sternotomy and fourth intercostal thoracotomy. The operating procedure was as follows: 1) mediastinal lymph nodes dissection before extracorporeal circulation, 2) aorto-coronary bypass (#8, #12), 3) final left lower lobectomy. He was histopathologically diagnosed as a rare case of endobronchial type of leiomyosarcoma. He has achieved a remarkable recovery, without tumor recurrence or angina pectoris for ten months postoperatively, and has been allowed to resume a normal life.


[A case of malignant localized visceral pleural mesothelioma].

We experienced malignant localized mesothelioma of which origin was visceral pleura. According to, 1) the preoperative chest X-ray and chest CT which showed extra-pleural sign, 2) the rapid tumor growth, and 3) the result from needle biopsy, we diagnosed malignant localized mesothelioma of which origin was parietal pleura. Surgical treatment was performed, and diagnosed that its origin was visceral pleura. The tumor invaded the lung. It is dangerous to diagnose by means of needle biopsy because of malignant cell implantation. We recommend that firstly the surgical treatment should be carried out for malignant mesothelioma, which needs extended resection for preventing its recurrence.


[Computers in urology].

The present state of computer utilization in urology has been described. Nowadays, use of computer is becoming essential in the urological diagnosis and treatment. Recently computers have been so rapidly developed so that it became much smaller and yet offers higher performance. The methods and problems of utilizing computers have been explained by presenting actual examples. An important point that must be recognized in utilizing computers is that the computer is meant to be a part of method in resolving problems and its use itself is not conclusion. In other words, computers are a means of methodology. Computers have been used for frequency analysis in urophonograms, diagnosis in a simultaneous pressure-flow study in lower urinary tract, and for supporting the data entry by photoscanner. Moreover, computers have been used for digital differentiation to materialize higher performance uroflowmeter. Computers have also been applied to litholytic fluid pressure-flow control system for renal stones, and played important role in long hours's intra pelvic pressure monitoring system in support of the large amount of data accumulation and noise reduction. Recently, in the expert system in the pressure-flow study etc., computer plays an essential role which covers most territory of the system. Finally, its future applications have also been speculated.


[Complete testicular feminization syndrome associated with thermolabile androgen receptor].

Radioreceptor assay and thermostability test for the androgen receptor in two cases with complete testicular feminization syndrome were performed in regard to the fibroblasts cultured from genital skin on the basis of dispersed whole cell binding assay (Eil et al., 1980). No [3H]dihydrotestosterone binding to the androgen receptor was observed in case 1 (receptor negative), while maximum binding capacity and dissociation constant of androgen receptor for [3H]dihydrotestosterone in case 2 were 21000 sites per cell and 1.67 x 10(-10) M (receptor positive). The specific binding of [3H]dihydrotestosterone to the androgen receptor in case 2 decreased remarkably to 6.6% after high temperature (42 degrees C) incubation in comparison with that at 22 degrees C incubation. The specific binding of [3H]dihydrotestosterone to the androgen receptor in normal controls decreased down to 81.6% at high temperature incubation. Thermostability test was useful to demonstrate qualitative abnormality of androgen receptor in receptor positive testicular feminization syndrome.


[Monotherapy with extracorporeal shock wave lithotripsy for renal and ureteral stones].

We performed extracorporeal shock wave lithotripsy (ESWL) as a monotherapy using the Medstone STS lithotripter on 288 patients with renal and ureteral stones between June, 1989 and June, 1991. We compared our results with previous reports on ESWL as used in combination therapy. Our cases consisted of 121 patients with renal stones and 167 patients with ureteral stones. A total of 437 sessions of lithotripsy were performed on 288 patients, for an average of 1.52 sessions of lithotripsy per patient. The percentage of stones measuring less than 4.0 mm in diameter that were fragmented was 94.3% for renal stones and 87.6% for ureteral stones. The stone-free rates 3 months after ESWL were 60.3% and 90.4%, respectively. Our results of the monotherapy with ESWL did not differ from those reported on ESWL as used in combination therapy, in terms of the rate of stone destruction and stone-free rates. We studied the other reports carefully and determined that ESWL monotherapy could have been performed in most those cases. We concluded that ESWL monotherapy is an excellent therapeutic method in the light of fewer complications and side effects compared with those from combination therapy, and the fact that the rate of recurrence for renal and ureteral stones is high makes ESWL monotherapy very useful because the procedure can be repeated.