Okayama University Medical School

Concentrations of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in eleven brain regions of rats following acute and repeated ethanol administration: (a) an intraperitoneal (i.p.) injection of 1, 2, 3 or 4g ethanol/kg body weight and (b) i.p. injection of 1 or 2g ethanol/kg body weight for seven consecutive days. After acute administration, the concentrations of monoamines and their metabolites appeared to be altered in all brain regions examined except substantia nigra and dorsal amygdala, with maximal variation 2 or 3h after 3g ethanol administration. After repeated administration, the alterations following injections of 2.0g/kg were more marked than the injections of 1.0g/kg. Generally, the levels of NE, DA and 5-HT were decreased while the levels of HVA, DOPAC and 5-HIAA were increased with a few exception. The most prominent findings were seen in the striatum, nucleus accumbens and locus coeruleus. These data indicate that concentrations of monoamines and their metabolites can be determined simultaneously in discrete brain regions and that monoaminergic systems in the brain respond region-specifically to ethanol treatment.</P>

1. Sinomenine and Irgapyrin, the two antirheumatics known to be capable of releasing histamine, caused a marked gastric secretion in the unanesthetized dog. 2. The facial edema and itching associated with histamine release by sinomenine was almost completely eliminated by NeoAntergan, but the gastric secretion was not suppressed, or rather increased - an observation also reported by Paton and Schachter with Compound 48/80. This indicates that the histamine release cannot be markedly prevented by antihistamine agents in this animal. 3. The gastric secretion induced by Irgapyrin was not suppressed by Neo-Antergan but Irgapyrin originally never caused other symptoms associated with histamine release. This is probably due to the antihistamine action inherent in this compound itself. 4. No such histamine-releasing activity, as determined by gastric secretion, could be observed in aminopyrine or butazolidine sodium, the components of Irgapyrin. 5. Sinomenine, differing from Irgapyrin and Compound 48/80, was ineffective by intramuscular injection.

The effect of a change in cecal volume on gastric motility was studied in 24 h fasted rats anesthetized with urethane (0.8 g/kg, i.p.). A cecal volume increase from 1 to 10 ml (in 1 ml steps) produced a decrease in the basal tone of the stomach. The maximal inhibitory response was produced with an 8 to 10-ml increase in cecal volume. The gastric inhibitory response continued as long as the increased cecal volume was maintained. It was abolished by a combination of a splanchnicotomy and vagotomy, or only a splanchnicotomy in a few cases. The inhibition of gastric motility by increasing the cecal volume also occurred after severance of dorsal roots between T8 and L4 and gastric branches of vagus nerves. It is suggested that an increase in cecal volume induces gastric relaxation mainly via the splanchnico-splanchnic pathway and partly via the vago-vagal and vago-splanchnic pathways. Therefore, retardation in transit of the gastric contents in germ free rats having an enlarged cecum may be attributed to an enhancement of the ceco-gastric inhibitory reflex. The ceco-gastric inhibitory response mediated by the splanchnic pathway was abolished by guanethidine (3-5 mg/kg, i.v.), but the response mediated by the vagal pathway was resistant to guanethidine as well as to atropine (0.2 mg/kg, i.v.). This result indicates that splanchnic postganglionic efferents are adrenergic, while vagal postganglionic efferents are non-adrenergic and non-cholinergic.

Mice were trained in an avoidance learning task. The incorporation of 3H-leucine into the hippocampal regions of trained mice was higher than that of control mice. When mice were injected with cycloheximide, a strong inhibitor of protein synthesis, impairment was evident in acquisition of learning. Cycloheximide produced morphological changes in mitochondria and microtubules of some brain axons. It is suggested that the cycloheximide-induced learning impairment may be due to the blocking of the synthesis of the specific protein necessary of neutral conductivity.

The effects of immobilization stress on the pharmacokinetics of omeprazole were studied in rats. The immobilization stress for 30 or 60 min immediately after oral administration of the drug caused an increase in the time to reach the maximum concentration. However, such stress did not alter the area under the plasma concentration-time curve (AUC). When administered intravenously, the half-life during the elimination phase was significantly prolonged by 30 min of immobilization stress, but the AUC value remained unchanged. The intestinal propulsive activity was significantly decreased by immobilization stress. These findings suggest that immobilization stress reduces gastrointestinal motility. A resulting delay during the absorption phase of omeprazole occurs, although the degree of influence on overall pharmacokinetics is relatively insignificant.

In guinea pigs the lumen of an excised jejunal segment was perfused to study the effect of intraluminal pressure on the frequency of rhythmic contraction waves. Within the range of 0 to 40 mmH2O, increases in intraluminal pressure caused increases in the frequency of contraction waves. At pressures of 10, 15, 20, 30 and 40 mmH2O the frequency was 7.9, 9.0, 10.9, 12.5 and 13.3 per min (mean of ten preparations), respectively. An exponential relationship was proved to exist between the pressure and the frequency.

Our aim was to study the effect of iron supplementation on the following aspects of erythrocyte metabolism in experimental hyperthyroidism: glutathione (GSH) levels, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities. Hyperthyroidism induced by L-thyroxine administrations significantly raised erythrocyte GSH, GSH-Px and SOD levels of the rats (P < 0.001). Likewise, we observed that iron supplementation induced significant rises in erythrocyte GSH, GSH-Px and SOD levels (P < 0.001) as compared with the control group. The erythrocyte GSH, GSH-Px and SOD levels of hyperthyroidism-induced iron-supplemented animals were significantly higher when compared with either the iron-supplemented group (P < 0.001) or the only L-thyroxine-administered hyperthyroid group (P < 0.001, P < 0.05, P < 0.01, respectively). The results of this study show that L-thyroxine administration and/or iron supplementation increases GSH, GSH-Px and SOD levels of erythrocytes.

We examined the effect of leg hyperthermia on oxidative stress in bedridden subjects with type 2 diabetes mellitus using 15-min sessions of far infrared rays over a two-week period. Four subjects (male 1, female 3) incapacitated by a stroke were recruited for this study. All patients were admitted to Takahashi Central Hospital and ate the same hospital meals. Fasting plasma glucose, HbA1c, tumor necrosis factor (TNF)alpha, free fatty acid, leptin, adiponectin and plasma 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) levels as a marker of oxidative stress were measured on admission, just before and 2 weeks after local heating of the leg. Results showed that plasma total 8-epi-PGF2alpha levels were decreased significantly while TNFalpha levels were increased significantly. On the other hand, glucose, HbA1c, free fatty acid, leptin and adiponectin levels were not changed during the study period. These results suggest that repeated leg hyperthermia may protect against oxidative stress.

The effect of various non-depolarizing neuromuscular blocking agents (gallamine, pancuronium, vecuronium, d-tubocurarine, metocurine, atracurium and pipecuronium) on [³H] acetylcholine release in the response to field electrical stimulation was investigated in vitro in preparations of the guinea pig right atrium. In this preparation, atropine enhanced and oxotremorine, a muscarinic agonist, reduced the release of [³H] acetylcholine. Atropine reversed the inhibitory effect of oxotremorine in a concentration dependent manner, indicating that there is negative feedback modulation of acetylcholine release from the vagal nerve. While pancuronium, gallamine and atracurium enhanced the release of [³H] acetylcholine, d-tubocurarine, metocurine, vecuronium and pipecuronium did not affect it. Pancuronium and gallamine also reduced the inhibitory effect of oxotremorine and the K_d value of pancuronium for muscarinic receptors located on cholinergic nerve terminals was 2.31 μM. These findings indicate that pancuronium and gallamine enhanced the release of acetylcholine from the atrial parasympathetic nerve, probably by inhibiting presynaptic muscarinic receptors.

1. Attempts have been made to confirm how the formazan formation is affected in the presence of oxygen gas when the cells are incubated with neotetrazolium salt and the subsrtates for the enzymes to be tested. 2. In the cases of succinoxidase formazan formation is minimized under pure O2tension, it increases with decrease in O2 tension, and reaches its maximum value under N2gas. 3. This relationship between the oxygen tension and the diformazan formmation can likewise be observed even after pretreatment of the system with KCN. 4. In measuring enzyme activity of the DPN-diaphorase system with L-glutamate and DPN as substrate and NT as hydrogen acceptor, the same relationships between the oxygen tension and the NT-reduction can be seen as in succinoxidase system. 5. In the determination of enzyme activity of the cytochrome-c-cytochrome oxidase system with p-phenylene-diamine as substrate and NT as hydrogen acceptor, likewise the diformazan formation is markedly affected by oxygen tension and increased with the reduced oxygen tension but under pure Ns gas the value is reduced. When the systen is pretreated with KCN, however, the diformazan formation reveals its maximum value under pure nitrogen gas, the values of which correspond to those values of endogenous reaction without substrate. 6. The above results show that the neotetrazolium salt can compete with O2 as hydrogen acceptor, and less values of formazan formation may be obtained under higher oxygen tension and the higher values under lower oxygen tension independently from the true activity of the enzyme.

To assess the effects of service dogs on health-related quality of life (HRQOL), we conducted a survey of 10 service dog owners using SF-36v2 (Medical Outcomes Study 36 Item Short-Form Health Survey Version 2.0) and compared it with a matched control group of people with physical disabilities who did not have service dogs but were eligible for one. The scores for mental health and role emotional of service dog owners were relatively high, and their mental component summary was higher than the general population norm. These results indicate that service dogs affect the mentality of their owners. The comparison with the control group indicated that service dogs alleviate the mental burden of daily activities, and subjectively improved the physical functioning of their owners. This study showed that service dogs have positive functional and mental effects on their disabled owners.

Our aim was to clarify the effect of a somatostatin analogue (octreotide) on glucose flux in conscious dogs. We monitored the effects with catheters in the portal vein, hepatic vein and femoral artery and Doppler flow probes on the portal vein and hepatic artery before and after oral glucose administration. A significant increase of portal vein plasma flow after oral glucose was completely suppressed by both 4 and 1 μg/kg octreotide. All doses of octreotide (4, 1 and 0.1 μg/kg) suppressed the glucose-induced increment of arterial glucose by dose response. Only 4 μg/kg of octreotide slightly but significantly suppressed hepatic glucose output. Marked suppression and delayed glucose absorption by the intestine was observed after 4 μg/kg of octreotide. One and 0.1 μg/kg octreotide also suppressed glucose absorption without delayed absorption. Total amounts of absorbed glucose during 3h after oral glucose were 24 ± 11% with 4 μg/kg of octreotide, 37 ± 16% with 1 μg/kg of octreotide, and 48 ± 8% with 0.1 μg/ kg of octreotide, all of which were significantly less than that of the control (73 ± 8%). Using 4 μg/kg of octreotide treatment, the liver took up only 5 ± 4% of the absorbed glucose, while the liver took up 35 ± 6% and 43 ± 9% of the absorbed glucose with 1 and 0.1 μg/kg of octreotide. These latter values were similar to that of the control value of 34 ± 4%. In conclusion, we found that octreotide administered before oral glucose had a remarkable stabilizing effect on postprandial glycemic surges. Both the direct inhibitory effect of octreotide on portal vein plasma flow and impaired glucose absorption would contribute to this decreased postprandial hyperglycemia, while its suppressive effect on other hormones, such as insulin and glucagon, did not seem to influence the reduction of hyperglycemia.

The purpose of the study was to investigate the over-time effects of physical, psychological and social resources on the incidence of depression in family caregivers of the disabled elderly. Data were collected twice at a one-year interval from 1,141 primary caregivers of a disabled older person in an urban area of Japan using a self-reported questionnaire survey. The questionnaire included physical health as an indicator of physical resources, caregiving satisfaction and intention to care as indicators of psychological resources, and instrumental and emotional support network and formal home care service utilization as indicators of social resources. The mental health outcome measure was the General Health Questionnaire 12-item version (GHQ-12). Complete data on 235 non-depressed female caregivers were separated into 3 groups according to the relationship type (wife, daughter and daughter-in-law) and analyzed separately. Multivariate logistic regression models controlling for duration of caregiving, care-recipient's gender, ADL dependency and behavioral problems demonstrated that significant predictors of depression were caregiving satisfaction and intention to care in wives, caregiving satisfaction in daughters, and physical health and emotional support network in daughters-in-law. Noteworthy, intention to care increased the risk of depression in wives, while decreasing the risk of depression in daughters-in-law. The findings indicate that the effects of caregivers' resources on mental health may differ by relationship type.

The effects of exposure to cigarette smoke on the pharmacokinetics and pharmacodynamics of zonisamide, an antiepileptic drug, were investigated in rats. Absorption of oral zonisamide was significantly inhibited by exposure to cigarette smoke. The Cmax, T1/2 and the area under the plasma concentration-time curve 0-24 values in the cigarette smoke exposure group were significantly lower than those in the control group. Although tonic extension (TE) induced by maximal electroshock was completely blocked by the administration of zonisamide in the control group, 50% of rats showed TE in the cigarette smoke exposure group. Exposure to cigarette smoke influences both the pharmacokinetics and antiepileptic effects of zonisamide. The effects of smoking on epileptic patients using zonisamide warrants further attention.

Retinal cells from chick embryos aged 7.5 days of gestation were cultured for two months in a non-adherent suspension culture dish to study the effects of growth factors and co-culture with retinal pigment epithelial cells on their differentiation. Dissociated retinal cells became cellular aggregates (multicellular spheroids) within a day, and rosettes were formed in the spheroids after 2 days. Ultrastructurally, neurons of the rosettes developed connecting cilia, ellipsoids (accumulation of mitochondria), and external limiting membrane, indicative of their differentiation into photoreceptor cells. Epidermal growth factor enhanced the expression of rhodopsin by rosette-forming neurons, while basic fibroblast growth factor induced the growth of Mueller cells at 4 weeks, and their transdifferentiation into lens-epithelial-like cells at 8 weeks. Co-culture of retinal cells with retinal pigment epithelial cells enhanced the formation of rosettes in spheroids. Multicellular spheroids formed in a dish for suspension culture would provide a convenient in vitro system to examine differentiation and transdifferentiation of the retina.

The effects of high fatty acids such as oleic, richinoleic, linoleic, linolenic, palmitic and stearic acids, on the respiration, glycolysis, organic phosphate synthesis of Ehrlich ascites tumor cells, were studied. The unsaturated fatty acids added to the media enhanced the respiration of the tumor cells at the concentration lower than 0.2 mM, after a short incubation period and inhibited the respiration in a high concentration 0.4 mM. The saturated fatty acids did not show such effect. All the fatty acids, both of saturated and unsaturated, effected the increase in lactate formation in tumor cells, especially markedly at higher concentration being accompanied by the WQ increase and RQ around 1. The respiration lowered by the fatty acids was ameliorated by the addition of glucose. The lactate formation from glucose was greatly enhanced by the addition of fatty acids but hardly from pyruvate. The unsaturated high fatty acids proved to have a strong uncoupling action for oxidative phosphorylation. This effect could be recognized slightly in the saturated fatty acids. The addition of high fatty acid resulted in the striking decrease in ATP and ADP with the increase in AMP. With these results the discussion was conducted concerning the specificity of tumor cell related to the glucose and fatty acid metabolism.

This study focused on the effects of different intervals between sessions of a hypercholesterolemia education class on post-intervention outcomes. The same comprehensive group-programme contents on hypercholesterolemia were delivered either monthly (for 6 months) or twice-monthly (for 3 months) by the same teaching professionals in a community setting. The twice-monthly programme included 46 participants (male/female = 7/39, average age: 65.8 years)and the monthly programme consisted of 48(male/female = 9/39, age: 66.4). At the beginning of the study, all subjects belonged to the 'contemplation' stage of diet and exercise habits within the Transtheoretical Model of Change. The stage-matched intervention helped many participants move to the 'action ' stage by 6 months after the last session, especially in the twice-monthly group. The change rate of exercise from the 'contemplation' stage to the 'action' stage was significantly higher in the twice-monthly group (76.1 percent) than in the monthly (54.2 percent ). In both monthly and twice-monthly formats, participants' satisfaction and understanding levels at the end of the programme were high, but were significantly higher in the twice-monthly group. Through favorable lifestyles and higher levels of satisfaction and learning, the twice-monthly format may produce more positive results in cholesterol management than the monthly format, as the shorter period of time makes the programme more intensive.

The Doppler-derived ankle pressure index (API) is a useful indicator of the necessity for peripheral vascular reconstruction of the lower extremities. But the API at rest dose not reflect the functional capacity of leg circulation, especially in the early stage of disease. Therefore, an asymptomatic but hemodynamically significant lesion in one leg is sometimes missed by pressure measurement at rest when there is a severe lesion with symptoms in the other leg. In this study, the API not only at rest but also after exercise was measured in twenty normal subjects and thirty-two patients with angiographically proven arteriosclerosis obliterans. About 60% of the patients had unilateral symptoms, although they had significant disease bilaterally. The API after exercise proved to be more sensitive than the API at rest and may be useful in assessing asymptomatic legs of such patients and determining their surgical indication.

The human tumor H. Ep. #3 maintained in rats could be transferred for 1-8 generations in treated guinea pigs. H. Ep. #3 grew in the subcutaneous and intramuscular sites in each host at the same time. The treatment with the combination of X-ray 250 r. and 80 mg/kg of cortisone turned out to be the optimal conditioning studied. The number of tumor takes averaged 95.7-100 per cent in the subcutaneous site in guinea pigs treated with optimal conditioning, but in the intramuscular site, the number of tumor takes was 65.2-93.8 per cent. Host mortality varied from 4.2-37.5 per cent in the hosts treated with optimal conditioning. The subcutaneous tumor weights in hosts treated with optimal conditioning averaged 3.3 gm, and their intramuscular tumor weights averaged 5.6-6.2 gm. Tumor weights in hosts treated with only cortisone averaged 1-2 gm in both subcutaneous and intramuscular sites. Histological findings. for the original tumors were found to be the same as that for the successful transplanted tumors in the guinea pigs. The malignancy of the tumor was evaluated by the criteria of anaplasia, invasion, rapidity of growth, and ease of maintenance of transplants. There was no metastasis found in any organs.