Reconstructing bifurcation diagrams only from time-series data generated by electronic circuits in discrete-time dynamical systems.

Bifurcation-diagram reconstruction estimates various attractors of a system without observing all of them but only from observing several attractors with different parameter values. Therefore, the bifurcation-diagram reconstruction can be used to investigate how attractors change with the parameter values, especially for real-world engineering and physical systems for which only a limited number of attractors can be observed. Although bifurcation diagrams of various systems have been reconstructed from time-series data generated in numerical experiments, the systems that have been targeted for reconstructing bifurcation diagrams from time series measured from physical phenomena so far have only been continuous-time dynamical systems. In this paper, we reconstruct bifurcation diagrams only from time-series data generated by electronic circuits in discrete-time dynamical systems with different parameter values. The generated time-series datasets are perturbed by dynamical noise and contaminated by observational noise. To reconstruct the bifurcation diagrams only from the time-series datasets, we use an extreme learning machine as a time-series predictor because it has a good generalization property. Hereby, we expect that the bifurcation-diagram reconstruction with the extreme learning machine is robust against dynamical noise and observational noise. For quantitatively verifying the robustness, the Lyapunov exponents of the reconstructed bifurcation diagrams are compared with those of the bifurcation diagrams generated in numerical experiments and by the electronic circuits.

Heart rate variability in response to psychological test in hand-arm vibration syndrome patients assessed by frequency domain analysis.

To investigate heart rate variability in response to psychological tests (Japanese version of Stroop color word test and mirror drawing test) in 29 hand-arm vibration syndrome (HAVS) patients, 16 of them with vibration-induced white finger (VWF) and 13 without VWF, and 10 healthy controls of similar age, heart rate variability during spontaneous and deep (6 cycles a minute) breathing in supine position before and after exposure to the psychological tests was examined calculating frequency domain components such as low frequency (LF) power-index of both the sympathetic and parasympathetic activity, high frequency (HF) power-index of the parasympathetic activity and LF/HF-index of the sympathovagal balance. The group of all patients and the group without VWF indicated significant increase in LF/HF in the deep breathing measurement after exposure to the psychological tests. The result suggests that the sympathetic tone in the sympathovagal balance predominated in the HAVS patients which means that they had larger sensitivity of the sympathetic nervous system to the psychological tests.

A novel series of N-(hexahydro-1,4-diazepin-6-yl) and N-(hexahydroazepin- 3-yl)benzamides with high affinity for 5-HT3 and dopamine D2 receptors.

A novel series of benzamides with a hexahydro-1,4-diazepine or hexahydroazepine ring in the amine moiety were prepared, and their binding affinities for 5-HT3 and dopamine D2 receptors were evaluated. The R isomer of the 1-ethyl-4-methylhexahydro-1,4-diazepinylbenzamide (R)-22 had potent affinity for both receptors. The R-enantiomer of the corresponding 1-ethylhexahydroazepinylbenzamide 28 showed potent affinity for dopamine D2 receptors with reduced affinity for 5-HT3 receptors, while the S isomer was found to be a potent and selective 5-HT3 receptor antagonist.

Synthesis and biological activity of 4-amino-5-chloro-2-ethoxy-3-hydroxybenzamides, metabolites of a new gastroprokinetic agent, mosapride.

To confirm the proposed structures of the minor metabolites of a potential gastroprokinetic agent, mosapride, 4-amino-5-chloro-2-ethoxy-3-hydroxy-N-(2-morpholinylmethyl)benzamide (3) and the N-(5-oxo-2-morpholinyl)-methyl analogue 4 were prepared. As the common intermediate, 2-ethoxy-3-hydroxy-4-nitrobenzoic acid (15) was prepared via the regioselective ethylation of 2,3-dihydroxybenzaldehyde (10) and subsequent nitration of the resultant 2-ethoxy-3-hydroxybenzaldehyde (11). The key intermediate 15 was converted into the benzamides 3 and 4. After enzymatic treatment of the isolated metabolites, their structures were identified by comparison with the synthetic compounds. Serotonin-4 receptor binding affinity of these metabolites was found to be lower than that of mosapride.

Urinary excretion of aluminium: effects of aging and diurnal variation.

Aluminium (Al) is neurotoxic and a relationship between Alzheimer's disease (AD) and Al in drinking water has been suggested in epidemiological studies. In 5 patients with AD, and healthy subjects of whom 5 were aged, 6 were middle-aged and 6 were young adults, Al excretion into the urine was measured using inductively coupled plasma emission spectro-analysis. In healthy subjects, there appeared to be a relationship between age and daily Al excretion, with the highest level in the aged group, followed by the middle-aged and young adult groups. A significant positive correlation between the amount of urine and the Al excretion in the healthy subjects was also observed. Daily A1 excretion in urine in the group of patients with AD tended to be higher than that of the age matched healthy group, but further studies are needed to account for effects of drugs containing Al compounds. The Al excretion in all the groups showed some variation with the time of day, but no definite diurnal variation common to all the subjects was noted. Because of this, the use of spot urine analysis for studying A1 excretion does not seem to be reliable.

Development of potent serotonin-3 (5-HT3) receptor antagonists. II. Structrue-activity relationships of N-(1-benzyl-4-methylhexahydro-1H-1,4- diazepin-6-yl)carboxamides.

Our studies on 4-amino-5-chloro-2-ethoxybenzamides led to the discovery that the N-(1,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)benzamide 9 and the 1-benzyl-4-methylhexahydro-1H-1,4-diazepine analogue 10 are potent serotonin-3 (5-HT3) receptor antagonists. Structure-activity relationship (SAR) studies on the influence of the aromatic nucleus of 9 and 10 upon inhibition of the von Bezold-Jarisch reflex in rats are described. Heteroaromatic rings such as pyrrole, thiophene, furan, pyridine, pyridazine, 1,2-benzisoxazole, indole, quinoline, and isoquinoline rings showed weak 5-HT3 receptor antagonistic activity. Within this series, use of the 1H-indazole ring as an aromatic moiety led to a substantial increase of the activity; the 1H-indazolylcarboxamides 54, 57, 97, and 102 showed potent 5-HT3 receptor antagonistic activity. The optimal compound identified via extensive SAR studies was N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indaz ole-3- carboxamide (54), whose effect was superior to that of the corresponding benzamide 10 and essentially equipotent to those of ondanbsetron (1) and granisetron (4).

Development of potent serotonin-3 (5-HT3) receptor antagonists. I. Structure-activity relationships of 2-alkoxy-4-amino-5-chlorobenzamide derivatives.

A new series of 2-alkoxy-4-amino-5-chlorobenzamide derivatives bearing five- to seven-membered heteroalicyclic rings in the amine moiety was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity by assaying the ability to antagonize the von Bezold-Jarisch reflex in rats. The five- to seven-membered heteroalicycles comprise pyrrolidine, morpholine, 1,4-thiazine, piperidine, piperazine, 1,4-oxazepine, 1,4-thiazepine, azepine, and 1,4-diazepine rings. Among them, some benzamide derivatives having a 1,4-diazepine ring showed a potent 5-HT3 receptor antagonistic activity. In particular, 4-amino-5-chloro-N-(1,4-dimethylhexahydro-1H-1,4-diazepin-6- yl)-2- ethoxybenzamide (96) and the 1-benzyl-4-methylhexahydro-1H-1,4-diazepine analogue 103 showed potent 5-HT3 receptor antagonistic activity without 5-HT4 receptor binding affinity.

Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxybenzamides with six- and seven-membered heteroalicycles as potential gastroprokinetic agents.

A new series of 4-amino-5-chloro-2-ethoxybenzamides 3b--f and 5--8 bearing six- and seven-membered heteroalicycles was prepared and evaluated for gastroprokinetic activity. Compounds 3b--e, derived by replacement of the morpholine oxygen of 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5- chloro-2-ethoxybenzamide (3a) with other atoms (sulfur, nitrogen and carbon), generally exhibited a potent gastric emptying activity. N-(4-Benzyl-3-morpholinyl)methylbenzamide (5a) and its analogues 5b--e had weaker activity. However, N-(4-benzyl-3-morpholinyl)ethylbenzamide 8 was as potent as 3a. Benzamides 6a--e, having seven-membered heteroalicycles, showed fairly potent activity. Molecular superimpositions of 5a, 6a and 8 upon 3a using computer graphics suggested that the direction of the N-benzyl group greatly influences the gastric emptying activity, whereas the location of the alicyclic nitrogen is less critical.

Synthesis and biological activities of metabolites of mosapride, a new gastroprokinetic agent.

In order to confirm the proposed structures of two metabolites 3 and 4 of the gastroprokinetic agent mosapride [4-amino-5-chloro-2-ethoxy-N-([4-(4-fluorobenzyl)-2-morpholinyl] methyl)benzamide, 2], the compounds were synthesized and their biological activity was examined. The structures of the metabolites were confirmed by means of comparison with the synthetic compounds. The serotonin 5-HT4 receptor agonistic activities of the metabolites were found to be less than that of mosapride.

Response to psychological stressors in hand-arm vibration syndrome patients.

We investigated urinary catecholamines' response to acute psychological stress test in hand-arm vibration syndrome patients. Thirteen patients with vibration-induced white finger (VWF) in higher frequency of attack, 7 patients with VWF in lower frequency, 6 patients without VWF and 17 healthy subjects were examined. All subjects were male and their average age (SD) was 59.2 (6.4), 56.3 (2.9), 58.2 (4.7) and 56.8 (4.9), respectively. After an initial rest for 1 hour, acute psychological stress test with stressors--mirror drawing, watching horror video and arithmetic under intermittent noise was performed for 1 hour. Subjective complaints to the stress test were greater in patients with hand-arm vibration syndrome than in the healthy controls. The patient group with VWF in higher frequency indicated significant increases of urinary catecholamines (p < 0.05); average values (SD) at rest period and at stress test were 2.42 (1.17) and 3.71 (1.82) micrograms/h for norepinephrine, and 1.47 (0.73) and 2.66 (1.79) micrograms/h for epinephrine, respectively. Increasing tendency of urinary catecholamines was observed in other three groups, however, they were not statistically significant. The sympathoadrenal medullary response to psychological stressors increased especially in hand-arm vibration syndrome patients with VWF in higher frequency.

Synthesis and biological activities of the optical isomers of (+/-)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl]benzamide (mosapride).

The enantiomers, (S)-(-)-1 and (R)-(+)-1, of (+/-)-4-amino-5-chloro-2-ethoxy- N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (mosapride) [(+/-)-1], a new and selective gastroprokinetic agent, were prepared from optically active [4-(4-fluorobenzyl)-2-morpholinyl]methylamines (S)-(-)-4 and (R)-(+)-4, respectively. The requisite (S)-(-)-4 and (R)-(+)-4 were prepared by optical resolution of [4-(4-fluorobenzyl)-2-morpholinyl]methyl p-toluenesulfonate [(+/-)-5] using (-)- and (+)-N-(p-toluenesulfonyl)glutamic acids, followed by amination of the tosyloxy groups of (R)-(-)-5 and (S)-(+)-5, respectively. The absolute configurations of (R)-(-)-5 and (S)-(+)-5 were determined on the basis of an asymmetric synthesis of (R)-(-)-5 from (S)-(+)-benzyl glycidyl ether [(S)-(+)-11]. Mosapride and its enantiomers, (S)-(-)-1 and (R)-(+)-1, were essentially equipotent in serotonin 5-HT4 receptor agonistic activity on the electrically evoked contractions in isolated guinea pig ileum.

Novel benzamides as selective and potent gastrokinetic agents. IV. Synthesis and structure-activity relationships of 2-substituted 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chlorobenzamides.

A new series of 2-substituted 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chlorobenzamides (4-39) including a few 4-fluorobenzyl analogues were prepared and evaluated for their gastrokinetic activity by determining their effects on the gastric emptying activity of phenol red semisolid meal in rats. The C-2 substituent comprises alkoxy and variously substituted alkoxy groups. Among the derivatives, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-2-(n-butoxy)-5-chlorobenza mide (5), its 4-fluorobenzyl (6), and 3-methyl-2-butenyloxy analogues (22) were superior to cisapride and essentially equipotent to the 2-ethoxy analogue (1b, AS-4370 as its citrate) in gastrokinetic activity. These compounds, like AS-4370, had no dopamine D2 receptor antagonistic activity.

Novel benzamides as selective and potent gastrokinetic agents. III. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-methoxy- and 2-ethoxy-N-[(4-substituted 2-morpholinyl)methyl]-benzamides.

A series of 4-amino-5-chloro-2-methoxy- and 2-ethoxy-N-[(4-substituted 2-morpholinyl)methyl]benzamides (11-64) were prepared and evaluated for gastrokinetic activity by determining their effects on the gastric emptying of phenol red semisolid meal in rats. The N-4 substituent includes alkyl, phenoxyalkyl, (4-fluorobenzoyl)alkyl, and heteroarylmethyl groups. The benzamide derivatives, having an isopropyl, isoamyl, neopentyl, 3-(4-chlorophenoxy)-propyl, or pyridylmethyl group at N-4, showed potent in vivo gastric emptying activity. In particular, 4-amino-5-chloro-2-ethoxy-N-[[4-(3-pyridylmethyl)-2- morpholinyl]methyl]benzamide (57b) was equipotent to the 4-fluorobenzyl analogue 1b (AS-4370 as its citrate) in the gastrokinetic activity on phenol red semisolid meal in rats and mice, and on resin pellet solid meal in rats. Moreover, compound 57b was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests. Structure-activity relationships of compounds with various substituents at N-4 are also discussed.

Novel benzamides as selective and potent gastrokinetic agents. 2. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl] benzamide citrate (AS-4370) and related compounds.

The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.

Novel benzamides as selective and potent gastric prokinetic agents. 1. Synthesis and structure-activity relationships of N-[(2-morpholinyl)alkyl]benzamides.

With the purpose of obtaining more potent and selective gastric prokinetic than metoclopramide (1), a new series of N-[(2-morpholinyl)alkyl]benzamides (17-52) were synthesized and their gastric prokinetic activity was evaluated by determining effects on the gastric emptying of phenol red semisolid meal and of resin pellets solid meal in rats and mice. The morpholinyl moiety was newly designed after consideration of the side-chain structure of cisapride (2) and produced the desired activity when coupled with the 4-amino-5-chloro-2-methoxybenzoyl group of both metoclopramide and cisapride. Modification of the substituents of the benzoyl group markedly influenced the activity. In particular, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (17) and the 4-(dimethylamino) and 2-ethoxy analogues (25 and 29) of 17 showed potent and selective gastric prokinetic activity along with a weak dopamine D2 receptor antagonistic activity.

[A study of the state-trait anxiety inventory (STAI) and its application to noise stress].

By using the STAI developed by Spielberger et al. we have investigated the validity and reliability of two scales, that is, State Anxiety (A-State) and Trait Anxiety (A-Trait), and at the same time have examined them under various conditions. The results obtained are as follows: 1) As a result of factor analysis concerning 40 items of the STAI used in this research, we have confirmed that both A-State and A-Trait have independent factor structures of their own, and that the items of the scales also carry their own validity. 2) After due consideration of the test-retest reliability of the two scales, we have found that A-Trait has rather high stability. Moreover, we have noticed that Cronbach's alpha coefficients, which show the reliability of the two scales, are high. In consequence, we have confirmed the high reliability of the two scales. 3) In comparing the scores of A-State and A-Trait obtained from young healthy people with those from healthy aged people, we have noticed that the aged get low scores on each of the two scales, and that each score distribution shows an excellent fit to the normal one. 4) We have found that A-State scores go up significantly when people are in a condition of emotional stress, but that there is not any change of A-Trait scores. 5) We have observed a significant increase of A-State scores at each noise level over 75 dB(A).(ABSTRACT TRUNCATED AT 250 WORDS)