Unusual spiral wave dynamics in the Kessler-Levine model of an excitable medium.

The Kessler-Levine model is a two-component reaction-diffusion system that describes spatiotemporal dynamics of the messenger molecules in a cell-to-cell signaling process during the aggregation of social amoeba cells. An excitation wave arising in the model has a phase wave at the wave back, which simply follows the wave front after a fixed time interval with the same propagation velocity. Generally speaking, the medium excitability and the refractoriness are two important factors which determine the spiral wave dynamics in any excitable media. The model allows us to separate these two factors relatively easily since the medium refractoriness can be changed independently of the medium excitability. For rigidly rotating waves, the universal relationship has been established by using a modified free-boundary approach, which assumes that the front and the back of a propagating wave are thin in comparison to the wave plateau. By taking a finite thickness of the domain boundary into consideration, the validity of the proposed excitability measure has been essentially improved. A novel method of numerical simulation to suppress the spiral wave instabilities is introduced. The trajectories of the spiral tip observed for a long refractory period have been investigated under a systematic variation of the medium refractoriness.

Selection of spiral waves in excitable media with a phase wave at the wave back.

Universal relationships between the medium excitability and the angular velocity and the core radius of rigidly rotating spiral waves in excitable media are derived for situations where the wave front is a trigger wave and the wave back is a phase wave. Two universal limits restricting the region of existence of spiral waves in the parameter space are demonstrated. The predictions of the free-boundary approach are in good quantitative agreement with results from numerical reaction-diffusion simulations performed on the Kessler-Levine model.

Is ACE gene polymorphism associated with lone atrial fibrillation?

ACE (angiotensin converting enzyme) gene genotypes have been shown to be a risk factor for development of left ventricular hypertrophy and cardiomyopathy, upon the assumption that the DD genotype is linked to higher cellular ACE activity leading to myocardial fibrosis. To test an analogous hypothesis that the DD genotype favors myocardial fibrosis in the atrium and thus promotes atrial fibrillation without any structural heart diseases, we determined the distribution of the ACE gene genotypes in 77 patients with lone atrial fibrillation and investigated the effects of the ACE genotypes on the clinical characteristics of atrial fibrillation. The distribution of ACE genotypes was not significantly different between the patients and healthy volunteers. Also, the ACE gene genotypes did not affect the types of atrial fibrillation and the age at the onset of atrial fibrillation. Thus, these results refuted the hypothesis of possible relationships between ACE genotypes and lone atrial fibrillation through myocardial fibrosis, and indicated some unknown differences between the atrium and ventricle.

Nonreentrant supraventricular tachycardia due to double ventricular response via dual atrioventricular nodal pathways.

Narrow and wide QRS tachycardias associated with various rhythm disturbances were recognized during 24-hour ambulatory eletrocardiographic monitoring in a 65-year-old man with coronary artery disease. Laddergram analysis revealed the presence of dual atrioventricular nodal pathways. Non-reentrant supraventricular tachycardia due to simultaneous fast and slow conduction through the dual atrioventricular nodal pathways was confirmed by electrophysiologic study. The atrial rate determined the occurrence of simultaneous conduction, and extrastimulation failed to induce a double ventricular response. Enhanced vagal activity was thought to play a critical role in provoking this phenomenon. Radiofrequency catheter ablation of the slow pathway eliminated the arrhythmias.

Activity of ecdysone analogs in enhancing N-acetylglucosamine incorporation into the cultured integument of Chilo suppressalis.

Ecdysone analogs with various side chains at the 17-position of the steroid structure enhanced the incorporation of N-acetylglucosamine as 20-hydroxyecdysone into the cultured integument prepared from Chilo suppressalis. Their activity in terms of the concentration required to give 50% of the maximum response varied with the structure. Piperonyl butoxide, an inhibitor of oxidation metabolism, did not enhance the in vitro effect of the compounds. The order of potency was ponasterone A > 20-hydroxyecdysone > cyasterone > inokosterone > makisterone A >> ecdysone.

Effect of isoproterenol on facilitation of electrical defibrillation by E-4031.

To determine whether isoproterenol could reverse enhancement of electrical defibrillation effectiveness by class III antiarrhythmic agents, we measured the internal defibrillation threshold (DFT) in 12 anesthetized dogs during infusion of (a) saline (baseline), (b) isoproterenol, (c) isoproterenol + E4031 (a new class III antiarrhythmic agent), and (d) E4031 alone. The isoproterenol infusion was adjusted so that heart rate (HR) was at least 30 beats/min greater than baseline. E4031 was given as a 40-micrograms/kg bolus at the beginning of the third stage of the study, followed by constant infusion at 2 micrograms/kg/min. Eight dogs completed the study. Although the energy-based DFT was not affected by isoproterenol (from 6.1 +/- 1.5 to 6.0 +/- 1.7 J), it was decreased to 3.7 +/- 1.6 J in the third stage by infusion of E4031 and isoproterenol (p < 0.01 vs. baseline and vs. isoproterenol). After the discontinuation of isoproterenol in the fourth stage, i.e., during infusion of E4031 alone, DFT was 3.4 +/- 1.6 J (p < 0.01 vs. baseline and vs. isoproterenol). Therefore, isoproterenol did not antagonize the effect of E4031 on the DFT, suggesting the possible clinical usefulness of class III agents for facilitating defibrillation even in the presence of augmented sympathetic activity.

Prolongation of intraventricular conduction time associated with fatal [correction of fetal] impairment of defibrillation efficiency during treatment with class I antiarrhythmic agents.

To test whether fatal deterioration of defibrillation efficiency during antiarrhythmic therapy can be prevented by avoiding extreme decrease in ventricular prevented by avoiding extreme decrease in ventricular conduction or toxic plasma drug levels, we determined the defibrillation threshold (DFT) before and during infusion of incremental doses of disopyramide (n = 8), mexiletine (n = 9), or flecainide (n = 9) in anesthetized dogs. Disopyramide did not alter DFT [from 4.4 +/- 1.5 to 4.4 +/- 1.6 J (3.1 +/- 1.2 micrograms/ml)]. Mexiletine tended to increase DFT [from 4.6 +/- 1.2 to 6.1 +/- 2.0 J (1.8 +/- 0.6 micrograms/ml); p < 0.05], and defibrillation eventually was unsuccessful in 3 of the 9 dogs. Although the plasma mexiletine level before refractory fibrillation was far beyond the human therapeutic range, prolongation of intraventricular conduction time (CT) was moderate (16 +/- 3%). Flecainide increased DFT from 4.2 +/- 1.3 to 6.1 +/- 1.5 J at a plasma level of 1.04 +/- 0.37 micrograms/ml (p < 0.0005). In 3 of 5 dogs that developed refractory fibrillation, plasma flecainide level before terminal ventricular fibrillation (VF) was not toxic, but prolongation of CT in the 5 dogs was remarkable (30 +/- 9%). Thus, VF resistant to defibrillation is not necessarily associated with both toxic plasma drug level and remarkably decreased conduction. Reliability of these valuables as indicators of fatally deteriorated defibrillation efficiency may vary among antiarrhythmic agents.

Attenuation of antifibrillatory effects of lidocaine by its metabolite, glycylxylidide: application of modulated receptor hypothesis.

Lidocaine, one of the drugs effective in treating ventricular arrhythmias in acute myocardial infarction (AMI), sometimes loses its efficacy after prolonged administration, possibly owing to the counteraction of glycylxylidide, one of the metabolites of lidocaine, through modulation of binding of lidocaine to sodium channels. To determine whether glycylxylidide interferes with the antiarrhythmic action of lidocaine, we compared the antifibrillatory effects of lidocaine, glycylxylidide, and their combination in 14 anesthetized open-chest dogs. Although glycylxylidide alone prolonged intraventricular conduction time (CT) and did not affect ventricular effective refractory period (VERP), it had different effects when added to lidocaine; i.e., it had no effect on intraventricular conduction time but shortened VERP. Although glycylxylidide alone did not change ventricular fibrillation threshold (VFT), the increase in VFT induced by lidocaine was decreased by addition of glycylxylidide, possibly as a result of competition for the same cardiac sodium channels between lidocaine and glycylxylidide with similar onset but different offset kinetics, which may explain, at least in part, the drug-resistance phenomena that ensue from prolonged lidocaine administration.

Contraction-excitation feedback in atrial reentry: role of velocity of mechanical stretch.

To determine the effects of atrial stretch on atrial flutter, we analyzed variations in atrial flutter cycle length (CL) caused by ventricular contraction in five dogs with artificially induced atrioventricular block. In contrast to absence of variations in CL during sustained ventricular asystole, atrial stretch by ventricular contraction consistently produced phasic variations in CL. The variations were not confined to any specific atrial sites, but depended on the time of ventricular contraction relative to atrial activation phase. The phase-response curve of the variations was closely related to that of the velocity of changes in the atrial pressure with no time lags, but not to that of the atrial pressure itself. Pharmacological denervation did not abolish the variations. Conventional electrophysiological study revealed greater changes in intra-atrial activation time by atrial stretch at a short pacing cycle length than at a longer one, suggestive of changes in repolarization by mechanical stretch. In conclusion, atrial stretch caused by ventricular contraction produces phasic variations in CL, the extent of which depends on the velocity of the mechanical stretch of atrial muscles.

Shock-induced refractory period extension and pharmacologic modulation of defibrillation threshold.

Shock-induced refractory period extension (RPE) has been suggested as a mechanism of electrical defibrillation. We measured RPE caused by localized field stimulation measured before and during infusion of disopyramide (n = 5), flecainide (n = 5), or E-4031 (n = 5) in anesthetized dogs and determined the effect of the drugs on the internal defibrillation threshold (DFT). In the baseline state (n = 15), 16 V/cm S2 field stimulation prolonged the effective RP by 36 +/- 15 ms (22 +/- 12% of RP without S2), whereas 4 and 8 V/cm S2 stimuli did not cause marked RPE. The RPE normalized by the RP without S2 was not significantly influenced by any drug (16 V/cm: disopyramide 30 +/- 11 vs. 27 +/- 11, flecainide 25 +/- 5 vs. 19 +/- 12, and E-4031 18 +/- 13 vs. 22 +/- 14%). Disopyramide did not alter the defibrillation threshold (4.2 +/- 0.6-4.4 +/- 0.6 J). In 2 dogs given flecainide, ventricular fibrillation became refractory to defibrillation. In contrast, E-4031 lowered the threshold from 4.5 +/- 2.4 to 2.2 +/- 1.2 J (p < 0.01). The results suggest that flecainide and E-4031 do not modulate defibrillation efficiency through their effects on RPE.

Slow abnormal conduction in the low right atrium: its anatomic basis and relevance to atrial reentry.

To characterize slow abnormal conduction in the low right atrium, which is known to be responsible for atrial flutter, electrophysiologic findings were correlated with anatomic features in a canine model of atrial flutter with ligation of the crista terminalis in the midright atrium. Activation in the low right atrium was mapped with a patch electrode containing 52 bipolar electrodes and a multiplexing system. A particular region in the low right atrium showed atrioventricular node-like electrophysiologic properties, a rate-dependent conduction delay, and Wenckebach periodicity. This area coincided with an area responsible for slow conduction during atrial flutter and unidirectional block at its initiation. Both pilsicainide and E-4031 preferentially blocked conduction in the specific area, leading to the termination of atrial flutter. Although refractoriness could not explain the abnormal conduction, anatomic studies consistently found the specific region to be in or around a thick muscle bundle, that is, the crista terminalis, or a thick pectinate muscle branching from the crista, located perpendicular to the wavefront of the pacing impulse and atrial flutter. These electrophysiologic and anatomic findings suggest that slow abnormal and atrioventricular node-like conduction over a thick muscle bundle, which is a normal anatomic feature of the low right atrium, plays a role in the initiation, maintenance, and termination of atrial reentry.

Parasympathetic activity is a major modulator of the circadian variability of heart rate in healthy subjects and in patients with coronary artery disease or diabetes mellitus.

Autonomic heart rate control was assessed by power spectral analysis of heart rate variability in 24-hour ambulatory electrocardiographic recordings from 23 healthy subjects, 14 patients with coronary artery disease without cardiac dysfunction, and 14 patients with diabetes mellitus. The log value of the ratio of the low-frequency component (LF = 0.04 to 0.15 Hz) to the high-frequency component (HF = 0.15 to 0.5 Hz) and logHF were employed as indexes of sympathetic and parasympathetic activity, respectively. Diurnal and nocturnal logLF, logHF, and log(LF/HF) values were calculated for heart rates of 60, 70, and 80 beats/min. Intergroup differences among these three variables were not significant at any heart rate. Although a heart rate-related decrease in logHF was generally observed, the relationship between log(LF/HF) and heart rate was not consistent. The correlation between diurnal and nocturnal logHF values was significant at all three heart rates (r = 0.63, 0.87, and 0.59), whereas the diurnal log(LF/HF) was correlated with the nocturnal value only at 70 beats/min (r = 0.77). These results suggest that the heart rate during normal daily activities is a reliable indicator of parasympathetic tone, if not sympathetic tone, in healthy subjects and patients with coronary artery disease or diabetes mellitus.

Autonomic nervous system activity in idiopathic dilated cardiomyopathy and in hypertrophic cardiomyopathy.

To assess autonomic nervous activity in patients with cardiomyopathies, analysis of heart rate variability was performed using 24-hour ambulatory electrocardiograms in 14 patients with idiopathic dilated cardiomyopathy (IDC), 15 with hypertrophic cardiomyopathy (HC) and 18 healthy subjects. Heart rate variability during the night and daytime was calculated using fast-Fourier transform, and power spectra were quantified in 2 frequency bandwidths: 0.00 to 0.15 Hz (low-frequency power [LF]) and 0.15 to 0.50 Hz (high-frequency power [HF]). Log(HF) was used as an index of parasympathetic nervous activity, and log(LF/HF), of sympathetic nervous activity. Log(HF) was significantly lower and log(LF/HF) was significantly higher in IDC. These changes were related to ejection fraction. In HC, lower log(HF) and higher log(LF/HF) were recognized only during the night, and these changes were independent of the degree of myocardial hypertrophy. Our results indicated attenuation of parasympathetic activity and enhanced sympathetic activity in HC during the night, and also in IDC. Assessment of autonomic imbalance by analysis of heart rate variability may be useful for understanding the pathophysiology of cardiomyopathies.

[Cefpiramide: antibacterial activity, pharmacokinetics, and clinical evaluation].

We determined MIC values of cefpiramide (CPM) against clinical isolates from 100 patients who were subjected to total hysterectomy between April 1986 and March 1988. We also investigated the concentrations of CPM in uterine tissue and assessed the clinical efficacy of postoperative prophylaxis. 1. Against bacteria isolated from clinical materials the MIC80 values of CPM were as follows: Staphylococcus epidermidis 1.56 micrograms/ml, Enterococcus faecalis 25 micrograms/ml, and Escherichia coli 6.25 micrograms/ml. 2. Peak concentrations of CPM in various tissues and tissue/serum ratios of AUC were as follows: cervix uteri 35 micrograms/g (39.5%), perimetrium 43 micrograms/g (44.9%), endometrium 39 micrograms/g (51.6%), myometrium 28 micrograms/g (26.8%), oviduct 67 micrograms/g (41.9%), and ovary 27 micrograms/g (45.8%). In all tissues examined CPM concentrations were above 4 micrograms/g after 600 minutes. 3. Serum half-lives were T 1/2(alpha) = 13.2 minutes and T 1/2(beta) = 260.2 minutes. 4. The efficacy rate in postoperative prophylaxis was 97.9%. 5. No serious side effects were observed.

[Pharmacokinetic and clinical studies on latamoxef in the field of obstetrics and gynecology].

Latamoxef (LMOX) 1 g was administered twice daily for 5 days to patients undergoing operation for myoma uteri and the time course of tissue concentrations of the drug and the prophylactic effect of the treatment on postoperative infection were studied. 1. Area under concentration-time curve (AUC) of LMOX was the highest in the perimetrium (45.3%), followed by the cervix uteri (39.2%), endometrium (35.9%), oviduct (35.1%), myometrium (29.5%), and ovary (24.4%). 2. Cmax was the highest in oviduct (46.9 micrograms/g), followed by Cmax's in perimetrium (44.2 micrograms/g), cervix uteri (35.8 micrograms/g), myometrium (26.9 micrograms/g), endometrium (25.6 micrograms/g), and ovary (24.3 micrograms/g). 3. Serum half-lives were T1/2(alpha) = 0.27 hour and T1/2(beta) = 1.81 hours. 4. Prophylactic efficacy against postoperative infections was 94.3%, and febrile morbidity was 5.7%. The preoperative and postoperative laboratory tests did not show appreciable changes, no adverse reaction was observed. In the present study, LMOX showed good transfer into gynecological tissues, suggesting its very high usefulness in the treatment of infection and in the postoperative management.

[Intraperitoneal versus intravenous infusion of cis-platinum in advanced ovarian cancer--examination of pharmacokinetics].

The pharmacokinetics of i.p.- and i.v.-infused cis-platinum (55 mg/m2) was studied in five patients with advanced ovarian cancer. The area under the concentration time (AUC) of non-protein-binding platinum in ascites had on anti-tumor activity 44 times larger with i.p. infusion than that with i.v. infusion. Comparing with the concentration curve of non-protein-binding platinum in plasma, there was little difference between i.p. and i.v. infusion, and the AUC of non-protein-binding platinum was almost equal between i.p. and i.v. infusion. In cases of low renal function, cisplatin was infused at 70 mg/m2 with sodium thiosulfate (STS). The AUC of ultrafiltrable platinum in plasma was 3 times larger in STS combination therapy. Therefore, STS was confirmed to be a powerful antidote against cis-platinum in plasma. Amounts of total platinum in 24-h urinary secretion were slightly less for i.p. than for i.v. infusion. Consequently, i.p. infusion of cis-platinum was shown to be highly effective on the local site and as effective as i.v. infusion on the whole body. Moreover, this route is effective for reducing ascites production and is expected to be effective against metastatic sites other than the abdominal cavity.

[Flow cytometric DNA analysis of gynecologic malignant tumors using paraffin-embedded tissue].

We have studied flow cytometric DNA analysis of gynecologic malignant tumors using paraffin-embedded tissue for histopathology. A close correlation was observed between the DNA indices obtained from fresh unfixed tissue and from paraffin-embedded tissue (r = 0.993). The coefficient of variation (CV) for the diploid G0G1 peak of the paraffin-embedded tissue was one and half greater than that obtained from fresh tissue on the average. In the DNA analysis of 64 endometrial carcinomas, DNA aneuploidy was detected in 3% of nuclear grade 1, in 25% of nuclear grade 2 and in 63% of nuclear grade 3. That is, the more abnormal the nuclear findings, the higher the percentage of DNA aneuploidy. In the analysis of 48 ovarian tumors, DNA aneuploidy was detected in 79% of serous adenocarcinoma, in no of mucinous adenocarcinoma, in 17% of endometrioid carcinoma, in all of clear cell carcinoma and dysgerminoma, that is, its incidence was different among histological subtypes.

[Ultrastructural study of the intercellular junction and lanthanum penetration in the mouse blastocyst].

Cell junctions in mouse blastocyst were ultrastructurally investigated with or without lanthanum tracer. Tight junctions, gap junctions and desmosomes were observed in the trophectoderm. The tight junction was located near the zona pellucida in all trophoblast interspaces, whereas the gap junction and the desmosome, which were infrequently observed, were localized far from the zona pellucida. However, the desmosomes in the trophectoderm of the expanded blastocyst after culture increased in number and came to be located near the zona pellucida. The trophoblast layer excluded lanthanum whose invasion was interrupted by the tight junction. There were a few intermediate junctions in the interspace between the trophoblast and the inner cell mass cell as well as between the inner cell mass cells. These findings indicate that a substances whose molecular weight exceeds that of lanthanum (138.9) may not flow into the blastocyst through the intercellular space. Moreover, it is speculated that the intercellular connection is strengthened during the expansion of the blastocyst.