Mid-diastolic potential is related to the reentrant circuit in a patient with verapamil-sensitive idiopathic left ventricular tachycardia

We report a case of verapamil-sensitive idiopathic ventricular tachycardia in which a mid-diastolic potential (MDP) 45 msec preceding the Purkinje potential (P potential) was recorded. Pacing during the tachycardia caused concealed entrainment, and the stimulus-QRS interval was equal to the P potential-QRS interval. The interval between the last pacing stimulus and the next P potential (postpacing interval) was longer than the ventricular tachycardia cycle length, but the MDP was orthodromically activated. These findings suggest that the MDP was on the reentrant circuit and the P potential was not on the reentrant circuit, but a bystander.     

Isolation and characterization of high-osmolarity-sensitive mutants of fission yeast

For the fission yeast Schizosaccharomyces pombe, adaptation to high-osmolarity medium is mediated by a mitogen-activated protein (MAP) kinase cascade, involving the Wis1 MAP kinase kinase and the Sty1 MAP kinase. The MAP kinase pathway transduces an osmotic signal and accordingly regulates the expression of the downstream target gene (gpd1(+)) that encodes NADH-dependent glycerol-3-phosphate dehydrogenase, in order to adaptively accumulate glycerol inside the cells as an osmoprotectant. We previously characterized a set of high-osmolarity-sensitive S. pombe mutants, including wis1, sty1, and gpd1. In this study, we attempted to further isolate novel osmolarity-sensitive mutants. For some of the mutants isolated, profiles of glycerol production in response to the osmolarity of the growth medium were indistinguishable from that of the wild-type cells, suggesting that they are novel types. They were classified into three distinct types genetically and, thus, were designated hos1, hos2, and hos3 (high osmolarity sensitive) mutants. One of them, the hos1 mutant, was characterized in detail. The hos1 mutant was demonstrated to have a mutational lesion in the known ryh1(+) gene, which encodes a small GTP-binding protein. Disruption of the ryh1(+) gene results not only in osmosensitivity but also in temperature sensitivity for growth. It was also found that the delta ryh1 mutant is severely sterile. These results are discussed with special reference to the osmoadaptation of S. pombe.     

Strictly Conserved Residues in Euphorbia tirucalli β‐Amyrin Cyclase: Trp612 Stabilizes Transient Cation through Cation–π Interaction and CH–π Interaction of Tyr736 with Leu734 Confers Robust Local Protein Architecture

The functions of Trp612, Leu734, and Tyr736 of Euphorbia tirucalli β‐amyrin synthase were examined. The aliphatic variants (Ala, Val, Met) of Trp612 showed almost no activity, but the aromatic variants exhibited high activities: 12.5 % of the wild‐type activity for the W612H variant, 43 % for W612F, and 63 % for W612Y. That is, the enzymatic activities of the variants increased in proportion to the increase in π‐electron density. Thus, the major function of Trp612 is to stabilize transient cations through a cation–π interaction. The Phe and Tyr variants caused a distorted folding conformation, especially at the E‐ring site, which generated the aberrantly cyclized products germanicol and lupeol. The L734G and L734A variants exhibited significantly decreased activities but yielded taraxerol in a high production ratio. The Val, Ile, and Met variants showed markedly high activities (56–78 % of wild‐type activity); therefore, appropriate steric bulk is required at this position. The aliphatic variants of Tyr736 showed markedly decreased activities, but the Phe mutant exhibited high activity (67 %), which indicates that the π electrons are critical for catalysis. Homology modeling indicated that Tyr736 and Leu734 are perpendicular to the substrate and are situated face to face, which suggests that a CH–π interaction occurs between Tyr736 and Leu734, reinforcing the protein architecture, and that Tyr736 cannot stabilize cationic intermediates through a cation–π interaction.     

Synthesis and biodegradation of copolyesterether of copoly(succinic anhydride/ethylene oxide) with polyether

The thermal properties and biodegradability of block copolyesterethers based on copoly[succinic anhydride (SA)/ethylene oxide (EO)] (polymer composition range SA/EO 42/58–49/51 mol %), synthesized by ring-opening copolymerization and poly(ethylene glycol) (PEG) or poly(propylene glycol) (PPG), were studied. The block copolyesterethers synthesized from higher than 7000 molecular weight (M_n) or high SA content copoly(SA/EO), SA/EO = 48/52 or 49/51, and PEG showed melting points and fusion heats (ΔH) similar to those of the prepolymers without leading to a microphase-separation structure. Enzymatic degradability of the block copolyesterethers synthesized from biodegradable copoly(SA/EO) with a low SA content (SA/EO = 42/58 mol %) and PEG was significantly smaller compared to that of the chain-extended copoly(SA/EO) used as a prepolymer. On the other hand, the block copolymers synthesized by an equimolar amount of copoly(SA/EO) and PPG showed evidence of a microphase-separation structure. An increase in propylene glycol (PG) content interfered with the formation of a microphase-separation structure. However, the block copolyesterethers including nonbiodegradable copoly(SA/EO), with a high SA content (SA/EO = 49/51 mol %), and PPG were found to be enzymatically degradable. In the biodegradation testing with standard activated sludge, the block copolyesterethers were degraded by microorganisms in activated sludge. The relationship between polymer composition and the biodegradation rate by activated sludge shows a similar trend to that of enzymatic hydrolysis. © 1998 John Wiley & Sons, Inc. J Appl Polym Sci 68: 2095–2106, 1998     

New interpretation and management of dry lung syndrome: a case report

A premature female infant with life-threatening respiratory distress which was diagnosed as 'dry lung syndrome' is reported. The mother had 4 weeks of large volume leakage of the amniotic fluid due to premature rupture of the fetal membranes (PROM) at 23 weeks' gestation. The infant was born after 27 weeks' gestation (birthweight, 1016 g) and was suffering severe respiratory distress. Although a chest radiogram and gastric juice microbubble test did not improve the possibility of respiratory distress syndrome (RDS), very high ventilator settings did not improve her respiratory disorders. Considering the infant's deteriorating respiratory status and the prolonged leakage of the amniotic fluid, we suspected the presence of pulmonary hypoplasia. Although an attempt at high frequency oscillation (HFO) to rescue this infant had no effect, intratracheal instillation of epinephrine (EP) showed dramatic improvement of her respiratory status. This clinical course showed that the patient did not have pulmonary hypoplasia but might have severe airway obstruction and this airway obstruction may be the major cause of 'dry lung syndrome'. We postulate that when a newborn with suspected pulmonary hypoplasia is unresponsive to respiratory support. HFO should be administered. If HFO is ineffective in relieving the respiratory distress, one should suspect the presence of airway collapse and administer a bronchodilator such as EP. If the infant improves, a diagnosis of 'dry lung syndrome' may be assumed.     

Phase I study of raltitrexed (ZD-1694)

A multicenter cooperative phase I study of ZD-1694 (raltitrexed), a novel, folate-based thymidylate synthase (TS) inhibitor, was conducted with single and repeated doses in 30 patients with various malignant tumors. ZD-1694 was intravenously infused over 15 minutes. In the single-dose study, the initial dose was fixed at 1.0 mg/m2 (1n), and the dose was escalated stepwise up to 3.5 mg/m2 (3.5 n). Based on the results of the single-dose study, in the repeated-dose study, doses of 2.5 n and 3 n were infused every three weeks (3 weeks/one course). In principle, patients received 2 courses or more. Of the 29 eligible patients, 16 were in the single-dose study and 13 in the repeated-dose study. Adverse reactions were evaluated in all eligible patients. In the single-dose study, neutropenia, nausea/vomiting, diarrhea, and transaminase (GOT, GPT) increases, of grade 3 or higher, occurred at high doses of 3 n and 3.5 n. These were regarded as dose-limiting toxicities (DLT). DLT of grade 3 or higher were observed in 1 of 4 patients given 3 n and 2 of 4 patients given 3.5 n. These results suggested that the maximum tolerated dose (MTD) of ZD-1694 was 3.5 n (3.5 mg/m2). In the repeated-dose study, DLT of grade 3 or higher was observed in no more than one third of each dose group, 2 of the 6 patients given 2.5 n and 2 of the 7 patients given 3 n. These results suggested that 3 n (3.0 mg/m2), a dose nearer to MTD, was the recommended dose for the phase II study. Although transaminase increases were observed in all patients, in 12 of them the increase was grade 2 or lower and reversible. A pharmacokinetic investigation showed the mean elimination half life of ZD-1694 plasma concentration was 91.5 hours in the single-dose group and 119.1 hours in the repeated dose group. It was suggested that ZD-1694 is metabolized to polyglutamates after uptake and retained in the cells for a long duration. However, no accumulation was seen in plasma concentration of ZD-1694 following repeated doses at 3-weekly intervals. One PR was observed in a patient with colorectal cancer receiving 2.5 n in the repeated-dose study. Based on these results, the recommended dosage and administration for the phase II study of ZD-1694 was 3 n (3.0 mg/m2) intravenously infused over 15 minutes every 3 weeks.     

Simulation of water-bloom in a eutrophic lake—IV Modeling the vertical migration in a population of Microcystis aeruginosa

Simulation of the water-bloom dominated by Microcystis (blue-green algae) was carried out by modifying the mathematical model presented previously on the rising and sinking of the algal colonies through a still water-column. In contrast to the earlier work on the simulation of single colonies, an overall behavior of many algal colonies, having not only the size distribution but also having distribution initially throughout the water-column was simulated. The points of the model modified are: (i) the specific growth rate was shown by a quadratic function of light intensity that takes the inhibitory effect into account and (ii) the extinction coefficient incorporated the light-shielding effect by the algal cells existent depthwise in the water-column rather than a linear function of the concentration of suspended materials in the water.The numerical solutions of the model (280 dimensions) were in agreement qualitatively with the observations ever reported on Microcystis behavior in eutrophic lakes. Factors relevant to the extinction coefficient underwater, i.e. the concentrations of either Microcystis colonies or other suspended materials were significant from the viewpoint to control the algal growth as a whole, assuming that no nutrients were limiting. The vertical mixing of lake waters was effective for decreasing the average value of the specific growth rate expecially when the concentrations of colonies or other materials were large. Consequently, an artificial aeration was suggested to be a commendable means to ward off the water-bloom.