Antiarrhythmic actions of tedisamil: Studies in rats and primates

Tedisamil is a new bradycardic agent, previously shown to block transient outward and delayed rectifier potassium currents in cardiac tissue [1,2]. In the present study tedisamil caused bradycardia and Q-Tc widening in rats and primates. Q-Tc widening is indicative of class III antiarrhythmic actions. In keeping with this, tedisamil had antiarrhythmic activity against electrical and ischemia-induced arrhythmias in rats. In rats, 0.5–4 mg/kg IV tedisamil caused parallel and dose-related increases in action-potential duration, Q-Tc interval, and refractory period; and decreases in maximum ventricular following frequency. In primates after 0.5–2.0 mg/kg IV, findings were similar for indices of Q-T widening and decreases in maximum ventricular following frequency. Tedisamil did not change QRS width, nor did it increase threshold currents for capture of ventricles, nor for fibrillo-flutter at doses below 4 mg/kg in rats. These findings were consistent with the lack of significant sodium-channel blockade. However, upon increasing the dose to 4 mg/kg, ventricular fibrillo-flutter could not be induced in rats by electrical stimulation; instead, only ventricular tachycardias with slow rates occurred. Ischemia-induced ventricular fibrillation was reduced in a dose-related manner by tedisamil in rats. The overall incidence of ischemia-induced ventricular tachycardia was not markedly reduced, but rates during tachycardic episodes were lower. When pacing was used to overcome tedisamil-induced bradycardia, antiarrhythmic actions during ischemia were more pronounced. These findings are consistent with the hypothesis that tedisamil increased refractoriness, which resulted in extended path lengths for reentry circuits and slower rates during episodes of ventricular tachycardia. High doses of tedisamil increased path lengths so much that the multiple reentry circuits of fibrillation could no longer occur. The limited study in primates suggests similar mechanisms could occur in humans.     

"Cross-talk" in recording evoked potentials.

When two potentials having large amplitude differences are simultaneously recorded, the large amplitude potential contaminates the small amplitude response. The small, early potentials generated by this contamination resemble far-field potentials. Although scalp-recorded SEP was contaminated by waves similar to the peripheral potential, peak latencies and wave form were not identical. Experiments simulating the recording situation verified the presence of "cross-talk." Capacitive coupling would shift peaks and alter the wave forms. Other possible mechanisms for the cross-talk and methods of minimizing it are offered. One should be cautious interpreting the results when potentials of large amplitude differences are simultaneously recorded.     

Proteus syndrome

The term Proteus syndrome was coined in 1983 to describe a disorder of skeletal, hamartomatous, and other mesodermal malformations. The syndrome was named after the Greek god Proteus, whose name means "the Polymorphous." Clinical features of this new syndrome are currently being defined. Including the case reported herein, we have found 34 patients with Proteus syndrome described in the English literature. Major clinical findings, defined as those findings seen in more than half of the cases, include hemihypertrophy, macrodactyly, exostoses, epidermal nevi, characteristic cerebriform masses involving the plantar or palmar surfaces, a variety of subcutaneous masses, and scoliosis. Histologic examination of subcutaneous masses has identified a variety of lipomatous, hamartomatous, and angiomatous tumors.     

The controversy over radiation safety. A historical overview

The hazards of ionizing radiation have aroused concern since a short time after the discovery of x-rays and natural radioactivity in the 1890s. Misuse of x-rays and radium prompted efforts to encourage radiation safety and to set limits on exposure, culminating in the first recommended "tolerance doses" in 1934. After World War II, the problems of radiation protection became more complex because of the growing number of people subjected to radiation injury and the creation of radioactive elements that had never existed before the achievement of atomic fission. Judging the hazards of radiation became a matter of spirited controversy. Major public debates over the dangers of radioactive fallout from atmospheric bomb testing in the 1950s and early 1960s and the risks of nuclear power generation in later periods focused attention on the uncertainties about the consequences of exposure to low-level radiation and the difficulties of resolving them.     

Effects of halothane on arrhythmias induced by myocardial ischaemia

The effect of halothane on arrhythmias induced by ischaemia was investigated in rats, isolated perfused rat hearts, and pigs. Responses to the occlusion of the left anterior descending coronary artery were determined in groups (n = 9) of chronically prepared rats treated with no halothane, 0.5, or 1.0 per cent halothane immediately after occlusion; in isolated rat hearts (n = 10) treated with no halothane, 0.5, 1.0, 2.0, or 4.0 per cent halothane for 15 min before and after occlusion; and 20–25 kg pigs (n = 11) anaesthetised with halothane or pentobarbital. The ECG, arrhythmias, blood pressure (BP), heart rate (HR) and extent of infarction were determined in each model. In pigs, left ventricular pressure, dp/dt_max and cardiac output were also measured. In chronically prepared rats, halothane anaesthesia started after occlusion was antiarrhythmic and decreased the incidence of ventricular fibrillation and resulting mortality. In isolated rat hearts, 0.5 or 1.0 per cent halothane had little effect on occlusion-induced arrhythmias. The highest concentration of halothane increased the incidence of ventricular fibrillation both before and after occlusion. Halothane decreased developed ventricular pressure in a dose-dependent manner. In acutely prepared pigs, halothane pre-treatment had no appreciable effect upon occlusion-induced arrhythmias when compared with pentobarbital anaesthesia. Thus, halothane is antiarrhythmic when treatment is initiated after occlusion in the rat but this action is not seen in isolated hearts or intact pigs. The antiarrhythmic action of halothane is, therefore, species and model dependent.     

Functional heterogeneity of macrophages: subclasses of peritoneal macrophages with different antigen-binding activities and immune complex receptors

Cell suspensions prepared from 24-hour cultures of adherent peritoneal exudate cells from rabbits were separated into density subclasses on discontinuous gradients of Ficoll. Of the five subclasses obtained, macrophages comprised over 95 per cent of the cells in the two least dense subclasses and over 90 per cent of the cells in the subclasses of intermediate density. The most dense subclass contained approximately 80 per cent macrophages and 20 per cent lymphocytes.The antigen-binding properties of the subclasses were studied with a selected number of ¹²⁵I-labelled antigens in the presence and absence of added antibodies. In the absence of antibody the subclasses differed from one another in antigen-binding activities; these differences were independent of both the test antigens and the state of antigen aggregation. In the presence of specific antibody, two macrophage subclasses bound substantially more antigen than the other subclasses. The enhanced responses of these subclasses were confirmed by studying the cells'' capacity to form rosettes when incubated with sensitized chicken erythrocytes. The results indicated that macrophages in these two subclasses differed quantitatively and/or qualitatively from other macrophage subclasses with regard to immunoglobulin receptor sites.These studies demonstrate the feasibility of using gradient separation procedures to obtain functionally distinct subclasses of cells rich in macrophages. The availability of well-defined macrophage populations should permit more precise studies of macrophage functions in immunity.     

Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group

BACKGROUND: Inhaled nitric oxide improves gas exchange in neonates, but the efficacy of low-dose inhaled nitric oxide in reducing the need for extracorporeal membrane oxygenation has not been established. METHODS: We conducted a clinical trial to determine whether low-dose inhaled nitric oxide would reduce the use of extracorporeal membrane oxygenation in neonates with pulmonary hypertension who were born after 34 weeks' gestation, were 4 days old or younger, required assisted ventilation, and had hypoxemic respiratory failure as defined by an oxygenation index of 25 or higher. The neonates who received nitric oxide were treated with 20 ppm for a maximum of 24 hours, followed by 5 ppm for no more than 96 hours. The primary end point of the study was the use of extracorporeal membrane oxygenation. RESULTS: Of 248 neonates enrolled, 126 were randomly assigned to the nitric oxide group and 122 to the control group. Extracorporeal membrane oxygenation was used in 78 neonates in the control group (64 percent) and in 48 neonates in the nitric oxide group (38 percent) (P=0.001). The 30-day mortality rate in the two groups was similar (8 percent in the control group and 7 percent in the nitric oxide group). Chronic lung disease developed less often in neonates treated with nitric oxide than in those in the control group (7 percent vs. 20 percent, P=0.02). The efficacy of nitric oxide was independent of the base-line oxygenation index and the primary pulmonary diagnosis. CONCLUSIONS: Inhaled nitric oxide reduces the extent to which extracorporeal membrane oxygenation is needed in neonates with hypoxemic respiratory failure and pulmonary hypertension.     

Follicular epithelial cell hypertrophy induced by chronic oral administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Harlan Sprague-Dawley rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) affects the thyroid morphologically and/or functionally in adult animals. Recently, the National Toxicology Program conducted a 2-year gavage study of TCDD in female Harlan Sprague-Dawley rats. The only treatment-related alterations found in thyroid follicles were decreased luminal size and increased height of the follicular epithelial cells, without prominent protrusion into the lumen. The present study elucidated the nature of these follicular lesions. Thyroid glands of 10 rats each from the control, high (100 ng/kg/day)-dose, and stop-study (100 ng/kg/day, 30 weeks; vehicle to study termination) groups in the 2-year study were evaluated microscopically. Twenty randomly selected follicles were measured morphometrically in each animal. TCDD treatment significantly decreased the mean ratio of luminal/epithelial areas and increased the mean sectional epithelial height of the high-dose group compared to controls. Thyroid sections were immunostained with antibody against minichromosome maintenance (MCM) proteins, a novel cell-cycle biomarker. The MCM labeling index of the high-dose group was significantly higher than that of the control; however, the TUNEL labeling index was also higher in the high-dose group than the control. All data from the stop group were comparable to those from controls. These results indicate that the follicular cell response was hypertrophic and reversible. This information should contribute to diagnosis of nonneoplastic thyroid follicular lesions in rats.