Proarrhythmia: a paradoxic response to antiarrhythmic agents

Antiarrhythmic drugs may effectively terminate and prevent symptomatic tachycardias, but they may also provoke life-threatening rhythm disturbances. The electrophysiologic mechanisms responsible for proarrhythmia can be extrapolated from the existing models of reentry and abnormal automaticity. Although all antiarrhythmic drugs may cause proarrhythmia with seemingly similar frequency, the profile of the disturbance with each class of agents appears somewhat distinct. All agents may cause an increased frequency of premature beats or new or worsened ventricular tachycardia, but the classic form of proarrhythmia due to type la agents is torsades de pointes. Recent information has provided clues to the underlying mechanism of drug-induced torsades de pointes and has provided a clinical picture of patients with this adverse effect. Types lb and lc agents only rarely precipitate torsades de pointes. The latter, however, may cause a rapid, sustained, monomorphic ventricular tachycardia in certain high-risk patients that can be resistant to resuscitation efforts. Amiodarone may cause a broad variety of arrhythmias that are complicated by their extended duration and difficulty in distinguishing proarrhythmia from simple inefficacy. Proarrhythmia is a relatively common, paradoxic side effect that necessitates the clinician to make careful risk-benefit decisions in choosing antiarrhythmic drug therapy.     

Effects of controllable vs. uncontrollable stress on circadian temperature rhythms

The effects of sustained stress on body temperature were investigated in rats implanted with mini-transmitters that permitted remote measurement of body temperature. Temperature was first monitored during control conditions. Following the control period, rats were either shaped to avoid/escape signalled around-the-clock intermittent footshock (controllable stress) or yoked to the controlling rats such that the controlling rat and the yoked rat received shock of the same duration, but only the controlling rat could terminate shock by pulling a ceiling chain. Under control conditions, rats demonstrated regular rhythms in body temperature which averaged 1 degree higher during the 12-h dark cycle than the light cycle. Stress disrupted the rhythm and markedly decreased the night-day difference in temperature, especially in the yoked rats in which almost no difference between light and dark cycle temperature was seen. The disruption was most marked for the first days of stress. A regular temperature rhythm was reestablished following about 5 days of stress although the stress condition continued. Leverpressing for food was also affected by the stress conditions with both stress groups leverpressing less than controls and the uncontrollable stress group pressing less than the controllable stress group. These data offer additional evidence of the increased pathophysiological effects of uncontrollable as compared to controllable stress.     

Examination of potential mechanism(s) of metallothionein induction by diethyl maleate.

Diethyl maleate (DEM) is a glutathione-depleting agent that can increase the levels of the sulfhydryl-rich protein metallothionein (MT) in liver. The purpose of the present study was to examine the mechanism(s) by which DEM increases mouse hepatic MT levels. DEM appears to be an indirect MT inducer as suggested by the lack of increase in MT levels when cultured mouse hepatocytes were exposed to DEM. Four possible mechanisms by which indirect MT inducers may cause an elevation in MT concentrations in liver were examined. Zn levels did not increase prior to the increase in hepatic MT, thus, a Zn redistribution to the liver is not the cause of the liver MT induction by DEM. The adrenal gland products were not required for MT induction in liver, as adrenalectomy did not abolish the increase in hepatic MT caused by DEM. The elevation in liver MT does not appear to be due solely to the decrease in liver glutathione (60%) in the initial hour after DEM, because phorone, which decreases liver glutathione (80%), produced only a fourfold increase in hepatic MT. Activation of macrophages does not seem to account for the rise in liver MT levels, as there was no increase in abundance of cytokine mRNAs for TNF-alpha, IL-1 beta, or IL-6 in the liver. These data suggest that the induction of hepatic MT by DEM does not occur in response to (1) an increase in liver Zn that precedes the increase in liver MT, (2) release of adrenal gland products, (3) decrease in liver glutathione, or (4) increased cytokine gene expression.     

Determination of needed radiographic room capacity to serve an emergency department

This study describes a method for determining the number of radiographic rooms devoted to emergency radiology that would be required to keep mean patient waiting time at a desired level. A desired mean waiting time for patients must be determined. In our setting, a mean waiting time of 8 minutes resulted in few complaints. The waiting time then sets the required utilization rate of available capacity. Daily and hourly volume and variability in volume of examinations were measured over a 3-month period. This represents the demand. The needed number of rooms is determined by comparing demand with effective available capacity for different numbers of rooms. To maintain an 8-minute mean waiting time, 50% utilization of capacity is required. Mean demand on Sundays is 176 examinations. Five rooms are required, since this gives a 180-examination effective capacity. Using waiting time as the primary decision criterion for making capacity decisions in emergency radiology has several advantages: the method is easy to use, volume variability is taken into account, and the focus is on service to patients.     

Induction of metallothionein by diethyl maleate.

Metallothionein (MT) is a sulfhydryl-rich protein whose levels are increased by administration of a variety of agents including metals, cytokines, and oxidative stress agents. Recent studies have suggested that MT is involved in protecting against various forms of oxidative stress, but little is known about the induction of MT by oxidative stress agents. Diethyl maleate (DEM) causes oxidative stress by depleting glutathione levels and is quite effective at increasing hepatic concentrations of MT. The purpose of the current study was to learn more about the relationship between induction of MT and oxidative stress by characterizing this increase in hepatic MT levels produced by DEM. Administration of DEM (3 to 9 mmol/kg, sc) increased hepatic MT concentration in mice as much as 37-fold to 213 micrograms MT/g liver, which is similar to the hepatic MT level seen after administration of other effective MT inducers, such as Cd. The maximal increase of hepatic MT took place 12 to 24 hr after administration of 5 mmol DEM/kg. This rise in MT was preceded by a 60% depletion of hepatic glutathione 3 hr after DEM and increases in both MT-I and MT-II mRNA, which reached a peak 6 to 9 hr after DEM. Administration of DEM (3-5 mmol/kg, sc) also increased MT levels in Sprague-Dawley rats. Pretreatment with DEM protected against Cd-induced hepatotoxicity in a fashion which suggested that a functional MT was being synthesized. In summary, DEM is a highly effective inducer of MT which increases MT at the mRNA level.     

Bioavailability of estradiol as a marker for breast cancer risk assessment

The search for a hormonal marker in breast cancer has centered on estrogens and their metabolites. However, direct measurements of total amounts of these steroids have shown no convincing or consistent differences between normal women and women with breast cancer. The purpose of this study was to measure the percentages of non-protein-bound estradiol (%NPBE) and of estradiol bound to albumin (%ABE) and the levels of sex hormone-binding globulin (SHBG) both in women with breast cancer and in those free of disease. Serum was collected and analyzed within 2 weeks, using an isodialysis method. The mean %NPBE and %ABE were significantly higher in 32 women with breast cancer (1.73 and 64.0%, respectively) than in 32 matched disease-free women (1.43 and 48.6%, respectively) (P less than 0.001). No significant difference was observed in the levels of plasma albumin when the above matched groups were compared. However, plasma levels of SHBG were significantly lower in the women with breast cancer than in either the control population or matched controls. In this finding we differ from previous studies which reported no significant differences in the mean plasma levels of SHBG. In our study, the increased %NPBE and %ABE in some patients with breast cancer may be related to a lower level of plasma SHBG; other factors, too, may affect the distribution of estradiol. Our results support the hypothesis than an increase in %NPBE and %ABE or both may indicate an increased risk of breast cancer.     

Near-total reduction in verapamil bioavailability by rifampin. Electrocardiographic correlates

We evaluated the significance of the interaction between rifampin and verapamil in six volunteers who received single doses of verapamil, 10 mg intravenously (IV), then 120 mg orally two days later. Subjects were then given rifampin, 600 mg orally every day for 15 days. After 13 and 15 days of rifampin therapy, the IV and oral doses of verapamil were repeated. Electrocardiograms (ECG) were done and serum verapamil and norverapamil concentrations measured before and for 12 h after each dose. For IV verapamil, there was a small decrease in area under the serum concentration-time curve and an increase in clearance after rifampin therapy (p less than 0.05). There were no changes in elimination half-life, volume of distribution, or AUC for percentage of change in P-R interval-time curve (AUCPR). For oral verapamil, there were marked decreases in peak concentration, AUC, oral bioavailability (all p less than 0.005), and AUCPR (p less than 0.001) after rifampin treatment. There were no changes in time to peak concentration or elimination half-life. For oral verapamil, significant P-R interval prolongation occurred only before treatment with rifampin. The decrease in oral bioavailability and the abolition of ECG response confirm that a highly significant drug interaction exists between rifampin and verapamil given orally but not intravenously.     

Professed religious affiliation and the practice of euthanasia.

Attitudes towards active voluntary euthanasia (AVE) and physician-assisted suicide (PAS) among 1,238 doctors on the medical register of New South Wales varied significantly with self-identified religious affiliation. More doctors without formal religious affiliation ('non-theists') were sympathetic to AVE, and acknowledged that they had practised AVE, than were doctors who gave any religious affiliation ('theists'). Of those identifying with a religion, those who reported a Protestant affiliation were intermediate in their attitudes and practices between the agnostic/atheist and the Catholic groups. Catholics recorded attitudes most opposed to AVE, but even so, 18 per cent of Catholic medical respondents who had been so requested, recorded that they had taken active steps to bring about the death of patients.